Gastrointestinal Diseases

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Gastrointestinal

Diseases

ATLAS OF NONTUMOR PATHOLOGY


.r

Editorial Director: Kelley S. Hahn


Production Editor: Dian S. Thomas
Editorial Assistant/Scanning Technician: Mirlinda Q. Caton
Copyeditor: Audrey Kahn
ATLAS OF NONTUMOR PATHOLOGY

First Series
Fascicle 5

Gastrointestinal
Diseases
Amy Noffsinger, MD
Cecilia M. Fenoglio-Preiser, MD
Dipen Maru, MD
Norman Gilinsky, MD

Published by the
American Registry of Pathology
Washington, DC
in collaboration with the
Armed Forces Institute of Pathology
Washington, DC

2007
ATLAS OF NONTUMOR PATHOLOGY

ED ITO R
Donald West King, MD

ASSOC IATE EDITORS


Leslie H. Sobin, MD
J. Thomas Stacker, MD
Bernard Wagner, MD

.
EDITORIAL ADVISORY BOARD
lvan Damjanov, MD
Cecilia M. Fenoglio-Preiser, MD
.. Fred Gorstein, MD
Daniel Knowles, MD
Vjrginia A. LiVolsi, MD
Florabel G. Mullick, MD
juan Rosai, MD
Fred Silva, MD
.Steven G. Silverberg, MD

..r

Manuscript Reviewed by:


Leslie H. Sobin, MD
Harvey Goldman, MD

Available from the American Registry of Pathology


Armed Forces Institute of Pathology
Washington, DC 20306-6000
www.afip.org
ISBN: 1-933477-43-1
r. ,·
978-1-933477-43-5

Copyright© 2007 The American Registry of Pathology

All rights reserved . No part of this publication may be reproduced or transmitted in


any form or by any means: electronic, mechanical, photocopy, recording, or any other
information storage and retrieval system without the written permission of the publisher.
INTRODUCTION TO SERIE S

This is the fourth Fascicle of the Atlas of Nontumor Pathology, a complementary


series to the Armed Forces Institute of Pathology (AFIP) Atlas of Tumor Pathology,
first published in 1949.
For several years, various individuals in the pathology community have suggested
tbe formation of a new series of monographs concentrating on this particular area.
In 1998, an Editorial Board was appointed and outstanding authors chosen shortly
thereafter.
The purpose of the atlas is to provide surgical pathologists with ready expert
reference material most helpful in their daily practice. The lesions described relate
principally to medical non-neoplastic conditions. Many of these lesions represent
complex entities and, when appropriate, we have included contributions from in-
ternists, radiologists, and surgeons. This has led to some increase in the size of the
monographs but the emphasis remains on diagnosis by the surgical pathologist.
Previously, the Fascicles have been available on CD-ROM format as well as in
print. In order to provide the widest possible advantages of both modalities, we
have formatted the print Fascicle on the World Wide Web. Use of the Internet al-
lows cross-indexing within the Fascicles as well as linkage to PubMed.
Our goal is to continue to provide expert information at the lowest possible
cost. Therefore, marked reductions in pricing are available to residents and fellows
as well as to pathology faculty and other staff members purchasing the Fascicles
on a subscription basis.
We believe that the Atlas of Nontumor Pathology will serve as an outstanding
reference for surgical pathologists as well as an important contribution to the lit-
erature of other medical specialties. ·

Donald West King, MD


Leslie H. Sobin, MD
J. Thomas Stock er, MD
Bernard Wagner, MD
PREFAC E

This Fascicle is devoted to benign gastrointestinal diseases and provides an in-


depth discussion of many lesions, both common and uncommon. This volume is,
for the most part, organized by category of disease rather than by anatomic site.
This approach allows us to cover each entity comprehensively and avoids redundant
descriptions of lesions that occur in multiple regions of the gastrointestinal tract.
Each disease entity is discussed from the point of view of its demo graphics, patho-
physiology, clinical features, gross and microscopic pathology, and treatment. The
text is heavily illustrated with diagrams and gross and microscopic photographs.
Numerous tables have been included in order to facilitate comparison of diseases
and generation of differential diagnoses. Because of the extreme importance of clini-
cal and endoscopic correlation with interpretation of gastrointestinal pathologic
specimens, we have included ·an actively practicing gastroenterologist among the
authors. He has added endoscopic pictures and provided clinical insights critical
to the understanding of gastrointestinal diseases.
In many areas we have provided text and references related to animal models
of disease since these have become very powerful tools for understanding gastroin-
testinal diseases, particularly in.:flammatory bowel disease, motility disorders, and
benign polyposis syndromes. Where it is most relevant, we provide a discussion of
some of the molecular alterations that are present since these provide an under-
standing of the pathophysiology of the disease. We also provide some discussion
of the genetic predispositio:r:s to gastrointestinal diseases that occur as a result of
genetic loss, mutation, overexpression of genes, or genetic polymorphisms.
A text such as this wou1d not have been possible without the close working
relationships we have been privileged to have had with other pathologists and gas-
troenterologists. Such relationships are most rewarding when there is a continuing
dialogue that provides increased understanding of disease processes in individual
patients. This book would also not have been possible without the numerous con-
sults we have received over the years from our colleagues in both pathology and
gastroenterology. This has enabled us to illustrate the majority of the entities we
discuss. Finally, the many residents and fellows that we have worked with over the
years have unknowingly contributed to this work by taking gross photographs, call-
ing our attention to interesting cases that we might not have seen otherwise, and
continuing to send us cases after they have left our training programs to practice.
•.·
We hope that readers will find that this book provides information not otherwise
available in a single reference.
Amy Noffsinger, MD
Cecilia M. Fen oglio-Preiser, MD
Dipen Maru, MD
Norman Gilinsky, MD
Permission to use copyrighted illustrations has been granted by:

American Roentgen Ray Society


American Journal of Roentgenology 1993;160:59-61. For figure 10-14.

Armed Forces Institute of Pathology


Atlas of Gastrointestinal Endoscopy & Endoscopic Biopsies, 2000. For figures 4-14, 5-1,
6-34, 7-17, 7-18, 8-4, 10-17, 10-18, 10-44, 10-58, 11-23, and 11-24.

Blackwell Publishing
Aliment Pharmacal Ther 2004;19:1051-61. For figure 8-5.

Lippincott Williams & Wilkins


Gastrointestinal Pathology, An Atlas and Text, 2nd ed., 1999;312. For figure 2-9.

Radiological Society of North America


Radiology 1975;117:519-21. For figure 4-5.
•.·
CONTENTS

1. General Features of the Gastrointestinal Tract and Its Evaluation . . . . . . . . . . . . . . . . . . 1


Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Gastrointestinal Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Mucosa............................................................ 2
Mast Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Eosinophils. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Submucosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Muscularis Propria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Adventitia or Serosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Vasculature. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Innervation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Gastrointestinal Endocrine System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Normal Features of Individual Gastrointestinal Sites . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Esophagus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Stomach........................................................... 12
Small Intestine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Colon...................... ... .......... ........ .. ................ 19
Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Anus.. .. .......................................................... 25
General Interpretation of Pathologic Specimens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2. Congenital Gastrointestinal Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Esophagus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Stomach and Duodenum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Intestine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Distal Colon, Rectum, and Anus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Positional Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Situs Inversus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Dextrogastria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Malrotations/Nonrotations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Abdominal Wall Defects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Gastroschisis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
01nphalocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Umbilical Hernia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Mesocolic Hernias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Congenital Diaphragmatic Hernia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

ix
Gastrointestinal Diseases

Atresia and Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47


Bronchopulmonary Malformations Including Congenital Bronchoesophageal
Fistulas, Bronchogenic Cysts, and Pulmonary Sequestration . . . . .. . . . . . . . . . . . 56
Duplications, Diverticula, Enterogenous Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Duplications and Enterogenous Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Congenital Diverticula. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Omphalomesenteric Remnants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Umbilical Fistula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Meckel Diverticulum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Annular Pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Peritoneal Encapsulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Heterotopias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Esophageal Inlet Patch .. ." . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Heterotopic Gastric Mucosa. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Heterotopic Pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Heterotopic Brunner Glaii.ds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Heterotopic Sebaceous Glands. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Heterotopic Salivary Glands· . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Heterotopic Prostate .. ........ ....... .................... . ......... ·: . . 74
Heterotopic Thyroid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Ectopic Renal Tissue . .. . ........................................ : . . . . . 74
Ectopic Uterus .... .. . ·. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Mullerian and Mesonephric Duct Remnants...... . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Microgastria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Anorectal Anomalies (Malformations). . ... ... .... . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Low Abnormalities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Intermediate Abnormalities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
High (Supralevator) Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Thymic-Renal~Anal-Lung Dysplasia............ . .... . ............ . . . . . . . . . . 80
Caudal Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Anorectal Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
3. Diseases of the Esophagus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
r.,·
General Pathologic Features. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Reflux Esophagitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Barrett Esophagus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
Eosinophilic Esophagitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Esophageal Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Bacterial Esophagitis ... .. ... .. ..... . .... ..... ....... .... . ..... .. ...... 104

X
Contents

Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Viral Esophagitis ... ............. . . . . ........ . ..... . ... . .. .. . ... ... . . . 105
Fungal Esophagitis ............ .... ........... . ........ . ............ .. 107
Corrosive Esophagitis ......... . ........ . .... .. ..... . ... . .. . .. ... . .. .. ... 110
Radiation Esophagitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Drug-Associated Esophagitis ............. .. .............................. 111
Mucosal Lacerations, Ulcerations, and Perforations . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Mallory-Weiss Syndrome .......... .............. ...... ... . . ... . . ... ... 112
Boerhaave's Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Melanosis . ........ . . .. . .. . ... ....................... . .......... . ..... 113
Nevus .................... ...... .................................... 113
Glycogen Acanthosis . . .................. ... .... . .. ..................... 114
Systemic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
Amyloidosis . ........ .. .. ... .. ............ .. . ... .. .. ... . .......... .. 114
Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
Cystic Fibrosis ...................... .. ............................... 115
Autoimmune Diseases . ......... .... . .......... ................... . ... 115
Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Dermatologic Conditions Involving the Esophagus . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Pemphigus ... .. ........... .. ..... . ..... .... . .. ............... . ..... 115
Benign Mucous Membrane Pemphigoid .................................. 116
Erythema Multiforme .. .. .. . ........... .. ............. . ............... 116
Epidermolysis Bullosa Acquisita ................. ........................ 116
Epidermolysis Bullosa Dystrophia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Lichen Planus ........ . .. ....... . . ..... .. ....... ... ... ·............... 116
Acanthosis Nigricans .......................... ........ . ...... . . . . . ... 116
Graft Versus Host Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Inflammatory Fibroid Polyps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Fibromuscular Hamartoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
4. Diseases of the Stomach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Clinical Presentation of Gastric Diseases and What the Clinician Wants to Know . . . 123
Mucosal Barrier: Structure and Function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Mucosal Repair .. ...... .............. .. .... ... . ... .. ....... ..... ..... .. 123
Pathologic Evaluation of Gastric Biopsies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
Examination of Surgical Gastrectomy Specimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Gastritis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Acute Gastritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Helicobacter Pylori Gastritis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

xi
Gastrointestinal Diseases

Helicobacter Heilmannii Gastritis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 7


Suppurative Gastritis ....... . . .. .... . ... ·. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Chemical Gastropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . 138
Chronic Gastritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Autoimmune Gastritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Chronic Antral Gastritis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Chronic Atrophic Gastritis ....... .... . ... : . .......... .. .. ... .. . .. . .. . .. 146
Metaplasia in Chronic Gastritis ....... ... ... ............ .. ... ....... .... 147
Lymphocytic Gastritis . . .. ... .... . ............ ....... . . ...... . ...... .. . . 151
Granulomatous Gastritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Infections Associated with Granuloma Formation . . . . . . . . . . . . . . . . . . . . . . . . . . 154
Gastric Crohn's Disease . . . . . . . ............... . . .... ... ... .. . ... .. . . ... 154
Foreign Body Granuloma .... . . .. . . ... .... ............................ . 155
Granulomatous Gastritis Associated with Malignancy . ... ... .. ... . . .. . ...... 157
Isolated Idiopathic Granulomatous Gastritis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Collagenous Gastritis . . . .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Hypertrophic Gastropathies . . . .. ......... . ..... ..... . . . . .... . . ..... . .. ... 159
Menetrier's Disease .............. ...... ........ . .. . . .. ... . ............ 159
Zollinger-Ellison Syndrome ... . .. ... ...... . ......... . .... . . . ..... . . ,, ... 162
Pseudo-Zollinger-Ellison Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
Hypertrophic, Hypersecretory Gastropathy....... .. . . . . . . .. . ... ..... .. .. . . 164
Hypertrophic, Hypersecretory Gastropathy with Protein Loss ............... . . 164
Helicobacter Pylori-Associated Hypertrophic Gastropathy .. . .. . . . . . ......... .. 164
Localized Hypertrophic Disorders . . . ..... . ...... ... . . ..... ... . .. . ... . .... . 165
Focal Hyperplasia .......... . .. . .... .... .... . . ... . . ... .. ... .. . . ....... 165
Gastric Polyps . . .. . ... . ...... . . .. .... . .. ...... ................ . . . .... .. 165
Hyperplastic Polyp . . . .. . ....... ... .. ..... .... .. ... .. .... . ............ 166
Fundic Gland Polyp .. . . . . . ..... ........... .... . . ....... .. . ...... . ... . 168
Isolated Hamartomatous Polyp .... .... . . . . .... .. . . . . ................... 169
Gastric Polyps in Polyposis Syndromes . ..... . ..... . .. ... ........... . .... . 169
Gastric Xanthoma . .. . .. .. .. ..... ...... . ... .... . .. . . .. . . . . . . . .. .. .... .. 169
Brunner Gland Heterotopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
,.,. 5. Peptic Ulcer Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 5
Normal Gastric Defense Mechanisms .... .... ..... .. . .. . . .. . . . . . . . .. ...... . 175
Pathogenesis of Peptic Ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 5
Role of Helicobacter Pylori . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 5
Role of Acid Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
Role of Nonsteroidal Antiinflammatory Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

xii
Contents

Role of Steroids .. ....... . ........ ......... . ..... ...... ............... 178


Role of Cigarette Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
Other Factors in Ulcer Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
Demography .......................................... . ............. 179
Gastric Peptic Ulcer Disease .............................................. 180
Duodenal Peptic Diseases . ...... .. ............. .. .. ........ ...... ........ 184
Role of Genetic Factors ........ .... .. .. .......... .. .. . . ................ 185
Peptic Duodenitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
Duodenal Ulcer .............................. .... .. ................. 187
Treatment and Prognosis for Patients with Peptic Ulcer Disease ................. 188
Zoliinger-Ellison Syndrome ................. . .... . .......... ..... ...... .. 188
6. Acquired Structural Alterations .. . ........... .. ......... . ...... ....... . ..... 195
Diverticula .......... . ......................... . ...................... 195
Esophageal Diverticula. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 5
Gastric Diverticula ....... ..... ..... . ....................... ........ . . 197
Small Intestinal Diverticula ............................................ 197
Appendiceal Diverticula. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
Colonic Diverticula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
Intussusception .......... . .... ........ ....... ........ .. ... ...... . .... . 207
Volvulus ...................... ..... .. .... ... ....... ... ..... ... . .. . ... 211
Gastric Volvulus ..................................................... 211
Small Intestinal Volvulus ........ ... .. ..... ... ........................ . 211
Colonic Volvulus ............................... . .................... 212
Rectal Mucosal Prolapse .......... . ... .. ... ...... . ......... . .. . .......... 213
Gastritis, Enteritis, and Colitis Cystica Profunda ..... . . ............ . . ... .. .. .. 218
Anal Fissures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Fistulas and Sinuses ................. ... .... ........ . .. .. .......... ..... 221
Lacerations, Perforations, Hematomas ........... ........................... 225
Strictures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
Changes Associated with Previous Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
Changes Associated with Eating Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
Arteriovenous Malformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
Caliber-Persistent Artery ................................................. 235
Hemorrhoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Varices .............................................................. 236
Portal Hypertensive Vasculopathy .......... .. ................ .... . .. ...... 239
Portal Hypertensive Colopathy ... . ..... .... ......... ........... . ....... 239
Portal Hypertensive Gastropathy ........................................ 240

xiii
Gastrointestinal Diseases

Gastric Antral Vascular Ectasia ....... .. ........... ... ..................... 241


Mucosal Telangiectasias .................. : . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
7. Ischemia and Other Vascular Disorders .. ............ . . .. . ...... ... ........... . 255
Gastrointestinal Ischemia ....................... ............. ............ 255
Demography ............................. . .......................... 255
Etiology .............................. . ............................ 255
Pathophysiology .......... .... .................. . .................... 25 7
Acute Mesenteric Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Chronic Mesenteric Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
Neonatal Necrotizing Enterocolitis ... ... ........ ............ .. .......... 271
Tropical Necrotizing Enterocolitis (Enteritis Necroticans) .................... 273
Acute Segmental Obstructive Enteritis ................................... 273
Bowel Infarction in Dialysis Patients ..................................... 274
Gastrointestinal Ischemia Secondary to Systemic Vasculitis ..................... 274
Polyarteritis Nodosa ................................. . ................ 275
Henoch-Schonlein Purpura ............................................ 276
Microscopic Polyangiitis .............................................. 276
Wegner's Granulomatosis ........ .... ......... ..... ..... . .. ......... ... 278
Churg-Strauss Syndrome ...........................................• .. . 278
Kawasaki's Disease ................................................... 279
Thromboangiitis Obliterans ................ ........ ....... .......... . .. 280
Malignant Atrophic Papulosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280
Segmental Arterial Mooiolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
Marfan's and Ehlers-Danlos Syndromes ... .... ........... .... ............ 281
Gastrointestinal Involvement in Collagen Vascular Diseases . . . . . . . . . . . . . . . . . . . . 281
Systemic Lupus Erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
Behcet's Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
Mesenteric Inflammatory Venoocclusive Disease ........................... 283
Mesenteric Phlebosclerosis ... ...... ... .................. .. ... .......... 283
Ischemia Due to Coagulation Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
Ischemia Caused by Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
r..· 9. Chemical Injury . ........................................................ 293
Introduction .......................................................... 293
Nonsteroidal Antiinflammatory Drugs . .. .... ... ...... . . ......... ..... .... . 294
Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
Chemotherapeutic Agents ...... ................................. .. ...... 307
Antimicrobial Drugs ............. ..... . . ......................... .. ... . . 312
Immunosuppressive Agents ..... ... ....... . ...... .... ................. . .. 313

xiv
Contents

Laxative Use .......................................................... 315


Enemas . . .. .... ......... ... ......... ...... ........... . ........ ..... .. 319
Kayexalate-Sorbitol Enema ............................................ 320
Radiographic Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
Caustic or Corrosive Injury .. ........ . ....... .. .......... .. .............. 322
Prostaglandin Therapy .......................... .. ........ . ........... .. 327
Bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
Heavy Metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
Colchicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
Pancreatic Enzyme Supplements and Fibrosing Colonopathy ................... 333
Estrogen and Progesterone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
Cocaine ..................... ...... .. ..... ............................ 335
Other Drugs and Chemicals Causing Ischemic Injury ..... . ........... ........ 336
Anticoagulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
Chemically Induced Eosinophilia .... . .......... ..... .. . . ......... . .. .. .. . 339
Changes Associated with Uremia and Chronic Renal Disease ................... 341
Diarrheic Shellfish Poisoning. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
Drug-Induced Neuromuscular Disorders ........... ... .. . ........ . . . ........ 343
Clofazimine-Induced Crystal-Storing Histiocytosis ............ .. ..... ... ...... 344
Drug Reactions Affecting Specific Gastrointestinal Sites . . . . . . . . . . . . . . . . . . . . . . . . 344
Drug-Related Esophagitis .............................................. 344
Chemically Induced Gastric Injury ...................................... 347
Chemically Induced Intestinal Injury ........ .. .. .. ... .... . .. . .. ... ...... 349
9. Physical Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
Radiation-Induced Injury ...... . ............ ... .. .. ........... ........... 365
Thermal Injury ........................................................ 382
Electrical Injury ............... ... ..... . ....... .... .. ..... .. ......... 384
Trauma and Hematomas . . .............................................. 385
10. Gastroin testinal Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 3
Introduction ............... . .... ... ..... ...... . ..... . ............... . . 393
Epidemiologic Settings in which Infections Occur .......................... 393
Diagnosis of Gastrointestinal Infections ..... ................. .. ..... .. ... 393
General Pathologic Features ............................................ 394
Bacterial Infections ..................................................... 395
Escherichia Coli ...................................................... 395
Enteropathogenic E. Coli .............................................. 395
Enteroaggregative E. Coli . ............................................. 396
Enterohemorrhagic E. Coli . ... ...... . . ..... .......... . .............. ... 396

XV
Gastrointestinal Diseases

Enterotoxigenic E. Coli . ..... ..... ....... . .. ....... ... . . ............... 399


Enteroinvasive E. Coli . . . .... . .......... : . .. ............... . ... . ... .... 399
Special Techniques for Identifying E. Coli ... .... .. ........ .. . : . ..... .. . . .. 400
Differential Diagnosis of E. Coli Infection . .. .. ...... ...... ..... .... , . .. . .. 400
Salmonella Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400
Shigella Infections ...... .. . ..... ...... .... ........... ·. . . . . . . . . . . . . . . . . 404
Staphylococcal Infections .................. . .. ...... ..... . . ... ...... .. 406
Campylobacter Infections ..... . . ..... .. ... . . ..... . ..... .. ...... .... . ... 407
Clostridium Dif{lcile Infections .... ....... . ............... .. . ....... ..... 408
Clostridium Septicum Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
Clostridium Perfringens and Clostridium Welchii Infections. . . . . . . . . . . . . . . . . . . . . 414
Vibrio Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
Aeromonas Infections .. ~ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
Plesiomonas Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
Yersinia Infections ..... . .................... .. ........................ 420
Mycobacterium TubercultJsis Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
Other Mycobacterial In-fections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
Neisseria Gononhoeae Infec~ions ............... . ......................... 425
Treponemal Infections ...................... . .. . ............... ... ., ... 427
Intestinal Spirochetosis ... . ................ . .. ... . ..... . ..... ....... .. 429
Granuloma Inguinale (Donovanosis) ...... .. ............................ 429
Chancroid .... ..... : . ......... .. . ..... .... .... . . .... .. .. . .. .. ·. . . . . . . 429
Actinomyces Infections- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
Trophe1yma Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
Chlamydia Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433
Anthrax ... . . ... ..... . . ... ... .... .... . . ..... ..... .. .. .. .. . ....... .. 435
Listeria Infections . ...... . .... ... .. .... .. . .. ....... ... .. .. .......... .. 436
Tropical Sprue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 7
Bacterial Overgrowth Syndromes .............. .. .............. . .... ... .. 438
Fungal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440
Candida Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440
Histoplasma Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
... Aspe1gillus Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
Blastomyces Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 7
Paracoccidioides Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 7
Zygomycosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
Clyptococcus Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
Coccidioides Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450

xvi
Contents

Viral Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450


Rotavirus and Rotavirus-Like Particle Infections ... ........... . ....... . ..... 450
Norwalk and Norwalk-Like Virus Infections ............................... 452
Sapporo and Sapporo-Like Virus Infections ..... ... . ... . . . . .. . ............. 452
Enteric Adenovirus Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452
Astrovirus Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
Herpesvirus Infections ... . . .... .. . ... . .... ... .. . ... . .................. 454
Varicella Zoster Virus Infections ...... . . . .... .. . . ....................... 458
Cytomegalovirus Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458
Human Papilloma Virus Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
Molluscum Contagiosum .. ......... . ...... . . . ... ...... .. .. .. . . .... . ... 463
Parasitic Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
Giardia Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
Amoeba Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
Balantidium Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
Clyptosporidium Infections ............. . . . ............................. 470
Cyclospora Infections ... .... .. . ..... .. ........................... . .... 473
Leishmania Infections ...... . ....... . ....... .. .. .. . . . ... ............... 474
Chagas' Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 76
Blastocystis Infections . ...... . . . ................ . . . .... . ... .. . ... . .... . 478
Ascaris Infections .. . . .... . .... .... .. ... . . ... ......................... 478
Hookworm Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480
Schistosoma Infections ...... . . . ...... . ... . ... . .... . ... . . ... .. . ... . .... 483
Anisakis Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
Enterobius Ve1micularis Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488
Trichuris Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
Strongyloides Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
Angiostrongylus Infections ... .. ... . . . . . . ... . . .. . ................ . .... . . . 496
Capillaria Philippinensis Infections ................. . ..................... 497
Tapeworm Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
Trematode Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
11. Gastrointestinal Diseases in Immunocompromised Patients .. ... ... . .......... . .. 539
Human Immunodeficiency Virus Infections .. .......... . . . ... .. . . ....... .. .. 539
HIV Enteropathy .... . . .... . . ......... . .. . . .. ... .. . .. .... . ..... . ... .. 546
HIV-Associated Diseases in Specific Gastrointestinal Locations ...... . .... ... .. . . 548
Esophageal Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 548
Gastric Disease ........................... . .... .. ....... . ......... .. . 549
Anorectal Disease .................... . ...... .... ........ .. .. . . . . .. . .. 549

xvii
Gastrointestinal Diseases

Bacterial Infections in Immunocompromised Patients .. .. . ... ... ·. ............. 550


Mycobacterium Avium Complex .......... : .............................. 550
Mycobacterium Tuberculosis Infections .................................... 553
Spirochetosis ................................................ ·....... 553
Viral Infections in Immunocompromised Patients ............................ 555
Cytomegalovirus Infections . ....... . ................................... 555
Herpes Simplex Virus Infections ... ...... .. ... .... ....... ....... .. ...... 559
Other Viral Infections ....... .... .... .. ... . .......... .. ..... .... ...... 560
Fungal Infections in Immunocompromised Patients ...... .. . ......... ...... .. 561
Candida Infections ................................................... 561
Histoplasmosis . .. . .. ........ ............ ................. ........... 562
Other Fungal Infections . ........ . . ...... ... ........... .. .. . . .......... 562
Disseminated Pneumocystis Carinii Infection ................................. 562
Parasitic Infections in Immunocompromised Patients ..... .................. .. 563
Clyptosporidium Infections . . ........................................... 563
Isospora Belli Infectionf ............................................... 565
Microsporidium Infections . ........... . . ... .. .. ... .......... .... ........ 566
Toxoplas1nosis ........ , .......... ............ .. .. ...... .. .. ...... ... 569
Other Parasites . .............. ...... .. ..... . ... ...... . ... ..... .. •..... 5 71
Graft Versus Host Disease ....... .......... ..... ........ .. .. .............. 571
12. Malabsorption Syndromes ................................................. 583
Introduction ......... ·................................................. 583
Demography .. ......... . ......... ...... ..... ....... .. ... . ... . . ........ 583
Etiopathogenesis .................................................... 583
Choice of Specimen . .. . . ... ....... ....... .. . ... .................... .. 583
Handling the Specimen ............................................... 584
Histologic Approach to Biopsies Obtained for Malabsorption . ........ . . ...... 585
Celiac Disease ......................................................... 589
Complicatio_ns and Related Disorders of Celiac Disease ....... . ............ .... 599
Refractory Sprue ..................................................... 599
Collagenous Sprue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600
Ulcerative Jejunoileitis ............................... . . .. . .......... .. 600
Enteropathy-Associated T-Cell Lymphoma .... . . .. ..... ... .. . .. ... ..... . .. 601
Other Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
Infections Causing Malabsorption. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
Bacterial Overgrowth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
Other Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
Malabsorption in Acquired Immunodeficiency Syndrome. . . . . . . . . . . . . . . . . . . . 602

xviii
Contents

Postoperative Malabsorption Syndromes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602


Extensive Small Bowel Resection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
Gastric Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
Systemic Diseases Causing Malabsorption ... ......... .... .... ·.......... ..... 602
Systemic Mastocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
Endocrine Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
Collagen Vascular Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
Immunologic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
Selective IgA Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
Common Variable Immunodeficiency .. ................................. 605
Other Immunodeficiency Conditions Leading to Malabsorption . .. . . ......... 607
Autoimmune Enteropathy ................................. . .. . ........ 607
Amyloidosis ... . ... ... ............. .... ... . .... . ......... .. ......... 607
Lipid Malabsorption. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
Abetalipoproteinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
Familial Hypobetalipoproteinemia ...................................... 608
Anderson's Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609
Drug-Induced Malabsorption ..... ........... .... . ....... ........ ......... 610
Malnutrition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610
Kwashiorkor ........................................................ 610
Vitamin Deficiencies ............... ............ . . ... .......... .. . ...... 610
Vitamin B12 Deficiency ............................................... 610
Folate Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
Vitamin A Deficiency ................................................. 611
Vitamin E Deficiency and Brown Bowel Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . 611
Zinc Deficiency and Acrodermatitis Enteropathica .. .. ....... ......... .. .... 613
Other Mineral Deficiencies ............................................ 613
13. Diseases of the Appendix ...... .. . .. ... ... .. ...... . ......... .... . .. .... .... 621
Congenital Anomalies .................................................. 621
Diverticula .......... ....... .... ........... . ... ..... .......... ........ 621
Intussusception ........ ........ .... .............. ....... ........... . .. 622
Septa .............................. . ............................... 623
Amyand Hernia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
Appendicitis .......................................................... 624
Specific Forms of Appendicitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628
Periappendicitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631
Neurogenic Appendicopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632
Myxoglobulosis . ... . . ........ . . .... . ...... ..... ........... . .. .. . ...... 633

xix
Gastrointestinal Diseases

Progressive Fibrous Occlusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633


Foreign Bodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634
Drug Effects .... .. . ..... : . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . 634
Inflammatory Bowel Disease .... ...... .... . . ... ............. ...... ·. . . . . . . 634
Crohn's Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634
Ulcerative Colitis .. . ..... .. . .. ............ .... ....... ..... . ......... . 636
Gynecologic Abnormalities Affecting the Appendix ........................... 636
Endometriosis ... .. .. .... ...... .... ......... ..... .. ... ..... ........ .. 636
Endosalpingiosis .... ... ........... .... .. .. . .... . ........... . . .. ...... 636
Decidual Nodules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 7
Mucocele ............................................................. 637
Cystic Fibrosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 7
Non-Neoplastic Polyps .. . •.. ...... ..... ... ..... .. ... . ..... . ... ......... . . 637
Hyperplastic Polyps ................... . .............................. 637
Other Polyps. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 7
14. Miscellaneous Intestinal Disorders ........................................... 643
Eosinophilic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Food Allergy ...........· . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Cow's Milk Intolerance and Related Disorders ...... ... ....... ..... .... ·.... 644
Eosinophilic Esophagitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644
Allergic Proctocolitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644
Eosinophilic Gastroenteritis .......... ....... .. .. ... .... ................ 646
Inflammatory Fibroid Pe"lyp. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648
Granulomatous and Xanthomatous Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650
Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650
Granulomas Associated with Foreign Material ............................. 651
Xanthomatosis .... .. .. .... .... ............ ............. ............. 651
Malakoplakia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
Immune-Mediated Diseases .............................................. 653
Autoimmune Enteropathy ............................................. 653
Microscopic Colitis .... . ............... ....... ....... . ... .. ........... 654
Lymphocytic Colitis .... ..... ............. ........ ........ .......... .. 654
Collagenous Colitis .................................................. 656
Storage Diseases ....................................................... 659
Lysosomal Storage Diseases ..... . . . . .......... ................. ....... . 659
Glycogen Storage Diseases ............................................. 659
Hurler's and Hunter's Syndromes (Mucopolysaccharidoses) .. . . ......... ...... 659
Niemann-Pick Disease ................................................ 660

XX
Contents

Gangliosidoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 660
Fabry's Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661
Wolman's Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661
Cholesterol Ester Storage Disease ..................... .. ...... ..... ...... 661
Neonatal Enteropathies ........ ..... . ......... .... ..... .. ...... . ........ 661
Microvillus Inclusion Disease .......................................... 661
Tufting Enteropathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
Small Intestinal Transplantation .......................................... 663
15. Inflammatory Bowel Disease ....... . ...... .... .... .... ..... .. ...... . ..... .. 675
Demography .......................................................... 675
Etiology .............................................................. 675
Genetic Factors ...................................................... 675
Environmental Factors ................................................ 677
Host Factors .................. . .. . .... ..... .. . ...................... 679
Immunologic Factors ................................................. 679
Crohn's Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
Ulcerative Colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700
16. Non-Neoplastic Polyposis Syndromes . . ................ ........ ............ .. 729
Peutz-Jeghers Syndrome ................................................. 729
Juvenile Polyposis Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734
Cowden's Syndrome (Multiple Hamartoma Syndrome) . . . . . . . . . . . . . . . . . . . . . . . . 739
Bannayan-Riley-Ruvalcaba Syndrome ...................................... 745
Cronkhite-Canada Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 745
Familial Hyperplastic Gastric Polyposis .. ..... .. ....... .. . ......... .. ..... .. 748
Lymphoid Polyposis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 748
17. Motility Disorders ........................................................ 755
Introduction ........................... ..... ... .. ..................... 755
General Clinical Features .............................................. 756
Pathologic Features .................................................. 756
Treatment .......................................................... 756
Development of the Enteric Nervous System ................................ 757
Neural Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 757
Hirschsprung's Disease ................................................ 758
Intestinal Neuronal Dysplasia .............. .... ..................... ... 766
Neuronal Maturational Arrest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 771
Internal Anal Sphincter Achalasia .... .... . .. .. ... .............. .. ....... 772
Absent Enteric Nervous System ..................... .. . ... ............. . 772
Familial Visceral Neuropathies . .. .... ................. .. ...... . . .... . . .. 773

xxi
Gastrointestinal Diseases

Paraneoplastic Pseudoobstruction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773


Infectious Causes of Motility Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 5
Idiopathic Ganglionitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777
Achalasia .............................................................. 777
Achalasia of the Cardia in Allgrove's Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 782
Autoimmune Autonomic Neuropathy ...................................... 782
Chronic Severe Idiopathic Constipation ...... : . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 782
Muscle Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 783
Megacystis-Microcolon and Intestinal Hypoperistalsis Syndrome . . . . . . . . . . . . . . 783
Hollow Visceral Myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785
Nonfamilial Primary Myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 788
Mitochondrial Myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789
Autoimmune Enteric Myositis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
Diffuse Leiomyomatosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
Motility Disorders Accompanying Connective Tissue Diseases . . . . . . . . . . . . . . . . . . 792
Scleroderma ............. ... ........ ......... . .. .. . . .... ........... . . . 792
Diabetes Mellitus .... ." ..... ............ ... ... ... .. ........ . .. ........ 797
A1nyloidosis ............. .. .. .. ............. ...... . ......... ...... . . . 801
Drug-Induced Motility Disorders ...... ..... ............... . . ....... .. . .: . .. 802
Index ................................................................ 815

xxii
GENERAL FEATURES OF THE
1 GASTROINTESTINAL TRACT
AND ITS EVALUATION

INTRODUCTION GASTROINTESTINAL STRUCTURE


The gastrointestinal (GI) tract is a remarkable In general, the gut consists of four concen-
organ with many functions and several distinct tric layers as one progresses outward from the
functional regions: esophagus, stomach, small lumen: the mucosa, submucosa, muscularis
intestine, colon, and anus. Although the cell propria, and serosa or adventitia (fig. 1-1). The
types in these various areas have many similari- mucosal features differ significantly from one
ties, important regional histologic differences region of the GI tract to another. The other
allow specific physiologic functions to be carried layers share many of the same characteristics
out in each area. The cellular rearrangements throughout the length of the gut, although
and migrations that accompany early embryo- some differences do occur.
genesis play a critical role in organizing the
eventual adult GI tract. Interactions between
cell populations regulate subsequent patterns
of gene expression and organ development (1).
The GI tract serves as the digestive organ of
the body, taking in everything that is swallowed,
converting it into nutrients, and discarding
what is left over as waste. These processes begin
in the mouth and terminate at the anus. While
digesting everything to which it is exposed
and breaking it down into smaller, absorbable
chemical substances, the gut is itself able to
withstand these processes and avoid autodi-
gestion. Complex neuromuscular interactions
move food and liquids from one section of the
GI tract to the next, while at the same time
controlling the passage of food in such a way
that allows maximum digestion and absorption.
Not everything that enters the GI tract is
healthy for the patient. The GI tract serves as a
major interface between the outside world and
other portions of the body. It is continuously
exposed to toxins and infectious organisms, yet is
often capable of eliminating these agents without ,_
any harm comirig to the body. Not surprisingly,
breakdown in these defense mechanisms often Figure 1-1
results in disease. This generally occurs when .
FOUR TISSUE LAYERS OF COLON
the integrity of the bowel wall becomes compro-
mised, as is discussed in many of the following Uppermost in the photograph is the mucosa, which is
composed of the epithelium, a supporting lamina propria,
chapters. As a part of this mucosal defense, the and the muscularis mucosae. Deep to this layer is the
GI tract serves as a major immune organ. It is submucosa, composed of connective tissue, vessels, and
the major site of the generation of mucosal nerves. Next is the muscularis propria. The outermost layer
immunity; hence the utility of oral vaccines. in this case is the subserosa. This layer contains abundant
adipose tissue underlying a mesothelial covering, the serosa .

1
Gastrointestinal Diseases

Figure 1-2
MUSCULARIS MUCOSAE
Left: Like the muscularis propria, the muscularis mucosae is comprised of two distinct muscle layers, an inner circular
layer and an outer longitudinal layer.
Right: Higher-power view shows the two muscle layers more distinctly.

Mucosa
The mucosa consists of an epitheJiallining, delicate, loose connective tissue containing
a supporting lamina propria composed of loose lymphocytes, plasma cells (fig. 1-3), eosinophils,
connective tissue rich in immune cells and cap- and mast cells. Most of the cells are plasma cells
illaries, and the muscularis mucosae. The lamina and lymphocytes. The majority of plasma cells
propria is most visible in the stomach, large secrete immunoglobulin (Ig)A; however, IgM-,
and small intestines, and appendix, and least IgG-, and IgE-secreting cells are also present. The
visible in the esophagus and anus. The smooth lamina propria also contains large numbers of
muscle cells in the muscularis m'l.lcosae are pre- macrophages (55), which play an important role
dominantly arranged in a circular orientation, in mucosal immunity and immunoregulation
although some longitudinal muscle fibers are (5,26,32, 45,52). Macrophages also engulf and
also present (fig. 1-2). remove apoptotic epithelial cells that are shed
The character of the epithelium differs sub- normally from the mucosal surface. As a result,
stantially in various regions of the GI tract, with lamina propria macrophages are sometimes im-
differences reflecting the differing functions of munoreactive with antibodies against epithelial-
each region. The squamous lining of the esoph- associated antigens, including carcinoembr-
agus protects it fro~ the passage of undigested yonic antigen, BerEp4, and cytokeratin (34). The
food over its surface. Likewise, in the anus, the highest number of lamina propria macrophages
squamous epithelium protects the mucosa from is present in the colon and rectum (42).
the damaging effects of the passage of solid Gut-associated lymphoid tissue (GALT)
waste. In the stomach, the mucosa facilitates primarily lies within the lamina propria. It is
... digestion by secreting acid. The epithelial lining distributed diffusely or appears as solitary (fig.
of the small intestine is uniquely suited to the 1-4) or aggregated nodules, which in the ileum
further digestion and absorption of nutrients and appendix are called Peyer patches. Larger
along a gradient from the duodenum to the il- aggregates contain germinal centers (fig. 1-4).
eum. The colon predominantly reabsorbs water. Peyer patches often span the muscularis mu-
The specific features of the various portions of cosae (fig. 1-5), creating gaps in this muscular
the gut are discussed below. layer. Solitary lymphoid nodules occur in the
The lamina propria represents the inter- esophagus, gastric pylorus, and along the small
glandular tissue of the mucosa. It consists of and large intestines.

2
General Features of the Gastrointestinal Tract

Figure 1-3
LAMINA PROPRIA
The lamina propria contains num-
erous immunocytes including lymph-
ocytes, plasma cells, and eosinophils,
which lie within a connective tissue
background.

Figure 1-4
PEYER PATCH
Above: Low-power view of the ileum of a 6-year-old child shows
prominent Peyer patches. The large lymphoid aggregate distorts the
overlying mucosa causing a loss of the normal villous architecture.
Right: Higher-power view shows a lymphoid aggregate with a well-
formed germinal center.

and amines. The cytoplasmic granules stain


Mast Cells
with dyes, such as toluidine blue and Alcian
Mast cells are an important, but heteroge- blue. In addition, mast cells stain immunohisto-
neous, component of the lamina propria and chemically with antibodies to CD117 (c-kit) and
submucosa. Mast cells are mononuclear and tryptase (fig. 1-7).
contain numerous cytoplasmic granules (fig. The relative proportion of mast cells differs
1-6). The granules contain various mediators, between anatomic sites, and their recognition
including peptides, proteins, proteoglycans, may be sensitive to formaldehyde fixation in

3
Gastrointestinal Diseases

0
Figure 1-5
PEYER PATCH . a~
...
Above: Hematoxylin and eosin (H&E)-stained section shows a .:t ,
lymphoid aggregate that extends from the submucosa across the -'
muscularis mucosae and into the mucosa.
Right: Immunohistochemical staining for actin demonstrates that
the muscularis mucosae in this area is disrupted. ~. _\\ -

Figure 1-7
LAMINA PROPRIA
Mast cells in the lamina propria are easily recognized
with the CD117 immunostain.

the intestinal mucosa (11,35,46). Mast cells are


often adjacent to blood or lymphatic vessels,
near or within nerves, and beneath epithelial
Figure 1-6 surfaces, particularly those exposed to environ-
LAMINA PROPRIA
mental antigens (3,19,33) . Mast cell infiltrates
On routine H&E-stained sections, mast cells appear
are often associated with increased numbers
eosinophilic and have prominent cytoplasmic granules of eosinophils. They degranulate after IgE-
(arrow). The nucleus is not !abated like that of an eosinophil. mediated stimulation. Following immunologic

4
General Features of the Gastrointestinal Tract

Figure 1-8
LAMINA PROPRIA
Eosinophils appear as red granular cells with bilobed
nuclei.

activation via the IgE receptor, mast cells release


cytokines, lipid-derived mediators, amines, pro-
teases, and proteoglycans, all of which regulate
adjacent cells and the metabolism of the extra-
cellular matrix.
By virtue of their location and number, mast
cells play a role in a wide variety of gastrointes-
tinal abnormalities. The most important include
food allergies, eosinophilic diseases, immunode-
ficiency syndromes, immediate hypersensitiv-
ity reactions, host responses to parasites and Figure 1-9
neoplasms, and immunologically nonspecific SUBMUCOSA
inflammatory and fibrotic conditions (4,30). Top: The submucosa is composed of loose connective
Mast cells are also important in angiogenesis, tissue containing nerves, clusters of ganglion cells, and
wound healing, peptic ulcer disease, reactions vessels. Adipose tissu e is also commonly present.
Bottom: Higher-power view shows a submucosal gan-
to neoplasms, and other chronic inflammatory glion, vessels, and bundles of collagen fibers.
conditions, including graft versus host disease
and inflammatory bowel disease (3,19,33).
Eosinophils have both beneficial and detri-
Eosinophils
mental roles in the host. They function in host
Eosinophils are commonly present within defense, including phagocytosis and killing of
the lamina propria (fig. 1-8). Their brightly bacteria and other microbes. They also mediate
eosinophilic cytoplasmic granules and bilobed allergic reactions, however, and the oxidative
nucleus are characteristic identifying features . products of eosinophils can damage cells. The
The cytoplasmic granules contain lysosomal eosinophilic products that are most damaging
hydrolases as well as many of the cationic pro- are the cationic proteins (53).
teins unique to eosinophils, including major
Submucosa
basic protein (7,21) and eosinophil peroxidase.
Eosinophils express receptors for IgG, IgE, and The submucosa is a more densely collagenous
IgA on their plasma membranes (2,8,22,53). and less cellular layer than the mucosa (fig. 1-9).
They also have receptors for complement com- Major blood vessels, lymphatics, nerves, gan-
ponents (9,20,23) and cytokines (29). glia, and occasionally lymphoid collections are

5
Gastrointestinal Diseases

0

• .:.1
,,. •. 0

t • I ..
0
" ..,
!'I

Figure 1-11
INTERSTITIAL CELLS OF CAJAL
Although difficult to identify on routine H&E-stained
sections, immunostaining for CD117 highlights the
interstitial cells of Cajal. The cells are associated with the
myenteric plexus, appear somewhat spindled, and have
scant cytoplasm. (Fig. 1-9A from Fascicle 32, 3rd Series.)

inner muscular layer is arranged in a concentric


circular fashion, while the outer muscle fi.bers
are arranged longitudinally. In the cecum and
Figure 1-10
in parts of the colon, the longitudinal muscle
MUSCU LARIS PROPRIA- is attenuated except in the areas where it forms
Low-power view shows a distinct in~r circular muscle thick cords, the taeniae coli.
layer and an outer longitudinal layer. The myenteric plexus In the stomach, the arrangement of the
contains nerve fibers and ganglion cells, and lies between
the two layers of smooth muscle. musculature is more complex because in some
areas there are three muscle layers. In the small
intestine, the innermost portion of the circular
located here. The submucosa may also contain layer consists of specialized muscle cells that are
adipose tissue in variable amounts. much smaller and more electron dense than
the bulk of the circular muscle. A large number
Muscularis Propria
of nerve fi.bers run between the muscle layers,
The muscularis propria is a continuous struc- and it has been suggested that some of these
ture made up of two smooth muscle layers that are sensory fi.bers working in conjunction with
extend from the upper esophagus to the anal ca- the smooth muscle cells to function as stretch
nal (fig. 1-1 0). The on ly exception to this occurs receptors (17,18) .
in the stomach, where three layers are present. The musculature also contains the interstitial
•.·
At the junctions between adjacent regions of the cells of Cajal (ICCs), which share ultrastructural
GI tract, the muscular coat rearranges to form features with fi.broblasts (38-40). ICCs are large,
sphincters (pharyngoesophageal, esophago- oval cells with light-staining nuclei and scant
gastric, pyloric, ileocecal, and anal sphincters). cytoplasm. They have two to five, long ramifying
In the upper esophageal and anal sphincters, primary cell processes, giving them a spindled or
skeletal muscle fibers may be admixed with stellate shape (fig. 1-11). They fmm a three-dimen-
smooth muscle fibers (10). In the portion of the sional network and are closely associated with
muscularis propria comprised of two layers, the ganglion nerve bundles; they also extend over

6
General Features ofthe Gastrointestinal Tract

Figure 1-12 Figure 1-13


SUBSEROSA/ADVENTITIA MUCOSAL VASCULATURE
The subserosa of the gastrointestinal tract contains A network of capillaries underlies the mucosal surface.
loose connective tissue, fat, blood vessels, and nerves. The
outermost aspect is covered by mesothelium, the serosa.

Vascu lature
the smooth muscle cells. The ICCs connect to The intestinal mucosa is a highly perfused
both the circular and longitudinal cells via gap organ. The largest arteries pass through the wall
junctions, creating a network of interstitial cells of the GI tract and are arranged longitudinally
that conduct electrical signals (27,28) . ICCs have in a submucosal plexus. The submucosal plexus
three major functions: they act as pacemakers sends arterioles and capillaries into the mucosa,
for the gastrointestinal muscle (13-15,48); they muscularis propria, and adventitia or serosa.
facilitate active propagation of electrical events; The mucosa contains an irregular capillary
and they mediate neurotransmission (15) . They plexus, often with its most terminal branches
may also act as mechanoreceptors (13-15,48). underlying the luminal surface epithelium (fig.
These unique cells appear to require the c-kit 1-13) . Veins arising in the mucosa anastomose
gene or stem cell factor in order to develop (41), in the submucosa and course with the arteries
as well as to elicit their pacemaker activity (24). out of the intestine. Valves are present in the
The cells of the muscularis propria contain adventitia or subserosa.
numerous receptors that allow them to respond The gut is richly supplied with lymphatic ves-
to neural as well as other stimulatory and in- sels, but their distribution, particularly in the
hibitory signals during the digestive process. mucosa, varies with the site within the GI tract.
Contraction of the circular layer constricts the The richest lymphatic distribution occurs in the
lumen; contraction of the longitudinal layer small intestine, where these vessels are intimately
shortens the digestive tube. involved in nutrient absorption (fig. 1-14). Larger
submucosallymphatics branch freely and contain
Advent it ia or Serosa
numerous valves. Smaller mucosal and submuco-
The adventitia is the outermost layer of the sallymphatics may be difficult to detect because
GI tract, and consists of loose connective tis- they are often collapsed and blend in with the
sue containing fat, collagen, and elastic tissue surrounding connective tissue. They are often
(fig. 1-12). If it is covered by mesothelium, the difficult to distinguish from small capillaries.
serosa, it is called the subserosa. A serosa and
Innervation
subserosa are present on the stomach, those
parts of the small intestine that are not retro- The enteric nervous system is the most
peritoneal, the appendix, and the large intestine complex portion of the peripheral nervous
above the peritoneal reflection. system. Three divisions of the nervous system

7
Gastrointestinal Diseases

docrine/paracrine cells differ in various parts of


the gut in their overall density, contents, and
structure. They are sensitive to chemical and
mechanical stimuli, to which they respond by
releasing extracellular mediators. The composi-
tion of enteroendocrine cells depends on their
position along both the vertical and horizontal
axes .of the GI tract. At least 16 types of endo-
crine/paracrine cells inhabit the mucosa of the
GI tract (Table 1-1).
Gastrointestinal endocrine cells have endo-
crine, paracrine, . and neurotransmitter func-
tions, constituting a complex system that regu-
lates many functions of the GI tract. Some sub-
Figure 1-14 stances produced by enteroendocrine cells act
SMALL INTESTINAL LYMPHATI€S as true peptide hormones. For example, gastrin,
A central lymphatic vessel (lacteal) lies within the core secretin, and cholecystokinin are secreted into
of this villus. The lacteals are often difficult to see unless the blood to reach their target organs (stomach,
there is some degree of lymphangiectasia. pancreas, and gallbladder) and soon after are
metabolized and eliminated. Some peptides,
(sympathetic, parasympathetic, and enteric) such as somatostatin, are released from entero-
contribute to the neural control of at least four endocrine cells into the local subepithelial
physiologic effector systems: 1) th~ visceral connective tissue or directly on other types of
smooth muscle responsible for motility and cells via long basal cytoplasmic processes. This
sphincteric functions; 2) the mucosa responsible influences cells and tissues in the ffnmediate
for gastric acid secretion and homeostasis of vicinity via a paracrine mechanism.
intestinal fluid and electrolytes; 3) the immune Interactions exist between different compo-
cells responsible for mucosal immunity; and 4) nents of the neuroendocrine system and the
the vasculature. Complex reflex activities in- neural system. Neurons interact with endocrine
volving gastrointestinal motility/ion transport, cells, endocrine cells interact with other endo-
and mucosal blood flow all occur in the absence crine cells, and endocrine cells may influence
of extrinsic autonomic and sensory input. neurons (47). In addition, many gastrointestinal
Functionally, the neurons of the enteric hormones interact with the hypothalamic-pitu-
nervous system fall into five types: 1) motor itary axis to orchestrate the secretory activity
neurons controlling smooth muscle tone in the and motility necessary for effective digestion
wall of the gut; 2) vasomotor neurons control- (25,36,47). Gastrointestinal hormones and
ling vascular muscle tone; 3) secretory neurons paracrine messengers control digestive processes
regulating exocrine a:r:d endocrine secretion; 4) such as acid secretion, bicarbonate secretion,
sensory neurons carrying sensory information enzyme secretion, and local blood flow. They
to the central nervous system; and 5) inter- also influence the immune system, metabolism,
neurons that provide communication between and gastrointestinal growth (49).
neurons and the gut wall (16). The interneurons The circulating levels of the gastrointestinal
intermingle in the myenteric and submucosal peptides are influenced by numerous factors.
ganglia, making their identification difficult. For endocrine cells that lie in contact with the
gastrointestinal lumen, such as gastrin cells
Gastrointestinal Endocrine System
(44), gastric inhibitory polypeptide cells (6),
Endocrine cells are widely distributed within and secretin-producing cells (43,51), direct
the epithelium of the stomach, small and contact with, and absorption of, nutrients and
large intestines, the distal esophageal glands, secretions are the most important stimuli. In
and anus. Some are also present in the lamina contrast, peptides like pancreatic polypeptide
propria in the stomach and the appendix. En- and insulin, produced in cells outside of the

8
General Features ofthe Gastrointestinal Tract

Table 1-1
GASTROINTESTINAL ENDOCRINE CELLS

Cell Location Product(s) Action


CCI<" Small intestine Cholecystokinin Stimulates pancreatic and biliary enzyme secretion
D Stomach Somatostatin Inhibit secretion and motility
Small intestine Vasoactive intestinal polypeptide
Colon
EC Stomach Serotonin Stimulate motility
Small intestine Motilin
Appendix Substance P
Colon
ECL Stomach Histamine Stimulates acid secretion
G Pylorus Gastrin Gastric acid secretion
Duodenum
GIP Small intestine Gastric inhibitory polypeptide Inhibits gastric acid secretion
Xenin
L Small intestine Glucagon-like peptides Stimulate hepatic glycogenolysis
Colon Peptide YY
M Small intestine Motilin Stimulates motility
N Small intestine Neurotensin
PID, Stomach Ghrelin
s Small intestine Secretin Stimulates pancreatic and biliary secretion
Serotonin
·• CCK = cholecystokinin cell; EC = enterochromaffin cell; ECL = enterochromaffin-like cell; GIP= gastric inhibitory poly-
peptide cell.

Figure 1-15
ENDOCRINE CELLS
Left: Gastric endocrine cells are difficult to visualize on routine H&E-stained slides. They are located in the neck of the
gastric gland, and often have relatively clear cytoplasm and round, regular nuclei (arrows).
Right: A chromogranin stain highlights the endocrine cells.

GI tract, depend on absorbed nutrients and Endocrine cells occur singly (fig. 1-15) or in
stimulation by other peptides in the nervous discontinuous clusters. They appear as small,
system. Endocrine cells are also influenced by clear cells with a broad basal cytoplasm that con-
the nature of the intraluminal microflora (SO). tains electron-dense granules. Some endocrine

9
Gastrointestinal Diseases

and submucosal glands (fig. 1-18). The basal


layer of the squamous epithelium consists of
cuboidal or columnar cells with central baso-
philic nuclei. This layer·typically comprises no
more than 10 to 15 percent of the total epithelial
thickness, although distally the basal cell layer
can be somewhat thicker, probably in response
to physiologic reflux. Melanocytic or endocrine
cells may be scattered among the basal cells (58).
Cells in the basal layer give rise to daughter cells
that migrate upward, differentiating as they
approach the luminal surface. The most super-
ficial layers may contain basophilic granules.
The cells of the superficial or functional zone
appear flattened, with their long axis parallel
to the mucosal surface. Papillae, which are
invaginations of vascularized lamina propria,
extend into the epithelium. These usually do
not penetrate more than two thirds of the way
into the overlying mucosa (fig. 1-18). The height
of a papilla (or rete ridge) is measured from
the basal lamina of the surrounding squamous
epithelium to the basal lamina at the top of the
papilla. Nonepithelial elements include lym-
phocytes and antigen-presenting et~lls (56,57).
Submucosal glands lie in straight rows that ex-
tend outward from the esophageallumen toward
Figure 1-16 the muscularis propria (fig. 1-19). The glands lie
ENDOCRINE CELL both within the mucosa and the submucosa.
An H&E-stained section demonstrates an endocrine cell
The glandular lobules connect to the lumen via
in the base of a colonic crypt. The cell contains prominent a straight duct. Mucous cells within the submu-
subnuclear eosinophilic granules. cosal glands often have a pyramidal shape and
contain numerous large, pale secretory granules.
Myoepithelial cells lie between the secretory cells
cells, particularly those in the colon, contain and the underlying basement membrane.
prominent eosinophilic granules (fig. 1-16). Although the esophageal mucosa is repeat-
Endocrine cells may be identified histochemi- edly exposed to potentially injurious materials
cally using Grimelius or Fontana-Masson stains. that are ingested or that reflux into the distal
Other markers of neuroendocrine differentia- esophagus, it is rare for injury to occur because
tion include antibodies to neuron-specific eno- preepithelial, epithelial, and postepithelial
lase, protein gene product 9.5, synaptophysin, defenses protect against injury. Preepithelial
and chromogranin (fig. 1-17) (12,31,37,54). defenses rely on intact neuromuscular function
Specific peptide hormones can also be identified to maintain lower esophageal sphincter pressure
immunohistochemically. and normal esophageal motility, thus minimiz-
ing gastroesophageal reflux and promoting clear-
NORMAL FEATURES OF ance of esophageal luminal contents. Gravity
INDIVIDUAL GASTROINTESTINAL SITES and normal peristalsis move the intraluminal
contents distally, thereby preventing prolonged
Esophagus
mucosal contact and protecting against mucosal
The normal esophageal mucosa is readily damage. The multilayered squamous epithelium
recognizable by its squamous epithelial lining also protects against damage from substances

10
General Features o(the Gastrointestinal Tract

Figure 1-17
GASTRIC ENDOCRINE CELLS
Left: Endocrine cells within the neck region of the gastric glands are highlighted with the chromogranin immunostain.
Right: Antral glands contain scattered G cells, as demonstrated with this gastrin immunostain.

-::::_-- -- --
--.. ~~- =:--

. .~-:.!-'·!= •. :.
~ ~ ::!. .... ;~-- . . . . . -

- - =- _#2<-..:5~ :
~". --

~...~ -·
·J:. _ -:--~
---
1

Figure 1-18
NORMAL ESOPHAGEAL HISTOLOGY
Left: The basal layer is only a few cells thick, and the papillae extend approximately to one third to half the thickness of the
epithelium. The underlying muscularis mucosae is thicker in the esophagus than in other parts of the gastrointestinal tract.
Right: Higher-power view shows a basal cell layer composed of only a few layers of cells and short papillae. Only rare
intraepitheliallymphocytes lie in the deep portion of the mucosa.

11
Gastrointestinal Diseases

Figure 1-19
SUBMUCOSAL GLANDS
Left: Smalllobules of glandular tissue are seen within the submucosa of the distal esophagus.
Right: Higher-power view shows glands with abundant intracytoplasmic mucin. The duct is lined by cuboidal to columnar
cells.

passing over it. When the protective mechanisms consists of tall, columnar, mucus-secreting
are overwhelmed, epithelial erosions or ulcers cells (fig. 1-20) that form an integral part of
develop. Four general situations predispose to the mucosal barrier. These cells have irregular,
esophageal injury: 1) motility disturbances, 2) the basally situated nuclei and apically, mucin-filled
presence of esophageal reflux, 3) infection, and 4) cytoplasm. The cardiac pits appear shorter than
dmg- or chemical-induced injury. Increased cell those in other regions of the stomach. The pits
proliferation and secondary basal cell hyperplasia are deepest in the antmm. Mucous n eck cells re-
compensate for cells lost to injury. side in the neck and isthmus in the middle and
upper parts of the gastric glands. They merge
Stomach
with both the glandular epithelium below and
The stomach has three major histologic the foveolar epithelium above.
compartments: the gastric pits and surface lin- In contrast to the foveolar and pit regions,
ing, the mucous neck region, and the glands the histology of the gastric glands, which empty
(fig. 1-20). Additionally, the stomach has four into the base of the gastric pits, differs in differ-
anatomic regions: the cardia, fundus, body, and ent regions of the stomach. Cardiac glands share
antropyloric region (fig. 1-21). The cardia, a nar- histologic features with esophageal submucosal
row, ill-defined region, is not grossly distinctive glands (fig. 1-22) and with pyloric and antral
and is histologicall}; identified by the presence glands. Oxyntic glands contain four cell types:
of cardiac glands. The fundus, the most superior mucous neck cells, endocrine cells, parietal
part of the stomach, protmdes above a horizontal (oxyntic) cells, and chief (zymogenic) cells (fig.
line drawn from the esophagogastric junction. It 1-22). Parietal cells constitute approximately one
blends imperceptibly into the major portion of third of the cells in the oxyntic mucosa and tend
'-··
the stomach, called the body. Oxyntic mucosa to be more numerous distally than proximally.
lines the body and fundus . The antmm compris- This contrasts with chief cells, which are found
es the distal third of the stomach just proximal in greater numbers in the proximal rather than
to the pyloric sphincter. It is a triangular zone the distal oxyntic mucosa. Parietal cells chiefly
that extends further along the lesser curvature localize to the mid portion of the oxyntic glands,
than along the greater curvature. whereas chief cells lie at the glandular bases.
Surface, or foveolar, cells line the surface and Some parietal cells are found in the antmm. The
gastric pits; they are histologically identical acid-secreting parietal cells are easily identified
throughout the stomach. Foveolar epithelium by their large size, pyramidal shape, large central

12
General Features of the Gastrointestinal Tract

Figure 1-20
NORMAL GASTRIC MUCOSA
Above: The gastric mucosa consists of surface epithelium, pits (in
the upper mucosa), and glands (in th e lower mucosa) . The mucous neck
region separates the two .
Right: Higher magnification of the foveolar epithelium that lines
both the luminal surface and the gastric pits.

nuclei, and intensely eosinophilic cytoplasm


(fig. 1-22). Chief cells, which make pepsinogen /
(fig. 1-22) and lipase, appear as triangular, low
columnar cells containing a coarse, granular,
pale, gray-blue, basophilic cytoplasm. The
nucleus contains one or more small nucleoli.
The stomach contains a diverse population
of endocrine cells. These are widely distributed
in various regions of the gastric mucosa. At
least seven distinct endocrine cell types exist:
enterochromaffin, G, enterochromaffin-like
(ECL), D, 01, P, and X cells. The predominant
antral endocrine cell, the gastrin-producing G
cell, causes ECL cell, parietal cell, and gastric
mucosal growth. Somatostatin-secreting D cells
are distributed uniformly throughout the antral
and oxyntic mucosa. They inhibit the release of
gastric acid, gastrin, intrinsic factor, and acetyl-
choline. ECL cells, the major endocrine cells of
the oxyntic mucosa, are usually found in the
fundus but they can occur more distally. They
play a pivotal role in mediating gastrin-induced
Figure 1-21
parietal cell secretion.
DIAGRAM OF THE NORMAL
Small Intestine ANATOMY OF THE STOMACH

The major functions of the small intestine The stomach is divided into different histologic regions.
The maj or feature differentiating them is the nature of the
are terminal digestion and absorption of nutri- glandular epithelium (see text).
ents. The anatomy of this region of the GI tract

13
Gastrointestinal Diseases

Figure 1-22
HISTOLOGY OF CARDIAC AND OXYNTIC MUCOSAE
A: Cardiac glands include mucin-filled glands and, occasionally, cystically dilated glands.
•.· B: Pits and glands of the oxyntic mucosa.
C: Higher magnification of the junction of the pit and mucous neck region.
D: Oxyntic glands with parietal cells and chief cells.

reflects these functions . Intestinal folds, known unique to the small intestine, and are finger- or
as plicae circulares, increase the surface area leaf-like mucosal evaginations. They are lined
available for absorption. Innumerable villi by epithelium overlying a connective tissue core
stud the intestinal surface, further increasing that contains a highly cellular lamina propria, a
the absorptive surface (fig. 1-23). The villi are capillary network, lacteals, and nerves. Simple

14
General Features o(the Gastrointestinal Tract

Figure 1-24
CRYPTS OF LIEBERKUHN
Straight crypts project downward from the base of the
villi. In this case, two crypts empty into the intervillous
space. Paneth cells are present in the crypt bases (arrow).

Villi vary in height and form in different


regions of the small intestine. The duodenum
has the greatest villous variability. The villi in
the proximal duodenum are shorter and broader
than elsewhere; jejunal villi show little variation
in their width from their base to their apex; and
Figure 1-23 in the ileum, the villi are broader and shorter
SMALL INTESTINAL VILLI
than in the jejunum.
Measurement of the ratio of villous height to
Top: Long finger-like villi project upward into the lumen
of the small intestine. crypt length is often required for the assessment
Bottom: Tangential sectioning demonstrates uniform, of small intestinal absorptive function. Well-
slender villous structures. oriented sections allow optimal examination
of the villous architecture. In adults, the villous
tubular invaginations (crypts of Lieberkuhn) at height is approximately three or more times the
the bases of the villi (fig. 1-24) extend downward depth of the crypts, whereas in children this ra-
toward the muscularis mucosae but do not pen- tio is lower, more typically 2 to 1 (fig. 1-25). The
etrate it. The openings to several crypts empty villous height is also lower in elderly patients
into the intervillous basin. (76). Villi are often stubby or absent overlying

15
Gastrointestinal Diseases

tive (fig. 1-26).


Goblet cells occur in both the crypts (fig.
1-27) and among the surface enterocytes, but
they progressively decrease in number as one
progresses toward the villus tip (fig. 1-27). Gob-
let cells increase in frequency along the length
of the small intestine, being most numerous
in the lower ileum: These cells are primarily
columnar in shape and contain large numbers
of mucin droplets in the supranuclear portion
of the cell. Goblet cells secrete mucin, ions, and
water into the overlying mucous gel that lines
and protects the mucosal surface.
Paneth cells populate the bases of the small
intestinal crypts. Paneth cells are also seen in
the right colon. These strongly eosinophilic,
pyramidal cells have the cytologic characteris-
tics of secretory cells (fig. 1-28). Irregular micro-
villi cover their apical surfaces. Paneth cells play
an important role in maintaining the relatively
sterile state of the small intestine because they
produce many substances with antimicrobial
properties (64,65,67-69,71,72,74) . They are also
phagocytic and secrete cytoplasmic granules
into the intestinal crypt lumen aft~r bacterial
Figure 1-25 entry. In addition, Paneth cells contain IgA and
NORMAL VILLUS IN AN ADULT IgE, possibly from phagocytosis of immunoglob-
A settion from the distal small intestine shows a villus ulin-coated microorganisms (77).
to crypt ratio of greater than 4 to 1. - Lymphoid Tissues. Small intestinal lym-
.r phoid aggregates split the muscularis mucosae;
they are partially mucosal and partially submu-
lymphoid areas, and frequently contain in- cosal, and often have a central germinal center
creased numbers of intraepitheliallymphocytes. (see figs. 1-4, 1-5). Lymphoid aggregates increase
The small intestinal crypts and villi represent in number along the length of the small intes-
two morphologically and functionally distinct tine, becoming confluent in the ileum where
compartments. Each crypt consists of a single they are known as Peyer patches. The duode-
clone of cells and several crypts contribute cells num may also contain well-formed lymphoid
to each villus. The epithelial lining harbors a nodules that extend from the surface to the base
heterogeneous cell population, including ab- of the mucosa. A lymphoid aggregate is com-
sorptive cells (enterocytes), goblet cells, Paneth posed of a follicular B-cell area, a parafollicular
cells, undifferentiated crypt cells, endocrine T-cell area, and the follicle-associated epithe-
cells, cup cells, tuft cells, and M cells. lium. The follicle-associated epithelium consists
Enterocytes are highly polarized cells with of enterocytes, M cells, rare mucus-secreting
"·'
an apical microvillous or brush border. The goblet cells, occasional tuft cells, and abundant
mature brush border, which covers the cell intraepitheliallymphocytes (61, 70, 78).
apex, consists of closely packed microvilli and Intraepitheliallymphocytes (IELs) constitute
the terminal web (fig. 1-26). Microvilli vary in a distinct population of intestinallymphocytes
length depending on the maturity of the cell, (81). IELs are T cells and are typically found in
increasing in height as one migrates up the the basal portion of the epithelium. They pos-
crypt villus axis (60,73,82). The microvillus sess small dense nuclei, contrasting with the pal-
brush border is periodic acid-Schiff (PAS) posi- er, more vesicular enterocyte nuclei (fig. 1-29).

16
General Features ofthe Gastrointestinal Tract

Figure 1-26
SMALL INTESTINAL BRUSH BORDER
Left: On H&E-stained sections, the brush border is visible as a slightly
refractile layer on the epithelial surface.
Above: A periodic acid-Schiff (PAS) stai n highlights the brush border
of the small intestine. The goblet cells are also PAS positive.

Figure 1-27
GOBLET CELLS
Left: A section from the intestinal villi shows scattered plu mp, pale-staining goblet cells among the columnar enterocytes.
The nuclei of the goblet cells are displaced to the basal portion of the cells by the abundant mucin contained within the
cytoplasm. ·
Right: Goblet cells are also present within the intestinal crypts .

The human small intestine contains a large lymphoid follicles are predominantly of B-cell
number of IELs, estimated to be approximately derivation (79).
1 IEL for every 6 to 10 epithelial cells (63,66,75). Lamina Propria. The jejunallamina propria
Lymphocytes account for up to 30 percent of the is estimated to contain several thousand cells
total cell population of the mucosal surface. In per mm 2 (66,75). Most are located in the region
contrast to the IELs in the villi, IELs overlying of the crypts rather than in the villi. These cells

17
Gastrointestinal Diseases

Figure 1-28
PANETH CELLS
.r Figure 1-29
Paneth cells are present in the bases of the intestinal
crypts. They contain characteristic coarse, eosinophilic INTRAEPITHELIAL LYMPHOCYTES
cytoplasmic granules (see also fig. 1-27, right) . Top: Scattered dark-staining lymphocyte nuclei are
interspersed among the small intestinal epithelial cells
(arrows) . Lymphocytes are relatively few in number (less
than one lymphocyte for every five or six enterocytes).
consist of immunocytes, particularly plasma Bottom: Larger numbers of intraepitheliallymphocytes
cells and lymphocytes (fig. 1-30). The major- are normally seen in the epithelium overlying lymphoid
ity are IgA-containing plasma cells, although follicles. A diagnosis of intraepitheliallymphocytosis should
not be made on the basis of lymphocyte counts from areas
IgM-, IgD-, IgG-, alfd IgE-containing cells are
such as this.
also present. Eosinophils are commonly found
within the lamina propria, but should not be
present within the epithelium. Neutrophils are
not present within the lamina propria under duodenum. Morphologically, Brunner glands
normal circumstances. resemble gastric antral glands. They are found
The lamina propria of the villus contains mainly in the submucosa but can extend focally
a central, blind-ending lacteal that is usually into the basal portion of the mucosa (fig. 1-32). In
collapsed. It also contains blood and lymphatic the first portion of the duodenum, where Brun-
vessels, nerve fibers, and smooth muscle cells ner glands are relatively large, bands of smooth
(fig. 1-31). muscle from the muscularis mucosae occasion-
Brunner Glands. Brunner glands are a con- ally lie between the acinar lobules (fig. 1-32).
tinuous series of branched or coiled tubular The glands produce a neutral glycoprotein
glands in the submucosa of the first part of the that stains with PAS, but not mucicarmine

18
General Features ofthe Gastrointestinal Tract

Figure 1-31
SMALL BOWEL LAMINA PROPRIA
The lamina propria of the villi contains inflammatory
cells, smooth muscle fibers, capillaries, lymphatics, and
nerves.

Colon
The mucosa of the large intestine is relatively
smooth (fig. 1-35) except distally in the rectum
where more prominent fo19s occur. No villi are
Figure 1-30
present. The surface of the colon is arranged in
SMALL BOWEL LAMINA PROPRIA a regular geometric way (83,85), with the flat
Scattered plasma cells, lymphocytes, and eosinophils are large intestinal mucosa regularly punctuated by
present. No neutrophils are seen. the openings of the colonic crypts (fig. 1-36).
Normal colonic epithelium consists of absorptive
cells (colonocytes), undifferentiated cells, mature
goblet cells, tuft cells, and endocrine cells. In
(62,80). In addition, they stain with antibodies addition, M cells occur in the epithelium over-
directed against lysozyme (fig. 1-33). Brunner lying lymphoid follicles, and intraepithelial T
glands also contain endocrine cells that store lymphocytes lie scattered within the epithelium.
somatostatin, gastrin, cholecystokinin, and Mature absorptive cells have numerous short,
peptide YY. Peptidergic nerves containing va- regularly spaced microvilli and function in ab-
soactive intestinal peptide (VIP), substance P, sorption of water and electrolytes. The nuclei
neuropeptide Y, and gastrin-releasing peptide are small, round, and basally located (fig. 1-37).
are also present (59). Goblet cells are numerous in the crypt epi-
Ampulla of Vater. The ampulla of Vater is thelium, with approximately one goblet cell for
located in the second portion of the duodenum every four absorptive cells (fig. 1-38). Their broad
and is the site where the common bile duct and shape creates the false impression that they
major pancreatic duct reach the intestinal lu- constitute the majority of the cells. As they dif-
men. The mucosa overlying this area is highly ferentiate, they migrate toward the mucosal sur-
variable in appearance. A complex network of face, becoming progressively filled with mucus
glands arranged in a lobular configuration can droplets. The nucleus is compressed into a small
be seen in the submucosa and passing through dense structure in the basal region of the cell.
the muscularis mucosae into the overlying mu- The colon has the least number of endocrine
cosa. These glands are surrounded by smooth cells of any region of the GI tract. Colonic endo-
muscle cells and a loose stroma (fig. 1-34). crine cells are primarily located in the proximal

19
Gastrointestinal Diseases

Figure 1-32
BRUNNER GLANDS
A: Glands resembling those of the gastric antrum lie within the submucosa of the duodenum. To the left and slightly
above this group of glands, another cluster lies in the deep mucosa.
B: Higher-power view shows the pale, vacuolated, mucin-containing cytoplasm of Brunner glands.
C: High-power view of the Brunner glands within the deep mucosa. The epithelium of the glands merges with that of
the deep portion of the intestinal crypts.
D: Brunner glands in the proximal duodenum often contain strands of smooth muscle, which extend between lobules
from the muscularis mucosae.

20
General Features of the Gastrointestinal Tract

Figure 1-33
BRUNNER GLANDS
Immunohistochemical stain for lyso-
zyme shows diffuse immunoreactivity in
the Brunner glands.

Figure 1-34
AMPULLA OF VATER
A: Numerous ducts enter the area through the sub-
mucosa. These ducts are surrounded by smooth muscle.
B: Higher-power view shows the presence of small glands
lined by epithelium rese mbling the biliary or pancreatic
ductal lining and intestinal type glandular epithelium.
C: Higher-power view of the small ductules entering
th e ampulla. The cells lining them are cuboidal and do
not contain mucin.

21
Gastrointestinal Diseases

Figure 1-35 •
COLONIC MUCOSA
-·. . . •
. . ...- ,
Above: The mucosal surface is relatively smooth and without villi. The
-- ..,.
--.. . . -
crypts are composed of straight, tubular glands. A lymphoid aggregate - :.- - ....
...
is on the left. (,•
.., , . .
Right: Higher-power view of nonbran~hing, regularly spaced crypts
.. .. .
,,. ..., ,,
·- .
•. r . •'
lined by absorptive and goblet cells. : ....~'!"


Figure 1-36 Figure 1-37
COLONIC MUCOSA COLON
An en face section shows evenly distributed, straight Absorptive cells outnumber goblet cells, although this is
glands. difficult to appreciate in histologic sections. The absorptive
r.,. cells, best seen at the luminal surface, are columnar with
basally situated nuclei, slightly eosinophilic cytoplasm,
and distal colon, particularly the rectum (84,86). and no mucin. ·
They are most prominent in the deep portions
of the crypts (fig. 1-39). Colonic endocrine
cells appear as small, round or pyramidal cells Scattered Paneth cells are usually present in
scattered among the nonendocrine epithelial the cecum and the proximal ascending colon
cells. The broad basal cytoplasm appears clear (fig. 1-40). They are absent from the remainder
or eosinophilic and contains basal granules. of the normal large intestine.

22
General Features of the Gastrointestinal Tract

Figure 1-38 Figure 1-39


COLONIC CRYPTS COLONIC ENDOCRINE CELLS
Goblet cells are numerous and appear identical to those The cells often appear eosinophilic, with fine, generally
in the small intestine. basal, cytoplasmic granules (arrows) .

Lamina Propria. The lamina propria of the


colon consists of loose, reticular connective
tissue that contains fibroblasts, capillaries, and
mononuclear cells, including macrophages,
plasma cells, lymphocytes, and scattered mast
cells. Eosinophils may also be seen. The area
immediately under the epithelium primarily
contains fibroblasts, myofibroblasts, and mac-
rophages. Isolated smooth muscle fibers may
also be seen in the lamina propria.
The lamina propria contains solitary lym-
phoid nodules that may be sufficiently large
to displace the crypts and extend into the sub-
mucosa. These follicles may additionally splay
apart the fibers of the muscularis mucosae, or
the underlying muscularis mucosae may be dis-
continuous (fig. 1-41). They increase in number
as one approaches the rectum.
Appendix
The appendiceal mucosa resembles that of
the large intestine, except for the presence of
a prominent lymphoid component. Straight,
unbranched crypts are lined by absorptive cells
and mucus-secreting goblet cells. As in the
colon, the proliferative zone lies in the basal
portion of the crypts. Immature cells migrate Figure 1-40
upward to the luminal surface, differentiating
COLONIC PANETH CELLS
into absorptive and goblet cells along the way.
Paneth cells are often seen in the bases of the colonic
The crypts also contain endocrine cells, Paneth crypts of the cecum and ascending colon. They are not
cells, and IELs (fig. 1-42). normally present in other parts of the colon.

23
Gastrointestinal Diseases

Like the ileum, the appendix contains nu-


merous lymphoid follicles. The appendiceal
epithelium is modified over the dome of each
lymphoid follicle with a structure similar to that
seen in the small intestine. The lymphoid fol-
licles of the appendix are regularly arranged at
the junction of the mucosa and submucosa (fig.
1-43). A well-defined lymphatic sinus surrounds
both the lateral and basal parts of the follicle
and empties into a system of fine collecting
lymphatics in the submucosa.
The appendix contains two populations of
endocrine cells: those in the crypts and those
in the lamina propria. Crypt endocrine cells
tend to lie near the base of the crypts, and oc-
cur singly or in small clusters (fig. 1-44). More
endocrine cells populate the distal than the
proximal appendix. Lamina propria endocrine
cells lie scattered near the crypt bases, appar-
ently unattached to crypt epithelium; they
are highlighted with silver stains or antibodies
such as chromogranin (fig. 1-44). Both crypt
and lamina propria endocrine cells contain
serotonin, somatostatin, VIP, and substance P.
Subepithelial endocrine cells also contain cyto-
Figure 1-41 keratin, as do the endocrine cells of the crypts,
supporting an origin from endocrine cells or
COLON
their progenitors in the intestin\11 crypts.
A lymphoid follicle lies within both· the mucosa and
submucosa. The smooth muscle of the muscularis mucosae
The histologic features of the appendix
is discontinuous in the region where itj.s traversed by the change with age. The appendix in the elderly
lymphoid follicle. appears small, with loss of its lymphoid tissue
and an increase in the amount of fat and fibrous

r..·

Figure 1-42
NORMAL ADULT APPENDIX
Left: Dark blue staining lymphoid cells are present diffusely in the deep mucosa and superficial submucosa. Like most of
the remainder of the GI tract, the muscularis propria is comprised of two layers of smooth muscle.
Right: Higher-power view shows that the mucosa resembles that of the normal colon.

24
General Features ofthe Gastrointestinal Tract

tissue. This occurs particularly at the distal tip


(see chapter 13). It is unclear whether atrophy
represents a physiologic change or a reaction to
previous disease.
Anus
The mucosa of the anal canal contains a com-
plex mixture of epithelial cell types. The mucosa
of the upper portion of the anal canal resembles
rectal mucosa except that the crypts may ap-
pear shorter and more irregular (fig. 1-45). The
anal transitional zone (ATZ) contains many
epithelial cell types. The cells comprising the
basal epithelial layer in this region frequently
appear small and contain nuclei arranged per-
pendicularly to the basement membrane. The
surface cells may appear columnar, cuboidal,
or flattened (fig. 1-46) (87-89). Mature goblet
cells are present (93). Surface cells may acquire
an umbrella shape, with distinct cell borders
superficially resembling urothelium.
Anal glands originate in the ATZ from anal
crypts. Four to eight anal ducts lie in the anal
canal of the adult. Each has a short tubular sub-
mucosal portion that branches into a sparsely
ramifying glandular pattern. Anal ducts follow
a tortuous course through the lamina propria
Figure 1-43
before penetrating the internal sphincter mus-
culature and extending into the fat. The lining APPENDIX
of the anal glands is variable in appearance (fig. This appendix from a 1-year-old child has prominent
lymphoid follicles with germinal centers.
1-47). Squamous type cells are commonly seen

Figure 1-44
APPENDICEAL ENDOCRINE CELLS
Left : An H&E-stained section shows an endocrine cell within an appendiceal crypt. The cytoplasm contains numerous
reddish secretory granules (arrow).
Right: Chromogranin highlights the endocrine cells in the basal portion of the crypts.

25
Gastrointestinal Diseases

at the gland opening, transitional epithelium is


seen in the middle, and simple columnar cells
are present in its deepest part. Goblet cells occur
in large numbers within the anal ducts, particu-
larly at their terminal portions. A characteristic
feature of the anal glands is the presence of
intraepithelial microcysts.
The nonkeratinized squamous epithelium of
the anal canal changes into keratinized strati-
fied squamous epithelium at the anus proper
(fig. 1-48). Melanocytes regularly populate the
squamous epithelium below the dentate line
and increase in number as one approaches the
anal margin (fig. 1-48). In addition, there may
be melanin-containing cells above the dentate
line (90).
Endocrine cells lie above the dentate line in
the colorectal mucosa, in the transitional mu-
cosa, in anal ducts and glands, in crypts, and
in perianal sweat glands (91,92). Like endocrine
cells elsewhere in the GI tract, those in the anal
region lie close to the basement membrane.
GENERAL INTERPRETATION
OF PATHOLOGIC SPECIMENS
Figure 1-45 Gastrointestinal pathology specimens fall
UPPER ANAL CANAL into three major categories: biopsy specimens,
The colonic type glands in the transition area of rectal resection specimens, and cytology specimens.
mucosa to anal canal have a more irregular appearance than Biopsies are taken to establish a specific diag-
those of the more proximal colon. The o~erlying epithelium nosis or to follow the evolution of a disease.
is squamous or transitional in appearance. They are also taken to determine disease extent

Figure 1-46
ANAL TRANSITION ZONE
Left: Transition from rectal type mucosa to anal mucosa.
Right: Higher-power view of the anal transitional mucosa. The basal cells are small and slightly darker than those in the
upper portions of the epithelium. The surface cells are cuboidal, and resemble the umbrella cells of urothelium.

26
General Features ofthe Gastrointestinal Tract

Figure 1-47
ANAL GLANDS
Left: The proximal portion of an anal duct is lined by transitional type epithelium .
Right: The more distal portions of the ducts are lined by simple columnar, mucin-producing epithelium.

:0. ·
' I

·"
Figure 1-48
ANUS
Left: The anus proper is lined by keratinizing, stratified squamous epithelium.
Right: Melanin pigment is frequently seen within the basal layer of the epithelium.

(as in inflammatory bowel disease) or to judge ischemia, severe ulcerating diseases, obstruc-
its severity, determine response to therapy, tions, and pseudoobstructions, as well as various
or detect neoplasia. Biopsies are also taken to other conditions. Resection specimens received
acquire tissues for other purposes, including in the fresh state should be examined as soon
microbial culture, biochemical examination, as possible to determine whether or not the
ultrastructural examination, or evaluation of specimen requires special handling for proce-
molecular markers. Biopsy interpretation is al- dures such as microbial cultures, ultrastructural
ways enhanced by an effective dialogue between examination, biochemical analysis, imprints,
the pathologist and the clinician. cytogenetic studies, or molecular studies prior to
Resections are performed to surgically treat fixation. Additionally, the specimen should be
cancer or precancerous lesions, life-threatening photographed if it contains an obvious lesion.

27
Gastrointestinal Diseases

When the specimen is photographed, it should Resection specimens should be opened longitudi-
be properly oriented and should include some nally and pinned out. If a specimen is pinned to
normal tissue for orientation. The specimen a cork board, gauze or paper towels can be placed
should also be cleaned to remove blood, stool, beneath the specimen to ·serve as a wick for the
and other substances present that may interfere fixative. Tissues should be adequately fixed prior
with obtaining information from the specimen. to sectioning. Specimens submitted to the histol-
Ten percent buffered formalin is the most ogy laboratory should be no more than 3-mm
commonly used fixative in histology labora- thick because they do not fit appropriately into
tories because it is stable and allows staining the cassettes and they fail to become adequately
with most of the histochemical and immuno- infiltrated during processing.
histochemical stains currently in use. It does, Histologic sections, whether from biopsy
however, induce substantial tissue shrinkage. or resection specimens, should be made with
In circumstances in which a more accurate the proper orientation. Optimally, the sections
rendering of the cytologic features is required, should be made in a plane perpendicular to the
additional fixatives can be used that contain mucosal surface. This allows for the evaluation
heavy metals, such as Bouin, BS, or Hollande of mucosal height and component parts. Care
solution. These fixatives cause less tissue shrink- must be taken with orienting small intestinal
age and permit analysis of nuclei that appear less biopsies because an interpretation of many
distorted. The latter fixatives, however, interfere diseases involves an analysis of the crypt/villus
with the ability to isolate high-quality nucleic ratio. Gastrointestinal biopsies are usually small
acids from the biopsy specimens Should this be and multiple levels should be examined in order
intended later. In addition, some immunohis- to adequately assess the histologic features, espe-
tochemical studies are difficult to perform on cially in biopsies that are not well oriented. This
tissues fixed by these methods. approach allows for the detection of focal le-
The specimen should be placed in a fixative sions, such as microorganisms and granulomas.
volume that is at least ten times that of the tissue.

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31
•.·
CONGENITAl GASTROINTESTINAl
ABNORMALITIES

The primitive gut forms in the 3rd to 8th


EMBRYOLOGY weeks as a result of the cephalocaudal and lat-
Gastrulation, which occurs 2 weeks after fer- eral embryonic folding that incorporates the
tilization, induces a massive rearrangement of dorsal endodennally lined yolk sac cavity. The
the embryo, transforming a relatively uniform amnion and yolk sac communicate through
cell ball into a multilayered organism with rec- the neurenteric canal (fig. 2-1). The neurenteric
ognizable body plans. Cells stream across the canal closes and the notochord grows forward,
embryo in a precise pattern that is maintained becoming intercalated within the endoderm.
across multiple species. A number of genetic The neural tube then separates from the ec-
signaling cascades link molecules that affect toderm. Mesoderm surrounds the notochord,
the movement of gastrulation to mechanisms separating the ectoderm and endoderm (10).
that cause cells to stick together and promote Gastrointestinal duplications associated with a
embryonic movement. Certain cells divide defective spinal cord and/or vertebra develop
faster than others, resulting in a change in em- if mesodermal ingrowth does not occur and
bryonic shape. Cells converge on the embryonic neural and gastrointestinal elements fail to
midline in a process of convergent extension. separate. Splanchnic mesoderm surrounding
As these cells crowd together, they push each the primitive gut forms the muscular and con-
other toward the future head and tail, and the nective tissue layers.
embryo lengthens. Paraxial protocadherin helps The former yolk sac elongates out under the
determine these motions (18). developing nervous system to form the primi-
There are two major steps in gastrointestinal tive foregut anteriorly and the primitive hindgut
development: formation of the gut tube and posteriorly. The central portion develops into
formation of individual organs, each with their the midgut, which freely communicates with
own specialized cell types (12). These events the yolk sac (the vitellointestinal duct) (fig. 2-1).
are regulated by homeobox-containing genes. The anterior abdominal wall develops by simul-
Each homeobox gene has a distinct rostrocaudal taneous cranial, caudal, and lateral infolding,
expression pattern in many tissues, including which attenuates the yolk sac. As a result, the
the gastrointestinal tract. Two homeotic genes, yolk sac becomes intracoelomic (fig. 2-1). The
Cdxl and Cdx2, are expressed only in the in- foregut is short at first, lying closely apposed to
testine whereas the remainder are expressed in the developing vertebrae from which it becomes
many sites. suspended by a short mesentery. It gives rise to
Gastrulation gives rise to three germ layers, the esophagus, stomach, duodenum as far as the
one of which, the endoderm, is the precursor ampulla of Vater, liver, pancreas, and respiratory
to the gastroimestinal epithelial lining. Endo- system, and it has its own arterial blood supply
dermal development requires the expression deriving from the celiac axis (13).
of the homeotic genes MIXER, SOX17a, and
Eso phagus
SOX17~ (8). Multiple interactions occur be-
tween the endoderm, mesoderm, and ectoderm The esophagus develops from the cranial end
during development. The endoderm induces of the primitive foregut, appearing at the 2.5-
the mesoderm to develop, conferring on it a mm developmental stage (approximately the
dorsal-ventral pattern. Endoderm and ectoderm 3rd gestational week) (Table 2-1) as an annular
contact one another in the 2- to 4-week embryo; constriction lying between the stomach and
the endoderm forms the yolk sac roof. the pharynx (3). As the esophagus elongates, it

33
Gastrointestinal Diseases

Primitive
gastrolntestinal
Brain
tube

Anterior

Pancreas

Primary
Vltellolntestlnal intestinal
Yolk sac duct loop
Yolk sac
B. C.

Figure 2-1
EMBRYONIC DEVELOPMENT WITH PROGRESSIVE GASTROINTESTINAL FORMATION
A: The gastrointestinal tract develops early as a primitive endodermal tube closely related to primitive neural tissue. The
neural and endodermal tissues communicate through the neurenteric canal.
B: With further embryonic development; the vitellointestinal duct begins to differentiate and the primitive gut divides
into a foregut, midgut, and hindgut. Diverticula start to develop that will eventually give rise to the lung and the liver.
C: Embryo viewed from the side and with detail of the umbilical cord. This diagrammatic representation is slightly later
in development than the embryo illustrated in B.

Table 2-1
compartments. Mesenchymal tissue grows into
APPROXIMATE RELATIONSHIP BETWEEN the ridges to form a septum that completely
FETAL AGE AND EMBRYO LENGTH
separates the esophagus and trachea (3,5). The
Postfertilization (days) Embryo Length (mm) esophagus lies dorsally; the trachea· and lung
22 1.5-2.0 buds lie ventrally.
2S 2.S-3.S The initially round esophageal lumen flat-
30 6.0-7.S tens. Later, extensive longitudinal folding of the
3S 1-1S wall begins. During the 7th and 8th weeks, the
40 20...23 esophageal epithelium proliferates and nearly
4S 24-28 fills the lumen, although complete occlusion
so 29-34 does not occur. The esophageal mucosal lining
ss 3S-41 progresses through a sequence of epithelial
60 42-SO changes before becoming stratified squamous
70 S3-67 epithelium (figs. 2-3, 2-4). Squamous epithelium
84 80-9S appears at 20 to 25 weeks, beginning in the
98 110-130
mid-esophagus and proceeding both caudally
112 130-1SO
and cephalad. Nests of embryonic esophageal
epithelial cells that persist in adults give rise to
126 lSS-180
some congenital abnormalities.
140 17S-20S
Stomach and Duodenum

r..· The stomach develops from a fusiform,


becomes increasingly tubular. At approximately primitive foregut swelling at approximately 4
4 weeks, a small outgrowth appears in the ven- weeks gestation (7 mm). It originates in the neck,
tral wall of the foregut, termed the respiratory descending into the abdomen during the next 8
or laryngotracheal diverticulum (fig. 2-2). Ini- weeks. The dorsal gastric wall grows more rapidly
tially, the cephalad esophagus and trachea lie than the ventral wall, leading to the develop-
within a common tube. Later, however, lateral ment of the greater curvature. As the stomach
epithelial ridges develop in the upper segment, rotates to the left, the esophagus deviates slightly
dividing the lumen into anterior and posterior to the left and the duodenum deviates slightly

34
Congenital Gastrointestinal Abnormalities

Laryngotracheal Figure 2-2

C'""""'"m ESOPHAGEAL DEVELOPMENT


A: The esophagus and early
trachea initially lie within a
single tube.
B,C : The laryngotracheal
diverticulum begins to develop
and grow in size.
D: A primitive septum starts
to form.
E: Eventually, the trachea and
the esophagus completely separ-
ate and the lung buds begin to
develop . Abnormalities in this
process lead to various forms of
esophageal atresia and stenosis.
A. B. C. D. E.

A. , B.

C. D.
Figure 2-3
CHANGES IN THE ESOPHAGEAL LINING EPITHELIUM DURING FETAL DEVELOPMENT
The epithelial lining changes from a pseudostratified epithelium (A) to one in which the cells are less stratified (B). They
become columnar with mucinous secretion (C) . Eventually, squamous epithelium develops (D).

to the right. Duodenal diverticula give rise to ture stomach. The enlarging thoracic contents
the subsequent pancreas and biliary system. By push the stomach and duodenum caudally.
the time the embryo reaches the 15-mm stage, Initially the stomach attaches to the back of
gastric dorsal expansion has created the ma- the abdomen by the dorsal mesogastrium and

35
Gastrointestinal Diseases

.,_

Figure 2-4
FETAL ESOPHAGUS
Left: The esophagus and trachea have separated from one another. In this photograph the esophagus lies below the trachea.
Right: High magnification of the esophageal lining shows that it consists of pseudostratified epithelium.

to the septum transversum (the diaphragm) 12-mm stage, the midgut lengthens, becoming
by the ventral mesogastrium. As the stomach tubular and growing away from the vertebral
enlarges, the dorsal mesogastrium b~comes the axis. It then coils, inducing dorsal mesenteric
greater omentum and the ventral mesogastrium development. During the 5th fetal week, the
becomes the lesser omentum. Characteristic midgut is U-shaped and suspended by a dorsal
gastric anatomic features (greater cui"vature, mesentery distributed around the superior mes-
lesser curvature, fundus, body, and pylorus) can enteric artery. The apex of the intestinal loop
be identified by 14 weeks (12). communicates with the vitellin duct, which
Early glandular differentiation of the gastric rapidly decreases in size. During the 5th to 6th
lining occurs at the 80-mm stage of fetal de- fetal weeks, increases in intestinal length, along
velopment. The stomach is initiaily lined by with the disproportionate amount of abdominal
stratified or pseudostratified epitb,elium; later, space occupied by the fetal liver, cause intestinal
cuboidal cells appear. The first differentiated herniation into a mesothelial-lined sac within
cell types to appear are the mucous neck cells. the umbilical cord (13). The cecum develops
These act as progenitors for other cell types. on the caudal limb and the vitellointestinal
Gastric pits are well developed by 5 to 7 weeks. duct lies at the apex. A small portion of the
Parietal cells appear by 9 to 11 weeks. Gastric caudal limb, between the attachment of the
glands begin to develop at 11 to 14 weeks; they vitellointestinal duct and cecum, forms the
grow by progressive branching, a process that terminal ileum. The appendix develops as a
continues until birth. Acid is found in the fetal cecal diverticulum.
stomach at 19 weeks (15). By term, 20 percent The midgut starts sliding back into the
of neonates exhibit the adult pattern of parietal abdomen between the lOth and 12th weeks,
cell distribution (11) . Mesoderm surrounding a process accomplished in three phases (fig.
the stomach differentiates into the gastric con- 2-5). The first is a 90° counterclockwise rotation
... nective tissue and the muscularis propria by the around the superior mesenteric artery. The sec-
end of the 2nd fetal month. ond phase occurs at about the lOth week when
there is enough room for the bowel to return to
Intestine
the abdominal cavity. The cranial loop of small
The duodenum distal to the bile duct as well bowel reenters the abdomen, first passing to
as the jejunum, ileum, cecum, ascending colon, the right of the superior mesenteric artery and
and proximal half to two thirds of the transverse rotating a further 180°, thereby making the total
colon derive from the midgut and are supplied rotation of 270°. Small intestinal loops fill the
by the superior mesenteric artery. At the 5- to central abdomen. The colon then returns, with

36
Congenital Gastrointestinal Abnormalities

Transverse
colon

Append ix Decending
colon

Sigmoid

Appendix
A. B. C.

Figure 2-5
DEVELOPMENT OF THE INTESTINAL TRACT
A: Schematic diagram of the primitive intestin al loop after a 180° counterclockwise rotation. The transverse colon passes
in front of the duodenum.
B: Intestinal loop after a 270° co unterclockwise rotation .
C: Intestinal loops in th eir final position with the development of the mesenteries.

the cecum being the last to return to the right


iliac fossa anterior to the duodenum and the
superior mesenteric artery and below the liver
(fig. 2-6). Later, the colon angulates as it crosses
the duodenum to form the hepatic flexure. The
distal transverse, descending, and sigmoid colon
(hindgut derivatives) are supplied by the inferior
mesenteric artery and occupy the left abdominal
periphery, completing the colonic distribution
around the small bowel.
The final phase is the fixation phase. The
mesenteries of the cecum, ascending and
descending colon shorten and are absorbed,
thereby attaching the large bowel to the poste-
rior abdominal wall. The transverse and sigmoid
portions of the colon retain a full mesentery (6).
Although an anatomically distinguishable
intestinal tract develops early in embryonic
life, functional absorptive cells do not appear
until later in gestation. A solid epithelial core
fills the fetal gut during the 8th and 9th weeks.
This core then vacuolates, creating the intestinal
lumen. Apoptosis probably plays a role in the
process. Intestinal differentiation occurs along Figure 2-6
a proximal to distal gradient. The epithelium DEVELOPMENT OF THE INTESTINAL TRACT
develops from simple endodermal tubules early Fo urteen -week fetus shows the small intestine lying
in embryogenesis, appearing as a multilayered to th e right side of the abdomen and the colon bunched
sheet of undifferentiated endodermal cells with on the left side. The fetus had not developed sufficientl y
for the rotation to have been complete. As a result, the
short microvilli. Deeper cells do not demon- intes-tines have no t reach ed their final positions in th e
strate any polarity; mitoses occur throughout ab-domin al cavity.

37
Gastrointestinal Diseases

Figure 2-7
DEVELOPMENT OF
THE ANORECTAL REGION
Figures A through C show the
progressive development of the
cloaca and its determination. At
the 6th fetal week, the hindgut
and urogenital sinus open to
· a common cloaca . The cloaca
continues into the allantois. The
inferior boundary is the cloacal
membrane. The urogenital sep-
tum grows caudally toward the
cloacal membrane, separating Anorectal canal
the posterior anorectum from the
anterior genital sinus (B,C). The
urogenital sinus forms the future
urethra and urinary bladder.

the epithelium. Villus formation, with mesen- (17) . The fetal anal canal has two components:
chymal infiltration into the villous core, begins the cloacal component contributes to its upper
at the 9th gestational week. Between 9 and 10 two thirds; the proctodeal component forms its
weeks, the stratified epithelium tonverts to lower third. In adults, the junction of the cloacal
simple columnar epithelium (5). The progenitor and proctodeal components (the site of the former
cell region, which gives rise to the crypts, local- anal membrane) is defined by the pectinate line
izes to the intervillous area (4) . Villi are long and anal valves. Coincident with the development
and tapering by 20 weeks; the muscle coats are of the urorectal septum, the mesenchyme around
obvious at this time. Enterocyte proliferation oc- the cloacal membrane proliferates, leading to the
curs along the entire villous length until several development of the genital tubercles and the anal
days before birth. The epithelium finishes its pit, on the floor of which is the cloacal mem-
morphologic differentiation in the 4 to 5 days brane. The deep anal pit produces the proctodeal
prior to birth (7). .r
canal, and its development is accompanied by
the shrinkage and ultimate disappearance of the
Distal Colon, Rectum, and Anus
tailfold and tailgut.
Hindgut development follows that of the mid- The cloacal membrane is divided into an anal
gut. The hindgut develops into the left transverse membrane posteriorly and the larger urogeni-
colon, descending colon, sigmoid colon, rectum, tal membrane anteriorly. The anal membrane
and upper anal canal. The descending colon covers the terminal rectum, separating it from
becomes fixed. The sigmoid retains a mesocolon the external environment until the end of the
that reduces in length as other hindgut deriva- 7th week when it ruptures. When the urogeni-
tives become fixed in the abdomen. tal membrane disintegrates, it is incorporated
The complex development of the anal canal into the urethral floor in the male and into the
depends on the coordinated development of the hymen in the female. After rupture of the anal
proctodeum and the urorectal septum. It also membrane, squamous epithelium begins to
depends on regression of the tail and tailgut and extend cranially from the dorsal cloaca to reach
on the development of the sacrococcygeal ver- the anal sinuses at about 180 mm of crown-
tebrae and lower spinal cord (2). The area must rump length (9,17). At this time the character-
also maintain the relational positions of the istic epithelium of the anal transitional zone is
uterus, adnexa, genitourinary tract, spinal sa- present. The anal cushions are also present early
crococcygeal region (1), and external genitalia. in fetal life (14).
A cloaca is identifiable by the 4th gestational The tailgut is a blind hindgut extension into
week; major development of the anorectal canal the tailfold, just distal to the cloacal membrane.
occurs between the 5th and 6th weeks (fig. 2-7) As it grows, the prododeum develops and the

38
Congenital Gastrointestinal Abnormalities

tailgut progressively resolves and is taken up patients (95 percent) have associated car-
into the lower cloaca. This process is completed diac defects. Major associated gastrointestinal
by 56 days of gestation (16,17). anomalies include annular pancreas, midgut
Developmental abnormalities of the urorec- volvulus, duodenal atresia, and mucosal duode-
tal seph1m result in a malpositioned rectum, nal diaphragm. Patients present in the neonatal
imperforate anus, and abnormal connections period with bilious vomiting and upper abdomi-
between the rectum and the genitourinary tract. nal distension. Duodenal atresia may cause a
All developmental anomalies that are associated "double bubble" sign with absent distal gas on
with fistulas between the gastrointestinal and plain abdominal radiographs . Upper barium
genitourinary systems relate to the defective contrast films are usually diagnostic. Jaundice
formation of the urorectal septum. Aberrant is common.
development of the lower spine or persistence Gross Findings. See definition.
of the tailgut and vestigial tail-like appendages Microscopic Findings. Situs inversus does
are associated with anal or rectal malformations. not change organ function or histology.
Treatment and Prognosis. The prognosis
POSITIONAL ABNORMALITIES in individuals with complete situs inversus is
An anatomic left-right asymmetry is estab- usually excellent. Prognosis is most adversely
lished during embryogenesis. Variation from affected by the presence of associated abnormal-
normal organ position (situs solitus) results in ities . The prognosis of these patients is generally
heterotaxy, expressed either as a randomization reflected in the severity of the upper respiratory
(situs ambiguous) or complete reversal (situs problems. Patients may also be infertile. Patients
inversus) of normal organ position. The term with Kartagener's syndrome may have a worse
heterotaxy refers to "other arrangements." prognosis. These patients have abnormal cilia
Familial heterotaxy occurs with autosomal and as a result produce thick, tenacious bron-
dominant, autosomal recessive, and X-linked chial and sinus secretions that lead to chronic
inheritance (25) . sinusitis and bronchiectasis. Common gastric
disorders may present in atypical ways in these
Situs Inversus
patients, possibly delaying diagnosis.
Definition. In situs inversus, the organs lie
Dextrogastria
in locations that are the mirror images of their
normal positions. When complete, it affects Definition. Dextrogastria exists when the
both thoracic and abdominal organs. When stomach and esophageal diaphragmatic hiatus
incomplete, it affects the abdominal organs . lie to the right of the midline and the first part
Limited situs inversus affects only the stomach of the duodenum lies to the left.
and duodenum. Demography. Dextrogastria affects ap-
Demography. Situs inversus affects 1/1,400 live proximately 1/6,000 to 8,000 births (24). As an
births and it fo1ms part of Kartagener's syndrome. isolated anomaly, it affects less than 1/100,000
Associated Findings. In 80 percent of cases, births.
partial situs inversus is associated with other Clinical Features. No specific clinical fea-
malformations, including asplenia and duode- tures result from dextrogastria. When the stom-
nal stenosis, and may have a genetic basis. Com- ach lies in an abnormal position, however, other
plete situs inversus is nearly always sporadic typical gastric diseases may present in atypical
and not accompanied by other abnormalities. ways. The endoscopist may experience some
Etiology. Complete situs inversus is the most difficulty in orientation if the anomaly is not
common chemically-induced congenital abnor- appreciated.
mality. Several chemical teratogens cause sym- Gross Findings. Dextrogastria occurs in three
metric body defects. Many children with situs forms: 1) associated with total situs inversus, 2)
inversus and a neural tube defect have mothers associated with dextrocardia but with no other
with insulin-dependent diabetes mellitus. transposition, and 3) as an isolated abnormality.
Clinical Features. Significant mortality is Microscopic Findings. There are no histolog-
associated with situs inversus because most ic abnormalities associated with this condition.

39
Gastrointestinal Diseases

Malrotations/Nonrotations Table 2-2


Defin ition . Intestinal malrotations or non- ABNORMALITIES ASSOCIATED
WITH SMALL INTESTINAL MALROTATION
rotations are those conditions in which vari-
ous gastrointestinal organs lie in an abnormal Prune-bell y sy nd rom e
position due to a failure to complete normal Natal teeth with intestinal pse udoo bstruction
fetal rotational events or retention of their non- Delayed gastric emptying
Duodenal dilatation
rotated location. Nonrotation occurs when the Patent du ctus arter ios us
midgut fails to rotate as it returns to the abdo- Annular pa ncreas
men, so that the duodenal-jejunalloop remains Midgut vo lvulus and fa cial an om alies
in the right abdomen. Malrotation presents as a Omphalocele
180° anti-clockwise extra-abdominal rotation
Gastroschisis
in which the cecum fails to descend into its
Craniofacial an omalies (especiall y in infan ts wi th
normal position in the right iliac fossa. Mixed or intra uterin e opiate or h eroin exposure)
incomplete rotation occurs when only the caudal Trisomy 13, 18, and 21
limb of the midgut loop rotates an additional Situs inversus
90° beyond the first counterclockwise 90° rota-
Atresias
tion of both limbs of the midgut. As a result, Esophageal atresia
the subpyloric cecum is partially fixed to the Biliary atresia or stenosis
posterior wall by fibrous bands that pass over Intestinal atresia or st enosis
the duodenum, occasionally causing extrinsic Hernias
compression. Reversed rotation occurs when the Diap h ragmat ic
Paradu oden al
midgut loop rotates an additional 180° in a Intern al
counterclockwise fashion. The duodel).um and OIES complex
superior mesenteric arteries lie anterior to the Omphalocele
transverse colon . Exstrophy of t he cloaca
Dem ograp h y. Intestinal malrotations affect Imperforate anus
Spinal defects
approximately 1/6,000 live births (22). Some
Sirenomelia
cases show a familial distribution with both
Un separated lower lim bs
autosomal recessive and autosomal dominant Absen t genital struchnes
inheritance patterns. "" Lower coloni c agenesis
Associated Findings. Three percent of pa- Renal agen es is
tients have associated abnormalities (Table 2-2)
(20,21,26- 28). Intestinal rotational abnormali-
ties are particularly common in patients with
polysplenia (left isomerism) and asplenia (right
isomerism) syndromes. Adults with intestinal malrotations often
Etiology. Intestinal malrotations or non - have a lifelong history of nonspecific abdomi-
rotations result from disordered or interrupted n al complaints, including acute symptoms
embryonic intestinal' counterclockwise rota- when they were children. The most common
tions around the superior mesenteric artery. symptoms are vomiting and chronic intermit-
Clinical Features. Malrotations frequently tent crampy abdominal pain from torsion,
cause symptoms in the neonatal period, due in obstruction, peritoneal bands, volvulus, or in-
,,. part to the presence of other associated malfor- tussusception (23). The incidence of volvulus is
mations. Patients with intestinal malrotation greater in the sigmoid colon than elsewh ere in
present with signs and symptoms of duodenal the large intestine, perhaps reflecting the solid
obstruction, intermittent volvulus, or intus- n ature of its luminal contents. Occasionally, a
susception. Patients develop bilious vomiting, malrotation becomes evident during pregnancy.
abdominal distension, and rectal bleeding. Patients often have a history of constipation and
Infants may develop malabsorption with steat- intermittent abdominal distension . The clinical
orrhea and protein-losing enteropathy due to presentation may b e as an acute bowel obstruc-
mesenteric lymphatic obstruction . tion. Plain abdominal film s are often diagnostic.

40
Congenital Gastrointestinal Abnormalities

splenic flexure may lie posterior to the stomach


and anterior to all, or part, of the pancreas, in
a location known as pancreatico-interposition.
They may also lie in a retrosplenic location.
The entire malpositibned bowel, from the
duodenum to the splenic flexure, remains un-
anchored, supported by a single mesentery with
a very narrow base, predisposing it to undergo
intestinal volvulus. The body attempts to correct
the unstable state of the mal positioned intestine
by forming fibrous bands or adhesions between
abdominal structures. These bands and adhe-
sions may cause future obstruction or volvulus.
Microscopic Findings. The histology of the
abnormally placed organs is normal unless there
is a coexisting abnormality, such as an atresia
or stenosis.
Treatment and Prognosis. Positional ab-
normalities in and of themselves require no
treatment. Infants presenting with obstruc-
tion without mucosal compromise (as in acute
volvulus), may undergo a laparoscopic Ladd
procedure to correct the malrotation, bypass-
ing the need for open abdominal surgery (19).
Unknown rotational anomalies, however, may
pose serious risks to patients. This typically oc-
curs when organs lying in an unusual location
Fi~:,'Ure 2-8 cause symptoms. Thus, appendicitis developing
INTESTINAL MALROTATION
in an unusual location is often clinically diag-
The small intestine in this term infant lies as a mass of
nosed as some other disorder. Subhepatic appen-
coiled bowel loops in the lower portion of the abdominal dicitis may mimic pancreatitis or cholecystitis,
cavity. The large intestine lies as a mass of coiled loops just resulting in a delayed diagnosis. Many of these
beneath th e liver. complications may only be diagnosed during
the course of a laparotomy for peritonitis.
ABDOMINAL WALL DEFECTS
Gross Findings. There is obvious intestinal
misplacement within the abdominal cavity The most common anomalies of the fetal
with malrotation. The intestines often lie to ventral abdominal wall are omphalocele, gas-
one side, appearing as a large mass of nonro- troschisis, and umbilical cord hernia.
tated bowel (fig. 2-8). The duodenum lacks the Gastroschisis
normal C-shaped configuration, lying vertically
downward and to the right of the superior Definition. Gastroschisis is the persistent her-
mesenteric vessels. The cecum lies in various niation of abdominal viscera through an abdomi-
locations, depending on the extent to which nal wall defect at the base of the umbilicus. The
it failed to rotate: in the left iliac fossa, in the abdominal organs remain outside the abdominal
midline of the pelvis, or in a subhepatic loca- cavity. No peritoneal sac or amniotic remnant
tion. The ascending colon retains its mesentery covers the eviscerated abdominal contents.
and runs upward, just to the left of the midline, Demography. The incidence of gastroschisis
lying below the gastric curvature where a loop of has risen, increasing from 0.48/10,000 births in
transverse colon connects to a normally situated 1980 to 3.16/10,000 in 1993 (41,42) . Young (15
descending colon . The transverse colon and to 19 years), socially disadvantaged women have

41
Gastrointestinal Diseases

Table 2-3
ABNORMALITIES ASSOCIATED WITH GASTROSCHISIS
Gastrointestinal
Intestinal atresia
Gastric heterotopia
Intestinal nonrotation
Pancreatic heterotopia
Abnormal intestinal fixation
Misplaced gallbladder
Ventricular septal defect
Cryptorchidism

the highest risk of having a child with gastro-


schisis (43). An increased risk of g!J.stroschisis
also is associated with the intrapartum use of
recreational drugs or smoking (41), exposure to
salicylates, and exposure to radiation (34). Gas-
troschisis predominates among mele infants.
Associated Findings. Gastroschi.sis is an iso-
lated malformation in up to 79 percent of cases
(31 ). Associated congenital malformations are seen
in 16 to 20percentofinfants (Table 2-3) (30,40,41).
Etiology. Gastroschisis probably results from
vascular injury and ischemia of the abdominal
Figure 2-9
wall during the 5th to 11th fetal weeks, lead-
ing to defective somatopleural q1esenchymal GASTROSCHISIS
differentiation (40). The ischemia results from The mass of abdominal organs remains outside the ab-
intrauterine disruption of the right omphalo- dominal wall in this premature infant. This includes the
intestines as well as the liver, spleen, and stomach. (Fig. 9.4
mesenteric artery. from Fenoglio-Preiser C. Gastrointestinal pathology, an atlas
Clinical Features. There is a strong associa- and text, 2nd ed. Philadelphia: Lippincott-Raven; 1999:312.)
tion with preterm delivery, low birth weight,
and perceived fetal distress as reflected by an
increased rate of emergency cesarean section fluid alpha-fetoprotein (AFP) levels because
(41). The average birth weight and gestational the exposed membrane surfaces allow AFP to
age of infants with gastroschisis are low, es- transude. Nearly all patients with gastroschisis
pecially for those with multiple anomalies have AFP elevations, and acetyl cholinesterase
(31). The degree of growth failure correlates is nearly always detectable in amniotic fluid,
with the level of prematurity. Exposure of the albeit at much lower concentrations than for
bowel to amniotic fluid leads to perivisceritis open neural tube defects (32).
and premature birth. The damaged bowel fre- Radiologic Findings. Antenatal ultrasound
•.·
quently develops secondary motility problems often allows an accurate diagnosis of gastroschisis.
and malabsorption, which may present even Gross Findings. Gastroschisis may involve
following surgical repair. Other complications only the intestines or it may affect many other
include obstruction due to coexisting malrota- organs. Parts of the stomach, small intestine,
tion, diverticulitis, ischemia, and perforation. and colon herniate through an abdominal wall
Patients with ectopic gastric mucosa in the defect, usually to the right of the umbilical cord
exteriorized bowel may present with a gastroin- (fig. 2-9). All infants with gastroschisis have
testinal hemorrhage. Gastroschisis is associated coexisting intestinal nonrotation and abnormal
with increased maternal serum and amniotic intestinal fixations.

42
Congenital Gastrointestinal Abnormalities

Microscopic Findings. The histology of the Table 2-4


various organs may be normal or changes may ABNORMALITIES ASSOCIATED WITH OMPHALOCELES
be present reflecting the presence of assoCiated
Heart anomalies
congenital abnormalities, heterotopias, atresia,
Intestinal atresia
meconium peritonitis, or perivisceritis. The
Chromosomal defects
last two entities lead to gastrointestinal wall
thickening, serosal edema, fibrinous exudates, Genitourinary anomalies (cloacal or bladder exstrophy)
and fibrosis. The intestinal muscularis propria Craniofacial defects
may become hypertrophic. Acute inflammation, Diaphragrnatic abnormalities
consisting predominantly of neutrophils and Liver and bile duct abnormalities
mononuclear cells, may be present and may Single umbilical artery
lead to postnatal bowel dysfunction. Syndromes
Treatment and Prognosis. Long-term out- OEIS complex
Major changes
come in the absence of major chromosomal Omphalocele
and structural abnormalities is excellent (37). Cloacal exstrophy
Patient prognosis depends in part on whether Imperforate anus
the gastroschisis is an isolated lesion or whether Spinal defects
Possible associated changes
there are associated abnormalities. The goal of Meningomyeloceles
the surgeon is to accomplish abdominal wall Lower limb defects
closure in a single stage. An alternate approach Colonic duplication
is to perform a staged closure using prosthetic Duodenal webs
Malrotation
materials while maintaining adequate nutri- Short bowel syndrome
tional support. Other considerations include Cryptorchidism
prevention and control of sepsis, maintenance
of respiratory status, and risk of dysfunction
of the kidneys, liver, and intestine because of
increased abdominal pressure. Necrotizing en-
terocolitis may affect as many as 20 percent of among different geographic regions, with espe-
infants following repair of gastroschisis and is cially high rates occurring throughout the British
responsible for significant morbidity (36). Other Isles (31). The male to female incidence is 3 to 1;
complications of the repair include motility however, a significant female excess exists among
disorders and abdominal wall hernias. the cases of omphalocele associated with neural
Animal Models. Gastroschisis occurs with a tube defects. The rare OEIS (omphalocele, cloa-
high frequency in the HLG inbred mouse strain. cal exstrophy, imperforate anus, spinal defects)
The risk of gastroschisis increases significantly complex affects 1/200,000 to 400,000 pregnan-
after exposure to irradiation with X rays during cies. In the United Kingdom and Ireland, there
preimplantation and its development involves is a tendency for omphaloceles to be associated
a recessively inherited HLG susceptibility al- with anencephaly and spina bifida.
lele. There is a possible locus responsible for Associated Findings. Up to 54 percent of
radiation-induced gastroschisis (Rigs1) in a infants with omphaloceles have associated
region of mouse chromosome 7 (34). anomalies (Table 2-4) compared with only 5
percent of those with gastroschisis (29,31).
Omphalocele
Omphaloceles complicate several syndromes
Definition. Omphalocele is an external mass (Table 2-4). Many fetuses with an omphalocele
of abdominal contents covered by a variably have an abnormal karyotype.
translucent peritoneal and/or amniotic mem- Etiology. OEIS complex occurs sporadically
brane . Synonyms include exomphalos and or it affects twins or siblings, suggesting that
exomphalocele. some cases have a genetic basis. There is often
Demography. Omphaloceles affect a history of maternal diabetes mellitus or hy-
2.5/60,000 to 2.0/3,000 live births. Significant dantoin or diazepam administration (35,38).
heterogeneity exists in the prevalence rates The OEIS complex arises from a single, localized

43
Gastrointestinal Diseases

Clinical Features. The average birth weight


and gestational age of infants with ompha-
locele are low. The amniotic membrane and
peritoneum protect the developing intestinal
loops from the damaging effects of exposure to
amniotic fluid seen in gastroschisis. This may be
important, since it has been suggested that am-
niotic fluid may be toxic to myenteric neurons.
Gross Findings. Omphaloceles range in size
from only a few centimeters to lesions that in-
volve almost the entire anterior abdominal wall.
The abdominal viscera lie within a sac (fig. 2-10)
that initially is moist and transparent but with
time becomes dry, fibrotic, opaque, friable, and
prone to rupture, resulting in secondary evis-
ceration. Abdominal skin may cover the sac base
and the umbilical cord is usually attached to its
apex or slightly to the side. Giant omphaloceles,
measuring 5 cm or more in greatest dimen-
sion, may contain the stomach, liver, spleen,
pancreas, and intestines. Smaller omphaloceles
usually only contain the intestines.
Microscopic Findings. The histology of the
displaced organs tends to be normal unless there
is a coexisting congenital abnormality. The lin-
ing of the sac that covers the eviscerated organs
consists of peritoneum internally and amnion
Figure 2-10 externally (fig. 2-11) .
OMPHALOCELE
Differential Diagnosis. The major entity
in the differential diagnosis of omphalocele is
The viscera within the omphalocele hat! twisted, leading
to infarction of the contents. umbilical hernia. The presence of an amniotic
membrane or peritoneal membrane serves to
distinguish the two lesions, since these are only
mesodermal defect early in development that present in patients with omphaloceles.
contributes to infraumbilical mesenchymal, Treatment and Prognosis. Patient prognosis
cloacal septum, and caudal vertebral abnor- depends on the associated anomaly(ies). Om-
malities. Some patients with omphalocele and phalocele repair is similar to that for gastros-
the Miller-Dieker syndrome have a deletion at chisis. Formerly, most infants with the OEIS
chromosome 17p13.3, suggesting that a gene(s) complex died. Today, long-term survival of such
in this region plays a major role in lateral fold patients can be achieved by successful corrective
closure or the return of the midgut from the surgery but the associated structural anomalies,
body stalk to the abdomen. Trisomy 18 affects including meningomyelocele and severe limb
some patients. aplasia or hypoplasia, influence the patient's
"··
Pat hophysiology. Four somatic folds (a ce- quality of life. The current treatment includes
phalic fold, two lateral folds, and a caudal fold) closure of the omphalocele, separation of the
define the anterior thoracic and abdominal gastrointestinal tract from the hemibladders,
walls during the 3rd gestational week. These and closure of the two hemibladders as a single
folds migrate centrally to fuse at the umbilical viscus. The colon can be pulled through in some
ring, usually by the 18th week. Arrested fold mi- cases either immediately or later. The bladder
gration or development results in anterior wall is augmented, sometimes using the stomach.
defects and a widening of the umbilical ring. Although two thirds of patients are genetic

44
Congenital Gastrointestinal Abnormalities

I I

Figure 2-11
SAC COVERING THE ORGANS IN THE OMPHALOCELE
Left: Histologically, the sac consists of amnion externally (left) peritoneum internally (right).
Right: The amnion is shown at higher magnification.

males, some advocate that they should be raised and the risk of incarceration or strangulation
as females because they lack adequate tissues to is negligible. Most close spontaneously during
construct a phallus (39). Magnetic resonance the first 24 months of life.
imaging (MRI) of the spine shows tethering of Gross Findings. The diameter of the defect
the spinal cord in all patients, which can be is rarely more than 2 cm.
released neurosurgically (39). Microscopic Findings. The defect is covered
posteriorly by peritoneum- and anteriorly by
Umbilical Hernia
skin. There is no amnion as there is in an om-
Definition. An umbilical hernia is a protrusion phalocele.
of the umbilicus that is more pronounced when Differential Diagnosis . The differential
the infant strains and reduces when the infant diagnosis of umbilical hernia includes epigas-
is supine and at rest. tric hernia, · omphalocele, and diastasis recti.
Demography. Umbilical hernias occur in 10 Epigastric hernias are small, midline bulges
to 30 percent of term infants and the incidence between the umbilicus and the xiphoid process
increases to as high as 75 percent in premature that result from preperitoneal fat that protrudes
children who weigh between 1.0 and 1.5 kg at through a small fascial defect. Omphaloceles are
birth (33). A fascial defect in the abdominal wall discussed in a previous section and represent a
allows intestinal contents to protrude through defect in the center of the abdomen with exteri-
the opening. Umbilical hernia is 6 to 10 times orization of the viscera. These are covered with
more likely to develop in African-American a translucent membrane and require surgery
infants than in white infants (33). Birth weight for treatment. Diastasis recti is a longitudinal
is a predisposing factor. More than 80 percent separation of the rectus abdominal muscle. It
of infants weighing less than 1,200 g have an is most commonly found in a supraumbilical
umbilical hernia compared with 21 percent of position but can also be suprapubic.
infants weighing more than 2,500 g. Treatment and Prognosis . Most umbili-
Etiology. An umbilical hernia develops cal hernias undergo spontaneous closure and
when the umbilical ring fails to close after cord surgery is not recommended unless the hernia
separation. persists beyond the age of 4 to 6 years or unless
Clinical Features. The diagnosis is made by the fascial defect is bigger than 1.5 to 2.0 cm
the presence of a bulge in the umbilicus coupled by 2 years of age. The size of the fascial defect
with an easily palpable fascial defect. The bulge rather than the amount of reducible omentum
becomes more apparent with crying, straining, or protruding bowel should be considered in any
or during defecation (33). It is rarely painful decision regarding surgical repair. If the fascial

45
Gastrointestinal Diseases

ring is not completely intact, spontaneous clo- ation, the stomach, intestines, and spleen her-
sure is unlikely. Referral to a pediatric surgeon niate into the thoracic cavity; 2) right postero-
is appropriate. The risk of incarceration and lateral (through the right Bochdalek canal). In
strangulation increases with age. this situation, the liver and intestines herniate
into the thorax; 3) retrosternal through the Mor-
MESOCOLIC HERNIAS gagni canals. This form occurs less commonly
Definition. When the descending mesocolon and only the liver and intestines herniate; and
fails to adhere to the posterior parietal perito- 4) hiatal hernia. The esophageal hiatus enlarges
neum, the small bowel can herniate into the and the stomach herniates. Rarely, the central
sac that forms between these layers, resulting tendon of the diaphragm is absent.
in what is known as a left paraduodenal hernia. Demography. Diaphragmatic hernias affect
Similarly, a right paraduodenal hernia can occur 1/2,000 to 5,000 births (44). The left postero-
in a sac formed by a nonadherent descending lateral hernia is the most common type of
mesocolon in the posterior parietal peritoneum. congenital diaphragmatic hernia.
When a defect occurs in the transverse mesoco- Associated Findings. Patients often have
lon, a transmesocolic or omentomesenteric parietal coexisting malformations, especially midgut
hernia occurs. The term mesentericoparietal hernia malrotation. Urinary tract abnormalities and
is also used. Wiedemann-Beckwith syndrome affect patients
Etiology. Mesocolic hernias result from the with congenital posterolateral diaphragmatic de-
abnormal return of the midgut after its physi- fects. Patients with the autosomal recessive Fryns
ological herniation into a defective mesenteric syndrome often have a lateral diaphragmatic
attachment, with formation of a retroperitoneal hernia and a number of associated abnormalities.
sac. Additional hernias can occur around the Etiology. There are four components contrib-
ileocecal valve, the bladder, and at the fm·amen uting to the diaphragm: 1) the pleural peritoneal
of Winslow. membrane, 2) the septum transversum, 3) the
Clinical Features. Patients present with dorsal mesentery of the esophagus, and 4) the
nausea, vomiting, abdominal pain, distension, body wall; these fuse by the 6th developmental
and dehydration. They may become obstipated, week. Defective development of one or more
with or without passage of eithe·r feces or gas. of these units results in diaphragmatic hernias.
The pain most typically occurs .!,n the perium- The ventral part of the diaphragm derives from
bilical region. Closed loop obstructions may the septum transversum, which separates the
occur. Mesocolic hernias may present as an embryonic heart from the abdominal contents.
acute abdominal emergency should the bowel Normally it fuses with the sternum and rib cage
become incarcerated. Conventional radiology leaving small canals known as the foramina of
may suggest the diagnosis. Occasionally, com- Morgagni lying laterally on either side of the
puterized tomography (CT) (with contrast) or sternum. The dorsal diaphragm forms from the
barium studies are required. dorsal mesentery, but posterolateral commu-
Gross Findings. The inferior mesenteric ar- nications, known as the canals of Bochdalek,
teries run near the orifice of left paraduodenal persist on either side between the pleural and
hernias whereas the superior mesenteric vessels peritoneal cavities. At first, only the pleural and
course near the orifice of right hernia sacs. The peritoneal membranes fuse. Later, muscle grows
transmesocolic hernia has a middle colic artery into them from the body wall. The thoracic
•.·
coursing on the right side of the orifice. and abdominal cavities are separate from one
another by the 8th to 9th weeks of gestation.
CONGENITAL DIAPHRAGMATIC HERNIA Diaphragmatic hernias result when there is
Definition. Congenital diaphragmatic her- agenesis of one or both diaphragmatic leaflets,
nia is the presence of abdominal contents in muscle aplasia with eventration, or defective
the thoracic cavity secondary to a congenital formation with herniation. A gap results which,
diaphragmatic defect. There are four types of depending on its size and location, allows ab-
diaphragmatic hernia: 1) left posterolateral dominal organs to herniate through it into the
through the left Bochdalek canal. In this situ- thoracic cavity.

46
Congenital Gastrointestinal Abnormalities

Clinical Features. Large diaphragmatic her- Apple peel atresia is a form of atresia in which
nias are frequently associated with both gastro- the bowel demonstrates a spiral configuration
intestinal and respiratory symptoms, mainly due in addition to the area of the atresia. Complex
to compressive effects. The mediastinal contents atresia is an atresia with additional complica-
(heart and thymus) may shift, compressing the tions, such as secondary ischemia.
contralateral lung. Cyanosis and dyspnea are Demography. Overall, atresia occurs more
the earliest neonatal manifestations, as well as often than stenosis, ranging in incidence from
gasping and vomiting. Clinically, respiratory 1/2,000 to 6,000 live births (75,89). It represents
movements and breath sounds are decreased the most common abdominal surgical disorder
or absent with audible peristaltic sounds in the of infants. Esophageal atresia is the most fre-
affected hemithorax. Patients with right postero- quent gastrointestinal atresia, followed by anal,
lateral hernias usually develop fewer pulmonary duodenal, jejunal, ileal, and colonic atresias.
complications because of the presence of the Esophageal atresia with a common TE fistula
liver. Torsion or volvulus of the gastrointestinal affects 1/800 to 1,500 live births. Complete
contents within the hernia can lead to obstruc- esophageal atresia affects 1/3,000 live births.
tion and ischemia if not corrected. A chest Infantile hypertrophic pyloric stenosis (IHPS)
radiograph should suggest the diagnosis. ranges in incidence from 0.28 to 6.80 percent
Gross Findings. The hernia wall consists of peii- of live births. The incidence depends on the
toneum and pleura, and the hernias may contain patient population studied (45). White race and
the stomach and various portions of small bowel male gender are associated with a higher inci-
and possibly liver. Diaphragmatic hernias tend to dence of IHPS; high birth order, older maternal
be smaller than diaphragmatic eventrations. age, higher maternal education, and low birth
Microscopic Findings. The histology of the weight are associated with a lower incidence.
herniated bowel is normal unless a complication The disorder usually affects the firstborn child,
such as obstruction or ulceration has occurred. with a male to female ratio of approximately
Then, the histology reflects the complication. 4 to 1. IHPS commonly affects whites; it rarely
Differential Diagnosis. Congenital hernias affects Latin Americans, blacks, or Asians (75) .
differ from acquired hiatal hernias in that the Pyloric atresia is extremely rare, with an inci-
diaphragmatic defect does not usually involve dence of 0.0001 to 0.0003 percent of live births
the hiatal orifice. (52); it accounts for less than 1 percent of all
Treatment and Prognosis. Congenital gastrointestinal atresias, as does the rare gastric
diaphragmatic hernias require surgical repair. atresia. Duodenal atresia is less common than
Patient outcome depends on the presence of duodenal stenosis. ]ejunoileal atresia affects
associated malformations and chromosomal 1/500 to 2,000 live births.
anomalies, as well as on the volume of the Large intestinal atresia accounts for less than
contralateral lung and the degree of coexist- 10 percent of all gastrointestinal atresias (54) .
ing pulmonary hypoplasia. Most untreated Atresias of the ascending and transverse colon
symptomatic patients die, often due to severe develop more commonly than distallarge intes-
pulmonary hypoplasia. tinal atresias. Colonic atresia unassociated with
atresia at other sites is uncommon and accounts
ATRESIA AND STENOSIS for 1.8 to 15.0 percent of all intestinal atresias.
Definition. Atresia means "not perforated"; The incidence of colonic atresia is 1/20,000 to
the term is applied to congenital anomalies in 50,000 live births, and affects both sexes equally.
which there is complete discontinuity of the Low birth weight premature babies and mono-
gastrointestinallumen. Stenosis refers to a nar- zygotic twins have a higher risk of intestinal
rowing of the gastrointestinal lumen without atresia than other infants. Multiple atresias oc-
complete obliteration. Tracheoesophageal (TE) cur in 4. 7 percent of infants. Intestinal atresias
fistula is an anomalous connection between a may be more common in blacks. Patients with
portion of the esophagus and the tracheobron- VATER (vertebral defects, anal atresia, TE fistula,
chial tree. TE fistulas frequently complicate and renal dysplasia) or VACTERL (vertebral or
esophageal atresia and stenosis. vascular defects, anal atresia, cardiac anomalies,

47
~ Gastrointestinal Diseases

TE fistula with esophageal atresia, renal agen- Table 2-5


esis, and radial or other limb defects) syndrome NONSYNDROMIC ANOMALIES
are most likely to be male (78). ASSOCIATED WITH ESOPHAGEAL ATRESIA
Associated Findings. Patients with all gas- Sacral dimple
trointestinal atresias frequently have other Abnormal palmar creases
congenital anomalies. Congenital ptosis
Esophagus. Approximately one third of pa-
Numerous ear abnormalities
tients with esophageal atresia have associated
Macro1;ia
congenital anomalies involving the cardiovas-
Bat ears
cular (29 to 37 percent), gastrointestinal (8 to
17 percent), neurologic (12 to 20 percent), geni- Pharyngeal pouch
tourinary (11 to 28 percent), or orthopedic (10 High arches
to 49 percent) systems (Tables 2-5, 2-6) (49,51, Undescended testes
62) . Infants with the VACTERL syndrome are Clicking hip
significantly more likely to have other defects, Down's syndrome
including diaphragmatic defects, oral clefts, Antley-Bixler syndrome
bladder exstrophy, omphalocele, and neural Cardiac anomalies
tube defects (48). Gastrointestinal anomalies
Stomach. Associated anomalies affect 6 to 12 Hiatal hernia
Pyloric stenosis
percent of infants with IHPS (50,51), especially Meckel diverticulum
intestinal malrotation, obstructive urinary tract Anorectal agenesis
defects, and esophageal atresia (45). Pyloric Imperforate anus
stenosis is associated with several chromosomal Duodenal atresia
Annular pancreas
aneuploid syndromes (Table 2-7) (96) . .
Intestine. Duodenal atresia frequently is asso-
ciated with other anomalies (Table 2-8) (59,84).
Familial jejunal atresia may be associated with
renal dysplasia and there is an increased fre - atresia may have a polygenic basis with envi-
quency of cystic fibrosis among infants with ronmental influences. There is no consistent
jejunoileal atresia (79). The apple peel atresia cause, although prenatal exposure to lead,
has the highest rate of associated anomalies thalidomide (72), cafergot (60), or alcohol (87);
(82). Colonic atresia may coexist with other gas- young maternal age (less than 20 years); and
trointestinal or laryngeal atresias, gastroschisis maternal shock, hypotension, and diabetes may
(95), and Hirschsprung's disease (64). represent risk factors. Thalidomide is a terato-
Multiple Atresias. Hereditary multiple gastro- gen with antiangiogenic properties that causes
intestinal atresias affect the gut from the pylorus stunted limb growth. Thalidomide may exert its
to the rectum. Patients with multiple intestinal antiangiogenic properties via the generation of
atresias may also have biliary atresia (95) or an toxic hydroxyl radicals which impair vasculo-
immunodeficiency syndrome (80). Cardiovas- genesis and angiogenesis during embryoid body
cular and other gastrointestinal malformations development (81). This compound also inhibits
are the most common associated major abnor- the angiogenesis induced by basic fibroblast
malities; these are a major cause of morbidity growth factor (55,63,74,94). Most intestinal
and mortality. Skeletal and limb defects are the atresias follow some form of ischemic injury
... most frequent minor anomalies . Epidermolysis (68). Small intestinal atresia may complicate
bullosa is associated with pyloric, esophageal, midtrimester amniocentesis (89), intrauterine
and anal atresia. intussusception due to a Meckel diverticulum,
Etiology. Esophageal atresia and TE fistulas or fetal infections.
result from the failure of the tracheal bud to Twins have a higher rate of small intestinal
develop normally from the primitive foregut atresia than single birth infants, possibly due
(see fig. 2-2). Intestinal atresia occurs as both to vascular disruption in monozygotic twins
a sporadic and a familial disorder. Esophageal (53). Chromosomal abnormalities occur in 5.2

48
Congenital Gastrointestinal Abnormalities

Table 2-6
ATRESIA AND STENOSIS: MULTIPLE ANOMALY SYNDROMES
Syndrome Prominent Features
VATER syndrome Vertebral defects, anal atresia, tracheoesophageal defects, renal dysplasia
VATER association 3 of the 5 anomalies seen in VATER syndrome
VACTERL anomaly (incidence VATER syndrome+ cardiac anomalies, vascular defects, radial or limb defects, single
1.6/10,000 live births umbilical artery
VACTERL-H syndrome (David- VACTERL +hydrocephaly
O'Callighan syndrome)
VACTERL-X X-linked fom1 of VACTERL-H syndrome with the absence of cardiac defects
Feingold's syndrome Hand and foot anomalies, microcephaly, esophageal/duodenal atresia, short palpebral
fissures, learning disabilities
Bartsocas-Papas syndrome Bilateral renal agenesis, esophageal atresia, hypoplastic diaphragm, unilateral renal
agenesis, agenesis of the penile shaft, anal atresia
MODED syndrome (Frydman) Microcephaly, type A brachydactyly, variable learning disabilities, short stature,
duodenal atresia, patent ductus arteriosus, hallux valgus, restricted elbow and
finger movements, mesophalangy, syndactyly of toes
CHARGE syndrome Coloboma, hea.rt disease, choana! atresia, growth and development retardation, geni-
tal hypoplasia, ear anomalies, micrognathia, cleft lip, cleft palate, renal anomalies
OEIS Omphalocele, exstrophy of the bladder, imperforate anus, spinal defects
Facio-auriculo-vertebral Asymmetric hypoplasia of malar, maxillary, and mandibular areas; microtia; deafness;
syndrome hemivertebrae; epibulbar dermoid; macrostomia; microphthaJmja; cleft lip/palate,
cardiac defects, hypoplastic lung; renal anomalies; rib defects
DiGeorge's syndrome Absent or hypoplastic thymus, absent or hypoplastic para thyroids, aortic arch defects,
conotruncal defects, unusual facies, mental deficiency
Down's syndrome Hypotonia, protuberant tongue, mental deficiency, brachycephaly, upslanting palpebral
fissures, small ears, Brushfield spots, short incurved fifth finge10s, cardiac defects,
loose skin at posterior neck
Trisomy 18 Severe mental deficiency, prominent occiput, short palpebral fissures, camptodactyly,
low arch dermal ridges, short sternum, congenital heart defects
Dyskeratosis congenita Irregu lar hyperpigmentation and patchy atrophic hypopigmentation of skin, leuko-
plakia, nail dystrophy, pancytopenia, osteoporosis, mental deficiency
Maternal phenylketonuria Microcephaly, mental retardation, growth deficiency, congenital heart disease
Opitz syndrome Genital anomaly in males, hypertelorism, widow's peak, hernias, cardiac defects, cleft
lip/palate

percent of patients with esophageal atresia. Rare breast feeding. Coexisting epidermolysis bul-
cases of esophageal atresia are associated with losa and pyloric atresia have a characteristic
a microdeletion of chromosome 22qll (56). integrin mutation (76). The familial pattern is
Chromosome 22q 11 deletion is also associated compatible with a multifactorial threshold of
with multiple jejunal atresias, including the inheritance or the effects of multiple interacting
apple peel deformity (97). Some patients with loci. Patients with apple peel atresia probably
anal atresia have.an A-·G mutation at nucleotide have an autosomal recessive inheritance.
position 3243 of mtDNA (58). Pathophysiology. Esophagus. The failure of
Patients with IHPS may have an autosomal the esophagus and trachea to separate complete-
recessive pattern of inheritance. The disorder ly during embryologic development gives rise to
is disproportionately common in monozy- a number of closely related congenital anomalies,
gotic twins. IHPS is more frequent in first-born broadly classified together as TE fistulas (fig.
children and is more common in males than 2-12). Unequal esophageal-tracheal division
females. Factors affecting the expression of IHPS leads to an absent esophagus, or an esophagus
include blood group type, time of birth (peaks consisting of only a thin fibrous cord without a
in the spring and autumn), and a history of lumen or only a fistulous communication to the

49
Gastrointestinal Diseases

Table 2-7
SYNDROMES ASSOCIATED WITH PYLORIC STENOSIS
Associated
Syndrome Prominent Features
Deletion llq Trigonocephaly, upslanting palpebral fissures, ptosis, epicanthal folds, short nose, anteverted nares,
clinodactyly of 5th finger, cardiac defects, hydronephrosis, polydactyly
Duplication 1q Mild growth deficiency, relative megalencephaly, profound mental deficiency, hypertelorism,
downslanting palpebral fissures, small malformed and low-set pinnae, long fingers, cardiac defects,
inguinal hernia
Duplication 9q Growth deficiency, cleft lip, cleft palate, cardiac defects, clubbed feet, camptodactyly, mental deft-
ciency
Marden-Walker Mental deficiency, failure to thrive, microcephaly, immobility of facial muscles, absent reflexes,
syndrome blepharophimosis, strabismus, joint contractures, arachnodactyly, kyphoscoliosis, altered palmar
creases
Ring 12 Growth deficiency, microcephaly, moderate mental deficiency, clinodactyly of 5th finger,
camptodactyly
Trisomy 18 Prenatal onset growth deficiency, profound mental deficiency, prominent occiput, narrow
bifrontal diameter, loW-set and malformed pinnae, micrognathia, camptodactyly, short and
dorsiflexed halux, short sternum, predominance of low arch dermal patterns, cardiac defects
Trisomy 21 Hypotonia, mental deficiency, brachycephaly, flat nasal bridge, epicanthal folds, Brushfield spots,
small and overfolded pinnae, short neck, 5th finger clinodactyly, single transverse palmar crease,
wide space between t1:1es I and Il, cardiac defects
Occasional Accompaniment of the Following
Apert's syndrome Irregular craniosynostosis, short anteroposterior cranial diameter, flat face, shallow orbits,
hypertelorism, strabismus, osseous and/or cutaneous syndactyly, cardiac defects
de Lange's Profound growth and mental deficiency, low-pitched cry, microbrachycephaly, synophrys, small
syndrome nose, anteverted nares, micrognathia, hirsutism, micromelia, phocomelia, oligodactyly
Opitz FG Mental deficiency, hypotonia, affable personality, short stature, prominent forehead, frontal hair
syndrome upsweep, hypertelorism, small ears, imperforate anus, broad thumbs and great toes, cryptorchidism
Smith-Lemli-Opitz Growth deficiency, moderate to severe mental deficiency, microcephaly, narrow forehead, ptosis,
syndrome epicanthal folds, strabismus, syndactyly of toes li and III, altered dermal ridge patterning,
cryptorchidism, hypospadias, cardiac anomaly
Zellweger's (cere- Hypotonia, high foreriead, flattened occiput, epicanthal folds, anteverted nares, loose skin at back of
brohepato-renal) neck, cataracts, cloudy corneas, hepatomegaly, lissencephaly, micropachygyria, multiple cortical
syndrome renal cysts

trachea. Tracheal dominance with esophageal Patients with pyloric atresia, epidermolysis
stenosis or atresia represents the most prevalent bullosa, and an integrin gene mutation may
form of unequal division; it is usually associated develop gastrointestinal atresia secondary to
with a fistula. an inflammatory reaction, which leads to mas-
Stomach. The muscular hypertrophy that sive fibrosis and secondary obstruction of the
characterizes IHPS is usually absent at birth. gastrointestinallumen. The sequence of events
It develops during the first few weeks of life; is initiated by bullous separation of the gastro-
pyloric growth continues into the third month. intestinal mucosa (70).
Excessive gastrin production (90,92), abnor- Intestine. There are three major theories to
malities in peptidergic innervation (90), and a explain intestinal atresias and/or stenoses: 1)
lack of nitric oxide (NO) synthetase (50) all play failed recanalization during the 12th fetal week;
a role in its development (69,90,92). Impaired 2) failure of epithelial growth to keep pace with
NO and vasoactive intestinal polypeptide levels mesenchymal tissue growth during the phase
lead to an excessively contracted, hypertrophied of rapid intestinal elongation, so that epithelial
pyloric muscle (66). IHPS patients may also lack continuity becomes compromised and atresia de-
gastrointestinal pacemakers, the interstitial cells velops; and 3) the occurrence of intrauterine vas-
of Cajal (90). cular accidents, intussusceptions, or intrapartum

50
Congenital Gastrointestinal Abnormalities

Table 2-8
ABNORMALITIES ASSOCIATED WITH INTESTINAL ATRESIA
Duodenal atresia Colonic atresia
Single umbilical artery Hirschsprung's disease
Down's syndrome
Annular pancreas Omphalocele
Malrotation
Cystic fibrosis HIPO syndrome
MOOED• syndrome Hemihypertrophy
Esophageal atresia Intestinal web
Tracheoesophageal fistula Preauricular skin tags
Anorectal anomalies Coronal opadty
Renal malformations
Cardiac malformations OEISI>
Tetralogy of Fallot
Abdominal situs inversus Sirenomelia

Apple peel atresia Renal agenesis


Microcephaly and hydrocephaly
Short stature Agenesis distal colon
Global developmental delay
Ocular anomalies Absent genitalia

Jejuna! atresia Imperforate anus


Gastroschisis
Umbilical ulceration Unseparated lower limbs
Volvulus
Meconium ileus
•MOOED =microcephaly oculo-digito-esophageal-duodenal syndrome.
hOEIS = omphalocele, exstrophy of bladder, imperforate anus, spinal defects.

Trachea-
Esophagus--

Diaphragm~

Stomach-----

A 8 c D E

Figure 2-12
ESOPHAGEAL ATRESIA$ AND STENOSES
A: In type I atresia, a segment of the esophagus is represented by only a thin, noncanalized cord with formation of an
upper blind pouch that connects to the pharynx. The lower pouch leads into the stomach. The atresia usually lies at or near
the tracheal bifurcation.
B: Rare type II atresia. The proximal and distal esophageal portions are completely separated from one another. The
proximal part connects with the trachea.
C: Type III is the most common anomaly. The lower pouch communicates with the trachea or the mainstem bronchus .
D: In type IV lesions, both the upper and lower pouches connect to the trachea.
E: Esophageal stenosis near the tracheal bifurcation. There is also a tracheoesophageal fistula .

51
, Gastrointestinal Diseases

asphyxia leading to segmental intestinal necro- chloremic alkalosis (46). Vomiting is followed
sis with subsequent fibrosis or tissue loss (80). by a voracious appetite. There are features of
The presence of meconium, bile, squamous gastric obstruction. As with any patient with
cells, or lanugo hair in the atretic areas supports chronic gastric outlet obstruction, G-cell hy-
intrauterine injury. Apple peel atresia probably perplasia develops, possibly contributing to the
results from a narrow mesenteric attachment, peptic ulcers that are found in long-standing
volvulus, and occlusion of the superior mesen- cases. Some patients become constipated. Physi-
teric artery distal to its proximal branches (82). cal examination discloses visible peristalsis and
Clinical Features. Esophagus. Prenatal ultraso- the presence of a firm, palpable, ovoid mass cor-
nographic detection of esophageal atresia relies responding to the hypertrophic pyloric muscle.
on finding a small or absent fetal stomach bubble Occasionally, there is localized hypertrophy of
associated with maternal polyhydramnios (85) the muscularis propria of the distal esophagus.
or the presence of a fluid-filled, blind-ending IHPS is usually diagnosed by ultrasound. An
esophagus. Air in the stomach and small bowel enlarged fetal stomach may herald the presence
indicates the presence of a distal TE fistula. Air of gastric outlet obstruction or duodenal atresia.
confined to the stomach raises the possibility Equivocal cases require endoscopy.
of associated duodenal atresia. Inability to pass Infants with the simultaneous appearance of
a nasogastric tube into the stomach confirms epidermolysis bullosa and pyloric atresia (EB-PA)
the diagnosis. A plain radiograph shows the tip have mixed skin lesions that include blisters and
of the tube lodged in a blind-ending proximal patchy lack of skin. Most have gastrointestinal
esophagus, usually located at the level of the obstruction due to overproliferation of connec-
2nd to 4th thoracic vertebrae. tive tissue.
Infants with atresia typically present in the Small Intestine. Duodenal atresia can be
first few hours or days of life with regurgitation, diagnosed ultrasonographically at 15 weeks
excessive drooling, choking, aspiration, cyano- of gestation by finding polyhydramn.tos, and
sis, and respiratory distress. If a child eats, he or intestinal dilatation proximal to the atretic
she typically eats hungrily. Coughing, gagging, intestine. Other findings include meconium
vomiting, and cyanosis soon follow. Preopera- peritonitis and ascites. Elevated maternal serum
tive ventilator dependence and associated major AFP levels and polyhydramnios occur in the
anomalies independently affect survival. second trimester of pregnancy in 50 percent
Esophageal stenosis is usually diagnosed of cases (93). Signs of distress or ischemia are
much later than atresia. Patients present with frequent. Approximately 50 percent of infants
dysphagia, regurgitation, and failure to thrive. with intestinal atresia are premature. Patients
Milder degrees of stenosis may be asymptom- with small intestinal atresias present in the neo-
atic. True dysphagia may develop when solid natal period with vomiting, unless a coexisting
foods are consumed. esophageal atresia is also present. The vomitus
Most patients present in the first few days of lacks bile when the obstruction lies proximal
life with bile-free vomiting, gastroesophageal re- to the ampulla of Vater. Duodenal atresia is also
flux, abdominal distenti0n, and stools decreasing suggested radiographically by the presence of
in quantity. Other signs include regurgitation, a double bubble on a plain abdominal X ray
excessive drooling, choking, aspiration, cyanosis, (fig. 2-13), particularly when gas is present in a
and respiratory distress. Perforate diaphragms distended stomach and proximal duodenum.
present later than imperforate ones, depending Some patients with duodenal stenosis re-
on the size of the opening. Hypochloremic, hy- main asymptomatic whereas others have an
pokalemic metabolic alkalosis may occur. intermittent or delayed history of duodenal
Stomach. Some infants with IHPS are symp- ulcer, symptoms associated with hiatal hernia,
tomatic at birth, but most remain well during gastritis, duodenogastric reflux, motility distur-
the first few weeks of life, only to return to the bances, duodenal diverticula, and bezoars (65).
hospital at about a month of age with regurgi- The small intestinal loops appear dilated and
tation, abdominal distension, and projectile, contain air-fluid levels; colonic gas is absent in
nonbilious, postprandial vomiting and hypo- complete jejunal or ileal obstruction. The more

52
Congenital GastrointestinaJ Abnormalities

Figure 2-14
ANTRAL MEMBRANE: BARIUM STUDY
The stomach is distended and the site of the membrane
is indicated by the defect in the barium within th e stomach.

sively narrows as one precedes proximally.


The atretic segment varies in length; the gap
between the blind upper pouch and the lower
end varies from 1 to 5 cm. The five types of
congenital esophageal atresias and TE fistulas
are illustrated in figure 2-12. The most common
form is type C in which the upper esophagus
ends as a blind pouch and the lower segment
forms a fistula with the trachea, usually com-
Figure 2-13 municating with it within 2 cm of its bifurca-
RADIOGRAPHIC APPEARANCE tion. This type accounts for approximately 90
OF THE DOUBLE-BUBBLE percent of cases (71).
The abdomen of the infant is distended. There is a larger Several types of congenital esophageal ste-
bubble in the proximal stomach and a smaller one in the nosis exist: 1) a localized area of muscular and
duodenum. submucosal hypertrophy; 2) the presence of
cartilaginous tracheobronchial remnants; and 3)
distal the atresia, the more severe the distension. a membranous diaphragm or web arising from
Microcolon may be present. A barium enema the esophageal wall, obstructing the lumen, and
should be performed to rule out Hirschsprung's containing a small central perforation.
disease and malrotation. Stomach. Type 1 gastric atresia (the most
Gross Findings. Atresia results from a com- prevalent form) consists of an internal web or
plete occlusion, whereas stenosis is either a diaphragm completely separating the stomach
narrowed intestinal segment or a luminal dia- from the duodenum (61). The diaphragm may
phragm with a small central aperture. In atresia, be perforate or imperforate. Grossly and radio-
a bowel segment is entirely missing, leaving a graphically, a large distal antral mucosal fold
proximal segment with a blind end separated lies perpendicular to the long axis of the antrum
some distance from the distal segment. Alter- (fig. 2-14). It often contains a central aperture
nately, the proximal and distal segments are measuring from 1 to 10 mm in diameter. The
united by a solid fibrous cord, or there is an gastric serosa may appear indented at the level
occluding mucosal diaphragm. Some patients of the diaphragm. Type 2 atresia consists of a
have multiple atresias (77). thin, fibrous cord which connects a blind gastric
Esophagus. In esophageal atresia, the esopha- pouch to a distal blind small intestinal segment.
gus appears normal at the cardia but it progres- Type 3 atresia consists of a blind gastric pouch

53
Gastrointestinal Diseases

Figure 2-15
DIFFERENT FORMS OF ILEAL ATRESIA
A: Type I: an imperforate septum
covered on each side by mucosa
stretches across an otherwise con -
tinuous bowel.
B: Type II: a thin fibromuscular
cord, with or without an associated
mesenteric defect, replaces the bowel.
C: Type Ill: a complete gap and
a corresponding mesenteric defect
separate the two blind intestinal ends.
D: Type IV: presence of atretic areas
with or without a mesenteric gap.
Different forms of atresia may coexist
and may be single or multiple.

and a blind distal intestinal pouch without a discontinuous bowel with an intermediate
intervening tissue. • fibrous cord and a gap that is usually replaced by
A concentrically enlarged pylorus character- pancreas or a mucosa-lined membranous atresia
izes IHPS. The pyloric channel appears two to (54). Annular pancreas coexists with a duodenal
four times its normal length, and its thickness diaphragm or stenosis in 50 percent of cases.
exceeds 1 cm (normal is 4 to 8 mm). The mus- There are four types of ileal atresia (figs. 2-15,
cularis propria hypertrophies up to 400 percent 2-16) and two types of intestinal stenosis. The
of its normal thickness. The hypertrophy of features differ depending on whether or not there
the pyloric canal affects both the muscle and is a complete gap in the bowel wall and/or mes-
the elastic tissue in the submucosa. The hy- entery and on the width of the distal ·segment.
pertrophy passes through a series of phases, One type of atresia affects the jejunum near the
presumably due to the neural abnormalities. ligament of Treitz. The bowel is short and there
The pylorus becomes extremely hard as the is a long defect in the mesentery. The distal small
hypertrophy increases and a fusiform mass with bowel is coiled in an apple peel configuration
the consistency of cartilage, measuring 3 to 5 around the supplying vessel (fig. 2-17).
cm, abruptly terminates at the duodenum. The Microscopic Findings. Esophagus. In esopha-
lesion reaches its greatest development between geal atresia, the esophageal and tracheal muscles
4 and 9 weeks of age. If surgical intervention intimately blend together. The muscle appears
is not necessary, the pylorus then begins to hypertrophic and it contains an extra myen-
relax, becomes smaller and softer, and heals teric plexus in the membranous portion of
by the time the infant is several months old. the trachea, a manifestation of the incomplete
The stomach becomes dilated and the antrum tracheal-esophageal separation (71).
hypertrophies. The clinical picture of gastric Distal esophageal stenoses usually contain
outlet obstruction occurs when the enlarged fibromuscular tissue. One form of esophageal
pyloric muscle measures more than 3 mm stenosis results from inadequate nitrergic in-
in thickness. Pyloric obstruction can lead to nervation (77,83) . Another form results from
secondary mucosal and submucosal edema the presence of intraesophageal cartilaginous
and ulceration, further aggravating the distal tracheobronchial remnants due to esophageal
obstruction. In extreme cases, IHPS distorts sequestration of a tracheobronchial anlage
the normal anatomy and elevates the pylorus, before embryologic separation. A third form
displacing the duodenum to lie adjacent to or consists of a membranous diaphragm or web
below the gallbladder. Endoscopy demonstrates arising from the esophageal wall, containing
pyloric narrowing and mucosal thickening. fibromuscular tissue with a small central per-
Intestine. Intestinal atresias may be multiple foration that obstructs the lumen.
or single, and are often associated with mes- Stomach. Antral cuboidal or squamous epithe-
enteric defects (91). Morphologically, there is lium lines both sides of the luminal diaphragm

54
Congenital Gastrointestinal Abnormalities

Figure 2-16
SMALL INTESTINAL ATRESIA
Left: Type I jejuna! atresia shows an area of narrowing.
Right: Type IV atresia: the intestinal loop ends blindly and there is a small communication with the next segment.

in gastric stenosis. The mucosa covers a central


submucosal core. The lesion appears variably in-
flamed. Heterotopic pancreatic tissue sometimes
lies within webs and diaphragms. Two thirds
of gastric atresias are membranous, consisting
of a diaphragm or a web, and usually involve
the pylorus.
IHPS usually consists of hypertrophy and hy-
perplasia of the circular muscle of the muscularis
propria of the gastric pylorus and hypertrophic
longitudinal muscle fibers. Children also have
focal and multinodular variants in addition to
the circular form. The submucosal vasculature
may appear dilated. Myenteric ganglion cells
degenerate and disappear, resulting in reduced
or absent nerves. Interstitial cells of Cajal may
be decreased in number (90). IHPS is associated Figure 2-17
with idiopathic focal foveolar hyperplasia sec-
APPLE PEEL CONFIGURATION OF INTESTINAL ATRESIA
ondary to G-cell hyperplasia (90).
The distal small bowel spirals around a vascular stalk.
Intestine. Normal small intestinal mucosa
lines both sides of the atretic or stenotic intes-
tinal segment. The height of the circular folds phic calcification and inflammation at or near
declines and the muscularis mucosae thickens as the atretic site suggest previous injury. The blind
one approaches the blind segment. In complex segment may contain dense fibrosis, meconium,
atresia, the proximal bowel appears dilated and keratinizing squamous cells, lanugo hair, bile
gangrenous. The circular folds widen due to pigment, and mucin, also suggesting previous
stromal edema. The villi may appear shortened injury. The intervening mucosa between atretic
or only simple tubular glands are seen. The villi areas is histologically normal. The muscularis
and crypts often appear necrotic or ulcerated, propria eventually becomes markedly hyper-
with only a few residual intestinal glands. As a trophic and the myenteric plexus may show
result, the mucosa contains granulation tissue, inflammatory or degenerative changes.
granulomas, foreign body giant cells, fibroblasts, Treatment and Prognosis. Treatment and
and hemosiderin-laden macrophages. Dystro- prognosis depend both on the specific atresia or

ss
Gastrointestinal Diseases

stenosis, as well as on the presence of associated duodenotomy with web excision, or duodena-
lesions. Infants with atresia can be evaluated by jejunostomy. Patients with jejunoileal atresia
chest and abdominal X rays and cardiac and are treated with resection (76 percent), tempo-
renal ultrasonography to detect any associated rary ostomy, and web excision. Patients with
anomalies. Sweat tests rule out cystic fibrosis colonic atresia are managed with initial ostomy
in babies with jejunoileal atresia, and a rectal and delayed anastomosis. Although apple peel
biopsy should be done in patients with a com- intestinal atresia is rare, it is associated with
bination of Down's syndrome and duodenal significant morbidity and a high mortality rate.
atresia to exclude Hirschsprung's disease. Such patients can be initially managed with
Esophagus. Neonates with esophageal atresia total parenteral nutrition. The dilated proximal
and/or TE fistula are stratified into prognostic bowel is resected and a primary anastomosis per-
categories based on birth weight, esophageal gap formed. Early morbidity is common but excel-
length (49), preoperative ventilator dependence, lent long-term outcomes can be achieved. Short
the presence of pneumonia, and the identifica- bowel syndrome develops in a percentage of
tion of associated congenital anomalies (49,86). patients (54). Ultrashort bowel syndrome (under
The main therapy is primary anastomosis in 40 cm) requires long-term total parenteral nutri-
infants at 3 months of age (57). Type A (long tion and can be complicated by cholestatic liver
gap) esophageal atresia without a fistula is treated disease and gallstones, particularly in patients
with native esophageal reconstruction or the with jejunoileal atresia. Growth factor therapy
missing esophagus is replaced with colon. Mor- and small bowel transplantation may improve
bidity associated with repair of these anomalies long-term outcome (54).
is high (88) and there are many cornplications. Animal Models . Intraperitoneal injections
These include stricture, leakage, recurrent TE of adriamycin produce esophageal atresia, TE
fistulas, pneumonia, wound infection; wound fistula, and VATER syndrome in animals (73).
dehiscence, and perforation (88) . Many patients Intestinal atresia has been produced -1n chicks
develop esophageal reflux after the repair (47) by temporarily occluding a branch of the om-
and may need partial wrap fundoplication (67). phalomesenteric artery or in fetal mammals by
Surgical repair is usually feasible in patients occluding the superior mesenteric artery (68).
with esophageal stenosis, but ·re -stenosis
commonly occurs, leading to aspiration and BRONCHOPULMONARY MALFORMATIONS
respiratory infections, secondary strictures, INCLUDING CONGENITAL BRONCHO-
esophagitis, Barrett esophagus, and hiatal hernia ESOPHAGEAL FISTULAS,
(67). Endoscopic dilatation may be necessary BRONCHOGENIC CYSTS, AND
but repeated attempts to dilate true congenital PULMONARY SEQUESTRATION
esophageal stenosis often fail. Definitions. Bronchopulmonary malforma-
Stomach . Treatment of gastric atresia or ste- tions are collections of pulmonary tissue lying
nosis consists of ablation of the diaphragm or either within the lung substance or separated
resection of the aplastic pylorus with a gastro- from the lung by a pleural covering, most com-
duodenal anastomosis. Successful endoscopic monly maintaining connections to a lobar or
incision of an antral membrane is possible. segmental bronchus. Communicating broncho-
Patients often have residual motility problems pulmonmy foregut malformations (CBPFMs) are
with consequent gastroesophageal reflux (47) rare tracheobronchial anomalies characterized
and pulmonary dysfunction. by a fistula between an isolated portion of re-
Patients with IHPS undergo pyloromyotomy spiratory tissue and the esophagus or stomach.
without tissue removal. This approach results If the communication between the pulmonary
in an excellent prognosis with few long-term tissue and the esophagus is lost, the pulmonary
sequelae. Complications include duodenal tissue appears as a sequestration. In esophageal
perforation, postoperative vomiting, and in- bronchus, the mainstem bronchus originates
complete myotomy. from the esophagus; this lesion is also called
Intestine. Patients with duodenal obstruc- esophageal lung (103). The lung receives its ar-
tion are treated by duodenoduodenostomy, terial supply from the pulmonary artery. The

56
Congenital Gastrointestinal Abnormalities

lesion differs from pulmonmy sequestration in geal dilatation. Radiologic investigation of a


which anomalous systemic arterial blood vessels suspected bronchopulmonary malformation
. supply the sequestration. begins with the injection of contrast material
Demography. Bronchopulmonary foregut through a feeding tube into the distal third
malformations are extremely rare and occur of the esophagus where an ectopic bronchus
much less commonly than tracheoesophageal is most likely to arise. Gastrostomy injection
abnormalities. Approximately equal numbers provides distal esophageal opacification by
of girls and boys are affected; patients range in gastroesophageal reflux when passing a feeding
age from newborn to 24 years. tube is contraindicated. When associated with
Associated Findings. Bronchopulmonary air bronchograms in the same area, absence of
malformations occur in combination with a mainstem bronchus during bronchoscopy is
other anomalies of the upper gastrointestinal diagnostic of an esophageal lung. Esophago-
tract, diaphragm, and pulmonary and sys- scopy with tracheobronchography is another
temic arteriovenous systems (98). These include confirmatory procedure.
rib and vertebral abnormalities, congenital Gross Findings. Extralobar sequestrations
diaphragmatic hernias, duodenal stenoses or usually lie in the posterior costodiaphragmatic
atresias, multicystic dysplastic kidneys, cardiac angle, adjacent to the esophagus; they may
anomalies, and gastric duplication cysts (102). communicate with the esophagus, often dis-
Rarely, they are associated with TE fistulas (102) tally presenting as bronchoesophageal fistulas
or VATER anomalies. (100). In a minority of cases, a supernumerary
Etiology. Bronchopulmonary malforma- lung bud arises from the lower portion of the
tions result from the imperfect separation of foregut and is associated with a congenital dia-
pulmonary and esophageal anlagen or from an phragmatic hernia. This form of sequestration
accessory esophageallung bud. The presence of generally occurs in the mediastinum along the
lung tissue arising from the primitive gastro- tracheobronchial tree or within the lung and
intestinal tube is a common occurrence in the typically has an anomalous blood supply. A
development of all forms of bronchopulmonary rare type of bronchoesophageal fistula com-
foregut malformations. Three important factors municates with the normal bronchial tree but
that determine the type of lesion are: 1) the it has a systemic arterial blood supply.
stage of embryologic development at which the Microscopic Findings. The histology of the
accessory lung tissue arises; 2) the direction in involved structures is that of normal bronchus
which the aberrant pulmonary tissue grows; and or respiratory tract (fig. 2-18).
3) retention or involution of the communica- Microscopic Variants. Tracheobronchial
tion between the accessory lung tissue and the chondroepithelial hamartoma is an uncommon
parent viscus. related lesion (91) that results from abnormal
Clinical Features. Patients usually present esophageal-tracheal separation. The hamartoma
in infancy with a mediastinal mass or repeated contains ciliated, mucus-secreting, tracheo-
pulmonary infections. Congenital bronchoeso- bronchial lining epithelium; seromucinous
phageal fistulas also present in adults (101). The minor salivary glands; cartilage; smooth muscle
diagnosis is suggested by long-standing, unex- cells; and sometimes ectopic thyroid or pancre-
plained respiratory symptoms such as coughing, atic tissue. Other bronchogenic cysts are lined
cyanosis, frequent pulmonary infections, or by respiratory squamous epithelium but they
even hemoptysis. Other signs and symptoms lack cartilage.
include vomiting, the presence of an extra- Differential Diagnosis. Other cystic lesions
thoracic mass, or chest pain. in the region of the esophagus fall into several
Radiologic Findings. Most patients with categories, including duplications, broncho-
bronchopulmonary malformations have an genic cysts, gastric duplication cysts, and neu-
abnormal chest radiograph due to the presence roenteric cysts. These lesions usually lie in the
of an anterior mediastinal mass, intraparen- distal esophagus (99).
chymal pulmonary lesion, tracheal deviation, Treatment and Prognosis. The majority of
lobar collapse or emphysema, and esopha- patients undergo surgical excision of the lesion.

57
Gastrointestinal Diseases

Figure 2-18
BRONCHOGENIC CYST INVOLVING THE WALL OF THE ESOPHAGUS
Left: Low-power magnification shows a cystic structure lined by epithelium, muscle, and loose connective tissue.
Right: At higher magnification, the lining resembles that of the normal respiratory tract.

----Main
DUPLICATIONS, DIVERTICULA,
Intestinal ENTEROGENOUS CYSTS
lumen\'
Congenital diverticula, duplications, and en-
terogenous cysts are related lesions. The major
distinction that separates them is their gross

B~ appearance (fi.g. 2-19).


Duplications and Enterogenous Cysts
Definition. A duplication is a. complete or
c. partial doubling of a variable length of bowel
containing all of the layers of the bowel wall.
(I/ Enterogenous cysts are cysts derived from cells
sequestered from the formative gut.
Demography. Thirty-nine percent of gas-
trointestinal duplications involve the foregut;
61 percent involve the midgut or hindgut.
Esophageal duplication cysts are present in
approximately 1/8,000 autopsies (118), and ac-
count for 10 to 20 percent of all gastrointestinal
Figure 2-19
duplications. Gastric duplications constitute
DIAGRAMMATIC COMPARISON OF 3.8 to 10.0 percent of all gastrointestinal du-
CONGENITAL DIVERTICULA, DUPLICATIONS,
AND ENTEROGENOUS CYSTS
plications (104). Intestinal duplications affect
1/4,000 births and are occasionally multiple.
A: Cystic duplication that does not communicate with
•.· the main intestinal lumen. This lesion is sometimes referred Bowel duplications most commonly occur in
to as an enterogenous cyst. the small intestine, usually in the ileum (50
B: Communicating cystic duplication that communi- percent of duplications affect the ileum), mostly
cates at one end . This is sometimes referred to as a in the area of the ileocecal valve (120); only 8 to
congenital diverticulum.
C: Long tubular duplication communicating at one end 16 percent are in the jejunum. Hindgut tubular
with the main intestinal lumen. duplications are rarer than other gastrointesti-
D: Complete duplication of the intestine without nal duplications. Approximately 30 percent of
communications.
intestinal duplications occur in the large intes-
E: Long tubular duplications with communication at
both ends. tine. The male to female ratio is 1 to 2.

58
Congenital Gastrointestinal Abnormalities

Table 2-9 with notochord development and lead to split-


LESIONS COEXISTING WITH GASTRIC DUPLICATIONS
ting of the notochord to bypass the adhesion.
This notochordal split is associated with defec-
Esophageal duplications
tive mesenchyme that allows the endodermal
Heterotopic pancreas
and ectodermal adhesions to persist (105,113,
Gastrointestinal malrotations
125). Small diverticula and epithelial islands in
Meckel diverticulum
the developing small intestinal mesentery may
Thoracic vertebral anomalies explain the presence of isolated intestinal dupli-
Pulmonary sequestration cations (123). Extensive intestinal duplications
Accessory spleen associated with multiple anomalies, including
Abnormally shaped spleen bladder anomalies, presumably result from
Urinary tract anomalies teratogenic insults that affect several develop-
Turner's syndrome ing organs.
Patent ductus arteriosus Clinical Features. Duplications and related
Ventricular septal defect lesions are usually detected early in life, al-
Vertebral anomalies though a minority remain undetected until
Esophageal duplications adulthood. Most patients present during the
first year of life. The size and location of the
duplication, and the resultant complications,
determine the clinical signs and symptoms.
Associated Findings. Duplications and en- The manifestations may be vague and diverse,
terogenous cysts, especially those in the foregut, usually resulting from compression of normal
often coexist with rotational disorders or verte- adjacent bowel. Signs and symptoms include
bral body defects. Duplications also are associ- pain, abdominal distension, the presence of a
ated with cloacal anomalies and situs inversus palpable mass, dysphagia, nausea, vomiting,
(115,124). If a spinal deformity coexists with weight loss, anorexia, dyspnea, wheezing or
an alimentary tract duplication, the anomaly coughing episodes, bleeding, and recurrent
probably arose during the 3rd fetal week when pneumonitis. Bleeding or melena results from
the neurenteric canal communicated with the presence of ectopic gastric tissue or isch-
the primitive ectodermal plate and yolk sac. emia. Complications include ulceration, fistula
Esophageal duplication cysts are associated with formation, perforation, gastrointestinal obstruc-
pulmonary cystic malformations (121) . Thirty- tion, or carcinoma.
five percent of patients with gastric duplications Most gastric duplications present as in-
have associated developmental anomalies (Table trathoracic or extragastric masses. Duodenal
2-9). Anorectal duplications are rare and are duplications may cause portal hypertension or
almost always associated with abnormalities of pancreatitis. Ileocecal duplications can act as
the bladder, mullerian structures, and external lead points for chronic or recurrent intussuscep-
genitalia (127). tion or volvulus. Rectal duplications may pres-
Etiology. Hypotheses to explain duplications ent as neonatal intestinal obstruction, chronic
include persistence of embryonic diverticula, constipation, a prolapsing rectal polyp, a vulvar
fusion of embryologic longitudinal folds (the growth, acute urinary retention, chronic rectal
most popular theory) (109), abortive twinning bleeding, intussusception, volvulus, perfora-
(117), defective luminal vacuolar breakdown tion, or obstruction.
(120), intrauterine intestinal ischemia (105 ,114, Gross Findings. Gastrointestinal duplica-
129), endodermal-neurodermal adhesions, tions occur anywhere in the gastrointestinal
and sequestration of embryonic tissues during tract and are usually single, but they may be
embryonic movement. The split notochord multiple (112), often lying in both the thorax
syndrome postulates that hindgut duplications and the abdomen. They can be complete or
result from ectodermal-endodermal adhesions incomplete, communicating or noncommuni-
during the development of the caudal end of cating. Communicating duplications open
the embryonic disc. These adhesions interfere proximally, distally, or at both ends.

59
Gastrointestinal Diseases

Figure 2-20
RADIOGRAPHIC STUDIES OF COLONIC DUPLICATIONS
Left: The duplicated segments may be th~ same size as the normal lumen or may be small and malformed.
Right: The duplicated segment lies adjacent to the main intestinal lumen.

Grossly, duplications appear as hpllow, cylin- with aberrant pancreatic ducts or with the main
drical or oval, cystic masses that J:ange in size pancreatic duct. Some gastric duplications take
from a few millimeters to up to 15 cm (116). Du- the form of a double pylorus, sometimes coex-
plications tend to be longer in their axial length isting with cystic duplication of the duodenal
than enterogenous cysts or diverticula. They bulb; the two pyloric channels are separated by
appear as tubular reduplications, usually with a a septum. Gastric duplications usua-lly fail to
common muscular wall between the normal and communicate with the gastric lumen, appearing
duplicated segments. They have thick walls and as closed spherical cysts (enterogenous cysts).
are filled with mucus. Because of t_heir location, Therefore, ultrasound is the diagnostic modality
duplications may fill with barium during gastro- of choice (124).
intestinal examination, and vary in length; they Intestinal duplications always lie dorsal to the
can involve long intestinal segments. Bleeding intestine (fig. 2-20), usually within the mesen-
can occur within the duplication or the adjacent tery between the spinal cord and the intestine.
mucosa, where a marginal ulcer may develop. They are sometimes intramural, lying within
Even a triple lumen may be present (110,115). the muscularis propria. Rarely, the duplicated
Sixty percent of esophageal duplication cysts segment remains completely isolated from the
originate in the lower esophagus; the remain- main intestinal tract, hanging freely on its own
der are equally distributed between the upper mesentery. The blood supply of the normal
and middle esophagus. The cysts lie posteriorly bowel usually runs in the wall of the duplicated
in a periesophageal location, protruding into gut so that surgical removal requires removal of
the posterior mediastinum, or they develop the normal segment as well.
within the esophageal wall. Esophageal cysts Distal large intestinal duplications fall into
are unilocular lesions, averaging up to 5 cm in two categories: those associated with urinary
diameter. Their outer surface is tan, smooth, bladder, urethral, or anorectal abnormalities
and glistening. The inner lining is smooth and and those that occur alone. Rectal duplications
contains thick, clear, mucinous material. present as presacral, intraspinal, or postsacral
Most gastric duplications lie on the greater enteric cysts or as a fistula between the rectum
curvature or on the anterior or posterior walls; and the postsacral skin. The structure of these
a third affect the distal stomach. Gastric dupli- hindgut fistulas varies. Most have a muscular
cations may be intimately related to the gastric wall that varies in thickness and an epithelial
wall or may be unattached to the stomach. lining that contains colonic, small intestinal,
Some adhere to the pancreas or communicate gastric, or mixed epithelium that sometimes

60
Congenital Gastrointestinal Abnormalities

Figure 2-21
GASTROINTESTINAL DUPLICATION
Left: Several intestinal lumens are present within the wall of this sa mple. Smooth muscle surro unds many of them.
Right: Another small intes tin al duplication in which th e muscular layer is much less obvious.

includes esophageal and bronchial epithelium. present in the gastrointestinal tract, particularly
Aberrant cartilaginous nodules may be present gastric mucosa. Ectopic gastric mucosa is pres-
(126). Distal intestinal duplications may be as- ent in a large percentage of duplications (107).
sociated with presacral teratomas or they may As a result, peptic injury often causes mucosal
be misdiagnosed as teratomas. erosions or ulceration and hemorrhage.
Duplicated ani appear as double perineal ani Esophagus. Esophageal dyplications are lined
that open externally, double ani with fistulas of by stratified squamous, simple pseudostratified
one or both duplicated segments to the genito- ciliated columnar, or gastric cells. The wall con-
urinary tract, or as one external anus and one tains two layers of smooth muscle fibers, with
imperforate anus (127). The bladder may be du- fibers of the outer layer oriented perpendicularly
plicated or septate with double urethral openings to those of the inner layer. The muscularis pro-
and there may be duplication of the utems and pria of the esophagus is continuous with the
the vagina. There may also be two penes or two muscle layer of the cyst wall. The outermost
clitorides or a combination of the above (127). layer consists of fibrous connective tissue con-
Enterogenous cysts may be single or multiple. taining small blood vessels, nerve twigs, and
They appear as rounded, cystic masses that fail ganglion cells. Pancreatic tissue may be present.
to communicate with the intestinal lumen. Stomach. The epithelial lining of a duplica-
They are usually filled with clear secretions. tion resembles or differs from that of the normal
Most measure 3 to 6 cm. stomach. Gastric and small intestinal or colonic
Microscopic Findings. Three criteria are epithelium may coexist within a single duplica-
required for the diagnosis of a duplication: 1) tion. Pancreatic tissue constitutes a prominent
an intimate attachment to the gastrointesti- component of the duplication wall in 37 percent
nal tract, 2) the presence of a smooth muscle of cases (124). Additionally, histologic components
coat, and 3) an alimentary mucosal lining (fig. of the upper respiratory tract, including respira-
2-21) . Of these, only the presence of a smooth tory mucosa, cartilage, and cemminous glands,
muscle coat is absolutely necessary to define may be seen. The amount of muscle varies. Peptic
the duplication. The absence of a muscle coat is ulceration due to the presence of parietal cells can
characteristic of an enterogenous cyst. Pressure cause cysts to mpture or hemorrhage.
within a cyst may result in muscular atrophy, Intestine. Generally, intestinal epithelium
causing it to appear incomplete. The lesions are lines intestinal duplications (fig. 2-21). They
typically lined by glandular mucosa that often may also contain heterotopic tissues including
contains one or more of the cell types normally stratified, squamous, or ciliated epithelium;

61
' Gastrointestinal Diseases

thyroid stroma; pancreas and gastric mucosa; Treatment and Prognosis. Treatment of
lymphoid aggregates resembling Peyer patches; enteric duplications depends on the age and
ciliated bronchial epithelium; lung tissue; and condition of the patient; the type, location, and
cartilage. Ectopic gastric or pancreatic mucosa extent of the lesion; and the presence or absence
is found in more than 50 percent of duplica- of associated abnormalities (104,106,119).
tions. Peptic ulcers may develop in duplications Many recommend complete surgical resection
containing heterotopic gastric tissue. Exception- when this is feasible. Surgery is especially rec-
ally, duplications are lined by benign neoplastic ommended for symptomatic duplications due
epithelium forming a mucinous adenoma (111). to the potential for obstruction, bleeding, and
The submucosal inner circular muscle layer and rupture. If the duplications are extensive and
myenteric plexus usually appear normal. do not allow complete excision, partial exci-
Differential Diagnosis. The types of develop- sion can be performed with internal drainage
mental cysts encountered in the mediastinum or removal of the mucosal lining to prevent the
are bronchogenic, esophageal, gastroenteric, possibility of acid secretions.
and pericardial. Distinction among the four is
Congenital Diverticula
simplified by the fact that gastroenteric cysts are
lined by gastric or duodenal type epithelium, Definition. Congenital diverticula are out-
whereas pericardial cysts are lined by flattened pouchings of the gastrointestinal wall that
mesothelium. The distinction between bron- contain all of the bowel layers. Duplications
chogenic and esophageal cysts is more difficult. that widely communicate with the bowel lumen
Because of the embryologic relationship that are sometimes termed congenital diverticula.
exists between the esophagus and the tracheo- Demography. Of the three related lesions,
bronchial tree, it may be difficult to distinguish duplications, enterogenous cysts, and congeni-
between esophageal duplication cysts and other tal diverticula, the latter are the rarest except
intrathoracic cystic lesions lined by respiratory for Meckel diverticula, which are discussed in
columnar, cuboidal enteric, stratified squamous, a subsequent section. Diverticula are rarer in
or gastric epithelium (108). Duplications usually the stomach than anywhere else in the gas-
have a duplicated muscularis propria. When cili- trointestinal tract. Approximately 2 percent
ated columnar epithelium is seen in.the cyst, the of all gastrointestinal diverticula are gastric, 9
presence of cartilage or respiratorx.glands indi- percent are esophageal, 60 percent are colonic,
cates bronchogenic differentiation. In contrast, and the remainder occur in the small intestine.
a cyst without cartilage, with a double layer of Congenital duodenal diverticula affect 1 to 2
smooth muscle, and an attachment close to the percent of all individuals.
esophagus, probably arose in the esophagus. Etiology. Congenital true diverticula arise
Since the precise etiology of mediastinal cysts embryologically, either from the persistence of
may be difficult to ascertain, some prefer to mucosal diverticula in the embryo or from small
refer to such lesions as foregut cysts or foregut blind duplications that subsequently enlarge.
duplication errors (108). Clinical Features. Patients with congenital
Other congenitalle5ions that may be in the diverticula may remain asymptomatic or pres-
differential diagnosis are lymphangioma and ent with one of the following: 1) abdominal dis-
malrotation. Lymphangiomas appear as multi- tension, pressure, pain, and possibly perforation
loculated cysts and are often manifested by due to diverticulitis; 2) ulceration and bleeding,
'··
abdominal pain, fever, vomiting, ascites, and usually from the presence of heterotopic acid-
a palpable mass. They can become infected secreting gastric mucosa; and 3) intussusception
and have an enhanced wall on abdominal CT leading to sudden pain and bleeding. Patients
scanning. They are not associated with either present with dysphagia which results when the
enteric fistulas or anemia (122,128). Malrota- diverticula enlarge and fill with food. Gastric
tions manifest with abdominal pain, intermit- diverticula usually do not cause symptoms,
tent obstruction, anemia, and an abnormally but if symptoms develop, they usually consist
positioned jejunum, but do not present as an of epigastric or lower chest pain. Duodenal
enteric cystic mass or enteric fistula. diverticula may enlarge, causing obstructive

62
Congenital Gastrointestinal Abnormalities

Figure 2-22
COMPARI SON OF CONGENITAL
AND ACQUIRED LARGE
INTESTINAL DIVERTICULA
Left: An acquired diverticu-
lum in which the mucosa and
submucosa herniate through the
muscularis propria, extending
variably out through the bowel
lumen. Acquired diverticula often
lack the muscularis propria.
Right: In contrast, congenital
diverticula are lined by the full
thickness of the gastrointestinal
wall, including mucosa, submu-
cosa, and muscularis propria.

Figure 2-23
CONGENITAL
ILEAL DIVERTICULA
Note the outpouchings of
the ileal wall. This child had
multiple congenital anomalies.

jaundice, pancreatitis, duodenal obstruction, diac position (132). They lie about 2 cm below
fistulas, hemorrhage, and perforation (131). the junction of the esophagus and stomach,
Symptomatic patients range in age from 10 to and about 3 cm from the lesser curvature. The
15 years (133). remainder originate in the antrum and pylorus.
Gross Findings. Both congenital and ac- Most measure less than 4 cm in length.
quired diverticula arise throughout the gastro- In the intestines, congenital diverticula pres-
intestinal tract. The features that distinguish the ent as localized outpouchings, and are often
two lesions are illustrated in figure 2-22. Con- multiple (fig. 2-23) . Some congenital duodenal
genital diverticula appear as solitary, sharply diverticula pass upward behind the stomach
defined, round, oval or pear-shaped pouches through a separate opening in the diaphragm to
that communicate with the gastric lumen via enter the right thoracic cavity where they attach
a narrow or broad-based mouth. Some form an to defective thoracic vertebrae. Eighty percent
intraluminal polyp (130). of solitary congenital cecal diverticula occur
Approximately 75 percent of gastric diver- within 2.5 cm of the ileocecal valve near the ce-
ticula arise from the posterior wall, in a juxtacar- cal tip. (See next section for Meckel diverticula.)

63
- Gastrointestinal Diseases

Figure 2-24
CONGENITAL
ILEAL DIVERTICULA
Diverticula are lined by the
same type of epithelium found
within the native lumen . They
contain the full thickness of the
bowel wall and the lining.

Microscopic Findings. Congenita! diverticu- OMPHALOMESENTERIC REMNANTS


la consist of all three bowel layers (fig, 2-24). The The various abnormalities caused by
lining epithelium is usually that of the site of omphalomesenteric remnants are illustrated
origin. Some diverticula contain heterotopic tis- in figure 2-25.
sues, similar to those found in duplications and
Umbilical Fistula
enterogenous cysts. Peptic ulcers may develop
within diverticula containing oxyntic mucosa. Definition. Umbilical fistula is a persistent
If the diverticular orifice becomes blocked, di- vitelline duct. The fistula tract communicates
verticulitis develops. . from the umbilicus to the small bowel.
Differential Diagnosis. Esophageal diver- Demography. Umbilical fistulas account for
ticula are of three types: congenital ~rue divertic- 2 percent of vitelline duct anomalies.
ula, traction diverticula, and pulsion diverticula. Pathophysiology. The umbilical cord repre-
Congenital true diverticula are very rare and sents the fusion of the yolk sac containing the
involve all layers of the esophageal wall. Pul- vitelline duct and the body stalk with its paired
sion diverticula are herniations of the mucosa umbilical arteries, the umbilical vein, and the
through intrinsic defects in the muscular wall. allantois. It contains primitive mesenchymal
Traction diverticula result from adhesions be- tissue (Wharton jelly) and is covered by an outer
tween the esophagus and an external structure layer of amnion. Normally, the vitelline duct
leading to stretching of the external wall and obliterates between the 5th and 9th weeks of
diverticulum formation. Acquired diverticula intrauterine life. When it fails to obliterate, an
usually herniate through the circular part of the umbilical fistula results.
muscularis propria so that the protruding sac Clinical Features. Umbilical fistula manifests
is lined by mucosa and covered by submucosa with persistent umbilical drainage. Its diagnosis
,,. and longitudinal muscle. In contrast, congenital may not be apparent on physical examina-
diverticula usually contain a complete muscu- tion. A fistulogram to define the abnormality
laris propria. is helpful. A small catheter is inserted into the
Treatment and Prognosis. Diverticula usu- umbilical opening and a radiopaque dye is in-
ally do not require therapy unless they bleed jected. The diagnosis is confirmed when the dye
or become inflamed. Inflamed diverticula may is visualized in the lumen of the small bowel.
mimic appendicitis, bowel perforation, or intra- Gross Findings. See definition.
abdominal abscess . Symptomatic diverticula Differential Diagnosis. When the vitelline
require surgical removal. duct is only partially obliterated, a vitelline cyst

64
Congenital Gastrointestinal Abnormalities

or a vitelline sinus may result. These lesions are


illustrated in figure 2-25. Vitelline cysts are rare
but can present as umbilical masses. Vitelline
sinuses present with persistent umbilical drain-
age and are usually diagnosed in older children.
Injection of contrast material delineates a blind-
ending sinus.
Treabnent and Prognosis. Persistently drain- A. B. c.
ing lesions are resected.
Meckel Diverticulum
Definitions. Meckel diverticulum is a partial,
proximal, persistent omphalomesenteric or
J
vitellointestinal duct. A Meckel diverticulum
strangulated in an external hernia is known as
a Littre hernia.
Demography. Meckel diverticulum is the E.
1 F.
most common congenital gastrointestinal
Figure 2-25
anomaly, occurring in 1 to 4 percent of the
population. It affects males and females equally. VITELLINE DUCT ABNORMALITIES
Meckel diverticulum has a higher incidence in A: Meckel diverticulum is an outpouching of the bowel
patients with trisomy syndromes. (terminal ileum) toward the abdominal wall.
B: A fibrous band attaches a Meckel diverticulum to the
Associated Findings. Approximately 30 per- abdominal wall. This abnormality differs from A in that
cent of patients have other congenital anomalies there is a residual obliterated fibrous tract from the tip of
including TE fistula, microcolon, or duplications. the Meckel diverticulum to the area of the umbilicus.
Etiology. Early in fetal life, the intestinal tract C: Umbilical fistula (omphaloileal fistula or patent
Meckel diverticulum) in which the entire length of the
communicates with the yolk sac via the vitel- yolk sac fails to involute and remains patent, connecting
line or omphalomesenteric duct. Typically, this the ileum to the umbilicus.
duct detaches from the bowel before its physi- D: Vitelline (umbilica l) cysts are cystic structures
ologic herniation and then regresses before the separated by fibrous bands located between the anterior
abdominal wall and the terminal ileum. Vitelline cysts are
bowel returns into the abdominal cavity. By the also called enterocystomas and result from patency of the
7-mm developmental stage, the vitelline duct mid portion of the vitellointestinal duct while the proximal
atrophies, leaving only a residual fibrous cord, ileal or distal umbilical end involutes. The cyst may connect
which connects the bowel with the umbilicus. to the ileum or umbilicus with fibrous bands and usually is
located at any level between them.
Subsequently, this band is absorbed. When the E: Umbilical sinus is a residual sinus tract that com-
vitelline duct fails to obliterate, various vitelline municates from the anterior abdominal wall to the ileum. It
duct abnormalities develop (fig. 2-25) (138). extends at a variable depth into the abdominal wall or cavity.
These include persistent fibrous cord, entero- F: Umbilical polyp results from patency of the distal
umbilical end of the vitellointestinal duct. The umbilical
umbilical fistula, and Meckel diverticulum. polyp projects above the abdominal surface, frequently
The persistent fibrous cord extends from the with a central dimple or sinus that may extend to the
umbilicus to the bowel wall, the tip of a Meckel abdominal wall.
diverticulum, or the mesentery.
Clinical Features. Only 5 percent of patients
with Meckel diverticula are symptomatic. The intussusception, volvulus, adhesions, com-
most frequent manifestations include hemor- pression by a mesodiverticular band, tumor,
rhage and pain, usually resulting from peptic heterotopic tissue, enteroliths, bezoars, or an
ulceration secondary to coexisting heterotopic incarcerated Littre hernia. Impacted enteroliths
gastric mucosa. Diverticulitis can develop sec- cause diverticulitis, gangrene, and perforation.
ondary to peptic ulceration; obstruction of The pathogenesis of the diverticulitis resembles
the diverticular orifice can clinically mimic that seen in acute obstructive appendicitis. If
appendicitis. Intestinal obstruction results from the diverticulum ruptures, peritonitis will occur.

65
Gastrointestinal Diseases

Figure 2-26
MECKEL DIVERTICULUM
The bowel of an infant who
died with multiple other abnor-
malities. The Meckel diverticu-
lum points down toward the 6
o'clock position.

.
Occasionally, a small bowel barium study dem- Differential Diagnosis. Clinically, acute
onstrates a Meckel diverticulum. Meckel diverticulitis mimics acute appendicitis,
Gross Findings. A Meckel diverticulum varies Crohn's disease, or pelvic inflammatory disease.
in length from 1 to 26 cm. It always lies on the Treatment and Prognosis. A Meckel diver-
antimesenteric ileal border (fig. 2-26). Varia- ticulum has no clinical consequences unless
tions in size, location, and shape are common. complications develop (Table 2-1 0). These include
In infants, it usually lies 30 cm proximal to perforation, vesicodiverticular fistula, hemonhage,
the ileocecal valve; in the adult, ~t usually lies intussusception, volvulus, intestinal obstruction,
within 100 cm of the ileocecal valve. An apical and the development of inflamrnatmy pseudo-
fibrous band may connect the di~erticulum to tumors and true neoplasms (134,136). The tumors
the umbilicus. A Meckel diverticulum may also include carcinoid tumors, adenocarcinomas, and
connect to other intestinal loops or mesenter- stromal tumors. These are more frequently en-
ies via a congenital band or via adhesions from countered in males. Surgical resection is curative. If
previous episodes of diverticulitis. surgery is required for hemorrhage, the bleeding
Sometimes, a giant Meckel diverticulum de- ulcer may be near the base of the diverticulum
velops, resembling an enterogenous cyst (137). or in the adjacent ileum.
Such lesions are sometimes called omphalo-
mesenteric cysts. Table 2-10 lists some of the ANNULAR PANCREAS
other conditions that may be associated with Definition. Annular pancreas is a ring of
Meckel diverticula. pancreatic tissue surrounding the second part
Microscopic Findings. Typically, normal of the duodenum.
small intestinal epithelium lines the Meckel di- Demography. The incidence of annular
... verticulum, but heterotopic pancreatic, gastric, pancreas is 1/20,000 births .
duodenal, jejunal, or colonic tissue may also be Associated Findings. Annular pancreas may
present. The pancreatic tissue sometimes acts as be part of a more generalized embryogenic disor-
the lead point of an intussusception or it may der associated with tr·isomy 21, TE fistulas, or car-
cause obstruction. Heterotopic gastric mucosa dim·enal abnormalities (140). When diagnosed in
(fig. 2-27) leads to peptic ulceration, bleeding, infancy, 80 percent of patients have associated
or perforation, especially if oxyntic mucosa is anomalies; anomalies are only found in about 20
present. Helicobacter pylori may colonize the percent of adults with annular pancreas.
foveolar epithelium (135). Etiology. The etiology is unknown.

66
Congenital Gastrointestinal Abnormalities

Table 2-10
ABNORMALITIES ASSOCIATED
WITH MECKEL DIVERTICULUM
Ectopias Complications
Gastric mucosa Diverticulitis
Pancreas Bleeding
Colonic tissue Peptic ulcer
Obstruction
Tumors Intussusception
Carcinoid Volvulus
Smooth muscle Gangrene
Adenomas Perforation
Carcinomas
Lymphomas

Microscopic Findings. Although the loca-


tion of the pancreas is abnormal, the pancreatic
histology appears completely normal. The het-
erotopic tissue contains ducts, acini, and islets.
Secondary inflammatory changes occur if the
patient develops duodenal stenosis or peptic
ulceration.
Treatment and Prognosis. The prognosis of
adults with this lesion is excellent and the lesion
is resected when it becomes symptomatic. In
children, the prognosis depends on the associ-
ated abnormalities.
Figure 2-27 PERITONEAl ENCAPSUlATION
HETEROTOPIC GASTRIC MUCOSA Definition. Peritoneal encapsulation is the
IN MECKEL DIVERTICULUM
encasement of the intestines by a peritoneal
membrane.
Clinical Features. Annular pancreas either Etiology. Peritoneal encapsulation probably
presents in the neonatal period or in the 4th results when an accessory peritoneal membrane
and Sth decades of life (139,140). The clinical forms from the mesocolon during the return of
presentation may mimic gastric outlet obstruc- the intestinal loop to the abdomen following its
tion. The usual neonatal presentation is that of herniation into the umbilical cord (lOth fetal
congenital duodenal obstruction. The presenta- week). The dorsal mesentery covers most of the
tion in adults includes duodenal stenosis, peptic small intestine. It eventrates and moves coun-
ulcers, upper abdominal pain, and chronic pan- terclockwise, fusing with the posterior abdomi-
creatitis; the lesion may be found incidentally. nal wall. Alternatively, the accessory membrane
Peptic symptoms result from gastric stasis and forms from part of the yolk sac peritoneum as
antral overdistension due to the partial duode- it is drawn back into the abdominal cavity with
nal obstruction. The stasis and antral distension the intestine (141).
lead to hypergastrinemia, hyperchlorhydria, Clinical Features. Patients usually remain
and peptic ulceration. asymptomatic and the lesion is detected inci-
Gross Findings. Pancreatography may dem- dentally. Nevertheless, patients may present
onstrate pancreatic side-branches encasing the with cramps, obstruction, abdominal pain,
second part of the duodenum. Barium duo- vomiting, and constipation alternating with
denography is remarkable for showing a smooth diarrhea (141,142). Peritoneal encapsulation
stenosis in the second part of the duodenum. may mimic left mesocolic hernia.

67
, Gastrointestinal Diseases

Gross Findings. The entire intestine may be


encapsulated within a thin peritoneal sac. This
sac tends to be free and not adherent to the
mesentery. The encased intestinal loops often
have their own mesenteries.
Microscopic Findings. Peritoneal encap-
sulations can measure up to 20 cm. A thin
peritoneum-like sac encases the entire small
bowel. The histology of the encapsulated organs
is normal. The histology of the membrane is
that of a fibrous band.
Differential Diagnosis. The differential diag-
nosis includes sclerosing encapsulated peritoni-
tis, usually a complication of peritoneal dialysis
or other abdominal interventions. Sclerosing
and encapsulating peritonitis is characterized
by a thick, grayish white fibrous nrembrane Figure 2-28
covering the small intestinal wall. Peritoneal ENDOSCOPIC APPEARANCE OF INLET PATCH
encapsulation must also be differentiated from There is a flame-shaped area of mucosa that appears red
the abdominal cocoon in which the small and velvety in contrast to the smooth squamous cell lining.
bowel is found totally or partially curled up in
a concertina-like fashion and encased in a dense
white membrane.
Treatment and Prognosis. Sympromatic Gross Findings. Inlet patches lie in the
patients undergo resection of the encapsulated subcricoid, upper sphincteric region,.. usually
bowel. Prognosis is excellent. within 3 cm of the sphincter. Grossly and en-
doscopically, inlet patches are easily visualized,
HETEROTOPIAS well-defined patches of ovoid, velvety, reddish
Heterotopia, or ectopia, is the presence of mucosa with distinct borders (fig. 2-28). They
normal tissue lying in an abnormy l location. vary in diameter from a few millimeters to
The term heterotopia derives from the Greek complete esophageal encirclement (164) . Oc-
implying "other place." There are many forms casionally, the mucosa ulcerates.
of gastrointestinal heterotopia. The ectopic gastric mucosa is easily detected
on full column, single contrast radiologic ex-
Esophageal Inlet Patch
amination. The typical radiographic finding is
Definition. The term inlet patch refers to the a discrete shallow depression surrounded by a
presence of ectopic gastric epithelium lying in subtle rim-like elevation on single contrast im-
the subcricoid, upper sphincteric region of the ages or a pair of small indentations at the level
esophagus. Synonyms· include ectopic gastric of the thoracic inlet on the same wall on full
mucosa and heterotopic gastric mucosa. column single contrast images (163).
Demography. Inlet patch affects from 7.8 Microscopic Findings. Histologically, inlet
to 21.0 percent of the population (145), with patches consist of oxyntic mucosa containing
the highest incidence in the first year of life. A chief cells, parietal cells, endocrine cells, and
subsequent decline in incidence with age sug- foveolar cells (fig. 2-29). Inflammation, if pres-
gests that the lesions regress with time. ent, induces secondary proliferative changes
Etiology. Inlet patch represents the per- and glandular distortion. Large amounts of
sistence of fetal columnar epithelium in the lymphoid tissue accompany smaller lesions, as
cervical esophagus. compared to larger ones, suggesting that the
Clinical Features. Inlet patches are usually lymphocytes play a role in lesional regression
discovered incidentally at the time of endoscopy (164). H. pylori may colonize the heterotopic
for other reasons. gastric epithelium (146) .

68
Congenital Gastrointestinal Abnormalities

Figure 2-29
HI STOLOGIC APPEARANCE OF INLET PATCH
Left: The tissue resembles normal gastric oxyntic mucosa.
Right: Sometimes the surface glandular epithelium is replaced by squamous epithelium.

Treatment and Prognosis. No treatment is of fetal rectal endodermal cells, or proliferation


necessary for inlet patches, although compli- of pluripotential cells.
cations may require therapy. Postinflamma- Clinical Features. Heterotopic gastric epi-
tory changes include the presence of cervical- thelium often remains asymptomatic only to
esophageal webs (147), spontaneous TE fistula, be discovered incidentally during endoscopy,
or carcinoma (161). at the time of surgery for an unrelated prob-
lem, or at the time of autopsy. Heterotopic
Heterotopic Gastric Mucosa
small intestinal gastric mucosa is most often
Definition. Heterotopic, or ectopic, gastric mu- encountered when patients are evaluated for
cosa is the presence of gastric mucosa in sites upper gastrointestinal complaints. Symptoms
outside the stomach. are usually secondary to peptic ulceration due
Demography. Heterotopic gastric tissue is to the presence of oxyntic mucosa. The lesions
the most common large intestinal heterotopia cause obstruction, spontaneous fistulas, and
(166). It occurs alone or it complicates other intestinal intussusception (148,154). In the
congenital malformations, including duplica- rectum, heterotopic gastric mucosa presents as
tions, Meckel diverticulum, and heterotopic hemorrhoids, fissures, or fistulas, manifested by
pancreas. Ectopic gastric mucosa is most fre- proctitis, pain, rectal bleeding, and proctalgia.
quent in the duodenum and in Meckel divertic- Gross Findings. Gastric heterotopia may be
ulum (152), and rarely affects the rectum. Rectal a single or multifocal lesion. It is most com-
gastric heterotopias are associated with other monly seen in the duodenal bulb because of
congenital anomalies, including rectovesicle the frequency of upper endoscopy (fig. 2-30). It
fistula, incomplete colonic rotation, vertebral typically forms small nodules and polyps mea-
body defects, duplication, rectal diverticula, suring less than 1.5 cm in maximum diameter.
scoliosis, and megacolon (158). Giant heterotopic gastric polyps occasionally
Etiology. Congenital heterotopias result measure up to 4.5 cm (152) . Heterotopic foci
from cellular entrapment during embryonic are usually surrounded by normal-appearing
morphogenetic movement. The congenitally mucosa. The cut surface of the ectopic tissue
displaced tissues differentiate along the lines may appear solid or cystic. Larger lesions with
of normal organogenesis in response to local central depressions may mimic superficial ulcer-
environmental factors. Rectal gastric heteroto- ating cancers (167). Heterotopic gastric tissue in
pias result from developmental abnormalities of the rectum frequently lies in the posterolateral
foregut formation, ectodermal adhesion in the region, 5 to 8 cm from the anal verge. It may
3- to 4-week-old embryo, a differentiation error form intrarectal polypoid lesions (162).

69
Gastrointestinal Diseases

Microscopic Findings. Histologically, con- Duodenal biopsies typically demonstrate intact


genital gastric heterotopias are well-organized duocj.enal villi and Brunner glands interrupted
structures, more or less recapitulating the nor- by discrete masses of gastric glands covered by
mal oxyntic mucosal architecture (fig. 2-31). foveolar epithelium. Rectal heterotopic gastric
Thus, they contain chief cells, parietal cells, epithelium may coexist with ectopic respira-
and mucus-secreting epithelium, sometimes tory epithelium, presumably representing the
colonized by H. pylori. Ulcers, necrosis, and equivalent of the heterotopic foregut. Gastric
granulation tissue may develop in nearby tissue. mucosa may line rectal duplications and ectopic
salivary gland tissue may also be present. Rarely,
the ectopic tissue develops diseases resembling
those seen in the native stomach, sometimes
manifesting as a gastric hyperplastic polyp in
the duodenum.
Differential Diagnosis. The major entity in
the differential diagnosis is gastric metaplasia.
Distinguishing between the two is relatively
easy, since congenital tissue recapitulates nor-
mal structures (fig. 2-32). In contrast, meta-
plastic tissues usually consist of either foveolar
epithelium lining the superficial duodenal
epithelium or pyloric or antral glands lying in
the basal intestinal mucosa. Gastric mucosal
components, including surface, mucous neck,
and glandular epithelia, are not present in
metaplasias.
Treatment and Prognosis. Heterotopic gas-
tric mucosa does not require therapy unless the
lesions are large and cause obstruction. The le-
Figure 2-30 sion is usually encountered serendipitously dur-
HETEROTOPIC GASTRIC MUCOSA
ing the performance of endoscopic or barium
IN THE DUODENUM "'" studies. When complications develop from
Endoscopically, the heterotopic tissue presents as a small peptic injury, the affected bowel may need to
mucosal nodule. be resected.

Figure 2-31
HETEROTOPIC
GASTRIC MUCOSA
The tissue recapitulates
nor-mal gastric tissue. Glands,
usually of the oxyntic type, lie
deep in the mucosa. The surface
is cov-ered by foveolar type
gastric epithelium.

70
Congenital Gastrointestinal Abnormalities

Figure 2-32
COMPARISON OF CONGENITAL
GASTRIC HETEROTOPIA WITH
ACQUIRED FORMS OF
GASTRIC METAPLASIA
Left: In congenital gastric ectopia,
intact gastric mucosa is present in the
basal portion of the mucosa, complete
with parietal and chief cells. Foveolar
cells line the surface.
Right: In cases of gastric
meta-plasia, in contrast, there is
either foveolar metaplasia as in
peptic duodenitis or antral gland
metapla-sia as in cases of chronic
Congenital gastric Gastric metaplasia small intestinal or large intestinal
damage. There is no recapitulation
ectopia of the normal mucosa as there is in
con-genital gastric ectopia.

Heterotopic Pancreas
Gross Findings. Heterotopic pancreas is usu-
Definition. Heterotopic pancreas is pancreatic ally a well-demarcated, solitary, solid or cystic,
tissue lying outside the pancreatic bed. It lacks tan, lobular, submucosal mass. The lesion typi-
any anatomic or vascular connection to the cally measures 0.2 to 4.0 cm in diameter. Entry
eutopic pancreas. of single or multiple ducts into the gastric lumen
Demography. Gastric pancreatic heterotopia produces a symmetric cone or nipple-like pro-
is seen in 0.25 to 0.50 percent of abdominal pro- jection (fig. 2-33) or a central umbilication. Less
cedures and in 0.55 to 13.00 percent of autopsies commonly, multiple, polypoid or pedunculated
(144, 153). It is particularly common in patients pancreatic heterotopias are seen. Approximately
with autosomal trisomy, especially involving 75 percent of heterotopic pancreatic tissue lies
chromosomes 13 and 18. It is also associated in the submucosa; the remainder involves the
with gastrointestinal atresias, duplications, and muscularis propria.
other congenital malformations. Heterotopic Microscopic Findings. The histologic fea-
pancreas is most frequent in the stomach, duo- tures of heterotopic pancreas vary considerably.
denum, jejunum, or Meckel diverticulum; it is In its most classic form, it consists of lobu-
the most common congenital anomaly seen in lated pancreatic acini and ducts surrounded by
the gastric antrum. Esophageal involvement is concentric layers of longitudinal and circular
uncommon, and when it occurs, it usually af- muscle fibers (fig. 2-34). Islets are present in
fects the distal end. only approximately 33 percent of cases. Deeper
Etiology. Similar to gastric heterotopia. lesions tend to appear more disorderly. Blockage
Clinical Features. Most patients with het- of the ducts causes secondary cysts, pancreatitis,
erotopic pancreas remain asymptomatic; the bleeding, pseudocyst formation, fat necrosis, ab-
lesion is found ~ncidentally at the time of en- scess formation, and fibrosis secondary to leak-
doscopy, surgery, or autopsy. Symptomatic pa- age of proteolytic enzymes and acinar damage.
tients develop crampy abdominal or epigastric Secondary changes may completely distort the
pain or fullness. Weight loss, hemorrhage, and histology of the heterotopic tissue (fig. 2-35).
intussusception also occur. Secondary lesions, Microscopic Variants. Heterotopic Brunner
including pancreatitis or tumor development, glands and/or gastric glands can accompany
may lead to obstruction, bleeding, epigastric heterotopic pancreas.
pain, pseudocysts, mucoceles, or pseudotumors Differential Diagnosis. If only pancreatic
(155). Pancreatitis may be precipitated by biopsy acini are present, the lesion may represent foci
or manipulation of the heterotopic tissue. of pancreatic metaplasia, especially if the cells

71
Gastrointestinal Diseases

lie near the gastroesophageal junction. Le-


sions containing only ducts surrounded by
the circular and longitudinal muscle layers are
sometimes erroneously referred to as adeno-
myomas. The orderly arrangement of the two
muscle layers around the ducts, however, serves
to separate the two lesions.
Mucinous pools without obvious adjacent
pancreatic tissue are sometimes identified and
may suggest a diagnosis of colloid carcinoma.
In contrast to mucinous carcinoma, the muci-
nous extravasation associated with heterotopic
pancreas shows significant inflammation and
fibrosis without overt cellular anaplasia. A diag-
nosis of invasive cancer should not be made in
the absence of significant cytologic atypia and
evidence of stromal desmoplasia.
Treatment and Prognosis. Heterotopic
Figure 2-33 pancreas does not require treatment unless
ENDOSCOPIC APPEARANCE OF complications develop. The lesions are usually
HETEROTOPIC PANCREAS .. treated by local resection. Endocrine or glandu-
The lesion presents as a submucosal nodule, often lar neoplasms may develop in ectopic pancreas
covered by intact gastric mucosa .

B
~

r..· Figure 2-34


HETEROTOPIC PANCREAS
A: The heterotopic pancreas lies external to the bowel
wall on the serosal surface of the jejunum.
B: Small intestinal heterotopic pancreas consists mostly
of smooth muscle fibers and ductal epithelium. This lesion
lies close to the surface and represents one variant of
heterotopic pancreas.
C: Higher magnification of the heterotopic pancreatic
tissue found in the stomach illustrated in figure 2-33.

72
Congenital Gastrointestinal Abnormalities

Figure 2-35
HETEROTOPIC PANCREAS IN THE DISTAL ESOPHAGUS
A: The tissue is markedly inflamed and fibrotic. Ductal
structures are present, as are areas of inflamma tion and
h emorrhage.
B: In some areas, the tissue is so inflamed that th e histo-
logic identity of the tissue is obscured.
C: In some areas, all that is left of the h eterotopic
pancreatic tissue are residual islets.

(143,150,151). Neoplastic transformation is of the skin. The lesion is a developmental ab-


rare. If carcinoma develops, it usually forms an normality.
intramural mass with relatively late mucosal Heterotopic sebaceous glands are normally
invasion. As a result, the malignancy may be found incidentally at the time of endoscopy.
difficult to diagnose by endoscopic biopsy (150). They present as multiple, small, yellowish mu-
cosal plaques, typically affecting the middle or
Heterotopic Brunner Glands
distal esophagus. Histologically, normal mature
Heterotopic Brunner glands are Brunner glands sebaceous glands underlie a normal squamous
lying in locations other than their normal loca- mucosa (fig. 2-36). This lesion has no clinical
tion. Heterotopic Brunner glands are often asso- significance.
ciated with heterotopic pancreas or heterotopic
Heterotopic Salivary Glands
gastric mucosa.
Heterotopic lesions occur in the pylorus Heterotopic salivmy glands are salivary glands
and gastric antrum, and resemble heterotopic in sites other than their normal location. They
gastric or pancreatic tissue. Microscopically, the represent a congenital abnormality. The lesions
heterotopia may contain Brunner glands alone may arise from vestiges of the postanal gut.
or the glands may coexist with smooth muscle Seromucinous tissue resembling salivary
fibers and heterotopic gastric or pancreatic tis- glands can occur in the rectal submucosa, ei-
sue . Histologically, the heterotopia resembles ther alone or associated with retrorectal cystic
duodenal Brunner gland hyperplasia. The lesion hamartomas or gastric mucosa (159,160,165).
has no clinical significance. Rarely, heterotopic salivary glands present as a
perianal fibroepithelial polyp. The lesions often
Heterotopic Sebaceous Glands
contain both serous and mucinous glands, al-
Heterotopic sebaceous glands are sebaceous though pure mucinous lesions occur. The lesion
glands located at sites other than the surface has no clinical significance.

73
Gastrointestinal Diseases

Figure 2-36
HETEROTOPIC SEBACEOUS
GLANDS IN THE ESOPHAGUS
Biopsy of squamous lining
epithelium shows prominent
nests of sebaceous cells that
appear histologically normal.
The only abnormality is their
location.

uterine fundus and two smaller contiguous


Heterotopic Prostate ..
nodules resembling fallopian tube. It is unclear
Heterotopic prostate is prostatic tissue in sites whether this lesion represents a heterotopia or
other than the normal prostate. This ectopic a monodermal teratoma (156).
tissue may represent a metaplasia from endog-
enous urothelial epithelium (149) or it may MULLERIAN AND
result from faulty embryogenesis. The presence MESONEPHRIC DUCT REMNANTS
of aberrant mesenchymal prostatic rests may Miillerian duct remnants are embryologic rem-
induce the prostatic epithelium. nants of the mi.illerian system that lie in sites
The tissue consists of prostatic glimds, usually where mi.illerian tissue is not normally present
lying in the submucosa of the anal canal. This after birth. Mullerian remnants fail to involute
lesion has no clinical significance. following fetal development.
Usually these lesions are clinically silent.
Heterotopic Thyroid
They may become symptomatic when second-
Heterotopic thyroid tissue is thyroid tissue lo- ary changes, such as abscesses, develop in them
cated outside the normal thyroid gland. Ectopic (168). Small glands consisting of primitive miil-
thyroid tissue may occur in the esophagus. It lerian or mesonephric tissue are embedded in
has the appearance of normal thyroid tissue and other tissues, often in the muscular wall of the
has no clinical significance. rectum or anus. They occur in patients with
associated congenital abnormalities or in the
Ectopic Renal Tissue
absence of other changes. These morphologic
Ectopic renal tissue lies in the colonic wall curiosities have no clinical significance.
encroaching on the colonic surface epithelium
of patients with caudal regression syndromes. MICROGASTRIA
r. ,·

Ectopic tissue demonstrates a full developmen- Definition. Microgastria is a smaller than


tal range of renal differentiation, from undiffer- normal stomach. Synonyms include tubular or
entiated blastema to primitive or well-formed fetal stomach and gastric hypoplasia.
glomeruli and tubules (15 7). Demography. Microgastria occurs alone or
it coexists with other anomalies.
Ectopic Uterus
Associated Abnormalities. The many abnor-
A single patient was reported to have an malities that complicate microgastria are shown
intramural ileal mass that had features of the in Table 2-11 (170,171).

74
Congenital Gastrointestinal Abnormalities

Etiology. The lesion probably results from the Table 2-11


failed development of the dorsomesogastrium ABNORMALITIES ASSOCIATED WITH MICROGASTRIA
or lack of differential growth of the primitive
Atresia
foregut. One theory suggests that the origin of Esophageal
the microgastria-limb reduction complex relates Anal
to the process of twinning (170). The presence Intestinal
of holoprosencephaly indicates a severe defect Intestinal malrotation
of gastrulation/blastogenesis predominantly Cardiac anomalies
affecting the cephalad structures. Pulmonary anomalies
Clinical Features. Symptoms usually appear Skeletal anomalies
in infancy and include failure to thrive, frequent Central nervous system anomalies
vomiting, and recurrent aspiration pneumonia Asplenia
due to the presence of an incompetent lower Growth hormone deficiencies
esophageal sphincter. Diabetes insipidus
Gross Findings. The stomach appears small, Diaphragmatic hernias
tubular, and often nonrotated. As a result, the
Multicystic, dysplastic kidneys
stomach lies in the midline and the greater and
Psychomotor retardation
lesser curvature do not develop. The esophagus
Holoprosencephaly sequence
may appear grossly dilated (169).
VACTERL" association
Microscopic Findings. The entire gastric wall
appears hypoplastic, making it difficult to dis- Tvemark syndrome
tinguish between the cardia, body, and antrum. "VACTERL =vertebral defects, anal atresia, cardiac anoma-
lies, tracheoesophageal defects, renal dysplasia, limb
Differential Diagnosis. The differential di- defects.
agnosis includes the CAVE (cerebroacrovisceral-
Early) lethality phenotype and the Pallister-Hall
syndrome. Imperforate anus and anol·ectal malformation
Treatment and Prognosis. The underde- are terms for anorectal anomaly. The term ano-
veloped lower esophageal sphincter becomes rectal anomaly is generally a better term than
incompetent and gastroesophageal reflux, with the term imperforate anus because of the wide
all its attendant complications (see chapter 3), range of malformations present in this region,
develops. all of which result from abnormal urorectal
septal development.
ANORECTAL ANOMALIES Demography. Anorectal anomalies are com-
(MALFORMATIONS) mon congenital, occasionally familial, malfor-
There is a broad spectrum of anorectal mations with an incidence of approximately
anomalies. Typically both the rectum and anal 1/3,000 to 5,000 births. Males outnumber
canal are affected. The Santuli International females 1.3 to 1.0 and are more likely to have
Classification system, commonly used to clas- high lesions (178) . Intermediate anomalies
sify anorectal malformations, is based on the are rare and include anal agenesis, anorectal
location of the termination of the rectum in stenosis, and the rare anorectal membrane
relation to the levator ani muscles and the pu- situated above the cloacal membrane. In one
bococcygeal or ischial lines (Table 2-12) (196). study, high-type deformities accounted for 26
Malformations are classified as high (supraleva- percent of cases; intermediate, 10.7 percent; and
tor), intermediate, or low (translevator) (fig. low, 57.2 percent. The most frequent deformity
2-3 7), based on the position of the air-filled is male anocutaneous fistula followed by male
rectum in the lateral projection with the infant rectoureteral fistula, and female anovestibular
held upside down. This radiograph is referred to fistula (180).
as the Wangensteen-Rice invertogram. Seventy- Associated Findings. Most patients exhibit
five percent of low anomalies are associated with associated developmental anomalies affect-
a fistula from the rectal pouch to the perineal ing multiple systems, including the vertebrae,
skin just anterior to a covered anal dimple. intestines, urologic system, and genital system

75
Gastrointestinal Diseases

Table 2-12
INTERNATIONAL CLASSIFICATION OF ANORECTAL ANOMALIES
Anomaly Female Male
Low (translevator) 1. Normal anal site 1. Normal anal site
a) Anal stenosis a) Anal stenosis
b) Covered anus complete b) Covered anus complete
2. Perineal site 2. Perineal site
a) Anocutaneous fistula (covered anus a) Anocutaneous fistula (covered anus
incomplete) incomplete)
b) Anterior perineal anus b) Anterior perineal anus
3. Vulvar site
a) AnoVL!lvar fistula
b) Anovestibular fistula
c) Vestibular anus
Intermediate 1. Anal agenesis 1. Anal agenesis
a) Without fistula a) Without fistula
b) Rectovestibular fistula b) Rectobulbar fistula
c) Rectovaginal fistula (low)
2. Anorectal •stenosis 2. Anorectal stenosis
High (supralevator) 1. Anorectal agenesis 1. Anorectal agenesis
a) Without fistula a) Without fistula
b) With rectovaginal fistula (high) b) With rectourethral fistula (high)
c) Rectoljoacal fistula c) Rectovesicle fistula
2. Rectal atresia 2. Rectal atresia
Miscellaneous
Imperforate anal membrane
Cloacal exstrophy
Others

(182, 191). Congenital heart disease. and esopha- normalities account for most deaths. The type
geal atresia with tracheoesophageal fistula occur of reconstructive surgery performed and the
in about a third of patients. Intestinal atresias, resultant sphincteric function is determined
malrotations, duplications, annular pancreas, by the status of the levator ani muscle (194).
bicornuate uterus, vaginal atresia, septate va- Because anal sphincter function is normal in
gina, absence of the rectus abdominal muscle, low anomalies, infants with these have less mor-
omphalocele, and bladder exstrophy occur. Less bidity and better surgical results than those with
commonly, anorectal anomalies are part of a other anorectal abnormalities (186) . Higher
multiple complex malformation syndrome (Ta- lesions require a colostomy followed by ano-
ble 2-13). An association with VACTERL should rectal reconstruction and subsequent colostomy
be considered in any infant with an anorectal closure. Lesions not requiring a colostomy can
anomaly. Some congenital anorectal malforma- be repaired in the newborn period with good
tions have a strong association with sacrococ- functional results.
cygeal teratomas, lesions sometimes referred to
Low Abnormalities
as "hereditary presacral teratomas" (173,188).
'·· Etiology. Mutations in the putative zinc finger Definition. Low malformations are those
b:anscription factor gene SALLl cause the Townes- that occur below the level of the levator ani
Brock syndrome (183), an autosomal dominantly musculature. They include the ectopic (perineal,
inherited malformation syndrome characterized vestibular, or vulvar) anus, covered anus, imper-
by anal, renal, limb, and ear anomalies. forate anus, anal atresia, and cloacal exstrophy.
Treatment and Prognosis. Mortality in The designation of lesions as being "covered"
children with anorectal malformations usu- indicates that no opening is seen. They are
ally relates to concurrent disease and not to characterized by the confluence of the rectum,
the malformation itself. Renal and cardiac ab- vagina, and bladder in a urogenital sinus.

76
Congenital Gastrointestinal Abnormalities

Table 2-13
SYNDROMES ASSOCIATED WITH ANAL ATRESIA
Ritscher-Schinzel syndrome (cranio-cerebello-cardiac
syndrome)
Pallister-Hall syndrome
Autosomal inheritance
8. Hypothalamic hamartoma
Polydactyly
Imperforate anus
Laryngeal clefting
Other abnormalities
Currarino triad
Anorectal stenosis or other low type anorectal
malformations
Anterior sacral defect
D. Presacral mass (teratomas, meningoceles, dermoids,
enteric cysts)
Opitz syndrome (midline defects)
Hypertelorism
Hypospadia
Lip-palate-laryngeal clefts
Imperforate anus
Townes-Brocks syndrome
Anal malformation (imperforate anus, anteriorly
F. placed anus or anal stenosis)
Hand malformation (preaxial polydactyly, broad bifid
thumb or triphalangeal thumb)
External ear malformation (microtia, "satyr" or "lop"
Figure 2-37 ear, preauricular tags or pits)
ANORECTAL ABNORMALITIES Sensorineural hearing loss
Additional features may include urinary tract malfor-
Figures A, C, and E represent alterations in the male,
mations, mental retardation, and pericentric
while B, D, and F represent those in the female.
inversion of chromosome 16
A,B: In anal stenosis, the anal canal narrows but there
is a functional opening to the external environment. This VACTERL association
contrasts with the situation that occurs with complete Vertebral defects
atresia in the female in which there is no visible opening Anal atresia
to the distal portion of the gastrointestinal tract. Tracheoesophageal defects
C: Anorectal agenesis without fistula. Renal dysplasia
D: Anorectal agenesis with fistula to the female genital tract. Radial or limb defects
E: Anorectal agenesis with fistula to the genitourinary
system.
F: In contrast to B, there is no external opening of the
anorectal region to the external environment.

Demography. Low malformations more often Etiology. Low anomalies result from incom-
affect males than females. Rarely, the abnormali- plete or inappropriate development of the anal
ties affect families (193). A true imperforate anus canal and anal membrane coupled with promi-
or membranous anal atresia with the persistence nent genital folds that contribute to the covered
of the anal membrane is rare (184, 186) and a appearance of the anus. Imperforate anus results
significant association exists between anal atresia from failure of the cloacal membrane to perfo-
and parental consanguinity. Cloaca exstrophy rate. The anomaly originates during the 6th to
is the most severe degree of imperforate anus, 8th week of embryonic development and results
affecting approximately 1/50,000 births. from detained ingrowth or an inadequate mi-
Associated Lesions. Patients with imperfo- gration in the rectal segment of hindgut. There
rate anus may have an associated neuropathic is often a history of maternal drug use and a
bladder (189), deafness (185), and rectal and paternal history of exposure to an occupational
sigmoid atresias (179). hazard. Chromosomal abnormalities associated

77
- Gastrointestinal Diseases

above it (9 percent) (172,173,182,184,188) . Fis-


tulas form between the rectum and some part
of the urogenital system, especially in type 3
and 4 imperforate anus. In .males, the fistulas
tend to be urinary (urethra, 25 percent; blad-
der, 33 percent; or perineal, 42 percent) and in
females, rectourinary or rectogenital (vaginal,
84 percent; perineal, 14.5 percent; and urinary
bladder, 1.5 percent). Rarely, the rectum opens
into the scrotum, the undersurface of the penile
shaft, or the prepuce (181).
In some low abnormalities, including ectopic
anus, the anus opens anterior to its normal posi-
tion, sometimes within the vulva. The ectopic
anorectum lies below the puborectalis muscle. A
congenital rectovestibular or rectovaginal fistula
opens into the vagina or the vulva but above the
puborectalis muscle (190) . In a related anomaly,
the covered anus, a bar of skin, derived from the
lateral genital folds, covers the anal canal. An
anocutaneous fistula passes anteriorly from the
Figure 2-38
anal canal to the exterior at the perineal raphe.
IMPERFORATE ANUS A misplaced external sphincter with conjoined
The anal orifice is completely covered . There is no fibers inserted behind the elongated, ventrally
evidence of an anal opening.
angulated terminal canal can functionally ob-
struct fecal passage even in patients with an
with imperforate anus include small deletions adequate anal canal and anal orifice.
of chromosome 13 (q32.2qter) and 13 (q32q34) Microscopic Findings. At first glance, it
(174), partial monosomy 10q, and partial tri- appears as though organs associated with
somy 9q (195). ..,. anorectal atresia are normal; however, careful
Clinical Features. Mothers of children with investigation of the entire thickness of the wall
anal atresia are more often likely to have threat- shows that oligoneuronal hypoganglionosis
ened abortion, oligohydramnios, and polyhy- of the myenteric plexus proximal to the anal
dramnios than other women. Cloacal exstrophy floor is present in 12 percent of patients and
is a complex spectrum of malformations and other patients may demonstrate defects in the
in the past was uniformly fatal. In addition to muscularis propria. The latter are characterized
imperforate anus, these babies have an ompha- by hypoplasia of the circular muscle layer and/
locele, two exotropic bladders between which or internal anal sphincter. Intestinal neuronal
there is an open cecurh, and a blindly-ending dysplasia of the submucosal plexus is frequently
colon hanging down in the pelvis from the ce- observed (12 percent) in high type anal atresia.
cum. The genitalia are ambiguous and most of The histologic changes in neuromuscular struc-
these children are raised as females. The urinary ture confined to the high type anal atresia are
' •' and gastrointestinal systems must be surgically not seen in intermediate or low types. Overall,
separated to insure survival. anomalies of the enteric nervous system are
Gross Findings. There are four types of im- present in 60 percent of anal atresias (187) .
perforate anus: 1) stenosis alone (11 percent); Treatment and Prognosis. Females with
2) imperforate anus with only a thin membrane cloacal anomalies must be recognized at birth
separating the anus and rectum (4 percent); 3) so that urologic evaluation can be performed.
imperforate anus with a widely separated anus Hydrocolpos and obstructive uropathy are
and rectum (76 percent) (fig. 2-38); and 4) nor- common and warrant urgent decompression
mal anus with the rectum ending some distance of the urinary tract with a vaginostomy and/or

78
Congenital Gastrointestinal Abnormalities

vesicostomy as well as a colostomy. It is also im- Fascicles of the pubococcygeus and the external
portant to recognize precursors to renal insuffi- sphincter become displaced laterally.
ciency including renal agenesis, renal dysplasia,
High (Supralevator) Abnormalities
and vesicoureteral reflux since their presence
mandates early consultation with a pediatric Definition. High malformations are the most
urologist. The morbidity and mortality associ- common anomalies seen in males. They are asso-
ated with the renal lesions often exceed that of ciated with a rectourethral fistula in males and a
the imperforate anus. Spinal cord anomalies are rectovaginal fistula in females. Sphincteric func-
also common and can be found in patients who tion is abnormal and there is a high frequency of
hav:e normal plain films and low defects. Spinal other malformations. High abnormalities include
ultrasonography or MRI should be performed in primitive cloaca, cloacal persistence, rectocloacal
all neonates to rule out occult spinal pathology fistula, and anorectal agenesis.
such as a tethered cord or lipoma of the cord. Etiology. Anorectal agenesis is a relatively
Early evaluation of patients with imperforate primitive defect reflecting a cloaca that has not
anus leads to the development of a carefully yet divided into separate urinary and alimentary
thought out plan which sets the stage for the canals. Rectal atresia is thought to occur as a re-
best possible outcome in later life. sult of vascular injury during fetal life. An intact
sphincter is usually present (186). Trisomy 4 is
Intermediate Abnormalities
found in some fetuses with anal atresia along
Definition. In intermediate anomalies, the with other congenital abnormalities.
blind segment ends at the level of the levator Gross Findings. In anorectal agenesis, the
ani muscle and at the level of a line joining the rectum reaches the upper surface of the pelvic
ischial tuberosities (the ischial line) (194). They floor, but the musculature of the entire anal
include anal agenesis with and without fistula canal and pelvic floor is absent and the rec-
and anorectal stenosis. The fistula can be recto- tum ends above the levator muscle. There is
bulbar in males, rectovestibular or rectovaginal a single external opening into which a short
in females. The internal sphincter is absent and urethra opens anteriorly and the rectum opens
the external sphincter is poorly formed in both posteriorly. The rectum opens into a posterior
sexes. Anal agenesis, anal stenosis, and anal canal urethra or bladder in males and into a posterior
agenesis are types of intermediate anomalies. vaginal fornix in females. In girls, failure of the
Demography. Although intermediate agen- mullerian systems to fuse normally creates two
esis affects both sexes, most cases occur in males uteri that open into the globular cloacal cav-
(194) . ity. A fistula enters either the dorsal wall of the
Etiology. Intermediate anomalies are thought cloaca or the caudal end of the septum between
to occur as a result of vascular injury during the bifid urogenital sinus portion of a double
fetal life. vagina. High rectovaginal fistulas usually near
Gross Findings. Intermediate abnormalities the anterior fornix; may also be present.
include stenoses in the upper end of the anal Variations of rectocloacal and rectovaginal
canal. The terminal bowel appears ectatic and fistulas ofthe high type are encountered (192).
thickened (17 5, 177), and a shortened anal canal Confusion centers around rectocloacal fistula
lies within the levator diaphragm. formation. In some cases, the cloaca appears to
In males, there is a clear separation between directly communicate with the vagina whereas
muscle fibers running toward the pubis and in others it appears to be a direct continuation
others running toward the perineal body and of the urethra. If a single peritoneal opening
bulbocavernosus muscle ventrally. Striated drains all of these viscera, it satisfies the criteria
muscle fibers of the pubococcygeus muscle are for a cloacal opening and any such pattern is
associated with the bowel wall. Fibers of the regarded as a rectocloacal fistula. In boys, the
puborectalis may be present dorsally and later- orifice of rectourethral fistulas appears quite
ally (17 6). Girls with a rectovestibular fistula large and a catheter passed through the urethra
lack the perineal body (central tendon), which usually enters the rectum rather than the blad-
normally lies between the rectum and vagina. der. The bowel usually terminates in a fistula

79
Gastrointestinal Diseases

to the lower third of the prostate in males, required for fully developed caudal dysplasia
although it may end blindly. syndrome; these may both be related to HLA -DR
Anal agenesis contrasts with anal atresia in genes (206,211,213).
that the rectum ends blindly above the level of Associated Findings. A~sociated anomalies
the pelvic floor. The anal canal appears anatomi- include meningomyelocele, anal and genital
cally normal. defects, absent fibula, and short femora. The
Microscopic Findings. The histology of the upper limbs are rarely involved. Congenital
organs is normal. anomalies of the heart and great vessels may
Treatment and Prognosis. A series of be present as may TE fistula (210). The most
planned surgeries may be required. A divert- extreme form of caudal dysplasia has associated
ing colostomy is followed by a pull-through sirenomelia (203,205,212).
procedure (anorectoplasty). Patients with low Etiology. The etiology and pathogenetic
anomalies achieve early continence while those mechanisms are poorly understood.
with high anomalies seldom do by school age. Gross Findings. Anal malformations are a
prominent component of the constellation of
THYMIC-RENAL-ANAL-LUNG DYSPLASIA abnormalities in caudal dysplasia, including
Thymic-renal-anal-lung dysplasia i-s a newly complete covered anus with or without fistula
described autosomal recessive error of early mor- formation and rectal atresia (205).
phogenesis. The patients present with a syndrome Microscopic Findings. Microscopic foci of
characterized by a unilobed or absent thymus, ectopic renal tissue encroach on the colonic
renal and ureter agenesis/dysgenesis~ and intra- surface epithelium in some patients. The renal
uterine growth retardation. Patients may also have tissue demonstrates a full developmental range,
an imperforate anus and a unilobed lung. from undifferentiated blastema to both primi-
Theories to explain the occurrence .of these tive and well-formed glomeruli and tubules.
developmental abnormalities include an autoso- Differential Diagnosis. Some o~per syn-
mal recessive inheritance and an unrecognized dromes that closely resemble caudal dyspla-
chromosomal imbalance. Renal, anal, and lung sia fall under the general heading of familial
dysplasia is present in three syndromes: Fraser- sacral dysgenesis. These include the Ashcraft
Jacquier-Chen (198), Pallister-HaH (199), and syndrome of familial hemisacruin (200) and
Smith-Lemli-Opitz II (197) syndromes. the Cohn-Bay-Nielsen syndrome of familial
The disease is detectable prenatally by the hemisacrum (200,202) .
presence of progressive oligohydramnios and Animal Models. Rumplessness, a condition
intrauterine growth retardation. Also seen are similar to caudal dysplasia, develops in chick
a unilateral echogenic cystic mass in the renal embryos who receive insulin (207). Studies in
fossa and low amniotic fluid disaccharidases in fetal rats suggest that fetal insulin production
association with an imperforate anus. may play a role in the genesis of sacral defects
(204). Administration of retinoic acid induces the
CAUDAL DYSPLASIA caudal regression syndrome in fetal mice (208).
Definition. Caudal dysplasia, also known as
caudal regression syndrome, consists of devel- ANORECTAL CYSTS
opmental anomalies at the caudal vertebrae, Definition. The nature and etiology of devel-
neural tube, urogenital and digestive organs, opmental anorectal cysts remain controversial.
and hind limbs, the precursors of which derive Some represent sequestered duplications; others
r.,·
from the caudal eminence. are considered to represent a form of teratoma;
Demography. Caudal dysplasia is associated still others are thought to arise from embryonic
with maternal diabetes or prediabetes (201, remnants of the postanal segment or tailgut
209), suggesting that the syndrome results from (215a,225). Anorectal cysts include cystic ham-
the presence of insulin antagonists (214) . The artomas, tailgut cysts, enteric cysts, and retrorec-
disease sometimes affects siblings. A combina- tal cyst-hamartomas (215a,216,218-220,228).
tion of the diabetic trait and unrelated genetic Demography. Anorectal cysts are uncom-
factors that encode skeletal differentiation is mon. They affect females more commonly

80
Congenital Gastrointestinal Abnormalities

than males, and they often coexist with other cate with the gut and are separated from it by a
congenital abnormalities, particularly spina dense fibrous connective tissue stroma.
bifida (209). The age distribution ranges from Microscopic Findings. Histologically, squa-
· the neonatal period to 73 years. mous, transitional, simple, mucinous, and cili-
· Associated Findings. Anorectal cysts may be ated columnar epithelia line the cystic spaces
associated with intraspinal and postsacral cysts. (fig. 2-39). All gastrointestinal epithelial types
Etiology. Anorectal cysts result from: 1) rem- (fetal and adult) can be found in these lesions.
nants of the caudal-postcloacal hindgut located There is usually some columnar or cloacogenic
within the embryonic tail, 2) cloacal rests, 3) type epithelium. They are surrounded by a
sequestered rectal duplication, or 4) nemo- muscle layer of varying thickness and degree of
enteric fistulas associated with sacral anomalies completeness, as seen in duplications. Such le-
or intraspinal cysts. sions also often contain heterotopic tissue such
Clinical Features. Anorectal cysts present as as pancreas or gastric tissue, similar to that seen
retrorectal or posterior anal masses in children in duplication cysts. Inflammation is present in
and young adults. Developmental cysts grow approximately half of the lesions.
slowly and frequently remain as asymptomatic Anorectal cysts may contain isolated smooth
lesions unless they enlarge, in which case they muscle bundles but a clearly defined wall of
cause sensations of pressure, fullness, constipa- smooth muscle is usually absent. A double
tion, urinary and/or fecal incontinence, and muscle layer (circular and longitudinal) is absent
perineal pain and numbness; they may cause and there is no submucosal or myenteric neural
pain in the rectal area or low back and the pain plexus. The cysts may be lined by a variety of
may occur during defecation. In symptomatic epithelial types, including ciliated columnar,
patients, the lesion averages 4.6 cm and in the mucin-secreting columnar, transitional, and
asymptomatic patients, 3.2 cm. When retrorec- squamous epithelia (223). Squamous epithelium,
tal developmental cysts become infected, retro- when present, has been attributed to metaplasia
rectal abscesses and anal fistulas form (215a). and the presence of inflammation but it may also
They may also manifest as obstructive extrinsic occur in infants without inflammation (215) sug-
rectal masses (216,218,221,222,224,227). gesting differentiation toward anal epithelium.
Gross Findings. Developmental cysts lie be- Differential Diagnosis. Anal developmental
tween the coccyx and the rectum. They range cysts differ from duplication cysts in that the
in size from 2 to 23 cm, with an average diam- musculature of duplication cysts appears much
eter of 3.9 cm. On barium exam they appear more orderly than the haphazard muscular ori-
as smooth eccentric masses that deform the entation seen in anorectal developmental cysts.
posterior rectal wall. Approximately half are They differ from retrorectal teratomas in that
multicystic and half are unilocular. Cysts that they lack all three germ cell layers; benign retro-
derive from the hindgut are large and unilocular rectal cystic teratomas should only be diagnosed
while those derived from tailgut remnants are when there is evidence of differentiation into
usually small, multilocular, and associated with all three germ cell layers (225). The differential
satellite cysts (223). The lesions are usually cir- diagnosis also includes chordoma.
cumscribed but unencapsulated. The cyst fluid Treatment and Prognosis. Anorectal cysts
varies from clear, thin, and colorless to opaque, can give rise to adenocarcinomas (217,225) and
brown, and pasty. The cysts do not communi- neuroendocrine carcinomas (226).

81
Gastrointestinal Diseases

Figure 2-39
RETRORECTAL CYSTS
A: Low-power magnification shows a cystic structure
deep in the wall of the rectum. ..
B,C: Higher magnification shows that ·it is lined by
cuboidal type epithelium.

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89
..r

'-··
3 DISEASES OF THE ESOPHAGUS

GENERAL PATHOLOGIC FEATURES Demography. The prevalence of patients


Since the esophagus responds to different with symptoms associated with GERD (heart-
types of injury in the same way, regardless burn or acid regurgitation) ranges from 40 to
of the cause, identical histologic features are 45 percent in the United States and Canada (9,
present in esophagitis of diverse etiologies. 24,38). Frequent symptoms (at least once per
Therefore, determination of the specific cause week) are reported by 20 percent of the general
of the esophagitis may be difficult unless there population (24). The incidence of GERD is lower
is a specific infection, in which case an etiologic in Eastern than in Western countries (7), but is
agent is identified. In general, esophagitis causes rising (34). Endoscopic evidence of esophagitis,
variable degrees of inflammation, epithelial ne- esophageal erosion, or ulceration is present in
crosis, and regeneration. Mild esophageal injury one third to half of patients with symptoms
results in mild reversible mucosal changes with (7,27,32,43). GERD affects more men than
transient inflammation, as well as the presence women, and men are more likely to develop
of balloon cells, vascular dilation, and infiltra- extensive erosive esophagitis.
tion of the epithelium by inflammatory cells, GERD is also common in children and rep-
particularly mononuclear cells and eosinophils. resents a frequent reason for pediatric patients
More severe damage results in epithelial destruc- to be referred to a gastroent~rologist (6). GERD
tion, in either the form of erosion, a superficial is particularly common in children with neuro-
lesion involving only the mucosa, or an ulcer logic or psychiatric disorders, or in those with
that extends deeper into the lamina propria or congenital esophageal or gastric abnormalities
submucosa. Neutrophils may be identified if (10,13,16). Cystic fibrosis predisposes to severe,
ulcers or erosions are present. With time, the complicated GERD.
damaged epithelium becomes hyperplastic, as In adults, predisposing conditions include in-
evidenced by basal cell hyperplasia and papil- creased intraabdominal or intragastric pressure
lary elongation. Patients with chronic damage as a result of pregnancy, ascites, obesity, or mo-
extending into the submucosa or beyond may tility disorders (23,25). GERD also complicates
develop submucosal fibrosis, sometimes with acquired structural abnormalities, including
stricture formation. Distal esophagitis in the hiatal hernias. Patients who undergo prolonged
absence of identifiable microorganisms most periods of recumbency (ventilator dependent,
likely results from gastroesophageal reflux. stroke, and immobile nursing home residents)
are prone to reflux esophagitis.
REFLUX ESOPHAGITIS Pathophysiology. GERD is a multifactorial
Definition. The term gastroesophageal reflux process with different abnormalities predomi-
refers to retrograde flow of gastric and some- nating in different patients (Table 3-1) (4,5,12,
times duodenal contents into the esophagus. 14,20,26). Factors predisposing to GERD include:
The term gastroesophageal reflux disease (GERD) 1) decreased esophageal sphincter pressure; 2)
describes the spectrum of clinical conditions diminished esophageal clearance secondary to
and histologic alterations resulting from gastro- defective esophageal peristalsis; 3) delayed gastric
esophageal reflux. Reflux esophagitis describes a emptying or abnormal gastric contractility; 4)
type of GERD with histopathologic esophageal decreased salivary flow; and 5) increased gastric
changes. Alkaline reflux refers to reflux of duode- acid production. Transient relaxation of the
nal contents and implies incompetence of both lower esophageal sphincter (LES) (a physiologi-
the pyloric and the gastroesophageal sphincters. cal occurrence in normal individuals) allows

91
Gastrointestinal Diseases

Table 3-1
CAUSES OF, OR PREDISPOSITION TO,
GASTROESOPHAGEAL REFLUX

Abnormal lower esophageal sphincter position or


pressure
Hiatus hernia
Certain foods, drinks
Alcohol
Smoking
Smooth muscle medications
Iatrogenic destruction of lower esophageal sphincter
Pregnancy
Motility disorders
Figure 3-1
Zollinger-Eliison syndrome
REFLUX ESOPHAGITIS
Decreased esophageal mucosal resistance secondary to
Infections Yellowish bile crystals are present in this biopsy specimen
Prior chemotherapy from a patient with reflux of duodenal and gastric contents
Nasogastric intubation into the esophagus.
Gastric outlet obstruction
Refluxed duodenal contents markedly risen. These opposing time trends
Esophageal or gastric structural abnormalities suggest that gastritis secondary to Helicobacter
pylori infection protects against GERD (7,16).
This hypothesis is consistent with geographic
reflux to occur (41). Esophageal dysmotility and ethnic distributions of GERD. Case control
contributes to poor clearance of the refluxed studies also indicate that patients with erosive
material, thereby leading to an increased esophagitis are less likely to have active or
mucosal contact time. With persistent reflux, chronic corpus gastritis than controls without
esophageal motor function becomes increas- esophagitis (8,32). The mechanism underly-
ingly abnormal, leading to further deterioration ing the "protective" effect of H. pylori on the
of LES pressure. Once esophagitisrdevelops, LES esophagus is likely related to its effect on gastric
pressure becomes further impaired, increasing acid output: patients with extensive H. pylori-
acid exposure in the distal esophagus. associated corpus gastritis have lower gastric
A mechanically defective LES, increased acid outputs than those without gastritis affect-
esophageal acid exposure time, and frequent ing the corpus of the stomach (6). As a result,
suboptimal peristaltic esophageal contractions esophageal acid load is reduced, and patients
during supine, upright, and meal periods cor- do not develop GERD (despite the fact that they
relate with the severity of the mucosal injury. may still have gastroesophageal reflux) (15).
The nature and amount of refluxed material Clinical Features. Adults. Patients with GERD
and the length of ti~e the refluxate remains present with diverse symptoms including epigas-
in contact with the esophageal mucosa also tric pain, pharyngeal burning, nausea, vomiting,
determine whether disease develops. Acid alone heartburn, regurgitation of gastric contents re-
causes relatively few changes. When combined sulting in a bitter tasting fluid into the mouth,
'"·' with pepsin, bile acids, or trypsin, however, dysphagia, hypersalivation, atypical intermittent
more severe damage results (11,36). Bile acids chest pain, hiccups, odynophagia, and globus
and trypsin are present if the refluxate contains sensation (21,29,35). Occasional patients pres-
duodenal contents (fig. 3-1). ent with angina-like chest pain (39); others
During the past three decades, hospital dis- present with pulmonary or pharyngeal symp-
charges and mortality rates of patients with toms, including hoarseness, coughing, asthma,
gastric cancer, gastric ulcer, and duodenal ulcer or recurrent pulmonary complaints (33). These
have declined, while those of patients with symptoms may be experienced daily, weekly, or
esophageal adenocarcinomas and GERD have only several times a month. The frequency and

92
Diseases of the Esophagus

Esoph.ageal
ulceration

Figure 3-2
REFLUX ESOPHAGITIS: ENDOSCOPIC APPEARANCE
Left: The esophageal mucosa appears diffusely erythematous with foci of h emorrh age.
Right: Long-standing reflux esophagitis with ulceration and stricture formation.

severity of symptoms from gastroesophageal or pneumonia caused by repeated episodes of


reflux do not correlate with the morphologic pulmonary aspiration. Severe dental caries are
changes seen in the esophageal mucosa (18,31). common. The best test for diagnosing and quc:m-
Some patients develop complications, in- tifying GERD in children is 24-hour esophageal
cluding erosions or ulcers, strictures, Barrett pH monitoring.
esophagus, and cancer. The symptoms associ- Gross and Endoscopic Findin gs. The gross
ated with esophageal peptic ulcers resemble appearance of the esophagus varies with disease
those associated with gastric or duodenal peptic severity. Areas of erythema and longitudinal
ulcers, except that the pain usually localizes to red streaks in the distal esophagus are the first
the xiphoid or high substernal region. Peptic endoscopic abnormalities. In severe reflux, the
stricture or peristaltic dysfunction causes pro- esophagus appears friable, diffusely reddened,
gressive dysphagia (17). Esophagitis may cause and hemorrhagic (fig. 3-2) . Mucosal erosions,
massive, but usually limited, hemorrhage. ulcerations, intramural thickening, strictures,
Children. Gastroesophageal reflux is common or Barrett esophagus are characteristic of severe
in infants, and is probably physiological, usually chronic disease. Most erosions and ulcers occur
resolving spontaneously (37). In such preverbal distally, tapering off proximally. Inflammatory
children, the classic adult history of heartburn polyps may be present at the Z-line margin.
cannot be elicited. General symptoms include Strictures develop close to the gastroesophageal
regurgitation, prolonged crying and irritability, junction or immediately proximal to a hiatus
vomiting, apnea, asthma, choking, stridor, and hernia.
respiratory distress. Older children may experi- Microscopic Findings. There are four stages
ence heartburn, dysphagia, odynophagia, night of reflux esophagitis: 1) acute (necrosis, inflam-
walking, hoarseness, chronic cough, and asthma mation, and granulation tissue); 2) repair (basal
(3). The most frequent complication of recur- cell hyperplasia and elongation of the papillae);
rent GERD is failure to thrive, resulting from 3) chronic (fibrosis and formation of Barrett
caloric deprivation and recurrent bronchitis esophagus); and 4) complications (dysplasia and

93
' Gastrointestinal Diseases

Table 3-2
HISTOLOGIC FEATURES OF REFLUX ESOPHAGITIS
Balloon cells
Basal zone hyperplasia (>15% to 20% of total epithelial
thickness)
Basal layer spongiosis (edema)
Nuclear enlargement
Mitoses in basal cell layer
Elongated papillae (>75% of total epithelial thickness)
Venular dilatation
Intraepithelial eosinophils
Increased intraepitheliallymphocytes
Polymorphonuclear leukocytes Figure 3-3
Erosions or ulcers, if severe
REFLUX ESOPHAGITIS
The superficial squamous epithelial cells demonstrate
hydropic degeneration in this case of severe gastro-
esophageal reflux disease.
adenocarcinoma). Repetitive episodes of tissue
destruction and healing produce histologic
features that reflect disease activity at the time Capillary ectasia affects up to 83 percent of
of examination, superimposed on those from GERD patients contrasting with its presence
previous injury. Biopsies are performed to con- in only 10 percent of control patients (2, 13).
firm the presence of esophagitis, to determine This change is often present in the absence
its nature (e.g., peptic- versus drug-induced) of any inflammation and corresponds to the
and severity, and to rule out the presence of endoscopically identified red mucosal'streaks.
a coexisting infection, such as Candida, cyto- Intercellular Edema (Spongiosis). Intercellular
megalovirus, or herpesvirus (particularly in im- edema often results from acid reflux. It is usu-
munosuppressed patients); Barrett. esophagus; ally most prominent in the basal layers, often in
or tumor development. Esophagitis can heal the absence of inflammation. The intercellular
completely or progress to any of tlie complica- fluid accumulation may make the intercellular
tions discussed below. bridges unusually prominent (fig. 3-4).
Since the histologic features of GERD are Epithelial Hype1plasia. Normally, the basal
not specific, several histologic features must be layer is only 1 to 4 cells thick and occupies less
assessed before a presumptive diagnosis can be than 15 percent of the squamous epithelial
made (Table 3-2). In addition, it is important thickness. Prolonged bathing of the esopha-
to be aware of the clinical and drug history of geal mucosa with acid accelerates mucosal cell
the patient. shedding and results in compensatory basal
Balloon Cells. BallOOTl cells are swollen, pale, cell hyperplasia. As a result, the basal cell lay-
globoid, periodic acid-Schiff (PAS)-negative ers increase in thickness (fig. 3-5). Since normal
cells with irregular pyknotic nuclei that develop individuals have mild epithelial hyperplasia 2
in the epithelial mid-zone (fig. 3-3). They are to 3 cm proximal to the LES, this feature is not
present in approximately two thirds of GERD useful in diagnosing GERD if biopsies are taken
•.· cases. Balloon cells develop in any damaged in this area. In contrast, epithelial hyperplasia
mucosa but in the absence of other more char- occurring 3 cm or more proximal to the Z line
acteristic features of GERD, they may be the is sufficient to suggest the diagnosis of reflux
only clue that a chemical injury has occurred. esophagitis (18) . Basal cell hyperplasia is most
Vasmlar Changes. Capillary ectasia (sometimes easily appreciated when these layers exceed
called vascular lakes) consists of dilated and con- 25 percent of the mucosal thickness. Stromal
gested venules located high in the lengthened papillae lengthen (fig. 3-5). The lamina propria
esophageal papillae. Red blood cells frequently papillae often extend into more than two thirds
extravasate into the surrounding epithelium. of the mucosal thickness. Riddell (27) suggests

94
Diseases of the Esophagus

Figure 3-4 Figure 3-5


REFLUX ESOPHAGITIS REFLUX ESOPHAGITIS
The squamous epithelium shows evidence of spongiosis, The squamous epithelium shows mild basal hyperplasia
making intercellular bridges appear prominent. and elongation of the papillae. In this case, the papillae reach
upward to approximately two thirds the epithelial thickness.
The surface squamous cells show ballooning change.
using the rule of thirds to evaluate the mucosa
for evidence of hyperplasia. This rule divides
the full epithelial thickness into thirds. Papillae
should not extend into the upper third. When
the lower third is divided in half, the basal cells
should be confined to the lower half; extension
beyond this is abnormal.
Regenerating basal epithelium is character-
ized by nuclear enlargement, hyperchromasia,
and mitotic figures in the basal cell layers (fig.
3-6). (Mitoses are rare in the normal, nonin-
jured esophageal mucosa.) Nucleoli may also be
prominent. The hyperplastic regenerating cells
lack the normal glycogenation characteristic
of superficial cells. Therefore, PAS stains show Figure 3-6
expanded PAS-negative areas.
REGENERATIVE SQUAMOUS EPITHELIUM
When the epithelium becomes very hyper- IN GASTROESOPHAGEAL REFLUX DISEASE
plastic, the elongated epithelial pegs extend
The squamous cells appear atypical with enlarged, but
deep into the underlying lamina propria, regular, nuclei and prominent nucleoli. The nuclear to
producing the lesion known as acanthosis. Ex- cytoplasmic ratio, however, is not increased to the degree
tensive acanthosis, also termed pseudoepithelio- seen in neoplasia, and there is normal maturation of the
matous hype1plasia, may mimic invasive cancer, squamous cells toward the mucosal surface. Despite the
cytologic atypia, the nuclei do not overlap, and normal
especially when the cells exhibit severe cyto- polarity is maintained.
logic atypia. Atypical cells have cytoplasmic
basophilia, an increased nuclear to cytoplasmic
ratio, glycogen depletion, and increased mitotic occurs in the more superficial cell layers. The
activity. The uniformly sized cell nuclei may individual cell keratinization characteristic of
contain prominent nucleoli. The reactive cells high-grade dysplasia is absent. The epithelial-
more or less maintain their normal polarity, the stromal boundary appears smooth, with an
nuclei generally do not overlap, and abnormal obvious basement membrane, unless extensive
mitoses are absent. Squamous cell maturation inflammation is present. The lamina propria

95
- Gastrointestinal Diseases

Figure 3-7
REFLUX ESOPHAGITIS Figure 3-8
The squamous epithelium contains an increased number
REFLUX ESOPHAGITIS
of intraepitheliallymphocytes. These appear as elongated
"squiggle" cells. Scattered intraepithelial eosinophils are often seen in
reflux esophagitis.

and submucosa may become very inflamed and averaging more than 6 cells per high-power
isolated reactive epithelial cells can drop into a field (22). Most intraepitheliallymphocytes are
severely inflamed and ulcerated stroma.-Desmo- CD3-positive T cells and a smaller proportion
plasia, however, should not be seen surrounding are S-100 protein-positive antigen-presenting
the epithelial cells. Antibodies to cytokeratin cells (42) .
may help distinguish a truly invasive cancer Intraepithelial eosinophils are considered by
from reactive endothelial cells in the underly- many to be the single most specific diagnostic
ing stroma. Such immunoreactioris should be feature of reflux esophagitis, as shown by esoph-
carefully interpreted since reactive..stromal cells ageal pH monitoring (1,19,43) . Their presence is
are occasionally cytokeratin positive. not a sensitive marker, however, since they are
Very small or poorly oriented biopsies, espe- seen in only 40 to SO percent of symptomatic
cially those with significant inflammation and individuals (fig. 3-8), and they can be found in
associated reactive atypia, may be impossible to control patients and occasionally in any of the
interpret. In this situation, repeat biopsies may entities listed in Table 3-3. Intraepithelial eo-
be necessary once the reflux has been treated. sinophils may be focal, necessitating a search for
Inflammation. Small numbers of lymphocytes them on serial sections and in multiple levels.
and plasma cells typically populate the normal There is also a group of patients with eosino-
esophageallamina pro'pria; their presence does philic esophagitis who have large numbers of
not establish a diagnosis of esophagitis. Mucosal eosinophils and no evidence of reflux by pH
lymphocyte numbers (intraepithelial and in the monitoring studies. It is important to note that
lamina propria) are conspicuously increased, in many cases, eosinophils are absent in biopsies
however, in patients with GERD. Intraepithelial with other features of GERD.
lymphocytes have been referred to as "squiggle Neutrophils, in either the squamous epithe-
cells" or "cells with irregular nuclear contours" lium or in the lamina propria, serve as evidence
because of their curved nuclei, which appear to of acute erosive or ulcerative esophagitis. Large
fit between the epithelial cells (fig. 3-7). They collections of neutrophils suggest that a biopsy
have almost no visible cytoplasm. Intraepithe- comes from an ulcer or an erosion. Although
lial lymphocytes are present in esophagitis of neutrophils provide evidence of erosions or ul-
diverse etiologies, but they are often present cers, they are not specific for GERD-associated
in large numbers in reflux esophagitis (42), esophagi tis. ·

96
Diseases of the Esophagus

Table 3-3 Table 3-4


DIFFERENTIAL DIAGNOSIS OF DIFFERENTIAL DIAGNOSIS OF
ESOPHAGEAL EOSINOPHILIA GASTROESOPHAGEAL REFLUX DISEASE

Primary disorders Infections


Eosinophilic esophagitis Fungal
Atopic Viral
Nonatopic Drug effects
Familial Azidothymidine (AZT)
Secondary eosinophilic disorders Chemotherapy (mucositis)
Hypereosinophilic syndrome Pill esophagitis
Eosinophilic gastroenteritis Caustic ingestion
Secondary noneosinophilic disorders Radiotherapy
Gastroesophageal reflux disease Systemic diseases
Parasitic infection Allergies
Fungal infection Behcet's disease
Recurrent vomiting Graft versus host disease
Drug-induced injury Crohn's disease
Inflammatory bowel disease Progressive systemic sclerosis
Esophageal leiomyomatosis Other collagen vascular diseases
Allergic vasculitis Eosinophilic gastroenteritis
Periarteritis nodosa Uremia
Scleroderma
Neoplasia Trauma

Multinucleated Epithelial Giant Cells. Multi- in those patients with intestinal metaplasia in
nucleated giant squamous epithelial cells with the cardia and elsewhere in the stomach (14).
histologic features simulating a viral cytopathic Differential Diagnosis. The histologic fea-
effect or dysplasia are seen in patients with tures discussed in the preceding sections suggest
many forms of esophagitis, including reflux the diagnosis of GERD, especially in the distal
esophagitis. Typically, the multinucleated cells esophagus, but none are specific for this entity
have a mean of 3 nuclei/cell (ranging from 2 to since they represent the pattern of response of
9) and there are typically 2 to 11 cells/biopsy. stratified squamous epithelium to diverse inju-
The nuclei may contain a single or multiple ries. Entities to be considered in the differential
eosinophilic nucleoli with a perinuclear halo diagnosis of GERD include those listed in Table
but the cells lack inclusions, hyperchromasia, 3-4. Reactive changes in biopsies from patients
or atypical mitoses. The giant cells are generally with GERD may appear so atypical that the differ-
confined to the basal epithelium, although occa- ential diagnosis includes malignancy. Similarly,
sionally they occur more superficially. Following when extensive pseudoepitheliomatous hyper-
treatment, these cells disappear (30). plasia is present, the question of an invasive car-
Carditis. Biopsies obtained from the cardiac cinoma or squamous dysplasia arises. The base of
mucosa immediately distal to the Z line in pa- ulcers may contain bizarre cells that mimic an in-
tients with GERD often contain large numbers vasive carcinoma. Granulation tissue, if present,
of acute or chronic inflammatory cells, even may contain prominent capillaries with enlarged
in areas appearing endoscopically normal. The endothelial cells that mimic an adenocarcinoma.
inflammation is limited to the gastric cardia in In patients with acquired immunodeficiency
the absence of similar changes in the remaining syndrome (AIDS), the lesion may resemble Ka-
stomach (27). Carditis may be a more sensitive posi's sarcoma. Marked lymphoid hyperplasia
marker of GERD than inflammation involving may simulate a lymphoma (28) .
the squamous mucosa as judged by pH moni- Immunohistochemical stains using antibod-
toring studies. This is a controversial subject, ies directed against endothelial and epithelial
however, with some believing that carditis is cells distinguish between the reparative reac-
associated with H. pylori infection, especially tions and malignancy. The presence of isolated

97
Gastrointestinal Diseases

cytokeratin-positive cells strongly suggests the toms are severe in children, gastroesophageal
presence of an invasive cancer, especially if the fundoplication and/or pyloroplasty may allevi-
cytokeratin-positive cells demonstrate signifi- ate the symptoms.
cant nuclear atypia and lie within a desmoplas- Complications of GERD range from superfi-
tic stroma. It is important to note that reactive cial erosion or deeper ulceration to transmural
mesenchymal cells are sometimes cytokeratin inflammation, circumferential fibrosis with
immunoreactive. · stricture formation and fixation to surrounding
The differential diagnosis of GERD with structures, development of Barrett esophagus,
ulcers or erosions includes infection, drug reac- and cancer.
tion, and many other entities. Patients whose
biopsies show significant atypia and irregular BARRETT ESOPHAGUS
epithelial nests, in a setting of severe inflamma- Definition. Banett esophagus (BE) is defined
tion, may need to have the diagnosis deferred endoscopically as visible columnar epithelium
until the inflammation subsides. in the esophagus which, on biopsy, is meta-
Treatment and Prognosis. Only a small pro- plastic columnar epithelium as defined by the
portion of patients with heartburn see a physi- presence of acid mucin-containing (Alcian
cian; the majority choose to self meeicate with blue-positive) goblet cells (68). Long segment
proprietary medications. Investigation is neces- BE is esophageal columnar mucosa with intesti-
sary in those with long-standing symptoms (to nal metaplasia located 3 cm or more proximal to
rule out Barrett esophagus), those with symp- the esophagogastric junction. Short segment BE
toms unresponsive to therapy, or-- those who is the presence of tongues and/or circumferen-
have alarming features (dysphagia, vomiting, tial columnar-appearing mucosa less than 3 cm
blood loss, or weight loss). Treatment depends above the proximal margin of the gastric folds.
on disease severity. Generally, therapy-is aimed A diagnosis of BE cannot be made without the
at reducing the reflux, enhancing esophageal identification of intestinal metaplasia .on biopsy
clearing, and minimizing the aggressive impact specimens obtained from the areas of suspected
of the refluxed material. Mild symptomatic esophageal columnar mucosa.
GERD is usually managed by lifestyle and di- Demography. Most cases of BE in the gen-
etary modifications along with treatment with eral population are unrecognized~ The clinical
antacids, H2-receptor antagonists, or proton prevalence is 22.6 cases/100,000 population and
pump inhibitors (40). Antacids, Gaviscon, and is much lower than the autopsy prevalence of
motor-stimulating drugs may be sufficient to 376/100,000 (59). The discrepancy may relate to
treat patients without histologic evidence of the fact that up to one third of patients do not
esophagitis who have occasional low-grade have reflux symptoms at the time of diagnosis
heartburn. Pro kinetic drugs are used to increase and many patients do not seek medical advice for
LES tone, enhance gastric emptying, and im- their hecutbum. Additionally, patients have access
prove peristalsis, thereby counteracting some to over-the-counter antacid drugs. BE develops in
of the abnormalities that lead to esophagitis. approximately 10 to12 percent of patients with
Once erosive or ulcerative lesions have GERD (66,69,71,77). The mean age at which BE
developed, more rigorous medical treatment, is diagnosed is approximately 60 years (56). Dis-
including the use of proton pump inhibitors, is ease incidence plateaus by age 70. Children also
mandatory. Patients with intractable symptoms develop this lesion (53,5 7). BE preferentially affects
require more intensive pharmacologic therapy, white males, and is less common in African-
often utilizing combination medications with Americans and Asians (49,61,70).
frequent dosing or antireflux surgery. Mechani- Etiology. BE results from the reflux of gastric
cal dilatation of strictures may relieve symptoms acid, bile salts, lysophospholipids, and activated
but if this is not possible, then surgery may pancreatic enzymes (70,72,77,78). It may also
become necessary. Prolonged reflux may cause accompany lye ingestion (71) or treatment
esophageal shortening which may dictate the with some chemotherapeutic agents . There
type of procedure necessary, should surgery be may be a genetic predisposition to developing
required to control symptoms. When the symp- BE (48,52,59).

98
Diseases of the Esophagus

Pathophysiology. BE may be viewed as an


adaptive response in which stratified squamous
epithelium is replaced by potentially acid-
resistant columnar epithelium (70). Recurrent
ulceration denudes the normal squamous epi-
thelium, which then becomes lined by colum-
nar epithelium. This columnar epithelium arises
from multipotential stem cells lying in the basal
mucosa. It is presumed that there is a neoplastic
progression that occurs in BE which goes from
chronic gastroesophageal reflux to esophagitis
to the presence of metaplastic columnar epithe-
lium. Dysplasia develops within this, followed
eventually, in some cases, by adenocarcinoma.
Clinical Features. The symptoms associated
with BE resemble those of the underlying re- Columnat··
flux esophagitis: heartburn, regurgitation, and
dysphagia. Many patients with BE are asymp-
tomatic (55,67). Strictures causing dysphagia
may develop, usually at the junction of the dis-
placed squamocolumnar junction. The advent
of dysphagia must be aggressively investigated
in order to differentiate between a peptic origin
and the onset of neoplasia. Unfortunately, the
presenting symptom of BE may be the develop-
ment of an adenocarcinoma.
Gross and Endoscopic Findings. Beefy red,
velvety areas lie proximal to the end of the gas-
tric folds. BE extends proximally in a continuous
sheet, as a circumferential lesion, in finger-like
or flame-like projections, or as isolated islands
in the tubular esophagus (fig. 3-9). These areas
contrast with the lighter pink-tan or white, Figure 3-9
smooth, native squamous epithelium. Distally,
BARRETT ESOPHAGUS
BE merges imperceptibly with the native gas-
Top: Endoscopically, a salmon-colored tongue of Barrett
tric mucosa. The junction with the esophageal mucosa extends upward into the esophagus. The adjacent
squamous epithelium may appear symmetric squamous epithelium is whitish tan.
or asymmetric, or as islands of normal mucosa Bottom: Resection specimen has a similar appearance.
alternating with BE. Short (less than 2 cm) Reddish columnar mucosa extends into the esophagus.
tongues of BE are most common in short seg-
ment BE. Island type BE accompanies less severe white" squamous epithelium. Discrete islands
epithelial injury than the circumferential type. of pink epithelium are sometimes seen. The
Biopsy Evaluation. The combination of mucosa may appear somewhat atrophic, similar
endoscopy and biopsy is the gold standard for to that seen in atrophic gastritis, with vessels
the diagnosis of BE. The mucosal changes are visible through the columnar lining. A finely
measured with respect to the gastroesophageal nodular or mammillary appearance has also
junction, which is usually recognized by the been described (73, 74).
proximal extent of the gastric folds (62,73,74). The suggestion of BE on endoscopic ex-
The columnar segment is described by terms amination prompts multiple biopsies to prove
including "salmon-pink tongues" and "flame- the diagnosis and exclude the possibilities of
like extensions" into the surrounding "pearly dysplasia and malignancy. The latter are not

99
Gastrointestinal Diseases

at pH 2.5 (fig. 3-10). The pattern of sulfomucin


staining may show a selective association with
dysplasia and adenocarcinoma (58,60, 78). The
columnar epithelium resembles either small
intestinal absorptive cells (complete intestinal
metaplasia) or colonic epithelium (incomplete
intestinal metaplasia). BE sometimes acquires a
villiform surface architecture.
The recent identification of intestinal meta-
plasia in the cardia, along with the observation
that it occurs in an inflamed cardiac mucosa, has
led to focus on the type and the condition of
the mucosa at the gastroesophageal junction and
its relationship to GERD. Specialized intestinal
metaplasia at the cardia is only found in inflamed
cardiac mucosa and its prevalence increases both
• with increasing acid exposure and the presence
of esophagitis. Intestinal metaplasia in the car-
dia is histologically indistinguishable from the
specialized metaplasia of BE (58). It could be
argued that it makes little difference whether
the specialized columnar epithelium lies in the
gastric cardia or in the distal esophagus, since
both conditions predispose patients to tumors
arising at the gastroesophageal junction (SO).
Figure 3-10 The incidence of adenocarcinoma of both the
BARRETT ESOPHAGUS esophagus and the gastric cardia has increased
The Alcian blue stain (pH 2.5) highlights the intestinal at a rate far exceeding that of any .other cancer
type mucin present in the goblet cells of intestinal (45,46) and short segments of intestinal metapla-
metaplasia in Barrett esophagus. Goblet cells stain blue, sia at the gastroesophageal junction may underlie
while the gastric foveolar type mucin staiii"s pink.
this phenomenon. Since cancer of the cardia and
cancer arising in typical BE share some demo-
seen endoscopically. Tytgat (7 4) suggests four- graphic features and predisposing factors, these
quadrant biopsies be taken every 2 cm of the two diseases may be related (51). Intestinal meta-
columnar lining, whereas Nishimaki (63) be- plasia detected in a biopsy, regardless of whether
lieves that the area just above the endoscopi- it comes from the cardia or from the esophagus,
cally obvious columnar segment must always serves as a marker of a cell population at risk
be biopsied carefully because it is a high-risk of neoplastic transformation. A conservative
zone for dysplasia and' malignancy. Additional approach would suggest that surveillance of
sampling of any associated elevated lesions or patients with intestinal metaplasia arising at
strictures must be done. Chromoendoscopy this site be undertaken until the controversy
(coating the esophagus with various dyes to surrounding this issue is settled by better data.
•.· identify BE/dysplasia) is also a useful tool. Diagnostic problems in BE include the pres-
Microscopic Findings. The current defini- ence of columnar epithelium in the esophagus
tion of BE requires intestinalized (specialized) which may be normal, and the fact that not
mucosa to be present, even if only a single bi- all goblet-shaped cells are metaplastic as evi-
opsy is examined. Such specialized epithelium denced by Alcian blue positivity, not all Alcian
is characterized by the presence of goblet and blue-positive cells are metaplastic, and the sig-
intestinal columnar cells (fig. 3-10). The goblet nificance of a few metaplastic epithelial cells is
cells contain acid mucins, predominantly sialo- unknown. Although distended gastric foveolar
mucins, which stain positively with Alcian blue cells may acquire a goblet cell shape (fig. 3-11),

100
Diseases of the Esophagus

Figure 3-11
BARRETT ESOPHAGUS
A: True intestinal metaplasia is seen on the left, and distended foveolar cells mimicking goblet cells on the right.
B: Higher-power view shows dystrophic foveolar cells. The mucin in the foveolar cells appears eosinophilic.
C: In contrast, the mucin in the goblet cells has a bluish tinge.
D: An Alcian blue stain may aid in differentiating between dystrophic foveolar cells and goblet cells. The goblet cells on
the left stain strongly, while the distended foveolar cells on the right appear light pink and unstained.

true goblet cells generally have a bluish appear- ing for cytokeratins (CK) 7 and 20, designated
ance with routine hematoxylin and eosin (H&E) as the Barrett CK7 /20 pattern, is sensitive and
stains, whereas dystrophic foveolar cells usually specific for the diagnosis of long segment BE
are deeply eosinophilic. Such cells are often when compared to the diagnosis of gastroin-
Alcian blue negative; it is important to note, testinal metaplasia (64). A strong band of CK20
however, that reactive gastric surface cells may staining is seen in the superficial portion of the
sometimes stain with Alcian blue (fig. 3-12). mucosa in BE; CK7 stains the epithelium dif-
Special Techniques. Cytokeratin immuno- fusely. In contrast, gastric intestinal metaplasia
reactivity patterns may be useful in the diag- shows patchy CK20 staining throughout the
n osis of short segment BE. Cytokeratins are full thickness of the mucosa, and an absence
epithelial structural proteins that comprise the of CK7 staining. A Barrett CK7 /20 pattern is
cytoskeleton of human cells. They preferentially present in 98 percent of patients with long
stain different types of epithelia. In the context segment BE (65) and in 82 percent of patients
of esophageal disease, a unique pattern of stain- with suspected short segment BE, whereas none

101
Gastrointestinal Diseases

Table 3-5
DIFFERENTIAL DIAGNOSIS OF BARRETT MUCOSA
Inadvertently sampled gastric mucosa (especially in
hiatal hernias)
Esophageal junctional mucosa
Cardiac-like mucosa located in distal 1-2 cm
Esophageal superficial cardiac glands
Often located in upper esophagus
Ectopic gastric fundic mucosa
Noted in upper esophagus of 4-10% of normal subjects

.•
peutic strategies is to eliminate the abnormal
epithelium and remove the risk of progression
Figure 3-12 to malignancy. Laser photoablation is emerg-
ing as a popular treatment method, although
BARRETT ESOPHAGUS
strictures or mediastinitis may occur. The most
Foveolar cells sometimes demonstrate Alcian blue
positivity, as illustrated here. Cells that do not mor-
striking patterns of squamous reepithelializa-
phologically resemble goblet cells should not be interpreted tion are seen in patients treated with photody-
as such on the basis of the Alcian blue stain alone. namic therapy. These patients develop extensive
squamous metaplasia deep within the Barrett
glands, with squamous epithelium overlying
of the patients with gastrointestinal metaplasia the columnar epithelium (44). Unfortunately,
have this pattern. This suggests that a Barrett a significant discrepancy exists between the
CK7 /20 pattern is an objective marker of Barrett endoscopist's assessment of squamous reepi-
mucosa in conjunction with appropriate clinical thelialization and the histologic findings in the
and endoscopic data (65). biopsy samples from these cases (44) .
Differential Diagnosis. The differential di-
agnosis of BE is listed in Table 3-5 : EOSINOPHILIC ESOPHAGITIS
Treatment and Prognosis. A,...major mile- Definition. Eosinophilic esophagitis is a form
stone in the management of patients with of esophagitis characterized by a prominent
BE and reflux esophagitis has been medical intraepithelial eosinophilic infiltrate.
management with proton pump inhibitors Demography. Patients with eosinophilic
and prokinetics. The proton pump inhibitors esophagitis (also referred to as idiopathic eosino-
reduce gastric acid output and also the volume philic or allergic esophagitis) are typically young
of the refluxate. Laparoscopic antireflux surgery males, but the disease affects both sexes and all
also may be appropriate for patients with BE ages. Symptoms include vomiting, epigastric or
(75). Management of BE involves treating the chest pain, dysphagia, and respiratory obstruc-
underlying reflux and monitoring the risk of tive problems (83,87). Many patients have a
adenocarcinoma. The current standard is to history of atopic disease (86).
treat all patients with BE with the most potent Etiology. The cause of eosinophilic esopha-
antisecretory medication available (currently, gitis is poorly understood, but is most likely
proton pump inhibitors), even if asymptomatic. associated with food allergy (84). Most affected
•.·
In some cases, BE has the potential to revert patients have clinical evidence of food and
to normal if the acid reflux is treated (47,54), air-borne allergen hypersensitivity (80). In ad-
although this is rare (76). When regression has dition, many patients report seasonal variation
occurred, squamous epithelium typically over- in their symptoms (84).
lies the columnar epithelium, especially near Gross and Microscopic Findings. Histologi-
the area of the squamocolumnar junction. cally, esophageal biopsies demonstrate epithe-
Various ablative techniques for eradicating lial hyperplasia and extensive infiltration of the
BE are being explored. The aim of these thera- mucosa by eosinophils (fig. 3-13) . Eosinophils

102
Diseases of the Esophagus

Figure 3-13
EOSINOPHILIC ESOPHAGITIS
Left: Eosinophilic esophagitis with marked basal hyperplasia and papillary elongation.
Right: On higher power, numerous intraepithelial eosinophils are seen (over 20 per high-power field).

Table 3-6
FEATURES DISTINGUISHING EOSINOPHILIC ESOPHAGITIS AND GASTROESOPHAGEAL REFLUX DISEASE (GERD)

Typical Features Eosinophilic Esophagitis GERD


Clinical
Presence of atopy Very common Normal (possibly in creased)
Sex preference Male Slight m ale
Abdominal pain, vomiti n g Common Common
Food impaction Common Uncommon
Endoscopic Findings
Endoscopic furrowing Very common Occasionally
pH probe Usually norm al Abnormal
Histologic Findings
Proximal involvement Yes No
Distal involvem ent Yes Yes
Epithelial hyperplasia Markedly increased Increased
Number of eosinophils >20/hpf' 0-7 /hpf
Eosinophils in clusters Scattered eosin ophils, n o clusters
"hpf = high-power field.

generally number in excess of 20 to 24 per diagnostic dilemma. The differential diagnosis


high-power field (83,85). In contrast, GERD is usually centers around reflux esophagitis, para-
characterized by lower numbers of intramucosal sitic infection, drug reactions, or eosinophilic
eosinophils, usually 7 or fewer per high-power esophagitis. The esophagus normally does not
field. Seven to 20 eosinophils per high-power contain any eosinophils, and therefore, their
field may be indicative of a combination of GERD identification represents a pathologic accumula-
and food allergy (85,86). The features that are tion in this site (80,85) . Esophageal eosinophilic
helpful in distinguishing eosinophilic esopha- disorders can be classified as primary or second-
gitis and GERD are summarized in Table 3-6. ary. Primary disorders are further categorized
Differential Diagn osis. Eosinophilic infil- into those that are associated with atopy, those
trates of the esophageal wall commonly pose a that are unassociated with atopy, and those that

103
Gastrointestinal Diseases

are familial. Secondary disorders may occur with


or without a coexisting systemic eosinophilic
disease. The differential diagnosis of esophageal
eosinophilic infiltrates is listed in Table 3-3.
Treatment and Prognosis. The treatment of
patients with eosinophilic esophagitis includes
avoidance of known specific food and airborne
allergens in atopic patients. In cases where
dietary changes are ineffective, an elemental
diet may improve symptoms (81). Administra-
tion of systemic or topical steroids may also
be of benefit (79,82). Gastric acid should be
neutralized, even in patients without GERD
(84). If left untreated, eosinophilic esophagitis
may progress, resulting in chronic scarring and
Figure 3-14
esophageal stricture formation. The risk for the
development of BE is unknown. • BACTERIAL ESOPHAGITIS
Large clusters of bacteria lie in the esophageal lumen
ESOPHAGEAL INFECTIONS and within the squamous epithelium. In addition, scattered
organisms invade the underlying tissues.
Because of the increased use of steroids, cy-
totoxic drugs, and other immunosuppressive
agents, as well as the increase in human im- most common infecting organisms are normal
munodeficiency virus (HIV)-associated disease flora of the mouth and upper respiratory tract.
worldwide, the prevalence of opportunistic in- Gross and Microscopic Findings. Grossly,
fective esophagitis has increased. The presence bacterial esophagitis features nonspe.cific mu-
of underlying GERD or an anatomic abnormal- cosal friability, plaques, pseudomembranes, and
ity may further predispose a patient to develop ulcerations. Histologically, bacterial infections
infectious esophagitis. As the population ages, produce a diffuse, acute necrotizing process
host defense mechanisms deteriorate, predis- characterized by the presence of an intense
posing elderly patients to infect!,ous diseases. neutrophilic exudate, cellular necrosis, and
Esophageal infectious diseases are discussed in degeneration. Sheets of bacteria (highlighted
detail in chapter 10. by Gram stains) invade the underlying tissues
(fig. 3-14). Often, several bacterial species are
Bacterial Esophagitis
present, supporting the polymicrobial nature
Clinical Features. Esophageal bacterial in- of the infections. The total number of bacteria
fections are uncommon and generally occur appears to be inversely related to the intensity
either in profoundly neutropenic patients or of the accompanying inflammation (89).
as a result of extension of an infection from
Tuberculosis
an adjacent structure. The pathogenesis of
bacterial esophagitis often involves a previous Clinical Features. Individuals at risk for
esophageal injury that damaged the integrity developing esophageal tuberculosis include im-
of the squamous mucosal barrier. Such injuries migrants from and natives of underdeveloped
r. ,·
include previous reflux esophagitis, radiation, countries and immunocompromised patients.
chemotherapy, or nasogastric intubation. Dis- Esophageal tuberculosis usually represents
ruption of the mucosal barrier allows bacteria a secondary manifestation of the disease in
to easily invade the underlying lamina propria, patients with primary pulmonary, intestinal,
especially in immunologically deficient indi- laryngeal, or mediastinal tuberculosis. Hema-
viduals. Other predisposing factors include togenous spread of miliary tuberculosis occurs
defective peristalsis, mechanical obstruction, less commonly than mediastinal extension.
ethanol abuse, ulceration from pills sticking in Patients present with dysphagia resulting from
the esophagus, or congenital abnormalities. The extrinsic esophageal compression by enlarged

104
Diseases of the Esophagus

Figure 3-15
TUBERCULOUS ESOPHAGITIS
A typical granuloma with central necrosis is seen.
(Courtesy of the Division of Gastrointestinal Pathology,
Armed Forces Institute of Pathology, Washington, DC.)
Figure 3-16
HERPES ESOPHAGITIS
Endoscopic view of a well-demarcated area of ulceration.

mediastinal lymph nodes. Rupture of medias-


tinal disease into the esophagus causes fistula
formation between the tracheobronchial tree
and the esophagus. ence of a viral infection, it qm be confirmed by
Gross and Microscopic Findings. Grossly, an ancillary technique such as immunohisto-
the lesions appear ulcerative, hyperplastic (pseu- chemistry or in situ hybridization.
dotumoral), or both (88). An esophageal mucosal Herpes Esophagitis. Clinical Features. Typical
biopsy might not yield relevant diagnostic tissue herpetic esophagitis, as seen in the immuno-
in patients with esophageal tuberculosis because compromised patient, presents with the acute
the esophagus is usually involved by direct exten- onset of odynophagia, fever, and retroster-
sion of mediastinal or thoracic disease; therefore, nal pain. When severe, herpetic esophagitis
a biopsy may not be deep enough to provide may cause hemorrhage (91). The disease also
diagnostic material. When the diagnosis is clear, develops in immunocompetent individuals,
the histologic features of tuberculosis resemble usually as a result of reactivation of latent viral
those seen elsewhere in the gastrointestinal tract, infection. Herpes esophagitis also occurs in
with the presence of caseating granulomas con- children and neonates. In neonates, the disease
taining epithelioid histiocytes, giant cells, and is acquired as an intrauterine, intrapartum, or
acid-fast bacilli (fig. 3-15). postnatal infection (93).
Gross and Microscopic Findings. The esophagus
Viral Esophagitis
is involved in about 90 percent of patients with
Viruses commonly infect the esophageal visceral herpes; the distal half is the most com-
mucosa, especially in immunocompromised monly affected region. Early in the course of
patients. It is important to recognize these infec- herpes infection, vesicular lesions develop on the
tions so that they can be treated appropriately. squamous mucosal surface. Because the vesicles do
It is also important not to overdiagnose viral not last long, the presence of isolated or confluent
infections so that needless, potentially harm- ulcers is a more common finding. The discrete,
ful drugs will not be administered. Pseudoviral "punched-out" ulcers have white exudates cover-
inclusions associated with nuclear pyknosis and ing their bases and erythematous or yellow raised
intranuclear cytoplasmic inclusions develop in margins (fig. 3-16). Typically, the ulcers appear
degenerating cells. If doubt exists as to the pres- shallow, even in extensive disease.

105
Gastrointestinal Diseases

Figure 3-17
HERPES ESOPHAGITIS
Left: Low-power view of reactive-appearing squamous epithelium and granulation tissue adjacent to an ulcer.
Right: Higher-power view of the squamous epithelium shows cells with typical herpesvirus inclusions. Many cells are
multinucleated and the nuclei are molded to one another. The nuclei appear glassy with marginated chromatin.

sions. Multinucleate syncytial squamous cells


contain molded nuclei and a typical "ground
glass" appearance (fig. 3-17). In immunocom-
petent patients, only a small number of viral in-
clusions are present, contrasting with the large
number present in immunosuppressed patients.
Cytomegalovirus. Clinical Features. Cyto-
megalovirus (CMV) infection is a common cause
of viral esophagitis. Like herpes simplex virus,
CMV exhibits a tendency to affect debilitated,
elderly, or immunocompromised individuals.
Symptoms associated with CMV esophagitis
are not specific, and include nausea, vomiting,
fever, epigastric pain, diarrhea, and weight loss.
Dysphagia, odynophagia, and retrostemal pain
occur less commonly than in patients with her-
pes infections (90,92), and symptoms manifest
more gradually. CMV affects the entire gastro-
intestinal tract, and esophageal involvement
Figure 3-18 may be its first manifestation.
CYTOMEGALOVIRUS ESOPHAGITIS
Gross and Microscopic Findings. Grossly, CMV
Endoscopic view of an area of ulceration due to
esophagitis appears as discrete superficial ulcers
cytomegalovirus (CMV) infection. in the mid or distal esophagus, similar in appear-
... ance to those associated with herpes infection
(fig. 3-18). Smaller ulcers may coalesce to form
Herpes esophagitis is usually easy to recog- giant ulcers, particularly in the distal esophagus.
nize histologically if a biopsy is taken from The characteristic cytopathic effects of CMV
the edge of the ulcer (fig. 3-17). The squamous infection include prominent eosinophilic,
epithelial cells in this region contain Cowdry intranuclear inclusions; cellular enlargement;
type A inclusions. A dark margin of condensed and occasional, granular basophilic cytoplasmic
chromatin at the nuclear membrane surrounds inclusions (fig. 3-19). The affected cells differ
large, intranuclear, glassy, eosinophilic inclu- from those seen in herpes infection in that the

106
Diseases of the Esophagus

Figure 3-19
CYTOMEGALOVIRUS ESOPHAGITIS
A: Biopsy from an area of ulceration secondary to CMV
esophagitis. The specimen consists of inflamed granulation
tissue.
B: A fibrin thrombus is in a vessel lying adjacent to the
area of ulceration.
C: A large endothelial cell contains a typical amphophilic
intranuclear inclusion with a surrounding halo.

cytopathic effects of CMV typically do not af- also predisposes patients to fungal infection.
fect squamous cells, but are commonly seen in Most commonly, fungal esophagitis results from
submucosal endothelial cells, macrophages, and Candida infection, although other organisms
fibroblasts in the granulation tissue of the ulcer such as Histoplasma, Aspergillus, Clyptococcus,
bases. CMV inclusions may also be seen in the Blastomyces, and Mucor also infect the esopha-
epithelium of submucosal glands (fig. 3-19) or gus. Fungal infections may be superimposed on
in the glandular cells of BE. As with herpes in- other types of infections.
fection, the use of specific antibodies or genetic Candida. Clinical Features. Candida infec-
probes for the virus may aid in the diagnosis. tion is the most common cause of infectious
esophagitis (95). Candida albicans, a yeast found
Fungal Esophagitis
in the normal human oral flora, is the predomi-
Like viral esophagitis, fungal esophagitis nant cause of fungal esophagitis. Other Candida
tends to affect debilitated individuals, such as species such as C. tropicalis, C. glabrata, C. para-
the elderly, diabetics, patients with cancer, and psilosis, and C. krusei are occasionally pathogenic.
those that are immunocompromised. Other Patients with Candida esophagitis frequently
predisposing factors include a damaged muco- have no symptoms, especially those who are
sal barrier secondary to previous esophagitis, immunologically competent. Such patients have
indwelling nasogastric tubes, chemotherapy, only scattered adherent esophageal plaques. Pa-
protracted periods of severe neutropenia, and tients with more severe immune dysfunction de-
prolonged use of antibiotics and steroids. Esoph- velop painful or difficult swallowing as the initial
ageal stasis resulting from dysmotility disorders manifestation of their disease. Other symptoms

107
Gastrointestinal Diseases

eosinophils lie in the superficial epithelium.


When Candida becomes pathogenic, it invades
the underlying tissues (fig. 3-21). As a result,
colonization of the epithelial surface, particu-
larly of devitalized tissue, does not necessarily
imply the presence of significant clinical disease.
Aspergillus. Aspergillus species are ubiquitous,
rapidly growing molds. The most important spe-
cies involved in human infections are A. fumiga-
tus and A. flavus . The fungi are characterized by
the presence of innumerable, dichotomously
branching, 45° septate hyphae with smooth,
parallel walls, ranging in size from 2 to 4 pm in
diameter (fig. 3-22). Aspergillosis rarely affects
the gastrointestinal tract, but when it does,
the esophagus is the usual site of involvement.
Invasive aspergillosis generally affects severely
debilitated individuals.
Histoplasma. Clinical Features. Histoplasma
Figure 3-20 is endemic in a broad area centered around the
ENDOSCOPIC APPEARANCE OF
.. Ohio and Mississippi River valleys in the United
CANDIDA ESOPHAGITIS • States, in the Caribbean, and in Central and
Numerous whitish plaques are present on the luminal South America. Even a brief exposure to this
surface of the esophagus. dimorphic fungus may result in infection. The
fungi usually gain access to the bodY. through
the lungs, with extrapulmonary dissemination
include chest pain or a globus sensation as food occurring particularly frequently in immuno-
passes through the esophagus. suppressed patients or those with malignancy.
Gross and Microscopic Findings. The esophagus The disease may extend to the esophagus from
is the preferential site for Candida..r
infection in the lungs or from mediastinal lymph nodes that
the gastrointestinal tract. Grossly, the esopha- contain large caseating granulomas. Dyspha-
gus may show areas of moderate erythema, gia results from extrinsic compression of the
hyperemia, and friability, or it may become esophagus by mediastinal lymph nodes or from
covered by a black membrane. Whitish, raised, progressive mediastinal fibrosis . Less common
longitudinally oriented, discrete or confluent are esophageal bleeding and esophagobronchial
plaques or membranes, measuring less than fistula formation (94).
1 cm, cover a friable, erythematous, ulcerated Gross and Microscopic Findings. Endoscopic
mucosa, particularly in the distal esophagus biopsies are unlikely to provide a diagnosis be-
(fig. 3-20). The fungi become densely adher- cause the esophagus is usually involved from its
ent to the esophageal mucosal surface and are external aspect inward. As a result, the mucosa
not easily removed. In advanced cases, the is rarely involved by the process. Histologically,
esophagus becomes narrowed, with a shaggy or the infection results in necrotizing granuloma-
cobblestoned appearance that is easily confused tous inflammation. Organisms are found within
"·' the cytoplasm of histiocytes and multinucleated
grossly with pseudodiverticulosis, strictures,
varices, or carcinoma. Langerhans type giant cells surrounding foci of
Histologically, the mucosa and lamina pro- caseating necrosis. The organisms appear round
pria of the esophagus appear acutely and chroni- to oval, and measure 2 to 4 pm in diameter.
cally inflamed; there are also areas of ulceration. Budding forms are commonly seen.
The fungal plaque consists of hyphae and bud- Mucor. Mucor mycosis develops in immuno-
ding spores embedded in a fibrinous exudate suppressed or malnourished patients. The fungi
and necrotic debris (fig. 3-21). Neutrophils and are ubiquitous in nature and grow as saprophytes

108
Diseases of the Esophagus

Figure 3-21
CANDIDA ESOPHAGITIS
A: Low-power view demonstrates reactive squamous
epithelium on the right and numerous fungi within an
inflammatory exudate on the left.
B: Hematoxylin and eosin (H&E)-stained section shows
squamous epithelium with numerous invading fungal
organisms . Candida appears as both yeast forms and
pseudohyphae.
C: The Grocott methenamine silver stain highlights the
fungal organisms.

Figure 3-22
ASPERGILLUS ESOPHAGITIS
Left: H&E-stained section shows scattered fungal organisms invading the submucosal tissues of the esophagus. Hyphae
are within the smooth muscle of vessel walls.
Right: Factor VIII and periodic acid-Schiff (PAS) dual staining highlights the angioinvasive character of Aspe1gillus.

on fruits and vegetable matter. They have blood vessels thereby causing thrombosis and
broad, rarely septate, haphazardly branched vascular damage.
hyphae that measure 10 to 15 pm in diameter, Coccidioides. Coccidioides, also a dimorphic
and characteristically stain deeply with hema- fungus, can be acquired via the pulmonary tract
toxylin. The fungi have a tendency to penetrate by travel through an endemic region. Esophageal

109
Gastrointestinal Diseases

Figure 3-23
CAUSTIC ESOPHAGITIS
A: Endoscopic view shows marked edema and erythema
of the mucosa.
B: Another case of corrosive esophagitis . The distal
portion of the specimen (right) shows a diffusely erythe-
matous and edematous mucosal surface. Adherent pseudo-
membranes are seen in some areas. (Courtesy of the Division
of Gastrointestinal Pathology, Armed Forces Institute of
Pathology, Washington, DC.)
C: There is extensive necrosis of the esophageallining.

involvement usually represents extension of rhage, perforation, and death. The acute phase
pulmonary disease. C. immitis..rgrows in soil lasts for several days or weeks, with pain as the
where rainfall is low and summer temperatures predominant symptom. Symptoms are unreli-
are high. In tissue, it is identified by the pres- able in predicting disease extent or severity.
ence of large globular sporangia measuring 30 The most severe injury occurs in areas
to 60 pm or more that contain sporangiospores of luminal narrowing, i.e ., those where the
measuring 1 to 5 pm in diameter. Hyphae can aorta or the left main stem bronchus cross the
sometimes be seen. The intact sporangia elicit esophagus. Alkalis produce liquefactive necro-
a granulomatous reaction consisting of histio- sis with intense inflammation of the mucosa,
cytes, epithelioid cells, and giant cells of foreign submucosa, and muscularis propria. Thrombosis
body or Langerhans 'type. of adjacent vessels leads to ischemic necrosis,
followed by bacterial or fungal colonization.
CORROSIVE ESOPHAGITIS Liquid agents tend to produce extensive geo-
Definition. Caustic injury results from the graphically continuous erosive esophagitis,
"• ingestion of strong alkaline or acidic agents or whereas granular agents produce more localized
very hot liquids. lesions. Acids produce coagulation necrosis that
Clinical Features. The extent of corrosive results in a firm protective eschar.
injury depends on the type of agent ingested, Microscopic Findings. Histologically, caus-
its concentration and quantity, patient physical tic strictures demonstrate dense, uniform,
state, and exposure duration (96,97). Corrosive mucosal and submucosal fibrosis throughout
esophagitis usually follows suicide attempts in the involved esophagus. The overlying surface
adults or accidental ingestion in children. When appears normal, inflamed, ulcerated, hypertro-
severe, the injury leads to esophageal hemor- phic, or atrophic, depending on when the tissue

110
Diseases of the Esophagus

is examined relative to the time of the acute


event and if recurrent damage has occurred (fig.
3-23). Another change that sometimes follows
. lye ingestion is the formation of metaplastic
epithelium resembling that seen with BE.
RADIATION ESOPHAGITIS
Clinical Features. Patients with radiation
esophagitis present with dysphagia, odynopha-
gia, or symptoms of dysmotility. Dysphagia
during radiation therapy probably results from
epithelial damage as well as disordered motility.
Whether or not esophagitis develops is related
to both the radiation dose and the tissue radio-
sensitivity. In addition, concomitant adminis-
tration of chemotherapeutic drugs may produce
radiosensitizing effects that increase the degree
of esophageal injury. These drugs may also be
directly toxic to the mucosa, predisposing it to
further damage by radiation. Severe esophagitis,
stricture formation, and rare fistulas develop in
patients treated with both chemotherapy and
radiation therapy.
Gross and Microscopic Findings. Radia-
tion esophagitis may be associated with areas
of ulceration, fibrosis, and stricture formation
(fig. 3-24) depending on the amount of time
that has elapsed following the radiation treat-
ment. Early in the process, the tissues appear
edematous, erythematous, and friable, with
erosions coalescing to form larger superficial
Figure 3-24
ulcers. Prominent endothelial cells lie in the
edematous granulation tissue. Bizarre (radia- RADIATION ESOPHAGITIS
tion) fibroblasts develop and suggest the diag- Top: Endoscopic view of an erythematous and eroded
nosis. The regenerating epithelium may show epithelium.
Bottom: Microscopically, the submucosa is edematous
features simulating dysplasia. with scattered enlarged, atypical-appearing stromal cells.
Histologic examination in the chronic or A submucosal vessel shows prominent intimal thickening.
late period discloses the presence of acanthosis,
parakeratosis, hyalinized blood vessels, submu-
cosal fibrosis, and muscular degeneration (fig. in Table 3-7. Age, posture, volume of a fluid
3-24). These changes result from ischemia due chaser, and dissolution pH of the medication
to the underlying vascular lesions. Esophageal all influence drug-mediated esophageal injury
strictures and webs develop during the chronic (98,100). Hiatal hernia, esophageal dysmotility,
period following large radiation doses. or stricture predispose to prolonged retention of
esophageal medication and enhance the ability
DRUG-ASSOCIATED ESOPHAGITIS of drugs to damage the mucosa.
No characteristic pathologic findings exist Some injuries result from physical entrap-
for drug-induced esophagitis because different ment of undigested medicines, especially those
drugs damage the esophagus via different that contain a hydrophilic swelling agent or
mechanisms. Drugs commonly implicated in fiber that ensures rapid disintegration when
drug-induced esophagitis include those listed the pills contact water (101). These medicines

111
Gastrointestinal Diseases

Table 3-7 Table 3-8


DRUGS ASSOCIATED WITH ESOPHAGITIS CAUSES OF ESOPHAGEAL PERFORATION

Acetaminophen Ibuprofen Penetrating wounds


Antimitotic agents Indomethacin Iatrogenic trauma
Acetylsalicylic acid Minocycline Iatrogenic intraoperative injury
Ascorbic acid Naproxen Iatrogenic endoscopic perforation
Barbiturates Pantogar Swallowed foreign body
Carbachol Phenylbutazone Blasr injury
Chemotherapeutic agents Phenobarbital Postemetic (Mallory-Weiss syndrome)
Chloral hydrate Phenoxymethyl penicillin Blunt trauma (such as auto accidents)
Clindamycin Potassium chloride Esophageal ulcers regardless of cause
Clinitest tablets Prednisone Esophageal diverticula
Cromolyn sodium Quinidine Esophageal cancer
Digoxin, digitoxin Tetracycline Ingestion of corrosives
Doxycycline Theophylline Severe inflammation
d-Penicillamine Tinidazole Sclerotherapy or other recent esophageal procedure
Emepronium bromide Tolectin
Erythromycin Zidovudine
Ferrous salts
MUCOSAL LACERATIONS,
ULCERATIONS, AND PERFORATIONS
Acquired perforations, whether transmural or
act as foreign bodies impacting in the esopha- intramural, usually result from instrumentation,
geallumen, especially if they are taken with a foreign body impaction, and trauma.(Table 3-8).
minimum of liquid. As the medication dissolves,
Mallory-Weiss Syndrome
localized esophageal damage, ranging from
inflammation to severe hemorrhage and even Definition. The term Mall01y~ Weiss syndrome
perforation, develops (100). · refers to painless gastrointestinal bleeding that
Other mechanisms of drug-io.duced esopha- results from esophageal or gastroesophageal
gitis are allergic in nature, and these may be mucosal laceration following an episode of
suspected based on the history or the presence vomiting.
of eosinophilia in the absence of reflux esopha- Clinical Features. The sequence of events
gitis. Still other drugs, such as chemotherapeutic suggests that the increased pressure created by
agents, directly damage replicating cells. Basal vomiting plays an important etiologic role. Most
cell hyperplasia, mild atypia, and numerous patients are males with a history of alcohol and/
mitoses, some of which may appear atypical, or salicylate abuse or associated hiatal hernia.
characterize recovery from chemotherapeutic Gross and Microscopic Findings. The lacera-
injury. Antibiotics account for at least half of the tions lie along the long axis of the distal esopha-
reported cases of drug-associated esophagitis, gus, crossing the esophageal-gastric junction or
with the tetracyclines, especially doxycycline, lying in the gastric fundus. The lacerations vary
being the usual offenders (100) . in depth, measuring on average 1.5 cm, often
•.· The most dangerous drug-related esophagitis only affecting the mucosa. They are acute in
results from potassium chloride ingestion. Sev- nature, without scarring, unless previous lacera-
eral patients have died of esophagitis directly tions have occurred.
related to its ingestion. Histologically, there is
Boerhaave's Syndrome
subepithelial edema, thickening of the stratum
corneum, and the presence of balloon cells (99). Definition. Boerhaave's syndrome is spontane-
The presence of balloon cells serves as an early ous, full-thickness esophageal rupture.
esophageal mucosal marker of chemical injury Clinical Features. The sudden development
but is not specific for it. of a pressure gradient between the internal

112
Diseases of the Esophagus

portion of the viscus and its external supporting


tissues is the common pathogenetic denomina-
tor in cases of gastrointestinal rupture (102).
·. The antecedent background varies: the viscus
may become overdistended by food, drink, gas,
or any combination thereof. Forced vomiting
is often sufficient to increase the intraluminal
pressure. Hiatal hernia, peptic esophagitis, and
atrophic gastritis are predisposing factors. In
Boerhaave's syndrome the pain is constant.
Hematemesis occurs at times, and the clinical
features and radiologic findings often point to
an intrathoracic catastrophe. Immediate surgi-
Figure 3-25
cal repair must occur if the patient is to survive.
Gross and Microscopic Findings. Character- ESOPHAGEAL MELANOSIS
istically, the laceration is linear, longitudinal, Melanin pigment is in the dendritic cells within the basal
portion of the squamous epithelium.
and lies in a left lateral posterior location, 1 to
3 cm above the gastroesophageal junction. This
is the weakest part of the esophagus. The tears Microscopic Findings. Histologically, mela-
measure 1 to 20 cm in length, with an average nosis consists of increased numbers of melano-
length of 2 cm; the mucosal part of the tear is cytes in the basal part of the mucosa, increased
usually longer than the muscular part. numbers of melanosomes in the melanocytes,
and melanosomal transfer to keratinocytes,
MELANOSIS stromal macrophages, and fibroblasts (fig. 3-25) .
Demography. Melanocytes lie in the epithe- The pigment is identified_with melanin stains.
lial-stromal junction in 4 to 8 percent of normal
esophageal specimens examined at autopsy NEVUS
(103), 21 percent of consecutive upper endos- White sponge nevus, a rare benign disorder of
copy specimens, and 29.9 percent of surgical the mucosal membranes with a familial distribu-
specimens of esophageal melanoma (103,104). tion, recently has been reported in the esopha-
There is a higher prevalence of melanocytes in gus (105,107). The pattern of inheritance seems
the normal esophageal mucosa in Japanese than to be that of an autosomal dominant disorder.
in Western populations. They are more common Most lesions exist at birth or have their onset
in patients with cancer. in infancy, childhood, or adolescence. The con-
Etiology. The etiology is unknown. Mecha- dition is usually seen in Caucasians. It is char-
nisms postulated to explain an increase in acterized by the presence of a thickened, deeply
epidermal melanocytes include: 1) prolifera- folded mucosa with a creamy white appearance.
tion of preexisting melanocytes; 2) activation The lesions are small and wart-like, or large,
of resting melanocytes following activation of moist, and white. Such areas are easily mistaken
melanogenesis; 3) migration of dermal mela- for Candida infections. They increase in size and
nocytes; and 4) differentiation of peripheral number after puberty and then stabilize.
neural cells (103). Histologically, the lesions are characterized
Gross Findings. Melanosis appears as single by irregular acanthosis with spongy hydropic
or multiple, discrete, 1- to 3-mm, circular or squamous cells in all levels except for the unin-
oval, brown or brownish black mucosal patches. volved basal layer, which forms an intact lower
The pigmented areas also appear as linear rete border. Mitoses may be seen but there is
streaks. These pigmented lesions may lie adja- no nuclear atypia (105). The finding of para-
cent to carcinomas. Although pigmentation can keratotic plugs appears to be pathognomonic.
affect the middle, upper, and lower esophagus, Because of surface fragmentation, the superficial
the distal esophagus is the most common site squamous cells may appear shaggy. Inflamma-
of involvement. tion is absent.

113
Gastrointestinal Diseases

Figure 3-26
GLYCOGEN ACANTHOSIS
Left: An esophagus from a patient with Cowden syndrome. Scattered whitish mucosal plaques representing glycogen
acanthosis are in the mid-esophagus. •
Right: Microscopically, the squamous cells are enlarged with pale pink cytoplasm.

Blue nevus has also been reported in the Differential Diagnosis. Histologically, the
esophagus (106). .. lesion may resemble the ballooning degenera-
tion seen in reflux esophagitis. PAS stains can
GLYCOGEN ACANTHOSIS distinguish the two lesions, since glycogen ac-
Demography. Glycogen acanthosis "is a rela- anthosis contains abundant glycogen whereas
tively common condition of unknown etiology ballooning degeneration does not.
that is felt by some to represent a normal variant
of esophageal histology. The presence of diffuse SYSTEMIC DISORDERS
esophageal glycogen acanthosis is an endo-
Amyloidosis
scopic marker of Cowden's disease (110,111).
Gross Findings. The lesion i.$ most easily Amyloid forms deposits in the gastrointestinal
recognized grossly. Glycogen acanthosis appears tract in all forms of generalized amyloidosis. The
as discrete, raised, white, plaque-like esophageal esophagus is involved in 35 to 100 percent of
lesions usually measuring less than 1 cm in di- cases (114,118). Because amyloid deposits ran-
ameter (fig. 3-26). When extensive, they coalesce domly in esophageal tissues, the disease presents
into larger plaques, but they rarely measure more in unpredictable ways, sometimes primarily re-
than 3 cm in diameter. A nodular appearance sembling a muscular disorder and sometimes re-
of the esophageal mucosa with double-contrast sembling a primary neural disturbance (114,118).
esophagograms is observed in 25.0 to 28.3 per- Patients with esophageal involvement present
cent of such studies (109) . Glycogen acanthosis with motility disorders, dysphagia, and gastro-
affects any part of the esophagus but primarily esophageal reflux disease (112,113,115, 116,119).
the distal third (108). Clinically, glycogen acan- Abnormalities occur in the LES, in the body of
thosis may resemble and be confused endoscopi- the esophagus, or both. Amyloid is deposited in
cally with fungal infections or leukoplakia. skeletal or smooth muscle, vagus nerve, myen-
Microscopic Findings. Histologically, the teric plexus, or vasa vasora (fig. 3-27). Patients
plaques consist of large clusters of enlarged with esophageal amyloidosis may present with
squamous cells of the prickle cell layer (fig. vascular complications. Perforation and he-
3-26). These contain abundant glycogen. Due to matemesis also occur (117).
the extraction of the glycogen during process-
Diabetes
ing, the cells appear clear. There is no inflam- .
mation and no basal cell hyperplasia. The lesion Esophageal motility abnormalities com-
can be accentuated by the use of the PAS stain. monly affect patients with diabetes mellitus

114
Diseases of the Esophagus

have rheumatoid nodules within the esopha-


geal wall. Patients may also have an associated
drug-induced esophagitis from treatment with
nonsteroidal antiinflammatory drugs (NSAIDs).
Rheumatoid vasculitis may also result in gas-
trointestinal manifestations. The vasculitis
typically occurs in the setting of severe arthritis,
rheumatoid nodules, and high titers of rheuma-
toid factor. Patients with Sjogren's syndrome
display esophageal connective tissue abnor-
malities (127,129,131): 10 percent of patients
have upper esophageal webs, 25 percent have
hiatal hernias, and 36 percent display motility
abnormalities (126,128-131).
Figure 3-27 Inflammatory Bowel Disease
AMYLOIDOSIS Crohn's disease may affect the esophagus and
A submucosal vessel shows a thick cuff of surrounding when it does, it may be difficult to distinguish
eosinophilic, hyaline-appearing amyloid protein.
from other forms of granulomatous esophagitis.
In bona fide cases of Crohn's disease, there may
(120,121). More than half of diabetics with be areas of acute and chronic inflammation,
peripheral or autonomic neuropathy have ulcers, sinus tracts, and possibly granulomas in
esophageal dysmotility resulting from neuro- the esophagus. The granulomas are compact and
pathic involvement of the vagus nerve. The sarcoid-like, without necrosis. They may be in-
neuropathy results in a secondary myopathy, filtrated by inflammatory cells. Muscular hyper-
eventually leading to atony. trophy and neural hyperplasia are often present.
In other cases, only granulomas are seen. Many
Cystic Fibrosis
patients only show a focal nonspecific inflam-
Recent attention has focused on the high mation deep in the esophageal wall, and it may
frequency of gastroesophageal reflux in patients be impossible to make a definitive diagnosis.
with cystic fibrosis because it increases the risk Patients with ulcerative colitis may have co-
of lung complications in these patients (122). existing esophagitis and ulcers, but this more
Gastroesophageal reflux begins during child- than likely reflects coexisting reflux esophagitis.
hood and becomes increasingly more trouble-
some as the patient ages (123-125). Numerous DERMATOLOGIC CONDITIONS
factors, including chronic persistent cough INVOLVING THE ESOPHAGUS
resulting in an increased pressure gradient A number of primary dermatologic disorders
between the peritoneal cavity and the thorax affect the esophagus (Table 3-9) . The esopha-
and a delay in gastric emptying, play etiologic geal changes resemble those seen in the skin,
roles in the reflux. a reflection of the fact that both sites are lined
by squamous epithelium. In some patients,
Autoimmune Diseases
esophageal disease develops in the absence of
Collagen vascular and rheumatoid diseases dermatologic evidence of the disease.
affect the esophagus through chronic inflam-
Pemphigus
mation, vasculitis, and variable degrees of vas-
cular obliteration. Scleroderma presents with Pemphigus vulgaris usually affects patients
dysphagia and is discussed in detail in chapter between the ages of 40 and 60 and is charac-
17. Patients with rheumatoid arthritis present terized by the development of flaccid dermal
with esophageal dysmotility and lowered LES and mucosal bullae. Involved mucosal surfaces
pressure, which results in reflux esophagitis. include the oral cavity, pharynx, larynx, con-
Rarely, patients with severe rheumatoid arthritis junctiva, esophagus, nasal mucosa, cervix, and

115
Gastrointestinal Diseases

anal canal. Pemphigus may also be induced by Table 3-9


drugs, including D-penicillamine and angio- DERMATOLOGIC DISEASES
tensin-converting enzyme inhibitors (135). If INVOLVING THE ESOPHAGUS
untreated, pemphigus vulgaris may be fatal. Acanthosis nigricans
Esophageal bleeding, webs, strictures, and for-
Behcet's syndrome
mation of epithelial casts may develop.
Benign mucous membrane pemphigoid
Histologic examination of esophageallesions
Darier's disease
shows the presence of a blister or erosion. The
Dermatitis herpetiformis
squamous epithelial cells separate from one
another in a process known as acantholysis. As Epidermolysis bullosa
a result, the cells lose their cohesive properties Erythema multiforme
and a suprabasal cleft forms. The disorder may Lichen planus
also present as eosinophilic spongiosis. Pemphigus
Scleroderma
Benign Mucous Membrane Pemphigoid
Toxic epidermal necrolysis
Bullous pemphigoid affects the esophagus Tylosis palmaris et plantaris
in the form of benign mucous membrane pem-
phigoid. This chronic disease of the elderly is
characterized by the presence of tense pruritic
skin bullae. Oral bullae develop in 20 percent of disease primarily affects the skin, but esophageal
cases. Esophageal bullae occur rare~y, but cause involvement can occur. Patients with severe
epithelial sloughing. disease present with dysphagia resulting from
Esophageallesions appear suddenly and may web-like stenosis of the upper esophagus.
persist for several days. They reappear at the
Epidermolysis Bullosa Dystrophia
same site, often following mild trauma such as
that induced by ingestion of hot foods or food Epidermolysis bullosa dystrophia includes a
passing over the mucosa. Patients may present group of hereditary mechanobullous disorders
with bullae and webs, or later with strictures that affect both the skin and gastrointestinal
(131,133) . Histologic examination shows the mucosa. Esophageal problems develop insidi-
presence of subepithelial bullae. ously, often in patients with previous skin le-
.r
sions. Bullae form in the esophagus, followed by
Erythema Multiforme
ulceration and edema. This eventually predis-
Erythema multiforme represents an acute self- poses to severe stricture or web formation (134).
limited eruption involving the skin and mucous
Lichen Planus
membranes. Mucosal involvement is referred
to as the Stevens-Johnson syndrome. Esophageal Lichen planus is a common disease of un-
disease ranges from mild to severe, with the known etiology that often affects the oral cavity.
severity of esophageallesions corresponding to Esophageal disease is rare and results in esopha-
the severity of the dermal disease. Endoscopi- geal papules and benign strictures. The papules
cally, the lesions resemble peptic esophagitis. are visible in the lower third of the esophagus
Keratinocytes become necrotic, containing in most cases, although occasionally the entire
homogeneous pink cytoplasm and pyknotic esophagus is involved. Histologically, there are
nuclei. Biopsies reveal areas of ulceration or submucosal band-like lymphocytic infiltrates.
r.,. inflamed granulation tissue.
Acanthosis Nigricans
Epidermolysis Bullosa Acquisita
Acanthosis nigricans is a distinctive dermato-
Epidermolysis bullosa acquisita, an acquired sis characterized by hyperpigmented, velvety
mechanobullous disease, is characterized by the plaques with a predilection for the neck and
presence of autoantibodies to type VII collagen. flexural areas. The disease may involve the entire
These antibodies localize to the anchoring fila- skin, including the palms, soles, and mucous
ments at the dermal-epidermal junction. The membranes (136) . Histologically, the squamous

116
Diseases of the Esophagus

epithelium displays hyperkeratosis, papilloma- small intestines, but they also develop in the
tosis, and slight and irregular acanthosis in the esophagus. These solitary lesions are raised and
valleys between the papillae. There is usually sometimes ulcerated, often with a prominent
no associated hyperpigmentation. Acanthosis submucosal component. They are often detect-
nigricans serves as a marker of internal disease, ed endoscopically or radiographically, and since
and may be associated with malignancy. they appear as polypoid lesions, clinically must
be differentiated from sarcomatoid carcinoma.
Graft Ve rsus Host Disease
Microscopically, inflammatory fibroid polyps
Graft versus host disease (GVHD) usually af- appear variably cellular and edematous. They
fects the upper third of the esophagus. The le- are often highly vascular, containing fibrous
sions are focal or diffuse and characteristically tissue, proliferating blood vessels, inflamma-
consist of desquamative or bullous esophagitis tory cells, fibroblasts, myofibroblasts, and
with web formation (137,138). The diagnosis histiocytes.
of GVHD is based on the history and presence
of single cell necrosis (apoptosis) as well as the FIBROMUSCULAR HAMARTOMA
failure to identify specific infectious agents. Of- Fibromuscular hamartoma presents in in-
ten, only nonspecific inflammation is evident. fancy with dysphagia due to compression of the
Infections often coexist with GVHD. cervical esophagus. The lesion consists of atro-
phic-appearing skeletal muscle fibers, fibrous
INFLAMMATORY FIBROID POLYPS connective tissue, and hyaline cartilage. The
Inflammatory (lbroid polyps (IFPs) commonly lesion may appear to have infiltrative margins.
arise in the submucosa of the stomach and

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129. Kjellen G, Fransson SG, Lindstrom F, Sokjer H, tensin-converting enzyme inhibitor-induced
Tibbling L. Esophageal function, radiography, pemphigus: three case reports and literature
and dysphagia in Sjogren's syndrome. Dig Dis review. Mayo Clin Proc 1994;69:1166-71.
Sci 1986;31:225-9. 136. Rogers DL. Acanthosis nigricans. Semin Der-
130. Palma R, Freire A, Freitas ], et al. Esophageal matol 1991;10:160-3.
motility disorders in patients w!th Sjogren's
syndrome. Dig Dis Sci 1994;39:758-61. Graft Versus Host Disease
131. Tsianos EB, Chiras CD, Drosos AA, Moutsop- 137. McDonald GB, Sullivan KM, Schuffler MD,
oulos HM. Oesophageal dysfunction in patients Shulman HM, Thomas ED. Esophageal ab-
with primary Sjogren's syndrome. Ann Rheum normalities in chronic graft-vs-host disease in
Dis 1985;44:610-3. humans. Gastroenterology 1981;80:914-21.
138. Minocha A, Mandanas RA, Kida M, ]azzar A.
Bullous esophagitis due to chronic graft-versus-
host disease. Am] Gastroenterol1997;92:529-
30.

122
DISEASES OF THE STOMACH

CLINICAL PRESENTATION OF Adherent mucus provides a stable, unstirred


GASTRIC DISEASES AND WHAT layer that allows surface neutralization of acid
THE CLIN ICIAN WANTS TO KNOW by mucosal bicarbonate secretion (1). Mucous
Dyspepsia, among the most common gas- cells also secrete lipid into the mucus, which
trointestinal symptoms (2,5 ,10), is treated coats the epithelium lining the gastric lumen
with empiric therapies. Treatment generally with a nonwettable surface, thereby protecting
reflects the physician's interpretation that the the mucosa against the action of water-soluble
symptoms are arising from the upper luminal hydrogen ions and pepsin. Tight junctions (3,6)
gastrointestinal tract. Unfortunately, one third and mucosal blood flow, as well as mucosal
of the patients with this symptom either fail to cytoprotectants (15), are other components of
respond (13), or relapse, necessitating investiga- the gastric mucosal barrier.
tions to establish a more definitive diagnosis to The gastric cytoprotectants include im-
guide additional therapy. It is in this setting that munoglobulins (9), prostaglandins (14), heat
the multidisciplinary efforts of the gastroenter- shock proteins (12), growth factors (7), sulf-
ologist, pathologist, and radiologist are required hydryl donors such as glutathione (11), and
to determine the etiology of clinically pertinent neuropeptides (4) . Growth factors stimulate
pathologic processes. While the relevance of gastric mucosal growth and accelerate healing
diagnosing fungating masses or large ulcerations of mucosal damage. Mucosal blood flow brings
is obvious, the pathologic diagnosis of clinically bicarbonate, oxygen, and nutrients to the lumi-
and endoscopically "overt erythema," "patchy nal surface and removes hydrogen ions from the
gastritis," or "erosive disease" constitutes a ma- same region (10) .
jor challenge to the clinician who must decide All of these defenses protect the mucosa from
whether to treat the patient and if so, with what. injury. When they fail, back diffusion of luminal
acid, tissue acidosis, vascular compromise, mu-
MUCOSAL BARRIER: cosal congestion, and tissue necrosis develop.
STRUCTURE AND FUNCTION
The mucosal barrier consists of preepithe- MUCOSAL REPAIR
lial, epithelial, and postepithelial defenses (fig. When the gastric mucosa is damaged, it re-
4-1); these defenses act against the diffusion of generates from a stem cell zone located in the
gastric acid and pepsin from the gastric lumen. mucous neck region (fig. 4-2). Various factors

H+ H+ Pepsin H+ H+ Pepsin H+
H+ Pe~sin -ill H+ H+ Pepsin
'-.,..../ V Low pH

Mucous layer- +
HC0 3
HCO 3
HC0 3
HCO 3
HC0 3 t
Neutral pH
Figure 4-1
STRUCTURE OF THE
Intercellular GASTRIC MUCOSAL BARRIER
junctions - -+-+2 See text for details.

123
Gastrointestinal Diseases

-~ ... ' :

Figure 4-2
MUCOSAL REGENERATION
Left: Histologic features of regenerating mucous neck region. The
mucous neck region contains occasional mitoses and a proliferating
epithelium characterized by an increased nuclear to cytoplasmic ratio
and nuclear basophilia .
Above: Ki-67 immunostaining shows expansion of the proliferative
zone of the mucous neck region.

PATHOLOGIC EVALUATION
contribute to gastric mucosal repair. Prosta- OF GASTRIC BIOPSIES
glandins limit the initial injury .to the surface A systematic approach to the histologic ex-
epithelium and lamina propria. A cap of mu- amination of gastric biopsies facilitates their
cus, cellular debris, and plasma""Proteins forms evaluation, and provides the discipline for es-
within seconds of the epithelial injury and traps tablishing a differential diagnosis that includes
plasma shed from the underlying microcircula- specific diagnostic entities. Sometimes, more
tion. This cap protects the lamina propria from than a single abnormality is present, as in coexist-
luminal acid and limits the extent of the injury. ing Helicobacter and cytomegalovirus infections.
Mucosal reepithelialization, a process that re- It is important to recognize that many agents
quires epithelial migration across an intact basal cause gastric injury without generating much
lamina, occurs rapidly, ensuring quick restora- inflammation, as typified by the chemical gastro-
tion of surface epith,elial continuity. pathies; the absence of significant inflammation
Proliferative responses of the pluripotential does not exclude the presence of mucosal injury.
stem cells in the mucous neck region also con- From time to time, a biopsy will simply defy a
tribute to epithelial reepithelialization. Stem diagnostic category; in this situation, one might
cells differentiate into foveolar cells above, and be left with a descriptive "diagnosis."
•.· specialized glandular epithelial cells below the Initial biopsy evaluation should begin with a
mucous neck region, reconstituting the normal careful examination of the requisition informa-
architecture within a few days. Proliferating tion to ascertain the relevant clinical features of
mucous neck cells appear mucin-depleted and the patient and to determine the site of origin of
contain abundant basophilic cytoplasm result- the biopsy. The latter is very important because
ing in an increased nuclear to cytoplasmic ratio, a biopsy that appears to be relatively normal,
increased mitoses, nuclei with vesicular chro- but which contains the wrong epithelial cell
matin, and a prominent, solitary, eosinophilic types for the location, indicates that metaplasia
nucleolus (fig 4-2). has occurred.

124
Diseases of the Stomach

Table 4-1
FEATURES TO BE EVALUATED IN GASTRIC BIOPSIES

· Are all parts of the biopsy the same, or are there focal differences? If focal differences exist, do they affect:
- the surface?
-the epithelium? If yes, then which part of epithelium (foveolar, glandular, or endocrine cells)
-the stroma?
- or all of these sites?
-the antrum?
- the fundus?
- the cardia?
Is there gastritis? If inflammation is present, is it:
- acute, chrome, mixed, granulomatous, eosinophilic, plasmacytic, lymphocytic?
-in the surface, pits, mucous neck region, glands, stroma?
-does it destroy the epithelium?
Is there an obvious etiology for the changes? Are there microorganisms or erosions?
Is there evidence of cellular differentiation? If not, is the lack of differentiation due to regeneration or neoplasia?
Is there obvious cancer or dysplasia elsewhere?
Is there architectural distortion? Can you line the glands up in your mind's eye in a more or less parallel fashion?
Is the ratio of the glands to stroma normal?
-if not, is the alteration due to too much stroma?
- is the alteration due to the loss of normal mucosal components?
-is there an increased cellularity of either component?
Is there atrophy? If so, where is it?
Is there metaplasia? If so, is it:
- intestinal?
-pyloric?
- pancreatic?
- ciliated?
Is the mucosa expanded? If so, is it by:
-inflammation?
-pit expansion?
-glandular expansion?
-an abnormal cellular infiltrate?
Are the vessels normal? If not, are they:
- dilated?
- thrombosed?
- thickened?
- dysplastic?
- neoplastic?

The first determination that should be made entity. Jumbo biopsies may be used to generate
is whether the biopsy is normal or abnormal. biopsy material in individuals in whom the
It should be examined for the presence of gastroenterologist suspects either the presence
gastritis, gastropathy, vasculopathy, mucosal of a submucosal mass or gastric mucosal fold
expansion, or other abnormalities. The biopsy disease. This suspicion must be present before
should also be examined to assess its overall the endoscopy is started, since a larger diameter
histologic architecture. Answers to the ques- endoscope must be used to accommodate the
tions listed in Table 4-1 allow recognition of the jumbo biopsy forceps. Additionally, this large
salient features of gastrointestinal injury and endoscope is not well tolerated by patients, who
initial categorization into a specific pathologic are awake during the procedure.

125
Gastrointestinal Diseases

EXAMINATION OF SURGICAL
GASTRECTOMY SPECIMENS
It is rare to receive a tesection specimen
today for a benign gastric disease, unless some
catastrophic event, such as a perforation, has oc-
curred. If such a specimen is received, the extent
of the resection specimen should be assessed.
The external surface of the stomach should be
evaluated for any alterations and it should then
be opened along the greater curvature, unless a
gross lesion is present in this site. It is easiest to
appreciate the extent of the gastric resection in
the opened specimen, since the tan-white mu-
cosa of the esophagus is readily differentiated Figure 4-3
from the pinkish red, granular gastric mucosa. EROSIVE GASTRITIS
When there is coexisting Barrett esophagus, There are small punctate areas of mucosal erosion and
pinkish granular mucosa may extend into the hyperemia .
esophagus. In this situation, the proximal ex-
tension of the stomach can be determined by recorded and/or photographed. Prior endoscop-
locating the proximal termination of the gastric ic or radiologic intervention, such as injection
folds. Distally, the duodenum is r~cognizable with hypertonic saline or epinephrine, electric
beyond the thickened pyloric sphincter. The cautery, or embolization, may influence the
mucosa usually is pinkish tan. If the patient pathologic findings.
has peptic disease, the duodenum may appear If it is necessary to take sections of the en-
finely granular due to the presence of peptic tire mucosa, strips can be rolled up, pim1ed, and
duodenitis and Brunner gland hyperplasia. placed in 10 percent formalin to be embedded in
In resections performed for peptic ulcer dis- paraffin to create an "anchovy-like" roll. The resec-
ease, it is important to identify th~ duodenum tion specimen should be fixed quickly due to its
and document its presence, since it indicates propensity to undergo autolysis. We find it useful
the adequacy of an antral resection. Similarly, to pin resection specimens out on a cork board
the proximal margin should be confirmed as and suspend them upside down in 10 percent
oxyntic to ensure that complete antrectomy neutr·al buffered formalin, placing paper towels or
is performed. The entire mucosa must be ex- other wicking substances between the cork board
amined, and the presence of erosions, ulcers, and the specimen itself. Once the stomach is
or other focal lesions noted. The nature of the completely fixed, sections can be taken carefully.
mucosal folds should be evaluated to determine Visible lesions should be sampled.
if they are flattened or increased in thickness.
When ulcers are identified, their number, depth, GASTRITIS
and diameter should be noted. It is important to Histologically, gastritis is defined as gastric
note whether an ulcer cavity is filled with blood inflammation. Clinically, gastritis presents as
or whether a visible vessel is present. In some abdominal discomfort, pain, heartburn, or
patients with multiple peptic ulcerations, a nausea and vomiting. Endoscopically, gastritis
... small duodenal gastrin-producing tumor may be is defined by the presence of visible mucosal
present. Careful examination of cross-sectional alterations (fig. 4-3). Terms used to describe
mucosal slices may be required to identify it. the endoscopic features are listed in Table
Suspicion that a gastrin-producing tumor may 4-2. Gastritis is usually divided into acute and
be present should be aroused if both multiple chronic forms. It is also classified by etiology
ulcers and gastric fold thickening are present. or by its dominant histologic features. Clinical
In this setting, the entire duodenal segment symptoms, endoscopic findings, and histologic
may be submitted for histologic examination. features often fail to correlate with one another.
Individual lesions should be diagrammatically Occasionally, when the endoscopist sees what

126
Diseases of the Stomach

Table 4-2
ENDOSCOPIC FEATURES OF GASTRITIS
Edema (swelling): This is readily diagnosed when severe. The mucosa appears glistening and may be paler than nonnal.
Erythema (redness): Unequivocal increase in the redness of the mucosa. A beefy red mucosa correlates with severe
erythema. The process may appear focal or diffuse.
Friability: Minor trauma, such as probing with a closed biopsy forceps, causes punctate hemorrhage or frank oozing.
Exudate: Gray-yellow (sometimes brownish or greenish) material adherent to the mucosal surface. Exudate may
tenaciously adhere to the mucosa. It may be punctate or form patches, streaks, or plaques. An underlying process
(e.g., ulceration) may be present.
Erosion: Break in the mucosa. Flat erosions correspond to necrotic foci that do not extend beyond the muscularis
mucosae. Their number and location may vary.
Raised erosion (varioliform erosion): Discrete lesions of elevated mucosa capped by a central defect. They are often
superimposed on the gastric folds.
Rugal hyperplasia or hyperrugosity (fold enlargement): The fo lds do not flatten (or only partially flatten) when the
stomach is insufflated with air.
Rugal atrophy: Thinning of mild or moderate degree or ultimate disappearance of the gastric rugae.
Vascular pattern: A vascular pattern is not visible endoscopically in the normal gastric mucosa. When it is present, it
results from mucosal thinning accompanied by the appearance of ramifying vessels.
Intramucosal bleeding spots: Loss of the vascular integrity leads to intramucosal or intralumin al extravasation of
blood . It appears as petechiae or as larger reddish brown or dark black ecchymotic spots, streaks, or flecks.
Nodularity (granularity): Lack of evenness of the mucosa. Elevated areas may be visible.

may appear to be severe gastritis, the pathologist Table 4-3


may find nothing remarkable, and vice versa. MAJOR CAUSES OF ACUTE GASTRITIS
Acute Gastritis Physiologic Stresses
Uremia
Definition. Acute gastritis has an acute onset Severe burns
and short duration. Inflammation, if present, Congestive heart failure
consists of polymorphonuclear leukocytes. Infections and sepsis
Major surgery
Cushing ulcers are associated with serious brain Trauma
injury, intracranial neurosurgical procedures, Respiratory failure
or increased intracranial pressure. Curling ul- Major central nervous system injury
cers affect bum patients. Other synonyms for Toxic Stresses
acute gastritis are active gastritis, acute hemor- Alkaline and bile reflux
rhagic gastritis, erosive gastritis, stress gastritis, Ingestion of
and ulcerative gastritis. The term chronic erosive Certain foods
Alcohol
gastritis is also synonymous with lymphocytic or Drugs, especially nonsteroidal antiinflammatory
varioliform gastritis. drugs (NSAIDs)
Demography. Acute gastritis accounts for up Corrosive agents
to 25 percent of hospital admissions of patients Circulatory Stresses
with acute upper gastrointestinal bleeding (26). Shock and hypovolemia
Etiology. Acute gastritis complicates toxic Ischemia
Portal hypertension
injury and major physiologic disturbances Hypotension
(Table 4-3). To determine the exact etiology,
correlation with the clinical features is required.
The major physiologic factors implicated any component of the mucosal barrier system.
in the development of acute gastritis are in- Mucosal ischemia is the common denominator
creased gastric acid secretion and failure of of stress-associated lesions, but reperfusion also

127
Gastrointestinal Diseases

significantly contributes to gastric mucosal injury numerous, small petechial hemorrhages (fig.
(22) . Systemic acidosis, a common finding in 4-4). Alternatively, the mucosa appears diffusely
shock, contributes to the development of mucosal hemorrhagic without a discrete lesion. In severe
erosions by lowering cellular pH levels. Cardiac diffuse hemorrhagic gastritis, the stomach may
dysfunction, hemorrhage, shock, and sepsis also be filled with blood.
redistribute blood flow away from subepithelial Radiographic studies reflect disease severity.
capillaries, causing mucosal hypoxia. The hypoxia Findings range from nonspecific thickening of
may persist after recove1y from the initial injury, the gastric folds and spasm, which are difficult
especially since mucosal arterioles contract, further to distinguish reliably from normal, to frank
reducing tissue oxygenation (72). ulceration (fig. 4-5). Classic air-contrast fluoros-
Pathophysiology. Hypoxia directly damages copy shows multiple, tiny contrast collections
the mucosa via oxygen metabolic deprivation, in shallow erosions.
tissue acidosis, vascular compromise, and muco- Microscopic Fin d ings. Mucosal changes
sal congestion, thereby destroying mucosal de- range from focal hyperemia, edema, surface
fenses and rendering the mucosa vulnerable to erosions, and acute inflammation to massive
acid and peptic attack. Neutrophils play a major mucosal necrosis, sloughing, ulceration, and
role in generating both ischemic and reperfu- eventual scarring (figs. 4-6, 4-7). The number
sion injury (38) . They release vasoactive media- and types of inflammatory cells present depend
tors that modify vascular tone, reduce mucosal on the etiology.
blood flow, and increase vascular permeability. Early acute gastritis exhibits superficial muco-
This leads to loss of normal mum-sal cytopro- sal inflammation, edema, and hyperemia with
tection, allowing mucosal injury to progress be- subepithelial hemorrhage but without actual
yond what would otherwise have resulted from erosion formation. Such a lesion may be difficult
the initial injurious event. Neutrophil-derived to distinguish from biopsy trauma. More severe
oxygen-free radicals also cause cellular damage. disease shows extreme vascular congestion and
Clinical Features. Patients with acute gas- dilatation with lamina propria hemori:hage (figs.
tritis typically present with gastrointestinal 4-6, 4-7). The mucosa contains superficial fibrin
pain and bleeding. Bleeding begins 3 to 7 days deposits (fig. 4-7) .
following a physiologically stres-sful event or Erosions result in tissue loss that does not
following the ingestion of injurious substances. extend into the submucosa. Sloughed necrotic
The bleeding ranges from occulf'" blood loss to tissue lies above a relatively normal mucosa
massive hemorrhage originating from innumer- (fig. 4-7). The eroded cavity may contain an
able foci of mucosal damage. When erosive exudate of proteinaceous fluid, cellular debris,
gastritis evolves into acute or chronic ulcers, the neutrophils, and red blood cells.
bleeding becomes more severe and hematemesis During its acute phase, acute gastritis shows
may result. vascular engorgement, interstitial hemorrhage,
Gross Findings. Acute gastritis is hemorrhag- superficial necrosis, neutrophils in the pits
ic or nonhemorrhagic, erosive or nonerosive. and glands, and variable epithelial damage.
Erosive gastritis and ,stress ulcers typically ap- During the healing phase, there is epithelial
pear as multiple lesions located anywhere in the regeneration (fig. 4-8), pit elongation, nuclear
stomach, although they tend to predominate enlargement, mucus depletion, and numerous
proximally. Erosions are discrete, superficial, mitoses. The superficial epithelium acquires a
oval or circular areas of mucosal necrosis and pseudostratified or syncytial appearance. Re-
tissue loss measuring less than 5 mm in diameter generating epithelium may exhibit alarming
(usually less than 2 mm). They typically have cytologic features that should not be mistaken
sharply defined edges (fig. 4-3) . Ulcers, if pres- for carcinoma. Table 4-4 compares the features
ent, usually measure less than 1 cm in diameter. of regenerative and neoplastic mucosae.
The ulcer base appears grayish yellow and hem- Differential Diagnosis. The differential diag-
orrhagic, with slightly raised, congested, regen- nosis of acute gastritis includes chemical gastro-
erative margins. The intervening gastric mucosa pathy, drug-induced gastritis, infectious gastritis,
often appears diffusely congested and contains and a number of other entities (Table 4-3).

128
Diseases of the Stomach

Figure 4-4
EROSIVE GASTRITIS
Gross appearance of the stomach opened along the greater curvature.
Left: Diffuse involvement of the gastric and duodenal mucosa by erosive changes. Both sites show marked mucosal
erythema without specific punctate hemorrhages.
Right: Erosive changes are confined to the proximal stomach and duodenum. Both diffuse and punctate lesions are
identified.

Figure 4-5
EROSIVE GASTRITIS
A spot radiograph of the
gastric fundus from a double-
contrast upper gastrointestinal
study shows multiple, complete,
varioliform, shallow erosions
surrounded by halos of edema.
The pattern is thought to be
more typical of chronic erosive
gastritis than acute hemorrhagic
gastritis in which the erosions
are often less complete and less
obvious radiographically. (Fig. 2
from Pop lack W, Paul RE, Gold-
smith M, et al. Demonstration of
erosive gastritis by the double-
contrast technique. Radiology
1975:117;519-21.)

Treatment and Prognosis. Treatment con- ies involve the production of vasoconstriction,
sists of removal of the inciting factor, acid reduc- diversion of gastric mucosal blood flow, and
tion with antisecretory agents, and administra- the administration of specific etiologic agents
tion of mucosal protectants, such as sucralfate. in various types of animals.
The acute gastritis usually heals days to weeks
Helicobacter Pylori Gastritis
following removal of the causative factor(s). In
patients with deeper lesions, complete regenera- Defin ition . Helicobacter pylori (HP) gastritis
tion of the gastric glands rarely occurs and mild includes the entire spectrum of gastric mucosal
mucosal scarring results. changes induced by HP infections.
Anim al Models. Numerous animal models Dem ography. HP infections occur world-
exist for producing acute gastritis. Animal stud- wide, and the age at which a patient becomes

129
Gastrointestinal Diseases

Figure 4-6
EROSIVE GASTRITIS
A: Fibrin thrombi and an eosinophilic coagulum are
often present at the surface. The surface epithelium becomes
denuded and the upper portions of the pits lack their
epithelial lining. This pattern mimics that seen in early
intestinal ischemia (see chapter 7) .
B: The superficial mucosa appears congested and shows
interstitial and subepithelial hemorrhage.
C: Higher magnification view of B.

' .. - ..
. ~ -4.... ~'\

:..
' .,,. .. ~er ..

-~ Figure 4-7
. .' " . ;.
' ·'
. . EROSIVE GASTRITIS
A: Extravasated red blood cells and edema replace the
normal architecture of the lamina propria .
B: A coagulum of extravasated red blood cells, dying
epithelial cells, and inflammatory cells is present. No
epithelium is identifiable on the surface.

.,..
C: Often, superficial portions of the lesion consist of
areas of coagulation necrosis and dying cells .

130
Diseases of the Stomach

infected reflects local h ygiene. High-density


living facilitates disease transmission and cor-
relates with a lower socioeconomic status, a fam-
. ily history of peptic ulcer disease, and pediatric
HP-related gastrointestinal illnesses. Infants and
children are most susceptible to HP infections.
HP infection is transmitted person-to-person
(77), from drinking infected water (47), and by
the fecal-oral route (67).
· The prevalence of HP infections increases
rapidly with age. Infection prevalence in devel-
oping countries can be as high as 75 percent by
age 25. In industrialized countries, 60 percent
or more of patients over age 60 have evidence
of HP infection. In the United States, blacks (70
percent) and Hispanics have higher rates of in-
fection than whites (34 percent) (58). Obesity or
type 11 diabetes predisposes to HP colonization
secondary to decreased gastric motility.
Pat h op hysiology. Bacterial motility and the
production of various enzymes, cytotoxins, and
hemolysins are important in the pathogenesis
of HP-associated gastritis and gastric ulcers. HP
normally resides in the unstirred layer overlying
the gastric mucosa. The organisms move down
through this viscous environment to attach Figure 4-8
to the apical cell membranes of foveolar cells MUCOSAL REGENERATION
(fig. 4-9), preferentially attaching at or near FOLLOWING EROSIVE GASTRITIS
intercellular junctions. Bacterial adhesins rec- The epithelial cells appear mucin depleted, with prom-
ognize specific cell surface proteins, facilitating inent nuclei increasing the nuclear to cytoplasmic ratio.

Table 4-4
COMPARISON OF REGENERATIVE VERSUS NEOPLASTIC MUCOSA

Change Regeneration Neoplasia


Cellular immaturity Present Present
Mucin loss Present Present
Increased N/C ratio" Usually absent, but may be present Present
Nuclear atyp ia If present typicall y minimal Us uall y present
Basa l location of nuclei Usually retai ned Ofte n lost
Atypical mitoses Us ually absen t Often present
Nucleoli Prom in en t and sin gle Multiple an d irregular in size and sh ape
Glandular architectu re Usually retained, with glands Often distorted; individual glands m ay
lying in parallel with one another appear very irregular
Relationship to intestin al May involve metaplastic epithelium Often in volves metaplasti c epithelium,
meta plasia especially in intestinal type gastric cancers
Acute inflammatory backgroun d Usually present Usually absent unless ulcerated
Chronic inflammatory background May be present Always prese nt unless atrophy has occurred
"N/C ratio =n uclear to cytoplasmic rati o.

131
Gastrointestinal Diseases

Figure 4-9
HELICOBACTER PYLORI
Left: Organisms are adherent to the foveolar epithelium.
Right: Numerous organisms lie in the muctnous layer overlying the epithelium. (Left and right figures are stained with
Alcian yellow. Mucin stains yellow; organisms stain blue.)

epithelial colonization (31,37). Bacteria unable promotes complement-dependent phagocytosis


to adhere to the epithelium are eliminated from and the killing of HP by neutrophils. Secretory
the mucosa. · IgA synergizes with IgG to promote antibody-
Differences in the availability of specific dependent cell-mediated cytotoxicity by human
receptors have been suggested as a nieans to neutrophils, monocytes, and lymphocytes.
explain genetic differences in susceptibility High levels of HP-specific IgG antibodies cor-
to infection with HP (21) . HP weakens the relate with severe antral gastritis and dense HP
intercellular junctions, allowing the organisms antral colonization. Some antibodies cross react
to penetrate junctional complexes and move with the gastric mucosa, contributing to the
down along lateral cell membranes ·(fig. 4-9). As development of chronic gastritis (53).
a result, intercellular spaces widen..and fill with Bacterial products mediating tissue injury
neutrophils. The latter phagocytize the HP. HP include lipopolysaccharides (61), chemotac-
also alters mucin release into the gastric lumen tic factors (32), vacuolating cytotoxin (VacA)
and causes mucous granule depletion, which, (56), cytotoxin-associated antigen (CagA) (19),
together with bacterial enzymes, results in loss of heat shock proteins (50), and outer membrane
mucosal barrier integrity, allowing mucosal acid inflammatory protein (81). The presence of
and pepsin diffusion to further contribute to mu- CagA is associated with a more prominent
cosal damage. HP also promotes neutrophil adhe- inflammatory tissue response and an increased
sion to endothelial cells and vascular emigration, risk of symptomatic outcome (20,71).
activities mediated by 'adhesion molecules on Relationship of HP to Gastric Diseases. HP
both the endothelium and neutrophils. plays a significant role in the genesis of several
HP infections generate significant cellular gastric diseases (Table 4-5). The development of
and humoral responses via antigenic stimula- gastritis, ulcers, gastric carcinoma, and gastric
tion of mucosal monocytes and T cells. These in- lymphoma all involve interactions between
flammatory cells produce numerous cytokines, environmental (i.e., infection with HP) and
prostaglandins, proteases, and reactive oxygen genetic factors (Table 4-6). The risk for develop-
metabolites which further damage the mucosa. ing gastric ulcers is highest in the nonatrophic
Some of the cytokines promote adhesion of leu- forms of gastritis, whereas cancer is associated
kocytes to endothelial cells; others recruit addi- with severe atrophic gastritis.
tionalleukocytes to the infected site. Stimulated Identification of HP Infection . Diagnostic
B cells differentiate into immunoglobulin (Ig) tests for HP include bacterial culture, histologic
M, IgA, and IgG antibody-producing cells. IgA or cytologic examination, rapid urease-based

132
Diseases of the Stomach

Table 4-5 Table 4-6


DISEASES SHOWING A STRONG RELATIONSHIP HELICOBACTER PYLORI-ASSOCIATED
WITH HEL/COBACTER PYLORI INFECTION DISEASE COMPARISON

Chronic gastritis High Acid Secretors Low Acid Secretors


Chronic active gastritis Antral gastritis Antral and corpus gastritis
Health y corpus Impaired antral and
Multifocal atrophi c gastritis
Increased antral gastrin corp us function
Follicular gastritis
du e to lost D-cell fu n ction Increased antra l gastrin
Gastric and duodenal ulcers Increased acid Decreased acid
Gastric adenocarcinoma Increased risk of duoden al lncreased gastric can cer
ulcer
Gastric lymphoma

tests, carbon 13 and carbon 14 breath tests, and The presence of radiolabeled C0 2 in expired air
serologic studies. Histologic examination equals confirms the presence of HP. Such tests are rapid
or even surpasses culture, especially when posi- and reasonably easy to perform. The test is often
tive. The patchy nature of the infection, how- used to confirm eradication of the infection.
ever, requires examination of a minimum of Another new noninvasive diagnostic test is a
two biopsies: one from the gastric antrum and stool antigen test (HpSA test). Sensitivity and
one from the body. The greater the number of specificity of this test vary compared to histo-
biopsies, the greater the diagnostic yield, espe- logic examination and urea breath tests (58J4).
cially in individuals with low bacterial densities. Various HP strains can be differentiated us-
Recommendations to maximize diagnostic yield ing restriction fragment length polymorphism
include the use of large-cup biopsy forceps, ob- (RFLP) analysis of polymerase chain reaction
taining at least three samples (from the lesser (PCR)-amplified DNA . Antibiotic-resistant
curve angularis, the greater curve prepyloric forms of the organism may be detectable by
antrum, and greater curve body), proper mount- ribotyping. Ribotyping also creates genetic
ing and preparation of specimens, and use of fingerprints and allows epidemiologic studies
an appropriate stain (35). to be performed on HP organisms.
The occasional need for an immediate diagno- Clinical Featu res. The clinical features of
sis prompted the development of the more rapid HP-associated gastritis include the presence of
Campylobacter-like organism (CLO) test, which upper abdominal pain, dyspepsia, and emesis.
is based on bacterial urease production. Gastric Many patients remain asymptomatic.
brushings or tissues are placed in a urea solution. Gross Findings. Endoscopic changes include
The HP, if present, produce urease, resulting in several antral changes, including erosions, mu-
ammonia production. The ammonia alkalinizes cosal nodularity, spotty erythema, and altered
a solution that contains a pH-sensitive indicator mucosal markings. Alteration in the endoscopic
causing a color change (fig. 4-10) . appearance of collecting venules is helpful in
Since culture, cytologic or histologic exami- differentiating normal from HP gastritis (63).
nation, and rapid urease-based examinations all Microscop ic Fin din gs. HP, a Gram-negative,
require endoscopy, noninvasive diagnostic tests motile, flagellated bacterium, measuring ap-
that do not require an endoscopic procedure proximately 0.3 pm in width and 5 pm in
were developed. The most popular of these are length, generally assumes a curved, sinuous,
the carbonl3 and carbon14 breath tests. Pa- or gently spiraled shape (fig. 4-9). HP is readily
tients with possible HP infection receive orally identified in hematoxylin and eosin (H&E)-
administered carbon-labeled urea. Bacterial stained sections as thin, wavy, blue rods lying
urease, if present, releases the labeled carbon in the mucus overlying or attached to foveolar
that is absorbed into the blood, converted to epithelium (fig. 4-1n in the crevices between
bicarbonate, and expired as radiolabeled C0 2 . the foveolar cells, or within the pit lumens .

. 133
Gastrointestinal Diseases

Detect '!le 11rease enzyme of


H11icobacter pylori
• Positive
Figure 4-10 = Negative Manufactured by
Delta West Pty Ltd
CLO TEST FOR H. PYLORI U.S Patent No 4,748,113 15 Brod1e Hall Drove
U.S Olstnbutor Tn·Med Specoaltoes Inc. Benrtey 6102
The upper slide is negative; 9531 Alden, l•ne~a KS 66215 Western Australia
the lower slide, positive. The
calor change in the well of the
lower slide is a result of urease
Detects tile urease enzyme of
reaction.
Helicokacter pylori
= ~ositive

= Negative Manufacture!! by
Delta West Pty ltd
U.S Patent No 4.748,113 15 Brodte Hall Drove
US Dlstnbutor Tn·Med Specialfles lnc Bentley 6102
9531111den, Lenexa KS 66215 Western Australia

Figure 4-11
H. PYLORI GASTRITIS
Several fragments of gastric
epithelium are present. Those
with residual mucin in the
foveolar cells are covered by
numerous H. pylori organisms.

HP sometimes become coccoid in shape when use of monoclonal antibodies may be especially
patients receive antibiotics, but helicobacillary helpful in identifying coccoid forms. We use an
forms invariably coexist with the coccoid forms. H&E-stained section to examine the biopsy, and
11, ·
Various special stains enhance bacterial if organisms are easily seen in such a preparation,
detection (Table 4-7) . A combination of Steiner, additional special stains are not used unless specifi-
hematoxylin, and Alcian blue stains (the Genta cally requested by the clinician. If we see chronic
stain) has the advantage of combining a silver- active gastritis and do not see obvious HP, then we
based stain for the organism and a stain that will perform special stains. We formerly used the
identifies areas of intestinal metaplasia on one Diff-Quik stain, but have recently replaced it with
slide (36). It also allows a more accurate distinc- an immunohistochemical/immunostain because
tion of the bacteria from mucinous debris. The the latter is easier tci interpret.

134
Diseases of the Stomach

Table 4-7
STAINS USED TO DETECT
HEL/COBACTER PYLORI INFECTION

Acridine orange Gram


Alcian yellow Immunohistochemical staining
Brown-Hopps Loeffler methylene blue
Cresyl violet Stein er
Dieterle silver Toluidine blue
Diff-Quik Warthin-Starry
Gent a Wright-Giemsa
Giemsa

HP-Associated Acute Gastritis . HP gastritis


always involves the antrum, but it may dif-
fusely affect the remaining stomach. HP infec-
tions begin as an acute gastritis with a marked
neutrophilic infiltrate in the mucous neck
region. Neutrophils do not usually infiltrate
the superficial epithelium where the organisms
are located. Both the neutrophils and the HP
destroy the epithelium, causing mucous neck
cell hyperplasia. The toxin produced by the
organism induces cytoplasmic swelling and
Figure 4-12
vacuolization, micropapillary change, mucin
loss, desquamation of surface foveolar cells, and CHRONIC ACTIVE GASTRITIS
erosions, resulting in loss of epithelial mucosal Top: This area of the mucous neck region contains
barrier function. Pure acute gastritis is almost mitotic figures and is infiltrated by neutrophils. The
surrounding lamina propria contains a mononuclear cell
never seen; by the time patients are biopsied, infiltrate consisting of lymphocytes and plasma cells;
they usually have chronic active gastritis. occasional neutrophils are present.
Chronic Active (Nonatrophic) Gastritis. In Bottom: Area of the mucous neck demonstrates mitoses
chronic active gastritis, the changes seen with and nuclear enlargement.
acute gastritis are superimposed on a back-
ground of chronic inflammation (fig. 4-12). mitotic activity, and hyperchromatic stratified
Neutrophils, eosinophils, basophils, macro- nuclei, changes sometimes mimicking epithelial
phages, monocytes, plasma cells, and mast cells dysplasia. The enlarged nuclei retain smooth,
infiltrate the mucosa. Neutrophils infiltrate the regular nuclear membranes. Within a few days
lamina propria and mucous neck region of the of HP eradication, the surface changes rapidly
gastric glands. In severe infections, neutrophilic reverse, and the epithelial cells acquire their
aggregates in the pit lumens form abscesses. normal shape and spatial organization. When
The superficial epithelium degenerates and active superficial gastritis becomes quiescent,
the epithelial loss leads to mucous neck cell the acute inflammation, edema, and vascular
hyperplasia . This results in elongated, dis- congestion disappear, and the epithelium re-
torted, tubular, and pseudopapillary structures. turns to normal. The lamina propria still con-
Regenerating cells form a multicellular layer tains increased numbers of mononuclear cells.
with indistinct intercellular borders, creating Early, the chronic inflammation, which
syncytial polypoid excrescences. The regener- consists of dense lymphocytic and plasma cell
ating mucous neck cells are characterized by infiltrates, remains confined to the superficial
mucin loss, cytoplasmic basophilia, increased gastric mucosa, often along the lesser curvature

135
Gastrointestinal Diseases

in the antrum. The lymphoplasmacytosis of the


superficial lamina propria then extends into the
glandular compartment. With time, the inflam-
mation becomes confluent and transmucosal.
Lymphoid aggregates develop in over 80 percent
of HP-infected patients, creating a lesion termed
follicular gastritis (fig. 4-13). Follicular gastritis,
an immune response to the bacteria, is most
prominent in the antrum and is significantly
less prevalent proximally. Its presence serves
as a useful histologic marker of HP infection.
Eventually, most patients with chronic HP in-
fections develop chronic pangastritis, followed
by multifocal atrophy. These changes result
from both the infection and the inflammatory
infiltrate. Additionally, HP-associated antibod-
ies that cross react with the gastric nrucosa and
other factors, such as bile reflux and dietary
irritants, induce further mucosal damage. As
atrophy develops, areas of intestinal metaplasia
replace the native gastric mucosa. ~
Chronic Atrophic Gastritis. In some individu-
als, chronic active superficial gastritis progresses
to atrophic gastritis (55). Such progression leads
to three patterns of atrophic gastritis: body pre-
dominant (diffuse corporal) atrophic gastritis,
antral predominant atrophic gastritis, and both
antral and body (multifocal) atrophic gastritis.
Antral predominant atrophic gastritis is the Figure 4-13
most common and multifocal atrcphic gastritis FOLLICULAR GASTRITIS
is the least common of the three (51). Prominent lymphoid aggregates form in the basal
The antral mucosa shows loss of antral glands, portion of the mucosa. They often contain germinal centers,
which can be identified by a decrease in the as in this case.
mucosal thickness. The atrophic antral glands
are replaced by metaplastic glands, most com- gastritis are compared in Table 4-8. Lymphocytic
monly of the intestinal type. In the early stages, gastritis differs from the chronic gastritis associ-
prominent lymphocytic infiltration is present in ated with HP infection in that an intraepithelial
the mucosa; this is replaced by fibrosis in the later lymphocytosis dominates the histologic findings
stage. Atrophic gastriti5 in the body has similar (see figs. 4-30, 4-31). If there is a proliferation
histologic findings as autoimmune gastritis. of lymphoid tissues in HP gastritis, the intense
Differential Diagnosis. The differential di- mucosal lymphocytic and plasmacytic infiltrate
agnosis of HP gastritis depends in part on which may be severe enough to require distinction
features predominate histologically. The presence from a mucosa-associated lymphoid tissue
of chronic active gastritis with neutrophils in the (MALT) lymphoma.
mucous neck region is virtually pathognomonic Treatment and Prognosis. Eradication of the
for HP. Lesser degrees of active chronic gastritis infection is achieved in more than 90 percent of
may also be seen in patients with Helicobacter hei- patients with a 14-day regimen of proton pump
lmannii infections. Once the active inflammation inhibitors together with two antimicrobial
subsides, the entities in the differential diagnosis drugs. Treatment of dyspeptic symptoms with
of chronic gastritis are autoimmune gastritis and proton pump inhibitors may alter the pattern of
lymphocytic gastritis. Fundic gastritis and antral HP infection as HP migrates from the antrum to

136
Diseases of the Stomach

Table 4-8
COMPARISON OF ANTRAL AND FUNDIC GASTRITIS
Features Antral Gastritis Fundic Gastritis
Distribution Antral and then spreads proximally Fundus and body, spares the antrum
Etiology H. pylori infection combined with dietary Antibody against W,K•-ATPase proton
factors pump in parietal cells
Acid levels Variable Hypochlorhydria or achlorhydria
Gastrin levels Low or normal Elevated
Antibodies to parietal cells Absent Present
Antibodies to intrinsic factor Absent Present
Pernicious anemia Absent Present
Peptic ulcers Present Absent
Metaplasia Intestinal, ciliated, pancreatic Intestinal, pyloric, ciliated, pancreatic
Endocrine cell hyperplasia Not usually present ECL' hyperplasia, antral G-cell hyper-
plasia, carcinoid tumors
Chronic active gastritis Present Absent
Pepsinogen levels May be low, depending on disease extent Low
Foveolar hyperplasia May be present May be present
Complications Peptic ulcer disease, gastric carcinoma, Gastric carcinoma, gastric carcinoid
MALTb lymphomas tumors
"ECL = enterochromaffin-like.
bMALT =mucosa-associated lymphoid tissue.

the fundus and activity of the antral gastritis is Demography. H. heilmannii (formerly called
decreased. A test to confirm eradication should Gastrospirillum hominis) infects both humans
not be performed within 4 weeks of the end of (children and adults) and small animals.
the treatment course. Etiology. H. heilmannii is closely related to
The prognosis of patients with HP infections HP. Like HP, H. heilmannii is a Gram-negative,
depends on the extent of the damage by the urease-producing bacterium, but is larger (size,
time the infection is detected and treated. In 3.5 to 7.5 pm) and more tightly coiled (more
patients with early lesions, treatment of the than three coils) than HP (17,44).
infection may stop gastric damage. In individu- Clinical Features. Patients with H. heilman-
als with atrophic gastritis, peptic ulcer disease, nii infections either remain asymptomatic or
or some form of malignancy, the prognosis is present with a gastritis that is generally milder
determined by the more severe consequences than that produced by HP organisms.
of the infection. Microscopic Findings. H. heilmannii more
Animal Models. Numerous animal models commonly infects the gastric antrum than the
exist for evaluating the pathophysiology of gastric body. Unlike HP, which closely adheres
HP infections and their ability to generate the to the gastric epithelium, H. heilmannii organ-
gastritis as well as ulcer disease, lymphomas, isms usually lie free in the gastric lumen or
and carcinomas. deep in the gastric pits and necks of the pyloric
glands, with little or no epithelial attachment.
Helicobacter Heilmannii Gastritis
The organisms are easier to see than HP because
Definition. Helicobacter heilmannii gastritis of their larger size (fig. 4-14). The resulting
consists of those mucosal changes that result chronic active gastritis is milder than that pro-
from infection with Helicobacter heilmannii. duced by HP (45).

137
Gastrointestinal Diseases

Etiology. Infections with pyogenic bacteria


cause suppurative gastritis. The most common
organisms that cause emphysematous gastritis
are Clostridium sp, Escherichia coli, Streptococcus,
Enterobacter sp, and Pseudomonas aeruginosa. Mi-
crobial culture identifies the specific organism.
Clinical Features. Patients present with
dramatic episodes of nausea, vomiting, fever,
and severe, acute, noncolicky epigastric pain,
which are associated with leukocytosis. Com-
monly, peritonitis or pleural effusions develop.
Some patients develop localized abscesses. The
clinical course resembles that of patients with a
perforated viscus; shock and death often ensue.
Gross Findings. The dilated stomach appears
extensively necrotic, with marked mural thick-
ening due to the presence of intense submucosal
edema. Gas-filled spaces are present and fibrin-
ous serous adhesions may be seen.
Microscopic Features. There is marked acute
inflammation, with or without microabscesses;
prominent edema; and hemorrhage. In some
cases, the mucosa appears focally necrotic; in
others, the mucosa is completely destroyed
and covered by a mucopurulent, exudate.
Widespread intravascular thrombosis involv-
ing mural vessels causes secondary ischemic
Figure 4-14 gangrenous necrosis. Transmural inflammation
H. HE/LMANN/1 INFECTION develops in severe cases. The muscularis propria
Long, tightly coiled bacteria are in.rthe mucus. The
appears variably inflamed and necrotic. Air
length (10 to IS J..lm) and coiled appearance differentiate spaces, similar to those in pneumatosis intesti-
H. heilmannii from H. pylori. (Fig. 2-30 from Emory TS, Car- nalis, are present. A Gram stain demonstrates
penter HA, Gostout C], Sobin LH. Atlas of gastrointestinal bacteria in the tissues.
endoscopy & endoscopic biopsies. Washington DC: Armed
Forces Institute of Pathology; 2000:91.)
Treatment and Prognosis. The mortality rate
approaches 100 percent unless the affected part
of the stomach is resected.
Treatment. Treatment is the same as for HP
gastritis. CHEMICAL GASTROPATHY
Definition. Chemical gastropathy is the pres-
Suppurative Gastritis
ence of foveolar hyperplasia, muscle fibers in
Definition. Suppurative gastritis is a severe the lamina propria, edema, and vasodilatation
form of gastritis resulting from bacterial infec- in the absence of an increase in acute or chronic
tion in patients with poor host defenses. It con- inflammatory cell infiltrates. Reactive gastropa-
sists of a marked acute inflammatory reaction thy is an alternative term for this condition;
and abscess formation in the gastric wall. When however, the morphologic changes of chemi-
air-filled spaces are also present, the entity may cal gastropathy indicate a number of specific
be termed emphysematous gastritis. etiologies and that is why we prefer to use more
Demography. Most examples of suppurative specific terminology than reactive gastropathy.
gastritis antedate the antibiotic · era and usu- Etiology. Chemical gastropathy results from
ally affect severely debilitated individuals with the presence of surface damaging agents in the
chronic illnesses. gastric lumen, including alkaline reflux, alcohol,

138
Diseases of the Stomach

nonsteroidal antiinflammatory drugs (NSAIDs), Gross Findings. The most common endo-
and probably a host of less well-defined eti- scopic abnormality in chemical gastropathy is
ologies. Similar changes also occur in uremic the presence of intramucosal hemorrhage; this
patients. The histologic features of all of the can vary in size from petechiae to large ecchy-
chemical gastropathies resemble one another, moses. There may be slow oozing rather than
making it impossible to determine the exact rapid blood loss.
etiology, in the absence of identifiable bile in Microscopic Findings. Chemical gastro-
the biopsy or a pertinent clinical history. pathy is suspected when pit expansion, mucus
Alkaline reflux gastritis develops in patients depletion, and superficial edema are present in
with abnormal pyloric sphincter function from the absence of an active inflammatory infiltrate,
previous surgical intervention, chronic alcohol bacteria, atrophy, metaplasia, ulcers, polyps, or
ingestion, or aging. Reflux can occur any time enlarged fold disease. The histologic features are
after the initial operation, and its onset may be subtle and often overlooked unless suspected.
delayed for decades. The surgical interventions Gastropathy may not even seem to be present.
that can cause secondary alkaline reflux include The principal histologic features are listed in
partial gastrectomy with anastomosis, truncal va- Table 4-9. All of the listed features may be pres-
gotomy with pyloroplasty, and cholecystectomy. ent, but are not needed to make the diagnosis
In reflux gastritis, alkaline secretions, pan- (fig. 4-15) .
creatic enzymes, and bile salts that are present The foveolar cells appear mildly mucin de-
in the duodenal contents damage the gastric pleted and vacuolated, especially in patients
mucosa. Bile salts increase mucosal permeabil- who have undergone previous gastric surgery.
ity to hydrogen ions by binding to the apical The lack of an inflammatory response contrasts
end of the foveolar cells. Bile inhibits mucosal with the degree of the hyperplasia.
bicarbonate secretion and therefore decreases Differential Diagnosis. The histologic
the pH gradient between the epithelium and the changes overlap with those seen in alcoholic
luminal acid (46) . The acid then either causes gastropathy, stress gastropathy, or NSAID-
vasoconstriction or directly damages the muco- induced gastropathy. Therefore, it is impossible
sal epithelium. The amount of reflux often cor- to determine the etiology of the gastritis (un-
relates with symptom severity, but endoscopic less bile is found in the biopsy) in the absence
and histologic features rarely correlate with one of the appropriate history, and even then it
another. The most severe changes occur in the may be impossible. Hyperplastic polyps may
antrum, where often there is clear-cut evidence have some overlapping features with chemical
of gastritis at the time of endoscopy, namely, gastropathy and they are frequently associated
hyperemia, edema, friability, and bile staining with prior gastrectomy. A clinical history of
of the gastric mucosa. The pathophysiologic polyp is helpful in establishing the diagnosis.
effects of NSAIDs are discussed in the section Often, however, the endoscopist describes bi-
on drug-induced gastritis. opsies from areas of chemical gastropathy as
Uremia damages mucosal barrier function and "nodular." Other features seen in hyperplas-
stimulates gastrin production (75). The latter tic polyps include cystically dilated glands,
results in cell proliferation in the mucous neck distorted glands with an irregular branching
region and preferential differentiation of stem and serrated appearance, and expansion of the
cells into parietal and enterochromaffin-like lamina propria by the glands.
(ECL) cells. The surface epithelial cells show Treatment and Prognosis. Treatment con-
increased acidification from the acid produced sists of administering prokinetic agents. In
by the expanded parietal cell mass. Mucus pro- reflux gastropathy, cholestyramine may bind
duction decreases, resulting in a thinned mucus bile salts and reduce the mucosal injury. Occa-
gel layer, which in the face of the increased acid sionally, surgical diversion is necessary.
levels, leads to further mucosal damage. Abnor- Animal Models. Numerous animal models
mal bile salt formation and increased bile acid exist for the production of alkaline reflux gas-
production also cause uremic gastropathy and tropathy, as well as other forms of chemical
ulcer formation. gastropathy.

139
Gastrointestinal Diseases

CHRONIC GASTRITIS A concise, widely accepted classification


Chronic gastritis is any gastritis in which the scheme for chronic gastritis has not emerged.
histologic features are dominated by the pres- The classification scheme commonly utilized is
ence of a chronic inflammatory cell infiltrate. the modified Sydney system (fig. 4-16) (27,29).
Chronic gastritis can be classified as active when Its goal is to relate the gastritis to its etiology.
neutrophils are present. The Sydney classification system requires that
biopsies be examined from both the antrum and
the body, since each area is assessed separately.
Five histologic variables are independently
Table 4-9
graded (fig. 4-16). Table 4-10 lists the definition
HISTOLOGIC FEATURES OF CHEMICAL GASTROPATHY and grading guidelines for each of the histologic
Mucosal edema features used in the Sydney system.
Hypercellularity and expansion of the gastric pits (with
Nonspecific chronic gastritis has many
increased mitotic activity) resulting in glandular etiologies, which produce similar or overlap-
elongation and tortuosity ping histologic features. This results in a poor
correlation among clinical symptoms, endo-
Capillary congestion and vasodilation within the
superficial lamina propria
scopic features, and histology. There are three
distinct forms of chronic gastritis based on the
Mucin depletion
topographic distribution of the damage: diffuse
Foveolar hyperplasia and villiform transformation of antral, fundic, and multifocal gastritis. Diffuse
the mucosa .. antral gastritis (DAG) and multifocal antral
Increased numbers of smooth muscle fibers in the gastritis (MAG) are sometimes referred to as
lamina propria type B, or environmental, gastritis, and they
Absence of acute inflammation except in the presence share HP infection as an etiologic factor. The
of an erosion major difference between the two is--that DAG
Bile in the glands (helpful .if present, but not always seen)
is not atrophic, and acid and pepsin secretion
probably also play an etiologic role .

...

Figure 4-15
CHEMICAL GASTROPATHY
Above: A patient taking nonsteroidal antiinflammatory dmgs (NSAIDs)
has pronounced tortuosity of the glands and edema of the lamina propria.
Right: In a patient with reflux due to prior gastric surgery, the mucosa
is minimally inflamed and glands are branched and appear regenerative.

140
Diseases of the Stomach

ETIOLOGY TOPOGRAPHY Figure 4-16

Etiology Antral SYDNEY SYSTEM OF


gastritis CLASSIFICATION
Pathogenic FOR CHRONIC GASTRITIS
associations Fundic
gastritis Pathologic features are
evaluated in several topographic
Pangastrltis areas. Five features are graded
and other features that may be
present are ungraded.

Table 4-10
DEFINITIONS AND GRADING GUIDELINES FOR THE SYDNEY SYSTEM

Feature Definition Grading Guidelines


Chronic inflammation Increase in lymphocytes and plasma Mild, moderate, or severe increase in density
cells in the lamina propria
Activity Neutrophilic infiltration of the lamina <1/3 of pits and surface infiltrated= mild;
propria, pits, or surface epithelium 1/3-2/3 =moderate; >2/3 = severe
Atrophy Loss of specialized glands from Mild, moderate, or severe loss
either antrum or corpus
Intestinal metaplasia Intestinal metaplasia (all subtypes) <1/3 of mucosa involved =mild; 1/3-2/3 =
of the epithelium moderate; >2/3 = severe
H. pylori Density of Helicobacter-like organisms Scattered organisms covering <1/3 of the surface
overlying epithelium = mild colonization; large clusters or a
continuous layer >2/3 of surface= severe;
intermediate numbers= moderate

The mucosa of patients with chronic gastritis dinavian or northern European origin and is
is often sampled in order to establish the pres- rare among other ethnic groups. Not only do
ence of the gastritis, to delineate its geographic patients have demonstrable antibodies against
extent, to judge the degree of activity, to detect parietal cells, but so do their first-degree rela-
the presence of HP organisms that may be heat- tives, suggesting that genetic influences play
ed, and to mle out the presence of complications a role in the pathogenesis of the disease (52).
such as peptic ulcer disease or various tumors. Etiology. The antibodies are directed against
the catalytic subunit ofthe H+K+-ATPase proton
Autoimmune Gastritis
pump and pepsinogen (59), and may develop
Definition. Autoimmune gastritis preferential- spontaneously. Patients receiving methyldopa
ly localizes to the fundus and body and results treatment also develop antibodies against pari-
from the presence of antibodies directed against etal cells and subsequent chronic autoimmune
parietal cells. Affected patients also often have gastritis (52). The gastritis disappears upon
antibodies against intrinsic factor and the gas- cessation of the drug. Atrophic autoimmune
trin receptor. Synonyms include fundic gastritis gastritis affects approximately 25 percent of
and type A gastritis. patients with dermatitis herpetiformis (69).
Demography. In most countries, only a Pathophysiology. The acid-secreting mucosa
minority of patients (less than 5 percent) with is progressively destroyed by immunologic in-
chronic gastritis have autoimmune gastritis jury directed primarily at the parietal cells; chief
(70) . The disease tends to affect people of Scan- cells, however, are also destroyed in the process.

141
Gastrointestinal Diseases

the presence of an elevated serum gastrin level


in the presence of achlorhydria is diagnostic.
Other patients present with the complications
of atrophic gastritis or the diagnosis is made dur-
ing the workup for other autoimmune disorders.
Symptoms referable to the gastrointestinal tract
include diarrhea, malabsorption, dyspepsia, or
symptoms related to a malignancy.
Gross Fin dings. The antrum is usually spared
with autoimmune gastritis except in severe cas-
es. The changes may coexist with HP-associated
gastritis. Gastric atrophy manifests as mucosal
thinning and loss of the rugal folds. The submu-
cosal vessels become increasingly more visible.
Endoscopically, the presence of easily discern-
ible gastric vasculature should alert the physi-
cian to the probability of atrophic gastritis . It is
useful for the endoscopist to determine the pH
of the resting gastric juice and biopsy all nod-
Figure 4-17
ules and visible lesions to exclude an associated
GASTRIC CARCINOID .. gastric carcinoid or other neoplasm (fig. 4-17) .
Gastric carcinoid is seen in the fundus of a patient with Microscopic Findings. There are three histo-
hypergastrinemia due to autoimmune atrophic gastritis. logic stages of autoimmune gastritis: superficial
gastritis, atrophic gastritis, and gastric atrophy.
Eventually, this results in the complete loss of The distinction between these three..stages re-
the specialized oxyntic mucosa and oxyntic lates to the location of the inflammation in the
glandular atrophy. Hypochlorhydria or achlor- mucosa and the extent of the glandular atrophy.
hydria develops and serum pepsinogen group 1 In superficial gastritis, the inflammatory infiltrate
levels fall. The hypochlorhydria stimulates an- remains localized to the superficial mucosa lying
tral G-cell hyperplasia. Increased .rserum gastrin between the gastric pits, and glandular atrophy
levels lead to enterochromaffin-like (ECL)-cell is minimal or absent. The lamina propria infil-
hyperplasia in the oxyntic mucosa and foveolar trate contains lymphocytes and plasma cells.
hyperplasia. In atrophic gastritis, the inflammatory infiltrate
Patients with autoimmune gastritis often involves the entire thickness of the mucosa,
have pernicious anemia due to the presence of and there is marked glandular atrophy with a
an autoantibody to intrinsic factor that inhibits severe reduction in the number of parietal and
distal ileal vitamin B12 absorption. The develop- chief cells (fig. 4-18). In gastric atrophy, there is
ment of pernicious anemia, particularly irt the complete loss of the glands and minimal in-
elderly, is insidious, typically occurring 6 to 18 flammation. Eventually, the fundic mucosa is
years following the initial diagnosis of gastritis. completely replaced by metaplastic pyloric or
The patients often have autoantibodies directed intestinal type glands. Sequential biopsy studies
against other organs as well. As a result, they show that autoimmune gastritis progresses from
may have coexisting Hashimoto's thyroiditis, superficial gastritis to atrophic gastritis over a
idiopathic hypoadrenalism, idiopathic hypo- period of 15 to 20 years (23).
parathyroidism, or insulin-dependent diabetes. Patients with long-standing autoimmune
The postpartum state aggravates autoimmune gastritis develop antral G-cell hyperplasia as a
gastritis in some patients (16). result of achlorhydria. G cells can be present in
Clin ical Features. In individuals with perni- large numbers in the antropyloric mucosa, usu-
cious anemia, the diagnosis usually becomes ally exhibiting an irregular and random spatial
obvious because the patient presents with distribution that ranges between one and four
chronic megaloblastic anemia. Alternatively, cells/gland. The foveolar mucosa may become

142
Diseases of the Stomach

Figure 4-18
AUTOIMMUNE (FUNDIC) GASTRITIS
A: Low-power magnification shows hypercellularity in
the mucosal biopsy.
B: Higher magnification discloses glandular destruction
and a marked mononuclear cell infiltrate in the glandular
region.
C: Focal aggregates of mononuclear cells are both within
the lamina propria as well as within the epithelium. In this
patient, there are no residual parietal or chief cells.

hyperplastic once G-cell hyperplasia develops. next stage, designated as micronodular hyper-
Multifocal gastric ECL hyperplasia, micronests, plasia, consists of solid micronodular ECL cell
and multifocal carcinoid tumors also develop nests measuring 100 to 150 mm in size (the
in the atrophic and metaplastic gastric body average diameter of a gastric gland). These can
secondary to the G-cell hyperplasia in the antral be seen using H&E-stained sections and are
mucosa (fig. 4-19). variously described as argyrophil cell clusters,
ECL-cell hyperplasia passes through a series microcarcinoids, or endocrine cell micronests.
of stages, ranging from a diffuse increase in The micronests may be bounded by an intact
argyrophilic cells, through linear and nodular basement membrane contiguous with that of
aggregates, to intramucosal and frankly invasive the rest of the gland or lie in the basoglandular
carcinoid tumors. Simple hyperplasia, the earliest portion of the mucosa disassociated from the
stage, consists of a diffuse increase in ECL cells, glands lying freely in the lamina propria abut-
scattered singly or in clusters of up to three ting the muscularis mucosae. Still others may
cells/gland. The cells appear somewhat enlarged appear trapped within a widened and somewhat
and although they are diffusely distributed ragged muscularis mucosae.
throughout the upper, middle, and lower third Adenomatous hype1plasia consists of inter-
of the mucosal thickness, they appear more glandular micronodular lesions, each with an
prominent in the lower third. The hyperplastic intact basement membrane. As each micronod-
cells are present in the atrophic fundic glands ule enlarges, the basement membrane breaks
and pyloric metaplastic glands but not in the down, and the nuclear to cytoplasmic ratio
intestinal metaplastic glands. Linear hype1plasia increases. This dysplastic stage marks the bor-
is diagnosed when a linear, semilinear, or daisy derline between the clearly hyperplastic stages
chain-like configuration of ECL cells is present preceding it and the neoplastic stage of a fully
along the glandular basement membrane. The developed carcinoid tumor. These lesions range

143
Gastrointestinal Diseases

Figure 4-19
ENTEROCHROMAFFIN-LIKE CELL HYPERPLASIA
A: Hematoxylin and eosin (H&E) stain of a gastric biopsy in
a patient with fundic gastritis. At low magnification, numerous
small, dark, cellular nests are seen in the lamina propria.
B: When stained with an antibody to synaptophysin, both
the intraglandular proliferations as well as proliferations in
the lamina propria are highlighted in a specimen from the
same biopsy.
C: Endocrine cell hyperplasia and endocrine micronests
are in the lamina propria in another patient.

in size from 150 pm to 0.5 mm and progress malignant. The dysplasia always arises in the
from enlarging micronodules to microinvasive intestinalized mucosa. Some patients have ade-
lesions and nodules with newly for-med stroma. nocarcinomas and coexisting multiple carcinoid
The carcinoid stage is characterized by nodular tumors in a setting of diffuse endocrine cell hy-
infiltrating growths measuring over 0.5 mm. perplasia and autoimmune gastritis. Antrectomy
Differential Diagnosis. The differential reverses the oxyntic endocrine cell hyperplasia,
diagnosis of autoimmune gastritis has several but it is not used in the absence of endocrine
aspects. The first is determining whether the neoplasia. Multiple small carcinoids arising in
chronic gastritis is autoimmune or a form of en- the setting of chronic atrophic gastritis are usu-
vironmental gastritis, or possibly both diseases. ally indolent, and do not warrant gastrectomy.
The diagnosis rests on examination of biopsies Patients deficient in vitamin B12 require life-
from the oxyntic mucosa that show evidence of long B12 administration. In the United States,
gastritis, parietal and chief cell destruction, or endoscopic surveillance is not considered to
atrophy. The next consideration concerns the be cost-effective; however, endoscopy must be
presence of glandular atypia and determining performed should symptoms referable to the
whether the glands are reactive, dysplastic, or upper gastrointestinal tract develop.
"·'
malignant. The presence of antral G-cell hyper- Animal Models. A murine model of autoim-
plasia raises another set of diagnostic possibilities mune gastritis results from neonatal thymec-
(Table 4-11). IfECL hyperplasia is present, gastric tomy (63).
carcinoid tumor is a diagnostic possibility.
Chronic Antral Gastritis
Treatment and Prognosis. Autoimmune gas-
tritis predisposes to the development of gastric Definition. Chronic antral gastritis begins in
adenocarcinoma through an intervening step of the antrum and then extends proximally.
intestinal metaplasia. The metaplastic mucosa Demography. Antral gastritis accounts for
becomes dysplastic (fig. 4-20) and then frankly most cases of chronic gastritis. The incidence of

144
Diseases of the Stomach

Table 4-11
DIFFERENTIAL DIAGNOSIS OF HYPERGASTRINEMIA
Primary
Zollinger-Ellison syndrome
Primary G-cell hyperplasia
G-cell hyperresponsiveness
Secondary
·Chronic atrophic gastritis
Retained excluded antrum
Acromegaly
Gastric outlet obstruction
Long-term therapy with H,-receptor blockers or
proton pump inhibitors
Chronic renal failure
Post vagotomy
Hypercalcemia
Systemic mastocytosis

antral gastritis varies from country to country


and parallels that of gastric cancer. In countries
v.rith a high incidence of gastric cancer, such as Figure 4-20
Japan or Colombia, antral gastritis appears early INTESTINAL METAPLASIA IN AUTOIMMUNE GASTRITIS
in life and increases to affect approximately 90 Areas of intestinal metaplasia (top) sometimes become
percent of the population by age 60 (16). dysplastic (bottom).
Etiology. Major contributors to the develop-
ment of antral gastritis are HP infection and a
high salt and nitrite intake. Microscopic Findings. Early, the inflamma-
Clinical Features. Patients with antral gas- tion is confined to the superficial gastric mucosa
tritis frequently become symptomatic because (superficial gastritis). Chronic superficial gastritis
of associated peptic ulcer disease rather than usually progresses to the next stage, chronic
the gastritis per se. Some patients with antral atrophic gastritis (figs. 4-22-4-24), over a period
gastritis have excessive excretion of acid, pepsin, of 15 to 20 years (25). Inflammation extends
and gastrin. deep into the mucosa, damaging the glands
Gross Findings. The distribution of gross and and causing chronic atrophic gastritis. Intestinal
endoscopic abnormalities varies, depending on metaplasia develops. The inflammation is char-
whether the patient has the diffuse or multifo- acterized by an intense, interstitial, mononuclear
cal form of chronic antral gastritis. Grossly and infiltrate that consists of mature lymphocytes
endoscopically, the stomach may appear normal and plasma cells (fig. 4-22). Follicular gastritis
or it may show evidence of mild gastritis as evi- occurs frequently. The epithelium may appear
denced by the presence of mucosal erythema. mucin depleted and there may be elongation of
When atrophic gastritis develops, the stomach the pits. All stages in the evolution of chronic
becomes lined by a thin, smooth mucosa with gastritis often coexist within a single stomach.
loss of the rugal folds (fig. 4-21). In severe atro- The lesions first appear on the lesser curva-
phy, the mucosa appears translucent with promi- ture (25) and then on both sides of the antral-
nent submucosal veins showing through it. corporal junction in the shape of an inverted

145
Gastrointestinal Diseases

Figure 4-21
GROSS APPEARANCE OF
CHRONIC GASTRITIS
Often, the rugal folds are lost
and the mucosa appears thinned
and diffusely hemorrhagic.

Figure 4-22
CHRONIC SUPERFICIAL GASTRITIS
Above: Early chronic gastritis shows restriction of the mononuclear
cell infiltrate to the upper. mucosa. The infiltrate appears as a dense
basophilic band.
Right: Higher magnification of superficial epithelium and upper
lamina propria shows a dense mononuclear cell infiltrate.

V. The inflammation spreads proximally along


Chronic Atrophic Gastritis
the lesser curvature. These atrophic foci coalesce
and, in advanced cases, cover extensive mucosal Definition. Chronic atrophic gastritis is char-
areas. Eventually, the entire stomach may be acterized by a marked or complete loss of the
replaced by metaplastic mucosa. Fundic glands specialized glands of either the antrum or the
never completely disappear, however, and per- fundus, depending on the etiology of the un-
nicious anemia rarely develops. derlying chronic gastritis.

146
Diseases of the Stomach

Figure 4-23
CHRONIC ATROPHIC GASTRITIS
Left: Inflammation is present throughout the full thickness of the
mucosa.
Above: Higher magnification shows the inflammation in the lower
portion of the mucosa and some evidence of glandular atrophy.

Etiology. Chronic atrophic gastritis can af-


Metaplasia in Chronic Gastritis
fect patients with any form of chronic gastritis.
Microscopic Findings. The pathologic fea- Definition. Metaplasia is the replacement
tures of chronic atrophic gastritis depend on the of one mature cell type for another. Five major
etiology of the gastritis. Both chronic antral and types of metaplasia affect the gastric mucosa:
autoimmune gastritis show a marked inflamma- intestinal, pyloric, pancreatic, ciliated, and
tory infiltrate consisting of plasma cells, lym- squamous. These metaplasias are defined by
phocytes, and variable numbers of eosinophils the type of epithelium that replaces the gastric
in all levels of the lamina propria (fig. 4-22). The epithelium indigenous to a particular region.
inflammation leads to cell dropout from both Thus, pancreatic metaplasia consists of pancreatic
the pits and glands. The distance between indi- acini replacing part of the mucosa; intestinal
vidual glands increases and the reticulin fibers of metaplasia is the replacement of the gastric
the lamina propria collapse upon one another. glands or pits by either small or large intestinal
Chronic progressive atrophy of the specialized epithelium; pyloric metaplasia is the replace-
epithelium results in an almost total loss of ment of the oxyntic mucosa by antropyloric
acid- and pepsinogen-secreting cells in chronic glands; ciliated metaplasia is the replacement of
fundic gastritis and antral glands in chronic the gastric glands anywhere in the stomach by
antral gastritis. As the mucosa thins, and as ciliated epithelium. This epithelium often lines
glands disappear, the bases of the pits come to cystically dilated glands. In the rarest form of
rest on the muscularis mucosae. The muscularis metaplasia, squamous metaplasia, the gastric
mucosae becomes hypertrophic and sometimes mucosa is replaced by squamous epithelium.
splits, sending smooth muscle strands into the Demography. Metaplasias are very common
overlying lamina propria. In advanced atrophic in the stomach affected by chronic gastritis. The
gastritis, the glands disappear, the inflammation two most common forms of metaplasia are in-
recedes, and the cellularity of the lamina propria testinal and pyloric metaplasia. The risk factors
returns to normal. Increasing degrees of atrophy for developing intestinal metaplasia resemble
are associated with cystic glandular dilatation, those of gastric cancer in high-risk populations.
epithelial atypia, and metaplasia. Diets deficient in fresh fruits and vegetables

147
Gastrointestinal Diseases

Figure 4-24
CHRONIC ATROPHIC GASTRITIS
Left: This patient has severe atrophic gastritis. Almost all of the glands have disappeared and the mucosa has become
thinned. •
Right: The end stage of chronic atrophic gastritis is gastric atrophy, as seen here. There are virtually no glands remaining
and the mucosa is extremely thin. The normal architecture of the pits is also distorted.

combined with a high salt and nitrite intake are Ciliated Cell Metaplasia. Ciliated cells develop
common to both conditions (25,73). Chronic deep to areas of intestinal metaplasia. They de-
gastritis precedes the metaplasia. - velop in the mucosa of patients with gastric ul-
Etiology. The usual etiology of all the meta- cers, dysplasia, or adenocarcinoma. The affected
plasias is chronic gastritis. cells resemble antral rather than metaplastic
Clinical Features. There are no specific intestinal cells since they make pepsinogen. As
clinical features associated with intestinal the atrophic, cystically dilated glands enlarge, the
metaplasia. The clinical features are those of intrinsic pressure of the retained mucus results
the underlying chronic gastritis. "'" in cellular atrophy and ciliary disappearance.
Gross Findings. No specific gross findings Intestinal Metaplasia. Intestinal metaplasia is a
are associated with the various forms of meta- common form of gastric metaplasia. It begins at
plasia. The gross features reflect the underlying the antral-corpus junction in a patchy, multifo-
disorder. Intestinal metaplasia usually occurs in cal fashion, and then spreads both distally and
an atrophic stomach. proximally to involve the antrum and fundus.
Microscopic Findings. Pyloric Metaplasia. It occurs most frequently, and with the most
The earliest stage of pyloric metaplasia is the loss intensity, along the lesser curvature, at the
of the specialized cells in the oxyntic mucosa junction of the pylorus and corpus. This area
(fig. 4-25). Instead of giving rise to specialized of intestinal metaplasia frequently coexists with
peptic or parietal cells, the mucous neck cells a band of metaplasia on both the anterior and
give rise to a simpler, mucin-secreting glandular posterior gastric walls at the junction of the
epithelium. Ultimately, the metaplastic glands pylorus and corpus. Gastric resections stained
'-,• become indistinguishable from the antral for alkaline phosphatase highlight the extent
glands . Pyloric metaplasia first affects body of the intestinal metaplasia (73).
glands closest to the antral junction, producing Intestinal metaplasia originates from the
antral expansion at the expense of the body mucous neck region. Intestinal goblet and ab-
mucosa. It may be very difficult to determine sorptive cells replace the superficial epithelium.
whether pyloric metaplasia is present if the Initially, only the type of epithelium changes,
location of the biopsy is not known, especially but later the mucosal architecture acquires a
if the patient has had a previous gastrectomy small intestinal villiform shape, often exhibiting
with removal of the distal stomach. Paneth cells at the base of the glands.

148
Diseases of the Stomach

;.~ · ··
•" j
...

Figure 4-25
PYLORIC METAPLASIA
Above: This patient with chronic fundic gastritis had three types of
metaplasia, two of which are shown here: pyloric and pancreatic.
Right: Higher magnification shows the cytologic features of both the
pyloric and pancreatic metaplasias.

Figure 4-26
COMPLETE INTESTINAL METAPLASIA
Left: The superficial portion of the mucosa h as glands with a normal pit lining as well as others lined by metaplastic cells.
These cells resemble those seen in the small intestine.
Right: Higher magnification of the lower portion of an antral gland partially replaced by complete intestinal metaplasia.

Intestinal metaplasia is divided into two types mal small bowel with mucin-negative absorp-
that are often delineated by the use of special tive cells and Alcian blue-positive goblet cells.
stains. The earliest metaplastic change, small In colonic metaplasia, both neutral and acidic
intestinal metaplasia, consists of enterocytes mucin-producing goblet cells are present, but well-
with well-developed brush borders alternating developed absorptive cells are absent. This type
with sialomucin-secreting goblet cells. Paneth of metaplasia is also called type II, or incomplete,
cells may be present. This type of metaplasia is metaplasia (fig. 4-27) . The absorptive cells lack a
also referred to as type I, or complete, metaplasia well-developed brush border and the goblet cells
(fig. 4-26) (49) . The epithelium resembles nor- contain sulfomucins (49). Paneth cells are absent.

149
Gastrointestinal Diseases

The nature of the mucin present is best appre-


ciated using special stains. Normal gastric sur-
face epithelial cells contain periodic acid-Schiff
(PAS)-positive, Alcian blue-negative neutral
mucin. The sialomucin of complete intestinal
metaplasia is PAS positive, Alcian blue positive
at pH 2.5, but Alcian blue negative at pH 0.5
(fig. 4-28) . It also stains with high iron diamine
stains. Sulfomucin is weakly PAS positive but is
Alcian blue positive at pH 2.5 and pH 0.5, and
contains a high iron diamine content. Both
types of metaplasia contain endocrine cells in-
digenous to either the small or large intestine.
Pancreatic Metaplasia. Metaplastic pancreatic
acinar cells usually lie among, or at the bottom
of, the gastric glands, where they form single
or multiple nests and lobules (fig. 4-29). The
metaplastic cells have a truncated pyramidal
shape, a rim of deeply basophilic basal cyto-
plasm, and numerous small, acidophilic, weakly
PAS-positive, refractile granules in the middle
and apical cytoplasm (29). The nuclei appear
round, relatively small, and centrally or basally
located, with a prominent nucleolus. The size
of each lobule varies, measuring up to 1. 7 mm
in diameter. The mucous cells intermingle with
the acinar cells within the lobules (fig. 4-29).
Larger lobules contain tubules or small cystic
Figure 4-27 spaces reminiscent of dilated ductules. The
INCOMPLETE METAPLASIA metaplastic tissue continues into the gastric
.r
Incomplete metaplasia more closely resembles colon. glands. Less commonly, acinar cells lie scattered

Figure 4-28
INTESTINAL METAPLASIA
Alcian blue-periodic acid-
Schiff (PAS) stains both acidic
(blue) and n eutral (red) mucins.

150
Diseases of the Stomach

Figure 4-29
PANCREATIC METAPLASIA
Left: Low-power microscopy shows lobules of pancreatic cells among islands of pyloric metaplasia in a patient with
chronic autoimmune gastritis.
Right: Medium-power view shows both pancreatic lobules and antral glands. This section is from the cardia .

individually or in small foci among the gastric carcinoma is higher in patients with type II (co-
glands, sometimes with neuroendocrine cells. lonic) metaplasia than type I (small intestinal)
The presence of pancreatic metaplasia signifi- metaplasia (70).
cantly correlates with the presence of chronic
gastritis or intestinal and pyloric metaplasia in LYMPHOCYTI C GASTRITIS
the adjacent mucosa (29) . Definition. Lymphocytic gastritis, also termed
Gastric pancreatic cells occur in 3.4 percent chronic erosive gastlitis, is an intense, intraepithelial,
of pediatric patients. They occur in the antrum T-cell infiltrate involving the gastric pits and sur-
on a background of either normal or minimally face epithelium. In its most severe form, lympho-
inflamed mucosa, without coexisting atrophy cytic gastritis is diagnosed as varioliform gastJ·itis.
or metaplasia (54). Pediatric lesions differ from Dem ography. Lymphocytic gastritis affects
th ose seen in adults due to the absence of the 0.83 to 4.50 percent of individuals, mainly
small duct-like structures present in adult cases. middle-aged and elderly men (40,41,78).
Additionally, pediatric cases contain amphicrine Etiology. The etiology is unknown. Recent
cells with a hybrid cell phenotype consisting of findings provide compelling evidence that
acinar and endocrine differentiation. lymphocytic gastritis can occur as a manifesta-
Differential Diagn osis. The main entity in tion of celiac sprue or sprue-like disease (26).
the differential diagnosis is pancreatic hetero- It may occur as a part of the intraepithelial
topia. Metaplastic pancreatic tissue differs from lymphocytosis seen in celiac sprue along with
pancreatic heterotopia in that well-delineated lymphocytic enteritis and lymphocytic coli-
nodules of pancreatic parenchyma, which often tis (80) . Lymphocytic gastritis is also seen in
include ducts and their surrounding muscle fi- patients with HP infection (64). Patients with
bers and islets, are absent. Heterotopic pancreas gastric lymphoma have an increased prevalence
usually lies in the submucosa and muscularis of lymphocytic gastritis (60), as do patients with
propria, whereas pancreatic metaplasia lies in gastric adenocarcinoma (43). Associations with
the basal mucosa and superficial submucosa. Menetrier's disease (39,71), human immuno-
Progn osis. The presence of intestinal meta- deficiency virus (HIV) infection (80), Crohn's
plasia serves as a useful marker for the presence disease (77), and ticlopidine administration
of chronic gastritis. The risk of gastric cancer (18) have also been suggested. The entity may
increases in proportion to the extent of gastric result from some form of autoimmune injury
intestinal metaplasia. The risk of dysplasia and or hypersensitivity to some unknown antigen.

151
Gastrointestinal Diseases

It may also reflect the presence of some dietary


substance, reflux of duodenal contents, or an-
other as yet unidentified factor.
Clinical Features. Most patients with lym-
phocytic gastritis present with epigastric pain
resembling peptic ulcer disease, dyspepsia,
anorexia, and weight loss. It is possible that
some symptoms result from the presence of
concurrent disorders, such as celiac disease
or lymphocytic colitis. Other patients remain
asymptomatic.
Gross Findings. The characteristic endo-
scopic change is the presence of enlarged,
bumpy, hyperemic, rugal folds, which result
from alternating areas of mucosal hyperplasia
and erosion. The enlarged folds bear variably
sized and shaped nodules showi'hg surface
erosions, or aphthous ulcers surrounded by
mucosal hyperemia (41). Thick mucus covers
the irregularly thickened folds. The mucosal
elevations persist after the erosions heal, and
they may resemble sessile hyperplastic polyps.
Lymphocytic gastritis in patients with celiac
disease is more likely to involve the antrum
whereas corpus-dominant lymphocytic gastritis
is more likely to represent HP infection (42,80).
Radiographically, the enlarged gastric rugal
folds exhibit distinctive 0.3- to 1.0-cm discrete Figure 4-30
nodules that appear as radiolucent halos; cen- LYMPHOCYTIC GASTRITIS
tral barium flecks are distributej along their The foveolar epithelium lining the surface and pits in
surfaces. These folds are most prominent in the the superficial portion of the mucosa is infiltrated by an
gastric body and fundus and occasionally they increased number of lymphocytes. The epithelium appears
extend into the antrum (78). mucin depleted.
Microscopic Findings. Biopsies demonstrate
areas of mucosal degeneration and regeneration
coexisting with marked intraepitheliallympho- often surrounds the lymphocytes. The gastric
cytosis (fig. 4-30). The epithelium shows loss pits acquire a corrugated and dilated appearance
of apical mucin and appears flattened. Mature and their lumens may contain abundant mucus
intraepithelial T lymphocytes crowd the surface admixed with polymorphonuclear leukocytes,
and the superficial pit epithelium (41,78). The forming pit abscesses. The lamina propria also
process spares the deeper glands. Normally, contains increased numbers of lymphocytes.
there are 4 to 6 lymphocytes/100 epithelial Lymphocytic gastritis may involve both the
cells, but in lymphocytic gastritis they are in- antrum and the body, and patients may develop
creased, with an average of 46lymphocytes/100 glandular atrophy. In the severe form of the dis-
epithelial cells. Usually, the number of epithe- ease, extensive surface erosion occurs (fig. 4-31).
lial lymphocytes is obviously increased and Differential Diagnosis. The differential diag-
formal counting is not required. If counting is nosis of lymphocytic gastritis has two aspects.
necessary, 25 lymphocytes/100 epithelial cells The first concerns the identity of the cells with
is considered the minimum for diagnosis (66). the prominent halos. A number of entities mimic
They display the CD8-positive cytotoxic sup- this pattern, including ECL hyperplasia, the pres-
pressor T-lymphocyte phenotype. A clear halo ence of dystrophic goblet cells, or the presence of

152
Diseases of the Stomach

Figure 4-31
LYMPHOCYTIC GASTRITIS
A: Low-power magnification of a biopsy with regener-
ating glands and surface erosions.
B: The erosions are shown at higher magnification.
C: At high power, intraepithelial lymphocytosis with
edema is seen in the lamina propria. The usual features of
chronic gastritis are not present .

..~.--.:~~·..;~)::., .
A t)
.· .. , ·.· .rr
". ;-:
~ ... , ~ \

a fixation artifact. Immunohistochemical stains As used here, the term granuloma refers to a
for lymphocytic, endocrine, and epithelial cell compact collection of mature mononuclear cells
lineages allow identification of the cell type. consisting of either macrophages or epithelioid
Once the cells are identified as lymphocytes, cells that exist alone or are accompanied by
then the differential diagnosis lies between a necrosis or other inflammatory cells. Multi-
neoplastic and a benign lymphoid infiltrate. In nucleated giant cells may or may not be present.
the stomach, most neoplastic lymphoid lesions Gastric granulomas complicate numerous
are MALT proliferations consisting of B cells. conditions (Table 4-13). The specific diagnosis
In contrast, lymphocytic gastritis results from depends on the clinical history, histologic ap-
an infiltration ofT cells (Table 4-12). Unlike pearance, evaluation of other gastrointestinal
lymphocytic gastritis, MALT lymphoma shows and visceral lesions, and the use of special
glandular destruction and lymphoepithelial stains or other ancillary diagnostic techniques.
lesions, which are defined as a group of three The identification of granulomas within gastric
or more lymphocytes clustered together in biopsies often prompts the use of specialized
the epithelium. In addition, lymphoma cells stains for mycobacteria and fungi to rule out
infiltrate the muscularis mucosae and have a a treatable infection. Interpretation of the
monocytoid morphology with Dutcher bodies. biopsy is facilitated by obtaining clinical In-
Treatment and Prognosis. Associated celiac formation with regard to: 1) travel history (to
disease should be excluded. If present, it should exclude certain infections); 2) the presence of
be treated with dietary modification. If present, associated disorders including Crohn's disease,
HP infection should be treated with antibiotics. immunosuppression, vasculitis, sarcoidosis,
tuberculosis, or histoplasmosis; 3) the presence
GRANULOMATOUS GASTRITIS of an associated gastric carcinoma; 4) the use of
Granulomatous gastritis is any gastric disorder illicit drugs; and 5) the presence of a sexually
associated with the presence of granulomas. transmitted disease.

153
Gastrointestinal Diseases

Table 4-12
DISTINCTIONS BETWEEN LYMPHOCYTIC GASTRITIS AND
MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA
Feature Lymphocytic Gastritis MALT Lymphoma
Lymphocyte number Significantly increased Significantly increased
Lymphocyte distribution Single cells or linear arrangement Clusters of three or more lympho-
in the epithelium cytes in the epithelium
Lymphocyte type and distribution Mature T cells; similar intensity of Monocytoid B cells; denser infiltrate
distribution of lymphocytes in in the deep lamina propria with
superficial and deep lamina propria predominant monocytoid B cells
Perilymphocytic halo Common Uncommon
Significant epithelial destruction No Yes
Cytologic atypia of the lymphocytes No Yes
Diff·use lamina propria infiltration and No Yes
gland destruction by atypical lymphocytes

Table 4-13
GRANULOMATOUS DISEASES OF THE STOMACH
.. The most common cause of granulomatous
gastritis is Crohn's disease (30,68), followed by
Infectious
Bacterial Syphilis idiopathic isolated granulomatous gastritis in
Mycobacterial infections one study (30) or sarcoidosis in another (68) .
Whipple's disease (rare) Most granulomas occur in the antrum.
Helicobacter priori (not typical)
Fungal Histoplasmosis Infections Associated with'
South American blastomycosis Granuloma Formation
Phycomycosis (rare)
Clyptococcus Granulomatous gastritis develops in response
Coccidioidomycosis
to several types of infection, including tuber-
Parasitic Anisakidosis
Schistosomiasis .r culosis, syphilis, and fungal and HP infections
Strongyloidiasis (Table 4-13). Granulomatous gastritis develops
Idiopathic Crohn's disease in 1.1 percent of HP cases (68). The granulo-
Sarcoidosis mas form late in the disease course, after the
Isolated granulomatous gastritis host has become sensitized to the organism.
Miscellaneous Chronic granulomatous disease of Small sarcoid-like granulomas lie in the gastric
childhood lamina propria and sometimes HP organisms
Allergic granulomatosis and vasculitis can be found within them. Macrophages may
Plasma cell granulomas
ingest antibody-coated bacteria, stimulating the
Tumoral amyloidosis
Rheumatoid nodules histiocytic response. Granulomas are also seen
Gastric perforation in patients with parasitic infections, especially
Complications of peptic ulcer disease in anisakidosis and schistosomiasis. Additional
Malakoplakia
Granulomas seen in drug addicts
features of each of these infections are more
extensively discussed in chapter 10.
Neoplastic Associated with gastric carcinoma
Associated with gastric lymphoma Gastric Crohn's Disease
Langerhans cell histiocytosis
Definition. Crohn's disease (CD) is an idio-
Foreign body Food
granulomas Suture pathic inflammatory disease that affects the
Barium gastrointestinal tract from the mouth to the
Retained surgical sponges or lap pads anus. It is extensively discussed in chapter 15.
Talc Demography. The stomach is the principal
Beryllium
location of CD in less than 4 percent of patients,

154
Diseases of the Stomach

but abnormalities may be appreciated endo- of the mucosal-muscularis mucosae junction. A


scopically in up to 15 percent (48). Microscopic prominent lymphoplasmacytic infiltrate often
inflammation is more common and may be surrounds the granulomas. Neural hyperpla-
detected in 8 to 75 percent of patients (65,79) . sia may also be present. Severe cases exhibit
In 50 percent of the patients, the inflammation transmural inflammation, fissures, and typical
is considered to be direct involvement by CD. undermining ulcers as well as prominent lym-
Gastric mucosal granulomas can be detected in phoid follicles, serosal and submucosal fibrosis,
approximately 10 percent of cases (79). Patients and possibly, sarcoid-like granulomas (fig. 4-32) .
with gastric involvement often have duodenal The diagnosis of gastric CD is easily made in
involvement as well. the presence of florid disease and in the setting
Clinical Features. Upper gastrointestinal of disease elsewhere in the gut. The diagnosis is
pain, nausea, and vomiting result from gastric more difficult, however, when gastric involve-
outlet obstruction. The lesions may simulate ment is the first manifestation of the disease.
a gastric malignancy clinically. Rare patients The diagnosis should be considered in patients
present with giant gastric ulcers. without known CD in whom irregularly dis-
Gross Findings. Endoscopic, radiographic, tributed inflammatory foci are seen in the
and gross abnormalities include mucosal gastric mucosa with the presence of glandular
granularity and nodularity with cobbleston- abscesses, focal fibrosis, and lymphoid prolifera-
ing; multiple aphthous, linear, or serpiginous tion in the lamina propria, particularly in the
ulcers; thickened antral folds; and antral nar- absence of HP infection. An ulcer that does not
rowing. Hypoperistalsis and duodenal strictures respond to antisecretory therapy should suggest
are present in patients with severe gastric CD. the possibility of gastric CD.
Extensive gastric involvement may resemble Differential Diagnosis. The differential
linitis plastica due to the prominent intramural diagnosis includes any of the entities listed in
thickening and rigidity, and luminal narrowing Table 4-13. The three main diagnostic entities
(33). Radiographically, the changes localize to are shown in Table 4-14. The other major differ-
the antrum, progressing to a "ram's horn" or ential diagnosis is with HP infection, since both
"shofar" configuration. disorders may present with predominantly an-
Microscopic Findings. Patients with CD tral disease, and both may exhibit granulomas,
gastritis have a pattern of patchy and focally acute inflammation, and chronic inflammation.
active gastritis with acute inflammation in the The focality of the lesions in CD, however,
pits (pit abscesses) or glands, producing a pat- contrasts with the diffuse nature of HP gastritis.
tern similar to the focal active colitis pattern Treatment and Prognosis. Protein pump
characteristic of CD colitis (68). Granulomas inhibitors may provide some symptomatic
affect 14 to 33 percent of patients. The focality improvement; otherwise, medical therapy is as
of the process should alert one to the possibility for intestinal disease. Occasionally, resection is
of CD, since focal inflammation is uncommon required for gastric outlet obstruction or intrac-
in antral biopsies from patients with HP infec- table symptomatic fistulas.
tions. There are often focal, subepithelial, dense
Foreign Body Granuloma
accumulations of macrophages throughout the
mucosa. A diffuse mononuclear cell infiltrate in Definition. Foreign body granulomas are col-
the lamina propria is associated with acute gas- lections of histiocytes and giant cells that sur-
tric pit inflammation and gastric gland atrophy. round foreign material.
This contrasts with a bland, noninflammatory Demography. Foreign body granulomas usu-
background observed in patients with sarcoid- ally affect postsurgical patients, patients with par-
osis (68). Normal mucosa separates the areas asitic infections, or those with ulcerating diseases.
of patchy, chronic, active gastritis, unless the Etiology. In patients with parasitic infections,
patient has HP infection. Lymphoid aggregates histiocytes and giant cells surround either the
are also common; they are found in all layers larvae (as in anisakidosis) or ova (as in schis-
of the bowel wall, contrasting with follicular tosomiasis) and form foreign body granulomas.
gastritis, which remains restricted to the area Suture granulomas occur in the anastomotic

155
Gastrointestinal Diseases

Figure 4-32
GASTRIC CRO HN'S DISEASE
Left: Low-power magnification shows fop! inflammation and a granuloma surrounded by a dense lymphoplasmacytic
infiltrate.
Right: Sometimes there is marked neural hyperplasia in the submucosa or the myenteric plexus.

Table 4-14
COMPARIS ON OF GASTRIC CROHN' S DISEASE, SARCOIDOSIS, AND ISOLATED GRANULOMATOUS GASTRITIS
Isolated Granulo-
Features Crohn's Disease Sarcoidosis matous Gastritis
Major location of changes Antrum Antrum Antrum
Focal active gastritis Present Absent Absent
Isolated lymphoid aggregates Present Absent Absent
Fissures and undermining ulcers "'" Present Absent Absent
Evidence of other gastrointestinal involvement Usually present May be present Absent
Compact granulomas Present Present Present
Associated nonspecific inflammation Present Present Usually absent

sites in postsurgical patients. Food granulomas particles. Food granulomas can undergo sec-
occur in individuals With current or past mucosal ondary fibrosis or calcification. Severe mucosal
ulcerating diseases. The small mucosal defects al- fibrosis may result in pyloric stenosis.
low gastric juice and small food particles access to Suture granulomas are discovered incidentally
deeper layers of the gastric wall. The gastric acid or present as masses consisting of variable fibro-
•.· produces partial necrosis, increasing the size of the sis, abscess formation, and granulomatous re-
mucosal defect, thereby allowing more food to sponses (fig. 4-34). When nonresorbable sutures
enter. Barium granulomas also affect the stomach. are used, residual suture material is evident.
Microscopic Findings. Food granulomas In barium granulomas, collections of mac-
(fig. 4-33) appear as amorphous, eosinophilic, rophages containing refractile, greenish gray,
granulomatous masses, sometimes containing foamy cytoplasm are typically seen. Nodules
vegetable cells recognizable by their thick, brick- may measure up to 2 cm in diameter.
like cell walls. Palisading epithelioid histiocytes Differential Diagnosis. The differential diag-
and foreign body giant cells surround the food nosis includes all the entities listed in Table 4-13.

156
Diseases of the Stomach

Figure 4-33
FOOD GRANULOMA
Left: Low-power magnification shows a mass-like lesion in the submucosa. The overlying mucosa is inflamed.
Right: Higher magnification of the granuloma with a central eosinophilic coagulum surrounded by palisading epithelioid cells.

Figure 4-34
SUTURE GRANULOMA
Giant cells surround suture
remnants in this biopsy taken
from an anastomotic line.

Granulomatous Gastritis
findings reflect those of the malignancy, not
Associated with Malignancy
the granuloma.
Definition. Granulomatous gastritis associated Microscopic Findings. The granulomas typi-
with malignancy is a granulomatous response cally lie in the basal part of the non-neoplastic
that forms in the gastric mucosa and the drain- mucosa (fig. 4-35). They also surround, or inter-
ing gastric lymph nodes of individuals with gas- mingle with, infiltrating tumor. The granulomas
tric malignancies (epithelial and hematologic). resemble those of sarcoid and may affect all
Etiology. The granulomas presumably result levels of the gastric wall.
from an immune response to the tumor. Prognosis and Treatment. The treatment is
Gross Findings. This form of granulomatous for the cancer. The impact of the presence of the
gastritis has no specific gross features. The gross granulomas on the cancer is uncertain.

157
Gastrointestinal Diseases

Figure 4-36
ISOLATED GRANULOMATOUS DISEASE
This patient had no evidence of sarcoidosis, Crohn's
disease, or other explanation for granulomas.

Clinical Features. Symptomatic patients


usually present over age 40 years with epigastric
pain, weight loss, and vomiting secondary to
pyloric obstruction. Approximately 25 percent
of patients develop hematemesis.
Gross Findings. The predominant findings
consist of antral narrowing and rigidity.
Microscopic Findings. The pathologic
Figure 4-35 changes of idiopathic granulomatous gastritis
GRANULOMA ASSOCIATED WITH MALIGNANCY parallel those seen in sarcoidosis and CD (fig.
Neoplastic epithelium is present .fn the mucosa. 4-36). Transmural, noncaseating granulomatous
Underlying it are two loose granulomas. inflammation is present predominantly in the
antrum. The inflammation and fibrosis rarely
extend beyond the mucosa. Ulcers similar to
Isolated Idiopathic Granulomatous Gastritis
peptic ulcers develop, but the slit-shaped ulcers
Definition. The diagnosis of isolated idio- and fissures typical of CD are absent. In a third of
pathic granulomatous gastritis is made when other cases, regional lymph nodes become involved.
entities associated with granuloma formation Differential Diagnosis. In a review, Shapiro
have been excluded. Excluding other entities et al. (68) analyzed all cases of granulomatous
that cause granulomas is increasingly difficult, gastritis occurring at the Cleveland Clinic
since HP infections are associated with granu- between 1975 and 1994, and concluded the
loma formation. It is assumed that the granulo- following: 1) in most cases of granulomatous
matous inflammation that coexists with chronic gastritis a diagnosis of CD or sarcoidosis could
r.,. active gastritis results from HP. be established; 2) the background inflammatory
Demography. The incidence depends on how pattern is helpful in suggesting a diagnostic
frequently other diseases can be excluded, most category for granulomatous gastritis; 3) granu-
notably gastric CD, sarcoidosis, or HP infection. lomatous gastritis is not associated with HP per
Etiology. This is unknown. Controversy ex- se; however, if known cases of CD and sarcoid
ists as to whether isolated idiopathic granulo- are excluded, an association with HP infection
matous gastritis represents a distinctive entity and granulomatous gastritis cannot be ruled
or whether it represents an isolated or limited out; and 4) isolated idiopathic granulomatous
form of gastric sarcoidosis or CD (33,68). gastritis, if it exists, is extremely rare.

158
Diseases of the Stomach

Table 4-15
M ORPH OLOGIC AND CLINICAL MANIFESTATIONS OF GIANT GASTRIC FOLDS
Surface Body Glandular Gastrin Protein ECL"
Mucous Cells ComEonent Level Ulcers Loss HrEerEiasia
Zollinger-Ellison syndrome Normal Hyperplastic Elevated Present Absent Present
Hypertrophic hypersecretory Hyperplastic Hyperplastic Normal Present Absent Absent
gastropathy
Menetrier's disease Hyperplastic Atrophy Normal Absent Present Absent
Hypertrophic hypersecretory Hyperplastic Hyperplastic Normal Absent Present Absent
protein-losing gastropathy
"ECL = enterochromaffin-Jike.

COLLAGENOUS GASTRITIS predominantly affecting the fundus and some-


Definition. Collagenous gastritis is a char- times affecting the antrum; 2) low acid levels;
acteristic thickening of the subepithelial col- 3) mucosal protein loss; and 4) histology that
lagen table lying beneath the surface foveolar consists of gastric pit hyperplasia and oxyntic
cells, coexisting with gastritis. It resembles the glandular atrophy.
subepithelial fibrosis that develops in the small Demography. Menetrier's disease is the most
intestine (collagenous sprue) and in the colon common hypertrophic gastropathy, accounting
(collagenous colitis). for two thirds of cases. It usually affects men
Demography. Collagenous gastritis is a rare (three times more frequently than women) in
form of gastritis. It develops in the gastric cor- the 4th to 6th decades of life (83) . Menetrier's
pus, in the setting of chronic gastritis. disease sometimes affects children and, very
Etiology. The etiology of collagenous gastlitis is rarely, young infants.
unknown and its relationship to collagenous sprue Etiology. The etiology is generally unknown.
and collagenous colitis remains to be defined. In children, allergies, autoimmune reactions,
Gross Findings. Grossly, the gastric corpus and infections may play an etiologic role, with
may appear nodular and erythematous. proteins, such as those in cow's milk, often pre-
Microscopic Findings. Biopsies reveal cipitating the disease. In pediatric cases and in
patchy, chronic, active gastritis with a strik- some adult cases, cytomegalovirus infection is
ing focal thick band of subepithelial collagen, suspected as the etiologic agent (87). There may
which measures 20 to 75 mm in thickness. also be a relationship to lymphocytic gastritis
(92) . Although not generally considered to be a
HYPERTROPHIC GASTROPATHIES genetic disorder, familial cases do exist, leading
Four well-defined hypertrophic gastropathies some to suggest that the disease is inherited in
exist (Table 4-15) . Distinct clinical features define both an autosomal dominant and an autosomal
each syndrome, although several entities show recessive fashion. Patients with Menetrier's
some overlap (83,91). Individual patients may disease may have a marked increase in the ex-
lack classic clinical, laboratory, or histologic fea- pression of transforming growth factor-alpha
tures. Additionally, some patients with hypertro- (TGFa) (84) or epidermal growth factor (EGF).
phic gastric folds are not easily classified and the Data from animal models suggest that growth
diagnosis requires knowledge of the histologic, factors may play an etiologic role.
clinical, endoscopic, and radiologic findings. Clinical Features. Adults. Menetrier's dis-
ease begins insidiously, and gradually becomes
Menetrier's Disease
increasingly symptomatic. Signs and symptoms
Definition. Menetrier's disease is characterized characteristically wax and wane, so that differ-
by the four following criteria: 1) a pure foveolar ent features come and go. Symptoms include
cell hyperplasia that creates giant mucosal folds epigastric pain, bloating, anorexia, vomiting,

159
Gastrointestinal Diseases

Figure 4-38
Figure 4-37 MENETRIER'S DISEASE
MENETRIER'S DISEASE Opened resection specimen shows thickening of the
Endoscopic appearance of enlarged gastric folds. gastric folds, especially proximally.

'
weight loss, diarrhea, peripheral edema, and Frank upper gastrointestinal bleeding develops
bleeding. Some patients describe a rash and in only 12 percent of children contrasting with
food hypersensitivity. There is diffuse-enlarge- 20 to 40 percent of adults. The antrum can be
ment of the gastric folds, especially proximally, markedly involved (87), contrasting-with the
with marked mucus hypersecretion. The latter adult form of the disease. Affected children
leads to severe hypoproteinemia, especially develop atypical lymphocytosis and transient
hypoalbuminemia and hypochlo.rhydria, and hepatosplenomegaly, and have cytomegalovirus
a tendency to develop peripheral edema. Eo- demonstrable in the blood, urine, and gastric
sinophilia affects up to 61 peromt of adults. tissues (87). Coexisting HP and cytomegalovirus
Laboratory findings include anemia, low IgG infections occur.
levels, and low total protein levels. Gross Findings. Grossly, the stomach ex-
Extraintestinal phenomena include severe or hibits a bulky, thickened wall characterized by
recurrent pulmonary infections and pulmonary marked enlargement of the mucosal folds. Mu-
edema. Some patients show an unusually fre- cosal folds vary from 4 mm to 4 cm in height
quent association with coexisting thrombotic and resemble cerebral convolutions. The disease
cardiovascular disease, predisposing them to predominantly affects the body and fundus,
myocardial infarcts, pulmonary emboli, small generally sparing the antrum (figs. 4-37, 4-38),
bowel infarcts, and venous thromboses occur- except in children where the reverse is true.
ring at a young age. Other associations include Thick mucin may cover the mucosa. In severe
coexisting esophageal or gastric cancer, and disease, the lesions may extend into the antrum.
anorexia nervosa. Not all manifestations of the Radiographic criteria for diagnosing Men-
disease are present at the same time. etrier's disease include: 1) thick, nonuniform,
Children. In young children, the disease is tortuous, angular gastric folds; 2) ragged,
usually self-limited, with spontaneous reversal nodular, crinkled and spiculated appearance
of protein loss (85,90). This contrasts with the of the greater curvature; 3) a thickened gastric
adult form of the disease that may be so pro- wall; and 4) a fine reticulated barium pattern
longed and severe that it may require gastrec- produced by irregular mucus mixing (fig. 4-39).
tomy. Marked periorbital or facial edema affects Motility disturbances include delayed gastric
88 percent of children. Emesis, abdominal pain, emptying, pylorospasm with antral narrowing,
and anorexia are other common symptoms. and sluggish peristalsis.

160
Diseases of the Stomach

Figure 4-39
MENETRIER'S DISEASE
Left: An image from a single-contrast upper gastrointestinal radiograph shows marked thickening and irregularity of the
folds in the proximal portion of the stomach relatively sparing the antrum. The finding is classic for Menetrier's disease but
not completely specific. Zollinger-Ellison syndrome, in particular, may show similar findings.
Right: Computerized tomography (CT) scan demonstrates the proximal fold thickening.

Figure 4-40
MENETRIER'S DISEASE
Left: The mucosal folds appear thickened due to an expansion of the gastric pits. Often, there are prominent cysts that
extend into the submucosa, as in this case.
Right: Mucosal expansion .

Microscopic .findings. The most striking his- cystica profunda. Superficial edema and vari-
tologic features of Menetrier's disease are foveo- able, but usually minimal, degrees of inflam-
lar hyperplasia and glandular atrophy. Foveolar mation are present in the lamina propria. The
cells that maintain their normal polarity line inflammatory infiltrate consists of neutrophils,
the elongated, tortuous, corkscrew-shaped and eosinophils, lymphocytes, and occasional plas-
dilated, mucin-filled gastric pits. The mucus- ma cells. Lymphangiectasia may develop. The
secreting cells in the elongated pits extend to muscularis mucosae becomes hypertrophic,
the base of the mucosa. The glands become hyperplastic, distorted, and fragmented, send-
variably cystic (fig. 4-40) and may extend into ing smooth muscle extensions into the lamina
the superficial submucosa, producing gastritis propria. The degree of protein loss correlates

161
Gastrointestinal Diseases

with the pit hyperplasia, edema, and superficial especially in children, and may also improve
inflammation. following antisecretory therapy. The associated
As the disease runs its. course, an atrophic protein-losing gastropathy may require specific
mucosa with intestinal metaplasia develops, nutritional support. Surgery may be necessary
with the loss of the superficial inflammation in intractable cases. Five percent of patients
and edema. Granulomas develop in some develop carcinoma; some concurrently, others
patients with spontaneous disease resolution. after the diagnosis of Menetrier's disease. It is
Progressive hypochlorhydria results from likely that the patients who develop cancer do
gradual replacement of the oxyntic glandular so from the associated chronic gastritis rather
compartment by expanding pit compartments, than the underlying Menetrier's disease, al-
thereby compromising the parietal cell mass though the associated elevated growth factor
and resulting in decreased acid secretion. levels may play a role in cancer development.
Differential Diagnosis. Mucosal biopsies Animal Models. A gastropathy resembling
document the presence or absence of classic Menetrier's disease occurs in transgenic mice
forms of the hypertrophic hyperplastic gastro- overexpressing TGFa (88).
pathies and rule out the presence of tumors
Zollinger-EIIison Syndrome
that expand the gastric wall. Gastr'i.c biopsies,
however, are inadequate for complete diagnosis Definition. Zollinger-Ellison syndrome (ZES)
since all giant fold disorders share an expanded combines peptic ulceration and hypergastrine-
mucosa and it is difficult to obtain a full thick- mia. It is also known as hypersecretmy hype7gas-
ness mucosal biopsy unless giant" forceps are trinemia with protein loss.
used. In Menetrier's disease, a biopsy usually Demography. ZES affects 0.1 percent of all
contains either pure foveolae, suggesting focal patients with duodenal ulcer disease. Studies
foveolar hyperplasia or the top of a hyperplas- among European populations show an inci-
tic polyp, or else the mucosa appears normal. dence of 0.2 to 0.4 cases/million pQpulation/
The presence of the hyperplastic foveolar cells year. The disease occurs in patients ranging in
in a biopsy alone is insufficient to establish a age from 7 to 90 years (89), with most patients
diagnosis of Menetrier's disease since foveolar diagnosed between the 3rd and 5th decades of
cell hyperplasia occurs in other ·settings. The life. There is no sex predominance.
differential diagnosis usually includes local- Etiology. ZES results from gastrin hyperse-
ized mucosal expansions, includrng those seen cretion by gastrinomas, endocrine cell tumors
at the margins of a peptic ulcer, the prolapsed located in the pancreas or in the bowel wall,
expansile mucosa of a gastroenterostomy stoma, particularly in the first portion of the duode-
reflux gastropathy, and some gastric polyps, num. Less commonly, gastrin is hypersecreted
particularly hyperplastic polyps and polyps from severe G-cell hyperplasia (85,93). In ap-
found with the Canada-Cronkhite syndrome proximately 20 percent of cases, the pancreatic
(see chapter 16). Biopsies of all of these lesions neoplasm is part of multiple endocrine neopla-
may look identical, particularly when they are sia syndrome type 1.
superficial in nature ...For this reason, it is im- Pathophysiology. Excessive gastrin produc-
portant to correlate the histologic findings with tion serves as the stimulus for increased gastric
the typical clinical syndrome. acid secretion and it is the excessive acid produc-
In adults, Menetrier's disease may also re- tion that produces many of the clinical features
semble lymphoma, acid hypersecretory states, of the syndrome. Gastrin is a trophic hormone
#!, •
or lymphocytic gastritis, especially since about with multiple cellular targets, the major one of
one third of patients with lymphocytic gastritis which is the parietal cell. These cells become
present with weight loss, anorexia, protein loss, hyperplastic, secreting acid and completing
and peripheral edema. Patients with Menetrier's a negative feedback loop by inhibiting G-cell
disease, however, lack marked intraepithelial secretion. Gastrin also increases the growth of
lymphocytosis. chief cells, ECL cells, and foveolar epithelium.
Treatment and Prognosis. Menetrier's A marked parietal and chief cell hyperplasia (83,
disease may undergo spontaneous remission, 91) expands the gastric glands, causing rugal

162
Diseases of the Stomach

Figure 4-41
ZOLLINGER-ELLISON SYNDROME
Left: Whole mount section of the diffuse mucosal thickening.
Right: Higher magnification shows that this is the result of a marked expansion of the glandular mucosa. The pits are
extremely shortened.

hypertrophy, acid hypersecretion, and subse- regions or higher, coming closer to the luminal
quent peptic ulceration. ECL hyperplasia results surface than usual. In some cases, parietal cells
in increased histamine production, further completely populate the mucosal glands. Large
stimulating acid production by parietal cells. numbers of parietal cells may be present in the
Clinical Features . The usual presenting antrum, an area that usually lacks parietal cells.
symptoms are recurrent abdominal pain and di- Foveolae appear· normal in length or shortened
arrhea. Abdominal pain affects 70 to 95 percent (fig. 4-41). Antral glands and pits ar·e of normal
of patients; diarrhea affects 33 to 75 percent of size (85,93). Hyperplastic ECL cells may be seen
patients. Both symptoms result from excessive among the fundic glands. Cystic changes are ab-
acid secretion. The acid hypersecretion may be sent, contrasting with Menetrier's disease.
mild and indistinguishable from that seen with Differential Diagnosis. The differential di-
ordinary duodenal ulcer. Some patients lack all agnosis includes the entities listed in Table 4-15
the features of ZES. Peptic ulcer may be absent, and pseudo-ZES (see below). In ZES, endoscopic
and diarrhea with steatorrhea may be the only biopsies may appear normal since the pits are
clinical manifestation. likely to be normal and the expanded glandular
Gross Findings. Giant rugal folds cover the component is not easy to appreciate. The only
body and fundus but spare the antrum. The sur- hint of ZES is the finding of hyperplastic parietal
faces of the folds appear uniformly exaggerated, cells high in the mucosa in the mucous neck
coarsely granular, or finely cobblestoned. These regions, a phenomenon not usually found in
expanded folds thicken the gastric mucosa other conditions.
11/z to 2 times normal. Endoscopically, ulcers, Treatment and Prognosis. The prognosis
often multiple, are seen. There may be copious of patients with ZES relates more to the type of
amounts of resting gastric juice, coexistent duo- tumor causing the disease than to the gastric
denal ulcers, and reflux esophagitis. changes. The main predictor of survival is the
Microscopic Findings. The oxyntic glands presence of liver metastasis. Resection offers the
become lengthened and contain hype1trophic only hope for cure. Up to 50 percent of primary
and hyperplastic parietal cells. The increased lesions are extrapancreatic. Proton pump inhibi-
parietal cell mass comprises a progressively larger tors are necessary to block the acid hypersecre-
percentage of the glands, filling their entire length tion and have been effective in reducing the
down to their bases and crowding out other cell morbidity and mortality from exsanguinating
populations. Parietal cells also extend into the neck upper gastrointestinal hemorrhage.

163
Gastrointestinal Diseases

Pseudo-Zollinger-EIIison Syndrome
Etiology. This syndrome may result from
Definition. Pseudo-Zollinger-Ellison syndrome hypersensitivity of the parietal cells to gastrin
(pseudo-ZES) results from primary antral G-cell stimulation rather than to hypergastrinemia
hyperplasia and hyperfunction. and may overlap with pseudo-ZES.
Demography. Pseudo-ZES is a rare pediatric Gross Findings. Endoscopically, · there is a
disorder in which G-cell hyperplasia, hyperfunc- diffusely nodular mucosa with prominent rugal
tion, or both occur without a clearly identifiable folds, resembling ZES.
or predisposing cause. Microscopic Findings. The histologic fea-
Etiology. The syndrome likely has a mul- tures resemble those found in patients with ZES.
tifactorial etiology. Most familial cases result
Hypertrophic, Hypersecretory
from a genetic defect in normal regulation of
Gastropathy with Protein Loss
G-cell function and/or proliferation. Patients
with nonfamilial forms of the disease have in- Definition. Hypertrophic, hypersecretory gas-
creased antral G-cell sensitivity to intragastric tropathy with protein loss consists of giant gastric
food stimulation. folds, hypersecretion, protein loss, and a clinical
Clinical Features. Pseudo-ZES causes clinical presentation that represents a cross between
and biochemical features that resemble peptic Menetrier's disease and ZES. It is also known as
ulcer disease and ZES. Children sometimes pres- mixed type of hype1plastic gastropathy.
ent with nonspecific symptoms of abdominal Demography. This is the rarest form of giant
pain or upper gastrointestinal bl~eding (84). fold disease.
The gastrin hyperfunction results in hyper- Clinical Features. Most patients complain
gastrinemic hyperchlorhydria, but it does not of epigastric pain, asthenia, anorexia, weight
always present clinically as ulcer disease. Rather, loss, edema, and vomiting. There may be no
it may only cause nonspecific gastrointestinal symptoms, hypersecretion, or protein loss, or
symptoms. The diagnosis requires a high degree there may be hypersecretion without protein
of clinical suspicion and demonstration of basal loss, depending on the degree of hyperplasia
hypergastrinemia and acid hypersecretion; dif- of the various components and the relative
ferentiation from duodenal ulcer. disease and proportion of the cell types. Enteric protein loss
classic ZES is critical for clinical management. and hypoalbuminemia exist in most cases. Oc-
Diagnosis is achieved using pro'lOcative tests. casionally, a concomitant gastric ulcer is found.
Patients exhibit basal acid hypersecretion, el- Some patients, however, remain asymptomatic.
evated fasting plasma gastrin levels, enhanced Microscopic Findings. There is foveolar
gastric response to meals, high basal serum hyperplasia with deep cysts and mild glandular
pepsinogen levels, and severe duodenal ulcer hyperplasia with increased numbers of lympho-
disease. cytes and plasma cells.
Microscopic Findings. The microscopic find-
Helicobacter Pylori-Associated
ings resemble those of ZES.
Hypertrophic Gastropathy
Treatment and Prognosis. Since patients
with primary antral G-cell hyperplasia do not Helicobacter pylori-associated hypertrophic gas-
have a gastrin-producing tumor, the hyper- tropathy is the hypertrophic gastropathy that
gastrinemia (which is of antral origin) reverts results from HP infection. This hypertrophic
to normal following antrectomy. gastropathy may represent a special form of HP
... Hypertrophic, Hypersecretory Gastropathy
gastritis (88).
Some patients with HP infection exhibit
Definition. Hypertrophic, hypersecret01y gas- hypertrophic gastric folds and a protein-losing
tropathy combines body glandular hyperplasia, enteropathy. Biopsies demonstrate the presence
normal surface components, and peptic ulcer of a chronic or mixed acute and chronic gastritis,
disease, but it differs clinically from ZES by the with or without ulceration. The pit-to-gland ratio
absence of hypergastrinemia. The patients lack is normal and the increased mucosal thickness
pancreatic tumors or G-cell hyperplasia. Some results from edema and inflammation. Eradicating
authors consider this a form of ZES (83). the HP infection restores the normal architecture.

164
Diseases of the Stomach

LOCALIZED HYPERTROPHIC DISORDERS

Focal Hyperplasia
Definition. Focal hype1plasia is localized mu-
cosal expansion.
Etiology. A number of entities cause localized
mucosal hyperplasia. The lesions lie adjacent to
healed peptic ulcers, neoplasms, and surgical
stomas. Polyps, which are believed to represent
an exuberant regenerative response of gastric
foveolar cells, develop in anastomotic sites 1
to 18 years following gastrectomy. Numerous
factors contribute to the genesis of the lesions
seen in the postsurgical stomach, including
chronic bile reflux, stomal ischemia secondary
to mucosal prolapse, and mucosal deformities Figure 4-42
resulting from the anastomosis. Patients who
LOCALIZED POLYPOID HYPERPLASIA
undergo Billroth II procedures may develop G-
cell proliferation after the procedure. Patients Localized polypoid hyperplasia overlying an anasto-
motic site.
with tumors may produce growth factors that
stimulate localized mucosal growth. There is a
direct correlation between the degree of mucosal intermediate stage between chronic stomal
thickening and EGF expression by some tumors. gastritis and stomal cancer.
Gross Findings. Focal hyperplasia creates le-
sions that measure up to 5 mm in diameter. They GASTRIC POLYPS
are frequently multiple and arise in the antrum. Gastric polyps are found in 2.0 to 8. 7 percent
Lesions surrounding stomas may present as a of gastric examinations, usually as incidental
solitary sessile polyp or as a linear arrangement findings (97,100). The polyps may be neoplastic
of polyps encircling the gastric side of the stoma. or non-neoplastic, with most (80 to 90 percent)
Microscopic Findings. The gastric pits have being non-neoplastic. They may be multiple or
an increased depth or diameter, with saccular solitary (50 to 87 percent of cases [100]), and
dilatations. The stroma increases and appears some complicate polyposis syndromes (Table
edematous and/or inflamed, widely separat- 4-16). Gastric polyps affect all age groups, but
ing the gastric glands. The base of the lesion they peak in the 5th to 7th decades, except
contains fibrous connective tissue replacing or in individuals with a polyposis syndrome, in
extending through the muscularis mucosae. which case they occur earlier.
Histologically, these proliferative lesions re- The two main types of non-neoplastic polyps
semble hyperplastic polyps in that they contain are hyperplastic polyps and fundic gland polyps
proliferating nondysplastic foveolar cells (fig. (96); less commonly, neoplastic (adenomatous)
4-42). The epithelium appears regenerative polyps develop. Lesions that may present as gas-
and surface erosions with cellular loss may be tric polyps include Brunner gland heterotopia,
found . The adjacent mucosa is often atrophic. inflammatory fibroid polyps, pancreatic hetero-
The hypertrophic muscularis mucosae appears topia, carcinoid tumors, and hamartomatous
irregularly frayed, and cystic glands penetrate polyps (96,105).
into the submucosa, producing gastritis cystica Symptoms, when present, are usually vague
profunda . Each of the mucosal protrusions and nonspecific. Some patients present with
closely relates to the rugal folds without distinct mild bleeding. Pedunculated lesions may pro-
borders between the lesions and the folds. lapse through the pylorus causing obstruction.
Treatment and Prognosis . The natural Clinical and endoscopic features are rarely able
history of these lesions is controversial, and to distinguish the various types of polyps prior
it remains unclear whether they represent an to histologic examination.

165
Gastrointestinal Diseases

Table 4-16
DIFFERENTIAL DIAGNOSIS OF GASTRIC POLYPS
Hyperplastic polyps
Fundic gland polyps
Inflammatory polyps
Inflammatory fibroid polyps
Hamartomatous polyps
Adenomas
Polyps in polyposis syndromes
Familial adenomatous polyposis
Peutz-Jeghers syndrome
Juvenile polyposis
Cowden's syndrome
Cronkhite-Canada syndrome
Carcinoid tumors
Heterotopic tissue
Pancreas
Brunner glands
Stromal tumors
Lipomas Figure 4-43
HYPERPLASTIC POLYP
Endoscopically, these lesions appear polypoid and
bosselated.

Hyperplastic Polyp
Definition. Hyperplastic polyps are localized, Multiple polyps that may appear confluent oc-
non-neoplastic mucosal expansions consisting cur in 20 to 33 percent of patients. Hyperplastic
of elongated, tortuous, sometimes cystically polyps develop throughout the stomach, in
dilated foveolae supported by an edematous both the body and antrum, and occasionally at
lamina propria and distended vessels. Syn- the gastroesophageal junction (95).
onyms include gastritis polyposa,"' retention polyps, Microscopic Findings. Most hyperplastic
and hype1plasiogenic polyps. polyps arise on a background of chronic gastri-
Demography. Forty-five to 90 percent of gas- tis. Histologically, they consist of a proliferation
tric polyps are hyperplastic (104,105). They de- of surface foveolar cells lining exaggerated,
velop in men and women with equal frequency, elongated, branched, sometimes cystically
with a median age of 69 years; these lesions also dilated pits (fig. 4-45). Mucosal cysts can be
arise in children. Some arise with concomitant quite prominent. Hypertrophic foveolar cells,
chronic atrophic gastritis, hypochlorhydria, low resembling goblet cells, may be present. The pits
levels of pepsinogen 1, and hypergastrinemia, extend from the surface deep into the stroma.
a setting consistent with autoimmune gastritis The glands in hyperplastic polyps are usually
(93,99) . A possible relationship exists with HP of the antral type, even when the polyps arise
infections (102). in the body or fundus (sometimes referred to as
Clinical Features. Larger polyps twist on mixed fundic-antral hype1plastic polyps), although
their stalks, leading to superficial ulceration, occasionally, oxyntic glandular mucosa is seen.
hemorrhage, or pyloric prolapse. The latter re- A prominent stroma separates the glands. This
sults in intermittent gastric outlet obstruction. stroma often becomes edematous and infil-
Gross Findings. Hyperplastic polyps are usu- trated by inflammatory cells, particularly by
ally small, smooth, lobulated, sessile or pedun- plasma cells, lymphocytes, and eosinophils.
culated (figs. 4-43, 4-44), sometimes umbilicated Smooth muscle fibers extend upward from the
lesions measuring less than 2 cm in diameter. splayed muscularis mucosae. Patchy fibrosis
Rare polyps are larger and simulate carcinoma. may develop.

166
Diseases of the Stomach

Figure 4-44
HYPERPLASTIC POLYP
Several hyperplastic polyps
with typica l lobu lated struc-
ture are in a partial resection
specimen.

Figure 4-45
HYPERPLASTIC POLYP
A: Mucosal expansion with foveolar hyperplasia and
elongation of the pits. The mucosa often appears congested.
B: Higher magnification of the hyperplastic foveolar
epithelium and inflamed stroma.
C: These lesions often become eroded, with superficial
telangiectasia and inflammation .

Erosion of the surface, with subsequent re- epithelium from adenomatous epithelium. In
generation, produces reactive atypia in the lin- order to separate the two, one should examine
ing epithelium, which is characterized by cyto- the suspicious cells within their context. The
plasmic eosinophilia, an enlarged nucleus, and presence of clear-cut regeneration in adjacent
a cuboidal cell shape. In some cases, it may be areas or inflammation should indicate a repara-
difficult to distinguish the regenerating foveolar tive and not an adenomatous lesion. Atypia is

167
- Gastrointestinal Diseases

either absent or minimal and often regenerative gland polyps have a lower male to female ratio,
in nature, especially in areas of surface erosion a younger mean age at diagnosis, and a higher
(fig. 4-45). Neutrophils are especially prominent proportion of multiple polyps. The youngest
in ulcerated areas. Eroded hyperplastic polyps patient in one study was 8. years old. In con-
may also contain atypical mesenchymal cells trast, non-FAP patients develop their polyps in
with marked nuclear pleomorphism and atypi- middle age.
cal mitotic figures. These cells blend in with Etiology. The etiology of these lesions is
the typical granulation tissue. Vascular prolif- unclear. Some believe that they represent ham-
erations resembling granulation tissue develop artomas. They are frequently found in patients
superficially near areas of inflammation. undergoing treatment with proton pump in-
Differential Diagnosis. Superficial biopsies hibitors. As a result, it has been hypothesized,
of small polyps disclose mixtures of hyperplastic but not yet proven, that these lesions result
and inflammatory tissue similar to that seen from the increased gastrin levels that follow
in areas of chronic gastritis. In such biopsies, inhibition of gastric acid secretion.
the polypoid nature of the lesion may not be The role of the germline mutation in the APC
readily appreciated if the appropriate clinical in- gene found in FAP patients in predisposing to
formation is not provided. The most important fundic gland polyps is unclear. A recent study
feature to be assessed is the presence or absence found ~-catenin gene mutations in 29 of 35
of adenomatous, dysplastic, or malignant epi- sporadic fundic gland polyps (103). APC muta-
thelium. The latter is extremely unlikely in the tions appear to occur in sporadic fundic gland
absence of intestinal metaplasia. polyps with dysplasia (94).
Treatment and Prognosis. The treatment of Clinical Features. The number of polyps may
hyperplastic polyps is endoscopic removal in decrease or increase over time. Circulatory dis-
order to determine their nature and te prove turbances of the pedicles, torsion, or mechanical
that the lesions are benign. Because hyperplastic traction resulting in autoamputation rniiY cause
polyps represent a reactive change of the nor- polyps to disappear.
mal mucosa, they are not genuine neoplasms; Gross Findings. Fundic gland polyps devel-
however, neoplastic changes can develop oping in the setting of FAP may result in a carpet
within them, especially in individuals with of several hundred polyps, each usually measur-
multiple polyps. Of interest is the report that
ol'
ing less than 5 mm in diameter. These polyps
hyperplastic polyps exhibit clonality and con- have a sessile base and a smooth-domed surface.
tain ras gene mutations (100). When dysplasia In sporadic cases, polyps usually number less
develops within hyperplastic polyps, it generally than SO; often they are solitary. They appear as
resembles the adenomatous epithelium found minute mucosal bumps measuring 1 to 5 mm
in the colon. Areas of adenomatous change in diameter. Fundic gland polyps are the same
are generally more extensive than the areas of calor as the surrounding mucosa. Most lesions
atypia seen in focally eroded polyps. arise in the fundic mucosa but rare lesions arise
in the antrum.
Fundic Gl~nd Polyp
Microscopic Findings. No histologic dif-
Definition. Fundic gland polyps, also known as ferences exist between PAP-associated fundic
cystic hamartomatous epithelial polyps, consist of gland polyps and non-PAP-associated lesions
localized expansions of oxyntic mucosa. (101). Histologically, they represent localized
Demography. Fundic gland polyps were ini- hyperplastic expansions of the deep epithelial
... tially described in patients with familial aden- compartment of the oxyntic mucosa (fig. 4-46).
omatous polyposis coli (FAP). The frequency of Masses of distorted oxyntic glands lie close to
fundic polyps in FAP patients ranges from 30 the luminal surface, and they contain scattered,
to 56 percent, affecting patients in the 2nd and cystically dilated pits and glands. The overlying
3rd decades of life. Fundic gland polyposis also pits appear shortened or absent. The branched
occurs in the absence of FAP, affecting up to 1.4 tubular glands are lined by chief cells, parietal
percent of the general population. Compared cells, and mucous neck cells, and they open into
with non-FAP cases, FAP patients with fundic the pits. The mucin in the surface foveolar cells

168
Diseases of the Stomach

but they serve as a marker for FAP, especially


in patients with multiple lesions who are not
taking proton pump inhibitors.
Isolated Hamartomatous Polyp
Definition. Isolated hamartomatous polyps
consist of a submucosal mass of oxyntic glands
in a framework of smooth muscle. They are also
termed submucosal heterotopia of gastric glands.
Microscopic Findings. Isolated hamartoma-
tous polyps consist of a mixture of haphazardly
arranged fundic type glands, smooth muscle
tissue, and focal accumulations of mature lym-
phoid tissue, supported by normal lamina pro-
pria. The glands may appear cystically dilated
or may be compact, as in the normal stomach.
There are mucous cells resembling those of the
gastric foveolar epithelium as well as rare antral
or cardiac type glands containing the endocrine
cells indigenous to the mucosal site.
Differential Diagnosis. The major entity in
the differential diagnosis is the Peutz-Jeghers
polyp. Clinically, patients with hamartomatous
polyps lack the classic features of Peutz-Jeghers
polyps, which are usually mucosally based le-
sions with possible submucosal extensions that
Figure 4-46 contain characteristic arborizing muscle bun-
FUNDIC GLAND POLYP
dles. In contrast, isolated hamartomatous pol-
The polyps result from expansion of the oxyntic glands
yps are predominantly submucosal in location
and the pits become shortened. Here, the junction of and lack arborizing smooth muscle bundles.
a fundic gland polyp is seen, with more or less normal
mucosa on the right. The polyp itself often develops cystic Gastric Polyps in Polyposis Syndromes
dilatations.
Many generalized polyposis syndromes affect
the stomach. Patients with juvenile polyposis,
stains intensely with the PAS stain, but is negative familial adenomatous polyposis, Peutz-Jeghers
with Alcian blue stains for acidic mucin. Most syndrome, Cronkhite-Canada syndrome, and
fundic gland polyps show an increase in smooth Cowden's disease all may develop gastric le-
muscle content, often in a pericystic distribution. sions. The polyposis syndromes are discussed
Fundic gland polyps probably develop from in chapter 16.
the progressive dilatation and infolding of glan-
dular buds to produce irregular tortuous glands GASTRIC XANTHOMA
and microcysts. Proliferating cells are found in Definition. Xanthomas are bland collections
the mucous neck region as well as in the epi- of foamy, lipid-containing histiocytes (xantho-
thelium lining the microcysts and in the glands ma cells) arranged in pavement-like patterns in
directly adjacent to microcysts. The presence of the upper lamina propria immediately beneath
these aberrantly located proliferative cells may the surface epithelium. Xanthelasma and lipid
explain the histogenesis of the polyp (101). islands are synonymous terms for this entity.
Treatment and Prognosis. Treatment con- Demography. The frequency of gastric xan-
sists of endoscopic removal to confirm their thoma is said to be 18 percent in gastrectomy
identity and to exclude other lesions. Fundic specimens and as high as 53 percent among
gland polyps have little malignant potential, autopsies (106-108).

169
Gastrointestinal Diseases

Figure 4-47
GASTRIC XANTHOMA
Endoscopic examination reveals a typical yellow island.

Etiology. The etiology of xanthomas is un-


known but they never occur in the normal gastric
mucosa. Patients often have evidence of bile re-
flux, varying degrees of gastritis, gastric surgery,
or even associated cancer. Some patients have
associated cholesterolosis of the gallbladder. They Figure 4-48
sometimes develop in patients witp cholestasis
GASTRIC XANTHOMA
and then regress once the cholestasis disappears.
Gross Findings. Xanthomas appear to the Clusters of pale-staining, foamy histiocytes are in the
lamina propria.
endoscopist as single or multiple, well-demar-
cated, circular-oval, whitish yellow plaques
measuring 1 to 10 mm but rarely exceeding 5
mm (fig. 4-47). They are often multiple and oc- fungal infections, such as histoplasmosis. These
cur frequently along the lesser curvature of the entities may be ruled out with the use of special
fundus and prepyloric region (106). stains. The differential diagnosis also includes
Microscopic Findings. These lamina propria- the diffuse form of gastric carcinoma. Signet
based histiocytic collections displace gastric glands ring cell carcinomas tend to be composed of
and foveolae and occasionally extend into the cells with eccentric nuclei. In contrast, xan-
submucosa. The cytologically bland cells contain thoma cells usually have central nuclei. In cases
abundant, foamy, finely vacuolated cytoplasm (fig. where there is doubt, a negative cytokeratin im-
4-48). The cells are PAS negative, and lymphocytes, munostain rules out diffuse gastric carcinoma.
plasma cells, and macrophages are associated with
Brunner Gland Heterotopia
the foam cells (106) . These lipid islands stain
with the macrophage marker KP1 and the foam Heterotopic Brunner glands may accompany
cells contain low-density lipoproteins (LDL) and heterotopic pancreas or may be seen alone. The
oxidized LDL (107). prepyloric antrum is the most frequently af-
Differential Diagnosis. The differential di- fected site. Histologically, the lesion resembles
agnosis includes Whipple's disease and certain duodenal Brunner gland hyperplasia.

170
Diseases of the Stomach

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with histologic pattern of gastritis and gastric Endoscopy 1994;26:659-65.
atrophy. Am] Surg Pathol 2001;25:500-7.
94. Abraham SC, Park S], Mugartegui L, Hamilton Gastric Xanthoma
SR, Wu TT. Sporadic fundic glai'ld polyps with 106. Domeloff L, Eriksson S, Helander HF, ]anunger
epithelial dysplasia. Am] Pathol 2002;161: KG. Lipid islands in the gastric mucosa after
1735-42. resection for benign ulcer disease. Gastroen-
95. Abraham SC, Singh V, Yardley ], Wu T. Hyper- terology 1977;72:14-8.
plastic polyps of the esophagus and esophago- 107. Kaiserling E, Heinle H, Ita be H, Takano T, Rem-
gastric junction: histologic and clinicopatho- mele W. Lipid islands in human gastric mucosa:
logic findings. Am] Surg Pathol2001;25:1180-7. morphological and immunohistochemical
96. Borch K, SkarsgardJ, Franzen L, Mardh S, Rehfeld findings. Gastroenterology 1996;110: 369-74.
]F. Benign gastric polyps: morphological and 108. Terruzzi V, Minoli G, Butti G, Rossini A. Gastric
functional origin. Dig Dis Sci 2003;48: 1292-7. lipid islands in the gastric stump and in non-
97. Dekker W. Clinical relevance of gastric and duode- operated stomach. Endoscopy 1980;12:58-62.
nal polyps. ScandJ Gastroenterol1990;25:7-12 .

..

174
PEPTIC ULCER DISEASES

A major insight of the last 10 to 20 years is Mucosal blood flow brings bicarbonate,
that gastric peptic ulcers primarily result from oxygen, and nutrients to the luminal surface
altered gastric mucosal defenses whereas duode- and removes hydrogen ions from the same
nal ulcers develop in association with increased region (4). The autonomic nervous system con-
acid production. It has also become clear that trols mucosal gastric blood flow. Nitric oxide,
Helicobacter pylori infection plays a vital role in prostaglandins, epidermal growth factor, and
peptic ulcer development in both sites. Other transforming growth factor-alpha also regulate
factors that play a role in peptic ulcer disease in- mucosal blood flow.
clude the use of nonsteroidal antiinflammatory Some cytoprotectants are naturally present in
drugs (NSAIDs), cigarette smoking, the presence the gastric mucosa. These include prostaglan-
of chronic renal disease, and excessive alcohol dins and sulfhydryl donors such as glutathione
consumption. Disturbed motility predisposes and neuropeptides (6,7,9,10). Prostaglandins
to active ulceration in the duodenum due to play a major role in mucosal protection (8) by
prolonged mucosal contact with acid contain- mediating mucus and bicarbonate secretion,
ing material from the stomach. inhibiting acid secretion at the level of the pa-
rietal cell, and regulating mucosal blood flow.
NORMAL GASTRIC DEFENSE MECHANISMS Normal mucosal defenses become altered in
The stomach has evolved a complex mucosal patients with gastric ulcers 8ecause of several fac-
cytoprotection system in order to withstand tors. One factor is an increased prop01tion of low
the hostile environment present within it (see molecular weight dextrans in the gastr-ic mucous
chapter 4). Adherent mucus provides a stable layer, which results in weaker mucus (13), reduced
unstirred layer that neutralizes acids at the lu- mucosal hydrophobicity, and impaired prostaglan-
minal surface. In addition, this unstirred layer din production in patients taking NSAIDs. The
acts as a permeability barrier to luminal pepsin. association between NSAID ingestion and peptic
Acid reaching the mucosal surface is neutralized ulcer formation is dramatic (see below).
by bicarbonate secreted into the mucus layer
covering the epithelium (1,12). The net result PATHOGENESIS OF PEPTIC ULCERS
is that the pH in the gastric lumen is approxi-
Role of Helicobacter Pylori
mately 2.0, while that at the mucosal surface is
increased to approximately 7.0 (3,11). Mucus It is now recognized that infection with the
also lubricates the stomach and facilitates the bacterium Helicobacter pylori (HP) is a major
movement of food, thereby avoiding mucosal etiologic factor in many forms of gastric disease,
abrasions from coarse foods. In addition, the including peptic ulcer. Approximately 95 per-
mucous cells secrete lipid, which coats the cent of patients with duodenal ulcers and 70 to
epithelial membranes lining the gastric lumen 93 percent of patients with gastric ulcers have
with a nonwettable surface, thereby protecting an associated HP infection (44). The mucosa,
them against the action of water-soluble hydro- weakened by HP infection, becomes susceptible
gen ions and pepsin (2,5). Tight junctions also to acid attack, especially in the presence of in-
constitute a major structural component of the creased gastric acid secretion, leading to peptic
gastric mucosal barrier. Breaking the mucosal ulceration (20,23,44,45)
barrier leads to mucosal damage because it al- The corkscrew-like movement of the organ-
lows hydrogen ions, pepsin, and bile acids to isms and their production of various enzymes
back-diffuse into the mucosa. play important roles in the pathogenesis of

175
Gastrointestinal Diseases

Figure 5-l
HEL/COBACTER PYLORI GASTRITIS
A: A Diff-Quik- stained preparation shows numerous
curved bacteria in the mucus overlying the mucosal surface.
Other organisms adhere to the apical and lateral aspects of
the gastric foveolar cells.
B: Wenger-Angritt stain shows abundant organisms. (Fig.
2-29 from Emory TS, Carpenter HA, Gostout C], Sobin LH.
Atlas of gastrointestinal endoscopy & endoscopic biopsies.
Washington DC: Armed Forces Institute of Path-ology;
2000:91.)
C: The inflammatory infiltrate associated with H. pylori
includes a dense population of lymphocytes and plasma
cells within the lamina propria, as well as neutrophils
infiltrating the necks of the gastric glands .

,
...

,,
} ,
I

~... "
/

gastritis and gastric ulcer (18,25,5,9,52- 54). The epithelial protective layer by digesting gastric
majority of HP organisms reside in the unstirred mucin (50,52,53). Organisms lying free in the
layer of the gastric mucus, but some organisms mucus cause less epithelial damage than organ-
bind to the luminal aspect of gastric foveolar isms located between, and even within, cells (33).
cells (fig. 5-l) . The organisms are motile, pos- The powerful enzyme, urease, is produced
sessing one to five polar flagella (17). These by HP and has many functions . It protects th e
flagella allow them to move freely within the organisms against the acid environment of the
mucous layer, and to reach the epithelial surface stomach by creating an alkaline microenviron-
to which they attach (19,28) . ment (54). It also acts as an epithelial cytotoxin
HP organisms prefetentially attach at or near (51,54) and disrupts the intercellular tight junc-
intercellular junctions, perhaps reflecting the tions in a manner that allows cells to remain vi-
availability of nutrients or preferred metabolites able but also allows luminal contents, including
diffusing through the junctional spaces. Once acid, to flow between them (51). Organisms that
the intracellular junctions become weakened, fail to produce urease are incapable of gastric
the organisms penetrate the junctional com- colonization and die in the acidic environment
plexes and move down along the lateral cell of the stomach (26,39,48).
membranes of the surface foveolar cells. Gener- HP organisms induce gastric inflammatory
ally, they do not invade the underlying lamina infiltrates composed of lymphocytes, plasma
propria (33,35). cells, macrophages, and neutrophils (fig. 5-l).
HP alters the release of intracellular mu- This inflammation invariably disappears follow-
cins into the gastric lumen (41). The proteases ing eradication of the organisms. The inflamma-
produced by the organism further damage the tion is probably induced by bacterial products

176
Peptic Ulcer Diseases

such as urease, porins, hemolysin, paf-acether, strains that do not produce the cagA protein.
and cytotoxins (24,29,36,38,58,61). HP water The presence of the cag pathogenicity island is
extracts can promote neutrophil endothelial associated with greater activity of gastritis and
interactions (63). an increased degree of surface epithelial degen-
Additionally, the organisms induce inflam- eration in the stomachs of infected individuals.
mation through direct contact with the gastric CagA positivity has been strongly associated with
epithelium and induction of subsequent cyto- the development of peptic ulcers in many studies
kine release (16). (32,43,46,55,56). In some populations, however,
HP infections result initially in acid hypose- cagA-positive HP strains do not appear to be as-
cretion, followed by normal gastric acid secre- sociated with increased disease risk (37,47).
tion, and finally, hypersecretion (27,40,42). The type and grade of gastritis strongly pre-
Gastric acid secretion increases due to several dict the risk of a coexisting peptic ulcer. The
mechanisms, and the acid hypersecretion re- risk of coexisting duodenal or gastric ulcers
verses with eradication of the infection (31,34). increases with the increasing grade of atrophic
Parietal cells gradually become atrophic as the antral gastritis and decreases with an increasing
HP-induced gastritis extends proximally to in- grade of atrophic gastritis in the gastric body.
volve the oxyntic mucosa, thereby decreasing These observations correlate with the fact that
gastric acid secretory capacity. Patients with an cagA-producing strains of HP are more likely
increased parietal cell mass and hyperchlorhy- to produce intense gastric inflammation, and
dria who become infected with HP organisms therefore, are more frequently associated with
exhibit antral restriction of the gastritis because the development of peptic ulcers. Ulcer recur-
the high acid levels protect the corpus from rence is less frequent in patients whose HP infec-
bacterial adhesion and inflammation. Such pa- tions have been eradicated than in those with
tients develop acid-induced duodenal foveolar continuing evidence of infection (57).
metaplasia, which becomes colonized by HP, A third potential virulence factor, iceA, has
eventually leading to active chronic duodenitis recently been identified. The iceAl allelic vari-
and, potentially, duodenal ulcer formation. ant of the HP iceA gene has been linked to the
Not all individuals colonized with HP de- development of peptic ulcer disease in one study
velop symptomatic gastric disease. This fact sug- (60). Other studies have failed to confirm this
gests that different strains of the bacteria vary in association (62).
their pathogenicity. Approximately 50 percent
Role of Acid Secretion
of HP stains possess a vacA gene that encodes a
vacuolating cytotoxin (22,29,36). The vacA cy- The increased acid secretion seen in duodenal
totoxin produces vacuolation in many types of and distal antral ulcer patients underscores the
epithelial cells (29,36). Essentially all HP strains importance of acid/peptic activity in the devel-
possess some form of the vacA gene, but it is a opment of peptic ulcer disease. In most patients,
specific allelotype (s1-m1) that is associated with the excess acid results from an increased mass
greater pathogenicity of the organisms (14, 15). of acid-secreting gastric mucosa. An extreme
Some studies have found that HP strains ex- example of this occurs in patients with gastri-
pressing the vacA cytotoxin are more commonly nomas and Zollinger-Ellison syndrome.
found in patients with peptic ulcer disease than
Role of Nonsteroidal Antiinflammatory Drugs
among HP-infected individuals with superficial
gastritis alone (22,29,30,43,49,55). NSAID use is the most common cause of
Another potential virulence factor produced macroscopic gastric injury. Gastrointestinal
by approximately 60 percent of HP strains is injury secondary to NSAID use is among the
cagA. A strong correlation is observed between most prevalent drug side effects seen in the
the presence of the cagA gene and the produc- United States: as many as 107,000 patients are
tion of vacuolating cytotoxin (21,59) . Recent hospitalized every year for NSAID-related ulcer
evidence suggests that the cagA gene is part of complications (71). NSAID use is now the most
the so-called cag pathogenicity island, a cluster common predisposing factor contributing to
of approximately 15 genes that is absent in HP hospital admissions for peptic ulcer disease in

177
Gastrointestinal Diseases

the elderly. The incidence of gastroduodenal le- Endoscopically, the lesions vary from ery-
sions in patients on chronic therapy varies from thematous patches or streaks to erosions and ove1t
31 to 68 percent (66,67,69); approximately SO ulcerations, particularly of the gastric antrum, pre-
percent of patients on long-term NSAID therapy pylmic area, and duodenal bulb. Histologically, the
have gastric erosions, and up to 25 percent have erosions or ulcers resemble stress-related changes
gastric ulcers. Severe and sometimes fatal upper or features of chemical gastropathy, although
gastrointestinal hemorrhage occurs, especially NSAIDs induce deeper pit inflammation than is
in individuals over the age of 75 (72). This may commonly seen in other chemical gastropathies
relate to the fact that gastric mucosal prosta- (fig. 5-2). There may be small superficial mucosal
glandin levels decrease with age (68), making defects and exh"avasated red blood cells in the
the mucosa more vulnerable to NSAID-induced underlying lamina propria. The mucosa often
injury. NSAIDs cause several types of injury, in- appears edematous and regenerative. The degree
cluding acute mucosal hemorrhages, erosions, of inflammation associated with these lesions
and chronic ulceration. tends to be minimal. Occasionally, neuh"ophilic
NSAIDs exert their effects on the gastric mu- infilh·ates are seen at the junction of necrotic
cosa through several mechanisms. They cause and viable tissues. Prominent eosinophilia may
defects in the normal gastric mucosal barrier, in also be present. The diagnosis of these lesions is
part through their inhibition of prostaglandin often problematic when based on biopsy evalu-
synthesis. This effect occurs because NSAIDs ation, particularly in the absence of a history of
act through inhibition of cyclooxygenase, NSAID ingestion.
a molecule essential for the production of
Role of Steroids
eicosanoids such as prostaglandil'ls E2 and I2.
Cyclooxygenase inhibition also results in the Steroids do not cause as much gastric damage
production of metabolites such as leukotrienes, as NSAIDs, but they increase luminal acid loss in
as arachidonic acid metabolism is shunted from the presence of aspirin or bile salts. Aqditionally,
the cyclooxygenase to the lipoxygenase path- the concomitant use of steroids and NSAIDs is
way (64). The analgesic effects ofNSAIDs occur associated with an up to 10-fold increased risk
mainly through inhibition of cyclooxygenase-2 of upper gastrointestinal hemorrhage (74). In
(COX-2), while inhibition of cyclooxygenase-1 addition, the severity of the ulceration may be
(COX-1) results in the deleterious effects on the increased with concomitant steroid and NSAID
gastric mucosal barrier. It is hope'd that with the use, particularly when COX-1 inhibitors are em-
recent development of NSAIDs that specifically ployed (75). Furthermore, steroids stimulate G-
inhibit COX-2, the negative effects of these cell hyperplasia (73), indirectly increasing acid
drugs on the gastroduodenal mucosa will be production by parietal cells. They also decrease
minimized. While recent studies suggest that the rate of epithelial turnover and mucin secre-
this may be the case (65), potential benefits tion, thereby impairing the healing process. For
can be negated by eo-therapy with salicylates. all of these reasons, steroid administration may
Unfortunately, the cost of COX-2 inhibitors is exacerbate underlying gastric mucosal damage.
two to three times thqt of conventional NSAIDs.
Role of Cigarette Smoking
NSAIDs also inhibit gastric mucosal secretion
and alter cell membrane permeability, leading to Cigarette smoking has been linked to both
acid back-diffusion into the lamina propria. In the initiation and the delayed healing of gastric
addition, they inhibit active bicarbonate secre- ulcers. Cigarette smoking has also been associ-
tion, alter surface phospholipids, and change ated with relapse of duodenal ulcers, with nico-
mucosal blood flow. tine exhibiting a dose-dependent effect on ulcer
NSAIDs usually produce acute mucosal lesions recurrence (76,79,80). Smoking increases the
within 7 to 14 days of adminish"ation. True ulcers likelihood that surgery will be required for the
develop despite the fact that mucosal adaptation treatment of peptic ulcer disease, and increases
occurs (70,72). HP infection makes the mucosa the risks of surgery (76).
more susceptible to NSAID-mediated damage. Numerous mechanisms have been proposed
Conversely, NSAIDs intensify HP-induced injury. to explain the effect of smoking on peptic ulcer

178
Peptic Ulcer Diseases

Figure 5-2
NONSTEROIDAL ANTIINFLAMMATORY DRUG (NSAID) INJURY
Left: Erosive gastritis secondary to NSAID injury. The lamina propria contains numerous acute inflammatory cells.
Right: A typical example of chemical gastropathy shows essentially no inflammation of the lamina propria, but reactive-
appearing epithelial cells. The glands have a corkscrew-like appearance.

development (Table 5-1) (77,78). Traditionally, Table 5-l


a close relationship has existed between peptic
EFFECTS OF SMOKING ON THE GASTRIC MUCOSA
ulcers and chronic lung disease, but this asso-
ciation may reflect the role of smoking in both Increased acid and pepsin secretion
conditions. Increased gastric motility and emptying
Reduced efficacy of H2-blocker therapy
Other Factors in Ulcer Development
Decreased prostaglandin synthesis
Pepsins are another factor in peptic ulceration. Decreased mucosal blood flow
These become irreversibly activated at an alkaline Decreased epidermal growth factor secretion
pH. An elevated level of pepsinogen 1 (PG 1) is
Increased risk of Helicobacter p)'lori-associated damage
a marker of gastric peptic ulcer disease (82); the
Increased free radical production
treatment of gastritis associated with peptic ulcer
disease results in reduced semm PG 1levels (83). Increased synthesis of cytokines
A specific pepsinogen C gene polymorphism may Increased bile reflux
predict gastric ulcer risk (81).
Demography
is in part explained by increased NSAID use for
The incidence of peptic ulcers depends on the the treatment of degenerative joint disorders
geographic region, the age and sex of the pa- in the elderly. The cumulative probability of
tient, and the method used to make the diagno- developing a peptic ulcer, however, is highest in
sis. Overall, gastric ulcers occur more frequently middle-aged men (aged 41 to 60 years) in whom
in individuals of increased age, a finding that chronic antral gastritis or chronic pangastritis

179
Gastrointestinal Diseases

Table S-2 Table S-3


GENETIC SYNDROMES ASSOCIATED SITES OF PEPTIC ULCERS
WITH PEPTIC ULCERS
Stomach
Multiple endocrine neoplasia type 1 Duodenum
Essential tremor, congenital nystagmus, and narcolepsy Barrett esophagus
Familial forms of systemic mastocytosis Meckel diverticulum
Van Alien form of amyloidosis with neuropathy, nephro- Surgical anastomotic sites and stomas
pathy, and peptic ulcer
Sites of ectopic gastric mucosa
Pachydermoperiostosis and hypertrophic gastropathy

is present (89). In populations at high risk for tritis, whereas gastric ulcers are associated with
developing gastric cancer (e.g., Japanese), gastric decreased gastric acid secretion and diminished
ulcers are more common than duodenal ulcers. mucosal defense mechanisms. Some genetic
A marked change has occurred in the in- syndromes are associated with an increased risk
cidence of peptic ulcer disease over the last of developing peptic ulcers (Table S-2)
century: current figures suggest that the overall Clinical Features. Episodic epigastric pain
incidence of peptic ulcer disease is declining constitutes the most prominent clinical feature
(85). Hypotheses to explain this decline include of gastric peptic ulcer disease. The pain, aggra-
changes in smoking habits (90), iriJ.proved liv- vated by meals or alcohol, often occurs at night,
ing conditions that decrease the likelihood of awakening the patient. Bleeding develops in
HP infection, decreased physical workload, and about 20 percent of patients and is massive in
decreased salt intake. In contrast, the incidence 5 percent. Endoscopic visualization of a bleed-
of ulcers in women is increasing. ing vessel or other signs of recent hemorrhage
Estimates of ulcer frequency in children have predict further bleeding and increased mortality
also increased in recent times. Twenty to SO per- (94,95). Juxtapyloric ulcers may cause obstruc-
cent of adults and 25 to 62 percent of children tion early due to the presence of coexisting
with ulcers (86,87) have a family history of pep- edema and pyloric stenosis as the ulcer heals
tic ulcer disease. Peptic ulcers in..children, like and fibrosis develops.
adults, may be associated with NSAID use (88). Occasionally, a large gastric ulcer high on
Primary peptic ulcers in children under the age the lesser curvature heals to produce a scarred,
of 6 are usually gastric and affect boys and girls constricted, hourglass-shaped stomach. Giant
equally (84). Most are located in the antrum. gastric ulcers are more likely to result in se-
vere hemorrhage or penetrate into contiguous
GASTRIC PEPTIC ULCER DISEASE organs. The risk of microscopic malignancy
Definition. Gastric peptic ulcer disease is a is significantly greater in giant ulcers than in
defect occurring in the mucosal surface of the the nongiant type (91). Rarely, peptic ulcers
stomach, usually as a result of the action of acid penetrate into the pericardium and heart (96),
and pepsin on a mucosa with impaired defense especially in patients with previous surgery
mechanisms. involving the esophagogastric region.
Etiology. Peptic ulcers fall into three etiologic Gross Findings. The term "peptic ulcer" re-
•. groups: those resulting from acid hypersecre- fers to any deep mucosal break resulting from
tion, as in Zollinger-Ellison syndrome; those exposure to gastric acid or pepsin. Such ulcers
due to NSAID use; and those associated with HP develop adjacent to any site containing oxyn-
infection. HP-associated ulcers form the largest tic mucosa, including those listed in Table S-3.
subset. Gastric and duodenal ulcers share over- Rarely, they arise in the acid-secreting mucosa
lapping epidemiologic and pathophysiologic itself. Acute peptic ulcers are often deep, are
features but also show significant differences. more than 0.5 cm in diameter, penetrate the
Prepyloric and duodenal ulcers arise in the set- muscularis mucosae, and have little fibrous
ting of increased acid secretion and antral gas- tissue at their base. Those that measure greater

180
Peptic Ulcer Diseases

Figure S-3
GASTRIC ULCER
Antrectomy specimen shows a punched-out, deep peptic
ulcer near the antral-corpus junction.
Figure S-4
BENIGN GASTRIC ULCER
The ulcer appears punched out and has a clean-appearing
base. The surrounding mucosa is flattened and atrophic.
than 3 cm in diameter are sometimes referred
to as giant gastric ulcers.
Gastric ulcers are usually solitary, although
about 30 percent of patients have associated Ulcer depth varies; deeper ulcers may perfo-
duodenal ulcers. Gastric peptic ulcers arise in rate through the stomach wall, extending into
any part of the stomach, but they typically adjacent structures. Giant gastric ulcers are more
develop on its lesser curvature, usually at the likely to penetrate than nongiant ulcers (91).
antral-corpus junction (fig. 5-3). Microscopic Findings. A gastric biopsy dif-
Benign ulcers typically appear as round to ferentiates benign gastric ulcers from ulcerated
oval, sharply punched-out lesions with perpen- invasive carcinomas. Multiple biopsies taken
dicular walls (fig. 5-4). The surrounding mucosa from the ulcer edge increase the chance of mak-
appears congested and edematous, and often ing a correct diagnosis. The likelihood of obtain-
overhangs the margin, forming a lip and some- ing a positive cancer diagnosis increases from
times imparting a flask-shaped appearance to 45 percent when four biopsies are taken to 99
the ulcer. The lip of a benign peptic ulcer should percent when eight or more are taken (92). It may
not appear rolled or heaped up. The mucosa be technically impossible, however, to perform
away from the ulcer also often appears atrophic this many biopsies under some circumstances.
with flattened mucosal folds (fig. 5-4). Scarring Histologically, four zones characterize chronic
at the ulcer base often causes puckering of the ulcers: 1) a superficial layer of polymorphonucle-
surrounding mucosal folds, causing them to ar leukocytes and fibrin debris; 2) an underlying
radiate away from the ulcer in a spoke-like fash- layer of coagulation necrosis; 3) a deeper layer
ion. The ulcer base should appear smooth and of granulation tissue; and 4) a deepest layer of
cream colored or pearly gray unless hemorrhage fibrosis at the ulcer base (fig. 5-5). The latter often
has occurred. In contrast, ulcerated carcinomas disrupts the muscularis mucosae and the submu-
tend to be shallow, irregular, bowl-shaped le- cosa, and can be highlighted using a trichrome
sions with rolled or heaped up, sloping borders. stain. The vessels at the ulcer base usually show
Their bases appear necrotic and flattened out. an obliterative endarteritis. The extent of this
The ulcer often distorts the rugal folds in such change governs the magnitude of hemorrhage
a way that they do not converge toward it or, that occurs should the vessels become eroded.
if they do, they terminate short of it. Candida may also colonize the ulcer base. If

181
Gastrointestinal Diseases

Figure S-5
ULCER HISTOLOGY
Left: Low-power microscopy shows the layers that comprise a typical peptic ulcer. A superficial layer of fibrin and an acute
inflammatory exudate are over a layer of granulation tissue. Under the granulation tissue is a layer of fibrosis.
Right: Higher-power view shows the inflamed granulation tissue in the ulcer base .
..,.

the organism does not invade the underlying Peptic ulcers begin to heal by the inward
tissues, it has no clinical significance, nor does migration of a single epithelial layer at the ulcer
it necessarily prolong the healing process. edge (fig. 5-7). The proliferating mucosa grows
Acute peptic ulcers do not contain the four downward and extends over the ulcer surface.
zones described above. A polymorphonuclear This single cell layer may entirely cover the sur-
exudate replaces the epithelium and moder- face of small ulcers (less than 2 cm). Simple mu-
ate amounts of granuJation tissue fill the ulcer cous glands also develop. Mucosal islands may
center. The remaining mucosa appears regenera- become entrapped in the fibrous or granulation
tive, with immature cells and occasional mitotic tissue, and may be mistaken for invasive carci-
figures. Scarring is absent. noma. Away from the ulcer, the mucosa appears
Histologic examination of bleeding gastric normal or exhibits chronic gastritis. Prominent
•.·
ulcers usually reveals a small, eroded artery in collections of chronic inflammatory cells that are
the ulcer crater (fig. 5-6). The larger the eroded associated with neural hyperplasia may be seen
artery, the more likely that death will result. in the gastric wall adjacent to the ulcer. This find-
Arterial diameter ranges from 1.5 to 3.4 mm in ing could suggest a diagnosis of Crohn's disease
25 percent of patients with fatal bleeding ulcers if one were unaware of the presence of a nearby
(94). Histologically, the blood vessel may show healing ulcer. The neuromuscular changes that
evidence of aneurysmal dilatation, intense ar- occur in association with peptic ulcers may
teritis, and endarteritis obliterans. result in disordered gastric motility.

182
Peptic Ulcer Diseases

Figure S-6
BLEEDING ULCER
A: Endoscopic view of an actively bleeding gastric ulcer.
B: Another ulcer that is not actively bleeding, but shows an overlying blood clot, suggesting a previous episode of
hemorrhage.
C: Endoscopic appearance of the ulcer following removal of the blood clot.

Figure 5-7 Figure S-8


HEALING ULCER EPITHELIAL CHANGES ADJACENT
A single layer of cuboidal epithelial cells is seen migrating TO A GASTRIC ULCER
inward to reepithelialize this gastric ulcer. Organizing The epithelium shows marked atypia with increased
granulation tissue underlies the new epithelial layer. nuclear to cytoplasmic ratios, large hyperchromatic nuclei,
and prominent nucleoli. Scattered acute inflammatory
cells are present, suggesting that the histologic changes
The serosa underlying a peptic ulcer often are likely reactive.
appears fibrotic, demonstrates fat necrosis, or
shows areas of mesothelial hyperplasia. The tinguish malignant cells from the regenerative
fibrosis and fat necrosis thicken the gastric wall. atypia invariably present in areas of gastritis
Adhesions develop and extensive areas of meso- adjacent to ulcers (fig. S-8) (93). Reactive fibro-
thelial hyperplasia may be trapped within the sis at the base or sides of a chronic ulcer crater
inflammatory process. Regional lymph nodes can distort the regenerating glands and suggest
become enlarged and reactive in appearance. the possibility of tissue invasion, particularly in
Differential Diagnosis. One of the most the presence of a partially healed ulcer where
difficult tasks facing the pathologist is to dis- epithelial regeneration is still occurring. Under

183
Gastrointestinal Diseases

b.*"
-, "l:4V'\.
Urease
production H. pylori Inflammation
q.nd ulceration
Figure 5-9
DUODENAL
ULCER DEVELOPMENT
The diagram depicts the path-
ophysiology of duodenal ulcer
t
Peptic duodenitis
with pyloric metaplasia
development.
t
Colonization
*\,;
Increased gastrin Increased acid
~'\,"''\,
output from G cells production by
parietal cells H. pylori

such circumstances, it is imperative to recognize ination of the muscularis propria. Deep ulcers
the classic cytologic hallmarks of tnalignancy and their scars result in fibrous replacement of
before making a diagnosis of cancer. the muscle layer, whereas the muscularis pro-
When the pathologist cannot unequivocally pria deep to a cancer usually remains intact and
distinguish regenerative epithelium from carci- nonfibrotic, and may even become accentuated.
noma, a subsequent rebiopsy, once the inflam-
mation subsides, may be warranted if a strong DUODENAL PEPTIC DISEASES
clinical suspicion for cancer exists. If, on the Peptic duodenitis and peptic duodenal ulcers es-
other hand, the clinical features suggest that sentially represent different phases of the same
the lesion is benign and reactive, the patient process. As a result, many patients who initially
can be treated medically for 4 to 6 weeks, then present with duodenitis later develop a duodenal
reevaluated and additional biopsies taken at ulcer. Peptic duodenitis results from chronic over-
that time. A useful rule of thumb is that any exposure to hydrochloric acid from the stomach
chronic gastric ulcer that has been histologi- and is usually confined to the duodenal bulb.
cally diagnosed as benign should be followed Peptic duodenitis progresses to erosive peptic
by the gastroenterologist until"'Ulcer healing duodenitis with superficial loss of the duodenal
is complete. Larger ulcers take longer to heal. mucosa and then to frank peptic ulceration.
Ongoing NSAID intake may retard healing. Factors leading to duodenal ulcer formation in-
The use of immunostains for cytokeratin may clude mucosal inflammation, weakening of the
help to determine whether or not single cells mucus bicarbonate barrier, superficial epithelial
have extended into the lamina propria. Such cell damage, increased serum gastrin levels with
preparations should be carefully interpreted defective feedback control, an increase in pari-
because isolated non-neoplastic cells can remain etal cell mass in some patients, and the develop-
entrapped in the gra,nulation or fibrous tissue ment of gastric metaplasia. Colonization by HP
at the base of gastriC ulcers. Alternatively, re- organisms further weakens mucosal defenses.
sidual epithelial remnants from the associated HP colonize areas of foveolar metaplasia in
gastritis may be present. Cytokeratin positivity peptic duodenitis and play a major role in the
occasionally can be found in nonepithelial cells, genesis of peptic ulcer disease (fig. 5-9) (99-103).
' ·' especially near the peritoneal surface. Such Patients with duodenal HP infection generally
cytokeratin-positive, spindled submesothelial have coexisting gastric infection. Once colo-
cells do not communicate with the gastric mu- nized, the organisms propagate and increase
cosa and usually fail to show other epithelial areas of the foveolar metaplasia (103). The meta-
features, such as epithelial membrane antigen plastic epithelium becomes inflamed by the
immunoreactivity. The cytokeratin-positive same mechanisms that exist in the stomach. The
cells are also vimentin immunoreactive. urease produced by HP in the stomach increases
The distinction between chronic ulcers and the gastric pH, which in turn stimulates antral
ulcerating cancers is further facilitated by exam- G cells, resulting in increased gastrin release and

184
Peptic Ulcer Diseases

increased gastric acid secretion. This then leads


to an increased duodenal acid load. Treatment
of the infection enhances ulcer healing and re-
duces ulcer recurrence, further confirming the
etiologic relationship of HP with duodenal ulcer.
Role of Genetic Factors
The increased incidence of duodenal ul-
cers among first-degree relatives and patients
with blood type group 0 (98) and an elevated
concentration of serum pepsinogen 1 suggests
that genetic factors play some role in duodenal
ulcer pathogenesis. This hypothesis is supported
by the discovery of familial clusters of ulcer
patients with elevation of the same pepsinogen
Figure 5-10
group 1 fractions. The hyperpepsinogenemia
reflects an increased gastric pepsin-secreting PEPTIC DUODENITIS WITH
GASTRIC FOVEOLAR METAPLASIA
and acid-secreting cell mass (97).
On the left, the epithelial lining is composed of cells
Peptic Duodenitis with an appearance similar to the gastric surface epithelium.
In the center, residual enterocytes and goblet cells that
Gross Findings. The gross appearance of normally make up the small intestinal epithelium are seen.
peptic duodenitis varies from simple mucosal Eosinophils are prominent.
erythema to mucosal friability and nodular-
ity. The erythema results from the shunting of HP organisms may colonize areas of foveolar
blood to the villous tips induced by increased cell metaplasia using the same mechanisms as
hydrochloric acid. Severe cases exhibit erosions in the stomach. The bacteria are much more
and ulcers. With long-standing disease, mucosal likely to be seen when the metaplasia is ex-
atrophy, thickening, or irregularity may be pres- tensive. The organisms inhibit the secretion
ent. Areas of nodularity usually correspond to of proximal duodenal mucosal bicarbonate.
areas of Brunner gland hyperplasia. The result is decreased acid neutralization in
Microscopic Findings. The principal his- the duodenal lumen and further exacerbation
tologic features of peptic duodenitis are: I) of peptic injury to the duodenal mucosa. The
inflammatory cells in the epithelium or lamina gastric metaplasia may disappear after treatment
propria; 2) altered epithelial cell morphology due of the HP infection.
to degeneration, regeneration, or metaplastic Endoscopically identified nodular duodenitis
changes; 3) mucosal hemorrhage and edema; and usually occurs secondary to hyperplasia of the
4) Brunner gland hyperplasia. In the most severe Brunner glands in the submucosa and mucosa
forms of duodenitis, villous atrophy can be seen. of the duodenum. Histologically, the glands
The presence of foveolar cell metaplasia appear identical to normal Brunner glands
(gastric surface epithelial metaplasia) provides except that they are increased in number and
a helpful clue to the diagnosis of peptic duode- size (fig. 5-11). The glands retain their lobular
nitis (fig. 5-10). Foveolar metaplasia probably architecture, but the lobules vary in size, and
represents an adaptive response to duodenal fibromuscular strands stretch between them. No
hyperacidity and may protect against ulcer- capsule surrounds the glands. Larger polypoid
ation because, like the surface epithelium of lesions may become superficially eroded.
the stomach, this epithelium has a number of Brunner gland hyperplasia is an adaptive
defense mechanisms that protect it from acid. response to the increased luminal acid that ac-
Histologically, the metaplastic cells appear as companies peptic duodenitis. Brunner glands
fully developed gastric mucous cells or they normally produce alkaline secretions that neu-
may demonstrate features intermediate between tralize duodenal luminal acid. Hypergastrinemia
gastric and intestinal cells. also plays an etiologic role in the hyperplasia,

185
Gastrointestinal Diseases

Figure 5-11 .
PEPTIC DUODENITIS WITH
BRUNNER GLAND HYPERPLASIA
A: Low-power view shows marked hyperplasia of Brunner
glands in a patient with peptic duodenitis.
B: Higher power shows a focus of foveolar metaplasia
in the mucosa overlying the hyperplastic Brunner glands.
C: Higher magnification of the foveolar metaplasia.

presumably through its trophic effects on and if particularly large, may lead to mechanical
the cells of Brunner glands. Occasionally, the problems including gastric outlet obstruction.
hyperplastic area may assume the characteristics Most of the histologic features of peptic duo-
of a polypoid mass that may ulcerate and bleed, denitis are nonspecific. Similar findings occur

186
Peptic Ulcer Diseases

Figure 5-12
DUODENAL ULCER
A deep ulcer in the proximal portion of the duodenum.

in patients with Crohn's disease, drug-induced


injury, stress-induced duodenitis, and certain
infectious diseases.
Duodenal Ulcer
Clinical Features. Patients with duodenal
ulcers experience general symptoms of dyspep-
sia and intermittent abdominal pain. Duodenal Figure 5-13
ulcers are more likely to perforate, bleed, or cause
DUODENAL ULCER
obstruction than are gastric ulcers. In some cases,
Top: Low-power view of a duoden al ulcer with adj acent
the bleeding may be massive. Recurrent bleeding peptic duodenitis. Even at low power, foveolar epithelium
affects 13.6 to 32.0 percent of patients, espe- can be appreciated at the ulcer edge.
cially those older than 60 years of age (104,108). Bottom : The ulcer is similar to those seen in the stomach .
Duodenal ulcers also occur in children. In young
patients, the clinical presentation is often atypi-
cal. Children with cystic fibrosis are particularly 3 cm in maximum diameter (fig. 5-1 2). Ulcers
prone to develop duodenal ulcers due to de- measuring greater than 3 cm in diameter are
creased duodenal bicarbonate secretion. unusual. Ulcers located in the posterior portion
Duodenal ulcers may be multiple. Patients of the duodenal bulb are more likely to bleed
with multiple ulcers have lower healing rates than those situated elsewhere (107) because two
and higher mean fasting and meal-stimulated sizable vessels, the pancreaticoduodenal and
serum gastrin levels than those with single the gastroduodenal arteries, lie in the vicinity.
ulcers. The presence of multiple ulcers should Penetration of the duodenal wall by an ulcer
arouse the suspicion of NSAID use or Zollinger- may result in erosion of one or both of these
Ellison syndrome. Patients with Zollinger- vessels, producing massive hemorrhage. Ulcer
Ellison syndrome also have ulcers in the second scarring may lead to the formation of a preste-
and third portions of the duodenum or jejunum notic diverticulum.
and/or repeated penetrating or perforating ul- Microscopic Findings. Histologically, duo-
cers in the third portion of the duodenum or denal ulcers resemble their counterparts in the
first portion of the jejunum. stomach. Features of peptic duodenitis are often
Gross Findings. Usually, duodenal ulcers seen in the adjacent nonulcerated mucosa (fig.
appear circular or oval, and measure less than 5-13) .

187
Gastrointestinal Diseases

TREATMENT AND PROGNOSIS FOR secretory agents (110). In addition, misoprostol


PATIENTS WITH PEPTIC ULCER DISEASE may be effective in preventing the development
The treatment of peptic ulcers depends on of gastritis and peptic ulcers in patients receiving
several factors, the most important of which NSAIDs (111). Some studies suggest that proton
are whether the patient is infected with HP pump inhibitors may be as or more effective than
and whether the patient is taking NSAIDs. In misoprostol in promoting ulcer healing in pa-
general, all patients with peptic ulcer disease tients on NSAIDs (106). Proton pump inhibitors
should be advised to stop smoking. Prophylaxis have fewer side effects and are better tolerated
with maintenance antisecretory agents may by most patients than misoprostol.
need to be considered in those patients who Another effective method of treating patients
present with an ulcer complication, those who with NSAID-induced ulcers is substituting a
have numerous co-morbidities, or those who nonspecific COX inhibitor for a specific COX-2
cannot discontinue anti-inflammatory agents. inhibitor. A recent study suggests that celecoxib
HP-Infected Patients. In 1994, a National (a COX-2 inhibitor) was as effective as diclof-
Institutes of Health consensus conference enac plus omeprazole in preventing recurrent
recommended that all patients l:Vith peptic bleeding from peptic ulcers (105). Major draw-
ulcer and HP infection should be given anti- backs to this therapy are renal toxicity, fluid
microbial therapy (109). Optimal therapy for retention, hypertension, possible associations
HP-associated peptic ulcer disease includes with cardiac events, and cost.
treatment with combinations o.f antibiotics Patients Without HP Infection or NSAID
and antisecretory agents. The antibiotics that Use. Peptic ulcer patients who are negative for
appear to be most effective in eradicating HP HP and are not taking NSAIDs can usually be
organisms are clarithromycin and metronida- successfully treated with antisecretory therapy
zole. These drugs may be used in combination alone. Either H 2 -blockers or proton pump in-
with other antibiotics such as tetracycline or hibitors may be used.
amoxicillin. The selection of an antibiotic regi-
men should depend on local prevalence rates of ZOLLINGER-ELLISON SYNDROME
antibiotic-resistant HP strains (U2). The addi- Etiology. The gastroduodenal changes in Zol-
tion of bismuth-containing compounds to the linger-Ellison syndrome (ZES) consist of two major
treatment regimen may enhanco€ ulcer healing alterations: peptic ulcer disease and hypertro-
through stimulation of prostaglandin synthesis phic gastropathy. ZES represents the prototypic
and bicarbonate secretion. hypersecretory gastropathy. It is characterized
First-line therapies are generally effective in by gastric mucosal hypertrophy and acid hy-
eradicating HP infection 90 to 95 percent of persecretion. The acid hypersecretion results
the time. In some patients, second-line therapy, in the development of multiple peptic ulcers,
consisting of a proton pump inhibitor, bismuth, usually in the duodenum. Excessive gastrin
tetracycline, and either metronidazole or clari- production serves as the stimulus for increased
thromycin, is necessary. The choice of whether gastric acid production, often as a result of a
to use metronidazole 'or clarithromycin depends gastrin-secreting tumor (gastrinoma) located
on which drug was initially given as a first-line either in the pancreas or in the intestinal wall. A
therapy: if metronidazole-containing first-line minority of patients with ZES show evidence of
therapy was unsuccessful, then the second-line gastric G-cell hyperplasia rather than a gastrin-
'·· treatment should contain clarithromycin, and producing tumor.
vice versa. Gastrin has multiple targets, the major one
Patients Taking NSAIDs. Optimally, patients of which is the parietal cell, which secretes
with peptic ulcers who are taking an NSAID hydrochloric acid in the stomach. Gastrin also
should stop the drug, if possible. In many cases, increases the growth of parietal cells, chief cells,
however, NSAID cessation is not an option. In enterochromaffin-like (ECL) cells, and foveolar
such patients, administration of the prostaglan- epithelium, a factor that accounts for the hy-
din El analogue, misoprostol, may facilitate ulcer pertrophy that occurs in the gastric mucosa in
healing when used in combination with anti- patients with this disorder.

188
Peptic Ulcer Diseases

Figure 5-14
ZOLLINGER-ELLISON SYNDROME
Left: Low-power microscopy demonstrates a marked
increase in the glandular component of the gastric oxyntic
mucosa.
Above: On higher power, parietal cells lie in the upper
portions of the gastric pits, where they are normally not
present.

Clinical Features. ZES affects 0.1 percent of substantial glandular lengthening due to in-
all patients with duodenal ulcer disease; studies creased numbers of parietal cells (fig. 5-14). The
among European populations have documented increased parietal cell mass comprises a progres-
an incidence of between 0.2 and 0.4 case/million sively larger share of the glands, filling their
population/year. The disease occurs in patients entire length down to the base. Parietal cells also
ranging in age from 7 to 90 years (113), with most extend into the neck regions or higher, coming
patients diagnosed between the 3rd and 5th de- closer to the surface than usual (fig. 5-14). In
cades of life. There is no major sex predominance. some cases, parietal cells completely populate
The usual presenting symptom is abdominal pain, the mucosal glands. Large numbers of parietal
which affects 70 to 95 percent of patients; dianhea cells can also be present in the antrum, an area
affects 33 to 75 percent of patients. that usually lacks these cells. The foveolae ap-
Some patients lack all features of ZES. Peptic pear normal in length or shortened.
ulcers may be absent, and diarrhea with steat- Treatmen t and Prognosis. The acid hyper-
orrhea may be the only clinical manifestation. secretion in patients with ZES can be controlled
The acid hypersecretion may be mild and in- with the use of inhibitors of H+fK+-ATPase, which
distinguishable from that seen with ordinary is present on the gastric parietal cell membrane
duodenal ulcer. The marked parietal and peptic (114). As a result, the acid-mediated manifesta-
cell hyperplasia (115) expands the gastric glands tions (ulceration, bleeding, perforation, dianhea,
and causes rugal hypertrophy and acid hyper- and reflux) are seldom fatal. These medications
secretion with subsequent peptic ulceration. do not influence tumor growth and spread. Con-
Gross Findings. Giant rugal folds spare the sequently, for many patients, the tissue bulk and
antrum but cover the body and fundus. The invasive effects of the gastrin-secreting tumor are
surfaces of the folds appear uniformly exagger- more problematic. While localization of small
ated, coarsely granular, or finely cobblestoned. lesions may be challenging, surgery, particularly
Microscopic Findings. Histologic examina- for localized, nonmetastatic tumors, affords the
tion of the hypertrophic gastric folds reveals best chance of cure (116).

189
Gastrointestinal Diseases

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Sourander L. Lifestyle, stress and genes in peptic 91. Chua C, ]eyaraj P, Low C. Relative risks of corn-
ulcer disease: a nationwide twin cohort study. plications in giant and nongiant gastric ulcers.
Arch Intern Med 1998;158:698-704. Am] Surg 1992;164:94-7.
80. Suadicani P, Hein HO, Gyntelberg F. Genetic and 92. Graham DY, Schw<!rtz]T, Cain GD, Gyorkey F.
life-style determinants of peptic ulcer. A study of Prospective evaluation of biopsy number in the
3387 men aged 54 to 74 years: the Copenhagen diagnosis of esophageal and gastric carcinoma.
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Other Factors in Ulcer Development 93. Isaacson P. Biopsy appearances easily mistaken
for malignancy in gastrointestinal endoscopy.
81. Azuma T, Teramae N, Hayakumo T, et al. Pep- Histopathology 1982;6:377-89.
sinogen C gene polymorphisms associated with 94. Swain CP, Lai KC, Kalabakas AA, et al. A corn-
gastric body ulcer. Gut 1993;34:450-5. parison of size and pathology of vessel and
82. Samloff IM, Varis K, Ihamaki T, Siurala M, Ratter ulcer in patient dying from bleeding gastric and
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serum pepsinogen 11 and gastric mucosal histol- A202.
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84. Deckelbaum R], Ray CC, Lussier-Lazaroff], Mo-
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85 . Gustavsson S, Nyren 0. Time trends in peptic Duodenal ulcer: incidence, risk factors, and
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86. Hyman PE, Hassall E. Marked basal gastric acid 98. Edwards ]H. The meaning of the associations
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194
6 ACQUIRED STRUCTURAL ALTERATIONS

DIVERTICULA diverticula, whereas mid-esophageal diverticula


A diverticulum is a circumscribed pouch or are traction diverticula. Pulsion diverticula re-
sac that originates from a hollow viscus. Gastro- sult from motility disturbances and associated
intestinal diverticula are mucosal outpouchings achalasia, diffuse esophageal spasm, or other
into or through the submucosa, or beyond. They motility diseases (11,24,38) . Zenker diverticula
are either congenital or acquired. Congenital arise from defective upper esophageal sphincter
diverticula are discussed in chapter 2; acquired function caused either by a failure to completely
diverticula are discussed here. Diverticula can inhibit cricopharyngeal muscle tone or from
be divided into true diverticula (with a wall muscular fibrosis that causes loss of sphincter
containing all of the mural structures) or false compliance (9). As a result, intrabolus pressure
or pseudodiverticula in which the wall lacks increases to maintain normal bolus flow. This
some mural component, such as the muscularis eventually leads to the development of a pulsion
propria. The presence of multiple diverticula is diverticulum at points of muscular weakness.
called diverticulosis. The presence of a Zenker diverticulum may
sometimes result in difficulty in intubating the
Esophageal Diverticula
esophagus at upper endoscopy, and as a result,
Definition . Esophageal diverticula can be may lead to inadvertent trauma.
divided into pulsion or traction types. The ac- Mid-esophageal traction diverticula are as-
tion of intraluminal pressure forces the mucosal sociated with mediastinal inflammation, which
outpouchings in pulsion diverticula. An extrinsic causes traction on the esophageal wall, pulling it
inflammatory process retracts or pulls the gut outward as the mediastinal inflammation begins
wall outward in traction diverticula . Esopha- to heal. Traction diverticula have decreased in
geal diverticula can also be classified by their frequency with a decline in the incidence of
location into pharyngoesophageal, thoracic or mediastinal tuberculosis.
epiphrenic diverticula. Epiphrenic diverticula are almost always pul-
Demography. Overall, esophageal diverticula sion diverticula. They arise because increased
are identified in 0 .15 percent of upper barium intraesophageal pressure pushes the mucosa
examinations (56). Zenker's (hypopharyngeal) is outward in areas of muscular weakness. For
the most common (up to 70 percent) esophageal this reason, epiphrenic diverticula frequently
diverticulum. It tends to affect middle-aged or coexist with inflammatory disorders, including
elderly individuals. Approximately 21 percent hiatal hernia, achalasia, diaphragmatic eventra-
of the remaining diverticula originate in the tion, carcinoma, Ehlers-Danlos syndrome, and
mid-esophagus; 8.5 percent originate in the su- primary motility disturbances (11,16,18,49,54).
pradiaphragmatic region. Epiphrenic diverticula Esophageal pseudodiverticulosis has several
tend to affect ~en beyond middle age, support- known associations, including Candida infection,
ing an acquired etiology. Patients with diffuse diabetes, gastroesophageal reflux disease (GERD),
esophageal intramural pseudodiverticulosis and chronic alcoholism, but it is unclear which
range in age from 11 to 83 years (28); mostly of these associated disorders plays a role in its
older individuals and males are affected. These pathogenesis, since many are so common that
lesions are rare, affecting less than 1 percent the relationships may be fortuitous rather than
of patients undergoing radiologic esophageal etiologic. The cysts of esophageal pseudodiver-
examinations (28). ticulosis form as a result of ductal obstruction
Etiology and Pathophysiology. Diverticula caused by inflammation, excess mucin, or
in the proximal and distal esophagus are pulsion squamous debris blocking the ductal orifices.

195
Gastrointestinal Diseases

Figure 6-1
TRACTION DIVERTICULUM OF THE ESOPHAGUS Figure 6-2
A large, wide-mouthed diverticular opening is in the
ZENKER DIVERTICULUM
mid-esophagus. (Courtesy of the Division of Gastrointestinal
Pathology, Armed Forces Institute of Pathology, Washington The diverticulum is lined by normal-appearing squamous
DC) epithelium . The wall of the diverticulum is composed of
muscularis mucosae, submucosal tissue, and strands of
muscle derived from the muscularis propria. (Courtesy of
the Division of Gastrointestinal Pathology, Armed Forces
Clinical Features. Patients with Zenker Institute of Pathology, Washington, DC.)
diverticula complain of dysphagia, halitosis,
regurgitation, and heartburn. When the diver-
ticulum fills with food and secretions, it enlarges
and compresses the esophagus, causing dys- the distal third of the esophagus, usually pro-
phagia, obstruction, and aspiration. Secondary jecting from the terminal4 cm of the-right pos-
bacterial colonization results in diverticulitis. terior esophageal wall. Esophageal diverticula
Mid-esophageal diverticula are almost always can become quite large (up to 10 cm), although
discovered incidentally. Patients with diffuse they usually measure less than 2 cm in diameter.
esophageal intramural pseudod1verticulosis In esophageal pseudodiverticulosis, the mul-
present with dysphagia and aq~te bolus ob- tiple, cystically dilated, submucosal glandular
struction, probably because of the association ducts produce a dramatic radiographic picture (3).
between intramural diverticulosis, dysmotility, "Flask" or" collar button"-like outpouchings vary-
and stricture formation (3,28,42). ing from 1 mm to 1 cm in diameter, lie evenly dis-
Gross Findings. Esophageal diverticula de- tributed along the esophageal wall and correspond
velop in the pharyngoesophageal junction, just to the distribution of normal esophageal glands.
above the diaphragm, and in the mid-thorax The cysts remain intramural, extending 3 mm
in a frequency of 7 to 1 to 2, respectively (56). or less beyond the esophageallumen (23); each
The proximally located Zenker diverticulum cyst connects with the lumen via a small ostium.
develops posteriorly 01' posterolaterally between Fifty percent of cases are diffuse and 50 percent
the pharyngeal inferior constrictor muscle and are segmental (35) . Segmental disease affects the
fibers of the cricopharyngeus muscle, in a trian- proximal third of the esophagus. Most patients
gular zone of sparse musculature termed Killian have associated strictures in the same location as
dehiscence or Killian triangle (10). the intramural diverticulosis (28,35).
Mid-esophageal diverticula develop as single Microscopic Findings. The walls of esopha-
or multiple saccular outpouchings of the geal diverticula consist of mucosa, submucosa,
esophageal lumen, usually near the tracheal and an attenuated muscularis propria (fig. 6-2).
bifurcation (24). Most are wide-mouthed. The A true muscular coat is usually absent. Squa-
diverticular walls consist of a variably inflamed mous epithelium lines all esophageal diverticula
mucosa and submucosa with an attenuated unless they develop in an area of Barrett esopha-
muscularis propria (fig. 6-1). The globular and gus . Variable inflammation and prominent
wide-mouthed epiphrenic diverticula arise in lymphoid follicles may be present.

196
Acquired Structural Alterations

In esophageal pseudodiverticulosis, dilated


submucosal ducts and glands are present, often
associated with acute and/or chronic inflam-
mation and desquamated epithelium (fig. 6-3) .
Bacteria and fungi may secondarily colonize the
cysts. Occasionally the cysts undergo squamous
metaplasia. Associated submucosal fibrosis
causes marked thickening of the esophageal
wall and results in stricture formation .
. Treatment and Prognosis. Complications of
Zenker diverticulum include dysphagia, inflam-
mation, mucosal ulcerations, and perhaps even
cancer (31). The incidence of carcinoma ranges
from 0.3 to 0.7 percent, affecting individu-
als over age 60 years who have long-standing
symptomatic diverticula. Diverticulectomy and/
or myotomy is the treatment of choice in those
cases in which surgery becomes unavoidable.
Complications of epiphrenic diverticula include
obstruction, diverticulitis, perforation, medias-
tinitis, hemorrhage, and cancer.
Figure 6-3
Gastric Diverticula
ESOPHAGEAL PSEUDODIVERTICULOSIS
Demography. Gastric diverticula are not as Several markedly dilated submucosal glands underlie
common as other gastrointestinal diverticula. the squamous epithelium.
They are found in 0.1 percent of upper gastro-
intestinal barium studies (56) .
Etiology and Pathophysiology. Gastric di- peptic ulcer disease, choledocholithiasis (21),
verticula usually result from underlying antral duodenal obstruction, and genetic or systemic
disease. Predisposing conditions include ulcers, disorders. Small intestinal diverticulosis, a het-
neoplasms, previous surgery, and radiation. erogenous disorder, affects 1.3 to 4.6 percent
Gross Findings. Pulsion dive1ticula typically mise of the population (26). It consists of single or
on the postelior wall of the proximal stomach near multiple diverticula predominantly involving
the cardia, in areas where the gastlic wall is con- the jejunum. ]ejunal diverticula develop seven
genitally weak. The lesion may be mildly inflamed. times more commonly than ileal diverticula
TJ·action dive1ticula arise in the antrum in areas of (51); men are affected twice as frequently as
previous damage from inflammatory processes. women and most patients are over age 40 (26) .
They are invariably inflamed (13). Underlying neuromuscular disorders predis-
Microscopic Findings. Gastric diverticula pose to small intestinal diverticulosis (26). The
consist of all the gastric layers but with an at- pathologic features of the underlying motility
tenuated muscularis propria. If the diverticulum disorders are described in chapter 17.
develops adjacent to an ulcer, then regenerative Etiology and Pathophysiology. Most duo-
epithelium, granulation tissue, or scar tissue denal diverticula develop as a result of chronic
may be present. peptic ulcer disease (12) . The ulcerating process
causes fibrosis of the muscularis propria and
Small Intestinal Diverticula
abnormal contractility. ]ejunal diverticula also
Demography. Most small intestinal diverticula result from areas of transmural fibrosis and
occur in the duodenum. Duodenal diverticula atrophy, or underlying neural or other abnor-
are found in 1 to 6 percent of radiologically malities. Uncoordinated muscular contractions
examined small intestines and in an average of lead to focal areas of increased intraluminal
8. 6 percent of autopsies (31). They complicate pressure, which cause mucosal and submucosal

197
Gastrointestinal Diseases

herniation through weakened areas in the


bowel wall. Diverticula begin as a pair of small
outpouchings along the mesenteric border
where the intestinal wall is weakest, where the
penetrating arteries pierce the muscular and
serosal coats. These outpouchings enlarge until
they meet and eventually fuse, forming a single
thin-walled diverticulum.
Clinical Features. Most patients with duo-
denal diverticula remain asymptomatic but
sphincter of Oddi dysfunction, obstructive
jaundice, hemorrhage, perforation, or acute
pancreatitis may develop (22,43,56). The vast
majority of patients with jejuna! diverticula are
asymptomatic; the diverticula are discovered
incidentally at the time of surgery, autopsy, or
radiographic examination. When small intes-
tinal diverticula cause symptoms, it is usually
due to inflammation, torsion, intussusception,
obstruction, bleeding, perforation, or malab-
sorption. The last is particularly likely when
patients develop large diverticula that act like
blind loops and accumulate microorganisms.
Vitamin B12 deficiency leading to mg.crocytic
anemia may develop because of bacterial over-
growth within the diverticulum (34).
Gross Findings. Acquired duodenal diver-
ticula usually develop in the first portion of
the duodenum when complicating peptic ulcer Figure 6-4
disease, and in a juxtapapillary location when
SMALL INTESTINAL DIVERTICULOSIS
they result from ampullary inflammation. They
Top: jejuna! resection specimen has multiple diverticular
are usually solitary (fig. 6-4) . In patients with outpouchings along its length.
diffuse small intestinal diverticulosis, diverticula Bottom: A large diverticulum (right) projects from the
tend to be larger in the proximal jejunum and wall of the small intestine.
become smaller and fewer distally. As many as
400 diverticula, ranging in size from 1 to 22 cm
in diameter, can be present (26) . Treatment and Prognosis. Small intestinal
Microscopic Findings. The diverticula are diverticula perforate, bleed, become inflamed,
lined by mucosa, mllscularis mucosae, sub- and undergo the complications listed in Table
mucosa, and an attenuated muscularis propria 6-1. These complications lead to morbidity and
(fig. 6-5). The mucosa usually demonstrates mortality rates as high as 40 percent. Resection
crypt hyperplasia, villous atrophy, and chronic is the treatment of choice.
inflammation. These changes probably result
Appendiceal Diverticula
from intestinal stasis and bacterial overgrowth.
Lipid-containing histiocytes often lie in the mu- Demography. Most appendiceal diverticula are
cosa, submucosa, and lymphatic vessels, close acquired (14). Both sexes are equally affected.
to the collar of muscularis propria surrounding Incidence estimates range from 0.004 percent
the diverticular neck (27). Pneumatosis intesti- to 2.8 percent (6,7,30). Acute appendicitis with
nalis complicates jejuna! diverticular disease in focal destruction of the muscularis propria
some instances (57). If diverticulitis develops, accounts for most appendiceal diverticula.
the inflammation localizes to the diverticulum. Patients with cystic fibrosis or tumors tend to

198
Acquired Structural Alterations

Figure 6-5
SMALL INTESTINAL DIVERTICULUM
A: Prominent small intestinal diverticula are seen. The
muscularis propria appears thicker than usual.
B: Low-power view shows the neck of the larger diver-
ticulum lined by normal-appearing small intestinal mucosa.
The muscularis propria is thickened and shows the typical
separation of muscle bundles seen in diverticular disease
in the colon.
C: The diverticulum is filled with inspissated fecal
material.

develop appendiceal diverticula secondary to


Table 6-1
chronic luminal obstruction.
Gross Findings. Appendiceal diverticula are COMPLICATIONS ASSOCIATED WITH
usually small and multiple, measuring 0.2 to SMALL INTESTINAL DIVERTICULOSIS
0.5 mm. They occur along the mesenteric and Acute mechanical intestinal obstruction
antimesenteric borders of the appendix, at the From enteroliths, diverticulitis, or volvulus
From pressure on the intestine by filled diverticula
site of penetrating arteries (19), giving the ap-
pendix a beaded appearance (7). They typically Chronic intestinal obstruction
Without apparent mechanical obstruction (pseudo-
arise in the distal appendix. obstruction)
Microscopic Findings. Appendiceal diver- From stricture or adhesions secondary to chronic
ticula resemble colonic diverticula. When they diverticulitis
become inflamed, the inflammation localizes Inflammatory disturbances varying from mild inflam-
to the diverticulum but may also extend into mation to gangrene
the remainder of the appendix producing ap- Intestinal hemorrhage
pendicitis, periappendicitis, or periappendiceal Intestinal stasis
abscesses. Extensive inflammation may distort, Bacterial stasis in diverticulum creating "blind loop
obliterate, or disrupt the diverticulum. syndrome" resulting in malabsorption, Bl2 deficiency
Steatorrhea, anemia, weight loss, and hypoproteinemia
Colonic Diverticula Rupture
Definition. In the colon, the term diverticulo- Foreign bodies
sis refers to the presence of multiple diverticula, Neoplasia
with or without the accompanying muscle

199
Gastrointestinal Diseases

abnormality found in classic diverticular dis- through weak points in the muscularis propria
ease. The term diverticular disease is used to de- (45), usually where penetrating arteries pierce the
scribe a specific clinical disorder with a defined muscularis propria. Diverticula arising between
radiologic and pathologic appearance in which the mesenteric and antimesenteric taeniae are
there is a characteristic muscle abnormality, usually more advanced than those located on
usually but not invariably accompanied by the the antimesenteric border, probably because
presence of diverticula. · When a muscular ab- the blood vessels entering the colonic wall are
normality occurs in the absence of established smaller in the latter location. The pronounced
diverticula, the term prediverticular disease is muscularis propria hypertrophy present in pa-
sometimes used (40) . tients with diverticular disease, even before the
Demography. The incidence of large intes- formation of diverticula, supports the increased
tinal diverticular disease varies with national colonic segmentation theory of pathogenesis.
origin, cultural background, and diet (50,52). The rarity of rectal dive1ticula may be related
Colonic diverticular disease is prevalent in the to the lower luminal pressure and greater retro-
United States and other Westernized countries peritoneal support in this region compared to
(8,52), and affects both sexes equally (53). the sigmoid colon.
The frequency correlates with advancing age. Genetic factors seem to play a role in the evo-
Diverticula are found in up to 66 percent of lution of diverticular disease, because diverticula
colons examined with barium enema in West- preferentially arise in the right colon among
ern countries (46). The increasing incidence Asians (53) and young patients, contrasting
of diverticular disease seen in JatJan (41,44), with a location in the sigmoid and left colon in
South Africa (50), and Israel (29) ·results from Caucasians and older individuals (4,47).
the introduction of a Western-type diet in Because diverticula often lack a muscular
these countries. Asians often have right-sided layer, secretions and fecal material easily enter
diverticulosis, although diverticulosis involving them. The feces are not easily expelleg and they
the right and left side of the colon (bilateral harden into fecaliths that block the diverticular
diverticular disease) has increased in incidence orifice, leading to diverticulitis.
in recent years (37). Some patients with a soli- Clinical Features. Most people with large in-
tary rectal diverticulum have scleroderma (48). testinal diverticulosis remain asymptomatic; 10
Children with colonic diverticulosis often have to 25 percent of patients become symptomatic,
underlying Marfan's or Ehlers-Danlos syndrome usually due to the development of diverticulitis
or associated polycystic kidney disease (1). (4) . Most symptomatic individuals are between
Etiology and Pathophysiology. Three major the ages of 50 and 70. The symptoms of diver-
factors are required for the development of colonic ticulosis may be accentuated by the increasing
diverticula: 1) a higher pressure within the colonic constipation seen in older patients.
lumen than the ambient peritoneal pressure; 2) Acute diverticulitis varies in severity. Clinical
a weak point within the intestinal wall through features of left-sided diverticulitis include lower
which the mucosa can herniate; and 3) biophysi- abdominal pain, made worse by defecation,
cal changes in the colonic wall as a result of aging. and signs of peritoneal irritation, including
Age-related changes in the tensile strength of the muscle spasm, guarding, rebound tenderness,
colonic wall cause contraction and sh01tening fever, and leukocytosis. Some patients develop
of the taeniae coli, and redundant mucosal folds recurrent, left lower quadrant, colicky pain
that narrow the colonic lumen. Aging; decreased without clinical or pathologic evidence of acute
dietary fiber intake; consumption of beef, beef fat, diverticulitis. Patients have alternating bouts of
and salt; lack of physical activity; and the presence constipation and diarrhea. Acute diverticulitis
of constipation all correlate with the development of the right colon ranges in frequency from
of diverticular disease. Decreased luminal fiber 0. 7 to 1.5 percent. Patients present with right
and lower stool volume requires more colonic lower quadrant abdominal pain and periumbili-
segmentation to propel fecal material forward cal pain radiating to the right lower quadrant.
(46). The increased segmentation generates great- Most patients have elevated levels of white
er intraluminal pressures; forcing the mucosa blood cells, erythrocyte sedimentation rates,

200
Acquired Structural Alterations

and C-reactive protein. Symptom duration may bunched, redundant mucosal folds. These can
be short and rectal examination may reveal the significantly narrow the colonic lumen and may
presence of a tender mass. cause obstruction, with dilatation proximal to
Once diverticulitis develops, the subsequent the area of obstruction.
clinical course depends on bacterial virulence Diverticula, mucosal flask-shaped outpouch-
and host defenses. Complications are more ings, can develop throughout the entire length of
common in individuals using nonsteroidal the colon, although most commonly they occur
anti-inflammatory drugs (NSAIDs) (2), perhaps in the distal colon. In the Western world, 90 per-
because the drugs mask the symptoms of earlier cent of patients have sigmoid involvement and
disease or because NSAlDs interfere with natural 20 percent have pancolonic involvement. In con-
mucosal defenses (see chapter 8). Life-threat- trast, Asians, particularly individuals from Japan,
ening complications occur more commonly Singapore, and China, develop multiple right
among patients with chronic renal failure or colon diverticula (5,52). When the diverticula
on high-dose steroid therapy (17) . are fully developed, they remain permanently
If acute inflammation involves all layers of distended and extracolonic in location. Since
the bowel wall, the diverticulum may perforate, symptomatic diverticulitis remains a relative
leading to peritonitis. Perforated diverticula contraindication to contrast studies, computer-
can also remain confined, especially when ized tomography (CT) best demonstrates acute
they occur in the mesentery, by local fibrosis left-sided colonic diverticulitis (15) and its com-
or abscess formation. Abscesses may track into plications, particularly abscesses (18).
the bladder or adjacent bowel, forming fistu- Since the muscular abnormalities are the
las. Fistulas that extend below the peritoneal most striking and consistent part of diverticu-
reflection can reach the skin, urinary bladder, lar disease, pronounced muscular hypertrophy
or adjacent loops of bowel. provides a clue to its presence (39). The taeniae
Bleeding affects 10 to 30 percent of patients coli are much thicker than normal, developing
with diverticular disease. It is usually overt an almost cartilaginous c6nsistency. The cir-
and clinically obvious, but may vary from oc- cular layer also thickens, gaining a corrugated
cult bleeding to massive hemorrhage. It often appearance, which corresponds to the inter-
results from erosion of the penetrating artery digitating muscle processes. These changes are
in the wall of the diverticulum by a fecalith. most prominent in the sigmoid colon and may
The bleeding typically occurs suddenly, with- extend for variable distances proximally.
out signs or symptoms of diverticulitis, and Diverticula commonly appear as two paral-
stops spontaneously in 70 to 80 percent of lel rows of beaded outpouchings between the
patients (33). The blood appears bright red or longitudinal muscle or taeniae coli at sites
maroon but can appear melanotic, especially if corresponding to the location of penetrat-
it comes from the right colon. Colonoscopy is ing arteries (fig. 6-6). The diverticula project
the investigation of choice for suspected lower through and beyond the circular muscle layer
gastrointestinal bleeds. Endoscopic intervention of the bowel wall so that they come to lie in
can be performed if a bleeding diverticulum is the pericolonic fat and are covered by a thin
identified; however, usually the bleeding is self- layer of longitudinal muscle. Diverticula usu-
limited, and the actual involved diverticulum ally measure less than 1 cm in diameter; rarely,
cannot be identified. they reach diameters up to 25 cm (fig. 6-7). The
Gross Findings. Barium enema often estab- diverticula associated with scleroderma differ
lishes the diagnosis of diverticulosis. An early from the usual diverticula in that they are of-
change is the presence of fine mural serrations ten square-mouthed. This results from almost
known as the prediverticular state or myocho- complete replacement of the muscularis propria
sis . "Sawtooth" luminal irregularities reflect by fibrous tissue. There are usually associated
associated muscle spasm. A contracted haustral broad bands of scarring.
pattern may also be seen. The sigmoid colon When bleeding occurs, the exact bleeding
becomes shortened and distorted, causing it point can be difficult to identify. If a bleeding
to acquire a concertina-like appearance, with point is seen, a histologic section through a

201
Gastrointestinal Diseases

Figure 6-6
COLONIC DIVERTICULOSIS
Numerous smooth, round
outpouchings project from the
colonic wall. They are aligned
in a row along the length of the
taeniae coli.

Figure 6-7
COLONIC DIVERTICULA
Left: Several large diverticula extend through the colonic wall.
Right: Endoscopic view in a patient with diverticulitis. The openings to several diverticula are visible (arrows) .

diverticulum can identify the bleeding source. leaf-like, smooth-surfaced "polyps" with broad
The chance of detecting the bleeding site in- bases (25). The lesions may be single or multiple.
creases by probing each diverticular opening Colonoscopic examination in patients with
... with a cotton-tipped probe. Arteriolar rupture diverticulosis-associated colitis shows confluent
always occurs on the side of the vessel facing granularity and friability affecting the area of
the bowel lumen. the sigmoid colon surrounding the diverticular
The mucosa surrounding diverticular orifices ostia (fig. 6-8). The colonic mucosa proximal
may become slightly elevated, simulating mu- and distal to the area of diverticulosis appears
cosal polyps. Tonic muscular contractions pro- endoscopically normal (39). Not uncommonly,
duce redundant, accordion-like mucosal folds. a diagnosis of Crohn's disease is entertained due
Grossly, these appear as localized swellings or to the segmental nature of the colonoscopic
exaggerations of the mucosal folds or as larger, findings. The biopsy can often differentiate

202
Acquired Structural Alterations

Figure 6-8
DIVERTICULITIS-ASSOCIATED COLITIS
Left: Opened colon in a patient with diverticulitis. The mucosal surface is markedly erythematous and granular. Adherent
inflammatory exudates have the appearance of pseudomembranes. There is marked thickening of the colonic wall.
Right: Endoscopically, the mucosal surface demonstrates foci of erythema and erosion. A diverticular opening is identifiable
in the upper right.

Figure 6-9
COLONIC DIVERTICULOSIS
Several diverticula of the
colonic wall are cut in cross
section on the outer aspect of
the specimen.

between the two entities if the pathologist is Later, the muscularis propria disappears as the
made aware of the presence of diverticulosis in diverticula extend beyond the colonic wall.
the segment of interest. The resulting thin-walled diverticula are un-
Microscopic Findings. The histologic fea- supported by other tissues. Many eventually
tures of the bowel wall depend on whether become inflamed.
there is simple diverticulosis or complications. The mucosa surrounding diverticula may be
The major pathologic abnormalities of uncom- thrown up into redundant mucosal folds (25) .
plicated diverticulosis include a thickened mus- Redundant mucosal folds appear polypoid, with
cularis propria and diverticular outpouchings increased mucosal height, crypt elongation,
(figs. 6-9, 6-10). The latter are usually lined by mucosal distortion, edema, vascular congestion,
the mucosa, muscularis mucosae, submucosa, and hemorrhage, and possibly associated with
and variable amounts of muscularis propria. thrombi, hemosiderin deposition, erosions,

203
Gastrointestinal Diseases

Figure 6-10
MUSCULAR CHANGES IN COLONIC DIVERTICULOSIS
Left: The muscularis propria is markedly thickened .
Right: The muscle fibers separate from one another creating a characteristic clefted pattern.

granulation tissue, and fibrosis. The fibers of in the context of the entire clinical, gross, and
the muscularis mucosae extend high into the endoscopic picture (20,32). All of these changes
lamina propria, producing changes resembling lie near the diverticula and are not present away
those seen in mucosal prolapse. The mucosa from the diverticula, distinguishing this lesion
may also appear hyperplastic or it may have from ulcerative colitis or Crohn's disease. In
a thickened collagen table, mimicking col- some cases, it may be impossible to distinguish
lagenous colitis. This resemblance is further between these entities.
accentuated if there is mild colitis associated Trauma within a diverticulum may induce
with the thickened 2ollagen table. asymmetric intimal vascular proliferations and
In diverticular disease-associated colitis (also vessel injury, predisposing it to rupture and
termed crescentic colitis or isolated sigmoiditis), bleeding (36). The arterial walls duplicate the
the histologic changes may exactly mimic those internal elastic lamina and exhibit eccentric
r.,-
found in inflammatory bowel disease (IBD) (fig. medial thinning, which is most marked on the
6-11). Changes include a lymphoplasmacytic and luminal side. The myenteric plexus may appear
eosinophilic expansion of the lamina propria abnormal and disorganized.
with cryptitis, crypt abscesses, basal lymphoid When diverticulitis develops, the diverticula
aggregates, distorted crypt architecture, basal become infiltrated by acute inflammatory cells,
plasmacytosis, surface epithelial sloughing, focal followed by chronic inflammation (fig. 6-12). As
Paneth cell metaplasia, and granulomatous cryp- the inflammation extends, the mucosa ulcerates
titis (32). The only way to distinguish isolated and abscesses, or fistulas may form. There may
sigmoiditis from IBD is to interpret the findings be broad areas of mucosal ulceration, directly

204
Acquired Structural Alterations

Figure 6-11
DIVERTICULAR DISEASE-ASSOCIATED COLITIS
A: A large area of ulceration is seen in the colon. The
adjacent intact mucosa shows mild architectural changes.
B: High-power view of the mucosa demonstrates the
presence of cryptitis and a crypt abscess. The surrounding
lamina propria contains a dense inflammatory infiltrate
composed mainly of lymphocytes and plasma cells.
C: Crypt rupture is also present.
D. The inflammation is transmural. Lymphoid aggregates
similar to those seen in Crohn's disease lie in the subserosa!
soft tissue.
E: Rarely, granulomas are seen, a feature that may also
simulate the histologic appearan/ce of Crohn's disease.

adjacent to fistulas or abscesses, or near the or in a structure outside the bowel. The most
diverticular orifices. important feature distinguishing the two is
Because diverticulosis occurs commonly in the absence of an intact muscularis propria in
the Western world, it often coexists with other acquired diverticula.
diseases, including adenomas and carcinomas, Another major diagnostic problem is dif-
idiopathic IBD, and other forms of colitis. Only ferentiating IBD from diverticulosis-associated
rarely do carcinomas arise within a diverticulum. colitis. Diverticulosis-associated colitis is clearly
Differential Diagnosis. It is important to diagnosed in a resection specimen from a pa-
distinguish between congenital and acquired tient with obvious diverticulosis or diverticulitis
diverticula, since the latter often result from and the inflammatory changes can be related
underlying pathology either in the bowel itself to the distribution of the diverticula. Given the

205
Gastrointestinal Diseases

Figure 6-12
DIVERTICULITIS
A: At the base of a colonic diverticulum, an associated
acute inflammatory infiltrate is seen in the submucosa.
B: Diverticular rupture results in extravasation of bile-
stained fecal material into the pericolonic soft tissues (left).
There is surrounding acute inflammation.
C: Higher-power view of the acute inflammatory
infiltrate in the pericolic fat.

206
Acquired Structural Alterations

frequency with which diverticulosis is encoun- INTUSSUSCEPTION


tered in the population and the frequency of Definition. An intussusception results from
colonic biopsies, however, diverticulosis-associ- the invagination or telescoping of an intestinal
ated colitis may cause unrecognized diagnostic segment (the intussusceptum) into the next part
difficulties when interpreting biopsy specimens, of the intestine, which forms a sheath around it
and may be falsely interpreted as representing (the intussuscipiens). Intussusceptions are classi-
either IBD or collagenous colitis. This is particu- fied as primary (without an identifiable cause) or
larly problematic because the chronic colitis of secondary (due to a preexisting lesion). Appendi-
diverticular disease shows a similar distribution ceal intussusception is sometimes referred to as
as·IBD. If the endoscopist biopsies both the area inside-out appendix, inverted appendix, appen-
around the diverticula and areas remote from diceal invagination, or appendiceal prolapse.
them, the biopsies will show a patchy distribu- Demography. Intussusception is one of the
tion of the inflammation, distinguishing the most common abdominal emergencies of early
changes of sigmoiditis from ulcerative colitis. childhood. Two thirds of cases occur in infancy,
Additionally, since diverticula rarely occur in with a peak incidence between 3 and 5 months of
the rectum, the "rectal sparing" that occurs age (58,65,80). It is also the most common cause
in colitis associated with diverticular disease of intestinal obstruction in children (69, 78). The
should help distinguish it from ulcerative incidence varies considerably in different parts
colitis. If it is not known whether the patient of the world (77). Some patients have a strong
has diverticulosis, then a diagnosis of Crohn's family history of intussusception (70). Interest-
disease may be considered, especially since ingly, there appears to be a high incidence of
lymphoid aggregates are commonly dispersed intussusception in doctors' families (81). In the
throughout the colonic wall in diverticulosis. United States there is a male predominance of 2
When diverticula rupture, forming abscesses to 1 and a seasonal prevalence with two peaks,
and peridiverticulitis, the features overlap with one in the winter and one in the summer (65).
those seen in Crohn's disease. Features that sug- Patients are typically well n ourished, without
gest the presence of Crohn's disease complicating a history of gastrointestinal disease.
diverticular disease include the presence of ulcers Etiology. There are numerous causes of intus-
away from the diverticula, fissures, and internal susception (Table 6-2) (68). Some infantile intus-
fistulas other than colovesical or colovaginal susceptions are primary without an identifiable
fistulas. If acute inflammatory masses are present cause. Most, however, result from an adenovirus
in diverticular disease, they may grossly resemble infection causing hyperplasia of Peyer patches.
a carcinoma. Additionally, the colonic wall may Children over age 6 and adults have a demon~
become thickened by pericolonic, postinflamma- strable lead point in 80 to 90 percent of cases
tory fibrosis, also grossly simulating a neoplasm (77); some are tumor related (66).
or IBD. To further complicate the matter, patients Pathophysiology. During an intussuscep-
may have both IBD and diverticular disease. tion, the intussusceptum is drawn into the
Patients with ulcerative colitis who also have di- intussuscipiens by peristalsis until it can go
verticulosis may have extension of their mucosal no further because of mesenteric traction. The
disease into a diverticulum, perhaps obliterating intussusceptum forms the lead point that be-
the underlying architecture, resulting in an comes ensheathed by the bowel distal to the
appearance of a primary fistula and creating point of the intussusception. The intussuscep-
changes that mimic those of Crohn's disease. tion constricts the lumen and compresses the
Treatment and Prognosis. Surgical resection mesentery between the inner intussusceptum
is performed in patients with complications of and the ensheathing intussuscipiens, blocking
diverticulitis, such as perforation, obstruction, both venous outflow and the arterial supply,
or hemorrhage. The complication rates are and leading to secondary ischemia. As a result,
highest in those patients in whom the surgery the intussusception continues to swell, causing
is performed as an emergency. Patients may die bowel obstruction and possibly gangrene.
from recurrent pericolic abscesses, peritonitis, Clinical Features. The diagnosis of an in-
fecal peritonitis, bleeding, or bowel obstruction. testinal intussusception is based on clinical

207
Gastrointestinal Diseases

Table 6-2 interval of complete relief (59). Infants with


CAUSES OF INTUSSUSCEPTION
prenatal intussusception present with intestinal
atresia and develop signs of intestinal obstruc-
Congenital Abnormalities
Congenital diverticula
tion immediately after birth. Babies usually have
Duplications a pathologic lead point an·d the colon is almost
Enterogenous cysts always involved (82).
Heterotopic tissues Appendiceal intussusceptions tend to affect
Malrotations
males, particularly in their adolescence, but
Infections patients range in age from 8 months to 75 years
Adenovirus
Epstein-Barr virus
(71,72,84). They present with features of acute
Herpesvirus appendicitis. The lesion may also remain as-
Mycobacteria ymptomatic, only to be discovered incidentally,
Yersinia e.g., when presenting as a cecal polyp. Duodenal
Clostridium diffzcile
Parasites
intussusception may produce symptoms of bili-
ary obstruction, and hematemesis may rarely
Tumor-Like Conditions
Endometriosis occur (60). Internal rectal intussusception can
Hamartomatous or inflammatory polyps• develop into total rectal prolapse (73) . Intussus-
Lipomatous hypertrophy of the ileocecal valve ceptions may be chronic or recurrent. Children
Localized lymphoid hyperplasia exhibit a high recurrence rate (20 percent) (78).
Pneumatosis intestinalis
Radiologic Findings. Intussusceptions are
Neoplasms
confirmed by the presence of the don ut, target,
Other coiled-spring, crescentic, or pseudokidney sign
Complications of surgery
Cystic fibrosis
during ultrasonography; such a sign is present
Fecaliths in over 95 percent of cases (61,64,67). Intus-
Foreign bodies, including bezoars susceptions tend to have a curved, sausage-like
Gastrojejunostomy tubes form with a concavity toward the 1:oot of the
Hematomas
Motility disorders
mesentery. The sensitivity and specificity of
Redundant sigmoid colon ultrasonographic examination are 98.5 and 100
percent, respectively (79). Intussusception may
also be detected by CT scans. When contrast
.,. is used, a characteristic "target" appearance of
symptoms, physical examination, and imaging concentric rings can be seen. Fluoroscopic im-
techniques that include plain films, ultrasound, ages obtained during air enemas can depict or
and barium or air enemas. The classic triad of exclude lead points, although this technique is
symptoms is intermittent crampy abdominal not very sensitive and many patients require
pain, vomiting, and passage of stool mixed with surgical exploration (7 4).
blood and mucus. Significant positive predictors Gross Findings. Ileocolic intussusceptions
of intussusception include the presence of a sau- account for more than 80 percent of cases. In
sage-shaped right upp,er quadrant mass (positive children, lymphoid hyperplasia associated with
predictive value [PPvj, 94 percent); gross blood an adenovirus infection often acts as the lead
in the stool (PPV, 80 percent); blood on rectal point and the ileum invaginates into the colon
examination (PPV, 78 percent); the triad of in- (59,62,63). Intussusceptions develop anywhere
termittent abdominal pain, vomiting, and right in the colon, but are most common at the he-
... upper quadrant mass (PPV, 93 percent); and the patic flexure (75) . They also affect the appendix
triad with occult or gross blood per rectum (PPV, and much of the small intestine. Duodenal and
100 percent) (67). Abdominal spasm and ten- gastric intussusceptions are rare (62).
derness may make the mass difficult to detect. Appendiceal intussusceptions take several
In infants, the pain manifests as episodic forms. In one form, the distal appendix intus-
screaming attacks that persist for 4 to 5 minutes. suscepts into the proximal appendix. In other
The infant pulls up its knees in distress. The forms, the proximal appendix intussuscepts into
acute episode is followed by a 10- to 20-minute the cecal appendicular valvular opening or the

208
Acquired Structural Alterations

whole appendix intussuscepts into the cecum,


presenting as a cecal"polyp."
No matter where the intussusception occurs,
the gross findings show the invaginated gastro-
intestinal segment if the intussusception has
not spontaneously reduced (fig. 6-13). Variable
external and internal signs of ischemia may be
visible, ranging from mild petechial hemorrhag-
es to frank gangrenous necrosis. If the patient
has had recurrent bouts of intussusception, the
serosal surface may show adhesions.
Microscopic Findings. The intussuscepted
bowel may show the features of the intussuscep-
tion, the pathology of the predisposing cause,
and secondary ischemia. The histologic changes
differ depending on whether it is an acute,
chronic, or acute superimposed on chronic in-
tussusception. In patients with chronic or recur-
rent intussusceptions, the muscularis mucosae
sometimes buckles upward, indicating the lead
point of the intussusception, and the subserosa!
or even intramural vessels may show evidence of
a "pulling artifact," with tethering in the same
direction as the muscularis mucosae. Similar
traction forces probably act on the mucosa,
muscularis propria, and subserosa! vessels .
Recurrent intussusceptions can produce florid
submucosal vascular proliferations that may be
so pronounced as to raise the possibility of a pri-
mary vascular neoplasm (7 6). Characteristically,
there are also prominent muscular hypertrophy
and neural hyperplasia.
In children with adenovirus infections, the
lymphoid tissue is markedly hyperplastic and
the epithelium overlying the lymphoid hy-
perplasia at the lead point is damaged or even
necrotic. Intranuclear viral inclusions appear Figure 6-13
as reddish globules surrounded by halos or as
INTUSSUSCEPTION
poorly demarcated purple nuclear smudges.
Top: The external aspect of a segment of intussuscepted
Most intussusceptions show variable degrees small bowel. The serosal surface of the intussusceptum is
of ischemia (fig. 6-14). The histologic features of granular and somewhat dusky.
the ischemia resemble gastrointestinal ischemia Bottom: Opened specimen shows the invaginated
due to other causes. They reflect the length of portion of intussuscepting intestine. The lead point appears
hemorrhagic.
time that the injury lasted and the degree of vas-
cular compromise that occurred (see chapter 7).
In appendiceal intussusceptions, the histol-
ogy appears "inside-out," with the epithelium especially if secondary ischemia has occurred.
lying on the external surface of the tissue and The submucosa becomes edematous and the
the submucosa and muscularis propria lying muscularis propria may appear hyperplastic,
inside the mucosa (see chapter 13). The epithe- fibrotic, or as though it has been subjected to
lium appears hyperplastic, inflamed, or eroded, traction. A helpful clue to the diagnosis is the

209
Gastrointestinal Diseases

Figure 6-14
INTUSSUS CEPTI ON
Left: An intussuscepted segment of small intestine shows diffuse ischemic injury to the mucosa with ulceration and
hemorrhage. ·
Right: Higher-power view shows glands with evidence of ischemic injury. The lamina propria contains dilated, congested
capillaries and a dense chronic inflammll'1ory infiltrate.

presence of both the circular and longitudinal muscularis propria; 3) focal submucosal fibrosis;
layers of the muscularis propria with its my- 4) marked telangiectasia; 5) evidence of healed
enteric plexus in the submucosa of a polypoid serosal disease, including adhesions; and 6)
lesion. The muscular layers maintain a normal localized mucosal hyperplasia. Sometimes the
relationship with one another and with the bowel wall is kinked on itself with only the
submucosa and mucosa . Sometimes the bowel muscularis propria demonstrating the twisted
wall appears to have two muscularis propriae. appearance of the previous intussusception. In
The amount of tissue inversion seen depends patients with neoplasms, special care must be
on the extent of the intussusception. taken to ensure that the neoplasm is evaluated
~. ·
Diagnosing a resected, unreduced intussus- appropriately for its stage as well as to ensure
ception is not difficult. Recurrent or past intus- that it has been completely resected.
susceptions that spontaneously reduce may be Treatment and Prognosis. Some intussus-
more difficult to recognize. Histologic clues ceptions reduce spontaneously. In those that
pointing to recurrent intussusception at any do not, radiologic reduction is often the first
site include the following: 1) marked disorga- line of treatment. Successful reduction with
nization of the muscularis propria, sometimes barium, saline, or gas enemas occurs in SO to
showing features of peristaltic drag; 2) fusion 90 percent of patients (59,83). A complica-
of the muscularis mucosae with the underlying tion of the treatment may be perforation and

210
Acquired Structural Alterations

pneumoperitoneum. Intussusceptions may also Table 6-3


be reduced manually during surgery without VOLVULUS: ETIOLOGY
a need to resect the gut. Between 15 and 20
Gastric Volvulus
· percent of cases must be resected. Indications Congenital diaphragmatic abnormalities
for a surgical resection include perforation, Lax esophageal hiatus
infarction, or irreducibility. Disease duration Periesophageal hernia
influences the necessity for intestinal resection. Congenital absence of intraperitoneal visceral
attachments
Those with symptoms of more than 24 hours'
duration are more likely to require intestinal Intestinal Volvulus
Intestinal bands
resection than those with symptoms of less Intestinal malrotation
than 24 hours (59). Intestinal diverticula
Infections and other inflammatory diseases
VOLVULUS Motility disorders
Redundant sigmoid colon
Volvulus, or torsion, is an axial twist of a part Endometriosis
of the gastrointestinal tract around itself or its Cystic fibrosis
mesentery. Pneumatosis intestinalis
Tumors
Gastric Volvulus Treatment with psychotropic drugs
Previous surgery
Pathophysiology. Gastric volvulus usually
occurs secondary to hiatal hernias (103). The
most common type of gastric volvulus, organ-
oaxial volvulus, accounts for approximately 60 Gross Findings. Radiologic abdominal films
percent of cases. The stomach twists around the show gastric distension with two separate fluid
longitudinal axis of the lesser curvature, a posi- levels.
tion that remains relatively fixed, causing it to
Small Intestinal Volvulus
turn upside down. The greater curvature rotates
upward, forward, and to the right, producing Definition. Intestinal volvulus is divided into
both proximal and distal obstruction. Anterior primary and secondary forms. Primary volvulus
rotation occurs more commonly than posterior develops in patients lacking a predisposing ana-
rotation. Mesenteroaxial volvulus represents 30 tomic abnormality. Secondary volvulus affects
percent of cases and occurs around a line that patients with an acquired or congenital abnor-
runs from the center of the greater curvature to mality that predisposes the bowel to rotate.
the porta hepatis. Mesenteroaxial and organ- Demography. Volvulus affects people of all
oaxial volvulus can coexist. As gastric volvulus ages, most often adults (90,92,97,104). Small
develops, the stomach progressively distends due bowel volvulus constitutes 8 percent of all cases
to the accumulation of food and secretions that of mechanical intestinal obstruction and up
cannot pass forward or be regurgitated due to the to 30 percent of small bowel obstructions in
presence of both distal and proximal obstruction. some countries, especially in Asia, Africa, and
Clinical Features. Gastric volvulus presents the Middle East, where high fiber diets are con-
either acutely or chronically. Acute gastric volvu- sumed. Volvulus is a rare cause of small bowel
lus results in gastric hemorrhage, ischemia, and obstruction in Western Europe, Australasia, and
infarction, and is easily diagnosed. Patients with North America. Half of the cases are primary
subacute volvUlus frequently go undiagnosed and half are secondary. Most patients are male.
because of the presence of vague, nonspecific Etiology. In Africa and Asia, the etiology of
symptoms (99). Chronic gastric volvulus presents intestinal volvulus is usually primary, while
with intermittent dysphagia, epigastric pain, in Western countries predisposing conditions
vomiting, abdominal masses, occasional he- usually initiate volvulus formation (Table 6-3).
matemesis, and gastroesophageal reflux disease Clinical Features. Small bowel volvulus is a
(98). Death can result from the sequence of ob- rare, but life-threatening, surgical emergency.
struction, strangulation, and ischemic necrosis Volvulus occurs acutely, causing complete ob-
due to compression of the gastric vasculature. struction, or intermittently, producing partial or

211
Gastrointestinal Diseases

complete obstruction with compromise of the (87,95,105) . There is also an association with
blood supply, ischemia, gangrene, perforation, mental abnormalities (85).
and peritonitis. Patients with intestinal ob- Pathophysiology. The proximal colon is af-
struction have severe abdominal pain1 nausea, fected by 15 to 20 percen.t of colonic volvuli,
bilious vomiting, abdominal distension, and usually due to a failure of the cecum and ascend-
rectal bleeding. Often the patient collapses due ing colon to develop normal attachments. The
to occlusion of the venous return by the mesen- sigmoid colon is also a common site of involve-
teric twist while arterial perfusion continues. As ment. A high fiber diet and chronic constipation
much as 50 percent of the blood volume may result in bulky stools with a volume that leads to
accumulate within the area of the volvulus. a persistently loaded colon. In time, the persis-
Obstipation, tachycardia, and fever occur less tently loaded sigmoid distends and elongates. Its
commonly (90). A history of recurrent similar two ends approximate one another, producing a
minor attacks is present in approximately 50 narrower mesenteric attachment. The base of the
percent of patients. sigmoid loop is narrow, providing a pinnacle for
Gross Findings. X rays show a closed-loop the 180° to 720° rotation. Fibrosis at the base of
obstruction. The whirlpool sign (wrapping of the mesosigmoid accentuates the narrow base.
the superior mesenteric vein and .mesentery The actual precipitating cause is often a minor
around the superior mesenteric artery) is used event, such as straining at stool or coughing.
to diagnose midgut volvulus. The sensitivity, In its early stages, a volvulus produces a
specificity, and positive predictive values of a check-valve effect, allowing flatus and fecal
clockwise whirlpool sign for midgut volvulus material to enter the loop but preventing them
are 92 percent, 100 percent, and 100 percent, from leaving. As a result, the bowel rapidly
respectively (101). In developing countries, the distends. As the volvulus tightens, a complete
resected small bowel is usually filled with undi- closed loop obstruction develops leading to
gested food. In ileosigmoid knotting, the ileum vascular compression and ischemic n_ecrosis.
twists around the base of the sigmoid and both A variant of cecal volvulus, known as cecal bas-
loops are often gangrenous. cule, consists of a mobile cecum but the ascend-
ing colon is fixed, allowing the cecum to fold
Colonic Volvulus
transversely and superiorly over the ascending
Demography. In Western countries, volvulus colon. Because it is not a true axial twist, vascular
is the third most frequent cause 6f large bowel occlusion and ischemia are uncommon.
obstruction, following cancer and diverticular Clinical Features. Large intestinal volvulus
disease. It accounts for 1 to 7 percent of large causes intestinal obstruction and ischemia
bowel obstructions in the United States and anywhere from the cecum to the sigmoid (87).
Britain. In developing countries, such as Africa, It presents with asymmetric intestinal disten-
Iran, Pakistan, and South America, where an sion or palpable tympanic swelling. Partial
unrefined diet is consumed, volvulus accounts volvulus with spontaneous twisting gives rise to
for up to 50 percent of large bowel obstructions recurrent bouts of lower abdominal pain (87).
(95). Consumption of large, high fiber meals The diagnosis can be made from a good history
after prolonged fasts leads to more forceful and careful interpretation of plain abdominal
peristalsis than usual, predisposing to the de- X rays, and is usually confirmed by barium
velopment of a volvulus (97). In one county in enema findings. Once a sigmoid volvulus has
Minnesota, its incidence is 1.47/100,000 people developed, it tends to recur, with patients de-
(87), compared to an incidence in Ghana of veloping subacute, slowly progressive attacks.
12/100,000 (100). Cecal and sigmoid volvulus Patients often provide a history of previous epi-
have a similar incidence in patients under 60 sodes of abdominal pain. Cecal rotations tend
years of age; over the age of 60 the incidence to occur during pregnancy or in patients with
of sigmoid volvulus increases. Sigmoid volvulus obstructing lesions in the left colon. When the
accounts for 40 to 80 percent of colonic volvuli rotation occurs, the cecum relocates to the left
(87,89), whereas volvulus of the transverse co- hypochondrium and becomes tensely distended
lon accounts for only 4 to 9 percent of cases and often infarcted.

212
Acquired Structural Alterations

Figure 6-15
VOLVULUS
Left: Autopsy photograph of a torsed segment of intestine. The segment that has undergone volvulus is dusky in appearance,
a reflection of ischemic injury.
Right: Gross photograph of a resecttion of a torsed segment of colon. The ischemic portion of the resected colon appears
dark blue-brown.

Gross Findings. Cecal volvulus produces a markedly attenuated (88). Some cases may
characteristic appearance of small bowel ob- show a reduction in the number of ganglion
struction: enormous distension of the cecum cells, perhaps a manifestation of an underly-
and proximal colon and displacement of the ing motility disorder or the massive dilatation.
cecum into the upper abdomen (fig. 6-15). The Histologically, the tissues show variable degrees
cecum can measure up to 35 cm in circumfer- of ischemia and necrosis. '
ence (88). The distension causes thinning of Treatment and Prognosis. Early preoperative
the intestinal wall. Radiographically, the tip of investigation and expedient surgery prevent
the "coffee-bean" deformity in a cecal volvulus bowel infarction. The initial treatment can be
points toward the left upper quadrant, contrast- nonoperative decompression by proctoscopy,
ing with the "bent inner tube" or "ace of spades" sigmoidoscopy, or colonoscopy, a procedure
deformity of sigmoid volvulus, which is usually successfully carried out in many patients. The
directed toward the right (87). A barium enema role of colonoscopic reduction in children is
may reveal a typical"bird's beak" deformity at limited to diagnosis, immediate relief, and help-
the point of the twist. A dilated sigmoid colon ing with bowel preparation before surgery (102).
that ascends cephalad to the transverse colon In patients who undergo surgery, the treatment
is a newly described and accurate finding of sig- is often simple untwisting of the bowel if the
moid volvulus. This finding has a sensitivity of bowel is viable. Patients with gangrene require
86 percent and a specificity of 100 percent (93). resection of the gangrenous segments and pri-
In resection specimens, the gut appears mary bowel anastomosis. The overall mortality
twisted and may show signs of ischemia or rate of patients with sigmoid volvulus is 19.7
infarction. The ischemia results from either percent, rising to 52.8 percent if gangrenous
obstruction of the arterial flow or interference colon is present and decreasing to 12.4 percent
with venous return. Pneumatosis intestinalis when the intestines are viable (86).
may be present. The mesentery often appears
thickened with large vessels, suggesting that re- RECTAL MUCOSAL PROLAPSE
current episodes of rotation have occurred. The Definition. Rectal prolapse is the protru-
thickening may help prevent ischemic necrosis. sion of some or all of the rectal layers through
Microscopic Findings. When the bowel the anus. Rectal prolapse is either complete
becomes massively dilated, the muscularis or incomplete, and categorized by degree as
mucosae and muscularis propria often appear shown in Table 6-4. Complete rectal prolapse is

213
Gastrointestinal Diseases

Table 6-4
CLASSIFICATION OF COMPLETE RECTAL PROLAPSE
1st degree Protrusion of full thickness of the rectum, including the mucocutaneous junction
2nd degree Complete prolapse without involvement of the mucocutaneous junction
3rd degree Concealed or internal prolapse in which the rectum intussuscepts but does not pass through the anus

Table 6-5 Table 6-6


SPECTRUM OF RECTAL PROLAPSE CAUSES OF ANORECTAL PROLAPSE
Solitary rectal ulcer syndrome Cystic fibrosis
Proctitis cystica profunda Acute diarrheal diseases
Inflammatory cloacogenic polyps Infections (bacterial, parasitic)
Inflammatory bowel disease
Inflammatory cap polyps
Lymphoid hyperplasia
Rectal intussusception
Chronic constipation
Connective tissue diseases
Radiation
either concealed (not externally visible at rest),
Previous surgery
externally visible with straining, or externally
visible without straining. When fue prolapse Hemorrhoids
remains in the upper anal canal, it is called a Bulimia nervosa
hidden prolapse. Complete rectal prolapse is Redundant sigmoid colon
also known as procidentia. Rectal polyps
Demography. A number of entities fall with- Neoplasms
in the spectrum of rectal prolapse (Table 6-5).
The frequency of rectal prolapse is unknown.
Rectal prolapse occurs in infants; it is uncom- vie floor, lack of normal rectal fixation with an
mon in childhood and early adulthood; then elongated mesorectum, redundant rectosigmoid
it increases in frequency after agg. 40 (122). Al- and sigmoid colon, and lax and atonic sphinc-
though 85 percent of affected adults are women, ters. These defects are probably consequences
solitary rectal ulcer usually affects men (122), of long-standing prolapse. Hemorrhoids may
and is more commonly seen in young adults also prolapse through the anus.
(113). Inflammatory cap polyp occurs more Repeated straining during defecation, possibly
commonly in females and is usually solitary. associated with muscular spasm, may create a
Inflammatory cloacogenic polyps may be seen shear on the rectal mucosa, causing traumatic ul-
in adults as well as children. ceration. Excessive straining also facilitates mild
Etiology. Rectal prolapse complicates a num- mucosal redundancy in the anterior rectal wall.
ber of disorders (Tabl~ 6-6) (106,111,112,118- The term "solitary rectal ulcer syndrome" is a
121, 123-127). Patients with mass lesions, such as misnomer, since frank ulceration is a late feature
polyps or tumors, often have recurrent prolapse. of the disease and the ulcers may be multiple.
Pathophysiology. Approximately 6 percent The ulceration that develops in mucosal pro-
... of patients with severe diarrhea develop rectal lapse syndrome is thought to result from one
mucosal prolapse (107). Rectal prolapse also oc- of the following: 1) pressure necrosis caused
curs in patients who strain during defecation. In by mucosal impaction in the anal canal; 2)
older individuals, it occurs as the musculature ischemia secondary to stretching and rupture
loses its normal tone. of submucosal vessels; 3) trauma during digital
Several anatomic abnormalities are present replacement of the prolapsing mucosa; and 4)
in patients with rectal prolapse, including an ischemia secondary to obliteration of mucosal
abnormally deep rectovaginal or retrovesicle capillaries by fibromuscular sclerosis of the
pouch, lax and atonic musculature of the pel- lamina propria (122).

214
Acquired Structural Alterations

Clinical Features. Patients often become wall intussusception (116). The mucosa may
symptomatic in their 3rd or 4th decades. Symp- appear erythematous or ulcerated. Polypoid
toms include rectal bleeding, diarrhea, anorectal lesions may be present. In solitary rectal ulcer
pain, pruritus, altered bowel habits, abdominal syndrome, solitary or multiple lesions are found
cramps, and difficulty defecating. The last pres- within 15 cm of the anal margin, usually lying
ents as constipation, straining, increased laxative on the anterior rectal wall. Inflammatory cap
use, or incomplete rectal evacuation necessitat- polyps develop on top of mucosal folds, mainly
ing digital manipulation. Patients complain in the rectosigmoid. They appear as multiple,
of perineal or intervaginal weakness, profuse often umbilicated, dark red areas of granulation
mucus discharge, and the presence of something tissue. Patients who develop proctitis cystica
protruding from the anus following defecation, profunda show mucosal edema, erythema, and
straining, or when the patient stands. Difficulty a lumpy-bumpy mucosa, with increased folds;
in initiating a bowel movement and a feeling of polyps or pseudopolyps; mucosal friability;
incomplete evacuation are common. Prolapse oval, linear, stellate, or serpiginous ulcers; or a
often starts with straining and as the straining cauliflower-shaped mass measuring up to 5 cm
continues, the rectal wall progressively infolds, in size. Cross-sections of the bowel wall show
filling up the rectal lumen. The tissues may the cysts. Surface ulceration is uncommon, but
remain within the rectal ampulla or prolapse loss of superficial lining cells occurs frequently.
through the anus. Fifty percent of patients Tracts sometimes extend from the mucosa to-
become incontinent due to overstretching and ward the mucinous cysts. The cysts may contain
weakness of the anal sphincter. The pudendal gelatinous or mucinous secretions.
or perineal nerve may become entrapped by the Radiographic features include the nonspecific
prolapsing rectal contents, resulting in subse- findings of rectal stricture, mucosal granularity,
quent neuromuscular dysfunction. and rectal thickening (112). Mucosal prolapse
Most patients appear physically fit without syndromes may be investigated by endoscopic
abnormalities until rectal examination is per- ultrasound examination. Ultrasonography dem-
formed. Ulcerated and indurated areas are often onstrates the normal layers and plays a role in
present on the anterior or anterolateral wall. distinguishing prolapse syndromes from malig-
Patients may have a palpable mass on digital nancy or Crohn's disease (114). Endoscopically,
examination. Ulcers often straddle a rectal fold mucosal reddening, ulceration, and edema are
and vary in size from a few millimeters to several seen (117).
centimeters in diameter. The rectum remains Microscopic Findings. The earliest histologic
freely mobile. Not all patients have ulcers, and manifestation of rectal prolapse may be nothing
in some, the only abnormality is an erythema- more than mucosal erosions or ulcers, or even
tous area, sometimes associated with polypoid just nonspecific inflammation with thicken-
mucosal projections (119). The most extreme ing of the collagen table producing changes
form of rectal prolapse is one that incarcerates mimicking collagenous colitis. Ulceration is
and cannot be reduced. Pressure on it may cause heralded by capillary dilation and congestion
perforation (115). beneath the surface epithelium. Ulcers covered
The diagnosis is easy to make if the prolapse by a fibrous exudate erupt from the mucosal
comes through the anus. The diagnosis of hid- surface in a volcano-like fashion, producing a
den prolapse can be difficult. Redness of the lesion reminiscent of pseudomembranous coli-
rectal mucosa, especially anteriorly at about the tis. The ulcers never penetrate deeply into the
6- to 7-cm level, provides a clue to the diagnosis. submucosa. Later, the lamina propria becomes
Inflammatory cloacogenic polyps present as replaced by smooth muscle cells and fibroblasts
small sessile polyps at the anorectal junction. that are arranged at right angles to the muscula-
Gross Findings. The various lesions listed ris mucosae (fig. 6-16) (110) . The glands appear
in Table 6-5 show overlapping features, and regenerative, with mucin depletion, branching,
the relationship among the four entities is and hyperplasia (fig. 6-16). The anal mucosa
confusing. Rectal prolapse involves all of the appears acanthotic, hyperkeratotic, congested,
layers of the rectum, essentially creating a rectal and chronically inflamed.

215
Gastrointestinal Diseases

Figure 6-16
MUCOSAL PROLAPSE
A: Low-power view of congested mucosa and submucosa.
The crypts are architecturally distorted.
B: The mucosal surface is congested, and proliferating
vessels appear granulation tissue-like. The features suggest the
possibility of past erosion of the mucosal surfa.ce in this area.
C: Hemosiderin pigment is in the de~p mucosa, an
indication of previous bleeding.
0: Strands of smooth muscle extend upward between
the colonic crypts in a direction perpendicular to the fibers
of the muscularis mucosae.
E: Fibromuscular changes are seen in the lamina propria
between the colonic glands .

' ··

216
Acquired Structural Alterations

Microscopic Variants. Inflammatory (Fibrin)


Cap Polyps. Prolapse induces colorectal and ano-
rectal inflammatory cap polyps. Histologically,
inflammatory cap polyps contain tortuous,
hyperplastic crypts; fibromuscular hypertrophy,
with obliteration of the lamina propria; and
goblet cell hypertrophy. The tortuous glands
have a serrated tubular architecture, resembling
a hyperplastic polyp. Abundant mucin secretion
· is often present. Fibromuscular tissue frequently
extends into the lamina propria in a radial
fashion (109,126). The lesions get their name
from the cap of granulation tissue and fibrin
that covers their surface.
Inflammatory Cloacogenic Polyps. The in-
flammatory cloacogenic polyp (ICP) is a non-
neoplastic polyp that results from transitional
zone prolapse. It presents as a small sessile polyp
at the anorectal junction. Histologically, ICPs
contain epithelium similar to that found in the
mucosa of the anal transitional zone. They may
exhibit a complex tubulovillous growth pattern,
often with a squamous "collar." Long, slender,
delicate bundles of proliferating fibrovascular
stroma, with smooth muscle fibers from the
muscularis mucosae, extend into a normal or
inflamed lamina propria. Simple columnar, Figure 6-17
colonic epithelium containing goblet cells and INFLAMMATORY CLOACOGENIC POLYP
compressed absorptive cells line the villous projec- Alternating villoglandular epithelium and squamous
tions (fig. 6-17). In cases with moderate to marked epithelium cover the polyp. (Fig. 2-62 from Atlas of Tumor
submucosal smooth muscle hyperplasia, bundles Pathology, Fascicle 32, Third Series.)
of smooth muscle-associated proliferating fibrous
stroma extend from the submucosa into the
lamina propria, usually in a plane perpendicular lamina propria and the epithelium becomes
to the surface. ICPs display a spectrum of mucosal hyperplastic and cystically dilated. Telangiec-
erosion, fibromuscular effacement of the lamina tasia is a common finding. The mucosa may
propria, thickened villiform surface mucosa, and become extremely hyperplastic and polypoid,
displaced epithelium and cysts in the submuco- and may even resemble adenoma because of the
sa. The cysts contain variable amounts of mucin villiform architecture that may develop. The
and inflammatory cells. Often, the epithelium features of solitary rectal ulcers include fibrous
at the surface appears hyperplastic. Regenerative obliteration of muscle fibers and mucosal reac-
changes may be pronounced, and may simulate tive hyperplasia with villous configuration or
dysplasia; this, coupled with displaced glands, mild pseudoinvasion. Fibrosis may be present,
can mimic carcinoma. but is usually a late event. This change may be
Solitary Rectal Ulcer Syndrome. Some of the accentuated using trichrome stains. Biopsies
histologic changes of solitary rectal ulcer syn- of these lesions often show the nonspecific
drome result from an impaired mucosal blood changes of mucosal inflammation, necrosis,
supply during the prolapse. In the acute phase and regeneration.
of the disease, the crypts appear elongated Colitis/Proctitis Cystica Profunda. Mucosal
and lined by immature basophilic epithelium. ulceration and healing can also lead to the
Fibrovascular components proliferate in the presence of cysts lined by colonic epithelium

217
Gastrointestinal Diseases

deep in the submucosa. The histologic features perpendicular organization of the muscle fibers
of proctitis cystica profunda resemble those of in ICP contrast with arborizing muscle fibers in
colitis cystica profunda (see next section). Other Peutz-Jeghers polyps and serve to distinguish
histologic findings reflect ischemia secondary the two lesions. Furthermore, ICP is usually an
to vascular compression, especially when the isolated lesion, whereas Peutz-Jegherspolyps usu-
prolapse becomes impacted in the upper end ally form part of a more generalized syndrome.
of the anal canal. Localized trauma, especially Endometriosis may mimic colitis cystica
if the prolapse is digitally replaced, also causes profunda and the distinction between the two
some of the histologic features. lesidns can be difficult. The major difference
Special Techniques. The pathophysiology of is the nature of the epithelium, particularly in
defecatory disorders is complex and multifacto- the absence of the typical endometrial stroma
rial, and requires multiple tests to provide the accompanying the endometrial lining epithe-
comprehensive information required to arrive lium in the latter. Immunostains for estrogen
at an appropriate diagnosis and therapeutic receptor, progesterone receptor, and CD10 may
planning. Among these, anorectal manometry is be helpful when the stroma is sparse. Proctitis
extremely useful since it provides objective evi- cystica profunda can also mimic a mucinous
dence of poor rectoanal coordination, weak anal carcinoma. The bland appearance of the glan-
sphincters, or changes that support a diagnosis dular epithelium, the presence of surrounding
of obstmctive defecation. Other tests, such as the lamina propria, the absence of an associated
balloon expulsion test, may serve as screening desmoplastic stroma, and the absence of a
tools for patients with constipatio:rt. In patients dysplastic surface lesion distinguish proctitis
with fecal incontinence, anal endosonography cystica profunda.
may localize the sphincter defect and aid surgi- Treatment and Prognosis. Rectal prolapse in
cal reconstmction. The pudendal nerve latency children usually corrects itself (113); otherwise
test provides a pathophysiologic basis for a injection sclerotherapy may be used to treat
weak anal sphincter. Imaging techniques, such rectal prolapse in children (108). Persistent rectal
as defecography, may provide useful informa- prolapse, especially in adults, is usually managed
tion regarding levator ani dysfunction (121). by surgery, with the most common technique
Defecography shows failed relaxation of the being rectopexy, with or without sigmoid resec-
puborectis muscle preventing bolus ..r
passage and tion. The surgical management can be expected
resulting in abnormal perineal descent (112). to alleviate the prolapse but not necessarily fecal
Differential Diagnosis. Rectal prolapse does incontinence. The surgical procedure should not
not usually pose a diagnostic problem. We have only correct the prolapse, but also help improve
seen instances, however, in which unrecognized bowel and sphincter function. Despite these sur-
prolapse in children has led to a misdiagnosis of gical techniques, there is an overall recurrence
IBD due to the presence of inflammation, fibro- rate of greater than 15 percent. In the future, the
sis, ulcers, or fistulas complicating the prolapse. development of new biocompatible materials
When the mucosal prolapse results in thickening may offer alternative therapies.
of the subluminal coJlagen table, the changes
may mimic those found in collagenous colitis. GASTRITIS, ENTERITIS, AND
ICPs may resemble neoplastic lesions since COLITIS CYSTJCA PROFUNDA
the disordered tubulovillous growth pattern and Definition. In gastritis, enteritis, and colitis
regenerative atypia of many suggest a neoplastic cystica profunda, glandular epithelium is dis-
r. •.
process. The overall benign reactive appearance placed into the submucosa, typically following
of the glandular epithelium, the lack of desmo- ulceration due to mucosal inflammation. Char-
plasia, and the fibromuscular hyperplasia of the acteristically, the displaced glands form submu-
muscularis mucosae and lamina propria in ICPs cosal cysts. These lesions are all similar and are
should make their diagnosis possible. The lesion named differently based on their location.
is also distinct from Peutz-Jeghers polyps that Demography. Enteritis cystica profunda
only rarely involve the anal canal. The nature occurs less commonly than its colonic coun-
of proliferating fibroblastic stroma along with terpart, colitis cystica profunda (128); gastritis

218
Acquired Structural Alterations

cystica profunda is even rarer. Patients with cosal spaces. These are often quite prominent
diffuse colitis cystica profunda (122) range in and glisten because of their mucinous content.
age from 4 to 68 years, with a mean of 33 years. They are variable in size, but may measure up to
Males outnumber females by a ratio of 7 to 1. 2 cm in diameter. The mucosa overlying such
Gastritis cystica profunda primarily affects men lesions usually demonstrates histologic evidence
in the 7th decade of life (134). of active or healed inflammation.
Etiology. Mucus submucosal retention cysts Microscopic Findings. Cysts in gastritis cys-
develop following episodes of inflammation tica profunda develop in the submucosa or in
and ulceration, such as occur in patients with the muscularis mucosae of the gastric body and
severe infection, ischemic enterocolitis, or IBD. antrum (fig. 6-18). They arise from displaced
Associated diseases include Crohn's disease mucin-producing heterotopic gastric glands.
(128,129), Peutz-Jeghers syndrome (133), con- Sometimes chief and parietal cells lie scattered
genital anomalies, and ulcerative colitis (140). among the mucin-secreting epithelial cells. A
Areas near lymphoid follicles represent points normal-appearing lamina propria usually sur-
of weakness in the muscularis mucosae, facili- rounds the displaced gastric glands. Coexisting
tating mucosal herniation (140). Colitis cystica areas of hemosiderin deposition and fibrosis attest
profunda may also follow pelvic radiation (138), to episodes of previous injmy, and suggest that the
neoadjuvant radio/chemotherapy for rectal or displaced epithelium does not represent a neoplas-
esophageal carcinoma, or previous surgery. In tic process. Sometimes the cyst lining disappears
the last situation, the cystic lesions are often in due to pressure atrophy from large intracystic
anastomoses. Displaced epithelium results from mucinous accumulations. The musculcuis mucosae
epithelial implantation into the submucosa, may appear hype1trophic and frayed.
muscularis propria, or serosa following mucosal In enteritis and colitis cystica profunda, flat-
ulceration, herniation (as occurs in adenomas or tened epithelium completely or partially lines
Peutz-Jeghers polyps), or formation of mucosal submucosal mucin-filled cysts. Cuboidal or
microdiverticula (132). Mucosal repair follow- columnar epithelium resembling normal small
ing regeneration of an ulcer leaves the detached intestinal or colonic mucosa usually lines newly
epithelium buried in the submucosa. It eventu- formed cysts (fig. 6-19). Since the submucosal
ally is covered by an intact mucosa. Displaced cyst lining appears benign, confusion with a
epithelium also results from epithelialization of malignant process is generally not a problem. Se-
fissures or fistulous tracts. rial sections may demonstrate a communication
Clinical Features. Patients may remain between the cysts and the mucosal surface. Older
asymptomatic or present with the signs and cysts often lack an epithelial lining and are sur-
symptoms of the underlying cause of the lesion, rounded by fibrous tissue and/or a polymorphic
i.e., infection, IBD, etc. Symptomatic patients inflammatory infiltrate, hemosiderin, or foreign
may present with rectal bleeding or passage body giant cells (136). The material in the cysts
of mucus and blood. Some patients have diar- may calcify or ossify. Fibrosis is usually moder-
rhea, tenesmus, and crampy abdominal pain. ate but can be significant, extending into the
Endoscopy may show the presence of a nodular muscularis propria or even into the serosa (128,
mucosa. Intestinal lesions can cause intestinal 130,133,136,137). As with gastric cysts, lamina
obstruction (131) or intussusception (135) as propria often surrounds the displaced glands
they enlarge and form a mass. (fig. 6-19), distinguishing the lesion from inva-
Gross Findings. Colitis cystica profunda sive carcinoma. If the patient has had a barium
presents either as a localized lesion or diffusely examination, the barium may extend into the
as multiple lesions. When multiple lesions are lumen of the displaced glands, further confirm-
present, they are scattered throughout the large ing the presence of epithelial displacement.
intestine. Localized colitis cystica profunda Differential Diagnosis. Sometimes it is
involves any portion of the colon, but usually difficult to determine whether the displaced
affects the rectum in the setting of prolapse. epithelium represents an invasive mucinous
Grossly, the bowel wall appears thickened. The carcinoma or merely displaced epithelium, es-
cut surface discloses numerous cystic submu- pecially when lamina propria does not surround

219
Gastrointestinal Diseases

Figure 6-18
GASTRITIS CYSTICA
PROFUNDA
Dilated glands are within
the submucosa of the stomach.
These are surrounded by normal-
appearing lamina propria.

Figure 6-19·
COLITIS CYSTIC PROFUNDA
Two nests of rectal mucosa with
lamina propria are embedded in the
fibromuscular stroma beneath the
distorted and altered mucosa. (Fig.
2-69 from Atlas of Tumor Pathology,
Fascicle 32, Third Series.)

the glands or when the benign epithelium pro- examination of the surface epithelium helps
duces excessive amounts of mucin, resulting in resolve the diagnostic dilemma. If the surface
large mucinous cysts containing scant epithelial epithelium appears dysplastic, the possibility of
r.,· elements. The traditional histologic and cyto- an invasive lesion increases.
logic features distinguish invasive from nonin- Another lesion that may superficially re-
vasive epithelium. Features that help to rule out semble colitis cystica profunda causing localized
malignancy include the absence of cytologic cystic masses with variable degrees of inflam-
atypia, lack of desmoplasia, and the presence mation is endometriosis. The endometrial epi-
of surrounding lamina propria. In some cases, thelial lining should not contain mucin and the
it may be impossible to determine whether one stroma surrounding the glands should be denser
is dealing with displaced epithelium or an in- endometrial stroma rather than the looser
vasive cancer. Sometimes, careful sampling and lamina propria typical of intestinal mucosa.

220
Acquired Structural Alterations

Treatment and Prognosis. No treatment is munodeficiency virus (HIV) infection (152).


necessary for this lesion. The underlying cause Histologically, anal fissures have granulation
of the inflammation and ulceration may require tissue, acute inflammatory infiltrates, and often
therapy, however. The preferred treatment is a foreign body type giant cell reaction.
local excision to avoid a local mass lesion (139). Treatment and Prognosis. Most patients
with a newly diagnosed anal fissure should have
ANAL FISSURES
an initial trial of conservative therapy, since
Definition. An anal fissure is a painful tear or most acute fissures will heal with this approach.
split in the distal anal canal. Most acute fissures In patients with less severe disease, topical glyc-
heal spontaneously, but some become chronic. erol trinitrate is the first line of treatment, since
Chronic anal fissures are defined in terms of it relieves the pain and causes the fissure to heal
chronology and morphology. Most surgeons (143). An alternative treatment is local injection
regard the persistence of a fissure for longer than with botulinum toxin, which leads to symp-
6 weeks to be an indication of chronicity. Mor- tom relief and scarring of the fissure (147,148) .
phologically, the presence of visible transverse Botulinum toxin decreases resting anal pressure
internal anal sphincter muscle fibers character- by preventing the release of acetylcholine from
izes a chronic anal fissure (151). presynaptic nerve terminals (142).
Demography. Anal fissures affect individuals Since internal anal sphincter tone is mediated
of all ages, including infants (145). They oc- by nitric oxide (NO), efforts have been made to
cur with greater frequency in individuals with provide exogenous sources of NO (153). Thus,
anal carcinoma, acquired immunodeficiency another treatment is the topical application of
syndrome (AIDS), tuberculosis, and sexually the nitrogen donor, isosorbide dinitrate. It re-
transmitted diseases (144). Anal fissures are also duces the anal pressure and increases anorectal
extremely common in patients with Crohn's blood flow, allowing fissures to heal (153).
disease (141,146,154). Patients unresponsive to medical therapy
Etiology. Chronic anal fissures develop sec- may undergo surgical treatment. Surgical proce-
ondary to persistent contraction of the internal dures for treating chronic anal fissures include
anal sphincter. Localized ischemia may also play anal stretch, open or closed lateral sphincter-
a role in their etiology (153). Patients with anal otomy, posterior midline sphincterotomy, and
fissures typically have high anal resting pres- less commonly, dermal flap coverage of the
sures and infrequent relaxation of the internal fissure (150) .
anal sphincter (143) . The posterior commissure
of the anal canal is less well perfused than the re- FISTULAS AND SINUSES
mainder of the anoderm, and increased activity Definitions. The term fistula ordinarily
of the internal anal sphincter further decreases implies the presence of an inflammatory tract
the blood supply to this region (149,153). between two epithelial-lined surfaces. The term
Clinical Features. Anal fissures are both sinus refers to a tract with only one open end.
easy to diagnose and easy for an inexperienced Enteroenteric fistulas are communications be-
examiner to miss. Anal fissures typically cause tween two portions of the gastrointestinal tract.
severe pain after defecation and bright red rectal Bouveret's syndrome is a cholecystoduodenal or
bleeding. They are diagnosed by everting the choledochoduodenal fistula resulting from the
anal canal using the opposing traction of the passage of a gallstone into the duodenal bulb
patient's buttocks . A sentinel skin tag may be with subsequent gastric outlet obstruction
present that alerts the examiner to the presence (161). Aortoenteric fistulas are communications
of a fissure. Anal and rectal ulcers commonly are between the gastrointestinal tract and the aorta.
associated with anal fissures. Gastrocutaneous and enterocutaneous fistulas are
Gross and Microscopic Findings. Anal a communication between the stomach and
fissures occur in the midline, particularly intestine, respectively, and the skin.
posteriorly. Fissures off the midline suggest Demography. Cholecystoduodenal or cho-
the presence of an underlying disorder, such ledochoduodenal fistula with gallstone ileus is
as Crohn's disease, carcinoma, or human im- a rare disease that affects primarily the elderly,

221
Gastrointestinal Diseases

Table 6-7 presence of oxyntic mucosa and secondary


ETIOLOGY OF GASTROINTESTINAL FISTULAS
peptic ulceration.
For several reasons, most anal fistulas develop
Cancer
in the posterior midline of the anorectal ring. First,
Trauma there is less muscular support for the skin and
Inflammatory conditions subcutaneous tissues in this region and as a result,
Appendicitis the skin in the area shows a greater tendency to
Behcet's syndrome
Chronic ctiarrhea split during descent and eversion of the anal canal
Crohn's disease during defecation. Second, the anterior rectal wall
Diverticulitis forms an almost straight line with the anus. This
Pancreatitis differs from the posterior wall where the rectal am-
Peptic ulcers
Vasculitis pulla bulges posteriorly toward the hollow of the
Chemical injury
sacrum so that it forms almost a right angle with
the anus. When defecation occurs, the posterior
Foreign bocties
area, which has the least muscular support, almost
Previous surgery entirely bears the weight of the fecal contents, and
Radiotherapy is, therefore, subject to injury.
Drugs Clinical Features. Esophagus. The symptoms
of esophageal fistulas often reflect the underly-
ing pathology. Esophageal-pulmonary fistulas
and demonstrates a female to mal~ ratio of ap- allow food to enter the lung, leading to pneu-
proximately 4 to 1 (157). Aortoen1eric fistulas monitis and pneumonia. Esophageal-aortic
also usually affect the elderly. Children with fistulas result in rapid death from exsanguina-
perianal abscesses, or fistula-in-ana, present from tion. Initial symptoms include acute epigastric
ages 22 days to 18 years (145) . The vast majority or retrosternal pain.
of affected children are boys. Small Intestine. Small intestinal fistulas most
Etiology. Fistulas result from three major eti- often result as a complication of Crohn's disease.
ologies: inflammation, trauma, and malignancy This entity is discussed in greater detail in chap-
(Table 6-7). Esophageal fistulas often result from ter 15. They may also develop when a patient
primary mucosal esophageal dj sease (reflux with large intestinal neoplasia has a tumor that
or cancer), disease extension in the lungs or grows into an adjacent loop of small bowel.
mediastinum (infection or cancer), or trauma Clinical symptoms result either from the inflam-
(esophageal intubation). mation or from the presence of an associated
Aortoenteric fistulas usually result from mass lesion. Enteric-aortic graft fistulas cause
disorders involving either the aorta (usually hematochezia or melena with hematemesis.
atherosclerosis or following the insertion of an Anus. Anal fistulas produce a persistent or
aortic bypass graft), or intrinsic gastrointestinal intermittent discharge from the fistula opening,
disease. The blood vessel most commonly per- leading to the development of perianal derma-
forated by an esophageal foreign body (such as titis. Patients tend to develop multiple fistulas.
a nasogastric tube) is the aorta, 1 to 5 cm from Circumferential spread of a septic process results
the origin of the subclavian artery, where the in horseshoe fistula, which demonstrates one or
esophagus lies closest to it. several openings connected to each other. The
Most anal fistulas represent a complication classification of anal fistulas is shown in Table
of infection of the anal glands . Fistulas may 6-8. Anal fistulas are intersphincteric, tram-
also develop secondary to other disorders, most sphincteric, suprasphincteric, and extrasphinc-
commonly Crohn's disease. Anal fistulas are teric, in decreasing order of frequency (158).
often complex lesions involving different tissue Gross Fin din gs. In Bouveret's syndrome, the
planes and causing varying degrees of sphincter usual route of fistulization is from the gallblad-
involvement and destruction. Anal fistula may der to the duodenum (164). A series of upper
also result from the presence of heterotopic gastrointestinal endoscopy studies is the best
gastric mucosa and duplications due to the way to visualize the lesion (157,160).

222
Acquired Structural Alterations

Aortoenteric fistulas involve the duodenum, Table 6-8


the esophagus, and other gastrointestinal sites. CLASSIFICATION OF ANAL FISTULAS
They develop in the abdominal aorta in 71
percent of cases and the descending thoracic Intersphincteric: The tract runs between the internal
and external sphincteric muscle. It is low if it runs
aorta in 29 percent.
low into the skin and high if it runs under the rectum.
In resection specimens, uncomplicated Simple low tract
chronic fistulas are often identified by the pres- High blind tract
ence of a cord-like thickening, which may be High tract with rectal opening
better appreciated by palpation than by visual Rectal opening without a perineal opening
inspection of the specimen. A fistulous tract Ectorectal extension
may also be probed in order to identify it (fig. Secondary to pelvic disease
6-20). Injection of methylene blue or some oth- Tram-sphincteric: The tract runs through the external
er dye helps delineate the course of the fistula. sphincter and through the ischiorectal fossa to the
The external opening of anal fistulas is usu- perianal gland.
ally within 5 cm of the anus. Magnetic reso- Uncomplicated
nance imaging (MRI) can be used to image the High blind tract
anorectal area in patients with fistula-in-ana, Suprasphincteric: The tract runs between and above
but it only correctly identifies the fistula in th e intersphincter space, above the external sphinc-
approximately 50 percent of patients. Fistula- ter and back into the ischiorectal fossa to the
in-ana may have internal openings or external perianal gland .
Uncomplicated
openings, or it may empty into an abscess cavity Blind tract
(163). Some patients have bilateral fistula-in-
ana. A relationship exists between the presence Extrasphincteric: This is secondary to pelvic sepsis
of perianal abscess and the development of rather than anal gland infarction and discharges
through the ischiorectal fossa to the skin.
fistula-in-ana (155) . Secondary to anal fistula
Microscopic Findings. The lining of fistu- Secondary to trauma
las usually consists of granulation or fibrous Secondary to anal rectal disease
tissue and variable amounts of inflammation,
depending on the age of the process. When

Figure 6-20
FISTULA
Left: A fistulous tract exists between the colon and small intestine.
Right: The tract is more easily seen when a probe is inserted into it.

223
Gastrointestinal Diseases

Figure 6-21
FISTULAS
A: Gastrocutaneous fistula . The tract is partially lined by gastric type and squamous epithelium.
B: The surrounding stroma shows chronic inflammation and fibrosis.
C: Fistula tract in a patient with Crohn's disease. No epithelial lining is present in this case. The tract is lined by granulation
tissue infiltrated with inflammatory cells.
D: Higher-power view shows granulation tissue, inflammation, and foreign body giant cell reaction.

the intestinal contents gain access to a fistula, a a simple fistula. This is pa1ticularly hue since only
granulomatous response may develop. Acute le- about SO percent of the fistulas developing in the
sions contain numerous inflammatory cells and setting of anal Crohn's disease contain sarcoid-like
granulation tissue along the length of the fistula granulomas suggesting the diagnosis. Hidradenitis
(fig. 6-21). Epithelial ingrowth can occur, especially suppurativa is differentiated by the presence of
•.·
in anal fistulas, at either end of the tract, leading multiple perianal skin openings and the fact that
to the development of a secondary epidermoid the opening in the anal canal lies distal to the den-
cyst (fig. 6-21). Giant cell reactions frequently tate line. A pilonidal sinus with perianal extension
complicate fistula-in-ana, especially if oil-based and infected perianal sebaceous cyst may also be
medications were used to treat the disease. considered. Additionally, carcinomas (mostly low
Differential Diagnosis. Anorectum. Several grade) may develop in long-standing fistulas
disorders must be considered in the differential after many decades. Anal canal carcinomas,
diagnosis of fistula-in-ana (Table 6-7). Crohn's particularly anal duct carcinomas, may present
disease is the most likely lesion to be confused with clinically as chronic fistulous tracts.

224
Acquired Structural Alterations

Treatment and Prognosis. Exsanguination is gastroesophageal junction. Stercoral perforations


the major cause of death when gastrointestinal are due to pressure necrosis from fecal masses.
fistulas involve blood vessels (159). Hematomas are localized collections of blood
The majority of anal fistulas are anatomically within the wall of the gastrointestinal tract.
simple and easy to treat, but others are high or Demography. Mallory-Weiss tears occur as
anatomically complex and have the potential a result of sudden, often violent increases in
to become major management problems. Tram- intraabdominal pressure compared to intratho-
sphincteric fistulas are more complex than racic pressure. This can occur during vomiting,
intersphincteric fistulas. Tram-sphincteric and childbirth, weight lifting, defecation, or trauma
high fistulas are more likely to occur in females (167,176,185,209). They also complicate upper
and in patients with previous perianal sepsis or endoscopy with an incidence of 0.07 to 0.49 per-
surgery for fistulas. Simple fistulas have external cent (179,195,199). In some patients, vomiting
openings close to the posterior midline whereas precipitates tears of preexisting ulcers or thermal
posterolateral external openings are predictive burns (173). Less traumatic events, even snoring,
of complex fistulas (156). can produce partial esophageal tears, usually
More advanced anal fistulas are treated with above the cardia (193). Most patients with Mal-
sphincterotomy, fistulotomy, marsupialization, lory-Weiss tears are in their 3rd to 5th decades
and endorectal advancement (158). Lateral and there is a slight male predominance (209).
internal sphincterotomy is the mainstay of Boerhaave's syndrome typically affects alco-
treatment for chronic anal fissures. Endorectal holic males between the ages of 40 and 60 years,
sonography allows identification of patients although the disease affects children (182,213)
who might be at increased risk for postoperative and neonates on rare occasion (171,191,201).
incontinence; an anal advancement flap can be The average age of patients with these lesions
used for these patients. Sphincterotomy perma- is 63. Ninety-five percent of spontaneous com-
nently weakens the internal sphincter and may plete tears (Boerhaave's syndrome) are associ-
lead to anal deformity and incontinence. Some ated with vomiting (171). Patients may also
fistulas recur. Factors associated with fistula have a history of NSAID use, hiatal hernia, or
recurrence include a complex form of fistula, gastroduodenal ulcer disease (169).
horseshoe extension, failure to delineate the The median age of patients with stercoral
lateral location of a fistulous opening, previ- perforations is 60 years, with an age range of 16
ously fistula surgery, and the experience of the to 89. Forty-five percent are men and 55 percent
surgeon (158). women. Twenty-three percent of patients are in
The complications of untreated anorectal chronic nursing homes or similar environments
infections include perirectal abscesses and anal, (206). Ingestion of the following materials may
rectovaginal, rectovesical, and ischiorectal fistu- predispose patients to constipation: aluminum
las. Anorectal strictures are a late complication, hydroxide, codeine or other narcotics, clay mix-
usually occurring 2 to 6 cm from the anal orifice. tures, constipating sedatives, and paper (pica)
Perianal abscesses are drained. (206). Many patients with stercoral perforations
have renal failure and severe constipation which
LACERATIONS, PERFORATIONS, HEMATOMAS is due to nonabsorbable antacids, particularly
Definition. Lacerations are mucosal tears that magnesium and aluminum hydroxide gels,
extend into but not through the gastrointesti- and cation exchange resins used to treat their
nal wall. Perforations are transmural gaps in the hyperkalemia (196,197,212).
integrity of the gastrointestinal wall that allow Etiology. Perforations result from many
air and luminal contents to exit the bowel into pathologic conditions (Table 6-9). In countries
the surrounding structures. The term Mallmy- with poor hygiene, infections often cause the
Weiss syndrome refers to painless gastrointes- perforation (166,178,181,198). In Western
tinal bleeding resulting from esophageal or countries, foreign bodies, ischemia, Crohn's
gastroesophageal mucosal lacerations, usually disease, tumors, trauma resulting from blunt or
following severe vomiting. Boerhaave's syndrome penetrating injuries, instrumentation, foreign
is a spontaneous rupture that occurs at the body impaction, diverticula, and radiation

225
Gastrointestinal Diseases

Table 6-9 abrupt movement of the diaphragm upward.


PERFORATIONS: ETIOLOGY
This coincides with a rapid increase in intra-
abdominal pressure leading to the propulsion
Appendicitis
of the gastric cardia into the thoracic cavity
Behcet's syndrome through the hiatus (190). If this is forceful
Boerhaave's syndrome enough, a longitudinal laceration follows.
Corrosive injury Hiatal hernia is found in over 75 percent of
Crohn's disease patients with Mallory-Weiss tears (194). With
Drug injury (numerous drugs) large hiatal hernias, the injury appears more
Ehlers-Danlos syndrome
distal because of the greater amount of herni-
ated stomach, whereas with absent or small
Gastrointestinal obstruction
hiatal hernias, the injury occurs at or just below
Infections the gastroesophageal junction (211). In the
Ischemia Mallory-Weiss syndrome, vomiting increases
Meconium ileus the pressure gradient between the abdomen
Motility disorders and the thorax, resulting in distal esophageal
Peptic ulcer disease ballooning or herniation of the stomach. Once
Radiation injury
the pressure gradient reaches a certain critical
level, the areas of least distensibility, such as
Struchual defects
the submucosa and mucosa, rupture while the
Trauma
muscular layer remains intact (188).
Tumors In Boerhaave's syndrome, the sudden de-
Ulcers due to any cause velopment of a pressure gradient between the
internal portion of the viscus and its external
supporting tissues usually is the cause gf gastro-
intestinal rupture (203). The antecedent events
therapy are the most common causes (184,200). vary. The viscus may become overdistended by
Eating, falling, the use of anticoagulants, or the food, drink, gas, or any combination thereof.
Heimlich maneuver may all precipitate esopha- Stercoral perforation most commonly occurs
geal perforations (168,204). Other antecedent in the rectosigmoid (177). Reasons for this are:
events include abdominal blows~ straining at 1) local pressure from structures surrounding the
stool, parturition, epileptic seizures, asthma, rectosigmoid that keep it from distending; 2) the
prolonged hiccups, and neurologic diseases presence of hard feces in this area; and 3) the
(171), as well as accidental introduction of com- presence of a relatively narrow intestinal lumen.
pressed air into the esophagus (165). Therapeu- Perforation often occurs during difficult bowel
tic intervention, such as dilatation, hemostasis, movements. Local pressure from the stool causes
stent placement, foreign body removal, cancer the ischemia and subsequent necrosis and perfo-
palliation, and endoscopic ablation techniques ration (175,178). The situation is made worse by
increase the risk of perforation from the inser- loss of normal mucosal barrier function, often
tion of flexible fiberoptic endoscopes (170, due to coexisting uremia as well as immunosup-
186,187,207,210). Esophageal perforations also pression in renal transplant patients.
result from surgical instrumentation or surgical Clinical Features. The clinical and patho-
procedures, most commonly fundoplication logic features of disruption of mucosal integrity
... and esophageal myotomy (205) . Esophageal depend on the depth of the tissue disruption
hematomas can be spontaneous or secondary and the site of the damage. The deeper the dis-
to trauma, toxic ingestion, or interventions. ruption, the more severe the clinical findings.
Pathophysiology. Nausea is associated The presentation of esophageal perforations
with closure of the pylorus, distension of the may vary with the site of injury. The classic triad
stomach, and retrograde pulsion of the gastric is pain, fever, and the presence of subcutaneous
contents from the antrum toward the cardia. If or mediastinal air. Respiratory complications
retching or forceful vomiting follows, there is are also common.

226
Acquired Structural Alterations

Most patients with Mallory-Weiss tears present


with gastr·ointestinal bleeding following retching
or emesis. In a minority of patients, melena or
hematochezia is the sole presentation.
Severe vomiting followed by excruciating,
constant chest pain are the classic clinical signs
of Boerhaave's syndrome. Hematemesis occurs
at times, and the clinical features and radiologic
findings often point to an intrathoracic catas-
trophe. The clinical features of Boerhaave's syn-
drome mimic those of instrument perforation,
with pain being the presenting symptom in the
majority of patients; 25 percent of patients are
in shock (165). Atypical chest pain may mimic Figure 6-22
an acute thoracic aortic dissection (183). The MALLORY-WEISS TEAR
nonspecific symptomatology delays the cor- A large, hemorrhagic defect is seen in the distal
rect diagnosis, often resulting in significant esophagus.
complications.
Patients with esophageal hematomas have
severe chest pain; they may also have dysphagia, the gastric fundus (fig. 6-22). Over 75 percent
odynophagia, and hematemesis. Patients are of lacerations are limited to the stomach. They
commonly thought to have an acute cardiac average 1.5 cm in length but may extend up to
event or dissecting aneurysm. Distinction from 4.0 cm or more. Grossly, these lesions have a
a cardiac ischemic event is critical because this linear or cleft-like appearance, and, if examined
condition is worsened by anticoagulation. Pre- acutely, are covered by clotted blood.
cipitating factors such as retching, vomiting, Boerhaave's syndrome may be diagnosed on
coughing, or foreign body impaction occur in CT scan by the presence of a collapsed esopha-
50 percent of patients (192). gus and air dissecting through the fascial planes,
Many patients with stercoral perforations in a circular fashion around the great vessels,
complain of a long history of chronic consti- and outlining the aorta and the esophagus. If
pation. Stercoral ulceration with perforation is radiographic contrast material is inserted into
uncommon but it can be fatal, since patients the esophagus, a large amount will enter the
often develop peritonitis. Such patients typi- mediastinum. Characteristically, in Boerhaave's
cally present with symptoms and signs sugges- syndrome the rent is linear and longitudinal,
tive of an acute abdomen. An abdominal mass and occurs most commonly in the left lateral
is sometimes palpable. posterior position, 1 to 3 cm above the cardio-
Gross Findings. Radiologic studies are the esophageal junction (189). This is the weakest
key to establishing the diagnosis of esophageal part of the esophagus. The tears measure 1 to
perforation. A standard chest radiograph and 20 cm in length, with an average of 2 cm; the
an upper abdominal X ray can establish the mucosal part of the tear is usually longer than
diagnosis by showing subcutaneous emphy- the muscular part.
sema, pneumomediastinum, and mediastinal Most small intestine perforations occur in
air fluid levels, ·or they may suggest the diag- the duodenum, especially in Western countries,
nosis by the presence of mediastinal widening, perhaps due to the presence of an underlying
pneumothorax, hydrothorax, pleural effusion, duodenal diverticulum, gallstones, or peptic
or pulmonary infiltrates (214). Contrast studies ulcer disease.
confirm the site of perforation. The most common site of colonic perfora-
In Mallory-Weiss syndrome, single or mul- tion is the sigmoid colon. The next site is the
tiple lacerations lie along the long axis of the rectosigmoid followed by the cecum, transverse
distal esophagus in the right lateral area, cross- colon, descending colon, and splenic flexure
ing the esophageal-gastric junction or lying in (206). Perforation is single in the majority of

227
Gastrointestinal Diseases

cases, although multiple perforations may oc- tients treated with primary repair of a perfora-
cur (208). Almost all perforations occur on the tion require additional surgery (180). Patients
antimesenteric border of the colon (208). Most with minimal symptoms of fever, absence of
resection specimens show features of colonic shock and sepsis, and wHh a nontransmural
loading with scybala and fibrinous exudates, or well-contained tear may be considered for
and external evidence of inflammation, ne- nonoperative management. Nonoperative
crosis, and friability. The mucosa is ulcerated therapy consists of broad-spectrum antibiotics,
in a geographic pattern, with rouno or ovoid parenteral alimentation, and diversion through
perforations occurring centrally in the ulcerated oral and nasoesophageal suction. Surgery is
area. Fecal material is often present within or the intervention of choice in patients with
through the bowel wall. large, noncontained esophageal perforations or
Microscopic Findings . Histologically, clinical signs of sepsis or shock. A gastrostomy
esophageal lacerations usually involve only or jejunostomy may be necessary to provide
the mucosa and submucosa; they rarely ex- nutritional support until the patient is able to
tend into the muscularis propria. At the base resume oral intake.
of the tear, acute inflammation and numerous Most patients with Mallory-Weiss tears have
ruptured arterioles and small veino6 are seen. a benign clinical course with evidence of heal-
Submucosal hematomas may form and dissect ing in the first 36 hours to 3 days. More than 90
for a distance beyond the tear. In rare situations, percent of lesions stop bleeding spontaneously.
Mallory-Weiss lesions present as a submucosal Patients with persistent active bleeding may
mass (202). In these cases, collectiens of blood require additional therapy. Endoscopic therapy
or inflammatory debris gain subm1:1cosal access with either multipolar electrocoagulation or
to form a pseudotumor. injection therapy is usually effective in stopping
The lesion in Boerhaave's syndrome is sel- the bleeding. Selective infusion of vasopressin
dom examined microscopically (except at the in the celiac or left gastric artery is SU!;Cessful in
time of autopsy in fatal cases). When it is, acute some cases (17 4). Gastric embolization may be
inflammation, fibrinous exudates, and necrosis needed. Surgical intervention with oversewing
are seen. is rarely necessary. Surgical resection is only
Stercoral ulceration features ulceration of the used if bleeding is massive; mortality is rare.
colonic wall with acute and chronic inflammation. The tears in Boerhaave's syndrome must be
Differential Diagnosis. Stercoral perfora- immediately repaired surgically if the patient
tions usually result from a localized hard fecal is to survive. Unfortunately, the syndrome is
mass, commonly of a diameter equal to or frequently misdiagnosed as an acute abdomen,
greater than the colon, with characteristics pancreatitis, or cardiac arrest. The current mor-
similar to those of a tumor. These fecal masses tality rate is approximately 31 percent (169).
are often referred to as fecal or stercoraceous Persistent reflux often follows repair of the
masses, fecalomas, stercoromas, and scybala. rupture (203).
Treatment and Prognosis. The optimal The mortality rate associated with stercoral
management of esophageal perforation is perforation is high, even following surgery.
controversial. Because the nature and sites of Patients treated conservatively have a much
perforation vary, the therapy chosen needs to higher mortality rate. Death usually results from
be tailored to the clinical setting. This includes uncontrolled sepsis.
consideration of the patient's esophageal pa-
thology, the hemodynamic consequences of STRICTURES
the perforation, and whether the perforation is Definition. Strictures are areas of narrowing,
confined. Despite the type of therapy chosen, usually due to scarring following an inflamma-
delays in diagnosis and treatment are associated tory condition.
with increased morbidity and mortality. Some Etiology. A number of conditions cause stric-
consider nonoperative management since there tures (Table 6-10).
is a high morbidity associated with emergency Pathophysiology. Repetitive, prolonged
esophagectomy (172). Up to SO percent of pa- exposure to any inflammatory agent can cause

228
Acquired Structural Alterations

transmural inflammation which leads to fibro- Microscopic Findings. Histologically, stric-


sis, loss of gastrointestinal wall compliance, and tures consist of variably inflamed fibrous tissues.
stricture development. The mucosal surface may appear eroded, or it
Clinical Features. The clinical presentation may be covered by epithelium that appears
·of strictures reflects their location. Strictures normal, atrophic, or regenerative, depending on
often develop over a period of time so that the underlying cause of the stricture formation.
symptom onset is insidious. In the esophagus,
strictures cause dysphagia. In the stomach, CHANGES ASSOCIATED
they cause gastric outlet obstruction. In the WITH PREVIOUS SURGERY
intestines, they cause partial or complete ob- Definition. The functional definition of short
struction. Two of the most common conditions bowel syndrome is the malabsorptive state that
associated with stricture formation are gastro- often follows massive resection of the small in-
esophageal reflux disease and Crohn's disease. testine. Anatomically, short bowel syndrome is
Strictures also complicate radiation therapy. defined as a residual jejunoileum measuring less
Clinically, strictures, especially focal ones, must than 75 cm in length (215,233,235). Anastomotic
be distinguished from carcinomas, which can ulcers develop at or near anastomotic sites. Many
develop at inflammatory sites. One of the most terms have been used to describe anastomotic
effective ways of evaluating a stricture is to per- ulcers following gastrectomy, including stomal
form endoscopic brushings of the surface of the ulce1~ gastrojejunal ulcer, and jejuna] ulcer.
lesion, since the densely fibrotic scar tissue may Demography. Short bowel syndrome follows
be exceedingly difficult to biopsy. small intestinal resection for many reasons
Gross Findings. Most strictures present as including malignancy, radiation injury, and
areas of thickening and/or narrowing (figs. vascular insufficiency. Intestinal transplanta-
6-23-6-25) . The cut surface typically shows tion is used to treat children with irreversible
varying degrees of fibrosis. intestinal failure who are dependent on total
parenteral nutrition. Pediatric candidates for in-
testinal transplantation are those who undergo
Table 6-10 extensive intestinal resections for necrotizing
CAUSES OF STRICTURES enterocolitis and intestinal congenital anoma-
Acute pancreatitis Ischemia lies, including total aganglionosis, volvulus,
Behcet's syndrome Peptic ulcer disease gastroschisis, and atresia (215) as well as those
Corrosive injury Radiation
with functional disorders such as intestinal
pseudo-obstruction, microvillous inclusion
Crohn's disease Reflux
disease, juvenile polyposis, and trauma (229).
Diverticulitis Sarcoidosis The incidence of extreme short bowel syndrome
Drug-induced injury Scleroderma in newborn infants is difficult to assess but it
Graft versus host disease Tumors is estimated to be between 0.3 and 0.5/10,000
InJections (tuberculosis, births a year (215). Volvulus and Crohn's disease
herpes simplex virus, may require massive small intestinal resection
cytomegalovirus) in both adults and children.

Figure 6-23
STRICTURE OF
THE ESOPHAGUS
The lumen is narrowed dis-
tally and dilated prox imally.
(Courtesy of the Division of Gas-
trointestinal Pathology, Armed
Forces Institute of Pathology,
Washington, DC.)

229
Gastrointestinal Diseases

Figure 6-24
SMALL INTESTINAL STRICTURE IN A PATIENT PREVIOUSLY TREATED WITH RADIATION
Left: Small bowel series shows a long segment of strictured small intestine. Only a thin line of barium is seen in the
narrowed segment of bowel.
Right: Spot film showing the strictured area.

Figure 6-25
SMALL INTESTINAL ISCHEMIC STRICTURE
Left: An unfixed specimen with scarring resembles a carcinoma-like apple core lesion . (Courtesy of the Division of
Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC.)
Right: A fixed specimen with marked narrowing of the small bowel lumen.

Pathophysiology. The impact of small intes- in different consequences. Ileal resections are
tinal resection depends on the site and extent less well tolerated than jejunal ones.
of the resection and the degree of morphologic No reliable data exist regarding the length
... and functional adaptation that occurs in the of small intestinal mucosa that can be resected
residual bowel (221,227,228,234). Adaptive before malabsorption occurs. Studies suggest
responses also affect the large intestine, increas- that one third of the jejunum can be resected
ing both its growth and mucosal permeability without severe effects and that resection of 40
(232). Intestinal digestive and absorptive func- to SO percent of the total length of the small
tions do not parallel the degree of compensa- intestine is usually well tolerated, but more
tory mucosal hyperplasia (224). Because the massive resection frequently results in short
small intestine differs in its functions along its bowel syndrome (225). In the case of distal il-
length, resections of different segments result eal resection, especially if the ileocecal valve is

230
Acquired Structural Alterations

removed, lesser degrees of resection may result and chronic inflammation. If the patient had a
in malabsorption. The loss of the ileocecal valve previous resection, the bowel may appear nor-
and proximal colon predisposes the residual mal or there may be histologic features of the
·small bowel mucosa to exposure to colonic disease for which the resection was undertaken.
microorganisms. Villous height increases following intestinal
Clinical Featu res. Changes Following Gastric resection. The degree of villous enlargement
Surgery. Patients often exhibit malabsorption is proportional to the amount of intestine
following gastric surgery. The afferent loop of a resected. Villous enlargement is greatest im-
Billroth II gastrectomy is at risk for the develop- mediately distal to the resection and tapers off.
ment of bacterial overgrowth. Vagotomy and There is an increase in the number of cells per
pyloroplasty contribute to reduced gastric acid unit length of villus. The number of intestinal
secretion, predisposing to bacterial or fungal stem cells also increases.
colonization of the blind loop. Anastomotic Ulcers . Nonspecific mucosal and
Short Bowel Syndrome. Malabsorption of both submucosal inflammation complicates surgi-
macronutrients and micronutrients is common. cal anastomoses. Villous atrophy and intense
In some patients, caloric and protein needs mucosal and submucosal inflammation may be
can be adequately met enterally but vitamin present. These chronic inflammatory infiltrates
and mineral deficiencies result. In the case consist of lymphocytes, eosinophils, mono-
of massive small bowel resection, the patient cytes, and histiocytes. The bowel wall becomes
rriay be committed to lifelong dependence on fibrotic and scarred, with destruction of the
parenteral nutrition or may require intestinal muscularis propria and the neural plexuses .
transplantation. Ileostomies. Biopsies of the ileostomy site
Gross Findings. Anastomotic Ulcers. The may show the effects of the surgery with suture
normal mucosal pattern disappears and the mu- granulomas, nonspecific inflammatory changes,
cosal folds become reddened, friable, irregular, dysplasia, or even carcinoma.
blunted, cobblestoned, and edematous, with Treatment and Prognosis. Short Bowel Syn-
areas of ulceration intermingled with punc- drome. Management of short bowel syndrome is
tate hemorrhages. In patients with a history a gradually changing, multistep process (230).
of antrectomy, anastomotic ulcers develop at During the early postoperative phase, parenteral
or near the anastomosis between the stomach nutrition is administered and the complications
and small bowel, most frequently on the jejunal of fluid and electrolyte imbalance rectified.
side, either opposite the stoma or in the efferent Gradual transition to continuous enteral nutri-
loop approximately 1 cm from the anastomotic tion and subsequent dietary therapy constitutes
line. Such ulcers tend to penetrate deeply, often the next phase of management. Complications
into adjacent organs such as the liver, pancreas, such as nutrient deficiency states, liver disease,
or transverse colon. Radiologically, only about and bacterial overgrowth may occur
half of such ulcers are correctly diagnosed since Potential long-term survival in infants with
a surgical deformity at the anastomotic site may short bowel syndrome depends on the length
mimic or conceal the ulcer. of intestine remaining, and whether or not the
Microscop ic Fin din gs. Changes Associated ileocecal valve is present. Overall, the mortality
with Previous Gastric Surge1y. Small intestinal mu- rate among infants with short bowel syndrome
cosal changes in patients who have undergone is 15 to 25 percent (215,217,219,220,222,226) . In
previous gastric surgery range from a completely adults, a remnant small bowel length of less than
n ormal appearance to mild, patchy, villous 50 cm correlates with increased mortality (223).
atrophy and crypt hypoplasia. Some patients Chronic complications of short bowel syn-
exhibit dense chronic inflammation. drome include cholelithiasis, parenteral nutrition-
Short Bowel Syndrome. The histologic features induced liver disease, nutrient deficiency states,
of short bowel syndrome differ, depending on and small bowel bacterial overgrowth (231). Fluid
the etiology. If it results from healed necrotiz- and sodium losses in patients with short bowel
ing enterocolitis, the intestinal wall will show syndrome can be treated with antidiarrheals, oc-
segmental fibrosis (often transmural in nature) treotide, omeprazole, or H2 blockers (to reduce

231
Gastrointestinal Diseases

rebound acid hypersecretion), but intravenous pothermia, and have an: extremely low weight.
supplementation is still required. Other findings associated with anorexia ner-
Animal Models. In experimental animals, 24 vosa include dry skin, hypercarotenemia, and
to 48 hours after bowel resection the remaining atrophy of the breasts. Laboratory findings are
small intestine undergoes an adaptive response often normal in these patients. Amenorrhea is
characterized by epithelial hyperplasia. The villi a cardinal manifestation of anorexia nervosa
lengthen and the intestinal absorptive surface but oligomenorrhea or amenorrhea may also
increases so that digestive and absorptive func- occur in patients of normal weight who have
tions gradually improve (216,218). The ileum bulimia nervosa (242). Gastric perforation or
has a greater capacity to adapt than the jejunum. Boerhaave's syndrome can complicate bulimic
attacks (240,24 1). Esophageal complications
CHANGES ASSOCIATED include esophagitis, erosions, and ulcers that
WITH EATING DISORDERS result from self-induced vomiting and frequent
Definition. Anorexia nervosa is defined by exposure of the esophageal mucosa to gastric
four criteria: 1) failure to maintain minimal acid (238). Patients with anorexia nervosa lose
weight for height and age; 2) fear of fatness; weight by self-induced starvation. Bulimic
3) distorted body image; and 4) cfmenorrhea. forms of the disease combine dietary restrictions
Bulimia nervosa is an eating disorder character- with episodes of binging, vomiting, and other
ized by periodic food binges that are followed forms of purging. The patients may develop
by purging. The purging usually takes the form rectal prolapse due to constipation, laxative
of self-induced vomiting, laxative abuse, and/or use, overzealous exercise, and increased intra-
diuretic abuse. Bulimia is defined by: 1) binge abdominal pressure from forced vomiting.
eating; 2) feeling of lack of control; 3) compen- Gross Findings. The esophagus may show
satory action to negate binge effects; 4) two erythema, erosion, or ulceration as a result of
binges/week for 3 months; and 5) overconcem induced vomiting. In patients who develop
with body weight and shape (239). Binge eating gastric perforation, the stomach appears dilated
disorder is a newly recognized entity in which and necrotic.
patients eat large amounts of food while feeling Microscopic Findings. Histologically, the
a loss of control over their eating. This disorder changes of severe reflux esophagitis are seen in
differs from bulimia nervosa in t!J.at the patients bulimic patients.
do not purge afterward.
Demography. Eating disorders affect an es- ARTERIOVENOUS MALFORMATION
timated 5 million Americans each year. These Definition. Gastrointestinal vascular anoma-
illnesses include anorexia nervosa, bulimia ner- lies occur in both inherited and genetic dis-
vosa, binge eating disorder, and their variants. orders; in the setting of previous injury or
Eating disorders typically affect adolescent girls radiation to the bowel; and with coexisting
or young women, although 5 to 15 percent of aortic valvular stenosis, cardiac, pulmonary, or
cases of anorexia nervosa and bulimia nervosa, hepatic disease, and hemodialysis. Camilleri et
and 40 percent cases of binge eating disorder, al. (251) suggest separation of vascular anoma-
occur in boys and men (236). An estimated lies into type 1, arteriovenous malformations
3 percent of young women have these disor- with angiodysplasia and vascular ectasia; type
ders (237) . The mortality rate associated with 2, multiple phlebectasias; type 3, telangiecta-
#!, •
anorexia nervosa (0.56 percent/year) is more sias including those with hereditary or genetic
than 12 times the mortality rate among young backgrounds; type 4, hemangiomas sometimes
women in the general population (243) . including hereditary forms; and type 5, disor-
Etiology. The disorders appear to be caused ders of connective tissue affecting blood vessels.
by a combination of genetic, neurochemical, The terms angiodysplasia and arteriovenous
psychodevelopmental, and sociocultural fac- (AV) malformation are often used interchange-
tors (237) . ably. At time of surgery, an AV malformation
Clinical Features. Clinically, patients are may be detectable as a pulsating mass. The
often hypotensive, with bradycardia and hy- lesion consists of a localized increase in the

232
Acquired Structural Alterations

number and size of blood vessels without the Clinical Fea t ures. Patients with angio-
features of hemangioma. dysplasia present either with overt gastrointesti-
Dem ography. The most common type of nal bleeding or anemia. Bleeding from these le-
·vascular malformation is angiodysplasia, which sions can be massive and recurrent. Coagulation
usually involves the right colon (252,256,259), abnormalities contribute to episodic bleeding
although it also affects other sites. The true (260). Numerous studies show an association
incidence of angiodysplasia is unknown since between bleeding from angiodysplasia and the
the lesion is difficult to demonstrate surgically presence of aortic stenosis (244,247,282). Valve
and pathologically. Angiodysplastic lesions are replacement causes cessation of the recurrent
incidental findings in 3 to 6 percent of indi- bleeding (252). This suggests that the aortic ste-
viduals undergoing colonoscopy and in up to nosis does not cause the lesion but contributes
25 percent of the elderly (245) . Angiodysplasia to the bleeding from it (247).
usually affects persons over SO years of age, Gr oss Find ings. Angiodysplasias are fre-
although it can affect individuals of any age; quently multiple, measure less than 5 mm in
average patient age is 70 years. diameter, and primarily involve the cecum and
Etiology. Controversy surrounds the etiol- right colon. The lesions are often flat. They usu-
ogy of angiodysplasia. Arguments favoring an ally consist of small (1 to 2 mm or less) or larger
acquired origin include its association with aortic (over 5 mm) cherry red, fan-shaped mucosal
stenosis, underlying inflammatory gastrointesti- lesions with a tense central vessel and radiating
nal conditions, and hereditary von Willebrand's foot processes (fig. 6-26). Mucosal erosions may
disease (252,260,282). Mechanical factors may be present. If the lesion is examined under the
play a role in some cases, with vigorous peristalsis dissecting microscope, multiple, often coales-
or increased intraluminal pressure causing shunt- cent vascular channels with adjacent arteries
ing of blood into the submucosal AV system. and veins stand out as "coral reefs" against the
Boley (246,247) has proposed that the lesions normal capillary "honeycomb" pattern of the
result from chronic low-grade obstruction of colonic mucosa. Sometimes a gross specimen is
submucosal veins. Normal intermittent disten- received in which the angiodysplasia has been
tion of the cecum and right colon causes recur- cauterized, in which case the lesion may appear
rent obstruction to venous outflow, especially as a heaped-up ulcer.
where veins penetrate the muscularis propria. Microscopic Findin gs. Histologically, angio-
This increases the back pressure, resulting in the dysplasia consists of abnormal numbers of
formation of AV shunts. The pattern of involve- dilated, distorted arteries and veins lined by
ment points to the dilatation of submucosal endothelium (fig. 6-27). The vessels have an
veins as the initial morphologic change, lending abnormal distribution and aberrant morphol-
credibility to the notion that recurrent obstruc- ogy, and probably represent true AV malforma-
tion plays a role in its etiology. This obstruction, tions. The earliest abnormality is the presence
repeated over many years during the muscular of dilated (twice normal diameter), thin-walled,
contraction and distention of the colon, results submucosal veins that may occur in the absence
in dilatation and tortuosity of the submucosal of mucosal involvement. The dilated, thin-
veins and then retrograde involvement of the walled vessels do not demonstrate sclerosis. The
venules of the arteriolar-capillary venular units. architecture of the overlying gastrointestinal
Ultimately, the capillary rings surrounding the glands is not altered and the lamina propria is
crypts dilate and the competency of the precap- not significantly inflamed.
illary sphincters is lost, thus producing a small As the disease progresses, mucosal abnor-
AV communication. malities become more pronounced. Increased
Pathophysiology. Local factors may be im- numbers of dilated and deformed vessels are
pmtant in the pathogenesis of angiodysplasia. seen in the mucosa and submucosa, eventually
These include intermittent venous obstruction, leading to distortion of the mucosal architecture
increased intraluminal pressure, intermittent and mucosal erosion. The walls of the vessels in
abnormal arterial flow, and local vascular de- the submucosa appear irregularly thickened and
generation. often massively dilated (fig. 6-28). As the lesions

233
Gastrointestinal Diseases

Figure 6-26
ANGIODYSPLASIA
A: Small, flat, stellate hemorrhagic lesions on the colonic
mucosal surface.
B: Endoscopic view with similar-appearing, flat,
hemorrhagic foci on the mucosal surface.
C: Endoscopic view of a larger area of angiodysplasia.

Figure 6-27
ANGIODYSPLASIA
Left: Several thickened, ectatic vessels lie within the colonic submucosa .
Right: Higher-power view shows the irregular, thickened, abnormal submucosal vessels making up the lesion.

234
Acquired Structural Alterations

advance, the mucosal glands become displaced


by the proliferating blood vessels. Only a layer
of endothelial cells may separate the vascular
channels from the intestinal lumen. Mucosal
lesions are always associated with submucosal
vascular abnormalities. Occasionally, the sub-
mucosal vessels show mild to moderate sclerotic
changes, sometimes with atheromatous emboli.
Organized and recanalized thrombi may be
present in larger veins. The walls of the vessels
in the submucosa appear irregularly thickened
and often massively dilated. Some vascular
ectasias extend the full thickness, from the
serosa through the muscularis propria to the
submucosa and mucosa.
Special Techniques. Most angiodysplasias
are mucosal and submucosal lesions that are
not always visible externally to the surgeon or
the pathologist, although transillumination
occasionally leads to their recognition. A help-
ful way to identify the vascular abnormality
in resection specimens is to have the surgeon
cannulate the major vessels at the time of the
resection, leaving the cannulas in place. When
the specimen is received in the laboratory, the
pathologist can inject a combination of India
ink and a radiopaque dye into the specimen and
then X ray it. The specimen can then be fixed
and sections taken. The India ink will remain Figure 6-28
visible within the abnormal vessels. HEMORRHOID
Differential Diagnosis. The presence of Dilated vascular spaces are underlying the anal mucosa
distorted and malformed vessels distinguishes and perianal skin. (Courtesy of the Division of Gastro-
this lesion from hemangioma or telangiectasia. intestinal Pathology, Armed Forces Institute of Pathology,
Washington, DC.)
Treatment and Prognosis. Some patients need
resection because of massive blood loss. Removal
of the involved segment cures the disorder. vessel. Today, however, it is considered to rep-
resent a congenital anomaly.
CALIBER-PERSISTENT ARTERY
Definition. Caliber-persistent artery is the HEMORRHOIDS
presence of an abnormally large artery lying Definition. Definitions of hemorrhoid-asso-
horizontally in the submucosa. This entity is ciated lesions are shown in Table 6-11.
also termed cirsoid anewysm and Dieulafoy lesion. Demography. The prevalence of hemorrhoids
Demography. Caliber-persistent artery tends is not increased in patients with portal hyperten-
to affect middle-aged and elderly men. The sion but the prevalence of anorectal varices and
median age of patients is 52 to 54 years, but colopathy is higher in these patients. Hemor-
patients range in age from 16 to 91 (274). The rhoids rarely develop in individuals under the
lesions most commonly involve the stomach, age of 30, except in pregnant women.
but they can occur anywhere in the gastroin- Pathophysiology. Hemorrhoids represent
testinal tract. the distal displacement of the anal cushions, tis-
Etiology. The lesion was previously thought sue that is normally present in the anal mucosa
to reflect aneurysmal dilatation of a submucosal and that becomes more prominent with age.

235
Gastrointestinal Diseases

Table 6-11
DEFINITION OF LESIONS ASSOCIATED WITH HEMORRHOIDS
External h emorrhoids: dilated venules at the inferior hemorrhoidal plexus located below the d e~tate line.
Internal h emorrhoids: the anal cushions located above the dentate line prolapse.
First degree h emorrhoid : anal cushions slide down beyond the dentate line upon straining.
Second degree hemorrhoids: the anal cushions prolapse through the anus on strain in g but reduce spontaneously.
Third degree h emorrhoids: the an al cush ions prolapse through the anu upon straining or exertion and require m anual
replacement into the anal can al.
Fourth degree h emorrhoids: the prolapsed hemorrhoid stays out all the time and cannot be reduced.
Strangulated hemorrhoids: when a sphincter spasm occurs in the presence of irreducible prolapsed h emorrh oids, both
the external and internal hemorrhoids become engorged, the blood supply is compromised, and the h emorrhoids
becom e strangulated.

These cushions consist of arterioles, venules, and hemorrhagic infarction with strangulation.
and AV communications. Hemorrhoids develop Hemorrhoidal thrombosis causes pain, induc-
when the supporting tissues of the anal cushion ing many patients to seek medical help. Later,
lose their strength and the mucosa becomes organization of thrombotic areas results in the
more susceptible to the effects of straining at formation of fibrous polyps or anal skin tags .
stool, resulting in bleeding and protrusion. The Microscopic Findings. Histologically, hem-
precise function of the anal cushions remains orrhoids consist of anorectal mucosa cover-
unknown, although they are believeq to play ing a plexus of thin-walled, dilated vascular
a role in anal continence. During the act of spaces (fig 6-28). These sometimes contain a
defecation, they become engorged with blood. large amount of smooth muscle in tlleir walls.
Hereditary and environmental factors, as well Variable degrees of hemonhage, thrombosis,
as individual habits, may account for variations ulceration, and fibrosis are present. Recanalized
in hemorrhoid size, presentation, or symptoms. thrombi are frequently present.
Factors that predispose to hemorrhoid formation Differential Diagnosis. A number of neoplasms
include chronic straining, pregnal'l.cy, low fiber may present clinically as hemorrhoids. These in-
diet, anal sphincter spasm, hereditary factors, clude squamous cell carcinomas, melanoma, and
and tumors (267). As the veins dilate, the overly- carcinoid tumors. For this reason, it is critical that
ing mucosa stretches until it eventually protrudes hemorrhoids be examined histologically.
into and down the anal canal. If further dilation Treatment and Prognosis. Hemorrhoidal
of the hemorrhoidal plexus occurs, then second- thrombosis may resolve spontaneously with
ary hemorrhoids form between the primary ones. eventual fibrosis or may require surgical re-
When internal hemorrhoids protrude through moval. Sometimes phenol is injected into the
the anal sphincter, t~ey become strangulated anorectal area in order to sclerose the vascula-
due to sphincter contraction. ture. Under these circumstances, there may be
Clinical Features. Patients complain of bright an interstitial inflammatory response that may
red blood on toilet tissue or coating the stool acquire granulomatous features .
and a vague feeling of rectal discomfort. The
#! , ·
discomfort increases when the hemorrhoids VAR ICES
enlarge or prolapse through the anus, an event Definition . Varices are dilatations of venous
often accompanied by edema and sphincteric channels. The veins become thickened and
spasm. Prolapse, if untreated, becomes chronic sclerotic.
as the muscularis stays stretched and the patients Dem ogr a p hy. Varices develop through-
complain of constant soiling of underclothing out the gastrointestinal tract, although they
with very little pain. Complications of hemor- are most common in the esophagus. Lower
rhoids include superficial ulceration, thrombo- esophageal varices develop in up to 90 percent
sis, necrosis, inflammation, fissure formation, of patients with cirrhosis, particularly in those

236
Acquired Structural Alterations

with alcoholic cirrhosis. Mean patient age is SO patients develop high systemic venous pressure
years, and there is a slight male predominance. in the presence of normal pmtal venous pressure,
Feldman et al. (261) found a frequency of large causing the formation of collateral vessels from
intestinal varices of 0.07 percent in an autop- the systemic to the portal veins. Varices can also
sied population. develop as isolated lesions secondary to splenic
Etiology. Sites where varices form reflect the vein thrombosis or complicate gastric torsion.
embryonic juxtaposition of visceral and sys- Small intestinal varices develop in the same
temic vascular plexuses. Portal hypertension not settings as esophageal varices, but they are less
only causes dilatation of the preexisting natural common and less well known. Varices result
shunts and creation of collateral vessels, but from liver disease in approximately 90 percent
also reopens embryonic vessels, particularly the of cases. The presence of adhesions, enterosto-
periumbilical veins, producing caput medusae. mies, or previous injury (248,2S3,283) favors
In patients with portal hypertension varices their formation, especially if portal hyperten-
develop at sites of portosystemic anastomoses. sion is present. Patients with pancreatitis and
The coronary-azygous system is the primary splenic vein thrombosis also develop colonic
portal-systemic channel in SO percent of cases; varices (249). Colonic varices may also occur
in 2S percent, the inferior mesenteric and on a familial basis in the absence of portal hy-
internal iliac systems represent the primary pertension (26 7,2 76).
portal-systemic channel. Portal-systemic com- Clinical Features. Varices usually do not
munications also exist in the rectum. cause symptoms until they rupture, at which
A common vascular bypass (the coronary- time they produce massive hematemesis or
azygous system) that becomes dilated in portal hematochezia. Rupture may occur without an
hypertension lies in the area below the esopha- apparent triggering event. Many patients with
gus. Here portal blood flow is diverted through esophageal varices have an antecedent history
the gastric coronary veins, into the esophageal of vomiting. In some patients, the bleeding
submucosal plexus veins, to the azygous veins, arises from concomitant portal hypertensive
and eventually back to the systemic circulation. gastropathy, Mallory-Weiss tears, or peptic ul-
This submucosal venous plexus dilates to form cer disease. Bleeding is usually substantial and
esophageal varices. The most common causes dramatic. Many patients have concomitant
of lower esophageal varices are cirrhosis, schis- coagulopathy as a result of impaired hepatic
tosomiasis, and extrahepatic portal venous ob- synthetic function, and thrombocytopenia due
struction. Upper esophageal varices result from to associated hypersplenism.
compression of the superior vena cava. Right- Gross Findings. Grossly, varices appear as dis-
sided cardiac insufficiency produces esophageal crete, large veins protruding into the lumen, or as
venous distention as part of the syndrome of multiple smaller venules occupying the lamina
congestive heart failure. Bleeding results from propria. Endoscopically, esophageal varices ap-
rupture, because of increased pressure, or from pear as bluish, sinuous, linear mucosal elevations
thinning of the overlying supporting struc- that are most prominent below the aortic arch,
tures, rather than from mucosal erosions caused especially as one approaches the distal esophagus
by acid pepsin digestion (286). Venous stasis and (fig. 6-29). Submucosal varices grossly appear as
subsequent anoxia produce necrosis and epithelial tortuous dilated veins distributed in the long
ulceration, thereby increasing the 1isk of bleeding. axis of the distal esophagus, protruding directly
Epithelial destruction occurs over extremely dilated beneath the mucosa (fig. 6-30). Varices may
superficial submucosal varices. Thrombosis is rare be difficult to detect at the time of pathologic
but perivenous edema and necrosis of the adjacent examination (usually at autopsy) because they
epithelium are often present, as are hemonhage and collapse unless special efforts are made to keep
submucosal inflammation. In long-standing stasis, them blood-filled. In some cases, transillumina-
fibrosis becomes prominent. tion highlights their presence.
Most patients with gastric varices have portal Gastric varices usually surround the cardio-
hypertension and esophageal varices. Gastric esophageal junction. They appear as localized,
varices also complicate portocaval shunts. The polypoid, or multiple rounded submucosal

237
Gastrointestinal Diseases

0 1 2 3 4 5 6 7
cml 1 I 1 I 1 I 1 I 1 I 1 I 1 I

~~-· · - - -
.. .
~
. .i· ( ~.
- ~- , !
-......._ --

Figure 6-29
ENDOSCOPIC APPEARANCE OF ESOPHA<;;EAL VARICES
Large, blue-black, dilated and congested veins bulge into
the esophageal lumen.
Figure 6-30
ESOPHAGEAL VARICES
projections. These vessels do not have the blu- Top: The veins appear enlarged and blue-purple.
ish cast seen in the esophagus due to increased Bottom: Another specimen shows prominent dilated
veins in the distal esophagus. Grossly, esophageal varices
mucosal thickness. Their varicose features are may be difficult to visualize in resected or autopsy specimens
usually obvious. Classically, gastric varices pres- because the congested veins collapse. A prominent vascular
ent radiographically as a cluster otsubmucosal, pattern, however, may be observed in the distal esophagus.
polypoid nodules near the gastroesophageal
junction. They may appear soft and pliable. It
is important that the endoscopist not biopsy Treatment and Prognosis. Patients with
"blue polyps," since they may bleed. varices and an alcoholic history have a poorer
Microscopic Findings. Histologically, varices prognosis than those with varices from other
appear as dilated, intraepithelial or subepithelial etiologies. The longer the duration of cirrhosis
blood-filled channels (fig. 6-31). Evidence of old and low-grade vascular lesions, the greater the
thrombosis, hemorrhage, superimposed inflam- risk of developing large varices. Patients with cir-
mation, or fibrosis suggests previous rupture. rhosis and ruptured esophageal varices stand a 40
Vessels deeper in the esophageal wall may be percent chance of dying from the initial bleed. If
massively thickened and sclerotic. Thrombosis they survive the initial episode, their probability
is rare but perivenous edema and necrosis of of remaining alive for 1 year is about 30 percent.
1!,· the adjacent epithelium are often present, as Beta-blockers are the treatment of choice
are hemorrhage and submucosal inflamma- to prevent variceal bleeding. During the acute
tion. In long-standing stasis, fibrosis becomes bleed, all patients should receive vasocon-
prominent. The histologic features of varices strictors and endoscopic treatment. Injection
throughout the gastrointestinal tract are similar. sclerotherapy controls acute variceal bleeding in
Differential Diagnosis. The differential di- many patients by either thrombosing veins or
agnosis of gastric varices includes portal hyper- fibrosing the overlying mucosa. Fibrosis occurs
tensive gastropathy and gastric antral vascular late and it is often transmural. Sclerotherapy
ectasia. These lesions may coexist. results in complications in over 20 percent of

238
Acquired Structural Alterations

_j

Figure 6-31
ESOPHAGEAL VARICES
Left: A large, dilated, submucosal vein appears partially thrombosed.
Right: Ruptured esophageal varix. The overlying mucosa is eroded, and the vessel wall is no longer intact.

individuals, including bleeding, reflux esopha- seen in association with portal hypertension.
gitis, necrosis, ulcers, tears, abscess formation, The changes may affect any region of the gas-
perforations, strictures, mediastinal steno- trointestinal tract, but are most commonly seen
sis, esophageal dysmotility, and bacteremia in the stomach. Other terms for this entity are
(246,250,289). Some of these complications p01tal colopathy, portal hypertensive colopathy, por-
are transient, whereas others are more chronic. tal hypertensive intestinal vasculopathy, and portal
Tracheoesophageal fistulas may result from hypertensive enteropathy. Colonic portal hypelten-
the treatment of esophageal varices and the sive disease is discussed here; portal hypertensive
placement of Sengstaken-Blakemore tubes . gastropathy is discussed separately below.
Prolonged placement of a tube weakens the Demography. In patients with portal hyperten-
esophageal wall, precipitating ulcer formation sion, both portal hypertensive enteropathy and
and eventually leading to fistula development. p01tal hype1tensive colopathy have been rep01ted.
Because of the high complication rate associated Most investigators report a frequency of vascular
with sclerotherapy, endoscopic ligation with an ectasias of between 48 to 52 percent (254,262,275),
elastic "0" ring offers an alternate therapy and with a risk of bleeding from portal hypertensive
has become the procedure of first choice for the colopathy estimated at between 0 and 8 percent
treatment of esophageal varices. The varices are (254,262). Although hemorrhoids and rectal vari-
ligated endoscopically and strangled with small ces are rep01ted to be the most common causes
elastic 0 rings, which drop off after a few days, of lower gastrointestinal bleeding in patients with
following thrombosis of the underlying varices. p01tal hype1tension (264,269), another cause of
The incidence of clinically significant compli- both acute and chronic lower gastrointestinal
cations is far less than with endoscopic sclero- hemorrhage in these patients is an increased
therapy. Multiple sessions may be required to incidence of changes of the intestinal microvas-
achieve variceal eradication. Treatment failure culature in the mucosa (262,277,287).
should lead to consideration of a transjugular Etiology and Pathophysiology. The under-
intrahepatic portosystemic shunt (257,272). lying mechanism for the formation of portal
hypertensive colopathy is unclear but both
PORTAL HYPERTENSIVE VASCULOPATHY portal hypertension and the associated hyper-
kinetic circulatory state may play a role in its
Portal Hypertensive Colopathy
genesis. A hepatic venous pressure gradient
Definition. Portal hypertensive vasculopathy of greater than 12 mm Hg is necessary for the
is a general term for the widespread gastroin- development of gastroesophageal varices and
testinal mucosal venous and capillary ectasia upper gastrointestinal bleeding (263) .

239
Gastrointestinal Diseases

there may be reactive changes in the crypt epi-


thelium as well as focal infiltration of the lamina
propria by neutrophils in some cases.
Treatment and Prognosis. Small intestinal or
colonic lesions may be treated with transjugular
intrahepatic portosystemic shunt placement.
Portal Hypertensive Gastropathy
Definition. Pmtal hype1tensive gastropathy con-
sists of gastric mucosal damage and gastric vas-
culopathy in the setting of portal hypertension.
Demography. Up to 95 percent of patients
with cirrhosis and portal hypertension develop
portal hypertensive gastropathy.
Etiology and Pathophysiology. Passive
congestion of the portal system and its associ-
ated hemodynamic disturbances play a role
in the genesis of the gastropathy (265) . The
Figure 6-32 patients exhibit increased mucosal blood flow
PORTAL HYPERTENSIVE GASTROPATHY
contrasting with the significant reduction seen
The endoscopic features are characteristic, with a
in patients with chronic gastritis (266).
reticular network imparting a "snakeskin" appearance to Clinical Features. Patients present with
the mucosa. gastric mucosal abnormalities, anemia, and
gastrointestinal hemorrhage.
Gross Findings. The mucosa appears "beefy"
Clinical Features. Patients with portal hyper- red, with multiple petechial hemori·hages, red
tension may bleed from variceal portosystemic spots, acute ulcers, and erosions. Often, a char-
collaterals or specific nonvariceallesions . Little acteristic mosaic pattern of a white reticular
information is available on portal hypertensive network outlines central erythematous areas
intestinal vasculopathy involving the small (fig. 6-32) (278) . This imparts a "snakeskin"
bowel or colon (258,273,277-280) . appearance to the mucosa.
Gross Findings. Endoscopically, the colonic Microscopic Findings. The hallmark of portal
mucosal changes in patients with portal hy- hypertensive gastropathy is venular ectasia af-
pertension include telangiectasias or angiodys- fecting mucosal capillaries and veins (fig. 6-33).
plasia-like lesions, erythematous patches, and This is accompanied by submucosal venous
varices (262,264,285) . Mucosal vascular changes dilatation. The vascular congestion damages the
occur throughout the entire colon in the setting mucosa, probably in a manner that resembles
of portal hypertension (273). Endoscopic find- the mechanisms seen in stress gastritis . The
ings that suggest va~cular lesions in cirrhotic congested, dilated vasculature predisposes the
patients with dilated vessels on histologic ex- mucosa to localized areas of hypoxia, thereby
amination include patchy erythema, punctate leading to localized erosions and inflammation.
red macules, telangiectasia, and occasionally Occasional cases demonstrate prominent arterial
visible vessels that are bleeding. intimal hyperplasia, diffuse duplication, and fo-
r., .
Microscopic Findings. Mucosal vascular cal fragmentation of the internal elastica. Gastric
dilatation is present in over 70 percent of cases. varices are usually present.
The spectrum of colonic lesions in portal hyper- Differential Diagnosis. The endoscopic di-
tension includes anorectal/colorectal varices, agnosis is usually characteristic and is not easily
angiodysplasia-like lesions, telangiectasias, and confused with gastric antral vascular ectasia
cherry-red spots (254,255,262,271,273,275,288). (GAVE), varices, or angiodysplasia. Pathologi-
Mucosal edema with erythema caused by dilated cally, however, portal hypertensive gastropathy
capillaries can also be present (287). In addition, may show features that overlap with those of

240
Acquired Structural Alterations

Figure 6-33
PORTAL HYPERTENSIVE GASTROPATHY
A: The mucosal venules are markedly dilated. The surrounding mucosa appears regenerative and the lamina propria is
infiltrated with chronic inflammatory cells.
B: Regenerative glands and a surface lined by foveolar cells that are mucin depleted . The capillaries are dilated.
C: Similar vascular changes may be found in the submucosa.

GAVE and varices. Portal hypertensive gastro- Patients range in age from 35 to 80 years, with
pathy usually affects the body of stomach, while an average age of 66.5 years (270).
GAVE affects the antrum. Etiology. The etiology of GAVE is unclear.
Treatment and Prognosis. Strategies that Many patients have cirrhosis; some have associ-
reduce the portal venous pressure (propranolol, ated autoimmune connective tissue disorders or
portosystemic shunting) may be necessary to have undergone bone marrow transplantation.
reverse the gastropathy should bleeding become Other factors that are possibly associated with
problematic. . GAVE include vascular disease of the liver, oral
busulfan as part of a conditioning regimen, and
GASTRIC ANTRAL VASCULAR ECTASIA
growth factor use after a transplant. Motility
Definition. Gastric antral vascular ectasia disturbances may also play a role. Some patients
(GAVE) affects the vessels of the antrum (hence have hypergastrinemia.
the name) and produces characteristic endo- Clinical Features. GAVE is an unusual, but
scopic and histologic changes (270,284). Water- important, cause of severe gastrointestinal
melon stomach is another name for this disease. bleeding and iron deficiency anemia.
Demography. GAVE predominantly affects Gross Findings. The distinctive endoscopic
women, with a female to male ratio of 17 to 4. appearance of nearly parallel, intensely red,

241
Gastrointestinal Diseases

Microscopic Findings. The characteristic


findings of GAVE consist of markedly dilated
mucosal capillaries that often contain fibrin
thrombi, with variable e.dema and interstitial
hemorrhage in the surrounding tissue. These
dilated capillaries are surrounded by fibro-
hyalinosis and coexist with fibromuscular
hyperplasia of the lamina propria (figs. 6-35,
6-36) . The fibrohyalinosis that appears as a ho-
mogeneous light pink substance in H&E-stained
sections helps differentiate GAVE from severe
portal hypertensive gastropathy (270,284). The
mucosa also usually shows a coexisting patchy,
mild, chronic inflammatory infiltrate in the
superficial lamina propria of the gastric antrum.
Atrophic gastritis with intestinal metaplasia
may be present. The muscularis mucosae may
appear thickened and hyperplastic. Submucosal
vessels appear dilated and congested but vascu-
lar malformations are absent. The lesions may
be associated with hyperplasia of vasoactive in-
testinal polypeptide- and serotonin-containing
endocrine cells. The serotonin may cause the
vascular dilatation and sclerosis.
Differential Diagnosis. The ~p.doscopic
findings are characteristic. The histologic dif-
ferential diagnosis includes gastric varices and
portal hypertensive gastropathy. These lesions
are compared in Table 6-12.
Treatment and Prognosis. The lesion may
be treated with laser therapy. Antrectomy may
be necessary in nonresponsive cases.
Figure 6-34 MUCOSAL TELANGIECTASIAS
WATERMELON STOMACH Definition. Telangiectasia generally refers to
Top: Endoscopic appearance shows linear mucosal dilation of preexisting vessels, whereas angio-
stripes. (Fig. 2-99 from Emory TS, Carpenter HA, Gostout CJ, matosis refers to new vessel growth.
So bin LH. Atlas of gastrointestinal endoscopy & endoscopic Demography and Etiology. Gastrointestinal
biopsies. Washington DC: Armed Forces Institute of Path- telangiectasias occur as isolated lesions within
ology; 2009:117.)
Bottom: At autopsy, lin'ear stripes are seen in the mucosa. the gastrointestinal tract where they occur
concomitantly with telangiectasias elsewhere,
especially in the skin. They may be spontane-
ously acquired or hereditary. The cause of tel-
angiectasia is unknown, however, there is an
'"·' longitudinal stripes situated at the crests of association with hemodialysis. Telangiectasias
hyperplastic mucosal folds and traversing the may also be the result of systemic or cutane-
gastric antrum promptedJabbari et al. (270) to ous diseases, including scleroderma, systemic
coin the phrase "watermelon stomach." These lupus erythematosus, syphilis, or cirrhosis.
stripes correspond to markedly dilated, tortuous Essential or idiopathic telangiectasias result
mucosal capillaries (fig. 6-34). Ultrasonography from progressive dilatation of blood vessels
may show hyperechoic focal thickening of the independent of preceding or coexistent skin
inner layers of the gastric wall. lesions in systemic disease.

242
Acquired Structural Alterations

Figure 6-35
GASTRIC ANTRAL VASCULAR ECTASIA
A: Antral mucosa with numerous dilated mucosal vessels.
B: Fibrin thrombi are in many of these vessels.
C: A partially thrombosed mucosal venule .

., ;.?;::·~..

Figure 6-36
GASTRIC ANTRAL VASCULAR ECTASIA
Left: Dilated vessels without thrombi and little surrounding gastritis.
Right: The vessels are more dilated. (Specimens in these two figures came from two different patients with characteristic
endoscopic features.)

243
Gastrointestinal Diseases

Table 6-12
COMPARISON OF PORTAL GASTROPATHY AND GASTRIC ANTRAL VASCULAR ECTASIA (GAVE)
Feabue Portal Gastropatby GAVE

Location Fundus and corpus Antrum


Degree of ectasia Mild ectasia Marked ectasia
Presence of cirrhosis Always 30% of patients
Presence of fibrohyalinosis No Yes
Presence of thrombosis No Yes
Vascular spindle cell proliferation No Yes
Anemia and hemorrhage Low incidence High incidence
Endoscopic lesions Diffuse erythema Appear as microvessels with antral stripes
Liver disease severity More severe Less severe
Sex More common in men Predominantly in women

Clinical Features. Generalized telangiecta- have telangiectasias involving many organs,


sias are characterized by widespread cutaneous including the skin and gastrointestinal tract.
distribution; progression or permanence of the Gross Findings. The telangiectatic areas ap-
lesions; accentuation by dependent position- pear as small, flattened and reddish lesions with
ing; absence of coexisting epidermal or dermal fern-like margins. The lesions can be detected
changes such as atrophy, purpura, and depig- endoscopically or angiographically.
mentation; and follicular involvement. Sponta- Microscopic Findings. Histologi~ally, tel-
neous bleeding does not occur but disease pro- angiectasias consist of dilated, thin-walled,
gression is common. Gastrointestinal mucosal distended vascular channels in the mucosa and
aspects of hereditary hemorrhagic telangiectasia submucosa.
include millet seed- to pinhead-sized bright red Treatment and Prognosis. Endoscopic abla-
spots in the mucosa that are circular and slightly tion of symptomatic lesions remains the treat-
raised (281). Patients with hereditary syndromes ment of choice.

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253
'-,·
ISCHEMIA AND OTHER
VASCULAR DISORDERS

GASTROINTESTINAL ISCHEMIA leading to mechanical obstruction of the blood


Ischemia is a generic term encompassing a flow, such as torsion, prolapse, herniation, or
number of conditions that lead to a decrease in intussusception, make up a large part of the
blood flow and oxygen supply to the intestinal ischemic lesions seen by pathologists.
wall, with or without an increase in oxygen Ischemia developing in a younger person
demand. Gastrointestinal ischemia includes a who has no apparent predisposing factors, such
broad spectrum of conditions, which differ in as cardiac failure, cardiac arrhythmia, or the use
onset, duration, cause of injury, and type of of drugs known to cause ischemia, should be
vessels involved. In the last 20 years, our un- investigated for an underlying primary vascular
derstanding of the etiology and pathogenesis of disorder. Gastrointestinal complaints are seen
ischemic conditions has evolved significantly. in 25 to 79 percent of patients with polyarteri-
Like many other gastrointestinal disorders, tis nodosa (1,3). Gastrointestinal involvement
ischemia is a diagnosis made after appropriate is seen in up to 75 percent of children with
correlation of clinical, radiologic, and histologic Henoch-Schonlein purpura (4); abdominal
findings . The pathologist should make an at- symptoms precede the typical purpuric rash of
tempt to identify the etiology of the ischemic this disease in 14 to 36 percent of cases.
injury since therapy is based on correction of Unusual causes of ischemia include hyperco-
its underlying cause. agulable states, infection, and vascular condi-
tions limited to the gastrointestinal tract. These
Demography
make up a small, probably underestimated,
The incidence of ischemic injury to the small component of gastrointestinal ischemia.
and large intestines varies depending upon the
Etiology
etiology. Acute mesenteric ischemia accounted
for 0.1 percent of admissions to a large tertiary Intestinal ischemia results from a wide variety
care center (2); chronic ischemia accounts for of causes (Table 7-1). The most common cause of
1/2,000 hospital admissions. acute mesenteric ischemia is a thromboembolic
Intestinal ischemia may affect any part of event superimposed on an atherosclerotic vas-
the gastrointestinal tract of individuals of any cular disorder (6). Atheromatous embolization,
age, including infants. The small intestine is either from migration of intracardiac mural
more prone to ischemic injury than other parts thrombi or following aortic catheterization,
of the gastrointestinal tract. In general, the can result in localized or widespread acute ab-
elderly are more prone to ischemic injury than dominal ischemia.
younger individuals. Small intestinal ischemic Nonocclusive mesenteric ischemia is an un-
necrosis following an acute ischemic event derdiagnosed condition with a relatively poor
predominantly affects elderly individuals with prognosis. It is caused by hypoperfusion of the
underlying cardiovascular diseases. Chronic gut and is precipitated by congestive cardiac
intestinal ischemia (abdominal angina) results failure, cardiac arrhythmia, hypotension, dehy-
from chronic mesenteric vascular insufficiency dration, shock, and large volume shifts. Nonoc-
and severe anoxia, without complete cessation clusive mesenteric ischemia is responsible for
of the blood flow. It tends to affect middle-aged 20 to 30 percent of cases of acute intestinal
or older patients with advanced vasoocclusive ischemia (5).
disease involving the celiac axis and the superior Mesenteric venous thrombosis is an uncom-
mesenteric artery, usually secondary to arterio- mon lesion seen in young patients with hyper-
sclerosis of the mesenteric vessels. Disorders coagulable states or as an idiopathic lesion in

255
Gastrointestinal Diseases

Table 7-1 Table 7-2


CAUSES OF INTESTINAL ISCHEMIA . GASTROINTESTINAL VASCULAR DISORDERS
Acute vascular occlusion Affecting large, medium, and small blood vessels
Thrombosis Takayasu's arteritis
Embolism Giant cell arteritis
Nonocclusive mesenteric ischemia Churg-Strauss syndrome

Atherosclerosis Predominantly affecting large and medium blood vessels


Crohn's disease
Necrotizing enterocolitis
Pig bel Predominantly affecting medium and small blood ves-
Neonatal necrotizing enterocolitis sels
Radiation damage
Vasculitides and vasculopathies (see Table 7-2) Polyarteritis nodosa
Hypercoagulable states Kawasaki's disease
Wegener's granulomatosis
Drug effects (see Table 7-4) Buerger's disease
Vascular compression Vasculitis associated with connective tissue diseases
Volvulus Fungal vasculitis
Intussusception Behcet's syndrome
Celiac axis compression Danlos-Ehlers syndrome
Infections (see Table 7-3) . Predominantly affecting smali blood vessels
Henoch-Schonlein syndrome
Amyloidosis
Hypersensitivity vasculitis
Radiation damage Hypocomplementemic vasculitis
Diabetes mellitus Cytomegalovirus vasculitis
Rickettsial vasculitis
Cryoglobulinemia
Predominantly affecting veins and venules
Table 7-3 Mesenteric inflammatory venoocclusive disease
Mesenteric phlebosclerosis "
INFECTIONS WITH AN ISCHEMIC PATTERN OF INJURY
Clostridium diffzcile
Enterotoxigenic Escherichia coli 0157:H7 Table 7-4
Staphylococcal enterocolitis DRUGS ASSOCIATED WITH INTESTINAL ISCHEMIA
Cytomegalovirus Nonsteroidal antiinflammatory drugs
Aspergillus sp Oral contraceptive pills
Candida sp Cocaine
Antibiotic-associated (pseudomembranous) colitis
Immunosuppressive agents
Potassium salts
older individuals. A number of small and large Digitalis
vessel vasculitides and vasculopathies cause
Alpha-interferon
intestinal ischemia (Table 7-2). Their diagnosis
lnterleukin-2
is based primarily on extraintestinal manifesta-
tions and laboratory evaluation.
A number of infections can cause ischemia
•. or an ischemic pattern of injury (Table 7-3) . membranous colitis) are the four most common
The most commonly involved organisms are causes of drug-induced ischemic injury.
Clostlidium difficile (pseudomembranous colitis), Mechanical obstruction can lead to ischemia
enterotoxigenic Escherichia coli 015 7:H7, and in a number of different conditions (Table 7-5).
cytomegalovirus. Although, a number of drugs Intussusception is the most common mechani-
(Table 7-4) have been associated with intestinal cal cause of vascular occlusion in pediatric pa-
ischemia, nonsteroidal antiinflammatory drugs tients. Adhesions, volvulus, and strangulated
(NSAIDs), cocaine, oral contraceptives, and cer- hernia are frequent causes of mechanical ob-
tain antibiotics (antibiotic-associated pseudo- struction in adults.

256
Ischemia and Other Vascular Disorders

Table 7-5 reduction in blood flow include increased


MECHANICAL CAUSES OF ISCHEMIA
oxygen extraction and oxygen redistribution
within the intestinal wall to those areas with
Adhesions high metabolic demands. If the blood supply
Intussusception is cut off for more than 2 hours, it takes ap-
Volvulus proximately 1 week for the mucosa to recover
Strangulated hernia (9). If reflow is not established, the bowel can
Severe obstruction become totally necrotic.
Cellae axis compression Reversible ischemic damage depends on
several factors: 1) the nature of the intestinal
Congenital bands
vasculature; 2) luminal bacterial vimlence; and
3) the duration of the ischemic episode (9). The
extent and duration of the ischemia determine
the depth of the tissue injury.
Pathophysiology
The first detectable sign of ischemic bowel
All forms of ischemic damage share the under- injury is increased capillary permeability, the
lying feature of a blood supply that fails to meet cause of the associated characteristic submuco-
the local tissue demands required to fulfill nor- sal edema. With prolonged ischemia, mucosal
mal functions and/or maintain normal stmcture. permeability further increases so that morpho-
The pathogenesis of ischemic damage depends logically detectable mucosal epithelial cell injury
on enough blood being supplied to the ischemic occurs. Mucosal cells are shed at an increased
segment to prevent complete death, but insuf- rate, and damage to the plasma membrane of
ficient blood flow to meet the metabolic needs unshed cells results in leakage of cytoplasmic
of the injured bowel. When the blood flow falls enzymes (8). Decreased cellular nucleotide
below a critical level so that oxygen uptake is metabolism, decreased mucus production, and
limited, the tissues become hypoxic. Prolonged anoxic necrobiosis associated with lysosomal
cessation of blood flow to any organ inevitably mpture all damage the mucosa and make it
results in cell death because of the diminished vulnerable to the action of lysosomal and diges-
delivery of oxygen and metabolic substrates and tive enzymes. Arteriolar spasm and decreased
the accumulation of potentially cytotoxic end perfusion pressure accentuate the extent of the
products of anaerobic metabolism. ischemic damage. Necrosis and subsequent bac-
When the blood supply to a tissue is inter- terial invasion develop when the mucosal barrier
mpted, a sequence of chemical events is initi- becomes defective. The initial pathologic result
ated that leads to cellular dysfunction, cellular of ischemia is submucosal edema and mucosal
and interstitial edema, and ultimately, cell coagulative necrosis. If flow is reestablished, an
death. Oxygen, as a basic cell fuel, is cmcial to acute inflammatory reaction develops.
cell function . Aerobic metabolism replenishes Pathophysiology of Ischemic Damage and
the high-energy phosphate bonds required for Reperfusion Injury. When a tissue becomes isch-
normal cell function. A lack of oxygen results emic, a sequence of chemical reactions is initi-
in anaerobic metabolism and an increased lo- ated that ultimately leads to cellular dysfunction
cal concentration of lactic acid. The resulting and necrosis. No single process represents the
acidosis alters normal enzyme kinetics. Fewer critical event in ischemia-induced tissue injury.
high-energy bonds are created, and the cell Depletion of cellular energy stores and accu-
is deprived of the energy needed to maintain mulation of toxic metabolites contribute to cell
homeostasis (10) . Different tissues and different death. Reestablishing blood flow (reperfusion) is
areas within the same tissue withstand hypoxia required to reverse the ischemic injury, since it
for different time periods. allows cellular regeneration and washout of toxic
The small intestinal blood supply must be metabolites. Thus, reperfusion is a prerequisite
reduced by more than SO percent to induce de- for recovery from ischemic injury.
tectable tissue injury (7). Adaptive mechanisms Reperfusion of ischemic tissues, however, also
that prevent injury with less than a SO percent leads to a sequence of events that paradoxically

257
Gastrointestinal Diseases

injures the tissues (11-13,15). In fact, most of Table 7-6


the injury that occurs in the ischemic gastroin- OXYGEN-DERIVED FREE RADICALS
testinal tract occurs during the period of reperfu-
Superoxide (0 2- )
sion, in a process known as reperfusion injury.
The severity of reperfusion injury depends on Inactivates specific enzymes
the duration of the preceding hypoxia. The Is the precursor to hydrogen peroxide (H 2 0 2)
reperfusion component of ischemic injury is Is a highly reactive hydroxyl radical
more pronounced after partial than total intes- Hydrogen peroxide (Hp 2 )
tinal ischemia (14). Reperfusion of the ischemic Is a powerful oxidant
intestine results in the production of reactive Inactivates DNA
oxygen metabolites and activated neutrophils.
Hydroxyl radicals (OH)
Role of Oxygen Free Radicals. A free radical
is defined as any molecule that possesses one or Form via Fenton reaction
more unpaired electrons in its outermost shell Most reactive of the free radicals
(27). Oxygen-derived free radicals (Table 7-6) Cause lipid peroxidation
are generated within the first 2 to 3 minutes of Inactivate enzymes
reperfusion or reoxygenation (27,29,32,36-38, Inhibit cell transport
42). Because of their ability to participate in reac- Perhydroxyl radicals
tions involving the transfer of single electrons,
Stronger oxidant than superoxide
most free radicals are highly reactive molecules,
Are cytotoxic
capable of inducing considerable clamage (28).
Oxygen radicals are capable of damaging almost Inactivate proteins
any molecule found in living cells, including Singlet oxygen
proteins, carbohydrates, DNA, and unsaturated Inactivates proteins
lipids within the cellular and mitochondrial Initiates Upid peroxidation
membranes (38) . The most damaging effect of Hypochlorite (HOC!)
free radicals is lipid peroxidation, which results
Damages cell membranes
in structural and functional cell damage (30).
Plasma membrane changes · result from
ischemic injury and lead to a loss of sodium
and calcium ion balance, follo"?Ved by acido-
sis, osmotic shock, chromatin clumping, and result is increased microvascular permeability
nuclear pyknosis (35). Sodium ions move into and mucosal damage.
the cell, drawing with them a volume of wa- Under physiologic conditions, small amounts
ter to maintain osmotic equilibrium with the of free radicals are produced in almost all aerobic
surrounding interstitial space. Potassium ions cells, but under normal conditions, the reactive
escape from the cell into the interstitium (20). oxidative molecules are effectively neutral-
These changes are accompanied by activation ized by endogenous free radical scavengers
of mitochondrial pho.spholipases, a precipitous such as superoxide dismutase and glutathione
loss of oxidative phosphorylation, and a drop peroxidase (28). After ischemia, however, the
in adenosine triphosphate (ATP) production sudden reintroduction of oxygen into the tis-
leading to a failure of synthetic and homeo- sues causes the unleashing of free radical cas-
static capabilities. Calcium overload leads to cades, which overwhelm endogenous defense
' ·· mitochondrial membrane dysfunction and mechanisms. Most oxygen radicals generated
irreversible damage (21). Secondary autolysis, in the reperfused intestine are derived from the
with swelling of lysosomes, dilatation, vesicu- hypoxanthine-xanthine oxidase system (23,41).
lation of the endoplasmic reticulum, leakage Xanthine oxidase is produced by enterocytes
of enzymes and proteins, and loss of cellular and endothelial cells (22).
compartmentalization follow. As a result of Neutrophils also represent a major source of
these factors, membrane integrity cannot be reactive oxygen metabolites (ROMs), including
maintained, and the cell dies (29). The end superoxide (0 2 -), hydrogen peroxide (Hp 2),

258
Ischemia and Other Vascular Disorders

hydroxyl (OH), hypochlorite (HOCl), and cer- Hypoxia induces endothelial cells to pro-
tain n-chloramines. Superoxide and hydrogen duce various adhesion molecules including: 1)
peroxide increase mucosal and vascular perme- integrins, 2) members of the immunoglobulin
ability, recruit and activate neutrophils, and act superfamily, and 3) selectins (45). These power-
as the precursors of more damaging hydroxyl ful chemoattractants and chemoactivators act
radicals via the Fenton and myeloperoxidase in concert to attract leukocytes and platelets
reactions (18,24,33,40). Transition metals, such to reperfused sites and to promote their adher-
as iron, play important roles in free radical reac- ence, transendothelial migration, and activation
tions, particularly in the formation of the ex- (51,52). As a result, a massive mucosal influx of
tremely reactive hydroxyl radical via the Fenton neutrophils occurs (44). Adhesion molecules
reaction. Hypochlorite acts as a potent oxidant slow the motion of leukocytes in the microvas-
that directly damages membrane-associated culature, causing them to roll in the vessels. This
targets or indirectly damages them by forming rolling behavior allows other adhesive mecha-
less reactive chloramines that diffuse across the nisms to operate. As a result, the slowly rolling
membrane and attack cytoplasmic components neutrophil firmly adheres to the endothelium
(18,24,39). Luminal aggressive factors (such as via the CD11/CD18 adherence glycoprotein
pancreatic proteases, especially trypsin) further complex (48). As the neutrophil becomes ac-
contribute to the mucosal damage (26) and po- tivated, CD11/CD18 expression increases and
tentiate bacterial translocation and sepsis. This L-selectin is shed from the neutrophil mem-
proteolytic activity may be especially important brane (49). Activated neutrophils adhere to and
in the rapid conversion of xanthine dehydroge- migrate across the endothelium and cause local
nase to xanthine oxidase (19). destruction by releasing free radicals, proteolytic
Nitric oxide (NO) is as an important intra- enzymes (collagenase, elastase, and cathepsins),
cellular messenger molecule that modulates peroxide, cytokines (46,53), platelet activating
immune function, blood vessel dilatation, and factor, and the eicosanoids, leukotriene B4 and
neural transmission (34). NO is generated by thromboxane B2 (50) . Intravascular adherence
the NO synthetase (NOS) present in macro- of red blood cells may plug the microvascula-
phages, granulocytes, neurons, endothelial cells, ture, particularly capillaries and venules, further
epithelial cells, and smooth muscle cells (17). contributing to the tissue hypoxia. Neutrophils
ROMs produced by activated macrophages and attract other neutrophils and platelets by releas-
neutrophils react with NO to form the cytotoxic ing chemotactic humoral mediators, such as
metabolite, peroxynitrate (OONO-) (16). NOS leukotriene B4, thromboxane A2, and platelet-
inhibitors provide nearly complete protection activating factor (54).
against reperfusion injury (31). Role of Platelets. Endothelial cells synthesize
The intestinal interstitium, which is continu- tissue plasminogen activator, which catalyzes
ously bathed in extracellular fluid, also provides the formation of plasmin, a protease that has
some interstitial and epithelial protection, since both aggregatory and inhibitory effects on plate-
it contains significant amounts of antioxidants, lets. Platelets attach to damaged endothelium
such as glutathione (25). The sustained produc- via specific receptors, and release a plasminogen
tion of neutrophil-derived oxidants by large activator inhibitor that neutralizes endotheli-
numbers of extravasated cells, however, over- um-associated plasminogen activator. Platelets
whelms this protective milieu and in the process also attach to stimulated neutrophils and mono-
alters normal intestinal structure and function. cytes, and bind to vascular walls by adhering to
Role of Neutrophils. Neutrophil-endothelial leukocytes already bound to the endothelium.
cell interactions are a prerequisite for the mi- Products released from aggregating platelets
crovascular injury induced by ischemia and re- enhance the expression of adhesive proteins by
perfusion (43,47). Following reperfusion, there the endothelium. Platelet activation enhances
is a significant increase in leukocytes. Far fewer endothelial production of endothelin 1, an
leukocytes adhere to the villous microvascula- extremely potent vasoconstrictor, and causes
ture than to that of the deeper mucosa, serosa, the formation and release of platelet activating
or mesentery. factor, a lipid inflammatory mediator. Platelet

259
, Gastrointestinal Diseases

activating factor induces platelet aggregation, Table 7-7


adhesion to endothelial cells, and release of ELEMENTS OF THE
vasoconstrictive substances. GASTROINTESTINAL MUCOSAL BARRIER
Role of Prostaglandins. The eicosanoids,
Luminal/Epithelial Function
a group of phospholipid mediators, are inti-
mately involved in ischemic injury. They also Epithelium Innate immune response
Antigen presentation
play a major role in the pathophysiology of Block penetration of ingested
the shock-like states associated with sepsis and/ antigen
or endotoxemia. Of particular interest is the Defensins Antimicrobial peptides
relationship that exists between prostacyclin Trefoil factors Protection from bacterial toxins,
(PGI2), responsible for vasodilatation and plate- chemicals, and drugs
let disaggregation from vascular endothelia, Mucus/mucin Entrap microbes
and thromboxane (TxA2), responsible for vaso- Block penetration of ingested
constriction and platelet aggregation. Platelets antigens
contain the enzyme thromboxane synthetase, Proteolytic enzymes Breakdown of ingested antigens
and hence synthesize TxA2. TxA2 production Secretory IgA Block adhesion of antigen to
increases as the platelets traverse ves.sels with epithelial surface
irregular endothelial surfaces (such as in arterio- Bile acids Breakdown of ingested antigens
losclerosis). The increased thromboxane levels Intestinal peristalsis Expel microbes
lead to vasospasm and thrombosis, thereby Block penetration of ingested
producing ischemia and infarctiol>l. On the antigens
other hand, normal vascular endothBlium lacks Indigenous microflora Competition for essential nutri-
thromboxane synthetase, but possesses pro- ents, secretion of antibiotic-
like substances, chemical
stacyclin synthetase, which leads to formation modification of fat and bile
of PGI2 and its stable end product PGFl-alpha. acids, stimulation of pJ=ristalsis
PGIZ is a vasodilator and potent inhibitor of Gut-associated lymphoid tissue (GALT)
platelet aggregation, and allows platelets to flow
IgA, IgG, lgM Systemic immunity
freely through the vessels.
Lymphoid follicles in Antigen clearance .
Another group of eicosanoids. produced lamina propria
through the lipoxygenase pathway are the leu-
Intraepithelial Innate and acquired immune
kotrienes. Leukotrienes C4, D4, atfd E4 cause lymphocytes response
vasoconstriction. Leukotriene B4 stimulates
aggregation and adhesion of leukocytes to the
vascular endothelium.
The most recently described group of eico- produce functional molecules such as defensins
sanoids is the lipoxins. Lipoxins A4 and B4 are (56), trefoil factors (58), and mucin, which
produced by the interaction between platelets protect the human host. Microbes of all types
and neutrophils. Lipoxins may represent nega- are trapped in the mucus layer and are expelled
tive regulators of leuko,triene action. They in- from the intestine by peristalsis. In addition,
hibit neutrophil chemotaxis and adhesion, and proteolytic enzymes facilitate the digestion of
cause vasodilatation. the harmful polypeptides and diminish their
Loss of Mucosal Barrier Function. The ele- immunogenic properties (60). These cells also
ments of the gastrointestinal mucosal barrier are express major histocompatability (MHC) class 11
r.,.
shown in Table 7-7 (55). Mucosal epithelial cells receptors which facilitate antigen presentation
function as a semipermeable barrier between to immune cells as needed.
the lumen and the intestinal wall. Typical in- Ischemic damage leading to leakiness in
testinal epithelial cells have microvilli on their the mucosal and microvascular barriers allows
apical surfaces, with a filamentous brush bor- the toxic metabolites that are generated dur-
der glycocalyx at the tip (59). These structures ing ischemia-reperfusion injury to gain access
help prevent foreign antigen penetration into to the systemic circulation. Mucosal damage
the underlying tissues. The epithelial cells also also allows luminal contents, such as bacteria,

260
Ischemia and Other Vascular Disorders

toxins, and proteolytic enzymes, to circulate elusion usually progresses slowly enough for
as well. These factors may contribute to both a collateral circulation to develop. Therefore,
sepsis and multiple organ failure following an intestinal infarction secondary to the atheroma-
episode of shock (57). tous occlusion of a single vessel is rare (approxi-
mately 50 percent of patients over the age of
Acute Mesenteric Ischemia
50 have atheromatous narrowing or occlusion
Definition. Acute mesenteric ischemia is a sud- of the celiac axis). Thrombi over atheromatous
den reduction of intestinal oxygen supply due plaques frequently occupy the proximal few
to alterations in mesenteric arterial or venous centimeters of the affected artery (66,7 4).
circulation. Acute intestinal ischemia is an alter- Embolic occlusion accounts for one third to
native term. half of cases of mesenteric vascular occlusion
Demography. The prevalence of mesenteric (95,104). Massive, acute, and often fatal embo-
vein thrombosis ranges from 0.003 percent in lism usually results from the migration of an
general hospital populations to 0.05 percent intracardiac mural thrombus complicating heart
of autopsied patients (107). Venous thrombo- disease. Cholesterol emboli migrate from aortic
sis accounts for 5 to 15 percent of all cases of plaques, especially following catheterization,
mesenteric ischemia and infarction (109). Isch- resulting in localized or widespread intraab-
emia can affect any age group; however, acute dominal ischemia. Valvular endocarditis may
mesenteric ischemia, particularly secondary shed small mycotic emboli.
to mesenteric arterial thrombosis and nonoc- Superior mesenteric artery emboli typically
clusive mesenteric ischemia, are more common lodge at bifurcation points or distal to the origin
in middle-aged to elderly persons. of a major branch point. An embolus present in
Etiology and Pathophysiology. Acute the superior mesenteric artery proximal to the
mesenteric ischemia generally stems from the origin of the ileocolic artery is called a major
interruption of blood flow within the superior embolus (73). An embolus present distally in the
mesenteric artery or vein. Acute intestinal isch- superior mesenteric artery or.one of its branches
emia is a gastrointestinal emergency that may is called a minor embolus. These differences
occur as a consequence of mesenteric arterial in location frequently dictate the therapeutic
occlusion, nonocclusive low flow states, mesen- approach (67). Multiple emboli are present in
teric vein thrombosis, or arteritis. Thrombosis approximately 20 percent of cases (75). The gen-
and embolization of the mesenteric artery are eralized mesenteric vasoconstriction that follows
the main causes (95) and occur with equal fre- embolism causes additional ischemic damage.
quency; nonocclusive mesenteric ischemia is Occlusions also result from aortic aneurysms,
the third most common cause, the incidence aortic dissections, vasculitis, and tumors that
of which has declined in the last two decades. externally compress vessels.
Acute colonic ischemia is often a reversible Ischemia in Low-Flow States (Nonocclusive Isch-
condition caused by a mismatch between blood emia). Low-flow states occur when the mesen-
flow and metabolic requirements in elderly teric arteries and veins are patent, but the blood
individuals. Common predisposing conditions flow through them is too slow to deliver enough
include atherosclerotic arterial diseases, hypo- oxygenated blood for the metabolic needs of
tension, chronic renal failure, and medications. the intestine. Such states usually result from
Conditions associated with acute ischemia are decreased cardiac output following primary
described in detail below. cardiac disease (infarction or arrhythmia), hy-
Arterial Occlusive Disease. Arterial occlusive dis- povolemia, shock, mesenteric arterial-to-arterial
ease occurs secondary to thrombosis, embolism, and arterial-to-venous shunting, and a combi-
or hemorrhage underlying an atheromatous nation of low mesenteric flow and mesenteric
plaque. The occlusion may involve one or all of arterial sclerosis and vasoconstriction (108).
the three intestinal arterial trees: the celiac axis, Even though the blood supply to the superficial
the superior mesenteric artery, and the inferior part of the mucosa is fairly well maintained dur-
mesenteric artery. The superior mesenteric artery ing shock, hypoxic injury still develops within
is most frequently affected. Atheromatous oc- 1 to 2 hours. Several pathogenic mechanisms

261
Gastrointestinal Diseases

account for the ischemic necrosis: 1) vasocon- Table 7-8


striction with increased resistance to blood FACTORS PREDISPOSING TO
flow; 2) redistribution of blood flow away from MESENTERIC VENOUS THROMBOSIS
the mucosa; 3) increased capillary filtration via Hypercoagulable states
relaxation of the precapillary sphincter smooth Oral contraceptives
muscle fibers; and 4) intestinal countercurrent Liver disease
mechanisms in the villi that shunt oxygen away Inflammatory bowel disease
Renal disease
from the villus tips (89) . Factor V Leiden mutation
During shock, blood flow velocity signifi- Protein C deficiency
cantly slows (90), requiring an effective short- Protein S deficiency
circuiting mechanism for oxygen at the base of Antithrombin Ill deficiency
the villi. Some oxygen short-circuiting also oc- Plasminogen deficiency
Heparin cofactor Il deficiency
curs in the villus countercurrent exchanger when Lupus anticoagulant
the villus exhibits a very low resting P0 2 (78). As Polycythemia vera
a result, regional hypoxia develops at the villous Estrogen therapy
Cryoglobulinemia
tips, even though the overall oxygen extraction Defective generation of plasminogen activator
efficiency remains high. This explains why the Hyperviscosity syndrome
villous tips become anoxic first, and why early Sickle cell anemia
and minimal injury always occurs first at the Thrombocytopenia
Thrombocytosis
villous tip. When sepsis complicates the shock, Paraneoplastic states (especially pancreatic cancer)
the splanchnic organs require increased oxygen
Vascular injury following surgery or trauma
(63,80). This further enhances the hypoxic in-
jury, leading to increased mucosal necrosis and Inflammatory conditions
Pancreatitis
bacterial penetration through the iQ.testinal Diverticulitis
mucosa, further increasing the level of sepsis. Appendicitis
Nonocclusive intestinal ischemia also Peritonitis
complicates hemodialysis and abnormalities Cholangitis
Inflammatory bowel disease
in acid-base balance. The latter reduces flow Pelvic or intraabdominal abscess
through the patent, but acutely . contracted, Phlebitis
arteries (103) . Drugs such as diuretics, digoxin,
Abnormal blood flow
anesthetics, alpha-adrenergic vas6constrictors,
and amphetamines (89) further reduce the cir- Postoperative dehydration
culating blood volume by causing splanchnic Sepsis
vasoconstriction. Digitalis acts at the level of Cirrhosis
arteriolar smooth muscle where it increases Blunt abdominal trauma
resistance to blood flow, resulting in hypoxia. Prior splenectomy
Mesenteric Venous Thrombosis. Mesenteric Disseminated intravascular coagulation
venous thrombosis is a relatively rare disease,
Parasitic infestations
primarily affecting per~ons in their 6th and 7th Schistosomiasis
decades of life (61). Conditions predisposing to Ancylostoma ceylanicum
mesenteric venous thrombosis are listed in Table Ascaris
7-8. When mesenteric venous thrombosis occurs Carcinoma
in younger persons, an underlying predisposing Pancreatic cancer
Carcinoma metastatic to the pancreas
"·· condition should be sought (75,77-79, 81,83,87 Carcinomatosis
,88,91,93,94,98,99, 101). There is no identifiable
Vascular compression by tumors or inflammatory processes
predisposing cause in 25 to 50 percent of cases.
Multiple etiologic factors may exist in any Impaired venous drainage
Volvulus
one patient. For example, a patient requiring Internal and external hernias
splenectomy may have a preexisting abnor- Portal hypertension
mality involving the coagulation system, may
Postrenal transplant
experience intraoperative trauma to regional

262
Ischemia and Other Vascular Disorders

veins, and may develop a transient thrombo- of the bowel wall, and "thumb printing" of the
cytosis caused by the splenectomy (98). bowel wall develop. Any radiologic abnormality
Approximately 95 percent of all mesenteric on plain X ray portends a poor outcome (7 4).
· thromboses involve the superior mesenteric Duplex Ultrasonography. Duplex ultrasonogra-
vein and lead to ischemia or infarction of the phy is useful to assess blood flow in the superior
small bowel or proximal colon (83). In the mesenteric artery and the portal vein. It can
remainder of cases, the inferior mesenteric detect occlusion and thrombosis of these vessels
vein is involved, with the principal changes (96) . It can only consistently evaluate proximal
affecting the distal colon. In a small number of portions of the major vessels (85); the peripheral
cases, thrombosis develops over an extended branches cannot be visualized (71). Patients
time period, permitting the development of with nonocclusive mesenteric ischemia may
collateral venous drainage from the involved have normal duplex ultrasonography results
intestinal segments. Thrombosis following hy- despite vasoconstriction.
percoagulable states originates in the smaller Computerized Tomography. CT scan may be
venous branches and progresses into the major helpful in diagnosing acute mesenteric isch-
trunks (7 4). Thrombosis secondary to cirrhosis, emia. Unfortunately, however, as with other ra-
neoplasia, or operative injury begins at the site diologic methods, the early signs on CT scan are
of obstruction and extends peripherally. relatively nonspecific (65). Early signs of acute
Regardless of the cause of the mesenteric ve- mesenteric ischemia include bowel wall thick-
nous thrombosis, egress of blood from the intes- ening and luminal dilatation. Highly suggestive
tine becomes impaired, causing the mesenteric late signs include pneumatosis and mesenteric
arterial pressure to rise and arterial blood flow to or portal venous gas, both of which indicate the
slow. This leads to the development of ischemia. presence of necrotic bowel (86,106) . Contrast-
Mechanical Obstruction of Venous Return. Me- enhanced CT scanning is the procedure of
chanical obstruction of venous return is caused choice to diagnose acute mesenteric venous
by a number of conditions (see Table 7-5). thrombosis (68,78,100). Lack of opacification, a
These mechanical alterations are discussed in centrallucency in the lumen, and dilated collat-
chapter 6. erals in the mesentery are diagnostic. Magnetic
Clinical Features. The clinical features of resonance angiography is also being utilized as
intestinal ischemia are frequently nonspecific a noninvasive diagnostic test.
in the early stages and require a high degree of Mesenteric Angiography. Direct imaging of the
suspicion to allow for early intervention and a splanchnic vasculature by mesenteric angiog-
favorable prognosis (7 4). Abdominal pain is the raphy is the mainstay of diagnosis in occlusive
usual presenting complaint (102). In later stages, and nonocclusive forms of mesenteric ischemia
patients develop features of paralytic ileus with (64,69,70,72). It has a high sensitivity (74 to
vomiting, abdominal distension, hypotension, 100 percent), and specificity (100 percent) with
and septicemia. minimal complications (74). Aortography is
Most of the abnormal laboratory findings are the best imaging technique to detect superior
associated with late-stage disease. These include mesenteric artery thrombosis. Emboli are de-
leukocytosis, metabolic acidosis, and elevation tected by the presence of one or more filling
of serum amylase, serum D-lactate, and serum defects, with partial or complete obstruction.
D-dimer (62,90,97). Angiography is the only means available to
Radiologic Findings. Imaging studies, par- diagnose nonocclusive ischemia. Nonocclusive
ticularly computerized tomography (CT) scans mesenteric ischemia shows the following diag-
with contrast enhancement, duplex ultrasonog- nostic features on angiogram: 1) narrowing and
raphy, magnetic resonance imaging (MRI), and irregularity of the superior mesenteric artery
mesenteric angiography, can pinpoint a specific branches; 2) spasm of the mesenteric arcades;
etiology in some cases. and 3) impaired filling of the intramural vessels
Plain X Ray. Abdominal plain films are usually (64,103). Angiography also helps to rule out oc-
normal in early ischemia (105). As the ischemia clusive causes of ischemia. In a small number
progresses, formless loops of bowel, thickening of patients with mesenteric venous thrombosis,

263
Gastrointestinal Diseases

angiography is required to delineate the throm- collateral circulation, which provides sufficient
bosed vein. blood to prevent symptomatic ischemic dam-
Treatment and Prognosis. Urgent lapa- age (112).
rotomy is appropriate when acute mesenteric Clinical Features. Since the gastrointestinal
vascular occlusion is suspected in a patient with tract requires a greater blood flow during the
shock. Time-consuming . radiologic workup in postprandial period (from 20 percent when fast-
such patients may lead to a delay in instituting ing to 35 percent postprandial) (112), patients
therapy in an urgent situation. characteristically complain of postprandial pain.
In other patients with arterial or venous They may also experience weight loss. Extensive
thrombosis, infusion of vasodilators or throm- workup to rule out gastric, pancreatic, biliary, or
bolytic agents may be used as treatment at the colonic pathology is negative. The radiographic
time of diagnostic study. Colonic ischemia in- techniques discussed below help establish the
volving the watershed area in the region of the diagnosis. Early diagnosis and treatment are
splenic flexure is invariably due to nonocclusive imperative to prevent intestinal infarction.
ischemia, and can be managed in most patients Endoscopic Findings. Endoscopy is helpful
without recourse to invasive radiology or surgery. in evaluating colonic ischemia. Ischemia af-
A number of growth factors like erythropoi- fects the colon more commonly at the splenic
etin, epidermal growth factor, and hepatocyte flexure and rectosigmoid due to poor collateral
growth factor are being evaluated as potential circulation in these areas. Characteristically, the
agents that may protect the intestinal mu- ischemia gives rise to segmental abnormalities
cosal epithelium against ischen'Iic damage including erythema, edema, and ulceration.
(66,74,104). For most, however, an unequivocal diagnosis
Patients with acute mesenteric ischemia have of ischemia cannot be made without a biopsy
a mortality rate of 60 to 100 percent (72,92). unless mucosal gangrene is present. The endo-
Those with colonic ischemia have a lower mor- scopic features and distribution of the changes
tality rate than those with acute mesenteric isch- may be similar to those resulting from toxigenic
emia. However, patients with gangrenous colonic Escherichia coli infection, NSAID-induced injury,
ischemia who require surgical resection, incur a tuberculosis, or Crohn's disease.
greater than 50 percent mortality rate (80). Gross Findings. Gross examination of in-
testinal resection specimens should not only
Chronic Mesenteric Ischemia
include evaluating the features of ischemia, but
Definition. Chronic mesenteric ischemia is a determining the extent of ischemic damage, the
gradually developing ischemic condition that viability of the margins, and the etiology of the
occurs most frequently in older females (112) . ischemia. Examination of the fresh specimen
It is also known as abdominal angina. helps identify the features of ischemia more eas-
Etiology. Chronic intestinal ischemia results ily than examination of a fixed specimen. Fea-
from chronic mesenteric vascular insufficiency tures of intestinal damage due to ischemia are
and severe anoxia, without complete cessation similar, no matter what the underlying cause is.
of blood flow. It tends to affect patients with Early on, the ischemic bowel appears edema-
advanced vasa-occlusive disease involving the tous and pale with submucosal edema, conges-
celiac axis and the superior mesenteric artery. tion, hemorrhage, and focal mucosal sloughing.
The occlusion is usually secondary to severe The muscularis propria usually appears normal
occlusive arteriosclerosis of the mesenteric in early lesions. As the disease progresses, the
1., •

vessels (111), but it may also complicate aortic serosa becomes dusky and dark red due to the
aneurysms. Chronic mesenteric ischemia is also accumulation of large amounts of intraluminal
caused by celiac artery compression syndrome, blood (fig. 7-1). The serosa loses its glistening ap-
in which the celiac artery is compressed by the pearance and appears dull. The mucosa becomes
median arcuate ligament or by a neoplasm. necrotic and ulcerated. The ulcers are discrete
Pathophysiology. Slowly growing athero- and can be serpiginous. Pseudomembranes may
sclerotic obstruction is usually the source of be present (fig. 7-2). In the advanced stage,
the ischemia. Most patients develop adequate transmural necrosis develops (fig. 7-3). The

264
Ischemia and Other Vascular Disorders

Figure 7-1
COLONIC ISCHEMIA
Left: The serosal surface of this cecectomy specimen appears dusky blue-brown.
Right: Another colon resection specimen shows patchy green-brown serosal discoloration. Green-yellow, fibrinopurulent
material adheres to the serosal surface in these areas.

Figure 7-2 Figure 7-3


COLONIC ISCHEMIA ADVANCED SMALL INTESTINAL ISCHEMIC INJURY
An opened colectomy specimen shows patchy erythema The ischemic intestine on the left is blue-black, while the
and adherent pseudomembranes. adjacent intestine on the right appears relatively unaffected.
Ischemic injury is often geographic, as depicted here,
depending on which portion of the blood supply is affected.
bowel wall becomes thin and friable and the
serosa becomes purplish green. Pneumatosis
intestinalis (gas within the bowel wall) develops Gross examination is as important as micro-
and a perforation may be present at this stage. scopic examination in deciding the underlying
Chronic or recurrent bouts of ischemia lead to etiology of the intestinal ischemia. Volvulus,
fibrosis and strictures (fig. 7-4). intussusception, and strangulated hernia are
The site and degree of ischemia vary depend- diagnosed either preoperatively or intraopera-
ing upon the size of the vessel involved. In most tively. Sometimes, an unreduced intussuscep-
cases of acute mesenteric ischemia, the superior tion is received in surgical pathology and gross
mesenteric artery or its branches are involved. examination helps to identify not only the
A classification (Table 7-9) based on the site of intussusception, but its components as well.
involvement of the superior mesenteric artery Mesenteric vessels should be examined
may be clinically useful (110). for the presence of possible thrombi, emboli,

265
Gastrointestinal Diseases

Table 7-9
FULLEN'S ANATOMIC CLASSIFICATION OF SUPERIOR MESENTERIC ARTERY INJURY
Ischemia
Zone Injured Ses:!!!ent Grade Class Bowel Affected
Trunk proximal to first major branch 1 Maximal Jejunum, ileum, right colon
Il Trunk between inferior pancreaticoduoden al 2 Moderat e Major segment, small bowel, right colon
and middle colic segments
Ill Trunk distal to middle colic segment 3 Minimal Minor segment of small bowel or right colon
IV Segmental branches 4 None No isch emic bowel

and may be deeply penetrating. The mucosa


in patients with Henoch-Schbnlein purpura ex-
hibits small, superficial petechial hemorrhages
and erosions associated with edema, hemor-
rhage, and congestion. Patients with Behcet's
syndrome preferentially develop ulcers in the
terminal ileum and cecum.
Microscopic Find ings . Biopsy Specimens.
Pathologists rarely encounter a small intestinal
biopsy for interpretation of ischemic changes.
More commonly, a diagnosis of ischemia is
made in colonic biopsies.
In the acute stage, early lesions are limited to
separation and loss of the surface epithelium.
The epithelial damage then progresses toward
the crypt bases. The lamina propria becomes
edematous and hemorrhagic, and contains di-
lated vessels (fig. 7-S) . Crypt dropout, mucosal
necrosis, and ulceration develop in the next
Figure 7-4
stage (fig. 7-6). The lamina propria shows fibrin
CHRONI C ISCHEMIC INJURY deposition in vessels or in the extravascular con-
Small intestinal resection specimen shows several areas nective tissue. In severe cases, the crypts dilate
of luminal n arrowing secondary to previous episodes of and become lined by an attenuated epithelium
ischemia .
(fig. 7-7) . Cryptitis and acute inflammation in
the lamina propria are present as reperfusion is
atherosclerosis, and nodularity. In addition, the established (fig. 7-8) . The crypts fill with mucus
mesenteric vessels should always be histologi- and inflammatory debris, eventually leading to
cally sampled to document their status. In some pseudomembrane formation (fig. 7-8). These
cases, a proximally located mesenteric artery changes are often patchy in distribution.
thrombosis is not present in the surgical pathol- After the initial ischemic event, fibrin and
ogy specimen. Mesenteric venous thrombosis granulation tissue replace areas of ulceration.
appears as numerous, cord-like thrombosed Acute inflammation disappears and chronic
veins lying in a thick hemorrhagic and edema- inflammatory cells, lymphocytes, plasma cells,
tous mesentery. and macrophages infiltrate the mucosa. Mac-
In patients with polyarteritis nodosa, a nodu- rophages enter the area to remove red blood
lar appearance of the artery is characteristic but cells from areas of h emorrhage, resulting in
uncommonly detected grossly. Mucosal ulcers hemosiderin-laden macrophages (fig. 7-9) .
seen in such patients are typically well demar- These iron-containin g cells are an important
cated, located on the antimesenteric border, diagnostic feature of ischemia.

266
Ischemia and Other Vascular Disorders

Figure 7-5
ISCHEMIA IN A COLONIC BIOPSY SPECIMEN
Left: The lamina propria appears hemorrhagic, and the crypts in the upper portion of the photograph have a mucin-
depleted, regenerative appearance.
Right: Another area shows lamina propria hemorrhage and loss of the superficial portion of the crypt epithelium . Scattered
neutrophils are present, an indication that some degree of reperfusion has taken place.

Figure 7-6 Figure 7-7


ISCHEMIC COLITIS ISCHEMIC COLITIS
More advanced ischemic injury than is seen in figure The crypts in this case of ischemic colitis appear
7-S . There is evidence of mucosal erosion and neutrophilic withered, and are lined by flat, attenuated epithelium.
infiltration. The lamina propria is hemorrhagic. Scattered neutrophils are present in the crypts. The
surrounding colonic glands are smaller than usual and
mucin depleted.
In chronic ischemia, the epithelium shows
architectural distortion, marked regenerative In addition to establishing a diagnosis of
activity, Paneth cell metaplasia, and endocrine ischemia, the pathologist should attempt to
cell hyperplasia (fig. 7-10). In some cases, a determine the underlying etiology of the injury.
prominent submucosal collection of mono- Clues to the etiology are shown in Table 7-10.
nuclear cells is present; this may present as lym- Resection Specimens. Bowel resection is the
phoplasmacytosis in the deep lamina propria, most common type of specimen on which
simulating inflammatory bowel disease. the diagnosis of intestinal ischemia is made.

267
Gastrointestinal Diseases

...
.·t~:~
• .'. ...
.......
lr~
' ... 4
..• :t·( ..{
.....'
'"t ..

·•.'•
...

r •.
,., ' t
t "'

-• I
, .

Figure 7-8
REPERFUSION INJURY
A: Typical ischemic necrosis of the colonic mucosa. The crypt architecture is still discernible, but the epithelium has been
lost. The lamina propria contains a dense.,.neutrophilic infiltrate, a sign that reperfusion of the area has occurred.
B: Higher-power view shows a dense neutrophilic infiltrate within the lamina propria and infiltrating the remaining glands.
C: Low-power view shows the presence of a pseudomembrane adherent to the mucosal surface following reperfusion.
The pseudomembrane is composed of neutrophils, fibrin, extruded mucin, and necrotic cellular debris.

Figure 7-9
HEALING ISCHEMIC COLITIS
Yellow-brown hemosiderin
is in the lamina propria in this
... colonic biopsy specimen. This
feature is often indicative of a
previous episode of ischemia.

268
Ischemia and Other Vascular Disorders

Figure 7-10
ACUTE AND CHRONIC ISCHEMIC INJURY
A: Low-power photomicrograph shows a segment of small
intestine with marked vascular congestion. There is patchy
ischemic necrosis. The patient had a history of previous
ischemic enterocolitis and mesenteric venous thrombosis.
B: Higher-power view shows patchy acute ischemic
injury superimposed on more chronic ischemic changes.
The acute injury is characterized by superficial epithelial
loss and surface erosion. The surrounding mucosa shows
distortion of the crypt architecture and prominent regen-
erative epithelial changes.
C: Crypt branching is present in this section, a feature
seen in chronic injury. The crypt epithelium appears mucin
depleted and regenerative. Occasional neutrophils are seen
in the surface epithelium and within the lamina propria.
Capillaries are dilated, malformed, and sinusoidal.

Table 7-10
The role of the pathologist in such cases is to
COAGULATION DISORDERS LEADING
determine the etiology of the ischemia, assess TO GASTROINTESTINAL ISCHEMIA
the viability of the resection margins, and rule
Hemolytic uremic syndrome
out other pathologic abnormalities.
Early damage includes epithelial detachment Thrombotic thrombocytopenic purpura
and intercellular edema. Membrane-bound Homocystinuria
cytoplasmic blebs develop on the basal side of Ki:ihlmeier-Degos disease
the enterocytes, leading to epithelial detach- Disseminated intravascular coagulation associated with
ment (fig. 7-11). The process advances from sepsis
the villous tips · to the crypt bases (fig. 7-12). Protein C deficiency
Gradually the lining epithelial cells detach and Protein S deficiency
ghosts of the villi are left behind. The lamina Paroxysmal nochunal hemoglobinuria
propria becomes edematous and congested,
leading to villous blunting and crypt dilatation.
Submucosal edema is one of the earliest signs
of ischemia. Depending on the duration and Intravascular fibrin thrombi may be identified.
severity of the injury, mucosal and submuco- Fibrin thrombi in necrotic areas can be either
sal necrosis may be present (fig. 7-12). In the the cause of or the effect of the necrosis (fig.
most severe cases, transmural necrosis occurs. 7-13). If similar intravascular fibrin thrombi are

269
Gastrointestinal Diseases

Figure 7-11
EARLY ISCHEMIC INJURY
A: The earliest visible changes of ischemia are shown here. The epithelium of this segment of small intestine has become
detached from the underlying basement membrane. The mucosal capillaries are congested.
B: Low-power photomicrograph of ischemic colitis shows an essentially normal mucosa on the left, and early ischemic
changes on the right. The ischemic mucosa appears congested, and the epithelium of the superficial portion of the crypts
is sloughing away from the basement membrane.
C: Higher-power view of the affected colonic crypts shows discohesive, sloughing epithelial cells.
D: Goblet cells in some affected glands have a dystrophic appearance.

found in non-necrotiC regions, it is likely that It is possible to identify the etiology of isch-
these are the cause of the ischemia. emia in some cases. Small and large vessels in
If reperfusion is established, marked conges- the intestine and mesentery should be evalu-
tion, hemorrhage, and emigration of neutro- ated for emboli or other occlusive diseases, as
... phils in the lamina propria occur. Intraepi- described above (fig. · 7-14). Unusual causes,
thelial neutrophils also become prominent and including viral infection, parasitic infection,
pseudomembranes develop. Pseudomembranes fungal vasculitis, certain connective tissue
consist of fibrin, neutrophils, other inflamma- diseases like scleroderma, and hypercoagulable
tory cells, and granulation tissue. In subacute states, may be diagnosed by light microscopy or
or chronic cases, fibrosis, hemosiderin-laden the use of special stains. The pathologic features
macrophages, and serosal adhesions are present. of specific lesions are described below.
The remaining epithelium may show marked Differential Diagn osis. Because ischemic
regenerative changes. changes are often segmental and patchy in

270
Ischemia and Other Vascular Disorders

Figure 7-12
SMALL INTESTINAL ISCHEMIA
A: Early ischemic injury with loss of the epithelium
overlying the villus tips. The superficial lamina propria is
congested.
B: More advanced ischemia with loss of the epithelium
lining almost the full length of the crypt.
C: In this case of duodenal infarction, there is full-
thickness coagulative necrosis of the small intestinal wall.
The tissues are congested and hemonhagic, but inflam-
matory infiltrates are not present because reperfusion did
not occur.

Neonatal Necrotizing Enterocolitis


distribution, the changes may mimic Crohn's
disease. Marked fibrosis and hemosiderin-laden Definition. Neonatal necrotizing enterocolitis
macrophages in the lamina propria, however, (NEC) is a rapidly progressive, acute ischemic
are more evident in chronic ischemic colitis condition that affects premature infants at the
than in inflammatory bowel disease. In ad- time of the initiation of enteral feeding.
dition, the older age of the patient; the pres- Demography. NEC affects 2 to 22 percent of
ence of coexisting systemic ischemic diseases, all premature infants (119) . It can occur at any
occlusive vascular changes in mucosal and time in the first 3 months of life, but its peak
submucosal arteries, and glandular ghosts; and incidence is around the time when infants are
the absence of rectal involvement, transmural started on oral foods (2 to 4 days old).
lymphoid aggregates, and granulomas are help- Etiology and Pathophysiology. Four fac-
ful features that differentiate ischemia from tors play a critical role in the pathogenesis of
other lesions. NEC: 1) prematurity; 2) establishment of enteral
Complications of Ischemic Injury. Untreat- feeding; 3) intestinal mucosal ischemia; and 4)
ed acute ischemia can lead to severe complica- the presence of luminal bacteria in the affected
tions. Transmural infarction leads to metabolic bowel loops (115, 116). Premature neonates have
acidosis, hypotension, cardiac failure, sepsis, a limited capacity to maintain oxygen uptake
and endotoxic shock. Reparative changes fol- during periods of hypoxia and feeding (113). In
lowing ischemia can lead to stricture formation addition, the immature enzymatic composition
as early as 2 to 8 weeks after the initial injury. of the premature neonatal intestine does notal-
Loss of a large segment of intestine can lead low complete digestion of food, thereby favoring
to short bowel syndrome with malabsorption. bacterial growth. Decreased cardiac output due
A shortened segment of bowel with impaired to fetal asphyxia also contributes to the ischemia
motility may lead to bacterial overgrowth. in most cases. Umbilical vein catheterization

271
Gastrointestinal Diseases

Figure 7-13
INTRAVASCULAR THROMBI IN ISCHEMIC INJURY
A: Fibrin thrombi are commonly seen in areas of ischemic necrosis. When present in an area of injury, it is not possible
to determine whether the thrombi represent a primary cause of the ischemia or are a secondary change in n ecrotic tissues.
B: Thrombi identified in non-necrotic tissues most likely represent primary phenomena that are probably responsible for
the ischemic injury seen in other regions of the bowel.
C: Sometimes thrombi of varying ages can be seen. The one depicted in this photograph appears to be organizing.
D: Later stage of organization demonstrating recanalization of a previously thrombosed vessel.

causes localized vasospasm, which can further matory mediators include interleukin-8, inter-
compromise intestinal blood flow. Intestinal leukin-2, and nitrous oxide (117,118) .
mucosal injury allows protein and bacterial Gross Findings. The gross findings of NEC
toxins to pass into the portal circulation. These are similar to those found in severe ischemia
'-,•
toxins reach the immature liver and then dam- (fig. 7-15). Pneumatosis intestinalis is com-
age Kupffer cells and hepatocytes, so that the monly present. NEC often involves the ileum
toxins are not detoxified and gain access to the and right colon; the stomach is also involved
systemic circulation. The endotoxemia leads to in a large number of cases (114). Affected bowel
hypotension and systemic shock. segments appear dilated, necrotic, friable, and
Intestinal ischemia, bacterial colonization, gangrenous. The external surface is shaggy, with
or formula feeding stimulates proinflammatory adhesions between the loops.
mediators, which activate a series of events Microscopic Findings. The histologic find-
leading to bowel necrosis (116). The proinflam- ings in NEC resemble those seen in severe

272
Ischemia and Other Vascular Disorders

Figure 7-14
ATHEROMATOUS EMBOLI
Clear, needle-like spaces typical of cholesterol emboli Figure 7-15
lie in submucosal vessels. (Fig. 3-114 from Emory TS, Car- NECROTIZING ENTEROCOLITIS
penter HA, Gostout C], Sobin LH. Atlas of gastrointestinal
endoscopy & endoscopic biopsies. Washington DC: Armed The entire bowel wall appears dusky. The mucosal surface
Forces Institute of Pathology; 2000:229.) is hemorrhagic and ulcerated. The gross features resemble
those of severe ischemia of any cause.

ischemia (fig. 7-16). Gas-filled cysts are present


in the submucosa due to pneumatosis intes- countries, where it is generally confined to
tinalis. As with other resection specimens, the adults with chronic disease (122). Ischemia is
status of the resection margins and the extent the initial insult. Dietary factors
/
and infections
of the ischemia should be evaluated as these contribute to its pathogenesis. The jejunum is
factors influence long-term outcome. If pos- the most frequently involved site. Pigbel, seen in
sible, the unaffected bowel should be examined Papua New Guinea, is a classic example of this
for other abnormalities including the absence group of diseases (123). This lesion is described
of ganglion cells, changes of cystic fibrosis, or in more detail in chapter 10.
presence of congenital viral infections.
Acute Segmental Obstructive Enteritis
Treatment and Prognosis. NEC is a devastat-
ing disease with a fatal outcome in up to 40 per- Definition. Acute segmental obstructive enteritis
cent of cases. Surgical resection of the affected is an uncommon pediatric ischemic condition
bowel is the treatment of choice. Chronic com- of unknown etiology which frequently involves
plications include short bowel syndrome, which the small intestine. Synonyms include segmental
may require intestinal transplantation (120), necrotizing enteritis, nonspecific jejunitis, regional
and neurodevelopmental morbidity (121). jejunitis, and segmental obstructing acute jejunitis.
NEC in Adults. NEC can develop in adults, Demography. This is primarily a pediatric
particularly in older individuals. Ischemia is disorder (125). The disease appears to be sea-
the underlying cause. The mechanism is poorly sonal in nature, with most cases occurring in
understood and vascular occlusion is not usu- summer and early fall (126). It was initially
ally demonstrable. The pathologic features are believed that acute segmental obstructive en-
identical to those seen in severe ischemia due teritis was limited to malnourished patients in
to other causes. third world countries. It has now been reported
in developed countries and in well-nourished
Tropical Necrotizing Enterocolitis
children.
(Enteritis Necroticans)
Etiology. The etiopathogenesis of this condi-
Tropical necrotizing enterocolitis, also known tion is unclear. It may be due to toxins produced
as enteritis necroticans, affects patients of all ages by Gram-negative bacilli or due to a localized
in developing countries. It is rare in developed allergic reaction (127).

273
Gastrointestinal Diseases

Figure 7-16
.NECROTIZING ENTEROCOLITIS
Left: Low-power photomicrograph of full-thickness coagulative necrosis of the small intestine.
Right: Higher-power view shows a few viable cells remaining within mostly necrotic mucosa and submucosa. The
muscularis propria in this area is still preserved.

Clinical Features. Clinically, the condition arterial disease. Hypotensive episodes, an anion
is characterized by bilious vomiting, fever, gap, and metabolic acidosis can aggravate the in-
leukocytosis, severe abdominal pain, and signs testinal ischemia. Many patients on dialysis have
of intestinal obstruction. Small bowel radio- accelerated atheromatous disease, particularly if
graphs show segmental narrowing with proxi- they are diabetic, and chronic constipation, re-
mal dilation, a feature diagnostically useful for sulting in increased intraluminal pressure, which
this condition (124). can result in decreased perfusion . .
Pathologic Findings . The jeju:imm is most The small and large intestines are equally af-
frequently affected, followed by th~ ileum (124). fected by the ischemic process (130). No unique
The colon is affected in only a few cases and is pathologic features are present in hemodialysis
associated with involvement of the small intes- patients. The changes resemble ischemia due to
tine. Varying degrees of segmental ischemia are other causes. Multiple infarctions may develop.
present on pathologic examination; the changes Up to 20 percent of the mortality rate of pa-
range from edema and minimal congestion to tients on dialysis is attributable to nonocclusive
gangrenous necrosis with multiple perforations. mesenteric ischemia (129). Early diagnosis is
Treatment and Prognosis. The disease usu- critical to prevent potential life-threatening
ally has a self-limited course and lasts 10 to complications.
14 days (124). Surgery is usually not required,
except in cases in which transmural ischemic GASTROINTESTINAL ISCHEMIA
necrosis and peritonitis develop. SECONDARY TO SYSTEM IC VASCULITIS
Ischemia can be caused by an immune- and/
Bowel Infarction in Dialysis Patients
... or nonimmune-mediated inflammatory process
Dialysis patients, particularly those on hemo- involving the blood vessels of the gastrointesti-
dialysis, are at risk for developing nonocclusive nal tract. Intestinal vasculitis is an unusual cause
mesenteric ischemia (128,131). Multiple factors of mesenteric ischemia. It results in chronic
play a role in the development of the ischemia. arterial insufficiency in most of the cases, and
Large volume shifts occurring during hemodi- sometimes in acute mesenteric ischemia. The
alysis stimulate splanchnic vasoconstriction and diagnosis is based primarily on extraintestinal
ischemia. In addition, patients with renal disease manifestations and serologic tests. Gastrointes-
are prone to develop hypertension and occlusive tinal vascular disorders are listed in Table 7-2.

274
Ischemia and Other Vascular Disorders

Polyarteritis Nodosa
Definition. Polyarteritis nodosa (PAN) is an
antineutrophil cytoplasmic antibody (ANCA)-
associated vasculitis affecting medium-sized
blood vessels.
Demography. Up to 30 percent of cases are as-
sociated with hepatitis B infection. An association
with hepatitis C has also been described (145).
Etiology. Immune complex damage has been
proposed as the etiologic mechanism for the
vasculitis, particularly in patients with hepatitis
B (136) . Circulating immune complexes con-
taining viral proteins have been implicated in
the pathogenesis. The majority of patients have
wild-type hepatitis B infection, characterized
by HBe antigenemia and high hepatitis B virus
replication (133).
Besides hepatitis B, other viruses, including
human immunodeficiency virus (HIV) and
parvovirus B19 have been proposed as etiologic
factors (133). Patients often have other autoim-
mune diseases, with rheumatoid arthritis and
systemic lupus erythematosus being the most
common. Deposition of immune complexes in
the blood vessels leads to fibrinoid necrosis and
thrombotic, occlusive, ischemic, and hemor-
rhagic events in the affected tissues.
Figure 7-17
Clinical Features. Abdominal symptoms
occur in 25 to 50 percent of patients with PAN POLYARTERITIS NODOSA
(133,138), and abdominal pain is the most Fibrinoid necrosis of the wall of a submucosal artery is
frequent complaint, followed by diarrhea and associated with a perivascular lymphocytic infiltrate. The
overlying mucosa appears normal. (Fig. 3-104 from Emory
other gastrointestinal symptoms. Thirty-six TS, Carpenter HA, Gostout C], Sobin LH. Atlas of gastro-
percent of patients exhibit only gastrointestinal intestinal endoscopy & endoscopic biopsies. Washington
manifestations (135). DC: Armed Forces Institute of Pathology; 2000:225.)
Mesenteric vessels are affected in 25 to 30
percent of the cases. Branching points are
most frequently involved (132). Other systemic finding. Well-demarcated ulcers develop on
manifestations include renal artery vasculitis, the intestinal antimesenteric border. Resection
central nervous system vasculitis, cutaneous specimens show varying degrees of ischemic
vasculitis, pulmonary vasculitis, mononeuritis damage. Perforation can be present and is a
multiplex, fever, and musculoskeletal symp- poor prognostic sign.
toms. Abnormal laboratory findings include a Microscopic Findings. The findings are
high erythrocyte sedimentation rate, anemia, limited to small and medium-sized arteries .
leukocytosis, and thrombocytosis. Transmural inflammation and edema of the
Mesenteric arteriograms are abnormal in up arterial wall are characteristic (fig. 7-17). The in-
to 80 percent of patients (133). Multiple saccular flammatory infiltrate predominantly consists of
abdominal fusiform aneurysms as well as arte- neutrophils and eosinophils, with a few mono-
rial tapering and beading are seen throughout nuclear cells. Fibrinoid necrosis accompanies
the celiac axis. the inflammation of the arterial wall. Giant cells
Gross Findings. The nodular appearance of are absent. Destruction of the arterial wall leads
the vessels is a characteristic but uncommon to pseudoaneurysm formation. Superimposed

275
Gastrointestinal Diseases

thrombosis can be present. In the resolving Endoscopic Findings. Any bowel segment
and healing stages, the acute inflammation is may be affected, but the duodenum, jejunum,
replaced by predominantly mononuclear in- and ileum are the most frequently involved.
flammation, granulation tissue, and fibrosis of Endoscopic findings include multiple irregular
the vessel wall. The bowel wall shows features ulcers, petechiae, and mucosal redness. Hema-
of ischemia, as described above. toma-like protrusions may be seen; these are
Treatment and Prognosis. Immunosuppres- associated with the presence of leukocytoclastic
sive agents like cyclophosphamide, methotrex- vasculitis on biopsy (141).
ate, and steroids are the mainstay of therapy. Gross Findings. The bowel appears edema-
The presence of gastrointestinal symptoms tous and congested, with mottling, purulent
is suggested to be a poor prognostic factor in exudates, and superficial erosions. Transmural
patients with PAN (132). Early diagnosis and infarction is rare. When submucosal hemato-
timely intervention are essential to prevent mas are present, they can act as lead points for
serious complications. intussusception (143).
Microscopic Findings. Variable features of
Henoch-Schonlein Purpura
ischemia are present in the vessel walls. The
Definition. Henoch-Schonlein purpura (HSP) is small vessels show fibrinoid necrosis, and neu-
a small vessel vasculitis that involves the skin, trophilic and mononuclear infiltrates in the
gastrointestinal tract, kidney, and joints. HSP is vascular wall and in the perivascular soft tissues
a multisystem disorder characterized by a sym- (fig. 7-18). Fibrin thrombi may be present. It is
metric, nontraumatic, nonthrombettic, painless prudent to examine the vessels in non-necrotic
purpuric rash largely involving the skin of the areas to evaluate the features of vasculitis and
legs and buttocks, along with arthritis, nephri- determine whether the vascular inflammation
tis, hematuria, and gastrointestinal injury. HSP is a primary or secondary event.
is also known as anaphylactoid pwpura. Treatment and Prognosis. Massi,y e gastro-
Demography. HSP is the most common intestinal bleeding, stricture formation, intus-
vasculitis in children, although it can develop susception, and pseudomembranous colitis are
at any age (142). complications that can occur in patients with
Etiology. The vasculitis is caused by immuno- HSP. Intestinal perforation and peritonitis may
globulin (Ig)A-dominant immune complex develop in a few cases.
deposition in small arteries, capilTaries, and ve-
Microscopic Polyangiitis
nules. HSP results from vascular entrapment of
circulating IgA immune complexes. As a result, Definition. Microsc9pic polyangiitis is a small
deposits of IgA, fibrinogen, and C3 lie in vessel vessel vasculitis involving arterioles, venules,
walls. Immune complexes, which have a relative and capillaries.
absence of other immunoreactants, distinguish Pathophysiology. Unlike HSP and PAN,
HSP from other forms of necrotizing vasculitis microscopic polyangiitis is not associated with
because the latter typically contain deposits of immune complex deposition. Rather, the disease
IgG or IgM rather than IgA. A number of drugs is associated with the antineuh·ophil cytoplasmic
have been implicated in the genesis of the im- antibody, p-ANCA. These antibodies are detected
mune response in HSP. Antigenic stimulation by their reactivity against neutrophilic myeloper-
also may result from respiratory tract infections, oxidase. Their titers may fluctuate, sometimes
insect stings, and immunizations. decreasing with treatment or during remission.
'· Clinical Features. Gastrointestinal involve- There is some evidence that AN CAs of IgM sub-
ment is present in up to two thirds of children class are associated with pulmonary hemorrhage
with HSP (143). Abdominal pain precedes the and severe glomerulonephritis (145) .
development of typical purpuric spots in 14 Clinical Features. Microscopic polyangiitis
to 36 percent of the cases. Patients also pres- is associated with pauci-immune crescentic
ent with gastrointestinal bleeding (139). Fifty glomerulonephritis. The kidney is the most
percent of patients have melena and 15 percent common organ involved, followed by lung,
develop hematemesis (140). skin, and gastrointestinal tract. Gastrointestinal

276
Ischemia and Other Vascular Disorders

Figure 7-18
HENOCH-SCHONLEIN VASCULITIS
Thrombosed submucosal venule with neutrophilic
destruction of the vessel wall (leukocytoclastic vasculitis).
The mucosa is acutely inflamed, making the underlying
vascular lesion difficult to recognize. (Fig. 3-102 from Emory
TS, Carpenter HA, Gostout C], Sobin LH. Atlas of gastro-
intestinal endoscopy & endoscopic biopsies. Washington
DC: Armed Forces Institute of Pathology; 2000:225.)

symptoms are reported in 29 to 58 percent of


cases (144). Abdominal pain is the usual com-
plaint followed by gastrointestinal bleeding.
Although common, gastrointestinal symptoms
are not usually the presenting complaint in
patients with microscopic polyangiitis. Figure 7-19
Endoscopic Findings. The endoscopic find-
MICROSCOPIC POLYANGIITIS
ings are similar to those described in HSP.
Microscopic Findings. Endoscopic biopsies A: The colon has the typical features of ischemic injury. A
submucosal vessel appears to be inflamed. In areas of ischemic
show features of ischemia and small vesselleu- damage, it is often difficult to separate primary vascular injury
kocytoclastic vasculitis as described in HSP (fig. from changes that occur secondary to ischemia.
7-19). Unlike PAN, medium-sized blood vessels B: Submucosal vessels in areas remote from the ischemic
are not involved. The diagnosis is primarily bowel show evidence of vasculitis, confirming a primary
vasculitic process.
based on the identification of extraintestinal C: Higher-power view of a small submucosal vessel with
manifestations and a positive p-ANCA titer. active transmural inflammation and fibrinoid necrosis .

277
, Gastrointestinal Diseases

Differential Diagnosis. The differential di- Table 7-11


agnosis includes other small vessel vasculitides DISEASES ASSOCIATED WITH
including HSP and drug-induced vasculitis. The ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES
differential diagnosis of ANCA-associated condi- Association with c-antineutrophH cytoplasmic antibody
tions is shown in Table 7-11. (ANCA)
Treatment and Prognosis. Immunosuppres- Wegener's granulomatosis
sive agents like cyclophosphamide and steroids
Polyarteritis
are the mainstay of treatment. Close monitoring
Association with p-ANCA
of renal function is required as patients may
develop rapidly progressive glomerulonephritis. Idiopathic crescentric glomerulonephritis
Churg-Strauss syndrome
Wegener's Granulomatosis
Polyarteritis nodosa with visceral involvement
Definition. Wegener's granulomatosis is a Ulcerative colitis
granulomatous necrotizing vasculitis that in- Crohn's disease with presentation resembling that of
volves small and medium-sized vessels of the ulcerative colitis
upper respiratory tract, lungs, kidney, and gas- Rheumatoid arthritis
trointestinal tract. Chronic hepatitis
Pathophysiology. Like microscopic polyan-
Primary sclerosing c;:holangitis
giitis, Wegener's granulomatosis is not associated
with immune complex damage. It is associated Primary biliary cirrhosis
with the antineutrophil cytoplasmiE antibody,
c-ANCA (antibody against proteinase 3).
Clinical Features. Gastrointestinal involve-
ment is unusual and the literature is limited to granulomatous inflammation of the respiratory
either case reports or small series of cases (147). tract, asthma, and peripheral eosinophilia.
When Wegener's granulomatosis does affect the Pathophysiology. CSS belongs to the ANCA-
gastrointestinal tract, any part may be involved associated pauciimmune vasculitides, along
from esophagus to colon (146). with microscopic polyarteritis and Wegener's
Microscopic Findings. The histologic find- granulomatosis. The ANCA-associated vasculi-
ings include nonspecific inflammation, isch- tides are compared in Table 7-11.
emia, vasculitis, and granuloma formation. The Clinical Features. Gastrointestinal involve-
granulomas characteristically are necrotizing, ment occurs in 50 percent of patients (148).
with palisading epithelioid histiocytes arranged Abdominal pain, bleeding, and, less often,
around the necrotic foci. The vasculitis involving perforation and infarction are seen (149,150).
small and medium-sized vessels is characterized Gross Findings. Resection specimens show
by infiltration by neutrophils and mononuclear multiple ulcers of irregular size and shape. The ul-
cells and fibrinoid necrosis of the vessel wall. cers may be deep and associated with perforation.
Multinucleated giant cells are frequently present Microscopic Findings. Gastrointestinal
in areas of vasculitis anp/or in the granulomas. involvement includes transmural eosinophilic
Differential Diagnosis. Infectious causes of infiltration of the stomach and duodenum re-
granulomatous inflammation should always sembling eosinophilic gastroenteritis, as well as
be excluded. multiple gastric, small intestinal, and colonic ul-
Treatment and Prognosis. Immunosup- cers (151). Histologic examination shows small
pressive agents like cyclophosphamide, metho- and medium-sized vessel vasculitis, necrotizing
trexate, and steroids are the primary mode of granulomas, and increased tissue eosinophils
therapy. Plasmapheresis has been suggested as (fig. 7-20). The vasculitis involves both arteries
an alternative in certain nonresponsive cases. and veins, and can be seen at all levels of the
intestinal wall. Patchy areas of infarction are
Churg-Strauss Syndrome
associated with the vasculitis.
Definition. Churg-Strauss syndrome (CSS) is Differential Diagnosis. The differential
a small vessel vasculitis that is associated with diagnosis includes other ANCA-associated

278
Ischemia and Other Vascular Disorders

Figure 7-20
CHURG-STRAUSS SYNDROME
Left: A cluster of colonic submucosal vessels shows evidence of vasculitis. The overlying mucosa is ischemic.
Right: A submucosal vein is partially thrombosed and infiltrated by inflammatory cells, many of which are eosinophils.
Numerous eosinophils are also present in the surrounding stroma. (Courtesy of Dr. John Hart, University of Chicago,
Chicago, IL.)

vasculitides (Table 7-11) and conditions associ- cytokines, polyclonal B-cell activation, and
ated with gastrointestinal mucosal eosinophilia. production of autoantibodies to endothelial or
Correlation with systemic manifestations and smooth muscle cells.
laboratory results is required to exclude CSS Clinical Features. The hallmark of Kawa-
as a possible cause of mucosal eosinophilia. saki's disease is the mucocutaneous lymph node
If pulmonary manifestations are present, CSS syndrome, which includes an erythematous
should be differentiated from allergic bron- rash, mucositis of the oropharyngeal mucosa,
chopulmonary aspergillosis. The presence of conjunctivitis, and nonsuppurative lymphad-
invasive fungal organisms in the lung biopsy enitis. Kawasaki's disease often has a component
is a diagnostic feature of the latter. of necrotizing arteritis, which affects medium-
Treatment and Prognosis. Cyclophospha- sized blood vessels. Kawasaki's disease is a lead-
mide and steroids are effective in most cases. ing cause of acquired heart disease in children
High-dose intravenous immunoglobulin is used in the United States.
in resistant cases. Gastrointestinal involvement is rare. When it
does occur, it can be of several types, including
Kawasaki's Disease
focal mucositis and focal colitis (152) . Intestinal
Definition . Kawasaki's disease is an acute pseudoobstruction and massive gastrointestinal
febrile illness associated with vasculitis of hemorrhage have also been described.
medium-sized arteries. Microscopic Findings. Histologic findings
Demography. Kawasaki's disease usually oc- include features of ischemia, vasculitis affect-
curs in children, with a peak incidence in the ing medium-sized blood vessels, and nonspe-
first year of life (154). cific acute and chronic colitis. The vasculitis
Etio l ogy. The pathogenesis of the dis- is similar to that seen in polyarteritis nodosa;
ease is unknown. Several theories have been however, the degree of necrosis is often less in
proposed, including the possibility of infection the vasculitis associated with Kawasaki's disease
by a toxin-producing microorganism and of a as compared to PAN. It is necessary to differenti-
superantigen-driven process (153). The vascu- ate Kawasaki's disease from PAN, as therapy is
litis results from an immunoregulatory defect different. Differentiation is primarily based on
characterized by T-cell activation, secretion of extraintestinal manifestations.

279
Gastrointestinal Diseases

Treatment and Prognosis. Intravenous im-


munoglobulin is often effective in controlling
the progression and coronary artery involve-
ment in Kawasaki's disease. The prognosis is
worse if the coronary artery is involved.
Thromboangiitis Obliterans
Definition. Thromboangiitis obliterans (TAO) ...
· v

is a nonarteriosclerotic, segmental, progressive,


inflammatory vasoocclusive disease of unknown
etiology. It is also known as Buerger's disease.
Demography. TAO occurs almost exclusively
in susceptible young men who are habitual
tobacco users, usually with onset of symptoms
before the age of 40 years. The condition is far
more common in Japan, India, and Israel than
in the United States and Europe. 'fhere is an
--. . ..
increased prevalence of the disease in patients
with human leukocyte antigen (HLA)-A9, HLA- Figure 7-21
B5, and HLA-DRBl. THROMBOANGIITIS OBLITERANS
Etiology. TAO affects the small af1d medium- A mesenteric vessel in a patient with extensive colonic
sized arteries and veins of the extremities. Its eti- ischemic necrosis secondary to thromboangiitis obliterans.
ology is unknown. The endothelial injury may The vessel lumen is almost completely obliterated by a
be caused by tobacco, cellular toxins produced proliferation of fibrous tissue.
during the phagocytosis of smoking byproducts,
or immune complexes. Microscopic Findings. The histologic find-
Clinical Features. TAO is primarily a disease ings are those of acute and chronic ischemia.
affecting the arteries of the distal extremities. Acute and chronic inflammation permeates the
Common symptoms are claudication, loss of arterial walls, accompanied by organized and re-
skin turgor, and hair loss. In advanced stages canalized vascular thrombosis (fig. 7-21). Char-
of the disease, ischemic ulcerations"" with gan- acteristically, vascular thrombi contain small
grenous necrosis develop. microabscesses, with aggregates of neutrophils
Gastrointestinal involvement is rare; less surrounded by macrophages and lymphocytes.
than 100 such cases have been described in Differential Diagnosis. An absence of me-
the literature. Mesenteric arteries are most dial necrosis and the nature of the associated
frequently involved, followed by small vessels. extraintestinal manifestations distinguish TAO
Mesenteric TAO can present as acute or chronic from PAN.
ischemia (155), although chronic ischemia Treatment and Prognosis . Treatment de-
is more common. Patients also present with pends upon whether the ischemic injury is
intestinal obstruction due to stricture and fi- acute or chronic. Smoking cessation is recom-
brosis. Acute mesenteric ischemia may lead to mended for all patients. Intestinal perforation
gastrointestinal bleeding, acute abdominal pain, with peritonitis is the most prevalent fatal
and peritonitis . complication of the disease.
... Gross Findings. The gross intestinal findings
Malignant Atrophic Papulosis
are similar to those of other forms of ischemia.
Acute ischemic injury is characterized by areas Definition. Malignant atrophic papulosis, also
of ulceration, mucosal edema, congestion, and termed Kohlmeier-Degos disease, is a rare multi-
perforation. Chronic ischemia shows fibrosis, system vasculopathic disorder (158,160).
stricture, and atrophy of the intestinal wall. The Demography. Malignant atrophic papulosis
lumens of small to medium-sized mesenteric occurs most commonly in early adulthood. The
vessels may be narrowed. disease is occasionally familial.

280
Ischemia and Other Vascular Disorders

Etiology. The etiopathogenesis is unknown. ner media. Accompanying alterations include


It may be an immune complex-mediated non- fibrinous linear deposits at the junction of me-
inflammatory vasculopathy (161). dia and adventitia, and replacement of the lysed
Clinical Features. Cutaneous lesions are the media by erythrocytes, fibrin, and granulation
initial manifestation, followed by multisystem tissue. Inflammation is inconstant and limited
involvement (157). Some patients with gastro- to periadventitial tissues. Ultrastructural exami-
intestinal involvement are asymptomatic while nation reveals transformation of the cytoplas-
others present with acute abdominal symptoms, mic contents of arterial medial smooth muscle
intestinal infarction, and perforation. Malab- into a maze of dilated edematous vacuoles.
sorption due to widespread involvement of the Treatment and Prognosis. Acute abdominal
intestines may develop (162). hemorrhage is the most serious complication
Gross Findings. The characteristic gastroin- (163). Elderly patients also present with chronic
testinallesions on gross examination are conical intestinal ischemia.
infarcts associated with thrombi.
Marfan's and Ehlers-Danlos Syndromes
Microscopic Findings. The small and me-
dium-sized vessels are affected. Early lesions Patients with Marfan's and Ehlers-Danlos
consist of cellular proliferation and intimal syndromes develop gastrointestinal complica-
edema. In intermediate lesions, the edema is tions due to defective collagen synthesis. These
replaced by smooth muscle proliferation. In include megaesophagus, intestinal hypomotil-
late lesions, there is acellular intimal sclerosis ity, giant jejunal diverticula, megacolon, and
with hyalinization and obliteration of the lu- bacterial overgrowth (166). Aneurysmal dilata-
men. The media of the vessels remains intact . tion of the mesenteric arteries is caused by the
in almost all cases (161). The intestine shows a disruption of the collagen fibers in the media.
variable degree of ischemic injury. The intestinal Medial hemorrhage may occur. In severe cases,
disease is recurrent and frequently fatal (158). mesenteric artery rupture and intestinal infarc-
Differential Diagnosis. Although the vas- tion occur (167).
cular lesions resemble those seen in lupus ery-
thematosus, the patients may or may not have GASTROINTESTINAL INVOLVEMENT
other features of the disease (156,160). IN COLLAGEN VASCULAR DISEASES

Segmental Arterial Mediolysis Systemic Lupus Erythematosus


Definition . Segmental arterial mediolysis Definition. Systemic lupus erythematosus (SLE)
(SAM), formerly known as segmental mediolytic is a multisystem autoimmune disorder that
arteritis, is a rare condition involving abdominal encompasses a wide range of clinical manifesta-
splanchnic and epicardial arteries (165). tions and autoantibody production.
Demography. Abdominal SAM generally af- Demography. Gastrointestinal complaints
fects elderly individuals, whereas coronary SAM are frequent in SLE patients. Gastrointestinal
affects neonates, children, and young adults. vasculitis, a devastating complication of SLE,
Etiology. The etiopathogenesis of this con- affects only 2 percent of patients (172).
dition is uncertain. A proposed mechanism is Etiology. Although the exact etiology of SLE
an inappropriate vasospastic response in the is unknown, a number of autoantibodies are
splanchnic vascular bed in response to shock associated with the disease. The most specific
or severe hypoxemia (164). SAM may be a pre- antibodies are anti-double stranded DNA and
cursor lesion of fibromuscular dysplasia (165). anti-Sm antibodies. Genetic factors have also
Gross Findings. This entity is most com- been suggested to play a role, since family mem-
monly encountered in resection specimens or bers have a high risk of developing SLE. Up to
at the time of autopsy. Aneurysms and dissect- 20 percent of clinically unaffected relatives have
ing hematomas also develop due to extensive detectable autoantibodies.
mediolysis (165). Clinical Features. Gastrointestinal symptoms
Microscopic Findings. Histologically, outer are common in SLE patients. Acute abdominal
mediolysis expands the vascular mid and in- pain is the usual presentation. Other symptoms

281
Gastrointestinal Diseases

include nausea, vomiting, and heartburn due Rheumatoid vasculitis is seen 1 percent of
to esophageal dysmotility. Malabsorption has patients. It appears in the setting of severe ar-
also been described (168). There is no difference thritis, rheumatoid nodules, and high titers of
in age, sex, or autoantibody profile in patients rheumatoid factor. These patients often have
with or without gastrointestinal vasculitis. No cutaneous vasculitis and peripheral neuritis.
laboratory tests help differentiate patients with Microscopic Findings. RA vasculitis involves
and without gastrointestinal vasculitis (170). the vessels in the intestinal wall or mesentery.
Gross Findings. The gross findings vary with Occasionally, patients develop proliferative
the stage and severity of the gastrointestinal endarteritis characterized by intimal prolif-
involvement. In severe acute disease, features of eration without vascular wall inflammation or
acute ischemia with ulceration are present. In necrosis. Visceral aneurysms may develop that
chronic damage, the vasculitis leads to atrophy cause intraabdominal hemorrhage. Ischemic
and thinning of the intestinal wall. mucosal ulceration, bowel necrosis, perfora-
Microscopic Findings. The vasculitis primar- tion, pancolitis, and appendicitis have all been
ily affects areas of the bowel supplied by the su- reported (fig. 7-22).
perior mesenteric artery, including the jejunum Treatment and Prognosis. The prognosis for
and ileum (170). Small vessel vasculifis involves patients with gastrointestinal vasculitis varies
arteries and venules. The necrotizing vasculitis depending on whether bowel perforation has
is frequently associated with bowel necrosis. occurred or not. Patients with perforation and
Other pathologic changes seen in the gastro- late-stage ischemic injury have a poor prognosis.
intestinal tract include dysmotility'due to atro-
Behcet's Disease
phy of muscle fibers, heterotopic calcification ·
of gastric mucosa, peptic ulceration, vascular Definition. Behcet's disease is a syndrome
ectasia, severe mucus inspissation in intestine, of oral, genital, and ocular inflammation and
serositis, hemorrhagic ileocolitis, and intussus- ulceration.
ception (169,171). Demography. The gastrointestinal tract is
Differential Diagnosis. The differential infrequently involved in Behcet's disease. The
diagnosis includes other causes of vasculitis. disease is more common in Japan than in West-
The final diagnosis depends on the systemic ern countries. Intestinal involvement is most
manifestations of the disease and ..rthe detection common in men in their 4th and Sth decades .
of autoantibodies. Etiology. The underlying disease is a vascu-
Treatment and Prognosis. The vasculitis litis involving small and large vessels.
leads to bowel perforation, peritonitis, and Clinical Features. The terminal ileum and
fatality in some cases. cecum are the most frequently involved gastro-
intestinal sites (174,175).
Rheumatoid Arthritis
Gross and Endoscopic Findings. Endo-
Definition. Rheumatoid arthritis (RA) is an scopically, the intestine shows single or multiple
autoimmune disorder that primarily affects the ulcers. Most of the ulcers are round to oval in
musculoskeletal system but may involve multi- shape. The ulcers are deep and the margins are
ple systems including the gastrointestinal tract. discrete (176). They develop on the antimesen-
Demography. Approximately 10 percent of teric aspect of the intestine and exhibit a marked
patients with RA have gastrointestinal involve- tendency to irregularly undermine surrounding
ment (173). tissues (177). Edema-like swelling with crater
Clinical Features. Patients with RA may formation characteristically produces a "collar
demonstrate esophageal dysmotility due to stud" appearance.
atrophy of the muscularis propria, peptic ul- Microscopic Findings. Histologically, the
cer disease, malabsorption, amyloidosis, and ulcer base frequently shows either a remnant
NSAID-induced gastrointestinal injury; the lat- of an underlying Peyer patch or a destroyed
ter is the most common finding. Fewer patients lymphoid follicle (177). Mononuclear inflam-
develop gastrointestinal vasculitis, the most mation around the vessels, intimal thicken-
serious complication of the disease. ing, thrombosis, and necrotizing lymphocytic

282
Ischemia and Other Vascular Disorders

Figure 7-22
RHEUMATOID ARTHRITIS: ISCHEMIC ENTERITIS
Left: The small intestinal mucosa shows congestion and loss of the epithelium overlying the villi.
Right: Many of the submucosal vessels show prominent vasculitis associated with fibrinoid necrosis of the vessel wall.

vasculitis affecting small venules are the usual Microscopic Findings. The disorder se-
histologic features. In chronic lesions, marked lectively affects veins and venules in the
submucosal fibrosis is present. Granulomas are submucosa, subserosa, and pericolonic soft
absent. The histologic features are not specific, tissue (179) . Arteries and arterioles are free of
however, and extraintestinal manifestations are inflammation. The phlebitis consists of varying
used to diagnose the disease. degrees of lymphocytic and/or granulomatous
Differential Diagnosis. The most common inflammation, with or without necrosis (178) .
entity in the differential diagnosis is Crohn's Myointimal hyperplasia is also present. There
disease. The diagnosis is primarily based on the may be associated thrombosis.
clinical findings. The presence of granulomas, Microscopic Variants. Idiopathic myointimal
neural hyperplasia, and minimal vascular con- hype1plasia of the mesenteric vein is a rare cause
gestion favors a diagnosis of Crohn's disease. of chronic intestinal ischemia. It is considered
to be an end stage of MIVOD. Histologically,
Mesenteric Inflammatory
the disorder is characterized by thick-walled,
Venoocclusive Disease
bizarre, hypertrophic, arterialized veins located
Definition. Mesenteric inflammatmy venooc- in the submucosa and mesentery (178).
clusive disease (MIVOD) is a slowly progressive, Differential Diagnosis . It is necessary to
chronic ischemic condition characterized by exclude other causes of vasculitis affecting
the inflammation of veins of the intestinal wall small veins, including drug-induced vasculitis,
and pericolonic soft tissue. Lymphocytic phlebitis Behcet's disease, vascular changes secondary
is another term for the disease. to enterocolic inflammation, and lymphopro-
Demography. MIVOD is a rare cause of di- liferative disorders.
gestive tract ischemia (180). It occurs twice as Treatment and Prognosis. The disease appears
often in men as in women, and patients range to have an indolent course following surge1y (178) .
in age from 24 to 78 years (181) .
Clinical Features. Unexplained ischemia is Mesenteric Phlebosclerosis
the most common presentation. Patients do not Definition. Mesenteric phlebosclerosis is a rare
have systemic disease. The diagnosis is possible chronic ischemic condition affecting small
only after examination of the resection specimen. mesenteric veins.
Gross Findings. Gross examination shows Demography. This rare nonthrombotic ste-
features of chronic ischemia as described earlier. nosis of mesenteric veins is primarily described

283
Gastrointestinal Diseases

in Asian populations. Affected patients range cification of small mesenteric veins, deposition
from 36 to 73 years of age. of collagen around the blood vessels, and the
Clinical Features. The disease has a gradual presence of foamy macrophages within the
onset, with progression over the course of several walls of blood vessels.
months to years. Right lower quadrant pain and Treatment and Prognosis. The long-term
diarrhea are the usual presenting symptoms. outcome of patients with this condition is cur-
Gastrointestinal bleeding is uncommon. rently not known.
Gross Findings. Endoscopically, the bowel
appears edematous, the normal vascular pattern ISCHEMIA DUE TO
disappears, the mucosa is bluish black, and lu- COAGULATION DISORDERS
mens are narrowed. The disease is characterized Diseases leading to microangiopathic throm-
by a continuous distribution variably extend- bosis can involve the gastrointestinal tract
ing from the terminal ileum to the colon. The (Table 7-1 0). These include hemolytic uremic syn-
right colon is the most frequently and severely drome/thrombotic thrombocytopenic pwpura (HUS/
affected site. The rectum is not involved and TTP), homocystinuria, factor V Leiden mutation,
there are no skip lesions. paroxysmal nocturnal hematwia, and disseminated
Gross examination of the resection: specimen intravascular coagulation.
shows thickening of the colonic wall, disappear- HUS/TTP is caused by toxin-producing en-
ance of plica semilunares, and a dusky mucosa. teric bacteria (see chapter 10). Gastrointestinal
The cut surface of the intestinal wall appears involvement is frequent in children with HUS.
dark purple and semielastic. .. About 20 percent of adults with HUS/TTP have
Radiographic Findings. Radiographic stud- abdominal complaints. Thrombosis of small
ies are helpful in establishing the diagnosis submucosal vessels and associated intramural
(182-184) . Plain films show multiple thread- hemorrhage are characteristic findings. In se-
like calcifications along the right hemicolon. vere cases, intestinal perforation and pJ:ritonitis
Abdominal CT scans show marked thickening develop.
of and calcifications along the colonic wall. Patients with clotting factor abnormalities
Superior mesenteric artery angiography shows (factor V Leiden mutation, protein C and S defi-
tortuosity of the vasa recta and di1atation and ciencies) have features resembling those seen in
tortuosity of veins along the vasa recta. HUS/TTP. Patients with homocystinuria develop
Microscopic Findings. Endoscopic"" biopsies episodic thrombosis followed by fibroblastic
show features of chronic ischemia. The diag- intimal proliferation of medium-sized arteries.
nosis is based on correlating the pathologic
findings with the characteristic radiographic ap- ISCHEMIA CAUSED BY INFECTIONS
pearance. A range of changes is present in resec- A number of infections involve the gastroin-
tion specimens. The mucosa appears congested, testinal vasculature. Fungal and cytomegalovi-
edematous, and fibrotic. The epithelium shows rus infections are the most common offenders.
features of ischemia with neutrophilic infiltrates Schistosomiasis has been shown to involve the
in the superficial epithelium. Hemosiderin- gastrointestinal vasculature in rare case studies
laden macrophages are also present. (185). These infections are discussed in greater
The distinctive features seen in the colonic detail in chapter 10.
wall are marked fibrous mural thickening, cal-

284
Ischemia and Other Vascular Disorders

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291
8 CHEMICAL INJURY

INTRODUCTION foods that contain chemicals; 7) consumption


Demography. Chemical injury is probably of supplements or substances found at health
far more common than is diagnosed, because food stores; or 8) via animal bites or stings. Drug
pathologists rarely have sufficient clinical in- injuries result from both the drugs themselves
formation to make the diagnosis. Presumably, or from byproducts of food-drug (chemical)
some of the nonspecific inflammation seen interactions. Host factors, specific meal com-
throughout the gut results from chemical or position and volume, and the drug or chemical
drug exposure. Approximately 2 to 8 percent of type determine the nature of the interactions.
patients receiving drugs experience an adverse General Clinical Features of Chemical In-
gastrointestinal reaction, with gastrointestinal jury. Most drugs and chemicals do not affect
bleeding accounting for the largest burden of the gastrointestinal tract uniformly. Therefore,
adverse drug-related admissions (4) . Up to one the clinical features depend on the location,
third of the drug injuries affect more than a nature, and extent of the injury, as well as on
single gastrointestinal site (3,4). the presence or absence of complications or co-
Etiology. Chemical injwy results from exposure existing conditions. When patients with chemi-
to drugs, chemicals, and toxins. Some of these are cally induced injury present with symptoms
exogenously derived, as in drug-induced injury; related to inflammation and ulceration, the
some result from the presence of gastrointestinal clinical presentation mimics other ulcerating
luminal materials in places where they ought diseases. Chemical injury may also manifest as
not to be, as in gastroesophageal reflux disease or malabsorption, a motility disorder, idiopathic
alkaline reflux gastlitis (gastropathy). inflammatory bowel disease (IBD), or infection.
Chemicals injure the gastrointestinal tract Endoscopic biopsies are usually performed to
in numerous ways (Tables 8-1 and 8-2). Some localize the lesions, to document their extent,
drugs become entrapped, particularly in the and rule out alternative causes of the clinical
esophagus, causing localized injury. Others are manifestations.
directly toxic, causing necrosis or inhibiting
cell growth. In other cases, toxicity results from
metabolic conversion and release of damaging Table 8-1
endogenous mediators such as the free radical MECHANISMS OF DRUG-
release seen in nonsteroidal antiinflamma- OR CHEMICAL-INDUCED INJURY
tory drug (NSAID) injury. Toxic injury gener- Act as toxins
ally exhibits dose-related effects. Other drugs Mediate immune reactions
cause ischemia via secondary events including Cause malabsorption
thrombosis, decreased blood flow, vasculitis, or Cause bleeding
vasospasm (Table 8-1). Still other drugs predis- Cause ischemia
pose to infection, such as antibiotic-associated Cause allergic reactions
Clostridium difficile infections, or they cause
Affect motility
motility problems.
Predispose to infection
Patients are exposed to chemical injury via 1)
Cause damaging food-drug interactions
accidental ingestion; 2) overdose as the result of
Cause caustic injury
suicidal intent; 3) therapies for numerous dis-
eases; 4) use of the drug as a preventive agent; Physical entrapment
5) use in diagnostic tests; 6) consumption of Cause foreign body reactions

293
Gastrointestinal Diseases

Table 8-2 endoscopic changes consistent with ischemia or


EXAMPLES OF CHEMICAL/DRUG INJURY
idiopathic IBD. The myriad of drugs used in the
transplant situation can cause an endoscopic
Agent Lesions
Antibiotics
appearance similar to that of other causes of
Pill-associated esophagitis
Pseudomembranous colitis gastritis, enteritis, and colitis. The clinician
Malabsorption (neomycin, often depends on the results of the pathologic
paraaminosalicylate) analysis to appropriately direct patient care and
Enterocolitis management.
Anticholinergic and Pseudoobstruction General Pathologic Findings of Chemical
antidepressant drugs
Injury. The pathologic features of chemically
Anticoagulant drugs Hemorrhages and hema-
tomas
induced injury are typically nonspecific, and
Cardiovascular drugs Focal esophageal ulcers
the diagnosis often depends on the history and
from pills (quinidine, the exclusion of other conditions. Common
vasopressin) histologic alterations include inflammation,
Gastric and duodenal ulcers erosions, necrosis, ulcers, ischemia, and apop-
(reserpine, ethacrynic acid)
Ischemic enterocolitis
tosis with epithelial loss in the proliferative
Malabsorption fmethyldopa) zones. Microscopic clues to drug-induced injury
Pseudoobstruction (ganglion include apoptosis, cytoplasmic vacuolation and
blockers) increased intraepithelial lymphocytes (1,2),
Caustic agents Ulcers and strictures of the melanosis coli, and eosinophils. These features,
esophagus a~d stomach however, are far from specific. Even with an
Chemotherapeutic drugs Ulcers and inflammation abnormal biopsy in which eosinophils and
Synergism with radiation
injury apoptosis are prominent and a drug-induced
Malabsorption etiology is suspected, proof positive requires
Enterocolitis resolution of the abnormalities when the drug
Enemas and laxatives "Proctitis" from enemas is withdrawn and reappearance of the lesions
Cathartic colon when the drug is reinstated (1,2). Since patients
Melanosis coli
are often on several drugs, these requirements
Estrogen and progesterone Hemorrhage, thrombosis,
and ischemia
are seldom fulfilled (5).
Complications include ulcers that may per-
Ethyl alcohol GastroduodtJ:titis
Mild effects on small forate, malabsorption from altered enterocyte
intestine morphology, pseudoobstruction from neuro-
Heavy metals Focal esophageal ulcers from muscular alterations, or stricture formation.
pills (ferrous sulfate)
Gastric ulcers (ferrous and NONSTEROIDAL
zinc sulfate) ANTIINFLAMMATORY DRUGS
Enterocolitis
Nonsteroidal antiinflam- Pill-induced esophagitis
Definition. NSAID injwy is gastrointestinal
matory drugs Gastroduodenitis damage resulting from the ingestion of non-
Focal intestinal ulcers steroidal antiinflammatory drugs, including
Mucosal diaphragms aspirin. Synonyms include NSAID gastropathy
and NSAID enteropathy.
Demography. NSAIDs are the most com-
monly prescribed drugs in the Western world; the
The clinician often needs to differentiate world market now exceeds $6 billion/year (29).
chemically induced abnormalities from other NSAIDs are also the drugs whose complications
disease processes that cause similar endoscopic most frequently necessitate hospitalization,
features. For example, drug-induced esophageal especially in elderly women (12,30). Women
ulceration may mimic gastroesophageal reflux over 75 years of age who take NSAIDs have a
injury, NSAID effects in the upper gastrointesti- 5-fold increased risk of gastrointestinal hemor-
nal tract may resemble peptic ulcers, and in the rhage or perforation (58). NSAIDs are primarily
lower gastrointestinal tract, NSAIDs can induce used to treat rheumatoid arthritis and other

294
Chemical Injwy

degenerative joint diseases, and to reduce the Table 8-3


incidence of cancer. Aspirin is used to prevent COMMONLY USED NONSTEROIDAL
cardiovascular and cerebrovascular thrombotic ANTIINFLAMMATORY DRUGS
events. Its antithrombotic effects are largely
Acetylsalicylic acid Misoprostol
mediated by its ability to acetylate and thus ir-
Azapropazone Naproxen
reversibly inactivate platelet cyclooxygenase-I
Diclofenac Oxyphenbutazone
(COX- I ), the rate-limiting enzyme in throm-
Diflunisal Phenylbutazone
boxane A2 synthesis. Patients on long-term
NSAID therapy have a IO- to 30-fold increased Fenoprofen Piroxicam
risk over that of the general population for the Ibuprofen Sulindac
development of a chronic refractory peptic Indomethacin Tolmetin
ulcer (34) . The risk of a significant gastroduo- Mefenamic acid
denal complication (bleeding, perforation, or
gastric outlet obstruction) is I to 4 percent/year
(9,35,53). Fortunately, there has been a decline cosal prostaglandin levels (44,56). NSAIDs in-
in serious NSAID-related gastropathies due to hibit prostaglandin synthesis via their effects on
two major factors: the use of lower doses com- COX. There are two different COX isoenzymes.
bined with the increased use of proton pump COX-I is constitutively expressed in many
inhibitors and the use of less toxic NSAIDs, tissues, including the stomach. In contrast,
particularly COX-2-specific inhibitors (27). rapidly inducible COX-2 is not expressed, or is
NSAIDs also damage the gastrointestinal expressed at very low levels unless the tissues are
mucosa of children, although the number of inflamed (56). Since selective COX-2 inhibitors
children developing significant gastrointestinal suppress prostaglandin synthesis only at in-
problems is low (37). flamed sites, they are less ulcerogenic than other
Etiology. A linear dose relationship exists NSAIDs (24,47). In addition to causing mucosal
between NSAID ingestion and gastrointestinal damage, NSAIDs interfere with the healing of
damage. This relationship is modified by host preexisting lesions, including ulcers, by interfer-
response, concomitant drug or alcohol use, ing with the action of mucosal growth factors,
route of administration, the specific drug used, decreasing epithelial cell proliferation, decreas-
and the presence of Helicobacter pylori infec- ing angiogenesis in the ulcer bed, and slowing
tion (36). Different preparations tend to affect granulation tissue maturation (57).
different portions of the gastrointestinal tract. Aspirin damages the gastric mucosa directly
NSAIDs that commonly induce gastrointestinal and indirectly, depending on the gastric pH.
injury are listed in Table 8-3. Since aspirin does not dissociate at a gastric pH
Pathophysiology. Esophageal Injury. Esopha- of 3.5 or greater, it damages the superficial epithe-
gitis develops in patients on NSAIDs of all sorts. lium directly by acting as a physical agent (SS) .
This is related, in part, to the development of Insoluble aspirin preparations become embed-
reflux esophagitis due to a reduction of lower ded in the mucosa, producing circular erosions,
esophageal sphincter pressure and impairment ulcers, or mucosal cracks. Drug particles falling
of cholinergic control of lower esophageal into these mucosal defects become "walled off"
sphincter contraction (I8,29). in mucus until they dissolve. In contrast, when
Gastroduodenal Injury. NSAIDs usually pro- gastric pH is 3.5 or less, aspirin indirectly dam-
duce acute mucosal lesions within 7 to I4 days ages the stomach by being absorbed. Aspirin is
of administration by the mechanisms shown in lipid soluble and salicylate forms following its
figure 8-I. The normal gastroduodenal mucosa absorption. The absorbed aspirin acts as a potent
contains high concentrations of the prosta- mitochondrial poison and cytotoxin, affecting
glandins PGE2 and PGI 2 , which inhibit gastric mucosal barrier function, stimulating sodium
acid secretion and increase mucus production transport, and increasing hydrogen ion (H+)
(see chapter 4) . The increased vulnerability of dissipation from the mucosal surface. Salicylates
the elderly to NSAID-induced injury may result also increase mucosal cellular exfoliation; ulcers
from an age-related reduction in gastric mu- develop when the rate of exfoliation exceeds

295
Gastrointestinal Diseases

Decreased
thickness of
the mucous layer

Increased
neutrophil -
adherence
Decreased
mucosal
blood flow

Figure 8-1
DIAGRAM OF THE EFFECT-5 OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS)
NSAIDs produce mucosal injury by inhibiting cyclooxygenase (COX) activity and reducing mucosal prostaglandin synthesis.
COX is the enzyme responsible for converting arachidonic acid to prostaglandins. Reduced prostaglandin synthesis leads to an
overall reduction in gastric mucosal defenses. Prostaglandins have a protective mucosal role and stimulate mucus secretion,
stabilize lysosomes, and inhibit acid secretion in the stomach. NSAIDs alter mucus and bicarbonate secretion, reduce mucosal
blood flow, and promote adherence of neutrophils to the vascular endothelium. NSAID-mediated cytologic damage results
from a cascade of events that increases mucosal permeability and luminal hydrogen ion and pepsin leakage into the cells.

the rate of cellular regeneration, Aspirin also approximately 60 percent of patients who take
strongly inhibits COX-I in the gastrointestinal NSAIDs have clinically silent gastroduodenal
mucosa, leading to its ability to .induce gastro- damage (11). The most serious complication
intestinal mucosal injury. This happens even in long-term NSAID users is gastrointestinal
at extremely low doses (21). Chronic NSAID bleeding (28,42), which occurs anywhere in the
ingestion often causes less damage than acute gut. Bleeding usually results from the presence
ingestion due to the mucosal adaptation that of mucosal erosions or ulcers. Patients may also
renders the mucosa resistant to epithelial ne- develop diarrhea and appetite loss. NSAIDs are
crosis (38,49,58). strongly associated with an increased risk of
Intestinal Injwy. The pathogenesis of small gastrointestinal perforation (40).
intestinal NSAID-induced injury is not as well Gastric erosions tend to occur acutely but
understood as gastric injury, in part, because they usually heal within a few days. Long-term
visibly assessing the damage in the small intes- NSAID users have an increased risk of gastric and
tine is more difficult. A key pathogenic factor duodenal ulcers and their complications, includ-
is increased mucosal permeability (17), which, ing bleeding, perforation, and death. Sometimes,
in conjunction with the NSAID effects on che- the pill is seen lying in the ulcer (fig. 8-2). Risk
motaxis and neutrophil function, injures the factors for NSAID-related peptic ulcer complica-
mucosa (16) and facilitates bacterial invasion tions include patient age (over 60), past history
and inflammation. NSAIDs and aspirin also of ulcer disease, use of higher-risk NSAIDs, con-
exacerbate underlying peptic ulcer disease and current use of anticoagulants or corticosteroids,
potentiate motility disorders. and the presence of serious systemic disorders.
Clinical Features. Clinically, over 25 percent Possible other risk factors include concomitant
of patients on NSAIDs experience nausea, heart- infection with H. pylori, cigarette smoking, and
bum, abdominal pain, or minor bleeding (39); alcohol consumption (8).

296
Chemical Injwy

Figure 8-2 Figure 8-3


NSAID-INDUCED GASTRIC ULCER NSAID-INDUCED GASTRIC ULCER
Endoscopic appea rance of gastric ulcer with three NSAID Large gastric ulcer in a patient on NSAID therapy.
pills lying in the middle of the ulcer bed.

In the small intestine, NSAIDs cause bleed- therapy (51). NSAID-induced ulcers are charac-
ing, ileal dysfunction, malabsorption, diarrhea, teristically large, shallow, discrete, mid-esoph-
changes in mucosal and vascular permeability ageal ulcers surrounded by a normal mucosa.
(14,36,41), protein loss, ulceration, mucosal Stomach. The stomach may appear perfectly
diaphragm disease, iron deficiency anemia, normal or there may be changes that resemble
perforation, and death. In the colon, NSAIDs those seen with stress ulcers. Endoscopic findings
cause perforation or bleeding of preexisting include mild erythema, petechiae, subepithelial
colonic diverticula, relapse of IBD, microscopic or intramural hemorrhages, superficial necrosis,
colitis, and strictures, and they may exacerbate focal punctate erosions, and acute or chronic
bleeding from angiodysplasias. Patients taking ulcers (fig. 8-3). The erosions often lie along the
NSAID-containing suppositories may develop lesser curvature and tend to involve all of the
localized anorectal erosions, ulcers, and stenosis stomach, in contrast to stress ulcers which typi-
(3 1) that may mimic anorectal Crohn's disease cally occur proximally and then spread distally.
or other causes of ulcerative proctitis. Erosions may extend into the duodenum. Antral
Gross Findin gs. In patients on NSAIDs, the flattening in the greater curvature is a useful
gastrointestinal tract may appear grossly and radiologic sign of NSAID-related gastropathy,
endoscopically normal. Additionally, erosions, particularly in individuals with associated erosive
ulcers, and mucosal diaphragms may develop gastritis. NSAIDs occasionally cause gastrocolic
anywhere in the gut. Because visibly assessing fistulas or pyloric channel strictures.
small intestinal damage is difficult, it has only Intestines. Intestinal lesions differ in the prox-
been relatively recently that the major small in- imal and distal small intestine. Patients who are
testinal effects of NSAIDs have become evident, chronic NSAID users may develop peptic duo-
largely through the use of radiolabeled isotopes denal ulcers. Hemorrhage and perforation occur
and subsequent radiologic investigation via ex- more commonly in NSAID-associated duodenal
clusion and permeability studies (15,22). peptic ulcers than in those without NSAID use.
Esophagus. Esophagitis, esophageal ulcers, Intestinal lesions may affect the entire intestine,
and esophageal strictures all complicate NSAID and include villou_s atrophy, ulcers, strictures,

297
Gastrointestinal Diseases

areas of bleeding, mucosal diaphragms (fig. 8-4),


and perforation. Duodenal lesions resemble
gastric lesions, with patchy hemorrhages and
erosions and acute inflammation that rapidly
resolve following drug cessation. Occasionally,
deep ulcers form. Smaller ulcers often surround
larger ones (7). The ileum is a common site of
intestinal injury.
Long-term NSAID treatment-related small
intestinal ulcers are single or multiple, and vary
from small, sharply demarcated, punched-out
lesions on the tips of mucosal folds (fig. 8-4) to
extensive deep ulcerations. The ulcers may re-
semble peptic ulcer disease with necrotic debris
and leukocytes admixed with fibrinous exudate,
often overlying granulation tissue. Fibrosis may
be present. Extensive erosions can -involve al-
most the entire small intestine (48).
Intestinal mucosal diaphragms are thought
to be pathognomonic for NSAID-induced injury Figure 8-4
(41,50). The features vary depending on the NSAID-INDUCED STRICTURE AND ULCER
stage of diaphragm development. The small Endoscopic view showing a distinctive diaphragm-like
intestine or colon is typically divided into vari- stricture with an ulcerated rim. (Fig. 4-129 from Emory TS,
able numbers of compartments by thin circum- Carpenter HA, Gostout C], Sobin LH. Atlas of gastrointes-
ferential membranes, creating a picture resem- tinal endoscopy & endoscopic biopsies. Washington DC:
Armed Forces Institute of Pathology; 2009:33S.) (Figs. 8-4,
bling that of a ring or a perforated diaphragm. 8-8-8-10, and 8-12 are from the same patient.)
Sometimes the luminal diameter narrows to less
than 1 mm. The serosal aspect of the intestine
usually appears normal; therefore; it is difficult are nonspecific. Patients may also develop reflux
to detect the intraluminal lesions by external esophagitis. Basal cell hyperplasia may not be
examination. Occasionally, however, the dia- present, since proliferation is inhibited by the
phragms cause small serosal constrictions that prostaglandin inhibitors (46).
are visible externally. The mucosa between the Stomach. Histologically, NSAIDs cause three
diaphragms usually appears normal, but it may major types of gastric injury: 1) acute mucosal
be ulcerated or regenerative. There are three hemorrhages and erosions that produce a pat-
patterns of mucosal diaphragm disease: 1) an tern resembling acute erosive gastritis (fig. 8-5);
extreme exaggeration of the normal plica circu- 2) ulcers; and 3) chemical gastropathy (fig. 8-6).
laris; 2) broad-based rigid strictures consisting Erosions and ulcers, when present, are usually
of dome-shaped lesions that cause a rounded small and sharply demarcated, and gastritis
hump projecting into the gastrointestinal lu- may or may not be present in the surrounding
men, often with a focal ulcer in the center of mucosa. These lesions heal in a manner similar
the hump (fig. 8-4); and 3) a conventional flat to that seen with stress ulcers. The ulcer surface
stricture. Circumferential linear ulcers may be reepithelializes with minimal fibrosis. When
the precursors of the mucosal diaphragm (32). ulcers are present, there is surprisingly little
Microscopic Findings. Esophagus. Patients inflammation in the surrounding mucosa, even
on long-term NSAID therapy may have an en- if the ulcers are chronic.
doscopically normal-appearing esophagus or Patients on NSAIDs also develop changes
there may be nonspecific changes, including that resemble those seen in bile (alkaline) reflux
basal cell hyperplasia. Alternatively, the esopha- gastritis (also known as chemical gastropathy),
geal mucosa may appear inflamed, eroded, or although the changes may be more subtle. These
ulcerated. The histologic features of the ulcers changes include pit elongation and foveolar

298
Chemical Injwy

Figure 8-5
EROSIVE CHANGES WITH MARKED
REACTIVE ATYPIA IN A PATIENT ON NSAIDS
Left: Low-magnification view shows eroded gastric mucosa with loss
of the surface epithelium. There is severe mucin depletion of the mucous
neck glands and gastric pits.
Above: Higher magnification shows significant cytologic atypia in
the regenerating glands.

Figure 8-6
CHEMICAL GASTROPATHY IN A PATIENT ON NSAIDS
The mucosa shows villiform transformation and irregularly shaped glands.
Left: Immaturity of the epithelium with mucin depletion.
Right: More mature foveolar lining epithelium.

tortuosity, vascular congestion, mucosal vil- of patients (25). Concurrent H. pylori gastritis
liform transformation, and muscular stranding may obscure the pathologic features. Acute and
up into the mucosa (fig. 8-7). There is a relative chronic inflammation usually surrounds NSAID-
paucity of inflammatory cells. The sensitivity of associated ulcers in H. pylori-infected individuals.
these latter histologic changes for NSAID injury No single histologic parameter reliably dis-
is low. Foveolar hyperplasia, one of the character- tinguishes NSAID-associated gastric ulcers from
istic features of chemical gastropathy, is absent in ulcers due to other causes. Moderate to severe
up to 66 percent of NSAID users and prominent foveolar hyperplasia, edema, and vascular ec-
muscle fibers are only present in 47 percent tasia are significantly more common in NSAID

299
Gastrointestinal Diseases

Figure 8-7
CHEMICAL GASTROPATHY DUE TO NSAIDS
A: Villiform transformation of the gastric mucosa and
eosinophilia of the lamina propria are seen.
B,C: Higher magnification shows that the eosinophilia
results from a proliferation of smooth muscle fibers within
the lamina propria .

users than in a control population (33). In some atrophy (fig. 8-10). There may also be broader-
patients, NSAIDs produce extremely reactive based diaphragms composed of more densely
epithelial atypia that can be quite alarming. hyalinized submucosal collagen interdigitating
These changes regress with drug-withdrawal. with the muscularis mucosae (fig. 8-11). There
Small Intestine. Early lesions in the small is often prominent mucosal eosinophilia. Sig-
intestine include patchy villous tip vacuoliza- nificant regeneration may be present (fig. 8-12).
tion followed by marked focal villous blunting Large Intestine. NSAIDs exacerbate preexisting
and lamina propria inflammation. Eventually, colonic diseases (Table 8-4). Mucosal ulceration
villous atrophy develops. In severe cases, mu- is among the most common side effects of
cosal erosions or ulcers develop on the tips of NSAID use and is generally histologically non-
the mucosal folds (fig. 8-8). Indeed, mucosal specific in nature.
ulceration is among the most common side ef- Several forms of colitis are associated with
fects of NSAIDs and is generally histologically NSAID use. The most common is nonspecific
nonspecific. A paucity of inflammatory cells in nature and difficult to distinguish from ul-
within the ulcer bed favors NSAID damage. cerative colitis early in its natural history. The
Mucosal diaphragms consist of mucosa and likelihood of a drug association increases if
'-,• submucosal fibrosis (figs. 8-8, 8-9) (16), often there is prominent apoptosis (43) and increased
oriented perpendicularly to the luminal surface. intraepitheliallymphocyte counts (microscopic
The mucosa overlying the submucosal fibrosis colitis). Collagenous colitis, eosinophilic colitis,
and along the luminal rim of the diaphragm and pseudomembranous colitis are also seen.
is usually mildly inflamed, with or without The diagnosis of NSAID-induced colitis may
ulceration, and it may show mild architectural be problematic since the histologic features
distortion due to repeated episodes of injury (fig. overlap with those present in other forms of
8-1 0). The mucosa closer to the perimeter of the colitis. The tissues often exhibit unexpected
diaphragm exhibits varying degrees of villous eosinophilia. Damage may be extensive,

300
Chemical Injwy

Figure 8-8
SMALL INTESTINE: MUCOSAL DIAPHRAGM DISEASE
Left: Exaggeration of the plica circularis and proliferation of connective tissue within the core of the plica. The tip of
this exaggerated fold is eroded.
Right: Another area of ulceration from the same patient shows dense fibrosis and ulceration of the surface.

Figure 8-9
SMALL INTESTINE: MUCOSAL DIAPHRAGM DISEASE
Above: Medium magnification of the thickened plica circularis shows
the damaged overlying mucosa and the proliferation of vessels and
connective tissue within the submucosal tissue.
Right: Higher magnification.

301
Gastrointestinal Diseases

Figure 8-10
SMALL INTESTINE: MUCOSAL DIAPHRAGM DISEASE
A: A portion of the small bowel mucosa adjacent to that shown in figures 8-8 and 8-9 demonstrates regeneration and
prominent mucosal eosinophilia.
B: Marked distortion of the surroundit'ig architecture.
C: Higher magnification of the architectural distortion.

Table 8-4
COLONIC EFFECTS OF NONSTEROIDAL
ANTIINFLAMMATORY DRUGS
Colonic ulcers
Nonspecific inflammation
Acute eosinophilic colitis
Pseudomembranous colitis
Eosinophilic colitis
Collagenous colitis
Lymphocytic colitis
Ischemic colitis
Chronic bleeding and perforation
Relapse of inflammatory bowel disease
Figure 8-11 Strictures
SMALL INTESTINE: MUCOSAL DIAPHRAGM DISEASE Complicated diverticular disease
An area of dense fibrosis is seen in the submucosa. Mucosal diaphragms

302
Chemical Injury

Figure 8-12
SMALL INTESTINE: MUCOSAL REGENERATION
IN MUCOSAL DIAPHRAGM DISEASE
Above: The surfaces of the villi are significantly mucin depleted and
have a somewhat hyperplastic appearance. Many syncytial-like cells
are apparent.
Right: There is a marked increase in the number of mitotic figures
in the crypts.

particularly in the proximal colon (26). Chronic preparations or in cystic fibrosis patients tak-
damage may result in significant pyloric meta- ing high-strength pancreatic supplements. The
plasia (fig. 8-13). Diclofenac can cause granu- concentric luminal diaphragmatic strictures,
lomatous colonic injury (10). Large intestinal however, are very characteristic of NSAID injury.
mucosal diaphragm disease resembles small The findings in diaphragm disease overlap with
intestinal diaphragm disease. those of neuromuscular and vascular hamar-
Differential Diagnosis. The gastrointestinal toma of the small bowel (20), and the latter
changes seen in NSAID injury are not specific may in fact be the same entity as mucosal dia-
for it. They can also be seen in stress gastritis, phragm disease. Mucosal eosinophilia can also
duodenitis, and many other forms of chemi- be seen in patients with parasites, allergies, IBD,
cal injury, including alcohol ingestion and eosinophilic gastroenteritis, connective tissue
bile reflux. Changes shared with other causes disorders, and neoplasia.
of chemical gastropathy include foveolar Treatment and Prognosis. The most effective
hyperplasia, mucosal edema, lamina propria method for preventing NSAID-induced injury
telangiectasia, a paucity of inflammation, and is discontinuation of the NSAID or reduction
prominent muscularis mucosae fibers extending in NSAID dosage. The use of COX-2-selective
into the mucosa. Acute inflammation tends to drugs also offers an effective way of reducing
be minimal, although occasionally it is seen at gastrointestinal complications (18,23,52) . These
the interface of necrotic and viable tissues. The drugs have the benefit of selectively targeting
histologic features may also overlap with those inflamed sites and leaving uninflamed sites
of ischemia. unaffected by the medication (34,54,59,60).
Focal colonic crypt injury, with neutrophilic Healing of NSAID-induced upper gastroin-
infiltrates producing cryptitis and crypt ab- testinal ulcers occurs if drug-induced injury is
scesses, occurs commonly in several diseases, recognized early. Early treatment with antacids,
including ischemia, infections, IBD, obstructive H2 antagonists, prostaglandins, and other gas-
colitis, and NSAID use. Intestinal strictures also tric cytoprotective drugs such as sucralfate may
occur in patients taking slow-release potassium facilitate mucosal healing. Sucralfate may also

303
Gastrointestinal Diseases

Figure 8-13
CHRONIC NSAID-INDUCED INJURY IN THE COLON
A: Low magnification shows marked architectural
distortion, with pyloric metaplasia in the basal portion of
the mucosa.
B: Higher magnification of the pyloric metaplasia.
C: The mucosa is very edematous with prominent crypt
branching.

help prevent NSAID-induced erosions (6,45). soluble (62), it directly damages the epithelium
Omeprazole may be used to tre'at or prevent by altering cell membranes, intercellular junc-
NSAID-related gastroduodenal ..,.ulcers and to tions, mitochondlia, endoplasmic reticulum, and
treat the dyspeptic symptoms (35). Symptom- the Golgi apparatus (64). There is focal separation
atic NSAID-induced strictures or stenoses need of the cell junctions accompanied by capillary
to be dilated or excised. Recently, treatment disruption and hemorrhage, with an outpouring
recommendations have been put forward based of mucus and fibrin into the damaged mucosa.
on risk assessment (Table 8-5) (19). This results in epithelial sloughing that then
The mortality rate attributable to NSAID- facilitates acid back-diffusion into the mucosa.
related gastrointestinal toxicity is 0.22 percent/ Alcohol stimulates gastric acid secretion, further
year, with an annual relative risk of 4.21 as com- augmenting the damage (fig. 8-14). Alcohol also
pared with the risk for·persons not using NSAIDs. damages the mucosal vasculature, leading to the
Gastrointestinal complications ofNSAID use may subsequent development of mucosal hemorrhag-
be responsible for more than10,000 deaths/year es and erosions. Mucosal vasoconstriction fur-
in the United States (8,13) . ther contributes to the mucosal injury. Patients
with H. pylori infection are more vulnerable to
.. ALCOHOL alcohol-mediated gastric mucosal damage due
Definition. Alcoholic gastritis/duodenitis devel- to the presence of an already damaged muco-
ops following excessive consumption of alcohol. sal barrier. In the duodenum, alcohol-induced
Pathophysiology. Alcohol-induced gastric injury exposes the underlying tissue to the ef-
damage correlates with the amount of alcohol fects ofluminal digestive enzymes. Neutrophil-
consumed (63). Gastric alcohol-mediated injury mediated cell injury further contributes to the
usually requires gastric alcohol concentrations alcohol-induced injury (66). The effects of
of over 10 percent (66). Since alcohol is lipid alcohol and NSAIDs are synergistic.

304
Chemical Injwy

Table 8-5
STRATEGIES FOR PREVENTION OF NONSTEROIDAL ANTIINFLAMMATORY DRUG INJURY BASED ON RISK•
Patient Group Strategies
Low risk (no risk factors) Least ulcerogenic NSAIDs at lowest effective doses
Moderate risk (1.-2 risk factors)b Least ulcerogenic NSAID + an antisecret ory agent or misoprostol
COX-2c inhibitor
High risk ( ~ 3 risk factors or concomitant COX-2 inhibitor+ PPI or misoprostol for con comitan t aspirin
aspirin, steroids, or warfar in) COX-2 inhibitor + misoprostol for con comitant warfarin
COX-2 inhibitor for concomitan t st eroids
Very high risk (history of recent ulcer Avoid NSAIDs altogether
complicati on) COX-2 inhibitor+ PPI and/or misoprostol
•Modified from Ch an FK. Preven tion ofNSAID gastrointestinal complications-review and recommendations based on risk
assessment. Aliment Pharmacol Ther 2004;19:1051-61.
bQld age, presence of cardiovascular diseases, use of high-dose or multiple NSAIDs, concomitant use of low-dose aspirin and
oth er antiplatelet drugs, steroids, or warfarin.
'COX-2 = cyclooxygen ase-2; PP! = proton pump inhibitors.

Direct Cell necrosis and


mucosal surface erosions
toxicity
Thinning of
mucus layer
H+
H+

Impaired mucus
Altered tight synthesis and
junctions _ _,i-- -1 secretion

Altered
blood flow _.~--..,... Neutrophilic
infiltration and
superoxide
Submucosal
release
edema - - - --

Figure 8-1.4
DIAGRAM OF THE PATHOPHYSIOLOGY OF ALCOHOL-INDUCED INJURY

Clinical Features. The clinical features differ Stomach. Alcohol ingestion results in both
depending on whether alcohol intake is acute or acute erosive and nonerosive gastritis. Many
chronic. In alcoholics, the clinical features may alcoholics present with gastrointestinal hem-
be dominated by the effects of coexisting portal orrhage from coexisting disease, e.g., varices,
h ypertension. Many chronic alcohol abusers portal gastropathy, peptic ulcer disease, or
develop abdominal discomfort, vomiting, diar- Mallory-Weiss tears. The m agnitude of the bleed
rhea, and anorexia due either to gastritis or to varies, depending on whether there is an as-
hepatic disease. sociated coagulopathy. Alcohol may also cause
Esophagus. Both acute and chronic alcohol acute "morning after" discomfort. Concomitant
ingestion cause esophageal dysmotility. Acute pancreatitis may need to be excludep in patients
alcohol intake also decreases lower esophageal with severe abdominal pain.
sphincter pressure (65) predisposing to reflux Intestines. Chronic alcohol ingestion can
esophagitis. cause intestinal epithelial immaturity with

305
Gastrointestinal Diseases

Figure 8-16
ALCOHOL-INDUCED EROSIVE GASTRITIS
The mucosa is markedly congested . (Figs. 8-16 and 8-17
are from the same patient.)

than gastric changes, presumably due to lower


alcohol concentrations.
Microscopic Findings. Esophagus. Alcohol
causes esophagitis and non-neoplastic prolifera-
tive mucosal changes (69).
Stomach. The gastric histology ranges from no
Figure 8-15
obvious damage to the presence of significant
ALCOHOL-INDUCED GASTRITIS: GROSS APPEARANCE disease. Most histologic changes resemble those
Th e entire gastric mucosa is reddened . Th ere are seen in either chemical gash·opathy or stress gas-
significant erosions at the gastroesciphageal junction and tritis. Usually, the gastric epithelial damage is mild
there is a tear across the junction.
and the inflammation minimal. There may be
superficial necrosis with subepithelial hemonhage
diminished enzymatic activity (61) that leads to (fig. 8-16) and prominent mucosal edema in the
chronic diarrhea or malabsorption. Alcohol con- adjacent nonhemorrhagic mucosa. The amount
sumption may also alter the bowel flora, further of hemorrhage tends to be slightly more than
contributing to malabsorption. Discontinuing that seen in patients on NSAIDs. In some patients,
alcohol consumption corrects the diarrhea, as the edema extends deeper into the interglandular
long as the malabsorption does not result from area (67). Superficial necrosis, erosions, and ulcers
coexisting pancreatic insufficiency. often coexist with these changes. The mucous neck
Gross Findings. Alcohol routinely damages region may appear reactive. Although controver-
the gastrointestinal mucosa, causing erosive sial, it is possible that chronic alcohol ingestion
and nonerosive esophagitis, gastritis (fig. 8-15), produces chronic antral gastritis. Peptic ulcer
and duodenitis (67). The gross and endoscopic disease, gastric vascular ectasia (fig. 8-17), pmtal
findings in the stomach and duodenum depend gastropathy, and gastric varices may coexist with
on the severity of the damage. The mucosa erosive gastritis or chemical gastropathy.
may appear congested, hemorrhagic, eroded, Intestines. Alcohol can induce acute erosive
or ulcerated. Most damage occurs in the an- duodenitis as well as erosive gastritis. The
trum (due to stasis), but the fundus can also changes mimic those induced by NSAIDs (fig.
be involved, as well as the mid and proximal 8-18). Increased numbers of goblet cells and
stomach. Small intestinal mucosal damage foveolar m etaplasia are seen in the duodenum,
primarily affects the proximal duodenum (68). and mild villous atrophy (68) may lead to
Small intestinal changes are usually less severe secondary malabsorption. Patients with portal

306
Chemical Injwy

Figure 8-17
ALCOHOL-INDUCED GASTRIC INJURY
Left: Dilated and congested vessels with areas of acute and chronic
inflammation.
Above: Higher magnification.

hypertension may also develop small or large


intestinal varices.
Differential Diagnosis. The histologic fea-
tures of alcohol-induced gastritis overlap with
acute stress gastritis and chemical gastropathy
due to other causes. It may be impossible to
distinguish among these entities without an ade-
quate history. The changes of pmtal hypertensive
gastropathy may mimic those of gastric antral
vascular ectasia. Many of these patients may also
be consuming aspirin- or ibuprofen-containing
products for their abdominal complaints so that
the endoscopic and histologic picture may there-
fore demonstrate overlapping features. Figure 8-18
Treatment and Prognosis. Cessation of
EROSIVE DUODENITIS SECONDARY
alcohol ingestion usually results in mucosal TO ALCOHOL EXPOSURE
recovery within a few days. The mucosa is congested and appears chronically
damaged.
CHEMOTHERAPEUTIC AGENTS
Definition . .Chemotherapy-induced gastroin-
testinal damage results from the toxic effects of fluoroxidin, 5-fluorouracil (5-FU) alone or in
chemotherapeutic agents on actively replicating combination with leucovorin, mitomycin, cis-
gastrointestinal epithelia. platin, or methotrexate. 5-FU is commonly used
Demography. The gastrointestinal tract is as an adjuvant in gastrointestinal cancer ther-
commonly injured by the chemotherapy used apy. It interferes with DNA synthesis and with
to treat cancer patients. RNA function (76). Cyclophosphamide damages
Etiology. Many chemotherapeutic agents jejunal crypt cells (77a). Vinca alkaloids, such
damage the gastrointestinal tract. The most as vincristine, cause intestinal ulceration, ady-
common are the antimetabolites, including namic ileus, and pseudoobstruction syndromes.

307
Gastrointestinal Diseases

Pathophysiology. Gastrointestinal damage pain and discomfort. Other symptoms associ-


results from both systemic therapy and selective ated with chemotherapy treatment include
hepatic artery infusion chemotherapy (HAIC) nausea, vomiting, stomatitis, anorexia, diarrhea,
used to treat hepatic tumors. Systemic chemo- abdominal pain, and il~us. Chemotherapy-
therapeutic agents primarily target mitotically related diarrhea is a common problem. Severe
active cells (those in the replication zones), diarrhea affects 15 to 20 percent of patients
inducing massive cell death (70); causing crypt receiving 5-FU and leucovorin. It can reduce
epithelial apoptosis, cuboidalization (72), mu- patient compliance and sometimes be a poten-
cosal ulceration, and inflammation; and pro- tially life-threatening disorder. Furthermore,
ducing a lesion known as mucositis (mucosal potential alterations in nutritional status can
inflammation). The degree of mucosal toxicity result from inadequate digestion and a de-
varies depending on the number of drugs used, crease in nutrient absorption. Chemotherapy-
their dosage, the complicating effects of surgery, induced vomiting can lead to Mallory-Weiss
the extent of tumor involvement, and the pres- tears, intramural hematomas, and esophageal
ence of concomitant radiotherapy or secondary perforation. Duodenal perforations complicate
infections. In HAIC, high drug concentrations continuous infusion of 5-FU and cisplatin (76).
may reach the stomach via an aber.rant or col- HAIC may result in localized duodenal or gas-
lateral circulation or catheter displacement. tric ulcers (87). Chemotherapeutic agents such
Inadvertent infusion of 5-FU into the gastro- as vinorelbine predispose to bezoar formation
duodenal or right gastric arteries causes necrosis (7 4) secondary to toxic damage to the myen-
and ulceration of the gastric wall. SQme chemo- teric plexus or they induce lactose intolerance
therapeutic agents also damage the myenteric (80). Malabsorption results from methotrexate
plexus, leading to motility problems. or colchicine treatment. Methotrexate can also
Small intestinal cytotoxicity may re.sult from cause toxic megacolon. Cytosine arabinoside in
vasospasm or a decrease in fibrinolytic activity; combination chemotherapy can cau~.e protein-
this results in decreased mucosal blood flow and losing enteropathy (85) . Paclitaxel has been
ischemic necrosis (73). 5-FU also causes direct associated with colonic perforation (82).
endothelial-independent vasoconstriction of Chemotherapy also predisposes patients to
vascular smooth muscle probably. as a result of mucosal infections, neutropenic ·enterocolitis,
activation of protein kinase C. 5-FU may also ischemia, hemolytic uremia syndrome, and
play a role in venous thrombosis;' perhaps due pseudomembranous colitis. The most com-
to activation of the coagulation cascade (73). mon opportunistic organisms include Candida
Both actinomycin D and adriamycin inhibit sp, herpesvirus, and cytomegalovirus. Some
DNA repair and enhance radiation effects (83). patients develop C. difticile-associated colitis.
They induce a recall phenomenon in which the Patients most likely to develop complications
drugs evoke further radiation damage after prior due to infection often have late-stage cancers
radiation at relatively low doses. Other drugs with the compounding effects of malnutrition,
that increase the effects of radiotherapy include ischemia, sepsis, or shock. Bowel perforation
5-FU, bleomycin, hyproxyurea procarbazine, can affect those with extensive necrosis. An
and vinblastine. Patients on paclitaxel and car- indirect complication of chemotherapy is ero-
boplatin develop submucosal hemorrhages in sion by intraperitoneal chemotherapy catheters
the stomach and patchy duodenal erythema. into the bowel wall.
There is a prominent arrest of cell division in Gross Findings. Chemotherapeutic agents
•.. the intestinal epithelium. Paclitaxel interacts cause mucositis, ulcers, erosions, strictures, and
with microtubule polymers and inhibits depoly- fistulas anywhere in the gut. The incidence of
merization of the microtubule, thereby blocking esophageal injury is high due to the frequent
the cell cycle (89). combination of chemotherapy and radiation
Clinical Features. Chemotherapy leads to a therapy used in an attempt to aggressively treat
high incidence of mucositis, which affects the tumors arising in the chest. The gross intestinal
oral, esophageal, gastric, and intestinal mucosa. findings vary considerably from virtually invis-
Patients with mucositis experience considerable ible to areas of frank ulceration and perforation.

308
Chemical Injwy

Figure 8-19
CHEMOTHERAPY-INDUCED GASTRIC INJURY
A: The mucosa appears slightly fibrotic and there is
villiform transformation of the mucosal architecture. The
epithelium is mucin depleted.
B: The pits and mucous neck region are shown at higher
magnification. The glands appear irregular and there are
many prominent atypical nuclei.
C: Mitotic activity is also increased.

Colonic disease tends to be less severe than ed, cuboidal epithelial cells, sometimes contain-
small intestinal disease. Chemotherapy-asso- ing pleomorphic nuclei (fig. 8-19). The atypia
ciated ulcers grossly resemble peptic ulcers. In is accentuated in the mucous neck region and
some cases, ischemia or infection complicates basal gastric glands. Mitoses range from rare or
the injury induced by the chemotherapeutic absent to numerous (fig. 8-19) with bizarre con-
agents. The typical gross findings of pseudo- figurations (81). The atypia is often more bizarre
membranous colitis or neutropenic enterocolitis than that seen in carcinoma; the atypical cells
may be present (see chapter 10 for a discussion tend to possess abundant cytoplasm (88). The
of these entities). pleomorphism presumably results from inter-
Microscopic Findings. Esophagus. Cytotoxic ference with nucleic acid metabolism. Pyknotic
agents damage the esophageal mucosa directly. smudgy nuclei, apoptotic bodies, and necrotic
Nonspecific areas of necrosis, inflammation, debris lie in both the damaged epithelium and
and granulation tissue occur in severe injury. In in the glandular lumens. Changes consistent
less severe injury, an intact squamous epithe- with chemical gastropathy may be present (fig.
lium may contain enlarged, atypical squamous 8-19). Intestinal metaplasia is usually absent un-
cells. The regenerative basal squamous epi- less the patient has coexisting chronic gastritis.
thelium may appear atypical, sometimes with HAIC can produce gastric ulcers and alarm-
atypical mitoses. Underlying stromal cells and ing epithelial regenerative atypia. The atypia
submucosal glands also often appear atypical. is easily confused with carcinoma due to the
Chemotherapy with cyclophosphamide, meth- presence of binucleated or multinucleated cells
otrexate, and 5-FU may cause Barrett esophagus. containing massive nuclei, sometimes with
Stomach. Histologic changes range from re- prominent nucleoli (71,77,81,88). The drug-
active glandular atypia to frank mucosal ulcer- induced cytologic atypia becomes most trouble-
ation. Crowded, irregularly shaped glands are some when only superficial gastric cells, such
lined by mucin-depleted, large, finely vacuolat- as those present in superficial gastric mucosal

309
Gastrointestinal Diseases

Figure 8-20
ILEAL BIOPSY FROM A PATIENT
STATUS POSTCHEMOTHERAPY
The ileal mucosa is almost completely destroyed. The
villi are lost; the inflammation is both acute and chronic.

brushings, are examined. The cytologic atypia from mild to complete villous atrophy (fig. 8-20).
resembles that seen in severe radiation damage. Macrocytosis may be readily apparent; it is often
Intestines. The mucosa of the small intestine is irregularly distributed from villus to villus or c1ypt
the region most sensitive to chemotherapeutic to crypt. The cellular density of the lamina propria
injury. Reduced mitoses occur within 3 hours of decreases. Ulcers may develop. Many glands are
drug exposure (86,87). Maximum injury occurs cystically dilated and contain cellular deb1is, apop-
after a day and persists for the duration of the totic cells, and numerous granulocytes. Stromal
treatment. The severity of the changes varies cells also show mild atypia.
from case to case. Usually, villous damage is Cellular regeneration occurs when therapy is
patchy in those receiving a single drug. More stopped. It is recognizable by a burst in mitotic
extensive injury with ulceration (fig. 8-20) affects activity and marked variation in nuclear size.
those receiving a combination of chugs or a com- Mitoses are present at all levels of the mucosa,
bination of chemotherapy and radiotherapy. even on the villus surface. These changes usually
Early, the epithelium becomes mucin de- occur within 2 weeks, but inflammation and
pleted and the cells appear cuboidal in shape telangiectasia persist for longer periods of time
(fig. 8-21). Surface epithelial cells become foamy, (77a). During the resolution phase, the crypt
and brush borders are lost; the enlarged pleo- epithelium appears hyperplastic or the crypts
morphic nuclei contain prominent nucleoli. The appear cystically dilated and lined by bizarre
nuclei in the crypt bases become pyknotic, lose cells. Histiocytic cell infiltrates may become
their polarity, and becwme karyorrhectic. Often prominent (78) . Chemotherapy also severely
the crypt bases show prominent apoptosis with depletes the normal intestinal lymphoid tissues,
the production of "popcorn" lesions (fig. 8-22). producing a hypocellular lamina propria and
Eventually, the damage progresses upward, re- loss of Peyer patches.
sulting in superficial mucosal necrosis. Within Severe, large, solitary duodenal ulcers or pol-
24 hours, little necrosis remains because the dead ypoid inflammatory lesions with striking archi-
cells or dead cell fragments are phagocytosed by tectural distortion and cellular pleomorphism
neighboring healthy enterocytes and mucosal develop in patients treated with 5-FU HAIC.
macrophages (79). After a few days, lymphocytes The changes affect the epithelium, stroma, and
and eosinophils infiltrate both the epithelium endothelial cells (84) . The most striking feature
and lamina propria. In cases of severe damage, in all cases is epithelial cell atypia occurring in
all crypts are affected and frank erosions or ulcers glands and in the surface epithelium. Mitoses
develop. The degree of villous blunting ranges may be numerous.

310
Chemical Injwy

Figure 8-21
CHEMOTHERAPY-INDUCED INJURY IN THE DUODENUM
Left: There is marked deformity of the villi with elongation of the crypts, which have an irregular architecture. Many
glands are smaller than normal. The mucosa is edematous and congested.
Right: Another area in the same patient shows glandular dropout as well as glandular regeneration. There is almost
complete absence of villi.

The effects of chemotherapeutic agents ture, recognition of similar atypical changes


on the large intestine are best described for in nearby stromal cells, the presence of atypia
5-FU treatment (75). The earliest recognizable that is more bizarre than that typically seen in
changes affect the crypt bases where the nuclei carcinomas, the lack of an infiltrative pattern
undergo pyknosis, loss of polarity, karyorrhexis, or tumor desmoplasia, the preservation of a low
and apoptosis (fig. 8-22) (75). The lesions may nuclear to cytoplasmic ratio, and late in the
progress to necrosis of the upper mucosa with regenerative process, a lack of mitoses.
inflammation in the crypt epithelium and Treatment and Prognosis. The treatment of
lamina propria. During the resolving phase, the chemotherapy-related diarrhea is nonspecific,
crypt epithelium becomes hyperplastic. Cystic with the aim at reducing the discomfort and
dilatation of crypts lined by bizarre epithelial inconvenience of frequent bowel movements,
cells may be present. Colonic biopsies, however, avoiding the necessity for oral and parenteral re-
often show only nonspecific colitis with crypti- plenishment of fluids and electrolytes, and wait-
tis, ulcers, and acute and chronic inflammation. ing for recovery from the acute damage of the
Collections of apoptotic cells in the crypt bases, intestinal mucosa induced by the antineoplastic
cytologic atypia, and glandular dilatation sug- drugs. Opioid agonists have been a mainstay of
gest the diagnosis. the diarrheal treatment. More recently, octreo-
Differential Diagnosis. Erythema, friability, tide is used to manage these manifestations.
and edematous folds with erosions or ulcer- The epithelium is replaced within several days
ations may occur focally or diffusely in the to 2 weeks following drug cessation. Vascular
colon, and may mimic IBD, cytomegalovirus dilatation and inflammation may continue for
infection, or ischemia. The atypical cytologic several weeks thereafter, leaving the patient
features of chemotherapeutic injury may simu- with the potential for bleeding.
late carcinoma. Features that favor the presence Long-term gastrointestinal sequelae of che-
of an acute chemotherapeutic effect include motherapy are unusual but include the conse-
the overall preservation of mucosal architec- quences of fissures, fistulas, and strictures. Most

311
Gastrointestinal Diseases

Figure 8-22
CYTOXAN INJURY
A: The crypts have a markedly regenerative appearance.
There are apoptotic figures in the base of the crypts creating
a "popcorn" lesion.
B: In some areas, the epithelium within the glands has
acquired an eosinophilic appearance.
C: The base of the glands shows increased proliferation
as well as apoptotic bodies. · 0

patients who develop significant problems have


been treated with multiple drugs or a combina-
tion of chemotherapy and radiotherapy. They
may have other complicating illnesses, such as
infection, ischemia, perforation, or sepsis.
ANTIMICROBIAL DRUGS
Demography. Antibiotics account for a sig-
nificant percentage of drug-associated esophagitis.
They also predispose the esophagus to viral and
fungal infection by damaging the esophageal
mucosal barrier. Antibiotics are the major cause
of C. difficile-associated colitis.
Etiology. Tetracyclines, especially doxycy-
cline, are the most common cause of antibiotic-
induced esophagitis (fig. 8-23) (92). Numerous
... antibiotics predispose to C. difficile infection .
This organism is discussed further in chapter
10. Penicillin and ampicillin cause a right-sided
colitis that differs from the antibiotic-associated
colitis attributable to C. difficile. Tetracycline,
Figure 8-23 neomycin, and erythromycin all cause small
ANTIBIOTIC-ASSOCIATED ESOPHAGITIS intestinal disease. Treatment with erythromycin
Tetracyclines are the most common cause of antibiotic- has recently been associated with hypertrophic
associated esophagitis, as shown in this endoscopic view. pyloric stenosis (92) .

312
Chemical Injwy

Pathophysiology. The pathophysiology of


antibiotic-induced injury, particularly in the in-
testine, varies. Neomycin disrupts micelles and
· decreases pancreatic lipase secretion, leading to
malabsorption of fat. Erythromycin produces
diarrhea by increasing motility and inhibiting
absorption of intestinal enterocytic neutral
amino acids, activity of Na+K+-ATPase (90,93),
and transport of sodium-dependent sugar. Peni-
cillin, ampicillin, tetracycline, isoniazid, and
chloramphenicol all cause vasculitis. Penicillin,
ampicillin, tetracycline, and erythromycin can
cause Henoch-Schbnlein purpura secondary to
a drug hypersensitivity reaction. Flucytosine Figure 8-24
causes ulcerative enterocolitis due to direct PSEUDOMEMBRANOUS COLITIS
mucosal toxicity. The patient was on antibiotic therapy and developed an
Clinical Features. The major adverse effects acute episode of severe colitis necessitating resection. The
of antibiotics include pill-induced esophagitis, colonic mucosa was erythematous and covered by discrete
malabsorption, diarrhea, and pseudomembra- and coalescing pseudomembranous lesions.
nous colitis. Neomycin, erythromycin, some
antimalarial agents, and paraaminosalicylate
cause malabsorption (92a). The antifungal small bowel biopsy whenever malabsorption is
drugs flucytosine and clofazimine, used to treat suspected in the absence of an overt pancreatic
leprosy, cause ulcerative enterocolitis. Antibiot- abnormality. In general, situations associated
ics may exacerbate symptoms associated with with villous atrophy (e.g., celiac disease), in-
ulcerative colitis. filtrations (e.g., amyloidosis), or chronic infec-
Gross Findings. The gross and endoscopic tions (e.g., giardiasis) are considered. In the
features of antibiotic-related damage reflect the colon, the differential diagnosis includes many
underlying abnormality and the site of dam- forms of colitis.
age in the gastrointestinal tract. Drug-induced Treatment and Prognosis. Many of the clinical
esophagitis may present with areas of erosion findings resolve upon cessation of the drug ther-
and ulceration. Antibiotic-induced C. difticile apy. C. difticile colitis requires specific treatment.
colitis may be associated with pseudomembrane
formation (fig. 8-24). Patients developing hyper- IMMU NOSUPPRESSIVE AGENTS
trophic pyloric stenosis following erythromycin Demography. Patients on immunosuppres-
prophylaxis have a pylorus with the mean sive therapies who develop gastrointestinal
thickness and length of a pylorus affected with problems are often transplant patients, pa-
idiopathic hypertrophic pyloric stenosis (91). tients with IBD, or patients with autoimmune
Microscopic Findings. Neomycin induces diseases. Immunosuppressive agents are now
villous clubbing, brush border fragmentation, widely used for many "benign conditions" such
microvillous loss, and ballooning degeneration as asthma, rheumatoid arthritis, IBD, chronic
of the epithelial cells. The small intestinal villi hepatitis, vasculitis, and other conditions with
may appear shortened and mitoses are increased. an autoimmune and chronic inflammatory
Rarely, the lamina propria becomes infiltrated basis, as well as for neoplastic disease.
with plasma cells, neutrophils, eosinophils, and Etiology. Immunosuppressive agents, includ-
periodic acid-Schiff (PAS)-positive macrophages. ing steroids, indomethacin, mycophenolate,
The histologic features of C. difticile-associated azathioprine, tacrolimus, and cyclosporine, all
enterocolitis are described in chapter 10. damage the gastrointestinal tract.
Differential Diagnosis. The differential di- Pathophysiology. Controversy exists as to
agnosis includes other causes of malabsorption whether steroids directly damage the gastro-
and enterocolitis. The clinician may perform a intestinal tract (98,99,106,109). Steroids do

313
Gastrointestinal Diseases

exacerbate underlying gastric mucosal damage Indomethacin in suppositories causes rectal


by: 1) stimulating G-cell hyperplasia (101); 2) ulceration. Abdominal pain and diarrhea are
increasing acid production by parietal cells; 3) the most common adverse reactions of myco-
decreasing epithelial turnover and inhibiting phenolate therapy (95,96,105). Mycophenolate
cellular regeneration and fibroblastic repair; also causes gastritis, ulcers, gastrointestinal
and 4) inhibiting mucin secretion. Other im- hemorrhage, perforation, esophagitis, and an-
munosuppressive agents directly injure the gut orexia (96). Neutropenic enterocolitis and toxic
and predispose individuals to gastrointestinal megacolon are serious, often life-threatening
infections, especially those caused by herpes- complications of mycophenolate.
virus, cytomegalovirus, Candida, Aspergillus, C. Gross Findings. Immunosuppressive drugs
dif{lcile, and less commonly, Microsporidia (96). lead to mucosal erosions and ulcerations.
Indomethacin inhibits mucosal bicarbonate Steroid-associated ulcers are usually superficial
production; induces villous necrosis, hemor- but deeper ulcerations may lead to perforation.
rhage, neutrophilic inflammation; and predis- Endoscopically, the mucosa appears edema-
poses the duodenal mucosa to peptic ulceration tous, with adecreased vascular pattern. Patchy
and enhanced bacterial translocation (111). erythema and erosive changes are frequently
Cyclosporine causes generalized small intes- observed in the stomach, small intestine, and
tinal microvascular injury (100). Tacrolimus, large intestine. Ulcerative lesions, if present,
a potent immunosuppressive drug, decreases may be discrete and require biopsy to exclude
mitochondrial adenosine triphosphate (ATP) ischemia, cytomegalovirus, or other opportu-
production, increases intestinal permeability by nistic infections.
a mechanism similar to that seen with NSAIDs Microscopic Findings. Indomethacin causes
(104), and predisposes patients to endotoxemia tissue eosinophilia and cytologic atypia, appar-
and impaired intestinal absorption (104). ·Re- ent in gastric brushings (102). Corticosteroids
cipients of organ allografts may develop a graft and azathioprine deplete lymphoid tissues,
versus host disease-like condition when doses including gut-associated lymphoid tissues (97),
of cyclosporine are tapered off, a phenomenon causing a decrease in the size of lymphoid fol-
possibly related to an autoimmune reaction. licles (fig. 8-25) and focal small erosions with
Mycophenolate mofetil is a 1'elatively new M-cell necrosis. This predisposes to bacterial
immunosuppressive drug that i:ghibits inosine invasion and subsequent perforation. The fol-
monophosphate dehydrogenase, a key enzyme licular regions become severely B-cell depleted.
in the de novo pathway of purine synthesis. It Steroids also cause inflammation and cellular
causes lymphocyte-selected immunosuppres- necrosis (fig. 8-26). They slow mucosal cell
sion. It is used to prevent allograft rejection renewal and decrease the reparative activity
and is usually administered together with of fibroblasts, further predisposing to perfora-
cyclosporin or tacrolimus and corticosteroids. tion. Mycophenolate causes colonic necrosis,
Its major adverse effects are on the gastrointes- secondary regenerative changes (fig. 8-27), and
tinal tract (96). intestinal changes that mimic graft versus host
Clinical Features: Patients on immunosup- disease (108). High doses of mycophenolate
pressive therapies experience various gastro- inhibit the proliferation of the basal epithelial
intestinal complications, some of which have cells in the intestinal tract (96).
an ischemic or infectious basis and others that Treatment and Prognosis. Drug withdrawal
result from the toxic effects of the drugs them- usually reverses the gastrointestinal damage,
selves. Ulceration, hemorrhage, and perforation unless severe complications have developed.
may result (94,108). Steroids can suppress clini- Steroid-induced ulcers are usually superficial
cal symptoms, leading to a delayed diagnosis of and heal with drug withdrawal, but deeper
either underlying conditions or diseases caused lesions may perforate. This is particularly a
by the steroids themselves. Intestinal side ef- problem in low birth weight neonates receiv-
fects of tacrolimus are frequent and include ing high-dose steroids (107,110). Octreotide
abdominal cramps, distension, nausea, vomit- may resolve the diarrhea associated with myco-
ing, diarrhea, and malabsorption (103, 105). phenolate therapy.

314
Chemical Injury

Figure 8-25
TERMINAL ILEAL BIOPSY IN A
PATIENT ON LONG-TERM STEROIDS
The biopsy is remarkable for its absence of Peyer patches
and for the relative hypocellularity of the lamina propria.

LAXATIVE USE
Definitions. Melanosis coli is the term used to
describe the dark brown mucosal pigmentation
that complicates the use of certain laxatives.
Cathartic colon is the end-stage colon that no Figure 8-26
longer effectively contracts, presumably due COLONIC BIOPSY IN A PATIENT WITH
to extensive damage of the myenteric plexus APLASTIC ANEMIA TREATED WITH STEROIDS
induced by long-term cathartic use (abuse). Top: The mucosa is inflamed and an increased number
Demography. The majority of patients with of mononuclear cells is seen in the lamina propria.
severe laxative-induced melanosis coli are Bottom: Higher magnification shows inflammation in
women who have had chronic constipation and the surface epithelium, immaturity of the epithelium, and
mucin depletion.
abdominal pain since early childhood and use
laxatives long-term. An obsession with bowel
movements is common; some patients have as part of the binge-purge syndrome (120).
a history of sexual abuse. Patients with eating Estimates of the incidence of laxative-induced
disorders, especially bulimic patients, patients changes is about 5 percent in endoscopic stud-
with motility disorders, and laxative abusers ies based on the presence of melanosis coli. The
constitute other major groups of patients with frequency of melanosis coli at autopsy ranged
laxative-induced injury. Bulimic individuals from 11 to 32 percent in the past, but it appears
typically consume large amounts of laxatives to be decreasing in incidence.

315
Gastrointestinal Diseases

Etiology. Anthraquinones, bisacodyl phe-


nolphthalein, and magnesium salts all damage
the gastrointestinal mucosa. Fleet enemas and
bisacodyl may cause sloughing of the rectal
surface epithelium; the lesions resolve in 7 days.
Melanosis coli results from use of cascara sagrada,
aloes, danthron, senna, frangula, and rhubarb.
Evidence is beginning to emerge that melanosis
coli does not result solely from laxative use. It
can also occur in patients with IBD (both Crohn's
disease and ulcerative colitis) who have not used
laxatives (121) and in individuals with diarrhea
unrelated to IBD who have not used laxatives.
Pathophysiology. Anthraquinones concen-
trate in the colon, particularly in the right colon,
where they are potent cellular poisons that cause
apoptosis, even when taken in small doses (122,
124). The apoptotic bodies are phagocytized by
macrophages and transformed into lipofuscin
pigment by lysosomal enzymes (125) . The mean
apoptotic count is significantly increased in those
with melanosis coli compared with a control
population. It takes 4 to 12 months for melanosis
coli to be visible and the same amount of time for
it to disappear. It is possible that any;condition
associated with increased apoptosis may result in
melanosis coli (113,115). When present in small
quantities, anthraquinones probably stimulate
neural tissues, leading to their purgative actions.
But the anthraquinones and other laxatives can
also damage the myenteric plexus, causing neu-
ronal loss, Schwann cell proliferation, axonal
fragmentation, axonal and dendritic swelling,
and smooth muscle damage (122-124). This
eventually leads to cathartic colon. Bisacodyl,
phenolphthalein, castor oil, and other agents
also cause cathartic colon.
Clinical Features. Laxatives are most com-
monly used by patients with chronic constipa-
tion or motility disorders. Laxative abuse occurs
in patients with eating disorders. Many patients
Figure 8-27
are syrnptomless, only to be diagnosed following
endoscopic examination for other reasons. Indi-
MYCOPHENOLATE COLONIC INJURY viduals with surreptitious laxative abuse typically
IN A RENAL TRANSPLANT PATIENT
present with unexplained chronic diarrhea. Some
Top: The mucosa is severely damaged with evidence
of chronic changes. The glands are branched and of
patients may have an obsession regarding their
irregular sizes and the lamina propria contains increased need to have a bowel "cleansing." In extreme
mononuclear cells. There is also evidence of marked cellular circumstances, individuals using (abusing) laxa-
regeneration. In some areas, the mucosa appears to have tives develop protein-losing enteropathy, mal-
been desqua-mated.
Bottom: Regenerated glands with dystrophic goblet cells
absorption, steatorrhea, hypokalemia or other
and irregularly shaped tubules. electrolyte imbalances (118), and cachexia; in

316
Chemical Injury

Figure 8-29
CATHARTIC COLON
The bowel is markedly dilated with loss of haustral folds,
areas of ulceration, and reddish discoloration.

those with motility disorders, hypogammaglob-


ulinemia (112), chronic constipation, and pseu-
doobstruction may occur (122).
Patients with cathartic colon present with
chronic constipation, a sense of constant
abdominal bloating or distension, pseudoob-
struction, abdominal pain, and incomplete
evacuation. These result from the toxic effects of
the drugs on the neural structures in the bowel
wall and secondary muscle damage (123). Nar-
cotic use often aggravates the symptoms. Severe
constipation leads to the formation of hard feca-
liths that can cause local chronic inflammation,
acute inflammation, stercoral ulceration, bleed-
ing, and perforation. In patients with stercoral
ulcerations it is difficult to determine whether
the laxatives are the cause of the changes or
are merely associated with them. Concomitant
medication use and previous intestinal surgeries
complicate the clinical picture.
Gross Findings. The endoscopic features of
chronic laxative use depend on whether the pa-
tient has only melanosis coli (fig. 8-28) or has a
cathartic colon (fig. 8-29). Melanosis coli begins
Figure 8-28 in the right colon and progresses distally as the
MELANOSIS COLI duration and intensity of cathartic use increases.
A: Endoscopic view of the mucosa shows intense The pigmentation tends to be heaviest in the
brownish pigmentation. right colon, including the appendix. Rectal mela-
B. Resection specimen shows brownish discoloration nosis coli signifies chronic laxative use. In severe
of the mucosa. Adenomas appear pink on the brownish
background. disease, the mucosa appears dark brown or black.
C: Intense melanosis coli. The mucosa is very blackened. The changes typically spare areas occupied by
The changes stop at the ileocecal valve. lymphoid follicles, adenomas, and carcinomas;

317
Gastrointestinal Diseases

Figure 8-30
MELANOSIS COLI
Left: Numerous pigmented histiocytic cells lie within the lamina
propria.
Above: In a case of long-standing laxative abuse, the pigmented
melanocytes eventually migrate into the underlying lymphoid follicles
at the junction of the muscularis mucosae, submucosa, and mucosa.

these areas usually stand out as lighter areas on brown, pigmented macrophages populate the
an otherwise darkened mucosa. lamina propria (fig. 8-30). The entii-e mucosa,
In patients with cathartic colon, the bowel submucosa, and eventually, mesenteric lymph
always shows melanosis coli. The proximal nodes may contain pigmented macrophages.
colon tends to develop patchy .pigmentation Pigmented macrophages migrate into regional
that resembles snakeskin. Eventually, the entire lymph nodes, resulting in sequential loss of
colon and even the terminal i leum become pigment from the superficial and deep lamina
atrophic and atonic. Redundant bowel loops propria (125). The pigment may also be found
are common. In severe cathartic colon, haustra in neurons. The lipofuscin pigment that accu-
disappear and the colon is converted into an ir- mulates is autofluorescent; sudanophilic; acid
regular, focally dilated or sacculated, flattened, fast; positive with PAS, Schmorl, and aniline blue
atrophic tube (fig. 8-29) (117). The muscularis sulfate stains; and shows an intense argentaffin
propria appears thinned and atrophic, and reaction that is abolished by bleaching, indicat-
submucosal fat becomes prominent, seeming to ing the presence of a melanic substance. Because
bulge from the cut eqges of a resected specimen. the autofluorescent pigment of melanosis coli
The ileocecal valve, which is invariably affected, contains melanin as well as glycoconjugates, it
becomes incompetent (122-125). has been suggested that the pigment be termed
Microscopic Findings. The histologic features "melanized ceroid." The ceroid pigment devel-
of laxative use range from mild melanosis coli ops from the abundant apoptotic epithelial cells
'-,•
to severe cathartic colon. In early stage disease, whereas the precursors of the melanic substance
pigmented macrophages lie in the superficial mu- may derive from the anthracoids (113). Sub-
cosa, often associated with nonspecific chronic luminal microgranulomas, often containing
inflammation and increased numbers of apoptot- pigment, may form. Magnesium sulfate can
ic bodies. The inflammation probably represents cause jejunal mucosal shedding (114), glandular
a nonspecific response to an underlying injury atrophy, thickening of the muscularis mucosae,
or to the stasis that may have been the cause for and atrophy of the muscularis propria. Fatty
the laxative ingestion, rather than a direct effect droplets may be seen within the regional lymph
of the laxative consumption. Refractile, golden nodes in patients who use mineral oil.

318
Chemical Injwy

In early cases of cathartic colon, the mucosa abusers. Promotility agents are occasionally suc-
appears mildly inflamed and glandular atro- cessful. Patients who require frequent enemas
phy may develop. Eosinophilic infiltrates may or who experience fecal impactions need to be
be present. There may also be mucosal ulcers. considered as having colonic inertia and may
Abnormalities of the myenteric plexus include benefit from subtotal colectomy.
neuronal swelling and pallor. Later, there is
loss of argyrophilic neurons, marked axonal ENEMAS
fragmentation, gliosis of the myenteric plexus, Etiology. The various agents used to prepare
and ganglionic vacuolization. The remaining the colon for endoscopic examination may
argyrophilic neurons appear dark and shrunken, induce minimal mucosal changes that can be
with clubbed or swollen processes. Often the mistaken for mild colitis. Most alterations oc-
myenteric plexus becomes inflamed. Degen- cur in patients using enemas containing Fleet
erative changes also involve the submucosal phosphosoda, bisacodyl (Dulcolax), hydrogen
plexus and include axonal ballooning, loss of peroxide, and other hypertonic solutions (126,
neural tubules and neurosecretory granules, and 130-132) . Oral sodium phosphate use is be-
increased lysosomes. Atrophy of the muscularis coming increasingly common compared with
propria develops secondary to denervation in- alternative preparatory agents due to better
jury following neural damage. The muscularis patient acceptance, superior comparable bowel
mucosae hypertrophies as a compensatory re- cleansing effects, and lower cost.
sponse to the atrophy of the muscularis propria. Clinical Features. Soap-containing enemas
Although these changes have been ascribed to can cause diarrhea and rectal bleeding. Cleans-
laxatives, it is possible that they represent a ing enemas can cause a chemical proctosig-
primary disorder of the enteric plexuses that moiditis and even a perforation (127,129) .
caused the initial constipation and subsequent Gross Findings. Both Fleet phosphosoda and
laxative ingestion. bisacodyl produce endoscopic alterations that
Special Techniques. Toxicologic analysis of mimic mild colitis, including obliteration of the
urine or stool for the metabolic byproducts of vascular pattern with mucosal hyperemia and
the drugs detects surreptitious laxative abuse mucosal friability. The nozzle/tubing may be
in patients with diarrhea of uncertain origin responsible for localized mucosal trauma. This
(116,119). Silver stains or immunostains may is generally easily recognized endoscopically
highlight the neural changes. as irregular and linear erosions or ulcerations.
Differential Diagnosis. The differential Microscopic Findings. Changes associ-
diagnosis of laxative-induced injury includes ated with enema use differ depending on the
an underlying primary or secondary muscular preparation (fig. 8-31) (130). Goblet cell mucus
disorder (see chapter 17). Melanosis coli can is often reduced and there is frequently a mild
resemble mucosal hemosiderin, which typi- hyperplasia of the crypt epithelium, nuclear
cally appears as larger, refractile, shiny granules . crowding, and mitotic figures higher in the
Iron stains confirm the presence of mucosal crypt than normal. Hypertonic phosphate
iron. Pigment deposition can also be seen in enemas may induce surface epithelial vacuol-
storage diseases and in chronic granulomatous ization and subsequent detachment from the
disease, but in those disorders the macrophage basal lamina, subepithelial infiltration by a
collections tend to be larger than those seen in small number of neutrophils, and edema in the
melanosis coli. In addition, with storage diseases lamina propria. Bisacodyl (Dulcolax) induces
other cells are often pigmented as well, includ- more severe changes, with a pale, vacuolated
ing nerve and smooth muscle cells. surface and crypt epithelium that extends deep
Treatment a nd Prognosis. Treatment con- into the mucosa and is associated with a neu-
sists of modifying the cathartic use and adding trophilic infiltrate of the epithelium and lamina
bulking and fluid supplements. Psychological propria. The changes elicited by both of these
support, particularly altering the patient's ex- agents can be mistaken for a mild colitis.
pectations and treating coexisting depression Saline enemas and oral hypertonic solutions
and obsessive behaviors, is important in laxative usually only cause mild edema of the lamina

319
Gastrointestinal Diseases

osmotic load from the sorbitol enema causes


vascular shunting, resulting in mild colonic
ischemia and colonic necrosis in a subset of
uremic patients.
Clinical Features. Patients with intestinal
injury present with an abrupt onset of severe
abdominal pain within hours of enema admin-
istration. Profuse rectal bleeding may occur.
Gross Findings. The endoscopic findings
of the upper gastrointestinal tract are abnor-
mal. Esophageal changes mimic esophageal
carcinoma, candidial esophagitis, and gastric
Figure 8-31 bezoars. Ulcers and erosions are present in most
LAXATIVE EFFECTS patients (136). Patients may develop serpiginous
There is marked edema with minimal inflammation. ulcers of the stomach, terminal ileum, or large
intestine (140). Patients with severe injury may
need bowel resection, at which time long seg-
propria without epithelial damage. Oral sodium ments of (or even the entire) colon and rectum
phosphate, a commonly used oral cathartic may appear necrotic.
agent, can cause aphthoid ulcers or a mild fo- Microscopic Findings. Kayexalate causes
cal active colitis in the colon and-rectum (135). esophageal, gastric, and colonic lesions (138,
There may be occasional neutropf..tilic infiltrates 139). Kayexalate and sorbitol induce local-
of both the epithelium and the lamina propria. ized coagulative necrosis, submucosal edema,
In addition to the presence of aphthous ulcers and transmural inflammation (138,139). The
and inflammation, cell proliferative indices changes resemble acute ischemia without reper-
increase. The proliferation rate correlates with fusion. They also superficially mimic autolysis,
the number of apoptotic bodies (126). although mild neutrophilic infiltrates may be
Soap-containing enemas or enemas contain- present. These changes occur anywhere in the
ing alcohol or hydrogen peroxide can cause gastrointestinal tract, although they are most
extensive necrosis, inflammation, and mucosal frequent in the stomach or colon. Mucosal dark
shedding, and can mimic mild"'i schemia (128, purple, PAS-positive, acid-fast-positive kay-
132). The changes are usually restricted to the exalate crystals are typically present (fig. 8-32).
mucosa. Hydrogen peroxide also causes pseudo- Differential Diagnosis. Rhomboid-shaped
lipomatosis. The gas bubbles in the lamina pro- crystals may also be found within the bowel.
pria result from the release of nascent oxygen They are bright orange-red rather than dark
from the peroxide (129,133,134). purple, and are red with PAS and bright pink
with acid fast stains (137).
Kayexalate-Sorbitol Enema
Treatment and Prognosis. In some cases,
Demography. Kc;tyexalate-sorbitol enemas elimination of the kayexalate enema results in
are used to treat hyperkalemia in patients with resolution of the gastrointestinal manifesta-
renal insufficiency. tions. Treatment is generally supportive, but
Etiology. The sodium polystyrene sulfonate occasionally, blood transfusion and even hemi-
(Kayexalate/sorbitol) causes the gastrointestinal colectomy may be necessary.
•.· injury.
Pathophysiology. Kayexalate is a cation ex- RADIOGRAPHIC SUBSTANCES
change resin that releases sodium ions in the Definitions. Barium causes three types of
large intestine. The sodium ions are replaced by gastrointestinal problems: 1) barium granulo-
potassium, and the excess potassium is evacu- mas, 2) bolus obstruction, and 3) an allergic or
ated in the stool. Since kayexalate can cause anaphylactic reaction from the carboxymethyl-
constipation or impaction, it is administered cellulose component of the barium sulfate
together with sorbitol, an osmotic laxative. The suspension. Barium granulomas are nodules of

320
Chemical Injwy

Figure 8-32
KAYEXALATE CRYSTALS ASSOCIATED WITH ACCUTE APPENDICITIS
Left: The basophilic polygonal kayexalate crystals often have a characteristic fish-scale appearance seen here on H&E stain.
Right: Higher magnification shows collections of histiocytic cells containing refractile material. (Courtesy of the Division
of Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC.)

histiocytes containing barium sulfate, usually masses that cause pain, constipation, and even
localized to the gastrointestinal submucosa. intestinal obstruction. If the bowel ruptures dur-
Demography. Allergic reactions to barium ing a barium enema, the patient may develop
sulfate affect less than 2 individuals/million barium peritonitis. Many perforations are lim-
(141,142). Perforation is an uncommon com- ited to the retroperitoneum. Intraperitoneal per-
plication of contrast media, affecting 1/40,000 foration results in acute peritonitis. Shock may
patients with barium enemas. When perfora- occur. Dense intraperitoneal adhesions are a late
tion occurs, it does so either following damage complication in survivors of the acute event.
caused by previous mucosal disease, such as Gross Findings. The gross appearance of
active colitis or diverticulitis (142, 144), or as a barium injury differs depending on whether an
result of mechanical damage caused by intro- allergic reaction is present or whether barium
duction of enema tips, balloons, and catheters. has extravasated into the surrounding tissues.
Etiology. By far the most common radio- Barium granulomas produce brownish green
graphic substance to cause alterations in the tumorous masses, fibrosis, and strictures that
gastrointestinal tract is barium. Water-soluble may grossly resemble a carcinoma. Most barium
radiographic contrast media may cause an acute granulomas develop in the rectum, approxi-
colitis (143). Gastrographin may produce a se- mately 10 cm proximal to the anal verge, often
vere colitis, probably due to TWEEN 80, which on the anterior wall. They vary in size, ranging
is used as a wetting agent. up to 10 cm in diameter, and usually are found
Pathophysiology. Radiologic contrast me- in the submucosa. Larger lesions may become
dia cause perforation, granuloma formation, centrally umbilicated. Sometimes, the barium
ischemic necrosis, acute appendicitis, bezoars, forms hard concretions in the bowel lumen.
and masses, as well as mucosal injury. Barium Allergic mucosal changes may be mild.
granulomas develop when barium contrast Microscopic Findings. Barium sulfate is often
extravasates during the administration of seen in the gastrointestinallumen, appearing as
barium enemas via mucosal tears, abrasions, fine, greenish, nonrefringent granules, or as larg-
or diverticula. Barium incites an inflammatory er, birefringent, rhomboid crystals, sometimes
reaction that is polymorphic and includes his- located in granulation tissue (fig. 8-32). These
tiocytes and foreign body giant cells. findings merely indicate prior use of barium in
Clinical Features. Most patients with small the patient and does not qualify as a diagnosis of
barium granulomas remain asymptomatic, and barium granuloma. When barium gains access
the granulomas are incidental findings. Patients to the submucosa, it elicits a granulomatous
with larger barium granulomas present with response (fig. 8-33). Barium granulomas consist

321
Gastrointestinal Diseases

Figure 8-33
BARIUM GRANULOMA
Left: Damaged mucosa overlies an area of displaced glands and a defect within the submucosa surrounded by inflam-
matory cells.
Right: Higher magnification of the inflammatory response with collections of histiocytes as well as mononuclear cells,
all containing refractile barium.

of collections of macrophag~s containing alkalis, or hot liquids. It can also result from instil-
brownish green-gray barium sulfate crystals, lation of caustic substances per rectum. Corrosive
surrounded by typical foreign body giant cells. esophagitis, corrosive gastritis, corrosive colitis, and cor-
The barium induces surprisingly little inflam- rosive proctitis occur depending on the site affected.
mation due to its inert nature. Small granular Demography. Corrosive ingestion gener-
crystals may be found in clusters. The barium ally results from accidents or suicidal gestures.
sulfate does not bend polarized light but it is The amount of corrosive agent ingested tends
refractile and easily seen when _the microscope to be less in accidental consumption than in
condenser is lowered. Allergic reactions tend to attempted suicide (152). Corrosive esophagitis
resemble other forms of allergic.rgastrointestinal most commonly affects young children who
diseases. Eosinophils dominate the histologic accidentally ingest household cleaning agents.
picture. The mucosa may be mildly edematous. Etiology. The degree and extent of dam-
Gastrographin does not elicit an inflammato- age induced by corrosive agents depend on
ry response. Morphologically, large rectangular the nature of the substances ingested, the
or rhomboid, light tan-yellow crystals are found morphologic form of the agent, the quantity
in the bowel lumen, sometimes associated with of the agent, and the intent of the patient.
an occasional giant cell. Ingestion of strong alkalis, acids, bleaches and
Differential Diagnosis. Clinically, other other household cleaning products, or very
mass lesions of the gastrointestinal tract mimic hot liquids causes corrosive esophagitis. Some
barium granulomas. The refractile greenish crys- of these agents include mineral acids, organic
tals, however, are pathognomonic for barium. acids such as carbolic acid (phenol) used in
Treatment and Prognosis. Treatment of pa- many commercial disinfectants, bleach (sodium
,.,. tients with asymptomatic barium granuloma is hypochlorite), liquid drain cleaner, Lysol, acetic
usually unnecessary and management generally acid, ammonia, and sodium acid phosphates
focuses on excluding other granulomatous dis- used as toilet cleaners. Automatic dishwasher
orders. Surgery plays a central role in the treat- detergents (metasilicates) are also very caustic
ment of acute perforations and obstructions. and can cause serious accidents. Alkalis with a
pH of over 12.5 usually injure the esophagus
CAUSTIC OR CORROSIVE INJURY more severely than the stomach; the reverse
Definition. Corrosive injwy is mucosal dam- occurs with acids, Alkalis reaching the stomach
age resulting from the ingestion of caustic acids, are rapidly neutralized by the acid within it.

322
Chemical Injury

Liquids tend to produce extensive, geograph- the esophagus and stomach. It also results in
ically continuous erosive esophagitis and gas- drooling and mucosal slough ulcers in the
tritis, whereas granular agents produce more oral cavity (152). Corrosive burns are typi-
· proximal and more localized lesions. Crystalline cally visible on the skin or mucosa around the
drain cleaners contain more than 50 percent so- mouth, oropharynx, esophagus, and stomach
dium hydroxide and they can produce transmural when corrosive injury occurs (162). Patients
injury if consumed in sufficient amount but pain develop systemic leukocytosis. Severe corrosive
usually limits the amount swallowed. Deep ulcers esophagitis leads to esophageal hemorrhage,
and strictures complicate ingestion of compounds perforation, and death. Lye-induced injuries are
with a pH over 13. Hair relaxers are a common often complicated by respiratory compromise,
cause of caustic ingestions (146). Heavy metal salts esophageal and gastric perforation, sepsis, and
such as zinc or mercmic chlmide and fenous sulfite death. Ingestion of fuming substances, such as
also cause corrosive injury. nitric acid or ammonia, causes severe irritation
One unique form of corrosive injury results of the upper respiratory passages and bronchi.
from the ingestion of button batteries used in hear- Burns that are limited to the mucosa resolve
ing aids, watches, and calculators. Most of these rapidly, whereas those that extend into the wall
contain a heavy metal such as mercury and an tend to persist (155).
alkaline electrolyte. Esophageal impaction results The typical clinical course of uncomplicated
in corrosive esophagitis leading to perforation. caustic ingestion has three phases: acute, latent,
Pathophysiology. Alkalis produce liquefac- and retroactive. In the acute phase, immediate
tion necrosis with intense inflammation and oral burning pain often limits the ingested vol-
saponification of the mucosa, submucosa, and ume. If enough volume is swallowed, however,
muscularis propria (149,150,155). Since alkalis chest pain and dysphagia immediately develop.
dissolve tissues, they penetrate more deeply Retching and vomiting follow. Esophageal dys-
than acids. Thrombosis of adjacent vessels motility and edema generally subside over the
leads to ischemic necrosis, followed by bacte- next 3 to 4 days. The acute changes may affect
rial or fungal colonization. Contraction of the the entire thickness of the wall and may result
lower esophageal sphincter protects the gastric in perforation (147). The patient usually has
mucosa from injury. Thus, esophageal alkaline- no further esophageal symptoms in the latent
induced injury is most severe in the mid and phase, and both the patient and the physician
distal esophagus. develop a false sense of security. The esophagus
Acids more regularly affect the stomach, pre- is most likely to perforate during the subacute
sumably due to less esophageal spasm and less or latent phase. Perforation is common in
esophageal retention of the acids. Acids cause corrosive injury. The third phase, scar retrac-
coagulative necrosis, resulting in a firm protec- tion, begins as early as the 2nd week and lasts
tive eschar that limits acid penetration and de- months. Clinically apparent strictures develop
lays injury (147). This results in extensive areas in 10 to 33 percent of patients. Strictures ap-
of hemorrhage and ulceration and the potential pear as early as weeks 3 to 8, often progressing
for perforation and stricture development. Even rapidly, advancing from mild dysphagia to the
though the esophageal mucosa is relatively re- inability to handle secretions in only a couple
sistant to acid damage, high acid concentrations of days. Strictures that appear after the second
eventually injure it. In the stomach, both acids month progress more slowly (155). Stricture for-
and alkalies predominantly damage the antrum mation is much less common with acid injury
due to stasis in this region. than with alkaline-induced damage.
The injury associated with button battery Patient symptoms are unreliable in predicting
in gestion occurs via four mechanisms: 1) disease extent or severity. If the patient survives
electrolyte leakage from the batteries, 2) alkali the acute injury, there is still the risk of the
produced from external currents, 3) mercury development of dysphagia, esophageal rigidity
toxicity, and 4) pressure necrosis. and shortening, gastroesophageal reflux, Bar-
Clinical Feat u r es. Ingestion of corrosive rett esophagus, and even carcinoma (145,160).
substances results in spasm and necrosis of Benign strictures must be distinguished from

323
Gastrointestinal Diseases

Figure 8-34
ENDOSCOPIC APPEARANCE OF CAUSTIC INJURY
A: Caustic geographic ulcerations of the esophagus.
B: Caustic injury of the stomach with edema and erythema.
C: Another view of the stomach showing the erythema.
D: Pyloric stenosis in a patient with previous caustic ingestion.

carcinoma, particularly when they develop years Gross Findings. Caustic agents cause bums
after the caustic exposure. Endoscopic brushings that remain limited to the mucosa or more
of the lesional surface should be performed, since diffusely involve the gastrointestinal wall (fig.
densely fibrotic scar tissue may be exceedingly 8-34). First-degree bums cause superficial mu-
difficult to biopsy. Many recommend periodic cosal involvement. Second-degree burns cause
surveillance for the detection of malignancy transmucosal involvement, with or without
beginning 20 years after caustic ingestion. submucosal involvement but without extension

324
Chemical Injwy

to the surrounding tissues. Third-degree burns


cause full-thickness injuries with extension into
adjacent tissues. The most severe injury occurs
in areas of luminal narrowing such as the area
where the aorta or the left main stem bronchus
crosses the esophagus at the tracheal bifurcation
or in the area of the sphincters.
In the esophagus, the acute injury phase lasts
4 to 5 days and consists of coagulative necrosis
variably extending into the esophageal wall.
Epithelial sloughing usually follows, sometimes
creating deep ulcers. The entire mucosa may also
slough in severe burns. Complete separation of
the squamous mucosa results in the formation
of a mucosal cast that the patient vomits up in
a condition referred to as esophagitis desiccans
superfi.cialis (161). Deep ulcers become fibrotic if
the patient survives the acute injury. Strictures
(fig. 8-35) cause dilatation and hypertrophy of
the esophagus proximal to the narrowed area.
Corrosive acids also may induce esophageal
intramural pseudodiverticulosis (154). Inflam-
mation of adjacent organs leads to mediastinitis
or peritonitis. Severe lesions, involvement of the
entire length of the esophagus, hematemesis,
and increased serum lactic dehydrogenase are
risk factors for the development of strictures
induced by caustic ingestion (158). Esophageal
strictures may be complicated by the develop- Figure 8-35
ment of Barrett esophagus or carcinoma (145). LYE INGESTION
Radiologic findings include solitary or mul- Esophageal stricture du e to previous lye ingestion.
tiple strictures of varying lengths, intramural
pseudodiverticula, and carcinoma in long-
standing corrosive injury (157) . Technetium narrowing (fig. 8-37), which can progress to
99M-labeled sucralfate radiography is an ac- complete gastric outlet obstruction.
curate technique for assessing the degree of The mildest form of gastric injury is charac-
esophageal injury after the ingestion of caustic terized by mucosal erythema, edema, and fri-
substances. It may also be used to document ability without necrosis or ulceration. Necrosis,
healing (156). Radiologic features seen in the ulceration, mucosal hemorrhage, and exudation
stomach include areas of scarring, particularly are encountered in second-degree injury, while
in the antrum, a linitis plastica type deformity, dark necrotic and ulcerated areas and sloughing
and multiple pseudodiverticula (157). of mucosa are seen in full-thickness burns. A
The gastric changes tend to be nonuniform, dark exudate in an aperistaltic and dilated or-
depending largely on the amount of agent in- gan suggests a full-thickness, third-degree burn.
gested and the patient's posture at the time of Sloughing mucosal necrosis often extends into
ingestion. The damage frequently localizes to the underlying muscular wall, and may result
the prepyloric region (fig. 8-36), because stasis in perforation.
in this area causes a relatively longer mucosal Charcoal deposits may be present in the
contact time with injurious agents than in other esophagus or stomach in patients who survive
areas of the stomach. If the patient survives, the acute event, appearing as linear, black, distal
fibrosis causes progressive antral and prepyloric esophageal or gastric lesions. These result from

325
Gastrointestinal Diseases

Figure 8-36 Figure 8-37


LYE INGESTION LYE INGESTION
Stomach and duodenum in a patient "" who ingested lye. X-ray demonstration of an area of healing ulceration
The most intense changes affect the pyloric region. There is following lye ingestion.
also damage in the duodenum, as evidenced by the reddish
discoloration of the mucosa.

the administration of activated charcoal as a Coagulative necrosis variably extends into the
therapy for overdoses in patients who have esophageal or gastric wall, with little or no in-
attempted suicide. Mucosal tears from either flammatory response (fig. 8-38). Mural necrosis,
intubation or vomiting allow the charcoal to ulceration, and inflammation are present. Sec-
gain access into the underlying submucosa, ondary bacterial infections may complicate the
where it persists for decades. damage. In the subacute phase, the superficial
Microscopic Findings. Pathologists most necrotic tissue sloughs off and the mucosa ulcer-
commonly see the acute effects of caustic injury ates, with subsequent repair by granulation tissue
at the time of autopsy, usually in the forensic that matures into collagenous connective tissue.
setting. The overlying surface appears normal, During the chronic phase, which lasts from
swollen, inflamed, hemorrhagic, ulcerated, 1 to 3 months, the ulcers reepithelialize and
hypertrophic, or atrophic, depending on when fibrosis begins to develop, sometimes evolving
the tissues are examined in relation to the acute into a stricture. Strictures consist of dense, uni-
event, and if recurrent damage has occurred. form, mucosal and submucosal fibrosis. Ulcer-
The acute phase is associated with edema, ation may be ongoing. Cytologically, the cells
acute inflammation, and vascular thrombosis. usually appear normal without much reactive

326
Chemical Injury

Figure 8-38
LYE INGESTION WITH COAGULATIVE NECROSIS
Left: The mucosa has undergone complete coagulative necrosis so that cellular detail is lost. In addition, the muscularis
mucosae is affected.
Right: The changes also affect the submucosa with the complete coagulation necrosis of the submucosal vessels.

atypia. The charcoal deposits, if present, consist Some patients are treated with steroids in an
of aggregates of coarse, black, foreign material. attempt to limit the edema and reduce stricture
The histologic features of the gastric changes formation (159). Patients treated with epider-
include coagulation necrosis, mucosal hemor- mal growth factor and/or cytokines may have a
rhage, and edema. Early, there is little inflam- reduced incidence of subs~quent stenosis (148).
mation. If the patient survives the acute event, Patients developing strictures are treated
emphysematous gastritis may develop due to before the strictures become tight, fixed, and
infection by gas-forming organisms (151). difficult to dilate. Once strictures develop,
Treatment and Prognosis. Initial treatment they are initially treated with dilatation of the
is directed toward the most life-threatening in- esophagus or eventual placement of stents.
juries. Perforation, peritonitis, fistula formation, Many patients do well with periodic dilations.
or massive hemorrhage necessitates surgery. Once well-developed strictures occur, surgical
In other patients, endoscopic evaluation of resection may be required. Colonic or jejunal
the esophagus and stomach determines injury interpositions may be necessary.
extent. Patients are stratified into four groups: Esophageal replacement using the right co-
those without injury, those with only gastric lon with the terminal ileum allows continuity
injury, those with linear esophageal injuries, of peristalsis in the interposed bowel segment
and those with circumferential burns. The less with an intact ileocecal valve that decreases the
severe the injury, the more likely that the pa- hazard of regurgitation. Patients with gastric
tient will survive without sequelae. First-degree outlet obstruction require endoscopic dilatation
injuries generally resolve spontaneously. Pa- or surgery. Some patients develop long-term
tients with second-degree injuries are observed motility disturbances. Esophageal carcinomas
and prophylactically treated with antisecretory may develop, with a latency period of about 30
agents before eating is allowed. Symptomatic to 40 years (145). Most tumors develop at the
patients without peritonitis are treated with area of the tracheal bifurcation.
nutritional support, intravenous HZ-receptor
antagonists (or proton pump inhibitors, if avail- PROSTAGLANDIN THERAPY
able), and prophylactic antibiotics until liquids Prostaglandins are used to treat congenital
can be tolerated. Patients with gastric or linear heart disease in neonates (164) and to maintain
esophageal burns may require hospitalization patency of the ductus arteriosus in infants with
for possible transmural extension of the injury. cyanotic congenital heart disease. Prostaglandin

327
Gastrointestinal Diseases

pressing the increased rate of bone turnover and


lowering the incidence of fractures (166,173)
during the postmenopausal period (176). The
drug binds to hydroxyapatite in bone, specifi-
cally inhibiting osteoclastic activity without di-
rectly affecting bone formation.
Pathophysiology. Alendronate damages the
esophagus both by its toxicity and from non-
specific irritation secondary to pill contact with
the esophageal mucosa in a manner similar to
that seen in other forms of "pill esophagitis" (see
below). The esophagitis results from swallowing
the medication with little or no water, lying
down during or after ingestion of the tablet(s),
Figure 8-39 and continuation of the drug after symptom on-
set. Because the patients are elderly, many have
PROSTAGLANDIN-INDUCED PYLORIC HYPERTROPHY
.
This neonatal stomach is completely distended and filled
reduced esophageal motility, predisposing them
with mucus due to outflow block secondary to mucosal to the drug injury. Coexisting H. pylori infection
hyperplasia in the pylorus. (Courtesy of Dr. Patrick Lanz, or the use of NSAIDs to treat arthritis may add
Wake Forest University, NC.) to the mucosal toxicity of the bisphosphonates
(170). Alendronate causes visible gastric muco-
E infusions induce mucosal hyperplasia, pyloric sal injury in the majority of patients studied,
stenosis, and gastric outlet obstruction in neo- and is severe in SO percent. Gastric ulcers are
nates and adults. Neonates present with feeding present in 8 percent of patients (170-172) .
problems, vomiting, and abdominal distension. Clinical Features. Alendronate is well toler-
The stomach appears enlarged and distended, ated in most patients but causes severe upper
and the intestine has a mucoid appearance (fig. gastrointestinal symptoms in approximately 1.5
8-39). Radiographic studies show antral narrow- percent (174) . Patients typically present with
ing suggestive of hypertrophic pyloric stenosis. dysphagia secondary to midesophageal inflam-
Serial ultrasonograms disclose progressive elon- mation or stricture (174,175). In some patients,
gation of the antral pyloric channel without the ulceration is severe enough to necessitate
mural thickening (164) . hospitalization (168,169). Bleeding is rare. Duo-
Histologically, the stomach shows foveolar denal damage does not appear to occur (170).
hyperplasia and elongation of the gastric pits, Gross Findings. Endoscopy shows an erosive
preferentially affecting the antrum. These esophagitis with erythema, ulcerations, an inflam-
changes may lead to pyloric stenosis (165). Drug matory exudate, and thickening of the esophageal
cessation resolves these effects. wall (166,169). The esophageal erosions and ulcers
may become confluent, developing into multiple
BISPHqSPHONATES deep, large ulcers. Visible gastric mucosal damage
Demography. Bisphosphonate injury tends resembles that seen with NSAID-induced damage,
to affect older individuals, especially women with the formation of antral ulcers or superficial
treated for osteoporosis. Only a fraction of mucosal erosions (170).
individuals develop severe adverse esophageal Microscopic Findings. The histologic
'-,•
reactions to the drug. Patients with serious in- esophageal changes are those common to
jury from bisphosphonates are usually taking many severe ulcerating esophageal disorders.
other medications as well (167) . Neutrophilic infiltrates are often present, as
Etiology. Alendronate (Fosamax), etidronate, is intraepithelial eosinophilia. The squamous
and pamidronate are amino bisphosphonates epithelium appears reactive, as evidenced by
used to treat osteoporosis in postmenopausal the presence of enlarged and hyperchromatic
women (17 5) and Paget's disease. These agents nuclei. There may also be small intraepithelial
are potent inhibitors of bone resorption, sup- vesicles. Clear, refractile, crystalline foreign

328
Chemical Injwy

material is often present in the fibroinflamma- cause gastrointestinal injury. Lead is toxic by
tory exudate, and is easily seen with polarizing ingestion, inhalation, and transcutaneous expo-
light. The crystals resemble those of crushed sure. Cadmium emissions have increased due to
alendronate tablets. Scattered, multinucleated dumping of batteries with the other household
giant cells may be associated with the crystals waste into landfills. Cigarette smoking is also a
(166). The histologic features of gastric injury major source of cadmium exposure. Heavy use
resemble those of NSAID injury. of calomel can produce watery diarrhea and
Differential Diagnosis. The differential high mercury levels in the colon (194) .
diagnosis includes other forms of acute and Pathophysiology. Ferrous sulfate pills attach
ulcerative esophagitis or gastritis. The diagnosis to the mucosa and produce localized ulcers, par-
is made with the appropriate history and some- ticularly in the esophagus (188). Ferrous sulfate
times by identifying the alendronate crystals. may also injure the stomach or small intestine.
Treatment and Prognosis. The changes re- Gold-induced enterocolitis results from either
solve with drug cessation. The development of direct mucosal toxicity or an immune-mediated
late-onset strictures is uncommon. hypersensitivity reaction. The presence of an
HLA DRB 1*0404 allele increases the risk of
HEAVY METALS developing gold-induced enterocolitis in patients
Definition. Gastrointestinal disease can with rheumatoid arthritis (180). Gold salts also
result from exposure to heavy metals such as predispose to cytomegalovirus infection (195) .
copper, gold, and arsenic. The gastrointestinal tract is the immediate
Demography. Many heavy metals are target organ in cadmium intoxication, since it
ubiquitous elements in the earth's crust and inhibits enterocyte Na+K+-ATPase activity (189) .
are transported environmentally by water Lead causes small bowel toxicity by modifying
(178) . The distribution of these elements in the biochemical properties of the enterocyte
the environment varies considerably with the surface, leading to microvillous damage (193).
geography, and in some places is very high. For Clinical Features. In general, the clinical
example, arsenic toxicity is particularly com- features of heavy metal gastrointestinal toxicity
mon in China, Taiwan, Thailand, Mexico, Chile, include nausea, vomiting, abdominal cramps,
Bangladesh, and India. Heavy metal injury may pain, and severe, watery, bloody diarrhea, a
occur in those who consume foods stored or condition sometimes referred to as "welder's
cooked in tin, antimony, or copper containers. fits" when it occurs within this working group
Children are exposed to lead in lead-containing due to their occupational exposure to heavy
paint and contaminated food or water. Intro- metal. In some situations, the clinical features
duction of lead-free gasoline has dramatically are typical and provide a clue to the existence
reduced environmental lead poisoning. The of heavy metal toxicity: patients with arsenosis
majority of patients with gold-salt toxicity are develop hyperpigmentation, hyperkeratosis,
women with rheumatoid arthritis. Exposure to and cutaneous malignancies.
mercury is largely through fish consumption, The enterocolitis associated with gold thera-
particularly the consumption of shark, sword- PY usually starts within several weeks of begin-
fish, and tuna. Certain fish from polluted fresh ning the drug. Patients present with nausea,
water, such as pike, walleye, and bass, should vomiting, profuse diarrhea, abdominal pain,
be especially avoided. fever, proteinuria, maculopapular rashes, and
Etiology. The native forms of heavy met- hypogammaglobulinemia. Occasionally, the
als are generally inert; most damage results gold-induced enterocolitis progresses to toxic
from their metallic salts, especially gold and megacolon, perforation, and death (179,181).
iron salts. The main threats to humans from Twenty-five percent of patients develop periph-
heavy metals are associated with exposure to eral eosinophilia.
lead, iron, cadmium, mercury, arsenic, and The features of acute lead poisoning include
gold salts. Gold salt therapy causes most heavy severe abdominal pain, vomiting, and diarrhea.
metal-induced enterocolitis (195) . Zirconium, Behavioral disturbances, anorexia, fatigue, and
silver, zinc, and aluminum (181,182,192) also irritability are also seen . Patients may develop

329
Gastrointestinal Diseases

Figure 8-41
GOLD-INDUCED GASTRIC INJURY
This biopsy shows marked edema of the mucosa.

(kidney, liver, bone marrow, heart) who use alumi-


num-containing antacids or sucralfate dmgs may
develop gastric mucosal calcinosis. Copper inges-
tion is associated with diarrhea, with or without
abdominal pain and vomiting (190).
Gross Findings. Any patient who has ingested
large quantities of a heavy metal will have acute
erosive esophagitis or gastritis. FerrouS' salts dam-
age any part of the gastrointestinal tract, causing
Figure 8-40 ulcers and hemorrhage. Most ferrous sulfate-in-
MERCURY INGESTION . duced lesions are superficial but if deeper ulcers
Opened stomach in an individual who cons umed
develop, fibrous strictures can occur, pa1ticularly
mercury. The mucosa appears reddened 'i:lnd mercury balls in the small intestine. Foreign body giant cell reac-
lie on the mucosal surface. tions may occur. Zinc sulfate may cause gastritis. In
those who have ingested mercury, balls of mercury
are seen within the gastric lumen (fig. 8-40). Any
ataxia, decreased consciousness, and seizures. gastrointestinal site may be damaged by gold salts,
Chronic exposure may lead to constipation. although the colon is most commonly affected.
Heavy metal salts such as zinc or mercuric The small and large bowel may show hemonhage,
chloride or ferrous or zinc sulfate cause gastritis. edema, and mural thickening. A focal or extensive,
Ingestion of large amounts of these substances but usually segmental, colitis, sometimes associ-
causes rapid injury which may be severe; such ated with pseudomembrane formation, with ero-
cases are usually only encountered by forensic sions and ulcerations simulating IBD, develops
pathologists. In these patients, there is evidence in those on gold therapy (186,191,192). Severe
of corrosive bums in the mouth and esophagus, gastrointestinal necrosis and strictures develop
as well as in the stomach. Oral ferrous sulfate after iron overdoses.
causes transient nausea and induces gastric Microscopic Findings. The stomach shows
mucosal edema and erosions (185) . nonspecific inflammation and edema in gold-
Iron overdose causes gastrointestinal necrosis associated injury (fig. 8-41). Histologically, the
and strictures. After prolonged contact, intestinal bowel is ulcerated, with diffuse acute and chronic
perforation may occur. Patients with aluminum inflammation, sometimes associated with crypt
toxicity develop enteropathy, encephalopa- abscesses. The glandular architecture is usually
thy, bone disease, and anemia (185) . Patients more or less preserved, although individual
with chronic renal failure or organ transplants crypts may drop out (fig. 8-42). Deep ulcers and

330
Chemical Injury

...

.,
.
.. . ,".. .
0

• •• •

. ., ..
-
,. ~-· ~ #

(
..... . . ....... ..
~
:tt'" • • ~... ,•. : · ~

'··. . .; -
., · ~ ·.~ ',. ··~ .. ; -t
...
.. ';

. .' ..... ..... ... .· ' •


,.. • -

.,tl .. :1 . , ; :.. : . ,.-_.


~t
..
iJ.~
' • fi
. .. .
:*' ,; ; 'A
t ,,.• ....
>.
'11
''

~ •,

' • .• · ' -,.; • :
I • t . t I
I+ ::r. .•..
•• a;.
.r

/ ...cl .'·:- . ,.
... "·'" , ..:.
• :...,
r ., ,
,..I

c
Figure 8-42
GOLD-INDUCED COLONIC INJURY
A: Colonic biopsy shows severe interstitial hemorrhage, edema, and glandular dropout.
B: Some of the glands have started to regenerate and appear more eosinophilic than normaL In this case, the gland in
the center shows little cytologic atypia.
C: Another area of regeneration shows cytologic atypia and glandular irregularity.
D: The cytologic changes extend to the surface.

diffuse mucosal inflammation (179,181), often may be present in the lamina propria, covered
with a prominent eosinophilic component, by an intact epithelium, adjacent to superficial
characterize the resultant fulminant enteroco- erosions or admixed with granulation tissue.
litis (183,187,188). Iron stains show iron covering the epithelial
Patients consuming large amounts of iron surface in the stomach, and extending into the
may have a layer of brownish crystalline iron superficial gastric pits (fig. 8-43). Iron deposits
lining the gastric or esophageal mucosa (177). coexist with superficial edema, inflammation,
The iron may be admixed with a luminal fibro- mild epithelial necrosis, and acute inflamma-
inflammatory exudate. Crystalline iron deposits tion. Ferrous sulfate may cause an acute erosive

331
Gastrointestinal Diseases

I ,_., •
·0

J} ~~· ,
I

..,.

~~"
I " ' '0 '

Figure 8-43
IRO N DEPOSITS IN THE GASTRIC MUCOSA
A layer of dark pigment. covers the surface epithelium. The iron stain (right) is positive.

COLCHICINE
Demography. Colchicine is widely used to
treat patients with gout. It also has a role as
an antifibrosing agent in patients with certain
forms of cirrhosis and chronic liver disease.
Pathophysiology. Colchicine leads to malab-
sorption by depressing intestinal enzyme produc-
tion and transport, mucosal surface area, and
water transport, and by retarding motility (197) .
Clinical Features. In most patients, colchi-
cine therapy causes mild nuisance symptoms,
including nausea, colicky abdominal pain,
vomiting, and diarrhea. In some patients,
however, small doses given regularly cause ste-
Figure 8-44 atorrhea, megaloblastic anemia, and abnormal
xylose absorption (196). Some patients develop
CHOLCHICI NE TOXICITY
life-threatening colchicine toxicity with fever,
Numerous mitotic figures are arrested in metaphase. pain, myalgia, lower extremity paresthesias,
Mitoses extend beyond the normal proliferative zone,
upward into the superficial half of the crypt. convulsions, alopecia, and even death (196).
Fatal toxicity is rare and characterized by intense
diarrhea and dehydration.
gastritis. Iron-containing thrombi may be found Microscopic Findings. The histologic chang-
in mucosal blood vessels. Mercury poisoning es accompanying colchicine toxicity include
may cause fibromuscular stenosis of the large villus atrophy and mitotic arrest with absent
r.,. intestine (184). mitotic spindles and bizarre chromatin configu-
Differential Diagnosis. The enterocolitis rations (fig. 8-44). The villi fuse and epithelial
associated with gold toxicity mimics IBD. The cytoplasmic and nuclear swelling develops.
various entities can be separated based on the Because of the mitotic arrest, the epithelium
clinical history. in the proliferative zone can no longer give rise
Treatment and Prognosis. Mild enterocolitis to new progeny, and villous atrophy and crypt
typically resolves with drug cessation. Patients hypoplasia develop (196).
with severe gold salt enterocolitis have mmtality Treatment. The changes disappear upon
rates as high as 35 to 42 percent (195). drug cessation.

332
Chemical Injwy

:olease of pancreatin
·rom enteric
oated granules

c.

Figure 8-45
DIAGRAM OF PANCREATIC ENZYME-INDUCED INJURY

PANCREATIC ENZYME SUPPLEMENTS the enzymes reach the distal small intestine or
AND FIBROSING COLONOPATHY colon. Prolonged colonic exposure could also
Demography. High-strength pancreatic en- result from stasis or obstruction. Epithelial abra-
zyme supplements are given to children with sions or focal lesions proximal to an obstruction
cystic fibrosis (CF) to correct their pancreatic provide intramural or submucosal access to
insufficiency and control intestinal malabsorp- high concentrations of proteolytic and lipolytic
tion. Patient age at diagnosis varies from 9 enzymes, which then elicit vigorous fibrosing
months to 13 years (204). The relative risk of reactions, particularly because the intramural
developing fibrosing colonopathy is 10.9 and pancreatin is dispersed within the submucosa
199.5 with doses of 24,000 to 50,000 units of by peristalsis. Other possible mechanisms of
lipase/kg/day and more than 50,000 units/kg/ injury include a colon-specific immune-related
day, respectively. Fibrosing colonopathy has disorder (201) or primary dysregulated colonic
also been described in adults on high doses of collagen synthesis (200) .
pancreatic enzymes in the absence of CF. Clinical Features. Clinically, patients present
Etiology. Pancreatin is an enzyme mixture with abdominal discomfort and distension due
that supplements defective pancreatic secretion to stricturing and intestinal dilatation. Other
in patients with end-stage pancreatic diseases, findings include ascites, constipation, frequent
enabling effective food digestion. Most prepa- passage of watery stools, severe anorexia, and
rations are derived from porcine pancreas and weight loss. The changes of fibrosing colono-
consist of amylase, proteases, and lipase. Con- pathy may be restricted to the cecum, ascend-
comitant use of H2 blockers, corticosteroids, ing colon, or rectum, or they may diffusely
laxatives, or recombinant human DNAase in CF affect the entire colon (200,202,203,207). An
patients increases the risk of developing fibro- intense perianal skin irritation affects infants.
sing colonopathy (199,200,205-207). Clinical recognition of fibrosing colonopathy
Pathophysiology. It is postulated that de- is complicated by the fact that gastrointestinal
layed disruption of microspheres in the colon obstruction affects up to 15 percent of children
or prolonged colonic mucosal contact due to with CF without the colonopathy (207).
the slower transit times seen in CF patients Gross Findings. The entire colon develops
treated with the pancreatic enzymes exposes the widespread submucosal fibrosis, thickening of
colonic mucosa to nonphysiologic amounts of the muscularis propria, and subserosa! hemor-
active enzymes, thereby leading to ulceration, rhages. Maturation and longitudinal contrac-
inflammation, and subsequent fibrosis (fig. tion of the fibrous tissue further distort and
8-45) (202). In addition, small intestinal pH is thicken the colon wall and narrow the intestinal
abnormally low in CF patients, possibly delay- lumen, although the external diameter remains
ing dissolution of the enteric coatings until normal, especially at the flexures. As the fibrosis

333
Gastrointestinal Diseases

The eosinophil count ranges from 26 to 164 per


high-power field, with a mean of 64 (202). The
submucosa contains dense mature collagen and
thick, nearly hyalinized collagen bands, sometimes
with a keloidal appearance (fig. 8-46). Ganglion
cells are unusually prominent and can usually be
found in the deep mucosa near crypt bases. The
muscularis propria becomes widened and fibrotic,
a process preferentially affecting the inner circular
layer. In rare patients, the muscle becomes com-
pletely attenuated and both layers of the muscu-
laris propria disappear (202). In some patients,
the process distorts the neural plexuses.
Differential Diagnosis. The differential diag-
nosis of fibrosing colonopathy includes sclero-
derma, since this disorder is associated with
submucosal fibrosis and tissue eosinophilia.
Clinical findings separate the two entities.
Treatment and Prognosis. It is recommend-
ed that the daily dose of lipase remain below
10,000 units/kg to reduce the incidence of this
complication (198). Surgery may be required for
mechanically significant stricturing.
ESTROGEN AND PROGESTERONE

· Figure 8-46
Demography. Most individuals with in-
jury due to estrogen or progesterone intake are
FIBROSING COLONOPATHY
women over age 50 years. Those with blood type
Histologic appearance of a dense fibros ing process in A, cigarette smokers, and hypertensive patients
the submucosa in a patient receiving pancreatic enzyme
supplements. (Courtesy of the il.ivision of Gastro- have an increased propensity to develop com-
intestinal Pathology, Armed Forces Institute of Pathology, plications from these hormones. Lesions usually
Washington, DC.) develop in individuals who have taken at least
0.5 g of drug/day for more than a year.
Etiology. Both estrogen and progesterone
continues, the mucosa acquires a cobblestoned cause small and large intestinal ischemia but the
appearance with areas of persistent or heal- incidence of damage is low (209-211,213,214) .
ing ulceration. The rectum becomes stenotic Pathophysiology. Estrogen, progesterone,
(199,208). Externally, the colon appears pale and oral contraceptives promote thrombus
and a fusiform band of mature fibrous tissue formation in the mesenteric arteries or veins.
extends over 10 cm or more in the lamina pro- This leads to segmental hemorrhage, ischemia,
pria and submucosa. and hemorrhagic infarction (211-213).
Microscopic Findings. There may be acute Clinical Features. The major clinical features
or chronic colitis with active cryptitis (200,202) . associated with hormone therapy are a result
•.·
The lamina propria contains variable amounts of ischemia. Some patients develop malabsorp-
of chronic inflammation, usually adjacent to tion. There is a general relationship between the
erosions; edema is prominent. The muscle fi- amount of dmg ingested and thrombotic sequelae.
bers of the muscularis mucosae become frayed, Gross Findings. These hormones damage
sometimes with complete disintegration and both the small and large bowel. Thrombosis
loss of the normal demarcation between the affects the superior mesenteric vein more com-
mucosa and submucosa. There is a moderate to monly than the superior mesenteric artery. The
severe infiltration of eosinophils and mast cells. gross features of ischemic injury from hormones

334
Chemical Injwy

Figure 8-47
ORAL CONTRACEPTIVE INJURY
Colon biopsy in a 27-year-old patient who was on oral contraceptives
and presented with rectal bleeding.
Left: The features are consistent with ischemia.
Above: Fibrin thrombi are seen in the vessels.

resemble those of ischemic enterocolitis due to that develop in body packers or "mules" who
other causes (see chapter 7). ingest multiple small drug-containing packets
Microscopic Findings. There are two types that subsequently leak. Affected patients tend
of histologic findings in patients with injury to be young males with a long history of co-
secondary to estrogen and progesterone: villous caine abuse (219,223). Older patients may also
atrophy and crypt hypoplasia (214), or ischemia be affected, particularly those who use cocaine
(fig. 8-47). The ischemic changes reflect the size sporadically.
of the thrombosed vessel and typically affect the Etiology. Newer, more toxic forms of cocaine,
intestines, sparing other pmtions of the gastro- including crack and "free-base" cocaine, cause
intestinal tract. In patients with disseminated acute gastroduodenal perforation and rupture.
intravascular coagulation, the changes tend to be Pathophysiology. Cocaine acts at the syn-
mild. Patients with thrombosis of a major vessel aptic level, altering neurotransmitter uptake
may present with widespread transmural ischemic and potentiating norepinephrine and dopa-
necrosis. Progesterones may also cause pseudode- mine effects (216). This results in intense
cidual reactions in the serosa or the mesentery that vasoconstriction, focal ischemia, and perfora-
have no clinical consequences (fig. 8-48). tion (219,223).
Differential Diagnosis. The differential di- Clinical Features. Preexisting gastric muco-
agnosis includes other causes of villous atrophy sal damage may predispose to cocaine-induced
and/or ischemia. Severe disease may mimic IBD. damage (216). Severe and prolonged ischemic
Treatment and Prognosis. Discontinuation episodes eventually result in bowel necrosis, per-
of the hormones cures the problem, but the pa- foration (215), peritonitis, or abscess formation.
tient may be left with the sequelae of removed Patients develop crampy abdominal pain and
bowel if resection was necessary. varying degrees of nausea, vomiting, anorexia,
bloody diarrhea, and abdominal rigidity, espe-
COCAINE cially in those with gastrointestinal perforations
Demography. Gastrointestinal injury from (215). Patients may also present with small
cocaine use is also known as body packer's bowel obstruction caused by ingestion of the
syndrome (225), which describes the changes packets of cocaine.

335
Gastrointestinal Diseases

Figure 8-48
PROGESTIN-RELATED PSEUDODECIDUAL NODULES IN THE MESENTERY
Left: Low-power magnification shows the location of the nodules in the mesentery.
Right: Higher magnificiftion shows the pseudodecidual response.

.Maternal use of cocaine during pregnancy visible within the granulomas (fig. 8-49). The
can affect both the mother (228) ..and the fetus granulomas have the appearance of dense sar-
(217,221,222,224). Cocaine is normally detoxi- coid granulomas, and usually lack a prominent
fied in the plasma and liver by cholinesterase, inflammatory response.
but plasma cholinesterase levels are very low Differential Diagnosis. Other causes of isch-
in fetuses and neonates, predisposing them to emic enterocolitis are in the differential diagnosis.
high blood drug levels. As a result, the fetus Treatment and Prognosis. The treatment of
and neonate develop transient or prolonged cocaine-associated bowel ischemia consists of
ischemic episodes, necrotizing enterocolitis, dealing with the ischemia and the individual's
perforation (218), and intestina'I atresia (217, addiction. Ischemic bowel is treated support-
222). Cocaine-induced vasospa-sm should be ively as it is generally reversible unless gangrene
considered in those with ischemic bowel who and peritonitis supervene. Ischemic involve-
do not have other vascular risk factors. Urinaly- ment of other organs, e.g., cardiac or cerebral,
sis for drugs or their metabolites can establish may coexist with mesenteric involvement.
the diagnosis in patients thought to be body
packers or users (226,227). OTHER DRUGS AND CHEM ICALS
Gross Findings. Radiologic examination is CAUSING ISCHEMIC INJURY
essential for the diagnosis and management of Demography. Most patients who develop
those with body-packer's syndrome. Plain ab- ischemic injury from drugs are elderly and have
dominal radiographs demonstrate the presence underlying cardiovascular disease (235) .
of drug packets. They are usually multiple, well- Etiology. A number of drugs cause ischemic
defined, homogeneous, oval or oblong dense packs injury (Table 8-6). Patients on cardiovascular
often sunounded by a crescent of air (the double- medications often develop ischemic changes,
'-··
condom sign) (220) . Grossly, cocaine effects although it may be difficult to distinguish the
resemble those of ischemia due to other causes. damage caused by the drugs and that due to the
Microscopic Findings. The gastrointestinal underlying heart failure. Injury caused by potas-
lesions associated with cocaine-induced dam- sium, NSAIDs, and oral contraceptives are the
age typically show classic ischemic in jury. best-documented as chemically induced causes
Granulomatous inflammation also affects the of ischemia. When the slow release form of
stomach of known cocaine addicts, presumably potassium chloride was introduced, the potas-
due to the foreign materials that are used to sium chloride salt was incorporated into a wax
cut the drugs. These substances are sometimes or plastic matrix so that the drug was released at

336
Chemical Injwy

Table 8-6
DRUGS AND CHEMICALS CAUSING ISCHEMIA
Induce Thrombosis
DDAVP' therapy in diabetes insipidus
Estrogens
Oral contraceptives
Potassium chloride
Progesterone
Induce Autoimmune Vasculitis
Aspirin
Erythromycin
Penicillin
Quinidine
Some NSAIDs
Tetracycline
Thiazide diuretics
Induce Vasospasm and/or Decreased Blood Flow
Alpha-adrenergic vasoconstrictors
Amphetamines
Anesthetics
Cocaine
Cyclosporine
Dialysis
Digitalis
Diuretics
Ergotamine-related drugs
IL2 therapy
Interferon
NSAIDs
Potassium chloride
Sorbitai
Figure 8-49 Vasopressin
Induce Vasculitis
FOREIGN BODY GRANULOMAS
Rutoside
IN A COCAINE ADDICT
'DDAVP = desmopressin; NSAID =nonsteroidal antiinflam-
Top: Significant chronic gastritis and nodular aggregates
matory drug; IL = interleukin.
are in the basal part of the mucosa.
Bottom: Higher magnification shows the foreign body
response.
cause a condition resembling solitary rectal
ulcer syndrome.
lower concentrations. This preparation reduced Pathophysiology. Drug-induced ischemia re-
the incidence of potassium chloride-associated sults from: 1) thrombosis or embolism, 2) auto-
injury but did not eliminate it (230,232). immune reactions, 3) vasculitis, 4) vasoconstric-
Scorpion and snake venoms also cause isch- tion or vasospasm, or 5) decreased blood flow
emic injury (233,234). Most scorpion and snake (Table 8-6). Potassium chloride causes localized
venoms contain a mixture of toxic proteins and ulceration of the small bowel leading to fibro-
enzymes that have numerous pharmacologic sis, obstruction, and perforation. Patients who
effects. Desmopressin (DDAVP), used to treat undergo aggressive hemodialysis may develop
diabetes insipidus, may cause widespread mes- alterations in blood volume or hyperviscosity
enteric venous thrombosis. Vasopressin causes that results in decreased peripheral blood flow.
arterial spasm and is used to stop or reduce This condition preferentially affects the right
hemorrhage. It is frequently administered into colon and the damage may be secondary to
an artery under radiologic control to reduce the generation of oxygen-derived free radicals
gastrointestinal bleeding. Ergot and methyser- (231). Venomous bites induce circulatory col-
gide also create vasospasm. Ergot compounds, lapse, hemolysis, coagulation abnormalities,
used to treat migraines, may cause ischemic and changes in vascular resistance, all of which
enterocolitis and ergot drugs in suppositories contribute to the ischemia.

337
Gastrointestinal Diseases

Table 8-7 scattered mucosal petechiae to widespread in-


flammatory involvement of the small intestine
CAUSES OF GASTROINTESTINAL STRICTURES
or colon, sometimes simulating active ulcerative
Congenital colitis. There may be an ipcrease in the number
Congenital gastrointestinal stenosis
of apoptotic bodies in the crypt bases.
Secondary to Mucosal Inflammation
Diverticulitis
Some drugs cause ischemic injury by induc-
Gastroesophageal reflux disease ing widespread venous thrombosis (fig. 8-50).
Infection Not surprisingly, the usual histologic features
Radiation of drug-induced injury resemble those found
Sclerotherapy
Epidermolysis bullosa in patients with ischemia due to other causes
Sarcoid (pyloric strictures) (see chapter 7).
Crohn's disease Differential Diagnosis. Table 8-7 lists com-
Peptic ulcer disease mon causes of gastrointestinal strictures.
Ischemia
Neonatal necrotizing enterocolitis Treatment and Prognosis. The ischemic
Chronic ulcerative ileojejunitis bowel is treated supportively, as the damage is
Graft versus host disease generally reversible unless gangrene or perfora-
Secondary to Chemical Injury tion occur, in which case resection is necessary.
Following caustic injury
Nonsteroidal antiinflammatory drugs (NSAIDs) ANTICOAGULANTS
Potassium salts
Fibrosing colonopathy secondary to pancreatic Demography. Hemorrhages and intramural
enzyme supplements hematomas affect 30 to 40 percent of patients
Secondary to Tumors taking anticoagulants. Significant bleeding af-
Endometriosis fects 1.2 percent of patients taking heparin and
0.2 percent of those taking coumadin (238) .
The risk of bleeding and other copplications
increases in those taking other medicines,
Clinical Features. The clinical features re- including NSAIDs, acetaminophen, or cortico-
semble those seen in patients with ischemia steroids (239). Hemorrhage is 3 to 4 times more
due to other causes (see chapter 7). common in males than in females.
Gross Findings. The lesions are often im- Etiology. Anticoagulants and antiplatelet
possible to distinguish from other causes of agents cause the injury. Patients on chemo-
ischemic necrosis, stricture, and ulceration. therapeutic agents may also develop significant
Enteric-coated potassium chloride preparations bleeding due to reduced numbers of platelets.
cause solitary or multiple, generally small ulcers Submucosal hemorrhages in the esophagus have
measuring 1.5 cm in diameter, most commonly been detected in patients receiving thrombo-
located in the jejunum or ileum (229). The mu- lytic therapy for myocardial infarction.
cosa surrounding the ulcers appears edematous Pathophysiology. Since anticoagulants in-
and hyperemic (230,236). Submucosal fibrosis hibit the clotting mechanisms, patients develop
leads to stricture formation. The gross features of hematomas at sites of trauma.
other cases of drug-induced ischemia are typical Clinical Features. Most lesions are small and
of ischemia due to other causes (see chapter 7). asymptomatic. When large hematomas form,
Microscopic Findings. Enteric-coated po- clinical findings can include pain and signs of ob-
tassium chloride tablets cause gastrointestinal struction or a mass. Bleeding can occur anywhere
edema, hemorrhage, erosions, and ischemic in the gashointestinal tract, but massive bleeding
infarcts. Enteric-coated potassium chloride is is rare. Clinical symptoms may also arise if the
also one of the more common agents to cause hematoma affects the area of the ampulla of Vater
deep ulcers and strictures (236). The ulcers with blockage of the biliary or pancreatic ducts.
resemble the ischemic ulcers caused by other Gross Findings. Hematomas can affect any
agents. One possible difference is the presence part of the gut. In one series, 59 percent affected
of pyloric metaplasia in the mucosa adjacent the jejunum; 25 percent, the ileum; 9 percent,
to drug-induced lesions. The lesions vary from the duodenum; and 7 percent, the colon (237).

338
Chemical Injwy

Figure 8-50
DESMOPRESSIN (DVAPP)-INDUCED INJURY
The patient had diabetes insipidus with widespread
venous thrombosis.
A: The mucosa is compl\=tely infarcted and the coagu-
lative necrosis extends into the underlying submucosa.
B: Higher magnification of the mucosa.
C: Cross section through the mesenteric vein with an
organizing thrombus.
D: Area adjacent to the acute infarct with portions of
regenerating small bowel, indicating that this is a recurrent
problem. This child had multiple episodes of acute abdom-
inal pain.

Microscopic Findings. The hematomas CHEMICALLY INDUCED EOSINOPHILIA


consist of pools of variably clotted, extravasated Definition. Chemically induced eosinophilia is
blood in the gastrointestinal wall (fig. 8-51). the infiltration of the gastrointestinal tract by
Treatment and Prognosis. Treatment con- eosinophils in response to exposure to or inges-
sists of a change of drug dosage or drug cessa- tion of various chemical substances.
tion. The majority of patients are treated with Etiology. Numerous drugs and chemicals
supportive care. Occasionally, intramucosal cause gastrointestinal eosinophilia (Table 8-8).
hematomas cause luminal obstruction or even Clinical Features. Trimethoprim-sulfa-
track longitudinally and perforate through the methoxazole can cause significant eosinophilic
serosal or mucosal section of the bowel wall, esophagitis (243). The eosinophilia-myalgia syn-
requiring surgical resection. drome usually follows ingestion of L-tryptophan

339
Gastrointestinal Diseases

Table 8-8
DRUG- AND CHEMICAL-INDUCED EOSINOPHILIA
Cow's milk intolerance
Food hypersensitivity reactions
Gold
Indomethacin
L-tryptophan
Nonsteroidal antiinflarnmatory drugs (NSAIDs)
Peritoneal dialysis
Reflux esophagitis
Soy allergen
Toxic oil
Trimethoprim-sulfamethoxazole

Figure 8-51
ANTICOAGULANT-INDUCED INJ':JRY
Submucosal hematoma in a patient on anticoagulants
who had suffered trauma as a result of a motor vehicle
accident.

Figure 8-52
(242,244). Patients present with profound eo-
sinophilia, abnormal hepatic prefiles, and myal- MUCOSAL EOSINOPHILIA IN DRUG-INDUCED INJURY
gias. Some patients develop a connective tissue The lamina propria is intensely infiltrated by eosinophils.
Some of these enter the glands.
disease that resembles scleroderma (240,241),
with dysmotility and diarrhea. Gastrointestinal
involvement leads to significant malabsorption Differential Diagnosis. The differential di-
with steatorrhea, hypoalbuminemia, and weight agnosis of gastrointestinal eosinophilia usually
loss. Mucosal eosinophilia also complicates ex- includes parasitic infections, lymphomas, poly-
posure to many drugs, including NSAIDs. arteritis nodosa, scleroderma, allergic gastroen-
Gross Findings. Usually none. teritis, eosinophilic gastroenteritis, allergic drug
Microscopic Findings. Histologically, dif- reactions, and IBD. Unfortunately, many times
fuse eosinophilic infiltrates (fig. 8-52) are seen the etiology of the mucosal eosinophilia is not
anywhere in the gastrointestinal tract. The obvious. Also, there appear to be geographic and
number of eosinophils is often quite impressive, seasonal variations in the number of eosinophils
numbering more than 25 per high-power field. in general in the gastrointestinal mucosa. The
They are usually seen in the mucosa, but can presence of an increased number of apoptotic
be present in the other layers of the bowel wall bodies in the base of the crypts, along with the
as well. When the eosinophils are present in eosinophilia, suggests chemical (drug) injury,
the lamina propria, we use the term "mucosal but this finding is not always present.
eosinophilia." If they also infiltrate the glands, Treatment and Prognosis. The eosinophilia
we use the term "eosinophilic gastritis, gastro- ceases with removal of the inciting material
enteritis, or colitis," depending on the location. from the diet or drug regimen.

340
Chemical Injwy

CHANGES ASSOCIATED WITH dialysis (251) and delayed gastric emptying


UREMIA AND CHRONIC RENAL DISEASE is found in patients with chronic renal failure
Definition. Many gastrointestinal abnor- (253). This may contribute to the nausea and
.malities affect patients with chronic renal dis- vomiting that are common complaints in such
ease. Systemic calciphylaxis is a rare condition patients. Ischemic colitis often complicates
of induced systemic hypersensitivity to appro- chronic uremia. Renal transplant patients also
priate challenging agents, along with calcium develop mucosal hemorrhages and they have
deposition (258), that occurs most commonly an increased incidence of complications from
in patients with end-stage renal disease. diverticular disease, an increased incidence of
Demography. Duodenal and gastric erosions ischemia, and increased use of toxic immunosup-
affect about 17 percent of dialysis patients or pressive drugs. Ischemic injury is known to result
patients with renal transplants (257). Up to 60 from both defective coagulation as well as acute
percent of uremic patients develop mucosal or fluid loss. Exacerbation of the diverticulitis may
submucosal hemorrhages, gastric or duodenal be the result of immunosuppressive therapy
erosions, and hemorrhagic vascular ectasias. (259). Patients also develop pseudomembranous
Pathophysiology. Patients with chronic colitis, possibly related to the ischemia.
renal failure and uremia experience a number Systemic calciphylaxis, a phenomenon
of gastrointestinal alterations. The gastrointes- consisting of severe and progressive ischemic
tinal complications of acute renal failure result necrosis, involves widespread anatomic regions,
from stress, hypotension, and multiple organ including the gastrointestinal tract (245). It most
failure. Sometimes it is difficult to determine commonly occurs in the setting of chronic renal
whether these result from the uremia itself failure, pa1ticularly in patients undergoing renal
or the treatment associated with it, including dialysis, often with secondary or tertiary hyper-
hemodialysis or transplantation. The cause of parathyroidism (254). Calciphylaxis is thought to
gastrointestinal lesions in patients with renal be due to extensive calcifications that result from
failure is uncertain, but they may result from increased plasma calcium and phosphorus levels
hypergastrinemia, altered gastric mucosal bar- that exceed the solubility end product (245), or
rier function, increased gastric acid secretion possibly from protein C deficiency (256). Medial
and mucosal blood flow, and effects possibly arterial calcification due to calciphylaxis, along
mediated by endothelial-derived nitric oxide with intimal edema and fibrosis, leads to isch-
(258). There may be increased bacterial conver- emia and necrosis (255). Rarely, gastrointestinal
sion of urea within the gastric lumen so that hemorrhage develops.
there is an increased concentration of ammonia, Gross Findings. The most commonly ob-
which may contribute to the mucosal damage. served gross abnormality in uremic patients is
The hypergastrinemia is proportional to the the presence of gastroduodenal petechial hem-
degree of renal dysfunction. Uremia may also orrhages or stress gastritis. The hemorrhages are
negatively impact platelet function, thereby frequently multiple and are more common in
predisposing to mucosal hemorrhage. The use of the stomach and duodenum (257,260). Patients
antiinflammatory or immunosuppressive drugs on chronic dialysis often have enlarged, some-
further aggravates the mucosal damage (246). times eroded, gastric mucosal folds. Multiple
Patients on chronic dialysis may develop amy- small ulcers develop in the upper gastrointes-
loidosis that results in colonic dilatation (252). tinal tract, including the small intestine. In
Clinical Features. Uremia injures all parts of contrast, ulcers in the colon tend to be larger
the gastrointestinal tract. The most commonly and solitary. Some patients, especially those on
affected sites are the stomach, duodenum, il- chronic dialysis, develop prominent mucosal
eum, cecum, and colon. The stomach typically telangiectasias (248).
develops small petechial mucosal hemorrhages Microscopic Findings. Gastroduodenal
in a pattern simulating acute hemorrhagic or mucosal and submucosal hemorrhages are
erosive gastritis (251). Patients with uremia sometimes associated with ulceration and
may have a more severe gastritis than the usual bleeding. The stomach shows a superficial gas-
patient. Peptic ulcer disease worsens during tritis, involving the antrum and fundus. There

341
Gastrointestinal Diseases

Figure 8-53
GASTROINTESTINAL INJURY IN PATIENTS WITH RENAL DISEASES
Patients with renal disease often have gastrointestinal injury either due to the complications of uremia or as a result of
antiinflammatory or immunosuppressiVe agents used for renal transplants. In some cases, it is difficult to know the exact
etiology of the changes that are seen due to the multifactorial nature of the damage.
A: Evidence of ischemia. There is a-pseudomembrane covering the mucosal surface.
B: Biopsy from a patient on mycophenolate shows the disappearing glands commonly seen in patients with toxic intestinal
injury. The glands become widely dilated and the epithelium appears attenuated, often resembling a dilated vessel.
C: A colonic biopsy in a patient on mycophenolate shows severe damage to the mucosa, with glandular dropout and
marked irregularity and distortion of the glands .

is foveolar hyperplasia with an increase in the the large intestine often resemble those seen
parietal cell mass and changes suggestive of in ischemic colitis (fig. 8-53). The calcifications
chemical gastropathy. Uremia-associated hyper- evident in calciphylaxis histologically resemble
gastrinemia leads fo mucosal hyperplasia via Monckeberg's medial calcific sclerosis in the
the trophic effects of gastrin (250). Patients on small vessels in the submucosa (247).
regular dialysis may develop multiple muco- Treatment and Prognosis. Many of the gas-
sal and submucosal telangiectasias, as well as trointestinal lesions resolve once the uremia
r.,·
Brunner gland hyperplasia, duodenal mucosal and renal failure are treated. Long-term com-
hypertrophy, and peptic duodenitis (250). These plications include hemorrhage, perforation, or
changes may regress following transplantation stricture formation.
(249). Heterotopic calcification may be seen in
patients who develop hyperparathyroidism. DIARRHEIC SHELLFISH POISONING
Patients with renal disease often undergo trans- Demography. Diarrheic shellfish poisoning
plantation and have secondary changes due affects individuals who consume shellfish, es-
to the presence of immunosuppressive agents pecially blue mussels that have fed on certain
(see earlier section) or infection: The lesions in species of marine phytoplankton (261).

342
Chemical Injury

Table 8-9
DRUGS AND CHEMICALS CAUSING PSEUDOOBSTRUCTION AND SEVERE CONSTIPATION

Alcohol Phenothiazines Clonidine


Amanita poisoning Cimetidine Theophylline
Anticholinergic drugs Ganglionic blockers Nonsteroidal antiinflammatory agents
Antihypertensive drugs Isoniazid Rat poisons
Antiparkinsonian drugs Laxatives Sympathomimetics
Jl;tropine Loperamide Tricyclic antidepressants
Azathioprine (AZT) therapy Minerals Vinca alkaloids
Calcium channel blockers Narcotic analgesics

Etiology. Toxins from the dinoflagellates of Etiology. Many drugs cause intestinal pseu-
the Dinophysis and Prorocentrum genera are the doobstruction (Table 8-9), the most common
main sources of shellfish poisoning (261-265). of which are tricyclic antidepressants, phe-
The major toxin responsible for diarrheic shell- nothiazines, anticholinergic drugs, and vinca
fish poisoning is dinophysistoxin 1. It contains alkaloids. It is unclear whether the drugs cause
okadaic acid, which alters cell function, en- the symptoms or unmask an underlying gastro-
hances protein phosphorylation, and increases intestinal motility disorder.
pericellular intestinal permeability. Pathophysiology. Certaip foods and drinks
Clinical Features. Symptoms, including and some drugs elevate lower esophageal sphinc-
diarrhea, nausea, vomiting, abdominal pain, ter (LES) pressure whereas others decrease it.
and chills, usually start within 4 hours after Clinical Features. The clinical features re-
ingestion and are rare after 12 hours. Occasion- semble those present in other motility disorders
ally, paraesthesias occur; paralysis is rare. This (see chapter 17). Reflux symptoms may be ag-
illness is often misdiagnosed and attributed gravated or occur de novo. Bowel dysmotility
to fish allergies, gastroenteritis, or nonspecific may present with crampy abdominal pain, dis-
neurologic disorders. tension, constipation, and diarrhea associated
Microscopic Findings. The toxin causes with bacterial overgrowth. Nausea is common
severe congestion of the villous and submuco- and vomiting may occur.
sal vessels; red blood cells extravasate into the Gross Findings. When the LES pressure de-
lamina propria. Microvilli degenerate, followed creases, the gross findings may be those of reflux
by localized desquamation of cells from the esophagitis (see chapter 3). If the LES pressure
villus tips. increases, the changes mimic achalasia (see
Differential Diagnosis. Other forms of food chapter 17). Patients may also develop intestinal
poisoning. pseudo-obstruction and dilation.
Treatment and Prognosis. The prognosis for Microscopic Findings. It is important to
patients with this invariably self-limited illness consider a diagnosis of toxic (chemically in-
is excellent. duced) visceral neuropathy in patients without
an obvious cause for their motility disorder,
DRUG-INDUCED particularly if inflammatory cells are present in
NEUROMUSCULAR DISORDERS the myenteric plexus, in the absence of cancer.
Demography. Drug-induced gastrointestinal Differential Diagnosis. Other motility dis-
dysmotility is a well-recognized phenomenon orders (see chapter 17).
(266) . Because of the types of medicines that Treatment and Prognosis. Treatment con-
induce pseudoobstruction syndromes, many of sists of withdrawal of the offending agent.
the patients have psychiatric diseases or Parkin- Symptoms may persist if another underlying
son's disease. motility disorder is present.

343
Gastrointestinal Diseases

CLOFAZIMINE-INDUCED ognized. In one large study, the incidence was


CRYSTAL-STORING HISTIOCYTOSIS 3.9 cases/100,000 population/year (275). Elderly
Demography. Clofazimine is used to treat patients are particularly at risk for developing
leprosy and other dermatologic disorders. esophageal drug injury for at least four reasons:
Clinical Features. Clofazimine is a rimino- 1) they take more medications; 2) they are more
phenazine compound that is well known for likely to have intrinsic or extrinsic esophageal
causing reddish discoloration of the skin. anatomic abnormalities or motility disorders;
Patients may present with epigastric distress 3) saliva production decreases with age; and 4)
and occasional vomiting unrelated to meals, thE7 spend more time in a recumbent position.
episodic and prostrating abdominal pain, ahd Injury is facilitated by ingestion of multiple tab-
malabsorption (26 7) . lets and inadequate liquid consumption. Hiatal
Gross Findings. Radiologic abnormalities hernia, esophageal dysmotility, or strictures also
include coarsening of the mucosal pattern predispose to prolonged esophageal retention of
and segmentation of barium in the ileum and medication and enhance the ability of drugs to
distal jejunum. Upper gastrointestinal series damage the mucosa. In patients who have other
and abdominal CT scans demonstrate irregular conditions, such as cardiac enlargement, nodal
mucosal and submucosal thickening of the disease, or an enlarged thyroid gland, the pills
jejunal mucosal folds, dilatation of the small may stick at these sites. They also stick at areas
intestinal loops, and enlargement of the mes- of strictures or rings.
enteric lymph nodes (269). Etiology. A large number of drugs cause
Microscopic Findings. Clofazimine crystals esophageal damage (Table 8-10). In younger
accumulate in mucosal macrophages, produc- individuals, the injury results from antibiotic
ing infiltrative lesions that radiologically mimic therapy, whereas cardiogenic medications and
lymphoma and other infiltrative 'disorders. bisphosphonates cause the esophageal injury
There is usually an associated lamina propria in the elderly (275). Potassium chloride pills
plasmacytosis that can simulate lymphoplasma- cause severe esophageal injury, including stric-
cytic lymphoma or multiple myeloma. Both tures (273) and significant hemorrhages. Reflux
granulomatous enteritis and eosinophilic en- esophagitis is a form of chemical injury but it
teritis may be seen. The crystals aiso accumulate is discussed in chapter 3.
within nodal macrophages. "' Pathophysiology. Chemical- and drug-
Clofazimine crystals appear red in frozen sec- induced injury in the esophagus occurs via sev-
tions, exhibiting a bright red birefringence. They eral mechanisms (Table 8-11). Most esophageal
are clear in routinely processed histologic sections damage results from focal mucosal entrapment
because they dissolve in alcohol and organic sol- that leads to localized burns and ulcerations.
vents. They also appear as clear crystalline spaces Tablets and capsules typically lodge in the mid-
in ultrastructural studies, but some osmiophilic esophagus, giving rise to discrete, multiple, and
bodies can be observed. The crystals do not stain sometimes serpiginous ulcers. Physical entrap-
with PAS or immunoglobulin immunostains. The ment of undigested medicines especially occurs
clear crystals are several times longer than the mac- with drugs that contain a hydrophilic swelling
rophage nuclei, and plasma cells and eosinophils agent or fiber that ensures rapid disintegration
are distributed between the crystals. when the pills contact water (279). These medi-
Treatment and Prognosis. Clofazimine en- cines act as foreign bodies impacting on the
teropathy regresses after drug withdrawal (268). esophageal lumen. Pills such as doxycycline,

tetracycline, ascorbic acid, ferrous sulfate, and
DRUG REACTIONS AFFECTING slow-release emepronium bromide produce a
SPECIFIC GASTROINTESTINAL SITES pH of less than 3.0 when dissolved in 10 mL of
water or saliva thereby injuring the esophagus
Drug-Related Esophagitis
(270) . Esophageal mucosal uptake plays a role in
Demography. The incidence of medication- doxycycline-, NSAID-, and alprenolol-induced
induced esophageal injwy (also termed pill esopha- injury (276). Other postulated mechanisms of
gitis) is unknown because many cases go unrec- injury include local hyperosmolarity, as with

344
Chemical Injwy

Table 8-10
EXAMPLES OF DRUG- OR CHEMICAL-INDUCED ESOPHAGEAL INJURY

Alprenol chloride Ascorbic acid Ferrous salts


Antibiotics Barbiturates Pantogar
Chloramphenicol Benadryl Pantozyme
Clindamycin
Cloxacillin Bisphosphonates Phenylbutazone
Doxycycline Carbachol Phenobarbital
Erythromycin Chemotherapeutic agents Phenoxymethyl penicillin
Lincomycin Actinomycin D Piroxicam
Minocycline Adriamycin
Penicillin Cytosine arabinoside Potassium chloride
Sulfa drugs Estramustine phosphate Prednisone and prednisolone
Tetracycline 5-Fiuorouracil Quinidine
Tinidazole
Chloral hydrate Sclerosants for varices
Antiinflammatory agents
Clinitest tablets Serrapeptase
Acetaminophen
Acetylsalicylic acid Co-trimoxazole Sodium amytal
Ibuprofen Cromolyn sodium Theophylline
Indomethacin
Digoxin, digitoxin Trimethoprim-sulfamethoxazole
Mefaminic acid
Naproxen d-Penicillamine Vasopressin
Piroxicam Emepronium bromide Zidovudine
Sulindac
Tolmetin

potassium chloride, or induction of reflux, as Table 8-11


with theophylline and anticholinergic agents. MECHANISMS OF CHEMICALLY INDUCED
Most young patients rarely have predisposing ESOPHAGEAL INJURY
factors other than improper pill ingestion. Direct toxicity
Clinical Features. Because the histologic Corrosion or acidic injury
features of chemically induced esophagitis are
Reflux esophagitis
nonspecific, the diagnosis is usually provided by
Heat production
the clinical history. Esophageal chemical injury
Physical entrapment of medication
usually falls into two major groups. One form
Allergic reactions
is transient and self-limiting, as exemplified by
Induction of vasculitis
tetracycline- and emepronium-induced injury
(see fig. 8-23). The second tends to be persistent, Altered motility or lower esophageal sphincter function
(see Table 8-12)
leading to stricture formation, as with NSAIDs
Predisposition to infection
or in patients with motility disorders in which
Induction of ischemia
drugs such as potassium chloride and quinidine
injure the mucosa due to delayed transit. En- Mucosal uptake
doscopic examination with biopsy is typically
done to determine the extent of the injury and
to rule out other causes of esophageal injury
such as infection or tumors. the patient's age and overall health status as
Patients with drug-induced esophageal injury well as the nature of the drug or chemical con-
often present with sudden odynophagia or sumed. Localized esophageal damage, ranging
other types of pain (277) and dysphagia. There from inflammation to severe hemorrhage and
may be hematemesis, melena, and stricture for- even perforation, develops as the medications
mation (278,280). The clinical features reflect dissolve (278).

345
Gastrointestinal Diseases

;'G

Figure 8-54 Figure 8-55


PILL-INDUCED ESOPHAGITIS ESOPHAGEAL BALLOONING DEGENERATION
The esophagitis resulting from medications often Swelling of the superficial epithelium to produce
resembles that due to reflux. Changes range from mild to balloon cells is a common response to chemical injury in
severe. In this case, the epithelium is markedly regener- the esophagus.
ative, congested, and slightly inflamed. In the absence of
a history, it would be impossible to make a diagnosis of
drug-induced injury. normal anatomic narrowing such as the aortic
arch or areas narrowed by pathologic processes.
Microscopic Findings. The histologic features
Patients frequently have the sensation that a of chemically induced esophageal ulcers are
pill is stuck in the esophagus before ·symptoms nonspecific: subepithelial edema, mucosal hy-
develop. Patients with antibiotic injury sud- perplasia, the presence of balloon ce11s, necrosis,
denly develop chest pain after drug administra- acute inflammation, ulceration, and edema dur-
tion. Patients on long-term potassium chloride ing the acute injury and granulation tissue and
therapy usually present with progressive dys- regenerative epithelium in the healing phase (fig.
phagia but little pain. Patients with acute quin- 8-54) (271) . The presence of balloon cells serves
idine-induced pill injury preseFJ:t with burning as an early esophageal mucosal marker of chemi-
pain and dysphagia related to edema and ulcer cal injury but it is not specific for any etiology.
development. Sulfa drugs and co-trimoxazole Balloon cells are recognizable by their distended
are implicated in up to 60 percent of cases of globoid shape (fig. 8-55). Trimethoprim-sulfa-
Stevens-Johnson syndrome (274). methoxazole as well as other medications cause
Gross Findings. Endoscopy usually shows significant eosinophilic esophagitis. Alendro-
one or more discrete, shallow, esophageal ulcers; nate is associated with multinucleated giant
the surrounding mucosa usually appears normal epithelial cells, which simulate viral cytopathic
but it may be inflamed or edematous. The ulcers effects. Stevens-Johnson syndrome is character-
are usually small, pinpoint lesions but large ized by marked inflammation of the lamina
circumferential lesions several centimeters long propria with eosinophilia and subepithelial
have also been described (281). Pill remnants bullae. Resection specimens from patients with
are occasionally identified at the injury site long-term damage may show full-thickness fi-
(278). Deeper injury results in mediastinitis or brosis. If crystals are seen, they may be the result
hemorrhage due to penetration through the of bisphosphonates or kayexalate and sorbitol.
esophageal wall. Extensive and deep penetra- These crystals lie in necrotic areas.
tion may cause circumferential ulcers that may Differen tial Diagnosis. The differential diag-
require dilatation or surgical resection. Rarely, nosis includes other forms of acute esophagitis,
medications cause a severe ulcerative esopha- especially reflux and viral esophagitis. The en-
gitis involving up to 10 cm of the esophageal doscopist should suspect drug-induced esopha-
mucosa, or its entire length. Most ulcers lie in gitis or ulceration when lesions lie proximal
the midesophagus (275,277), usually in areas of to areas where reflux-associated abnormalities

346
Chemical Injury

occur. The lesions m ay be circumferential and Table 8-12


associated with a significant edematous and CHEMICALLY INDUCED GASTRIC INJURY
erosive reaction. Symptoms may be dispropor-
tionate to the endoscopic findings . Alcohol: chemical gastropath y, ulcers, erosions, chronic
gastritis
Treatm ent and Prognosis. Most uncompli-
Alkaline reflux: chemical gastropathy, ulcers, erosions,
cated cases of pill-induced esophageal injury chronic gastritis
heal with symptom resolution in a few days to Anticoagulants: gastric hematomas
a few weeks. Antacids, H2-receptor antagonists, Bromocriptin e: gastric ulcers
and sucralfate are often prescribed, particularly
Corrosive agents: severe gastric necrosis
when gastroesophageal reflux exacerbates the
Chemotherapeutic agents: gastric necrosis
injury. Severe odynophagia may necessitate par-
Corticosteroids: gastritis and ulcers
enteral hydration or gastrotomy with manual
Ferro us sulfate: gastritis and ulcers
disimpaction (272) . Acute inflammatory and
edematous strictures may resolve spontaneously Fluorides: gastric damage
but chronic strictures may require dilatation lnterleukin 4: acute gastric mucosal injury and hemorrhage
or surgical resection. The symptoms of drug- Mercuric chloride: acute gastritis
induced esophagitis may continue if gastro- Methyldopa : autoimmune gastritis
esophageal reflux disease is present. Nonsteroidal antiinflammatory drugs (NSAIDs):
The most dangerous drug-related esophagitis chemical gastropathy, ulcers, erosions
results from potassium chloride. Several patients Potassium chloride: ulcers, bleeding, perforation, and
stricture form ation
have died of esophagitis directly related to its
Omeprazole: chronic atrophic gastritis
ingestion. Complications, such as strictures,
Prostaglandins: mucosal hyperplasia
usually result from ingestion of caustic sub-
stances, such as iron or potassium salts (270). Ticlopidine: lym phocytic gastritis
Tooth bleaching agents: gastric ulcers
Chemically Induced Gastric Injury Tumor necrosis factor: acute gastric mucosal injury and
h emorrhage
Demograph y. Chemically induced gastric in-
Zinc sulfate: gastric ulcers
jury is very common. It appears in two major
forms: as acute gastJitis or as a chemical or reactive
gastropathy. Drug-related gastrointestinal injury
accounts for over 33 percent of adverse drug intravenously or orally, suggests that mucosal
reactions among hospitalized patients (284a); contact need not occur to produce the damage.
33 percent of gastric ulcers results from drug use. Ethanol, NSAIDs, and bile acids are all lipid
Etiology. Almost any drug can irritate the soluble. They dissolve in the membranes of an-
gastric mucosa (Table 8-12). Some gastric injuries tral surface foveolar cells, damaging the mucosal
result from therapeutic drug interactions whereas mucus-bicarbonate barrier and facilitating back-
others result from accidental or suicidal inges- diffusion of h ydrogen ions into the mucosa. The
tion of strong alkalis, acids, and other toxic sub- acid in turn causes mucosal injury either due to
stances. The agents most commonly implicated direct damage or via vasoconstriction and the
in gastric injury are aspirin and other NSAIDs, development of an acute gastritis. These agents
alcohol, potassium chloride, and iron tablets also exacerbate preexisting peptic ulcer disease.
(282,283). Long-term fluoride supplementation H2-receptor antagonists (famotidine [Pepcid],
also causes gastritis, as do chemotherapeutic cimetidine [Tagamet], and ranitidine [Zantac]),
agents. Reflux of duodenal contents into the and proton pump inhibitors such as omeprazole
gastric lumen causes chemical injury as well. (Prilosec) block gastric acid secretion, significant-
Pathophysiology. Some drug-induced and ly decrease the consequences of peptic disease,
stress-induced ulcers share common pathoge- and promote ulcer healing. Chronic inhibition of
netic events with chemically induced injury, gastric acid secretion secondarily leads to G-cell
but the factors that lead to the initial cellular hyperplasia and hypergastrinemia. The degree
damage may differ. The fact that many drugs of antral G-cell hyperplasia occurring secondary
produce similar changes, whether administered to acid blockade varies from patient to patient.

347
Gastrointestinal Diseases

Clinical Features. Patients with acute gastri-


tis typically present with upper abdominal pain,
nausea, and vomiting. These may be perceived by
the patients as an abrupt onset of acute burning.
Patients with skeletal fluorosis, a crippling bone
disease caused by excess fluoride ingestion, have
gastrointestinal symptoms, the most common
being abdominal pain. The discomfort tends
to be constant and may be aggravated by food.
Pancreatitis or even cholecystitis may need to be
considered in the clinical differential diagnosis.
Gross Findings. Endoscopically, gastritis
is usually present. Variable changes include
edema, erythema, scattered petechiae, and
mucosal surface friability. Large areas of hem-
orrhage may be present, ranging from multiple
mucosal streaks to diffuse mucosafinvolvement
with superficial erosions. The endoscopist may
diagnose such cases as acute hemorrhagic gas-
tritis or acute erosive gastritis. These lesions are
typically confined to the antrum but they may
extend more proximally. Assocfated duodenal
changes may be present. Patients with chemi-
cal gastropathy are often described ·as having a
nodular antrum or showing erosions.
Microscopic Findings. The histologic fea-
tures of all of the chemical gastropathies can re- Figure 8-56
semble one another, often making it impossible CHEMICAL GASTROPATHY
to determine the exact etiology in the absence The gastric mucosa shows mild villiform transformation,
of identifiable bile or a pertinynt clinical his- muscle stranding in the lamina propria, vascular congestion,
tory. Early histologic changes consist of edema, and mucin depletion of a reactive-appearing epithelium.
congestion, and patchy hemorrhages in the su-
perficiallamina propria (fig. 8-56). The changes
overlap with those of the potential traumatic associated with alkaline reflux gastritis resemble
effects of the biopsy procedure (284). Other those seen in other forms of chemical gastropa-
changes include surface and foveolar cell hyper- thy and these lesions cannot be distinguished
plasia (fig. 8-5 7), gastric pit elongation, minimal unless bile is seen in the gastric lumen or gas-
degeneration of the foveolar and pit epithelium, tric pits. Alkaline reflux gastritis is suspected in
a relative paucity of acute inflammation, and those patients who have had prior antrectomy
regeneration in the mucous neck region (fig. and gastrojejunostomy.
8-58). Milder lesions remain limited to the up- Long-term use of antisecretory agents can
per mucosa and are frequently associated with result in mucosal hyperplasia, sometimes ap-
focal dilatation of gastric pits. The underlying pearing endoscopically as tiny gastric polyps.
glands are not involved. Vascular congestion is Histologically, these areas appear as small
often a prominent feature (fig. 8-56). There may mucosal cysts lined by flattened parietal and
be areas of erosion or ulceration. chief cells. A diffuse (fig. 8-59), linear, and/or
Mononuclear cells may be present in the micronodular hyperplasia of enterochromaffin-
lamina propria, and intestinal metaplasia may like (ECL) cells has been described in patients
be present. Chronic atrophic gastritis may de- on long-term treatment with omeprazole. The
velop. There is a relative paucity of neutrophils presence of concomitant H. pylori infection is an
despite evidence of mucosal injury. The changes important factor for the progression of fundic

348
Chemical Injwy

Figure 8-57
BILE REFLUX GASTRITIS
Irregularly shaped glands are
lined by foveolar epithelium.

gastritis and the development of argyrophil Table 8-13


cell hyperplasia during long-term antisecretory CLUES THAT SUGGEST CHEMICAL
treatment. Patients on proton pump inhibitors INJURY IN THE STOMACH
also often develop vacuolization of the parietal
Pit expansion
cells, which occasionally may be quite striking
Mucus depletion
(fig. 8-59). Features suggesting the presence of a
Superficial edema
chemical gastropathy are listed in Table 8-13.
No organisms present"
Differential Diagnosis. The differential diag-
nosis includes other forms of acute toxic gastri- No metaplasia
tis, including infections, allergic disorders, and No polyps
chronic active gastritis. The changes also overlap No enlarged folds
with those of acute stress gastritis. Muscle fibers extending into the mucosa from the
muscularis mucosae
Treatment and Prognosis. The abnormali-
ties reverse following withdrawal of the offend- Villiform transformation
ing agent. "Helicobacter pylori infection may be superimposed on a
chemical gastropathy, confounding the histologic features.
Chemically Induced Intestinal Injury
Demography. Intestinal damage commonly
follows drug or chemical exposure. Patient lin and ampicillin cause C. difticile-associated
demographics vary depending on the type of pseudomembranous colitis. In addition, they
injury caused and the agent(s) to which the cause a hemorrhagic right-sided colitis that
patient is exposed. Many have been discussed differs from the antibiotic-associated colitis.
in earlier sections. The pathogenesis of this form of disease is un-
Etiology. The most common drugs affecting known, but ischemia is thought to play a role.
the intestines are listed in Table 8-14. Probably Chemicals, such as alcohol, are injected into the
the most commonly diagnosed drug-induced colonic submucosa to facilitate chemical muco-
injury in the colon is pseudomembranous sal debridement. 1.0 normal sodium hydroxide
colitis associated with antibiotic use. NSAIDs, produces second-degree colonic mucosal burns
gold, potassium chloride, and antibiotics are within 10 minutes of exposure. It also causes
other common causes of chemically induced moderate third-degree injury of the underlying
intestinal injury. Many of these have already muscularis propria (286). Rectal formalin instil-
been discussed in previous sections. Penicil- lation is used to treat the hemorrhagic proctitis

349
Gastrointestinal Diseases

Figure 8-58
CHEMICAL GASTROPATHY
A: Figures A and B show the irregularly shaped glands typical of chemical gastropathy. The patient was a known NSAID
user. The superficial mucosa is lined by foveolar cells with abundant mucin.
B: In alkaline reflux gastritis, a basophilic epithelium lines the glands; the epithelium is much more reactive in appearance
than in A.
C: Prominent villiform transformation and muscle strands in the lamina propria.

associated with radiation injury (287). Fmmalin- bowel distension. Long-term use of the phlebo-
induced proctitis following instillation of 4 percent tonic drug, cyclo-3-FORT, causes lymphocytic
formalin in sequential aliquots of a small volume colitis. Enalapril (Vasotec) causes angioedema of
heals within 2 weeks without long-term changes the small bowel, which presents as abdominal
in rectal compliance or collagen content (288). pain, nausea, vomiting, and diarrhea.
Formalin is used to stop rectal bleeding and is Granulomatous reactions develop when oils
effective in the majority of patients (289). Silver are inserted into anal fistulas or abscess cavities.
11, ·
nitrate sticks and 1.25 percent formalin produce These reactions result from the escape of oily
first-degree mucosal burns (286). substances used to soften the feces. Oils are
Isotretinoin (Accutane), a synthetic analogue also used to inject hemorrhoids. The degree of
of 13-cis-retinoic acid, or vitamin A, precipitates the reaction depends on the type of oil used.
IBD. Isotretinoin and acyclovir cause allergic Vegetable oils produce less severe reactions than
colitis; toxic megacolon complicates metho- animal fats; mineral oils cause the most damage.
trexate use. Ergotamine tartrate sometimes Pathophysiology. Drugs injure the intes-
causes solitary rectal ulcer formation. Alumi- tine in various ways. They cause apoptosis,
num hydroxide gel causes constipation and exacerbate preexisting intestinal lesions, lead

350
Chemical Injwy

Figure 8-59
GASTRIC CHANGES IN PATIENTS
ON PROTON PUMP INHIBITORS
A: Clear cells are prominent in th e glands . These correspond to
endocrine cells .
B: Synaptophysin immunostain confirms endocrine cell hyperplasia.
C: Vacuolization of the cytoplasm of parietal cells occurs in patients
on long-term proton pump inhibitor therapy.

to neuromuscular damage, and predispose to Patients with oil granulomas present with pain,
infections or ischemia. constipation, or bleeding.
Clinical Features. The clinical features vary Gross Findings. The gross appearance of
depending on the pathogenesis of the injury. drug- or chemical-induced injury varies de-
Patients with anorectal granulomas may present pending on the type of damage produced. Most
with masses easily mistaken for cancer. Patients agents causing disease in the intestine have
exposed to glutaraldehyde develop a self-limited already been discussed in previous sections.
syndrome of cramps, abdominal pain, tenes- Endoscopic or radiographic features of glutar-
mus, and rectal bleeding within 48 hours of aldehyde injury tend to show a left-sided dis-
uncomplicated sigmoidoscopy or colonoscopy tribution. Patients with drug-induced strictures
(285). The diagnosis should be suspected in have lesions that can be short or long, single or
individuals developing hemorrhagic colitis multiple. Oil granulomas present as rounded,
immediately after undergoing colonoscopy. annular or ulcerated, submucosal anorectal

351
Gastrointestinal Diseases

Table 8-14 tumors, occurring as high as the rectosigmoid


CAUSES OF INTESTINAL CHEMICAL INJURY
junction. The tumorous masses may become
fixed to other structures. They consist of firm,
Chemotherapeutic agents: damage replicating cells
causing mucositis; predisposition to infection
yellowish gray masses of dense fibrotic tissue
containing entrapped globules of oil that ooze
Nonsteroidal antiinflammatory drugs (NSAIDs) :
erosions, ulcers, diaphra&"ms, focal enterocolitis from their cut surfaces. ·
Methotrexate: crypt hypoplasia and villous atrophy Microscopic Findings. Most drugs and
Neomycin: malabsorption, minimal histologic damage
chemicals produce a nonspecific histologic
to villous atrophy and mucosal inflammation picture easily confused with idiopathic IBD,
Drugs causing ischemia (see Table 8-6) ischemia, or infectious colitis. Many drugs are
Laxatives and bowel-cleansing agents: mild inflamma- implicated in the production of intestinal mal-
tion absorption but they do not usually result in his-
Enemas and cathartics: mild inflammation tologic abnormalities. The presence of cystically
Isotretinoin : acute colitis dilated glands adjacent to reactive-appearing
Heavy metals: enterocolitis glands suggests the presence of chemical or
Agents causing strictures (see Table 8-7) toxic injury in the intestines (fig. 8-60). Local-
Oily liniments: granulomatous inflammafion, usually in ized, nonspecific proctitis results from supposi-
anorectal area tory insertion or sulfasalazine enemas. Drugs
Agents causing motility disorders (see Table 8-9) such as methyldopa and penicillamine cause
Agents causing eosinophilia (see Table 8-8) a diffuse colitis. Long-term therapy with im-
Caustic agents: mucosal burns munosuppressive agents or corticosteroids may
Antibiotic-associated colitis: colitis with' or without result in cytomegalovirus infections, thrombus
pseudomernbranes formation, and ischemia.
Drugs or chemicals causing hypersensitivity-reactions Oil-based granulomas (oleogranulomas)
Immunosuppressive agents: inflammation, predispo- found in the anorectal region exhibit a char-
sition to infection acteristic histology that varies with the stage
of development. Characteristically, irregular

..
Figure 8-60
CHEMICAL INJURY OF THE COLON
Above: The mucosa has a distorted glandular architecture with
glandular dilatation and thinning of the epithelium.
Right: There is prominent apoptosis in the base of the crypts, with
inflammation and edema.

352
Chemical Injwy

spaces are surrounded by macrophages with tissues. Fat is not easily identified in tissues that
prominent fibrosis. Giant cells are usually have undergone routine processing but can
sparse. Sarcoid type granulomas are absent. In easily be identified in frozen sections using fat
some cases, there is significantly more inflam- stains. This is generally not necessary, however,
mation, perhaps reflecting the nature of the since the morphology is so distinctive.
oily substance or the time in the evolution of Differential Diagnosis. The foreign body
the lesion, with changes being more acute than giant cell reaction associated with oleogran-
normally seen. The spaces that are present result ulomas distinguishes them from the granulomas
from lipid extraction during slide preparation. seen in Crohn's disease or those associated
In the early stages, there is acute inflammation with certain infections, such as Yersinia or tu-
with many eosinophils. Increasing fibrosis and berculosis. Oleogranulomas lack the compact
zones of mononuclear phagocytes, epithelioid epithelioid appearance seen in Crohn's disease.
cells, giant cells, and a peripheral boundary of In addition, there is often fat necrosis associ-
proliferating fibrous connective tissue gradually ated with oleogranuloma that helps distinguish
replace the acute inflammation. Round spaces this lesion from granulomas associated with
are lined by mononuclear cells or multinucle- infections or Crohn's disease. The histologic
ated histiocytes. Prominent fibrosis may be features of oleogranulomas can also be confused
present. Variable numbers of eosinophils and with those of lymphangiomas or pneumatosis
lymphocytes are associated with the reactive intestinalis.

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chronic dialysis. Arch Intern Med 1967;120: Jpn Soc Sci Fish 1980;46:1405-12.
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252. Ikegaya N, Kobayashi S, Hishida A, Kaneko E, Drug-Induced Neuromuscular Disorders
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253 . Kao CH, Hsu YH, Wang S] . Delayed gastric
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254. Khaffif RA, DeLima C, Silverberg A, Frankel R. 267. Atkinson A] ]r, Sheagren ]N, Rubio ]B, Knight
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'"·' cular calcification and peripheral necrosis teropathie a la clofazimine. Une observation
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270. Bonavina L, DeMeester TR, McChesney L, 62:435-9.
Schwizer W, Albertucci M, Bailey RT. Drug- 281. Stoschus B, Allescher HD. Drug-induced dys-
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363
...
9 PHYSICAL INJURY

RADIATION- INDUCED INJURY therapy or through imaging studies. Radiation is


.Definition. Gastrointestinal radiation injury also used as a conditioning agent for bone mar-
is the damage that develops anywhere in the row transplants. Individuals are also exposed to
gastrointestinal tract either as a result of acute radiation during warfare or nuclear accidents.
radiation toxicity or as a long-term consequence Etiology. The effects of radiotherapy depend
of the vascular disease that develops in response on the duration of the therapy and the particle
to radiation injury. Ionizing radiation may be type. Radiation comes in two forms: electro-
characterized by the way that the energy is emit- magnetic waves and particle radiation (Table
ted, propagated, and absorbed. Radiant energy 9-1). Radiation particles have variable charges,
absorbed from a source outside the body is and include beta-particles (electrons), protons,
known as external radiation. Correspondingly, alpha-particles, and neutrons. The most com-
energy from a source located inside the body, mon type of radiation injury results from X rays
such as a radionuclide, is termed internal radia- containing low or moderate energy photons
tion, and the source is referred to as an internal with a relatively high tissue penetrance.
emitter. By convention, radiation pathology is The effects of radiation differ not only by
divided into early and delayed effects. Early ef- its type but also by its energy. Radiation that
fects are those that occur within the initial 60 causes dense ionization along its tract, such
days post-exposure; delayed effects are those as alpha-particles and neutrons, is called high
occurring thereafter. Types of gastrointestinal linear energy transfer (LET) radiation, a physi-
radiation injury include radiation esophagitis, cal parameter to describe average energy release
radiation gastritis, radiation enteritis, radiation coli- per unit length of the tract. In contrast, low LET
tis, radiation proctitis, and radiation enteropathy. transfer radiation produces sparse ionization
Demography. Two seminal events in the along its tract. High LET is more destructive
19th century changed our thinking with respect than low LET radiation at the same dose. The
to radiation injury. The first was the discovery localized DNA damage caused by dense ioniza-
of X rays and the other was the demonstration tion from high LET radiation is more difficult
of naturally occurring radioactive materials in to repair than the diffuse DNA damage caused
the earth's crust. Add to this knowledge of the by sparse ionization from low LET radiation.
long-term effects of nuclear warfare and nuclear
accidents in the following century, and we have
an increased understanding of the long-term Table 9-1
effects of this form of physical injury. TYPES OF RADIATION
Energy that results in human irradiation is Tissue
predominantly derived from two sources: natu- Type Major Source Penetration
ral or background radiation and technologically Electromagnetic Waves
induced or enhanced radiation. The relative de- Gamma rays Isotope Deep
gree to which these two sources contribute to an X rays Diagnostic machine Deep
individual's annual exposure depends primar-
Particuiate Matter
ily on where the person lives, the individual's
Beta Isotope Intermediate
occupation, and the degree of technological
development in the local environment. Most Proton Isotope Intermediate
patients who develop radiation injury have re- Alpha Isotope Superficial
ceived the radiation as a consequence of cancer Neutron Isotope Superficial

365
Gastrointestinal Diseases

Table 9-2 tract, from the esophagus to the anus, and the
FACTORS THAT ENHANCE RADIATION INJURY
pathologic effects are similar in all areas. Epithe-
lial and vascular injuries are common.
Radiation doses of ;, 4,500 rads The frequency of gastrointestinallesions var-
The way radiation is given (accelerated fractionation ies as a result of local radiosensitivity and radia-
increases the incidence of late radiation enteropathy) tion dose. Varying sensitivity of different parts
Presen ce of other diseases of the gastrointestinal tract results from the fact
Diabetes
Hypertension
that radiation preferentially affects intermitotic
Severe atherosclerosis cells with short reproductive cycles. The most
Previous intestinal injury severe damage occurs in areas of intestinal fixa-
Cardiovascular disease tion, such as in the duodenum, terminal ileum,
Prior surgery or in bowel loops fixed by adhesions.
Prior radiation Radiation damages DNA, impairs cell replica-
Drugs tion, and results in cell death, either by necrosis
Adr.i amycin and other chemotherapeutic agents or apoptosis; it also causes mutations. Ionizing
An empty intestinal lumen during radiation therapy irradiation rapidly generates oxygen radicals by
water radiolysis (22,58, 70), yielding superoxide,
hydrogen peroxide, and hydroxyl radicals (36) .
Endothelial cells are very sensitive to these
The degree of radiation damage is determined molecules (23). Recent evidence suggests that
by many factors (Table 9-2) (1,6,16';46,51,52,95). microvascular endothelial apoptosis represents
Certainly the radiation dose rate Influences the a major lesion in gastrointestinal radiation-
degree of damage. Injuries seldom occur at doses induced damage. A close correlation exists
less than 4,200 rads. There is a 1 to· 5 percent between crypt dysfunction and the intensity of
risk of gastrointestinal ulceration, perforation, the microvascular endothelial apo_ptosis (61).
fibrosis, and obstruction at 4,500 rads. At 6,000 The damaged endothelium produces proinflam-
rads, the risk increases to 25 to 50 percent (68). matory mediators (41) and upregulates adhesion
A single whole body dose of external radiation molecule expression, causing leukocytes to roll,
is more lethal than regional fractionated doses become activated, and adhere to the endothelial
with shielding. Total body exposure in the range cells. The activated leukocytes then produce a
of 1,000 to 2,000 rads is fatal with in 10 days due second oxygen radical burst, inducing further
to the extensive gastrointestinal injury, which microvascular dysfunction (57,58). If the cells
results in severe loss of water, electrolytes, and undergo extensive damage or if they are un-
proteins, as well as hemorrhage and sepsis (92). able to repair the damage, they enter apoptosis.
Fractionated doses allow time for cellular repair. Apoptotic cells remain confined to stem cells at
Delayed enteric injury follows fractional radia- the crypt bases (64). Free radical scavengers and
tion doses above 4,000 rads (44). antioxidants protect against radiation injury.
Pathophysiology. None of the morpho- Microvascular function regulates expression
logic events that result from radiation injury of radiation-induced crypt stem cell clonogen
is unique. Each of the alterations encountered damage in the evolution of radiation injury to
in irradiated cells is found with other forms of the gastrointestinal mucosa (48). Beta-fibroblast
gastrointestinal injury, such as those caused by growth factor ( ~-FGF) is radioprotective by
ischemia, heat, cold, or toxic substances. preventing crypt shrinkage. The protection af-
' ··
Radiation injury causes two types of gastro- forded by ~-FGF results in an increased number
intestinal damage. One is the radiation damage of surviving crypts, thus improving the likeli-
itself; the second is the long-term consequence hood of restitution of the intestinal mucosa
of radiation, i.e., ischemic changes or cancer de- (48). The pericryptal myofibroblast sheaths
velopment. Radiation-induced gastrointestinal may also be a critical determinant in the type
damage is associated with loss of barrier func- of injury. Crypt luminal cells return to normal
tion and inflammatory responses. Radiation at the end of treatment, but the effects of ra-
injury affects all parts of the gastrointestinal diation on the pericryptal sheaths are longer

366
Physical Injwy

lasting (65,97). Transforming growth factor- Table 9-3


beta (TGF-~) is a differential growth factor for RADIATION-INDUCED CARCINOGENESIS
intestinal epithelium and is synthesized in part
by the myofibroblast sheaths. Increased levels Mutation (clirect effects)
have been reported in intestinal tissue following Oncogene activation
Tumor suppressor gene inactivation
radiation (8) . Also following radiation, members
Genetic Instability (indirect effects)
of the WNT signaling pathway are lost from the Chromosome instability (aneuploidy, breaks, deletion,
luminal cells and the surrounding fibroblasts, amplification)
including E-cadherin and beta-catenin (85). Minisatellite mutation (germ cell mutation)
Additionally, cytokines are activated during Microsatellite instability (replication error)
radiation-induced damage (39); cytokines are
proinflammatory in nature.
Other changes to the gastrointestinal tract
include loss of intestinal barrier integrity, with induced ionizations act directly or indirectly via
increased leakage of proteins, and alterations in water-derived radicals, thereby injuring cellular
intestinal absorption due to the immaturity of components. The major damage in single cells
the cells or due to motility defects as a result of is single- or double-strand DNA breaks. Double-
damage to the enteric nervous system. Damage to strand breaks are more difficult to repair by
the ileum, which is particularly sensitive to radia- nonhomologous enjoining or homologous
tion injury, may result in the impaired absorption recombination. Erroneous rejoining of broken
of vitamin B12 and bile acids. Both of these are ends may occur, resulting in cell death or the
absorbed in the terminal ileum by specific trans- induction of mutations that activate proto-
pmters located within the villous epithelial cells. oncogenes or inactivate tumor suppressor genes.
Our understanding of the acute conse- Clinical Features. The clinical manifesta-
quences of whole body exposure in humans is tions of radiation injury depend on whether an
primarily derived from Japanese atomic bomb individual has experienced an acute whole body
survivors, victims of nuclear accidents, and exposure or has received small doses of radia-
patients irradiated therapeutically. The acute tion targeted to a particular area. Most patients
effects of ionizing radiation range from frank who receive small radiation doses experience
necrosis at high doses, death of proliferating early acute symptoms of bowel injury, includ-
cells at intermediate doses, and no histologic ing tenesmus, urgency, bleeding, diarrhea, and
effects at doses of less than 50 rads (88) . Radia- incontinence. These symptoms usually resolve
tion injury eventually leads to mucosal atrophy. within 2 to 3 months following cessation of the
Acute cell death, especially of endothelial cells, radiation exposure, although a small percentage
causes delayed organ dysfunction months to of patients develop chronic problems.
years after the radiation exposure. In general, The most common problem following pel-
this delayed injury results from a combination vic radiation is proctitis followed by enteritis,
of parenchyma! cell atrophy, ischemia due to anorectal stricture, and fibrosis (63). Neural,
vascular damage, and fibrosis. Malabsorption muscular, or neuromuscular damage results in
results from radiation-induced dysmotility that localized or generalized gastrointestinal dys-
leads to bacterial overgrowth-related radiation motility, esophageal dysmotility, gastroparesis,
enteropathy (37,38) and impaired ileal function or intestinal pseudoobstruction. Radiation alters
with defective lactose and bile acid absorption. mucosal barrier function and causes malabsorp-
Many patients receiving radiotherapy also tion. The gastrointestinal tract of patients who
receive drugs with radiosensitizing effects (30). receive radiotherapy for primary gastrointesti-
These drugs are directly toxic to the mucosa (see nal malignancies may perforate due to tumor
chapter 8), predisposing it to further radiation necrosis. Most moderate to severe intestinal
damage. Factors that increase the incidence of injuries develop within 2 to 5 years after radia-
radiation injury are listed in Table 9-2. tion, with a cumulative 10-year incidence of 8
Mechanisms of radiation-induced carcino- percent for moderate injuries and 3 percent for
genesis are summarized in Table 9-3. Radiation- severe injuries.

367
Gastrointestinal Diseases

Table 9-4
CLINICAL FEATURES OF THE ACUTE .RADIATION SYNDROME

Whole-Body
Category Dose (rem) Symptoms Prognosis
Subclinical <200 Mild nausea and vomiting 100% survival
Lymphocytes <1,500/mm 3
Hematopoietic 200-600 Intermittent nausea and vomiting Infections
Petechiae, hemorrhage May require bone marrow transplant
Maximum neutrophil and platelet
depression in 2 weeks
Gastrointestinal 600-1,000 Nausea, vomiting, diarrhea Shock and death in 10 to 14 days
Hemorrhage and infection in 1 to 3 weeks even with replacement therapy
Severe neutrophil and platelet depression
Lymphocytes <500/mm 3
Central nervous >1,000 Intractable nausea and vomiting Death in 14 to 36 hours
system Confusion, somnolence, convulsions
Coma in 15 min to 3 hours
Lym~hocytes absent

Mucosal biopsies are generally performed in dose dependent. The most frequent prodromal
cases of suspected radiation injury in order to symptoms are anorexia, nausea, and vomiting;
confirm the presence of a radiation effect or to 2) latency period: the prodromal stage rarely
exclude the presence of recurrent tumor, the exceeds 24 hours. This is then followed by an
reemergence of a new tumor, or the presence asymptomatic period, the duration of which is
of an opportunistic infection. The endoscopist inversely proportional to the radiatiem dose. In
must exercise caution whenever utilizing large patients with large radiation exposures (those
biopsy devices to obtain tissue from areas with in excess of 1,000 rads), the prodromal phase
poor vascularity or suboptimal healing potential often merges with either gastrointestinal or
as perforation or fistulization constitute possible acute incapacitation syndrome. These are gener-
complications. "' ally fatal, so that the latency period may not be
Progressing and unrelenting fibrosis, par- apparent. At lower doses, the duration of the la-
ticularly in the small bowel, results in part tency period primarily reflects the time required
from vascular insufficiency. It also results from for the untoward consequences of cell depletion
persistent functional loss of mucosal cells that to become clinically evident. This specifically
lack the appropriate nutrients for healing. There affects mitotically active cells; and 3) principal
is also increased expression ofTGF-~ in the area phase: during the third and principal phase, the
of radiation injury. There may also be alterations syndrome can be subcategorized on the basis of
in the coagulation cascade that may contribute the mode of death and the organ system most
to the progression of delayed injury. conspicuously involved. These include hema-
Acute Whole Body Exposure. Whole body topoietic syndrome, gastrointestinal syndrome,
irradiation is potentially lethal; the clinical or central nervous system syndrome (Table 9-4).
manifestations are dose dependent. They are Localized Exposure. Esophagus. The esophagus
,., typically described as acute radiation syndrome was initially thought to be radioresistant, but it
or radiation sickness. In radiation accidents and has now been shown that esophageal squamous
atomic warfare, single radiation exposures in the epithelium, stroma, and blood vessels all have
range of 1,000 to 2,000 rads may cause death. sufficient radiosensitivity to result in early and
Acute radiation syndrome or radiation sickness delayed complications after exposure to thera-
is characterized by three successive phases: 1) peutic doses of radiation. The radiosensitivity
prodromal phase: this transient period gener- of the esophagus is comparable to that of other
ally develops within a few hours of exposure. regions of the gastrointestinal tract. Radiation
The severity and duration of symptoms are doses of 4,500 to 5,000 rads or more adminis-

368
Physical Injwy

tered to a previously normal esophagus produce Fifty percent of patients with gastric doses of
significant esophageal injury. 5,500 or more rads develop clinical evidence of
Radiation esophagitis follows radiation gastric mucosal injury (70). It is not unusual for
therapy for cancers arising in the head and the stomach to receive doses of radiation rang-
neck, thyroid, thymus, lung, mediastinum, and ing from 4,000 to 6,000 rads during treatment
esophagus. Symptoms of radiation esophagitis of lower esophageal tumors and tumors of the
begin about 2 weeks after the initiation of radia- biliary tract, pancreas, and the stomach itself.
tion therapy. They tend to occur earlier and be The stomach may also be in radiation fields for
more severe with increasing radiation dose and treatment of lymphomas or Hodgkin's disease
decreasing time of the dosage spread. Patients involving periaortic lymph nodes.
with radiation esophagitis present with dys- Irradiation causes direct mucosal damage as
phagia, odynophagia, substernal burning, and well as capillary endothelial cell abnormalities
esophageal dysmotility. Motility disturbances are and acute thromboses. Gastric ulcers are the
common, especially in those receiving over 4,500 most important complication of gastric radia-
rads over a 6- to 8-week period. The dysphagia tion exposure. Ulcers may occur as early as 9
results from interruption of primary peristaltic weeks following therapy completion. They are
waves. The symptoms may subside on their own, indistinguishable from ordinary peptic ulcers.
they may persist for a short period of time, or The ulcers are usually solitary, measuring 0.5
they may persist for up to 2 to 3 months and re- to 2.0 cm in diameter. Since gastric acid and
quire analgesic therapy. Ulcers can develop at the peptic secretion is reduced, the ulcers do not
end of the therapy or shortly thereafter and may respond to dietary or antacid treatment. They
persist but they usually heal spontaneously (44). may heal spontaneously but the accompanying
Late esophageal effects manifest clinically by submucosal fibrosis can produce antral fibrosis.
difficulty swallowing secondary to fibrosis and Other nonacute clinical syndromes compli-
stricture formation, and motility disturbances. cating gastric radiation are: 1) dyspepsia, arising
Rare complications include pseudodiverticula 6 months to 4 years after radiation exposure
development and fistula formation. without clinical or radiographic signs and 2)
Medical conditions associated with increased gastritis, arising 1 to 12 months from the com-
radiation sensitivity include collagen vascular pletion of radiation, accompanied by evidence
diseases, diabetes, ataxia-telangiectasia, Bloom's of antral spasm or stenosis. Gastroscopy reveals
syndrome, and acquired immunodeficiency smooth mucosal folds and mucosal atrophy.
syndrome (AIDS) (13). These all constitute Fistulas sometimes complicate radiation therapy
contraindications to high-dose radiation to the for gastric cancer (18).
esophagus due to an increased risk for the devel- Small Intestine. The small intestine is very sen-
opment of late complications (12). The clinical sitive to radiation; abdominal radiotherapy re-
situation is often complicated by the presence of sults in chronic gastrointestinal complaints in 10
esophageal superinfection as a result of immune to 30 percent of patients (15,32,34,42). Fixed por-
suppression due to the underlying disease, or tions of the small bowel sustain a greater degree
concomitant administration of chemotherapy, of injury than mobile ones. The duodenum has
other myelosuppressive agents, and other a particularly low tolerance to radiation because
medications that may have local topical erosive of its fixed position. The irradiated duodenum
effects. The clinician and pathologist, therefore, may be further injured by exposure to gastric
often have to determine whether more than one juice, bile, and pancreatic digestive enzymes.
pathologic process is present and which factor The lower small intestine is frequently exposed
is predominant in increasing clinical disease, during treatment of neoplasms involving the
namely radiation, opportunistic infection, acid bladder, prostate, and female reproductive tract
reflux, or drug-induced inflammation. as well as the lower large intestine.
Stomach . Acute gastric lesions (gastritis) Because of the frequency of neoplasms in this
follow total body irradiation or local gastric area, radiation injury involving the distal small
irradiation (25,27). Gastric glandular necrosis intestine is one of the most common radiation
can follow as little as 1,200 rads of therapy. injuries seen in the gastrointestinal tract. The

369
Gastrointestinal Diseases

radioresponsiveness of the small intestine often and is exposed to radiation just as frequently,
results in modification of radiotherapy plans for yet diffuse radiation injury occurs less com-
other diseases. monly. Nevertheless, there is a high incidence
At 4,500 rads, there is a 1 to 5 percent risk of of radiation damage because of the frequent
ulceration, perforation, fibrosis, and obstruction. use of radiation to treat pelvic tumors and the
In the range of 5,000 to 6,000 rads, 20 to 50 fixed position of the rectosigmoid. Between 75
percent of patients develop clinical enteritis (66), to 90 percent of all intestinal complications af-
mainly in the terminal ileum or in bowel loops fect the distal colon (2), with the rectum being
fixed by adhesions. Acute radiation enteropathy most commonly involved (16,55).
is usually self-limited, but up to 31 percent of Acute, symptomatic rectosigmoid lesions are
patients require surgery. Over 6,000 rads, about very common and are almost invariably due
75 percent of patients develop clinical symp- to therapy for pelvic neoplasms with doses of
toms, usually by the middle of the 2nd week of 3,000 to 4,000 rads delivered within a 3- to 4-
therapy. Patients often have acute but temporary week period. Transient diarrhea accompanied
diarrhea during, and immediately after, a course by tenesmus, incomplete evacuation, mild
of abdominal radiation. Nausea, vomiting, and abdominal cramps, and a mucoid or bloody
abdominal cramps also develop. The- acute mani- discharge can be expected as a result of acute
festations usually subside within weeks, due to mucosal cellular injury (45) . Pain, alterations in
rapid mucosal regeneration. At this dose, the risk bowel habits, and bleeding are also prominent
of perforation is 25 to 50 percent (69). symptoms (45). Bleeding is due to the under-
Chronic radiation enteropathy develops lying vascular changes (76). Severe proctosig-
months, years, or decades following treatment. moiditis follows radiation therapy in 2.4 to
Patients present with diarrhea, crampy abdomi- 5.0 percent of patients; it is more common in
nal pain, nausea, and cachexia. Villous atrophy patients treated with over 6,000 rads over 6
results in malabsorption. Late complications weeks. Restricted function of the iq}ernal anal
tend to persist (19,42,83). A small percentage of sphincter is important in causing intestinal
patients experience a chronic deteriorating dis- disease. Diffuse pancolitis may develop, as may
ease, referred to as severe late radiation enteropathy. ulcerations, stenosis, necrosis, and fistulas, all
It is characterized by diarrhea, pain, malabsorp- caused by progressive intramural vasculitis with
tion, small bowel obstruction, acute or chronic submucosal and subserosa! fibrosis.
gastrointestinal bleeding, intestinal perforation, Delayed lesions resemble those seen in the
and pseudoobshuction (42). Strictures predispose small intestine, and include strictures, perfora-
to intestinal stasis and blind loop syndrome. tion, intestinal pseudoobstruction (91), vascular
Late changes develop secondary to intramural obliteration, and mural fibrosis (28,91). The
vasculitis, with resultant ulcer, stricture, and fis- frequency of chronic radiation damage varies
tula formation. Chronic radiation injury is a ma- from 0.5 to 30.0 percent (77). Delayed procto-
jor cause of intestinal ischemia. Small intestinal sigmoiditis with intermittent bleeding of mild
ischemia with perforation or fistula formation to moderate severity occurs 6 months to 5 years
accounts for 16 perce-nt oflate intestinal compli- following therapy but can be delayed for as
cations of radiotherapy (19). Patients may also many as 30 years. Other intestinal symptoms
develop radiation-induced intestinal obstruction include a mucoid rectal discharge, tenesmus,
or pseudoobstruction (59) . In these situations abdominal distension, and abdominal pain.
the clinician is often confronted with the task Radiation also induces solitary rectal ulcers (14).
of excluding other disease processes affecting Anus. Radiation-induced changes often af-
the small bowel, including Crohn's disease, fect the anus because the common therapy for
mycobacterial infections, lymphoma, and other advanced cervical or prostate cancer includes
infiltrative disorders. As the radiologic features radiotherapy. Secondary changes as a result of
invariably overlap, the clinician is dependent soiling and fungal skin infections are common.
on the pathologist to confirm the diagnosis. Gross Findings. Esophagus. The location of
Large Intestine. The large intestine has a radio- radiation esophagitis depends on what part of
sensitivity as great as that of the small intestine the esophagus was exposed to the radiation.

370
Physical Injwy

Figure 9-2
RADIATION-INDUCED ESOPHAGEAL INJURY
Cross section through the esophageal wall of a patient
with esophageal cancer who was treated with preoperative
radiotherapy. No residual tumor was present in the resected
specimen. The wall of the esophagus shows an area of
fibrosis. The small white nodule just to the left is a small
leiomyoma.
Figure 9-1
RADIATION ESOPHAGITIS
Endoscopic appearance of the eroded reddened mucosa Computerized tomography (CT) of radiation-
in a patient with radiation esophagitis.
induced gastritis shows nonspecific gastric
thickening. In the acute phase, small ulcers may
Radiation esophagitis presents as areas of ero- be visible and the mucosa may appear shaggy.
sion, ulceration (fig. 9-1), fibrosis, and/or stric- Narrowing and deformity of the antrum and
ture. Esophageal ulcers and esophageal fistulas pylorus, without ulceration, are more frequent
develop during the subacute phase. The ulcers during chronic injury (7).
may become quite large, measuring up to 5 cm Small Intestine. Both early and delayed com-
in diameter; these may perforate into adjacent plications develop. The delayed complications
structures causing hemorrhage (71). Esophageal are responsible for many of the changes related
strictures, mucosal webs, and mucosal stromal to radiation injury in the small bowel. Delayed
bridges (60) develop during chronic radiation complications result from fibrosis and vascular
injury, usually 13 to 21 months after the initia- injury; these changes are progressive and often
tion of therapy. Stricture length depends on the relentless. Patients also develop acute ulcers
size of the radiation field. The most consistent with underlying granulation tissue contain-
radiologic finding is abnormal motility; esopha- ing prominent vessels. In acute and subacute
geal strictures or ulcers occur less frequently (29). radiation-induced enteritis, barium studies
Late changes include mural fibrosis (fig. 9-2). often show nodular filling defects or thumb-
Stomach. Patients receiving radiation in doses printing. These features result from arteriolar
over 4,000 rads demonstrate both acute and obliteration. The mucosa has a marked regen-
chronic gastritis, with areas of epithelial necrosis erative ability and erosions heal rapidly, the
and shallow ulcers (17), many of which involve edema subsides, and mucosal integrity is rapidly
the antrum and pylorus. Radiographic changes restored. Some injury, however, may remain,
include irregular antral contractions and gastric altering the underlying mucosal histology and
ulcerations (29). If sufficient peptic acid secre- function. Additionally, the microvasculature
tion persists, the ulcers resemble usual peptic develops telangiectasias and endothelial cell
ulcers, with a necrotic base over a prominent functions can be lost.
fibrinoid layer, beneath which are successive Late radiation injury results in bleeding,
layers of chronic active granulation tissue and fistula formation, and obstruction. The bowel
dense fibrosis (see chapter 5). and its mesentery shorten; mucosal ulceration

371
Gastrointestinal Diseases

and submucosal fibrosis are present. In late stage


disease, mucosal atrophy is invariably present.
Eventually, the serosa acquires a matte-white
appearance as adhesions develop; the bowel
appears markedly thickened and fibrotic (29).
When the bowel is resected, it often appears
mottled red and gray with a markedly thickened
serosa. The changes are identical to those seen
in ischemia. The fatty tissue of the mesentery
does not extend over the surface of the small
intestine as it does in Crohn's disease. Mesenter-
ies are thickened and indurated. The valvulae
conniventes may be irregular and thickened,
with focal erosions in the central areas. The Figure 9-3
submucosa appears whitened. The muscularis
RADIATION PROCTITIS
propria becomes hypertrophic. Dense adhesions,
The right half of the specimen shows mucosal dis-
with kinking of loops of small bowel, are often coloration whereas the left half shows loss of mucosal folds.
present. The bowel proximal to strictures distends.
Often, the abnormal bowel merges imperceptibly
with the noninjured bowel, making it difficult associated with inflamed perirectal fat. An in-
to identify the exact junction of the-injured and crease in the presacral space of more than 1 cm
uninjured bowel. This can cause problems at the in anteroposterior diameter and a thickening of
time of resection because the surgeon may place an the perirectal fascia typify chronic radiation-
anastomosis in a damaged prut of the intestine that induced proctitis and create the so-called halo
grossly appears normal. If this occurs, postopera- effect. Complications such as fistulg_;; and ab-
tive anastomotic leaks can develop. Frozen section scesses are seen on CT scan.
monitoling helps determine whether the resection Barium studies of acute radiation-induced
mru·gins are histologically normal or whether they, colitis often demonstrate spasm, mucosal ir-
too, ru·e affected by underlying radiation damage. regularity, and nodular submucosal thickening,
CT provides useful information regarding the which results in a cobblestoned pattern. Efface-
extent of the bowel wall thickening and mesen- ment of the valves of Houston and inter haustral
teric fibrosis. Separation of bowel loops results folds is observed. Chronic radiation-induced
from mural fibrosis. Long segment strictures colitis often manifests as strictures that may be
may be present. In cases of moderate radiation long or short, and generally have tapered and
damage, CT shows the affected small bowel smooth margins. In some cases, ulcers, fistulas,
loops as accurately as barium studies. CT is accu- and sinus tracts are seen (9). Radiation changes
rate also for detecting fistulas and abscesses. On in patients who have received treatment for
CT, a thickened intestinal wall, configured with pelvic malignancies are invariably confined to
a middle layer of low attenuation surrounded that area of the bowel within the pelvis.
on each side by layers of higher attenuation, Microscopic Findings. General Features. Ra-
has been termed the "target sign." Fat density diation damage occurs within several hours of
target sign is useful in identifying patients with administration and mucosal loss occurs within
chronic radiation enteritis (10). 1 to 2 days. Acute ulceration, edema (fig. 9-5),
Large Intestine. Early colorectal changes in- and vascular fibrinoid necrosis are seen in the
clude mucosal edema, mucosal discoloration or acute period. Chronic effects include mucosal
duskiness, and loss of normal mucosal vascular atrophy, telangiectasia (fig. 9-6), atypical stro-
patterns (fig. 9-3). Pallor, loss of mucosal folds, mal cells (fig. 9-7), fibrosis (fig. 9-8), submucosal
and irregular shallow ulcers may be present. neuronal proliferations, and degeneration of
Strictures develop late in the disease (fig. 9-4). the muscle fibers of the circular layer of the
On CT, radiation-induced proctitis has muscularis propria. Vascular injury affects all
regular and symmetrical rectal wall thickening gastrointestinal sites (fig. 9-9). Following the

372
Physical Injwy

Figure 9-4
RADIATION-INDUCED STRICTURE
Left: There is marked thickening of the intestinal wall with narrowing
of the lumen. The gross appearance resembles that of certain types of
adenocarcinoma.
Above: Radiographically, an area of narrowing is seen.

Figure 9-5 Figure 9-6


ACUTE RADIATION DAMAGE AFFECTING THE RECTUM ACUTE RADIATION INJURY IN THE COLON
Acute changes in the J;ectal mucosa in a patient receiving Mucosal telangiectasia is characteristic of early radiation-
radiation. Mucosal edema is prominent. induced lesions .

initial vascular injury, the blood vessels develop tion, and thrombosis. The likelihood of finding
subintimal fibrosis and fibrosis of the muscle arteriolar damage with severe myointimal thick-
wall, degeneration of the internal elastic lamina, ening and lipophages depends on the time fol-
and severe luminal narrowing. Capillaries may lowing radiation exposure rather than the dose.
become thrombosed and obliterated or ectatic. In chronic radiation damage, the vasculature of
The organs supplied by these damaged vessels the bowel is markedly compromised by progres-
become ischemic, atrophic, and fibrotic. Other sive endarteritis. Late radiation effects include
vascular changes include subendothelial accu- progressive hyalinization of vascular walls,
mulations of lipid-laden macrophages, calcifica- obstruction of vascular lumens, ischemia, and

373
Gastrointestinal Diseases

Figure 9-7 Figure 9-8


RADIATION-INDUCED ESOPHAGEAL INJURY RADIATION-INDUCED INJURY
Prominent atypical cells are in the stroma in this esoph- Dense submucosal fibrosis with swallow-tailed radiation
ageal biopsy from a patient receiving radiation therapy. These fibroblasts distributed throughout.
atypical cells can be quite striking. The esophageal squamous
epithelium shows some disorganization, intercellular edema,
nuclear enlargement, and loss of polarity.

Figure 9-9
RADIATION-INDUCED VASCULAR INJURY
Left: Fibrinoid necrosis of the vascular wall.
Right: Long-standing radiation-induced obliterative endarteritis. There is a marked proliferation of fibrous tissue within
the intima. An inflamrn,atory response surrounds the damaged vessels.

tissue necrosis. Atypical stromal cells surround form larger superficial ulcers . Prominent endo-
the damaged vessels. Stromal changes persist thelial cells lie in the edematous granulation tis-
'-··
longer than epithelial changes, although the sue. Degenerated epithelial cells show cytoplasmic
mucosal damage is usually more obvious. enlargement, vacuolization, and multinucleation.
Esophagus. Early changes in the esophageal Both radiation- and chemotherapy-associated
mucosa include epithelial swelling and vacuol- esophagitis result in large, bizarre-appearing, squa-
ization, an absence of mitoses in the basal layer, mous epithelial cells with increased cytoplasmic
thinning of the squamous cell layer, and focal volume and increased nucleoplasm (fig. 9-7). Nu-
basal epithelial cell necrosis (apoptosis). The cleoli are usually not prominent. Dead or dying
tissues appear edematous, erythematous, and tumor cells may be seen. Fibrin-platelet thrombi
friable, with superficial erosions coalescing to may be visible in capillaries and small veins.

374
Physical Injwy

Figure 9-10
RADIATION-INDUCED ESOPHAGEAL FIBROSIS
Left: Dense fibrosis in the submucosa, with atypical stromal cells.
Right: Fibrosis of the muscularis propria.

Patients who develop odynophagia and/or


dysphagia typically have discrete ulcers. If ulcers
develop, there is often acute and chronic in-
flammation, fibrosis, and numerous fibroblasts
containing large hyperchromatic nuclei. Bizarre
(radiation) fibroblasts and vascular changes sug-
gest the diagnosis. Epithelial hyperplasia devel-
ops in an effort to reepithelialize the mucosal
surface. Mitotic figures may appear more numer-
ous in the mucosa than normal. The regenerat-
ing epithelium may show features simulating
dysplasia. Nuclear membrane irregularities and
multinucleation may be present. The chromatin
usually remains finely granular. If bizarre epi- Figure 9-11
thelial or stromal cells are found in an area of
RADIATION-INDUCED MUSCULAR CHANGES
unexplained esophagitis or fibrosis, it is always
wise to query the clinician concerning a history Changes of the muscularis propria in a patient radiated
for esophageal carcinoma . The muscle cells appear to be de-
of previous radiation exposure if this history generating. In the center are some residual viable tumor cells.
has not already been provided. Eventually, the
epithelial lining regenerates, with an increase
in the basal cell layer and a possible increase in may also be smooth muscle fiber fragmenta-
the overall epithelial thickness. tion. Atypical fibroblasts may be embedded in
Histologic examination in the late period dense collagenous tissue. Submucosal glands
discloses the presence of acanthosis, parakera- become atrophic, with acinar loss and dilata-
tosis, hyperkeratosis, hyalinized blood vessels, tion, and inspissation of the ductular contents.
submucosal and muscular fibrosis (fig. 9-10), A mild inflammatory infiltrate may be present.
and muscular degeneration. The myenteric Patients who receive brachytherapy in addition
plexus becomes inflamed and fibrotic. The mus- to external beam therapy develop more severe
cularis propria appears degenerated (fig. 9-11); mucosal injury. If a boost of 1,000 to 1,500
the muscularis mucosae may appear normal or rads of brachytherapy is added to 5,000 rads
fibrotic. The mucosa may be thrown up into of external beam therapy, the mucosa that was
folds by scarring and contraction of the underly- previously normal adjacent to the carcinoma
ing tissue, especially in areas of stricture. There being treated can develop severe erosions,

375
Gastrointestinal Diseases

present and the arterioles and venules appear


thick-walled and hyalinized or fibrotic. Submu-
cosal esophageal glands and their ducts may
show atypical squamous metaplasia, mimicking
early carcinoma.
Stomach. Gastric radiation injury assumes
several forms. Acute radiation gastritis develops
a few days to a few months following radiation
exposure. Patients develop erosive and ulcerative
gastritis characterized by extensive glandular
necrosis and superficial ulceration. Chief and
parietal cells are damaged first; the surface epithe-
lium is damaged later. By the 8th day of therapy,
karyopyknosis develops within the gastric pits,
with loss of secretory granules in the chief cells
and parietal cells. Acute vascular changes de-
velop. The connective tissue in the mucosa and
submucosa develops edema, congestion, telan-
giectasia, swelling of the collagen bundles, and
fibrin exudates. Lymphocytes and plasma cells
infiltrate the lamina propria in the 2nd and 3rd
weeks. Glandular atypia develops by 21 days. The
degree of epithelial and stromal atypia resembles
that found in patients receiving chemotherapy
via intraarterial hepatic infusion (see chapter 8).
When the epithelium sloughs, it is replaced
from the mucous neck region. As the mucosa
Figure 9-12 heals, it regenerates and the gastric pits elon-
RADIATION-INDUCED GASTRIC INJURY
gate, but variable degrees of atrophy, fibrosis,
The gastric pits are elongated and t.I:J.e glands are mildly
edema, and endarteritis persist (fig . 9-12).
atrophic. The submucosa is densely fibrotic and there is also The regenerating glands are surrounded by a
fibrosis of the muscularis propria. mononuclear cell infiltrate. Gastric ulcers may
develop due to desquamation and erosion of
the damaged mucosa as well as alterations in
which may be circumferential. These may heal the underlying vasculature.
spontaneously, but they may also progress to Eventually, severe atrophic gastritis develops.
chronic ulcers or even strictures. The intensity of the inflammation diminishes
Patients develop motility abnormalities and the submucosa develops capillary telan-
following radiation, usually within 4 to 12 giectasia and arterial wall hyalinization with
weeks after exposure. The ganglion cells of the intimal fibrosis. Bizarre endothelial cells and
submucosal and myenteric plexuses, however, "radiation fibroblasts" develop. Some patients
generally appear normal. This does not rule out develop a deep acute ulcer 1 to 2 months follow-
the possibility of abnormal function. ing radiation exposure, which usually walls off
The most common long-term complication before perforation occurs. The ulcer represents
of radiation therapy is stricture formation. The the long-term effects of vascular damage and
wall is thickened, and the epithelium appears has an ischemic etiology. The only clues to
atrophic with parakeratosis, although the epi- its etiology are the clinical history, an unusu-
thelial layer may also be thickened. The submu- ally prominent antral fibrosis with obliterative
cosa appears fibrotic and there may be irregular endarteritis (fig. 9-13) involving the submucosal
bundles of eosinophilic and hyaline collagen. blood vessels, and the presence of radiation
Numerous atypical, swallow-tail fibroblasts are fibroblasts (see fig. 9-8). Biopsies in late-stage

376
Physical Injury

Figure 9-13 Figure 9-14


RADIATION-INDUCED OBLITERATIVE ACUTE RADIATION CHANGES
ENDARTERITIS IN THE SUBMUCOSA IN THE SMALL INTESTINE
The vascular lumen is almost completely obstructed by The lamina propria is edematous and contains scattered
a proliferation of intimal fibrous tissue. inflammatory cells. The nuclei appear to have inclusions
within them and are extremely hyperchromatic. There is
early apoptosis and cells are megaloblastic.

radiation gastritis show an atrophic mucosa


with scar tissue, thick-walled blood vessels, and of fat, protein, carbohydrates, and bile salts is
distended lymphatics. Some patients develop abnormal. A macrocytosis develops that may
arteriovenous malformations. be irregularly distributed, varying from crypt
Healing can result in scarred and sclerosed to crypt or villus to villus. Paneth cells often
gastric segments that are sometimes difficult to are unusually prominent. The lamina propria
distinguish from tumor. Rarely, sharply defined becomes infiltrated by neutrophils and other
submucosal or muscular areas become densely inflammatory cells. Plasma cells increase in
hyalinized (81) . number in the lamina propria and radiosen-
Small Intestine. Acute radiation effects range sitive lymphocytes decrease. The capillary
from barely visible epithelial damage to mas- endothelium swells and the vessels become
sive intestinal necrosis. Morphologic changes telangiectatic. Increases in vascular permeability
include loss of enterocyte columnar shape immediately following radiation lead to edema
and nuclear polarity, epithelial degeneration, and fibrin deposition in the interstitial spaces
ulceration with mucosal denudation, nuclear and blood vessel walls. These changes tend to
pyknosis and karyorrhexis, crypt disintegration, disappear within 1 to 2 months.
mucosal edema, enlarged bizarre nuclei (fig. Radiation changes may revert to normal de-
9-14), absent mitoses, mucin depletion, crypt pending upon the degree of damage. Complete
abscesses with prominent eosinophilic and neu- structural recovery usually occurs within 2 to 3
trophilic infiltrates, and numerous apoptotic weeks of therapy cessation but villous atrophy
bodies in the crypt bases (87). and abnormal crypts may result in subclinical
During acute injury, the damaged epithelium malabsorption. Disordered glandular prolifera-
sheds into the crypt lumen. Cell loss from the tion and persistent ulceration ultimately result in
villus tips exceeds cellular replacement from prominent fibrosis, radiation fibroblasts, and ec-
the crypts, leading to surface erosions, ulcers, tatic vessels in the lamina propria. Distorted villi
alterations in the crypt to villus ratio, and severe and ulcerations are characteristic of advanced
villous atrophy with crypt hyperplasia or crypt injury. Fibrosis causes secondary lymphangiecta-
hypoplasia. Decreased mitotic activity indicates sia. Patients with systemic sclerosis may exhibit
defective cellular replication. The total epithelial exaggerated fibrosis in irradiated areas (78).
surface decreases by almost 50 percent in 2 to 4 Patients who have undergone total lymphoid
weeks. During this period of time, absorption radiation treatment in preparation for bone

377
Gastrointestinal Diseases

marrow transplantation may show depletion of come increasingly fibrotic and the muscularis
lymphoid follicles in Peyer patches. As a result, mucosae becomes hypertrophic (87) . Fibrosis
Peyer patches appear smaller than usual, but and parenchyma! atrophy subsequently replace
with a normal architecture. The follicular cells the tissues. Lymphangiectasia develops second-
are reduced to a very small number of cells; T ary to lymphatic obstruction, presumably due to
cells are almost completely absent. The lamina the submucosal fibrosis. Epithelial displacement
propria throughout the intestine appears hy- into the submucosa produces enteritis cystica
pocellular. profunda. Radiation fibroblasts are present in
Acute lesions develop shortly after high-dose the deeper layers of the bowel wall. Neuronal
radiation exposure and usually affect individu- proliferation and muscular changes are promi-
als exposed during radiation accidents or atomic nent in patients presenting with pseudoobstruc-
warfare. During the first few weeks following ex- tion; the ganglion cells may appear bizarre.
posure there are aggressive mucositis, epithelial Vascular alterations, which are random and
swelling, cytoplasmic vacuolization, and atypi- focal and often require multiple sections to be
cal multilobated nuclei and prominent nucleoli seen, characterize late lesions. Vascular damage
(47). If the exposure involves the entire body, ranges from isolated endothelial cell injury to
including the bone marrow, then a neutrophilic complete capillary and venule obliteration.
response is often conspicuously absent (47). In Thrombosis can be seen as well as areas of
the first 8 hours there is extensive cell death in fibrinoid necrosis. Focal acute vasculitis in-
the proliferative segment of the bowel and mi- volves small arterioles, which may be heavily
totic activity ceases. Maximum karyopyknosis infiltrated with lymphocytes and neutrophils.
and cellular sloughing occur in 6·to 8 hours. A Muscular arteries demonstrate marked intimal
transient proliferative burst, sometimes with thickening, with fib1:osis and luminal narrowing
atypical mitoses, occur between 8 and 24 hours. leading to endarteritis obliterans. Abnormal cell
This ceases and the cells continue to migrate and proliferation as well as the fibrosis ..of the vas-
desquamate without being replaced; this results cular intima and media narrow the lumen and
in a progressive loss of the epithelial covering reduce blood flow to the bowel. Smaller vessels
of the villi. Compensatory crypt hyperplasia exhibit marked hyaline sclerosis and obliterative
develops, the villi become shorter, and the cells vasculitis. Progressive vascular damage, with
are retained longer before being desquamated increasing intimal fibrosis, leads to ischemia.
(99). In spite of the compensatory mechanisms, The complications of the ischemia include
the villi are denuded by 5 to 7 days and the strictures, perforation, fistulas, malabsorption,
individual dies of sepsis, hemorrhage, protein and pseudoobstruction (95) .
loss, and electrolyte loss (25). Lmge Intestine. Large intestinal changes re-
Late effects of gastrointestinal radiation semble small intestinal lesions. During acute
injury lead to chronic ilmdiation enteritis. This injury, the characteristic changes usually remain
progressive disease results from underlying confined to the mucosa. They include crypt
progressive fibrosis and vascular damage. Villi cell damage, crypt abscesses, inflammatory
appear short and broad; there is atrophy of the cell infiltrates, nuclear atypia, reduced mitotic
muscularis propria with interstitial fibrosis. activity, loss of nuclear polarity, crypt loss, and
Characteristic changes of chronic radiation mucosal sloughing (fig. 9-15). Eosinophils are
damage include the presence of telangiectasia often prominent. Other acute effects are cryp-
and hyalinized blood vessels. Enterocyte nuclei titis (fig. 9-16), prominent submucosal edema,
appear larger than normal and exhibit atypical ulcers, inflammatory polyps, mucosal telangi-
features such as stratification; there may be a ectasia, and sometimes ischemia. There may be
relative increase in the number of endocrine glandular proliferation with mild cellular atypia.
cells (62). The submucosa appears irregularly The changes may simulate dysplasia. Most of
fibrotic, and occasionally, there is distinct hype- the changes resolve within a month, and al-
reosinophilic hyalinization of the collagen that though mild atrophy and inflammatory cells
may resemble amyloid (52,54) . As the lesions may remain up to 3 months following treatment
evolve, the lamina propria and submucosa be- cessation (7 4), they eventually regress.

378
Physical Injwy

Figure 9-15 Figure 9-16


ACUTE RADIATION DAMAGE ACUTE RADIATION PROCTITIS
INVOLVING THE APPENDIX Individual crypts are disappearing while others h ave
The entire mucosa has sloughed, making the tissue a h eavy infiltrat ion of acute inflamm atory cells. Acute
completely unrecognizable. inflammation is also present in the lamina propria.

Mucosal lesions that develop in the delayed Biopsy features that suggest a diagnosis of ra-
period include erosions, ulcers, perforations, diation damage include the patchy nature of the
fistulas, cytologic atypia, and neoplasia. Vas- process, marked telangiectasia, enlarged nuclei
cular changes include petechiae, hemorrhages, in either the epithelium or the stroma, and, if
hyalinized arterioles, areas of healed necrosis one is lucky enough to have submucosa in the
in the vessels, thrombi, and fibrous intimal biopsy, typical vascular changes sometimes as-
plaques. Stromal changes include submucosal sociated with characteristic radiation fibroblasts.
fibrosis, leading to strictures, interstitial fibrosis In other cases, the tissue appears nonspecifically
of the muscularis propria, serosal fibrosis, and chronically damaged. The lamina propria con-
loss of sphincter control. tains excessive numbers of chronic inflammatory
Chronic features include crypt architectural cells. The fibroblasts have enlarged nuclei and
distortion with variable atrophy (fig. 9-17), the cytoplasm tends to become basophilic. The
goblet cell loss, shortened crypts, a thickened cells may acquire a swallow-tailed appearance.
and distorted muscularis mucosae, epithelial The arterioles often show intimal proliferation,
atypia, intestinal wall fibrosis (fig. 9-18), serosal sometimes with foamy endothelial cells, par-
thickening, vascular sclerosis (fig. 9-19), lym- ticularly earlier in the disease.
phangiectasia, and thickening of the collagen Late effects of radiation damage include mu-
layer beneath the surface and crypt epithelium cosal, submucosal, and muscular fibrosis with
(16,33). The changes may mimic collagenous stricture formation (fig. 9-20). Biopsies of the
colitis. Paneth cell metaplasia may be present. strictures typically show portions of distorted
Marked hyalinization of the submucosal vessels colorectal mucosa with fibrosis in the lamina
(fig. 9-18) may mimic amyloidosis. Variable dis- propria and vascular dilatation.
tortion of the intestinal wall results in glandular Differential Diagn osis. The gross appear-
entrapment deep in the bowel wall, causing ance of chronic radiation damage may resemble
colitis cystica profunda, focal discontinuity of that of Crohn's disease but without fissures and
the muscularis mucosae, mucosal erosions, deep without the creeping growth of the mesenteric
ulcers, vascular ectasia, and serosal thickening fat . The gross appearance can also mimic a
(24,26,54). The atypical nuclei in the displaced carcinoma. Histologic changes of radiation en-
glands may simulate an invasive carcinoma. teritis may mimic those seen in other diseases
Submucosal neuronal proliferations and mus- (Table 9-5). Radiation colitis mimics other large
cular degeneration also develop. intestinal inflammatory disorders, including

379
Gastrointestinal Diseases

Figure 9-17
CHRONIC CHANGES ASSOCIATED WITH RADIATION PROCTITIS
Left: There is almost complete loss of the glands. A superficial lining
is present. The lamina propria is infiltrated with acute inflammatory cells
and there is telangiectasia. The tissue has the appearance of granulation
tissue, due to the ongoing damage from the underlying vascular lesions
involving the major vessels in the submucosa.
Above: Glandular regeneration with marked variation in the size of
individual crypts.

the large intestinal surface epithelium thickens,


the differential diagnosis includes collagenous
colitis. Tumors arising in radiation strictures
sometimes mimic areas of colitis cystica pro-
funda. The vascular damage to arterioles, myo-
intimal hyperplasia, and subintimal collections
of foamy macro phages may be seen in radiation
damage, chronic allograft rejection with medial
sclerosis, fibrinoid necrosis, and thrombosis in
varying degrees and combinations (78). Because
the mechanisms of radiation injury resemble
those seen in ischemia and reperfusion injury,
it is not surprising that the histologic features
Figure 9-18 of both ischemia and radiation injury resemble
RADIATION-INDUCED SUBMUCOSAL FIBROSIS one another.
WITH MARKED VASCULAR CHANGES Treatment and Prognosis. Given the recent
The portion of an epithelial-lined structure on the right surge in terrorist activities, which could involve
represents epithelium displaced into the submucosa. No the use of radioactive material, scenarios have
lamina propria surrounds it.
•.· been developed for dealing with such acts. A
consensus document was developed by the
infectious, microscopic, ischemic, or drug-in- Strategic National Stockpile Radiation Working
duced colitis, as well as idiopathic inflammatory Group (96) to provide a framework for physi-
bowel disease, particularly if only a superficial cians in medical subspecialties for evaluation
biopsy is examined. The presence of macrocyto- and management of large-scale radiation in-
sis can also be seen in patients with folic acid or juries. Since this is not the major emphasis of
vitamin B12 deficiency, or in patients receiving this text, the readeris referred to the document
chemotherapy. If the collagen table underlying prepared by this group for further details.

380
Physical Injwy

Figure 9-20
LATE EFFECTS FOLLOWING RADIATION
Biopsy from a rectal stricture in a patient who had
received radiotherapy for prostate cancer many years
previously. The lamina propria is completely fibrotic.

Table 9-5
CONDITIONS THAT MIMIC RADIATION ENTEROPATHY

Celiac disease
Infectious gastroenteritis
Cow's milk intolerance
Soy or soy protein sensitivity
Figure 9-19 Malnutrition
RADIATION-INDUCED VASCULAR DAMAGE Kwashiorkor
Radiation-induced vascular damage affects not only Microvillous inclusion disease
the vessels of the submucosa but also the perirectal tissues.
Familial enteropathy
Marked fibroblastic proliferation and edema affect the
intima and media. Collagenous sprue
Graft versus host disease
A tremendous amount of effort has been Common variable immunodeficiency
directed at reducing the harmful effects of radia- Acquired immunodeficiency syndrome (AIDS)
tion. These include careful planning of radiation enteropathy
fields, surgical procedures to elevate and keep Crohn's disease
the small bowel away from radiation fields, and Eosinophilic gastroenteritis
the use of substances such as prostaglandin in- Zollinger-Ellison syndrome
hibitors and sulfhydryl and thiol compounds, an Dermatitis herpetiformis
emphasis on diets high in polyunsaturated fats,
Lymphoma
and attempted reduction of bile and/or pancre-
Ischemic enteritis
atic enzymes in the intestinal contents. These
efforts sometimes are helpful, but sometimes Dmg effects
they contribute to further injury. Therefore these Autoimmune enteritis
strategies are under continual investigation,
particularly the surgical interventions.
Numerous agents, including antimicrobials, dietetic care, have been used or are being evalu-
local and systemic analgesics, antiinflamma- ated for the palliation of radiation-induced gas-
tory drugs, antidiarrheal drugs, and mucosal trointestinal symptoms. Argon plasma coagula-
protectives (11), alone or in combination with tion may play a role in control of hemorrhagic

381
Gastrointestinal Diseases

lesions in the setting of radiation-induced injury stomach (40), or colon (49,73,79,89). The can-
(86). These agents often increase the quality of cers include adenocarcinomas, squamous cell
life for patients subjected to radiotherapy. The cancers (92), and sarcomas, including malig-
mainstay of medical therapy has been sulfasala- nant fibrous histiocytoma or angiosarcoma
zine, steroids applied orally and per rectum, and (4,12,53,56,75,84,93,100). The neoplasms fol-
bile acid sequestering resins. low exposure to both low and medium radiation
Sucralfate, an aluminum hydroxide complex doses, and they develop after a long latency
of sulfated sucrose used in the treatment of period (40,66). Women radiated for gyneco-
gastric ulcers, prevents some radiation-induced logic cancers have a relative risk of subsequent
bowel discomfort or rectal bleeding (11,35). colorectal cancer of 2.0 to 3.6 (68). Diagnostic
Sucralfate is also useful in treating radiation- criteria to establish a radiation-induced tumor
induced mucositis (35,50,82,90). Topical su- include the following: 1) the tumor must arise
cralfate induces lasting remissions in many in the irradiated field; 2) it must be histologi-
patients (43). Octreotide is often used to manage cally different from the tumor that was radiated;
radiation-induced dianhea in cancer patients and 3) there must be a latency period of at least
(3). It reduces the acute mucosal changes and 2 years. The latency period ranges from 37
markedly ameliorates acute muco9'al injury as months to SO years (4,9,53,100). Malakoplakia
well as subsequent chronic structural alterations may also develop in previous radiation fields.
(94). Growth hormone is sometimes used to
modify the response of the intestinal mucosa THERMAL INJURY
to radiation through its effect on the cell cycle Definition. Thennal injury follows exposure to
or by increasing cell mass (66). Supplemental temperature extremes. Most examples of gastro-
dietary arginine accelerates intestinal mucosal intestinal thermal injury result from exposure to
regeneration (31). Glutamine administration is excessive heat. Bum victims develop gastrointes-
currently under investigation in clinical trials tinal mucosal stress ulcers (Curling ulcers).
(72). Formalin instillation and endoscopic ob- Demography. Thermal injury to the gastro-
literative therapy are sometimes used to control intestinal tract results from two major categories
the bleeding that results from radiation-induced of exposure: gastrointestinal damage that occurs
telangiectasias (21). Symptomatic strictures may in bum victims and localized damage to the gas-
be amenable to endoscopic dilation, and stent trointestinal tract from the consumption of hot
placement may have a role for those who ex- fluids, as a result of therapeutic interventions
perience frequent restricturing and those with using cautery, or along bullet tracks sustained
unremitting fistulas . Radiation strictures in the from gunshot wounds (113,115). Gauchos, the
colon and elsewhere (esophagus, small bowel) original cattle herders of Argentina, were par-
are particularly resistant to endoscopic dilation, ticularly fond of drinking hot mate in a way that
often requiring repeat interventions that result burned the esophageal mucosa, thereby leading
in a significant perforation rate. to the development of esophagitis and eventu-
Surgical treatment of large bowel radiation ally esophageal carcinoma (113,115). There
injury can cause subs~antial morbidity but can is an increasing possibility of gastrointestinal
be successful in patients with strictures, perfora- thermal injury from the use of laparoscopic
tions, or fistulas. The success rates are worst after procedures to remove gastrointestinal tissues
fistula repair (67). Arteriodigestive fistulas may or to perform other forms of pelvic or intra-
complicate intraoperative and external beam abdominal procedures.
therapy following surgery for gastric cancer. Pathophysiology. During the shock that fol-
A long-term consequence of radiation ex- lows severe burns, the blood volume decreases
posure is cancer development. An excess in and blood flow shunts away from the gastro-
cancer-related deaths was first noted in victims intestinal tract. When bums involve more than
of atomic bomb exposure (80). Most of these 20 percent of the total body surface area, the di-
effects are non-gastrointestinal but cancer can version of the blood flow causes gastrointestinal
develop at any gastrointestinal site that has been functions to diminish or stop entirely, leading
irradiated, including the esophagus (5,20,40,79), to ileus and gastrointestinal dysmotility.

382
Physical Injwy

The gastrointestinal erosions seen in se-


verely burned patients have an ischemic basis
and their pathophysiology resembles that of
stress ulcers. They occur within 5 hours of in-
jury (107) and result in enterocyte membrane
disruption and mucosal barrier breakdown
(109) . This is mediated in part by transient
intestinal hypoperfusion and increased intes-
tinal permeability with increased transcellular
permeability (103,107) . The damaged mucosal
barrier allows macromolecules to be absorbed
(101)03,104,106) and bacteria to translocate
from the gut. Bacterial and luminal endo-
toxins gain access to the systemic circulation
(1 04,115, 116). Systemic infections may also
alter the integrity of the bowel and make the
patient less tolerant of enteral feedings (111).
Gastric distension is common due to delayed
gastric emptying.
Clinical Features. Gastrointestinal disorders, Figure 9-21
including gastric and duodenal ulcers (see fig. CURLING ULCER
9-22), ileus, constipation, and diarrhea (110), A well-circumscribed, punched-out defect is in the
are common in burn patients. Severe burns lead duodenal mucosa. The surrounding mucosa is hyperemic.
to a disruption in the gastrointestinal mucosal
integrity and facilitate bacterial translocation.
Patients with hypotensive episodes and sep- 9-21). Smaller punctate ulcers are also present.
sis are at risk for developing ischemic bowel The duodenal mucosa is markedly hyperemic.
disease. Those who develop ischemia have a Microscopic Findings. The microscopic fea-
statistically significant larger percentage of total tures of Curling ulcers resemble those of peptic
burned surface area compared to those with ulcers, stress ulcers, or ischemic ulcers, depend-
other gastrointestinal complications. Hemor- ing upon the stage of development.
rhage results from the ulcers and ischemic bowel Probably the most common form of ther-
and rarely, perforations also develop. Curling mal injury that pathologists encounter is that
ulcers develop in 11 to 86 percent of patients secondary to cautery. Cautery may be part of
who do not receive ulcer prophylaxis. the biopsy procedure itself or may represent
Acute pseudoobstruction is a rare complica- secondary effects from inadvertent injury dur-
tion of bums. Factors implicated in its patho- ing laparoscopic procedures. Typically, there
genesis include bed rest, the use of narcotic is evidence of coagulation necrosis (fig. 9-22).
medications, hypokalemia, sepsis, and surgery Treatment and Prognosis. Enteral nutrition-
(108). Early diagnosis, the use of prokinetic and al support is the primary mode of treatment in
cathartic agents, and attempts at decompres- patients with severe surface burns. Prophylactic
sion are essential in patients who develop acute introduction of antacids, mucosal protective
pseudo-obstruction. There is an increased risk agents, and nutritional supplements, as well as
of sepsis and thrombotic complications from H2 blockers may help prevent the gastric injury.
parenteral hyperalimentation in burn patients. Intravenous proton pump inhibitors may be-
The severely elevated intraabdominal pressure come the standard of care in the future. Surgery
associated with pseudoobstruction sometimes re- may be necessary in patients with ischemia,
quires surgical treatment by laparotomy to avert intractable hemorrhage, perforation, or pseudo-
cardiac, respiratory, and renal compromise (112). obstruction (108). Treatment with bombesin
Gross Findings. Curling ulcers are large, helps restore the mucosal barrier of the burned
dark, irregular, geographic mucosal defects (fig. gut by increasing biliary secretory IgA levels and

383
Gastrointestinal Diseases

Figure 9-22
CAUTERY DAMAGE
A: Mild cautery damage to the gastrointestinal mucosa.
The epithelium tends to be preferentially affected and the
cells become elongated, with nuclei appearing to stream
like a school of fish.
B: Another area of injury due to cautery with marked
edema.
C: Intense coagulation necrosis of the submucosa at the
base of a mucosal biopsy.

increasing mucosal height (105). Butyrate also stimulation (119). Thermal injury also results
hastens the restoration of barrier function (114). from lightning strikes.
Animal Models . Administragon of epider- Pathophysiology. Electrical injuries cause
mal growth factor in burned rodents attenu- disruption of cardiac rhythm and breathing,
ates the internal organ damage. It significantly burns, gastrointestinal injury, vascular dam-
reduces intestinal necrosis (102). age, disseminated intravascular coagulation,
and peripheral and spinal cord injury. Some of
Electrical Injury
the gastrointestinal damage occurs directly and
Definition. Electrical injwy is a unique form some occurs indirectly. Damage to the central or
of thermal damage. The extreme heat generated peripheral nervous system can cause pseudoob-
by tissue resistance to the passage of a high struction. Massive gastrointestinal hemorrhage
voltage electrical current (1,000 volts or more), may result from duodenal or gastric ulcers.
the unpredictable course of electricity through Segmental esophageal aperistalsis may follow
the body, and the variation in response of indi- esophageal injury (120).
vidual tissues separates these injuries from other Clinical Features. Many electrical injuries in-
types of thermal injury. volve the skin so that treatment requires atten-
Demography. Major electrical burns consti- tion to these direct wounds. The complications
tute approximately 3 percent of all admissions of electrical injuries can also affect almost every
to major burn centers (117). Approximately one organ, including the gastrointestinal tract. There
third of high voltage injuries affect electrical may be direct injury to intraabdominal struc-
workers, one third occur in construction work- tures from abdominal contact points. In both
ers, and the remainder result from nonworker lightning and high voltage injuries, impaired
home accidents. An exceptional case of death mental status often means that the patient can-
from electrocution complicated autoerotic not complain of the abdominal pain. Transient

384
Physical Injwy

segmental aperistalsis may develop in the distal common, followed by injury to the colon and
esophagus (122). There may also be abdominal stomach. Colonic trauma accounts for only 3
wall and gastric perforation (121). Intraabdominal to 5 percent of blunt abdominal injuries (129);
injury is ruled out by peritoneal lavage, CT scan, most affect the descending colon, ascending
laparotomy, or ultrasonography. Ileus can lead to colon, or cecum (129,135) .
abdominal distension, vomiting, and aspiration. Blunt abdominal injuries usually result from
Patients may have long-term gastrointestinal func- motor vehicle or athletic accidents, falls, physical
tional abnormalities, which include increasing abuse, or cardiopulmonary resuscitation (130,
stool frequency and urgency. Inner anal sphincter 132). Hemophiliacs, patients with von Wille-
control may remain abnormal (118). brand's disease, and patients with idiopathic
Gross Findings. The presence of submu- thrombocytopenic purpura, as well as those on
cosal hemorrhages scattered throughout the drugs that decrease the number of platelets such
gastrointestinal tract is the most frequent find- as chemotherapeutic agents, are at increased risk
ing in electrical injury. Curling ulcers may be for hematomas following trauma. Blunt abdomi-
present. Other injuries include gastric necrosis nal trauma causes rupture of hollow gastrointes-
with general intestinal necrosis and intestinal tinal organs in 11 to 18 percent of patients (136).
perforation (119,121). If the thermal injury The midabdomen is particularly vulnerable to
causes disseminated intravascular coagulation, direct blows and results in compression injuries
then ischemia may affect any part of the gas- to viscera anatomically fixed against the spine.
trointestinal tract. The most common mechanism of traumatic
Microscopic Findings. The histologic find- bowel or mesenteric injury in children is mo-
ings often resemble those of ischemic injury. tor vehicle accidents. Children are particularly
Treatment and Prognosis. The residual ef- prone to lap belt injuries (124) . Other common
fects of electric injury are frequent and often mechanisms of pediatric injury include being
unapparent for months. Late complications hit by a car, bicycle handlebar injuries, and
often result in recurrent dysfunction of the child abuse. Visceral trauma is the second lead-
gastrointestinal tract . A nasogastric tube is ing cause of death in child abuse after central
useful in preventing distension, vomiting, and nervous system injury.
aspiration. Use of antacids and H2 blockers Gastrointestinal hematomas most com-
decreases the incidence of duodenal and gastric monly result from trauma or occur in patients
stress ulcers. Bleeding gastrointestinal lesions with underlying coagulopathies or who are on
are managed in a similar manner to other stress- anticoagulation therapy (131). In the esopha-
related mucosal lesions . gus, hematomas complicate esophageal tears
(Mallory-Weiss tears) and perforation of the
TRAUMA AND HEMATOMAS esophageal wall (Boerhaave's syndrome). Other
Definition. Physical injuries are classified predisposing factors include recurrent vomiting
as penetrating and blunt injuries. Perforations and episodes of food impaction (126). Hema-
are defects involving less than 20 percent of tomas also result from surgical or endoscopic
the luminal circumference, lacerations involve intervention.
between 20 and 70 percent of the luminal Trauma may also result from the use of enema
circumference, and disruptions involve over 70 tubes or the insertion of various objects into
percent of the luminal circumference (128). the rectum for sexual gratification. Lacerations,
Demography. Hollow visceral injuries are abrasions, and perforations lead to exsanguinat-
far less common with blunt abdominal trauma ing hemorrhage, especially if the foreign bodies
than with penetrating abdominal trauma: more are inserted when the patient is under the influ-
than 95 percent of intestinal injuries are pen- ence of illicit psychoactive drugs or excessive
etrating. The nature of the penetrating agent alcohol consumption. Lacerations also occur
varies and includes gunshot and stab wounds, in severe impactions.
iatrogenic injuries, automobile accidents, and Tubes or foreign bodies in the esophagus cause
war wounds, in a decreasing order of incidence. local irritation, ulceration, and acute inflamma-
Blunt trauma injury to the small bowel is most tion. Pill esophagitis occurs when medications

385
Gastrointestinal Diseases

hematomas cause dysphagia, occasionally in the


absence of pain (126) . These hematomas may
follow instrumentation.
Most alert patients h .ave physical findings
suggestive of mediastinal or peritoneal irritation,
with tenderness or guarding. Symptoms of peri-
toneal irritation include abdominal pain, tender-
ness, and rigidity, and usually occur following
rupture. Vomiting due to obstruction occurs in
patients with large hematomas. A palpable mass
may be found. The clinical features depend on
the size of the hematoma and include acute or
chronic pain, obstruction, bleeding, anernia, and
hemoperitoneum (123,125). The most accurate
and safest abdominal assessment methods in he-
modynarnically unstable individuals with suspect-
ed abdominal injuries following blunt trauma are
immediate laparotomy and diagnostic peritoneal
lavage, and CT evaluation (134). Trauma may
also lead to acute pseudoobstruction.
Rare spontaneous retroperitoneal or mesen-
teric hemorrhage involves the root of the small
bowel mesentery. It is characterized by severe
bleeding into the retroperitoneum or intraperi-
toneum. Its clinical presentation depends on the
exact site of the bleeding. In most cases, hemor-
rhage from large vessels follows an acute course
and patients have abrupt abdominal pain with
Figure 9-23 severe blood loss or hemorrhagic shock. Such
ESOPHAGEAL LACERATION hemorrhages usually resolve spontaneously or
"'
Esophageallaceration in an individual who was involved they may go undetected. The etiology of these
in a motor vehicle accident. It extends down into the lesions is uncertain. Predisposing factors include
submucosa. The upper muscularis propria was involved but hypertension, arteriosclerosis, arterial malfor-
it was not a full-thickness injury. mations, inflammation, and anticoagulant
therapy or underlying coagulation disorders.
become stuck in the esophagus (see chapter 8). Gastrobronchial or esophagobronchial fis-
Diaphragmatic eventrations also result from tulas complicate trauma. Esophageal rupture
trauma, as in automobile accidents. Some run- or laceration sometimes complicates motor ve-
ners develop an entity called cecal flap syndrome, hicle accidents (fig. 9-23). Gastric rupture is an
which is repeated microtrauma to the cecum as unusual catastrophe following blunt trauma or
it hits against a hypertrophic muscular wall. cardiopulmonary resuscitation. The lesser cur-
Pathophysiology. The extent of gastro- vature of the stomach is the most frequent site
intestinal damage varies with the cause. The of traumatic rupture because of its fixed char-
pathologic spectrum ranges from hematomas to acter and its position anterior to the vertebral
full-thickness lacerations that, if not repaired, bodies. The antrum is also in danger because of
lead to fistulas, perforation, and peritonitis. its intermediate position between the mobile
Clinical Features. Patients with esophageal body and fundus and the fixed pylorus (130).
hematomas may present with pain high in the Tears tend to be larger on the serosal side than
epigastrium or retrosternal region, which is on the mucosal side because the initial disrup-
aggravated by swallowing. The pain may be ac- tion, even in blunt trauma, is the muscular coat
companied by vomiting or hematemesis. Larger and the mucosa is only secondarily involved

386
Physical Injwy

(130). The anterior wall is more often affected


than the posterior wall (132,136).
Gross and Radiologic Findings. CT scans
are useful in demonstrating esophageal he-
matomas, which are viewed as esophageal
masses with a density similar to that of blood.
A typical barium contrast study usually shows
an indentation into the esophageal lumen,
but occasionally may reveal a false lumen. CT
findings in children with bowel or mesenteric
trauma include free intraperitoneal air, free
retroperitoneal air, extraluminal oral contrast
material, free intraperitoneal fluid, bowel wall
defect, bowel wall thickening, mesenteric Figure 9-24
stranding, fluid at the mesenteric root, focal SUBMUCOSAL HEMATOMA
hematoma, active hemorrhage, and mesenteric Submucosal hematoma in a patient injured in a motor
pseudoaneurysm. Occasionally, angiography vehicle accident. Large amounts of extravasated red blood
is required to identify the responsible vessel cells are within the submucosa. There is no evidence of
should hematomas enlarge or reaccumulate organization.
following initial evacuation. Some radiologic
findings, such as free intraperitoneal air and gain access to the bowel lumen. The diagnosis
focal bowel wall thickening, are associated with of a hematoma is suggested radiographically by
a strong likelihood that the bowel injury will mass effects or unusual fold patterns. CT shows
require surgical repair. the presence of a high-density intramural mass.
The seromuscular tear is the hallmark of in- If the blood gains access to the bowel lumen,
testinal injury due to seatbelt syndrome and is then the bowel wall appears grossly normal but
an unambiguous lesion similar in all segments of contains large amounts of fresh blood. Patients
the bowel. It is caused by a tear that separates the with gunshot wounds have lacerations in the
inner muscularis from the submucosa. It is char- tissue and hemorrhage.
acterized by a wedge that strips the mucosa from Microscopic Findings. The histologic chang-
the inner circular muscle; a bending retraction es associated with trauma depend on whether
of the torn muscularis toward the uninvolved the tissue is examined during an acute phase
bowel; and mucosal-submucosal fold effacement or after repeated traumatic episodes. Acutely,
causing the mucosal-submucosal bridge span- there is hemorrhage and possibly inflamma-
ning the tear to become paper thin. The vulner- tion, depending on the age of the injury. If re-
ability of this bridge to ischemia is such that 35 peated trauma has occurred, mucosal distortion
percent of tears culminate in incipient or frank may be present. The tissue along bullet paths
perforations or gangrene (133). Large seromuscular demonstrates coagulation injury. Patients who
tears, particularly the circumferential degloving have prolonged intubation may show esopha-
type, are most prone to these complications. Tears geal hyperkeratosis or parakeratosis. Patients
cluster in three major sites: the ileocecal region, with hematomas typically have collections of
the sigmoid, and the jejunum. Perforations are extravasated red blood cells in the submucosa
the principal lesion in the jejunum and seromus- (fig. 9-24). Patients with lacerations often have
cular tears at the other locations. Multiple sites mucosal tears that variably extend through the
are commonly affected in individual patients. wall of the affected gastrointestinal segment.
This suggests the simultaneous action of differ- Treatment and Prognosis. As endoscopists
ent traumatic mechanisms on the bowel and its are loath to biopsy bleeding lesions, endoscopic
mesenteries in seatbelt injuries sustained during biopsies are seldom performed in the acute
motor vehicle accidents (133). setting. Those patients who continue to expe-
Hematomas complicate blunt trauma if a rience significant bleeding despite therapeutic
blood vessel is damaged and the blood does not endoscopic intervention may require radiologic

387
Gastrointestinal Diseases

embolization or surgery. Unfortunately, endo- if rupture occurs. Mortality is influenced by


scopic interventions may result in trauma to the. time interval between the injury and the
bowel, e.g., postpolypectomy hemorrhage or surgical intervention. Complications include
bowel perforation. Fortunately, the majority of fistulas, obstruction, sepsis, and peritonitis.
the bleeding complications are managed con- Antibiotics are used in patients with penetrating
servatively or endoscopically, and perforations wounds. In patients with multiorgan trauma, as
diagnosed early before ·peritoneal contamina- in automobile accidents or other severe injuries,
tion has occurred may be treated by primary death may not be the result of gastrointestinal
surgical closure. wounds but of central nervous system injury
Perforation as a result of blunt abdominal or injuries to other vital organs, such as liver,
trauma is usually treated by simple closure fol- spleen, and pancreas.
lowed by resection and anastomosis, or simple Management of esophageal hematoma is
closure plus the creation of a proximal ostomy conservative. Intravenous fluids and analgesics
(127) . Surgical evacuation is necessary only for usually cause symptoms to remit within a few
large hematomas; smaller hematomas resolve days. Surgery is occasionally required for late
spontaneously. Surgical intervention is required perforation or uncontrolled bleeding.

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r., ·

392
10 GASTROINTESTINAL INFECTIONS

INTRODUCTION Table 10-1


The gastrointestinal mucosa acts as a major FACTORS ASSOCIATED WITH CHANGES IN
interface between the individual and the envi- THE SPECTRUM OF INFECTIOUS DISEASE
ronment. As a result, mucosal barrier defenses Globalization of the food supply with many fruits and
have evolved to protect against pathogen in- vegetables being grown in developing countries
vasion. A continuous monolayer of columnar Increased travel to endemic areas of infection
epithelial cells, sealed by circumferential tight
Increased immunodeficiency secondary to increasing age
junctions, covers a surface area of nearly 200 of the population, transplantation surgery, and
m 2 , protecting it from passive diffusion of small acquired immunodeficiency syndrome (AIDS)
and large solutes, particles, microorganisms, and Emergence of drug-resistant infections
cells. The epithelial cells composing the lining Large scale food production, distribution, and retailing
function together in terminal digestion, solute (fast food chains)
and water transport, host defense, and barrier
function. Proper barrier function is required for
efficient transport of water and solutes and for recently reported that in the United States, food-
host defense. Mucosal barrier damage predis- borne pathogens or contaminants account for
poses individuals to gastrointestinal infections. 76 million illnesses, 325,000 hospitalizations,
and 5,000 deaths annually (1).
Epidemiologic Settings in which Infections Occur
Diagnosis of Gastrointestinal Infections
There has been a relatively recent change
in the types of gastrointestinal infections that If the patient undergoes endoscopic examina-
people now develop. This change is attribut- tion and has features that suggest an infectious
able to a number of factors, including the fact process, the endoscopist may submit tissue for
that individuals live longer and travel more bacterial, mycobacterial, and viral cultures, as
extensively. In addition, there is an increasing well as for parasitologic, toxicologic, or mo-
incidence of chronic disease, an increasing lecular examination. The pathologic diagnosis
incidence of immunodeficiency due to tissue of gastrointestinal infection depends on the
transplantation and acquired immunodefi- recognition of several factors, including specific
ciency syndrome (AIDS), and globalization of pathogens, specific tissue reactions, and specific
food products (Table 10-1). cytopathic effects of the infection.
Worldwide, diarrhea is second only to car- The recognition of specific pathogens re-
diovascular disease as a cause of death (2,6). In sults from several factors, one of which is their
the United States alone, an estimated 211 to localization to specific tissue sites, including
375 million episodes of acute diarrheal illness the epithelial apical surfaces, intestinal lumen,
occur each year; accounting for approximately lamina propria, submucosa, muscularis propria,
73 million doctors' office visits, 1.8 million or myenteric plexus (Table 10-2). Special stains
hospital admissions, and 3,100 deaths (3-5). performed on tissue sections, particularly Gram,
Worldwide, intestinal infections are responsible acid fast, fungal, and Giemsa, can confirm the
for the deaths of 3 to 4 million individuals presence of infections, particularly in the setting
annually, the majority of whom are preschool- of diffuse histiocytic infiltrates or granulomas
aged children. The World Health Organization (Table 10-3). More specialized studies help
(WHO) estimates that 70 percent of diarrheal identify specific pathogens. For ·example, the
episodes result from biologically contaminated use of immunohistochemical reagents or in situ
food (6). The Center for Disease Control (CDC) hybridization reactions may identify specific

393
Gastrointestinal Diseases

Table 10-2 Table 10-3


LOCALIZATION OF GASTROINTESTINAL INFECTIONS SPECIAL STAINS USED TO
IDENTIFY MICROORGANISMS
Attachment to epithelial lumin al surfaces
H elicobacter pylori Acid-fast stain
Clyptosp01idium All acid-fast bacteria
Spirochetes AJcian yellow
Giardia
H elicobacter pylori
Enteroadherent Escherichia coli
Ascaris Giemsa
H . pylori
Intraepithelial localization Microsporidia
Isospora
Clyptosporidiwn
Microsporidi a
Candida Gram stain
Cytomegalovirus Gram -n egative and Gram-positive bacteria
Herpes simplex virus Microsporidia
Aden ovirus Grocott methenamine silver
Localization in the lamina propria Fungi
' Cytomegalovirus Periodic acid-Sch iff
Strongyloides Trophe1yma whipplei
Mycobacterium Amoebae
Trophe1yma whipplei Fungi
Histoplasma
Microsporidia Trichrome
Leishmaniasis Escherichia coli
Schistosomiasis Giardia

Localization in the submucosa or in areas of ulceration Warthin-Starry


Candida Spiroch etes
Histoplasma Campylobacter species
Aspergillus H. pylori
Zygomycosis
Entamoeba
Balantidium
Schistosoma
the multiple types of microbial agents that can
infect the gut, their differing degrees of invasive-
Localization in the muscularis propria or myenteric
p~~ s ~ ness, and the variety of their virulence factors.
Chagas' disease At one extreme, some infections cause dramatic
Cytomegalovirus or even lethal physiologic derangements but
produce no significant pathologic alterations,
as in cholera infections. Conversely, diseases
bacterial or viral products. In some cases, such associated with significant histopathologic le-
as with microsporidiosis, ultrastructural ex- sions do not always h ave clinical fe atures that
amination facilitates the diagnosis. Genetic tests correlate with the degree of inflammation.
identify specific organisms by finding specific The histologic features of bacterial infections
microbial DNA, and differentiate among several differ depending on the mechanism of bacterial
strains of the same organism, as in Escherichia virulence. Many pathologists have learned to
coli enterocolitis. Finally, serologic tests confirm recognize the classic features of invasive bacte-
the presence of some infections. rial infection when a lesion known as acute
self-limited colitis (ASLC) is produced (fig. 10-1).
General Pat hologic Features
The most important histologic changes occur
The endoscopic findings of gastrointestinal in the first 4 days following the onset of clini-
infections include mucosal granularity, ero- cal disease. There is a prominent neutrophilic
sions, ulcers, bleeding, friability, mass lesions, infiltrate within the crypts and lamin a propria,
and pseudomembran es . The changes usually sometimes with adherent pseudomembranes.
resolve rapidly and spontaneously. Cryptitis occurs more commonly than crypt
It is difficult to generally characterize the abscesses. Lamina propria edema and hemor-
histopathology of intestinal infections given rhage are often present, whereas architectural

394
Gastrointestinal Infections

. .. ..
.
f~
0.
tll
. a(l

Figure 10-1
ACUTE SELF-LIMITED COLITIS
Left: The overall architecture of the colonic mucosa is preserved . The lamina propria is mildly edematous and contains
an increased number of inflammatory cells.
Right: Higher-power view demonstrates mucosal edema and scattered neutrophils in the lamina propria.

abnormalities, including glandular distortion, aggregative, enterohemorrhagic, enterotox-


granulomas, and giant cells, are usually absent igenic, and enteroinvasive types (Table 10-4).
or inconspicuous. Later, the colonic mucosa
Enteropathogenic E. Coli
appears regenerative and lymphoplasmacytic
infiltrates may be seen in the lamina propria. Demography. Enteropathogenic E. coli (EPEC)
Many viruses cause gastrointestinal infec- was the first group of the genus to be identified
tions. Rotavirus, Norwalk virus, and enteric as a causal agent of dianhea. These organisms do
adenoviruses are characterized by invasion of not produce toxins and do not invade cells (43).
mature small intestinal enterocytes. Mucosal The incidence of EPEC infection has declined in
injury leads to villous atrophy, crypt hyper- industrialized countries and routine serotyping
plasia, and increased cellularity of the lamina has been discontinued in many laboratories. In
propria. Viral infections are associated with a developing countries, however, it remains an
chronic inflammatory cell infiltrate and some- important cause of infantile diarrhea.
times with eosinophils. Some viruses, such as Pathophysiology. EPEC organisms do not
cytomegalovirus (CMV), herpesvirus (HSV), and produce classic toxins, but do possess a number
adenovirus, are identified because they produce of virulence factors. The organisms adhere to
characteristic inclusions. host enterocytes or M cells causing localized
Parasites often cause prominent mucosal destruction of the brush border microvilli and
eosinophilia. The organisms or their ova may distortion of the apical cytoplasmic membrane.
be found in the tissues. Fungal infections are This initial contact is probably mediated by
usually recognized by the identification of the plasmid-encoded bundle-forming pili (34). At-
specific organism on hematoxylin and eosin tachment results in rearrangement of the actin
(H&E)-, periodic acid-Schiff (PAS)-, or Grocott- cytoskeleton of the cell with formation of a cup-
stained sections. like indentation at the site of bacterial contact
("attaching and effacing lesion") (55) . Formation
BACTERIAL INFECTIONS of these attaching-effacing lesions is mediated
by a group of approximately 40 genes contained
Escherichia Coli
within a pathogenicity island on the bacterial
Infections are caused by any of the patho- chromosome (30). The formation of the attach-
genic species of Escherichia coli. These organisms ing-effacing lesion results in the introduction of
are classified into enteropathogenic, entero- bacterial products into the host cell, resulting in

395
Gastrointestinal Diseases

Table 10-4
ESCHERICHIA COLI INFECTIONS
Organism Disease Epidemiology
Enteropathogenic Severe fatal diarrhea in newborns Spread by ingestion of contaminated food or water
Escherichia coli (EPEC) Traveler's diarrhea Neonates and adults infected
Enterohemorrhagic E. coli Hemorrhagic colitis E.coli 015 7:H7 infections occur sporadically and in
(EHEC) Hemolytic uremia syndrome outbreaks
Thrombotic thrombocytic purpura Affect s the oldest and youngest in the population
Spread by ingestion of contaminated water and
person-to-person contamination
Enterotoxigenic E. coli Traveler's diarrhea Acquired by ingestion of contaminated food and water;
(ETEC) Infant diarrhea in developing world person-to-person transmission
Enteroaggregative E. coli Persistent diarrhea in infants in the Affects mainly infants and children, but also adults and
(EAEC) developing world travelers to endemic areas

disruption of the integrity of the cell membrane, Clinical Features. EAEC characteristically
and leading to diarrhea (53). produces watery, often protracted, diarrhea.
Pathologic Findings. In EPEC infections, E. Diarrhea may be associated with abdominal
coli organisms are intimately attached to the cramping, borborygmi, and low-grade fever
apical epithelial cell membraneA effacing the (12,40,62). Occasionally, gross mucus or blood
brush border microvilli. is present in the stool (20,7 4). EAEC also causes
Treatment and Prognosis. Risk factors for intestinal inflammation in the absence of diar-
death from EPEC infections inchide young rhea. Children with such infections develop
patient age and bacterial virulence. Almost all malnutrition and have impaired grt>wth (74).
deaths occur in patients younger than 2 years Pathologic Findings. EAEC causes moderate
of age (16). Treatment is supportive: replace- to severe small and large intestinal mucosal
ment of fluids and electrolytes lo.s t as a result of damage, irregularity of the surface epithelium,
diarrhea. In addition, antibiotic treatment with and subnuclear vacuolization of the crypt
trimethoprim-sulfamethoxazol@"or a fluoroqui- epithelium. Clumps of bacteria adhere to the
nolone is recommended (37). mucosal cells, especially in immunocompro-
mised patients. Heavily colonized cells show
Enteroaggregative E. Coli
marked cytologic changes (70). The lamina
Demography. Enteroaggregative E. coli (EAEC) propria is populated by increased numbers of
is a recent addition to the diarrheagenic classes lymphocytes, plasma cells, and eosinophils,
of E. coli. The name comes from the "stacked- but neutrophils are generally not seen. Rarely,
brick like" adherence to cultured epithelial cells villous atrophy results.
(29). These organisms are a significant cause of Treatment and Prognosis. Eradication of
diarrhea in developing countries and are most EAEC is desirable because of the risk that the
notably associated with prolonged, chronic diar- organism may cause protracted diarrhea. Most
rheal illness in children (50,5 7). EAEC outbreaks, strains of EAEC are susceptible to ciprofloxacin,
however, are increasingly being recognized in but antibiotic susceptibility testing should be
developed countries (40,48,64). EAEC is a cause performed in all cases, since many EAEC strains
of traveler's diarrhea in countries where the or- are resistant to multiple antibiotics (25,38,59).
ganism is endemic (33). Many individuals may In patients with persistent diarrhea, nutritional
be asymptomatic carriers of these organisms (SO). support may be necessary.
Pathophysiology. EAEC produces several
Enterohemorrhagic E. Coli
toxins including the enteroaggregative heat
stable enterotoxin (29) and two heat labile Demography. In 1982, two outbreaks of
toxins (9,31). Their aggregative adherence is hemorrhagic colitis associated with consump-
mediated by at least two fimbriae (21). tion of improperly cooked hamburgers took

396
Gastrointestinal Infections

place in the United States (68). Investigation results in intravascular coagulation, not just in
into these incidents led to the discovery of a the gut, but also in other organs including the
novel E. coli phenotype, now known as entero- kidney, pancreas, heart, and brain (60). The
hemorrhagic E. coli (EHEC). E. coli 0157:H7 is metabolic events leading to intravascular coagu-
the most common EHEC serotype seen in the lation may also lead to thrombocytopenia, mi-
United States. The mean annual infection rates croangiopathic hemolytic anemia, erythrocyte
range from 2.0 to 12.1/100,000 population (61). fragmentation, and renal failure characteristic
The infections are now sufficiently prevalent of hemolytic uremic syndrome (63).
that the American Gastroenterologic Associa- Disease-producing strains of EHEC usually
tion termed the infection "an emerging national also produce virulence factors other than Shiga
health crisis" (19). Populations most susceptible toxins. These include adhesins similar to those
to the infection are the very young and the very seen in enteropathogenic E. coli (32) .
old, or those with immunodeficiency states. Clinical Features: Infection with EHEC is
EHEC outbreaks are established through associated with a range of symptoms. Most
three principal routes of transmission: 1) con- patients initially present with abdominal
taminated food and contaminated drinking or cramps and watery diarrhea. Within 2 to 3 days,
swimming water, 2) person-to-person transmis- bloody diarrhea develops (42) . The passage of
sion, and 3) animal contacts. Outbreaks develop gross blood or clots occurs in severely affected
from the ingestion of infected common food patients. The diarrhea is more prolonged in
sources or organism exposure in communities, children than in adults (9.1 versus 6.6 days) (65) .
nursing homes, daycare centers, kindergartens, Generally, however, the illness is self-limited
and children's wading pools (11,14,44). (63,70,79). In the most severe cases, ischemic
Cattle are the principal reservoir of E. coli colitis or perforation may develop (49) . Ap-
0157:H7 . Overall, the prevalence ofthis organ- proximately half of the patients also experience
ism in cattle feces and hides is 28 percent and nausea and vomiting. Fever is uncommon, and
11 percent, respectively (28). Epidemiologic when present, is usually low grade. The infec-
surveys have revealed that EHEC strains are also tious dose of EHEC has been estimated to be
prevalent in the gastrointestinal tracts of domes- fewer than 100 organisms (57). As a result, fam-
tic animals, including dogs and cats (7,81) . Oth- ily members of affected individuals frequently
er sources of infection are other meat products, have evidence of concurrent infection, although
butter, unpasteurized milk, cheese, vegetables, they are commonly asymptomatic (51) . The
and fruits (8,13,22,23,26,47,56,67,68,71), espe- incubation period is usually 1 to 6 days, but
cially in the setting of mass food production. may be as long as 14 days (18).
The mortality and morbidity associated with Not all strains of EHEC carry a risk for the
several recent large disease outbreaks highlight development of hemolytic uremic syndrome
the threat that EHEC poses to public health (36). (HUS). HUS develops in 5 to 8 percent of pa-
Pathophysiology. The main virulence factors tients with EHEC infection (58) . High white
of E. coli 015 7:H7 result from the production of blood cell counts, elevated C-reactive protein,
Shiga-like toxins, some of the most potent hu- and fever early in the course of the disease are
man toxins. E. coli 0157:H7 organisms possess indicators of risk for the development of HUS
one or two cytotoxin genes encoding verotoxin (10,15,24,41,46).
1 and verotoxin 2, both of which are nearly Gross Findi n gs . EHEC causes marked
identical to the Shiga toxin, the principal extra- hemorrhagic mucosal necrosis with mucosal
cellular cytotoxin of Shigella dysenteriae (45,7 5). congestion, erythema, and patchy ulceration,
This toxin binds to host cells and is internalized usually with surface exudates and occasional
through endocytosis. Within the cell, the toxin pseudomembranes. Blood may ooze from the
disrupts the integrity of ribosomes, resulting mucosal surfaces . Submucosal edema causes
in cessation of protein synthesis and cell death radiologic thumbprinting. The gross and endo-
(69) . Interestingly, intestinal enterocytes are scopic changes may be indistinguishable from
partially resistant to the effects of the toxin, those of ischemic colitis. A gradient of injury
but endothelial cells are susceptible to it. This is present, with the most severe disease in the

397
Gastrointestinal Diseases

In patients with HUS, the histologic findings


include marked endothelial cell injury, with
swollen vascular lining cells pulling away from
the basement membrane, and the presence of
fluffy deposits and thrombotic microangio-
pathy. Renal changes include swollen and
detached glomerular endothelial cells with
deposition of fibrin and platelets in the renal
microvasculature, particularly in the glom-
erulus (66). Thrombotic lesions also occur in
the microvasculature of the bowel, brain, and
pancreas.
Treatment and Prognosis. Complications
Figure 10-2 associated with E. coli 015 7:H7 infection in-
ESCHERICHIA COLI 0157:H7 INFECTION
clude end-stage renal disease, hypertension,
The colonic mucosa shows prominent epithelial injury;
and central nervous system (CNS) damage. CNS
the superficial epithelium is lost in a pattern"similar to that complications include lethargy, severe head-
seen in ischemia. The lamina propria contains numerous ache, seizures, cerebral edema, encephalopathy,
extravasated red blood cells and inflammatory cells. An stroke, and coma. Rare and unusual complica-
acute inflammatory exudate is present overlying the eroded
mucosal surface.
tions of EHEC infections are rhabdomyolysis,
pancreatic necrosis with subsequent diabetes
mellitus, and acute intestinal obstruction from
proximal colon and less severe disease in the intestinal hematomas (63).
rectum (35), a distribution mimicking Crohn's The objectives of therapeutic strategies are
disease. The entire colon may be involved, par- 3-fold: 1) to limit the severity and/qr duration
ticularly in children. of the gastrointestinal symptoms; 2) to prevent
Microscopic Findings . E. coli 0157:H7 life-threatening systemic complications such as
causes the most severe histologic changes of HUS; and 3) to prevent infection spreading to
all E. coli infections. The histologic patterns of close contacts. Since patients affected by EHEC
ischemia and infectious colitis overlap due to may progress to HUS, close observation fol-
the presence of both epithelial and endothelial lowing the onset of diarrhea for symptoms of
injury (fig. 10-2). Microscopic features associat- HUS leads to earlier intervention and improved
ed with an infectious histologic pattern include initial management (73). Treatment of E. coli
prominent neutrophilic infiltrates within the 0 15 7: H 7 infection consists of rehydration
crypts and lamina propria and adherent pseudo- during the hemorrhagic colitis, monitoring for
membranes. Cryptitis occurs more commonly blood loss, and patient support during the mul-
than crypt abscesses and in all cases the neutro- tiple systemic complications of HUS. Antimotil-
philic infiltrates are focally accentuated rather ity drugs should be avoided (37). Antibiotics are
than uniform in appearance. Features associated not beneficial, and may in fact increase the risk
with ischemia include focal marked submucosal of HUS (80). Improved clinical management and
edema, hemorrhage, pseudomembranes, bland renal dialysis have reduced the mm·tality associ-
mucosal necrosis, ulcers, abundant intramural ated with HUS in recent decades. Nonetheless,
fibrin deposits, and thrombi. The ischemia leads some individuals develop chronic renal insuf-
... to extensive mucosal necrosis, leaving ghosts ficiency, hypertension, and neurologic deficits.
of crypts filled with neutrophilic infiltrates. Preventive approaches include educating
The necrosis may extend into the submucosa the public on the danger of eating under-
or even transmurally. The mucosa between the cooked meat, increasing physician awareness
ulcerated areas shows a range of changes from of the signs and symptoms of E. coli 0157:H7
mucus depletion and occasional neutrophils infection, mandating case reporting (76), and
to epithelial dropout, fibrin deposition, and promoting safe food preparation and food han-
hemorrhage. dling practices (77) ~

398
Gastrointestinal Infections

Enterotoxigenic E. Coli
Demography. Enterotoxigenic E. coli (ETEC)
was first identified as a cause of diarrhea in
1970, and is now known to be a major cause of
diarrhea worldwide (39). ETEC infections are as-
sociated with poor sanitation and hygiene, and
are therefore of most importance in developing
countries. Transmission is through ingestion of
contaminated food or water. Outbreaks also oc-
cur secondary to person-to-person spread (18).
Pathophysiology. Once the bacteria colonize
the small intestine, they produce two toxins: a
heat labile toxin (LT) resembling cholera toxin,
Figure 10-3
and a heat stable toxin (ST) that activates gua-
nylate cyclase and impairs colonic water resorp- ENTEROTOXIGENIC E. COLI INFECTION
tion (54). These structurally and functionally The colonic mucosa appears edematous, but there is no
different enterotoxins bind to different mem- significant inflammatory cell infiltration .
brane receptors and induce active fluid secretion
without injuring the enterocytes. Special toxin
assays are required to differentiate ETEC from
normal flora E. coli.
Clinical Features. ETEC infections are the
Enteroinvasive f. Coli
most common cause of traveler's diarrhea
(17,52,78) and are an important cause of secre- Demography. Enteroinvasive E. coli (EIEC) is
tory infantile dianhea in developing countries. a significant cause of morbidity and mortality
The incubation period is 24 to 48 hours. The in children in both developing and developed
disease often begins with upper intestinal dis- countries (18).
tress followed by watery diarrhea. The clinical Pathophysiology. The central pathogenetic
course may be extremely mild or it may be very mechanism of EIEC is the ability to invade epi-
severe, mimicking cholera and producing severe thelial cells. This invasive capability correlates
dehydration and rice-water stools. Symptoms, in- with the presence of a 140-MDa plasmid also
cluding the sudden onset of abdominal cramps, found in Shigella organisms (39,72).
nausea, borborygmi, and malaise, are generally Clinical Features. The symptoms of EIEC
most severe on the first day of the infection. The infection generally begin 2 to 3 days following
acute watery diarrhea may be accompanied by ingestion of contaminated food (42). The organ-
low-grade fever and chills. The diarrhea is usually isms invade the colonic mucosa and cause a
self-limited, lasting only 3 to 4 days. dysentery-like illness. The presenting symptoms
Gross Findings. Toxigenic E. coli infections include watery diarrhea, tenesmus, cramps, and
occur throughout the colon, usually inducing low-grade fever. The diarrhea may be associated
mucosal edema. Ulcers are usually absent. Pseu- with the passage of small amounts of blood and
domembranes are rare. mucus. White blood cells are usually found in
Microscopic Findings. ETEC infections cause the stool. The clinical symptoms resemble those
mucosal edema, sometimes with extravasa- found in patients with Shigella infection.
tion of red blood cells (fig. 10-3). E. coli can Pathologic Findings. EIEC penetrates the
sometimes be seen adhering to the epithelium intestinal epithelium, producing acute inflam-
without inducing structural mucosal damage. mation and ulceration of the mucosa in a man-
Treatment and Prognosis. ETEC infection ner similar to that seen with Shigella infection.
is usually self-limited and therefore requires Treatment and Prognosis. Antibiotics
mainly supportive care. Trimethoprim sulfa- (trimethoprim-sulfamethoxazole or a fluoro-
methoxazole or fluoroquinolones may be used quinolone) may be administered in addition to
for treatment (37). supportive care (3 7).

399
Gastrointestinal Diseases

Special Techniques for Identifying E. Coli of cases of salmonellosis has been increasing
steadily during the past decade. In the United
Techniques that identify specific E..coli o~gan­ States, Salmonella has been estimated to be
isms or their toxins include serotypmg, tissue
responsible for 18,000 aQ.nual hospital ad~is­
culture immunochemical methods, DNA hy-
'
bridization studies, and polymerase cham .
reac-
sions, 500 deaths, and $50 million in mediCal
costs (97). More than 95 percent of Salmonella
tions (PCR). Stool samples should be examined
infections are foodborne, and salmonellosis ac-
for E. coli by both culture and toxin detection
counts for approximately 30 percent of deaths
methods in order to identify the specific type of
from foodborne illness in the United States
E. coli and to differentiate disease-causing E. coli
(117a). Outbreaks of Salmonella gastroenteritis
from the normal colonic flora. It is particularly
have been linked to ingestion of contaminated
important to detect EHEC organisms in stool.
fish, poultry, eggs, cheese, dry cereal, ice cream,
EIEC organisms are difficult to identify using
fresh sprouts, juice, cantaloupes, and a variety of
standard microbiologic techniques and most
fresh vegetables (90,91,96,110,127). Less com-
microbiologists overlook lactose nonfermenting
monly, the infection is acquired from household
organisms if they are not of the Salmonella, Shi-
pets (reptiles and birds), direct personal cont~ct
gella, or Yersinia genus. EIEC can t:e identified
with other infected individuals, nosocomial
with DNA technology (27).
sources, contaminated water, and contaminated
Differential Diagnosis of E. Coli Infection drugs or solutions (86,92,93,110).
Poultry serve as the major reservoir for infec-
The clinical differential diagnosis of E. coli
tion with non typhoidal Salmonella strains (127).
infections includes other infections, inflam-
The northeast United States, parts of Europe,
matory bowel disease (IBD), intussusception,
South America, and Africa have experienced a
acute appendicitis, pseudomembranous colitis,
marked increase in food poisoning due to S. en-
and ischemic enterocolitis. Antibodies to E.
terica serotype enteritidis (128,132). T}].e increase
coli 0157:H7 distinguish this infection from
relates to increased consumption of infected
other causes of ischemic enterocolitis (76). The
eggs and poultry. Widespread antibiotic use to
histologic changes of EHEC infection may re-
improve animal growth has contributed to the
semble those seen in Campylobacte1~ Salmonella,
emergence of multiple antibiotic-resista~t Sal-
and early amoebic infections. Toxicologic and
monella strains that cause serious human disease
microbiologic assays help to dif~rentiate these
and the increase in occurrence of symptomless
entities. Other Enterobacteriaceae can produce
excreters. The incidence of salmonellosis has
Shiga toxins that cause serious gastrointestinal
steadily increased as Salmonella organisms have
disease and HUS. The most notable of these
become antibiotic resistant. .
is S. dysenteriae type I, the cause of bacillary
The peak incidence of infection occurs in
dysentery.
infancy, although all individuals at the extremes
Salmonella Infections of age appear to be at risk. Other risk factors in-
clude alteration of the endogenous bowel flora
Definition. Salmonella infection leads to
as a result of either antibiotic therapy or surgery,
two forms of disease' affecting the gastrointes-
diabetes, malignancy, rheumatologic diseases,
tinal tract. Typhoid fever, a protracted systemic
altered function of the reticuloendothelial
disease, results from the translocation of Sal-
system (as occurs in malaria, sickle cell disea~e,
monella from the intestinal or renal epithelium
or some infections), and immunocompromise
to the reticuloendothelial system. In the latter,
(110,130). AIDS patients have a 20-fold higher
the bacteria multiply within phagocytes in the
incidence of recurrent non typhoidal Salmonella
liver, spleen, lymph nodes, and Peyer patches.
infections, with or without clinical enteritis.
Salmonella food poisoning or gastroenteritis is usu-
Etiology. Salmonellae are Gram-negative,
ally a mild self-limited disease that develops 3
nonspore-forming, highly motile rods that be-
to 48 hours following organism ingestion (132).
long to the family Enterobacteriaceae. Homolo-
Demography. Salmonella infections are a
gous genes in Salmonella and E. coli average 85
global health problem with a devastating social
percent sequence identity, suggesting that the
impact in developing countries. The number

400
Gastrointestinal Infections

lineages split over 100 million years ago (123). Table 10-5
However, the Salmonella genome also consists of SALMONELLA SPECIES THAT
material that is absent in E. coli (113,122). The CAUSE INFECTIONS IN HUMANS
Salmonella species that cause gastrointestinal
disease in humans are listed in Table 10-5. S. typhimurium S. agona
Pathoph ysiology. Following oral ingestion, 5. typhi S. javiana
Salmonella organisms colonize the intestines S. paratyphi 5. oranienburg
and invade the intestinal mucosa. The organ- 5. enteritidis 5. schottmuelleri
isms have the ability to penetrate, invade, and S. choleraesuis'b S. amatum
multiply in many cell types. One of the hallmarks "Most likely to affect patients with acquired immunodefi-
of systemic infection is the ability of the bacteria cien cy syndrom e (AIDS) .
to spread from intestinal tissues via lymphatics ~> caus e bacteremia with localized infections; ileitis rare.
into the blood stream and to multiply within
macrophages ofthe liver and spleen (89,101).
The disease pattern reflects species virulence, a group of Salmonella outer proteins (Sop) (136)
the number of organisms ingested, and the pres- including SopA, SopB, SopD, and SopE. SopE, for
ence of normal flora in the upper intestinal tract. example, is required for efficient bacterial entry
Plasmids integrated into the bacterial genome into cells. It functions to directly stimulate actin
encode virulence factors involved in the adher- cytoskeletal rearrangements in the host cells,
ence to, invasion of, and growth within epithelial allowing bacterial entry (107).
cells. Salmonella organisms are the only species TTSS-1 also plays a major role in the induc-
of bacteria that contain two type Ill secretion tion of intestinal secretory and inflamma-
systems, encoded by two distinct gene clusters, tory responses. SopB (also known as SigD in
referred to as Salmonella pathogenicity islands-1 S. typhimurium) is an inositol phosphate phos-
and -2 (SPI-1 and SPI-2). These two type Ill secre- phatase that is capable of hydrolyzing several
tion systems play different roles in Salmonella inositol phosphates (121) : This results in tran-
pathogenesis. SPI-1 is required for invasion sient elevation of intracellular levels of inositol
of host cells, while SPI-2 is necessary for the 1,4,5,6-tetrakisphosphate which antagonizes
subsequent systemic stages of infection (111). closure of chloride channels, resulting in fluid
Invasion of intestinal epithelial cells is a secretion. Salmonella-infected epithelial cells
characteristic feature of Salmonella infection. secrete chemokines and prostaglandins that act
When injected into ligated ileal loops of calves, to recruit inflammatory cells to foci of infection.
Sa lmonella invades enterocytes and M cells This is probably mediated, at least in part, by
within minutes (102) . Upon contact with host Sop proteins (103).
cells, the organisms induce degeneration of In the lymphoid tissue underlying infected
surface microvilli (134). Next, they elicit apical epithelial cells, Salmonella organisms are phagocy-
membrane ruffles on both M cells and entero- tosed by resident macrophages. The organisms are
cytes, a change that results in their uptake into able to survive and replicate inside the phagocytic
membrane-bound vesicles. vacuoles in these cells, and in this way are able to
The invasion of epithelial cells is dependent use the macrophages as a vehicle for dissemination
on secretion of type Ill secretion system-1 (TTSS- to other organs (82, 101,114,118). Survival and
1) proteins. Many of these TTSS-1 proteins are proliferation within host cells may be mediated by
encoded on SPI-1, but some components are genes encoded on SPI-2 (108). The bacteria then
encoded elsewhere in the bacterial genome. replicate in the liver, spleen, and bone marrow,
TTSS-1 proteins can be loosely divided into two leading to bacterial sepsis, organ failure, and pos-
groups, the translocators and the translocated sibly death of the host. SPI-1 proteins mediate
effectors. The translocator proteins are essential a cytotoxic effect on macrophages, leading to
for movement of the protein effectors across apoptosis and cell death (94).
the eukaryotic cell membrane and into the host Clinical Features. Salmonella organisms pro-
cell. Translocator proteins include SipB, SipC, duce five clinical syndromes: 1) gastroenteritis
and SipD (98). TTSS-1 effector proteins include (70 percent of infections); 2) bacteremia, with

401
Gastrointestinal Diseases

or without gastrointestinal involvement; 3) be prolonged, with 1 to 4 percent of patients


typhoid or enteric fever; 4) localized infections becoming long-term carriers.
in bones, joints, and meninges; and 5) a carrier Salmonella infections in the elderly, AIDS
state. Typically, Salmonella gastroenteritis is a patients, or immunosuppressed individuals may
mild, self-limited illness that develops 8 to 48 be unusually severe and these patients have a
hours after ingestion of the organism, but 2 to poorer prognosis than do younger, immuno-
5 percent of infected individuals develop bacte- competent individuals. These patients have a
remia and sepsis-associated complications (84). higher incidence of bacteremia, disseminated
Signs and symptoms of Salmonella gastroenteri- extraintestinal infections, and relapse than im-
tis vary widely, but most patients present with munocompetent patients. Recurrent bacteremia
nausea, vomiting, abdominal cramps, fever, occurs despite treatment and the relative pau-
and diarrhea that sometimes becomes bloody. city of gastrointestinal manifestations.
Symptoms usually last for 3 to 12 days. The Gross Findings. Because the major portal of
duration of the carrier state, however, depends entry for bacteria causing gastroenteritis is in
on the age of the infected patient. Children the area of Peyer patches, the lymphoid follicles
under 5 years of age carry non typhoidal strains become hyperplastic, swollen, congested, and
for approximately 12 weeks, wh~reas adults ulcerated, often resulting in typical longitudi-
clear the organism after 4 weeks (85). Chronic nally oriented ulcers and areas of hemorrhage
carriers are individuals who continue to excrete (115,119). Edema, fibrinous exudation, and
organisms in their stool for a year or more after vascular thrombosis precede the ulceration.
the symptoms of Salmonella gastwenteritis or Aphthous ulcers sometimes develop (99).
enteric fever have passed. Salmonella is also a In typhoid fever, bacterial sequestration in
cause of traveler's diarrhea (116a). the reticuloendothelial system causes lymphoid
Infections with S. enterica serotype ,typhi and, hyperplasia, lymphadenopathy, and spleno-
to a lesser extent, S. enterica serotypes paratyphi, megaly. The disease primarily affect.~ intestinal
schottmuelleri, and hirschfeldii, follow an en- lymphoid tissues of the ileum, appendix, and
teric fever pattern. Dissemination is common colon. Four sequential stages of the disease
and ileal lymphoid proliferation at the site of have been described, each of which lasts a
invasion is prominent during the first 1 to 2 week: hyperplasia, necrosis, ulceration, and
weeks of infection. Patients with typhoid fever healing (131). Hyperplasia develops during the
remain relatively asymptomati<..'"'d uring a 1- to incubation period with the onset of fever. The
2-week incubation period. The onset of bacte- Peyer patches enlarge and become elevated and
remia is heralded by fever and malaise. Other hyperemic. The necrotic stage corresponds to
signs and symptoms include nausea, vomiting, the phase of maximal fever. The necrosis begins
vague abdominal discomfort, headache, cough, in Peyer patches as isolated, localized foci with
myalgia, and reactive bradycardia (83,87,133). fibrinous exudates in the surrounding mucosa.
Physical examination typically shows abdomi- The ulceration stage begins when the necrotic
nal tenderness and hepatosplenomegaly. Com- tissue sloughs. This event occurs approximately
plications occur in 10 to 15 percent of patients the same time as the lysis of the fever. The ulcer
(124). Gastrointestin'al complications include bases typically lie on the muscularis propria but
massive intestinal hemorrhage, perforation, they occasionally penetrate the entire thickness
intussusception, mesenteric lymphadenitis, of the bowel wall. They are oval, longitudinal,
peritonitis, fistulas, toxic megacolon, and and located on the antimesenteric borders. With
'-,·
paralytic ileus (100,112). The bleeding results progressive disease, the bowel wall becomes
from ulceration of Peyer patches. The stool paper thin and susceptible to perforation (100).
acquires a "pea soup" appearance because of Microscopic Findings. Nontyphoidal Sal-
the purulent material shed from the ulcerated monella organisms cause acute infectious ileo-
mucosa. A prolonged convalescent stage of 3 colitis indistinguishable from other infectious
months is usual. Relapse occurs in 5 to 10 per- colitides (117). The changes are self-limited and
cent of patients and is usually milder than the the mucosa returns to normal in approximately
original attack (124). Bacterial shedding may 2 weeks.

402
Gastrointestinal Infections

Figure 10-4
SA LMONELLA COLITI S
Left: Low-power view shows preservation of the mucosal architecture. The lamina propria is somewhat edematous and
contains an increased number of inflammatory cells. Most of the crypts are lined by flattened, regenerative epithelium.
Right: Higher-power view shows regenerative glands and inflammatory cells within the lamina propria.

Figure 10-5
SALMONELLA COLITIS
Left: The mucosa overlying the lymphoid follicles is ulcerated.
Right: Higher magnification shows changes resembling those of acute self-limited colitis. The mucosal architecture is
preserved. There is evidence of mucosal erosion associated with lamina propria edema and inflammation. Some crypts contain
infiltrating neutrophils and a crypt abscess is present. (Courtesy of the Division of Gastrointestinal Pathology, Armed Forces
Institute of Pathology, Washington, DC.)

Histologically, mild cases of Salmonella gas- those with persistent diarrhea, have mild crypt
troenteritis show nonspecific changes including distortion and branching.
edema, congestion, and focal inflammation (fig. During the hyperplastic phase of typhoid
10-4). More severe cases show crypt abscesses fever, the mucosa appears intact but contains
with prominent neutrophilic infiltrates in de- foci of neutrophilic cryptitis . The germinal
generating crypts. The neutrophilic infiltration centers, mantle zones, and interfollicular areas
is more intense in the lamina propria than in of the lymphoid follicles become progressively
the glands. Areas of hemorrhage and ulceration infiltrated by macrophages, and have promi-
are also present (fig. 10-5). Microthrombi fill nent erythrophagocytosis and tingible bodies.
small vessels in the mucosa and submucosal The follicles eventually are obliterated by this
venules, simulating the features of acute isch- process. Plasma cells and immunoblasts increase
emic colitis. Occasional patients, especially and infiltrate into the underlying submucosa.

403
Gastrointestinal Diseases

The lymphatics at the edges of the Peyer patches result in prolonged shedding of the organism
appear dilated and contain numerous lympho- (110,120). Since the intestinal lesions heal with
cytes, monocytes, and immunoblasts. minimal fibrosis, stricture formation is unusual.
During the necrotic phase of the disease, vari- Antimicrobial therapy should be instituted in
able portions of the Peyer patches remain viable. patients with severe gastroenteritis, or in those at
Areas of ulceration develop in the mucosa (fig. risk for developing disseminated disease. Usually
10-5). A fibrinous exudate on the peritoneal 3 to 7 days of treatment with fluoroquinolones,
surface may underlie these deep ulcers. During trimethoprim-sulfamethoxazole, ampicillin, or a
the healing stage, the ulcers are covered by a third generation cephalosporin is adequate (110) .
thin layer of granulation tissue and a layer of Resistance to antibiotics by these organisms is
intestinal epithelium. Healing occurs rapidly, becoming increasingly common.
usually with little fibrosis or stricturing. Typhoid fever is a chronic systemic illness
Special Techniques. The gold standard for with a mortality rate that can reach SO percent
diagnosis of typhoid fever is culture of S. enterica in untreated individuals in some parts of the
serotype typhi from blood, stools, or urine. New world (109,125,129). Treatment reduces the
enzyme-linked immunoabsorbent assay tests mortality rate to less than 1 percent. There is
and rapid antigen detection methodli are being strong evidence that fluoroquinolones such as
developed to meet the need for inexpensive ciprofloxacin are the most effective drugs for the
and reliable diagnostic techniques in under- treatment of typhoid fever (88,95,104,106, 135).
developed countries (126). Once Salmonella is Quinolone-resistant Salmonella strains have
identified, it is important to determine whether emerged. These are often resistant to multiple
the isolate is S. enterica serotype typhi because drugs, and are usually treated with azithro-
antibiotics are efficacious for typhoid fever. mycin or cephalosporins. A subset of patients
Differential Diagnosis. A substantial overlap with severe infection or complications requires
of clinical symptoms exists between enteric surgical intervention.
fever and other gastrointestinal inflammatory The most important infection control mea-
conditions. Colonic infections generally mimic sure for salmonellosis is awareness that the
ulcerative colitis or other forms of infectious organism is present in many foods and recogni-
colitis (116) . The changes of salmonellosis dif- tion of the postsymptomatic and asymptomatic
fer from those of IBD by the relative scarcity of carrier states. Food should be cooked well to kill
chronic inflammatory cells in th~ former and organisms and hands and utensils should be
their frequency in the latter. In severe cases of washed thoroughly after coming in contact with
salmonellosis, giant cells or histiocytic aggre- uncooked foods. More prudent use of antimicro-
gates are present. When these coexist with trans- bial agents in farm animals and more effective
mural inflammation, a diagnosis of Crohn's disease prevention on farms are necessary to
disease might be entertained. The giant cells, reduce the dissemination of multidrug-resistant
however, do not form compact granulomas, as strains and to slow the emergence of resistance
seen in Crohn's disease. The differential diagno- to additional agents in this and other strains of
sis of the histiocytic aggregates includes mucin Salmonella (105).
granulomas as well as other bacterial infections,
Shigella Infections
including those caused by Campylobacter, Yer-
sinia, Shigella, E. coli, and mycobacteria. Demography. Shigella infections are an im-
The lesions in the bowel and mesenteric portant cause of morbidity and mortality in de-
lymph nodes may also mimic Kikuchi-Fujimoto veloping countries, especially in areas with poor
disease and Rosai-Dorfman disease, as well as hygiene and overcrowding. Person-to-person
infections caused by non-Salmonella bacteria. transmission and consumption of contami-
Treatment and Prognosis. In the absence nated food and water cause the disease (143,
of systemic infection, no treatment other than 149). Children and young adults are the main
supportive care is warranted. In fact, studies sug- victims, with over 500,000 deaths occurring as
gest that antibiotic treatment in patients with a result worldwide (144,146,156,160). Shigella
mild to moderate Salmonella gastroenteritis may infections are also a significant problem among

404
Gastrointestinal Infections

institutionalized children in nurseries and men- Eventually, microulcers develop in the surface
tal hospitals, and the organism is implicated as epithelium. Endotoxin absorption leads to
a cause of traveler's diarrhea (156). thrombosis, hemorrhage, and vascular insuf-
Etiology. Shigella organisms are nonmotile, ficiency, causing further crypt damage.
Gram-negative bacilli that are among the more The severe diarrhea that develops in patients
virulent human enteropathogens. The Shigella with Shigella results from the bacterial induc-
species (dysenteriae, fl.exneri, boydii, and sonnei) tion of macrophage apoptosis (161). Dying
cause colitis, diminishing in severity from the macrophages infected with the organism release
first type to the last (147). Cases of mixed infec- interleukin-1 (159). The cytokine elicits a strong
tion with both S. boydii and S. sonnei have been inflammatory response that is a central compo-
described (139). Multiple drug-resistant strains nent to the pathogenesis of shigellosis (152).
are a common characteristic in the epidemic Clinical Features. Shigella causes a range of
form of the disease. symptoms varying from mild watery diarrhea
Pathophysiology. Shigella gains access to to bacillary dysentery. The usual disease incuba-
the intestinal epithelium through invasion of tion period ranges from 1 to 3 days. The typical
M cells (154). The ability to invade epithelial clinical presentation of bacillary dysentery is
cells represents a property that is required for crampy abdominal pain, rectal burning, and
the organism's virulence (151). As many as 27 fever, accompanied by small-volume, bloody,
genes are required for entry of the bacteria into mucoid bowel movements. This presentation,
host cells. Most of these genes are located in two however, occurs in only a few patients. The
operons in the Shigella virulence plasmid. One most common symptoms are abdominal pain
operon, termed mxi-spa, encodes a specialized and diarrhea. Fever is present in 40 percent of
activatable type III secretory apparatus similar patients, and the typical dysenteric mucoid
to that found in enteropathogenic E. coli or stool is present in less than one third. Many
Salmonella (139b). After a complex signaling patients have a biphasic illness that begins with
process, these proteins cause major rearrange- fever, abdominal pain, and watery, nonbloody
ments of the actin and microtubular cytoskel- diarrhea. This is followed within 3 to 5 days by
etal network, thereby allowing bacterial entry tenesmus, typical dysenteric bowel movements,
by a macropinocytotic event (139b,15 7,158). and lower abdominal pain.
Epithelial signaling caused by apical bacteria Patients with prolonged diarrhea often de-
induces adherence and transmigration of basal velop severe complications, including anal or
neutrophils, further facilitating bacterial inva- perianal disease that causes fissures, fistulas,
sion (153). Once inside the epithelial cell, they hemorrhoids, or mucosal prolapse. Other com-
lie in phagocytic vacuoles, multiplying, caus- plications include malnutrition, pneumonia,
ing mucus secretion, goblet cell depletion, and and septicemia (139) . Extraintestinal manifesta-
inducing neutrophilic infiltrates. The neutro- tions include convulsions, disturbances of con-
phils further injure the epithelium, facilitating sciousness, shock, disseminated intravascular
Shigella invasion (148) . The bacteria lyse their coagulopathy, nerve paralysis, severe anemia,
phagocytic vacuole and initiate intracytoplas- and HUS (141). Dysentery can be a life-threat-
mic movement due to polar assembly of actin ening illness in infants, elderly, or malnourished
filaments caused by a bacterial surface protein, individuals. In patients with fatal infections,
IcsA. The bacteria move within the cell and particularly children, death results from severe
spread laterally into adjacent cells and into the colitis often complicated by septicemia, con-
adjacent lamina propria (153). This allows very comitant malnutrition, and pneumonia (139).
efficient colonization of the host cell cytoplasm Factors that predict mortality include younger
and passage to adjacent cells via protrusions that age, decreased serum protein, altered conscious-
are engulfed by a cadherin-dependent process. ness, and thrombocytopenia (138).
This cycle of intracellular and intercellular in- Gross Findings. Gastrointestinal changes
fection allows colonization of large epithelial caused by Shigella infection range from rela-
surfaces while the bacteria remain protected tively mild mucosal inflammation with contact
from host immune surveillance mechanisms. bleeding, edema, and hyperemia to ragged

405
Gastrointestinal Diseases

ulcerations, sometimes associated with pseu- rehydration. Treatment with fluoroquinolones


domembrane formation (137,145,155). Serpigi- or trimethoprim-sulfamethoxazole is often
nous ulcers develop on the free edges of mucosal effective (139a). Shigella susceptibility test-
folds. The intervening mu·cosa appears granular ing should be performe'f, since resistance to
and hemorrhagic; aphthous ulcers may be pres- antibiotics is common. Patients who develop
ent. The continuous, diffuse lesions begin in megacolon require surgery (138).
the rectosigmoid, with the intensity of inflam-
Staphylococcal Infections
mation decreasing as one moves proximally. In
fatal cases, pancolitis is common (140). Demography. Staphylococci are a common
Microscopic Findings. Biopsy evaluation of cause of food poisoning worldwide. Staphylo-
patients with shigellosis shows the typical fea- coccal food poisoning accounted for 16 percent
tures of other forms of acute self-limited colitis. of outbreaks of foodborne illness in France
The earliest lesions occur at the portal of entry between the years 1999 and 2000 (164).
and consist of small aphthous ulcers overly- Etiology. Most cases of staphylococcal food
ing lymphoid follicles. Extensive ulceration is poisoning are due to toxin-producing Staphylo-
associated with invasion of epithelial cells by coccus aureus . Enterotoxins are also produced by
the organism. There is marked mvcus deple- S. cohnii, S. epide1midis, S. xylosus, and S. haemoly-
tion of the epithelium and crypt hyperplasia. ticus (162) . S. inte1medius is the only non-S. aureus
Other changes include acute inflammation with species that has clearly been linked to outbreaks
neutrophilic infiltrates, occasional superficial of staphylococcal food poisoning (166) .
crypt abscesses, goblet cell depletion, edema, Pathophysiology. Staphylococcal food
vascular congestion, and minimal.lymphocyte poisoning results from consumption of food
and plasma cell infiltrates (150). Eventually, the contaminated with preformed toxins. Fourteen
mucosa reverts to normal (142), altho~gh some different, but related, S. aureus enterotoxins
residual distortion of the crypt architecture may have been described (167). These toxins cause
persist (137,139). disease in several ways. Toxin binding to class
Special Techniques. The definitive diagnosis I histocompatibility antigens on macrophages
depends on demonstrating the organism in or mast cells may stimulate these cells to re-
stool cultures or by genetic analysis of the tis- lease large amounts of soluble mediators, such
sues or stool specimens. as interleukin 1 and tumor necrosis factor
Differential Diagnosis. The gross findings (165), which induce diarrhea and vomiting
resemble those present in Campylobacter and (168). Alternatively, the toxins may stimulate
Salmonella infections or ulcerative colitis. When proliferation and lymphokine production by T
pseudomembranes form, the differential diag- lymphocytes. This occurs as a result of cross-
nosis includes Clostridium diff!cile-associated linking of the T-cell receptor with the major
colitis, ischemia, amebiasis, and other disorders histocompatability complex (MHC) class 11
associated with pseudomembranes. The histo- molecule of an antigen presenting cell, leading
logic features usually allow the disease to be dis- to nonspecific T-cell activation and massive
tinguished from ulcerative colitis due to the lack secretion of interleukins (169).
of architectural disto'rtion and other chronic Clinical Features. Staphylococcal food poi-
changes. Distinction from other acute infec- soning is an explosive, but self-limited, gastro-
tious diseases is generally not possible based enteritis associated with ingestion of infected
solely on the histologic appearance. Definitive food. Patients develop nausea, vomiting, and
'"·'
diagnosis requires organism identification and watery, nonbloody diarrhea, usually within 30
clinical correlation. minutes to 8 hours after ingesting contaminated
Treatment and Prognosis. Therapy for Shi- food. The symptoms usually remit within 24
gella gastroenteritis is not always necessary. Mild hours (167).
disease is usually self-limited and a prolonged Pathologic Findings. In most cases, the dis-
carrier state virtually never occurs. Moderate to ease resolves before endoscopy and biopsy are
severe disease, however, should be treated with necessary. In severe cases, however, patients pres-
antibiotics and systemic support, especially oral ent with nonspecific enterocolitis with intense

406
Gastrointestinal Infections

mucosal congestion, necrosis, and ulceration duce diarrheal illness by two mechanisms: 1)
(163). The histologic features resemble those intestinal adherence and toxin production and
seen with other intestinal bacterial infections. 2) bacterial invasion and proliferation within
Treatment and Prognosis. Because the dis- intestinal epithelial cells. The bacteria attach to
ease results from ingestion of a preformed toxin and invade enterocytes (177-179,185). When
and is self-limited, no treatment is necessary. the organisms contact the cell surface, the epi-
thelium becomes damaged and bacteria invade
Campylobacter Infections
the cells (177-179,185).
Demography. Campylobacter species are C. jejuni strains produce an enterotoxin and
widespread in mammals and birds, and they sur- at least one cytotoxin, the cytolethal distend-
vive well in the environment. As a result, sources ing toxin (CDT) (191). Although the role of this
of human infection include animal contact, food, toxin in the pathogenesis of diarrhea in humans
milk, and water. Campylobacter is one of the most is not yet clear, in vitro studies have demon-
frequently isolated stool pathogens (172,195), and strated that this protein causes eukaryotic cells
its incidence differs from country to country. In the to become arrested in the G 7 phase of the cell
United States and other industrialized countries, cycle (200). In vivo, this could affect the rapidly
Campylobacter is responsible for 2 to 7 times as dividing cells of the intestinal crypts, leading
many cases of diarrhea as is Salmonella, Shigella, to loss of function and erosion of the epithelial
or E. coli (17 4,197). C. jejuni is a common cause lining of the gut. Some strains of C. jejuni may
of bacterial gastroenteritis (185a), with approxi- elaborate additional toxins (192,194). C. jejuni
mately 1 percent of the population of the United organisms are more often enterotoxigenic and
States becoming infected each year (171). Campylo- possibly more virulent than C. coli and C. Zm·idis.
bacter infections affect persons of all ages, but they Clinical Features. Campylobacter organisms
peak in incidence in infancy, with a smaller peak cause both gastrointestinal and extragastro-
between 15 and30years of age (175,196). Campy- intestinal illnesses. The incubation period ranges
lobacter outbreaks are associated with consump- from 1 to 7 days. The clinical features of the
tion of unpasteurized milk and contaminated infection are not specific enough to allow distinc-
water, meat, vegetables, and especially, poultry. tion from other enteric infections. Typically, C.
Person-to-person transmission also occurs (173). jejuni infection results in an acute, self-limited
Household pets may serve as reservoirs for the gastroenteritis characterized by diarrhea, fever,
infection (172,174,198). and abdominal cramps. A prodrome of head-
In developing countries, Campylobacter infec- ache, myalgias, chills, and fever may precede
tions are hyperendemic among young children, the diarrhea. The abdominal pain may be severe
especially those younger than 2 years of age enough to mimic acute appendicitis. The diar-
(170). In underdeveloped countries, asymp- rhea may be watery or bloody. White blood cells
tomatic infection is common in both children are identifiable in the stool. Symptoms usually
and adults, whereas in developed countries, resolve within a week, with or without treatment,
asymptomatic infection is uncommon. but they persist from 1 to 3 weeks in about 20
Etiology. Campylobacter organisms (from the percent of patients. Recurrences or chronic
Greek "curved rod") are Gram-negative, spiral, symptoms occur, particularly in infants (181).
highly motile bacteria. Numerous Campylo- Human immunodeficiency virus (HIV) -
bacter species exist, however, the vast major- infected patients typically develop persistent,
ity of cases (over 95 percent) are caused by C. severe C. jejuni infections that require prolonged
jejuni and C. coli (180,187,188). A number of antimicrobial therapy; these patients are more
additional species cause disease in humans likely to develop bacteremia than non-HIV pa-
(183,184,186-189,199). tients. The organism fails to clear because of the
Pathophysiology. Once ingested, organ- underlying immunodeficiency and the bacteria
isms that survive the gastric acid reach the tend to become antibiotic resistant (176,190).
bile-rich microaerobic upper small intestine, Local complications of Campylobacter infec-
an environment that promotes their growth. tions occur as a result of direct spread of the
Campylobacter organisms are thought to pro- organisms from the gastrointestinal tract, and

407
Gastrointestinal Diseases

include cholecystitis, pancreatitis, and peri- other forms of bacterial enterocolitis. Unlike
tonitis. Massive gastrointestinal hemorrhage chronic ulcerative colitis, the changes tend to
may occur. Extraintestinal disease is rare, but be segmental in nature. Poorly formed muco-
includes meningitis, endocarditis, septic arthritis, sal granulomas may be present, suggesting the
osteomyelitis, and sepsis. Postinfectious Guillain- diagnosis of Crohn's disease, however, suppura-
Barre syndrome develops in 1 to 2 infected per- tive foci in the granulomas distinguish Campy-
sons/100,000 in the United States (170). lobacter infection.
Gross Findings. Campylobacter causes both Treatment and Prognosis. Complications,
small and large intestinal disease. Jejunallesions including sepsis, meningitis, toxic megacolon,
are more common than those occurring in the pseudomembranous colitis, massive gastroin-
ileum or colon. In fatal cases, the jejunum and testinal hemorrhage, arthritis, endocarditis, and
ileum are always affected. A patchy, bloody, genital and urinary infections occur rarely and
edematous, erythematous enterocolitis devel- tend to affect debilitated persons. Campylobacter
ops, characterized by multiple, superficial ulcers infections occurring during pregnancy are as-
measuring up to 1 cm in diameter. The ulcers sociated with spontaneous abortions, stillbirths,
sometimes develop over the Peyer patches. The prematurity, and neonatal sepsis.
normal vascular pattern disappears. The ap- Guillain-Barre syndrome complicates Campy-
pendix and lymph nodes may also be involved. lobacter infections and results from cross-reac-
Severe cases resemble severe ulcerative colitis tivity between neural and C. jejuni antigens
with pancolitis, toxic megacolon, and colonic (201). The bacterial gene NeuB encodes a surface
perforation (182). molecule on C. jejuni that is antigenically similar
Microscopic Findings. The histologic fea- to a ganglioside found in high concentrations
tures of Campylobacter infection resemble those in the nervous system. This close resemblance
seen in other infections and range J:rom mild tricks the immune system into attacking ner-
mucosal edema and increased cellularity of vous tissue as well as the invading bacteria.
the lamina propria to full-blown acute colitis The immune system produces antibodies that
(175,193). In the small intestine, mucosal con- cross-react with peripheral nerves, thereby
gestion, inflammation, edema, neutrophilic damaging them.
infiltrates, goblet cell depletion with cryptitis, Most patients recover fully from their infec-
crypt abscesses, and hemorrhagic necrosis are tion, either spontaneously or after antibiotic
seen. The ulcer bases are acutely i:'nflamed, with therapy. When antibiotics are indicated for
granulation tissue and prominent vascularity the treatment of Campylobacter enteritis, eryth-
but little fibrosis. Architectural villous changes romycin or a fluoroquinolone such as cipro-
include broadening, distortion, flattening, and floxacin is the drug of choice (170).
atrophy. The histologic features of Campylo-
Clostridium Difficile Infections
bacter appendicitis and colitis are mucosal infil-
tration by polymorphonuclear leukocytes and Demography. Clostridium dif{lcile is present
eosinophils, crypt abscesses, mucosal edema, in normal colonic flora in 2 to 5 percent of the
and histiocytic colle~tions that may resemble general population, but its prevalence increases
granulomas. The Warthin-Starry stain may in hospitalized individuals (224). Colonization
highlight the curved rods of Campylobacter. rates increase in the elderly, and are probably
Special Techniques. Since biopsy findings dependent on the use of antibiotics and the
are nonspecific, bacterial culture or other diag- amount of time spent in institutions such as
r. ,· nostic techniques are necessary to establish the nursing homes or hospitals (223) . C. dif{lcile is
exact diagnosis. The diagnosis of Campylobacter the most frequent cause of nosocomial diarrhea,
infection is usually established by isolating developing in as many as 1 percent of hospital-
the organism from the stool. A simple rapid, ized patients receiving antibiotics (212,218).
specific, and sensitive approach to strain dif- The hospital environment is variably contami-
ferentiation is DNA hybridization. nated with the organism (20 to 70 percent of
Differential Diagnosis. Campylobacter infec- sampled sites) (224). Heat-resistant C. dif{lcile
tions clinically mimic appendicitis, IBD, and spores persist in the environment for months,

408
Gastrointestinal Infections

so that the organism can be cultured from many epithelial cell damage. After binding to the
items commonly used in hospital rooms or cell, toxin A is internalized, causing secondary
wards where patients with C. difficile-associated cytoskeletal changes of cell contraction, round-
diarrhea have been recently treated. C. difficile ing, and nuclear migration (211). The cellular
organisms have also been isolated from domesti- rounding enhances the permeability of the mu-
cated animals including horses, cows, pigs, dogs, cosal barrier, exposing the deeper cell layers to
and cats, although no evidence exists to suggest the luminal toxins. The cellular injury results in
that C. difficile infection represents a zoonosis. recruitment of neutrophils to the site. Toxin A
Etiology. C. difficile is a Gram-positive, spore- binding also triggers mediator release from the
forming, anaerobic bacillus that causes a spec- basolateral aspects of the enterocytes thereby
trum of diseases ranging from an asymptomatic altering tight junction permeability and cyto-
carrier state to full-blown pseudomembranous skeletal structure, and damaging the mucosal
colitis. C. difficile-associated diarrhea usually barrier. Toxin B also binds to specific enterocyte
follows antibiotic use. Clindamycin, ampicillin, receptors and stimulates chemokine release from
and the cephalosporins are most commonly macrophages, leading to hemorrhagic necrosis,
associated with the disease, but virtually any fluid secretion, and altered smooth muscle func-
antibiotic may produce it. Chemotherapeutic tion. Toxin B is approximately 1,000 times more
agents cause C. difficile-associated colitis (209). potent than toxin A (205). Both ultimately in-
Pathophysiology. The colon normally con- duce apoptosis in infected cells (210,216).
tains a lush commensal bacterial population Clinical Features. Patients with C. difficile
that keeps pathogenic bacteria at bay. Agents infections exhibit various clinical manifesta-
such as antibiotics, which alter the normal eco- tions ranging from an asymptomatic carrier
logical balance, predispose the colon to C. diffi- state to fulminant colitis with bloody diarrhea,
cile infection. Factors that determine whether or transmural inflammation, and necrosis. The
not a patient develops the infection include: 1) most severe forms of the disease are the least
the nature of the fecal flora; 2) whether the flora common. In adults, C. diffi'C ile infection usually
is disrupted by antibiotics, other medications, or causes mild to moderate diarrhea, sometimes
medical procedures; 3) the size of the C. difficile accompanied by lower abdominal cramps. The
population (a reflection of a loss of the mucosal average symptom duration is 8 to 10 days (204)
protective barrier of normal flora); 4) cytotoxin and the incubation period in early onset disease
production; 5) the presence of virulence fac- ranges from 1 to 10 days after the inciting an-
tors; 6) other organisms that affect C. difficile tibiotic is started. More frequently, symptoms
toxin expression or activity; 7) the presence of may be delayed for 2 to 6 weeks following
predisposing host risk factors, such as advanced antibiotic discontinuance (late onset disease).
age, severe underlying illness, immune status, C. difficile toxins are present in the stool at this
and a prolonged hospital stay; and 8) the use of time, but endoscopic and histologic findings are
enemas, gastrointestinal stimulants, and stool frequently normal in patients with mild disease.
softeners (217). In severe cases, diarrhea can occur 20 to 30
C. difficile produces two exotoxins, classically times/day and can last up to 2 to 3 months if
referred to as A and B, which cause both the not treated. Patients with severe colitis with-
diarrhea and the colitis. Nontoxigenic bacte- out pseudomembrane formation present with
rial strains are not pathogenic. The two toxins profuse debilitating diarrhea, abdominal pain,
are encoded on a pathogenicity locus on the abdominal distension, and toxic megacolon.
bacterial DNA. Both toxins A and B are large, Common systemic manifestations include fever,
single-chain peptides, measuring 308 kDa and nausea, anorexia, malaise, and dehydration. Pe-
270 kDa, respectively (202). The two toxins are ripheralleukocytosis and increased numbers of
SO percent homologous at the amino acid level, fecalleukocytes are common (213,224). Patients
and have similar primary structures. Both tox- may experience occult colonic bleeding; rarely,
ins bind to cells, entering them by endocytosis frank hematochezia develops.
(222). Toxin A binds to a glycoprotein receptor The most dramatic form of the disease, pseu-
on brush border membranes, causing direct domembranous colitis, clinically resembles C.

409
Gastrointestinal Diseases

Figure 10-6
PSEUDOMEMBRANOUS COLITIS
Left: Multiple foci of adherent yellow-green pseudomembrane in a patient with C. difticile pseudomembranous colitis.
Right: In another patient, a large area of tHe mucosa is covered by an attached pseudomembrane.

difticile colitis without pseudomembranes ex- sis, neutrophilic infiltrates, and an edematous
cept that the diarrhea, abdominal tenderness, lamina propria. Pseudomembrane formation is
and systemic manifestations are rr!"ore severe. initiated by epithelial breakdown and eruption
Megacolon develops as intestinal muscular tone of the exudate into the intestinal lumen. The
disappears, resulting in a paradoxical decrease linear deposition of neutrophils and Gram-posi-
in the diarrhea. Other changes that can occur tive sporulating bacilli within the fibrin strands
with C. difticile infection include protein-losing and mucus imparts an almost pathognomonic
enteropathy and HUS. appearance (fig. 10-7).
Gross Findings. The gross and endoscopic Type II lesions are better developed and
features of C. difticile colitis reflect d.isease sever- consist of well-demarcated groups of disrupted
ity. Patients with mild disease may lack gross crypts that lose their superficial epithelial lining
abnormalities or show only a patchy colitis. and become distended by mucin, neutrophils,
Patients with early pseudomembranous coli- and eosinophils. The epithelial damage extends
tis have 2- to 10-mm, raised, yellowish white into the lower crypts as the process continues.
plaques with erythematous bases that are sepa- The changes resemble those found in ischemic
rated by a normal or only mildly edematous or colitis. Fibrin thrombi may be found in super-
erythematous mucosa (fig. 10-6). Patients with ficial mucosal capillaries. Focal mushroom-
severe disease may have coalescing mucosal shaped or volcanic pseudomembrane eruptions
plaques covering large mucosal areas. Edema, attach to the necrotic mucosa. The pseudo-
blurring of the vascular pattern, and thickening membranes contain epithelial debris, red blood
and blunting of the haustral folds develop. The cells, fibrin, mucus, and inflammatory cells. The
lesions are most prominent in the large intestine changes are patchy in nature and the mucosa
but the distal small bowel (214) and even the between the individual pseudomembranes of-
appendix (207) occasionally become involved. ten appears normal.
Microscopic Findings. The histologic fea- Type Ill lesions show complete structural
tures of C. difticile colitis reflect the disease stage. mucosal necrosis with only a few surviving
C. difticile can produce a wide range of muco- glands covered by cellular inflammatory debris,
sal appearances, sometimes exhibiting only mucin, and fibrin. The edematous, congested,
congestion and edema or nonspecific colitis. and hemorrhagic lamina propria bulges into
Only slightly more than 50 percent have classic the intestinal lumen. Marked mural edema ex-
pseudomembranous lesions (220). tends into the muscularis propria. There may be
Type I lesions of pseudomembranous colitis transmural colonic inflammation with massive
(the earliest lesions) show focal epithelial necro- mural edema and even toxic megacolon (206) .

410
Gastrointestinal Infections

Figure 10-7
PSEUDOMEMBRANOUS COLITIS
A: A thick pseudomembrane adheres to the colonic mucosa.
B: The exudate erupts from areas of mucosal erosion in a pattern that has been described as resembling lava erupting
from a volcano.
C: Neutrophils and fibrin form the pseudomembrane that covers the mucosal surface. The neutrophils demonstrate a
linear alignment within the fibrin that exudes from areas of erosion.
D: On higher power, the crypt damage resembles ischemic injury. The epithelium lining some crypts is flattened and
regenerative. The lamina propria is edematous and contains numerous acute inflammatory cells. Cryptitis and crypt abscesses
are present.

Rarely, signet ring cells are found in colonic isolation of the organism and detection of the
biopsies of patients with toxic megacolon result- specific bacterial toxins. C. difticile is a fastidious
ing from pseudomembranous colitis (219, 221). anaerobic bacterium that must be cultured in
These degenerating cells are usually confined anaerobic conditions quickly. Failure to culture
within the basement membrane of the crypts C. difticile organisms from individuals who are
without infiltrating other tissues, a feature that infected may result from delays in specimen
can be highlighted with pancytokeratin immu- transport and processing. Since bacterial cul-
nostains. The nuclei of the signet ring cells are tures detect all C. difticile colonies irrespective of
not enlarged but have uniform chromatin and their pathogenicity, the colonies must be tested
inconspicuous nuclei. for their toxin production. If pseudomembranes
Special Techniques. The laboratory diag- are identified endoscopically, stool specimens
nosis of C. difticile is based on microbiological should be sent for C. difticile toxin analysis and

411
Gastrointestinal Diseases

Table 10-6
DIFFERENCES BETWEEN ISCHEMIA AND BACTERIAL ENTEROCOLITIS

Feature Ischemia Bacterial Ent~rocolitis

Focal process Often Sometimes


Pseudomembranes Common Present in Clostridium difficile infectio n
Mucosal changes of chronicity Sometimes No
Hemosiderin-laden macrophages in lamina propria Common No
Inflammation extending into submucosa Common Common
Crypt abscesses No Sometimes
Glandular ghosts Yes Yes
Granulomas No Usually no, but are seen in Yersinia infection
Atrophic microcysts Common No
Lamina propria fibrosi s Common No
Basal plasmacytosis No No
Mesenteric vessels May be abnormal Normal

.
biopsies should be obtained in orqer to confirm Treatment and Prognosis. A number of
the diagnosis. Testing for either toxin A or B strategies have been used to treat or prevent C.
results in misdiagnosis more frequently than difticile-associated disease: 1) discontinuation of
testing for both toxins (215). - the inducing agent; 2) use of antibiotic therapy
Differential Diagnosis. Clinically, other dis- directed against C. difticile; 3) use 'of resin to
eases that may mimic C. difticile colitis include bind the toxins; 4) replacement of the normal
other infections, an acute episode of a chronic colonic flora; and 5) use of probiotics to prevent
condition, drug reactions, or cm;nplications of the initial infection. For uncomplicated diar-
procedures. Infections that clinically resemble rhea, a conservative approach is recommended,
C. difticile colitis include those ..caused by Shi- including cessation of the inciting antibiotic and
gella, Salmonella, Campylobacter, Candida, E. coli oral rehydration to compensate for fluid loss. In
(0157:H7), amoebae, fungi, and viruses. Pa- patients with moderate diarrhea, metronidazole
tients with chronic conditions such as Crohn's or vancomycin may eradicate the organism.
disease, diverticulitis, and ischemia have acute Vancomycin therapy, however, is associated with
episodes of diarrhea that clinically resemble C. disease relapse and there is increasing vancomy-
difticile infection. cin resistance. Metronidazole may be preferred to
Histologically, the two major entities in the reduce the risk of vancomycin resistance among
differential diagnosis are ischemic colitis and other organisms in hospitals. Anion exchange
severe IBD. When :rimcosal necrosis becomes resins (colestipol) and cholestyramine can bind
confluent, it may be impossible to distinguish C. toxins A and B but estimates of the effectiveness
difticile colitis from other forms of severe colitis of these agents are currently unclear (203). When
associated with extensive necrosis. Pseudo- severe, pseudomembranous or fulminant colitis
membranous colitis due to C. difticile exhibits a requires surgical resection to avoid perforation.
more patchy distribution than ulcerative colitis Some studies suggest that concurrent antibiotic
and the rectum may be spared. Secondary infec- and probiotic treatment may prevent the develop-
tions can complicate ischemic injury and, con- ment of antibiotic-associated diarrhea (208).
versely, bacterial toxins may cause thrombosis Symptoms recur in 7 to 20 percent of patients
and secondary ischemic damage, so that it may due to both relapse and reinfection. Over 90
be impossible to differentiate between ischemia percent of first recurrences can be treated suc-
and bacterial toxin-induced injury. Ways to dif- cessfully in the same manner as initial cases.
ferentiate the two are listed in Table 10-6. Combination treatment with vancomycin plus

412
Gastrointestinal Infections

rifampin or the addition of the yeast Saccharo- therapy damages the gastrointestinal mucosa
myces boulardii to vancomycin or metronidazole by destroying the rapidly dividing epithelium.
treatment may prevent subsequent diarrhea in Alternatively, neoplastic infiltrates may cause
patients with recurrent disease (212). breaks in the mucosal barrier. Loss of mucosal
Prevention. An important aspect of the treat- integrity, when coupled with the neutropenia,
ment and prevention of C. difficile infection is allows bacteria to invade the bowel wall and
infection control using measures designed to sepsis to develop. Ischemia also undoubtedly
prevent horizontal transmission. The preven- plays a role in the genesis of the lesion. Isch-
tion of nosocomial spread requires patient isola- emia likely results from vascular invasion by
tion and enforced hand washing. It also includes bacteria and the development of disseminated
the use of gloves in handling body substances intravascular coagulopathy. Other causes of
and replacement of electronic thermometers ischemia include perivascular neoplastic infil-
with disposable devices. The most successful trates, episodes of hypotension following sepsis,
control measure directed at reduction in symp- and mucosal hemorrhage complicating severe
tomatic disease is antimicrobial restriction. thrombocytopenia.
Clinical Features. Neutropenic enterocolitis
Clostridium Septicum Infections
affects both children and adults. Most patients
Demography. C. septicum infections are are profoundly neutropenic (less than 1,000
rare but are often associated with serious if not cells/mm3 ). Patients are typically neutropenic
fatal outcomes. They are not associated with for at least a week before symptom onset (232).
a single specific defect in cellular or humoral Patients usually present with a dramatic onset
immunity, but can be seen in patients with of fever, watery or bloody diarrhea, right upper
multiple medical problems, including leukemia, quadrant pain, abdominal distension, rebound
solid tumors, cyclic neutropenia, diabetes mel- tenderness, nausea, and vomiting. The presence
litus, and severe arteriosclerosis (225,228,231). of fever, rigors, and shock suggest the develop-
The incidence of neutropenic enterocolitis is ment of sepsis or colonic perforation. The dis-
increasing, particularly in patients with acute order is often fatal unless aggressively treated,
myelogenous leukemia who undergo high-dose usually by resection of the involved bowel
cytosine arabinoside chemotherapy. segment. Because infected patients receive an-
Etiology. C. septicum is a rod-shaped, spore- tibiotic therapy, they may have a coexisting C.
forming, saprophytic, anaerobic, Gram-positive difficile antibiotic-associated colitis. Mortality
bacterium that grows well on devitalized tissues rates range from 5 to 100 percent and average
with a low pH because the latter provide the 40 to 50 percent (233). Death results from cecal
perfect environment for clostridial spore germi- perforation, bowel necrosis, and sepsis.
nation (227). They also grow well in the cecum. Gross Findings. The lesions of neutropenic
Pathophysiology. The marked pathoge- enterocolitis center around the terminal ileum
nicity of the organism is related to its lethal and right colon, and consist of patchy areas of
alpha-toxin. It becomes pathogenic during transmural edema and necrosis. The process
neutropenia when protease levels are too low preferentially involves the cecum due to the
to neutralize the toxin (226). The production of luminal stasis that occurs at this site. Rarely,
bacterial exotoxins or other bacterial virulence other bowel segments become involved. Some
factors further damages the mucosa and leads patients develop pneumatosis intestinalis.
to necrosis of the bowel wall. The organism Abdominal computerized tomography (CT)
also produces a number of enzymes, including and ultrasound are not only useful in evaluat-
fibrinolysin, deoxyribonuclease, and several ing patients with neutropenic colitis, but are
hemolysins that increase its ability to aggres- preferable to contrast enemas, since the bowel
sively invade tissues (229). This also leads to is often massively dilated, very fragile, and likely
bowel wall necrosis and ischemia. to perforate if contrast medium is inserted into
Other factors that play a role in the pathogen- its lumen. CT findings include symmetrical
esis of the disease are neutropenia and mucosal bowel wall thickening, pericecal inflammation,
barrier damage due to chemotherapy. Chemo- and, if perforation has occurred, a mass.

413
Gastrointestinal Diseases

and degeneration of the muscularis propria


(fig . . 10-10). Vascular damage produces subtle
or profuse intramural and intraluminal hemor-
rhages, and fibrin thrombi are often present in
the submucosal vessels. Additionally, changes
characteristic of chemotherapeutic injury, in-
cluding prominent apoptosis in the crypts, fo-
cal crypt dropout, arid glandular regeneration,
are often present (fig. 10-9). There is a striking
paucity of inflammatory cells, despite the de-
gree of mucosal damage, and neutrophils are
absent. The absence of neutrophils in the face
of significant cell injury confirms the diagnosis
Figure 10-8 of neutropenic enterocolitis.
COLONIC RESECTION SPECIMEN FROM
Differential Diagnosis. C. septicum is the
A PATIENT WITH NEUTROPENIC ENTEROCOLITIS major cause of neutropenic enterocolitis; how-
The colonic mucosal surface appears utcerated and ever, other organisms can cause the disease.
focally hemorrhagic. There is marked edema. In children, the infections usually result from
Pseudomonas or E. coli, whereas in adults C.
septicum is the usual infecting organism. The
The gross features of neutropenic enteroco- histologic features overlap with those of C.
litis vary due to the influence of the multiple difticile-associated pseudomembranous colitis.
etiologic factors. The changes range from areas Unlike the traditional pseudomembranous
of mucosal erythema and hemorrhagicnecrosis colitis associated with C. difticile in which there
with moderate degrees of edema to severe trans- are large numbers of neutrophils pres~]lt in the
mural edema and diffuse hemorrhagic necrosis exudate, patients with neutropenic enterocolitis
(fig. 10-8). In some patients, the hemorrhagic lack a neutrophilic infiltrate. The features also
features predominate, whereas in others, the overlap with ischemic enterocolitis and infec-
edema predominates. Usually, the bowel ap- tious enterocolitis, but the absolute lack of
pears markedly thickened, edematous, and neutrophilic infiltrates only occurs in ischemia
dusky, with scattered serosal eccHYmoses. The prior to reperfusion injury.
mucosa often appears beefy red, eroded, and Treatment and Prognosis. Mortality ap-
ulcerated. Pseudomembranes develop, probably proaches 100 percent if care is not rendered
from the accompanying ischemia. within 12 to 24 hours (230). Patients may
Microscopic Findings. Histologically, there develop secondary infections that complicate
is evidence of transmural edema, necrosis, and the histologic picture; the most common are
microbial invasion with a minimal cellular re- infections due to C. difticile, Candida, or CMV.
sponse (fig. 10-9). Severe necrotizing colitis is Clostridium Perfringens and
associated with markeo edema, vasculitis, and Clostridium We/chii Infections
stromal hemorrhage with patchy to complete
epithelial necrosis. Degenerated epithelial cells Demography. C. perfringens is a widely oc-
detach from the basement membrane and lie curring pathogenic bacterium readily found
within dilated glandular lumens. This process in soil and in the intestines of humans and
starts superficially and progressively involves animals (242). It is associated with outbreaks of
the remainder of the crypt, frequently extend- foodborne diarrhea, as well as with antibiotic-
ing to the base and producing the glandular associated diarrhea (234,235,245,248,254,259).
dropout typical of ischemia. The mucosa be- C. perfringens infections tend to affect the elderly,
comes variably ulcerated and a pseudomem- and often result in hospitalization (234,245,259).
brane containing fibrin and necrotic cellular In Papua, New Guinea and several other
debris covers the luminal surface. In severe developing countries, C. perfringens and C.
cases, the bowel exhibits transmural necrosis welchii cause a segmental, necrotizing enteritis

414
Gastrointestinal Infections

A
Figure 10-9
NEUTROPENIC ENTEROCOLITIS IN A PATIENT UNDERGOING TREATMENT FOR LEUKEMIA
A: Prominent submucosal edema.
B: The colonic mucosa is also edematous, and shows gland dropout secondary to chemotherapy for leukemia.
C: Higher-power magnification depicts the regenerative glands and lamina propria. A fibrin thrombus occludes a mucosal
vessel. No neutrophils are identifiable.

sometimes referred to as "pigbel." This disease af- following consumption of food contaminated
fects children who are chronically malnourished, with enterotoxin-producing C. perfringens.
and is commonly associated with ingestion of The contaminated food is almost always heat-
large quantities of contaminated protein-rich treated, which kills competing bacteria but not
foods as occurs at feasts. In rare instances, it is the spores of C. perfringens. Type C C. perfrin-
encountered in developed countries, where the gens causes necrotizing enteritis. The disease is
infection is generally confined to individuals mainly due to production of the ~-toxin with
with severe chronic illnesses (240,250,252,260). contribution from o- and 8-toxins (239,243).
Etiology. C. .perfringens is a Gram-positive, Pathophysiology. Food poisoning due to
nonmotile, straight rod with blunt ends, that C. perfringens results from the action of the
occurs singly or in pairs. C. perfringens can pro- clostridial enterotoxin (CPE). CPE is capable of
duce over 13 different toxins, although each forming cation-permeant pores in the apical
bacterial strain produces only a subset of the cell membranes of intestinal epithelial cells in
total (251). The production of four major lethal culture (241). This action most likely accounts
toxins, designated a, ~~ E:, and 1, are used to type for the diarrheagenic properties of the toxin.
isolates A toE (Table 10-7) (237,244,257,258). Necrotizing enteritis results from ingestion
C. perfringens type A is associated with self- of organisms capable of producing the C.
limited foodbome diarrhea. The disease occurs perfringens ~-toxin. This toxin is inactivated

415
Gastrointestinal Diseases

Figure 10-10
NEUTROPENIC ENTEROCOLITI S IN A PATIENT WITH
RHEUM ATOID ARTHRITIS AND FELTY'S SYNDROME
A: The transmural area of necrosis led to small bowel
perforation.
B: Higher-power view taken from the edge of the ulcer.
Numerous bacteria lie in the luminal debris and invade the
necrotic tissues.
C: There is an absence of neutrophils in the ulcerated
area.

\ .....
,.,\.

I •
':.
.- . • g ~
. i? '' ...
,.,~ .. 'c.~ ·,

..:· ,,

Table 10-7
TOXINS PRODUCED BY CLOSTRIDIUM PERFRINGENS
C. Perfringens Type a-Toxin ~ -Toxin e-Toxin t-Toxin Enterotoxin
A + +
B + + + +
c + + +
0 + + +
E + + +
Gene plc cpbl, cpb2 etx iap, ibp cpe
Genetic location Chromosome Plasmid Plasmid Plasmid Plasmid/chromosome

...
rapidly in the gastrointestinal tract by trypsin. development of necrotizing enteritis, is as-
Therefore, another important factor in the sociated wit h decreased trypsin activity and
pathogenesis of the disease is the presence further predisposes to the disease (238,246,247,
of trypsin inhibitors that prevent intestinal 250,255,257). In addition, sweet potatoes, an
degradation of the toxin and reduce intestinal important dietary staple in areas where pigbel
motility, thereby favoring stasis and local toxin is endemic, contain trypsin inhibitors that
accumulation (257). Protein malnutrition, a further contribute to disease development (246,
factor that is commonly associated with the 247,253).

416
Gastrointestinal Infections

Clinical Features. C. perfringens type A food becomes infiltrated with polymorphonuclear


poisoning develops 8 to 12 hours after eating leukocytes, mononuclear cells, and eosinophils.
contaminated food. Symptoms include abdomi- Arterial walls appear edematous and infiltrated
nal pain, nausea, and diarrhea. The disease is by inflammatory cells, and demonstrate fibri-
generally self-limited, lasting approximately 24 noid necrosis. If the patient survives, areas of
hours. Elderly or very young patients may die scarring develop due to extensive and deep
of the disease, usually secondary to dehydra- disease. Pneumatosis and pseudomembranes
tion (236). may be present.
Patients with necrotizing enteritis present Special Techniques. C. perfringens organisms
with severe, progressive abdominal pain, vomit- may be identified as a result of their ability to re-
ing, diarrhea, progressive dehydration, blood- duce nitrate; ferment glucose, lactose, maltose,
stained feces, and finally, constipation lasting sucrose, and other sugars; and liquefy gelatin.
for several days. The necrotic bowel predisposes Primers specific for the clostridial cpa and cpb
to midgut volvulus, jejuna! and ileal ileus, and genes can help diagnose the infection (252).
other forms of small bowel strangulation Differential Diagnosis. The histologic fea-
(249,250). Occasionally, C. perfringens is respon- tures of clostridial infection overlap with those
sible for the genesis of suppurative gastritis or seen in neutropenic enterocolitis and ischemia.
pneumatosis intestinalis. Neutropenic enterocolitis can be distinguished
Gross Findings. Clostridial necrotizing en- from necrotizing enteritis by the absence of
terocolitis variably affects the upper jejunum, neutrophils in the former and their presence in
ileum, and colon. The duodenum is only mini- the latter. The changes cannot be distinguished
mally involved. In approximately 25 percent of from ischemia purely on histologic examination.
cases, one or more yellowish serosal patches are Treatment and Prognosis. Clostridial food
present, corresponding to areas of full-thickness poisoning requires no specific treatment since
infarction. These areas are paper thin and fri- the disease is usually self-limited. Fluid and
able, and balloon outward; therefore, they tend electrolyte replacement should be provided as
to perforate. The affected bowel becomes dilat- needed. Necrotizing enteritis often requires sur-
ed, edematous, thickened, rigid, and markedly gical intervention for resection of necrotic seg-
congested, with a reddened serosal surface. The ments of bowel. Even with treatment, as many
small intestinal valvulae conniventes become as one quarter of patients die of the disease (256).
very prominent, imparting a "washboard" ap-
Vibrio Infections
pearance to the mucosal surface. As the necrotic
mucosa sloughs, extensively ulcerated areas Demography. Vibrio is a motile, Gram-neg-
remain that may extend into the underlying ative, curved, rod-shaped bacterium that lives
muscularis propria. in marine or brackish water. Vibrio-associated
Microscopic Findings. In resection speci- illnesses, therefore, tend to occur in coastal
mens, the histologic features of necrotizing areas in the summer and fall when the wa-
enterocolitis resemble those found in ischemic ter is warm and bacterial counts are highest
injury. The small intestine from the duodenum (261-263). Cholera occurs in relatively localized
to the cecum shows segmental ischemic necro- epidemics, usually in developing countries.
sis, starting at the villus tips and progressing The disease is endemic in southern Asia, parts
toward the base. The mucosa appears severely of Africa, and Latin America. Cholera is also
necrotic and hemorrhagic. Mural thickening becoming endemic along the Gulf Coast (274)
results from marked submucosal edema. Fibrin and Chesapeake Bay area of the United States. It
thrombi are often present in the inflamed ar- is estimated that 5 to 7 million cases of cholera
eas. The mucosa lying between the thickened occur each year worldwide, resulting in over
valvulae may appear variably normal, whereas 100,000 deaths (272) . In the United States,
the surface of the valvulae appears damaged. A cholera is associated with the consumption of
clearly defined junctional zone exists between raw oysters and clams, or improperly cooked
the necrotic and non-necrotic tissues, as in seafood (262,271). In other countries, cholera is
other forms of ischemic injury. The mucosa associated with drinking contaminated water or

417
Gastrointestinal Diseases

eating contaminated shrimp, cockles, mussels, spectrum of cholera varies from asymptomatic
clams, and dried fish. carriers to patients with voluminous diarrhea
Etiology. Cholera is caused by the Gram- that kills within hours of onset. In the acute
negative bacterium Vibrio cholerae. The species phase of the disease, the water secretion from
includes at least 206 different serogroups, of the small intestine is greater than the ability of
which only the 01 or 0139 serogroups cause the colon to absorb the water loss. Daily outputs
the disease (265). Other Vibrio species also cause of 15 to 20 L of fluid have been observed when
gastrointestinal disease including V. vulnificus adequate fluid replacement is given. The severity
and V. hollisae. of the disease is related to many factors including
Pathophysiology. Pathogenic V. cholerae inoculum size, biotype of the infecting organism,
organisms carry a set of virulence genes that and absence of preexisting immunity (272).
is required for pathogenesis in humans. These V. Vulnificus Infection. Three major clinical syn-
genes include those encoding the cholera toxin, dromes result from infection with V. vulnificus:
a colonization factor referred to as toxin eo- primary septicemia, wound infections, and gas-
regulated pilus (TCP), and a regulatory protein, trointestinal illness without septicemia or wound
ToxR, that coregulates the expression of cholera infection (268). Acute diarrhea is the usual symp-
toxin and TCP (266). The genes for the cholera tom of gastrointestinal illness. The disease is char-
toxin reside within a lysogenic phage (CTx) inte- acterized by a 24-hour incubation period followed
grated into the bacterial chromosome (276). The by the sudden onset of septicemia, fever, chills,
CTx phage is capable of horizontal transfer to hypotension, nausea, vomiting, bloody diarrhea,
non toxin producing V. cholerae strai-ns provided and rash. The symptoms and duration are not as
the recipient bacterium expresses ·TCP, which severe as in cholera. The skin lesions consist of
acts as the phage receptor. Other potential viru- large hemorrhagic bullae that progress to necrotic
lence factors have been identified and include ulcers. Although the infection is uncommon, the
HA protease, RTX toxin, Vac a-like toxin, and mortality rate is as high as 50 percent. ,.
the CTx~ structural proteins, Ace and zonula V. Hollisae Infection. V. hollisae causes severe
occludens toxin (270). gastroenteritis (264) .
Vibrio organisms enter the small intestine Gross Findings . Gross specimens are usu-
where they begin to express low levels of TCP, ally only seen at the time of autopsy in those
presumably in response to an as yet unidentified who die of cholera. The bowel appears slightly
luminal factor. Expression of TCP"'allows the or- edematous and only mildly abnormal. The in-
ganism to adhere to the intestinal epithelium. A testinal mucosa appears intact.
second environmental signal induces increased Microscopic Findings. Because most cases
expression of TCP, increased colonization of are examined at the time of autopsy, autolysis
the intestinal mucosa, and production of the can be confused for cholera-induced effects.
cholera enterotoxin (269) . Biopsy results show that the mucosa remains
Cholera enterotoxin, the prototype for secre- intact, even during the active stages of the
tory enteritis and toxigenic diarrhea, has a direct disease (267) . Histologic changes include dam-
secretory effect on crypt cells. This results in age to the surface and/or crypt epithelium,
the most overwhelming feature of cholera, ex- epithelial regeneration, altered mucin secretion,
treme fluid loss resulting in "rice-water" stools. and mucosal hyperemia and edema. Dilated
The toxin enters the intestinal epithelial cell intestinal crypts appear mucus depleted and
through the apical cell membrane by means of if goblet cells are present, they appear empty.
a complex mechanism, and ultimately activates The lamina propria exhibits mild edema and
adenylyl cyclase on the basolateral cell mem- vascular dilatation. Occasional inflammatory
brane. This results in massive salt and water cells are present but significant inflammation is
efflux from the intestinal mucosa with resultant absent. The mildness of the histologic features
watery diarrhea (270). is in marked contrast to the clinical features.
Clinical Features . V. Cholerae Infection. Correlation with microbial, immunological, and
Incubation periods range from 6 to 48 hours; clinical information is critical to establishing
most patients recover in 2 to 7 days. The clinical the appropriate diagnosis.

418
Gastrointestinal Infections

Treatment and Prognosis. Cholera is a lead- contrast, adults tend to present with a more
ing cause of death in some parts of the world. chronic disease associated with vomiting and
The large volume fluid depletion associated with abdominal cramps (282,297,304). The mean
the massive diarrhea leads to acidosis and renal duration of illness and length of hospitalization
failure. Death can occur within 3 to 4 hours of is longer in infants aged 2 to 6 months than
disease onset, with fecal outputs exceeding ILl at other ages. The spectrum of gastrointestinal
hour at the height of the disease. Untreated, diseases ranges from a self-limited diarrhea to
the mortality rate ranges between 50 and 75 acute persistent dysentery (291,300). The most
percent (272,275). Proper rehydration decreases common symptom is diarrhea, followed by ab-
the mortality rate to less than 1 percent (273). dominal cramps and pain, fever, and vomiting.
The disease may result in dehydration, acide-
Aeromonas Infections
mia, and azotemia. The duration of the illness
Demography. Aeromonas is ubiquitous in is usually more than 10 days (302).
fresh and brackish water; soil; foods including Gross Findings. The gross findings of Aero-
meats, fish, and vegetables; and in the intestines monas infection resemble those of other forms
of apparently healthy humans (289). Infections of bacterial enterocolitis. Sigmoidoscopy reveals
usually occur during the summer months (278) a friable mucosa, sometimes with frank ulcer-
and are acquired via consumption of infected ation, associated with acute proctosigmoiditis.
water (288,291), trauma involving soil expo- Microscopic Findings. Histologic changes
sure, or minor trauma sustained while cleaning range from alterations that resemble celiac
aquariums, snorkeling, or handling fish (292). disease, to edema and a plasmacytosis of the
Transmission of infection via infected food as lamina propria, to the presence of a full-blown
well as human-to-human transmission probably enterocolitis with acute and chronic inflam-
also occur (280,293,298). The organism most matory cells in the lamina propria and frank
commonly affects young children (302), and has abscesses. The changes resemble those found
been isolated from acute diarrheal outbreaks in in other forms of bacterial colitis.
daycare centers (285). The organism can also be Special Techniques. The diagnosis is made
isolated from patients with traveler's diarrhea by microbial culture of the stool or tissues.
(286,301). Aeromonas species are also commonly Differential Diagnosis. The differential diag-
isolated from healthy humans, and therefore nosis includes other acute colitides, including
their role in the causation of diarrheal illness infections and ulcerative colitis.
remains somewhat controversial. The difficulty Treatment and Prognosis. Treatment with
in definitively determining their pathogenic sulfamethoxazole and trimethoprim results in
role results from the fact that so many species clinical improvement.
and subgroups of the organism exist, and only
Plesiomonas Infections
a small proportion represent pathogens (295).
Pathophysiology. Aeromonas is a facultative Demography. Plesiomonas is an increasingly
anaerobic, Gram-negative bacillus with a single recognized cause of diarrhea around the world,
polar flagellum. The three species that most but it is especially common in Asian countries
commonly infect man are A. hydrophila, A. ve- (306,309,312-314). It is associated with eating
ronii biovar sobria, and A. caviae (281,283,290, uncooked fish or seafood, and with foreign
295,296). Aeromonas produces a number of po- travel. The causative organism, Plesiomonas
tential virulence factors including enterotoxins, shigelloides, is a facultative anaerobic, Gram-
cytotoxins, hemolysins, aerolysins, hemaggluti- negative, rod-shaped bacterium.
nins, and proteases (277,279,284,285,287,291, Pathophysiology. P. shigelloides produces a
299,304). In addition, the organism is able to cholera enterotoxin-like protein (305), as well
adhere to and invade intestinal epithelial cells as thermostable and thermolabile enterotoxins
in culture (294,303). (311). In addition, the organisms may produce
Clinical Features. Children with Aeromonas cytotoxins and ~-hemolysins (307,308). The ex-
infection present with severe diarrhea com- act mechanism by which the organism produces
monly containing mucus and blood (302). In diarrheal illness, however, is not yet understood.

419
Gastrointestinal Diseases

Clinical Features. Children with Plesiomonas blood transfusions (342) . Infants, children, and
infection most commonly present with watery young adults are most often affected.
diarrhea and fever, while adults usually pres- Etiology. Yersinia enterocolitica is a facultative,
ent with diarrhea and abdominal pain (313). anaerobic, nonlactose-ferrnenting, Gram-nega-
The symptoms are most commonly mild and tive coccoid bacillus in the genus Enterobacte-
self-limited. Occasionally, chronic diarrhea is riaceae. Over 30 serotypes and several biotypes
reported (310,314). Rarely, severe enterocolitis, have been identified. In Europe, sporadic infec-
pseudoappendicitis, osteomyelitis, and bactere- tions result from serotypes 0:3 and 0:9. In the
mia develop. The changes mimic those of other United States, outbreaks are associated with
forms of severe bacterial enterocolitis. multiple serotypes, the most common of which
Pathologic Findings. The gross and micro- is 0:8 (3 19). Recently, Lamps et al. (331) sought
scopic findings resemble those found in other to determine the presence or absence of Y. en-
forms of bacterial enterocolitis. terocolitica and Y. pseudotuberculosis in patients
Special Techniques. The diagnosis is estab- diagnosed with granulomatous appendicitis.
lished by cultures. Overall, 2S percent of their cases were positive
Differential Diagnosis. Other forms of acute for pathogenic Yersinia: SO percent for Y. entero-
colitis. colitica and SO percent for Y. pseudotuberculosis.
Treatment and Prognosis. The disease is Pathophysiology. The pathogenicity of
usually self-limited without complications. Pa- Yersinia species is determined by a number
tients with severe or prolonged symptoms may of virulence factors encoded by the bacterial
be treated with antibiotics. chromosome or by the virulence plasmid p YV
(316-318,338). These factors include various
Yersinia Infections
adhesins, invasin and attachment-invasion
Demography. The incidence of . Yersinia locus. In addition, the pYV proteins make up a
infection is highest in cold months and in type Ill secretion system similar to th,gt seen in
cold climates. The disease is more common in pathogenic E. coli and Salmonella.
Canada and Europe than in the United States. Bacteria in the lumen of the small bowel or
There is a high incidence of the disease in colon adhere to M cells or absorptive cells in
Scandinavia, Japan, and Belgium (343). The areas of the follicle-associated epithelium. Y.
geographic distribution of the infection may enterocolitica penetrates into the lamina propria
reflect differences in culinary pra't"tices or host by passing through the enterocyte cytoplasm
reservoirs, or it may simply reflect more inten- in a manner similar to that exhibited by Sal-
sive surveillance in some countries. Belgium has monella. Chromosomally encoded proteins
the highest disease incidence, probably strongly facilitate bacterial intestinal attachment, mu-
correlating with Belgium's consumption of raw cosal penetration, survival, and proliferation
pork (343). Infections are more common in (327,329,333,334,336). Once inside the cell,
patients who have had gastrectomies, suggest- the bacteria become enclosed by membranous
ing that gastric acid normally protects against vesicles (344) . Only potentially pathogenic
Yersinia infection (3Z3). Immunosuppressed strains invade the lamina propria. Y. entero-
patients often develop severe, fatal Yersinia colitica organisms subsequently multiply within
bacteremia. lymphoid follicles in Peyer patches, then drain
Infection usually follows ingestion of con- into the mesenteric lymph nodes, eventually
taminated meat, vegetables, water, and milk giving rise to systemic infections.
(31S,330), and pigs are an important reservoir Clinical Features. Yersinia causes a wide
for infection (320,323-32S). Yersinia infections spectrum of clinical changes that ranges from
are an occupational health risk to hog slaughter- asymptomatic infection to self-limited en-
ers (332). The organism has also been isolated terocolitis or even potentially fatal systemic
from numerous other animals, including dogs, infection. Patients present with gastroenteritis,
cats (319,326), birds, amphibians, fish, insects, acute diarrhea, low-grade fever, pharyngitis,
and crustaceans (326,339,340). Transmission abdominal pain, ileocolitis, diffuse mesen-
can occur via person-to-person contact and by teric lymphadenitis; sepsis, and endocarditis

420
Gastrointestinal Infections

(322,323,328,335,341,345). Diarrhea is the


most common symptom, but fever and crampy
abdominal pain are also frequent. Occasionally,
the abdominal pain localizes to the right lower
quadrant, mimicking acute appendicitis. In
patients under age 5, the usual disease pattern
is a mild, self-limited gastroenteritis indistin-
guishable from other gastrointestinal infections
(321) . Typically, the disease lasts 2 to 3 weeks;
infrequently, infants develop chronic dianhea
lasting for months. Older children and adults
develop mesenteric lymphadenitis and have a
syndrome that mimics acute Crohn's disease
or tuberculosis. Intestinal perforation occurs Figure 10-11
rarely (33 7) YERSINIOSIS
Gross Findings. Because Yersinia organisms Numerous necrotizing granulomas are located within the
preferentially invade the area around Peyer mucosa and submucosa. The adjacent mucosa is edematous
patches, Yersinia infections typically affect the and the colonic glands appear regenerative.
terminal ileum, appendix, and proximal colon.
The rectosigmoid may also be involved, but hyperplasia, and neutrophilic infiltrates with
this is uncommon. The bowel wall appears irregular areas of necrosis. The lymph nodes
thickened, inflamed, congested, and edematous. may contain large collections of macrophages,
Patients develop aphthous, diffuse, or focal ul- imparting a "starry sky" appearance.
cers. Even though the ulcers may be numerous, Special Techniques. The organism can be
they are rarely very deep. CT scans demonstrate cultured from lymph nodes and intestinal
mesenteric lymphadenopathy. The enlarged tissue. If the pathologic specimen is received
mesenteric lymph nodes may become matted fixed, the presence of Yersinia can be confirmed
and contain yellowish microabscesses. Fistulas serologically. PCR-based assays distinguish be-
and ileal stenosis are unusual. tween pathogenic and nonpathogenic strains
Microscopic Findings. The affected bowel of the organism.
appears congested, edematous, and ulcerated. Differential Diagnosis. Clinically, radio-
A characteristic microscopic feature is sharply graphically, and grossly, Yersinia infections
demarcated lymphofollicular hyperplasia; mi- mimic tuberculosis and Crohn's disease because
croabscesses and prominent germinal centers the most severe disease centers around the ileo-
are in the mesenteric lymph nodes and bowel cecal region and the organism produces nodu-
wall. Small, punctate aphthoid ulcers, covered larity of the bowel wall, mucosal thickening,
by fibrinopurulent exudates and measuring 1 and aphthous ulcers. Yersinia infections seldom
to 2 mm in diameter, overlie the hyperplastic thicken the bowel wall to the same degree that
lymphoid follicles (322,328). Large numbers Crohn's disease does nor does it usually cause
of Gram-negative coccobacilli may be present. fistula formation. The absence of well-formed
Epithelioid granulomas with central necrosis, granulomas in Yersinia infections differentiates
polymorphonuclear cells, and microabscesses them from brucellosis and mycobacterial infec-
are seen (fig. 10-11). The granulomas can be tions. Granulomas may also be seen in Shigella
found throughout the bowel wall. The changes or Salmonella enteritis, although they are seldom
superficially resemble those found in cat-scratch a dominant histologic feature, and when pres-
fever. The muscularis propria and serosa become ent, are small and lack necrosis.
infiltrated by pleomorphic cellular infiltrates The differential diagnosis of the mesen-
that often include eosinophils. teric lymph node lesions includes tuberculosis,
Mesenteric lymphadenitis is common. The brucellosis, tularemia, histoplasmosis, and cat
characteristic lesion consists of necrotizing scratch fever. Similar changes in the lymph
paracortical epithelioid granulomas, B-cell nodes are seen with Y. pseudotuberculosis, but

421
Gastrointestinal Diseases

in the latter case, a distinct granulomatous proteins from the glycine-rich PE-PGRS family,
component surrounds the microabscesses in play a key role in mycobacteria viability within
the lymphoid tissues (322). macrophages (355). Infected macrophages then
Treatment and Prognosis. Antibiotic treat- migrate to the regional lymph nodes where they
ment is usually unnecessary, as the illness stimulate cell-mediated immunity and eventual
is typically self-limited. Patients with severe granuloma formation.
infection or bacteremia; and those who are Tuberculous gastroenteropathy presumably
immunocompromised, may be treated using follows swallowing organisms from pulmonary
combination antibiotic therapy including sites of infection. Another probable pathoge-
doxycycline, aminoglycosides, trimethoprim- netic mechanism involves rupture of, or disease
sulfamethoxazole, or fluoroquinolones (328a). extension from, tuberculous lymph nodes. In-
testinal lesions can spread to the serosa by direct
Mycobacterium Tuberculosis Infections
extension or hematogenously from the lung.
Demography. The tuberculosis bacterium, Clinical Features. The signs and symptoms
Mycobacterium tuberculosis, has been called the associated with enteric tuberculosis vary consid-
world's most effective pathogen, since it kills an erably. The signs and symptoms of gastrointesti-
estimated 2 million people each yea~;, and lurks nal and peritoneal tuberculosis are nonspecific
in one third of the world's population. Globally, and the diagnosis is easily missed or delayed
M. tuberculosis causes more deaths than any oth- unless there is a high index of suspicion. Gas-
er infection (354). Until recently, tuberculosis trointestinal tuberculosis may be limited to
was uncommon in North America and Europe, the abdomen or it may be part of a systemic
but was endemic in Asia where it represented a disorder. Only 15 to 20 percent of patients have
major health problem. During the last several concomitant active pulmonary disease (353).
decades, however, it has emerged as a wqrldwide Esophageal tuberculosis manifests with dys-
problem, not just restricted to underdeveloped phagia, odynophagia, and bronchial aspiration
or Asian countries (351,352,356). The number due to tracheoesophageal fistulas (3'49,361).
of cases diagnosed in Western countries has Compression of the esophagus from enlarged
dramatically increased due to the appearance of mediastinal lymph nodes may cause dysphagia.
AIDS and the migration of many people from Symptoms of gastric tuberculosis are usually
areas with a high tuberculosis incidence to areas nonspecific and may mimic a resistant ulcer,
with a lower incidence. ,. gastric outlet obstruction, or fistula (349). Py-
Pathophysiology. Transmission of the infec- loric ulcers or tuberculomas may result in ob-
tion occurs by inhalation of aerosolized droplet struction in a manner similar to that caused by
nuclei containing the organism, ingestion via malignancy or peptic ulcers. Although unusual
the gastrointestinal tract, or infection through in most communities, tuberculosis is a common
a skin lesion. Mycobacteria are intracellular cause of pyloroduodenal obstruction among
pathogens that reside almost exclusively within South African blacks (349).
macrophages of infected individuals. They are Patients with abdominal disease present with
opsonized via complell_lent (C)3 or the comple- abdominal lymphadenopathy, splenomegaly,
ment receptors CRI, CR3, and CR4 (357) . Inter- hepatomegaly, ascites, and intrasplenic or intra-
nalization into macrophages requires the associ- hepatic masses (350). Massive lymphadenopa-
ation of the complement cleavage product C2A thy may exist without bowel involvement (349).
with mycobacteria to form C3 convertase (358). Central lymph nodes along the mesentery and
r..· Pathogenic mycobacteria initiate long-term nodes around the ileocecal and pyloroduodenal
infections by causing extensive remodeling of region are usually involved. Patients may have
their vacuolar environment to prevent vacuolar recurrent abdominal pain, palpable abdominal
acidification and lysosomal fusion (346,347). masses, subacute intestinal obstruction, and
Replication in macrophages is crucial for patho- the effects of compression on major organs.
genic mycobacteria. Normally, macrophages Chronic nonspecific abdominal pain is the most
phagocytize and destroy the organisms. Certain common complaint. Other symptoms include
genes, particularly those encoding virulence diarrhea, hemorrhage, and severe wasting.

422
Gastrointestinal Infections

Intestinal tuberculosis causes fever, weight


loss, malaise, severe enterocolitis, massive hem-
orrhage, perforation, obstruction, fistula forma-
tion, strictures, malabsorption, a right lower
quadrant mass, and severe secretory diarrhea.
The most common form of gastrointestinal dis-
ease is ulcerative ileocecal tuberculosis. Patients
with primarily ulcerating disease have a virulent
course and a high mortality rate. Patients with
primarily stenosing changes present with signs
and symptoms of bowel obstruction or malabsorp-
tion. The malabsorption is due to villous atrophy,
lymphatic obstruction, stagnation of luminal con-
tents, blind loops, and fistula formation. Figure 10-12
Perirectal tuberculosis often presents as ano- TUBERCULOSIS
rectal fissures and fistulas . Anal tuberculosis The wall of the cecum (cut in cross section) is diffusely
may result in the development of abscesses and thicke ned, and numerous whiti sh foci of necrosi s,
fistulas between the abscesses. which correspond to caseating granulomas, can be seen
Gross Findings. Tuberculosis can involve throughout the full thickness of the colonic wall.
any part of the gastrointestinal tract from the
tongue to the anus. Ileocecal involvement af- around the ileocecal valve that can clinically
fects 90 percent of patients and results in ileoce- mimic cecal carcinoma.
cal valve distortion. Other affected locations in Ulcerating disease appears as ragged, un-
decreasing order of frequency are the ascending dermining ulcers that may be single, multiple,
colon, appendix, jejunum, duodenum, stom- large, or small. The intestinal wall in these ul-
ach, esophagus, sigmoid, and rectum (349,361). cerated areas becomes thickened and fibrotic.
Esophageal tuberculosis usually represents Granulomas typically stud the serosa and re-
extension from mediastinal disease into the gional mesenteric lymph nodes are involved.
esophagus. This may result in the formation The hypertrophic form is thought to be the
of fistulas between the tracheobronchial tree result of an exuberant fibroblastic reaction to
and the esophagus. Radiographic findings of the infection and may produce a mass lesion
tuberculous esophagitis range from focal ulcer- that clinically and grossly mimics a carcinoma.
ated lesions to stricture and fistula formation . The ulcerohype1trophic form is an intermediate
Gastric lesions are usually multiple, ulcerated, lesion with features of ulceration, nodularity,
and infiltrated, and situated along the lesser hyperplasia, and stricture formation. The wall of
curvature. The edge of the ulcer is ragged, thick- the colon may be so extensively damaged by the
ened, edematous, and undermined, differenti- inflammatory process that the small intestine
ating it from carcinoma (361) . The lesions can is indistinguishable from the colon in an ilea-
be serpiginous with violaceous edges or consist colectomy specimen. Necrotizing granulomas
of superficial tubercles in the vicinity of ulcers. are easily appreciated on the cut surface of the
Typically, intestinal disease is transmural, thickened bowel wall or in enlarged regional
consisting of confluent necrotizing granulomas mesenteric lymph nodes. The normally smooth
with overlying ulceration (fig. 10-12). Intestinal visceral and parietal peritoneal surfaces become
tuberculosis assumes one of three gross forms: studded with miliary tubercles. Mesenteric
1) ulcerating: characterized by the presence of nodes may also become infected and hypertro-
multiple ulcers; 2) hypertrophic: characterized phic. In patients with severe disease, there may
by the presence of scarring, fibrosis, and heaped be widespread studding of the peritoneal surface
up mass lesions; and 3) ulcerohypertrophic: char- with thousands of individual nodules and mat-
acterized by thickening and ulceration of the ting of individual loops of bowel.
intestinal wall associated with an inflammatory Tuberculous disease of the anorectal region
mass, stricture, or an apple-core lesion centering appears in four types: ulcerative, varicose, lupoid,

423
Gastrointestinal Diseases

Figure 10-13
TUBERCULOSIS
A: At low power, scattered large, well-formed, submucosal granulomas are seen.
B: A caseating granuloma and an adjagmt granuloma with a multinucleated giant cell.
C: Scattered acid-fast organisms are within the necrotic center of a granuloma (Ziehl-Neelsen stain).

or miliary. Ulcers are the most common. They histiocytes and Langerhans cells. Langerhans
are bluish, resemble amoebic colitis, and pro- giant cells typically have nuclei marginated at
duce a thick mucopurulent discharge. Varicose the cell membrane. Granulomas may be intact
forms are rare, presenting as warty growths. or display several types of central necrosis.
Lupoid forms are infrequent, nodular, and ulcer- They are often large and irregular, producing
ated, and cause lower abdominal pain, proctitis, an appearance of stellate necrosis. Caseation
ischiorectal abscesses, fistulas, and perianal le- consists of eosinophilic material in which the
sions (359,360) . ghosts of cells are still visible. The bacteria are
Microscopic Findings. Biopsies are often highlighted by the Ziehl-Neelsen stain (fig. 10-
not helpful in establishing the diagnosis. Gas- 13); they may be extremely difficult to find or
... trointestinal tuberculosis occurs anywhere in may be numerous .
the gut, and typically manifests with caseating In the intestine, granulomas usually begin in
granulomas that may be isolated or, in more the Peyer patches or lymphoid follicles, impart-
severe disease, confluent (fig. 10-13). Noncase- ing a cobblestoned appearance to the mucosal
ating granulomas or disorganized collections of surface. As the disease progresses, they tend to
macrophages may also be present. encircle the entire bowel wall, and multiple
The granulomas consist of histiocytes ag- granulomas may stud the serosa and mesentery.
gregated around an area of central necrosis. Confluent necrotizing granulomas can com-
Macrophages may take the form of epithelioid pletely destroy the underlying architecture of

424
Gastrointestinal Infections

the bowel wall and extend into the pericolonic ferential, with their long axis perpendicular to
or periileal fatty tissues. Giant cell granulomas the lumen, without fissuring. The granulomas
with obvious caseation occur more frequently in of tuberculosis are more florid and numerous
ulcerative than in hyperplastic lesions. They lie than those of Crohn's disease and caseation is
throughout the entire thickness of the intestinal found in larger granulomas. Even when necrosis
wall. Ulcers may contain acid~ fast bacteria, even is not especially prominent in the intramural
in the absence of granulomas. The nonulcerated lesions of tuberculosis, the associated lymph
mucosa usually appears markedly edematous nodes usually show evidence of caseation.
and focally hemorrhagic. Perirectal fissures and Tr eatment a n d Prognosis. Mortality has
fistulas may contain giant cells; granulomas are fallen from 50 to 3 percent with the introduc-
not always present. tion of antituberculous treatment and support-
In order to establish the diagnosis of tuber- ive nutritional therapy (348). Factors that still
culosis, multiple deep biopsies of the ulcer bed contribute to the death of patients are compli-
and its margins must be performed. In some cations, late presentation, a delay in institu-
instances, the lymph nodes are completely tion of antituberculous therapy due to failure
replaced by confluent necrotizing granulomas to diagnose the disease early, and coexisting
and there may be small granulomas on the factors such as cirrhosis, alcoholism, diabetes,
serosal surface. immunocompromise, and gross debilitation. If
Tuberculous peritonitis consists of granu- the small bowel is seriously affected, parenteral
lomatous inflammation involving both the nutrition may be needed. Successful treatment
visceral and parietal peritoneum. Ascites is of patients with extrapulmonary tuberculosis
often present, with an increase in peritoneal requires the use of multiple antibiotic agents for
fluid protein concentration and a lymphocyte long periods of time. Multidrug-resistant strains
predominance in the differential count. The of mycobacteria have recently emerged. Surgery
diagnosis is made by culturing the ascitic fluid. is reserved for patients with complications such
Special Techniques. The first step in the as obstruction or fistulas or for those in whom
detection of acid-fast bacteria is suspicion of the uncertainty exists in the diagnosis .
disease so that an acid-fast-stained preparation
Other Mycobacterial Infections
can be examined. Granulomas or disorganized
collections of macrophages are the usual clues. Mycobacterium avium complex infections are
Isolated acid-fast bacilli can be seen in the tu- predominantly seen in AIDS patients. Therefore,
bercles and lymph nodes with the use of special they are discussed in chapter 11.
stains or they are recoverable by culturing the
Neisseria Gonorrhoeae Infections
tissue. The measurement of adenosine deaminase
levels in ascites may represent a major diagnostic Demography. Neisseria gononhoeae is a cause
advance in tuberculous peritonitis, particularly of proctitis in those engaging in anal inter-
in underdeveloped areas where the disease is course or in those with urogenital infections.
common and laparoscopy may not be available The disease affects both men and women. The
(353). It is useful in distinguishing tuberculosis prevalence of gonococcal infections in sexually
from other causes of exudative ascites. abused children in North America ranges from
Differential Diagnosis. The clinical differ- 0 to 11 percent (365). N. gononhoeae probably
ential diagnosi.s of tuberculosis anywhere in represents the most common cause of acute and
the gut includes carcinoma and other causes of chronic proctitis in AIDS patients.
granulomatous inflammation. In the intestines, Etiology. N. gonorrhoeae is the causative or-
it mimics Crohn's disease, Yersinia colitis, and ganism. The most obvious route of inoculation
fungal infection. Crohn's disease and Yersinia is direct implantation by rectal intercourse, but
infection tend to concentrate around the il- in women, the infectious vaginal discharge from
eocecal valve and all three diseases produce genital gonorrhea may also infect the anorectal
granulomatous ileocolitis with strictures, aph- mucosa everted during defecation (362) . Risks of
thous ulcers, and fistulas. In contrast to Crohn's sexual transmission and acquisition include un-
disease, tuberculous ulcers tend to be circum- protected anal intercourse and oral-fecal contact.

425
' Gastrointestinal Diseases

Pathophysiology. Stratified squamous an instrument. A copious amount of pmulent


epithelium resists bacterial invasion, while the exudate overlies the mucosal changes (362).
columnar and transitional epithelia of the anal Microscopic Findings. Smears taken from
canal and rectum are more easily penetrated by purulent exudates of patients with gonorrhea
bacteria. This explains the preferential localiza- demonstrate numerous neutrophils, many of
tion of the infection to the rectal rather than which, but not all, are packed with cytoplasmic
the anal mucosa. The neutrophils associated gonococci. Histologically, biopsies of the ano-
with gonococci are often packed with intact, rectal region show acute or subacute proctitis
seemingly viable, intracellular bacteria or have affecting the upper anal canal, including the
gonococci bound to their surfaces. This suggests area of the anal crypts and ducts. Although not
that neutrophils are unable to kill the infecting common, epithelial ulceration and disorgani-
bacteria. The massive influx of neutrophils that zation may be seen (364). Plasma cells of the
accompanies a gonococcal infection is in part IgA-secreting type and lymphocytes may also
generated by complement components that be present within the infiltrate, as may neutro-
serve as strong chemotactic factors. An outer phils. Histologic features resemble those found
membrane protein I (PI), produced by the bac- in IBD, stressing the importance of culture or
teria, is inserted into the cytoplasmic membrane Gram stain on the tissues in order to identify
of neutrophils causing depolarization of the cell the organism. The histologic findings reflect
(363). This may inhibit intracellular killing of the clinical and gross findings. Many patients
gonococci by inhibiting the release of granule with culture-proven rectal gonorrhea lack any
proteins. A second mechanism by which phago- histologic abnormalities. Mildly symptomatic
cytosis can be impeded involves the attachment disease often only manifests as a slight increase
of gonococci to the neutrophilic surface in a in lymphocytes and plasma cells within the
manner that inhibits their ingestion. Gonococ- lamina propria (364,366).
cal surface components appear to be involved Special Techniques. The diagnosis is best
in this process. made using a Gram stain prepared from a rectal
Clinical Features. Two thirds of patients with swab or by microbial culture of a distal rectal
anorectal Neisseria infections remain asymp- mucosal swab, rather than by biopsy. Gram
tomatic (362). Patients with severe symptoms stains demonstrate the presence of Gram-pos-
develop anorectal discomfort, copigus purulent itive intracellular diplococci. Not all patients
anal discharge, burning or stinging rectal pain, with the disease have a positive smear.
blood or mucus in the stools, and tenesmus. Differential Diagnosis. Sexually transmitted
Milder cases may be characterized by the pres- gastrointestinal diseases result in proctitis, proc-
ence of perianal itching or burning with some tocolitis, and enteritis due to one or multiple
'purulent staining of underwear. Physical exami- pathogens. Evaluation should include appropri-
nation shows a moist or stained perianal area; ate diagnostic procedures such as endoscopy or
a large percentage of patients have coexisting sigmoidoscopy, stool examination, and culture.
condyloma acuminata (362). In symptomatic Empirical therapy for acute proctitis in persons
patients, an extremely florid proctitis is present who have recently practiced receptive anal
and the patient often has difficulty tolerating intercourse should be chosen to treat N. gonor-
the examination due to the pain. Inflamma- rhoeae and Chlamydia trachomatis infections.
tion may extend high into the rectum. Deep The differential diagnosis includes IBD, usually
•.·
perirectal ulcers or abscesses develop that may as ulcerative colitis. Biopsies help distinguish
contain large numbers of bacteria. between the two lesions.
Gross Findings. The rectal mucosa appears Treatment and Prognosis. Penicillin is the
normal in a large percentage of patients (364); drug of choice. In the United States, antimi-
others present with the gross features of procti- crobial resistance in N. gono7Thoeae continues
tis. The disease does not involve the bowel more to evolve and coinfection with C. trachomatis
proximally than the rectum. In severe cases, is a serious problem. Gonococci are capable of
the mucosa appears reddened and edematous. prolonged survival in untreated areas and they
It bleeds easily when touched with a swab or frequently reinfect patients with considerable

426
Gastrointestinal Infections

mucosal and systemic immune responses to the Gastrointestinal syphilitic involvement


infection. Multiple mechanisms account for the occurs either from direct infection from the
high reinfection rate: 1) variations in surface anorectal region or from acquisition of the
antigen expression; 2) production of an extracel- disease from the mother. The latter is uncom-
lular IgA protease by the organism; 3) presence mon today, at least in Western populations.
of an antigen that preferentially stimulates the Syphilitic involvement of the gastrointestinal
host production of antibodies that block the tract presents as gastritis, enteritis, or anorectal
killing activity of other antibodies; 4) masking disease. Esophageal syphilis is rare. In the past,
of critical epitopes by chemical modifications of when syphilis was more common, esophageal
surface structures; 5) molecular mimicry of host gummas, diffuse ulceration, and esophageal
antigens; 6) shedding of antigens in the form strictures could be seen in patients with tertiary
of outer membrane blebs; and 7) subversion of syphilis. Additionally, syphilitic aortic aneu-
certain nonimmunologic antimicrobial defenses rysms could rupture into the esophagus. Unless
by the bacterium. Moreover, gonococci are ca- they are secondarily infected, the lesions usually
pable of considerable phenotypic adaptation remain painless. Patients may have coexisting
to changing environmental conditions in vivo. sexually transmitted rectal infections, including
herpesvirus, N. gonorrhoeae, or C. trachomatis.
Treponema! Infections
Gross Findings. The radiographic features of
Demography. The venereal infection syphilis gastric syphilis vary depending on the stage of
was considered to be a primary public health the disease. In early disease, there are no radiolog-
concern in the United States for a long period ic manifestations. During the secondary phase,
of time but with the development of effective a small percentage of patients develop acute
antibiotic treatment, prevalence decreased gastritis that radiographically appears nonspe-
dramatically. Recently, the rates have again cific, with diffusely thickened folds that become
increased with the emergence of the AIDS epi- nodular with or without detectable ulcers (fig.
demic. Rates of primary and secondary syphilis 10-14). In late stage disease (tertiary syphilis), a
have been declining in the United States since number of extragastrointestinal manifestations
the last national epidemic in 1990 (367). The are present and a mass or gumma may develop in
rate of syphilis is higher in the South than in the gastric wall. The changes may evolve into a
the rest of the country; it is highest in blacks fibrotic narrowing of the stomach, leading to the
and lowest in Asians and Pacific Islanders. development of a funnel-shaped deformity (fig.
Clinical Features. In the primary phase of 10-14) (368). Gastric syphilis usually presents as
the infection, Treponema pallidum enter the endoscopically visible gastritis, but may simulate
body through the skin or mucous membranes the appearance of gastric lymphoma (369).
and invade the blood or lymphatic vessels, In the small bowel, involvement consists of
eventually accumulating in the regional lymph multiple ulcers, gummatous plaques, or diffuse
nodes. Several weeks later, a firm, relatively fibrosis with scarring and stenosis. The latter
painless ulcerating nodule or chancre forms sometimes exhibits an annular infiltrative pat-
at the site of initial invasion. If this infection tern grossly simulating a carcinoma. Depending
remains untreated, it progresses to second- on disease stage, the anorectal lesions can ap-
ary syphilis, which is characterized by rash, pear as either proctosigmoiditis or a mass lesion.
fever, lymphadenopathy, and mucocutaneous Large, papular perianal skin lesions, referred to
inflammation. If patients develop gastritis, as condylomata lata, may be seen in patients
symptoms of vomiting and abdominal pain with secondary syphilis.
occur. Patients with tertiary syphilis develop a Microscopic Findings. The histologic fea-
variety of extragastrointestinallesions, includ- tures of syphilis include perivascular lympho-
ing the classic findings of aortitis, parenchyma! plasmacytic infiltrates and obliterative endarte-
or skeletal gumma formation, and tabes dorsalis ritis (fig. 10-15). Crypt abscesses and granulomas
associated with neuropathic joint disease . At may also be present.
this stage, a mass or gumma may form in the Specia l Techniques . In tissue sections,
gastrointestinal wall. Warthin-Starry silver, immunofluorescent, or

427
Gastrointestinal Diseases

Figure 10-15
GASTRIC SYPHILIS
Top: Almost complete mucosal destruction by an
infiltrate that consists of mononuclear cells and neutrophils
is seen with the hematoxylin and eosin (H&E) stain.
Remnants of glands are present.
Bottom: Warthin-Starry stain demonstrates numerous
spirochetes. (Courtesy of Dr. D. Schwartz, Atlanta, GA.)

immunoperoxidase stains identify the organ-


ism. Warthin-Starry and other silver-based
stains are hard to read and the immunoperoxi-
dase stain offers an attractive alternative. Most
Figure 10-14 often the diagnosis is established by conven-
GASTRIC SYPHILIS
tional serologic tests.
Differential Diagnosis. Gastric syphilis can
Top: Acute syphilitic gastritis. Single contrast upper
gastrointestinal image of a 33-year-old woman with mimic a wide range of lesions, including gas-
postprandial vomiting. The gastric rugal folds are markedly tritis and benign ulcer disease, as well as gastric
thickened and irregular in the body and antrum. carcinoma and lymphoma. The differential
Bottom: Antral deformity after treatment of tertiary diagnosis includes other causes of gastritis or
syphilis. Radiograph from a double-contrast upper gas-
trointestinal study shows smooth antral tapering and chronic intestinal inflammation. In the small
foreshortening extending distally from the midportion of intestine or proximal colon, the differential
the study. The classic deformity of the antrum and proximal diagnosis includes Crohn's disease, Yersinia
duodenum has been compared to the appearance of a ram's infection, or tuberculosis.
horn. (Figs. 5 and lA from]ones BV, Lichtenstein]E. Radio-
graphic manifestations of gastric syphilis: pictorial essay. Treatment and Prognosis. Syphilis is treated
A]R 1993:160;59-61.) with penicillin.

428
Gastrointestinal Infections

Intestinal Spirochetosis
dried smears made by crushing biopsy tissue be-
Homosexual men have the highest preva- tween the slides, fixing the slides in methanol,
lence of spirochetosis, and the disease is com- and staining them with the Wright-Giemsa or
monly seen in the HIV-positive population. This Warthin-Starry stain. Using this method, Dono-
entity is discussed further in chapter 11. van bodies appear as rounded coccobacilli lying
within cystic cytoplasmic spaces in the mono-
Granuloma Inguinale (Donovanosis)
nuclear cells. They resemble bluish black safety
Demography. Granuloma inguinale (dono- pins due to bipolar chromatin condensations.
vanosis) is a highly contagious, venereally trans- Differential Diagnosis. Clinically, the dif-
mitted, chronically progressive, autoinoculable ferential diagnosis includes syphilis, amoebiasis,
ulcerating disease that involves the skin, mucosa, chancroid, and lymphogranuloma venereum.
and lymphatics of the perianal and genital area. Histologically, donovanosis must be distin-
The disease is endemic in the tropics, but has a guished from rhinoscleroma, leishmaniasis, and
patchy geographic distribution. It is relatively histoplasmosis. The diagnosis is confirmed with
common in Papua New Guinea and parts of the use of special stains.
South Africa, India, Australia, and Brazil (375). Treatment and Prognosis . Complications
The disease is uncommon in the United States. of the disease include deep ulcers, chronic scar-
Etiology. The disease results from an intra- ring, lymphedema, and exuberant epithelial
cellular Gram-negative microorganism identi- proliferations grossly resembling carcinoma.
fiable morphologically as the Donovan body. Squamous cell carcinoma may complicate long-
The causative bacterium is Calymmatobacterium standing disease. Patients may also develop
granulomatis, which is antigenically related to disseminated disease involving bone and other
the Klebsiella species. In fact, there has been a organs. Disseminated disease frequently leads to
recent proposal to rename the organism Kleb- debilitation and death.
siella granulomatis (371). Granuloma inguinale is_treated with antibi-
Clinical Features. The incubation period otics. Doxycycline is most commonly used in
is usually 1 to 4 weeks, but longer periods are developed countries, but trimethoprim-sulfa-
common (374,376). The anorectum, particularly methoxazole, chloramphenicol, erythromycin,
in females, is most commonly affected. The and azithromycin are also effective (373) . Peni-
infection consists of inflammatory nodules, cillin is not an effective treatment (372,377).
fissures, fistulas, and extensive fibrosis . The Patients with severe fissures and fistulas unre-
fibrosis causes obstruction of the lymphatics sponsive to medical therapy may require surgi-
and perianal elephantiasis. cal intervention (370).
Pathologic Findings. Inflammatory nodules
Chancroid
may be present and feel like firm tumors in the
bowel wall. The scarring fibrosis leads to defor- Demography. Chancroid results from in-
mity and strictures. Chronic ulceration and scar- fection by Haemophilus ducreyi. It is the most
ring may resemble that of lymphogranuloma common cause of genital ulcer disease in many
venereum. Perianal granuloma inguinale also developing countries (392), and has recently
resembles the condylomata lata of secondary become established as a significant sexually
syphilis. Locally destructive lesions and second- transmitted disease in the United States (382,
ary infections may lead to severe morbidity or 389,390,396). The disease affects both males
even death. and females, although the male to female ratio
Histologic studies reveal the presence of in one study was 27 to 1 (397).
marked acanthosis and pseudoepitheliomatous Etiology. H. ducreyi is a Gram-negative, short,
hyperplasia of the squamous mucosa. The lam- slender organism with blunt ends. In smears,
ina propria contains collections of histiocytes, the organisms are typically seen in pairs or in
monocytes, and plasma cells. Capillaries and short or long chains, the appearance of which
blood vessels appear prominent. Inclusion bod- has been likened to a "school of fish" (398).
ies, or Donovan bodies, are present in enlarged Pathophysiology. H. duaeyi produces anum-
histiocytes. The organisms are best seen in air- ber of potential virulence factors including pili,

429
Gastrointestinal Diseases

extracellular toxins, and hemolysin (379,380, isolation are extensive (386). By using a single,
384,395,399). The organism enters the skin or enriched, selected medium in optimal cultural
mucosa through microabrasions that develop conditions, the isolation rate of H. ducreyi from
during sexual intercourse. After a variable incu- presumptive chancroidall.llcerations is estimat-
bation period, an erythematous papule arises at ed to be between 60 to 70 percent, with higher
the affected site. This papule evolves to a pustule rates achieved if two media are employed (393).
that, after 2 to 3 days, undergoes necrosis, form- More recently, PCR-based tests have been used
ing a pathognomonic, tender, nonindurated to diagnose the infection (381,394,400).
ulcer with undermined margins. Inflammation Treatment and Prognosis. The disease is
spreads to the draining lymph nodes (386,397). treated with antibiotics including erythromycin,
Clinical Features. The incubation period azithromycin, ceftriaxone, ciprofloxacin, and
for chancroid is short, varying between 3 and spectinomycin. Resistance to other commonly
5 days; this period may be longer in patients used antibiotic agents has been reported (387).
with HIV infection (397). Tender ulcers with a
Actinomyces Infections
tendency to bleed on touch develop at the site
of infection. Unilateral, regional lymphade- Demography. Although Actinomyces is a
nopathy commonly accompanies th€ ulcer. The normal commensal inhabitant of the digestive
lymph nodes are tender, swollen, and matted tract, especially in the oropharyngeal region, A.
together, ultimately forming a single fluctuant israelii infections do develop. These infections
aggregate. Spontaneous rupture may result in a are more common in patients with impaired im-
single discharging sinus in the ingHinal region mune defenses. Occasionally, the organisms are
(385,388,391). encountered in otherwise normal individuals.
Gross Findings. The organism produces Etiology. A. israelii is a filamentous, Gram-
single or multiple, painful anal ulcers; abscesses positive bacterium that is part of the normal
form in the draining lymph nodes. The ulcers flora of the oral cavity. Abdominal tpfections
develop at the inoculation site. When multiple usually result when swallowed organisms es-
ulcers are present, they often differ in their stage cape destruction in the stomach. Other cases of
of development. The ulcer begins as a macule invasive abdominal actinomycosis result from
that rapidly becomes pustular and ruptures, appendiceal or colonic perforations following
leaving a shallow, saucer-shaped ulcer sur- acute appendicitis, diverticulitis, or abdominal
rounded by a narrow erythematoliS margin. The trauma, including surgery.
ulcers have ragged edges and a base covered by Clinical Features. A. israelii can cause seri-
a grayish necrotic exudate (397). ous small intestinal and colonic infections,
Microscopic Findings. Histologic sections often at the ileocecal valve or in the rectum
of well-developed chancroid ulcers reveal three (403,406). Changes in bowel habits, low-grade
distinct layers. The superficial layer consists fever, malaise, weight loss, abdominal pain,
of red blood cells, polymorphonuclear leuko- and a palpable abdominal mass may lead to a
cytes, histiocytes, fibrin, necrotic debris, and misdiagnosis of carcinoma. Actinomyces infec-
intracellular and extrficellular Gram-negative tions also present as sinuses that drain to the
coccobacilli (H. ducreyi) at the ulcer base. Vas- abdominal wall. Rectal lesions demonstrate
cular proliferations and edema characterize areas of induration, with or without ulceration,
the middle layer. Thrombosis with subsequent fistulas, or strictures.
tissue necrosis and ulceration may result from Gross Findings. In patients with severe disease,
'"·· endothelial swelling. The deep layer contains the affected bowel appears thickened with mul-
a dense infiltrate of plasma cells, lymphocytes, tiple suppurative foci, sinus tracts, and scar tissue.
and polymorphonuclear leukocytes (383). Thick-walled abscesses with tough fibrous walls
Special Studies. Gram stains of the exudate enclosing loculi and filled with yellow or white
obtained from ulcerations are unreliable (378), pus can be found along the sinus tracts. Ulceration
and isolation of the causative bacterium, H. may be minimal, but fistulas can develop, result-
ducreyi, is difficult because the organism is ing in full-thickness intestinal involvement and
fastidious and the media required for primary extension into surrounding tissues.

430
Gastrointestinal Infections

Special Procedures. In Brown-Brenn-stained


sections, Gram-positive, slender, branching,
beaded bacilli can be demonstrated tangled in
the center of the granules.
Differential Diagnosis. Based on gross find-
ings, the differential diagnosis includes other
stenosing and fistula-producing infections,
such as Crohn's disease, tuberculosis in the
intestine, or Chlamydia in the anorectal region.
Some cases clinically and grossly resemble car-
cinoma (404,405). The differential diagnosis
is easily resolved by finding the characteristic
organisms on histologic examination. The dif-
ferential diagnosis also includes Nocardia infec-
tion, which also forms loose masses without
the club-shaped peripheral edge and, unlike
Figure 10-16 Actinomyces, is acid fast.
ACTINOMYCOSIS Treatment and Prognosis . Abdominal ac-
Fragments of colonic mucosa are admixed with a large tinomycosis can be successfully treated with
colony of Actinomyces (bottom center) . penicillin (402,404).
Tropheryma Infections
Microscopic Findings. The characteristic Demography. Whipple 's disease, the common
microscopic lesion is an abscess, which is often term for Trophe1yma infection, is a rare disorder
multiloculated, surrounded by a zone of vascu- that is most commonly encountered in Cauca-
lar granulation and scar tissue with extensive fi- sians living in mid-Europe or the United States.
brosis. Large, foamy macrophages surround the It tends to affect middle-aged individuals (mean
suppurative centers of the lesions and scattered age at diagnosis is 50 years), and is eight times
lymphocytes and plasma cells are in the granu- more common in men than women (420,438).
lation tissue (401). Fistulous tracts often extend Several familial cases have been reported, but
into the surrounding tissues. The diagnosis is most analyzed cases do not suggest a familial
based on finding the distinctive-appearing or- component (413,424,441). The HLA B27 haplo-
ganisms usually floating in the pus (fig. 10-16). type is found in 26 percent of infected patients
They consist of rounded masses of branching (418); however, this characteristic is not found
filaments measuring approximately 300 J.lm in in all populations (408,440).
diameter, readily seen with Gram or H&E stain. Etiology. Whipple's disease results from
A radial corona of eosinophilic material, called infection with the bacterium Trophe1yma whip-
Splendore-Hoeppli fibers, surrounds the bacte- plei. The habitat of the organism is unknown.
rial masses, producing the characteristic sulfur It has been cultured from sewage in Germany,
granules. The Gram-positive bacterial colonies and from feces of patients without evidence of
have a club-shaped Gram-negative edge. Whipple's disease (411,425,430). In addition,
Occasionally, the organisms are encountered PCR-based studies have shown that bacterial
in the absence .of any inflammation. If they are DNA sequences can be amplified in saliva, gas-
seen in the esophagus or stomach in the absence tric fluid, and duodenal biopsy samples from
of significant inflammation, it is unlikely that healthy patients (412,416,431). The ability to
the organisms are causing disease. They are amplify bacterial DNA from these sites appears
likely to be the result of swallowing organisms to be dependent on the geographic region in
from the tonsillar region or passage on the which the individual lives (411).
endoscope. The significance of organisms in Pathophysiology. It is thought that patients
the absence of inflammation in large intestinal who develop Whipple's disease may have some
biopsies is less clear. form of persistent monocyte or macrophage

431
Gastrointestinal Diseases

dysfunction that predisposes to the infection.


Although numerous immunologic abnor-
malities have been described in patients with
Whipple's disease, it is likely that the defect is
subtle and specific for the causative organism,
T whipplei, since these patients do not show
an increased susceptibility to other infections
(435). Only a few reports suggest an increased
frequency of Whipple's disease in immunode-
ficient individuals (immunosuppressed or AIDS
patients) (426.429,432,437).
Populations of T cells in the lamina propria
and in the circulation of patients with active
Whipple's disease show a shift toward a mature Figure 10-17
T-cell population, and a decreased CD4/CD8 T- WHIPPLE'S DISEASE
cell ratio (414,433,434). In addition, peripheral The lamina propria is distended with histiocytes. The
T cells show a reduced proliferative re.sponse to a villi are distorted by the infiltrate. Clear lipid globules lie in
number of factors (418,423). Some patients have dilated lacteals and in the lamina propria. (Fig. 3-56 from
an inhibitory serum factor that dowmegulates Emory TS, Carpenter HA, Gostout C], Sob in LH. Atlas of gas-
trointestinal endoscopy & endoscopic biopsies. Washington
the T-cell response (423,434). D.C.: Armed Forces Institute of Pathology; 2000:202.)
Macrophages in infected patients show de-
creased intracellular degradation (409) and a
decrease in phagocytosis (428). In addition, with able. A periumbilical mass representing enlarged
active disease, the macrophages show decreased mesenteric lymph nodes is sometimes palpable.
expression of CD11b, a molecule that facilitates Whipple's disease of the CNS may ~~ the pri-
microbial phagocytosis (415); they may also mary manifestation (407,445).
show defects in the production of interleukin Gross Findings. Whipple's disease typically
12, a cytokine important in the regulation of involves the small intestine. Endoscopically, the
cell-mediated immunity (433,434). small intestinal mucosa has areas that appear
Clinical Features. In most cases, the initial pale yellow and shaggy alternating with areas
manifestation of Whipple's diseas~ is a chronic, that appear erythematous, eroded, or friable
migratory, nondestructive polyarthropathy that (421,439). In some cases, whitish yellow plaques
affects mainly the peripheral joints (435). The with a patchy distribution are seen.
arthropathy may precede the diagnosis of Whip- Grossly, the bowel wall is thickened and rigid.
pie's disease by as many as 8 years (436). At the Yellowish subepithelial and peritoneal plaques
time of diagnosis, intestinal disease with diarrhea and massive infiltration of the mesenteric fat
and malabsorption dominate the clinical picture. are characteristic. Mesenteric thickening and
The diarrhea is usually watery and malodorous, lymphadenopathy characterize advanced dis-
often associated with steatorrhea. The diarrhea is ease, with lymph nodes sometimes measuring
frequently accompanied by abdominal pain and as much as 3 to 4 cm in diameter.
distension, and may contain occult blood (420). Microscopic Findings. Whipple's disease is
Weight loss is invariably present. characterized by collections of foamy histiocytes,
Systemic manifestations include polysero- sometimes accompanied by lymphocytes, neu-
r..·
sitis, low-grade fever, pericarditis, cardiac val- trophils, and eosinophils, infiltrating the lamina
vular stenosis or insufficiency, mesenteric and propria, distorting the mucosal architecture, and
peripheral lymphadenopathy, hepatospleno- pushing the crypts and villi apart (fig. 10-17).
megaly, and CNS disease (417,420,422,435,438, Subtotal or total villous atrophy characterizes
442-444) . Lymphadenopathy, the most com- severe disease. Finely granular, grayish histiocytes
mon physical sign, affects approximately 50 are most numerous just beneath the luminal
percent of patients. The enlarged lymph nodes epithelial basement membrane; they decrease
are typically firm, nontender, and freely mov- in number as one progresses toward the submu-

432
Gastrointestinal Infections

Figure 10-18
WHIPPLE'S DISEASE
Left: The lamina propria contains numerous histiocytes with foamy cytoplasm.
Right: Characteristic periodic acid-Schiff (PAS)-positive bacilli are in the histiocyte cytoplasm. (Figs. 3-5 7 and 3-58 from
Emory TS, Carpenter HA, Gostout C], Sobin LH. Atlas of gastrointestinal endoscopy & endoscopic biopsies. Washington
D.C.: Armed Forces Institute of Pathology; 2000:203.)

cosa. The enterocytes appear relatively normal, with Mycobacterium avium, histoplasmosis, stor-
although there may be patchy vacuolization. age diseases, and macroglobulinemia. Although
Rarely, necrosis and fibrosis are seen. Lymphangi- the histiocytes may resemble one another in
ectasia is characteristically present. It results from these diseases, fatty deposits and lipogranulomas
lymphatic obstruction due to massive histiocytic are usually only present in,Whipple's disease.
collections in the enlarged lymph nodes. Treatment and Prognosis. The disease was
The diagnosis depends on the demonstration uniformly fatal prior to the use of antibiotic
of multiple, rounded or sickle-shaped, PAS- therapy. Most patients respond well and rapidly
positive, diastase-resistant bacterial fragments to treatment with antibiotics such as trimetho-
in the infiltrating histiocytes, smooth muscle prim-sulfamethoxazole, but some patients have
cells, endothelium, and fibroblasts (fig. 10-18). chronic relapsing disease (419,42 7). Antibiotics
Widespread fatty deposits and lipogranulomas should be administered for at least 1 year (419).
are present in both the mucosa and in the intra- The prognosis of patients with CNS Whipple's
abdominal lymph nodes, reflecting lymphatic disease is much less favorable than of patients
obstruction with fatty extravasation. Regional with involvement limited to the bowel (427).
lymph nodes lose their normal architecture and
Chlamydia Infections
become fibrotic.
Special Techniques. Ultrastructurally, the Definition . Lymphogranuloma venereum
histiocytes contain bacteria in various stages of (LGV) is a tropical and subtropical, chronic
degeneration (41 0). Today, a PCR test diagnoses scarring disease transmitted sexually, caused
Whipple's disease in intestinal biopsies. Testing by certain serogroups of Chlamydia trachomatis.
of cerebrospinal fluid in patients with Whipple's Infections caused by LGV strains of C. trachoma-
disease yields a high rate of positive results, tis affect travelers from endemic areas or indi-
even in patients without neurologic symptoms viduals with sexual contacts from endemically
(446). The recent cultivation of the bacterium of infected populations.
Whipple's disease may allow the development Demography. LGV has a worldwide distri-
of a serologic test for the disorder (443). bution. Its prevalence varies from country to
Differential Diagnosis. The differential di- country; it is most common in tropical and
agnosis of the PAS-positive, diastase-resistant subtropical countries (448).
lamina propria histiocytes includes mucosal Etiology. Both LGV and non-LGV chla-
xanthomas, collections of muciphages, infection mydial serotypes cause gastrointestinal disease

433
Gastrointestinal Diseases

(449). LGV results from an organism that is tissues. The fibrosis causes mural thickening,
biologically and serologically distinct from the rigidity, and stenosis. The rectal strictures usu-
C. trachomatis strains that cause trachoma or the ally have an abrupt line of demarcation with the
more common sexually transmitted chlamydial uninvolved, more proximal large intestine. The
diseases such as cervicitis and urethritis. Infec- inflammatory changes may extend proximally
tion by both LGV and non-LGV chlamydial as far as to the transverse colon, although the
serotypes results from direct anal inoculation disease tends to remain confined to the distal
by infected partners or secondary to lymphatic bowel. Fistulas are common. Endoscopic find-
spread from a penile lesion or from infected ings range from mild erythema and friability
vaginal secretions. In women, anorectal infec- to severe mucosal disease with ulceration and
tions with LGV or non-LGV strains of C. tracho- fistula formation.
matis can also arise from contiguous spread of Microscopic Findings. The histologic find-
infected secretions along the perineum or by ings are as variable as the clinical features. Early
spread via the pelvic lymphatics. Patients may inflammatory reactions of LGV consist of neu-
have other associated diseases, including genital trophilic infiltrates particularly involving the
herpes or syphilis (450). superficial epithelium, sometimes associated
Clinical Features. The spectrum OF intestinal with pseudomembranes (fig. 10-19). Crypt ab-
chlamydial infections ranges from asymptomatic scesses, superficial ulcers, stellate abscesses, and
infection to severe granulomatous proctocolitis. granulomas develop. As the ulcers enlarge, the
Some patients with proven infection remain mucosa is completely replaced by granulation
asymptomatic, while at the opposite extreme, pa- tissue. After a short period of time, the inflam-
tients can present with significant pain, bleeding, mation evolves into a mixed or predominantly
and mucopurulent discharge. The clinical mani- mononuclear cell response with large numbers
festations and histopathologic features. of chla- of histiocytes. Lymphoid follicles form. Late-
mydial infections depend on organism serotype, stage disease is associated with fistula,.develop-
host immune status, and the presence or absence ment and marked fibrosis.
of concurrent infections. LGV chlamydial infec- Special Techniques. The diagnosis is estab-
tions produce much more severe inflammation lished by isolation of the organism in culture,
than non-LGV chlamydial infections. direct immunofluorescence testing of biopsies
Clinically, LGV infection is divided into three or rectal swabs, application of genetic probes to
stages. Primary lesions develop :3 to 30 days the tissues, or by a positive serologic test.
after the initial infection. The primary lesion Differential Diagnosis. The disease mim-
is transient, often imperceptible, and painless, ics Crohn's disease because of the presence of
and may heal rapidly with subsequent scarring. proctitis associated with fibrosis, strictures, deep
Lymphadenitis with suppurative inflammatory fissures, ulcers, granulomas, and sometimes
reactions, known as buboes, characterizes the skip lesions. The lesions associated the LGV,
secondary stage. The tertiary stage usually af- however, are rarely seen proximal to the mid-
fects the gastrointestinal tract, often presenting portion of the descending colon, contrasting
as rectal strictures, rectovaginal or rectovesical with Crohn's disease (447). The disease also
fistulas, or perirectal abscesses. LGV proctitis mimics herpetic or gonorrheal proctitis and
causes diarrhea, a bloody or mucopurulent other causes of infective colitis/proctitis.
discharge, fever, and inguinal and perirectal Treatment and Prognosis. Complications of
lymphadenopathy. untreated anorectal infection include perirectal
•.· Gross Findings. The lesions begin as a pap- abscesses, fistula-in-ana, and rectovaginal, rec-
ule that ulcerates and develops into a painless tovesical, and ischiorectal fistulas. Secondary
elevated area of beefy red granulation tissue. In bacterial infection contributes to the complica-
chronic cases, the ulcers are large and irregularly tions. Anorectal strictures are a late complication,
shaped, with serpiginous extensions. The rectal usually occurring 2 to 6 cm from the anal orifice.
mucosa in LGV loses its haustral folds, appear- Strictures may be mistaken for carcinoma. There
ing ulcerated, friable, nodular, hemorrhagic, is the possibility of the late development of ad-
and edematous, with fibrosis of the underlying enocarcinoma or squamous carcinoma.

434
Gastrointestinal Infections

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'
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,_, i.'· ·~, ., . , t ~.., .. r-· lf·· 1 ... · r/•
trJ~~ • • ,IJ I : /.' ; 1, •: • ' /I t
·'·
'1'/ ' ~ '1 I y . ,, _., 1, ' , ' '
I • ?I • ,, .. I• .u~ ' . .. ' ' .• I
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~ ' . ; ' •, {;', . : ,.~~~
: ' ' ' ' I
' '•, l , d ' 't
,, j , I , J (•, I , , I • f' F~ ·
: , , I. J I ' . I .. . t I • t . I ,/ '/ J

I , , I I , ''* I,., t ~ •t./, j f '· If


' / ' r .,,. "",; •· ;. .. : .. . '~P.
, f , I., '• t*•~ I • ;t>?lft '
• J 1 ~, ,J~-!rr' I '
1
j / I '
I I i / ., "1• I • .I I // I ,. ; ) ; , I
, I " •. '~ I I ,, , - ':'. ; •• :~ ;

·t'".::·r, . /,~
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I I
'' '" •· r ' I
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' "' I I ,. ; ·' ~ J I
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1'/ ' .... . .. ,..
~ 1 ~....._ I 11 '!.. I , t ~

Figure 10-19
LYMPHOGRANULOMA VENEREUM
Left: Nonspecific submucosal inflammation of the anus.
Right: Higher-power view of the inflammatory infiltrate shows numerous neutrophils and scattered lymphocytes and
plasma cells.

The bacterial endospores do not divide, have


Anthrax
no measurable metabolism, and are resistant to
Defin ition. Anthrax is an often fatal infection drying heat, ultraviolet light, gamma radiation,
that occurs when Bacillus anthracis enters the and many disinfectants (461). Endospores in-
body through abrasions in the skin or by inha- troduced into the body ar~ carried to regional
lation or ingestion. It is the zoonosis to which lymph nodes. These germinate inside macro-
most mammals, especially grazing herbivores, phages and become vegetative bacteria (459).
are considered susceptible. They are then released from the macrophages
Demography. Anthrax is a particular problem and multiply in the lymphatics. They then enter
in tropical environments in Africa, Asia, South the bloodstream, eventually creating massive
and Central America, and the Caribbean. B. septicemia (453).
anthracis is ubiquitous and the infection occurs The major virulence factors of B. anthracis are
in semi-arid rural agricultural countries where encoded on two virulence plasmids, pX01 and
animal husbandry is economically important. It PC02. The toxin bearing pX01 encodes genes
is also a problem in locations where veterinary that produce secreted exotoxins. The toxin gene
services are lacking and traditions and economic complex consists of a protective antigen, lethal
conditions lead to the use of meat, hide, and factor, and edema factor (45 7).
wool from animals that die suddenly (451, Path oph ysiology. Gastrointestinal anthrax
452A56A60). The infection is usually acquired is thought to result from penetration of the
from sick animals or from infected urban labor- mucosa by bacterial spores, with subsequent
ers who deal with contaminated hides and bone germination to the vegetative form. The portal
meal. Recently, exposure to anthrax has resulted of entry is considered to be either in the stom-
from biological terrorism. ach, the cecum, or the terminal ileum.
Etiology. B. anthracis is a large, spore-form- Clinical Features. The four clinical forms of
ing, encapsulated, aerobic, nonmotile, toxin- human anthrax-cutaneous, oral-oropharyn-
producing, Gram-positive rod. It measures 1 x geal, gastrointestinal, and inhalational-are
3 to 10 pm in size. Anthrax spores are formed determined by the portal of entry. The vast
in the soil and in dead animal tissues. Human majority of cases are of the cutaneous type.
infections result from contact with contami- Gastrointestinal anthrax is rare and contracted
nated animals or animal products. There are no by eating contaminated meat (45 1A52A60).
known cases of human-to-human transmission. The signs and symptoms are similar to many

435
Gastrointestinal Diseases

other causes of gastroenteritis: fever, diffuse (462,474,477,477a). Most commonly, Listeria


abdominal pain, and rebound tenderness. There causes severe systemic illness in immunocom-
may also be constipation and diarrhea and the promised persons (471,475), including sepsis,
stools may be blood-tinged or exhibit melena. meningitis, and encephalitis. It also affects pre-
Ascites develops with concomitant reduction viously healthy people. Less commonly, Listeria
of abdominal pain, 2 to 4 days after symptom causes gastroenteritis.
onset. The ascites fluid may be clear to purulent Etiology. L. monocytogenes, a Gram-positive
and often yields colonies of B. anthracis if cul- bacterium, grows at low temperatures and
tured (453). Ulceration of the gastrointestinal causes several illnesses in humans and animals.
tract and invasion of regional lymphatics are Acquisition of the organism has been described
common, and hemorrhagic gastritis or ileocoli- following consumption of infected coleslaw,
tis may cause obstruction or perforation. Death hot dogs, delicatessen meats, seafood, fresh veg-
results from electrolyte imbalance, fulminant etables, milk, and cheese (463,464,467,472,482,
diarrhea, and progressive ascites. 484,485). In a recent outbreak, 72 percent of
Gross Findings. The stomach and/or intes- people exposed to infected corn reported symp-
tines appear phlegmonous and hemorrhagic, toms and 19 percent were hospitalized due to
and contain serpiginous ulcers. The pathologic the severity of the symptoms (463).
findings of the ileocecallesion include a solitary, Pathophysiology. The major portal of entry
hemorrhagic, necrotic, edematous mucosa and of Liste1ia in humans is thought to be the intesti-
hemorrhagic mesenteric lymphadenitis. nal tract. The bacteria likely enter through Peyer
Microscopic Findings. Histologtcally, bacilli patches (480,481). Listeria is able to penetrate
are seen microscopically in the mucosal and sub- many cell types, including enterocytes and M
mucosallymphatics and there is evidence of mes- cells (478). Entry into host cells is mediated by
enteric lymphadenitis (454). Ulceration always two bacterial surface proteins belonging to the
occurs. There is also massive edema and mucosal internalin family, In1A and In1B (4,69, 473).
necrosis (455). The stomach or intestines show These proteins interact with receptors on the
massive edema and moderate perivascular hem- host cell, E-cadherin and c-met (478,486). This
orrhage. Intramurallymphatics contain anthrax interaction leads to receptor-mediated internal-
bacilli. Involvement of regionallymphatics paral- ization of the bacteria into the host cell.
lels that seen in the mediastinum. Once the Listeria organisms are inside the cell,
Special Techniques. The diagnosis is con- they manufacture a pore-forming protein called
firmed by culturing the organism or through listeriolysin 0, which tunnels into phagosome
the use of serologic or immunologic tests. In ad- membranes, dissolving them, and setting the
dition, newer molecular diagnostic techniques microbes free within the cytoplasm. A Listeria
focus on the use of PCR to amplify markers PEST (P, Prog; E, Glu; S, Ser; T, Thr) sequence
specific to B. anthracis. prompts the protein degrading machinery of
Treatment and Prognosis. Patients with the bacteria's host macrophages to eliminate
systemic infection resulting from inhalation of the pore-forming protein. The PEST tag ensures
the organism have a mortality rate approaching that, once freed from the vacuoles, the proteins
100 percent, with death usually occurring within are destroyed or disabled before they damage
a few days after the onset of symptoms (458). the host cell membrane, killing the cell in which
High-dose penicillin G is the treatment of choice; the Listeria organisms reside (468).
streptomycin, erythromycin, and tetracycline Following their release into the cytoplasm, the
r.,.
have also been used. Intensive supportive care is bacteria proliferate and polymerize cellular actin
often necessary. Other potential new treatments (465,466). Bacteria move from cell to cell via
include the administration of antitoxins (453). membranous extensions of the host cell plasma
membranes. These extensions protrude into ad-
Listeria Infections
jacent cells where they are lysed by two bacterial
Demography. Listeria monocytogenes causes toxins, PleA and PleB, allowing the organisms
approximately 2,500 cases of serious illness, to enter the cytoplasm of the neighboring cell
and 500 deaths per year in the United States (466). Listeria produces no known enterotoxins.

436
Gastrointestinal Infections

Clinical Features. Unlike other foodborne eral microorganisms are suspected pathogens
infections, the clinical manifestations of L. including Escherichia coli, Klebsiella pneumoniae,
morwcytogenes infection usually result from and Enterobacter cloacae, but no one organism is
sepsis or involvement of the CNS, often in im- common to all patients.
munocompromised persons. Sometimes, how- Clinical Features. For tropical sprue to de-
ever, gastrointestinal symptoms are produced, velop, a person must reside in or visit a country
including diarrhea, nausea, vomiting, and in which the disease is endemic. Characteristic
abdominal cramps, often accompanied by fever clinical features of severe tropical sprue include
(463,467,483,485). The organism requires a brief malabsorption, nutritional deficiencies, anorex-
incubation period of 24 hours to cause disease ia, abdominal distension, and persistent diarrhea.
with gastrointestinal symptoms and fever (463); Symptoms of nutritional deficiency include pal-
some have reported shorter incubation times of lor, weakness, edema, and night blindness. Severe
18 and 20 hours (467,483). vitamin B12 malabsorption can cause neurologic
Pathologic Findings. No gross lesions as- signs; the malabsorption occurs secondary to
sociated with listeriosis have been described. mucosal damage. Chronic tropical sprue occurs
Histologically, Listeria organisms are associated if the acute phase does not completely resolve.
with localized acute inflammation of the small When the disease develops in expatriates, its
intestine and appendix (470,476,479) initial manifestations may appear in temperate
Differential Diagnosis. The differential di- countries, sometimes years after emigration
agnosis includes all other forms of foodborne from an area where it is endemic (489). Jejunal
gastroenteritis. biopsies are necessary to establish the presence
Treatment and Prognosis. In immunocom- of the characteristic morphologic abnormalities
petent patients, Listeria produces a mild, self- and to exclude other disorders such as Whipple's
limited gastroenteritis. No antibiotic treatment disease, parasites, or lymphoma.
is warranted in such individuals. In immuno- Gross Findings. The major changes affect
compromised patients, however, Listeria may the jejunum and the ileum. Radiographic ab-
produce a severe invasive enteritis with a high normalities are nonspecific and include small
risk for systemic dissemination of the organism. intestinal thickening, coarsening of the mucosal
These patients should be treated aggressively folds, and barium segmentation.
with antibiotics. Listeria is generally susceptible Microscopic Findings. The early changes
to a wide range of antibiotic agents (476). of tropical ·sprue resemble those seen in celiac
disease. The jejunal mucosa appears normal or
Tropical Sprue
only slightly abnormal, with increased numbers
Definition. A working definition of tropical of intraepithelial lymphocytes. Later, villous
sprue that is supported by most investigators is atrophy and crypt hyperplasia develop (fig. 10-
"malabsorption of two unrelated test substances 20). A marked mononuclear infiltration with
by a patient from an appropriate geographic lymphocytes and plasma cells develops in the
area with exclusion of other diseases such as lamina propria and epithelium. Eosinophils
those of parasitic origin and nontropical sprue" may be present. Less than 10 percent of patients
(488,490,493). develop a completely flattened mucosa. Nuclei
Demography. Tropical sprue is a major of crypt enterocytes appear megaloblastic. Pan-
health problem among natives of, visitors to, eth cells are normal in number and endocrine
and expatriate's from selected countries largely cells are increased. The basement membrane
located between the Tropic of Cancer and the underlying the surface epithelium is thickened.
Tropic of Capricorn. The disorder is well docu- Differential Diagnosis. The histologic fea-
mented in Asia, parts of Central and South Af- tures completely mimic those seen in celiac dis-
rica, the Philippines, the East Indies, the West ease. Therefore, clinical correlation is required.
Indies, and parts of central and northern South Serologic tests specific for celiac disease may
America. It also occurs in India (487,488,492). exclude tropical sprue . Additionally, the symp-
Etiology. Most believe that tropical sprue toms of tropical sprue do not remit when the
results from infection by toxigenic bacteria. Sev- patient adheres to a gluten-free diet. Diagnostic

437
Gastrointestinal Diseases

Figure 10-20
TROPICAL SPRUE
Left: Mild to moderate villous atrophy of the small intestine. There is an increase in intraepitheliallymphocytes similar
to that seen in celiac disease.
Right: Higher-power view shows the intraepitheliallymphocytosis and prominent lymphoplasmacytic infiltrate within
the lamina propria.

Table 10-8
Treatment and Prognosis. Treatment for 6
FACTORS PREDISPOSING TO months with a poorly absorbed sulfonamide
BACTERIAL OVERGROWTH (sulfaguanidine) or sulfasuxidine is very effec-
Gastric hypochlorhydria or achlorhydria tive (491).
Atrophic gastritis
Partial gastrectomy Bacterial Overgrowth Syndromes
Vagotomy
Proton pump inhibitor therapy
Definition: Bacterial overgrowth syndromes are
characterized by excessive numbers of bacteria in
Surgical factors
Resection of ileocecal valve the proximal small intestine. Patients who typi-
Billroth II cally develop bacterial overgrowth syndromes
Surgical blind loop are those who have had surgical procedures that
Anatomic factors create an anastomotic blind loop, those with
Intestinal obstruction underlying motility disorders, or those with
Duodenal-jejuna! diverticulosis
Gastrocolic or enterocolic fistula
multiple small intestinal diverticula. Certain
medical conditions and advanced age may also
Dysmotility syndromes
Scleroderma
predispose to bacterial overgrowth (Table 10-8).
Idiopathic intestinal pseudoobstruction Pathophysiology. Bacterial overgrowth alters
Diabetic autonomic neuropathy normal gastrointestinal function via direct mu-
Others cosal injury or through disturbed brush border
Other medical conditions function. A number of functional consequences
Crohn's disease of this damage occur, including decreased di-
Chronic pancreatitis
Cirrhosis saccharidase activity; decreased transport of
Immunodeficiency monosaccharides, amino acids, fatty acids; and
End-stage renal disease protein-losing enteropathy.
Fat malabsorption occurs because bacteria of
the small intestine decon{ugate bile salts, result-
evaluation of tropical sprue also requires its dif- ing in impaired transport of lipids through the
ferentiation from parasitic diarrheal diseases. In damaged epithelium. Water soluble, conjugated
contrast to bacterial or viral infections, which bile salts form mixed micelles with partially
are short-lived, tropical sprue usually fails to digested dietary lipids. When bile salts are de-
improve after returning to a temperate climate. conjugated by the action of bacteria, micelle

438
Gastrointestinal Infections

formation is impaired, leading to fat malabsorp- Vitamin B12 deficiency accompanying


tion. In addition, the free bile salts formed in bacterial overgrowth syndrome results in mac-
this process may be directly toxic to the small rocytic and megaloblastic anemia. In severe
intestinal epithelium, leading to further muco- cases, neurologic damage occurs, including
sal damage (501). peripheral neuropathy and cognitive defects.
Carbohydrate malabsorption also occurs in Malabsorption of fat-soluble vitamins may lead
bacterial overgrowth syndromes. This is likely to night blindness, osteomalacia, coagulopa-
the result of a combination of factors including thy, or vitamin E deficiency syndromes (499).
intraluminal degradation of carbohydrates by lu- Iron deficiency anemia may occur as a result
minal bacteria, impaired disaccharidase activity, of chronic occult blood loss from the damaged
and damage to the brush border of the epithe- mucosa (496).
lium. Luminal bacteria metabolize malabsorbed Pathologic Findings. In mild cases, focal,
carbohydrates to form short-chain organic acids mild, patchy histologic abnormalities may be
that increase the osmolarity of the luminal easily missed by a single random biopsy or eas-
contents, thus contributing to diarrhea. Protein ily overlooked in the specimen. In severe cases,
malabsorption may also occur secondary to the spectrum of changes ranges from patchy,
impaired absorption of amino acids, utilization villous broadening and flattening to complete
of luminal protein by bacteria, or as a result of a villous atrophy with crypt hyperplasia or hypo-
protein-losing enteropathy that may occur as a plasia. Numerous microorganisms adhere to the
result of damage to enterocytes (495,498,499). mucosa or embed in the unstirred mucus layer
A classic manifestation of bacterial overgrowth overlying the epithelium.
is vitamin B12 deficiency that cannot be correct- Special Techniques. The diagnosis of bac-
ed by replacement of intrinsic factor. Anaerobic terial overgrowth relies on three criteria: 1)
bacteria competitively absorb vitamin B12 bound presence of increased intestinal volume; 2) the
to intrinsic factor, leading to diminished avail- demonstration of increased bacterial concentra-
ability of this vitamin to the host (502). tions; and 3) a positive response to antibiotic
Another factor that may contribute to diarrhea therapy. Bacterial overgrowth syndromes can
in bacterial overgrowth is the formation of bacte- also be diagnosed by jejunal culture, gas-liquid
rial metabolites that stimulate water and electro- chromatography of jejunal fluid, and 14 C-D
lyte secretion from enterocytes. Such products xylose or hydrogen breath tests. Of these, the
include free bile acids, hydroxylated fatty acids, most sensitive is jejunal culture.
and other organic acids. Experimental evidence Differential Diagnosis. The differential diagno-
suggests that bacterial overgrowth may induce sis of bacterial overgrowth includes other entities
dysmotility in the small intestine, predisposing leading to malabsorption (see chapter 12).
to further bacterial proliferation (497). Treatment and Prognosis. The main objec-
Clinical Features. The symptoms experienced tives in the treatment of bacterial overgrowth
by patients with bacterial overgrowth depend syndrome are correction of the underlying small
on the predisposing small bowel abnormality. intestinal abnormality if possible, elimination
Patients with small intestinal strictures, obstruc- of the bacteria through the use of antibiotics,
tion, dysmotility, or surgically formed blind and treatment of any coexisting dysmotility
loops usually complain of vague abdominal dis- syndrome with prokinetic agents. Nutritional
comfort, periumbilical cramping pain, and bloat- deficiencies should also be corrected.
ing, followed later by diarrhea and malabsorp- In most patients, a single course of antibiotic
tion. The symptoms of bacterial overgrowth in treatment results in marked improvement in
patients with Crohn's disease, chronic intestinal symptoms. In some, however, cyclic treatment
pseudoobstruction, and short bowel syndrome is necessary because of recurrent symptoms.
may be masked by symptoms attributable to Numerous antibiotics are effective including
the primary diagnosis. Weight loss may occur amoxicillin-clavulanic acid (494), cephalexin
in association with steatorrhea in any of these and metronidazole, colistin and metronida-
patients. Hypoproteinemia is common, and zole, ciprofloxacin, and trimethoprim-sulfa-
may be of sufficient severity to cause edema. methoxazole (500).

439
Gastrointestinal Diseases

FUNGAL INFECTIONS intestine. In the small bowel, the rapid passage of


Fungi are ubiquitous in nature, since they luminal contents due to peristalsis and the pre-
are associated with plants; animals, and insects. vention of Candida mucosal interactions by bac-
Humans are continually exposed to many fungal terial antagonism reduce the likelihood of fungal
types by various routes, but particularly, by in- colonization. The normal gastrointestinal flora
gestion of food, allowing colonization of the gas- profoundly antagonizes and suppresses Candida
trointestinal tract. Depending on the interaction growth in a variety of ways (512,513). Symptoms
between the host mucosal defense mechanisms due to Candida infection in the gut relate primar-
and fungal virulence factors, colonization may ily to tissue invasion, although hypersensitivity
be transient or persistent, or local disease may mechanisms and, possibly, byproducts of fungal
develop. Of the various pathogenic fungi, yeasts growth, may induce functional abnormalities.
of the Candida species are the most frequent fungi The ability of Candida to form hyphae under
responsible for human gastrointestinal infections. certain environmental conditions is considered
an additional virulence factor. Transcription
Candida Infections factors that are activated during morphogenesis
Demography. Typically, candidiasis affects may induce expression of genes involved not
patients on antibiotics, hemodialysis, or che- only in the formation of hyphae, but those that
motherapeutic agents; immunocompromised also encode virulence factors (51 0). In addition,
individuals; immunocompetent patients with Candida organisms secrete a variety of protein-
serious postoperative complications, cancer, ases and phospholipases, which contribute to
severely debilitating diseases, and penetrating their ability to invade tissues (510,514).
abdominal trauma; and patients with indwell- Clinical Features. Esophagus. Patients with
ing vascular access devices. Increasing numbers Candida esophagitis are frequently asymptom-
of cases are acquired in the hospital setting. atic, especially when immunologically intact,
Candida organisms also commonly colonize and have only scattered adherent plaques
blind loops, sites of bacterial stasis, and necrotic within the esophagus. Asymptomatic patients
tissue. Candidiasis develops in three stages: seldom undergo endoscopy and the prevalence
colonization by the organism, followed by of fungal esophagitis among patients with mi-
epithelial infection, then deeper invasion. The nor abnormalities of motility or immunity is
degree of underlying immune su~pression is the probably under reported. When symptomatic,
most important determinant of the prevalence patients with Candida esophagitis present most
and consequences of Candida infection (504). commonly with dysphagia, odynophagia, and
Etiology. The most common species of Can- retrosternal pain. Constitutional symptoms, in-
dida are C. albicans, C. tropicalis, C. glabrata, C. cluding fever, occasionally occur. Vomiting and
parapsilosis, and C. lausei. C. glabrata is respon- bleeding are rare. In some patients, epigastric
sible for approximately 15 percent of mucosal pain is the dominant symptom. Most patients
and systemic candidiasis. In the immunocom- have underlying hematologic malignancies or
promised host, there is a higher frequency of AIDS, or have undergone transplantation.
disseminated C. tropicalis than C. albicans. In AIDS patients, there may be a complete
Pathophysiology. C. albicans expresses a lack of symptoms (504). In those who are par-
number of adhesion molecules capable of in- ticularly prone to esophageal Candida infec-
teracting with ligands on a variety of different tion, the diagnosis can often be derived from a
cell types. These adhesins recognize and bind careful history and physical examination. The
r. ,-
to proteins such as fibronectin, vitronectin, and presence of both esophageal symptoms and
laminin, among others (506,509,514-516) . C. oral candidiasis has a positive predictive value
glabrata organisms also avidly adhere to epithe- for esophageal candidiasis of 100 percent; the
lial cells via an adhesin encoded by the EPA-1 absence of symptoms and oral candidiasis has
gene, which recognizes a specific carbohydrate a negative predictive value of 96 percent (517).
molecule (505). Despite the presence of this Stomach. The role of acid in influencing
adhesion molecule, Candida has difficulty colo- gastric carriage rates of Candida is controver-
nizing nonsquamous cell sites such as the small sial, since the yeast thrive in a wide pH range

440
Gastrointestinal Infections

and can proliferate and germinate at low pH.


Nonetheless, Candida infections in the stom-
ach occur far less frequently than those in the
esophagus. For this reason, the stomach appears
to be intrinsically more resistant to Candida in-
fections. Generally, the organism only invades
preexisting gastric lesions, particularly gastric
ulcers (benign and malignant), as well as sites of
gastric resection. The extent of gastric Candida
infection ranges from colonization only, to su-
perficial overgrowth of the surface of an ulcer,
to histologically confirmed mucosal_invasion.
Most frequently, the yeast are seen in superficial
exudates, especially overlying ulcers.
It is difficult to determine the exact symp-
toms associated with gastric candidiasis because
it usually coexists with another medical prob- Figure 10-21
lem, such as a gastric ulcer. When symptoms are GASTRIC CANDIDA: GROSS APPEARANCE
present, they include epigastric pain, nausea,
Fungi colonize areas of erosion or ulceration.
and vomiting.
Small Intestine and Colon. Autopsy surveys of
adults with hematologic malignancies and other
debilitating diseases, including AIDS, show that Intestine. Candida enteritis may involve
enteric and colonic mucosal invasion by Can- multiple intestinal sites, and multiple candidal
dida occurs (511). Infection of the small bowel ulcers or perforations can be seen.
is found at autopsy in 20 percent of patients Microscopic Findings. Endoscopy with brush-
with gastrointestinal candidiasis (507). These ings and biopsy is currently the gold standard
patients generally have an ulcerated mucosa. technique for diagnosis of esophageal infections
Patients with intestinal candidiasis have watery because the sensitivity and specificity are superior
and sometimes explosive diarrhea, occasional to those of radiography in the diagnosis of Candida
cramps, mild diffuse abdominal tenderness, esophagitis. Histologically, Candida organisms are
and weight loss. Multiple, variably sized ulcers 4- to 6-pm, budding, yeast-like forms admixed
with heaped-up edges and necrotic bases are with nonseptate pseudohyphae that stain posi-
distributed throughout the colon. They grossly tively with PAS and silver stains (fig. 10-22).
resemble CMV infection. In some cases, anal- Candida infections may be classified as either
lergic reaction to the fungi may be responsible noninvasive or invasive. In noninvasive disease,
for the associated diarrhea (503) . the fungi grow in devitalized tissues without in-
Gross Findings. Esophagus. Candida esopha- vading underlying intact tissues, as commonly
gitis is characterized by adherent, white or tan occurs in tissues overlying gastric ulcers (fig.
mucosal plaques (fig. 10-21). Additional find- 10-23). In invasive infections, the organisms are
ings include hyperemia, areas of ulceration, a seen within viable tissues. The organism often
cobblestoned appearance of the mucosal surface, invades the vasculature, leading to ischemia and
and disordered motility. There is occasional nar- candidal sepsis. If the patient has preexisting
rowing of the esophageallumen. Rare complica- ischemia, the disease may worsen.
tions include perforation and fistula formation. Special Techniques. Fungal stains highlight
A reliable diagnosis is only made by histologic organismal structure and allow assessment of
evidence of tissue invasion in biopsy material. the extent of tissue or vascular invasion.
Stomach. Plaque-like lesions can be seen en- Differential Diagnosis. Other opportunistic
doscopically in the stomach, and when found, infections in immunocompromised patients.
are usually superimposed on preexisting gastric Treatment and Pr ognosis. The decision
ulcers or gastritis. whether to use topical therapy, oral systemic

441
Gastrointestinal Diseases

Figure 10-22
CANDIDA ESOPHAGITIS
Left: Esophageal brush specimen shows nmperous squamous cells with admixed fungi. Both yeast forms and pseudohyphae
are present.
Right: A methenamine silver stain highlights the fungal organisms.

Figure 10-23
CANDIDA
Left: Candida spores are present in the exudate overlying an ulcer (ulcer not shown).
Right: Fungal hyphae grow in the devitalized tissue.

therapy, or intravenous therapy to treat Candida is sometimes necessary in patients with severe
infections is based on the degree of immuno- invasive esophageal candidiasis with transmural
compromise present in the affected patient, necrosis and perforation (508) . After therapy
and whether or not there is invasive disease. with antifungal drugs, patients generally recover
For patients with a normal immune system, with no persistent sequelae. Patients who pres-
nystatin suspension or clotrimazole is effective. ent with severe fungal esophagitis complicated
Immunocompromised patients require systemic by fistula formation, perforation, or stricture
therapy with agents such as fluconazole. Caspo- may have residual anatomic defects follow-
fungin is also effective (518). Prophylaxis is not ing the antifungal therapy. Granulocytopenic
recommended. Severe infections may require patients with severe esophagitis may succumb
treatment with amphotericin B. Mere coloniza- from disseminated fungal infection or from
tion of gastric ulcers does not require therapy. changes of renal toxicity due to amphotericin
Esophageal resection with antifungal therapy B therapy.

442
Gastrointestinal Infections

in calcified granulomas that remain following


Histoplasma Infections
the initial infection. This may also represent
Demography. Histoplasma capsulatum has a a source of reactivation in the event that the
worldwide distribution, occurring in the cen- patient becomes immunocompromised.
tral region of the United States from the Gulf Macrophages ingest the yeast after opson-
Coast to the Great Lakes, including a broad ization with antibody or complement, or follow-
area along the Ohio and Mississippi River Val- ing direct binding of the organism to the beta-2
leys. It is the most common endemic systemic or CD18 integrins on the surface of phagocytes
mycosis in the United States. It is also endemic (523) via the fungal adhesin HSP60s (532). The
in ·the Caribbean, and in Central and South organism is internalized via a phagosome that
America. Skin testing reveals that most people subsequently fuses with lysosomes within the
living in endemic areas become infected. The macrophage cytoplasm.
fungus grows in soil with a high nitrogen con- Once inside the lysosome, Histoplasma em-
tent, particularly that enriched by bird and bat ploys several mechanisms to escape destruc-
guano. Even a brief exposure to the fungus may tion. The major Histoplasma-secreted antigen,
result in infection. Disseminated histoplasmosis the M antigen, is thought to be a hydrogen
is rare and predominantly affects immuno- peroxide-degrading catalase (548). This cata-
compromised individuals. It also affects some lase may neutralize the harmful effect of host
patients without an identifiable immunological cell-generated hydrogen peroxide. Survival of
defect. Immunosuppressed patients develop intact viable fungus in the hostile environment
particularly severe infections. of phagolysosomes within the macrophages re-
Etiology. H. capsulatum is a dimorphic as- quires Histoplasma protein synthesis (534,546),
comycete with a saprophytic infectious, but indicating an active role of the organism in
nonpathogenic, mold morphotype, and host- promoting its own survival. It may accomplish
adapted pathogenic yeast morphotype. Three this by moderating the microenvironmental pH,
variants within the species exist: H. capsulatum reducing its acidity. This function may occur
var. capsulatum, H. capsulatum var. duboisii, and through a fungal protein pump (537). Addition-
H. capsulatum var. farciminosum. The first two ally, the mode of entry of the organism into
variants infect humans and other mammals, macrophages via alternative nonopsonophago-
while the third does not (535). The morphologic cytic mechanisms may help the organism avoid
features of the fungus depend on the tempera- or suppress host defenses against it (544).
ture. In the soil at 25°C, it exists as a mold (hy- Hosts also defend against pathogens via se-
phae or mycelia) and asexual spores, whereas questration of essential nutrients, such as free
at 3 7°C (in the mammalian host) it exists as a iron, that are necessary for pathogen survival.
budding yeast. Temperature switches are suffi- Most iron in the mammalian host is not freely
cient to induce the change in the morphology. available, but is bound to host proteins such as
Pathophysiology. H. capsulatum is an effec- transferrin. The host response to microbial in-
tive intracellular parasite of macrophages. The fection may include reduction of the iron satu-
organism is acquired by inhalation of spores ration level of transferrin and downregulation of
or mycelial fragments. Once inside the host, host cell transferrin receptors (524). Histoplasma
the organism converts to its pathogenic yeast acquires iron through several mechanisms. The
form, which survives and multiplies within organism secretes low molecular weight, iron-
macrophages. It is thought that in most cases chelating siderophores that scavenge ferric iron
the host mounts a fungistatic, rather than fungi- (528,529,540). H. capsulatwn also has the ability
cidal, response, leading to the establishment of to reduce ferric iron, allowing the organism to
persistent inactive infection. The infection can utilize ferric salts as a source of usable iron (539).
later be reactivated if the host pathogen balance Histoplasma is resistant to calcium depriva-
becomes disrupted (535,545,547). It is thought tion as occurs in phagolysosomes. A low calcium
that the organism remains quiescent within the concentration within the phagolysosome acts
reticuloendothelial system and perhaps in endo- as an environmental signal for expression of
thelial cells as well. Organisms can also be found the fungal proteins necessary for intracellular

443
Gastrointestirzal Diseases

survival. The organisms secrete a calcium-bind-


ing protein, CBP1, that allows them to grow in
this calcium-poor environment (519,520).
H. capsulatum also has defense machinery
that interferes with the fusion of phagosomes
and lysosomes and blocks acidification of
phagolysosomes, a step that may be necessary
for activation of lysosomal enzymes (525). This
may be accomplished in part by exclusion of
the host vacuolar ATPase/proton pump from
phagocytic vacuoles in which the organisms
are located (538).
Clinical Features. The fungi usually gain
access to the body through the lungs. Inhaled
spores reach the bronchioles or alveoli and
germinate within 48 to 72 hours, producing
the yeast form of the fungus. If only a few or
a moderate number of spores are inhaled, the
pulmonary lesions are asymptomatic. Heavy
spore inhalation causes symptomatic illness, Figure 10-24
even in immunocompetent indiViduals. In a COLONIC HISTOPLASMOSIS
small percentage of individuals, a more severe Endoscopic photograph demonstrates yellowish plaque-
form of progressive pulmonary infection or dis- like lesions in the colon of a patient with disseminated
seminated disease occurs. These patients often histoplasmosis.
have some form of immunocompromise.
The clinical syndromes associated with H. In patients with mediastinal granuloma
capsulatum include acute self-limited syndrome, syndrome, the enlarged lymph nodes obstruct
disseminated histoplasmosis, chronic pulmo- and encroach upon the esophagus producing
nary histoplasmosis, mediastinal granulomata, obstruction, motility problems, and sometimes,
and fibrosing mediastinitis. The acute syndrome perforation. Patients with sclerosing mediasti-
in the normal host is generally mird, manifested nitis have similar features.
by fever, headaches, chills, cough, and chest Gross Findings. A spectrum of gross findings
pain in at least two thirds of patients (527) . may be seen in patients with gastrointestinal
Gastrointestinal histoplasmosis usually appears histoplasmosis. The most common is muco-
as part of disseminated disease and is acquired sal ulceration; other findings are submucosal
by the hematogenous route. Isolated gastroin- plaques or nodules (fig. 10-24), foci of hemor-
testinal histoplasmosis may also occur (530) . rhage, and obstructive mass lesions. The mucosa
Gastrointestinal involvement by Histoplasma may appear normal in up to one quarter of cases
may affect any site, including the esophagus, (531). Extensive disease leads to widespread tis-
stomach, small bowel, and large bowel. Mani- sue destruction and even perforation.
festations include nausea, vomiting, diarrhea, Microscopic Findings. Histoplasmosis is
fever, hepatosplenomegaly, gradual weight loss, predominantly an intracellular mycosis of re-
fatigue, and weakness. Terminal ileum involve- ticuloendothelial cells. Histologically, mucosal
... ment predominates in one third of the cases. In plaques consist of diffuse histiocytic collections
severe disease, perforation and peritonitis may filled with organisms that expand the lamina
occur (522) . Masses or ulcers in the gastrointes- propria. Small particulate'bodies are seen within
tinal tract often mimic IBD or carcinoma (526). the histiocytes, even in H&E-stained prepara-
AIDS patients with disseminated histoplasmosis tions. The yeast-like phase is a round to oval
often have acute severe symptoms associated spore with rigid cell walls from which the
with shock, respiratory failure, and dissemi- cytoplasm has often retracted, measuring 2 to
nated intravascular coagulation (543). 4 pm in diameter (fig. 10-25). It reproduces by

444
Gastrointestinal Infections

Figure 10-25
SMALL INTESTINAL HISTOPLASMOSIS
A: A granuloma in the deep mucosa is surrounded by a
lymphoplasmacytic infiltrate.
B: Higher-power view of a well-formed granuloma due
to Histoplasma infection.
C: Methenamine silver stain showing Histopla sma
organisms within the tissues and inside histiocytes. The
organisms are small (2 to 4 pm) yeast forms that occasionally
show evidence of budding.

budding. In severe disease, fungi fill the mac- molecular testing methods for the diagnosis of
rophages. The organisms are easily visualized infection have become available (521,533,536).
with PAS and other fungal stains. Although oc- Differential Diagnosis. Histologically, the
casionally the organism lies within well-formed fungus-containing histiocytic infiltrates morpho-
granulomas, more often, diffuse histocytic logically resemble those seen in various disorders,
infiltrates are present (531). Following therapy, including Whipple's disease and mycobacterial
degenerating and dead organisms are seen. Long infections. The characteristic organisms are eas-
after disease remission, there may be fungal cell ily distinguishable from Whipple's bacilli or
wall remnants within macrophages. Mycobacteria with special stains. Other entities
Special Techniques. The diagnosis of dis- in the differential diagnosis are other fungi with
seminated disease is usually accomplished by yeast-like forms (Table 10-9). If well-formed
demonstrating the fungus in cultured material granulomas are present, the differential diagno-
from blood, urine, liver, bone marrow, or other sis includes xanthoma, tuberculosis, yersiniosis,
affected tissues. In patients with limited disease, Crohn's disease, and foreign body granulomas.
however, cultures are frequently negative (542). Treatment and Prognosis. Therapy is re-
Patients with systemic histoplasmosis and AIDS quired for disseminated disease, since the mor-
have positive blood cultures in 83 percent of tality rate for untreated patients is extremely
cases and positive bone marrow cultures in 71 to high. Amphotericin B is the drug of choice for
75 percent, making these tissues the best sources fulminant disease and patients receive at least
of Histoplasma organisms for microbiologic 35 mg/kg total dose for 3 to 4 months. Over 90
study (549). Serologic testing may be helpful percent of AIDS patients relapse, and therefore,
in detecting Histoplasma antigens. Recently, maintenance therapy with oral itraconazole

445
Gastrointestinal Diseases

Table 10-9
M ORPHOLOGIC FEATURES OF FUNGI THAT OCCUR AS YEAST-LIKE CELLS IN TISSUE

Histoplasma
capsulatum Blastomyces Paracoccidioides
var capsulatum dermatitidis brasiliensis Candida sp. Torulopsis glabrata
Size (pm) 2-4 7-15 5-60 3-6 2-5
Shape Spherical or oval Spherical Spherical Spherical or oval Spherical or oval
Number of buds Single Single Multiple; "steering Single; chains Single
wheel" forms
Attachment of buds Narrow Very broad Narrow Narrow Narrow
Thickness of cell wall Thin Thick Variable Thin Thin
Pseudohyphae and/or Rare Rare Rare Present Absent
hyphae
Number of nuclei Single Multiple Multiple Single Single
Mucicarmine reaction ±

is recommended indefinitely. In non-AIDS ent in the ventilation system or in areas near


patients, amphotericin B treatment should be construction or renovation sites.
followed by oral itraconazole for 6 tc5 18 months Etiology. Approximately 600 species of As-
(542) . Itraconazole is an excellent alternative to pergillus are recognized. The most frequent dis-
amphotericin B in patients with mild m mod- ease-causing species are A. fumigatus, A. flavus,
erately severe infections (541). If the patients A. niger, and occasionally, A. ten·eus. Aspergilli
have developed sclerosing mediastinitis as part are molds that reproduce by means of spores,
of the disease and the fibrosing process compro- termed conidia.
mises the esophagus, surgical resection may be Pathophysiology. As with other molds,
required. Esophageal complications from his- Aspergillus organisms have a tendency toward
toplasmosis are generally treated with
..,. surgery. vascular invasion, producing thrombosis, ische-
mia, infarction, and tissue necrosis. Most infec-
Aspergillus Infections
tions originate in the lungs and then spread to
Demography. Aspergillus species are ubiqui- other organs .
tous, rapidly growing, environmental pathogens Clinical Features. Aspe1gillus is primarily a
that occur worldwide. Risk factors for acquiring pulmonary pathogen that infects patients with
the infection include granulocytopenia and the preexisting pulmonary disease. Invasiveness is
use of immunosuppressive drugs, cytoreduc- promoted by factors that suppress granulocyte
tive agents, broad-spectrum antibiotics, and function such as high-dose corticosteroid ther-
steroids (557,559,560). Patients with chronic apy in patients with obstructive airway disease.
granulomatous disease may present with inva- In profoundly immunocompromised hosts,
sive Aspergillus because of the inability of their Aspe1gillus behaves aggressively, affecting many
phagocytes to generate microbicidal substances. organs. Aspe1gillus infection is particularly severe
Inhalation of spores from the environment is in patients with cancer and AIDS where it may
believed to be the most frequent route of infec- cause deep mucosal lesions in the esophagus that
tion. Accordingly, upper respiratory tract, sinus, can lead to tracheoesophageal fistula formation
and pulmonary diseases are the major sequelae (556) . Patients typically p1'esent with symptoms
of Aspergillus infection. There may also be inva- of painful or difficult swallowing, weight loss,
sion from cutaneous sources, such as central and concurrent mucosal candidiasis. Colonic
venous catheters. Aspe1gillus infections pose involvement may also occur, in which case the
particular problems in hospitalized populations affected patients usually present with lower
when patients are exposed to organisms pres- gastrointestinal bleeding. Perforation may occur

446
Gastrointestinal Infections

secondary to angioinvasion by the fungi, with used imidazoles, ketoconazole and fluconazole.
resultant ischemia. Itraconazole, an absorbable imidazole delivative,
Gross Findings. Although most infections in- is active against Aspergillus organisms and may
volve the esophagus, gastric, small intestinal and be useful in the treatment of mucosal Aspergillus
colonic disease also occur. Vascular invasion by the infection (SS2,SS3). Surgical therapy alone or in
organisms results in thrombosis and infarction, combination with antifungal chemotherapy is
leading to ulceration, hemorrhage, and perfora- used in patients with localized disease. A critical
tion (SSO,SS4). Aspergillus is rare in the stomach factor in optimizing therapy is removal of the
but may produce pseudomembranous gastritis immunosuppression, if possible (SSS) .
(SS8,S61); colonic lesions are characterized by
Blastomyces Infections
submucosal ulcers and confluent necrosis (SSS).
Microscopic Findings. The diagnosis of in- Demography. Blastomyces dermatitidis in-
vasive aspergillosis depends on the histologic fections occur worldwide but are endemic in
demonstration of typical Aspergillus hyphae in certain geographic regions. In the United States,
the tissues. The organism tends to invade vessels, blastomycosis occurs in the same areas as his-
causing vasculitis, thrombosis, ischemia, and in- toplasmosis: along the Mississippi and Ohio
farction. Often, the organisms are visible on rou- River Valleys.
tine H&E-stained material. Methenamine silver Etiology. B. dermatitidis is a species of dimor-
and PAS stains demonstrate the dichotomously phous, round, budding yeast. It grows in tissues
branched septate hyphae of aspergilli and occa- as a thick-walled, round cell measuring 8 to 1S
sionally show the characteristic conidiophores. pm in diameter and reproduces by broad-based
Special Techniques. Endoscopic brushings budding. Multiple nuclei are seen in well-fixed
and biopsies are essential for an accurate diag- sections. The organism spreads in the intestine
nosis of Aspergillus esophagitis. The fungi are by invading submucosal lymphoid tissue, with
easily demonstrated using fungal stains. subsequent erosion into the mucosa and gas-
Differential Diagnosis. The differential di- trointestinallumen.
agnosis of Aspergillus infection includes other Clinical Features. The infection begins with
fungi that exhibit hyphal forms in tissue. They the inhalation of spores into the lung, followed
are distinguished from one another by exam- by control of the infectious process by lung
ining the length and width of the hyphae, the macrophages (S62). Gastrointestinal involve-
presence or absence of septation, the frequency ment is rare and usually manifests with lesions
of septa, the pattern of branching and the ori- in the mouth or oropharynx. Disease distal to
entation of the branches, the uniformity of the the oropharynx is very rare and usually due to
size and shape of the hyphae, the presence or disseminated infection (S62).
absence of natural brown pigmentation, and Gross Findings. Endoscopically, mucosal
the presence of blastoconidia or arthroconidia. friability or erythema is seen.
The lesion somewhat resembles mucormycosis Microscopic Findings. The typical histologic
which also tends to penetrate blood vessels and picture consists of granulomatous inflammation
disseminate through the vasculature. with superimposed pyogenic inflammation.
Treatment and Prognosis. Therapy for inva- Lesions without secondary infections resemble
sive disease is inadequate. Mortality rates range the epithelioid granulomas of sarcoidosis. The
from SO to 100 percent, depending on the un- organism is demonstrable with fungal stains.
derlying disorder (SS1) . Pulmonary or cerebral Treatment and Prognosis. Ketoconazole is
Aspergillus in bone marrow transplant patients used to treat mild to moderate infections and
is associated with a 9S percent mortality rate, amphotericin B severe infections (S63).
regardless of therapy (SS 1). The mainstay of
Paracoccidioides Infections
therapy for invasive Aspergillus organisms is still
intravenous amphotericin B, with doses ranging Demography. Paracoccidioides infection
from 0.6 to 1.S mg/kg/dayforthe duration of the (also known as South American blastomycosis) is
neutropenia, for a total dose of l.S to 4.0 g. This is an important public health problem in South
because Aspergillus are resistant to the commonly America; it does not usually extend further

447
Gastrointestinal Diseases

Figure 10-26
PARACOCC/D/0/DES INFECTION
Left: Low-power view of the inflammatory exudate from an ulcer due to paracoccidioidomycosis. The exudate contains
numerous eosinophils, neutrophils, macroph~ges, and scattered large fungal organisms.
Right: The intestinal mucosa contains a dense inflammatory infiltrate of eosinophils, neutrophils, macrophages, and
scattered multinucleated giant cells.

north than Central America and Me}cico, unless their large size (fig. 10-26), but they also can
an infected person travels into a nonendemic be highlighted by fungal stains. The fungi are
area. Brazil is the center of the endemic region. often surrounded by a granulomatous reaction
Etiology. In tissue, Paracoccidioides grows to be combined with pyogenic inflammation. The
a large, round, oval cell measuring 5 to 15 pm in distinctive feature of the fungus in ti-ssue is an
diameter that reproduces by single or multiple occasional large cell that, when hemisected,
budding. Budding cells can measure up to 20 pm reveals peripheral buds protruding from a
or more. The disease has a long la~ency period thin-walled, round, mother cell, a pattern that
of up to 30 years (565). The infection is acquired sometimes looks like a ship's wheel.
when conidia are inhaled into the lungs. This Differential Diagnosis. Clinically, intestinal
results in a chronic granulomatous process that paracoccidioidomycosis simulates idiopathic
begins with an asymptomatic pulmonary infec- IBD, but finding the organisms resolves the
tion. When the organisms disseminate outside differential diagnosis.
the lungs, they form ulcerating granulomas. Treatment and Prognosis. Ketoconazole is
Clinical Features. Paracoccidioidomycosis is usually given for prolonged periods of time,
a systemic disease that disseminates to several usually 12 to 18 months (564). The triazoles,
organ systems. The portal of entry is the lung. itraconazole and fluconazole, are extremely suc-
From there it disseminates to other organs, in- cessful in producing disease remission with less
cluding the gastrointestinal tract. Paracoccidio- toxicity than ketoconazole (564). Sulfadiazine
idomycosis infects both the large and small or long-acting sulfonamides can also be used.
intestines. Recently, the organism has been
Zygomycosis
shown to be associated with ascites and colonic
"•
malakoplakia (566). Demography. Zygomycetes are ubiquitous
Gross Findings. The ulcerative lesions of and generally saprophytic, rarely causing dis-
paracoccidioidomycosis have a characteristic ease in immunocompetent hosts. They have a
rolled border with a white exudative base and propensity to affect acidotic, usually diabetic
small hemorrhagic dots. These lesions are due patients, but they also affect patients with acido-
to the formation of multiple granulomas. The sis secondary to uremia, diarrhea, or aspirin use
draining lymph nodes are often involved. (aspirin abuse). The most prevalent underlying
Microscopic Findings. The fungi are eas- conditions are kwashiorkor, amebiasis, uremia,
ily seen in H&E-stained sections because of typhoid fever, and gastric neoplasms.

448
Gastrointestinal Infections

Etiology. The most common infectious zy- characteristic pleomorphic, broad, aseptate,
gomycete is Rhizopus anhizus (R. 01yzae), which irregularly right-angled, branched hyphae mea-
tends to produce an acute and rapidly fatal suring 10 to 20 pm in diameter that are well
· infection, mucormycosis, despite early diagnosis seen in H&E-stained sections (fig. 10-27). They
and treatment. can also be highlighted by PAS and methena-
Pathophysiology. The major defect lead- mine silver stains. They invade the surrounding
ing to gastrointestinal tract zygomycosis is the tissues and blood vessels, causing local tissue
disruption of mucosal integrity as occurs in destruction, vascular thrombosis, and ischemic
peptic ulcers. The organisms have a predilection necrosis. Histologically, the ulcer bases contain
for invading major blood vessels and causing necrotic tissue with a surrounding rim of acute
ischemia, infarction, and necrosis of adjacent polymorphonuclear leukocytes and occasional
tissues. giant cells, unless patients are on chemothera-
Clinical Features. Zygomycosis has five peutic drugs, in which case the inflammatory
major clinical forms: rhinocerebral, pulmonary, response may be negligible.
abdominopelvic and gastric (gastrointestinal), Treatment and Prognosis. Successful treat-
primary cutaneous, and disseminated. Each is ment of zygomycosis requires a high index
associated with various abnormalities and host of clinical suspicion for rapid diagnosis. Mor-
defense mechanisms (568). tality rates as high as 85 percent have been
Gastrointestinal zygomycosis is uncommon documented. Treatment requires reversal of the
and results from ingestion of the organism by underlying condition, possible surgical removal
malnourished individuals, individuals with of the infected tissue, and intravenous ampho-
chronic renal failure, or those with underlying tericin B. The fungus is relatively resistant; high
gastrointestinal tract disease. The infection usu- doses are needed to treat it and the prognosis
ally affects the stomach and colon, producing remains poor.
necrotic ulcerations, ischemia, and gangrene
Cryptococcus Infections
(567). Occasionally, the organisms colonize
benign gastric ulcers without invading further. Demography. Cryptococcus neoformans, a
More frequently, they cause mucosal infiltra- yeast-like fungus, occurs worldwide, and is seen
tion and vascular invasion. The presence of the with increased frequency in immunocompro-
mucosal infiltration and tissue invasion may mised patients. It is a life-threatening fungal
simulate malignancy. infection in HIV-infected patients. The most
Infections also occur in the ileum. In most important environmental source of infection is
cases, dyspepsia, abdominal pain, and diarrhea soil contaminated by bird droppings. Gastroin-
are present. There may be vomiting and gas- testinal cryptococcal infections are rare, occur-
trointestinal bleeding. Perforation may occur, ring either as part of disseminated disease or as
resulting in peritonitis. The fungal pathogens an isolated finding (571) that complicates AIDS
may then extend from the gut lumen to the and hematologic malignancies, or in patients
gallbladder, liver, pancreas, and spleen. Gas- on corticosteroids (5 70,5 73).
trointestinal involvement is usually rapidly Clinical Features. The most common clinical
progressive, resulting in death within a few days. forms of the disease are subacute progressive
Gross Findings. Zygomycosis shows a pre- meningitis followed by pulmonary infection.
dilection for the stomach and colon. Patients Esophageal infections have been seen primarily
develop mucos·al ulcers that lead to bloody in HIV-positive patients (572). Gastrointestinal
diarrhea. The organism produces discrete mu- involvement is rare (569,570,573) .
cosal erosions and deep ulcers, causing hemor- Pathologic Findings . Cryptococcus may
rhage, necrosis, and perforation as the infection involve the stomach, duodenum, and colon.
spreads into the bowel wall. Transmural hemor- Grossly, the mucosa may have a nodular or
rhage and necrosis may also be present. ulcerated appearance. Histologically, yeast cells
Microscopic Findings. The organisms of are visualized in affected tissues.
zygomycosis are ordinarily recognized in large Special Techniques. Fungal cultures should
numbers in the lesions. The organisms have exclude other fungal pathogens.

449
Gastrointestinal Diseases

Figure 10-27
MU.COR COLONIZING A GASTRIC ULCER
Left: Numerous ribbon-like hyphae are in the inflammatory debris overlying the ulcer.
Right: Higher-power view of the organisms.

Treatment and Prognosis. The standard tions in immunocompetent patients are short-
therapeutic regimen for acute cryptococcal lived and self-limited, biopsy is rarely required
infection is a combination of amphotericin B to make the diagnosis. Immunocompromised
plus flucytosine. Optimal treatment for gastro- patients frequently develop viral infections,
intestinal disease is unknown. most notably infection with HSV or CMV. In
such patients, biopsy is necessary to make the
Coccidioides Infections
correct diagnosis.
Demography. Coccidioides immitis is a dimor-
phic fungus found predominantly in the south- Rotavirus and Rotavirus-Like
western United States and nou hem Mexico. Particle Infections
Predisposing factors that lead to dissemination Demography. Rotaviruses are the most com-
and infection include pregnancy, age under 5 mon cause of infantile gastroenteritis world-
years and over 50 years, and Hispanic, Asian, or wide, accounting for an estimated 140 million
African descent (574,577,578). Gastrointestinal cases of diarrhea, 1 million deaths in young
coccidioidomycosis is rare. children, and the most hospital admissions
Etiology. Infection is acquired by inhalation for diarrhea in children under 2 years of age
of arthroconidia. In the host, these enlarge and (589,593, 606,628). Most affected patients are
form spherules containing endospores. between 5 months and 4 years of age, although
Clinical Features: Weisman et al. (579) de- individuals of any age may become infected.
scribed a gastrointestinal infection with massive Each year in the United States rotavirus infec-
chylous ascites and extensive abdominal and tions account for an estimated 3.5 million cases
lymphatic involvement. Coccidioidal peritoni- of diarrhea, 500,000 physician visits, 50,000
r. ••
tis also occurs (57 6). hospitalizations, and 20 deaths among children
Pathologic Findings. Histologic examina- less than 5 years of age (593).
tion may show the presence of necrotizing In children in temperate climates, rotavirus
granulomatous inflammation surrounding the infections are acquired more frequently in win-
organisms (575). ter months, but such seasonal variation does not
occur in adults (584,602,606,616). Geographic
VIRAL INFECTIONS variation influences the frequency of rotavirus
Gastrointestinal viral infections are common infection, with the higher rates of infection be-
causes of diarrhea worldwide. Since most infec- ing reported in Japan, Australia, Indonesia, and

450
Gastrointestinal Infections

Mexico relative to those reported in the United Repeat infections are generally less severe than
States and Europe (587,588,591,603,611,612, primary infections (622).
618,620). Rotavirus infections also affect trav- In adults, rotavirus infection may or may not
. elers (often to Mexico or the Caribbean), im- be symptomatic (594,607,627). Symptoms begin
. munosuppressed patients, and the elderly (580, 2 to 6 days following contact with the virus, and
582,585,598,610,619,623). last for 1 to 4 days. When symptoms do occur,
Etiology. Rotaviruses are members of the they include fever, headache, malaise, nausea,
Reoviridae family of RNA viruses. Intact infec- cramping pain, and diarrhea (608,624-626).
tious rotaviruses measure approximately 100 Microscopic Findings. Viral replication
nm in diameter and consist of three protein within the enterocytes leads to enterocyte ly-
layers surrounding a viral genome composed of sis, epithelial shedding, crypt hyperplasia, and
11 segments of double-stranded RNA (581). The inflammatory cell infiltration of the lamina pro-
RNA encodes six viral proteins that compose pria (586,599). The ratio of the crypt depth to
the viral capsid, and six nonstructural proteins. villous height increases. Severe infection causes
Pathophysiology. Rotavirus most commonly gross destruction of the villous architecture.
spreads from person to person via a fecal-oral Special Techniques. The diagnosis of a ro-
route. Rarely, the virus may be foodborne or wa- tavirus infection is usually made by examining
terborne (583,600). Once acquired, the infection the stool for the presence of the virus. Negative
usually spreads from the proximal small bowel contrast electron microscopy demonstrates
to the ileum over a period of 1 to 2 days. Rota- characteristic 70-nm wheel-like particles, and
viruses have very specific cell tropism, infecting was the technique initially used for diagnostic
mature enterocytes on the villus tips and dif- purposes (592). Enzyme-linked immunosorbent
ferentiated enterocytes in the dome epithelium assay (ELISA) and enzyme-interface immuno-
overlying Peyer patches. Interaction of the virus assay (EIA) are now commercially available
with the host enterocyte is probably a multistep and commonly used. These techniques require
process involving the binding of more than one the presence of large numbers of virions to
cell surface receptor (581). The virus enters the generate a positive result (628,629). PCR is a
cell either via calcium-dependent endocytosis more sensitive technique that is currently be-
or via direct entry. Once inside the enterocyte, ing used in a research capacity for detection of
the virus replicates. The new viral particles may the virus (628).
then infect additional downstream enterocytes, Differential Diagnosis. There are four major
or may be excreted in the feces. subclassifications of gastroenteritis-causing vi-
The mechanisms by which rotaviruses cause ruses: rotavirus and rotavirus-like viruses, enteric
diarrhea are not yet fully understood. Potential adenoviruses, caliciviruses (including Norwalk
mechanisms include reduction of the absorp- and Norwalk-like viruses), and astrovirus. These
tive surface of the intestine through damage to entities are usually distinguished from one an-
the villi, impaired absorption due to decreased other using ultrastructural, microbiologic, or
brush border transport functions (597,609,615), serologic tests. Rotavirus infections destroy vil-
altered epithelial permeability (590,604,617), lous epithelial cells, contrasting with parvovirus
stimulation of the enteric nervous system (614), infections which destroy crypt epithelial cells.
or direct enterotoxigenic effects of the rotavirus Treatment and Prognosis. Because the diar-
protein NSP4 (601). rhea is more severe than that seen in many other
Clinical Features. Primary rotavirus infec- gastrointestinal infections, rotavirus causes
tion typically occurs in infants and children a disproportionate number of deaths (589).
between the ages of 6 months and 2 years. In- Treatment is symptomatic and consists of fluid
fection may occur in younger children, usually replacement and supportive care. Severe cases
in a hospital setting. The classic presentation of rotavirus diarrhea have been successfully
is fever and vomiting for 2 to 3 days followed managed with administration of oral human
by the onset of watery, nonbloody diarrhea immunoglobulins directed against the virus
(595). The diarrhea may be profuse, with 10 to (596, 605,613). A rotavirus immunization would
20 bowel movements per day being common. be capable of preventing over 1 million cases

451
Gastrointestinal Diseases

of diarrhea in the first 5 years of life (621). In occurs year round (644). Viral shedding may
1999, shortly after approval of a rotavirus vac- occur for as many as 3 weeks after the onset of
cine, an excess of cases of intussusception was symptoms (645).
noted among recently vaccinated infants, and Microscopic Finding~. Volunteers who
the vaccine was withdrawn from the market. experimentally receive Norwalk virus develop
histologic abnormalities in the small intestine
Norwalk and Norwalk-Like Virus Infections within 12 to 48 hours. The abnormalities include
Demography. N01walk-like viruses cause more mucosal inflammation, enterocyte changes,
than 96 percent of outbreaks of acute nonbacteri- villous shortening, and crypt hyperplasia with
al gastroenteritis in the United States and Europe increased epithelial cell mitoses. Mononuclear
(637,640,649). The degree to which the infection cells and neutrophils infiltrate the lamina pro-
is endemic is unknown, because most individu- pria. The changes persist for at least 4 days and
als who are affected do not seek medical care. clear by 6 to 8 weeks after the acute illness (647).
Norwalk and Norwalk-related viruses have a cos- Special Techniques. Diagnostic tests include
mopolitan distribution, infecting both adults and immunoelectron microscopy, enzyme immu-
children. Outbreaks occur in a variety of settings, noassay, and reverse transcriptase (RT)-PCR for
including military installations, nursing homes, detection of the virus.
restaurants, schools, daycare facilities, summer
Sapporo and Sapporo-like Virus Infections
camps, and cruise ships (635-638,640). The
infection is most commonly acquired through Demography. Sapporo-like viruses are another
consumption of food directly contaminated by genus in the Caliciviridae family of viruses.
an infected food handler (638). As a·result, cold These viruses occur worldwide, and affect pre-
foods such as salads, sandwiches, and bakery dominantly infants and young children (650,
products are most frequently implicated in out- 650a). Rarely, Sapporo virus gastroenteritis oc-
breaks (634). Food may also be contaminated at curs in the elderly. Older children al);.d adults
its source; for example, oysters harvested from are virtually never affected (650a).
contaminated water are commonly associated Etiology. Sapporo-like viruses are antigeni-
with Norwalk virus outbreaks (631,639,648). In cally distinct from Norwalk and Norwalk-like
addition, the virus may be spread by person-to- viruses.
person contact (630,641). Airborne transmission Clinical Features. Sapporo virus causes
likely also occurs (642,643,646). "" gastroenteritis in young children and infants.
Etiology. Norwalk-like viruses are small (27 Ninety-five percent of patients develop diarrhea,
to 32 nm), single stranded RNA viruses that and vomiting occurs in 60 percent (650a). These
constitute one genus in the family Caliciviridae. symptoms are often accompanied by abdomi-
Multiple strains of these viruses circulate at any nal pain, cramps, nausea, and fever. The stools
given time, although at certain times, one strain may contain mucus, but are not bloody. The
may predominate (633). median duration of symptoms is 6 days (645).
Clinical Features. Norwalk-like viruses have Viral shedding is of shorter duration than for
an incubation period of 12 to 48 hours (632), Norwalk viruses.
and the resulting disease usually runs its course
Enteric Adenovirus Infections
in 1 to 3 days, although symptoms may persist
for longer, especially in children (633,645). The Demography. Enteric adenovirus infections
most common symptoms of the infection are account for up to one sixth of cases of viral diar-
diarrhea and vomiting. Patients may also experi- rhea in children in Britain and the United States
ence low-grade fever, abdominal pain or cramp- (653,654a,655,667). Adenoviral illnesses usually
ing, nausea, malaise, myalgia, and headache affect children under age 2, particularly those in
(633,645). Vomiting is more common among the first year of life (654a,661,665). The infec-
children, while diarrhea tends to predominate tions do not demonstrate seasonality. Severe
in adults. In temperate regions, the disease is infections affect immunodeficient individuals
more prevalent in winter months, although and bone marrow transplant recipients, some-
Norwalk-like virus-associated gastroenteritis times causing death (651,669). Adenovirus can

452
Gastrointestinal Infections

Figure 10-28
ADENOVIRUS COLITIS
A: At low power, the colonic mucosal architecture
appears relatively preserved.
B: Higher-power view shows numerous apoptotic bodies
within the glands.
C: Apoptotic bodies are seen within and underlying the
surface epithelium. Some of the goblet cells and colonocytes
contain slightly eosinophilic, smudgy nuclear inclusions.

be isolated from the stool of from 4 to 18 percent patients as a result of terminal ileal lymphoid
of HIV-infected patients (656,659,662,664,666). hyperplasia accompanying nonenteric adeno-
Etiology. Some adenoviruses, in particular virus infection (654,657,658).
serotypes 40 and 41, produce gastroenteritis, Gross Findings. The endoscopic appearance
but unlike conventional adenoviral serotypes, of the colonic mucosa is either normal or shows
enteric adenoviruses do not primarily produce erythematous raised lesions measuring several
nasopharyngitis or keratoconjunctivitis. millimeters in diameter.
Clinical Features. Adenovirus infections Microscopic Findings. The histologic changes
affect the stomach, small intestine, and colon. of adenovirus infection are relatively nonspecific
The clinical features of adenovirus infection and include villous atrophy and inflammation.
in children are diarrhea, fever, vomiting, and The diagnosis relies on finding the nuclear viral
mild dehydratiqn (661). Vomiting and fever are inclusions. Adenovirus-infected cells have char-
less prominent than with rotavirus infection acteristic amphophilic or eosinophilic nuclear
(663) . Affected children may also complain inclusions, predominantly affecting the goblet
of associated abdominal pain and respiratory cells in the epithelium and the upper parts of
tract infection (661). Adenovirus infections in the crypts (fig. 10-28) (668). The enlarged nuclei
HIV-infected patients typically last from 5 to sometimes have a smudgy appearance or appear
12 days, producing protracted, watery, nonmu- crescenteric; they lie at the cell bases. Other
coid, nonbloody diarrhea and weight loss (659). changes include budding of the epithelium and
The diarrhea results from extensive epithelial shedding of the epithelium into the lumen.
sloughing. Intussusception may occur in some Rare glands become necrotic and inflamed. The

453
Gastrointestinal Diseases

infection often spares cells in the lamina pro- Clinical Features. Clinically, astrovirus infec-
pria, such as endothelial cells or smooth muscle tion causes diarrheal disease resembling rota-
cells. In AIDS patients, adenovirus infection viral illness, although the disease is less severe
may coexist with CMV infection. (672,688). Patients may experience fever and
Special Techniques. The diagnosis can be es- vomiting. The median duration of the disease
tablished by ultrastructural examination of the is 3 days (688) .
stool, viral cultures, monoclonal antibody-based Microscopic Findings. The changes resemble
immunoassays, PCR, or in situ hybridization re- those found in other pediatric viral diseases.
actions. Ultrastructurally, pathognomonic viral Special Techniques. Ultrastructural viral
particles are seen in the nuclei of the mucosal identification relies on identifying the charac-
epithelium. The cells contain irregular, hexago- teristic viral morphology. Astroviral antibodies
nal paracrystalline arrays of virions averaging are detectable using indirect fluorescence. The
73 to 80 mm in diameter (652). organism is detected with RT-PCR (678).
Differential Diagnosis. The differential diag-
Herpesvirus Infections
nosis depends on the clinical presentation. If the
patient presents with intussusception, then the Demography. Neonates, children, and adults
various causes of intussusception coiiJe into the all suffer from herpetic infections. In the case
differential diagnosis, including an adenovirus of neonates, the disease is acquired as an intra-
infection with lymphoid hyperplasia. If, on the uterine, intrapartum, or postnatal infection.
other hand, viral inclusions are seen, then the Herpes simplex virus type I (HSV-I) is a frequent
differential diagnosis is that of othe.tviral infec- cause of esophagitis in patients who have
tions that cause nuclear inclusions., especially underlying malignancies, diabetes, previous
CMV infection (660). radiation therapy, or HIV disease, or have been
Treatment and Prognosis. There i_s no ef- treated with steroids or other cytotoxic agents.
fective therapeutic agent for adenovirus. As a Herpes esophagitis is found in the same clinical
result, treatment is supportive. settings as esophageal candidiasis. It 'inay also
occur in otherwise healthy individuals without
Astrovirus Infections
underlying immunologic problems. Herpetic
Demography. Astrovirus infection is the esophagitis is especially common following
second most common cause of gastroenteritis trigeminal nerve surgery. Two possible interre-
in children (672,686,688). The v-iruses affect lated predisposing conditions may account for
children below the age of 7 years much more fre- this association: 1) oropharyngeal shedding of
quently than older children and adults. Infants HSV frequently follows trigeminal surgery, and
under 2 years of age are particularly vulnerable. 2) esophageal intubation during the surgery
Astrovirus infections are more common in the produces secondary mucosal trauma. Reactiva-
winter and spring than in the summer in tem- tion of a latent herpetic infection should be
perate climates (672,683,686). They are associat- considered when patients develop odynophagia
ed with diarrheal outbreaks in newborn nurser- following esophageal instrumentation (705).
ies and pediatric wards, in community settings, Colonic herpes infections are extremely rare,
and in nursing homes (673-676,680,682, 687). and usually occur in the setting of immuno-
Most children acquire antibodies to the virus by compromise (689,691,693,696,701,703). They
5 years of age (673,679). Immunocompromised have also been found in patients with IBD (698)
patients are also susceptible to astrovirus infec- and in neonates (695). Herpetic proctitis often
tion (671,677). results from HSV-II infections, but HSV-I proc-
Etiology. Astrovirus is a 28-nm, single- titis may also occur (709) . Disease transmission
stranded RNA virus that belongs to the family requires direct contact with infectious lesions
Astroviridae. Astrovirus infections are acquired or secretions.
through ingestion of contaminated foods, of- Etiology. Two distinct types of herpes simplex
ten shellfish or raw fish (681), and potentially virus exist, HSV-I and HSV-II. Each is composed
through contaminated water or fomite trans- of numerous distinctive viral strains. HSV-I pre-
mission (670,684,685). dominantly causes nasal, labial, oropharyngeal,

454
Gastrointestinal Infections

and esophageal infections, while HSV-II causes Herpes colitis is uncommon, but may occur
genital and perianal herpes. Both viruses are in patients with disseminated disease. Symp-
acquired through close personal contact with toms include fever, bloody diarrhea, and dehy-
· infected individuals. dration. The colon may perforate (695).
Pathophysiology. The virus enters the host Anogenital herpes infections may occur in
via the mucous membranes. It replicates locally immunocompetent or immunocompromised
within epithelial cells, leading to cell destruc- patients. Herpetic ulceration is probably the most
tion and resultant formation of vesicular and common anal manifestation of AIDS (711). The
ulcerated lesions. The virus can invade periph- clinical presentation usually begins with itch-
eral neural tissues where it may remain latent ing and soreness in or around the anus. Severe
within sensory nerve ganglia. During primary anorectal pain follows. The pain may be so intense
infection, an immune response evolves but usu- that the patient becomes reluctant to have a bowel
ally matures only after neuronal invasion. This movement and develops constipation and impac-
immune response eliminates the local mucous tion. Patients also present with fever, inguinal
membrane infection but cannot eliminate the adenopathy, tenesmus, anorectal discharge, and
latent virus residing within the sensory nerve bleeding. Neurologic symptoms develop in the
root ganglion. Reactivation of latent virus distribution of the sacral roots in some patients.
within a ganglion leads to a recrudescence of Abdominal pain can simulate a bowel obstruction.
viral replication at a mucous membrane site The disease often resolves within a couple of weeks
innervated by the nerve root. Reactivation of but recurrences are common.
HSV from its latency in nerve and ganglion cells Gross Findings. The middle and distal thirds
leads to viral DNA replication, transcription, of the esophagus are the most commonly af-
translation, encapsulation, and viral shedding, fected portions of the gastrointestinal tract
features that depend on host-virus interactions. (692,704), followed by the anus. Small vesicles
In healthy individuals, reactivation episodes are the earliest endoscopically identifiable
are milder than the initial infection due to esophageallesions. These vesicles subsequently
the presence of partial immunity. In contrast, rupture to form discrete, superficial ulcers of the
in immunocompromised patients, activations esophageal mucosa. These discrete "punched
are more frequent and more severe. Thus, the out" ulcers have white exudates in their bases
prime determinants of disease severity are the and erythematous or yellow raised margins.
immunocompetence of the host and whether Typically, the ulcers appear shallow, even in
the infection is primary or recurrent (699). extensive disease, and they do not extend
Clinical Features. Typical herpetic esopha- through the muscularis mucosae. Large areas
gitis is seen in immunocompromised patients of denuded mucosa develop in severe disease.
but also develops in immunocompetent indi- Herpetic ulcers usually stop at the gastroesopha-
viduals (69 7, 706), especially following trigeminal geal junction, although rare cases of herpetic
nerve surgery (705). Herpes esophagitis usually gastritis occur (fig. 10-29). The changes of her-
manifests clinically by the sudden onset of severe petic esophagitis occur alone or they develop
odynophagia and/or dysphagia, fever, heartburn, superimposed on preexisting tissue damage
and retrosternal pain (706). Nonspecific findings resulting from nasogastric tubes, caustic esopha-
include epigastric pain, nausea, and vomiting. geal burns, or reflux esophagitis. The presence
Constant retrosternal pain may be present as well of preexisting damage may obscure the classic
as hematemesis. ·when severe, herpetic esopha- pathologic features of the viral infection.
gitis may cause hemorrhage (707). Intestinal Colonic involvement is rare, and usually
bleeding can be the presenting sign, especially presents as diffuse colitis, typically most severe
if platelet counts are low. Clinically, esophageal in the sigmoid colon. Colonoscopy shows ery-
herpes infections remain underdiagnosed unless thema and friability of the mucosa, aphthous
there is a high degree of suspicion for the virus ulcers, inflammatory polyps, and areas of ulcer-
because the patient is in a high-risk group. The ation (696). Sigmoidoscopic features of herpetic
presence of herpetic vesicles (blisters) on the lips proctitis include mucosal friability and distal
may suggest the diagnosis. rectal ulcers or vesicles.

455
Gastrointestinal Diseases

Figure 10-29 Figure 10-30


HERPES GASTRITIS HERPES ESOPHAGITIS
The stomach contains an intense mononuclear cell The squamous epithelial cells contain characteristic
infiltrate. A single viral inclusion is in a gastric glandular inclusions. The nuclei appear glassy, with marginated
remnant in the center. chromatin. Multinucleated giant cells have molded nuclei
that also contain typical viral inclusions. (Courtesy of the
Division of Gastrointestinal Pathology, Armed Forces Insti-
Microscopic Findings. Herpesvii:!J.Ses usually tute of Pathology, Washington, DC.)
infect squamous mucosa, although they can
infect enterocytes as well. The virus penetrates
the epithelium, causing cytolysis and a localized nuclei are adjacent to the infected epithelium.
inflammatory reaction. In over 50 percent of The presence of such aggregates of macrophages
cases, characteristic viral inclusions are present highly suggests an inflammatory response to
(706). Herpetic esophagitis is usually easy to herpetic esophagitis.
recognize if a biopsy is taken at the edge of the Histologic examination of biopsy material in
herpetic ulcer. The squamous epit:Q.elial cells at patients with colonic herpes simplex infections
the margin of the ulcer contain Cowdry type demonstrates lamina propria edema, lympho-
A inclusions (fig. 10-30). A clear .zone with an plasmacytic infiltrates, and areas of ulceration.
outer dark margin of condensed chromatin at Typical viral inclusions and multinucleated cells
the nuclear membrane surrounds large, intra- may be seen, but may be small in number and
nuclear, eosinophilic inclusions. Multinucleated patchy in distribution (696).
syncytial squamous cells containing molded nu- Histopathologic findings in herpetic proctitis
clei and a typical"ground-glass" appearance are are often nonspecific, with crypt abscesses and
also common. In immunocompetent patients, increased numbers of neutrophils in the lamina
only a small number of viral inclusions are pres- propria. Some patients have more characteristic
ent, contrasting with a large number present findings, including perivascular lymphocytic
in immunosuppressed patients. Occasionally, cuffing in the submucosa, intranuclear inclu-
there is histologic evidence of herpetic infec- sions, and multinucleated giant cells with
tion in the ducts and acini of the submucosal ground-glass nuclei in the submucosa. The
glands underlying areas of ulceration. Biopsies viral inclusions occur alone or in a setting of
taken from the base of herpetic ulcers only re- diffuse necrosis.
veal the presence of nonspecific inflammation, Special Techniques. The diagnosis is often
necrosis, granulation tissue, and desquamated made clinically and confirmed by cultures
epithelial cells. or biopsy of the ulcer. Viral culture not only
The diagnosis of herpetic esophagitis may be increases the diagnostic yield on the tissues
difficult in AIDS patients, since the characteris- but distinguishes among viral infections with
tic nuclear inclusions and multinucleated giant overlapping histologic and cytologic features.
cells may be absent. Instead, aggregates of large The virus grows readily in diploid fibroblasts
mononuclear cells that contain convoluted or rabbit kidney cells, and cytopathic changes

456
Gastrointestinal Infections

Table 10-10
FEATURES OF GASTROINTESTINAL VIRAL INFECTI ONS

Virus Gross Features Location Histology


HSV" Multiple discrete Esophagus (HSV) common site Biopsy of ulcer base: only granulation ti ssue;
vzv shallow ulcers although in severe in fection both inflammation; n ecrosis; epithelial ballooning;
can be found in the esophagus inclusions in epithelium at ulcer edge
CMV Resembles HSV Involves the stomach and intestin es Cytopathic effects involve submu cosal glands,
more frequently than esophagus endothelium, stromal fib roblasts; infection of
squamous cells is rare
HIV May resembl e HSV Esophageal involvem en t h ard to No specific changes
and CMV document
HPV Normal or pap il- Esophagus and anorectum Koilocytosis, condylom a or normal-appearing;
lomas virus found by antigenic or molecular
biologic tests
EBV Deep, linear ulcers Midesophagus Resembles oral leukoplakia
"HSV =herpes simplex virus; VZV = varicella zoster virus; CMV = cytomegalovirus; HIV = human immunodeficiency virus;
HPV = human papillomavirus; EBV = Epstein-Barr virus.

are usually evident within 24 to 96 hours (694) . most common coexisting infection; other op-
The use of immunohistochemistry or in situ portunistic infections include Mucor, Aspergillus,
hybridization for HSV nucleic acids confirms or Torula. Another infectious agent that may
the diagnosis if the exact nature of the viral coinfect the esophageal mucosa, particularly in
inclusions is u ncertain. In addition, immuno- the immunocompromised host, is CMV.
histologic stains may highlight infected cells Herpes esophagitis in immunocompetent
that do not show the morphologic changes patients requires only symptomatic treatment
characteristic of HSV. with analgesics, viscous lidocaine, and antacids,
Differential Diagnosis. The differential diag- because the illness is self-limited and complete
nosis includes other infections and acute causes resolution of symptoms occurs in 1 to 2 weeks
of esophagitis, enteritis, colitis, and proctitis. (699, 710). Specific treatment with acyclovir
The differential diagnosis of herpetic esopha- is required in patients who are debilitated,
gitis includes drug-induced esophagitis, reflux immunocompromised, or have severe odyno-
esophagitis, caustic esophagitis, and radiation phagia (700,702). Acyclovir is recommended in
esophagitis. These conditions are almost always a dose of 5 mg/kg intravenously every 8 hours
differentiated from herpetic esophagitis by the for 7 to 10 days. Intravenous hydration may
clinical history and presentation. It is important be necessary for patients to maintain adequate
to distinguish herpetic esophagitis from other fluid intake because of the painful swallowing.
fo rms of infectious esophagitis, particularly The prodrugs famciclovir and valacyclovir are
other forms of viral esophagitis, because specific also effective (700).
drugs exist to treat each of the diseases. The Resistance to acyclovir is uncommon in her-
features that differentiate HSV and CMV infec- petic infections occurring in immunocompetent
tions are summarized in Table 10-10. hosts. In immunocompromised patients, how-
Treat ment and Progn osis. Complications ever, resistance is frequent, occurring in 4 to 7
from herpetic esophagitis include hemorrhage, percent of patients (690,708) . Resistance occurs
fistula formation, and viral dissemination. in viral strains with mutations in the thymidine
Submucosal fibrosis can lead to subsequent kinase gene, a gene required for phosphoryla-
esophageal stricture. Some patients die of herpes tion of the drug to its active form. Foscarnet
pneumonia or hepatitis. Another complication inhibits viral DNA polymerase and does not
is superinfection of the denuded esophagus require phosphorylation and is therefore recom-
with fungi and bacteria. Candida albicans is the mended for resistant strains.

457
Gastrointestinal Diseases

Varicella Zoster Vi rus Infections


Dem ography. On rare occasions, varicella zos-
ter virus 0JZV) infects the esophagus in children
with severe disseminated chickenpox. It has also
been reported to infect the small intestine in
immunocompromised individuals (718). In addi-
tion, it has been hypothesized that VZV is respon-
sible for some motility disorders such as achalasia
and Ogilvie's syndrome (712,713a,717).
Etiology. VZV is a double-stranded DNA virus
morphologically identical to HSV. Fatal VZV
infections usually affect children with cancer or
those who are otherwise immunocompromised
Figure 10-31
(713, 716). Adults who develop symptomatic
infections usually have reactivation of a viral VARICELLA ZOSTER VIRUS
INFECTION IN THE ESOPHAGUS
infection acquired during childhoosJ. as occurs
with HSV infections. The squamous epithelial cells are spongiotic. A multi-
nucleated cell is in the center. Eosinophilic inclusions are
Clinical Features. Primary VZV infection in the multinucleated cell, as well as in scattered individual
in children causes the characteristic general- squamous cells.
ized vesicular eruptions of chick..enpox. The
disease is more severe in immunocompromised
children, 20 to 30 percent of whom exhibit results in a positive serology in approximately
visceral dissemination and a mortality rate of 7 80 percent of the world's adult population
to 30 percent (7lla). Symptomatic esophageal (719a). Like HSV, CMV exhibits a tendency to
involvement in children with chickenpox is affect debilitated, elderly, or immunDcompro-
uncommon but does occur, usually in severely mised individuals. Populations at highest risk
immunocompromised or very ill patients. for disseminated gastrointestinal infection are
Gross Findings. Esophageal le.s ions consist neonates, allograft recipients, HIV-infected
of necrotizing esophagitis with superficial and individuals, pregnant women, malnourished
deep esophageal ulcerations . The endoscopic patients, those with malignancy, or the elderly.
features of VZV are indistinguishable from CMV infection is also seen in immunocompe-
those of HSV. tent patients as well as in patients with IBD.
Microscopic Findings. The histologic features Pathophysiology. CMV infection is classified
of VZV are characterized by edema, ballooning as primary infection, reactivation infection, and
degeneration, and vesicles lined by multinucle- superinfection. CMV is usually not eliminated
ated giant cells with intranuclear eosinophilic from the body after a primary infection. Rather,
inclusions (fig. 10-31). Intranuclear eosinophilic it persists as a low-grade chronic infection or it
inclusion bodies can be seen in the epithelium, remains in a latent state. This allows reactiva-
endothelium, and stromal cells. Immunohisto- tion or increased viral excretion at a later time
chemical staining with monoclonal antibodies and further viral transmission to new hosts. The
to VZV antigens confirms the diagnosis. macrophage serves as the infection reservoir
Different ial Diagnosis. The differential di- during latent periods (724).
agnosis of VZV infection mainly includes HSV, A number of host and viral factors determine
but also includes other infectious etiologies. the outcome of CMV infection. The most im-
Treatment and Prognosis. Treatment is accom- portant is a shift in favor of the virus when the
plished with acyclovir or famciclovir (714,715). host's immune system becomes compromised or
is immature. The determinants of acquisition of
Cyt omegalovirus Infect io ns
CMVinfection vary among newborns, organ or
Dem ography. Cytomegalovirus (CMV) is a bone marrow transplant recipients, HIV-infected
ubiquitous herpesvirus whose incidence var- persons, or blood transfusion recipients. CMV
ies significantly by geographic location but is transmitted to neonates transplacentally, by

458
Gastrointestinal Infections

passage through a contaminated birth canal, or Complications include bleeding, gastric outlet
by ingestion of infected breast milk. In adults, obstruction, and perforation. Unusual presenta-
CMV is sexually transmitted or transmitted via tions include gastrocolic fistula (719), recurrent
infected organs, blood, or needles (723). stomal ulcer with afferent limb obstruction
· Analysis of tissues by in situ hybridization in the postgastrectomy patient, submucosal
shows that latent CMV affects most organs in antral mass, and acute self-limited gastropathy
the body (728). The predominant tissue site re- associated with a protein-losing enteropathy
mains unknown, but circulating lymphocytes, and pediatric forms ofMenetrier's disease (729).
monocytes, neutrophils, and endothelial cells CMV enterocolitis causes nausea, vomiting,
all·probably contain latent virus (727). Both and crampy abdominal pain, often accompa-
humoral and cellular immune responses func- nied by profuse persistent or intermittent fever,
tion to control CMV infection and, therefore, weight loss, and severe wasting. A typical colitis
primary CMV infections in immunosuppressed pattern of bowel movements develops, includ-
patients tend to be more severe than those oc- ing tenesmus, bloody stool, hematochezia, and
curring in immunocompetent patients. small volume movements with regular frequen-
The underlying pathogenic mechanism relates cy. The cecum and right colon become infected
in part to CMV infection of the vasculature. Im- more commonly than distallocations (721), al-
munocompromised individuals develop CMV though the rectum and sigmoid colon may also
viremia, endothelial viral infection followed by be affected (732). Malabsorption, protein-losing
endothelialitis, submucosal ischemia, and sec- enteropathy, perforation, and peritonitis may
ondary ulceration. CMV-associated vasculitis in also occur (720,730). Additionally, CMV infec-
the gastrointestinal tract is especially well docu- tion may affect the gastrointestinal innervation,
mented in the AIDS population, where it pref- possibly leading to motility disturbances.
erentially involves the colon in up to 67 percent Patients with disseminated CMV infections
of patients. Both arteries and veins are affected often demonstrate circulating cytomegalic
and undergo segmental necrosis, perivascular inclusion-containing cells in the peripheral
hemorrhage, and possible thrombosis (725,734). blood. These are endothelial in origin and con-
Clinical Features. Diverse symptoms are the tain viral capsids within the nucleus, and virus
result of CMV infection in many organ systems. particles and dense bodies in the cytoplasm. The
The presence of CMV organisms does not always circulating cytomegalic cells can disseminate
equate with clinical disease, and virologic evi- the infection throughout the body (722).
dence of CMV must be interpreted within the Gross Findings. In CMV esophagitis, discrete
clinical context before treatment is considered. superficial ulcers occur in the mid- or distal esopha-
Immunocompetent individuals with primary gus. In some patients, one or more large, relatively
infections usually remain asymptomatic, but flat, serpiginous or oval ulcers, surrounded by a
may have a mononucleosis-type illness. radiolucent rim of edematous mucosa, develop.
Symptoms of gastrointestinal CMV infection These coalesce to form giant ulcers, particularly
generally depend on the location and severity in the distal esophagus. The presence of one or
of the infection and the immune status of the more giant esophageal ulcers suggests the diag-
patient. CMV infects the esophagus, stomach, nosis of CMV. Fistulas may also form.
small intestine, appendix, colon, and anal In CMV gastritis the stomach appears vari-
region, often appearing as an erosive or ulcer- ably congested and atrophic. The entire small
ative process. The onset of symptoms of CMV bowel may be involved by CMV infection,
esophagitis is more gradual than that seen although some patients have disease limited
in herpes infection. Nausea, vomiting, fever, to the ileocecal region. The organism charac-
epigastric pain, diarrhea, and weight loss are teristically causes colonic ulcers that tend to
usual, whereas painful, difficult swallowing and localize in the ileocecal region. Rare patients
retrosternal pain occur less often than is seen develop CMV pancolitis. Colonoscopy shows
with HSV infections (726,735). ulcers or dark violaceous lesions resembling
Patients with CMV gastritis also present Kaposi's sarcoma. A mildly abnormal interven-
with epigastric pain, nausea, and vomiting. ing mucosa separates discrete ulcers in many

459
Gastrointestinal Diseases

Figure 10-32
CYTOMEGALOVIRUS GASTRITIS
A: Eosinophilic inclusions are within the glandular
epi-thelium. There is a patchy increase in the number of
mono-nuclear cells in the lamina propria.
B: The gastric epithelium appears regenerative and the
lamina propria contains viral inclusions.
C: Cytomegalovirus (CMV) infection in another
patient with less obvious gastritis but more numerous viral
inclusions.

sions; cellular enlargement; and occasional


granular basophilic cytoplasmic inclusions.
The affected cells differ from those seen in HSV
infections in that CMV cytopathic effects typi-
cally develop in the glandular epithelium (as
opposed to the squamous cells), submucosal
endothelial cells, macrophages, and fibroblasts
in the granulation tissue of the ulcer bases (fig.
10-32). The cells in the stroma often appear
enlarged or cytomegalic, with conspicuous
intranuclear inclusions.
CMV is notorious for its ability to invade
Figure 10-33 muscle cells, ganglion cells, and endothelial
CYTOMEGALOVIRUS INFECTION
cells (fig. 10-33). Endothelial infections may
The endothelial cell is enlarged and contains a large
lead to the development of venulitis. Addition-
intranuclear CMV inclusion surrounded by a clear halo. ally, the virus causes endothelial proliferation
and secondary vascular occlusion by swollen,
plump endothelial cells, particularly small ves-
patients. In its most severe form, multiple ulcers sels. The vascular damage predisposes the vessels
and perforations occur throughout the gut. The to thrombosis. Other lesions form, including
gross appearance may resemble ischemic colitis. a granulomatous-like lesion characterized by
Microscopic Findings. The characteristic histiocytic collections without giant cells, which
cytopathic effects of CMV infection include surrounds the vascular wall. Viral inclusions are
prominent eosinophilic, intranuclear inclu- not always identifiable within the endothelium

460
Gastrointestinal Infections

Figure 10-34
CYTOMEGALOVIRUS ESOPHAGITIS
Left: CMV inclusions in esophageal submucosal glands. The nuclei of the affected cells contain eosinophilic, glassy
inclusions as well as basophilic cytoplasmic inclusions. (Both figures courtesy of the Division of Gastrointestinal Pathology,
Armed Forces Institute of Pathology, Washington, DC.)
Right: The immunohistochemical stain for CMV shows strong nuclear positivity.

Figure 10-35
CYTOMEGALOVIRUS COLITIS
Left: Colonic mucosa with an area of ulceration (left).
Right: On high power, an enlarged cell with a characteristic nuclear inclusion lies within a vessel in the lamina propria.

of the affected vessels, probably due to sampling In the intestinal tract, CMV is associated with
problems; however, they are present in the hemorrhage and ulceration. The virus appears
nearby vicinity. to have a special affinity for cells in and around
Histologically, CMV esophagitis is charac- small vessels (fig. 10-35). The infected cells are
terized by large cells in the subepithelial layer often significantly enlarged (cytomegalic), with
and in areas of ulceration. These cells contain an increase in both nuclear and cytoplasmic
amphophilic and intranuclear inclusions and volume, although these changes are not al-
may also have cytoplasmic inclusions (fig. 10- ways present. Typical nuclear and cytoplasmic
34). The presence of the virus is confirmed by inclusions may be seen. CMV infection of the
either immunohistochemical staining or in situ duodenum may cause papillary stenosis and
hybridization for CMV DNA (fig. 10-34). sclerosing cholangitis in AIDS patients (733) .

461
Gastrointestinal Diseases

In the colon, the histologic changes range Identification of the characteristic cytomegalic
from isolated inclusions with no accompany- inclusions rules out other entities.
ing tissue reaction to the presence of discrete Treatment and Prognosis. Progressive
. ulcers to more diffuse inflammatory changes intestinal disease and de.a th are frequent in
characterized by edema, erythema, mucosal immunocompromised patients. In one study,
erosions, pseudomembranous colitis, toxic however, mortality from CMV infections was
megacolon, and perforation. The diagnosis of significantly greater in normal patients than in
a CMV infection in mucosal biopsies is often transplant, HIV-positive, or other immunosup-
not difficult. In severely immunosuppressed pressed patients (731). Mortality is also greater
patients, numerous CMV-infected cells are easily in individuals over 65 years of age and when
identified by the presence of both nuclear and time to institution of therapy is great. The site of
cytoplasmic inclusions. Inclusion-bearing cells infection in the gut has no impact on prognosis
are most numerous in ulcerated areas, especially (731). Ganciclovir and foscarnet are effective
in the ulcer bases and the endothelium. They drugs for treating CMV infection.
also occur in granulation tissue, pseudopolyps, Prevention. Screening of blood products
and the intervening mucosa in both stroma and for CMV antibodies significantly decreases the
epithelial cells. More subtle infectien requires morbidity and mortality from primary CMV
an awareness of, or high suspicion for, the pos- infection among CMV-seronegative organ trans-
sibility that the infection might exist so that plant recipients. Ganciclovir can also be used as
multiple sections can be carefully examined to prophylactic treatment.
find the characteristic inclusion-bearing cells.
Human Papilloma Virus Infections
In severe cases, ischemia causes many of the
pathologic features because viral infection of Demography. Human papilloma virus (HPV)
small vessels results in endothelialitit5, stimu- is the causative agent of genital warts, the most
lating the formation of microthrombi and sec- common sexually transmitted viral ii}fection in
ondary ischemic damage. The nonendothelial the United States (745) . Anorectal and perianal
cells surrounding the infected vessels are also condylomata frequently develop in individuals
commonly infected. Occasional CMV infection who have engaged in anal intercourse, and their
involves medium-sized arteries, resulting in en- incidence has increased by about 50 percent
dothelial inclusions, inflammation, panarteritis, in the past several decades (73 7, 740). Most af-
necrosis, and large mucosal ulcera tions. fected patients are male, many of whom admit
Special Techniques. CMV is detected by di- to homosexual lifestyles. Men with advanced
rect viral isolation from clinical specimens via HIV disease have a high prevalence of anal
growth in conventional tissue culture or rapid HPV infections and potentially precancerous
viral culture systems. The virus is also detected anal disease. An increased incidence of anal
using serologic methods for CMV-specific IgG and perianal condylomata also exists in women
antibodies. Direct histologic and immunohisto- with cervical and/or vulvar warts.
chemical techniques detect viral particles and Etiology. Condyloma acuminatum results from
CMV antigens, respectively, in fixed tissue sec- infection by double-stranded DNA-containing
tions, or in cytologic or cytospin preparations. HPV. HPV 6 and 11 are the usual HPV types found
The virus may also be detected via various DNA in genital warts (738,741,748,749). HPV infects
detection systems, including in situ hybridiza- the basal cells of the squamous epithelium,
tion, dot blot hybridization, or PCR. although it can infect transitional and cuboi-
'-,·
Differential Diagnosis. The clinical dif- dal epithelia as well. The infection is thought
ferential diagnosis of CMV infection includes to occur after trauma to the epithelium and it
various entities, depending on the organ system. results in cellular hyperplasia of the basal cells
In the esophagus, the differential diagnosis (7 4 7). Infectious viral particles are produced only
includes herpes esophagitis, Candida esophagi- by completely differentiated cells of the upper
tis, and gastroesophageal reflux disease. In the epithelium, because cellular differentiation is
intestines and colon, the differential diagnosis required for the HPV growth cycle (736). Infec-
includes many forms of infectious enterocolitis. tion with HPV can lead to clinical, subclinical,

462
Gastrointestinal Infections

or latent infection, as well as the development


of dysplasia and cancer. Subclinical or latent
HPV infections are common and may persist
for long periods of time (746) . Squamous cell
carcinomas of the anus are strongly associated
with genital or anal warts; HPV types 16, 18, and
31 are found in these lesions (739,742) .
Clinical Features. HPV infections may or
may not result in clinically apparent lesions.
Perianal condylomas are the most common vis-
ible manifestation of anal HPV infection (7 43) .
These lesions are raised and often papillary, and
are seen on physical examination in the perianal
region. They are often multifocal and may grow Figure 10-36
to a large size. Subclinical lesions often occur HUMAN PAPILLOMA VIRUS
within the internal anal canal or rectal mucosa. In situ hybridization for human papilloma virus (HPV)
Gross Findings. The gross features of con- types 6 and 11 in an anal condyloma. The viral DNA is
dylomata vary widely, with the spectrum of stained blue, and can be seen within nuclei of squamous
lesions ranging from single to multiple growths cells in the upper half of the epithelium.
and from small benign tumors to extensive
superficial lesions covering large mucosal ar- of condylomas but lack the prominent acan-
eas. Patients with anal condylomas frequently thotic growth pattern typical of the more com-
have lesions on the penile mucosa, perineum, mon condyloma acuminatum. Venereal warts
perianal area, anorectal junction, cervix, or treated with podophyllin may appear histologi-
vulva. Condylomas assume a characteristic cally alarming and mimic dysplasia.
soft, grayish pink to purple, papillary, warty,
Molluscum Contagiosum
cauliflower-like appearance. Occasional lesions
are pigmented. Areas of erosion may be present Molluscum contagiosum, a contagious disease
and may distort these features. resulting from a viral infection, is characterized
Microscopic Findings. Histologically, con- by the appearance of multiple, small, waxy
dylomata are acanthotic, papillomatous squa- papules that have characteristic umbilicated
mous growths showing variable thickening of centers. The most common sites of involve-
the stratum corneum, superficial parakeratosis, ment are the abdominal skin and the skin of
and dyskeratosis. The superficial cells appear the perineum thigh, penis, scrotum, and vulva;
large and contain clear cytoplasm with a central the buttock and perianal regions are sometimes
hyperchromatic nucleus and perinuclear halo, affected. Histologically, the lesions consist of
features known as koilocytosis. These koilocy- a lobular epidermal proliferation that extends
totic features are the histologic hallmark of HPV into the dermis. Prominent inclusion bodies are
infection. Anisokaryosis, nuclear hyperchroma- characteristic of the lesion (fig. 10-37).
sia, and the presence of binucleate cells correlate
with the presence of HPv; as detected by in situ PARASITIC INFECTIONS
hybridization (fig. 10-36) (744). Scattered mi-
Giardia Infections
totic figures, some of which may appear bizarre,
may be present in the acanthotic epithelium. Demography. Giardia is found worldwide
The stroma contains a chronic inflammatory and infects domestic as well as wild animals
cell infiltrate, and the tissue may appear edema- (776,786). Giardiasis is the most commonly di-
tous and show vascular dilatation. agnosed intestinal parasitic infection in public
Some condylomas grow in a flat pattern health laboratories in the United States and
similar to that seen in the cervix. Such lesions, around the world. Worldwide, it is estimated that
sometimes referred to as condyloma planum, 1.5 to 20.0 percent of humans are infected with
show koilocytosis and other cytologic features Giardia (764,772). There is an approximately

463
Gastrointestinal Diseases

water for several months and can survive the


chlorine concentrations usually present in mu-
nicipal water systems (769) .
Pathophysiology. Cysts are ingested and
excystation begins in the stomach. Trophozoites
emerge in the duodenum and upper jejunum
where they colonize the intestines. Bile salts
stimulate their excystation, growth, and replica-
tion, perhaps accounting for the fact that the
duodenum and proximal jejunum represent
their favorite habitat (760). They lie in the
intestinal fluid phase, attach to mucus strands
in the lumen, or penetrate the mucus gel layer
and attach to the epithelial microvilli via their
Figure 10-37
ventral suction disc. Attachment of the microor-
ganism to the epithelial cells leads to alterations
MOLLUSCUM CONTAGIOSUM in brush border enzyme activity, with resultant
Characteristic eosinophilic molluscum bodies are present malabsorption (7 52,7 59, 785). In addition, the
in the superficial squamous epithelium.
organism may cause rearrangements in F-actin
and alpha-actinin in cells in the duodenum,
equal sex distribution. Rates of infection are resulting in abnormalities in electrical resistance
the highest among children under 5 years of across the cell membrane (787) . Villous blunt-
age, followed closely by persons aged 31 to 40 ing and shortening may occur (775) . Epithelial
years. Most cases are reported during late sum- damage may develop as a result of toxin pro-
mer and early fall. duction by the organisms (766). Other factors
Giardiasis occurs sporadically, although that may play a role in the pathogene'sis of the
outbreaks also occur. Giardia infection is most diarrhea induced by Giardia include bacterial
commonly spread through contact with con- overgrowth, bile salt deconjugation, and bile
taminated water. This may occur as a result of salt uptake by the organism.
drinking contaminated tap water or through Variations in the clinical manifestations
recreational exposure in lakes, rivd:s, and swim- of Giardia infection result from differences in
mingpools (768,771,774,781). Person-to-person virulence among organisms or from immune or
spread also occurs, and has been documented nonimmune host factors in the intestinal micro-
in daycare centers (780) and among male ho- environment. An intact immune system plays
mosexuals (758,773,782). The organism may an important role in eradicating the infection
additionally be transmitted through contami- and in the development of protective immu-
nated food (777, 779). nity. Immunosuppression increases infection
Etiology. Giardia exists in two morphologic severity (775). IgA-defi.cient individuals develop
forms: the motile troplwzoite and the infective persistent infections (753). There may also be a
cyst. The pear-shaped trophozoite measures 12 genetic predisposition to infection (783) .
to 15 pm in length and 5 to 9 pm in width. A Clinical Features. Giardia infections may
pair of nuclei is located in the anterior half of remain self-limited and asymptomatic or they
the organism, with basal bodies lying between may persist for years, causing diarrhea, malab-
'·' the anterior poles of the nuclei. Four pairs of sorption, weight loss, and failure to thrive in
flagella originate from the basal bodies: one children (750,784). The most common presen-
pair on the ventral surface and three pairs on tation is the acute onset of dianhea lasting 5 to
the periphery. The elliptical cyst measures 6 to 7 days following an incubation period of 1 to 3
12 x 6 to 10 pm. It contains two to four nuclei weeks. The acute illness varies in severity. Some
and the flagellae are retracted into axonemes. patients experience an abrupt, explosive onset
A median body and curved fibrils may also be of frequent, watery, foul-smelling stools while
present. Cysts remain viable in cold or tepid others have only a few loose bowel movements.

464
Gastrointestinal Infections

Figure 10-38
GIARDIA
A: At low power, the villous architecture of the small
intestinal mucosa is preserved and there is no increase in
inflammatory cells in the lamina propria. Clusters of pale
pink Giardia organisms can be seen within the lumen.
B: Higher-power view shows grayish pink, pear-shaped
Giardia within the small intestinal lumen. The organisms
are approximately the size of an epithelial cell nucleus.
C: Occasional organisms adhere to the small intestinal
epithelium. No significant inflammatory reaction can be
appreciated in this case, as is typical of Giardia infestations.

Some patients present with abdominal cramps, One of three mucosal patterns is seen histo-
abdominal pain, flatus, lassitude, malabsorp- logically in association with Giardia infection.
tion, and progressive weight loss. Less often, In some patients there are no alterations pres-
fever and vomiting occur. ent. In others, the villous architecture is nor-
Patients with chronic giardiasis develop in- mal, but increased numbers of intraepithelial
termittent diarrhea that is less severe than that lymphocytes and immunoglobulin-containing
seen in the acute illness. Occasionally, allergic cells are in the lamina propria, with a relative in-
and other inflammatory phenomena develop crease in the number of IgA- and IgG-containing
(756) . Chronic diarrhea may lead to rectal pro- cells. Still others show partial or complete vil-
lapse. Giardia cysts can be excreted in the stool lous atrophy and crypt hyperplasia associated
intermittently for weeks or months, resulting in with variable degrees of inflammation, large
a protracted period of communicability (780). numbers of intraepithelial lymphocytes, and
One possible sequela of Giardia infection is reac- IgA- and !gM-containing cells in the lamina pro-
tive arthritis or synovitis (770). pria. Villous height tends to be low in patients
Microscopic Findings. In H&E-stained with large numbers of trophozoites. Focally,
biopsy material, Giardia organisms appear neutrophils may infiltrate the mucosa.
pear-shaped, about the size of an epithelial cell Special Techniques. Traditionally, the diag-
nucleus, with two nuclei (fig. 10-38). The organ- nosis of Giardia infection is made by the direct
isms are gray or faintly basophilic. They have an detection of characteristic cysts in the stool (fig.
elliptical shape, with one nucleus visible when 10-39). However, stool examinations are only
seen in profile. When present, they are often diagnostic in a portion of patients with known
numerous. Giardia organisms, however, often infection. In recent years, numerous rapid im-
have a patchy distribution, and are therefore munologic detection assays have been developed
not always seen on biopsy material, even in for the detection of Giardia antigens in stool.
symptomatic patients. These tests are highly sensitive and specific for

465
Gastrointestinal Diseases

feces are used as fertilizer. In these areas, patients


most commonly acquire the organism by inges-
tion of infected water, although contaminated
food is also a source. Spread within households
is common as a result of direct fecal-oral con-
tact. Individuals at the highest risk for infection
are travelers to endemic regions, immigrants
or migrant workers, immunocompromised
persons, and institutionalized patients (798).
Etiology. Amebiasis results from infection
with Entamoeba histolytica. A recently recog-
nized species of Entamoeba, E. dispar, is mor-
phologically similar to E. histolytica, but does
Figure 10-39
not produce invasive disease (789,791,796). It is
GIARDIA TROPHOZOITE$ IN A FECAL SMEAR now thought that this species is responsible for
The organisms are pear shaped, and have a central most of the asymptomatic infections formerly
axostyle straddled by two nuclei, which give the organisms
an "owl's eye" appearance.
attributed to E. histolytica (792).
E. histolytica has two life forms: the invasive
motile trophozoite, which measures 12 to 60
the organisms (761,762,767J88). There is also pm in size, and the 10- to 20-pm cyst. Amoebae
a PCR assay for detecting Giardia [n stool (765). propagate through cysts, the resistant form in
Differential Diagnosis. The differential diag- their life cycle. They are immediately infectious
nosis includes celiac disease or other disorders and can survive outside the host for weeks to
associated with intraepithelial lymphocytosis. months in moist environments. Cysts resist the
Immunohistochemical findings help distinguish chlorine concentrations used in sewage systems.
giardiasis from celiac disease, since a relatively Pathophysiology. Ingested E. histolytica cysts
high number of IgG- and IgA-containing cells are resist gastric digestion and pass to the ileocecal
present in giardiasis as compared with the large region where they excyst and divide, giving rise
number of !gM-containing cells iri celiac disease. to trophozoites that then colonize the colon. The
Treatment and Prognosis . !Yfany effective organisms are able to degrade the mucus barrier
treatment alternatives are available for symp- overlying the colonic mucosa through secretion
tomatic patients. Metronidazole is the treatment of a number of enzymes, including glycosidase,
of choice in the United States. Other effective galactosidase, mannosidase, fucosidases, xylo-
agents include tinidazole (750) and ornidazole sidase, glucosidase, amylase, and hyaluronidase
(778), neither of which is available in the United (797,807,809). The organisms then attach to the
States. Albendazole has been reported to be as epithelial cells by means of a multifunctional
effective as metronidazole with fewer side effects adherence lectin that is also involved in signal-
in children (754,757,763). Nitazoxanide has ing cell lysis, and that also protects the organism
recently been approved in the United States for from the attack complex of complement (792,
the treatment of the diarrhea caused by Giardia 802,804). Proteases secreted by the organism
in patients 1 to 11 years of age (751). A recent degrade the extracellular matrix and aid in lysis
study suggests that in some patients Giardia of target epithelial cells (790,799, 801). The result
infection may trigger functional irritable bowel is an erosion of the mucosal surface into which
"·' disease, leading to prolonged symptoms not the organisms invade. Once within the ulcerated
amenable to anti-Giardia therapy (755). tissue, the organisms appear to modulate the
host immune response, predominantly through
Amoeba Infections
interaction with neutrophils and macrophages.
Demography. Amebiasis has a worldwide Macrophage migration to areas of infection may
distribution. It is more prevalent in the tropics be inhibited by elaboration of a macrophage
than in temperate climates, in areas with primi- locomotion-inhibitory factor produced by the
tive or nonexistent sanitation, or where human organism (794).

466
Gastrointestinal Infections

It is not known why some infected patients Patients with fulminant disease develop
are predisposed to develop severe amebiasis dehydration, severe abdominal pain, and hy-
whereas others are not. Both host and parasite potension. Localized or generalized peritonitis
factors probably play a role in determining the and toxic megacolon are sometimes seen. Ame-
· ultimate outcome of exposure to the organism. bomas cause numerous symptoms, including
Factors that may be essential for initiating the alternating diarrhea and constipation, weight
infection and promoting severe disease include loss, and low-grade fever. In endemic areas,
poor nutrition, a tropical climate, decreased cramping, lower abdominal pain, and a palpable
host immunocompetence, the integrity of the mass suggest the diagnosis.
mucosal barrier, altered colonic bacterial flora, Laboratory findings are nonspecific. There
trauma, and other host immune or genetic fac- may be a mild elevation of the white count
tors. Different zymodemes (enzyme populations in patients with severe disease. Eosinophilia is
or patterns) characterize different populations usually absent.
of E. histolytica and they may be markers of Gross Findings. Asymptomatic or mildly symp-
pathogenicity (795,806). Additionally, there tomatic patients seldom show any specific endo-
may be genetic differences in a cysteine protease scopic findings. Colonoscopy allows assessment
that also serves as a virulence factor (808). of the entire colon for the presence of ulcerating
Clinical Features. Amebiasis affects indi- disease or amebomas. Ulcerating changes are most
viduals of all ages, including infants. Many in- often seen in the cecum followed by the sigmoid
dividuals remain asymptomatic but fulminant and descending colon and rectum. The appendix
amebic colitis and even death may occur. The may also be affected, but it is rare for the terminal
infection may remain limited to the gastroin- ileum to become involved. The transverse colon
testinal tract or it may extend to the liver and is commonly spared.
other organs. Intestinal amebiasis presents in Developing ulcers have irregular, hyperemic
four clinically recognized forms: 1) as a typical mucosal outlines with markedly undermined,
dysenteric infection with intermittent bloody overhanging edges, producing a characteristic
diarrhea and lower abdominal cramps; 2) as flask-like shape. The ulcers generally are dis-
fulminant amebic colitis; 3) as amebic ap- crete, smooth, and round, with only a slight
pendicitis; and 4) as a localized mass lesion in elevation of the borders. The intervening
the colon, the ameboma (792). Extraintestinal mucosa appears relatively normal. Ulcers vary
lesions may also occur, most commonly in the in size from a couple of millimeters to several
liver as abscesses. centimeters in diameter. They may be few in
Mild cases of amebiasis are characterized by number or so prevalent as to be confluent. In
mild diarrhea, cramps, or abdominal discom- the most severe circ.umstances, the ulcers extend
fort, often with mucus in the stool and perhaps through the entire colonic wall to the serosa.
some blood. Malaise and anorexia may be pres- Amebomas present as localized, often circum-
ent. Low-grade fever is uncommon. ferential areas of bowel wall thickening, stric-
Patients with the dysenteric form of the tures, mucosal excrescences, or large tumor-like
disease experience gradually increasing lower masses. They result from persistent ulceration
abdominal discomfort, loose stools, malodorous and granulation tissue formation, with fibro-
flatus, and recurrent bouts of diarrhea. Intermit- blastic proliferation and inflammation, and may
tent constipation also occurs. Within a period of be up to 15 cm in diameter.
3 to 4 days, tlie number of stools may increase Microscopic Findings. The only specific
to 25 per day, causing weakness and prostration. diagnostic finding is the identification of the
Nausea, vomiting, and right-sided cramps are organism in either the trophozoite or cyst form
usual. Amebic colitis often persists for weeks, (fig. 10-40). Typical trophozoites are large,
months, or years. Patients with chronic diarrhea round to ovoid structures, varying from 6 to
may develop rectal prolapse. Patients may have 40 J.lm in diameter. They contain voluminous
mild anemia or a mildly elevated white blood pinkish purple cytoplasm with a distinctive
cell count. The dysenteric form affects less than foamy, vacuolated, or granular appearance.
10 percent of patients in temperate zones. The cytoplasm is PAS positive and, unlike

467
Gastrointestinal Diseases

Figure 10-40
AMEBIC COliTIS
A: Low-power view of a large ulcer with slightly
undermined edges. Necrotic debris exudes from the ulcer
surface.
B: On higher power, numerous large, round organisms
are seen within the necrotic debris.
C: The amoeba trophozoites have abundant eosinophilic
cytoplasm and a single nucleus. Some organisms are
surrounded by a clear halo, a fixation artifact that is
commonly seen.

nonpathogenic amoebae, contains ingested Minimal inflammation surrounds superficial


red blood cells. Erythrophagocytosis is easily mucosal ulcers, whereas a dense fibrotic inflam-
demonstrated with the Heidenhain iron he- matory response often accompanies submucosal
matoxylin stain. In tissue sectionS, the amoeba penetration into the circular or longitudinal
may be surrounded by a clear space, a fixation- muscles. Prolonged inflammation leads to the
induced shrinkage artifact. production of inflammatory pseudopolyps
Amebic colitis is an ulcerating disease that and strictures. Extensive undermining leads to
begins with small areas of necrosis in the colonic widespread ulceration and perforation. As the
mucosa, presumably due to the enzymatic activ- ulcers extend, the organisms are found in tis-
ity of the trophozoites (fig. 10-40). A few amoe- sue spaces and small vessels, usually in groups
bae may lie in the lamina propria, surrounded in areas of necrosis and tissue disruption. In
by a mild inflammatory response (803). Early patients with severe disease, trophozoites may
amebic lesions appear as small, yellow mucoid extend through the bowel wall to lie free in the
elevations containing necrotic material and the abdominal cavity or serosal fat.
parasite. The lesions rupture, undermining the Because amebic ulcers develop slowly, fibrosis
adjacent intact mucosa and creating discrete, occurs, often protecting against perforation.
... oval-shaped ulcers with overhanging edges. As Some lesions eventually heal without significant
the ulcers enlarge, they produce the characteris- scarring, but others progress to chronic fibrosis
tic flask shape that extends into the underlying with persistent or recurrent focal ulceration.
submucosa. Necrotic cellular debris and fibrin Patients with long-standing infections and
cover the base of the ulcer. The mucosa between exuberant tissue reactions develop tumorous,
ulcers appears normal, although some areas may exophytic, cicatricial, inflammatory masses
appear polypoid due to the presence of hyper- known as amebomas. These can develop
emia and edema adjacent to areas of ulceration. anywhere in the colon, and usually occur in

468
Gastrointestinal Infections

untreated or inadequately treated patients years Balantidium coli infections produce similar his-
after the last recognized dysenteric attack. His- tologic changes. Balantidium coli, however, is a
tologically, amebomas consist of granulation larger organism, measuring 30 x 150 x 40 J.lill
tissue with round cell infiltration and giant cells. in contrast to Entamoeba which measures 30
Fibrous tissue is absent or uncommon. to 40 J.lill in largest diameter. The trophozoites
Special Techniques. Stool examination is the must also be distinguished from histiocytes.
usual way of demonstrating E. histolytica. Cysts, Histiocytes tend to be smaller, less intensely
trophozoites, and Charcot-Leyden crystals are PAS positive, and contain a clearly identified
seen. Three stools are collected over a several- nucleus.
day period, since amebic cysts are shed inter- Treatment and Prognosis. Complications of
mittently. Since the trophozoites only survive a amebiasis often occur as a result of the hema-
short time outside the intestines, the specimen togenous dissemination of organisms to distant
should be examined within 30 minutes or a sites. Trophozoites may migrate to the liver to
preservative should be added to it. The use of form an amebic abscess. They may also invade
supravital stains, such as buffered methylene adjacent structures including the pulmonary
blue, facilitates recognition of trophozoite parenchyma, peritoneum, and pericardium.
nuclear detail. In fixed stool specimens, the Amoebae also disseminate to the brain (798).
trichrome or iron hematoxylin stain identifies A number of drugs are available for treating
the trophozoites. Repeatedly negative stool ex- amebiasis and the treatment regimen depends
aminations do not rule out the disease. on the clinical state of the patient, the avail-
PAS stains and the use of direct fluorescent ability of drugs, and physician experience. The
antibodies on ethanol-fixed material are more Infectious Disease Society of America's recom-
sensitive for recognizing amoebae in biopsies mended treatment guidelines for amebiasis
than the three conventional detection methods include metronidazole plus either diiodohy-
(H&E, trichrome, and phosphotungstic acid droxyquin or paromomycin (793a).
hematoxylin [PTAH]) (793).
Balantidium Infections
Serologic tests have superior sensitivity and
predictive value in recognizing invasive disease Demography. Balantidiasis has a cosmopoli-
than do biopsies (800). They also are unaffected tan distribution, but most infections occur in
by substances that may have been used to treat tropical and subtropical regions. The infection is
the symptoms, such as antibiotics, antacids, or uncommon, accounting for less than 5 percent
enema products, which may decrease the vi- of cases of acute diarrhea in countries where the
ability of the trophozoites. A DNA hybridization organism is endemic (811,814,816). Balantidia-
probe recently has been developed (805) but it sis is usually contracted through ingestion of
has not been used extensively. contaminated water, but the disorder may also
Differential Diagnosis. In severe cases, the be transmitted from person to person. Since pigs
symptoms of patients with amebiasis mimic serve as reservoirs for the infection (811-813),
those of ulcerative colitis and toxic megacolon, the infection is most often seen where pigs and
especially in geographic areas where amoebia- humans are in close contact.
sis is not endemic. Like IBD, chronic amebic Etiology. Balantidium coli, the largest pro-
colitis may begin insidiously and exhibit cyclic tozoan to infect man, has both a cyst and tro-
remissions. In the United States, the symptoms phozoite form. It is the only ciliated protozoan
in younger individuals suggest Crohn's disease known to infect humans. The oval to spherical,
or appendiceal abscess; in older individuals, refractile cysts represent the infectious form
colonic cancer or diverticulitis are suggested. If of the organism, and measure 40 to 65 J.lm in
pseudomembranes are present, the differential diameter. Young cysts are covered by cilia that
diagnosis includes antibiotic-associated coli- disappear as they age. Trophozoites are liberated
tis due to C. difticile ischemia and shigellosis, from the cysts in the small intestine and invade
among others. the large intestine. They continue to excyst as
Histologically, amoebae can easily be mis- they descend through the large intestine. The
taken for white blood cells or other protozoa. oval trophozoites contain a characteristic large

469
Gastrointestinal Diseases

tions. Symptoms may persist for years (815,817).


Gross Findings. The right half of the colon
and cecum are most commonly involved, but
the rectum, sigmoid, anc~ appendix can also
become infected. Endoscopically, shallow ul-
cers and pseudomembranes are present (810).
Most ulcers are superficial and multiple, but
when deep ulcers develop, they may perforate,
particularly in fulminant disease.
Microscopic Findings. Invasion of the colon
by B. coli produces mucosal ulcers containing
numerous trophozoites and demonstrating
prominent submucosal inflammation (fig. 10-
41). The histologic features mimic those of am-
ebiasis, including the presence of flask-shaped
ulcers containing trophozoites separated by
intervening normal mucosa. The intervening
mucosa may also appear edematous or hemor-
rhagic. Pseudomembranes containing neutro-
phils and fibrin cover the ulcers. The diagnosis
rests on identifying the parasite.
Special Techniques. The diagnosis of bal-
antidiasis is made by finding the parasite in
the stool. It is almost always present in the
trophozoite form.
Differential Diagnosis. The disease mimics
Figure 10-41 amebiasis but the two diseases are distinguished
BALANTIDIUM COLI
by finding the large ciliated protozoan.
Scattered large trophozoites are in the submucosa of the
Treatment and Prognosis. Balantidium coli
colon. The organisms contain a characteristic kidney-shaped is sensitive to tetracycline and iodoquinol. Met-
macronucleus. "' ronidazole is also effective (813).
Cryptosporidium Infections
kidney-shaped macronucleus with a small or Demography. Since the first reported case of
round micronucleus. The cytoplasm contains human oyptosporidiosis in 1976, Oyptospolidium
two contractile vacuoles and numerous food has become one of the most common enteric
vacuoles. The pointed anterior end contains a pathogens in both immunocompetent and im-
funnel-shaped cytosome. munocompromised patients worldwide (845). In
Clinical Features. B. coli infections are as- developed countries, cryptosporidial infection
sociated with a range of presentations from accounts for 2.2 percent of cases of diarrhea in
asymptomatic cyst passage to chronic diarrhea immunocompetent adults and 7 percent of cases
and fulminant colitis. When patients are symp- in children (832) . The rate of infection is higher
tomatic, the most common clinical pattern is in developing countries where cryptosporidiosis
~.· chronic disease, characterized by alternating occurs in 6.1 percent of adults and 12.0 percent
diarrhea and constipation. The symptoms can of children with diarrhea. The rates in all geo-
last from days to months; patients have up to 15 graphic regions are higher for immunocompro-
bowel movements per day. In contrast, patients mised patients, especially those with AIDS (832).
with severe acute disease exhibit nausea, vomit- Cryptosporidial infections are frequently ac-
ing, anorexia, abdominal pain, and up to 30 quired through the ingestion of contaminated
bloody, mucus-filled bowel movements per day. water including untreated surface water, filtered
Perforation and hemorrhage are rare complica- swimming pool water, and even chlorinated or

470
Gastrointestinal Infections

filtered drinking water (845). In 1993, an out- Mature


break of cryptosporidiosis occurred in Milwau- oocyst
kee, Wisconsin as a result of contamination of
the municipal water supply. As many as 403,000
people were infected, representing 52 percent of
those individuals served by the contaminated
water supply (840) . Clyptosporidium may also
be spread through contaminated foods (845) .
Human-to-human transmission also occurs
by-means of either a direct fecal-oral route, or
Asexual Reproduction I' .....
indirectly through fomites (820) . Zoonotic Schizogony ""'
transmission from infected animals (cattle and
sheep) has also been documented (842,844).
Etiology. Cryptosporidia are intracellular
.. ·: : I
protozoal parasites. Most cases of human crypto- • • • • • • • ._6
sporidiosis are attributable to infection with Clyp-
tosporidium parvum, although C. meleag~idis, C.
felis, and a dog genotype of C. parvum have also
been identified in stools of infected HIV-positive
patients, as well as in apparently immuno-
/

~
OR

': - --,__ ' ''' ,,


....
-
competent children in Peru (846,848,857).
Pathophysiology. Infection in humans oc-
curs following ingestion or inhalation of crypto-
• •••••• Sexual Reproduction
Schizogony
sporidial oocysts. The life cycle of the organism
is depicted in figure 10-42. Once inside the host, Figure 10-42
each oocyst excysts in the gastrointestinal tract, DIAGRAM OF THE LIFE CYCLE OF CRYPTOSPOR/0/UM
releasing four infective sporozoites. Excystation
is thought to be facilitated through contact with
bile salts, and possibly small bowel enzymes
(837) . Sporozoites attach to intestinal epithelial stood. An enterotoxin-like activity has been
cells via Gal/GalNAC-specific lectins (821), dis- detected in stool extracts, but no actual en-
rupting the microvilli on the host cell surface. terotoxin has been identified. Attachment of
Attachment of the organism to the enterocyte the parasite to intestinal epithelial cells does
induces reorganization of the host cell cytoskel- result in some alterations in cell function (828) .
eton, and protrusion of the host cell cytoplas- In in-vitro cultures, the initial encounter of
mic membrane around the sporozoite to form the organism with a host intestinal epithelial
a vacuole around the organism (821,823,855) . cell results in expression of neutrophil- and
The internalized organism undergoes asexual lymphocyte-targeted chemokines (838,841). In
reproduction to produce merozoites. The mero- addition, infection with Clyptosporidium triggers
zoites are then released into the intestinal lumen. the apoptotic machinery of the host cell; how-
Merozoites may infect other intestinal epithelial ever, parasite-mediated activation ofthe nuclear
cells, or they may mature into gametocytes, the factor-kappa B (NF-kappa B) system has been
sexual form of the parasite. Fertilization of ga- demonstrated in infected biliary epithelial cells,
metocytes results in oocyst formation. Oocysts a function that may circumvent the apoptotic
are then passed into the environment in the signal within the host cell (822). The organism
feces. Oocysts may also sporulate, releasing does appear to induce apoptosis in neigh boring
more sporozoites and producing cycles of auto- uninfected cells through activation of the Fas
infection, leading to persistent infection with a receptor-Fas ligand death pathway (819).
heavy parasite burden (845,847). Clinical Features. Diarrhea is the key clinical
The mechanisms by which cryptosporidia feature of cryptosporidiosis. In immunocompe-
produce diarrheal illness are not fully under- tent individuals, the disease usually presents as

471
Gastrointestinal Diseases

Figure 10-43
CRYPTOSPOR/0/UM
Left: H&E stain demonstrates numerous round blue organisms that appear attached to the surface epithelium.
Right: Giemsa-stained section shows numerous blue-stained organisms on the surfaces of the villi.

an acute, mild to moderate, self-lirp.ited illness ach, esophagus, pancreas, and respiratory tract
usually lasting 3 to 4 days (825), although it may (824,829,836,839,849,856).
persist for longer periods. Patients experience Pathologic Findings. The diagnosis of cryp-
nonspecific clinical manifestations including tosporidial infection requires close scrutiny of
passage of watery, nonbloody stools, vomiting, all epithelial surfaces, including those in the
anorexia, abdominal cramps and pain, and pos- lumens of intestinal or gastric glands, for the
sibly malabsorption. Most patients with a fully presence of the characteristic organisms. The or-
functional immune system are free .o f symptoms ganisms appear as spherical or ovoid basophilic
within a few weeks and of parasites in a few or golden brown bodies attached to the lumi-
months (835,852) . Immunocomp.€tent patients nal surface of the epithelium (fig. 10-43). The
who acquire symptomatic cryptosporidiosis organisms measure 2 to 4 11m in diameter, and
may secrete oocytes for 8 to more than 50 days, can easily be overlooked or mistaken for mucus
with a mean duration of 16.5 days (852, 853). droplets. Conversely, cellular debris and mucus
Oocyst secretion may persist despite resolution clinging to the epithelium can be mistaken for
of the patient's symptoms. cryptosporidia. Unlike the apical mucin droplets
Symptoms of cryptosporidiosis in immuno- that they resemble, however, cryptosporidia are
compromised patients depend in part on the mucicarmine negative. Instead, the organisms
degree of immunocompromise present. Four stain deep blue with Giemsa and Gram stains,
clinical syndromes nave been described in are positive with PAS stains, and are negative
AIDS patients with C7yptosporidium infection: 1) with the Grocott methenamine silver (GMS)
chronic diarrhea (36 percent of patients), often stain (fig. 10-43). In esophageal cryptosporid-
with severe weight loss; 2) cholera-like disease iosis, organisms attach to the superficial squa-
•.· (33 percent of patients); 3) transient diarrhea (15 mous mucosa and the luminal borders of the
percent of patients); and 4) relapsing illness (15 submucosal glands and ducts.
percent of patients) (843) . AIDS patients with A spectrum of intensity of infection exists.
CD4 counts of less than 50/mm 3 may develop Low-intensity infections are usually associated
a fulminant diarrheal illness with passage of with normal intestinal or colonic histology,
more than 2 L of stool per day (818). In addi- whereas severe inflammation and villous atro-
tion, immunocompromised patients may show phy complicate high-density infections (830,
atypical disease presentations with involvement 831). The mucosa may show an acute inflam-
of unusual anatomic sites including the stom- matory reaction and an apparent increase in

472
Gastrointestinal Infections

intraepitheliallymphocytes. The infected cells intestinal lumen from which they may either
show a range of changes, from only minimal invade other intestinal cells, or mature into
injury and fragments of organisms in the cells either microgametocytes or macrogametocytes.
to focal necrosis. A variable degree of villous Fertilization of gametocytes results in the de-
and crypt atrophy may be present. velopment of oocysts, which are shed into the
Special Techniques. Most cases of crypto- environment in the feces. Oocysts leave the host
sporidiosis are diagnosed by the detection of in an unsporulated, noninfective form. They
oocysts in stool samples stained with a modi- must undergo sporulation, in which the oocyst
fied acid-fast stain. Other methods of diagnosis differentiates into a sporocyst containing two
include direct and indirect fluorescence micros- sporozoites, prior to becoming infectious. The
copy and ELISA (833,854). PCR-based assays are environmental conditions that induce sporula-
also used to detect the organisms (827,834). tion are not yet understood (870).
Treatment and Prognosis. There is no rou- Clinical Features. Symptoms of cyclo-
tinely effective antiparasitic therapy for crypto- sporiasis develop 1 to 7 days after suspected
sporidiosis. Nonspecific, supportive treatment, exposure, and include diarrhea associated with
including rehydration and nutritional support, nausea, anorexia, malaise, and abdominal
remains the mainstay of management. Anum- cramping. Symptomatic periods alternate with
ber of compounds have been used with variable periods of apparent remission (859). The diar-
responses. Antimicrobial drugs that have been rhea is watery, and may last 3 to 7 weeks in im-
employed with some success include paromo- munocompetent individuals and may continue
mycin (854), paromomycin plus azithromycin for up to 4 months in HIV-infected patients
(851), and nitazoxanide (826,850). (868,870). With prolonged illness, weight loss is
severe (874). Patients can also be asymptomatic
Cyclospora Infections
excreters of oocysts, although this is not com-
Demography. Cyclospora cayetanensis, a coc- mon (864,866,871,875).
cidian protozoan, is a recently recognized cause Microscopic Findings. Cyclospora organisms
of waterborne and foodborne diarrhea. The can be seen in duodenal aspirates but they have
organism affects many animal species, includ- not been seen in biopsies of the distal duodenum
ing man. It occurs widely in Europe, Asia, North (860). The jejunal histology of Cyclospora infec-
Africa, and Central and South America (875). In tion varies from essentially normal to changes
most developed countries, the disease is most resembling tropical sprue. Jejunal biopsies show
commonly associated with foodbome outbreaks partial villous atrophy, villous blunting and fu-
or in travelers to developing countries. Cyclospora sion, lymphocytic infiltration of the lamina pro-
outbreaks in the United States have been rep01ted pria, crypt hyperplasia, and increased numbers of
in association with consumption of contaminated intraepitheliallymphocytes. The epithelial cells
berries imported from Central America and with show both focal vacuolization and disruption of
contaminated water (858,863,865,876). the brush border. The enterocytes change their
Etiology. There are 17 species of Cyclospora. shape from columnar to cuboidal.
Currently, humans are the only known hosts for Special Techniques. The diagnosis relies
Cyclospora cayetanensis, and an environmental on detecting the organism or its DNA in stool
source of infection or animal model has not yet samples. Almost all cases are diagnosed by de-
been identified (861). tecting oocysts in stool samples or jejunal or
The infective form of the organism is the duodenal aspirates (871). Because Cyclospora
oocyst. Within the sporulated oocyst, two oocysts may be passed intermittently, sporadi-
sporocysts can be identified, each of which cally, or in small numbers, techniques to con-
yields two sporozoites. Oocysts excyst in the centrate oocytes are used as part of the routine
small intestine, typically the jejunum, and diagnostic procedure (862). Acid-fast stains,
sporozoites are released. The sporozoites invade such as the Ziehl-Neelsen, enable detection of
intestinal epithelial cells where they undergo oocysts 8 to 10 pm in diameter (870); however,
asexual reproduction to produce two genera- some ova do not pick up the stain and appear
tions of merozoites (870). Merozoites enter the as glassy, wrinkled spheres (862).

473
Gastrointestinal Diseases

Table 10-11
COMPARISON OF MICROSCOPIC APPEARANCE OF CYCLOSPORA, ISOSPORA, AND CRYPTOSPOR/0/UM

Feature Cyclospora Isospora Cryptosporidium


Size range ().lm) 8-10 20-33 X 10-19 4-6
Appearance in formal- Spherical refractile, greenish Oval; usually unsporulated Not usually seen
ether concentration central morula; unsporulated when passed in feces
when passed in feces
Sporulated oocyst 2 oval sporocysts, each con- 2 spheri·cal sporocysts, each Spherical or slightly ovoid;
taining 2 sporozoites containing 4 sporozoites 4 sporozoites
Appearance in modified Acid fast, variable staining; Acid fast; sporoblasts stain Acid fast; staining variable;
Ziehl-Neelsen stain some do not stain and appear deep red; oocyst wall "erythrocyte" staining
as glassy, wrinkled spheres outlined by stain precipitate common
Appearance under ultra- Bright blue autofluorescence No effect No effect
violet light
Fluorescence with Poor Variable Good; bright yellow discs,
aura mine often with erythrocyte
pattern
Fluorescence with mono- Absent Absent Good; often shows suture
clonal antibody to line on surface of oocyst
Clyptosporidium

Depending on the degree of staining, the supportive measures. The drug of choice is tri-
oocysts range from colorless to light pink to an methoprim-sulfamethoxazole. Cotrimoxazole
intense, deep reddish purple. Staining also var- is beneficial in some cases (867). Guil1ain-Barre
ies in different parts of the smear. More recently, syndrome may be a late complication (873).
a safranin staining procedure has been devel-
Leishmania Infections
oped, which includes heating in il microwave,
that appears to be superior for identifying the Demography. Visceral leishmaniasis is endemic
organism (862,869). '"" in 62 countries, but over 90 percent of cases occur
Size is an important criterion in the identifi- in India, Bangladesh, Nepal, Sudan, and northeast-
cation of the protozoan cysts and the measure- ern Brazil (883). The population at risk totals 350
ment of the oocyst helps establish the correct million people with 0.5 to 2.0 million new cases
diagnosis. Unstained, oocysts appear as spheri- diagnosed per year (881,882) and 41,000 resultant
cal bodies containing a refractile, greenish cen- deaths (892). In endemic areas, leishmaniasis is
tral morule. The organisms autofluoresce bright transmitted by sandflies, but the disease is also
blue when examined with ultraviolet (UV) transmitted via blood transfusions, congenital
epifluorescence microscopy. Ultrastructural infections, person-to-person contact, hypodermic
examination of the parasite provides confirma- needles, or sexual contact. Risk factors for the
tory evidence. development of the disease include malnutrition,
A PCR assay recently has been developed to treatment with immunosuppressive drugs, and
detect Cyclospora. It takes advantage of amplifi- HIV infection (877,878,880).
cation of a small subunit ribosomal RNA coding Etiology. Most cases of visceral leishmaniasis
region (872) . are caused by Leishmania donovani, an obligate
Differential Diagnosis. Cyclospora infections intracellular protozoan ..In the Mediterranean
clinically resemble cryptosporidiosis, micro- area and South America, two other species of
sporidiosis, and isosporiasis. Cyclospora, Isospora, Leishmania also cause the disease, L. infantum
and Clyptosp01idia are compared in Table 10-11. and L. chagasi, respectively. Humans are the
Treatment and Prognosis. The disease only known reservoir for L. donovani, but L. in-
appears to be self-limited. The mainstay of fantum and L. chagasi may be carried by canines,
treatment is oral rehydration and appropriate particularly domestic and stray dogs (883).

474
Gastrointestinal Infections

Leishmania organisms have a dimorphic life


cycle. The infection is acquired through bites
of infected, blood-sucking, female sandflies of
dther the genus Phlebotomus (Old World) or
Lutzomyia (New World). In the insect vector,
Leishmania appears as a motile, spindle-shaped
promastigote, measuring 2 to 4 pm x 15 to 20
pm, that possesses a single anterior flagellum.
After mononuclear phagocytosis in humans, the
promastigotes lose their flagella and multiply as
small, round or oval, intracellular amastigotes
measuring 2 to 4 pm in diameter.
Clinical Features. Visceral leishmaniasis con-
sists of a complex constellation of clinical manifes-
.tations that follow chronic infection with L. don-
ovani and related members of this genus. Clinically,
leishmaniasis manifests as visceral, cutaneous,
and mucosal syndromes. Visceral leishmaniasis,
particularly in the Indian subcontinent, may result
in enteric infections. Gastrointestinal symptoms
include dianhea, odynophagia, esophagospasm,
dysphagia, abdominal pain, malabsorption, and
incontinence (885,890, 891). The disease affects
the esophagus, stomach, small intestine, colon,
rectum, and anus, as well as regional lymph nodes
and extragastrointestinal sites such as the bone
marrow, oral mucosa, liver, lungs, spleen, brain,
and skin (884) . Figure 10-44
Gross Findings. Radiologic examination of LEISHMANIASIS
the upper gastrointestinal tract and small bowel Discrete, round, uniform blue Leishmania organisms fill
shows thickening of the small intestinal folds histiocytes within the lamina propria. (Fig. 3-59 from Emory
and increased separation of the bowel loops TS, Carpenter HA, Gostout C], Sobin LH . Atlas of gastro-
due to edema. Endoscopy is normal in half of intestinal endoscopy & endoscopic biopsies. Washington
D.C. : Armed Forces Institute of Pathology; 2000:204.)
patients (885) .
Microscopic Findings. The Leishmania amas-
tigotes are often detected in biopsies of what characteristic black dots corresponding to the
macroscopically appears to be normal small or nucleus and the kinetoplast. The organisms
large intestine. Alternatively, the lamina propria appear blue in Wright-Giemsa- stained prepara-
of the intestines and stomach can be obliterated tions. At high magnification, a dark red, slightly
by an infiltration of macrophages containing flattened, eccentrically placed nucleus and a
abundant cytoplasmic Leishmania amastigotes. rod-shaped kinetoplast may be discerned. The
In immunocompetent hosts, granulomas form enterocytes lining the crypts and villi appear
and an inflammatory response with increased normal and do not contain organisms.
numbers of histiocytes, plasma cells, and Special Techniques. The diagnosis requires
lymphocytes occurs in affected organs. The microscopic identification of characteristic
granulomas are absent or poorly formed in im- Leishmania amastigotes in smears, touch
munocompromised individuals. preparations, or biopsy specimens; culture of
The intracellular amastigotes are readily the organism; or serologic positivity for the
seen on either H&E- or Giemsa-stained sections protozoan. Microscopic diagnosis is usually
(fig. 10-44). The organisms are round to oval, carried out on aspirates or biopsies of bone mar-
measure 1 to 3 pm in diameter, and have two row, spleen, liver, or lymph nodes (883) . PCR

475
Gastrointestinal Diseases

techniques are highly sensitive for detecting prefer to inhabit mud huts with cracked walls
infection (879,889) and thatched roofs. Thus, infections most com-
Differential Diagnosis. Digestive leish- monly affect poor socioeconomic classes who
maniasis must be differentiated from other inhabit such dwellings. Parasites occasionally
opportunistic protozoal, bacterial, and fungal pass from the mother to the fetus and cause
infections. The only organism that may contain spontaneous abortion or congenital Chagas'
a characteristic kinetoplast similar to that found disease. Rarely, the disease is transmitted by
in Leishmania is Trypanosoma. Leishmaniasis blood transfusions. Laboratory workers may
must also be differentiated from other infections also become accidentally infected.
predominantly resulting in histiocytic infil- Adult insects ingest trypomastigotes (try-
trates including disseminated histoplasmosis, panosomes) when taking blood from infected
Mycobacterium avium-intracellulare infection, animals or humans. The life cycle ofT. cruzi in-
and cryptococcosis. Histoplasma and Cryptococ- volves a reproductive phase in the host as well as
cus stain with silver methenamine stains, and in the insect. T. auzi trypomastigotes are ingested
M. avium-intracellulare stains with acid-fast by the insect, and transformed in its gut into
stains, contrasting with the staining reactions epimastigotes, flagellate forms with an anterior
of Leishmania. In AIDS patients, intracellular kinetoplast. Epimastigotes multiply by binary
organisms that need to be differentiated from fission, then migrate to the hindgut where they
Leishmania amastigotes are Penicillium mameffei change to infective, metacyclic trypomastigotes.
and Toxoplasma gondii. These are excreted in the insect feces. The hu-
Treatment and Prognosis. Penfavalent anti- man host is infected by rubbing the triatomid
monials (sodium stibogluconate and meglumine insect bite, thereby assisting penetration of the
antimoniate) are the mainstays of therapy metacyclic trypomastigotes through the skin. The
for patients with leishmaniasis in most of the protozoans penetrate the skin, enter the blood-
world. Parasite resistance to these drugs, how- stream, and circulate, invading smooth muscles
ever, does occur (887). Other drugs that may be and the myocardium. Inside the host cells, they
used include amphotericin B and pentamidine form small (3-pm) amastigotes. These amastigotes
(881,883). Treatment of immunocompromised multiply by binary fission, enlarging the cell and
patients with leishmaniasis is difficult, and re- leading to its rupture. New circulating trypomas-
lapse rates approach 60 percent ~886,888). tigotes then invade other cells and the cycle is
repeated. In this way, a cycle is established that
Chagas' Disease
alternates asynchronously between intracellular
Demography. Chagas' disease, or American tJy- multiplying forms and nondividing but infective
panosomiasis, is a zoonosis resulting from human forms that circulate in the bloodstream.
infection by the protozoan Trypanosoma cruzi. Pathophysiology. The mechanisms by which
The chronic form of the disease is endemic in T. cruzi infection damages the gastrointestinal
all Central and South American countries, where system are poorly understood. Several lines of
it is a major cause of morbidity and mortality evidence suggest that immunologic mecha-
among poor people: According to the World nisms, including possible autoimmune cross-
Health Organization estimates, approximately reactivity between antibodies to T. cruzi and
25 percent of the Latin American population mammalian nervous tissues, are of significance
is at risk for the disease and 16 to 18 million (893,896,899).
people are infected (892). Of these, 30 percent Clinical Features. Chagas' disease comprises
are likely to develop severe clinical symptoms, a variety of clinical and pathologic manifesta-
and 10 percent will die (895). Males are affected tions ranging from severe, such as cardiomyopa-
more than females. Chagas' disease is also found thy, to insignificant (893). Acute illness occurs
in parts of the southern United States. in childhood. Initial spread of the parasites from
Etiology. The organism parasitizes over the site of entry and their multiplication may be
100 species of mammals, including domestic accompanied by fever, malaise, and edema of the
animals, rodents, and humans. Triatomid in- face and lower extremities, as well as generalized
sects act as the main disease vector. The insects lymphadenopathy and hepatosplenomegaly.

476
Gastrointestinal Infections

Figure 10-45
MEGAESOPHAGUS IN A PATIENT
WITH CHAGAS' DISEASE
Figure 10-46
The esophagus is markedly dilated in this patient with
long-standing Chagas' disease. The gross appearance mimics ACUTE CHAGAS' DISEASE INVOLVING THE INTESTINE
that of achalasia. (Courtesy of the Division of Gastroin- An organism is adjacent to the myenteric plexus.
testinal Pathology, Armed Forces Institute of Pathology,
Washington, DC.)

many years and varies considerably in terms


The muscles, including the heart, are often of its extent in individual patients as well as in
heavily parasitized and severe myocarditis de- different segments of the gastrointestinal tract.
velops in a small proportion of patients (897). The histologic features of Chagas' disease reflect
In rare cases, the organism invades the CNS the stage of the disease. During the acute infec-
causing meningoencephalitis (897). The acute tion, the organism lies in or near the myenteric
illness resolves spontaneously over 4 to 6 weeks plexus (fig. 10-46). Early degenerative changes
in most patients. involve the muscularis propria and the myen-
Approximately 10 to 20 percent of patients teric plexus. In late-stage disease, the myenteric
develop chronic disease, which may become plexus becomes fibrotic and neurons disappear.
manifest as long as 10 or more years after the Histologic examination of the wall of the colon
initial infection (897). Gastrointestinal involve- shows depletion of the neural cells in the my-
ment is common at this time. Gastrointestinal enteric plexus, with fibrous tissue replacing the
dysfunction in the form of megaesophagus or plexus. Focal inflammation and hypertrophy of
megacolon is a major problem for many patients the muscularis propria occur.
with chronic Chagas' disease. Patients with Special Techniques. A complement fixation
colonic involvement complain of constipation, test for T. cruzi infection is usually positive in
abdominal distension, and pain. Megacolon patients with chronic Chagas' disease. Esopha-
can be complicated by fecal impaction, volvu- geal manometry studies confirm the absence
lus, enterocolitis, or toxic megacolon. Clinical of peristalsis in the body of the esophagus and
signs and symptoms of the latter include pain, failure of coordinated relaxation of the lower
progressive abdominal distension accompanied esophageal sphincter in response to swallowing.
by fever, severe toxemia, and shock. Differential Diagnosis. Clinically, the
Gross Findings. Both megaesophagus and disease mimics any of the chronic idiopathic
megacolon develop in patients with chronic intestinal pseudoobstruction syndromes and
Chagas' disease (fig. 10-45). Chest radiographs achalasia. Histologically, late-stage disease may
show cardiomegaly and a dilated esophagus with resemble scleroderma.
air-fluid levels. The gross features of the esopha- Treatment and Prognosis. Two drugs are
gus resemble those seen in achalasia. The colon available for the treatment of Chagas' disease,
can reach immense proportions, with a length benznidazole, the drug of choice, and nifur-
of over 2 m and a capacity of 30 to 40 L (898). timox (894). Prevention of the disease is of
Microscopic Findings. The process of nerve primary importance. Once the neurons of the
destruction usually develops insidiously over myenteric plexus are destroyed, progressive dila-

477
Gastrointestinal Diseases

tation of the gastrointestinal tract is inevitable. flatulence, and weight loss (903, 904,909,910,91
Medical therapy for gastrointestinal symptoms 2,916,919,923,924) . In acute forms of the illness,
includes stool softeners and laxatives for chronic diarrhea may be profuse (919).
constipation, and antireflux measures for gastro- Pathologic Findings. Grossly, the colonic
esophageal reflux. Surgery may be necessary for mucosa usually appears normal, although rarely
medically nonresponsive symptoms, for patients it appears erythematous and friable (901,905,
with massive dilatation of aperistaltic gastroin- 907). Biopsies from infected persons also often
testinal segments, or for volvulus. appear normal. When abnormal, they may ex-
hibit only mild nonspecific inflammation (90 7).
Blastocystis Infections
Rarely, the organism causes colonic mucosal
Demography. In many studies, Blastocys- destruction and invasion of tissues (900;920).
tis hominis represents the most commonly Special Techniques. The parasite is directly
encountered intestinal parasite in humans identifiable by immediate examination of feces.
(902,915). Organism prevalence ranges from Rarely, the organism is identified in the duode-
2 to 18 percent in the United States, 3 to 13 nal secretions obtained by string tests.
percent in Canada, and 3 to 7 percent in Great Treatment and Prognosis. Treatment with
Britain (912,918). The prevalence is"as high as metronidazole or trimethoplim-sulfamethoxazole
50 percent in the developing world (913,914). is effective in eradicating the organism (908,911).
B. hominis infection is particularly common
Ascaris Infections
among immunocompromised patients (902).
Travelers to tropical locales are at risk (906). Demography. Ascaris is the most prevalent
Etiology. B. hominis is a protozoan in the intestinal helminth infecting humans, affect-
subphylum Sporozoa. This strict anaerobe re- ing as much as 25 percent of the population in
produces by binary division or sporulation. It some areas (934). These parasites have profound
exhibits three major morphologic forms: vacu- health, social, and economic implications for
olar, granular, and ameboid (913). The vacuolar developing countries and certain regions of
form is variable in size, measuring from 2 to 200 developed nations. The worms exhibit a world-
J..lm (917,922), with an average diameter of 2 to wide distribution, although they are most com-
15 J..lm (920) . This form of the organism contains monly encountered in tropical and subtropical
a single nucleus at the edge of the ryt:oplasm and regions of Asia, Africa, and South America. In
a large, central, optically empty body surrounded the United States, Ascaris is prevalent in rural
by the peripheral cytoplasm containing other areas of the south. Infection may also be seen
cellular organelles. If two nuclei are present, they in travelers and migrants from endemic areas.
are at opposite poles of the cell. Sometimes, four Ascaris infection is most common in areas
nuclei line up at the edges of the protozoan. The with overcrowding and poor sanitation (931).
granular form is spherical and has a diameter It occurs at all ages but is seen more often in
of 10 to 60 J..lm (921). It contains reproductive preschool and young school-aged children, espe-
granules that correspond to the offspring, round cially in the 5- to 9-year-old group. Transmission
or tubular-like lipidic cytoplasmic bodies, and a usually occurs by a hand-to-mouth route. Chil-
central body. The ameboid form has a diameter dren acquire the infection by ingesting mature
of 10 to 25 J..lm and measures up to 100 J..lm in eggs from contaminated soil where they play;
length. It has irregular edges and its pseudopo- ova may also be ingested in fecally contaminated
dia extend and retract as it feeds on bacteria. food and water. In endemic areas, the ova are
r..·
Clinical Features. B. hominis is found in as- recovered from many surfaces including utensils,
ymptomatic patients, and in those presenting furniture, money, door handles, food items, and
with symptoms of acute or chronic gastroenteritis. fingers (933). There are also rare reports of neo-
Because the organism is so commonly identified natal transmission (929). The balance between
in asymptomatic individuals, the pathogenicity of exposure rate and rate of loss of the infection
Blastocystis is debated. When present, symptoms due to host immune defenses determines the
are nonspecific and include abdominal pain, intensity of infection (927). Some of these fac-
cramps, diarrhea, anorexia, nausea, vomiting, tors may be genetically determined (935).

478
Gastrointestinal Infections

Larvae enter Larvae enter


gastrointestinal the venous
tract ~ system from the
\intestine

Figure 10-47

Adult worms DIAGRAM OF THE


in small intestine LIFE CYCLE OF ASCARIS

_;
Immature
.
--, l
I
Man
ingests
eggs
egg
"-.!~~~i~ation

~ Infective
egg

Etiology. Ascaris lumbricoides is the largest hu- from gast1ic and duodenal digestion. They malt
man nematode, measuring up to 40 cm in length. into second-stage larvae that penetrate the jejunal
The worm is elongated, cylindrical, and tapered at mucosa and pass to the liver via the pmtal system,
both ends. Females measure 20 to 35 cm in length and then to the hea1t and lungs. It takes 2 to 3
and 3 to 6 mm in diameter; males are 15 to 30 cm weeks following ingestion for infective larvae to
and 2 to 4 mm in diameter (933). The male pos- develop in the intestine, penetrate the mucosa,
terior end is curved and has a copulatory spicule. and reach the portal venous system. Migration to
The cuticle or outer skin is striated with two lateral the lungs takes 3 to 4 days and after 2 to 3 weeks
lines. The color of the parasite varies from yellow the larvae penetrate from the capillary bed into
to white with a pinkish hue. It is characterized by the alveoli where they malt into third-stage larvae.
a constricted area known as a vulvar waist (genital The latter migrate up the tracheobronchial tree,
girdle) located at the junction of the anterior and are coughed up and swallowed again. Fourth-stage
middle thirds of the body. larvae reach the small intestine and develop into
After mating, the female worms deposit eggs adults where they copulate and reproduce (940).
that are excreted from the host in the feces. Fe- Following migration, the adult worms (one to
males may release over 200,000 ova per day (937). several hundred) develop in the small intestine
Fertile eggs are <?VOid, measure 6 to 40 pm, and (usually mid-jejunum) where they anchor them-
acquire a golden brown color due to bile staining. selves to the mucosal surface. Adult worms live
The outer shell of a fertilized egg appears mam- 12 to 18 months. The life cycle of Ascaris is
millated, while unfertilized eggs are smooth. Eggs summarized in figure 10-4 7.
become infective in soil 3 to 4 weeks after excre- Clinical Features. Three phases of disease
tion. Survival of such infective ova is variable, may be present: first, a larval migration phase;
although some survive for up to 15 years (939). second, a migration/oviposition phase; and
Eggs ingested by humans hatch into first- third, a complications phase (933). In many
stage larvae within a few hours in the jejunum cases, the infection is asymptomatic. Patients
due to the action of larval enzymes with assistance with low worm burdens may experience only

479
Gastrointestinal Diseases

can develop in any organ, including the intes-


tines, or on the peritoneal surfaces.
Special Techniques. The diagnosis of asca-
riasis is usually made by detecting eggs in the
feces. Three types of eggs are found: the typical
fertilized egg, the unfertilized egg, and the de-
corticated fertilized egg. Regular fertilized eggs
measure SS to 7S x 3S to SO pm and have thick
shells with a bile stained, prominent, outer albu-
minoid, mamillated coat. Decorticated fertilized
eggs measure 30 to 40 pm in diameter and lack
mammillation. Eggs are usually abundant so that
only direct microscopic examination of a fecal
smear is necessary. Concentration techniques,
such as flotation, sedimentation, formalin ethyl
acetate, centrifugation, or the Kato-Katz tech-
nique are useful in mild infections.
Differential Diagnosis. Other helminthic
Figure 10-48
infections are the entities in the differential
ASCARIS diagnosis.
Endoscopic photograph of Ascaris in tl;le lumen of the Treatment and Prognosis. A number of anti-
stomach of a patient who had abdominal pa!n and vomiting. helminthics are available for treating intestinal
ascariasis. The drug of choice is mebendazole
(Vermox) or a single dose of pyrantel pamoate
vague abdominal pain. In patients with heavy (Antiminth) or albendazole (Zentel) (926,936-
worm burdens, more severe symptoms occur 938). Ascaris cure rates are over 97 percent (92S).
including intestinal obstruction, perforation, and In endemic areas, where multiple helminthic
peritonitis (928,930,932,941). Masses of worms infections are common, the initial treatment
may obstruct the common bile and pancreatic can be followed by 100 mg of mebendazole
ducts, producing cholangitis and pancreatitis. In taken orally. Retreatment is often necessary,
severe cases, the liver may be involved. Repeat especially in endemic areas. Cases of complete
infection can sometimes lead to serious hypersen- obstruction due a worm bolus with signs of an
sitivity reactions in sensitized individuals. Such acute abdomen require surgery.
patients develop urticaria, angioneurotic edema,
Hookworm Infections
and bronchospasm, as well as elevated IgE levels.
Gross Findings. As adults, most Ascaris para- Demography. Hookw01ms infect an estimated
sites reside in the jejunallumen where they are 1.3 billion people worldwide (943). They are partic-
grossly and endoscopically evident (fig. 10-48). ularly common in moist, tropical, rural areas where
Radiographic examin,ation of the intestine may there are inadequate hygiene and lack of footwear,
reveal parallel cylindrical filling defects that and where crops provide shade or are cultivated
show a string-like shadow of barium in the under tall trees. Most heavy infestations occur in
worm's intestine. In cases of bowel obstruc- people who live where coconuts, cocoa, coffee
tion, abdominal films may show the outline of beans, tea, sugar cane, sweet potatoes, or mulberry
interlocking worms. trees are grown (94S). Necator americanus is more
Microscopic Findings. The cross section of common in Asia, the Americas, Africa, Australia,
the worm may be seen in histologic sections. and the Pacific islands; Ancylostoma duodenale is
Once the infection clears, there are only residual found in Africa, India, China, Japan, and parts of
traces of their presence. The organisms are seen Australia and South America. Both species coexist
as small polypoid structures lying within the in several parts of the world. Zoonotic ancylosto-
submucosa and surrounded by fibrotic reactive miasis (A. caninum) can be acquired from domestic
tissue. Granulomas may also be present. They pets in developed urban communities (948).

480
Gastrointestinal Infections

migrate through the bronchi and trachea to the


Larvae travel
esophagus where they are swallowed.
to lung via In the small intestine, the larvae mature into
~·,;~ adult worms. The adult worms attach them-
selves to the intestinal epithelium via a buccal
capsule that is armed with teeth (Ancylostoma)
or cutting plates (Necator). Large, anterior glands
secrete proteases and anticoagulants that act
to digest host tissues. Worms change position
every 4 to 6 hours, possibly in response to tis-
sue depletion or the onset of local inflamma-
tion (946). Adult Ancylostoma probably survive
in the host for only 6 to 12 months, although
individual infections may persist for years as a
result of intermittent reactivation of hypobiotic
larvae. In contrast, adult Necator organisms
survive an average of 5 years, although survival
for as long as 18 years has been recorded (947).
The nematodes measure approximately 0. 7
to 1.3 cm in length. Males are slightly smaller
than females and Necator is smaller than
egg
Ancylostoma. They are cream to gray-white and
possess a distinctive oral or buccal capsule in
Figure 10-49
which is situated a bilateral pair of fused teeth
DIAGRAM OF THE LIFE CYCLE OF THE HOOKWORM in A. duodenale and a ventral and dorsal pair of
semilunar cutting plates in N. americanus . The
posterior tip of the male forms a distinctive
Etiology. The most significant human para- broad, transparent, umbrella-like structure,
sites in the hookworm group are A. duodenale the copulatory bursa, used to hold the female
and N. americanus. A. duodenale sometimes is during insemination. The female deposits im-
referred to as the old-world hookworm, whereas mature eggs in a fecal stream that are usually
N. americanus is referred to as the new-world in a 2- to 8-cell stage when seen in fresh stool
hookworm; however, the geographic distribu- specimens. The eggs of the two species are in-
tion of these two species overlaps. distinguishable from one another.
The principal mode of human infection is Pathophysiology. The invasive stage of the
through percutaneous penetration by the lar- nematode releases hyaluronidase, metallo-
vae. Infectious filariform larvae invade the skin proteinases, and cysteine proteinases, which
through bare feet or other exposed skin surfaces. serve as potential allergens and induce an eo-
A purpuric, papular, or vesicular eruption devef- sinophilic enteritis via a type I hypersensitivity
ops at the entry site. Adult hookworms live in response (942,944). These enzymes also degrade
the small intestine of human beings (fig. 10-49). glycoproteins and play a role in tissue break-
Under optimal conditions, the eggs in the feces down and mucosal invasion (945).
hatch in moist, warm soil within 24 hours to Clinical Features. Once filariform larvae
release first-stage larvae. Second-stage larvae penetrate the skin, a pruritic, erythematous,
develop 3 days later. One week after hatching, papular, or vesicular urticarial rash may occur at
the filariform larvae develop, migrate to the the entry point. Secondary pyogenic infections
surface of the soil, and remain viable for weeks. commonly develop at these sites. This is accom-
The filariform larvae then penetrate the skin panied by intense itching, edema, erythema,
of the host and enter the venous or lymphatic and neutrophilic and eosinophilic infiltration of
system where they are carried to the lung. The the site. The skin eruption may last for several
larvae emerge in the alveolar spaces. They then weeks. Pulmonary manifestations of the disease

481
Gastrointestinal Diseases

Figure 10-50
HOOKWORM INFECTION
A: A duodenal biopsy specimen shows villous blunting
and increased inflammatory cells within the lamina propria.
B: The inflammatory infiltrate contains numerous
eosinophils and occasional neutrophils.
C: A cross section of a hookworm is near the opening
of a duodenal crypt.

""
are similar to those seen with ascariasis. Patients responses may result from the attachment of
may develop a mild transient cough. Many the worms to the intestinal mucosa. Worms
patients remain asymptomatic after the larvae suck blood and plasma vigorously, and often
reach the small intestine. Dyspepsia, nausea, abandon one site and move to another, leaving
and epigastric discomfort may occur early in the old site oozing blood and plasma. A. caninum
the disease. In untreated patients, symptoms is often diagnosed by identifying the 1-cm-long
progress, with anemia, constipation, or diar- worm in gastrointestinal biopsies or duodenal as-
rhea developing. In severe cases and chronic pirates, especially in patients with heavy parasitic
infections, malnutrition, hypoproteinemia, and infections. The mucosa may appear hemorrhagic,
profound anemia with cardiac decompensation eroded, congested, and edematous. Focal or dif-
may be seen. The severity of the symptoms fuse eosinophilic infiltrates are commonly seen
depends on the number of worms present and (fig. 10-50). Increased numbers of eosinophils in
the host's nutritional and immune status. Labo- the lamina propria are particularly prominent
ratory examination typically shows peripheral near areas of parasitic attachment. Charcot-
eosinophilia and elevated IgE levels. Leyden crystals and eosinophil degranulation
Gross Findings. Radiographic studies usu- are often present. Granuiomas may sometimes
ally demonstrate nonspecific changes, such as be seen. Some patients develop focal crypt hy-
excessive peristalsis and "puddling" changes, perplasia and villous atrophy.
particularly in the proximal jejunum. Special Techniques. Stool examination usu-
Microscopic Findings. Small erosive lesions, ally reveals the presence of hookworm eggs. The
hemorrhages, tissue cytolysis, and neutrophilic eggs are thin-shelled, ovoid, and measure 65 x

482
Gastrointestinal Infections

40 pm. Direct fecal smears examined micro- Three schistosoma! species cause most human
scopically usually reveal the eggs, but in light infections: S. mansoni, S. japonicwn, and S. hae-
infections a concentration technique is needed. matobium. S. mansoni is endemic throughout
Rhabditiform larvae measuring 0.3 to 17.0 pm Africa and is also found in many areas of Latin
1hay be found in the feces if the stool specimen America, the West Indies, Puerto Rico, and the
is stored in the laboratory for hours prior to Middle East. S. japonicum is confined to Asia,
examination. The larvae can be differentiated with most cases found in China, especially
from those of Strongyloides stercoralis by the pres- along river basins. The parasite is also found in
ence of a long buccal capsule and the indistinct scattered areas of Taiwan and the Philippines.
genital primordia. S. stercoralis larvae have a S. haematobium is endemic in Africa and the
short buccal cavity and large genital primordia. Middle East. Rare infections with S. intercalatum,
A . caninum can be diagnosed by total serum S. mekongi, and S. mattheei also occur. S. inter-
IgE assay and serologic testing with ELISA and calatum infections occur in Africa and S. mekongi
Western blot assay using the excretory secretory is found along the Mekong River and adjacent
antigens of A. caninum. parts of Southeast Asia, including Indochina. S.
Differential Diagnosis. The edema, eosino- mattheei is found in South Africa.
philic infiltration of the gut wall, ascites, and All schistosomes have similar life cycles (fig.
regional lymphadenopathy are identical to that 10-51). Eggs are passed by urine or stool into
seen in eosinophilic gastroenteritis, which falls fresh water where they hatch. Ciliated larvae,
within the differential diagnosis (949) . called miracidia, are released and penetrate into
Treatment and Prognosis. Antihelminthic appropriate snails. Sporocysts develop in each
therapy is necessary to eradicate the adult intes- snail from which thousands of daughter sporo-
tinal worms. The infection is treated with me- cysts form. These forms emerge from the snail
bendazole, albendazole, or pyrantel pamoate. in 3 to 5 weeks as fork-tailed, free-swimming
Anemia should be treated with 50 to 100 mg of organisms called cercariae. As many as 100,000
ferrous sulfate daily along with a high protein may develop from a single miracidium. The
diet and vitamins. This regimen is continued cercariae penetrate the human skin on contact
until the hemoglobin levels stabilize for several and enter the venous circulation, terminating
months. In patients with severe anemia, blood in various places. Larvae of S. mansoni termi-
transfusions and intravenous iron supplements nate in the venules of the inferior mesenteric
may be required. venous system; S. haematobium terminates in
the inferior, hemorrhoidal, and vesicle plexuses;
Schistosoma Infections
and larvae of S. japonicum primarily reside in
Demography. Schistosomiasis is one of the the inferior mesenteric system, with some lar-
world's most prevalent diseases, ranking second val worms terminating and developing in the
only to malaria as a cause of serious global mor- superior mesenteric veins (951). The worms are
bidity. It is estimated to afflict as many as 200 slender, being 0.5 mm in diameter and about 6
million people worldwide (953): 120 million to 20 mm in length. The female lies in the lon-
of these are symptomatic and 20 million suffer gitudinal body cleft of the male and both reside
from serious disease. Eighty to 85 percent of cases within their predetermined venous system in
of schistosomiasis occur in sub-Saharan Africa, a copulatory position. To lay eggs, the females
where the estimated mmtality reaches 280,000 migrate peripherally to terminal venules over
per year (962). The disease is also endemic in the the bowel and bladder walls. Eggs subsequently
Middle East, Brazil, Venezuela, the Caribbean, laid generally move through the venules to the
China, Indonesia, the Philippines, Cambodia, bowel or bladder wall and many are swept to the
and Laos. Environmental changes resulting from liver or lungs by venous drainage. The eggs work
the development of water resources, population their way through the bowel and bladder tissue
growth, and migration have facilitated the to their respective lumens. After reaching the
spread of the disease to new areas (960). lumen, the eggs are passed to the outside world
Etiology. Schistosomiasis is an infection and the cycle is complete. Eggs are first detected
caused by trematodes in the genus Schistosoma. 6 to 10 weeks after cercaria! penetration.

483
Gastrointestinal Diseases

Eggs migrate
from veins into
intestinallumen
9 ·
,.1----;

/ "
Figure 10-51
DIAGRAM OF THE LIFE
CYCLE OF SCHISTOSOMA Cercariae

;;g~ted\
penetrate
skin and enter
in feces venous system
;

Eg{J r~ria
~ '\.. ~ ____...,.,. @,
Miracidium Snail

Clinical Features. Schistosomiasis occurs in to palpation. Splenomegaly is frequent. Labo-


three stages: initial penetration, an acute con- ratory studies show eosinophilia and elevated
dition known as Katayama fever, and chronic IgG and IgE levels. The syndrome usually lasts
disease. In the initial penetration stage, cercarial days to weeks.
penetration of the skin results j.n a maculo- Many patients in the chronic phase are
papular eruption at the site. In unsensitized asymptomatic, particularly if the infection is
individuals, the faint red macules appear within mild. With heavier infection, mild chronic
12 hours; in others, the skin reactions appear diarrhea develops, sometimes associated with
up to 1 week later (961). hypogastric or left iliac fossa pain. Mucus and
The acute stage, also called stage II or Kata- small amounts of blood may be present in the
yama fever after a valley in ]apan where the stool but gross hemorrhage is unusual. Iron de-
disease was endemic, generally starts 4 to 6 ficiency anemia can result from persistent blood
weeks and sometimes as late as 10 weeks or loss. There may be mild weight loss or difficulty
more following infection. It coincides with the maintaining weight, as well as fatigue. Severe
initial egg production of the newly acquired chronic disease may result in colonic or rectal
worms. This stage is seen commonly in areas stenosis. S. mansoni infections may result in
with high transmission rates (961). Symptoms colonic polyposis associated with diarrhea and
are thought to be mediated by immune com- protein-losing enteropathy (957,959). Chronic
"·'
plexes that form in response to egg deposition. deposition of eggs in the liver via the portal sys-
Patients most frequently present with fever, tem leads to portal hypertension, splenomegaly,
headache, generalized myalgias, right upper and esophageal varices. ·
quadrant pain, and bloody diarrhea. Respiratory Gross Findings. In the early stages of the
symptoms occur in up to 70 percent of patients infection, acute proctitis and colitis are accom-
infected with S. mansoni, but are less common in panied by edema and hemorrhage as ova are
patients infected with other Schistosoma species discharged into the bowel lumen. Morphologic
(950,954,955). The liver is enlarged and tender features of chronic infection include localized

484
Gastrointestinal Infections

Figure 10-52
SCHISTOSOMIASIS
A: Colonic biopsy shows a well-form ed granuloma in
the deep mucosa.
B: Schistosoma ova are present in the lamina propria.
C: Schistosoma ova are surrounded by a prominent
eosinophilic infiltrate.

or diffuse mucosal ulcers, pronounced submu- Eosinophils and histiocytes surround the ova.
cosal thickening due to fibrosis and lymphoid A sarcoid-like reaction eventually envelops the
hyperplasia, strictures due to extensive granu- eggs, which become embedded in a granuloma-
lomatous or fibrous reactions, pericolic masses, tous focus of epithelial histiocytes and giant cells.
polyposis, and masses of granulation tissue . As the disease becomes more chronic, concentric
Schistosoma-associated polyps range from small fibrosis develops around the ova.
to quite large, may be pedunculated, and may Histologic examination of schistosoma!
bleed. They are most common in the distal polyps usually demonstrates an inflammatory
colon and rectum. Granulomas may be seen polyp containing Schistosoma ova surrounded
grossly as sandy patches or small yellow nodules by dense infiltrates of eosinophils and lympho-
on the serosal surfaces. cytes. The surfaces of the lesions become eroded.
Microscopic Findings. The diagnosis depends Special Techniques. The diagnosis of schisto-
on the histologtc recognition of Schistosoma eggs somiasis is usually made through identification
and the granulomas and colitis they induce of the characteristic ova in the stool or urine.
(fig. 10-52). The eggs measure 100 to 180 pm in The shedding of eggs may be intermittent, and
length and about 70 pm in width. Those of S. therefore, examination of multiple specimens
mansoni are marginally longer than S. japonicum may be required in some patients. Stool exami-
and have a distinctive subterminal lateral spine. nation by direct smear or concentration may be
The shell has a light brown, translucent appear- used. The greatest sensitivity is achieved using
ance, and in the case of S. mansoni, contains a formalin-ether concentration method (956) .
acid-fast material. This feature is diagnostically Differential Diagnosis. The disease may
helpful if only the shell fragments are present. grossly mimic Crohn's disease or carcinoma.

485
Gastrointestinal Diseases

Treatment and Prognosis. Praziquantel is the seawater where they undergo one or two
the schistosoma! drug of choice. Praziquantel malts, then hatch, releasing the first- or second-
cures 60 to 90 percent of patients and substan- stage larvae into the water. Second-stage larvae
tially decreases worm burden in those who are are eaten by small pelagic crustaceans in which
not cured of the disease. A second course of they malt again, developing into third-stage
the drug is usually successful in treating these larvae (969). The infected crustaceans are then
patients. Resistance to praziquantel has been re- ingested by susceptible marine fish or squid.
ported (958,963). Alternative treatments include In these hosts, the larvae migrate into the peri-
oxamniquine for S. mansoni infections and toneal cavity, viscera, and musculature where
metrifonate forS. haematobium, although the they encapsulate without undergoing further
latter drug is no longer available commercially. development (970). The life cycle is completed
Patients with colonic or rectal stenosis or when infected fish or squid are eaten by marine
those with large inflammatory masses may re- mammals in which the parasite matures. Hu-
quire surgical resection. Some patients develop man beings are accidental or unsuitable hosts
colonic carcinoma, presumably due to continu- and no maturation takes place in human tis-
ing mucosal inflammation and proliferation in sues. When humans eat raw fish contaminated
a manner analogous to that seen witb ulcerative by the larvae, the latter attach to the mucosa
colitis (952). of the stomach or the intestines, causing lo-
cal ulceration, penetration, and perforation.
Anisakis Infections
The organism usually invades the gastric wall.
Demography. Anisakidosis is a parasitic in- Intestinal anisakidosis occurs less commonly.
fection caused by anisakid nematodes belong- Clinical Features. The majority of cases of
ing to the family Ascaridoidea. The infection anisakidosis involve the stomach (97 percent),
is zoonotic, acquired following ing~stion of although small intestinal involvement is also
parasitized marine fish. The causative organ- seen (987,988). Both invasive and noninvasive
isms (Anisakis simplex, and less commonly, forms of infection occur. Infection with P. de-
Pseudotenanova decipiens) are widely distributed cipiens is usually localized to the stomach, and
geographically, affecting fish in many differ- is a noninvasive disease (965). These infections
ent oceans and seas (973,974,97.6-978,989). produce mild or no symptoms. Some patients
Over 95 percent of cases of anisakidosis occur report a "tingling" sensation in the throat. Ex-
in Japan, where 2,000 cases are reported annu- pectoration of worms may occur days or weeks
ally (972,983). The incidence is lower in North following infection (986).
America and Europe, but is increasing as the Infection with A. simplex may result in more
popularity of sushi and sashimi rises in these serious disease, with invasion of the gastric or
areas (966). In North America, the disease is intestinal mucosa, and larval migration to ex-
most frequently associated with eating salmon tragastric sites (971,986). Patients with gastric
and rockfish. The prevalence of Anisakis larvae involvement develop intense epigastric pain,
in wild coho and chum salmon in the Pacific nausea, and vomiting 2 to 5 hours after ingestion
Northwest is as high ~s 100 percent (979,980, of raw fish. The pain is generally self-limited. In-
982,991). Cooking the fish to a temperature of testinal anisakidosis presents as lower abdominal
60°C for a few minutes, however, is sufficient to pain that generally subsides after several days.
kill infective larvae (984). Freezing also elimi- Some patients develop acute abdominal signs
nates the risk of infection. Larvae are able to and symptoms that mimic acute appendicitis
survive cold smoking, brining, and marination and result in laparotomy due to their potential
(967,968,992). seriousness; bowel obstruction may occur (985).
Etiology. Anisakidosis is transmitted to Slight fever and leukocytosis with eosinophilia
humans by ingestion of seafood products har- may occur in both forms of the disease.
boring the infective third-stage larvae of the In invasive disease, the parasite may penetrate
anisakid nematodes. Adult anisakids infect sea the gastric or intestinal wall, migrating to the
mammals, including seals, sea lions, whales, peritoneum, mesenteric lymph nodes, greater
porpoises, and dolphins. Ova are released into omentum, liver, and gallbladder. The prognosis

486
Gastrointestinal Infections

Figure 10-53
ANISAKIS EOSINOPHILIC ABSCESS
A: The appendix was removed for symptoms of acute
appendicitis. A large abscess lies in the lower portion of
the photograph.
B: Higher-power view shows eosinophils at the edge of
the abscess cavity.
C: A necrotic helminth is present in the center of the
eosinophilic abscess.

of patients with this form of infection is usually sometimes made by seeing the worm at the time
worse than for those with other forms. of endoscopy or on radiographs (989).
Allergic reactions to the organisms may oc- Microscopic Findings. Larval entrance into
cur, with patients developing systemic allergic intestinal mucosa elicits a granulomatous re-
symptoms ranging from urticaria to anaphy- action around the worm, with infiltration of
lactic shock. These symptoms result from an neutrophils, eosinophils, and histiocytic giant
allergic reaction to the heat-stable antigen of cells. Several days later, the submucosa becomes
the parasite that is conserved even when fish is edematous and there is massive infiltration of eo-
frozen or cooked (964,981). sinophils, lymphocytes, monocytes, neutrophils,
Gross Findings. Anisakidosis usually in- and plasma cells. Eventually, an abscess develops
volves the stomach and small intestine; only that is characterized by necrosis, hemorrhage,
rarely does it involve the colon or regional and eosinophilic infiltrates (fig. 10-53). Worms
lymph nodes (975). The gastric or small intes- are often found in the early lesions but they are
tinal wall appears thickened due to edema and eventually destroyed by the inflammation.
inflammation. Indurated nodules that may be When larvae are identified, they are typi-
identified on the mucosal surfaces mimic be- cally surrounded by eosinophils and other
nign or malignant tumors or Crohn's disease, inflammatory cells (fig. 10-54). They measure
particularly when regional lymph nodes are in- approximately 500 pm in diameter, and have
volved. Superficial ulcers or patchy hemorrhages a cuticle ranging from 5 to 7 pm in thickness
may be seen. When colonic involvement does (965). A glandular esophagus and ribbon-like,
occur, it is usually right-sided. The diagnosis is large, unpaired excretory glands are often seen

487
Gastrointestinal Diseases

Figure 10-54
ANISAKIDOSIS
A: Anisakis, seen in cross section, lies within a granuloma
in the perigastric soft tissue.
B: Higher-power view of the worm cut in cross section.
C: The adjacent tissues contain an intense eosinophilic
infiltrate. (Courtesy of Dr. John Hart, Chicago, IL.)

in cross sections of the organism ..:rhe organisms cords. The Y-shaped gastrointestinal lumen of
also have Y-shaped lateral cords (965,975). the organism contains numerous tall columnar
The lymph nodes demonstrate sinus histio- cells, which are usually prominently featured
cytosis and eosinophilic infiltration without in cross sections. Reproductive organs appear
granuloma formation (990). Eosinophilic granu- immature or absent.
lomas may form around a track containing sec- Treatment and Prognosis. In] apan, endos-
tions of the nematode larvae (975). copy is widely used for diagnosis, especially
Special Techniques. Anisakidosis is diag- for gastric infections. Surgical resection of the
nosed by radioallergoabsorbent tests, ELISA, inflamed intestine is the only definitive treat-
or immunofluorescent antibody assays. The ment for intestinal anisakidosis; there are no
diagnosis is also made when worms are seen effective antihelminthic drugs currently in use.
on endoscopic examination in acute infections.
Enterobius Vermicularis Infections
Differential Diagnosis. Anisakidosis clinical-
r..· ly mimics gastric cancer, gastric ulcers, Crohn's Demography. Enterobiasis is a ubiquitous
disease, appendicitis, ileus, and peritonitis infection, occurring more often in temperate
(984,985). It morphologically resembles other and colder climates. The pinworm, Enterobius
roundworm infections. The anisakid larvae vermicularis, infects approximately 200 mil-
morphologically resemble Ascarid larvae. Asca- lion people worldwide, but is most common
rid larvae are smaller in diameter and possess in young schoolchildren. It is also prevalent in
bilateral alae that are absent in anisakid larvae. individuals living in overcrowded conditions
Anisakid larvae have a polymyarian type of and in male homosexuals (996). Four methods
musculature with prominent Y-shaped lateral of transmission exist: 1) direct infection from

488
Gastrointestinal Infections

the anal canal and perianal regions by fingernail


contamination (autoinfection) and soiled night
clothes; 2) exposure to viable eggs on soiled bed Ingestion of
linen and other contaminated environmental ova

~
objects; 3) contamination by dust containing
embryonated eggs (from bed clothes, paja-
mas, toys, furniture, and animal fur); and 4)
retroinfection, i.e., after hatching on the anal
mucosa, larvae migrate into the sigmoid colon
and cecum (996).
Etiology. The adult worms are small, yellow- Ova picked up
while scratching
white, and lancet shaped; typically, they inhabit perianal area
the cecum, the appendix, and adjacent areas
Worms
of the ileum and ascending colon, although migrate
immature worms have occasionally been seen
in the rectosigmoid. Females measure 8 to 13
mm in length and the infrequently seen males
measure 2 to S mm in length. The gravid female
migrates through the anal canal at night, depos-
its approximately 10,000 eggs on the perianal
skin and then dies. The eggs typically measure
SS x 2S pm and have a characteristic convexity
on one side and flattening on the other. They Figure 10-55
are infective and fully mature within several DIAGRAM OF THE LIFE CYCLE OF ENTEROBIUS
hours after being laid and are able to survive
for up to 15 days outside the body. They can be
found under fingernails and on skin, clothing, the worms penetrate the intestines, leading to
sheets, doorknobs, and other objects. After the peritoneal signs, and penetrating worms may
egg is ingested by a host, the larva emerges in form granulomas in the anal canal (995,1003).
the small intestine and migrates distally to the Gross Findings. Enterobius infections are
cecum. In less than a month, newly developed generally mild, and produce no grossly visible
gravid females again discharge ova in the peri- lesions. Severe infections, however, may lead
anal region. The life cycle of the organism is to superficial ulceration of the colonic mucosa.
summarized in figure 10-55. Occasionally, adult worms are visible on the
Clinical Features. The predominant symp- surface of the perianal skin.
tom of patients with enterobiasis is anal pmritus, Microscopic Findings. Specific identification
thought to possibly be an allergic reaction to the of adult worms in tissue sections depends on
worms or their eggs. In children, these symptoms demonstrating a pair of cuticular crests, typi-
often lead to irritability, restlessness, and insom- cal eggs in the utems of the parasite, and the
nia. A severe scratching response to the pmritus characteristic narrow meromyarian (a type of
may lead to local bleeding, secondary pyogenic musculature that consists of two or three muscle
infection, and. lichenoid changes. Continued layers per quarter section divided by four cords).
scratching causes local excoriation and weep- Worms are most frequently found in the
ing of the skin surfaces. Most patients, however, lumen of the appendix where they fail to
remain asymptomatic. In female children, the elicit an inflammatory response, except for
worms may lay eggs on the vulva, producing mild mucosal eosinophilia (fig. 10-56) (1002).
vulvar itching and vulvovaginitis. In very rare Severe infections cause pathologic lesions in the
cases in girls, adult worms migrate into the colon, cecum, appendix, and lower ileum. The
cervix, utems, fallopian tubes, ovaries, or perito- usual manifestations include superficial ulcer-
neum (997-1000) . In the latter case, abdominal ation, petechial hemorrhages, and sometimes
pain may be present. In rare circumstances, mucosal or submucosal abscesses (993,1002).

489
Gastrointestinal Diseases

Figure 10-56
ENTEROBIUS VERM/CULAR/5
Left: Cross sections of numerous E. venn icularis organisms in the appendiceal lumen of a child.
Right: Higher-power view shows worms without any associated reaction in the adjacent appendiceal mucosa. (Both figures
courtesy of the Division of Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC.)

The parasite only rarely invades the mucosa, 11 mg/kg to a maximum of 1 g (994) or a single
but when it does, granulomas form. A rim of dose of 100 mg of mebendazole given orally.
granulation tissue, enclosed by a fibro_us capsule, Family members of the affected individual
surrounds an eosinophilic center. Eosinophils, should be treated as well since it is likely that
lymphocytes, giant cells, and Charcot-Leyden they also harbor the organism. "
crystals infiltrate the granulomas. The granu- Prevention. Personal cleanliness is the most
lomas eventually fibrose and hyalinize, and effective means of prevention. Hands should be
may form obstructive masses when located in frequently washed and the fingernails should be
the appendix. Rarely, Enterobius is a cause of cut short. Infected children should sleep alone
eosinophilic colitis (1001). In S'o me cases, the and wear tight-fitting pajamas that discourage
adult worms migrate into the peritoneum and direct finger contact with the perianal region.
omentum, where they induce a foreign body
Trichuris Infections
inflammatory reaction.
Special Techniques. Conventional stool Dem ograph y. Trichuriasis, caused by the
examination for ova frequently misses the whipworm, Trichuris trichiura, is most com-
diagnosis. The best method of demonstrat- mon in warm, moist, tropical and subtropical
ing the eggs is to apply clear cellophane tape regions, but it also occurs in temperate areas.
to the perineum an.d then place it sticky side It is estimated to infect over 1 billion persons
down on a microscope slide under low power, worldwide (1005a), including 114 million pre-
examining it for the eggs. The optimum time school age children and 233 million children
for applying the tape is early in the morning ages 5 to 14 years (1005). In the United States,
before the patient has bathed or defecated or Trichuris is found in rural communities of the
'-,• when the child is awakened by itching. Three South. Humans are the principal host for the
cellophane tapes are sufficient for diagnosis in organism, although it may also infect pigs, le-
over 90 percent of cases. murs, and monkeys (1007,1012). Another species
Treatment and Progn osis. Asymptomatic of Tlichuris, T. vulpis, infects dogs, and has been
patients do not need treatment. If patients are reported in humans as well (1009). Humans ac-
taught appropriate hygiene to eliminate the quire trichuriasis by ingesting embryonated eggs
risk of autoinfection, the infection becomes from contaminated hands, soil, food, and water.
self-limited. Symptomatic patients are treated Etiology. T. trichiura worms are found in the
with pyrantel pamoate given as a single dose of large intestine with their anterior ends deeply

490
Gastrointestinal Infections

Gradually, the immature worms make their way


to the cecum. They then migrate to the large
Eggs ingested intestine where they mature into adults in about
by man 30 to 90 days. The slender heads embed them-
selves into the crypts. Here, the adults mate and
the females eventually produce 3,000 to 7,000
eggs daily. In severe infections, worms may be
found in sites other than the cecum including
the wall of the appendix, terminal ileum, and
rectum (1011).
Clinical Features. The severity and con-
sequences of Trichuris infection vary widely,
depending on the parasite burden, site of infec-
tion, and state of the host including age, general
health, iron reserves, and history of previous
exposure to the organism (1006,1010). Patients
with mild infection remain asymptomatic. Mod-
erate infection results in diarrhea, abdominal
pain, nausea and vomiting. Severe infections
may result in Trichuris dysentery syndrome, a
condition associated with mucus and bloody di-
arrhea, tenesmus, abdominal pain, nausea, vom-
iting, anorexia, dehydration, and weight loss.
Figure 10-57 Rectal prolapse commonly accompanies severe
DIAGRAM OF THE LIFE CYCLE OF TRICHURIS infections. In addition, volvulus or intussuscep-
tion may occur. Large aggregates of worms can
obstruct the appendiceal lumen and cause ap-
pendicitis. Peripheral eosinophilia is common.
embedded in the mucosa. The males measure Gross Findings. The worms burrow into the
3.0 to 4.5 cm in length and have a coiled pos- walls of the small intestine, producing eosino-
terior end. The females are 3.5 to 5.0 cm and philic granulomatous lesions that are associated
possess a blunt posterior end. Usually the worms with edema, and thickening and induration of
are found in the cecum, with their slender whip- the bowel wall. In cases of rectal prolapse or in
like anterior portion buried in the mucosa. In patients undergoing endoscopic examination,
severe infections, they can be found through- the worms can be visualized directly (fig. 10-58).
out the large intestine and occasionally in the Endoscopy also demonstrates the presence of
appendix and terminal ileum. The bile-stained the inflammatory changes.
eggs measure 50 to 54 x 22 to 23 pm and have a Microscopic Findings. In many cases, the
characteristic bipolar barrel shape with a three- parasites only elicit minor histologic changes
layer shell. The eggs must incubate at least 3 (1008). In some patients, however, the whip-
weeks in soil under the proper conditions before worm produces a small inflammatory reaction
the infective larvae emerge (1011). Trichuris eggs at the site of its attachment to the colonic
are sensitive tc:i desiccation and a combination mucosa. This may be associated with superfi-
of heat and low humidity is detrimental to their cial mucosal erosions and colitis (1004). Acute
survival. Exposure to sunlight kills them. inflammatory lesions contain neutrophils and
The life cycle of Trichuris is shown in figure eosinophils; more advanced lesions form granu-
10-5 7. After ingestion, eggs pass through the lomas with central necrosis and a peripheral
stomach and hatch in the small intestine, where zone of macrophages, multinucleated giant
the larvae embed themselves in the intestinal cells, and other inflammatory cells.
villi. They temporarily penetrate the crypts of Li- Differential Diagnosis. The infected bowel
eberkuhn where they feed and develop further. appears edematous and diffusely thickened,

491
Gastrointestinal Diseases

Disseminated hyperinfection affects indi-


viduals with compromised T-cell immunity as-
sociated with steroid use, neoplasms, malnutri-
tion, aging, or AIDS. Outl)reaks occur in mental
institutions and certain urban areas. The disease
may also be venereally transmitted (1032).
Etiology. Strongyloides is a small nematode
measuring 2.0 x 2.0 x 0.4 mm that exists as both
a free-living organism and as a tissue parasite
within the mucosa of the duodenum or upper
jejunum. Strongyloidiasis occurs in one of three
major ways (fig. 10-59). In the direct develop-
ment cycle, rhabditiform larvae that are present
in feces develop in the soil into infective filari-
form larvae that then infect man by penetrating
the skin. In the indirect developmental cycle,
the rhabditiform larvae undergo several molts in
the soil and subsequently mature into free-living
adult organisms. Under favorable environmen-
Figure 10-58 tal conditions, this cycle is self-perpetuating.
TRICHURIS TRICH/URA In the autoinfection cycle, rhabditiform larvae
The size and appearance of this worm s~ggest whipworm
convert into infective filariform larvae within
infection. (Fig. 4-43 from Emory TS, Carpenter HA, Gostout the host intestine or on the perianal skin and
C], Sobin LH. Atlas of gastrointestinal endoscopy & endo- invade the host directly. This particularly occurs
scopic biopsies. Washington D.C.: Armed Forces Institute in well-established infections. ,,
of Pathology; 2000:301.)
The rhabditiform larvae (200 to 300 pm
in length) are found in soil contaminated by
grossly resembling Crohn's disease. The differ- human feces, where they go through four
ential diagnosis also includes other helminth stages to become male (0. 7 mm in length) and
infections. female (1 to 2 mm in length) adults. If the cli-
Treatment and PrognosiS. Patients are matic conditions are unfavorable, these larvae
treated with 100 mg of mebendazole given change directly into filariform or strongyloid
two times a day for 3 days. The cure rate is ap- larvae, measuring approximately 400 pm in
proximately 80 percent with this treatment and length. They cannot survive for more than a
in those who are not completely cured, there few weeks in the external environment but
is a marked reduction in worm burden (1013). they can continue development in man. The
Albendazole is also effective (1011). filariform larvae penetrate the skin where they
enter blood vessels and travel to the lung. In
Strongyloides Infections
the lung, they pass through the alveolar spaces.
Dem ography. Strongyloidiasis is estimated The adolescent worms migrate into the bronchi,
to affect from 30 to 100 million people world- trachea, larynx, and esophagus, where they are
wide (1019,1022). The disease is caused by two swallowed. They mature into adults in the in-
species of Strongyloides, S. stercoralis and S. fuel- testine, usually in the duodenum and jejunum.
1'! , ·
leborni. The most common species, S. stercoralis, After having fertilized the females, the males are
occurs worldwide, but is more common in tropi- rapidly expelled with the feces while the females
cal and subtropical areas. In the United States, penetrate the intestinal mucosa. Here, they
it is endemic in Kentucky and eastern Tennes- deposit up to 30 eggs a day that develop into
see (1014, 1028,1038); endemic areas are also rhabditiform larvae. The rhabditiform larvae
present in central and southern Europe (1033). burrow out of the mucosa, into the intestinal
S. fuelleborni occurs sporadically in Africa and lumen, and are excreted with the feces. Alter-
· rapua New Guinea (1019,1020,1026). natively, the rhabditiform larvae may transform

492
Gastrointestinal Infections

Adult female
deposits ova
in intestine

i ~~fo•m ~
Internal
autoinfection
Figure 10-59
DIAGRAM OF THE LIFE
CYCLE OF STRONGYLOIDES

S/ ~
\ Egg ' 'C....._
' ~
Qf
~
~~ Rhabditiform
larva in feces

/Free-living adult worms


: / " ."......., Male and female mate

into filariform larvae within 24 hours and then and include diarrhea, abdominal discomfort,
reinvade the host either through the intestinal bloating, and anorexia (1014,1020,1026).
mucosa (internal autoinfestation) or through Chronic sb:ongyloidiasis is usually asymptomat-
the perianal skin (external autoinfestation). ic. Some patients, however, may exhibit intermit-
Pathophysiology. The adult form typically tent gastrointestinal symptoms such as vomiting,
lives in the small bowel but autoinfection can af- diarrhea, constipation, and borborygmus. Pmlitus
fect the large bowel, especially when infestation ani, urticaria, and rash are also common (1031).
is heavy. Chronic infection results from the host's Recurrent asthma and nephrotic syndrome have
inability to eliminate the adult worms from the been repmted (1027,1029,1034,1037,1039).
small bowel, to prevent colonic reinfection by Hyperinfection is a term that describes a
filariform larvae, and to destroy larvae that are syndrome of accelerated autoinfection that
in transit back to the intestine. The pathogenesis commonly, though not always, is the result of
of strongyloidiasis is related to the host-parasite a change in immune status. Patients who were
relationship. Cellular immunity plays an impor- previously asymptomatic may develop gastroin-
tant role in keeping the parasite under control. testinal or pulmonary symptoms. Symptomatic
When cellular immunity is disrupted, the para- patients may experience an exacerbation of their
site can multiply internally and disseminate. symptoms. Larvae are increased in number, but
Clinical Features. The clinical symptoms dissemination beyond the gastrointestinal or
of Strongyloides infection are variable, ranging respiratory tract does not occur. In such severe
from asymptomatic cases to severe, debilitating infections, patients may experience upper and
disease. Four basic clinical syndromes occur: lower intestinal bleeding, jejunal perforation,
acute strongyloidiasis, chronic strongyloidiasis, ileus, and bowel obstruction (1016,1018,1023,
hyperinfection, and disseminated disease. In 1030,1036). Malabsorption also occurs. Some
acute disease, the earliest manifestation is a pru- patients may develop protein-losing enteropa-
ritic erythematous rash at the site of filariform thy leading to hypoalbuminemia, peripheral
larval penetration. Some patients develop urti- edema, and ascites (1021,1024).
cariallesions. Migration of the larvae through Extraintestinal manifestations occur in dis-
the pulmonary alveoli may result in cough. seminated disease, and include pneumonia,
Tracheal irritation simulating bronchitis also sepsis, meningitis, and brain abscess. Marked
occurs. Gastrointestinal symptoms begin ap- peripheral eosinophilia is common but can be
proximately 2 weeks after the initial infection absent in patients with overwhelming infections.

493
Gastrointestinal Diseases

Figure 10-60
STRONGYLOIDIASIS
Adult female worms lie with-
in the crypts of the small intes-
tine. (Courtesy of the Division
of Gastrointestinal Pathology,
Armed Forces Institute of Path-
ology, Washington, DC.)

Gross Findings. Most filariforrp. larvae lie In immunocompromised patients, there may
within the intestinallymphatics, af!d they con- be edema, hyperemia, and scattered ulcerations
centrate in the mesenteric and retroperitoneal of the bowel. Granulomas are less well devel-
lymph nodes. The intestines acquire a dusky red- oped and Langerhans giant cells are rare. In
purple calor and a granular mucosa. In· patients severe disease, there may be diffuse ulceration
with well-developed enteritis, the bowel appears of the large bowel with edema and hemorrhage;
grossly thickened, with flattened mucosal folds gravid female worms may be seen nestled in the
due to the presence of submucosal edema. Hem- mucosa as low in the gastrointestinal tract as the
orrhagic and ragged mucosal surfac~s are covered colon. The appendix is a frequent site of larval
by friable, greenish tan pseudomembranes. Sig- penetration but appendicitis is rare.
moidoscopy and colonoscopy may.help establish Special Techniques. The parasitologic diag-
the diagnosis. Erythema, ulcerations, hemor- nosis of strongyloidiasis requires the detection
rhage, and rarely, polyps are present along with of 5. stercoralis larvae or adults in feces, sputum,
aphthoid erosions (1015,1035). or duodenal aspirates. It may be necessary to ex-
Microscopic Findings. Rhabditiform larvae amine several specimens due to the low number
are usually identified in the crypts and the sub- of larvae present. In 10 to 30 percent of patients,
mucosa of the duodenum. They measure 400 sampling of duodenal contents by the string test
pm in length and 20 to 25 pm in width, and or endoscopic duodenal aspiration may be needed
are characterized by a short buccal cavity, bulbar to demonstrate the organism. A clinical diagnosis
esophagus, and longer intestine. Adult female is suggested by the presence of eosinophilia and
worms may also be seen in the crypts (fig. 10- a history of travel to an endemic area. In dissemi-
60). The mucosa may become edematous and nated disease, parasites may be found in unusual
usually contains cellular infiltrates composed sites including sputum, bronchoalveolar lavage
•.· of numerous eosinophils and mononuclear fluid, cerebrospinal fluid, ascites fluid, or urine.
cells (fig. 10-61). Reactions around the worms Serologic tests or Western blot analysis also
may be seen in the lamina propria. Necrotiz- detects the disease. Serologic tests for Strongy-
ing granulomas may also be present. In severe loides are particularly helpful, since extensive
cases, mucosal atrophy, villous flattening, and, stool microscopy fails to detect the disease in a
in long-standing infections, fibrosis with ulcer- significant number of patients (1031).
ation may be present. Most acute lesions affect Differential Diagnosis. The rhabditiform lar-
the small intestine but similar changes are also vae of 5. stercoralis must be differentiated from
seen in the stomach and colon. those of hookworm and other nematodes. They

494
Gastrointestinal Infections

Figure 10-61
STRONGYLOIDIASIS
A: The lamina propria of the colonic mucosa has a dense
infiltrate composed of lymphocytes, plasma cells, and
numerous eosinophils. A somewhat ill-defined granuloma
is also present.
B: Higher-power view shows a gran uloma with a
surrounding intense eosinophilic infiltrate.
C: A Strongyloides larva is present within the lamina
propri a. The organism is surrounded by numerou s
eosinophils.

can be distinguished by noting either the short Treatment and Prognosis. Because there is
buccal cavity and large genital primordium of a risk of disseminated disease, strongyloidiasis
the rhabditiform larvae of 5. stercoralis or the should be treated (1020,1026). Immunocom-
long buccal cavity of hookworm larvae. The petent patients with uncomplicated infections
filariform larvae of 5. stercoralis have a notch are treated with thiabendazole, 20 mg/kg orally
in the tail that differentiates them from hook- twice a day for 2 days (1020,1040). This treat-
worms and other larvae. ment can be repeated, since it is only effec-
Eosinophilic gastroenteritis is a disorder often in tive in approximately two thirds of patients.
the differential diagnosis of patients with strongy- Retreatment is often necessary. Side effects
loidiasis. Eosinophilic enteritis shows mild villous of thiabendazole include nausea, vomiting,
blunting with increased numbers of eosinophils malaise, dizziness, and headache. Albenda-
and mononuclear cells in the lamina propria and zole and ivermectin are alternative choices
epithelium. Parasites, however, are absent. Crohn's (1013a,1026). Ivermectin is recommended for
disease also shows mucosal eosinophils but there the treatment of patients with disseminated
are usually signs of more extensive damage, in- disease (1017). Sometimes, antibiotics are given
cluding the presence of ulcers and strictures, as to treat concomitant bacterial infections. Even
well as occasional granulomas. Crohn's disease with treatment, disseminated disease frequently
often concentrates in the distal ileum and co- results in patient death. Mortality rates due to
lon, while intestinal strongyloidiasis most often hyperinfection or disseminated disease are as
involves the duodenum and jejunum. high as 87 percent (1025) .

495
Gastrointestinal Diseases

Angiostrongylus Infections tion, obstruction, or gastrointestinal bleeding


Demography. Angiostrongylus is a nematode may result (1043,1044,1047,1052).
that is prevalent in Central and South America On physical examination, the abdomen is
from Mexico to Argentina. The disease predomi- usually tender in the right lower quadrant,
nantly affects children, usually boys; most cases and signs of peritonitis may be elicited. Rectal
occur during the rainy season (1043,1047,1049). examination can be painful. Patients exhibit
Humans appear to be accidental hosts to the peripheral leukocytosis and eosinophilia. Oc-
organism, and the mode by which. the infection casionally patients are ill for months with
is acquired is unknown (1045). relapsing episodes of abdominal pain (1044).
Etiology. Angiostrongylus (Parastrongylus) Gross Findings. Pathologic changes are usu-
(1054) costaricensis is a metastrongyloid intes- ally seen in the cecum, appendix, and terminal
tinal nematode found primarily in snails and ileum. Yellow granulomas in the subserosa, asso-
veronicellid slugs, the obligatory intermedi- ciated with edema and rigidity of the intestinal
ate hosts, and in rodents, the definitive hosts wall, are common findings. The appendix is
(1049). Man is an accidental host. It is thought often inflamed and may be perforated. Patients
that human infections occur when persons in- may present with gangrenous ischemic entero-
gest vegetables contaminated with third-stage colitis or ileitis, sometimes with perforation
larvae from infected slugs (1 045,1049). The time (1056) . In such cases, the intestinal wall appears
interval from the possible date of ingestion to thickened. Multiple confluent ulcers, some of
onset of symptoms is 14 days to several months, which perforate, can be observed, particularly
or even years (1051,1052,1055) . .. in the terminal ileum.
In rodents, larvae penetrate the gastrointes- Microscopic Findings. A. costaricensis causes
tinal wall and mature in lymphatics and lymph an intense, eosinophilic, necrotizing arteritis
nodes to migrate through the vasculature of associated with thrombosis, which leads to
the ileocecal region. Adult worms are found in severe ischemic necrosis and infarction (1044,
cecal and mesenteric arteries of the definitive 1046). An intense eosinophilic inflammatory
hosts and other rodent species. Fertilized eggs infiltrate involves the entire thickness of the
embolize to the capillary endothelium where intestinal wall. Perforation may occur (1056).
they penetrate and occupy the subendothelium Dead organisms may be found in the wall. The
in the submucosal regions. The~.eggs embryo- worms are characterized morphologically by a
nate and first-stage larvae hatch from the eggs, thin (2- to 3-pm) keratin cuticle, a lack of lateral
migrate through the mucosa, and pass into the cords, and intestines lined by cuboidal to low
lumen to be excreted into the feces. In humans, columnar cells. The worms typically lie within
however, the eggs degenerate in the intestinal arterial lumens (1056). Eggs are ovoid, usually
wall, inciting a granulomatous reaction. Snails lying within the submucosa, and possess thin,
and veronicellid slugs, the obligatory interme- pale, eosinophilic shells. Eosinophilic granulo-
diate hosts, ingest the larvae in rodent feces. mas may surround eggs and larvae.
The ingested first-stage larvae develop in the Special Techniques. Larvae and eggs are not
digestive tract of the i:nollusk into second- and found in the stool. In some cases, serologic tests
third-stage larvae, which are infectious to cer- are available.
tain rodents, monkeys, and humans. Differential Diagnosis. The differential
Clinical Features. Angiostrongyliasis causes a diagnosis includes Trichuris trichiura, another
•.· highly symptomatic eosinophilic gastroenteritis organism that often lies in the cecum. Trichuris
involving the terminal ileum, cecum, appendix, adult worms embed within crypts, and are not
and ascending colon (1050,1056). The clinical seen within vascular structures. Gastrointesti-
presentation often mimics acute appendicitis or nal schistosomiasis may also affect this region.
other intra-abdominal emergency lesions and as Adult Schistosoma organisms, however, are typi-
a result, surgery is performed. Right lower quad- cally found in the venous system, not in the
rant pain and fever are the main symptoms but arteries. Like Angiostrongylus, Schistosoma ova
nausea, vomiting, diarrhea, or constipation also may produce granulomas that progress to fibro-
occur. A palpable mass may be present. Perfora- sis. Anisakid larvae may be similar in size to the

496
Gastrointestinal Infections

adults of A. costaricensis, but are distinguished by fields from which feces are washed into water
their thick multilayered cuticles, large Y-shaped bodies by torrential tropical rains. The eggs
lateral cords, and intestines lined by tall colum- embryonate in water in 5 to 10 days and hatch
nar cells (1042). Finally, angiostrongyliasis may after ingestion by small freshwater fish. The
mimic Crohn's disease (1046). larvae emerge and grow into infective forms in
Treatment and Prognosis. The treatment 3 weeks. When the fish is eaten raw, C. philippin-
of A . costaricensis infections is often surgical. In ensis larvae mature into adult males and females
some cases, surgery is performed because the in 12 to 14 days in the small intestine. After mat-
patient presents with what clinically appears to ing, the females produce larvae and they in turn
be appendicitis. No drug is currently available for mature and the second generation of females
the treatment of abdominal angiostrongyliasis. produce eggs that pass in the feces. Autoinfec-
Although vermicidal agents do exist, there is sig- tion continues by means of a few larviparous
nificant concern about the possibility of inducing female worms that are always present, resulting
greater harm to the patient if worms die in their in hyperinfection.
intravascular location (1041,1048,1053). The Clinical Features. Capillaria causes diar-
case-fatality rate among symptomatic patients rhea and malabsorption (1061,1062) . Disease
ranges from 1.8 to 7.4 percent (1044,1047). onset is acute, with severe malabsorption and
35 percent mortality. Initially, patients present
Capillaria Philippinensis Infections
with borborygmus, with or without abdominal
Demography. Persons infected with Capil- pain. Weeks or a month later, patients develop
laria philippinensis often live in the Philippines voluminous watery stools passed 5 to 10 times/
and Thailand, where it is common to eat raw day, malaise, anorexia, nausea, and vomiting
freshwater fish. It is also reported in Japan, (1057,1058,1060,1063) . There is widespread
Korea, Taiwan, Iran, Egypt, the United Arab malabsorption. Patients exhibit hypokalemia,
Emirates, and India (1059,1062,1064-1067). hypocalcemia, hypoproteinemia, and protein-
Approximately 2,000 cases have been described. losing enteropathy. The disease progresses over
The parasites typically inhabit the mucosa of months and the patients exhibit muscle wasting,
the small intestine, with the jejunum being the weakness, hypotension, cardiac abnormalities,
most heavily infiltrated site. abdominal distension, tenderness, edema, ana-
Etiology. C. philippinensis is a tiny nematode sarca, or hyporeflexia. Patients may die of ex-
closely related to Trichuris and Trichinella spe- treme malnutrition, dehydration, or secondary
cies. A fish-bird cycle plays a role in the infec- bacterial infections. The period between symp-
tion. Male worms measure 1.5 to 3.0 mm in tom onset and death is usually 2 to 3 months.
length and females measure 2.5 to 5.0 mm in Gross Findings. The worms inhabit both the
length. C. philippinensis has a long stichosome, large and small intestines, although they are
which consists of stichocytes surrounding the primarily located in the jejunum. Grossly, the
esophageal tube, with a thin anterior end. The small intestine appears thickened, indurated, and
posterior portion of the worm is wider and hyperemic, and contains large amounts of fluid.
contains intestines and reproductive organs. Thousands of adult worms, larvae, and ova are
Females range in length from 2.5 to 5.3 mm. seen within the jejunum and the upper portion
The vulva is at the end of the stichosome and of the ileum; occasionally, they are seen in the
the uterus may contain thick-shelled biopercu- duodenum, and less frequently, in the stomach,
lated eggs with ·a mucoid coat, thin-shelled eggs esophagus, and colon. Patients with severe infec-
with a mucoid coat, or embryos. The organism tions have many worms embedded in the small
is diagnosed by finding the characteristic ova. bowel mucosa. Barium examinations show dif-
The barrel-shaped eggs have flattened bipolar fuse involvement of the small bowel with loss
plugs and fully developed larvae. The eggs of of the normal mucosal pattern, narrowing of
C. philippinensis average 36 x 19 to 45 x 21 pm, the lumen, and separation of the bowel loops.
and they resemble those of Trichuris trichiura . Microscopic Findings. The worms enter the
Eggs passed in the feces reach the water by crypts which subsequently become atrophic.
indiscriminate defecation in or near water or in The villi appear flattened, mucosal glands are

497
Gastrointestinal Diseases

denuded, and the lamina propria becomes solium are problems in Mexico and other Latin
infiltrated with plasma cells, lymphocytes, American countries, parts of Europe, China,
macrophages, neutrophils, and eosinophils. India, and Africa. They are rare in the United
Histologically, parasites are seen in the intestinal States. T. saginata infection is highly prevalent
lumen, within the crypts of Lieberkuhn, and in in parts of Europe, Africa, and Asia, and is oc-
the lamina propria. casionally reported in the United States.
Special Techniques. The diagnosis is made Infections are associated with eating raw
by identification of C. philippinensis eggs, larvae, pork and beef. Steak tartare (raw ground beef) is
or adults in the feces. The parasite is also found a favorite dish in Europe and America, as is raw
in aspirates or biopsies of the duodenum and pork in Southeast Asia. In Taiwan, T. saginata
jejunum. Repeat stool examinations may be infections are also acquired by eating wild boar
required. The eggs are 36 to 45 x 21 pm, have and some strains of domestic pig.
a characteristic shape, bipolar plugs, and a mu- Diphyllobothrium latum and other Diphyl-
coid coat. They must be differentiated from the lobothrium species are fish tapeworms that are
eggs of T. trichiura. acquired by humans through consumption of
Treatment and Prognosis. In severe cases, raw fish. Diphyllobothriasis occurs worldwide,
treatment consists of electrolyte replacement and is commonly reported in Russia and parts
and antidiarrheal medications. The antihel- of Japan (1069). Commonly implicated fish
minthics thiabendazole, mebendazole, or include salmon, whitefish, rainbow trout, pike,
albendazole eliminate the organism. Parasites perch, turbot, and ruff (1073).
disappear from the stools in 3 ro 4 days and Hymenolepis nana, the dwarf tapeworm, and
most patients are asymptomatic-after a week. H. diminuta, the rat tapeworm, parasitize both
Long-term treatment with effective antihelmin- rodents and humans, and insects serve as their
thics is required because of the worms' ability intermediate host. H. nana has a cosmopolitan
to multiply in the host. Relapses result from distribution but is more commo]) in warm
incomplete treatment. climates (1068). It is the most common autoch-
thonously acquired tapeworm infection in the
Tapeworm Infections
United States. Most infections occur in the south-
Definition. Tapeworms are ribbon-shaped, ern states, and are more common in children and
segmented, hermaphroditic, cestode worms institutionalized patients. The infection spreads
that inhabit the intestinal trac'f of many spe- by an oral-fecal route. Feces of infected children
cies. Taeniasis is an infection caused by adult and rats are the usual reservoirs. In some coun-
tapeworms belonging to the family Taeniidae, tries, 25 percent of people in rural populations
particularly Taenia solium (pork tapeworm) and have H. nana infection, presumably due to drink-
T. saginata (beef tapeworm). These worms lack ing of contaminated water. H. nana is unique in
a digestive tract and absorb their food through that this parasite can be transmitted directly by
their integument. The worm's body is divided the egg or by ingestion of fleas or beetles infected
into three regions: scolex or head, neck, and with larval cysticercoids.
strobila, which consists of immature, mature, Etiology. Species that commonly infect hu-
and gravid proglottids or segments. Cysticercosis mans in the West include the beef tapeworm,
is the term used to denote infections by the T. saginata; the pork tapeworm, T. solium; and
larval stage of T. solium or T. saginata. the fish tapeworm, D. latum. Adult T. saginata, T.
Demography. Taeniasis has a worldwide dis- solium, and D. latum are among the largest para-
r.,·
tribution. Most cases of cysticercosis result from sites to infect humans. T. saginata measures 1 to
fecal contamination of food and water, related to 4 meters in length whereas T. solium measures 2
poor hygiene and poverty. Therefore cysticercosis to 4 meters. T. saginata may have 1,000 to 2,000
is most commonly seen in lower socioeconomic proglottids but T. soliwn has less than 1,000.
classes in Latin America, Eastern Europe, India, The number of uterine branches in the gravid
Pakistan, Indonesia, and China. The incidence proglottids differs in the two worms, with those
of this disorder has increased with migration ofT. saginata being more than12 and those of
of infected individuals (1074). Infections ofT. T. soliwn being less than12. The scolex of a T.

498
Gastrointestinal Infections

solium worm has a rostellum armed with rows of armed rostellum. Approximately 200 proglot-
hooklets. The rostellum is lacking in T. saginata tids are present which are characterized by
but the scolex of both has four suckers. The two their three globular testes. The eggs are oval or
species of Taenia produce eggs indistinguishable spherical and measure 30 to 40 pm in diameter.
from one another. The eggs are round, measure When the eggs of H. nana are ingested by a final
30 to 40 pm in diameter, and have a thick, radi- host, the oncospheres are released in the small
ally striated shell containing an embryo with intestine where they burrow into the villi and
six hooklets. The eggs are passed individually in develop into cysticercoids in 4 days. In about 2
feces or in gravid proglottids that detach from weeks, the larvae reenter the intestinal lumen
the strobilae and pass from the host. When and attach to the intestinal wall where they
ingested by intermediate hosts, the eggs hatch become adult worms within the next 2 weeks.
and hexacanth embryos or oncospheres migrate Some eggs released by the adult worms hatch in
to the muscles of the animal. These larvae sub- the intestine resulting in autoinfection.
sequently develop into fluid-filled, translucent Pathophysiology. All tapeworms are para-
cysts with an invaginated scolex, termed cys- sitic. They spend their adult lives in the small
ticerci. When humans eat the infected beef or intestinal lumen of the host. Mucosal attach-
pork, raw or uncooked, the cysticercus ruptures ment occurs via suction cups or grooves located
in the small intestine and the scolex everts and on the head or scolex. The various species of
attaches to the mucosa. The parasites reach tapeworms are distinguished by counting the
sexual maturity and egg production begins in number of teeth or cutting plates on the buc-
10 to 12 weeks. These parasites may live in the cal cavity. Behind the scolex is a short neck,
intestines for as long as 20 years. from which proglottids develop to form the
D. latum is the largest cestode to infect hu- chain-like strobila of the worm. As each pro-
mans, measuring 2 to 15 meters in length and glottid becomes gravid, eggs are released. Adult
a maximum of 20 mm in width. The scolex worms produce up to 20,000 eggs/day, which
or bothrium is 2 x 1 mm and has dorsal and disseminate into the environment via stool.
ventral sucking grooves that serve to attach the Once stuck to the mucosa, the worms suck
worm to the intestinal wall. The strobila has blood from it. The amount of blood lost varies
4,000 proglottids, each with gravid proglottids with the parasite species. Since the worms lack a
having male and female sex organs and uteri gastrointestinal tract, adults absorb predigested
filled with eggs. The uterine pore is midventral food across the tegumental surface of each seg-
and discharges eggs continuously. Eggs passed ment. Elimination of Hymenolepis, for instance,
in the feces reach cool, fresh water and mature involves actions by mast cells and hyperplastic
in 10 to 14 days into a ciliated hexacanth larva goblet cells, with histamine and mucus each
called a coracidium. The coracidium leaves the egg playing defensive roles (1072). The goblet cell
through the opened operculum and swims freely hyperplasia requires an intact immune system,
in the water until ingested by the first intermediate particularly T cells. Increased mucus from hy-
host, a cmstacean species, the copepod. It develops perplastic goblet cells entraps the worms, re-
into a procercoid larva in the body cavity of the stricting their attachment and expediting their
copepod. The infected copepod is then eaten by expulsion by peristalsis.
a fish, the second intermediate host. The procer- Clinical Features. Usually only one tape-
coid larva migrates from the fish intestines to the worm is present in the intestine but occasionally
muscles and develops into a plerocercoid larva, two or more are found. Most infected individuals
or sparganum. When the fish is eaten raw by the remain asymptomatic and are unaware of the in-
final host, the plerocercoid larva develops into an fection until spontaneous passage of proglottids
adult in the intestine in 3 to 5 weeks and produces occurs through the anus or in the feces. The most
large numbers of eggs. The worms are known to common symptom is intense perianal itching.
live in humans for 10 years or more. Abdominal pain, nausea, anorexia or increased
H. nana is the smallest tapeworm infecting appetite, weight loss, headache, and constipa-
man, measuring 1 to 4 cm in length and 1 mm tion or diarrhea may be present. Abdominal
in width. Its scolex has four suckers and an pain and nausea are usually more common in

499
Gastrointestinal Diseases

the morning and are relieved by eating breakfast. the diagnosis. Eggs are present in feces and can
Allergic manifestations include urticaria, pruritus, be detected microscopically, either directly or
or other skin conditions; eosinophilia; and el- after concentration of fecal samples. Perianal
evated IgE levels. The worms also cause intestinal, specimens on cellophane tape swabs may reveal
appendiceal, biliary, or pancreatic obstruction. T the eggs .
solium may survive 25 years and T saginata 10 Treatment a nd Progn osis. The drug of
years. Therefore, symptomatic patients may have choice for the treatment of Taenia infection is
a protracted clinical course. praziquantel given after a light meal. T saginata
The major clinical manifestations associated may also be treated with niclosamide, which can
with diphyllobothriasis are diarrhea and per- result in complete relief of abdominal symp-
nicious anemia (1070). The parasite splits the toms within a short period of time (1071). Di-
vitamin B12 intrinsic factor complex, thereby phyllobothriasis is treated with antihelminthic
preventing vitamin B12 absorption by the host. agents . This causes a disappearance of the
Most patients with H. nana infection remain diarrhea and the pernicious anemia. The stool
asymptomatic or have only mild symptoms. should be examined for the scolex. If the scolex
Severe infections cause headaches, dizziness, is not removed, the strobila can regenerate and
diarrhea, abdominal distress, restlessness, and the parasite may become reestablished.
sometimes convulsions. The clinical manifesta-
Tremat ode Infections
tions are probably the result of local irritation
and absorption of toxic byproducts produced Demography. Several species of trematodes
by the parasite. infect humans including those belonging to the
Gross Fin dings. Sometimes the worm is genera Fasciolopsis and Heterophyes. Fasciolopsis
found in the intestinal lumen. It measures species infect both humans and pigs, and occur
meters in length. T saginata can be. detected most commonly in parts of India and Southeast
on X-ray films of the small bowel as a long, Asia. Feces from the host reach Wqter bodies
translucent filling defect (1071) . Most patients containing planorbid snails and freshwater
with D. latum infection have the parasites in the plants. Among these plants are water chestnuts,
jejunum. More than one worm can be detected. water bamboo, water lily, water hyacinth, and
Microscopic Findings. The pathologic fea- watercress, and any can be the source of infec-
tures of the intestines in taeniasis are rarely tion if uncooked.
described. Much more commonly described are A number of tiny trematodes of the genus
the features of cysticercosis. The adult worms Heterophyes infect humans but the most com-
apparently do not seriously damage the gastro- mon is H. heterophyes. Another important
intestinal tract except for some superficial dam- heterophyid is Metagonimus yokogawai. Most
age to the lining mucosa at the site of parasitic heterophyid infections occur in the Far East
attachment (1068). Attachment of the scolex, except for H. heterophyes, which also occurs in
especially that of T solium, may cause local ir- the Middle East, the Mediterranean, and parts
ritation. The infections cause crypt hyperplasia of Africa. M. yokogawai is also reported in Asia.
and a significant increase in the number of en- Etiology. Fasciolopsis species are indigenous
docrine cells. Developing H. nana cysticercoids to China, Taiwan, Laos, Thailand, Bangladesh,
damage villi and large numbers invading the and India, and most infections occur in these
tissue are responsible for enteritis. areas. F. buski is the largest intestinal fluke.
Sp ecial Tech niques. Diagnosing tapeworm It measures 20 to 75 mm x 8 to 20 mm and
r..·
infection requires identification of the proglot- has an oral and ventral sucker. There are two
tids or eggs in the stool. The eggs of the various intestinal ceca, two branched testes that oc-
Taenia species resemble one another and are cupy most of the body, a central ovary, and
thus not diagnostic of a species. Therefore, the a coiled uterus. Eggs pass from the organism
gravid segments or the scolex must be exam- into the feces and must reach the water where
ined for characteristic morphologic features. a ciliated larva, a miracidium, develops in 3
The finding of white, often motile, 1- to 2-cm to 7 weeks. The larva emerges and swims in
proglottids passing out of the anus also confirms the water seeking a specific snail. A sporocyst

500
Gastrointestinal Infections

develops in the snail and releases rediae, which inflammation, bleeding, ulceration, and exces-
produce daughter rediae that escape and leave sive mucus secretion, as well as obstruction or
the snail. The cercariae encyst on aquatic plants abdominal distension, hunger pains, increased
where they develop into metacercaria. If these appetite, and diarrhea. Absorption of parasitic
aquatic plants are eaten raw, then the metacer- secretions may cause generalized edema, ascites,
caria excyst in the small intestine, attaching to nausea, vomiting, cachexia, and leukocyto-
the mucosa, and develop into adults within 3 sis with eosinophilia. When death occurs in
months. In the intestines, the worms may live patients with massive infections, it is usually
for 6 months or more. attributed to toxemia .
. Heterophyids are tiny worms measuring 1 to 2 Pathologic Findings. In heterophyiasis,
mm in length. They have oral and ventral suckers; worms in the intestine and upper ileum cause
tegumentary spines surround the oral sucker. The mild inflammation and necrosis. When heavy
eggs are small, measuring 27 to 30 x 15 to 17 pm, infection is present, chronic diarrhea, upper ab-
operculated, ovoid, and yellowish brown. The eggs dominal pain, anorexia, nausea, vomiting, and
contain a miracidium which, when laid, hatches abdominal tenderness, similar to peptic ulcer
after being eaten by the snail intermediate host. symptoms, can be present. These tiny eggs may
Development in the snail is similar to that of other be carried into the lymphatics or venules and
tr·ematodes. The cercaria encyst in fresh water fish. disseminate to widely dispersed ectopic sites.
When the fish is eaten raw or undercooked, the Special Techniques. The diagnosis is con-
metacercariae are digested from the fish tissue firmed by finding eggs in the feces. Fasciolopsis
and excyst. Tiny parasites develop into adults eggs are large, measuring 130 to 140 x 80 to 85
in the small intestine in 1 to 2 weeks. pm, thin-shelled, and operculated.
Clinical Features. The presence of large Treatment and Prognosis. The drug of
numbers of worms causes morbidity, including choice is praziquantel. Niclosamide is also used.

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causing severe di&rrhea in Egypt .] Egypt Sac diminuta: intestinal goblet cell response to
Parasitol 1999;29:483-93. infection in male CS 7 mice. Exp Parasitol
1058. Belizario YY, de Lean WU, Esparar DJ, Galang 1990;71:9-20.
]M, Fan tone], Verdadero C. Compostela Val- 1073. Munoz]. Foodborne diseases: seafood. Pediatr
ley: a new endemic focus for Capillaria philip- Infect Dis] 1999;18:910-1.
11,·
pinensis. Southeast Asian ] Trap Med Public 1074. Nash TE, Neva FA. Recent advances in the di-
Health 2000;31:4 78-81. agnosis and treatment of cerebral cysticercosis.
1059. Chen CY, Hsieh WC, Lin]T, Liu MC. Intestinal N EnglJ Med 1984;331 :1491-6.
capillariasis: report of a case.] Formosan Med
Assoc 1989;88:617-20.

538
GASTROINTESTINAL DISEASES IN
11 IMMUNOCOMPROMISED PATIENTS

Gastrointestinal diseases are extremely com- Table ll-1


mon in the growing population of immuno- DEFINITION OF ACQUIRED
compromised and immunosuppressed patients, IMMUNODEFICIENCY SYNDROME (AIDS)
including those with human immunodefi- Any patient with one or more of the following reliably
ciency virus (HIV) infection and those who diagnosed diseases in the absence of a known cause
have undergone solid organ or bone marrow of immunodeficiency; laboratory evidence regarding
transplantation. Symptoms of gastrointestinal human immunodeficiency virus (HIV) infection
either positive or not available:
origin in this group of patients occur as a result Candidiasis of esophagus, trachea, bronchi, or lungs
of opportunistic infection, drug-induced injury, Cryptococcosis, extrapulmonary
or as a direct result of the process that initially Cryptosporidiosis with diarrhea persisting more than
led to the immune dysfunction. 1 month
Cytomegalovirus disease, extranodal, in patient > 1
month of age
HUMAN IMMUNODEFICIENCY
Herpes simplex virus infection with ulceration persist-
VIRUS INFECTION ing >1 month
Definition. Acquired immunodeficiency syn- Kaposi's sarcoma in patient <60 years of age
Lymphoma, brain (primary), in patient <60 years of age
drome (AIDS) results from infection with HIV. Lymphoid interstitial pneumonia or pulmonary
It is associated with a number of defining ab- lymphoid hyperplasia in child < 13 years of age
normalities (Table 11-1). Mycobacterium avium-intracellulare or M. kansasii
Demography. More than 30 million people disease, disseminated
Pneumocystosis
are infected with HIV-1 worldwide. The major Progressive multifocal leukoencephalopathy
risk groups for developing AIDS vary with geo- Any patient with one or more of the following reliably
graphic locale. In Africa and Asia, the major risk diagnosed diseases plus laboratory evidence of HIV
group is sexually active heterosexuals; women infection :
are more often infected than men (17,45). In Bacterial infections, multiple or recurrent, in child
<13 years of age
the United States, over 70 percent of cases Coccidioidomycosis, disseminated
affect homosexual or bisexual men; another HTV encephalopathy
15 percent develop in intravenous drug users. Histoplasmosis, disseminated
Other high-risk groups include prostitutes, Isosporiasis with diarrhea persisting more than 1 month
Kaposi's sarcoma at any age
hemophiliacs, children born to HIV-positive Lymphoma, brain (primary), at any age
mothers, patients transfused with HIV infected Other non-Hodgkin's lymphomas of certain types
blood or blood products, and heterosexual Mycobacteriosis caused by mycobacteria other than M .
contacts of any of the above groups (SO). HIV- tuberculosis, disseminated
Tuberculosis, extrapulmonary
infected mothers pass the virus transplacentally, Salmonella (nontyphoid) septicemia, recurrent
through the birth canal at the time of delivery, HIV wasting syndrome
or through breast milk. AIDS especially affects
Hispanics and African-Americans (15). The
AIDS patient population in the United States is recent years (15), probably due to an increased
disproportionately male, black, and poor (9). awareness in at-risk populations and the intro-
In 1994, 18 percent of patients in the United duction of antiretroviral therapies.
States were women. Sexual transmission is now Since 1996, profound changes have taken
the dominant route by which women become place in the epidemiology, clinical presentation,
infected (20). HIV is also endemic in Central complications, and management of HIV infec-
Africa and Haiti. Substantial declines have oc- tion. Primarily, these changes are the result of
curred in AIDS incidence and related deaths in the introduction of highly active antiretroviral

539
Gastrointestinal Diseases

Reverse AIDS cases develop in HIV-2-infected than in


Transcriptase
HIV-1-infected populations. Viral transmission
is similar for both viruses, except that perinatal
transmission occurs less frequently with HIV-2
infections. HIV-2 also has a longerlatency period
P18 before AIDS appears, the course is less aggressive,
and the mortality rate is lower than for those
with HIV-1 infection. HIV-2-infected patients
typically have a lower viral load and higher
CD4 counts than HIV-1-infected individuals.
HIV easily mutates, leading to the emergence
of new viral strains that can resist immune at-
tack or drug therapy or alter the clinical or his-
topathologic features of the disease. The number
of active replicating viruses is proportional to
the number of CD4-positive lymphocytes .
The HIV virion measures approximately 100
nm in diameter and contains a dense cylindri-
cal core (fig. 11-1). Its life cycle is shown in
gP120 figure 11-2. The virion contains two single RNA
strands, structural proteins, and the enzymes
Figure 11-1 required for viral replication. The HIV genome
SCHEMATIC DIAGRAM OF THE is diagramed in figure 11-3. HIV genes encode
HUMAN IMMUNODEFICIENCY VIRUS (HIV) VIRION core proteins (GAG), reverse transcriptase,
The envelope proteins (GP120 and GP41) and nuclear protease, an endonuclease (Pol), and envelope
capsid proteins (P24 and PIS) are identified. The diploid glycoproteins (Env). At least five other genes
RNA genome contains reverse transcriptase and an RNA- exert regulatory functions that may affect viral
dependent DNA polymerase.
pathogenicity including: vif, tat3, rev, nef, and
vpr (Table 11-2). The viruses use the enzyme
treatment (HAART). Gastrointesp nal and hepa- reverse transcriptase to transcribe viral RNA
tobiliary complications were universally recog- into proviral DNA in host cells. The proviral
nized during the course of HIV infection; how- DNA resides in the cells during viral latency.
ever, in the era of HAART, these complications The lipid envelope surrounding the viral core is
have dramatically decreased. Monkemuller derived from the host cell surface as the virions
et al. (36) showed a substantial reduction in bud from the infected cell. As a result, this lipid
the number of opportunistic infections associ- envelope contains host membrane protein rem-
ated with HIV infection in a group of patients nants as well as the viral envelope glycoprotein
on HAART. Although substantially effective gp120 and the transmembrane protein gp41 ,
in suppressing opportunistic infections, the two proteins involved in viral attachment and
antiretroviral medications are associated with entry into host cells (fig. 11-2) (29).
gastrointestinal side effects in up to 10 percent The CD4 protein and its co-receptor, CXCR4,
of cases (8). Currently, drug-induced side effects and possibly CD26 on helper T-cell surfaces,
and nonopportunistic diseases are among the serve as high affinity receptors for the viral
•.
most common causes of gastrointestinal symp- envelope gp120, mediating rapid, firm cellular
toms in HIV-positive patients (11,36) . attachments. T-cell trophic viruses requiring
Etiology. Two HIV types exist: HIV-1 and CXCR4 for entry are termed X4 viruses (4) .
HIV-2 . Both viruses belong to the lentivirus Some HIV strains (named R5 viruses to
family of nononcogenic retroviruses. HIV-1 is reflect their co-receptor requirement) bind to
the predominant virus in the United States, macrophages via the beta-chemokine receptor
Europe, and eastern Africa; HIV-2 infection CCR5 (1,39,51) . Genetic polymorphisms in the
predominates in parts of western Africa. Fewer chemokine receptor genes that mediate HIV

540
Gastrointestinal Diseases in Immunocompromised Patients

CD4
binding Internalization

Figure 11-2
HIV LIFE CYCLE
Following the interaction of
gP120 with the CD4 membrane
receptor, gP41-mediated mem-
brane fusion occurs, leading to
viral entry into the cell. Reverse
Unintegrated transcription of the viral RNA
circular proviral results in the production of
DNA
double-stranded DNA from the
virus. The viral integrase pro-
motes insertion of the viral DNA
duplex into the host genome.
The first mRNA produced corres-
ponds to the multiply spliced
variants of viral DNA encoding
the tat, rev, and nef regulatory
LATENT INFECTION proteins. Subsequently, viral
OF CD4+ T CELLS structural proteins are produced,
OR MACROPHAGES allowing the assembly of viral
particles. Free HIV-1 virions are
0 Budding then released by viral budding
/
(D 0 CELL ACTIVATION from the host cell membranes,
Mature HIV
AND PRODUCTIVE which may then reinitiate the
INFECTION IN CD 4+ retroviral life cycle.
production

'
T CELLS

\
Cell
lysis

Transactivates
Antirepression
Mechanisms
Required for
Production of Infectious
Virions t Transactivates HlV
Expression

GAG 3' LTR

~
LTR


Core Proteins
POL
vpr
ENV
+ .
Envelope Protems
(gP120, gP41)
net

!
Downregulates
HIV Gene Expression

Figure 11-3
HIV GENOME
Each of the genes of HIV-1 are depicted, as are their primary functions. The 5' and 3' long terminal repeats (LTRs) contain
regulatory sequences recognized by various host transcription factors. The positions of the tat and rev RNA response elements
and the nef response element are also shown.

541
Gastrointestinal Diseases

Table 11-2
HIV-ENCODED PROTEINS

Envelope Envelope surface (SU) protein


Gag Capsid (CA) structural protein; matrix (MA) protein-myristoylated: role in budding; nucleocapsid
(NC) protein: helps in reverse transcription
gP4 Required for fusion and entry into host cell
gP1 20 Involved in chemokine receptor bindin g
Integrase (IN) Viral cDNA integration
Nef Removes CD4 surface expression or infected cells by acceleratin g endocytosis; enhances infectivity of
cell free virus
Polymerase (Pol) Reverse tran scriptase (RT); RNase H-inside core
Protease (PR) Post-translation al processing of viral proteins
Rev Involved in RNA splicing and RNA nuclear-cytoplasmic tran sport; regulation of viral mRNA expression
Tat Promotes viral transcri ption
Tev Tat/rev activities
V if Tran sport s virio ns to cell nucleus; stabilizes virion DNA intermediates; increases virus infectivity and
cell-cell tran smission
Vpr Allows transport of vira l RNA into the nucleus of n ondividing cells and upregulates viral gene
expression; induces..G2 arrest in dividing cells
Vpu Membran e spannin g protein that binds CD4 in the endoplasmi c reticulum and targets it for proteoly-
sis, downregulating its expression; enhan ces virion release from infected cells; h elps in virion release
Vpx Helps in infectivity

disease progression affect disease expression dissemination occurs. HIV can be cultured from
(37). Cells with absent or reduce<;} CCRS expres- the plasma 1 to 2 weeks after infection (38) .
sion or CCRS mutation have a reduced sensitiv- The gastrointestinal mucosa serves as an im-
ity to HIV infection (31,42), ami· these cells are portant reservoir for HIV, with lamina propria
resistant to HIV infection even in the face of a macrophages frequently harboring the virus (2,
high risk of infection (31). 30). The gastrointestinal epithelium and lamina
Pathophysiology. The most common mode propria are also a rich source of CD4-positive
of HIV-1 infection is sexual transmission through T cells. These cells are also abundant in the
the anogenital mucosa . Monocytes, macro- regional lymph nodes. The intestinal mucosa
phages, dendritic cells, and CD4-positive T lym- becomes profoundly and selectively depleted of
phocytes are the primary viral targets (29). The CD4-positive cells within days of the infection,
vims is initially acquired via one of the following: even before similar changes occur in peripheral
rectal mucosal tears, Mcells overlying lymphoid lymphoid tissues. In contrast, CD8-positive T cells
follicles, direct infection of the rectal epithelium, increase early in the infection and then display in-
or infection of lamina propria dendritic cells creased levels of activation antigens and abnormal
subjacent to the anorectal epithelium (48). major histocompatibility class (MHC)-restricted
r..· HIV-1 adhering to the luminal membranes HIV-specific and -nonspecific cytotoxic abilities.
of rectal M cells are endocytosed and delivered A specific increase in apoptotic CD8-positive T
to intraepithelial lymphocytes, macrophages, cells eventually leads to their depletion (30). This
and the mononuclear cells of the lymphoid change, sometimes referred to as the CDB lym-
follicles (2). The infected cells fuse with CD4- phocytosis syndrome, predominantly affects black
positive lymphocytes and spread into deeper males who have MHC human leukocyte antigen
tissues. Within 2 days of the initial infection, (HLA) DRS; it is associated with a favorable host
viruses can be detected in draining internal response (24). A nearly complete absence of
iliac lymph nodes . Shortly thereafter, systemic CD4-positive intraepithelial lymphocytes and

542
Gastrointestinal Diseases in Immunocompromised Patients

decreased CD11 -positive intraepithelial lym- AIDS develops after a long latent period,
phocytes characterizes the intestinal mucosa averaging 7 to 10 years following the initial in-
of severely ill AIDS patients (22) fection. During the latency period, the immune
Host factors also play a major role in the system remains relatively intact, preventing
· pathogenesis of HIV-related disease. A complex most secondary infections, but viral replica-
network of endogenous cytokines provides a tion actively continues in lymphoid tissues
delicate balance between HIV induction and (47). A CD4 count less than SOO/mL heralds
suppression. The ~-chemokines RANTES, MIP- the development of clinical AIDS. A drop to
1a, and MIP-1~ act as suppressors of macro- less than 200/mL defines AIDS and indicates
phage-trophic HIV strains (19) and elevated a high probability of developing AIDS-related
~-chemokine expression levels probably help infections, neoplasms, and death.
control HIV load and replication in individuals Diarrhea affects 30 to SO percent of North
who do not progress to AIDS (1,49). American and European and 90 percent of Afri-
Clinical Features. Acute HIV-1 infection is a can HIV-infected patients (17,26). AIDS patients
transient, symptomatic illness associated with who present with diarrhea have a greater degree
high viral titers and a robust immunologic of immunosuppression than those without diar-
antiviral response (27). Signs and symptoms rhea, predisposing the gut to the infections that
of acute HIV-1 infection occur within days contribute to morbidity and death. Diarrhea
to weeks of the initial viral exposure. In the occurred in up to 90 percent of patients in the
several days or weeks after the infection is ac- pre-HAART era. More recent data suggest that
quired, 30 to70 percent of patients experience diarrhea is still a frequent complaint, but is
an acute viral syndrome that includes the first more commonly attributable to drug-induced
gastrointestinal symptoms. The most common injury or non-HIV-related pathologic processes.
systemic signs and symptoms are fever, fatigue, Diarrhea in HIV-infected patients, therefore,
a maculopapular rash, headache, lymphade- results from the presence of: 1) enteric patho-
nopathy, pharyngitis, myalgia, arthralgia, genic infections; 2) complications of the drugs
aseptic meningitis, retroorbital pain, weight used to treat the HIV infection; 3) the presence
loss, depression, gastrointestinal distress, night of 11 AIDS enteropathy" or 11 AIDS gastropathy";
sweats, and oral or genital ulcers . The acute 4) AIDS-related motility disturbances; and S)
illness coincides with a small decline in the tumor development. Often it is impossible to
number of CD4-positive cells. Later, the CD4- attribute any AIDS-associated gastrointestinal
positive cell count decreases further, the CDS- sign or symptom to a specific underlying cause,
positive cell count increases, and the CD4 to since patients usually have numerous gastroin-
CDS ratio becomes inverted. The acute illness testinal pathologies (Table 11-3). The coccidian
lasts for a few days to more than 10 weeks, but parasites C7yptosporidium parvwn, Isospora belli,
averages less than 14 days (46) . Since the early and Cyclospora, and the microsporidia account
signs and symptoms are nonspecific, acute HIV- for at least SO percent of cases of persistent diar-
1 infection is frequently confused with other rhea in the industrialized and developing world,
viral illnesses. Initial laboratory studies may with major contributions from Mycobacterium
show lymphopenia and thrombocytopenia avium complex and other bacteria, as well as
but atypical lymphocytes are infrequent (18). cytomegalovirus (CMV) infection (23) .
Standard serologic tests only become positive 3 The gastrointestinal manifestations of HIV
to 4 weeks after the initial infection (10). Severe change according to the stage of the infection.
and prolonged symptoms correlate with rapid Early and intermediate gastrointestinal mani-
disease progression (3). festations include diarrhea without detectable
After the initial infection, there is rapid vire- pathogens (AIDS enteropathy) and low-grade
mia resulting in widespread viral dissemination, bacterial overgrowth. Well-established infections,
seeding of lymphoid organs (14), and entrap- particularly parasitic and viral infections, charac-
ment by follicular dendritic cells (2S). Individu- terize late-stage disease. Severe recurrent systemic
als with the highest viral loads have the highest or gastrointestinal parasitic, viral, fungal, and
rates of disease progression (33). protozoal infections, along with the development

S43
Gastrointestinal Diseases

Table 11-3
GASTROINTESTINAL LESIONS IN PATIENTS WITH AIDS

Infections Parasites HIV enteropathy


Bacteria Entamoeba histolytica
Spirochetosis Giardia Iamblia HIV ganglioneuritis
Salmonella typhimurium Cyclospora species
Shigella species Enterobius vermicularis Motility problems
Mycobacterium tuberculosis Clyptosporidium
Mycobacterium avium-intracellulare Toxoplasma Idiopathic esophageal ulcers
Escherichia coli Taenia saginata
Campylobacter species Isospora belli Tumors
Aeromonas hydrophilia Microsporidia group Anal condylomas
Neisseria gonorrheae Leishmaniasis Kaposi's sarcoma
Lymphogranuloma venereum Strongyloides Smooth muscle tumors
Syphilis Blastocystis hominis Lymphomas
Various carcinomas
Chlamydial infections Fungi
Candida Traumatic lesions
Viruses Histoplasma
Epstein-Barr virus (EBV) Blastocystis hominis Drug effects
Cytomegalovirus (CMV) Pneumocystis carinii
Herpes simplex virus (HSV) Aspergillus fumigatus Nutritional deficiencies
Human immunodeficiency virus (HIV) Clyptococcus neoformans
Human papilloma virus (HPV) Lymphoid change
? Rotavirus Depletions
? Adenovirus Hyperproliferation

of neoplasms and other HIV-associated patholo- nal bleeding is an uncommon clinicai feature of
gies, often result in a fatal outcome. AIDS, affecting less than 1 percent of the patient
Esophageal symptoms like dysphagia and population (41) . Studies have found that upper
odynophagia were reported to otcur in up to gastrointestinal bleeding is most commonly
one third of AIDS patients before HAART was associated with non-HIV-related causes like
available. Opportunistic infecti ons, particu- peptic ulcer (5). The most common cause of
larly Candida infections, are a frequent cause lower gastrointestinal bleeding in HIV-positive
of esophageal symptoms. Infections with viral patients is CMV colitis (6,16).
organisms like herpes simplex virus (HSV) and Anorectal signs and symptoms seen in HIV-
CMV are infrequent. The incidence of HIV-un- infected patients include perirectal abscesses,
related causes of esophageal symptoms such as anal fistulas, infectious proctitis, and idiopathic
gastroesophageal reflux disease and pill-induced ulcerations. Human papilloma virus (HPV)-
esophagitis is rising (36). Severe odynophagia associated squamous lesions are also common
is more likely to be associated with idiopathic in these patients.
ulcerative esophagitis or possibly a neoplasm. Infants born with HIV infections tend to be
Abdominal pain in AIDS patients may or may small for their gestational age and display vari-
not be related to HIV infection. Abdominal pain ous abnormalities, including diarrhea, failure to
is more severe, however, when associated with thrive, and weight loss. Some manifestations be-
the consequences of HIV infection (40). The pain come life threatening (7,47) due to the presence
is variable in character; it ranges from the dull, of opportunistic infections, increased gastroin-
aching pain of infectious enteritis to the acute, . testinal permeability (32), lymphoproliferative
severe pain of perforation and pancreatitis. diseases, and cancer. In children with AIDS,
Depending upon the etiology, diarrhea can be infections are more severe, often relapse, and
transient or chronic. It may be associated with are harder to eradicate than in adults. Children,
blood in stool, tenesmus, malabsorption, and especially those in the developing world, are
other gastrointestinal complaints. Gastrointesti- prone to develop diarrhea.

544
Gastrointestinal Diseases in Immunocompromised Patients

Endoscopic procedures on AIDS patients started on treatment. The goal of therapy is to


with gastrointestinal symptomatology should decrease the HIV RNA level to an undetectable
determine whether the gut is directly affected amount or to have at least a decrease of 1.0 log
by the AIDS virus (e.g., AIDS enteropathy) in the viral load. Failure of therapy and the need
or whether a complication related to the im- to change therapy is signaled by an HIV RNA
munosuppressed state is present. The latter increase of 0.5 log or greater.
includes opportunistic infections or the devel- Treatment and Prognosis. In recent years,
opment of neoplasias (e.g., Kaposi's sarcoma, significant advances have been made in the
lymphoproliferative disorders). The endoscopist prevention and treatment of opportunistic infec-
relies on the pathologist to utilize specialized tions, including Pneumocystis carinii pneumonia,
staining techniques to determine this. In ad- CMV retinitis, disseminated Mycobacteliwn avium
dition, sufficient tissue should be obtained to complex infection, and mucosal candidiasis, due
allow histologic, immunologic, viral, and even to use of intensive, highly active antiretroviral
mycologic analyses. Communication between therapies (39). Mortality overall in AIDS patients
the endoscopist and specialized laboratories is has declined in excess of 80 percent since the
important as the clinician may not always be introduction of HAART (34,35) .
aware of how specimens are best transported to A recent panel of experts recommended im-
obtain optimal results. mediate therapy be considered for persons with
Special Techniques. In the past, the best acute HIV infections (12,13). Early treatment
predictor of AIDS onset was the percentage or restores the virus-specific cellular immune re-
absolute number of circulating CD4-positive T sponses required to control early viremia (44) so
cells. Currently, viral quantification in plasma that the extent of viral dissemination is limited,
is a better predictor of progression to AIDS and the damage to the immune system is restricted,
death. Measurements of viral burden also cur- antigen-presenting cells are protected, and the
rently form the basis for decisions concerning chance of disease progression is reduced. There
initiation and modification of antiviral therapies. are drawbacks to the institution of such therapy,
Still, the CD4 cell count monitors the immune however, and recent trends are leaning toward
system and is a useful guide for decisions con- more conservative treatment with HAART. Recent
cerning prophylaxis for opportunistic infections. recommendations are that HAART be instituted at
In addition, the CD4 count helps predict the type a time when CD4 counts suggest an immediate
of infection that may be responsible for a given risk of progression to AIDS, or in patients at risk
patient's symptoms. A CD4 count greater than of dying (12,43). Risks of early therapy include the
200/mL suggests common bacteria as possible adverse effects of these drugs on the quality of the
infectious agents. In patients with CD4 counts patient's life as well as potential serious side effects
above 200/mL, nonopportunistic pathogens that may result from drug toxicity. In addition,
should be considered in the differential diagnosis. the duration of the beneficial effects of HAART
When CD4 counts are lower than 100/mL, fungi, is currently unknown (34). Previously treated
mycobacteria, CMV, and unusual protozoa should patients are known to experience a poorer re-
be considered as possible causative agents. sponse to the reinstitution of HAART, perhaps
Three techniques are currently available for as a result of acquisition of some degree of drug
viral load testing: reverse transcriptase poly- resistance (28,34).
merase chain reaction (RT-PCR), nucleic acid Five classes of drugs have been approved for
sequence-based amplification, and branched the treatment of HIV infection: 1) nucleoside
chain DNA (bDNA) analysis. Viral load testing reverse transcriptase inhibitors, 2) nucleo-
should be obtained prior to initiation of anti- tide reverse transcriptase inhibitors, 3) non-
retroviral therapy, 3 to 4 weeks after initiating nucleoside reverse transcriptase inhibitors, 4)
or changing therapy, and periodically, perhaps protease inhibitors, and 5) fusion inhibitors.
on the same schedule as CD4 counts, i.e., every In addition, various new anti-HIV drugs are
3 to 4 months. under clinical or preclinical development (21).
In general, patients with viral loads of more Updates for treatment guidelines are available
than 5,000 copies/mL of plasma should be from the World Wide Web site of the HIV I AIDS

545
Gastrointestinal Diseases

Treatment Information Service (ATIS) at http:/ I


www. hivatis.org.
HIV Enteropathy
Definition. HIV enteropathy, in its broadest
sense, refers to gastrointestinal damage result-
ing from an HIV infection. A more specific
definition of HIV enteropathy is the presence
of chronic (more than 1 month's duration)
diarrhea, malabsorption, and wasting without
evidence of an enteric infection after complete
evaluation (SS). Synonyms include AIDS enter-
opathy and AIDS enterocolitis.
Etiology. Multiple enteric pathogenic bac-
teria cause diarrhea in AIDS patients including
Campylobacter jejuni or C. fetus, Clostridium dif- Figure 11-4
ficile, Enterobacter aerogenes, Salmonelja, Shigella HIV ENTEROPATHY
flexneri, Klebsiella, and other Gram-negative Numerous apoptotic bodies lie in the bases of the crypts.
bacilli. The most common etiologic agent The histologic changes are similar to those seen in graft
versus host disease (see figs. 11-23, 11-24).
detected in the large bowel of AIDS patients is
CMV followed by Mycobacterium aviym. Patients
may also have fungal or parasitic infections pattern. The features are nonspecific and the
(Table 11-3). The degree of inflammation seen diagnosis is by exclusion of other pathologies,
in AIDS enteropathy correlates with mucosal especially opportunistic infections.
levels of p24 antigen and clinical symptoms, Microscopic Findings. The intestinal inflam-
supporting an etiologic role for HIV. mation is often nonspecific in AIDS-associated
Pathophysiology. Proposed explanations for enteropathy (fig. 11-4). It consists of degran-
HIV-associated enteropathy include any or all ulating eosinophils, activated lymphocytes,
of the following: 1) the presence .of an occult and plasma cells with increased numbers of
enteric infection (56); 2) the direct effect of the intraepithelial and lamina propria T lympho-
virus on the gastrointestinal epithelium; 3) the cytes (52). Early in the disease, the lymphocyte
indirect effects of a localized immunologic dys- density is normal but lymphoid depletion
function; 4) an immune-mediated enterocolitis; develops in patients with full-blown AIDS. In
5) a drug-induced change; or 6) an effect of some this latter phase, macrophage and eosinophilic
nutritional deficiency. Arguments in favor of a infiltrates are prominent and apoptosis is com-
direct HIV-related viral cytopathic effect include mon. In end-stage disease, opportunistic infec-
the identification of the virus in epithelial cells tions are present together with eosinophilia,
by in situ hybridization or Southern blot analy- neutrophilia, apoptosis, and tissue injury.
sis and the absence of other pathogens. Either the mucosal T-cell alterations in AIDS
Clinical Features. biarrhea often develops or the direct viral infection of the enterocytes
before full-blown AIDS develops, sometimes may alter the mucosal architecture and produce
only occurring during the clinically latent pe- an enteropathy or colopathy. This is character-
riod. Patients may develop steatorrhea and low ized by a decreased villus to crypt ratio second-
... lactase activity secondary to epithelial damage . ary to villous atrophy and crypt hyperplasia
Vitamin B12 deficiency and abnormalities of xy- (56). The epithelial mitotic index varies with
lose absorption also occur. Overt bleeding, in the respect to disease duration and severity; it in-
absence of coexisting anal disease, is unusual. creases early and then decreases.
Gross Findings. The colonoscopic mucosal Histologically, the intestinal mucosa ex-
pattern shows diffuse abnormalities consisting hibits nonspecific apoptosis, edema, enlarged
of contact bleeding, edema, superficial ulcer- nuclei, increased numbers of mononuclear
ations, exudates, and loss of the normal vascular cells in the lamina propria, and intraepithelial

546
Gastrointestinal Diseases in Immunocompromised Patients

resents the end stage of the epithelial apoptosis


that causes the crypts to appear to vanish from
the mucosa. The crypts superficially resemble di-
lated lymphatics. Closer examination discloses
that the cystic spaces in the lamina propria are
lined by variably flattened epithelium; often,
the lumens contain apoptotic cells.
Vascular calcification with intimal fibrosis,
fragmentation of the internal elastic lamina, and
fibrosis of the media with luminal narrowing,
changes designated as AIDS arteriopathy, develop
in the small to medium-sized systemic arteries,
including those in the gastrointestinal tract and
within the mesocolon. This may lead to second-
ary ischemic changes and mucosal ulceration.
Figure 11-5
Small collections of foamy histiocytes may
DUODENAL IRON PIGMENT DEPOSITION superficially suggest the presence of Mycobac-
IN A PATIENT WITH ACQUIRED
IMMUNODEFICIENCY SYNDROME (AIDS)
terium avium complex or Whipple's disease but
Blue-stained iron pigment granules are in the lamina
these are negative for microorganisms. These
propria of the villus tips . The patient also has crypto- lesions are relatively common in the colon and
sporidiosis, seen here as blue dots on the villus surface probably represent a nonspecific response to
(iron-stained section). mucosal damage from many etiologies. In our
experience, it is always wise to stain biopsies
containing these collections for the presence of
lymphocytosis. Aphthous ulcers may be present. mycobacteria and fungi, especially if the collec-
The apoptotic changes seen in AIDS resemble tions are large and prominent.
the apoptosis in grade I graft versus host dis- Another change that may affect the intestines
ease. As the disease evolves, cell loss results in is a nonspecific motility disorder. This may be
a population of functionally immature entero- the result of the drug therapy causing muscle
cytes incapable of absorbing nutrients due to the fiber atrophy or due to the presence of CMV
immaturity of their brush border enzymes. The within enteric ganglia.
changes resemble those seen in celiac disease Special Techniques. In tissue sections, HIV
(see chapter 12). is detected by in situ hybridization in both the
Another change that affects the small intes- crypt cells and in the stromal cells of the lamina
tinal mucosa of AIDS patients more often than propria (54).
non-AIDS patients is pseudomelanosis. The Differential Diagnosis. The changes of AIDS
reason for this is unclear. It appears as areas of enteropathy may resemble microscopic colitis,
spotty brownish or blackish pigmentation in celiac disease, or graft versus host disease. The
the duodenal mucosa that can be seen at the clinical setting, results of HIV testing, and tis-
time of endoscopy; it is maximal in the second sue transglutaminase status serve to distinguish
portion of the duodenum. Most patients have among these possibilities.
received oral iron supplements. Histologically, Treatment. In the absence of the identifica-
iron pigment is seen in the villus tips (fig. 11-5). tion of a specific treatable pathogen or disease
Colonic biopsies show a more or less normal process by stool studies or endoscopic examina-
architecture with nonspecific inflammatory tion with biopsy of the upper and lower diges-
changes and a mixed cell infiltrate, including in- tive tracts, consideration of a trial of antimicro-
traepitheliallymphocytosis, focal crypt epithe- bial therapy (e.g., ciprofloxacin, metronidazole)
lial cell apoptosis, endothelial tubuloreticular may be reasonable in the hope of treating an
bodies, lymphocytes, and monocytes (53). elusive infection or the presence of bacterial
Other changes include crypt atrophy coexisting overgrowth. Nutritional, fluid, and electrolyte
with regenerative crypts. This presumably rep- support is important, and the clinician may

547
Gastrointestinal Diseases

have to employ parenteral means in order to Microscopic Findings. The histologic fea-
replace ongoing losses. Luminal agents (fiber tures of the esophagus depend on the etiology
preparations, cholestyramine) may add bulk to of the lesions. In the absence of endoscopic le-
the stool. Antimotility agents (loperamide, di- sions, biopsies rarely yield significant histologic
phenoxylate with atropine, codeine, paregoric, findings. The most common infections are CMV
morphine, tincture of opium) may be necessary and HSV when ulcers are present and Candida
for support. Octreotide may be effective in some if plaques are present. The viruses are identified
patients, but its use is controversial and should by the presence of characteristic inclusions. Pro-
not be employed indefinitely if no response is spective evaluation of the number of biopsies
achieved in a few weeks. required for the diagnosis of viral esophagitis in
HIV patients discloses that at least 10 may be
HIV-ASSOCIATED DISEASES IN SPECIFIC required. Three biopsies are usually sufficient
GASTROINTESTINAL LOCATIONS to diagnose CMV infection (59). Esophageal
M. avium complex usually represents an exten-
Esophageal Disease
sion of mediastinal nodal infection, so that
Demography. The majority of AIDS patients the organisms may only be present deep in the
with esophageal erosions or ulcers have no esophageal wall and not in the mucosa. This im-
known etiologic agent or have viral or fungal plies that one needs to examine deep biopsies if
infection. Esophageal candidiasis occurs so com- the clinical question is "mle out mycobacteria."
monly that it is an AIDS-defining lesion. Esophageal biopsy specimens should first be
Etiology. AIDS patients often present with examined with hematoxylin and eosin (H&E).
esophageal disease due to 1) infection (Candida, Silver and acid-fast stains should be performed if
CMV, HSV, Epstein-Barr vims [EBV], Mycobacterium a fungal or mycobacterial infection is suspected
avium, C!yptosporidium, Pneumocystis, Leis!zmania); but not seen with H&E stains.
2) the development of a tumor (papilloma, Ka- In the absence of a specific infection, the
posi's sarcoma, lymphomas); 3) idiopathic ulcers; esophagus exhibits variable inflammatory reac-
4) ordinary gastroesophageal reflux disease; 5) pill- tions, erosions, and ulcers. Alternatively, there
induced esophagitis; and 6) strictures secondary to may only be focal edema coexisting with rare
healed inflammatory disease. apoptotic cells. Large numbers of apoptotic
Clinical Features. The clinical symptoms of bodies can be seen in the cells immediately
esophageal disease include dysphagia and severe adjacent to idiopathic esophageal ulcers, con-
odynophagia. Ulcers develop in the first month tl·asting with the lack of apoptotic bodies in
or so following the HIV infection, complicating esophageal ulcers with known etiologies. This
a mononucleosis-like febrile illness. Progressive feature is thought to be a manifestation of the
weight loss results from the presence of multiple HIV infection. The submucosa may become
hypopharyngeal and esophageal ulcers. The densely infiltrated with neutrophils, and a few
ulcers often become quite large, sometimes de- mononuclear cells extend to the level of the
veloping into "giant esophageal ulcers." These muscularis propria (60). Many patients have
can progress to a life-tfueatening size, eroding ordinary gastroesophageal reflux disease and all
vessels, limiting oral nutrition, and leading to of its complications (see chapter 3).
secondary pulmonary problems, including fis- Special Studies. Infections are evaluated by
tula formation. Healing predisposes to stricture culture, special stains, immunohistochemical
development, especially if gastroesophageal re- studies, in situ hybridization, and polymerase
flux is also present. The majority of esophageal chain reaction (PCR). The decision to use these
problems encountered are readily treatable on modalities depends on the clinical implications
an ambulatory basis. of the diagnosis. For example, every effort must
Gross Findings. Gross findings include areas be made to exclude an opportunistic infection
of whitish exudates, plaques, erosions, and when a diagnosis of an idiopathic esophageal
ulcers ranging in size from aphthous ulcers to ulcer is being entertained. If three levels of H&E-
giant esophageal ulcers. Most patients with stained sections fail to document the infection,
Candida have plaques. Strictures may be present. special stains should be used to rule out the

548
Gastrointestinal Diseases in Immzmocompromised Patients

presence of the organism if the clinicians plan sarcoma. Cryptosporidial (58) and syphilitic
to aggressively treat the infection. In this situa- infections of the antral mucosa cause isolated
tion, the pathology request form typically states antral narrowing.
"rule out ... "We rarely use any in situ or PCR Microscopic Findings. CMV viral inclusions
reactions to diagnose viral infections. are frequently seen in the gastric epithelium. H.
Treatment. Idiopathic esophageal and aph- pylori gastritis is more severe in AIDS patients.
thous ulcers respond well to corticosteroids, Phlegmonous gastritis shows marked acute
with symptomatic response generally occur- inflammation, vascular thrombosis, necrosis,
ring within several days. Thalidomide (which and hemorrhage. The histologic features of
reduces tumor necrosis factor) is also useful in AIDS gastropathy are similar to those of chronic
this situation. Resolution of severe ulcerative atrophic gastritis described in chapter 4.
disease may result in stricture formation and the Kaposi's sarcoma is predominantly submu-
development of dysphagia. Endoscopic dilata- cosal and can be missed on endoscopic biopsy.
tion is the strategy of choice in this case. Patients Highly vascularized nodules composed of elon-
with tracheoesophageal fistulas often experience gated spindle cells with narrow thin blood vessels
dramatic relief from their intractable cough fol- are characteristic. Pink acellular globules are ad-
lowing placement of an esophageal stent. Gash·o- mixed with the spindle cells. Gastric B-celllym-
esophageal reflux is treated along conventional phoma is the second most common neoplasm
lines by means of acid suppressive therapy. One seen in AIDS patients. Low-grade lymphoma of
needs to be cognizant of the potential for severe mucosa-associated lymphoid tissue (MALT) type,
drug interactions if prokinetic agents are used. follicular center cell lymphoma, and diffuse large
B-celllymphoma have been described.
Gastric Disease
Treatment. Treatment is targeted against the
Etiology. In AIDS patients, infectious gastri- offending agent.
tis, other than that related to Helicobacter pylori,
Anorectal Disease
usually results from bacterial, viral, and proto-
zoal infections; of these, CMV is the most com- Demography. Anorectal disease is very
mon. H. pylori infections may be particularly common in AIDS patients. Traumatic injury,
virulent in AIDS patients. The AIDS-associated infection, condylomas, and anal squamous cell
viruses and the inflammation associated with neoplasia are the most common lesions.
it causes mucosal damage. Etiology. The anorectal lesions found in
Some patients develop AIDS gastropathy, a active homosexuals result from opportunistic
disorder characterized by a reduction in pari- infections (HSV, HPV, syphilis, Chlamydia,
etal cell mass, and gastric acid and pepsinogen CMV, scabies, molluscum contagiosum), tumors
secretion, and an increase in mucus secretion (lymphoma, squamous cell carcinoma, Kaposi's
(60). The disease is mediated by the presence of sarcoma), and trauma. Ulcerative disease of the
antiparietal cell antibodies. Hypochlorhydria anorectum may be due to trauma, Chlamydia,
results in high bacterial counts in the stomach HSV, syphilis, benign fissures, idiopathic AIDS-
and predisposes the patient to intestinal bacte- related ulceration, and malignancies. Trauma
rial infections. Kaposi's sarcoma and lymphoma from the use of rectal instruments and the in-
represent the most prevalent gastric malignan- sertion of foreign bodies can cause significant
cies seen in AIDS patients. AIDS patients also mucosal inflammation and sphincter damage,
develop suppurative gastritis. predisposing to fecal incontinence.
Clinical Features. Abdominal pain is com- Clinical Features. Pain may be due to HSV
mon and usually secondary to gastritis, ulcer, proctitis, which often involves the sacral root.
or gastric outlet obstruction. Other signs and Constant discomfort may be due to an abscess
symptoms include dyspepsia, bloating, and or neoplasm. Pain on defecation is usually due
rarely, upper gastrointestinal bleeding. to a fissure or ulceration. Lacerations, abrasions,
Gross Findings. Gross findings include red and perforations leading to exsanguinating
inflamed mucosa due to gastritis, ulcer, or mass hemorrhage occur, especially if foreign bodies
lesion secondary to lymphoma or Kaposi's are inserted into the rectum when the patient is

549
Gastrointestinal Diseases

under the influence of illicit psychoactive drugs Treatment of syphilitic proctitis consists of in-
or excessive alcohol consumption. tramuscular benzathine penicillin while rectal
Herpetic ulceration is probably the most gonorrhea, with or without proctitis, usually
common anal AIDS infection, whereas Neis- responds to a single dose of ceftriaxone intra-
seria gononhoeae probably represents the most muscularly followed by a 10-day course of doxy-
common infective cause of acute and chronic cycline. It is recommended that these patients
proctitis in this population. Masses may be be reevaluated after 3 months as recurrence of
due to tumor, condylomata, or even mucosal infection is common.
prolapse. Chlamydia trachomatis!lymphogranu-
loma venereum may mimic Crohn's disease BACTERIAL INFECTIONS IN
and is a cause of chronic stricturing fistulas IMMUNOCOMPROMISED PATIENTS
and painful proctitis. AIDS-related idiopathic
Mycobacterium Avium Complex
anal ulceration occurs more proximally than
benign fissures. Demography. Mycobacterium avium and My-
Rectal lymphoma may mimic an anal fissure cobacterium intracellulare (collectively referred to
or present as a mass lesion. Kaposi's sarcoma as Mycobacterium avium complex) are ubiquitous
presents as submucosal raised puq~le lesions. organisms, isolated worldwide from soil, dust,
The patient often has difficulty tolerating the fresh water, ocean water, animal feed, poultry,
anorectal examination because of the pain (57), and animals commonly used as meat (67,77).
and topical and even general anesthesia may In non-AIDS patients, Mycobacterium avium
be necessary to completely examin..e this area. complex (MAC) is characteristically restricted
Gross Findings. Findings incl!Jde diffuse to the lung. Disseminated infection is almost
hemorrhage, anal fissures, ulcers, fistula-in-ano, exclusively seen in AIDS patients, although the
perianal abscesses, and condyloma acuminata. incidence of colonization and infection has de-
Lymphogranuloma venereum produces stric- clined in the era of HAART (65). The frequency
tures and proctitis and may be difficult to dis- of disseminated MAC infection among AIDS
tinguish from idiopathic inflammatory bowel patients is not influenced by patient sex or the
disease (for further discussion, see chapter 10). route of infection (67). Hispanics are less likely
Microscopic Findings. The us~al anorectal to acquire the infection than non-Hispanic
abnormality is acute inflammation, a feature whites or blacks. Persons acquire the infection
seen more often in patients wit.h pathogens through environmental exposure to organisms
than in those without pathogens. Chronic in aerosols, water, food, and soil (68,74--76). The
inflammation suggests the presence of an frequency of the infection declines with age.
infection. When the mucosa is examined, an The major risk factor for infection is the level of
extremely florid proctitis is present. The in- immune dysfunction, as reflected by the CD4-
flammation may extend high into the rectum. positive cell count. Between 76 and 90 percent
Deep perirectal ulcers or abscesses develop, and of MAC infections develop late in the course of
they may contain large numbers of bacteria. AIDS when other AIDS-defining diagnoses have
Prominent lymphoid aggregates are often pres- already developed and CD4 counts measure less
ent. Gram stains demonstrate numerous cocci. than 60/mm 3 (67).
Syphilitic chancres mimic fissures, fistulas, or Pathophysiology. Disseminated MAC usual-
malignant tumors. There is increased apoptosis. ly results from primary infection. Asymptomatic
Parasitic infections are common. colonization of the respiratory or gastrointesti-
•.
Treatment. Anal fissures may be treated nal tract often precedes disseminated disease.
with high fiber diet and topical antiinflam- The organisms bind to the apical surface of en-
matory agents, including nitrates. Sphincter- terocytes, and are internalized via a mechanism
otomy should be avoided as it may precipitate that involves rearrangement of the cytoskeleton
incontinence. Perianal suppuration must be of the affected cell (63). Growth of the organism
drained and cultured to include acid-fast or- within epithelial cells results in expression of an
ganisms. Anorectal HSV and CMV are treated invasive phenotype (73). Significant differences
with standard therapies as for disease elsewhere. in virulence exist among different strains (72).

550
Gastrointestinal Diseases in Immunocompromised Patients

Clinical Features. In AIDS patients, the gas-


trointestinal tract is involved twice as frequently
as the lungs (78). At the time of autopsy, up to
two thirds of AIDS patients with MAC infec-
tion have gastrointestinal involvement (69). All
gastrointestinal segments become infected but
the most dramatic changes occur in the small
bowel, particularly the duodenum. Occasion-
ally, MAC causes discrete esophageal ulcers, but
this is uncommon. Rarely, localized infections
develop (66).
Patients typically present with nausea,
chronic diarrhea, abdominal pain, malab-
sorption, fever, sweats, chills, weight loss, Figure 11-6
lymphadenopathy, hepatosplenomegaly, and ACID-FAST STAIN IN A PATIENT WITH
pancytopenia. Peripancreatic and porta hepatis DISSEMINATED MYCOBACTERIUM AVIUM
lymph node involvement may obstruct the bile COMPLEX (MAC) INFECTION
duct, causing jaundice. Lymphoid hyperplasia Thousands of organisms pack the cytoplasm of the
in Peyer patches and lymph nodes predisposes histiocytes within the lamina propria.
to intestinal intussusception.
Rising cholestatic liver enzymes in the ab-
sence of dilated bile ducts on imaging suggests tracellular location and the presence of large
hepatic infection, drug effect, or sclerosing chol- numbers of intracellular organisms sometimes
angitis. Patients with hepatic MAC involvement arranged in stacks are distinctive (fig. 11-6). In
often have easily palpable hepatomegaly. Mul- patients with extensive disease the infiltrates
tiorgan involvement invariably occurs and the are easily recognized in H&E-stained sections
diagnosis may be made relatively noninvasively using low-power microscopy (fig. 11-7). A dif-
from culture of blood, stool, urine, or sputum, fuse histiocytic infiltrate fills the lamina propria,
or bone marrow examination. Occasionally, pushing apart the crypts and causing mucosal
liver biopsy may be necessary. atrophy with villous blunting and distortion.
Gross Findings. Endoscopically, MAC may The severity of the infection determines both
appear as yellow-white nodules. The duodenum the number of intracellular organisms and the
and small bowel are often involved. The colonic number of infected histiocytic cells. Focal dis-
mucosa may be edematous and erythematous. ease is harder to detect and may require the use
Involvement may be patchy and asymptomatic. of special stains. Duodenal biopsies or bmshings
Ulceration may occur, and may be complicated often contain the organism.
by fistulization, hemonhage, and perforation. Lymphocytes, plasma cells, and neutrophils
Occasionally, the mucosa appears endoscopi- are sparse, if present at all. Occasionally, there
cally normal and the disorder is diagnosed by are poorly circumscribed, noncaseating, epithe-
random biopsies taken during the workup of lioid granulomas containing lymphocytes and
unremitting diarrhea. Regional lymph nodes rare multinucleated giant cells. These granulo-
typically enlarge., grossly resembling lymphoma mas are less well formed than the granulomas
until the nodes are cut and examined in cross typical of M. tuberculosis infection and they
section. These enlarged nodes are often visible lack necrosis. Villous blunting accompanies
on computerized tomography (CT) scans. the infiltrate in the lamina propria, leading
Microscopic Findings. Mycobacteria are to malabsorption. Gastric and large intestinal
beaded rods measuring 4 to 6 pm in length infiltrates tend to be less prominent than those
and less than 1 pm in diameter. These acid-fast in the small intestine. Rarely, mycobacteria-
bacilli are not distinguishable by their shape containing macrophages are seen in all of the
or size from other mycobacteria, including bowel layers. Small bowel and regional lymph
Mycobacterium tuberculosis. However, their in- nodes are commonly massively infiltrated in

551
Gastrointestinal Diseases

Figure 11-7
MAC INFECTION
Left: Low-power view of a duodenal biopsy specimen from a patient with disseminated MAC infection. The lamina propria
contains a dense infiltrate of eosinophilic histiocytes. This infiltrate distorts the normal architecture of the duodenum,
separating the crypts and blunting the villi.
Right: Higher-power view of the dense histiocyte collection . No granulomas are formed.

disseminated disease but single, scattered, in- organism responsible for classic tuberculosis his-
fected histiocytes may also be seen. - to logically resembles M. avium. It is important
Special Techniques. The diagnosis of gas- to distinguish between the two specie~ since the
trointestinal MAC infection is best made by treatment for M . tuberculosis differs from that for
endoscopic biopsy. Fecal smear is less sensitive M. avium. Features that favor a diagnosis of MAC
than culture. Mycobacterial cultvres require 1 include diffuse histiocytic aggregates containing
to 2 weeks for organism growth, contrasting large numbers of bacteria in the lamina propria,
with light microscopic interpretation of biopsy without granulomas or caseation.
sections, which requires 1 to 2 days. The organ- Treatment and Prognosis. Prophylactic
ism can also be identified by the use of DNA treatment is recommended for -the prevention
probes applied to primary cultures. The most of disseminated MAC in AIDS patients with CD4
commonly used test is the Gen-Probe culture counts under 200/mm3 (71). Prophylactic ther-
confirmation test, which uses hybridization apy with rifabutin, clarithromycin, and azithro-
probes complementary to ribosomal myco- mycin is effective and synergistic effects can be
bacterial RNA (62). PCR analysis also identifies expected when they are administered together
the organism. Culture, which takes from a few unless the organisms have become resistant to
weeks to several months, is helpful in establish- the drugs (70). Two quadruple drug regimens
ing drug sensitivity. provide benefits to patients with disseminated
Differential Diagnosis. MAC histologically disease. The first regimen includes amikacin plus
resembles both Whipple's disease and severe His- ciprofloxacin, ethambutol, and rifampin (64); the
... toplasma infection because all three infections second regimen includes isoniazid, ethambutol,
cause periodic acid-Schiff (PAS)-positive mac- ansamycin, and clofazimine (61) . Mycobacterial
rophages to accumulate in the lamina propria. therapy with clarithromycin can significantly re-
The PAS-positive globules seen in Whipple's duce the bacteremia and improve the quality of
disease are larger than the positively staining life and the rate of survival in patients with dis-
MAC bacteria. Additionally, MAC are acid-fast seminated MAC. More than 12 weeks' therapy is
while the Whipple's bacilli are not. Histoplasma required to decrease bacterial load and to improve
are larger organisms and are easily identified us- symptoms. Lifelong suppressive therapy is often
ing the Grocott methenamine silver stain. The required to prevent relapse.

552
Gastrointestinal Diseases in Immunocompromised Patients

Mycobacterium Tuberculosis Infections Spirochetosis


Demography. Tuberculosis occurred so com- Defin ition. Intestinal spirochetosis is an over-
monly in HIV-infected patients that it became growth of spirochetes or an infestation of the
an AIDS-defining illness in 1987 (80). Although intestinal epithelium by spirochetes. The diag-
extrapulmonary tuberculosis is still common nosis requires a biopsy.
in AIDS patients, luminal gastrointestinal tract Demography. Spirochetosis is common in
involvement remains infrequent (82). Tuber- homosexual men, including those without
culosis may be diagnosed before or after the AIDS evidence of immunodeficiency. The infection
di~gnosis. Patients with both diagnoses tend to was present in 53.7 percent of rectal biopsy
be Haitian, black (other than Haitian), or Hispan- specimens from homosexual men attending
ic. AIDS patients with tuberculosis are younger a sexually transmitted disease clinic (88). Spi-
(median age at diagnosis of tuberculosis, 34 years rochetosis also affects a small percentage of
compared with 44 years) and are more likely to healthy heterosexual individuals.
be male than patients without AIDS. Etiology. A heterogeneous group of phe-
Pathophysiology. In immunocompetent notypically and genotypically distinct, non-
individuals, macrophages ingest the bacterium, treponema!, weakly beta-hemolytic, intestinal
and process and present mycobacterial antigens spirochetes cause diarrheal disease in humans.
to host T cells. Lymphokines secreted by CD4 Patients with symptomatic disease usually have
cells, the cell population that becomes selec- Se1pulini jonessii infection, whereas asymptom-
tively depleted in AIDS patients, enhance mac- atic persons are more likely to have Brachyspira
rophage capacity to ingest and kill the bacteria. alborgia infection (87). Se1pulini pilosicoli may
In AIDS patients, however, the CD4 depletion also be etiologically responsible for the infec-
makes them very susceptible to tuberculosis. tion (83,88).
Patients acquire the infection through reacti- Clinical Features. Spirochetes colonizing the
vation of latent tuberculosis or by developing intestines may be true pathogens or they may
a primary infection. Reactivation of latent tu- be enteric commensals that become opportu-
berculosis occurs secondary to defective T cell nistic pathogens when the local environment
and/or macrophage function (79). is altered by changes such as chronic stasis.
Clinical Features. Newly acquired tubercu- The bacteria can cause various gastrointestinal
lous infections in HIV-infected patients progress disturbances, including chronic diarrhea, rectal
rapidly to disseminated active disease (81). AIDS bleeding, constipation, purulent discharge, and
patients are more likely to have extrapulmonary abdominal and perianal pain (84). Some have
tuberculosis and a nonreactive tuberculin skin suggested that the clinical symptoms result from
test than are non-AIDS patients (80). Gastroin- an immune reaction elicited by the penetration
testinal infections result from swallowing the of the spirochetes into the mucosa rather than
organisms. Abdominal mycobacterial infec- from the bacteria themselves (84).
tions affect the intestine, peritoneum, liver, Gross Findings. Spirochetosis does not usu-
psoas muscles, and stomach. The pattern of ally produce any gross or endoscopic lesion.
bowel involvement parallels the distribution of The diagnosis is made by careful examination
lymphoid tissue so that the ileocecal and rectal of biopsy specimens.
areas are most commonly infected. The infec- Microscopic Findings. The colonic epithe-
tion is generally segmental, contrasting with lium and lamina propria usually appear normal,
the more diffuse involvement seen with MAC but the surface epithelium has a dense, blue
infections. Typical symptoms include weight luminal fringe measuring 2 to 3 pm in thick-
loss, fatigue, abdominal pain, and fever. Diar- ness (fig. 11-8) due to the presence of hundreds
rhea and hematochezia occur less commonly. of adherent spirochetes. The organisms stain
Laboratory findings include anemia and abnor- strongly with PAS and Warthin-Starry stains
mal liver function tests. Acid-fast stains of stool and weakly with Alcian blue (fig. 11-9). They
smears may be positive. The pathologic features also stain with Giemsa, Fontana-Masson, and
resemble those seen in patients without AIDS Dieterle silver stains. The rare patients with
(see chapter 10). endoscopic evidence of colitis may have ulcers,

553
Gastrointestinal Diseases

Figure 11-8
INTESTINAL SPIROCHETOSIS
Left: Low-power photomicrograph shOW!). relatively well-preserved colonic mucosal architecture. There is no significant
increase in inflammation within the lamina propria. A faint bluish fringe covers the luminal surface of the epithelial cells.
Right: High-power view of numerous adherent organisms aligned on the mucosal surface .

.r.,.

Figure 11-9
SPIROCHETOSIS
Left: The Warthin-Starry stain highlights the organisms attached to the surface of the epithelial cells.
Right: An immunohistochemical stain for spirochetes (Treponema pallidum) also confirms the presence of the organisms.

554
Gastrointestinal Diseases in Immunocompromised Patients

extensive superficial cell necrosis, and acute Pathophysiology. Immunocompromised


inflammation of the mucosa and lamina pro- individuals with decreased CD4 lymphocyte
pria. Bacteria can extend down into the crypts, counts (below 100/mL) tend to develop CMV
causing a conspicuous inflammatory response viremia, endothelial infections, endotheliolitis,
consisting of macrophages in the underlying submucosal ischemia, and secondary ulceration
lamina propria (85,86). (94,95). CMV-associated vasculitis in the gastro-
Special Studies. Ultrastructural examina- intestinal tract is especially well documented
tion discloses the presence of numerous thin, in the AIDS population, where it preferentially
spiral-shaped microorganisms attached to the involves the colon in up to 6 7 percent of CMV-
epithelial surface, situated between and paral- infected patients. The affected vessels, including
lel to the microvilli or parallel to the epithelial arteries and veins, undergo segmental necrosis,
surface. Intestinal spirochetes are differentiated perivascular hemorrhage, and thrombosis,
by the number and arrangement of periplasmic predisposing to secondary ischemia. CMV also
flagella, and the number of more axial filaments predisposes to bacterial or fungal infection by
linearly inserted somewhat subterminally at compromising mucosal barrier integrity.
each end. B. alborgia have four flagella (85); S. pi- Clinical Features. Adults typically acquire
losicoli have 8 to 12 periplasmic flagella per cell. CMV infection prior to alterations in their im-
Treatment and Prognosis. In some patients, mune status (91). In contrast, children acquire
treatment results in an improvement in symp- primary CMV infection either at the same time
toms; in others, therapy fails to induce any or after they become immunocomprornised (96).
changes. The organism can be eradicated with CMV-infected HIV-positive individuals exhibit
metronidazole, but symptoms often persist, two major types of problems: those related to
raising questions as to the relevance of the the CMV infection and those related to the HIV
organism with respect to symptom generation. infection. Some postulate that CMV acts as a
cofactor in the pathogenesis of AIDS. Indeed,
VIRAL INFECTIONS IN HIV-infected infants who acquire CMV infection
IMMUNOCOMPROMISED PATIENTS in the first 18 months of life have a significantly
higher rate of disease progression and central
Cytomegalovirus Infections
nervous system involvement than those infected
Demography. Enteric CMV infections are a by HIV alone (96). In infants, the CMV infection
well-recognized problem in immunodeficient appears to progress more rapidly than the HIV
patients and CMV is the most common viral infection, and more than half of the infants
pathogen identified in autopsied AIDS patients. born with CMV infection have an AIDS-defining
The presence of colonic or distal ileal CMV condition or die by 18 months of age.
infection usually signifies the presence of dis- CMV infections occur throughout the gastro-
seminated disease. The frequency of CMV colitis intestinal tract, from the esophagus to the anus
among AIDS patients is about 13 percent (97); (96), often showing the most serious complica-
however, recent data suggest that the incidence tions in the large bowel. The symptoms generally
of CMV reactivation in the AIDS population is depend on the location and severity of the infec-
decreasing in the era of HAART (98, 100). CMV tion and the immune status of the patient. The
infection is also common in transplant patients most common presentation is abdominal pain
and in those with primary immunodeficiencies. associated with chronic diarrhea. Other common
CMV may additionally infect patients with manifestations include odynophagia, dysphagia,
inflammatory bowel disease who are on immu- dyspepsia, nausea, vomiting, malabsorption,
nosuppressive or chronic steroid therapy. Most weight loss, gastrointestinal bleeding, protein-
cases of CMV infection in immunocompro- losing enteropathy, severe wasting, colitis, ulcers,
mised patients probably represent reactivation perforation, peritonitis, obstruction from the
of latent infection. Approximately 1 to 2 percent formation of inflammatory masses, and appen-
of newborns, 10 to 40 percent of children, and dicitis. Abdominal pain may be marked and
SO to 90 percent of adults in the general popula- rebound tenderness is often present, indicating
tion are seropositive for CMV (89,92). full-thickness involvement of the bowel wall.

555
Gastrointestinal Diseases

The clinical presentation of CMV esophagitis


differs from other viral and fungal infections in
that symptom onset occurs gradually. Painful,
difficult swallowing and retrosternal pain occur
less commonly than in herpetic esophagitis,
although odynophagia is almost uniformly
present.
Gross Findings. CMV can involve the entire
alimentary tract, usually producing multiple
mucosal erosions and ulcers.
Esophagus. Most typically, CMV esophagitis
affects the mid to distal esophagus as superficial
erosions with geographic, serpiginous, non-
raised borders. These vary in number, size, and
appearance. Because of their lack of endoscopic
uniformity, they are easily confused with other
ulcerating esophageal conditions. Most ulcers
measure less than 1 cm in greatest diameter but
giant ulcers are seen in 28 percent of patients.
Endoscopically, there is diffuse erosive disease,
deep linear ulcers, mucosal friability, erythema, Figure 11-10
and sometimes pseudotumoral masses. As the ENDOSCOPIC APPEARANCE OF
infection progresses, ulcers extend from 10 to 15 CYTOMEGALOVIRUS (CMV) COLITIS
cm in length. Complications include strictures, A large ulcer is present in the colon.
bacterial infection, and bronchoesophageal fis-
tulas (90). Patients become rapidly nutritionally
depleted as dysphagia and odynophagia compli- fuse erythema with submucosal hemorrhages,
cate their wasting disease. Biopsies must be taken to erosions and discreet deep ulceration (fig.
in order to determine the cause of the ulcer. 11-10). Superinfedions may be superimposed
Stomach. Gastric CMV usually produces an and toxic megacolon may occur, leading to
endoscopic appearance of nonspecific gastritis. perforation and peritonitis. Colectomy may be
Other gastric manifestations include thickened necessary and should not be withheld in situ-
and edematous mucosal folds, erosions, and ations of medically intractable disease. A CMV
ulcers. Mucosal biopsy is necessary to establish endotheliolitis may result in ischemia with
the diagnosis. Gastroparesis with recurrent resultant complicating thromboses.
vomiting may occur as a complication. Microscopic Findings. The histologic diag-
Intestines. Although any region of the gastr·oin- nosis of CMV in fixed tissues usually requires
testinal tract may be involved, the colon is most finding characteristic intranuclear or cytoplas-
commonly affected. CMV colitis reveals a spec- mic inclusions. Sampling error leads to a lack
trum of nonspecific changes, including ulcers, of sensitivity of the histologic examination, but
granularity, thumbprinting, a coarse mucosal when the virus is identified, histology has a high
pattern, edematous folds, and nodular defects degree of specificity. CMV infects epithelium,
often corresponding to pseudomembranes. CT endothelium, smooth muscle cells, fibroblasts,
"'·· scans may show a focally or diffusely thickened histiocytes, and ganglion cells. CMV-infected
colonic wall, a finding that correlates with his- cells appear enlarged (cytomegalic) and they of-
tologic evidence of submucosal inflammation. ten contain eosinophilic intranuclear inclusions
The cecum and right colon are more com- surrounded by a halo and granular basophilic
monly infected than the distal colon; the rec- cytoplasm (fig. 11-11). Nuclear and cytoplasmic
tum and sigmoid colon may also be involved. inclusions often coexist. Atypical inclusions
The endoscopic appearance of CMV colitis is may appear as irregular smudgy cells with
highly variable, ranging from normal to dif- basophilic nuclear enlargement and elongated

556
Gastrointestinal Diseases in Immunocompromised Patients

eosinophilic cytoplasm or cells containing small


granular cytoplasmic inclusions. Deep biopsies
may be necessary to detect stromal disease.
The intensity of the inflammation and
necrosis generated by CMV infection varies
widely. The pathologic changes range from
a relatively bland lesion to extensive acute
and chronic inflammation with widespread
necrosis and gastrointestinal perforation. The
accompanying inflammatory infiltrate consists
of lymphocytes, histiocytes, plasma cells, and
polymorphonuclear leukocytes. The number of
inclusions generally parallels the severity of the
inflammation, although occasional cases show Figure 11-11
numerous inclusions in the absence of signifi- CMV COLITIS
cant inflammation. Tissues examined from the A characteristic CMV inclusion-bearing cell lies in the
base of CMV-induced ulcers show acute inflam- lamina propria (center). The cell is large, and contains a
mation and granulation tissue. slightly eosinophilic nuclear inclusion surrounded by a
CMV may be difficult to demonstrate histo- clear halo.
logically. If CMV is suspected, numerous biopsies
should be taken in order not to miss the cyto- and the infection is very subtle. One may have
megalic or inclusion-bearing cells. Goodgame et to search for a long time to find characteristic
al. (95) obtained 8 to 10 biopsy specimens from inclusions. The lamina propria in either pat-
mucosal erosions and ulcers in AIDS patients tern may appear normocellular, hypercellular,
known to have CMV infection and found that or hypocellular.
often only one revealed cytomegalic inclusion- Intestines. Intestinal lesions also vary in their
bearing cells. Diagnostic cytologic brushings severity. Inclusion-bearing stromal (fig. 11-15)
exhibit characteristic cytomegaly, marginated or epithelial cells are associated with variable
chromatin, large basophilic intranuclear inclu- degrees of inflammation. Some intestinal lesions
sions surrounded by a clear halo, and granular exhibit severe CMV-related occlusive vasculitis.
eosinophilic intracytoplasmic inclusions. Cytomegalic inclusions occur within endothelial
Esophagus. The esophageal squamous epi- cells of medium-sized mteries and veins, as well
thelium virtually never becomes infected by as arterioles, venules, and capillaries. The affected
CMV. Rather, the virus affects the stromal cells endothelial cells appear enlarged, leading to
underlying ulcers (fig. 11-12). CMV inclusions partial or complete vascular occlusion with oc-
may sometimes be seen in the epithelial cells casional thrombus formation. A leukocytoclastic
of the esophageal submucosal glands (fig. 11- vasculitis and lymphoplasmacytic perivascular
13). Coexisting Candida or HSV infection may infiltrate develops, leading to lost vascular in-
complicate the histologic features . Perivascular tegrity with complete or segmental necrosis,
macrophage aggregates in the granulation tissue ischemia, intestinal ulceration, and perforation.
and exudates of esophageal ulcers can be found The vasculitis may be associated with exuberant
in CMV esophagitis. These lesions do not usu- fibroblastic reactions that are especially promi-
ally contain viral inclusions and immunostains nent in ulcer bases (99). Small blood vessels with
must be used to demonstrate the virus. endothelial cells containing cytomegalic inclu-
Stomach. There are two major patterns of sions lie among the fibroblasts. The surrounding
gastric involvement. One pattern consists of tissues show ischemic changes.
abundant CMV cytoplasmic and nuclear inclu- Special Techniques. The diagnosis of gas-
sion-bearing cells in the gastric glands (fig. 11- trointestinal CMV infection is best established
14) and stromal cells, including macrophages, by demonstrating viral cytopathic effects in
endothelial cells, and smooth muscle cells. The tissue specimens. Alternatively, immunohisto-
second pattern occurs with less severe disease chemical techniques can be used to detect viral

557
Gastrointestinal Diseases

Figure 11-12
CMV ESOPHAGITIS
A: Low-power photomicrograph of a large esophageal
ulcer from a patient with a previous history of radiation
therapy for lung carcinoma. The biopsy shows reactive-
appearing squamous epithelium and a fibrin thrombus in
an underlying vessel. The presence of such fibrin thrombi
should raise the possibility of CMV infection because of the
tendency of the virus to infect endothelial cells.
B: An enlarged endothelial cell highly suspicious for
CMV infection is in another vessel.
C: Higher-power view shows a more typical CMV
inclusion-containing cell within the stromal tissue.

--.... .,
..
.~

Figure 11-13 Figure 11-14


CMV INCLUSION CMV GASTRITIS IN AN AIDS PATIENT
Esophageal submucosal gland contains an epithelial cell Numerous inclusions are within the cells lining the
with a typical CMV inclusion . gastric glands.

558
Gastrointestinal Diseases in Immunocompromised Patients

.. _ · -~ - -~ .. . : ...:'f'"-:.. ~/~, f ' ~., :_..r ••. _..·


.-. }"'> ,,' '\ '.: ' :'(_;;::- .~~·· •.......- ...... ..:

, ,~ . .

Figure 11-15 Figure 11-16


CMV COLITIS IN SITU HYBRIDIZATION FOR CMV
An inclusion-bearing cell lies in the lamina propria . Numerous brown-staining nuclei are present in cells
within the base of an esophageal ulcer. This staining in-
dicates the presence of CMV viral DNA in the affected cells.
antigens in fixed tissue sections or cytologic
preparations (fig. 11-16). The virus may also be
detected using various DNA detection systems, apy to foscarnet. Cidofovir is the newest agent
including in situ hybridization, dot blot hybrid- that has similar efficacy rates as ganciclovir but
ization, or PCR on DNA extracted from paraffin has the advantage of having a longer half-life.
sections of small biopsies. CMV may be detected Each antiviral agent has unique toxicities, but
by direct viral isolation from clinical specimens in general, remission may be achieved in up to
via conventional tissue culture or rapid shell 90 percent of patients. The role of maintenance
viral culture systems, or by serologic methods therapy is currently being studied. Many CMV
used to detect CMV-specific immunoglobulin patients have other co-morbidities that adverse-
(Ig)G antibodies. Cultures for CMV are usually ly impact long-term survival. Relapse is com-
positive when inclusions are present, but they mon when therapy is discontinued and most
are less sensitive and specific than histopatho- patients require lifelong maintenance therapy.
logic identification (94).
Herpes Simplex Virus Infections
Differential Diagnosis. In the esophagus,
the clinical differential diagnosis includes HSV, Demography. Predisposing factors to HSV
varicella-zoster virus, and Candida infections. In infection in immunocompromised patients in-
the stomach, the infection may produce pseu- clude nasogastric intubation, steroid therapy,
dotumors that mimic neoplasia. Colonic CMV and anticancer therapies (102).
infections mimic numerous other pathologic Pathophysiology. In immunosuppressed
processes, especially idiopathic inflammatory patients, HSV infections are either a primary
bowel disease or ischemia. Violaceous CMV infection or result from reactivation of latent
lesions may resemble Kaposi's sarcoma, while infection when CD4-positive cells fall below 50/
white-yellow plaques and nodules suggest isch- mm 3 (101). AIDS patients may have esophagitis
emia or pseudomembranous colitis. due to either HSV type I or type II. In contrast,
Treatment and Prognosis. CMV infection non-HIV and immunocompetent patients are
can independently contribute to AIDS-related most commonly infected with HSV type I.
morbidity and mortality and can be an inde- Clinical Features. Most immunocom-
pendent predictor of death (93). Treatment with promised patients develop herpetic esophagitis.
foscarnet, acyclovir, or ganciclovir reverses many Proctocolitis and severe perianal ulceration
of the disease manifestations. Most patients re- with a prominent mucopurulent discharge oc-
spond to intravenous ganciclovir, using a 2- to cur, but are much less common. Odynophagia
3-week induction period. Partial responders may and chest pain affect the majority of patients
benefit from a repeat course or switching ther- with esophageal disease. Pain and tenesmus

559
Gastrointestinal Diseases

gitis is usually easy to recognize if a biopsy is


taken at the edge of the herpetic ulcer. Multi-
nucleated giant cells contain characteristically
molded nuclei and Cowdry type A intranuclear
inclusions (fig. 11-17) . The diagnosis rests on
identifying the characteristic epithelial viral in-
clusions. This may be difficult in AIDS patients,
in the absence of clear inclusions or multinucle-
ated giant cells. Instead, only large mononuclear
cell aggregates containing convoluted nuclei
lying adjacent to the infected epithelium may
be seen. The presence of macrophage aggregates
highly suggests the diagnosis. Occasionally,
there is histologic evidence of herpetic infection
in the ducts and acini of the submucosal glands
Figure 11-17
beneath the ulcer.
HERPES ESOPHAGITIS Special Techniques. Immunohistochemistry
This biopsy taken from the edge of an esophageal ulcer or in situ hybridization may be required to ei-
shows numerous herpes simplex virus (HSV)-infected ther confirm the nature of an inclusion that is
squamous epithelial cells . The nuclear inclusions are
glassy in appearance, and the chromatin is marginated to found or even to detect the presence of the virus
the periphery of the nucleus. Numerous giant cells have in the absence of characteristic inclusions. Viral
multiple, molded nuclei that contain typical inclusions. culture not only increases the diagnostic yield
on the tissues, but also distinguishes between
predominate in large intestinal disea.se. Sacral viral infections with overlapping histologic and
nerve involvement is accompanied by urinary cytologic features.
bladder problems. Differential Diagnosis. The dffferential
Gross Findings. Esophageal involvement diagnosis of HSV includes other viral or fungal
develops in approximately 90 percent of pa- infections, particularly in the esophagus. It also
tients with visceral HSV infection. The middle includes idiopathic esophageal ulcers or disease
and distal thirds of the esophagus are the most related to reflux esophagitis. In the large intes-
commonly affected areas. Mucosa-l involvement tine, the differential diagnosis usually involves
begins as bullous lesions with central umbili- other infectious diseases. The appropriate diag-
cated areas and a pale yellow peripheral rim. nosis can be established by finding characteristic
Rupture gives rise to a multiple, sharply defined, inclusions or with the use of special stains or
punched-out, linear ulcers with elevated mar- genetic probes.
gins and a hemorrhagic base. The ulcers may Treatment. Acyclovir is the treatment of
develop an overlying pseudomembrane. The choice, administered orally for 2 to 3 weeks or
intervening mucosa often appears normal un- intravenously for 7 days. Long-term treatment
less the patients hav~ concomitant Candida or may be necessary for recurrences. Foscarnet may
CMV infection. Large areas of denuded mucosa also be used but resistance is common following
develop in severe disease. Herpetic ulcers usually repeated viral exposure.
stop at the gastroesophageal junction. Hemor-
Other Viral Infections
rhage, stenosis, and fistulas may occur. The pres-
•.· ence of preexisting damage by other causes like A number of other viruses including Nmwalk
gastroesophageal reflux or drug-induced injury virus, astrovirus, and picornavirus (103) have been
may obscure the classic pathologic features of identified in both symptomatic and asymptom-
the viral infection. atic AIDS patients. Their overall contribution to
Microscopic Findings. HSV predominantly diarrheal disease is small (104).
infects squamous epithelium. It causes erosions Adenovirus infection, although uncommon,
that coalesce to produce ulcers surrounded by can be overlooked due to the subtle associated
dense inflammatory exudates. Herpetic esopha- morphologic changes . Adenovirus affects the

560
Gastrointestinal Diseases in Immunocompromised Patients

stomach, small intestine, and colon (107,110). Clinical Features. Upper gastrointestinal
Occasional cases of hemorrhagic colitis due to symptoms include abdominal pain, upper gas-
adenovirus infection have been described (106). trointestinal bleeding, or refractory nausea and
The adenovirus-infected epithelial cells appear vomiting. Dysphagia and odynophagia cause
amphophilic because of the presence of intra- significant discomfort and represent a major
nuclear inclusions that vary in shape and size cause of weight loss in infected patients. The
(see chapter 10). These intranuclear inclusions infection is associated with weakness, fatigue,
are often overlooked or are mistaken for those and a diminished quality of life; patients may
of CMV (108). Adenovirus is usually seen only also remain asymptomatic.
in mucosal cells, especially goblet cells, sparing The clinical presentation of intestinal candi-
cells of the lamina propria, such as endothelial diasis consists of watery, sometimes explosive
cells and smooth muscle cells, which are fre- diarrhea, occasional cramps, mild diffuse ab-
quent targets of CMV. The virus can be detected dominal tenderness, and weight loss. Candida
by in situ hybridization, electron microscopy, colitis consists of multiple, variably sized ulcers
or culture of inflamed colonic tissue (1 OS, 109). with heaped-up edges and necrotic bases distrib-
uted throughout the colon, grossly resembling
FUNGAL INFECTIONS IN CMV infections (112).
IMMUNOCOMPROMISED PATIENTS Gross Findings. The endoscopic appearance
of esophageal candidiasis is characteristic and
Candida Infections
consists of multiple creamy yellow plaques, of-
Demography. The most common opportunis- ten in a longitudinal arrangement. Plaques may
tic disease in HIV-infected individuals is Candida also be diffuse. Mucosal friability and erosive
esophagitis, a disease that represents an AIDS- disease underlie the plaque. Esophageal candi-
defining illness. Candida infection affects up to diasis may involve the entire esophagus; more
90 percent of AIDS patients (113) . Patients with often it remains localized to the distal region.
low CD4 counts and a low CD4 to COS ratio are With increasing severity, scattered mucosal
most likely to develop candidiasis. Disease preva- plaques coalesce, resulting in circumferential
lence va1ies considerably among various high-risk disease and luminal impingement. Complica-
groups, and is particularly high among blacks (80 tions such as strictures and fistulas may develop.
percent) (113). Candida gastritis and enteritis are Microscopic Findings . The diagnosis is
less common than esophageal disease, presumably usually made by demonstrating the organism
because neutrophil function usually remains intact in smears, cytologic preparations, or biopsies.
in AIDS patients, thereby effectively preventing Some believe that brushings are preferable
widespread fungal dissemination. to biopsies to confirm a diagnosis that is fre-
Oral thrush often predicts concurrent quently endoscopically obvious (111) . Micro-
esophageal involvement, with a positive and scopically, characteristic budding yeasts and
negative predictive value of 90 and 82 percent, pseudohyphae, associated with varying degrees
respectively (114). of inflammation, are seen (fig. 11-18). The
Candidiasis also affects patients on antibiot- grossly visible plaques consist of desquamated,
ics, hemodialysis, and chemotherapy; trans- superficial, hyperplastic, and hyperkeratotic
plant patients; and immunocompetent patients squamous epithelium; inflammatory cells; fun-
with serious postoperative complications, can- gi; and bacteria. Surface colonization typically
cer, severely debilitating diseases, penetrating consists of yeast on intact mucosal surfaces or
abdominal trauma, or with indwelling vascular confined to the necrotic tissue. It is rare to see
access devices. fungus invade underlying tissues. If invasion
Etiology. Although most cases of Candida is present, however, it is important to transmit
esophagitis result from Candida albicans organ- this information to the clinician. Penetration of
isms, other fungi, such as C. tropicalis and C. hyphal-like elements into the underlying tissues
glabrata also cause disease. The pathophysiology characterizes invasive disease.
of Candida infection is discussed in more detail Treatment and Prognosis. Given the high
in chapter 10. frequency of Candida esophagitis in patients with

561
Gastrointestinal Diseases

Figure 11-18
CANDIDA ESOPHAGITIS
Left: Hematoxylin and eosin (H&E)-stained section of an esophageal biopsy demonstrates keratin, desquamated squamous
epithelial cells, and admixed fungal organisms.
Right: The yeast and pseudohyphal forms are easily seen on a Grocott methenamine silver-stained section.

AIDS, the current recommendation is to treat mesoappendix, abdominal lymph nodes, dia-
new-onset esophageal symptoms empirically phragm, pancreas, and thyroid gland (116, 117).
with oral fluconazole for 2 weeks. Fluconazole Gross Findings. Small intestinal changes
taken prophylactically reduces the frequency of consist of large patches of necrosis af{~cting the
esophageal candidiasis, especially in those with serosal side of the bowel wall. The correspond-
50 or fewer CD4-positive lymphocytes/mm 3 . ing mucosal surface appears normal. Mesenteric
The drug does not reduce overall mortality. lymph nodes are enlarged, with areas of soft
caseous necrosis.
Histoplasmosis
Microscopic Findings. There is widespread
In advanced HIV disease, a CD4 count below mucosal destruction by foamy histiocytes con-
200/mm3 predisposes patients to disseminated taining organisms similar to those seen in the
histoplasmosis. Histoplasmosis is discussed pulmonary alveoli. The lesions appear eosino-
further in chapter 10. philic and acellular on stained slides. Numerous
P. carinii cysts are evident within histiocytes in
Other Fungal Infections
Giemsa- or Grocott-stained sections. The en-
Fungal infection due to Penicillium marnef- larged, lymphoid-depleted mesenteric lymph
fei has been reported as a cause of colitis and nodes show paracortical angiomatous transfor-
chronic diarrhea in AIDS patients in Southeast mation and contain necrotic areas surrounded
Asia (115). Coccidioidomycosis and oyptococcal by eosinophilic material. The eosinophilic mate-
infection of the gut are rare and usually occur rial consists of masses of P carinii trophozoites
in the context of systemic disease. These organ- and cysts. Vacuolated macrophages, foreign
isms more frequently involve the liver than the body giant cells, small numbers of neutrophils,
•.·
luminal gastrointestinal tract. and fibroblastic proliferations surround the
necrotic foci.
DISSEMINATED PNEUMOCYST/5 Differential Diagnosis. The differential diag-
CAR/NI/ INFECTION nosis includes all lesions associated with diffuse
Demography. Disseminated Pneumocystis histiocytic lamina propria infiltrates.
carinii infection affects AIDS patients. Treatment. The recommended treatment for
Clinical Features. Disseminated infections extrapulmonary infection is intravenous tri-
involve the lungs, stomach, jejunum, ileum, methoprim-sulfamethoxazole or pentamidine.

562
Gastrointestinal Diseases in Immunocompromised Patients

Figure 11-19
GASTRIC CRYPTOSPOR/0 /UM INFECTION
Left: The lamina propria of the stomach shows patchy acute inflammation.
Right: High-power microscopy delineates numerous bluish organisms adhering to the apical surface of the epithelial cells.

PARASITIC INFECTIONS IN Since AIDS patients with CD4 counts under


IMMUNOCOMPROMISED PATIENTS 180/mm3 cannot clear the organism, the infec-
tion often persists throughout the patient's life,
Cryptosporidium Infections
manifesting as chronic illness with exacerba-
Demography. Oyptosporidium parvum, a coc- tions and remissions. Gastroduodenal involve-
cidial organism, causes diarrhea in 3 to 11 per- ment may produce partial gastric outlet obstruc-
cent of AIDS patients in the United States and tion. Patients with only a colonic infection tend
in 40 to SS percent of AIDS patients in develop- to have less severe symptoms. Patients with CD4
ing countries (122a). It is the most frequently counts over 180/mm3 often experience sponta-
encountered protozoan parasite among AIDS neous resolution within a few weeks.
patients. HIV-positive patients with self-limited Gross Findings. Radiologically, the muco-
infections have significantly higher CD4 counts sal folds in the proximal small intestine are
than patients with persistent infections (123, thickened and blunted, and occasionally, the
124). The latter frequently have CD4 counts gastric antrum is thick and contracted (121).
measuring less than 100 cells/mm 3 , usually Endoscopically, the mucosa is generally well
even less than SO cells/mm 3 • Oyptosporidium preserved and the diagnosis is made by exami-
also infects immunocompetent patients, and nation of the biopsy specimen.
is discussed in detail in chapter 10. Microscopic Findings. Cryptosporidia in-
Clinical Features. The clinical features of volve the esophagus, stomach, bile ducts, and
cryptosporidiosis in immunocompromised pa- intestines. The sensitivity of endoscopic mu-
tients differ depending on where the organisms cosal biopsy in detecting the organism varies
are located. Patients with infection in the proxi- by anatomic location as follows: stomach, 11
mal small intestine typically have mild diarrhea percent; duodenum, 53 percent; terminal ileum,
that progresses to voluminous, debilitating, wa- 91 percent; and colon, 60 percent (127). The
tery diarrhea associated with dehydration, mal- presence of gastroesophageal infection usually
absorption, and profound weight loss. Secondary reflects concomitant intestinal involvement.
malabsorption often occurs and is related to de- The diagnosis of cryptosporidial infection
creased absorptive surface area in heavily infested requires close scrutiny of all epithelial surfaces,
individuals. The chronic, relentless diarrhea lasts including those in the lumens of intestinal or
for months and is accompanied by vomiting, gastric glands for the presence of the character-
anorexia, cramps, and abdominal pain. istic organisms (fig. 11-19). The latter appear as

563
Gastrointestinal Diseases

Figure 11-20
SMALL INTESTINAL CRYPTOSPORIDIOSIS
A: Low-power view shows mild villous blunting. The
epithelium appears regenerative.
B: The inflammation is acute and chronic.
C: The apical surfaces of many epithelial cells are
covered with round, faintly bluish-staining Cryptospor-idium
organisms.

clusters of spherical or oval bluisb..,bodies, mea- In tissue sections, cryptosporidia stain deep blue
suring 2 to 4 pm in diameter, attached to the with H&E, Giemsa, and Gram stains; positively
epithelial surfaces (fig. 11-20). In the esophagus, with PAS stains; and negatively with the Gomori
the organisms are attached to the superficial methenamine silver (GMS) stain. A fluorescein-
squamous mucosa and the luminal borders of labeled IgG monoclonal antibody to the wall of
the submucosal glands and ducts. All stages of cryptospmidial oocysts is very sensitive (126) and
cryptosporidia can be found at all levels of the can detect small numbers of organisms in tissue
gastrointestinal tract. sections or gastrointestinal brushings.
Low intensity infections have a normal his- Special Techniques. The diagnosis of cryp-
tology, whereas high ihtensity infections show tosporidiosis is most reliably made by detec-
severe inflammation and varying degrees of tion of oocysts in stool specimens. The 5-pm
villous atrophy (including complete villous flat- acid-fast oocysts are found in concentrated
tening with crypt hyperplasia) (122) and mild to fresh stool specimens examined by modified
... moderate chronic inflammatory cell infiltrates Ziehl-Neelsen, Kinyoun, auramine-phenol,
(fig. 11-20). Focal cryptitis, crypt abscesses, gland or safranin-methylene blue staining methods
dilatation, and crypt rupture also occur. There (118-120) . Individual stool samples are insensi-
may be associated intraepitheliallymphocytosis. tive for diagnosis, since only 53 percent demon-
Eosinophils and prominent neutrophilic infil- strate the organism; in contrast, when multiple
trates may be present. Since cryptosporidiosis is stool samples are evaluated from a patient, 73
commonly associated with other bowel pathogens, percent of patients demonstrate C. parvum in
the intensity of the inflammation reflects the en- at least one stool sample. Immunofluorescent
tire spectrum of organisms that are present. detection methods have greater sensitivity and

564
Gastrointestinal Diseases in Immunocompromised Patients

specificity than conventional staining methods it can spread to the stomach, esophagus, biliary
(120). Enzyme immunoassay kits allow simple, tree, and large intestine; only rarely does it dis-
rapid, and less subjective ways of detecting seminate to extraintestinallymph nodes (131),
cryptosporidia in fecal samples submitted to liver, or spleen.
busy diagnostic laboratories (125). The life cycle involves a sexual (gametocytes)
Differential Diagnosis. Cryptosporidia can and asexual (trophozoites) phase. During the
be easily overlooked or mistaken for mucus schizogonous (asexual) phase, each trophozoite
droplets or cellular debris. They can be dif- divides into numerous merozoites which, when
ferentiated from mucin by the Giemsa stain released from parasitized cells, invade other
combined with the Alcian blue, neutral red, or epithelial cells. Each merozoite may then pass
mucicarmine stain. Cryptosporidia are mucicar- through one or more repetitive cycles of asex-
mine negative. Cyclospora cayetanensis produces ual division or proceed to the sexual phase by
an unsporulated oocyst that occurs in feces maturing into macrogametes (female) and mi-
and resembles Clyptosporidium. The oocyst of crogametes (male). Zygotes, resulting from the
Cyclospora is larger, however, typically measur- fertilization of the gametes, mature into oocysts.
ing 8 to 10 pm in diameter. Ultrastructurally, These are released into the bowel lumen, pass-
Cyclospora organisms develop within a vacuole ing into stool where they undergo sporulation.
at the luminal end of the enterocyte cytoplasm Released trophozoites parasitize downstream
rather than in the brush border, as is seen with enterocytes, reinitiating the reproductive cycle.
Clyptospmidium. The features of Cyclospora infec- All stages of both asexual (trophozoite, schizont,
tion are discussed in detail in chapter 10. and merozoite) and sexual (macrogametocyte)
Treatment. To date, there is no effective phases of the parasitic life cycle occur within the
therapy for cryptosporidiosis. The agent that epithelial cytoplasm, always enclosed within a
has shown most efficacy is paromomycin, an parasitophorous vacuole. The nonsporulated
oral aminoglycoside (128). Some have reported (immature) oocytes excreted in stool mature
resolution of cryptosporidial infections with into infective mature oocysts within 48 to 72
spiramycin (123a), bovine colostrum (127), so- hours. They can also remain dormant for long
matostatin (119), zidovudine, and other agents. periods of time. Isospora organisms do not
Although not pathogen specific, the most effec- sporulate until they are passed from the host
tive therapy for cryptosporidiosis in HIV-positive and are exposed to oxygen and temperatures
patients is HAART. Correction of the dehydration below body temperature.
and electrolyte imbalance may require hospi- Clinical Features. The symptoms produced
talization for intravenous replacement. Most by Isospora resemble those seen in crypto-
patients are able to continue with a good qual- sporidial infections but the distinction between
ity of life on conventional antidiarrheal agents. the two infections is important, since Isospora
infections are easily treated by appropriate an-
Isospora Belli Infections
tibiotic therapy. The infection usually remains
Demography. Most Isospora belli infections confined to the small intestine. The immuno-
affect patients in tropical and subtropical coun- competent host presents with watery diarrhea
tries, particularly in Africa and South America. lasting 3 to 5 weeks (130,132); diarrhea in AIDS
They account for diarrhea in 15 percent of AIDS patients may last for months. Patients experi-
patients in Haiti and 0.2 percent in the United ence weight loss, severe colicky abdominal
States. The organism spreads by ingestion of pain, anorexia, malaise, nausea, vomiting,
contaminated food or water or via homosexual steatorrhea, and wasting. About 50 percent of
transmission. patients develop peripheral eosinophilia. Fat
Etiology. I. belli infections follow the inges- malabsorption, vitamin B12 deficiency, and
tion of infective sporulated oocysts. These ex- lactose intolerance can occur.
cyst in the proximal small intestine, releasing Microscopic Findings. Isospora organisms
eight sporozoites that invade epithelial cells lie within small intestinal villous enterocytes,
where they become trophozoites. Although the or less commonly, in the colonic mucosa. They
organism preferentially infects the small bowel, cause moderate mucosal villous atrophy, crypt

565
Gastrointestinal Diseases

hyperplasia, and lamina propria inflammation oocyst is considerably larger (2S to 30 pm in


by lymphocytes, plasma cells, polymorpho- length) than Cryptosporidium (4 to S pm), with
nuclear leukocytes, and eosinophils. Eosino- a thin wall enveloping two large sporoblasts or
phils may be so prominent that a diagnosis of a single large zygote (an immature oocyst) when
eosinophilic enteritis is suggested. The flattened shed in the feces. The oocyst of Cyclospora, also
mucosa may show clubbed tips, marked dilata- in the differential diagnosis, measures 8 to 10
tion of the vascular spaces, and excessive lamina pm in length.
propria collagen deposits. The epithelium gen- Treatment. The most effective antimicrobial
erally appears well preserved except for focal agents for I. belli are trimethoprim-sulfameth-
vacuolization. Close epithelial examination oxazole and ciprofloxacin. The infection recurs
usually discloses intracellular organisms in dif- in as many as SO percent of patients, however,
ferent stages of the sexual and asexual life cycles. requiring repeated and sometimes long-term
The organisms are difficult to see on routine suppressive therapy (129). Pyrimethamine has
H&E-stained sections, but Giemsa staining also been recommended.
highlights them. The organisms stain faintly
Microsporidium Infections
with H&E, dark blue with Giemsa or H&E plus
Alcian blue, and red with PAS stains. The large Demography. Miaosporidia have an extensive
schizont stage is best seen in over-stained Gi- host range, including most invertebrates and all
emsa preparations. classes of vertebrates. Most animals acquire the
As parasitized cells are destroyed, the adjacent infection through ingestion. Microsporidia are
cells remain intact and appear normal. Occa- primarily waterborne, but foodborne disease also
sional extracellular merozoites may be seen in occurs. Microsporidiosis predominantly, but not
the intestinal lumen and in the lamina propria exclusively, affects severely immunodepressed
near or within lymphatic vessels. Rare schiz- persons with AIDS. In fact, Microsporidium species
onts are present in the lamina propria and the has emerged as one of the most common intes-
submucosa. Mesenteric lymph nodes may also tinal infections in persons with AIDS', varying
become involved. The merozoite has a banana from 1S to 39 percent (141,143, 148,1S7,1S9).
shape and is seen at all levels in the enterocyte Patients with microsporidial infections are usu-
cytoplasm. The central nucleus, large nucleolus, ally homosexual with a history of foreign travel
perinuclear halo, and location within a thick or residence in tropical regions. The prevalence
parasitophorous (PAS-negative) -vacuole give of Enterocytozoon bieneusi infection ranges from
the merozoite a characteristic appearance. Free 10 to SO percent in AIDS patients with unex-
merozoites and gametocytes are more difficult plained diarrhea and no other known pathogens
to detect than intracellular organisms. (134,147,1S2). The organism infects both adults
Special Techniques. Patients with isospor- and children. Infected individuals tend to have
iasis intermittently shed oocysts, so that mul- profound immunosuppression with less than
tiple stool specimens should be examined to in- 100 CD4-positive cells/mL.
crease the likelihood of detecting the organism. Etiology. Microsporidia constitute a separate
The oocysts are cono:~ntrated from fresh stool phylum of ubiquitous, spore-forming, obligate
samples by sucrose flotation and highlighted by intracellular protozoans that cause a wide range
the Kinyoun acid-fast stain. Fecal specimens are of diseases, including enteritis. They are ancient,
best examined after 1 to 2 days at room tem- intracellular, eukaryotic spore-forming protozo-
perature, allowing oocysts to mature. ans that lack mitochondria. Distinctive features
Ultrastructurally, unizoite tissue cysts occur of the phylum Microspora include: 1) a lack of
with a single organism in a parasitophorous mitochondria; 2) a merogonic and sporogonic
vacuole. The zoite lies within a multilayered life cycle that gives rise to generations of spo-
wall. The middle of the parasite has a well- roblasts which become mature spores; and 3)
defined nucleus and the posterior part contains spores with a coiled polar filament; the number
a crystalloid body. of coils is unique to each species (134). Many
Differential Diagnosis. The differential diag- microsporidial species infect humans, predomi-
nosis includes cryptosporidiosis, but the Isospora nantly AIDS patients, including Enterocytozoon

S66
Gastrointestinal Diseases in Immunocomprom ised Patients

bieneusi, Enterocytozoon, Nosema, Pleistophora, x 1.5 pm that replicates by binary fission . The
Microsporidium bieneusi, and the encephalito- nuclear division sometimes outstrips cytoplasmic
zoons, Encephalitozoon hellem, E. cuniculi, and division, leading to binucleate and tetranucleate
E. intestinalis, formerly Septata intestinalis forms. As a result, organisms aggregate within a
(153,154) . Of these genera, only Enterocytozoon vacuole in the host cell cytoplasm. The second
and Encephalitozoon intestinalis infect the gut. E. stage, the sporont, divides by binary fission, each
bieneusi is the most frequently identified micro- producing two or four sporoblasts (135) . Sporo-
sporidian. Three distinct genotypic forms of E. blasts are uninucleate organisms that develop a
bieneusi infect humans. E. intestinalis probably polar tube and as these mature, these organelles
only accounts for 10 to 20 percent of cases of become more conspicuous. Transformation to
intestinal microsporidiosis (139) and is the sec- the final or fourth stage of the spore is marked
ond most prevalent microsporidian infection by the development of a thick coat. The spores
reported in AIDS patients (138). measure approximately 2.0 x 1.2 pm and con-
Two phases of the life cycle of E. bieneusi are tain a single nucleus and a polar tube, as well as
identified ultrastructurally: 1) a proliferative some other organelles. They infect target cells by
phase (merogony) and 2) a spore-forming phase sticking to the cell membrane by means of the
(sporogony) . During the proliferative phase, anterior attachment organ and injecting sporo-
the organisms appear as small, electron-lucent, blasts into the host cell via the polar tube. This
round objects containing 1 to 6 nuclei. The is followed by merogony.
spore-forming phase begins with the presence Clin ical Features. Clinically, microspori-
of stacks of electron-dense discs that later ag- diosis in HIV patients is indistinguishable from
gregate end-to-end to form the curved profiles cryptosporidiosis, although the symptoms are
of polar tubes. The nuclei continue to divide, usually milder in the former. The diverse clini-
resulting in larger organisms with up to 12 nuclei cal manifestations of microsporidiosis include
surrounded by several coils of the polar tube. intestinal, biliary, pulmonary, ocular, muscular,
These large multinucleated forms break up into and renal disease, depending on the infecting
sporoblasts (immature spores) that then develop organism (143,151). E. bieneusi tends to remain
into mature spores. The mature spores are very localized to the gastrointestinal tract, spreading
electron dense, have a single nucleus, and possess from the small intestine to contiguous intralumi-
an exceptional tubular extrusion apparatus for nal structures such as the biliary tract, the colon,
injecting spore contents, termed "sporoplasm," the pancreatic duct, and the upper respiratory
into host cells. The extrusion apparatus consists tract (149). E. hellem and E. intestinalis behave
of several coils of polar tube, an anchoring tube, more like classic mammalian microsporidia. E.
and a polarplast. Each spore also contains a poste- cuniculi, E. hellem, and E. intestinalis not only
rior polar vacuole, and a polar filament with 5 to spread contiguously, but infect macrophages and
7 overlapping coils of the polar tubules, which disseminate from their points of entry to the
appear in cross section as a series of doublets. respiratory tract and other organs (150).
Spores are infective when released in the Primary E. bieneusi infections preferentially
feces. Intracellularly, spores differentiate into involve the proximal small intestine. The cardi-
trophozoites that undergo asexual multiplica- nal feature is persistent diarrhea with increased
tion to form merozoites. The merozoites invade fecal volumes of up to several liters/24 hours.
new host cells and certain types develop into The chronic diarrhea (lasting up to 30 months)
male and female microgametes. Fertilization causes severe wasting (134) and fluid and elec-
produces oocysts that are either excreted or trolyte imbalance.
produce sporozoites in situ to repeat the cycle. E. intestinalis causes similar gastrointestinal
E. intestinalis has a life cycle with four stages: disease but it is also associated with systemic dis-
meront, sporont, sporoblast, and spore. Like E. ease (134). The initial symptoms usually localize
bieneusi, the spores contain a polar tube that to the gastrointestinal tract, but the organisms
injects membrane-bound sporoplasm into unin- disseminate to bronchi, renal tubules, and nasal
fected host cells. The earliest stage, the meront, epithelium (151), leading to renal failure and
is an ovoid, uninucleate organism measuring 2. 7 rhinosinusitis (142).

567
Gastrointestinal Diseases

Figure 11-21
MICROSPORIDIOSIS
Left: Low-power view of a duodenal biopsy specimen from an AIDS patient with microsporidiosis. The normal villous
architecture is distorted, and the crypts appear hyperplastic.
Right: Higher-power view of the duodenal epithelium shows minimal changes on a routine H&E-stained section.

Gross Findings. Endoscopically, 2atients with tion of the parasite in the lining epithelium
microsporidial infections usually lac~ discrete ul- of the duodenal mucosa, although massive
cers or masses, but the villi often appear abnormal infestations also occur (fig. 11-21). The most
under the dissecting microscope. Exceptionally, typical changes include villous atrophy, crypt
the infection may cause severe ulcerating disease, hyperplasia, enterocyte pleomorphism, and
and even lead to perforation (155). intraepithelial lymphocytosis. Neutrophils
Microscopic Findings. E. bieneusi occurs are not typically present. Increased numbers
throughout the length of the small intestine. of macrophages or plasma cells are present in
E. intestinalis infects both the small and large the lamina propria. The enterocytes become
intestines (139,151). Microsporidial infections increasingly abnormal as the villi shorten and
can be diagnosed by identifying .spores in the become broader and more irregular. Infected
stool, by small bowel biopsy, by microscopy cells have irregular hyperchromatic nuclei,
of intestinal aspirates, and by examination of vacuolated cytoplasm, and irregular outlines.
touch preparations of mucosal brushings (158). The tips of the villi appear progressively more
The intracellular organisms have a pale blue disorganized, with aggregates of crowded cells
cytoplasm and irregularly shaped, supranuclear that pile up, degenerate, and become necrotic.
eosinophilic nuclei that indent the nucleus in In heavier infections, disorganized aggregates
Giemsa-stained preparations (153,154). The lack of crowded, irregularly shaped, degenerating
of contrast between the organisms and host cell necrotic cells that often contain organisms and
cytoplasm makes it difficult to appreciate their spores affect the villus tips, which eventually
presence. Stool examination for microsporidial slough into the lumen. Since the organisms are
spores using the modified chromophobe stain more frequently found in degenerating cells
is the simplest method, and perhaps the most than in intact ones, it is useful to examine the
sensitive method, for diagnosing the intestinal detached and degenerating surface epithelium

infection (154). as well as intact tissue fragments. Individual
The histopathologic features of intestinal enterocytes may contain multiple stages of the
microsporidiosis parallel the parasite burden and E. intestinalis life cycle (154).
consist of a spectrum of degenerative changes. The clustered, dark, refractile, oval spores
Characteristically, the parasitic burden and measure approximately 0.7 to 1.0 pm in width
histopathologic changes of E. bieneusi affect and 1.0 to 1.6 pm in length, and are less frequent
the villus tip; E. intestinalis may also infect the than the parasite. They lie in a supranuclear
deeper crypt. Typically, there is a focal distribu- location, and are surrounded by an inner unit

568
Gastrointestinal Diseases in Immunocompromised Patients

Table 11-4
COMPARISON OF MICROSPORIDIA
Appearance in Size
Organism Polar Tubes Enterocytes Infection (Diameter) Treatment
E. bieneusi Double coil Organism free in Restricted to gut; only 1-2 pm No specifically effec-
cell cytoplasm infects epithelium tive treatment
E. intestinalis Single coil Organism encased Disseminates widely; 1.2-2.5 pm Albendazole
in parasitophor- infects epithelium,
ous vesicles fibroblasts, macrophages,
endothelial cells

membrane, an electron-lucent endospore, and Evaluation of urinary sediment may aid in


a thin electron-dense exospore. Spores are often the diagnosis of disseminated E. intestinalis.
seen in degenerating enterocytes. The use of fluorescent stains is a sensitive and
Microsporidia are often missed, even on rapid method for detecting microsporidia
careful examination, and even by experienced spores in stool and intestinal fluid, biopsy im-
pathologists, because of their small size, in- prints, tissue specimens, and archival material
tracellular location, and poor staining with (137). Encephalitozoon organisms may also be
usual tissue stains. Therefore, visualization of diagnosed using an antibody for a panspecific
the parasite is best accomplished by staining antiexosporum (140). The immunologically
methods that enhance the contrast between based assays may be fraught with serologic cross
the very small microsporidial spores and other reactivity between microsporidian species (139).
cellular contents and background debris. Stains PCR evaluation of stool provides a powerful tool
that are helpful in this regard include acid-fast, for the specific diagnosis in epidemiologic inves-
Giemsa, Brown-Hopp, PAS, and methenamine tigations of enteric microsporidial infections. A
silver stains. Spores are more easily seen as re- 12/65 base-pair fragment of the small subunit
fractile objects when the microscope condenser ribosomal RNA (RRS) gene can be amplified in
is lowered or removed. patients infected with E. bieneusi. A 930 base-
Schwarz (154) recommends identification pair fragment of the RRS gene can be amplified
of the microsporidia to the level of the genus, from patients infected with E. intestinalis (144).
since Encephalitozoon has the propensity to The organism may also be identified by in situ
disseminate, whereas Enterocytozoon does not. hybridization (156).
Furthermore, they each exhibit different drug Treatment. Effective therapy for micro-
sensitivities (Table 11-4) (139,151). sporidia has not been fully defined. Symp-
Special Techniques. Microsporidia can be tomatic improvement has been shown with
identified to the level of species by electron mi- metronidazole and atovaquone. Albendazole is
croscopy, indirect immunofluorescence (133), effective for E. intestinal is but not for E. bieneusi
and Western blot and genetic analyses. The (139). Like cryptosporidiosis, institution of
best way to classify microsporidia, however, is HAART in HIV-infected individuals may result
by ultrastructural examination. The diagnosis in resolution of diarrhea and loss of the patho-
is based on the · ultrastructural features of the gen from stool and small bowel biopsies (136).
spores in the proliferative forms, the method of Left untreated, small bowel infection can lead
division, and the nature of the host cell-parasite to perforation and peritonitis (155). Octreotide
interface. E. bieneusi is uniquely characterized by can control the diarrhea.
its development up through late sporogony as
Toxoplasmosis
large, multinucleated plasmodia that maintain
intimate contact with the cell cytoplasm (145). Demography. Toxoplasma gondii most fre-
Development of polar filaments or tubules from quently affects patients with AIDS, although
discs derived from clear cleft-like structures also those who have lymphomas, have received
represent a unique feature (fig. 11-22) (146). transplants, or have chronic inflammatory

569
Gastrointestinal Diseases

Figure 11-22
MICROSPORIDIOSIS
A: Thick epon-embedded, toluidine 1Jn1e-stained section of the biopsy shown in figure 11-21. Numerous dark-staining
microorganisms lie within the supranuclear cytoplasm of many of the enterocytes .
B: Transmission electron micrograph shows the organisms more clearly within the enterocyte cytoplasm .
C: A typical coiled polar filament is identifiable in some of th e organisms, a diagnostic feature of microsporidia.

diseases of the connective tissues are also af- cysts from contaminated soil or undercooked
fected by this pathogen. meat from infected animals. Oocysts excyst
Pathophysiology. T. gondii is an obligate, in- in the duodenum, releasing sporozoites that
tracellular coccidian protozoan that frequently invade the intestinal tissues. Within the tissues,
infects birds and mammals, including humans. T. gondii exists in two forms. Tachyzoites infect
Infection is usually asymptomatic in normal many different cell types. They multiply within
human hosts, but in immunodeficient individu- infected cells, eventually destroying them.
als frequently results in symptomatic ocular, Bradyzoites arise as the host begins to develop
... central nervous system, or pulmonary disease. an immune reaction to the infection. This T.
Gastrointestinal manifestations of toxoplasmo- gondii form preferentially infects muscle and
sis occur but are infrequent. nervous tissue. The cysts containing bradyzoites
T. gondii most commonly infects cats, the may remain in the host in a latent state, only
host in which they undergo the sexual repro- to be reactivated at a later time when the host's
ductive phase of their life cycle. Oocysts are immune system becomes impaired.
formed in the intestinal mucosa and passed into Clinical Features. Most immunocompetent
the environment in the feces. Human infection persons with acute Toxoplasm a infection are
occurs as a result of ingestion of infective oo- asymptomatic. Occasionally, acute infection may

570
Gastrointestinal Diseases in Immunocompromised Patients

produce a transient flu-like illness. In immuno- age, and the nature of the immunosuppressive
compromised patients, toxoplasmosis may regimen the patient has undergone. GVHD may
represent a life-threatening illness primarily occur even in fully matched MHC donors and
as a result of its central nervous system effects. recipients due to incompatibilities in minor
Gastrointestinal toxoplasmosis is rare, and histocompatibility antigens (172,176,192). The
occurs in the setting of disseminated infection incidence of GVHD is possibly higher in African-
where it occurs in 6 to 20 percent of patients Americans than in other individuals (171).
(162-164). Any or all gastrointestinal sites may Etiology. The basic requirements for GVHD
be involved. Patients most commonly complain to occur include the following: 1) the graft
of-abdominal pain, but diarrhea, nausea, vom- must contain immunocompetent cells; 2) the
iting, and anorexia may also occur (160,161). host must be sufficiently genetically different
Ascites may be present. from the graft to be perceived as antigenically
Gross Findings. Endoscopically, ulcers or foreign; and 3) the host must be unable to reject
thickened gastric folds may be seen in associa- the graft. These conditions allow engrafted cells
tion with gastrointestinal toxoplasmosis. Thick- to react to the host through immunologically
ening of the gastric wall and antral narrowing mediated processes (166).
may be seen radiographically (161). The principal target organs of GVHD are skin,
Microscopic Findings. The microscopic gastrointestinal tract, biliary tree, bone marrow,
features of toxoplasmosis in the gastrointestinal and lymphoid tissues. These organs have high
tract are a result of the variable acute and chron- cell turnover rates and may continually express
ic inflammation. The diagnosis is established by differentiation antigens, resulting in increased
the identification ofbradyzoites, tachyzoites, or immune surveillance (188). Alternatively, cells in
cysts in the tissues. these organs may harbor latent viruses that could
Special Studies. Bradyzoites in cysts are PAS act as targets for donor immune surveillance.
positive. In addition, organisms may be identi- Pathophysiology. CD8-, CD3- and TiA1-
fied with the use of immunohistochemistry or positive cytotoxic T cells mediate epithelial cell
PCR (161). death in GVHD (167,193). CD8 cells recognize
class II MHC-restricted antigens which produce
Other Parasites
the lymphokines that lead to the development
AIDS patients develop a number of other of the enteropathy associated with GVHD
parasitic infections. Among the more common are (175,180) . Apoptosis may occur through the
giardiasis and amebiasis. In addition, Strongyloides Fas/Fas ligand pathway (183).
infections occur in some immunocompromised Clinical Features. Acute GVHD occurs with-
patients. These are discussed in chapter 10. in days (7 to 100) in recipients who are not HLA
matched or in patients without any prophylaxis.
GRAFT VERSUS HOST DISEASE Rarely, acute GVHD occurs later than 100 days
Definition. Graft versus host disease (GVHD) is post-transplant (175). The typical clinical pre-
an immunologic disorder that may result in severe sentation of acute GVHD includes rash, nausea,
gastrointestinal damage. GVHD most commonly anorexia, profuse watery diarrhea, intestinal
follows bone marrow or organ transplantation, hemorrhage, crampy abdominal pain, abdomi-
and represents the response of immunocompetent nal tenderness, paralytic ileus, malabsorption,
donor cells to t_h e histocompatibility antigens and jaundice. The intestine and stomach are
of the recipient. Less commonly, it complicates involved in most patients; colonic involvement
maternal-fetal cell transfer in immunodeficient is less frequent (168,190,191,194). Esophageal
children (178) or transfusion of nonirradiated cells GVHD may also be seen (181,182,184).
and blood products (165,170). Chronic GVHD is less common than acute
Demography. The incidence of GVHD in GVHD and occurs more than 100 days following
bone marrow transplant patients ranges from transplantation, either as an extension of acute
less than 10 percent to more than 80 percent, GVHD or following a quiescent disease-free in-
depending on the degree of incompatibility, terval. Fifteen to 40 percent of long-term trans-
the number of T cells in the graft, the patient plantation survivors have chronic GVHD (177).

571
Gastrointestinal Diseases

Figure 11-23 Figure 11-24


..
GRAFT VERSUS HOST DISEASE GRAFT VERSUS HOST DISEASE
There are atypical white plaques. The honeycomb muco- There is ulceration with mucosal sloughing in the ter-
sal pit pattern is accentuated, suggesting mucosal edema. minal ileum. (Fig. 4-124 from Emory TS, Carpenter HA,
(Fig. 4-123 from EmoryTS, Carpenter HA, Gostm~t C], Sobin Gostout C], Sobin LH. Atlas of gastrointestinal endoscopy
LH. Atlas of gastrointestinal endoscopy & endoscopic biop- & endoscopic biopsies. Washington DC: Armed Forces
sies. Washington DC: Armed Forces Institute of Pathology; Institute of Pathology; 2009:333.) "
2009:332.)

The degree to which the endoscopic appearance


Table 11-5
correlates with a histologic diagnosis of GVHD
HISTOLOGIC GRADING OF varies from study to study (169,173,187).
GRAFT VERSUS HOST DIStASE Microscopic Findings. Mucosal biopsy pro-
Grade Histology vides a sensitive test for detecting GVHD in the
Mild necrosis of individual crypts gastrointestinal tract. The biopsy should not be
2 Crypt abscesses and crypt cell flattening taken during the first 3 weeks of immunosup-
pressive therapy because all patients show some
3 Dropout of many crypts
degree of inflammation in the immediate post-
4 Flat mucosa
transplant period. The lesions of acute GVHD
range from necrosis of individual crypt cells to
total mucosal loss (Table 11-5). Apoptotic bodies
It may result from long-living lymphocytes of are the sine qua non of the diagnosis. Apoptotic
donor origin that have become sensitized to bodies collect at the crypt bases in the intestine,
unknown antigens, probably minor histocom- and in the neck region of the gastric glands
patibility antigens of the host (177). Symptoms (fig. 11-25). As a result, the base of the glands
of chronic GVHD are nonspecific and include may appear dilated and may contain apoptotic
diarrhea, nausea, vomiting, and in some cases, debris (194).
complete gastrointestinal intolerance necessitat- As the lesions evolve, an entire crypt may
ing total parenteral nutrition (186). drop out, creating single crypt loss. The mu-
Gross Findings. Endoscopic findings in pa- cosal architecture is progressively lost with
tients with GVHD are variable, ranging from increasing ulceration, mucosal denudation, and
normal to severely inflamed, with erythema, submucosal edema (fig. 11-26). The epithelium
ulceration, and exudates (figs. 11-23, 11-24). may appear degenerated and cuboidal. In some

572
Gastrointestinal Diseases in Immunocompromised Patients

."~

I
\
r•
.'~1
,y

.
.

Figure 11-25
GRAFT VERSUS HOST DISEASE
Left: Low-power photograph of the colonic mucosa from a patient with early graft vers us host disease (GVHD). The
mucosal architecture is normal, and there is no evidence of inflammation.
Right: On high power, scattered apoptotic bodies are within the colonic glands (arrows) .

cases, the epithelium appears as a flattened immunodeficiency associated with features of


monolayer. Ulcer healing leads to fibrosis and GVHD (195). Some patients have other autoim-
stricture formation. mune diseases. This entity probably overlaps
In chronic GVHD, there is segmental lamina with autoimmune enteropathy.
propria fibrosis and submucosal fibrosis extend- Histologic features similar to those of GVHD
ing to the serosa. These lesions occur through- may be a result of dmg injmy. Mycophenolate mo-
out the entire length of the gastrointestinal fetil, a dmg used to reduce acute graft rejection in
tract, from the esophagus to the colon. solid organ transplant patients, may produce such
Occasional patients pass ropey, tan material a pattern of injury (fig. 11-27) (179,185).
resembling strands of sloughed mucosal tis- It is important to rule out the possibility of
sue, known as mucosal casts, per rectum. The CMV infection in patients suspected of GVHD
composition of the material is rarely clear-cut. since this virus commonly infects immunocom-
It usually contains fibrin, neutrophils, cellular promised patients, and has histologic features
debris, bacteria, or fungi, and very little identifi- similar to GVHD (179,190,194).
able tissue (189). The presence of free intestinal Treatment and Prognosis. The treatment
epithelium may be confirmed by immuno- for patients with both acute and chronic GVHD
staining for cytokeratin (189). is increased immunosuppression. Despite im-
Differential Diagnosis. Changes similar to provements in immunosuppressive regimens,
those found in GVHD sometimes occur in im- some patients are refractory to therapy. Patients
munosuppressed or immunodeficient patients, with chronic intestinal GVHD usually have mul-
without a history of transplant or transfusion. tisystem or multiorgan involvement. Complete
Patients have various associated diseases includ- recovery occurs in slightly more than half of
ing lymphoma, leukemia, combined immune patients. Mortality is approximately 18 percent
deficiency, or severe T-cell deficiency. The signs (186). Extracorporeal photopheresis is a novel
and symptoms resemble those developing fol- therapeutic intervention that may be efficacious
lowing bone marrow transplantation but they in some patients refractory to increased immu-
occur more rapidly and tend to be associated nosuppressive therapy (17 4). Clinical responses
with a higher fatality rate. A novel T-lymphocyte to this treatment have been reported in patients
population has been identified in combined with both skin and visceral GVHD.

573
Gastrointestinal Diseases

Figure 11-26
GRAFT VERSUS HOST DISEASE
This patient had more severe disease than the patient
in figure 11-23.
A: Low-power view of the colonic mucosa demonstrates
areas of glandular loss.
B: There is mild architectural change and the lamina
propria contains an increased number of inflammatory
cells. Scattered crypt abscesses are present.
C: Higher-power view shows apoptotic colonic epithelial
cells (arrows). The crypts are infiltrated by netttrophils.

,.,.

574
Gastrointestinal Diseases in Immunocompromised Patients

Figure 11-27
MYCOPHENOLATE MOFETIL COLONIC INJURY
Left: Individual crypts appear to be dropping out of the mucosa. The center crypt contains apoptotic and inflammatory
debris. The epithelium is flattened.
Right: Cryptitis with a crypt abscess.

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drome: autopsy evidence for respiratory acqui- cerebral toxoplasmosis in AIDS. Histological
sition. Arch Pathol Lab Med 1992;116:660-8. and immunohistological findings based on 80
154. Schwartz DA, Sobottka I, Leitch G], Cali A, autopsy cases. Pathol Res Pract 1993;189:428-
Visvesvara GS. Pathology of microsporidiosis: 36.
emerging parasitic infections in patients with
acquired immunodeficiency syndrome. Arch Graft Versus Host Disease
Pathol Lab Med 1996;120:173-88. 165. Anderson KC, Weinstein HJ. Transfusion-
155. Soule ]B, Halverson AL, Becker RB, Pistole MC, associated graft-versus-host disease . N Engl ]
Orenstein ]M. A patient with acquired immuno- Med 1990;323:315-21.

581
Gastrointestinal Diseases

166. Billingham RE. The biopsy of graft-versus-host malities in chronic graft-versus-host disease in
reactions. Harvey Lect 1966-1067;62:21-78. humans. Gastroenterology 1981;80:914-21.
167. Burdick JF, Vogelsang GB, Smith WJ, et al. 182. Minocha A, Mandanas RA, Kida M,Jazzar A. Bul-
Severe graft-versus-host disease in a liver-trans- lous esophagitis due to chronic graft-versus-host
plant recipient. N Engl] Med 1988;318:689-91. disease. Am J Gastroenterol1997;92:529-30.
168. Cox G], Matsui SM, Lo RS, et al. Etiology and 183. Nagata S. Apoptosis by death factor. Cell1997;
outcome of diarrhea after marrow transplan- 88:355-65.
tation: a prospective study. Gastroenterology 184. Otero Lopez-Cubero S, Sale GE, McDonald GB.
1994;107:1398-407 . Acute graft-versus-host disease of the esopha-
169. Cruz-Correa M, Poonawala A, Abraham SC, et gus. Endoscopy 1997;29:S35-6.
al. Endoscopic findings predict the histologic 185. Papadimitriou}C, Cangro CB, Lustberg A, et al.
diagnosis of gastrointestinal graft-versus-host Histologic features of mycophenolate mofetil-
disease. Endoscopy 2002;34:808-13. related colitis: a graft-versus-host disease-like
170. Dinsmore RE, Straus DJ, Pollack MS, et al. Fatal pattern. IntJ Surg Pathol2003;11:295-302.
graft-v-host disease following blood transfusion 186. Patey-Mariaud de Serre N, Reijasse D, Verkarre
in Hodgkin's disease documented by HLA typ- V, et al. Chronic intestinal graft-versus-host
ing. Blood 1980;55:831-4. disease: clinical, histological and immunohisto-
171. Easaw S, LakeD, Beer M, Seiter K, Feldman EJ, chemical analysis of 17 children. Bone Marrow
Ahmed T. Graft-versus-host disease. Possible Transplant 2002;29:223-30.
higher risk for African American patients. Can- 187. Ponec RJ, Hackman RC, McDonald GB. Endo-
cer 1996;78:1492-7. scopic and histologic diagnosis of intestinal
172. Falkenburg}H, van de Corput L, Marijt EW, Wil- graft-versus-host disease after marrow trans-
lemze R. Minor histocompatibility antigens in plantation. Gastrointest Endosc 1999;49:612-
human stem cell transplantatiOJ].. Exp Hematol 21.
2003;31:743-51. 188. Sale GE, Shulman HM, Galluci BD, Thomas ED.
173. Forbes GM, Rule SA, Herrmann RP, et al. A Young rete ridge keratinocytes are preferred
prospective study of screening upper gastroin- targets in cutaneous graft-versus-host disease
testinal (GI) endoscopy prior to and after bone in man. Am J Pathol1985;118:278-87.
marrow transplantation (BMT). Aust N ZJ Med 189. Silva MR, Henne K, Sale GE. Positive identifica-
1995;25:32-6. tion of enterocytes by keratin antibody staining
174. Foss FM, Gm·gun G, Miller KB. Extracorporeal of sloughed intestinal tissue in severe GVHD.
photopheresis in chronic graft~versus-host dis- Bone Marrow Transplant 1993;12:35-6.
ease. Bone Marrow Transplant 2002;29:719-25. 190. Snover DC. Mucosal damage simulating acute
175. Glucksburg H, Storb R, Fefar .A., et al. Clinical graft-versus-host reaction in cytomegalovirus
manifestations of graft-versus-host disease colitis. Transplantation 1985;39:669-70.
in human recipients of marrow from HLA- 191. Snover DC, Weisdorf SA, Vercelloti GM, Rank B,
matched sibling donors. Transplantation Button S, McGlave P. A histopathologic study
1984; 18:295-304. of gastric and small intestinal graft-versus-host
176. Goulet 0, Revillon Y, ]anD, et al. Small-bowel disease following allogeneic bone marrow
transplantation in children. Transplant Proc transplantation. Hum Pathol 1985;16:387-92.
1990;22:2499-500. 192. Storb R. Marrow transplantation: the Seattle ex-
177. Graze PR, Gale RP. Chronic graft-versus-host perience. Tokai] Exp Clin Med 1985;10:75-83.
disease: a syndrome of disordered immunity. 193. Takata M. Immunohistochemical identification
Am] Med 1979;66:611-20. of perforin-positive cytotoxic lymphocytes
178. Grogan TM, Odom RB, Burgess JH. Graft-vs- in graft-versus-host disease. Am J Clin Pathol
host reaction. Arch Dermatol1977;113:806-12. 1995;103:324-9.
179. Gulbuhce HE, Brown CA, Wick M, Segall M, ]es- 194. Washington K, Bentley R, Green A, Olson ],
surunJ. Graft-versus-host disease after solid organ Treem WR, Krigman HR. Gastric graft-versus-
•. transplant. Am] Clin Pathol2003;119: 568-73 . host disease: a blinded histologic study. Am J
180. Mason DW, Dallman M, Barclay AN. Graft- Surg Pathol 1997;21:1037-46.
versus-host disease induces expression of la 195. Wirt DP, Brooks EG, Vaidya S, Klimpel GR,
antigen in rat epidermal cells and gut epithe- Waldmann TA, Goldblum RM. Novel T-lym-
lium. Nature 1981;293:150-1. phocyte population in combined immunode-
181. McDonald GB, Sullivan KM, Schuffler MD, ficiency with features of graft-vs-host disease.
Shulman HM, Thomas ED. Esophageal abnor- N Engl] Med 1989;321:370-4.

582
12 MALABSORPTION SYNDROMES

reduced local bile salt concentration. The second,


INTRODUCTION and most common group of disorders that a sur-
· Malabsorption syndromes result from the gical pathologist is likely to face, is that of muco-
deficient uptake of various types of nutrients, sal diseases. Mucosal defects are due to anatomic
so that there are insufficient nutrients and calo- or biochemical alterations in the epithelium, the
ries available to maintain normal homeostasis. presence of microorganisms, or inflammatory or
Although malabsorption and maldigestion are infiltrative processes affecting the lamina propria.
related in terms of clinical presentation and The third group of disorders is the postmucosal dis-
complications, pathophysiologically they are eases. Malabsorption occurs because of lymphatic
different. Maldigestion results from defective obstmction, vascular disease, or congestive cardiac
intraluminal hydrolysis of nutrients, while failure. Table 12-1 summarizes the various causes
malabsorption occurs secondarily to defective of malabso1ption.
mucosal nutrient uptake following digestion. In Because clinically diagnosed malabsorption
addition, intestinal motility, solubilization of may be due to diverse causative factors, it is es-
nutrients, and various exocrine and endocrine sential that the pathologist be supplied with suf-
hormones are involved in normal absorption. ficient clinical information, including results of
laboratory or serologic tests, before any attempt
Demography
to arrive at a specific diagrrosis is undertaken.
Malabsorption syndromes affect people of all The presence of a normal small intestinal biopsy
ages. Age incidence depends upon the underly- does not exclude many conditions leading to
ing etiology. Celiac disease, the most common malabsorption (Tables 12-2, 12-3). Table 12-4
cause of malabsorption in developed coun- lists the information that should be provided
tries, is detected at almost any age. Congenital to the pathologist interpreting small bowel
enzyme deficiencies present as malabsorption biopsies for malabsorption.
in children. In elderly patients, chronic intes-
Choice of Specimen
tinal ischemia, congestive heart failure, and
bacterial overgrowth are common causes of Small intestinal biopsies can be obtained
malabsorption. The prevalence of a particular by either a suction capsule or by forceps after
type of malabsorption syndrome may also vary endoscopic visualization. The suction capsule
in different ethnic groups. For example, celiac method requires radiographic guidance and
disease is the most common cause of malabsorp- is more expensive than the more commonly
tion in Western Europe and the United States used forceps biopsy. Studies have shown no
while infectious diseases, lactase deficiency, and significant difference in diagnostic yield be-
nutritional deficiencies are the usual causes of tween these two techniques (2). Focal or patchy
malabsorption.in the developing world. lesions can be visualized and then biopsied by
the endoscopic method (1,3). This technique
Etiopathogenesis
also permits visualization of the gastrointestinal
Malabs01ption syndromes occur by one of three tract, and radiation exposure associated with
broad categories of pathogenetic mechanisms. suction biopsy is avoided. Capsule biopsies are
These categories form the basis of the laboratory still preferred to endoscopic biopsies by some
approach used to make a specific diagnosis. gastroenterologists when a diagnosis is being
The first category is that of premucosal dis- sought in a child younger than 2 years of age.
ease. Defective digestion and absorption result Either the duodenum or the jejunum is an
from pancreatic or other systemic diseases and appropriate site for biopsy. Most endoscopic

583
Gastrointestinal Diseases

Table 12-1 Table 12-2


CAUSES OF MALABSORPTION CAUSES OF MALABSORPTION WITH
NORMAL-APPEARING PROXIMAL JEJUNAL BIOPSIES
Inadequate Digestion
Postgastrectomy steatorrhea Dermatosis other than dermatitis herpeti.formis
Deficient activation of pancreatic lipase Pancreatitis
Chronic pancreatitis
Pancreatic carcinoma Alcoholism
Cystic fibrosis Cirrhosis
Pancreatic resection
Reduced intestinal bile salt concentration (with Hepatitis
impaired micelle formation) Iron deficiency anemia
Abnormalities in Bile Production and Metabolism Ulcerative colitis
Parenchyma! liver disease
Postgastrectomy without bacterial overgrowth
Extrahepatic biliary obstruction
Interrupted enterohepatic circulation of bile salts Malignancy outside the gastrointestinal tract
Inadequate Absorptive Surface Secondary to Surgical Cholera
Procedures Biliary obstruction
Blind loop syndrome
Ileal resection
Drugs
Neomycin forceps biopsies are procured from the duode-
Calcium carbonate
Cholestyramine
num. The biopsy should be procured no more
Colchicine proximal than the second part of the duodenum
Lymphatic Obstruction to avoid artifacts due to prominent Brunner
Intestinal lymphangiectasia glands or the nonspecific duodenitis commonly
Whipple's disease seen in the bulb and proximal duodenum.
Lymphoma There are no definite established guidelines
Inflammatory or Infiltrative Disorders regarding the number of biopsy fragments that
Crohn's disease should be taken. In general, three to four frag-
Infectious enteritis
Tropical sprue ments, procured preferably by jumbo forceps,
Eosinophilic enteritis should be sufficient for diagnosis. Biopsies
Cellae disease ... may also be procured with the use of the more
Collagenous sprue routinely used smaller forceps; in this case, the
Radiation enteritis
Amyloidosis number of biopsies taken should be increased
Scleroderma to four to six.
Mastocytosis In many cases, prior communication be-
Biochemical or Genetic Abnormalities tween the gastroenterologist and pathologist
Disaccharidase deficiency is necessary to decide whether a portion of
Hypogarnmaglobulinemia
Abetalipoproteinemia
the specimen is to be kept for enzyme or other
Hartnup's disease biochemical studies, electron microscopy, or
Cystinuria microbiologic examination. The clinical history
Monosaccharide malabsorption and endoscopic findings should be provided on
Endocrine and Metabolic Disorders the surgical pathology requisition slip.
Diabetes mellitus
Hypopara th yroidism Handling the Specimen
Adrenal insufficiency
Hyperthyroidism A nonfragmented, well-oriented biopsy speci-
Zollinger-Ellison syndrome men aids in establishing an accurate diagnosis.
Carcinoid syndrome Biopsies of 3 to 4 mm in thickness preferably
Cardiovascular Disorders procured by a jumbo forceps give reproducible re-
Constrictive pericarditis sults. Immediate orientation by the gastroenter-
Congestive heart failure
Mesenteric vascular insufficiency ologist is best, but is impractical in regular clini-
Vasculitis cal practice. The optimal method of orienting
the specimen is to put the base of the mucosa on

584
Malabs01ption Syndromes

Table 12-3
MALABSORPTION WITH NORMAL VILLI BUT OTHER DIAGNOSTIC FEATURES

Disease Specific Histologic Features


Abetalipoproteinemia Vacuolated enterocytes containing lipids involving upper two thirds of the villi;
acanthocytes
Crohn's disease Noncaseating granulomas; transmural inflammation
X-linked immunodeficiency Absent lamina propria plasma cells
Lipid storage disease Vacuolated ganglion cells, capillaries, and macrophages
Amyloidosis Congo red-positive material in muscularis and blood vessels
Chronic granulomatous disease Pigmented vacuolated macrophages in lamina propria
Melanosis Brown pigmented macrophages in lamina propria
Systemic mastocytosis Mast cell infiltrates in lamina propria
Hemochromatosis Iron deposits in epithelium and macrophages
Mycobacterium avium complex PAS' -positive diastase-resistant macrophages containing acid-fast organisms

' PAS =periodic acid-Schiff.

Table 12-4
by asking an experienced histotechnologist to
CLINICAL INFORMATION REQUIRED FOR
INTERPRETATION OF SMALL BOWEL embed the biopsies on edge.
BIOPSIES FOR MALABSORPTION Although Bouin, Hollande, and B5 fixatives
yield little shrinkage artifact and give optical
Patient age
nuclear detail, most pathology departments
Patient sex use neutral buffered formalin as the fixative.
Ethnicity Adequate fixation for histology and superior
Country of domicile preservation of DNA for ancillary studies are
Travel history possible with formalin fixation. Formalin is also
Reason for the biopsy inexpensive and easy to discard.
Drug use There is a lack of consensus among patholo-
gists regarding the number of slides and levels
History of associated diseases
that should be prepared and examined histo-
Acquired immunodeficiency syndrome
logically. Examination of multiple sections and
Neoplasias levels increases the likelihood of finding patchy
Infections changes and well-oriented villi.
Metabolic diseases
Histologic Approach to Biopsies
Immune deficiencies
Obtained for Malabsorption
Prior surgery
A systemic approach for the evaluation of
each compartment of the small intestinal mu-
filter paper and float it upside down in a bottle cosa and submucosa is necessary in order to
of fixative. This technique allows the villi in the identify a pattern of injury and to determine a
specimen to float freely, minimizing artifactual possible cause of the patient's symptoms.
distortion of the mucosal architecture. Appro- Assessment of Villi. An adequate small
priate orientation can also be achieved by scan- intestinal biopsy should have a row of at least
ning under a dissecting microscope. An initial four well-oriented villi in the section (fig. 12-1).
impression of the villous architecture can also Obliquely sectioned villi are the most common
be obtained by this method. Its applicability in source of diagnostic misinterpretation. Such
clinical practice, however, is limited. In most poorly oriented villi look broad and flat and
institutions, adequate orientation is achieved have a multilayered epithelial lining (fig. 12-2).

585
Gastrointestinal Diseases

Figure 12-1
NORMAL VILLOUS ARCHITECTURE
Normal villous architecture is best assessed in areas where
at least four adjacent, well-oriented villi are identifiable. In
this section, the villi are three to four times the length of
the intestinal crypts.

Villi may appear atrophied, normal, or hyper-


trophied in patients presenting with malabsorp-
tion. The latter is rare. Villi should be assessed by
their normal relationship with the small intes-
tinal crypt. In adults overall, the villous height
Figure 12-2
is approximately three or more times the depth
of the crypts, whereas in children this ratio is ARTIFACTUAL CHANGES MAKING
VILLUS ASSESSMENT DIFFICULT
typically 2 to 1. Villous height is also lower in
elderly patients. The duodenal crypt/villus ratio Oblique sectioning and poor orientation of small
intestinal biopsies make interpretation of the architecture
is 3-1 to 7-1, whereas the ileal crypt/villus ratio difficult. In this section, the specimen was oriented upside
is 4 to 1. Villi overlying lymphoid aggregates are down on a piece of filter paper, making the villi appear
often stubby or absent, and therefore, should blunted. In addition, the biopsy is tangentially sectioned
not be evaluated in these areas. Causes of villous making the epithelial layer appear stratified.
atrophy are listed in Table 12-5. Villous atrophy
occurs in three different patterns. This pattern is seen in advanced celiac disease,
Villous Atrophy and Crypt Hype1plasia. This cytotoxic drug-induced injury, and vitamin B12
is the usual type of injury pattern observed, and folic acid deficiencies.
and is typical of celiac disease as well as many Villous Hype1plasia. This unusual pattern is
other disorders. The villous enterocytes are the seen following intestinal resection or with glu-
target of the injury. The villus to crypt ratio is cagonoma. The length of the villi and depth
decreased and crypts show elongation and a of the crypts are both increased, resulting in
marked increase in mitotic activity (fig. 12-3). A minimal alteration of the villus to crypt ratio.
system for grading the degree of villous atrophy Other changes, including villous expansion
'· is shown in Table 12-6. Such grading helps as- due to lamina propria alterations, erosion,
sess the severity of damage. Evaluation of the metaplasia, and the presence of microorgan-
degree of villous atrophy present in a biopsy is isms, should be evaluated in all small intestinal
also necessary to apply the Marsh classification biopsies taken for malabsorption.
in celiac disease (see below). Enterocyte Changes. The appearance of
Villous Atrophy with Crypt Hypoplasia. In this the brush border, size and shape of the cells,
pattern of injury, the crypt is the site of damage. intracytoplasmic and nuclear alterations, and
The crypt to villus ratio is minimally altered. regenerative activity should be evaluated.

586
Malabs01ption Syndromes

Table 12-5 Table 12-6


CAUSES OF VILLOUS ATROPHY GRADES OF VILLOUS ATROPHY

Sprue Syndromes Mild


Celiac Sprue Most villi appear branched, broadened, or fused; some
Refractory sprue remain normal
Collagenous sprue Surface epithelium appears abnormal
Mesenteric lymph node cavitation syndrome loss of polarity
Other protein injury (soy, milk) increased intraepithelial lymphocytes
Increased mitoses outside the normal proliferative
Infectious Causes
Gastroenteritis compartment
Increased acute and chronic inflammatory cells in
Parasitic infections (Giardia most common)
Mycobacterial infections lamina propria
Fungal infections (histoplasmosis most common) Moderate (partial villous atrophy)
Viral infections (cytomegalovirus most common) Villi broadened and shortened
Tropical sprue Cuboidal surface epithelium
Whipple's disease Large numbers of intraepitheliallymphocytes
Bacterial overgrowth Increased mononuclear cells in the lamina propria
Immunologic Disorders Severe (subtotal or total villous atrophy)
IgA deficiency Villi almost or completely absent
Common variable immunodeficiency Marked mononuclear cell infiltrates
X-linked agammaglobulinemia
Acquired immunodeficiency syndrome (AIDS)
Autoimmune enteropathy
Nutritional Deficiency Disorders
Kwashiorkor
Zinc deficiency
Vitamin B12 and folic acid deficiencies
Others
Crohn's disease
Graft versus host disease
lmmunoproliferative disorders (lymphoma, macro-
globulinemia)
Intestinal lymphangiectasia
Zollinger-EIIison syndrome
Microvillous inclusion disease
Radiation enteropathy
Eosinophilic gastroenteritis
Chronic ischemia

Figure 12-3
Enterocyte changes can be nonspecific, but may
indicate a specific etiology in certain cases. VILLOUS ATROPHY AND CRYPT HYPERPLASIA

Nonspecific injury often results in an attenu- The mucosal surface of this duodenal biopsy specimen
is nearly flat, and the crypts are markedly elongated.
ated or absent brush border. The enterocytes
lose their normal columnar shape and become
more cuboidal. The cytoplasm becomes am-
phophilic to basophilic with vacuolization and clusions and parasites are also seen (see chapter
the nuclei are irregular in size and shape. The 10). Macrocytosis is often seen in vitamin B12 or
regenerating enterocytes show tufting, and folic acid deficiency or following treatment with
mitoses are present higher in the crypt than chemotherapeutic agents. Increased apoptosis
normal (fig. 12-4) . is seen in autoimmune enteropathy and graft
Specific changes include the presence of versus host disease (see chapters 11 and 14).
intracytoplasmic accumulations, for example, Intraepithelial lymphocytosis is seen most
iron in hemochromatosis; characteristic vacu- frequently in association with celiac disease.
olization ofthe enterocytes in abetalipoprotein- The causes of intraepitheliallymphocytosis are
emia; or microvillous inclusion disease. Viral in- listed in Table 12-7.

587
Gastrointestinal Diseases

Table 12-7
CAUSES OF INTRAEPITHELIAL LYMPHOCYTOSIS

Cellae disease
Relatives of patients with celiac disease
Autoimmune enteropathy
Systemic autoimmune disorders like systemic lupus
erythematosus, rheumatoid arthritis
Nonsteroidal antiinflammatory medications
Crohn 's disease
Infections
Lymphocytic colitis and enterocolitis

disease. The presence of large numbers of eo-


sinophils suggests allergic injury, parasitic infec-
tion, or eosinophilic gastroenteritis. Mast cells
are increased in mastocytosis, allergic disorders,
and Crohn's disease.
Inflammatory infiltrates that are predomi-
nantly histiocytic in nature may be seen in
infections such as Mycobacterium avium complex
infection, histoplasmosis, and Whipple's dis-
ease. In addition, various storage diseases may
present with diffuse lamina propria histiocytic
Figure 12-4 collections.
CELIAC DISEASE It is also important to determine which cell
The intestinal crypts in this biopsy from a patient with types are not present in the biopsy. For example,
celiac disease are hyperplastic. Numerous mitoses extend an absence of plasma cells is a strong indicator
upward into the superficial portion of th ~ crypts.
of immunodeficiency disease, particularly com-
mon variable immunodeficiency. A decreased
number of chronic inflammatory cells is seen in
Crypt Changes. Crypts may show hyper- patients who are on steroids or who have other
plasia or hypoplasia as described previously. types of immunodeficiency.
Although not specific, increased numbers of Lymphatic dilatation is seen with lymphangi-
Paneth and endocrine cells are commonly seen ectasia or lymphatic outflow obstruction. Blood
in celiac disease. Paneth cell abnormalities are vessels are primarily affected in ischemic dis-
also seen in acrodermatitis enteropathica (3). eases, radiation injury, amyloid deposition, and
Lamina Propria changes. The character of thromboembolic disorders. The lamina propria
any lamina propria inflammatory infiltrate may may also show deposition of material as occurs
help to determine the etiology of the patient's in amyloidosis, macroglobulinemia, melanosis,
malabsorption. It is important to note that a and hemochromatosis. The conditions leading
11, · mild degree of lymphoplasmacytosis is normal to mucosal deposits are listed in Table 12-8.
in duodenal biopsies. A marked increase in Submucosal Chan ges. The submucosa may
chronic inflammatory cells is seen in many not be present in some biopsy specimens. If
conditions including celiac disease, peptic present, blood vessels, lymphatics, inflamma-
duodenitis, drug injury, infection, and nonspe- tion, Brunner gland hyperplasia, and metaplas-
cific chronic duodenitis. Acute inflammation tic changes should be evaluated. If available,
suggests etiologies such as peptic duodenitis, the submucosal plexus should be evaluated for
drug-induced injury, and Crohn's disease. Crypt ganglion cell changes. It is not uncommon to
abscesses indicate acute enteritis or Crohn's find ganglion cells in the muscularis mucosae

588
Malabs01ption Syndromes

Table 12-8 also have the disease (29, 45), although a sig-
CAUSES OF INTESTINAL MUCOSAL DEPOSITS
nificant proportion (about SO percent) remain
asymptomatic and are said to have latent celiac
Amyloid light chains disease (29,45).
Macro globulins Pathophysiology. The complex etiology of
Collagenous sprue and collagenous enterocolitis celiac disease results from the interaction of
Infantile systemic hyalinosis environmental agents, genetic predisposition,
and immunologic factors to produce intestinal
Lipid proteinosis
injury (fig. 12-5).
Melanosis
Gluten and Other Prolamines. Celiac disease
Pseudomelanosis has been recognized as an autoimmune enter-
Xanthomas opathy triggered by ingestion of wheat gluten
Muciphages (gliadins), barley (hordeins) , rye (secalins),
Storage diseases and possibly oats (avenins). Gluten is found in
Tangier disease grains such as wheat and buckwheat, as well
Fabry's disease as in many processed foods such as gravies,
sausage, beer, ale, bread, and bread products.
Tay-Sachs and other gangliosidoses
Gluten can be separated electrophoretically
Niemann-Pick disease into four major fractions : alpha, beta, gamma,
Wolman's disease and omega gliadins (6). Gliadins are prolamines
Cystinosis with a high content of proline and glutamic
Mucopolysaccharidoses acid. All four types appear to be toxic, although
alpha-gliadin has the most pathogenic proper-
ties (11) . Toxic gliadins contain pro-ser-gln-gln
or lower mucosa of the small intestine. These and gln-gln-gln-pro amino acid sequences.
should not be interpreted as representing neu- These sequences are absent from nontoxic pep-
ronal dysplasia (see chapter 17). tides (15,59). A recent study demonstrated that a
33-mer peptide generated by digestion of alpha-
CELIAC DISEASE gliadin with intestinal enzymes in vivo and in
Definition: Celiac disease is a malabsorptive vitro is a highly stimulatory antigen for CD4-
disorder in which the small intestinal mucosa of positive T cells (56). This peptide is resistant
sensitive individuals is injured as a result of inges- to further digestion by intestinal brush border
tion of gluten-containing foods. Synonyms in- enzymes and is a highly specific substrate for
clude celiac sprue and gluten-sensitive enteropathy. deamidation by tissue transglutaminase. This
Epidemiology. Celiac disease is the most com- 33-mer peptide is not present in cereal proteins
mon cause of malabsorption in Western popula- that do not cause celiac disease.
tions. The disease prevalence in most of Europe is A possible pathogenetic role of enteric
estimated at approximately 1/1,000, but is up to pathogens has been suggested in the etiology
10-fold higher in many Western European coun- of celiac disease. This hypothesis was supported
tries (8,9,31,40,47,48,52,54). Recent estimates of by a study in which analysis of alpha-gliadin
the disease prevalence suggest that worldwide as demonstrated an amino acid region that was
many as 1/266. people are affected (18) . Celiac homologous to the 54-kDa E1b protein coat
disease is rarely seen in Japanese, Chinese, and of adenovirus (32). In addition, patients with
African individuals. The disorder affects women celiac disease have been reported to have a sig-
more commonly than men. nificantly higher prevalence of past adenovirus
Celiac disease appears to have a strong ge- 12 infection than control subjects (5) .
netic component, demonstrating a higher inci- Celiac disease demonstrates the strongest
dence in siblings than in the general population association of any illness with a specific class II
(43,53) . There is 70 percent concordance for human leukocyte antigen (HLA) molecule (28,
celiac disease in identical twins (23). About 10 41,42,60,61). The disorder is triggered by an
percent of first -degree relatives of celiac patients environmental insult (gluten consumption),

589
Gastrointestinal Diseases

~ .,. ~"
.,
~ Gluten
Enterocyte
damage
f.1 1r ru J, .~1~
I I •'

~"...

. · ~·
..
A~
~~
·~

Helper
....... ·--- ---+"""
\ )'Y (Antti_bo_did":s
,.. ,. T cell
an 19 11a m,
tTG • TCR activation ~ tTG, etc.)

Cytokines
Antigen ----tiJ!o~ (IFN-y, IL4, TNFa)
presenting
cell

Figure 12-5
PAT!-IOPHYSIOLOGY OF CELIAC DISEASE
Dietary gluten is absorbed from the intestinal lumen and enters the lamina propria of the small intestine. Gliadin is
presented, in conjunction with HLA-DQ2 or DQS cell surface antigens on antigen-presenting cells, toT lymphocytes expressing
the a/~ T-cell receptor (TCR). Tissue transglutaminase deamidates the gliadin, generating negatively charged glutamic acid
residues from neutral glutamines on the gliadin molecule. These negatively charged glutamate residues interact wit.ll positions
4, 6, and 7 in the antigen-binding groove of the human leukocyte antigen (HLA) molecule, eliciting an enhanced T-cell
response to the antigen. Activated T lymphocytes then activate other lymphocytes, resulting in the production of cytokines
and immunoglobulins that damage enterocytes.

and the HLA haplotype acts as a classic immune within gluten exist. Lamina propria antigen-
response gene that operates at eitB.er the T cell presenting cells that express HLA-DQ2 or
or antigen-presenting cell level to favor gliadin- -DQ8, present gliadin peptides bound to their
specific responses (41,60,61). The primary HLA a/p heterodimer antigen-presenting grooves
association in the majority of patients is with to sensitized T lymphocytes that express the
DQ2 (61); fewer patients are of haplotype DQ8. a/p TCR. These lymphocytes then activate B
An increased risk for celiac disease also exists lymphocytes to produce immunoglobulins,
among individuals who are DR3-DQ2 homozy- and stimulate other T cells to produce cytokines
gous and DR3-DQ2/DR7-DQ2 heterozygous (40). including interferon (IFN)-y, interleukin (IL)4,
In addition to the HLA linkage, celiac disease IL5, IL6, ILIO, tumor necrosis factor (TNF)-y, and
has been linked to several other chromosomal transforming growth factor (TGF)-P (fig. 12-5).
regions. Linkage to 2q33, an area of regulation Tissue Transglutaminase (tTG) and Other Au-
for T-lymphocyte activation, has been seen in toantigens. tTG is expressed in many different
a Finnish family (27). Linkage to other regions tissues, and is found both extracellularly and
on other chromosomes has additionally been intracellularly. tTG is expressed just beneath the
reported (22,35,48,51,65,70), but linkage to epithelium in the gut wall. Calcium-dependent
5p31-33 is the most consistently identified tTG catalyzes selective cross-linking or deami-
(22,37,48). dation of protein-bound glutamine residues.
Gluten-reactive T cells can be isolated from Deamidation of the glutamine residues of gliadin
small intestinal biopsies of celiac patients but by tTG prepares the gliadin molecule to bind
not from nonceliac controls. These T cells are with HLA-DQmolecules (46,66). In addition, tTG
CD4 positive and express the a/p T-cell recep- can cross-link glutamine residues of peptides to
tor (TCR). A number of distinct T-cell epitopes lysine residues in other proteins, including tTG

590
Malabsmption Syndromes

itself. This may result in the formation of gluten- Table 12-9


tTG complexes. These complexes may permit CONDITIONS ASSOCIATED WITH CELIAC DISEASE
gluten-reactive T cells to stimulate tTG-specific
B cells by a mechanism of intramolecular help, Common Associations
thereby explaining the occurrence of gluten- Developmental delay
Short stature
dependent tTG autoantibodies, a characteristic Dermatitis herpetiformis
feature of active celiac disease. Furthermore, Vasculitis
tTG-catalyzed cross-linking and consequent Arthritis
haptenization of gluten with extracellular matrix Autoimmune hepatitis
Polyglandular autoimmune syndrome
proteins allow for storage and extended avail- Autoimmune thyroid disease
ability of gluten in the mucosa. tTG is necessary Insulin-dependent diabetes
for activation of TGF-~ which is involved in the IgA nephropathy
differentiation of intestinal epithelium (54), Lymphoma
Carcinoma
regulates immunoglobulin (Ig)A expression (14),
Uncommon or Rare Associations
and modulates immune responses. In addition, Ulcerative colitis
antibodies to tTG in patients with celiac disease Sarcoidosis
interfere with fibroblast-induced differentiation Primary biliary cirrhosis
of epithelial cells, possibly by inhibiting the Pericarditis
Cystic fibrosis
cross-linking activity of tTG. Epilepsy
Cell-Mediated and Antibody-Mediated Immune Facial anomalies
Responses. Gluten ingestion in untreated pa- Hypoparathyroidism
tients with celiac disease induces nonprolifera- Bronchiolitis
Interstitial pulmonary fibrosis
tive activation of CD4-positive T a/~ receptor- Alopecia areata
positive cells in the lamina propria. This is Alpha-1-antitrypsin deficiency
accompanied by proliferative activation of in-
traepitheliallymphocytes (a/~- and y/8-positive
T cells) in the epithelial compartment. plasma cells within the mucosa (7,69) . These
Activated CD4-positive T cells activate B antibodies are directed against gliadin, trans-
lymphocytes and plasma cells to produce auto- glutaminase, endomysium, reticulin, and
antibodies. These T cells also stimulate other T enterocyte actin. The exact physiologic role of
lymphocytes to secrete cytokines, most notably these antibodies is still unclear.
IFN-y, but also IL4, ILS, IL6, ILlO, TNF-y and Recent evidence suggests that gliadin or its
TGF-~. These cytokines not only damage the metabolites may directly injure the intestinal
enterocytes, but also induce expression of ab- mucosa. Up-regulation of mucosal HLA-DR
errant HLA class 11 cell surface antigens on the and intercellular adhesion molecule within 2
luminal surface of enterocytes. This facilitates hours of in vitro exposure to gliadin suggests an
additional direct antigen presentation by these early effect that may not be immune mediated
cells to the sensitized lymphocytes. Cytokines (49). This early effect is followed by activation
produced by DQ2-restricted T cells are of Th1 of CD4-, CD25-positive T cells, producing the
type and are dominated by the secretion of immunologic injury.
IFN-y. Cytokines produced by DQ8-restricted T Associated Diseases. Table 12-9 shows the
cells have a ThO profile. Increased y/8 T cells in wide variety of systemic diseases that are as-
the epithelium and lamina propria of the small sociated with celiac disease. Dermatitis herpeti-
intestine have also been observed in celiac pa- formis and celiac disease are both associated
tients, and these cells persist even after gluten with IgA-mediated epithelial injury. Initially,
withdrawal. These cells may play a protective dermatitis herpetiformis was considered a skin
role through activation of a nonspecific im- disease that occurred often concomitantly with
mune response that helps to lessen the antigen- celiac disease, but currently it is believed that
specific immune response. dermatitis herpetiformis is a cutaneous manifes-
Celiac disease characteristically results in the tation of celiac disease, affecting approximately
accumulation of IgA-, IgM-, and IgG-producing 25 percent of patients. tTG, the autoantigen

591
Gastrointestinal Diseases

for antiendomysial antibody, is also the auto-


antigen in dermatitis herpetiformis (34). Restric-
tion of patients to a gluten-free diet is essential
in the treatment of both conditions.
Another IgA-mediated autoimmune disease
associated with celiac disease is IgA nephropa-
thy. Patients with IgA nephropathy carry a risk
of contracting celiac disease; however, there
is no increase in celiac-type HLA-DQ in IgA
nephropathy patients. It has been hypothesized
that the increased intestinal permeability in
IgA nephropathy may predispose genetically
susceptible patients to celiac disease.
Many hepatobiliary diseases occur in associa-
tion with celiac disease, including asymptom-
Figure 12-6
atic elevations of liver enzymes, nonspecific
hepatitis, nonalcoholic fatty liver di.sease, and LYMPHOCYTIC COLITIS
autoimmune and cholestatic liver disease. The lamina propria of the colon contains an increased
Increased levels of alanine aminotransferase, number of lymphocytes and plasma cells. Numerous
intraepithelial lymphocytes are also present. The normal
aspartate aminotransferase, and/or alkaline mucosal architecture is preserved.
phosphatase are seen in up to 47 percent of ce-
liac disease patients (4). Two main mechanisms
underlying the development of the liver dam-
age have been proposed: 1) celiac dise_ase may ever, these are not exactly related conditions.
result in increased intestinal permeability to The intraepitheliallymphocytes in lyn:t_phocytic
toxins and antigens injurious to the liver and 2) colitis are predominantly CD8-positive unlike
chronic intestinal mucosal inflammation may those of celiac disease. In addition, epithelial
represent a primary trigger. abnormalities and increased mononuclear in-
Other associated autoimmune disorders in- flammation are more prevalent in patients with
clude insulin-dependent diabetes, autoimmune lymphocytic colitis. The watery diarrhea that is
thyroid disease, Addison's disea-se, Sji::igren's characteristic of lymphocytic colitis often does
syndrome, alopecia areata, and rheumatoid not respond to a gluten-free diet.
arthritis. Approximately 5 percent of insulin- Clinical Features. The clinical spectrum of
dependent diabetics have associated celiac celiac disease is diverse and includes the follow-
disease, and one third of insulin-dependent ing forms . Typical celiac disease is fully expressed
diabetics with DQ2 have celiac disease (58,63). gluten-sensitive enteropathy associated with
It is possible that chronic autoimmune stimula- the classic features of malabsorption. The full
tion of lymphocytes in the intestine predisposes expression includes positive serology for en-
to increased formation. of other autoantibodies. domysia! and tTG antibodies and a diagnostic
Another impmtant association is with trisomy biopsy. This form of the disease usually affects
21 (Down's syndrome) (57). The prevalence of younger patients.
cellae disease is 20 times that of the general popu- In atypical celiac disease, fully expressed
lation in patients with Down's syndrome (57). gluten-sensitive enteropathy is associated with
There is a well-established relationship be- atypical manifestations including short stature,
tween celiac disease and lymphocytic colitis and anemia, and infertility.
lymphocytic gastritis (figs. 12-6, 12-7). Rectal Patients with latent celiac disease have normal
gluten challenge in patients with celiac disease small bowel villous architecture on biopsy, but
induces a mild proctitis characterized by lym- villous atrophy develops later on. Two variants
phocytosis of the rectal lamina propria (38). Pa- have been described. The first includes patients
tients with celiac disease and microscopic colitis diagnosed in childhood and who recovered com-
share certain predisposing HLA-DQgenes; how- pletely with gluten-free diet. The disease then

592
Malabsmption Syndromes

the damage and their age at presentation. The


classic presentation is that of steatorrhea with
abdominal cramps and vomiting. In infants, the
symptoms begin after weaning, when cereals
are first introduced into the diet. Signs of nu-
tritional deficiency, such as anemia, occur next
in frequency in children. Other manifestations
include failure to thrive, short stature, muscle
wasting, hypotonia, abdominal distension, and
watery diarrhea. Atypical modes of presentation
include neurologic manifestations, osteopenia,
and primary presentation with associated con-
ditions like dermatitis herpetiformis without
gastrointestinal manifestations. The most com-
mon neurologic finding is ataxia, followed by
epilepsy, cerebral calcification, cerebral white-
matter lesions on magnetic resonance imaging
(MRI), myelopathy, peripheral neuropathy, and
myopathy (25,68).
Celiac disease in adults is most often diag-
nosed in the third and fourth decades of life, but
may develop at any age. Approximately 20 per-
cent of cases are diagnosed in individuals over
the age of 60 (26). Women are more frequently
affected than men and are generally diagnosed
Figure 12-7 at a younger age. Many adult patients present
LYMPHOCYTIC GASTRITIS
with diarrhea, but as many as SO percent do not
ASSOCIATED WITH CELIAC DISEASE (17,39) . Since the introduction of highly sensi-
The gastric glands contain numerous intraepithelial tive autoantibody tests, the number of patients
lymphocytes. Lymphocytes are somewhat increased in presenting with classic features of celiac disease
number in the lamina propria. has decreased. In fact, iron deficiency anemia,
formerly regarded as an atypical presenting sign,
is now the most common presentation of adult
remains latent in these individuals even after patients (17). Iron deficiency is primarily due to
normal diet is adopted. In the second variant, a iron malabsorption. Gastrointestinal bleeding
normal mucosa was present on early biopsies while does occur occasionally, and may represent an
the patient was consuming gluten, but more typi- indicator of disease complicated by ulcerative
cal features of celiac disease develop later. jejunoileitis or malignancy.
Those with potential celiac disease never had Other extraintestinal features of the disease
biopsy changes but have characteristic immuno- include vague abdominal pain, bone disease,
logic abnormalities. HLA-DQ2 is more frequent abnormal peripheral blood smear findings, in-
in these patients and they frequently have a fertility (both male and female), amenorrhea,
first-degree relative affected by the disease. recurrent abortion or low birth weight babies,
Asymptomatic patients with positive sero- hypoglycemia, peripheral neuropathy, ataxia,
logic autoantibodies and diagnostic biopsy have and seizures (13,16,23,67). Up to 8 percent of
silent celiac disease. Patients with refractmy celiac patients are detected by mucosal changes on
disease have severe, symptomatic, intestinal at- duodenal endoscopy performed for other condi-
rophy that does not respond to at least 6 months tions like gastroesophageal reflux disease or gas-
of a strict gluten-free diet. tritis (23); 7 to 15 percent are detected through
The clinical presentation of any given patient serum antibody tests performed because of a
with celiac disease depends on the severity of family history of celiac disease.

593
Gastrointestinal Diseases

Table 12-10 munosorbent test. This test is less expensive and


EXTRAINTESTINAL SYMPTOMS OF CELIAC DISEASE
easier to perform than the test used to detect IgA
endomysia! antibodies. The test for IgA tTG has
Deficiency Manifestations a sensitivity of 95 to 98 p~rcent and a specific-
Iron Hemorrhage, hemolysis, microcytic ity of 94 to 95 percent (17,62). Like endomysia!
anemia antibody tests, sensitivity is lower in children
Vitamin BlZ Macrocytic anemia younger than 2 to 3 years.
Calcium Osteomalacia, bone pain, com- IgA and IgG Antigliadin Antibodies. The IgA
pression fractures antigliadin assay has a sensitivity of 75 to 90
Vitamin D Osteomalacia, compression frac- percent and a specificity of 82 to 95 percent.
hues The IgG antigliadin assay has a sensitivity of
Vitamin A Night blindness, follicular hyper- 69 to 85 percent and a sensitivity of 73 to 90
keratosis of the skin percent (17). Most reports suggest that tests for
Vitamin B Neuropathies antigliadin antibodies are more sensitive than
Pituitary, adrenal, Endocrine gland h ypofunction endomysia! antibody studies in infants and chil-
and parathy- dren younger than 2 to 3 years. High antigliadin
roid hormones
antibody levels, however, have been reported in
some normal individuals (64) .
Physical examination shows changes that are Assays for IgA endomysia! and IgA tTG anti-
attributable to malabsorption and deficiency of bodies are used interchangeably as first-line tests
minerals, vitamins, and other essentJal nutrients for the diagnosis of celiac disease. In patients with
(Table 12-10). The clinical presentation often IgA deficiency, IgG tTG testing is recommended
reflects the degree of malabsorption present. as the first-line serologic test. Antibody levels de-
Serologic Testing. In the last decade, the ap- crease during treatment with a gluten-free diet and
plication of serologic testing for autoantibodies are useful in assessing dietary compli~~e. An IgA
has changed the clinical evaluation of patients antigliadin antibody test is the most commonly
with malabsorption syndromes. Tests for IgA used marker to monitor response to a gluten-free
endomysia! and IgA tTG antibodies are based on diet. A normal baseline value is reached within
the target antigen tTG. IgA antigliadin antibody 3 to 6 months of dietary restriction. Currently,
(AGA) and IgG AGA evaluations are based on experience with IgA tTG antibodies in assessing
the target antigen gliadin (44). ~Antireticulin dietary response is limited.
and antismooth muscle actin antibodies are Other Laboratory Tests. Biochemical tests
additional autoantibodies that may be seen in performed in the evaluation of celiac disease
celiac patients, but are not generally evaluated patients include serum iron, folate, albumin,
in routine clinical practice. calcium, and potassium levels. Liver function
IgA Endomysia! Antibodies. Endomysia! anti- studies should be tested since serum transami-
bodies bind to the connective tissue surrounding nases are elevated in up to 40 percent of patients
smooth muscle cells (10,44). In the laboratory, with untreated celiac disease (4).
IgA endomysia! antibQdies are usually detected Peripheral blood smears show features of iron
by indirect immunofluorescence examination of deficiency anemia in the form of hypochromic
sections of human umbilical cord (69) . The test microcytic anemia with low mean cell volume
is reported as either positive or negative. The IgA (MCV) , mean cell hemoglobin (MCH), and
endomysia! antibody test has a sensitivity of 85 mean cell hemoglobin concentration (MCHC).
to 90 percent and a specificity of 97 to 100 per- Many target cells, siderocytes, Heinz bodies,
cent (10,20,44). Antibody levels decrease when and Howell-Jolly bodies are seen in patients
the patient is placed on a gluten-free diet, and with splenic atrophy. Patients with folic acid or
may become undetectable in treated patients vitamin B12 (unusual) deficiency have macro-
(33). The sensitivity of this test is lower in chil- cytosis and ovalocytosis with hypersegmented
dren younger than 2 years of age. neutrophils on peripheral blood smears.
IgA tTG Antibodies. IgA tTG antibodies are Microscopic stool examination to detect ste-
detected by an automated enzyme-linked im- atonhea as a screening test for malabsorption is

594
Malabs01ption Syndromes

Figure 12-8
ENDOSCOPIC FINDINGS IN CELIAC DISEASE
Left: The duodenal folds have the scalloped appearance typical of celiac disease.
Right: In this view, the mucosa appears atrophic with a mosaic-like appearance.

useful in the early stages of patient evaluation. tion are seen. Patients with mild to moderate
Quantitative estimation of stool fat content is disease show involvement of the proximal small
necessary to document steatorrhea. This and intestine. In severe cases, the distal small intes-
the D-xylose absorption test, however, do not tine may be affected. Barium studies can exclude
provide a specific diagnosis and are not part of other causes of malabsorption such as Crohn's
the routine workup of celiac patients. disease or bacterial overgrowth. They are pri-
Endoscopic Findings. Endoscopic examina- marily used, however, to exclude complications
tion with biopsy is considered the gold standard of celiac disease including lymphoma and car-
for the diagnosis of celiac disease. Celiac disease cinoma. Abdominal computerized tomography
can be patchy in its early stages and targeted (CT) maybe useful in documenting the presence
biopsy of affected areas is necessary. Endoscopic of hyposplenism, ascites, lymphadenopathy,
findings include loss of villi, a mosaic pattern af- and mesenteric lymph node cavitation.
fecting the mucosa, scalloping of the duodenal Microscopic Findings. Small intestinal biopsy
folds, micronodularity, and visible vascularity is not only the gold standard for diagnosing celiac
(fig. 12-8). The endoscopic findings, however, disease, but is essential in excluding other causes of
are not specific for celiac disease, as similar malabsorption, assessing the severity of the dam-
changes are seen in patients with eosinophilic age, and identifying life-threatening complications
gastroenteritis, giardiasis, tropical sprue, and of the disease. Histologic changes are seen in villi,
other diseases (SS) . A biopsy is necessary to crypts, enterocytes, and lamina propria.
define the presence and extent of injury. The Intraepithelial Lymphocytosis. The hallmark of
severity of the changes seen on biopsy appears celiac disease is intraepithelial lymphocytosis
to correlate well with the endoscopic findings. (fig. 12-9), which may be seen in the absence
Radiologic Findings. Small bowel barium of villous atrophy (fig. 12-10). Intraepithelial
studies may be normal in early celiac disease. In lymphocyte counts should be performed on
well-developed cases, intestinal dilatation and 3- to 4-J.lm, well-oriented sections. Normal
an abnormal mucosal pattern with obliteration small bowel epithelium contains up to 20
of mucosal folds, flocculation, and segmenta- lymphocytes/100 enterocytes on hematoxylin

S9S
Gastrointestinal Diseases

and eosin (H&E)-stained sections (19). Slightly


greater numbers of lymphocytes may be ob-
served in immunostained sections. Higher
numbers of lymphocytes ar~ also seen overlying
lymphoid follicles and lymphoid aggregates.
As a result, intraepitheliallymphocytes should
not be counted in these areas. According to the
modified Marsh classification for the diagnosis
of celiac disease (Table 12-11), a significant in-
crease in intraepitheliallymphocytes is defined
as more than 40 lymphocytes/100 surface or
upper crypt enterocytes. In addition, some au-
thors report that the clustering of lymphocytes
(greater than 12) in the epithelium at the tips of
Figure 12-9
the villi and extending evenly along the sides
of the villus, is strongly indicative of celiac
INTRAEPITHELIAL LYMPHOCYTES IN CELIAC DISEASE disease (21) . Others have observed a significant
Intraepithelial lymphocytes are markedly increased in increase in villus tip lymphocytes in early celiac
number in celiac disease, as shown here. Lymphocytes in
the surface epithelium in this case number more that 30/100
disease compared to controls, but did not find
enterocytes, and are concentrated at the tips of the villi. any difference in distribution of intraepithelial

...

Figure 12-10
LYMPHOCYTIC ENTERITIS
Left: Low-power view shows an essentially normal villous architecture in the small intestine.
Right: On higher power, a prominent increase in intraepithelial lymphocytes is seen despite the normal appearance of
the mucosal architecture.

596
Malabs01ption Syndromes

lymphocytes between controls and patients mitotic activity. The enterocytes at the bases of
with early celiac disease (30). Intraepithelial the crypts appear regenerative and goblet cells
lymphocytosis is not specifically diagnostic for are decreased in number.
celiac disease, but may also seen in a number Lamina Propria Changes. Edema, vascular con-
of other conditions (see Table 12-6). gestion, and a variable degree of inflammatmy cell
Enterocyte Changes. Enterocytes show non- infiltration of the lamina propria are seen in cellae
specific changes in celiac disease including disease patients. The inflammatory infilh·ate con-
attenuation of the brush border, a cuboidal sists predominantly of lymphocytes and plasma
appearance, supranuclear cytoplasmic vacuola-
tion, cytoplasmic basophilia, loss of polarity,
and loss of basal nuclear orientation (fig. 12-11). Table 12-11
Surface erosion is uncommon, but can be seen MODIFIED MARSH CLASSIFICATION
in severe cases. OF CELIAC DISEASE
Villous Atrophy. Villous atrophy in celiac dis- Marsh
ease is due to increased enterocyte destruction Type IEL" Crypts Villi
by immune-mediated injury. Villous atrophy Type 0 <40 Normal Normal
is variable in degree, with complete atrophy Type 1 >40 Normal Normal
only present in severe cases (fig. 12-12). Villous
Type2 >40 Hypertrophic Normal
atrophy is nonspecific, and can be seen in other
conditions as well (see Table 12-5). Type 3a >40 Hypertrophic Mild atrophy
Crypt Hype1plasia. Crypt hyperplasia and Type 3b >40 Hypertrophic Marked atrophy
elongation accompany the villous atrophy (fig. Type 3c >40 Hypertrophic Absent
12-13). The proliferative zone of the crypt is "IEL = lntraepithelial lymphocytes/100 enterocytes.
expanded and there is an increase in enterocyte

Figure 12-11
ENTEROCYTE CHANGES IN CELIAC DISEASE
A: The surface epithelial cells appear cuboidal and nearly
flattened. Few goblet cells are identifiable. Note the large
number of intraepitheliallymphocytes.
B: The normal brush border is no longer recognizable .
C: Supranuclear vacuolization of the enterocyte
cytoplasm is seen focally.

597
Gastrointestinal Diseases

Figure 12-12
VARIABLE VILLOUS ATROPHY IN CELIAC DISEASE
A: This biopsy shows a mildly altered villous architecture.
Many villi are still identifiable.
B: Biopsy from another patient with celiac disease shows
more prominent villous blunting.
C: Complete villous atrophy is seen in another patient.

cells, although eosinophils, and ~~ometimes, the duodenum. The microscopic features be-
neutrophils are also seen (fig. 12-14). The pres- come less severe and patchier in the distal small
ence of cryptitis and crypt abscesses is very un- bowel, particularly in the ileum.
usual in patients with celiac disease, and points The severity of the histologic changes does
to another etiology such as infection or Crohn's not correlate well with the clinical signs and
disease. IgA-, IgG-, and !gM-producing cells symptoms. The extent of the small intestinal
are increased 2- to 6-fold, with IgA-producing disease, however, does correlate with the clinical
cells predominating. As a result, patients with severity the disease. Celiac patients with severe
IgA deficiency and celiac disease show a lower villous atrophy can be asymptomatic provided
intensity of chronic inflammatory infiltration that the length of involved small bowel is short.
in the lamina propria. Immunophenotypically, On the other hand, minimal histologic changes
lamina propria T lymphocytes in celiac patients involving a longer segment of intestine can be
are CD4-positive and intraepithelial T lympho- associated with clinical symptoms. It has been
cytes are CD8-positive, a distribution that is suggested that in clinically severe disease, a
· similar to that seen in normal mucosa. longer length of small intestine is exposed to
As previously mentioned, the histologic higher concentrations of dietary gluten.
changes of celiac disease are often patchy in dis- Histologic Response to Gluten-Free Diet. Table
tribution. As a result, multiple biopsy specimens 12-12 shows the chronology of the clinical and
from endoscopically normal and abnormal histologic responses to a gluten-free diet. Partial
areas should be examined in order to establish villous atrophy is seen in more than SO percent
the diagnosis. The histologic changes are most of patients on a gluten-free diet. The degree of
pronounced in the second and third parts of intraepithelial lymphocytosis, however, does

598
Malabs01ption Syndromes

Figure 12-13
CRYPT HYPERPLASIA IN CELIAC DISEASE
The crypt is markedly elongated and villi were com-
pletely absent from the mucosal surface. The number of
intraepitheliallymphocytes is increased. Figure 12-14
CELIAC DISEASE
decrease with gluten restriction, and is probably Top: The lamina propria contains a mixed inflammatory
infiltrate composed of lymphocytes, numerous plasma cells,
a more specific indicator of dietary response and variable numbers of eosinophils.
than is villous atrophy. The resolution of abnor- Bottom: Neutrophils are present in some cases, as seen
mal histologic changes occurs distal to proximal here.
in the small intestine. Therefore, it may take
more than 6 months of gluten restriction before The prognosis is excellent for those patients
histologic improvement is seen in the duode- who are diagnosed early, and adhere strictly
num. In some patients, histologic improvement to the gluten-free diet. Late diagnosis or non-
may take as long as 2 years (24). compliance with dietary restrictions may result
Treatment and Prognosis. Removal of glu- in malnutrition and debilitation. In general,
ten from the diet is essential for the treatment both treated adult and pediatric patients have
of patients with ·celiac disease, and generally is life expectancies similar to those of the general
required lifelong. Symptomatic response to the population (12,36).
institution of a gluten-free diet is often rapid,
with many patients responding within 48 hours COMPLICATION S AND RELATED
(50); in others, weeks or even months may be DISORDERS OF CELIAC DISEASE
required before clinical remission is achieved.
Refractory Sprue
In addition to a gluten-free diet, patients with
severe celiac disease may require supplemental Definition. Refi·actory sprue is defined as
therapy to correct nutritional deficiencies re- symptomatic, severe villous atrophy that does
lated to malabsorption. not respond to a strict gluten-free diet for at least

599
Gastrointestinal Diseases

Table 12-12
Collagenous Sprue
DIETARY RESPONSE IN CELIAC DISEASE
Definition . Collagenous sprue is diagnosed
Normal Diet
Malabsorption
histologically and is characterized by the devel-
Flat small intestinal biopsy (absent or severely blunted opment of a subepithelial collagen band thicker
villi) with : than 10 Jlm.
Damaged surface epithelium Demography. Collagenous sprue typically
Numerous intraepitheli.allymphocytes
Chronic inflammation in lamina propria
affects patients with a long history of celiac
Crypt hyperplasia disease, but has been regarded by some as a
Short-Term Gluten-Free Diet (1 Week to 3 Months)
distinct entity.
Early onset of clinical improvement Clinical Features. The typical clinical his-
Within days, evidence of diminish ed surface epithelial tory is of a patient with celiac disease who
damage initially responded to a gluten-free diet, but
Reduced number of intraepithelial lymphocytes
Reduced chronic inflammation
subsequently became refractory to treatment.
Mild to moderate villous atrophy Microscopic Findings. The small bowel bi-
Gluten-Free Diet >3 Months opsy shows a variable degree of villous atrophy
Villi gradually become normal and other features typical of celiac disease. In
No crypt hyperplasia addition, a prominent subepithelial collagen
Decreased mitoses band is present (fig. 12-15). This thickened col-
Chronic inflammation diminished
lagen table can be highlighted with the use of
Gluten Challenge
Early increase in intraepitheliallymphocytes
a trichrome stain.
Eventual return of all other histologic abnormalities Treatment and Prognosis. Although patients
Malabsorption rehnns with collagenous sprue should be given a trial
of a gluten-free diet, the prognosis is poor and
many patients develop other complicati-ons such
as ulcerative jejunoileitis and lymphoma (73).
6 months. Since refractory sprue is a diagnosis
Ulcerative Jejunoileitis
of exclusion, the possibilities of inadvertent
gluten ingestion and other causes of villous Definition . Ulcerative jejunoileitis is an un-
atrophy including disaccharidas!;_! deficiency, common, but serious complication of celiac
protein enteropathy, and bacterial overgrowth disease, characterized by multiple, chronic small
should be ruled out. intestinal ulcers. Although this entity has been
Etiology. Recent evidence suggests that re- regarded by many as synonymous with lym-
fractory sprue may represent a manifestation phoma, ulcerative jejunoileitis without any
of an aberrant clonal intraepitheliallymphocyte- evidence of lymphoma has been documented
mediated neoplastic process. Cellier et al. (71) in a few cases (75) .
demonstrated that intraepitheliallymphocytes in Clinical Features. The ulcers affect adults,
patients with refractmy sprue represent a mono- generally after many years of malabsorption.
clonal population that lacks CD8, a marker found Patients typically present with worsening of
in normal intraepitheliallymphocytes. These his- their malabsorption symptoms, abdominal
tologically undetected monoclonal T cells may be pain, and complications including obstruction,
designated Clyptic intestinal T-cell lymphoma (72). perforation, and hemorrhage (74). Patients are
The lymphocyte-induced injmy leads to intestinal often diagnosed late in the course of the dis-
'"·'
ulceration and lymph node cavitation in some ease (74) . Radiographic studies, and in some
patients. In some, but not all, the condition pro- cases laparotomy, are required to establish the
gresses to full-blown lymphoma. diagnosis. Intestinal perforation and peritonitis
Treatment. At present, patients with sus- may develop.
pected refractory sprue are given a trial of glu- Pat hologic Findings. The linear and shal-
cocorticoids. In steroid-unresponsive cases, a low ulcers have a transverse orientation and
search for clonal TCR gene rearrangements and little surrounding fibrosis, but are morpho-
immunostains for CD8 are advised. logically nonspecific, usually multiple, and

600
Malabs01ption Syndromes

Figure 12-15
COLLAGENOUS SPRUE
A: This duodenal biopsy was taken from a patient
with long-standing celiac disease who recently became
symptomatic despite strict adherence to a gluten-free diet.
The biopsy shows features typical of celiac disease including
villous atrophy, crypt hyperplasia, and intraepithelial
lymphocytosis. In addition, the subepithelial collagen table
appears thickened.
B: Trichrome stain highlights the thickened collagen.
C: In contrast, a trichrome stain from another patient
with celiac disease shows a barely discernible subepithelial
collagen layer.

predominantly jejunal in location (fig. 12-16).


Histologically, the bases of the ulcers consist of
purulent exudate overlying granulation tissue
and fibrosis. The inflammation extends into the
submucosa or even the muscle. The serosa may
appear edematous and inflamed.
Treatment and Prognosis. Surgical excision
is the most effective therapy. Some patients
respond to glucocorticoids and azathioprine.
Diffuse or multifocal enteropathy-associated
T-cell lymphoma develops in the majority of
untreated patients.
Enteropathy-Associated T-Cell Lymphoma
Definition. Enteropathy-associated T-cell
lymphoma (EATL) is a T-cell lymphoma that
occurs in the setting of celiac disease. It is a
life-threatening complication that occurs in a
small percentage of patients. Figure 12-16
Demography. A variable incidence in EATL
ULCERATIVE JEJUNOILEITIS
has been reported, ranging from 3 to 15 percent.
Endoscopic view demonstrates the presence of numerous
Lymphoma usually occurs late in the course of ulcers within the small intestine.

601
Gastrointestinal Diseases

Malabsorption in Acquired
celiac disease, frequently 20 to 30 years after
Immunodeficiency Syndrome
the original onset of the disease. As a result, it
is seen in an older age group, with the majority Opportunistic bacterial, fungal, or protozoal
of patients more than SO years of age. infections; impaired oral intake; acquired im-
Clinical Feat ures. The clinical features of munodeficiency syndrome (AIDS)-associated
EATL are similar to those of refractory sprue and motility disorders; drug-induced injury; and
ulcerative jejunoileitis. Radiographic studies malignancy affecting the small intestine are all
may show a mass lesion. The overall prognosis causes of malabsorption in human immunode-
is extremely poor, with a 5-year survival rate of ficiency virus (HIV)-positive patients. HIVI AIDS
approximately 10 percent. is discussed in detail in chapter 11.
Other Malignancies POSTOPERATIVE
Small bowel adenocarcinoma is the most com- MALABSORPTION SYNDROMES
mon nonlymphomatous malignant neoplasm
Extensive Small Bowel Resection
seen in celiac patients. Patients may also devel-
op nodal lymphomas and carcinom<as in other The severity and type of malabsorption that
gastrointestinal sites, the oropharynx, or breast. occurs following small bowel resection depend
upon the length and portion of small intestine
INFECTIONS CAUS ING MALABSORPTION resected. Jejunal resection leads to water and
nutrient malabsorption. Ileal resection leads to
Bacterial Overgrowth ~
malabsorption of vitamin B12 and disruption of
Bacterial overgrowth occurs following intesti- bile acid-mediated absorptive processes. When
nal resection, gastrectomy, or in patie!lts with the ileocecal valve is compromised loss of neu-
diverticulosis or stasis due to disorders affecting rohumoral mechanisms, slow intestinal transit
intestinal motility. Bacterial overgrowth leads to time, and bacterial overgrowth contiibute to
malabsorption due to increased deconjugation the malabsorption.
and dehydroxylation of bile salts, rendering The symptoms are worst in the immediate
them unavailable for absorption of fat. In ad- postoperative period. Later, intestinal adaptation
dition, unconjugated bile salts and bacterial in the form of hypertrophy and hyperplasia of the
proteases damage the brush border, decreasing remaining intestine occurs. This increases absorp-
absorption. Bacteria also compete for nutrients. tion of some nutrients and symptoms improve to a
The diagnosis is established by an appropriate ce1tain extent. Careful pathologic examination of
clinical history and radiologic examination. the resected bowel segment is necessary to exclude
Biopsy has no role in this diagnosis, other than an additional etiology of malabsorption.
to exclude other causes of malabsorption.
Gastric Surgery
Other Infections
Rapid transit through the stomach, hypo-
Multiple protozoal organisms may infect acidity leading to bacterial overgrowth, and
the small intestine and result in malabsorp- dilution of pancreatic enzymes by rapid empty-
tion. Common organisms include intracellular ing of gastric liquid are some of the mechanisms
protozoa such as Isospora and microsporidia causing malabsorption following gastric surgery.
and extracellular organisms such as Giardia Unlike small bowel resection, the malabsorption
and Clyptosporidium. Whipple's disease, tropical is mild and not specific to any nutrients.
sprue, viral gastroenteritis, and bacterial infec-
tions also cause malabsorption. Infections with SYSTEM IC DISEASES
such organisms reduce the absorptive capacity CAUSING MALABSORPTION
of the small intestine as a result of their inva-
Systemic Mastocytosis
sion of the epithelium or by the damage they
cause to the brush border. Infections leading to Definition . Systemic mastocytosis is a clonal pro-
malabsorption are discussed in detail in chapters liferation of mast cells, which accumulate in skin,
10 and 11. bones, lymph nodes, and parenchyma! organs.

602
Malabsmption Syndromes

Demography. Mastocytosis in children is mucosal edema, and clumps of mast cell infil-
generally limited to skin manifestations (84). trates in the lamina propria (fig. 12-17). Large
Adult-onset mastocytosis is usually a systemic numbers of mast cells infiltrate the lamina
disease that results from a clonal proliferation propria, muscularis mucosae, and submucosa,
of mast cell precursors. with aggregates of mast cells within the gland
Etiology. Systemic mastocytosis is associ- lumens and evidence of glandular destruction.
ated with activating mutations in the c-kit Eosinophils may also be seen. Immunohisto-
gene within mast cell progenitor cells. The chemical stains for tryptase or CD117 highlight
protein product of c-kit is a receptor tyrosine the presence of the mast cells (fig. 12-17).
kinase that is activated when bound by stem
Diabetes Mellitus
cell factor, the major mast cell growth and dif-
ferentiation factor (7 6, 78,84). Gastrointestinal Diabetes mellitus can cause malabsorption by
symptoms occur as a result of the release of several different mechanisms. There is a known
active mediators from the proliferating mast association between insulin-dependent diabe-
cells or from infiltration of tissues by these tes and celiac disease. Diabetics may also have
neoplastic cells. abnormalities in pancreatic exocrine secretion
Clinical Features. Eighty percent of patients and develop bacterial overgrowth leading to
present with dermatologic findings, usually malabsorption. Steatorrhea occurring in the
urticaria pigmentosa (87). Typical symptoms absence of these conditions in diabetic patients
include pruritus, flushing, tachycardia, asthma, may be attributed to rapid intestinal transit.
and headache, all thought to result from the
Endocrine Abnormalities
release of histamine from the proliferating mast
cells (80,81). Fifty to 80 percent of patients have Hypothyroidism is associated with celiac dis-
gastrointestinal symptoms, including peptic ul- ease and partial villous atrophy. Malabsorption
cers, malabsorption, steatorrhea, nausea, vom- associated with hypothyroidism is characterized
iting, copious watery diarrhea, and abdominal by the failure of multiple endocrine organs due
pain (80-82). These features are also thought to autoimmune damage (autoimmune poly-
to be due to effects of histamine and prosta- glandular syndrome type 1). Hyperthyroidism
glandins on the intestinal and gastric epithelia can cause malabsorption by altering intestinal
(77,79-81,85). Symptoms are often induced secretion and altering intestinal transit time.
by alcohol consumption (80). The hyperhista- Other endocrinopathies that may result in
minemia produces gastric hypersecretion (77, malabsorption include Addison's disease and
83). Gastric acid levels correlate with the degree hypoparathyroidism.
of histaminemia and with the presence of acid
Collagen Vascular Diseases
peptic disease, including peptic duodenitis
(77,83). The release of mediators from mast cells Collagen vascular diseases, particularly sclero-
results in increased intestinal permeability and derma, cause malabsorption as a result of their
altered smooth muscle function (88). Malab- effects on gastrointestinal motility. In patients
sorption may also be related in part to mucosal with scleroderma or other connective tissue
infiltration by mast cells. diseases, the muscularis propria may undergo
Endoscopic and Radiologic Findings . atrophy and fibrous replacement, resulting in a
Endoscopically, urticaria-like lesions are seen predisposition to bacterial overgrowth (fig. 12-
in the gastrointestinal tract. Radiographically, 18). Associated vasculitis may also contribute
"bulls-eye" lesions resembling metastases, to impaired nutrient absorption.
edema, thickened folds, and a nodular mucosal
pattern may be present (86). Small intestinal IMMUNOLOGIC DISORDERS
involvement may be suggested radiographi-
Selective lgA Deficiency
cally by the presence of small nodular filling
defects, particularly in the duodenum. Definition. Selective IgA deficiency is a condi-
Microscopic Findings. Histologic changes tion in which the major mucosal immunoglobu-
include mucosal villous atrophy, marked sub- lin, IgA, is not produced.

603
/

Gastrointestinal Diseases

Figure 12-17
SYSTEMIC MASTOCYTOSIS
A: Low-power photomicrograph demonstrates mild
villous blunting in a patient with systemic mastocytosis.
B: The lamina propria contains numerous infiltrating
cells including eosinophils and mast cells. Mast cells also
appear to be infiltrating the glandular epithelium.
C: An immunostain for mast cell tryptase highlights the
mast cell infiltrate.

Demography. Selective IgA deficiency is the The presence of suppressor cells specific for IgA
most common immunodeficiency in Caucasians, synthesis causes the abnormalities (89).
occurring in about 1/600 individuals in the gen- Most patients have defective B-cell matura-
eral population (95,97). The incidence varies, tion with abnormal terminal differentiation of
however, depending on the population being membrane IgA-positive B cells into IgA-secreting
studied. Published figures range from 1/400 in plasma cells. A smaller percentage of individuals
Finland to 1/1,500 in Japan (91). IgA deficiency have a defect in the immune regulation of a pu-
is 10 to 15 times more common in patients with tative suppressor T cell that selectively inhibits
celiac disease than in tli.e general population. IgA production.
Etiology. In most cases, the cause of the Clinical Features. Many patients with selec-
immunoglobulin deficiency is unknown. The tive IgA deficiency lack clinical abnormalities due
disease may be congenital or induced by viral in- to a compensatory increase in IgM (90). Other
... fections, leukopenia, and drugs (89,92,94,96,98, patients, especially if deficient in IgG subclasses,
100-102). Unusual cases result from deletion present with diarrhea, malabsorption, autoim-
of an IgA gene on chromosome 14 (100). Selec- mune disease (93,99,103), or bacterial infections,
tive IgA deficiency is associated with extended including gastrointestinal, sinus, and respira-
HLA haplotypes that include either a C4A null tory infections. Patients with IgA deficiency
allele (C4AQO), 21-hydroxylase gene deletions also frequently have antibodies directed against
in the HLA class III region, or rare class IIIC cow's milk and ruminant serum proteins, im-
gene haplotypes (98), especially in Caucasians. munoglobulins, thyroglobulin, and collagen.
These haplotypes are rare in blacks and Asians. Selective IgA deficiency leads to depletion of

604
Malabs01ption Syndromes

Figure 12-18
LUPUS ERYTHEMATOSUS
A: Low-power view of a segmen t of colon resected from
a patient with lupus erythematosus and severe generalized
gastrointestinal dysmotility. The muscularis propria is
extremely thin and atrophic.
B: Higher-power view shows atrophy of the smooth
muscle and fibrosis.
C: The fibrous tissue is highlighted with a trichrome
stain.

IgA-producing plasma cells in the lamina pro- levels of immunoglobulins and an inability to
pria. Serum IgA levels are low to undetectable. mount an antibody response to antigens. Syn-
Pathologic Findings. Biopsies in IgA-deficient onyms include acquired hypogammaglobulinemia,
patients may appear completely normal with a adult-onset hypogammaglobulinemia, and dysgam-
seemingly full complement of lymphocytes and maglobulinemia
plasma cells in the lamina propria, especially Demography. CVID is the second most com-
in adults. In some patients, slightly decreased mon primary immunodeficiency, following isolated
numbers of lymphocytes and plasma cells are IgA defidency. It affects 6 to 12/1 million live births
seen. Immunohistochemical analysis for im- (105,111,117). The disorder is almost equally dis-
munoglobulins demonstrates that the lamina tributed between the sexes. The disease is usually
propria plasma cells produce IgM and IgG, but sporadic, but familial clustering assodated with an
not IgA. Patients.may also have evidence of coex- autosomal dominant mode of transmission occurs
isting celiac disease or bacterial infection. Rarely, in 20 percent of patients (122).
patients with a selective IgA deficiency present Etiology. The major defect in CVID is a failure
with a completely flat mucosa in the absence of of B-cell differentiation, with impaired secretion
bacterial overgrowth or Giardia infection. of immunoglobulins, but it is not clear whether
this is due to a primary B-cell defect or abnor-
Common Variable Immunodeficiency
malities in T cells. B cells in CVID are immature,
Definition. Common variab le immunodefi- and show impaired upregulation of markers
ciency (CVID) represents a heterogeneous group of activation (104,112,115). In some patients,
of immunologic diseases characterized by low a defect in IgV gene somatic hypermutation

605
- Gastrointestinal Diseases

Figure 12-19
COMMON VARIABLE IMMUNODEFICIENCY
Left: At low power, the biopsy features of common variable immunodefiency (CVID) appear quite similar to those of
celiac disease. There is prominent blunting of the villi and crypt hyperplasia.
Right: Higher-power view shows numerous mitoses in the hyperplastic crypts. (Courtesy of Dr. John Hart, Chicago, IL.)

is present, an abnormality that results in the panied by a deficiency in jejunal brush border
production of immunoglobulins with reduced enzymes (108). Achlorhydria, due to the pres-
or absent affinity for antigens (120). In aadition ence of chronic atrophic gastritis, is seen in 33
to B-cell abnormalities, CVID patients also show to SO percent of patients (116). Patients·develop
abnormalities in T cell function. CVID patients a pernicious anemia-like syndrome with intrinsic
exhibit decreased T-cell proliferation and acti- factor deficiency, gastric atrophy, loss of parietal
vation, defective antigen-driven response, and cells, and low vitamin B12 levels. Lactose and
reduced production of cytokines (113,118,123). gluten intolerance may result from mucosal in-
Since some cases of CVID appear to be fa- flammation and increased mucosal permeability.
milial, an active search for the responsible ge- Pathologic Findings. Histologically, variable
netic abnormality has been sought. Haplotype degrees of villous atrophy are seen, and in some
analysis and linkage studies indicate that the cases, the histologic picture closely resembles
HLA-DQJDR locus is the major site of involve- that seen in celiac disease (fig. 12-19). In con-
ment (119). An association between CVID and trast to celiac disease, however, a marked intra-
homozygosity for genes encoding HLA class II epithelial lymphocytosis is not present. In addi-
molecules, especially HLA-DQ, has been report- tion, the lamina propria in CVID appears variably
ed (109). In some patients, there is an associa- cellular, with a distinct absence of plasma cells
tion with the TNF-a +488 A allele (121). In one (fig. 12-20). Other inflammatory cells, including
recent study, 4 of 32 patients with adult-onset eosinophils and neutrophils, may be present.
CVID demonstrated a homozygous deletion of Infection, particularly with Giardia, should be
the ICOS gene, an inducible co-stimulator found ruled out microscopically in all patients.
•.·
on activated T cells (114). Treatment and Prognosis. The mainstay of
Clinical Features. Chronic and recurrent therapy for patients with CVID is replacement of
sinopulmonary infections are the hallmark of immunoglobulins. As a result, patients receive im-
the disease (106,124,125). Approximately 60 munoglobulin intr·avenously every 3 to 4 weeks.
percent of patients with CVID develop diarrhea Some patients report side effects from therapy
(126). Twenty to 30 percent of patients have such as fatigue, malaise, vomiting, chills, and fe-
mild to moderate malabsorption frequently due ver. Rarely, anaphylactic reactions occur. In some
to small intestinal infection with Giardia. The patients with impaired T-cell function, long-term
CVID-associated enteropathy may be accom- tr·eatment with IL-2 has been administered (11 0).

606
Malabs01ption Syndromes

Figure 12-20
COMMON VARIABLE IMMUNODEFICIENCY
Left: The lamina propria appears hypercellular as in celiac disease, but plasma cells are absent from the infiltrate.
Right: The surface epithelium contains scattered neutrophils, but the prominent increase in intraepitheliallymphocytes
characteristically seen in celiac disease is not present. (Courtesy of Dr. John Hart, Chicago, IL.)

Overall, the 20-year survival for CVID patients toms (127). Diarrhea may be mediated by
following diagnosis is 64 to 67 percent (107). In rapid intestinal transit time due to autonomic
comparison, the 20-year survival rate is 92 to 94 neuropathy and intestinal myopathy. Malab-
percent for individuals in the general population. sorption may occur because the deposition of
amyloid is a physical barrier to nutrient absorp-
Other Immunodeficiency Conditions
tion. In addition, the motility disorder that
Leading to Malabsorption
occurs in patients with amyloidosis may result
Severe combined immunodeficiency and chronic in bacterial overgrowth. Symptoms that occur
granulomatous disease are other disorders in as a result of involvement of other organs may
which malabsorption can occur. Malabsorption help in establishing the diagnosis.
is not the primary mode of presentation in pa- Microscopic Findings. The small intestinal
tients with these conditions. The basic injury biopsy shows amyloid deposition around blood
leading to malabsorption is recurrent infection vessels, and in the lamina propria, muscle layer,
by a variety of microorganisms. and enteric nerves. The changes may be patchy
in distribution. Congo red stains or immuno-
Autoimmune Enteropathy
stains for amyloid protein are confirmatory.
Autoimmune enteropathy is a rare cause of mal-
absorption. Antienterocyte antibodies, and in LIPID MALABSORPTION
rare cases, antigoblet cell antibodies are present Lipid malabsorption and accumulation of
and lead to intestinal injury. Histologically, the lipids in enterocytes are seen in a number of
disease is similar .to celiac disease. Increased apop- conditions (Table 12-13).
totic activity is seen in the enterocytes. This en-
Abetalipoproteinemia
tity is discussed more extensively in chapter 14.
Definition. Abetalipoproteinemia is an auto-
Amyloidosis
somal recessive genetic disease characterized
Demography. Primmy amyloidosis involves by the virtual absence of apolipoprotein (apo)
the gastrointestinal tract and may produce B and apoB-containing lipoproteins in plasma.
malabsorption, primarily in elderly individuals. It is also known as Bassen-Komzweig syndrome.
Clinical Features. Diarrhea, steatorrhea, Demography. Affected patients are usually
weight loss, and anorexia are the usual symp- individuals of]ewish or Mediterranean descent.

607
Gastrointestinal Diseases

Table 12-13 with time, in part because affected patients learn


CAUSES OF INTESTINAL LIPID ACCUMULATION
to avoid dietary fats.
Acanthocytes are characteristically seen in
Abetalipoproteinemia the peripheral blood. Serum hypolipidemia is
Familial hypobetalipoproteinemia present, with reduced cholesterol, triglycerides,
Diabetes mellitus low density lipoproteins (LDL), and chylo-
Gluten-sensitive enteropathy microns. Patients have undetectable levels of
Cow's milk enteropathy (and related entities)
serum apolipoprotein B.
Endoscopic Findings. Examination of the
Anderson's disease (chylomicron retention disease)
small intestine demonstrates a "gelee blanche,"
Fasting states or "white hoarfrost," appearance to the muco-
Impaired chylomicron metabolism sal surface (128,130,133,137). This feature is a
Juvenile nutritional megaloblastic anemia reflection of the infiltration of mucosallipids.
Tropical sprue Microscopic Findings. On low-power ex-
amination, the villous architecture is minimally
abnormal. The diagnostic changes are seen in
the enterocytes, which appear pale with vacu-
olated cytoplasm (fig. 12-21). This appearance
Approximately one third of the cases result from is due to numerous subnuclear and apical fat
consanguineous marriages, and family studies microvacuoles within the enterocyte cytoplasm.
suggest an autosomal recessive mod~ of inheri- These cytoplasmic droplets do not stain for mu-
tance (129). The sex ratio is 1 to 1. . cin, but are positive with oil red-O. The lamina
Etiology. In abetalipoproteinemia, chy- propria may contain macrophages with bizarre
lomicron assembly is defective as a r~sult of inclusions. Acanthocytes may occasionally be
mutations in the microsomal triglyceride seen in the lumens of mucosal capillaries. In
transfer protein (MTP) (131,132,134-136) . contrast to other conditions associated with
MTP is a resident lipid transfer protein within lipid accumulation, abetalipoproteinemia is
the endoplasmic reticulum of hepatocytes and not associated with dilation of lacteals or lipid
enterocytes. It is a heterodimer composed of accumulation within the lamina propria.
a unique large subunit and a small subunit, Treatment and Prognosis. Early diagnosis
protein disulfide isomerase. It ca-talyzes the and treatment are essential to avoid growth
transport of a wide variety of neutrallipids and retardation and neuroretinal complications in
phospholipids in in-vitro assays. The absence of patients with this disease. Many of the gastro-
MTP in abetalipoproteinemiil occurs secondary intestinal symptoms can be relieved by placing
to mutations in the gene for the large subunit affected patients on lipid-poor diets. Essential
of the protein. The absence of MTP results in fatty acids may be replaced by dietary enrich-
an absence of apoB100 and apoB48 from the ment, or may be provided parenterally. Lipid-
plasma, because apoB-containing lipoprotein soluble vitamin replacement, particularly of
assembly is disrupted in. the liver and intestine. vitamin E, should be undertaken. Interestingly,
Clinical Features. At birth, infants with patients rarely achieve normal plasma alpha-to-
abetalipoproteinemia are asymptomatic. Signs copherollevels despite long-term therapy (129).
and symptoms begin within months after birth,
Familial Hypobetalipoproteinemia
once a diet rich in lipids has been started. The
r. ,· initial symptoms are diarrhea, bloating, and Definition. Familial hypobetalipoproteinemia,
vomiting. Over time, anemia, weight loss, and also known as homozygous hypobetalipopro-
failure to thrive occur. Spinocerebellar degen- teinemia, is a rare inborn error of metabolism
eration, peripheral neuropathy, and retinitis characterized by the inability to synthesize
pigmentosa occur as a result of deficiencies in the apoproteins required for the export of li-
fat-soluble vitamins (vitamin E levels are charac- poproteins from mucosal cells. By definition,
teristically extremely low). The gastrointestinal patients present with low density lipoprotein
manifestations of the disease often improve (LDL) levels in the lowest fifth percentile (140).

608
Malabsmption Syndromes

Figure 12-21
ABETALIPOPROTEINEMIA
Left: Low-power view shows the normal villous architecture.
Right: On higher power, the enterocytes are pale staining and vacuolated .

Demography. This autosomal eo-dominant recessive disease of intestinal lipid transport in


disorder is characterized by very low levels of which apoB48 is absent.
total and LDL cholesterol, triglycerides, and Clinical Features. Symptoms begin during
apolipoprotein B. Betalipoprotein levels in the first few months of life and include chronic
heterozygous individuals are about 50 percent diarrhea, significant fat malabsorption, and
of normal; these patients usually remain as- failure to thrive (142) . Unlike abetalipopro-
ymptomatic except for mild fat intolerance. teinemia, acanthocytosis rarely occurs and
Homozygous individuals suffer the sequelae neuromuscular manifestations are much less
of intestinal fat malabsorption (138,139). Al- severe. Fasting triglyceride levels are normal
though typically decreased, the LDL fraction but fat-soluble vitamins, especially A and E, are
and apoprotein B are present in blood. severely decreased. Plasma cholesterol levels
Etiology. The disease results from mutations are low but do not reach the levels observed in
in the APOB gene, leading to the formation of abetalipoproteinemia. ApoB, apoAI, and apoiV
prematurely truncated apoB proteins. are decreased. Immunoperoxidase localization
Clinical Features. Heterozygotes for familial of apoB in fasting biopsy specimens shows
hypobetalipoproteinemia are usually asymp- normal to elevated staining of the lipid-laden
tomatic, but have LDL cholesterol and apoB intestinal epithelial cells (142) .
plasma levels that are 25 to 33 percent that of Pathologic Findings. Morphologic studies
normal individuals. The clinical features seen in demonstrate that the enterocytes contain large
compound heterozygotes or homozygotes are numbers of fat particles (chylomicrons) in the
similar to those ·seen in patients with abetali- endoplasmic reticulum and the Golgi complex.
poproteinemia. Thus, the defect appears to be in the transloca-
Treatment and Prognosis. Treatment for tion of Golgi-derived vesicles to the plasma
homozygous patients includes restriction of membrane for excretion. Hence, little or no
fats from the diet. fat is observed in the intercellular spaces and
lacteals (142). The ultrastructural features dif-
Anderson's Disease
fer from those seen in abetalipoproteinemia in
Definition. Anderson's disease, also known as that chylomicrons and larger lipid vacuoles are
chylomicron retention disease, is a rare autosomal seen in the apical enterocyte cytoplasm (141) .

609
Gastrointestinal Diseases

Table 12-14 Etiology. Kwashiorkor results from severe


DRUGS AND SUPPLEMENTS protein deprivation. Nutrient malabsorption
ASSOCIATED WITH MALABSORPTION exacerbates the protein-caloric malnutrition,
Acarbose Octreotide
further damaging the gut, . impairing immune
competence, and increasing the risk of infec-
Alcohol Olestra
tions. Most organs are adversely affected due to
Antacids Oral contraceptive agents malnutrition or concomitant infections.
Anthraquinone laxatives Orlistat Clinical Features. Typical clinical findings
Biguanides Paraaminosalicylate include growth retardation, peripheral edema,
Bisacodyl Phenolphthalein a protuberant abdomen, intestinal distension,
Carbamazepine Phenytoin hepatomegaly, and characteristic changes in-
Cholestyramine Phytates volving the skin and hair. Children with kwashi-
Colchicine
orkor are typically lethargic and apathetic.
Proton pump inhibitors
Pathologic Findings. The small intestinal
Glucocorticoids Pyrimethamine
abnormalities are indistinguishable from those
Histamine-2 receptor agonists Sulfonamides of untreated celiac disease. Histologically,
Methotrexate Tetracycline • the mucosa appears flattened. The crypts are
Methyldopa Thiazides elongated and coiled, but show a lower than
Neomycin Triamterene normal mitotic index. The crypt changes are
not uniformly distributed. The villi may be
atrophic in some areas, whereas in others they
appear normal or hyperplastic (162). Epithelial
DRUG-INDUCED MALABSORPTION cell height decreases and the nuclei are arranged
Many chugs and clietaiy supplements lead to mal- irregularly. Ultrastructurally, the microvilli ap-
absorption. Some of these a1·e listed in Table 12-14. pear shortened or deformed with branching and
fusion. Free ribosomes are markedly reduced.
MALNUTRITION In fatal cases, severe hypoplasia develops along
Severe nutritional deficiency can produce with megaloblastic changes in the enterocytes.
marked small intestinal abnormalities (150) as Paneth cells are reduced in number. The lamina
is seen in the severe form of childhood malnu- propria becomes infiltrated with mononuclear
trition known as kwashiorkor. Miinutrition of cells and the basement membrane thickens
this severity seldom occurs in developed coun- (148). The presence of neutrophilic infiltrates
tries, but less severe forms may be recognized suggests a coexisting infection. Affected patients
after gastric surgery or in patients with chronic respond to reinstitution of a normal diet with
diseases. Malnutrition results from a lack of a concomitant improvement in the histologic
suitable diet, faulty metabolism, and inadequate appearance of the intestinal mucosa.
absorption of dietary constituents. Since the gas-
trointestinal mucosa is constantly renewed, it is VITAMIN DEFICIENCIES
highly sensitive to protein-calorie malnutrition.
Vitamin B12 Deficiency
Kwashiorkor
Etiology. The ileum is the primary site of
Definition. Kwashiorkor is a disease with absorption of vitamin B12. Mucosal disease or
characteristic clinical findings caused when resection of the terminal ileum leads to vitamin
physiologic stress is superimposed on chronic B12 malabs01ption. Vitamin B12 malabsorption
protein-calorie malnutrition. may also be congenital as a result of isolated
Demography. Kwashiorkor is one of the most absence of intrinsic factor secretion, a selec-
common pediatric illnesses of underdeveloped tive ileal absorptive defect known as Imerslund
areas of the world. It was first reported in Africa, syndrome, or absence of transcobalamin 11.
particularly in eastern and southern Africa, but More common causes of B12 deficiency include
can be seen in many parts of the developing autoimmune gastritis (see chapter 4), caloric
world, mainly in the tropics and subtropics. malnutrition, eating disorders, the presence of

610
Malabsmption Syndromes

ileal diseases such as Crohn's disease, or com- border appears indistinct and the nuclei of the
plicating chemotherapy. surface epithelium are rounder than normal.
Normally, vitamin B12 ingested in the food Goblet cells and Paneth cells are normal. Neu-
is released by acid digestion in the stomach. trophils and plasma cells may be seen infiltrat-
The free B12 is preferentially picked up by R ing the lamina propria.
protein secreted by the salivary glands. Bound
Vitamin A Deficiency
B12 is then transported to the small intestine
where proteolysis by trypsin releases it for sub- Vitamin A deficiency affects the mucous
sequent binding to intrinsic factor in the distal membranes, particularly of the respiratory tract
ileum. The intrinsic factor-B12 complex binds (165), but small intestinal abnormalities occur
to the brush border of ileal enterocytes and is as well. These take the form of crystalline lyso-
taken up and transported across the basolateral somal inclusions in Paneth cells (157).
membrane. Here it is picked up by transcobala-
Vitamin E Deficiency and
min II for transport to the portal circulation.
Brown Bowel Syndrome
Defects in vitamin B12 absorption can result
from decreased B12 in the diet, failed synthesis Definition. Brown bowel is a rare syndrome
of intrinsic factor as in gastritis, decreased acid characterized by lipofuscin deposition in the
release of B12, loss of ileal receptors in a host of smooth muscle cells of the muscularis propria
mucosal diseases, or defective receptors as seen of the intestine, although any part of the gastro-
in some immunologic diseases. intestinal tract may be affected. Vitamin E defi-
Clinical Features. Vitamin B12 deficiency ciency is associated with brown bowel syndrome.
results in megaloblastic anemia, leukopenia, Demography. Vitamin E deficiency occurs
thrombocytopenia, and neurologic changes alone or complicates other diseases. Brown bow-
predominantly involving the posterolateral el syndrome is endemic in the Thai-Lao ethnic
spinal tracts. group (159) and is induced in various species of
Microscopic Findings. Histologically, the mu- animals by vitamin E deprivation (164).
cosa shows macrocytosis from the deficiency state. Etiology. Vitamin E is an antioxidant that
serves to scavenge free radicals throughout the
Folate Deficiency
body. The lipofuscin pigment deposition that
Etiology. Congenital folate malabsorption is occurs in brown bowel syndrome is the result of
rare. Most cases of folate deficiency occur because oxidative injury to smooth muscle cells.
of insufficient dietary intake. Folate is found Clinical Features. Vitamin E deficiency has
in wheat flour, beans, nuts, liver, and green, been associated with both eosinophilic enteri-
leafy vegetables. It is heat labile, and therefore tis (154) and brown bowel syndrome. Patients
becomes depleted from many cooked foods. range in age from the 20s to the late 70s, with
In addition, oral contraceptives, antiepileptic an average age of 51 years (151). They present
agents, chronic diseases, malabsorption syn- with epigastric pain, mild diarrhea, and chronic
dromes, alcohol, and smoking all impede folate malabsorption. Brown bowel syndrome oc-
absorption and metabolism. casionally produces intestinal pseudoobstruc-
Clinical Features. Patients develop megalo- tion, but this is uncommon (147, 161). It is not
blastic anemia secondary to folate deficiency. known whether the pigment deposition causes
Patients with eating disorders or malnourished intestinal smooth muscle dysfunction.
alcoholics .with severe nutritional folic acid Pathologic Findings. Grossly, the outer as-
deficiency who have secondary folate deficien- pect of the bowel appears variably orange-brown
cies have gastrointestinallesions. These changes and is often retrospectively described as darker
reverse following therapy (144,149). than usual by the surgeon. The segmental or dif-
Pathologic Findings. Some patients develop fuse brownish discoloration can be appreciated
partial villous atrophy. The small intestinal villi from the serosal aspect of the gastrointestinal
appear stunted or club-shaped, and in some tract as well as on cut section (151). The disorder
areas the mucosa appears flat. The enterocytes more commonly affects the small intestine and
may also appear megaloblastic. The brush the stomach, but it can involve the colon. The

611
. Gastrointestinal Diseases

Figure 12-22
BROWN BOWEL SYNDROME
The smooth muscle cells of the muscularis propria
contain a coars ely granular, light brown pigment
(hematoxylin and eosin [H&E] stain).

esophagus may also be affected. No correlation


exists between the degree of pigmentation and
the severity of the associated symptoms-.
Histologically, the mucosa usually appears
normal, although occasionally, the villi appear
blunted. There is usually no inflammation or t' --. -·L~
""' " "

fibrosis present, although eosinophils may


populate the submucosa and muscular layer.
Coarsely autofluorescent, granular, g<2Jden brown
lipofuscin fills the smooth muscle cells of the
muscularis propria, muscularis mucosae, and
vascular walls (fig. 12-22). The pigment ap-
pears as round to oval granules, often lying in
a perinuclear or central cellular location. The
muscularis mucosae contains only minimal
amounts of pigment; however, the vascular
smooth muscle of the submucosa and subserosa
frequently contains abundant pigment granules.
The muscle fibers themselves may appear frayed.
In advanced cases, large lipofuscin deposits result
in considerable smooth muscle cell loss. In areas
of minimal involvement, the pigment is barely Figure 12-23
visible. Macrophages also contain collections of
BROWN BOWEL INVOLVING THE ESOPHAGUS
pigment, especially in the muscular layer.
A: H&E-stained section from an esophageal ulcer in a
The pigment granules are positive with pe- patient with severe malnutrition and known vitamin E
riodic acid-Schiff (PAS) after diastase digestion deficiency. Many of the smooth muscle fibers in the ulcer
and fail to stain for melanin (fig. 12-23). The base contain light brown pigment.
Fontana-Masson stain is the most sensitive stain B: Fontana-Masson stain highlights the lipofuscin
granules.
for detecting the pigment, especially when the C: The lipofuscin also stains with periodic acid-Schiff
cells contain scant amounts (fig. 12-23). (PAS).

612
Malabs01ption Syndromes

Zinc Deficiency and


Acrodermatitis Ent eropathica
mediated immunity, and recurrent viral, fungal,
and bacterial infections (152,153,163). Diarrhea
Defin ition. Acrodermatitis enteropathica is an and anorexia occur commonly, especially in
autosomal recessive inborn error of metabolism infants. Growth retardation, alopecia, weight
resulting in zinc malabsorption and severe zinc loss, and recurrent infections are prevalent in
deficiency. toddlers and schoolchildren. The diagnosis is
Etiology. Zinc is a normal constituent of more made clinically and by documentation of the
than 100 enzymes. As a result, zinc deficiency zinc deficiency. Zinc levels in serum, urine, and
has an overall detrimental effect on nucleic acid hair are approximately 50 percent of normal. Ad-
metabolism and protein and amino acid synthe- ministration of zinc supplements leads to rapid
sis, eventually leading to growth arrest. Acquired and complete recovery. Severe cases may be fatal.
deficiencies result from decreased zinc intake (as in Pathologic Fin dings. Small intestinal biop-
total parenteral nutrition), increased zinc excretion sies of zinc-deficient individuals demonstrate
(such as occurs in hepatic cirrhosis, proteinuria, focal villous shortening with mild crypt hy-
burns, and penicillamine therapy), decreased perplasia and slight infiltration of the lamina
intestinal absorption (as occurs in malabsorption propria by mixed inflammatory cells. Electron
syndromes, chronic alcoholic pancreatitis, and microscopy of Paneth cells demonstrates
Crohn's disease), and increased zinc demands (as the characteristic pleomorphic cytoplasmic
occurs in growth states, such as pregnancy or in inclusion bodies typical of acrodermatitis
patients with anemia) (143,156,158) . enteropathica (145,146). The ultrastructural
Zinc deficiency is associated with reduced abnormalities disappear after initiation of zinc
absorption of unsaturated fats and impaired therapy (145).
desaturation of linoleic and alpha-linoleic acids
Other Mineral Def iciencies
or their metabolites.
Clin ical Features. The clinical manifestations Experimental animals made selenium defi-
of zinc deficiency include rash, stomatitis, glos- cient develop eosinophilic enteritis (160). Eo-
sitis, conjunctivitis, alopecia, nail dystrophy, sinophilia also complicates magnesium deficiency
growth retardation, psychologic disturbances, (155). The magnesium deficiency prompts mast
hypogonadism, photophobia, diarrhea, an- cell degranulation and histamine release, causing
orexia, impaired wound healing, defective cell- subsequent tissue eosinophilia.

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J Dig Dis 1968;13:619-33. 141. Boldrini R, Biselli R, Bosman C. Chylomicron
retention disease- the role of ultrastructural
Abetalipoproteinemia examination in differential diagnosis. Pathol
128. Akamatsu K, Sakaue H, Mizukami Y, Yamaguchi Res Pract 2001;197:753-7.
S, Tanaka A, Ohta Y. A case report of abetalipo- 142. Bouma ME, Beucler I, Aggerbeck LP, Infante
proteinemia (Bassen-Kornzweig syndrome): the R, Schmitz ]. Hypobetalipoproteinemia with
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129. Berriot-Varoqueaux N, Aggerbeck LP, Samson- in intestinal cells: immunoenzymatic and bio-
Bouma ME, Wetterau JR. The role of the chemical characterization of seven cases of An-
microsomal triglyceride transfer protein in derson's disease. J Clin Invest 1986;78:398-410.
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663-97. Malnutrition
130. Delpre G, Kadish U, Glantz I, Avidor I. Endo- 143. Atkinson RL, Dahms WT, Bray GA, ]acob R,
scopic assessment in abetalipoproteinemia. Sandstead HH . Plasma zinc and copper in
Endoscopy1978;10:59-62. obesity and after intestinal bypass. Ann Intern
131. Narcisi TM, Shoulders CC, Chester SA, et al. Med 1978;89:491-3.
Mutations of the microsomal triglyceride trans- 144. Bianchi A, Chipman D, Dreskin A, Rosensweig
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Hum Genet 1995;57:1298-310. loblastic changes in the small-bowel epithe-
132. Ohashi K, Ishibashi S, Osuga]I, et al. Novel mu- lium. N EnglJ Med 1970;282:859-61 ~
tations in the microsomal triglyceride transfer 145. Bohane TD, Cutz E, Hamilton JR, Gall DG.
protein gene causing abetalipoproteinemia. J Acrodermatitis enteropathica, zinc, and the
Lipid Res 2000;41:1199-204. Paneth cell. A case report with family studies.
133. Scully RE, Mark EJ, McNeely WF, McNeely Gastroenterology 1977;73:587-92.
BU. Case records of the Massachusetts general 146. Braun OH, Heilmann K, Rossner ]A, Pauli W,
hospital. N Engl J Med 1992;327'!"628-35. Bergmann KE. Acrodermatitis enteropathica
134. Sharp D, Blinderman L, Combs KA, et al. Cion- zinc deficiency and ultrastructural findings .
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proteinemia. Nature 1993;365:65-9. obstruction in coeliac sprue. Neth J Med
135. Shoulders CC, Brett DJ, Bayliss]D, et al. Abetali- 1987;31:300-4.
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1993;2:2109-16. tional megaloblastic anaemia corrected by folic
136. Wetterau JR, Aggerbeck LP, Bouma ME, et al. acid therapy. J Clin Pathol 1971;24:131-5.
Absence of microsomal triglyceride transfer 150. Duque E, Bolanos 0 , Lotero H, Mayoral LG.
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'·· L'abetalipoproteinemie. A propros de deux cas. 151. Gallager RL. Intestinal ceroid deposition-
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138. Malloy MJ, Kane JP. Hypolipidemia. Med Clin 152. Golden MH, Harland PS, Golden BE, Jackson
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618
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153. Hambidge KM, Hambidge C, ]acobs M, Baum 159. Nye SW, Chittayasothorn K. Ceroid in the
]D. Low levels of zinc in hair, anorexia, poor gastrointestinal smooth muscle of the Thai-Lao
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Res 1972;6:868-74. 160. Reddy CC, Massaro EJ. Biochemistry of se-
154. Hong CB, Chow CK. Induction of eosinophilic lenium: a brief overview. Fund Appl Toxicol
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E and selenium deficiency. Exp Mol Pathol 161. Ruchti C, Eisele S, Kaufmann M. Fatal intestinal
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Br J Nutr 1985;53:47-5 3.

619
DISEASES OF THE APPENDIX

CONGENITAL ANOMALIES luminal pressure and causes mucosal herniation


Congenital anomalies involving the appen- and 2) increased muscular contractions and
dix are rare, and include congenital agenesis and muscular hypertrophy may lead to increased
complete or partial duplication (4). Appendiceal intraluminal pressure and mucosal herniation.
agenesis has an incidence of 1/100,000 appen- The mucosa herniates through areas of weakness
dices examined at the time of autopsy (3) . The in the appendiceal wall. This occurs in areas
agenesis may occur in the presence of a normal where blood vessels pass through the muscularis
cecum or in association with cecal dysgenesis. propria, or in areas weakened or destroyed by
Appendiceal agenesis also sometimes accompa- previous episodes of inflammation and necrosis.
nies ileal atresia (7), thalidomide ingestion (1), Patients with mucoceles, regardless of their
or trisomy 18. Patients with trisomy 18 usu- cause, may develop outpouchings of the ap-
ally display multiple congenital abnormalities pendiceal wall, presumably as the result of the
involving the gastrointestinal tract as well as increased pressure of the accumulated mucus in
other organ systems (3) . the appendiceal lumen. A similar mechanism
Appendiceal duplication is found in 1/12,500 may be responsible for the relatively high fre-
patients treated for appendicitis (4). Three types quency (14 percent) of appendiceal diverticu-
of appendiceal duplication exist as described by losis in patients with cystic fibrosis (10). Thick
the Cave-Wallbridge classification. Type A con- mucus accumulates in the appendiceal lumen,
sists of incomplete duplication in which both sometimes massively distending it.
appendices have a common base; type B consists Clinical Features. The symptoms of patients
of complete appendiceal duplication in which with appendiceal dive1ticulitis may mimic those
each appendix arises at a different location; and of acute appendicitis. Diverticulitis, however,
type C consists of complete duplication of the is generally seen in older patients than those
cecum in which each cecum has an accompa- with acute appendicitis, and symptom onset
nying duplicated appendix (2,6). Triplication of may be insidious, occurring over the course of
the appendix can also occur (5) . several days or weeks. In addition, some patients
complain of previous similar symptoms (12).
DIVERTICULA Gross Findings. Acquired diverticula are
Demography. Diverticula affect 2 to 3 per- commonly multiple and lie along the mes-
cent of histologically examined appendices enteric and antimesenteric borders, usually
from surgical and autopsy material (9,11). of the distal third of the appendix. Their size
They can be single or multiple, and are usually varies from 2 to 5 mm. When multiple, they
asymptomatic and discovered incidentally at may give the outer surface of the appendix a
the time of surgery for other reasons. Occasion- beaded appearance. Like their counterparts in
ally, however, they become inflamed, leading the colon, appendiceal diverticula are subject
to symptoms of acute appendicitis. Diverticula to inflammation or perforation. Fecaliths lying
affect both sexes equally. in their lumens predispose to the development
Etiology. Most appendiceal diverticula are of diverticulitis.
acquired (Sa). In one series, acquired diver- Microscopic Findings. Normal-appearing
ticula were present 10 times more frequently mucosa lines the diverticula (fig. 13-1). The walls
than their congenital counterparts (8). Several contain muscularis mucosae, submucosa, and
factors may play a role in the development of the longitudinal muscle of the muscularis pro-
appendiceal diverticula: 1) luminal obstruction pria. Acquired diverticula lack the circular mus-
with distension of the appendix increases intra- cular coat; congenital diverticula, in contrast,

621
Gastrointestinal Diseases

have all of the normal layers of the bowel wall.


When a diverticulum becomes inflamed, the
inflammation is often localized to it, but it
sometimes spreads to involve the appendix
proper, producing appendicitis or periappen-
dicitis. When extensive, the inflammation may
distort, obliterate, or disrupt the diverticulum.
Histologically, early diverticulitis is character-
ized by a peridiverticular neutrophilic infiltrate.
Later, this infiltrate is replaced by mononuclear
cells. When the inflammatory process spreads
to the periappendiceal tissues, an abscess may
result. Perforation is common in the setting of
diverticulitis (8a,ll).
INTUSSUSCEPTION Figure 13-1

Definition. An intussusception results from APPENDICEAL DIVERTICULOSIS


invagination or telescoping of the distal ap- Low-power view demonstrates several diverticula of the
pendix into the proximal appendix or cecum. appendix. Each diverticulum is lined by normal-appearing
appendiceal mucosa and submucosa, and an attenuated
Clinical Features. Appendiceal intussuscep- layer of smooth muscle.
tion is rare, occurring in 0.1 percenrof patients
undergoing appendectomy (13). It is' more com- appearance of appendiceal intussusception. In
mon in males, presents in patients of all ages, but one form of the disease, the distal appendix in-
is most frequently seen in the first decacle of life tussuscepts into the proximal appendix. In other
(14,15). The symptoms often suggest acute ap- forms, the proximal appendix intussuscepts into
pendicitis, although the lesions may also remain the cecoappendicular valvular opening or the
asymptomatic. Factors that may predispose to whole appendix intussuscepts into the cecum,
the development of appendiceal intussusception sometimes presenting as an edematous cecal
include the presence of a fetal cone-shaped ap- "polyp" that maybe seen endoscopically (19). Bi-
pendix, an unusually thin mesoaBPendix, and opsy of such "polyps" demonstrates a histologic
the presence of endometriosis, lymphoid hyper- picture that appears to be the reverse of normal
plasia, or appendiceal neoplasms (16-18,20). (fig. 13-2). The epithelium lies on the external
Endoscopic Findings. Currently employed surface and the submucosa and muscularis
endoscopes are unable to enter the appendiceal propria lie inside the mucosa. The submucosa
lumen. The stoma of the appendix opening can becomes edematous and the muscularis propria
be inspected, however, and has the appearance may appear hyperplastic, fibrotic, or as though
of a diverticulum with characteristic surround- it has been subjected to traction. The epithelium
ing folds at the convergence of the muscle lay- sometimes appears hyperplastic, inflamed, or
ers at the apex of the cecum. Occasionally, this eroded, especially if secondary ischemic damage
stoma may be the site of a polypoid growth, develops. A helpful clue to the diagnosis is the
inflammatory change, or other lesions that presence of both the circular and longitudinal
could be sampled if removed endoscopically. An layers of the muscularis propria with its my-
inverted appendiceal stump or intussusception enteric plexus in the submucosa of a polypoid
may assume a polypoid appearance and may lesion. The amount of tissue inversion seen
confound an unsuspecting endoscopist. Snaring depends on the extent ofthe intussusception.
such a lesion with a polypectomy snare could Occasionally, the appendix undergoes au-
result in perforation and resultant peritonitis. toamputation following intussusception or
Pathologic Findings. Intussusception should volvulus. The presence of cecal scarring and
be suspected when the concentric ring sign is hemosiderin in the absence of other cecal ab-
seen on ulh·asound, an appearance that probably normalities provides clues that the appendix
corresponds to the "coiled spring" radiographic was present at birth.

622
Diseases of the Appendix

Figure 13-2
INVERTED APPENDIX
A: Endoscopic view of an inverted appendiceal stump .
The lesion has a polypoid appearance.
B: Low-power view of a biopsy specimen of a "cecal
polyp." The polyp is composed of mucosa, submucosa,
and muscularis propria arranged in an "inside out" fashion .
C: Higher-power view shows the mucosa and submucosa
of the inverted appendix.

SE PTA
AMYAND HERNIA
Single or multiple, complete or incomplete
septa consisting of mucosa and submucosa may The finding of an appendix in an inguinal
divide the appendiceal lumen into compart- hernia constitutes an Amyand hernia . Acute
ments. The presence of complete septa predis- appendicitis or its complications in inguinal
poses the appendix to appendicitis. Septa occur hernias are rare, and a symptomatic appendix
most often in the second decade of life; there is lying in an inguinal hernia is not usually sus-
a clear male predominance (21). pected preoperatively (22,23).

623
. Gastrointestinal Diseases

APPENDICITIS
Demography. Acute appendicitis is one of
the most common and readily curable inflam-
matory diseases of the gastrointestinal tract.
Seven to 12 percent of the population in the
United States will develop appendicitis at some
time in their life (42). Acute appendicitis may
develop at any age, but the peak incidence is
in the second decade of life (25,26,50). Ap-
pendicitis affects males more commonly than
females, particularly during early childhood
(25,26A6,50,57). In addition, there is seasonal
variation in the incidence of acute appendicitis
n
(25 ,26,5 with a peak in the summer months.
Appendicitis occurs more commonly in West- Figure 13-3
ern than in Eastern countries, although the FECALITH
overall incidence has declined in many regions
Fecal material composed of vegetable material, bacteria,
in recent years. (25,27A8J1). This variation in and amorphous debris can be seen in the appendiceal lumen.
disease incidence is likely attributable to dietary
differences between populations (64) . Appendi-
citis develops less frequently in count'l.'ies where Both appendiceal calculi and fecaliths may
the population consumes a high-fib-er diet, as obstruct the appendiceal lumen (fig. 13-3). Fe-
opposed to a higher incidence in populations caliths are hard, but crushable, fecal material,
that consume a low-residue, high-sugar diet whereas true calculi are hard, calcified, non-
(24,27,34,56). Heredity may also play a role in crushable stones. Fecaliths and calculi form when
the pathogenesis of the disorder (31,38, 40). Fi- feces and mucus trapped in the appendiceal
nally, hygiene represents an additional etiologic lumen remain continuously bathed in minerals
factor (29,30). and become inspissated. The inspissated concre-
Although appendicitis more commonly af- tions then serve as a continuous irritant, causing
fects younger individuals, it also occurs in the pressure necrosis and ulceration. The fecalith or
elderly. The incidence of appendicitis"' in the calculus progressively increases in size until it
elderly may, in fact, be increasing due to longer obstructs the lumen and elevates distal intralu-
life expectancies. When the disease affects the minal pressure. Fecaliths occur more commonly
elderly, there is a high mortality and complica- than calculi, but calculi are more likely to lead to
tion rate (35A4A5,52). perforation and periappendiceal abscess forma-
Pathophysiology. Acute appendicitis is as- tion (61). The prevalence of calculi ranges from
sociated with luminal obstruction in most cases. less than 1 to 2 percent (66). Fecaliths are seen in
Secretions accumulate under pressure behind 2 percent of appendices removed incidentally
the obstruction and normal peristaltic drain- and in 11 percent of patients with appendicitis.
age fails to occur. The increased intraluminal Acute appendicitis may also occur secondary
pressure then leads to a compromised blood to obstruction from passed gallstones or from
flow, which in turn leads to ischemic damage. obstructing aggregates of helminths.
Mucosal damage occurs early, impairing mu- Reactive lymphoid hyperplasia causing par-
cosal defenses to infection. Once an infection tial appendiceal obstruction following some
becomes established, arteriolar occlusion by form of antigenic stimulation (infectious,
intravascular thrombi, by pressure from inflam- allergic) probably accounts for the high rate
matory edema, or by a fecalith predisposes to of appendicitis in young individuals, as they
the rapid development of gangrene, perforation, have more abundant lymphoid tissue than
and peritonitis. With age, as the appendix be- the elderly. When an older patient develops
comes progressively fibrotic, it is less likely to appendicitis, one should suspect, and rule out,
distend from partial obstruction. appendiceal obstruction due to a neoplasm of

624
Diseases of the Appendix

the appendix (e.g., carcinoid) or of the cecum Table 13-1


(e.g., adenoma or carcinoma). ORGANISMS ASSOCIATED WITH ACUTE APPENDICITIS
Organisms Associated with Appendicitis. No
single microorganism-bacterial, viral, or para- Bacteroides fragilis
sitic- is regularly associated with appendicitis. Bilophila wadsw01thia
In some cases, multiple organisms cause the Campylobacter jejuni
disease. Organisms enter tissues in which the Eggerthella lenta
mucosal barrier is already damaged secondary to Escherichia coli
obstruction and ischemia. The organisms com-
Fusobacterium nucleatum
monly cultured from patients with acute ap-
pendicitis are listed in Table 13-1 (28,32,55,58) . Haemophilus influenzae
The appendix may become involved in patients Klebsiella
who have a more generalized bacterial enteroco- Lactobacillus
litis, such as that caused by Salmonella, Shigella, Peptostreptococcus micros
Campylobacter, and Yersinia (see below) (36,58) . Pseudomonas
Clinical Features. Acute appendicitis initially Shigella
causes periumbilical, colicky pain that later
Staphylococcus aureus
localizes to the right lower quadrant. The pain
~ - H e molyti c Streptococcus group A
usually develops over a short period of time, and
is often accompanied by nausea, vomiting, or Streptococcus milleri
localized jejunal ileus. A mass may be palpable Streptococcus pneumoniae
on rectal examination. Fever and leukocytosis Streptococcus anginosus
develop with the onset of peritoneal inflamma- Yersinia enterocolitica
tory signs in the right lower quadrant. These
classic symptoms often do not occur in elderly
patients with acute appendicitis: abdominal
pain may be of longer duration and fever may tant sites such as the liver where they establish
be absent (45,67) . secondary bacterial infections, cholangitis, and
Atypical clinical symptoms of acute appendi- hepatic abscesses. If infective thrombophlebitis
citis may be seen when the appendix is situated occurs, the patient may develop sepsis, shock,
in an aberrant location or when inflammation and disseminated intravascular coagulopathy. If
spreads to involve adjacent organs. Occasion- the inflammation becomes walled off by fibrous
ally patients present with urogenital symptoms connective tissue, then a localized periappendi-
including right renal colic, dysuria, frequency, ceal abscess forms . Fistulas may form between
and urinary retention (39) . the appendix and other structures of the gas-
Complications of appendicitis are relatively trointestinal tract, vagina, or bladder. Other
common, particularly in very young children or complications include fibrous adhesions, lum-
in the elderly. The most common complication bar abscesses, and appendicocutaneous fistulas.
is perforation, which can lead to generalized A recurring clinical problem is that many dis-
peritonitis, periappendiceal or subdiaphrag- eases masquerade as acute appendicitis. In the
matic abscess formation, and serosal pneuma- past, the mortality associated with appendiceal
tosis. The frequency of perforation in infants perforation was so high that most patients with
is as high as so·percent, but is less (10 to 20 symptoms suggestive of appendicitis underwent
percent) in individuals aged 10 to 40 years. The laparotomy and appendectomy (47). This prac-
frequency of perforation rises to 30 percent in tice continues to some degree even today. As a
patients 60 years of age, and in those over 75, result, every pathologist will encounter an ap-
increases to 50 percent or more (49,62,67) . pendix that was removed with the clinical diag-
Suppurative pyelophlebitis is an additional nosis of appendicitis but appears histologically
complication. Infected thrombi involve the normal. The rate of negative appendectomy
small vessels of the serosa and medial appendix; in some centers is as high as 20 to 30 percent
these thrombi may extend or embolize to dis- (33,47). More recent studies in which active

625
· Gastrointestinal Diseases

Figure 13-5
ACUTE APPENDICITIS
A more advanced case of acute appendicitis than that
seen in figure 13-4 shows a purple-black serosal surface, and
Figure 13-4 an area of inflammatory exudate in the proximal portion
of the specimen. (Courtesy of the Division of Gastroin-
ACUTE APPENDICITIS testinal Pathology, Armed Forces Institute of Pathology,
Top: The serosal surface is erythematous, and a yellowish Washington, DC.)
white inflammatory exudate is present in on ~ area.
Bottom: The mucosa of the opened specimen appears
erythematous and ulcerated. · further reduces the blood flow so that gangrene
develops, causing possible rupture. By the time
observation of patients with potentia1 acute full-blown gangrenous appendicitis develops,
appendicitis was performed show lower rates the organ appears soft, purplish, and-hemor-
of negative appendectomy (47,51). rhagic, sometimes with visible thrombi in the
Endoscopic Findings. Endoscopy plays no mesoappendix (fig. 13-5).
role in the diagnosis of acute appendicitis, and Microscopic Fin dings. The gross and micro-
is contraindicated when this diagnosis is being scopic appearance of the appendix often closely
entertained. . .,. correlate with one another (53) . The histologic
Gross Findings. Acute appendicitis can be changes seen in acute appendicitis depend on the
classified as simple, gangrenous, or perforated duration and severity of the disease. They range
based on operative and pathologic features. Nor- from minimal inflammation to marked necrosis
mally, the appendiceal mucosa appears smooth with complete mural destruction and rupture. In
and light yellow-tan. The serosa is pink-tan, early lesions, neutrophils appear at the base of
smooth, and glistening. Dilatation and con- the crypts adjacent to a small epithelial defect.
gestion of serosal vessels in acute appendicitis White blood cells collect in the lamina propria
produce localized or generalized hyperemia and or in the glandular lumens, sometimes forming
constitute the earliest visible external changes. crypt abscesses (fig. 13-6). Acute inflammatory
In contrast, an appendix with well-developed cells can be easily identified migrating through
acute appendicitis shows marked congestion the vasculature (fig. 13-7). Some appendices
with a serosal granular fibrinous or purulent contain a prominent eosinophilic infiltrate (fig.
coating and vascular engorgement (fig. 13-4). 13-8). Submucosal edema and congestion are
The mesoappendix appears edematous and also often prominent. After the inflammatory
contiguous structures may become inflamed. process reaches the submucosa, it spreads quickly
Upon opening the appendix, purulent material to involve the remaining appendix. Eventually,
often exudes from the surface and an impacted the mucosa becomes eroded, the wall becomes
fecalith or calculus may be seen in the lumen. necrotic, and vascular thrombosis occurs (fig.
The acute inflammatory process can localize to 13-9). If the appendix becomes perforated, an
one segment of the organ or the entire appendix intense, nonspecific, serosal inflammatory and
may be affected. Extension of the inflammation fibrous process ensues.

626
Diseases of the Appendix

Figure 13-7
ACUTE APPENDICITIS
Neutrophils are migrating through the wall of an artery.
An adjacent vein contains a fibrin thrombus .

-
...... ,.~...'
• •- "»
':" \

...

Figure 13-6 Figure 13-8


ACUTE APPENDICITIS ACUTE APPENDICITIS
A: Patchy mucosal erosion and ulceration. The lamina Top: The mucosal inflammatory infiltrate contains
propria contains numerous neutrophils. numerous eosinophils.
B: Neutrophils infiltrate the muscularis propria. Bottom: Numerous eosinophils are also seen infiltrating
C: Neutrophils are also present in the periappendiceal fat. the muscularis propria.

627
. Gastrointestinal Diseases

Figure 13-9
ACUTE APPENDICITIS
Left: Low-power view of a specimen from the appendix of a patient with necrotizing appendicitis. There is widespread
necrosis of the mucosa and underlying tissues. The histologic changes are reminiscent of ischemic injury.
Right: Fibrin thrombi are in submucosal and mucosal vessels.

Patients who develop acute appendicitis with produces characteristic irregular granulomas
perforation are often treated with antiblotics, and containing a central zone of necrotizing inflam-
then, after a period of 6 to 8 weeks, undergo appen- mation. The granulomas contain neutrophils
dectomy. Such appendices frequently dem6nstrate and are surrounded by palisading histiocytes
the presence of granulomatous or xanthogranulo- and a cuff of lymphocytes (fig. 13-10~ (54).
matous inflammation (41). In addition, changes Eosinophils may be quite prominent. Grossly,
resembling Crohn's disease may sometimes be mesenteric lymph nodes appear enlarged, mat-
seen, including transmural lymphoid aggregates, ted, fleshy, and reddish gray with central yellow-
mural fibrosis, distortion of crypt architecture, ish microabscesses. The histologic changes often
focal cryptitis, and fo1mation of cryyt abscesses. remain limited to the mucosa and submucosa,
Later signs or symptoms of Crohn's disease do not sparing the muscularis propria and serosa. Trans-
develop in these patients (41). mural inflammation may also be seen, however,
making the distinction of Yersinia appendicitis
Specific Forms of Appendicitis
from Crohn's appendicitis difficult. Organism-
Campylobacter Appendicitis. Most patients specific polymerase chain reaction (PCR) or
with Campylobacter infection are children who serologic tests establish or confirm the correct
present with a clinical picture of appendicitis. diagnosis. Crohn's disease initially presenting
The appendix may appear normal, but the as appendicitis, without associated ileocecal or
mesenteric lymph nod~s are usually enlarged other involvement, although rare, does occur.
and swollen (69). The findings resemble those Tuberculosis Appendicitis. Tuberculous
seen with Campylobacter colitis. Histologic appendicitis usually represents extension of
features include mucosal infiltration by neutro- disease from the ileocecal area or occasionally
phils and eosinophils, crypt abscesses, mucosal the urogenital tract. In extensive cases, the ap-
· edema, and histiocytic collections that may pendix may become incorporated into a large
resemble granulomas. The curved rods of Cam- granulomatous tissue mass that also involves
pylobacter organisms can be identified with the the cecum and mesoappendix. The presence
Warthin-Starry stain, electron microscopy, and of confluent, nondiscrete, necrotizing granu-
immunologic stains. lomas containing acid-fast bacilli confirms the
Yersinia Enterocolitica Appendicitis. Yer- diagnosis. In tuberculosis, the necrosis and
sinia enterocolitica is a common cause of granu- fibrosis tend to destroy the muscularis propria
lomatous appendicitis (32,54). The organism whereas in Crohn's disease the structure of the

628
Diseases of the Appendix

Figure 13-10
YERSINIA APPENDICITIS
Left: Low-power view of the appendiceal wall in a 12-year-old patient with symptoms of acute appendicitis. Two necrotizing
granulomas are present.
Right: Higher-power view shows epithelioid histiocytes, giant cells, and central necrosis.

muscularis propria is preserved, even though it lymphoid tissue of Peyer patches. As the infected
may contain granulomas. Additionally, Crohn's lymphoid follicles enlarge, they temporarily
disease-associated granulomas are almost exclu- block the outflow of luminal secretions from the
sively non-necrotizing. appendix, producing characteristic symptoms
Actinomycosis Appendicitis. Actinomyces associated with appendicitis' (fig. 13-11).
israelii is part of the normal intestinal flora Patients with viral appendicitis occasionally
in approximately 5 percent of people. Yet the undergo appendiceal intussusception; therefore,
same organism can become pathogenic, produc- a viral infection should be suspected in patients
ing chronic suppurative appendicitis. Mycelia with appendiceal intussusception without an
are easily identifiable in inflamed areas (43). obvious underlying mechanical basis.
Actinomyces israelii preferentially involves the Fungal Appendicitis. Mucormycosis is an
ileocecal area, sometimes causing formation of acute mycosis that usually develops in immuno-
a granulomatous mass or multiple sinus tracts suppressed or debilitated patients. The fungi are
that drain through the overlying skin. The ubiquitous in nature, growing as saprophytes
fluid draining from the sinuses usually contains on fruits and vegetables. They have broad, very
characteristic "sulfur granules." A dense fibrous rarely septate, haphazardly branched hyphae
connective tissue mass surrounds the actinomy- that characteristically stain deeply with hema-
cotic mycelia. It is important to recognize true toxylin. The irregular branching contrasts with
acute actinomycotic appendicitis when it occurs the regular branching seen in Aspergillus. Mucor
and treat it because it may spread locally and has a tendency to invade blood vessels, causing
cause pelvic abscesses. The diagnosis should be thrombosis and vascular dissemination. Fungi
suspected in any patient who develops sinus are demonstrable in the appendiceal lumen
tracts or fistulas following appendectomy. and invading the underlying tissues. Extensive
Viral Appendicitis. The appendix is seldom mucosal necrosis and ulceration result.
removed in patients with viral appendicitis be- Histoplasma capsulatum may be identified in
cause the disease usually remains self-limited. the appendix of individuals living in endemic
Patients often complain of generalized symptoms areas. When present, it produces granulomatous
associated with viral illness, including fever, inflammation. South American blastomycosis,
headache, pharyngitis, and myalgias. Appendi- cryptococcosis, geotrichosis, and sporotrichosis
citis results from viral infections localized to the also affect the appendix.

629
Gastrointestinal Diseases

'
i

Figure 13-11
REACTIVE LYMPHOID HYPERPLASIA
Left: The patient h ad symptoms of acute appendicitis. There is massive lymphoid hyperplasia, resulting in marked
narrowing of the appendiceal lumen.
Right: Higher-power view of the mucosa overlying the hyperplastic lymphoid follicles. No acute inflammatory infiltrates
are present. The changes are li kely due to viral infection.

transmission of the infection (3 7). Children


are especially susceptible to the infection. En-
terobiasis is more fully discussed in chapter 12.
E. vermicularis, also referred to as pinworm or
threadworm, is the causative agent. Adult female
worms measure 6 to 12 mm and males, 2 to 5
mm in length. The ova hatch in the duodenum
where the larvae malt and become sexually ma-
ture. Mating of adults takes place in the cecum,
appendix, or, occasionally, the ileum. The males
die soon after copulation; females migrate to the
perianal and perineal regions to lay eggs. The
females die shmtly after oviposition. The eggs of
Figure 13-12 Enterobius species are highly contagious and highly
ENTEROBIUS VERM/CULAR/5 APPENDICITIS resistant to commonly used disinfectants.
A cross section of a worm is seen in the lumen of th e
Adult worms are sometimes found in tissue
appendix. Th e two cuticular crests characteristic of the sections. They are most commonly identified
organism are easily seen. within the lumen of the appendix (fig. 13-12).
Usually, they fail to elicit an inflammatory re-
sponse, except for mild mucosal eosinophilia.
Enterobius Vermicularis Appendicitis. En- Severe infections cause pathologic lesions in the
terobius has a worldwide distribution, but the colon, cecum, appendix, and lower ileum, in-
1., ·
organism appears more frequently in temperate cluding superficial ulceration, petechial hemor-
and cold climates than in the tropics. Enterobius rhages, and sometimes mucosal or submucosal
vermicularis is found in approximately 3 to 4 per- abscesses (59) . The parasite only rarely invades
cent of appendix specimens in the United States the mucosa, but when it does, granulomas form.
and European countries (59, 70) . Infection rates Schistosom a Appen dicitis. Schistosomiasis,
among children in Asian countries are 25 to 75 a waterborne trematode infection, represents
percent (63). Poor sanitation, crowded habita- one of the most widespread parasitic diseases.
tion, and lack of exposure to sunshine all favor An estimated 300 million people are affected

630
Diseases of the Appendix

Figure 13-13
SCHISTOSOMA APPENDICITIS
A: Low-power view of necrotizing acute appendicitis.
B: On higher power, numerous Schistosoma ova are seen
in the appendiceal wall.
C: Ova are also in the periappendiceal soft tissues.

worldwide (60). In endemic areas, schistosomes The histologic findings resemble those seen in
are found in 1 to 15 percent of appendiceal resec- the small intestine or colon. Granulomas can
tion specimens (62,65). Granulomatous appen- form around the eggs of the dead adult or larval
dicitis develops in younger patients during the forms. Eosinophils may be quite prominent.
early phase of egg laying in the appendix when
acute granulomatous inflammation surrounds PERIAPPENDICITIS
viable ova (fig. 13-13). Concomitant tissue ne- Definition. Periappendicitis is an inflamma-
crosis, tissue eosinophilia, and neutrophil exuda- tion in the periappendiceal soft tissues.
tion ensue. Obstructive appendicitis develops in Clinical Features: A commonly encountered
older individuals. It results from fibrosis of the problem when assessing acute appendicitis is
appendiceal wall secondary to a long-standing the presence of an acute inflammation restricted
inflammatory reaction to the Schistosoma eggs; to the appendiceal serosa. In this situation, it is
these may appear calcified in tissue sections. likely that the patient has inflammatory disease
Other Parasites Causing Appendicitis. Asca- elsewhere in the abdominal cavity or pelvis
ris, Fasciola, Amoeba, Balantidium coli, Toxocara that has extended to involve the appendiceal
species, Trichuris, Rictularia, Strongyloides, Tae- serosa. Periappendicitis occurs most commonly
nia, and Capillaria hepatica may all affect the in boys below the age of 12 years and in females
appendix, either alone or in conjunction with between the ages of 17 and 21. Primary causes
infestation of other parts of the intestine. Ap- include pelvic inflammatory disease, diverticu-
pendiceal amebiasis shows the typical flask-like litis, inflammatory bowel disease, or inflamma-
ulcers seen elsewhere, a feature that should alert tion associated with intestinal tumors (Table
the pathologist to look for typical trophozoites. 13-2). Serious complications develop in a large

631
Gastrointestinal Diseases

percentage of patients preoperatively presumed Pathologic Findings. The histologic findings


to have acute appendicitis, but who are subse- reflect the duration of the inflammatory process
quently found to have periappendicitis. This and its nature. Most commonly, acute inflam-
finding suggests that establishing a diagnosis mation and edema are limited to the serosa and
of periappendicitis has clinical significance muscularis propria (fig. 13-14). In some cases,
and merits further clinical investigation into there is a prominent fibrinous exudate with
its cause (72). little associated inflammation. As the process
begins to resolve, fibrous tissue and chronic
inflammatory cells replace the acute inflamma-
Table 13-2
tion and edema, and fibrosing strands penetrate
CAUSES OF PERIAPPENDICITIS the mesoappendix.
Appendicitis in another appendiceal segment NEUROGENIC APPENDICOPATHY
Pelvic inflammatory disease
Definition . Neurogenic appendicopathy is
Ectopic pregnancy
a condition in which neural abnormalities
Urologic disease within the appendix produce symptoms that
Inflammatory bowel disease mimic acute appendicitis. This condition is also
Colonic neoplasms referred to as neurogenic appendicitis and new·o-
Colitis immune appendicitis.
Colonic diverticular disease Pathologic Findings. The rate of negative ap-
Abdominal aortic aneurysm
pendectomy in patients with symptoms sugges-
tive of acute appendicitis ranges from 10 to 20
Chlamydia! infections
percent. Histologic evaluation of such appendi-
ces reveals the presence of distinct neuroma-like
lesions in from 45 to 57 percent of cases, (7 4,7 5).

Figure 13-14
PERIAPPENDICITIS
A: The appendix was removed from a patient with
a tuboovarian abscess . The subserosa is thickened and
contains inflammatory cells. The remainder of the
appendix, however, appears normal.
B: Higher-power view of the appendiceal mucosa shows
no evidence of inflammation.
C: High-power view shows acute appendiceal serositis.

"··

632
Diseases of the Appendix

Figure 13-15
MYXOGLOBULOSIS
Left: There is a rounded collection of mucinous material containing rare cells.
Right: Higher-power view of the relatively acellular mucin making up the lesion.

These lesions are characterized histologically as time of laparotomy or autopsy. Perforation is an


collections of pale-staining, spindle-shaped cells infrequent complication, with the usual conse-
located within the lamina propria or in an area quence of either peritonitis or pseudomyxoma
of fibrous obliteration. These cellular aggregates peritonei. In some perforated appendices, the
stain with S-100 protein. The significance of white globules become walled off by fibrous
this finding remains controversial, although adhesions in a pericecal collection.
one recent study found that appendices dem- Grossly, the characteristic finding is a group
onstrating such neuromatous collections also of opaque white globules consisting of calcified
produced the neurotransmitters substance P and amorphous material without an underlying
vasoactive intestinal peptide (73). The elabora- architecture. The factors that lead to the trans-
tion of such substances may be associated with formation of mucin into the globular masses
the symptoms of abdominal pain that these are unknown. The lesions may form around a
patients report. Other studies have shown that mucin or necrotic tissue core that acts as a nidus
histologically noninflamed appendices from for the concentric deposition of mucin.
patients with symptoms of acute appendicitis
frequently produce inflammatory cytokines PROGRESSIVE FIBROUS OCCLUSION
including tumor necrosis factor alpha, inter- Definition. Progressive fibrous occlusion refers
leukin-2, cyclooxygenases 1 and 2, and prost- to a process in which the normal appendiceal lu-
aglandin E2 (76,77). men is obliterated and replaced by fibrous tissue.
Etiology. Fibrous occlusion (fibrous oblit-
MYXOGLOBULOSIS
eration) probably occurs as part of the natural
Definition. Myxoglobulosis is a variant of aging process. The process starts distally and
appendiceal mucocele characterized by the progresses proximally, eventually resulting in
presence of mucinous, occasionally calcified, the loss of the normal appendiceal mucosa and
pearl-like globules in the lumen of the appendix Peyer patches. Fibrosis replaces the mucosa and
(fig. 13-15) (78,79). The distinctive features of submucosa (fig. 13-16).
the globules have given rise to terms such as Pathologic Findings. Distal fibrous occlusion
''ftsh-egg" or "caviar" appendix. may be accompanied by neural hyperplasia. The
Clinical and Pathologic Features. The incidence of neural hyperplasia varies geographi-
incidence of myxoglobulosis ranges between cally, but it is more common in countries with a
0.35 and 8.0 percent of mucoceles (78,79). The high incidence of appendicitis. A Western-style
lesions can present clinically as acute appen- diet may induce the hyperplasia, possibly even-
dicitis or may be an incidental finding at the tually resulting in the formation of carcinoid

633
Gastrointestinal Diseases

vaguely whorled pattern. These features may be


best appreciated using immunostains for neural
markers such as S-100 protein, PGP9.5, or Leu-7.
FOREIGN BODIES
Foreign bodies lodged in the appendix may
cause localized appendicitis. Fecaliths represent
the most common foreign body encountered
(80, 80a), accounting for about 44 percent of
all foreign objects found in the appendix. Other
common foreign materials include barium and
parasites. Almost every other type of conceiv-
able foreign body may be present, such as pins,
nails, bubble gum, teeth, and seeds.
DRUG EFFECTS
Drugs affect the appendix in a manner similar
to that seen in the remainder of the intestines.
Chemotherapy severely depletes the normal
lymphoid tissues, producing a hypocellular
lamina propria and loss of Peyer patches. The
epithelial cells may appear necrotic or megalo-
blastic. Thalidomide is associated with appen-
diceal agenesis (81,82).
INFLAMMATORY BOWEL DISEASE
Both ulcerative colitis and Crohn's disease may
affect the appendix. The diagnosis of appendiceal
ulcerative colitis and Crohn's disease relies on a
Figure 13-16 combination of clinical manifestations, radio-
FIBROUS OBLITERATION OF THE APPENDIX logic features, and morphologic findings. When
Top: Low-power view of a cross section of the distal
the disease remains isolated to the appendix,
portion of the appendix. The lumen has been obliterated as happens in fewer than 5 percent of patients,
by a proliferation of loose connective tissue. one must rely on the histologic features alone
Bottom: Higher-power view demonstrates the presence (83,87,89) . The histologic changes resemble
of numerous pale-staining spindled cells admixed
with lymphocytes and plasma cells. Several clusters of
those seen in the remainder of the colon.
lymphocytes are present, which represent the remains of Crohn's Disease
the submucosal lymphoid aggregates characteristically seen
in the normal appendix. The appendix is involved in as many as
SO percent of patients with evidence of ileal
tumors. The distinction between neural hy- Crohn's disease (87). Appendiceal disease can
perplasia, neuroma, and normal is subjective. also be found synchronously with disease at a
When the neural proliferation is associated with considerable distance from the ileocecal region,
fibrosis or when the histologic pattern becomes such as in the rectum or upper small intestine.
disorganized, resembling that seen in amputa- Grossly, the appendix appears enlarged,
tion neuroma, we prefer to designate the prolif- thickened, and sometimes adherent to the ter-
eration as hyperplasia. Histologically, there are minal ileum or cecum. Mesenteric lymph nodes
small nodules of Schwann cells with spindled may be enlarged. A transmural mixed cellular
comma-shaped nuclei and scant indistinct infiltrate, consisting of lymphocytes, plasma
cytoplasm. These are aggregated in onionskin- cells, neutrophils, and eosinophils, is usually
like lamellae in a myxoid stroma, producing a present (fig. 13-17). The prominent transmural

634
Diseases of the Appendix

Figure 13-17
CROHN'S DISEASE INVOLVING THE APPENDIX
The appendiceal mucosa shows evidence of distortion
of the crypt architecture and active inflammation with the
formation of crypt abscesses.

inflammation is characterized by fibrosis and


giant cell epithelioid granulomas. The deep
submucosa and muscularis propria/serosa junc-
tion are particularly involved by the disease,
although granulomas can be seen anywhere.
Granulomas often lie in a paravascular or para-
lymphatic location. Lymphoid aggregates lie in
the thickened serosa and are associated with the
granulomas. Hypertrophy of the muscularis pro-
pria develops in about half of the cases. Other
findings include marked mucosal ulceration, fo-
cal crypt inflammation, crypt abscesses, fissures,
ulcers, perforation, abscess formation, neural
hyperplasia, and sometimes, subserosa! fibrosis.
An accompanying spectrum of acute inflam- Figure 13-18
mation also occurs. Epithelioid granulomas are GRANULOMATOUS APPENDICITIS
often seen in the periappendiceallymph nodes. IN A PATIENT WITH CROHN'S DISEASE
The histologic differential diagnosis includes A: Numerous well-formed, compact, non-necrotizing
other entities that produce granulomatous ap- granulomas are present in the mucosa.
pendicitis (fig. 13-18) including tuberculosis; B: The mucosa contains abundant lymphoid tissue, but
is not actively inflamed.
yersiniosis; parasitic, fungal, and actinomycotic C: Higher-power view shows one of the compact sarcoid-
infections; and sarcoidosis. like granulomas. A multinucleated giant cell is present.

635
Gastrointestinal Diseases

Figure 13-19
ULCERATIVE COLITIS INVOLVING THE APPENDIX
A: Focal ulceration of the appendiceal mucosa.
B: There is architectural distortion of crypts as charac-
terizes inflammatory bowel disease.
C: Higher-power view of the mucosa shows a large crypt
abscess and dense chronic inflammation of the lamina
propria.

Ulcerative Colitis "'


Perforation may also develop (92). Endometriosis
Approximately 50 percent of patients with usually involves the serosal surface or the mus-
ulcerative colitis have appendiceal involvement cular layers of the appendix, and only rarely
(85), usually in continuity with cecal involve- involves the mucosa. Grossly, endometriosis ap-
ment. Isolated appendiceal ulcerative colitis pears as discrete brownish foci, although more of-
may also be seen in some patients with left sided ten it is an incidental histologic finding that was
disease that spares the proximal bowel (" cecal not appreciated grossly. Both endometrial glands
patch") (84-86,88). It may be very difficult to and stroma are associated with variable amounts
distinguish between acute appendicitis and ul- of fibrosis and hemosiderin deposition.
cerative colitis, particularly if the entire clinical
Endosalpingiosis
history is unknown. The histologic features of
ulcerative colitis in the appendix are identical Endosalpingiosis, the ectopic location of be-
'-,• to those in the colon (fig. 13-19). nign glandular epithelium resembling that lining
the normal fallopian tube, often involves the
GYNECOLOGIC ABNORMALITIES peritoneal surfaces. It can also be encountered on
AFFECTING THE APPENDIX the serosal surface of the bowel, including the ap-
pendix (90,91), where it affects either the serosa
Endometriosis
or the muscularis propria. The distinction of this
Endometriosis affects approximately 1 percent lesion from endometriosis is relatively straight-
of appendices (94,95). It can present as appendi- forward because the endometrial epithelium
citis or appendiceal intussusception (93,96,97) . and stroma, areas of periglandular hemorrhage,

636
Diseases of the Appendix

and hemosiderin-laden macrophages present in


endometriosis are absent in endosalpingiosis.
The identification of mtillerian types of cells
differentiates this lesion from mesonephric
remnants and mesothelial inclusion cysts. The
absence of goblet cells precludes a gastrointes-
tinal origin.
Decidual Nodules
Decidual nodules may stud the appendiceal
serosa (fig. 13-20). The masses of decidual cells
may be quite prominent. Histologically they
resemble decidua found elsewhere. This change
is usually seen in those who are pregnant or are
undergoing a postpartum tubal ligation with Figure 13-20
elective appendectomy.
DECIDUAL NODULES
MUCOCELE A small cluster of decidualized cells is present on the
serosa of the appendix. This patient had recently been
Definition. The term mucocele refers to any pregnant.
dilatation of the appendiceal lumen resulting
from mucus accumulation, but it does not indi-
cate a specific pathogenic mechanism or under- mucin content and the appendix swells and
lying histologic diagnosis . Both neoplastic and becomes hyperdistended with inspissated eo-
non-neoplastic lesions can produce a mucocele. sinophilic secretions (fig. 13-22). Appendicitis
Clinical Features. Non-neoplastic mucoceles results when the lumen is obstructed by the
occur in middle-aged individuals, and affect thick secretions. Symptomatic patients often
both sexes equally. Patients often present with present with appendiceal abscesses at the time
abdominal pain, with or without a palpable of surgery (98,99).
mass. The mucocele results from obstruction
of the appendiceal lumen. NON-NEOPLASTIC POLYPS
Pathologic Findings. Progressive accumula-
Hyperplastic Polyps
tion of mucinous debris within the appendix
causes cystic dilatation associated with flatten- Localized, small hyperplastic polyps arise in
ing and atrophy of the epithelium (fig. 13-21). the appendix but their incidence is unknown.
The wall of the appendix may be focally fibrotic Histologically, they resemble hyperplastic polyps
and contain chronic inflammatory cells. Rup- occurring elsewhere in the large intestine. The
ture of a retention mucocele produces localized glands have serrated lumens lined by benign
mucin accumulations that are usually easily epithelium demonstrating an orderly progression
resectable. The mucin does not reaccumulate of cellular maturation. The collagen table appears
under these circumstances. The epithelium thickened and cytologic atypia is absent.
lining a non-neoplastic mucocele may also Sessile serrated polyps and serrated adenomas
become hyperplastic, resembling that seen in also affect the appendix. Differentiation of these
hyperplastic polyps. lesions from hyperplastic polyps is important
because they are associated with an increased
CYSTIC FIBROSIS risk for the development of adenocarcinoma.
The common denominator for the gastroin-
Other Polyps
testinal abnormalities occurring in the setting
of cystic fibrosis is abnormal mucus production. Both Peutz-Jeghers and juvenile polyps can af-
In the appendix, increased numbers of hyperdis- fect the appendix as part of a more generalized
tended goblet cells line the entire length of the syndrome. They resemble similar polyps arising
crypts. The goblet cells release their abnormal elsewhere in the gut.

637
Gastrointestinal Diseases

Figure 13-21
NON-NEOPLASTIC MUCOCELE
A: A dilated appendix is filled with thick mucinous
material.
B: Low-power view shows im attenuated appendiceal
wall and abundant luminal mucin.
C: The mucosa appears flattened and atrophic. No
adenomatous changes are present in this mucocele.

Figure 13-22
CYSTIC FIBROSIS
Left: The appendiceal lumen is filled with dense eosinophilic mucinous secretions.
Right: The epithelium contains numerous hyperdistended goblet cells and dilated crypt lumens.

638
Diseases of the Appendix

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Gastrointestinal Diseases

91. McCluggage WG, Clements WD. Endosalpin- 96. Sakaguchi N, Ito M, Sano K, Baba T, Koyama M,
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of a case with perforation and review of the Endoscopic appendectomy in a case of appen-
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93. Nycum LR, Moss H, AdamsJQ, Macri CL Asymp- mimicking a cecal polyp. Am J Gastroenterol
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855-8.

"'

'•

642
14 MISCELLANEOUS
INTESTINAL DISORDERS

EOSINOPHILIC D ISEASES mucosal epithelial villi, increased protein loss


from the gut, and increased absorption of for-
Food Allergy
eign antigens. Eosinophils, lymphocytes, and
Demography. Up to 45 percent of the popu- monocytes are attracted to the reaction site
lation report adverse reactions to food (1). The where they release additional inflammatory
incidence appears to be increasing, although mediators and cytokines. Repeated ingestion of
this may reflect increased reporting of allergic an allergen stimulates mononuclear cells to se-
symptoms by patients and physicians (2). Food crete histamine-releasing factors, some of which
sensitivity occurs particularly commonly in interact with IgE molecules bound to basophil
infants and young children. and mast cell surfaces (3) . If significant mast cell
Etiology. Numerous antigens may play a role degranulation occurs, mast cell mediators may
in the pathogenesis of conditions loosely termed provoke potentially fatal systemic anaphylaxis.
"food allergies," and many conditions are associ- Clin ical Features. The clinical manifesta-
ated with an allergy to food (Table 14-1). Patients tions of food allergy vary widely in location,
with diseases such as eczema and asthma exhibit severity, and time of onset, and correlate with
a clear-cut relationship between exposure to in- the site and extent of mast cell degranulation.
gested allergens and symptom development. A The principal organ systems affected by allergic
definitive diagnosis of a food allergy requires the food reactions are the intestinal tract, skin, and
demonstration of an unequivocal clinical reac- lungs. In some patients, the signs and symptoms
tion after a controlled food challenge and elimi- of an immediate reaction remain limited to the
nation of the symptom complex subsequent to gastrointestinal tract, with cramping, bloating,
removal of the offending food. nausea, vomiting, diarrhea, growth failure in
Pathophysiology. The increased susceptibil- children, and weight loss in adults. Factors such
ity of infants to food allergic reactions results as the quantity and quality of the food ingested,
from their general immunologic immaturity and the presence of other existing medical con-
and the overall immaturity of their gastroin- ditions, may also influence the clinical features.
testinal tracts (4,5). The majority of allergic
reactions to food are immunoglobulin (lg)
E-mediated, mast cell-dependent, immediate Table 14-1
hypersensitivity type reactions. The interaction
CONDITIONS ASSOCIATED WITH FOOD ALLERGY
of an antigen with an antibody or immunocyte
triggers the allergic reaction. It is mediated by Systemic an aphylaxis
soluble factors from activated neutrophils, mast Rhinitis
cells, and macrophages, or by direct membrane Conjunctivitis
interactions between immune cells and antigens Asthma
on their cell surfaces. Released cytokines and Allergic alveoliti s
inflammatory mediators act directly on the epi-
Celiac disease
thelium, endothelium, or muscle, or indirectly
Cow 's milk prot ein enteropathy
through nerves and mesenchymal cells. The
Urticaria
immediate consequences of these mediators
include a local change in vascular permeability, An gioedema
stimulation of mucus production, increased Atopic eczema
muscle contraction, stimulation of pain fibers, Dermatitis h erpetiformis
recruitment of inflammatory cells, edema of

643
. Gastrointestinal Diseases

Gross Findings. Affected regions of the gastro- Table 14•2


intestinal tract may appear grossly unremarkable, CLINICAL SYNDROMES ASSOCIATED
or may demonstrate variable degrees of edema. WITH COW'S MILK INTOLERANCE
Microscopic Findings. Biopsies of the small Clinical
intestine may show partial villous atrophy Presentation Syndrome
with vacuolated cytoplasm, particularly at the Quick onset Acute cow's milk allergy
surface, and prominent eosinophilic infiltrates. Slow onset Cow's milk esophagitis
Eosinophils may aggregate in the lamina propria Cow's milk sensitivity enteropathy
or infiltrate into the epithelium. Since these
Cow's milk colitis
infiltrates are usually focal, multiple biopsies are
Varied Multiple food allergy
often required to make the diagnosis.
Cow's Milk Intolerance and Related Disorders
Demography. An adverse reaction to the in-
gestion of cow's milk is the most common food Pathologic Findings. Cow's milk esopha-
allergy in young children. It affects 0.1 to 7.5 gitis is characterized by dense infiltration of
percent of children in developed countries (6,7). eosinophils into the esophageal mucosa. The
Etiology. Sensitivity to cow's milk is the most histologic changes are indistinguishable from
frequent cause of an intolerance reaction, but it eosinophilic esophagitis (see chapter 3). In
also occurs with soy, egg, and wheat ingestion. cow's milk enteropathy, the intestinal mucosa
Pathophysiology. Reactions to GOw's milk typically appears thin, with patchy areas of vil-
proteins are classified clinically as quick onset lous atrophy that produce a pattern resembling
(symptoms develop within 1 hour of food inges- celiac disease (8-11). Biopsy specimens reveal
tion) or slow onset (symptoms develop mQre than flattened villi, edema, a prominent mononucle-
1 hour from food ingestion). Quick-onset allergic ar cell infiltrate of the epithelium and lamina
reactions are IgE-mediated, and do not result in propria, and an accompanying small 'number
structural gastrointestinal damage (12). Slow-onset of eosinophils. Intraepitheliallymphocytes are
reactions may also be IgE-mediated, or they may usually fewer than seen in celiac disease.
be the result ofT-cell-mediated immune reactions. Treatment and Prognosis. Patients recover
Such reactions may result in macrophage influx following elimination of milk, soy, or other of-
associated with cytokine release and d'frect damage fending antigens from the diet.
to gastrointestinal tissues (12).
Eosinophilic Esophagitis
Clinical Features. Several clinical syndromes
associated with cow's milk allergy have now Eosinophilic esophagitis most likely represents
been defined (Table 14-2). Patients with cow's food allergy. This entity is discussed in detail in
milk esophagitis present with symptoms similar chapter 3.
to those of gastroesophageal reflux disease.
Allergic Proctocolitis
Infants with cow's milk enteropathy or colitis
generally present at 1, week to 3 months of Demography. Allergic proctocolitis commonly
age with protracted vomiting, malabsorption, affects infants ranging from a few days to 1 year
diarrhea, and dehydration (lOa) . Infants with a of age (20).
more insidious symptom onset have diarrhea, Etiology. The disorder often results from
protein-losing enteropathy, iron deficiency exposure to cow's milk or soy protein in the
anemia due to chronic intestinal blood loss, formula (13,16-18). It also occurs in infants
weight loss, and failure to thrive. Fecal exami- receiving breast milk (15).
nation demonstrates occult blood, neutrophils, Clinical Features. Affected infants present
and eosinophils. The abnormalities resolve on primarily with acute rectal bleeding, with or
a cow's milk-free diet and only recur on cow's without associated diarrhea (14,19,21). Other
milk challenge. Important predisposing factors common manifestations include weight loss,
are age less than 3 years, transient IgA immu- an allergic history, ant!mia, and peripheral eo-
nodeficiency, atopy, and early bottle feeding. sinophilia (19,20).

644
Miscellaneous Intestinal Disorders

Figure 14-1
ALLERGIC PROCTOCOLITIS
Biopsy specimen from a 1-month-old infant with cow's
milk intolerance.
A: The overall mucosal architecture of the rectum is
preserved.
B: On higher magnification, numerous eosinophils
populate the lamina propria.
C: Eosinophils are also seen infiltrating the glandular
epithelium.

Gross Findings. Allergic proctocolitis involves eosinophilic infiltrate varies, not only between
any colonic segment, but the rectosigmoid is biopsies at different sites but within individual
preferentially involved. Endoscopic features biopsy specimens. Biopsy specimens appear
include focal erythema (19), a friable-appearing normal in about 50 percent of patients; in other
mucosa, and increased mucosal nodularity sug- patients, only one or two biopsies may be abnor-
gestive of lymphoid hyperplasia. Zones of en- mal. No significant correlation exists between
tirely normal mucosa separate abnormal areas. In the number of mucosal eosinophils, patient
severe cases, there is decreased mucosal vascular- age, illness duration, endoscopic appearance,
ity, multiple superficial aphthous erosions, or and type of inciting allergen.
frank ulceration covered by a surface exudate. The overall mucosal architecture is main-
Microscopic Findings. Increased numbers tained in allergic proctocolitis without histo-
of eosinophils populate the lamina propria, logic features of chronicity, such as distorted,
particularly surface epithelium, crypt epithe- branched, or atrophic crypts; Paneth cell meta-
lium, and the IflUScularis mucosae (fig. 14-1). plasia; basally located lymphoid aggregates; or
Eosinophils are characteristically present in diffuse plasmacytosis (fig. 14-1). The eosino-
large numbers (over 60 eosinophils per 10 philia is an excellent marker of infantile allergic
high-power fields in the lamina propria). In proctocolitis, but given the focal distribution of
addition, numerous intact or degranulated the lesion, multiple mucosal biopsy specimens
eosinophils may be seen in the deep mucosa must be obtained, and several levels of each
and interspersed among muscle fibers of the should be examined (13,19,20).
muscularis mucosae (13,19,20,22). Often, the Treat ment and Prognosis. Pediatric patients
eosinophilic aggregates are closely associated with allergic proctocolitis generally respond
with lymphoid nodules. The intensity of the promptly to dietary changes.

645
Gastrointestinal Diseases

Eosinophilic Gastroenteritis
neurotoxins damage gastriC nerves and muscles,
Definition. Eosinophilic gastroenteritis is a causing gastroparesis and obstruction.
diagnosis applied to a diverse group of diseases Clinical Features. The clinical manifesta-
seen in patients who share the following: 1) tions of eosinophilic gastroenteri~is correlate
gastrointestinal symptoms; 2) gastrointestinal with the depth of the eosinophilic infiltration
eosinophilic infiltrates; and 3) no demonstrable of the bowel wall and its location. A preponder-
cause of the eosinophilia such as parasitic infec- ance of eosinophils in a particular portion of the
tion or a specific allergic response. gut wall is the basis for classifying the disease
Demography. Eosinophilic gastroenteritis into mucosal, muscular, and serosal subtypes
is an uncommon condition, with an estimated (32). Patients with predominantly mucosal
frequency of less than 1/100,000 population disease experience postprandial nausea, vom-
(32). The disease affects all races and ages, from iting, abdominal pain, diarrhea, and protein-
infancy to adulthood, but the incidence peaks losing enteropathy (34). The muscular pattern
between the 2nd and 6th decades of life. The of disease results in thickening and rigidity
incidence is slightly higher in males, in a ratio of the muscularis propria, causing functional
of 3 to 2 (24,29). Approximately 70 percent of gastric outlet obstruction and motility distur-
patients have a history of allergy, inclflding hay bances. Subserosa! involvement is associated
fever, allergic rhinitis, eczema, asthma, drug with higher levels of peripheral eosinophilia
sensitivities, or elevated IgE levels (30,40,42). and bloating (45). Occasionally, patients pres-
Some patients have associated connective tissue ent with an acute abdominal emergency such
diseases, specifically scleroderma, scleroderma as acute appendicitis or intestinal perforation
variants, polymyositis, and dermatomyositis. (27) . Rare fatalities have been described (31,47).
Etiology. Food allergy has been postulated Gross Findings. Involvement of gastrointes-
as an etiologic factor in this disease since many tinal segments measuring up to SO cm in length
patients have food-specific antibodies of the IgE produces diffuse bowel thickening (24,46). A
isotype (25). In most cases, however, there is no variable degree of antral stenosis with mucosal
specific allergen that triggers the disease and some irregularity or gastric pseudopolyposis may be
patients have few or no allergic features (40). seen in the stomach on barium studies. Endo-
Pathophysiology. The mechanis"m(s) where- scopically, the bowel may appear normal or may
by eosinophilic infiltrates cause gasJrointestinal show nonspecific features such as erythema,
dysfunction remains unclear. Eosinophils are friability, erosions, ulcerations, and nodularity
attracted to the site of inflammation by eotaxin, (32). Ascites may be present, and is thought to
a substance produced by epithelial cells (23). In develop when eosinophils infiltrate the serosa
addition, eosinophils produce various cytokines, or muscularis propria.
including transforming growth factor, granu- Microscopic Findings. Establishing the
locyte-macrophage colony-stimulating factor, diagnosis of eosinophilic gastroenteritis by
interleukin (IL)3, and ILS (48). These cytokines endoscopic biopsy can be problematic (37). In
are known to be chemotactic for eosinophils, and about 10 percent of cases, mucosal biopsies are
therefore, contribute to the propagation of the nondiagnostic, either because of the sampling
inflammatory response in an autocrine fashion. error inherent in diagnosing a patchy process,
Eosinophils produce a number of inflammatory or due to mucosal sparing (fig. 14-2). In these
mediators that may contribute to tissue dam- instances, the diagnosis is established by mul-
age including leukotrienes, platelet activating tiple biopsies, full-thickness biopsy, or surgical
factor, major basic protein, eosinophil-derived resection. An eosinophil count of greater than
neurotoxin, eosinophil cationic protein, and 20 cells per high-power field is generally used
eosinophil peroxidase (32); all of these can to define eosinophilic gastroenteritis histologi-
directly damage gastrointestinal tissues. Major cally (33,45,49).
basic protein and eosinophil peroxidase also In the stomach, mucosal edema, capil-
cause indirect injury by activating mast cells and lary lymphatic dilatation, and an intense but
by releasing histamine and other potentially patchy eosinophilic infiltrate displace and
harmful substances (28,36). Eosinophil-derived destroy gastric pits and glands. Often, there is

646
Miscellaneous Intestinal Disorders

/ ..

~.<./~/~ . Figure 14-2


EOSINOPHILIC GASTROENTERITIS
A: Low-power view shows 'p rominent submucosal edema
in a resected segment of small intestine from a patient
with eosinophilic gastroenteritis. Eosinophils infiltrate the
muscularis propria and deep submucosa.
B: The mucosal architecture is preserved.
C: Higher-power view shows that the mucosa is spared
by the heavy eosinophilic infiltrates. If lesions involve the
deeper bowel layers, mucosal biopsy is often nondiagnostic.

B· ·:'t
. .it:
·:••

·. · ·~
~ <f , • •

.: :. ·:.:..
.. :: ;>,..
.. t. '• ,

a concomitant increase in the number of IgE- hyperchromatic, enlarged, and irregular, with
secreting plasma cells. Epithelial necrosis and reactive nuclei separated by eosinophils. The
degeneration develop, but frank ulceration submucosa, muscularis propria, and even the
rarely occurs. There may be pronounced hy- subserosa! soft tissue may show some degree of
pertrophy of the muscularis propria, and the eosinophilic infiltration (fig. 14-3). Sometimes
smooth muscle bundles become separated by the mesenteric lymph nodes become hyperplas-
dense eosinophilic infiltrates. Charcot-Leyden tic and infiltrated with eosinophils.
crystals can be found in these areas. In some Differential Diagnosis. Eosinophilic gas-
cases, loose granulomas develop and acute vas- troenteritis must be distinguished from other
culitis affects small arteries. Postinflammatory disorders associated with eosinophilia. These
fibrous strictures sometimes complicate in- include parasitic infections, collagen vascular
volvement of the muscularis propria. diseases, inflammatory bowel disease, and
In the small intestine, localized eosinophilic neoplastic processes including Langerhans cell
infiltrates cause crypt hyperplasia, epithelial histiocytosis and lymphoma (Table 14-3).
cell necrosis, and villous atrophy. In a minor- Treatment and Prognosis. Patients generally
ity of cases (approximately 10 percent), diffuse respond dramatically to a short course of corti-
enteritis develops, with complete villous loss costeroid therapy (33,39,45). Some patients are
producing an appearance identical to that seen treated with cromolyn sodium (26,41,49). Other
in celiac disease. Submucosal edema is com- therapies include elimination diets (30) and the
mon, and destruction of the wall and fibrosis use of antihistamines and other drugs used for
may occur (fig. 14-2). Contiguous smooth asthma therapy (ketotifen, montelukast, and
muscle fibers in the muscularis mucosae appear suplatast tosilate) (35,38,43,44).

647
Gastrointestinal Diseases

Table 14-3
INTESTINAL LESIONS CHARACTERIZED
BY EOSINOPHILIA

Parasitic infec tions


Crohn 's disease
Allergic enteritis
Eosinophilic gastroenteritis
Hypereosinophilic syndrom e and eosinophilic leukemia
Cow's milk in tolerance and related entities
Hyperimmunoglobulinemia E
Gluten-sensitive enteropathy
Peptic duodenitis
Magnesium deficiency
Vitamin E deficiency
Selenium deficiency
Toxic oil syndrome
L-tryptophan-associated mya lgia syndrome
Peritoneal dialysis
Inflammatory fibroid polyps
Non -Hodgkin's lymphoma
Hodgkin 's disease

INFLAMMATORY FIBROID POLYP


Definition . InflammatOJy fibroid polyp (IFP) is
a pseudotumorous lesion of the gastrointestinal
tract. It was first described by Vanek in 1949 (7 5),
and therefore is also known as Vanek's polyp.
Demography. IFPs are relatively rare tumors
that affect all areas of the gastrointestinal tract
(59 ,62,65) . They are most common in the
stomach and small intestine (74). Coloriic and
esophageal IFPs are rare (51,53,56,66,71,73).
Most lesions develop in adults, although some
occur in children (54,65). The average patient
is 63 years old (74) .
Etiology. IFPs are postulated to occur as a
result of a reactive process (allergic or foreign
body reaction). It is likely that the lesion rep-
resents a peculiar form of granulation tissue
(61,68) . Associated lesions include Helicobacter
pylori infection (69,71), gastric ulcer, adenoma
Figure 14-3 (61), and carcinoma (68).
EOSINOPHILIC GASTROENTERITIS Clinical Features. Man y patients with IFPs
A: Th e submucosal eosinophilic infiltration is intense. are asymptomatic (57). When symptoms do
B: Large numbers of eos inophil s ex tend into the develop, they vary depending on the site of
muscularis propria . involvement within the gastrointestinal tract
C: Subserosa! collections of eosinophils are present.
and the size of the polyp. Patients with gastric

648
Miscellaneous Intestinal Disorders

Figure 14-4
INFLAMMATORY FIBROID POLYP
Left: A polypoid mass arises in the small intestine. The mucosa overlying the polyp is, for the most part, intact.
Right: On cut section, the polyp appears to arise in the submucosa. It has a uniform, white-tan cut surface without areas
of necrosis or hemorrhage.

IFPs present with nausea, vomiting, vague abundant cytoplasm and pale, spindle-shaped
abdominal pain, anemia, or bleeding (57,72). nuclei. Occasional mitotic figures are seen, but
Patients with small intestinal IFPs present with these are not usually numerous. Atypical forms
diarrhea, small bowel obstruction, or intussus- are never present. Varying numbers of inflam-
ception (50,52,67,70). matory cells infiltrate the lesions . Eosinophils
Gross Findings. Grossly, IFPs are sessile or may be seen in large numbers, but not in all
polypoid, solitary or multiple masses ranging in cases. Multinucleated giant cells can also be
size from less than 1 to 12 cm in diameter (64) . observed. The distinction of the lesion from
Most lesions measure less than 3 cm. surrounding tissue becomes blurred and there
IFPs originate in the submucosa, where they is no pseudocapsule.
appear as circumscribed, oval to round nodules IFPs characteristically demonstrate diffuse
of firm, gray-tan connective tissue that project immunostaining for vimentin, and focal stain-
into the lumen of the stomach or intestine (fig. ing for smooth muscle actin, CD68, CD34, and
14-4). This gross appearance simulates an ulcer- CD31 (55,58,61,63). The tumors are negative
ated leiomyoma with its homogeneous white- for CD117 (55,61).
gray color and firm consistency. Occasionally, Differential Diagn osis. The differential di-
IFPs present as nodular thickenings of the wall agnosis includes inflammatory lesions as well
near an area of ulceration. Small bowel lesions as mesenchymal tumors. Eosinophils may be
sometimes extend into the muscularis propria prominent in IFPs (fig. 14-5). As a result, other
and may reach the serosa. The mucosa overlying eosinophil-containing lesions must be consid-
the polyp may be eroded or ulcerated, although ered in the differential diagnosis. Eosinophilic
it is frequently intact. gastroenteritis is distinguished from IFP by the
Microscopic Findings. Histologically, IFPs younger age of the patient, by the diffuse in-
consist of loosely structured fibrous tissue (fig. filtration of eosinophils that may involve long
14-5) . The predominant cell types are spindled bowel segments, and by the presence of pe-
fibroblast or myofibroblast-like cells inter- ripheral eosinophilia. In addition, eosinophilic
mingled with inflammatory cells. Whorls of gastroenteritis usually does not show a marked
spindle cells surround thin-walled vessels in a proliferation of fibroblasts and blood vessels.
concentric or onion-skin-like fashion. Vascular- Differentiating IFP from mesenchymal tumors
ity and cellularity vary from lesion to lesion. such as leiomyomas and gastrointestinal stromal
The spindle cells appear uniform and contain tumors is usually not difficult since these lesions

649
Gastrointestinal Diseases

Figure 14-5
INFLAMMATORY FIBROID POLYP
Left: Low-power view of a gastric inflammatory fibroid polyp. The lesion is composed of spindle cells with numerous
admixed inflammatory cells. The borders of the polyp are poorly demarcated and difficult to discern from the adj acent
submucosal connective tissue and muscle. The overlying mucosa is intact.
Right: On higher power, the tumor is composed of myofibroblast-like spindle cells and numerous inflammatory cells.
Eosinophils are particularly prominent.

Table 14-4 almost never contain abundant inflammatory


GASTROINTESTINAL DISEASES cells. In difficult cases, immunohistochemical
ASSOCIATED WITH GRANULOMAS . staining distinguishes these lesions.
Treatmen t and Prognosis. IFPs are benign
Foreign Body Granulomas
Food granulomas lesions. They may be resected endoscopically or
Suture granulomas surgically in symptomatic patients.
Barium gra nulomas
Talc granulomas GRANULOMATOUS AND
Beryllium granulomas
XANTHOMATOUS DISEASES
Infectious Granulomas ..,.
Syphilis Gastrointestinal granulomas form in many
Mycobacterial infections disorders (Table 14-4). The etiology of granulo-
Helicobacter pylori infe ction
Yersiniosis mas or histiocytic collections differ depending
Lymphogranuloma venereum on whether they are compact or loose, diffuse
Hi stoplasmosis or localized, contain giant cells or not, and are
Coccidioidomycosis
Zygomycosis associated with areas of necrosis or not. Small
Blastomycosis crypt-associated mucin granulomas complicate
Amebiasis infections and other forms of mucosal injury.
Prototheca infection
Anisakiasis Vessel-associated histiocytic collections compli-
Schistosom iasis cate certain infections, especially cytomegalovi-
Strongyloidiasis rus infection. Histiocytic cells surround foreign
Neoplastic bodies or the air spaces characteristic of pneu-
Assodated with carcinoma
Associated with lymphoma
matosis intestinalis. Necrotizing granulomatous
Lan gerhans cell histiocytosis inflammation may accompany infection with
Miscellaneous mycobacteria or fungi (see chapter 10). Small,
Crohn's disease compact granulomas are seen in Crohn's disease
Sarcoidosis (see chapter 15) and sarcoidosis.
Chronic granulomatous disease of childhood
Allergic granulom atosis and vasculitis Sarcoidosis
Wegener's granulomatosis
Tumoral am yloidosis Definition . Sarcoidosis is a systemic granulo-
Rheumatoid nodules
matous disease that preferentially affects lymph

650
Miscellaneous Intestinal Disorders

nodes, lungs, and spleen, but also involves


many other organs, including, rarely, the gastro-
intestinal tract.
Demography. Sarcoidosis is a relatively
common disease, occurring in 3 to 500 per-
sons/100,000 in Europe (88). In the United
States, the disease is seen in 5/100,000 Cau-
casians and in 40/100,000 African-Americans
(105). The disease usually affects the 20- to
40-year-old age group, and in some studies,
occurs more commonly in women (98). The
incidence of gastrointestinal involvement in
these patients is not known.
Etiology. The etiology of sarcoidosis in un-
known. Figure 14-6
Clinical Features. The gastrointestinal abnor- SUTURE GRANULOMA
malities that may occur in patients with sarcoid- Fragments of old suture material are surrounded by
osis include achalasia, gastric ulcer and localized epithelioid histiocytes and giant cells. The suture granuloma
hypertrophic gastropathy, upper gastrointestinal was taken from the serosal surface of the colon of a patient
hemorrhage, malabsorption, protein-losing en- who had previous abdominal surgery. The suture fragments
are easily seen under polarized light.
teropathy, diarrhea, hematochezia, constipation,
and abdominal pain (77, 82-84,91,94,95,108).
Lymphangiectasia may develop secondarily to lamas recognizable under polarized light by the
lymphatic obstruction from abnormal lymph presence of a distinctive "Maltese cross." Acci-
nodes (101). Small bowel or colonic obstruction dental entry of barium into the intestinal wall
has also been reported as a result of stricture during radiologic examinations may provoke
formation (78,80,86,87, 109). Rarely, colonic barium granulomas. The histiocytic collections
polyps simulating adenomas occur (110). contain birefringent granular material of a pale
Pathologic Findings. It is not possible to green calor.
make a definitive diagnosis of sarcoidosis in the
Xanthomatosis
absence of classic disease in the liver or lungs.
Histologically, gastrointestinal sarcoidosis con- Small mucosal histiocytic aggregates are en-
sists of compact, bland granulomas that lack countered throughout the gastrointestinal tract
necrosis. These may involve both the bowel wall and are most common in the rectum (fig. 14-7).
and the regional lymph nodes. If a prominent The lesions are sometimes detected endoscopi-
rim of lymphocytes and plasma cells surrounds cally as yellowish nodules. The cells comprising
the granulomas, a diagnosis of Crohn's disease these aggregates are muciphages, and presum-
should be excluded. Areas of necrosis suggest ably represent vestiges of some prior minor
the presence of an infectious process such as mucosal damage. Generalized or localized mu-
tuberculosis or Yersinia infection. ciphage collections may complicate motility
disorders (107). True xanthomatosis consists of
Granulomas As~ociated with Foreign Material
accumulations of lipid-laden macrophages that
Granulomas develop around foreign material form mural plaques or nodules. Gastrointestinal
such as talc or sutures. Suture granulomas usually xanthomatosis occurs in patients with hyper-
contain a central suture surrounded by palisad- cholesterolemia and hypertriglyceridemia (81).
ing histiocytes and foreign body giant cells (fig.
14-6). Talc granulomas typically contain foreign MALAKOPLAKIA
body type giant cells and can be distinguished Definition. Malakoplakia is a distinctive, rare
from other granulomas by the use of polarizing granulomatous lesion that usually involves the
lenses, which reveal typical birefringent crystals. urinary bladder. The colon is the most common
Starch-based glove powders also produce granu- site of extraurogenital involvement.

651
Gastrointestinal Diseases

Table 14-5
DISEASES ASSOCIATED WITH
COLONIC MALAKOPLAKIA

Inflammatory bowel disease


Neurofibromatosis
Immunodeficiency diseases
Alpha cha in disease
Miliary tuberculosis
Tuberculosis
Mycobacterium avium complex infection
Klebsiella infection
Escherichia coli infection
Lymphoreticular diseases
Villous aden om a
Carcinoma

with colonic malakoplakia have symptoms


(102) . Adults present with rectal bleeding, diar-
rhea, and abdominal pain (92) . Patients with
extensive disease experience intractable diar-
rhea, bowel obstruction, ulcers, fistulas, and
even death. Children present with fever, failure
to thrive, bloody diarrhea, and malnutrition
Figure 14-7
(79,93,89,99,103,104).
XANTHOMA Gross Findings. Endoscopically, gastrointes-
A collection of foam y histiocytes is present in the tinal malakoplakia assumes three gross forms:
superficial mucosa in this gastric biopsy. This lesio n 1) unifocallesions, 2) widespread mucosal mul-
appeared as a small yellowish white plaque at the time of
endoscopy. ..,. tinodular lesions, and 3) large mass lesions. Ra-
diographic features vary. Colonic involvement
is segmental or diffuse, with the rectosigmoid
Demography. Patients with colonic mala- and cecum being the most commonly affected
koplakia range in age from 6 weeks to 88 years. sites. Early lesions appear soft, flat, and yel-
The sex distribution is equal (79,96,100,106) . lowish tan. Later, lesions become raised and
Etiology. Malakoplakia complicates various tan-gray, with an irregular h yperemic margin
diseases (Table 14-5), including infections with and a central depressed area (85) . Submucosal
Escherichia coli, Klebsiella, and Mycobacterium lesions secondarily elevate the mucosa into
tuberculosis (9 3,9 7). soft yellow-tan plaques or nodules. Often the
Pathophysiology. Malakoplakia results from overlying mucosa appears intact.
an abnormal macrophage lysosomal response Microscopic Fin din gs. Histologic exami-
and abnormal microtubule assembly, which nation of the lesions reveals the presence of
lead to defective handling of phagocytosed bac- numerous histiocytic granular cells with eosino-
'· . teria. These abnormalities may result from an philic cytoplasm (fig. 14-8). Ultrastructurally,
immunologic defect affecting cellular digestion, these histiocytes contain giant phagolysosomes
absence of the necessary lysosomal enzymes, or containing various forms of mineralized debris
decreased levels of cyclic guanosine monophos- and partially digested bacteria (89). The pres-
phate (GMP) (76,90,93,111 ,112). ence of characteristic intracellular and extracel-
Clinical Features. The gastrointestinal tract, lular Michaelis-Gutmann bodies clinches the
particularly the colon, is the dominant site of diagnosis. Michaelis-Gutmann bodies vary in
involvement in most patients. Most patients size from 2 to 10 Jlm and have a round, dense,

652
Miscellaneous Intestinal Disorders

Figure 14-8
MALAKOPLAKIA IN A PATIENT PREVIOUSLY
TREATED FOR COLONIC ADENOCARCINOMA
A: Low-power microscopy shows a dense infiltrate
composed of chronic inflammatory cells and numerous
histiocytic cells.
B: Higher-power view shows typical targetoid, slightly
basophilic, Michaelis-Gutmann bodies in the histiocytes.
C: A small foc u s of recurrent adenocarcinoma is
surrounded by histiocytes and other inflammatory cells .

or targetoid appearance due to the presence of


concentric laminations (fig. 14-8). These stain IMMUNE-MED IATED DISEASES
blue with hematoxylin and are highlighted with
Autoimmune Enteropathy
the Von Kossa stain for calcium or with iron
stains. They also contain lipid and are periodic Definition. Autoimmune enteropathy is a life-
acid-Schiff (PAS) and Alcian blue positive. Be- threatening disorder of infancy characterized by
cause malakoplakia tends to be associated with intractable diarrhea and a constellation of as-
both adenomas and carcinomas, the tissues sociated autoimmune diseases, including mem-
should be carefully evaluated for the presence branous glomemlonephritis, insulin-dependent
of these neoplastic conditions (fig. 14-8). diabetes, hemolytic or sideroblastic anemia,
Differential Diagnosis. Malakoplakia su- autoimmune hepatitis, sclerosing cholangitis,
perficially resembles several other disorders, and hypothyroidism (120). The disease rarely
including storage diseases, Whipple's disease, occurs in adults (114,116,118).
Mycobacterium avium-intracellulare infection, Pathophysiology. Infants with autoimmune
and fungal infections because of the histiocytic enteropathy have circulating systemic antibod-
infiltrates, but none of the other disorders con- ies against enterocytes (115). The autoantigen
tain the pathognomonic Michaelis-Gutmann is a 75-kDa protein encoded on chromosome
bodies. Special stains identify the specific infec- 19p 13, and has homology to the tumor suppres-
tion in fungal or tuberculous lesions. sor MCC gene, and has therefore been named
Treatment and Prognosis. Surgical resection MCC2 (119,121,122). Some patients also have
is usually curative in limited disease. antigoblet cell antibodies.

653
Gastrointestinal Diseases

Figure 14-9
ArUTOIMMUNE ENTEROPATHY
Left: On low power, a duodenal biopsy shows villous blunting and crypt hyperplasia.
Right: The lamina propria contains a prominent lymphoplasmacytic infiltrate. Intraepithelial lymphocytes are mildly
increased in number in some areas, but not to the extent normally seen in celiac disease. Note the absence of goblet cells.

Clinical Features. Affected infants present Treatment and Prognosis. Tacrolimus may
with unexplained episodes of protracted diarrhea be useful in treating autoimmune enteropathy
and no response to dietary therapy. The diarrhea in patients who do not respond to steroids or
usually develops after the first 8 weeks of life cyclosporin (113,118). Mycophenolatc:~· mofetil
(117). The course of the disease is typically severe may also be effective (124).
and is often refractory to treatment, and as a re-
Microscopic Colitis
sult, may be fatal. Only a subset of patients has
an immunodeficiency, even though the etiology Read et al. (142) introduced the term micro-
is thought to be related to abnormaJ T-cell or B- scopic colitis to describe patients with diarrhea
cell regulation (123). Some patients demonstrate of unknown origin who had a normal barium
associated IgA deficiencies and T-cell abnormali- enema and colonoscopic examination but
ties (123). At least SO percent of patients have whose colorectal biopsies showed mucosal in-
antienterocyte antibodies as shown by indirect flammation. The histologic features of biopsies
immunofluorescent microscopy. taken from many such patients show a distinc-
Pathologic Findings. The histologic features tive lymphocytic infiltration of the colonic
may be surprisingly subtle and may involve epithelium, and therefore, the term lymphocytic
the large and small intestines. The histologic colitis has been applied to these cases (133,134).
changes may be minimal and patchy. Often, the Others show a prominent thickening of the
most consistent feature is a nonspecific increase subepithelial collagen table, and therefore, the
in lymphocytes involving both the epithelium term collagenous colitis has been used to describe
and the lamina propria. Apoptotic bodies are these biopsies.
' ·· prominent in the crypts, a finding that mimics
lymphocytic Colitis
graft versus host disease. Small bowel biopsies
may show partial or complete villous atrophy, Demography. In Europe, the incidence
crypt hyperplasia, a mononuclear cell infiltrate of lymphocytic colitis is 4 to 16 cases/100,000
of the lamina propria, and increased expression people/year (125,136,140). Lymphocytic coli-
of major histocompatibility complex (MHC) tis occurs most commonly in middle-aged or
class II antigens (fig. 14-9) (113). Goblet cells elderly patients. The median age at diagnosis
may be completely absent from the biopsies in is 65 to 70 years, and the female to male ratio
patients with antigoblet cell antibodies. ranges from 1.6-5.0 to 1 (125,131,135).

654
Miscellaneous Intestinal Disorders

Figure 14-10
LYMPHOCYTIC COLITIS
Left: A biopsy specimen from a patient with chronic watery diarrhea . The overall mucosal architecture is preserved, but
the lamina propria contains a dense mononuclear infiltrate.
Right: On higher magnification, the intraepitheliallymphocytosis is apparent in both the crypts and on the mucosal surface.

Pathophysiology. The pathogenesis of Gross Findings. Endoscopically, the bowel


lymphocytic colitis is unknown. A number almost invariably appears normal, accounting
of hypotheses, however, have been proposed. for the use of the term "microscopic" colitis.
First, the disease shows a female predominance, When changes are present, they usually in-
and therefore, may have an autoimmune or volve patchy mucosal erythema, congestion,
hormonal basis. Autoantibodies, such as an- decreased vascular markings, or mild friability.
tinuclear antibody and rheumatoid factor, are The relationship of the bowel preparation to
found in up to 50 percent of patients with lym- the endoscopic changes is not clear.
phocytic colitis (133) . In addition, patients with Microscopic Findings. The most distinctive
lymphocytic colitis commonly have associated feature of lymphocytic colitis is the presence of
autoimmune diseases including thyroid disease, increased intraepithelial lymphocytes, particu-
rheumatoid arthritis, celiac disease, and diabetes larly at the luminal surface (fig. 14-10). To be of
mellitus (129,130,135,139). diagnostic significance, the increase of lympho-
Several milk-associated or waterbome out- cytes must average at least 20 lymphocytes/100
breaks of diarrhea endoscopically and histologi- epithelial cells (126). This threshold compares
cally similar to lymphocytic colitis have been with an average of 4 to 5 lymphocytes/100 epi-
reported, but to date no associated infectious thelial cells in the normal colon, inflammatory
agent has been identified (128,137,141). bowel disease, and infectious colitis (127); a
Clinical Features. Patients with lymphocytic mean of 8.4 in GSE cases without colonic epithe-
colitis present with chronic watery diarrhea that lial lymphocytosis; and a mean of 25.0 to 32.4 in
can be intermediate or continuous, ranging in patients with lymphocytic colitis without con-
duration from 2 months to 25 years. Related current GSE (fig. 14-10) (143) . The lamina propria
symptoms include mild crampy abdominal pain, also contains increased numbers of lymphocytes
moderate weight loss, and an essentially normal and eosinophils (fig. 14-10). Occasional neutro-
physical examination. Nocturnal diarrhea and phils may be present. Unlike collagenous colitis,
incontinence may develop . Up to one third the histologic features of lymphocytic colitis are
of patients with histologic evidence of gluten- usually uniform throughout the large bowel.
sensitive enteropathy (GSE) in the small bowel Differential Diagnosis. Increased intraepi-
exhibit lymphocytic colitis and this accounts for thelial lymphocytes are common to several
the steatorrhea present in some patients (129). diseases (Table 14-6), but when diffusely present

655
Gastrointestinal Diseases

Table 14-6 Table 14-7


DISEASES ASSOCIATED WITH INCREASED COMPARISON OF FEATURES OF
INTRAEPITHELIAL LYMPHOCYTES LYMPH OCYTIC AND COLLAGENOUS COLITIS

Reflux esophagitis Collagenous Lymphocytic


Feature Colitis Go litis
Lymphocytic gastritis
Patient age Middle aged, Middle aged,
Gluten-sensitive enteropathy elderly elderly
Tropical sprue Female to male up to 20 to 1 1.6-5.0 to 1
Whipple's disease ratio
Giardiasis Collagen table Markedly Not thickened
thickened
Cryptosporidiosis
Intraepithelial Increased Markedly
Lymphocytic enteritis lymphocytes increased
Small bowel transplant rejection Distribution May be patchy Diffuse
Lymphocytic colitis Autoimmune Associated Associated
Crohn's disease diseases
Graft versus host disease Gluten-sensitive Not associated Associated
enteropathy
Human immunodeficiency virus (HIV) disease
Changes in small Occasionally Occasionally
intestine
Changes in stomach Occasionally Occasionally
they are more likely to be associated with lym-
phocytic colitis. Focal lesions, sometimes tak-
ing the form of lymphoid aggregates, are more
likely to be associated with polyps, diverticula, to 68 years, but the age range is wide (163). The
or Crohn's disease. Table 14-7 compares-collag- disorder sometimes affects children (155) and
enous colitis and lymphocytic colitis. is sometimes familial (157,168). A significant
Treatment and Prognosis. Few treatment percentage of patients have a history of using
trials have been performed to date on patients nonsteroidal antiinflammatory drugs (NSAIDs)
with lymphocytic colitis. Antidiarrheal therapy (144,152,166). Other agents such as lansopra-
with loperamide hydrochloride or diphenoxy- zole, ticlopidine, and flutamide have also been
late hydrochloride/atropine is fre.,.q uently ef- suspected, but a definite association has not
fective, particularly for patients with mild to been proven (146,167,171).
moderate diarrhea (139). If these agents are not Etiology. The female predominance of
effective, bismuth subsalicylate is beneficial in collagenous colitis and its association, like
many patients (132,138,139). Other drugs that lymphocytic colitis, with other autoimmune
have been used with variable success in refrac- diseases suggests the possibility of an autoim-
tory colitis include sulfasalazine, mesalamine, mune etiology (149a) .
or corticosteroids (138). Pathophysiology. Surface epithelial damage
appears to cause secretory diarrhea, whereas the
Collageno.us Colitis
thickened subepithelial collagen table appears
Definition. The term collagenous colitis was to represent a variable response to the surface
introduced in 1976 by Lindstrom (162) to de- damage. The injury in collagenous colitis may
scribe a disease in which patients suffered from result from bile acid malabsorption (165), mast
chronic, watery diarrhea and had accumulations cell infiltration (145,164), and use of NSAIDs
of a collagenous ground substance containing (144, 152,166), and possibly, other drugs. The de-
amorphous proteins and immunoglobulins in velopment of clinical symptoms correlates with
the subluminal colonic basement membrane, the thickness of the collagen deposits and the
at the lamina propria interface. total epithelial surface area involved (150,151) .
Demography. There is a marked female Clinical Features. Symptoms include watery,
predominance, with the female to male ratio nonbloody diarrhea with up to 20 stools per day.
ranging from 6-20 to 1 (149a,164a). The median The diarrhea can last for months, or even years.
age at which collagenous colitis presents is 58 Colicky abdominal pain occurs in up to three

656
Miscellaneous Intestinal Disorders

Figure 14-11
COLLAGENOUS COLITIS
A: An essentially normal ,:olonic mucosal architecture
is seen at low power. A prominent eosinophilic collagen
band underlies the surface epithelium, which appears to
be lifting away in a strip.
B: On slightly higher magnification, an increase in
intraepitheliallymphocytes within the surface epithelium
is appreciated. Lymphocytes number more than 10/100
colonocytes.
C: The thickened collagen table is highlighted by a
trichrome stain.

quarters of patients (149a). Nausea, vomiting, colitis, the subepithelial collagen band measures
flatulence, urgency, incontinence, and weight greater than 10 pm in thickness, and contains
loss vary in frequency. enh"apped capillaries, red blood cells, and inflam-
Joint disease, including chronic arthritis, matory cells. There is little, if any, extension of
affects some patients (149,153,169). Abnormal the thickened collagen table around the crypts.
thyroid function (149a,156,159), the CRST The thickened subepithelial layer stains light
(calcinosis, Raynaud's phenomenon, sclerodac- pink with the PAS and green with the Masson
tyly, telangiectasia) syndrome (161), and discoid trichrome stain. The changes are most marked in
lupus (148), are also associated with collagenous the proximal colon, with the distal portion being
colitis. Autoantibodies such as antinuclear and spared. The changes are often continuous, but
antireticulin antibodies or rheumatoid factor may also exhibit a patchy distribution.
are found some patients (154, 164a). Additional histologic findings include epi-
Gross Findings. The colon appears grossly thelial vacuolization and desquamation, as well
and endoscopically normal, although mild as intraepithelial lymphocytosis (fig. 14-ll).
erythema is sometimes seen. The intraepitheliallymphocytosis seen in col-
Microscopic Findings. The histologic hall- lagenous colitis, however, is not as dramatic
mark of collagenous colitis is chronic mucosal as that seen in lymphocytic colitis (147). Fo-
inflammation associated with a broad, continu- cally, the superficial lamina propria contains
ous, hypocellular, eosinophilic, linear, subepithe- slightly to moderately increased numbers of
lial fibrous band immediately subjacent to the lymphocytes, plasma cells, and mast cells ad-
surface epithelium (fig. 14-ll). In collagenous mixed with variable numbers of eosinophils

657
. Gastrointestinal Diseases

Table 14"8
FEATURES OF DISEASES THAT MIMIC COLLAGENOUS
COLITIS ON BIOPSY

Collagenous colitis: Subluminal collagen thickening,


intraepitheliallymphocytosis, inflammation in upper
mucosa.
Ulcerative colitis: Diffuse continuous process with
numerous crypt abscesses, cryptitis, glandular
destJ:uction, and signs of chronicity; no subluminal
collagen thickening.
Radiation colitis: Mucosal telangiectasia, submucosal
vascular changes, atypical fibroblasts, fibrosis .
Infectious colitis: Diffuse lamina propria inflammation,
significant neutrophils in lamina propria; usually no
subluminal collagen thickening.
Mucosal prolapse syndromes: Glandular distortion,
Figure 14-12 mucosal ulceration, mucosal fibrosis, perpendicular
COLLAGENOUS COLITIS
smooth muscle fibers in lamina propria .
Prominent eosinophils and other inflammatory cells are Ischemic colitis: Coagulative necrosis, fibrin thrombi,
architectural distortion if disease is chronic, mucosal
entrapped within the collagen layer, but are also numerous
fibrosis, glandular dropout.
in the lamina propria.
Amyloidosis: Perivascular, muscular, or lamina propria
eosinophilic deposits; positivity with Congo red stains.
Progressive systemic sclerosis: Fibrosis along all
and neutrophils (fig. 14-12). Eosinophils can basement membranes, including crypts.
be focally prominent. Damaged epithelial cells Diverticulosis: Chronic inflammation, thickened
appear flattened, mucin depleted, vacuolated, basement membranes .
and irregularly oriented. Focally, small strips of Diversion colitis: Prominent nodular lymphoitl
interglandular surface epithelium lift off their hyperplasia, ulceration, acute inflammation, aphthous
ulcers, cryptitis.
basement membrane and a subepithelial cleft
filled with neutrophils and eosinophils forms
(fig. 14-12). Despite all of these changes, the
crypt epithelium appears relativ~y normal. prolapse syndrome, fecal stream diversion, and
Frank ulceration and active inflammation may diverticular disease. Biopsies with increased
be signs of NSAID-associated injury (160) . subepithelial collagen deposition from patients
Differential Diagnosis. Subepithelial colla- without characteristic clinical symptoms gen-
gen thickening occurs in various diseases. As a erally come from the rectum or rectosigmoid.
result, the diagnosis of collagenous colitis can Since collagenous colitis generally affects the
only be made in the proper clinical and histo- proximal colon more severely, the most reliable
logic settings. Tangential sectioning of normal biopsies for the diagnosis of collagenous colitis
colonic mucosa results in an artifactually thick- come from that region. Features that distinguish
ened basement membrane and such cases can the diseases that mimic collagenous colitis are
be wrongly interpreted as collagenous colitis. listed in Table 14-8.
If biopsies lack the characteristic inflammatory Treatment and Prognosis . Spontaneous
pattern, a tangentially cut thick basement mem- remissions and relapses are characteristic; oc-
... brane should be ignored. The key to a correct casionally the disease resolves spontaneously
diagnosis of collagenous colitis is analyzing the (164b) . Symptoms may resolve following treat-
summation of various inflammatory changes ment with bismuth subsalicylate. Refractory pa-
plus the subepithelial collagenization. tients may respond to treatment with octreotide,
Other entities in the differential diagnosis are methotrexate, cyclosporine, or antibiotics (164a).
lymphocytic colitis, ulcerative colitis, ischemic Fecal stream diversion can induce clinical and
colitis, radiation colitis, amyloidosis, progres- histopathologic remission of collagenous colitis
sive systemic sclerosis, acute infectious colitis, (158) . Collagenous colitis may rarely contribute
colonic carcinoma, hyperplastic polyp, mucosal to patient mortality (170).

658
Miscellaneous Intestinal Disorders

STORAGE DISEASES be necessary to demonstrate their accumula-


A number of forms of storage disease affect tion. Thus, when a lysosomal storage disorder
the gastrointestinal tract. These include lyso- is suspected, a piece of unfixed tissue must be
somal, glycogen, and lipid storage disorders. snap-frozen for further analysis. Ultrastructural
examination confirms · the histologic changes
Lysosomal Storage Diseases
and demonstrates the characteristic ultrastruc-
Definition. Lysosomal storage diseases occur in tural features for each group of diseases.
patients with defectively functioning lysosomal
Glycogen Storage Diseases
enzymes. In these patients, the substrate of
the defective enzyme is incompletely digested Etiology. Glycogen storage disease lA (GSDlA)
and accumulates within the lysosomes, lead- results from a deficiency of the microsomal
ing to cellular dysfunction. Lysosomal storage enzyme glucose-6-phosphatase in liver, kidney,
diseases are classified into three categories: 1) and intestinal mucosa. Its activity is normal
sphingolipidoses (Gaucher's disease); 2) muco- in glycogen storage disease lE, but cytoplasmic
polysaccharidoses (Hurler's and Hunter's dis- glucose-6-phosphatase is not transported to
eases); and 3) glycogen storage disease, such as the endoplasmic reticulum by the glucose-6-
Pompe's disease. phosphate translocase Tl.
Etiology. Lysosomes contain various hydro- Clinical Features. Impaired gluconeogenesis,
lytic enzymes that function in the acid milieu fasting hypo glycemia, hepatomegaly, lactic aci-
present within lysosomes. These hydrolytic dosis, hyperlipidemia, hyperuricemia, impaired
enzymes are synthesized in the endoplasmic re- platelet function, and bleeding diathesis are
ticulum and transported to the Golgi apparatus, common to both glycogen storage diseases lA
where they undergo post-translational modifica- and lB (174). Glycogen storage disease lB is
tions. They are then transported into lysosomes additionally complicated by recurrent pyogenic
where they function to hydrolyze various macro- infections caused by apparent neutropenia and
molecules derived from the outside environment neutrophil dysfunction not observed in glyco-
or from other intracellular organelles. gen storage disease lA (183) .
The lysosomal storage disorders result from Pathologic Findings. The gross and histo-
various enzymatic defects, which include the logic features of glycogen storage disease lB are
absence of an enzyme activator or a protective indistinguishable from those of Crohn's disease,
protein, lack of a substrate activator protein, including ileal mucosal irregularities, colitis,
lack of a transport protein required for egress stenosis involving the right side of the colon,
from the lysosome, defects in post-translational and granulomatous inflammation (173, 184).
processing, or synthesis of catalytically inactive This inflammatory bowel disease-like presenta-
proteins (185). The sites where the lysosomal tion may be the result of defective neutrophil
storage disorders become manifest represent function.
those sites where the material that needs deg-
Hurler's and Hunter's Syndromes
radation occurs.
(Mucopolysaccharidoses)
Special Techniques. The lysosomal disor-
ders are usually diagnosed by enzymatic assay Etiology. Patients with mucopolysaccharidoses
of white blood cells or fibroblasts or by rectal have genetically determined deficiencies of the
biopsy. Acid phosphatase stains highlight the lysosomal enzymes involved in the degradation
cellular inclusions present in lysosomal storage of mucopolysaccharides, which lead to their
diseases. The tissues may also be examined by accumulation in the cell. Patients with Hurler 1S
PAS, Luxol fast blue, and Sudan black stains; for syndrome (mucopolysaccharidosis [) accumulate
acid phosphatase activity; and under ultraviolet heparan sulfate and dermatan sulfate, as do
light to show the accumulation of autofluores- patients with Hunter 1s syndrome (mucopolysac-
cent material. The use of both histologic and charidosis I[). Hurler's syndrome is inherited
ultrastructural examination to demonstrate as an autosomal recessive disorder, whereas
the disease is advocated. Because the stored Hunter's is inherited as an X-linked recessive
substances are often lipids, frozen sections may disorder. The mucopolysaccharides accumulate

659
. Gastrointestinal Diseases

Figure 14-13
• NIEMANN-PICK DISEASE
Left: Macrophages with vacuolated cytoplasm lie in the lamina propria of the colon.
Right: The macrophage cytoplasm is foamy with prominent round vacuoles containing sphingomyelin. (Courtesy of Dr.
Lisa Yerian, Cleveland, OH.)

within the cells due to a failure to cleave the ter- the affected macrophages contain membranous
minal sugar from the polysaccharide molecule. cytoplasmic bodies that resemble concentric la-
Clinical Features. Patients with Hurler's and mellated myelin figures. Parallel palisaded lamel-
Hunter's syndromes present with involvement lae impart an appearance of zebra bodi~.s (175).
of many organs, including the gastrointestinal
Gangliosidoses
tract (178,181). The disease course is chronic and
progressive, although the age of onset and the Etiology. Tay-Sachs disease is the prototype of
severity of the symptoms vary significantly (182). the gangliosidoses. It results from a deficiency
Pathologic Findings. Fibroblasts, endothe- of the enzyme hexosaminidase A. This disease
lial cells, and smooth muscle cells 'fuay appear is particularly prevalent among Ashkenazi]ews.
vacuolated. Ultrastructurally, the intracellular, Hexosaminidase A catalyzes the degradation of
membrane-bound lysosomes contain variable GMZ ganglioside and because of the absence of
amounts of opaque, flocculent lamellae repre- the enzyme, this material accumulates within
senting mucopolysaccharides. the cells, particularly of the nervous system.
Adult GMl gangliosidosis is a recently identified
Niemann-Pick Disease
rare form of hereditary neuronal storage disease.
Etiology. Niemann-Pick disease results from Clinical Features. Hexosaminidase deficiency
absence of sphingomyelinase, so that sphingo- leads to lipid accumulation within cortical,
myelin accumulates in many organs throughout cerebellar, and spinal tissue. Patients also develop
the body, including the viscera. diarrhea and autonomic dysfunction, including
Clinical Features. In severe cases, extreme motility disturbances. Adult GM1 gangliosidosis
visceral accumulations of sphingomyelin are has a benign clinical course with cerebral lesions
present along with progressive wasting, and restricted to the basal ganglia (179).
patients often die in the first few years of life. Pathologic Findings. Rectal biopsies play a
Pathologic Findings. Macrophages accumu- role in the diagnosis of gangliosidosis by the
late sphingomyelin in many tissues, including demonstration of the characteristic changes in
the lamina propria of the gastrointestinal tract the autonomic neurons (172,176,177,180). The
(fig. 14-13). Sphingomyelin can be highlighted biopsies need to be deep enough to include the
with the use of special stains for lipids, includ- submucosal plexus. Ultrastructurally, ganglion,
ing Sudan black and oil red-O. Ultrastructurally, Schwann, perithelial, and endothelial cells, as

660
Miscellaneous Intestinal Disorders

well as histiocytes, all contain characteristic Pathologic Findings. The liver and spleen
inclusions. The neural tissues contain electron- enlarge and serum cholesterol becomes elevated.
dense bodies, zebra bodies, and membranous Numerous foamy macrophages filled with cho-
cytoplasmic bodies. In patients with Tay-Sachs lesterol esters populate the muscularis mucosae
disease, these bodies are not found in other and submucosa. Lipid droplets accumulate due
cell types. In contrast, patients with Sandhoff's to a block in the transport of cholesterol into
disease (hexosaminidase AB deficiency) exhibit lacteals. Lipid droplets are found in macrophages
similar structures in nerves as well as mesen- in the lamina propria of both the large and small
chymal tissues, such as endothelial cells and intestine, alongside the lacteal endothelium, in
fibroblasts. Membrane-bound clear vacuoles the smooth muscle, and in vascular pericytes.
are occasionally seen in the cytoplasm of rectal The histiocytes that contain the cholesterol es-
and cutaneous fibroblasts. The axons of the ters and carotenes impart an orange tinge to the
unmyelinated nerves appear normal. mucosal surface. The myenteric plexus is vacu-
olated secondary to cholesterol ester deposits.
Fabry's Disease
The epithelium appears normal.
Etiology. Fabry's disease, an X-linked disorder
of lipid metabolism, results from a deficiency of NEONATAL ENTEROPATHIES
the enzyme alpha-galactosidase A that leads to
Microvillus Inclusion Disease
accumulation of ceramide trihexosidase.
Clinical Features. Malabsorption sometimes Definition. Microvillus inclusion disease is a
affects patients with small intestinal involvement. severe enteropathy resulting from a defect in
Patients with Fabry's disease also present with en- microvillus formation. It is associated with
terovesical fistulas and lymphadenopathy. watery diarrhea, and often presents on the first
Pathologic Findings. The neurons and day of life. Synonyms include congenital micro-
nerve fibers of Meissner plexus, vascular endo- villus atrophy, familial microvillus atrophy, and
thelial cells, and histiocytes appear foamy and Davidson's syndrome.
vacuolated. Their lipid content stains strongly Demography. Microvillus inclusion disease
with Sudan black, Luxol fast blue, PAS, and oil has been identified worldwide in infants from
red-O stains on frozen sections. Ultrastructural varying ethnic backgrounds. The disease may
examination shows the presence of zebra-like, have a familial component as it sometimes
lamellar, lysosomal inclusions. occurs in multiple siblings (187). A genetic eti-
ology is further supported by the observation
Wolman's Disease
that the disease appears to cluster in infants of
Etiology. Wolman's disease (lysosomal acid Navajo descent (195,199).
esterase deficiency) is a lethal heritable disorder Etiology. The mechanism by which micro-
affecting children. villus inclusion disease develops is not known.
Clinical Features. It is characterized clini- The underlying defect is thought to be a genetic
cally by hepatosplenomegaly and enlarged calci- alteration that leads to abnormal trafficking of
fied adrenal glands. Patients develop persistent membrane proteins to the apical surface of dif-
diarrhea and rarely survive for more than 1 year. ferentiated epithelial cells (198).
Pathologic Findings. Fat-laden histiocytes Clinical Features. Infants with microvillus
containing cholesterol and triglycerides infil- inclusion disease present with severe, watery
trate the superficial lamina propria. The mucosal diarrhea. In some cases, the diarrhea can be so
accumulations are most marked in the jejunum. watery that it can be mistaken for urine. The
volume of stool output in this disease may ex-
Cholesterol Ester Storage Disease
ceed that seen in association with cholera (198).
Etiology. Cholesterol ester storage disease is a As a result, affected infants die of dehydration
rare inherited disorder of lipid metabolism also unless adequate fluid replacement is provided.
due to a deficiency of lysosomal acid esterase, Pathologic Findings. Duodenal biopsies
but it has a much more benign clinical course demonstrate the presence of villous atrophy,
than Wolman's disease. with little or no associated crypt hyperplasia.

661
Gastrointestinal Diseases

Figure 14-14
MICROVILLUS INCLUSION DISEASE
Left: Transmission electron micrograph sfwws typical inclusions lined by microvilli in the apical cytoplasm of the
enterocytes.
Right: Higher-power view shows that the micr_ovilli lining the inclusions contain all components normally present in
brush border microvilli. (Courtesy of Dr. Margaret Collins, Cincinnati, OH.)

The lamina propria does not contain an in- sometimes be seen in a more basal location.
creased number of inflammatory cells. The The inclusions are lined by a complete brush
epithelium lining the villi appears disorganized, border that includes the microvillus membrane,
with focally piled up cells with vac'bolated api- microfilaments, the terminal web, and a sur-
cal cytoplasm. The brush border focally appears face filamentous coat. Another characteristic
poorly defined. PAS stains highlight the brush ultrastructural feature is the presence of apical
border loss, and also stain the apical cytoplasm secretory granules or vesicular bodies. These
of enterocytes, a finding not seen in normal structures are membrane bound, and contain a
duodenal mucosa (194). Immunostains for mixture of amorphous granular material, small
villin, carcinoembryonic antigen (polyclonal), vesicles, and membrane fragments.
or CD10 highlight the intracytoplasmic micro- Treatment and Prognosis. Microvillus inclu-
villus inclusions that characterize the disease sion disease is a severe, intractable enteropathy
(189,190). Microvillus indusions are not present requiring total parenteral nutrition and intrave-
in every cell, and sometimes multiple levels on nous fluid support. The condition is inevitably
multiple blocks must be examined in order to fatal if these measures are not implemented.
make the diagnosis. Inclusions may be found Small intestinal transplantation is often neces-
not only in duodenal epithelial cells, but also sary. A less severe variant of the disease, which
in colonocytes, gastric epithelial cells, renal presents later and is associated with lesser symp-
tubular cells, and gallbladder epithelial cells toms and a better prognosis, may occur (193).
(187,192,197).
Tufting Enteropathy
Special Techniques. Transmission electron
microscopy demonstrates the diagnostic mi- Definition. Tufting enteropathy, also known as
crovillus inclusions in surface epithelial cells intestinal epithelial dysplasia, is a chronic watery
(fig. 14-14). These inclusions are most com- diarrhea syndrome presenting in the first few
monly found in the apical cytoplasm, but may months of life. The disorder is characterized by

662
Miscellaneous Intestinal Disorders

foci of clustered enterocytes with characteristic ischemia, desmoid tumors, trauma, or motility
apical cytoplasmic projections. disorders (208).
Etiology. The etiology of this disorder is un- Pathologic Findings. In preservation injury,
known. The disease is thought to have a genetic the surface epithelium detaches from the un-
basis since it tends to cluster in certain families derlying edematous lamina propria. No active
(188,196). Tufting enteropathy may develop inflammation is present (209). The degree of
secondary to abnormalities in the epithelial epithelial separation can be minimal to severe.
basement membrane or in expression of epi- When reperfusion is established, the crypt
thelial adhesion molecules (188,191). epithelium actively regenerates. Mild neutro-
Clinical Features. Most patients present with philic infiltrates may develop within 2 hours
chronic watery diarrhea that begins shortly after postperfusion.
birth. The disease may rarely develop in older Lymphatic regeneration needs to occur fol-
patients (186). lowing the graft to establish the lymphatic
Pathologic Findings. Jejunal biopsies dem- drainage critical to the nutritional functions of
onstrate partial or total villous atrophy associ- the small bowel, including the absorption of
ated with crypt hyperplasia. There is no increase chylomicrons. If this does not occur, lymph-
in inflammatory cells within the lamina propria. edema will develop. Impaired gut barrier func-
Intraepitheliallymphocytes are normal in num- tion may eventually lead to sepsis and multi-
ber. The characteristic feature of the disease is organ failure.
the presence of focal epithelial"tufts" composed Nerve regeneration also needs to occur.
of clusters of closely packed enterocytes with Within a year following surgery, ectopic large
rounded, tear-drop-shaped projections of their neurons gradually increase in number, not only
apical cytoplasm. in areas adjacent to the anastomoses but also in
Treatment and Prognosis. The prognosis for the remaining tissues up to 10 cm away from the
patients with tufting enteropathy is variable. lesion. Large ganglion neurons decrease. Out-
Most patients require total parenteral nutrition growth of neuron-specific enolase (NSE)-con-
in order to remain adequately nourished for taining nerve fibers from the severed stumps,
normal growth and development. usually within a couple of weeks of transection,
occurs. Weeks later, numerous bundles of fine
SMALL INTESTINAL TRANSPLANTATION nerve fibers interconnect the oral and anal ends
Demography. Intestinal transplantation is of the cut myenteric plexus. The regenerating
used to treat patients with irreversible intesti- nerve fiber bundles initially lie among irregu-
nal failure and dependence on total parenteral larly arranged smooth muscle cells. When failed
nutrition (TPN). The introduction of TPN in grafts are evaluated, they demonstrate a lack of
the 1970s revolutionized the treatment of such extrinsic adrenergic and perivascular fibers in all
patients, but some patients still experience life- layers of the bowel wall but intrinsic peptidergic
threatening complications ofTPN. Patients with nerves and their receptors are retained following
TPN-associated liver disease, loss of vascular ac- transplantation (201).
cess, or recurrent sepsis are candidates for small Detection of rejection after small intestinal
intestinal transplantation. transplantation is difficult and relies on histo-
Etiology. In pediatric patients, intestinal fail- pathologic examination of the graft (209). Re-
ure may occur in those who undergo extensive jection represents a patchy, often ileal-centered
intestinal resections for necrotizing enterocolitis process that progresses to mucosal ulceration
and intestinal congenital anomalies, including and eventual fibrosis of the wall (212). A rejected
total aganglionosis, volvulus, gastroschisis, graft demonstrates edema, cellular infiltration
and atresia (203). Intestinal failure also occurs of the mucosa and submucosa, and epithelial
in children with functional disorders such as damage. Early acute rejection usually occurs
intestinal pseudoobstruction, microvillous in- within 12 days, although it can occur later.
clusion disease, juvenile polyposis, and trauma Endothelial and crypt damage occurs within
(215). In adults, intestinal failure occurs most 3 days. Acute allograft rejection exhibits vary-
often secondary to resection for Crohn's disease, ing combinations of crypt injury, mucosal

663
· Gastrointestinal Diseases

Figure 14-1 5
MILD SMALL BOWEL TRANSPLANT REJECTION
A: The architecture of the small intestine is distorted by
the loss of the normal villi. The lamina propria contains an
increased number of mononuclear cells.
B: Numerous apoptotic bodies are in the bases of the
crypts.
C: Neutrophils focally infiltrate the crypts.

infiltration primarily by mononuclear cells, along with varying degrees of mucosal edema
intraepitheliallymphocytes includin g blast-like and lymphatic dilatation. Markedly enlarged
lymphocytes, and increased crypt cell apoptoses Peyer patches, expanded by prominent accumu-
(more than 2/10 crypts) (fig. 14-15). The lamina lations of blastic lymphocytes, are found in the
propria appears edematous. Cellular infiltrates first month following transplant. This infiltrate
can be present in the muscle and submucosa in consists predominantly of mononuclear cells
the absence of mucosal changes. admixed with lesser numbers of eosinophils and
In mild rejection, the inflammatory infiltrate neutrophils. Pronounced mucosal eosinophilia
surrounds small venules and capillaries in the may develop.
deep mucosa at the crypt bases. These appear as In severe rejection, allografts show unevenly
early as 2 weeks and as late as 12 months after distributed mucosal damage with an intact
transplantation. The number of lymphocytes mucosa in the proximal and mid-jejunum,
between the muscularis mucosae and crypts and flattening of the villi. Moderate glandular
adjacent to the crypt epithelium is increased. loss is seen in the distal jejunum and proximal
r:,· . Vessels between the crypts frequently appear ileum, with granulation tissue and regeneration,
reactive, with enlarged endothelial cells. Some- although the morphologic changes are distrib-
times lymphocytes are seen in the vascular lu- uted unevenly along the intestinal allograft
mens. Other inflammatory cells are occasionally (fig. 14-16).
present, including plasma cells, eosinophils, and Full-thickness biopsies may be helpful in
neutrophils (fig. 14-15). diagnosing rejection, since sometimes the char-
With more substantial involvement, the acteristic lesions are not seen in the mucosa,
inflammatory infiltrate becomes more widely but only in the submucosa and muscularis,
dispersed in a patchy or coalescent distribution especially in patients on cyclosporine therapy

664
Miscellaneous Intestinal Disorders

Figure 14-16
SEVERE REJECTION
A: Low-power view shows a small amount of residual
glandular tissue with adjacent inflammation and ulceration.
B: Higher-power view of an area of ulceration containing
infiltrating mononuclear cells.
C: The residual crypts show evidence of apoptosis.
Occasional neutrophils infiltrate the epithelium.

(205-207,210,211). These changes include fi- If the patient survives the episodes of acute
brinoid necrosis, mononuclear cell infiltration, graft rejection, the patient becomes susceptible
and vascular luminal obliteration. to the post-transplantation complications seen

665
Gastrointestinal Diseases

Table 14-9 Table 14-10


DISORDERS ASSOCIATED WITH COMPLICATIONS OF SMALL
INCREASED APOPTOSIS INTESTINAL TRANSPLANTATION

Graft versus host disease Preservation injury


Drug therapy Graft failure
Chemotherapy for malignancy Ischemic damage
Radiation therapy Infection
Transplant rejection Graft rejection
Zinc deficiency Graft versus host disease
Fasting Post-transplant lymphoproliferative disorders
Inflammatory bowel disease
Acquired immunodeficiency syndrome (AIDS) enteropathy
Viral infections Treatment and Prognosis. The use of in-
Autoimmune enterocolitis testinal transplantation can lead to long-term
survival rates of 50 to 75 percent in some centers
(216). The complications of transplantation are
in other transplant patients. Chronic graft re- listed in Table 14-10.
jection is characterized histologically by villous Immunologic complications of transplantation
atrophy and T-cell infiltration associated with include intestinal allograft rejection, post-trans-
obliterative arteriopathy and muscular fibrosis plant lymphoproliferative disease, cytomegalovi-
(200,204,209). The lamina propria is' infiltrated rus infection, and graft versus host disease. Other
by CD3-positive, CD25-positive lymphocytes complications include intestinal perforation, intes-
and CD25-positive macrophages; there is tinal leaks, dehiscence with evisceration, bleeding,
abrasion of the cell surface epithelium and intraabdominal abscess, and ascites. Graft loss oc-
ultimately, mucosal sloughing (202,214). The curs as a result of rejection, infection, and technical
obliterative arteriopathy primarily affects the complications, as well as the complications ofTPN
large arteries of the serosa and mesentery, which after graft removal (213).
show patchy luminal narrowing secondary to A high incidence of infection complicates
myointimal hyperplasia and sub,.endothelial small bowel transplantation. Infections result
accumulation of foamy macrophages and scat- both from excessive immunosuppression and
tered lymphocytes. compromised barrier function of the native or
Crypt cell apoptosis is a variable but some- engrafted small bowel. Small bowel transplant
times striking feature of intestinal rejection (fig. patients who develop rejection or graft versus
14-15). Apoptotic bodies occur in the normal host disease may have shifts in the intestinal
mucosa; the upper limit in native and normal microflora toward potentially pathogenic
allograft specimens is 2/10 consecutive crypts. organisms and bacterial translocation into re-
Apoptotic cells are not specific for rejection, cipient tissues. One may see massive bacterial
however, but may also 'be seen in other states overgrowth in the native intestine in patients
(Table 14-9) (205,207,211). with graft versus host disease.
Biopsies following treated rejection often Complicating cytomegalovirus infections
demonstrate fibrosis with focal glandular loss, occur as early as 2 days or up to years following
regenerative glands with reparative atypia, and transplantation (209) and the changes resemble
atrophy with a thin mucosa and blunted villi. those described in chapter 10. Many patients
These changes occur more commonly follow- develop Epstein-Barr virus (EBV)-related post-
ing severe or persistent rejection, although they transplant lymphoproliferative disorders
are not always present. Patients may develop (PTLD). PTLD may develop as early as 41 days
moderate to severe eosinophilia. after transplantation or may take years; the
When the bowel is successfully transplanted, median time to the development of PTLD is
the histologic features resemble those of the 306 days (209). The tissues contain activated
non transplanted bowel at the anastomotic ends. lymphocytes with crypt epithelial apoptosis and

666
Miscellaneous Intestinal Disorders

lymphoid tissue without apoptosis. The chief There are also large transformed lymphocytes
feature is a dense but heterogeneous lymphoid typical of polymorphous PTLD. Eosinophilia
infiltrate comprised of small lymphocytes, may also be present. EBV in situ hybridization
plasma cells, and plasmacytoid lymphocytes. reactions help make the diagnosis.

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bowel by 1,2-dimethylhydrazine, methylazoxy- 216. Vanderhoof ]A. Short bowel syndxome in
methanol acetate, and gamma-rays. Cancer Res children and small intestinal transplantation.
1989;49:6342-6 . Pediatr Clin North Am 1996;43:533-50.

...

674
15 INFlAMMATORY BOWEl DISEASE

Idiopathic inflammatory bowel disease (IBD) IBD occurs worldwide: the incidence is rela-
includes two chronic gastrointestinal disorders tively low in Asian, Mediterranean, and Middle
of unknown etiology: ulcerative colitis (UC) Eastern countries (3), and higher in European
and Crohn's disease (CD). The natural history of countries, the United States, Canada, Austra-
IBD differs from patient to patient, and depends lia, and New Zealand. This may reflect racial,
on which disease is present. Disease severity ethnic, and genetic factors. Prevalence rates
at the onset, disease extent, and patient age at for IBD among non-Caucasians in the United
the time of diagnosis, along with other patient States are lower than rates for Caucasians. In
variables, determine overall disease severity and one study, the prevalence rates for CD were
the likelihood of subsequent morbidity and 43.6/100,000 for Caucasians, 29.8/100,000 for
mortality. Once established, IBD patients suffer African-Americans, 4.1/100,000 for Hispan-
episodic acute flares and relapses that become ics, and 5.6/100,000 for Asians (4). A study
superimposed on chronic disease. As a result, of African-American children reported a CD
the patient is likely to suffer from disabling incidence rate of 7 to 12/100,000 (6). Among
disease for decades. ethnic groups, Jews in the United States have a
greater risk for developing IBD than non -Jewish
DEMOGRAPHY Caucasians (8). The incidence rate is 2 to 4 times
Both CD and UC are predominantly diseases greater and the prevalence 2 to 9 times greater in
of young adults, occurring with a peak incidence this group. Ashkenazi]ews exhibit a particularly
between 15 and 30 years of age. After age 10, high IBD risk (1), especially those originating in
there is a rapid incidence increase for both dis- Middle Europe, Poland, or Russia (8,9).
eases. Age-specific incidence rates are slightly
greater for males with UC and for females with ETIOLOGY
CD (2). Both diseases show three peak incidence The pathophysiology of IBD involves com-
rates: the first and highest occurs between ages plex interactions between genetic, environmen-
20 and 24 years, the second at ages 40 to 44 tal, and immunologic factors (fig. 15-1).
years, and the third at ages 60 to 64. In females,
Genetic Factors
the first peak appears at ages 15 to 19, 5 years
younger than in males (10,11). By age 60, the There is considerable evidence that the devel-
incidence of UC exceeds that of CD. opment of both CD and UC is determined, at
Epidemiologic studies show that the inci- least in part, by genetic factors. Overwhelming
dence and prevalence of IBD vary significantly evidence shows that IBD clusters within fami-
depending on the patient's geographic location lies. This finding is true for both UC and CD.
and racial or ethnic background. There has been In population-based studies, 5 to 10 percent of
an increase in the incidence of CD in the past sev- individuals with IBD have an affected family
eral decades in Western countries; the incidence member (22,37,47). In fact, having a family
of UC has also increased somewhat. In addition, member with IBD represents the greatest risk
the mean age at diagnosis of patients with CD factor for developing the disease. Individuals
has decreased in recent times (5). The annual with a first-degree relative with IBD have a
incidence ofiBD in the United States is estimated 10- to 15-fold increased risk of also developing
at approximately 6/100,000 population (5). the disease compared with those without an
Incidence rates for both diseases are higher in affected family member (42,43,48). Approxi-
urban than in rural areas, and in industrialized mately 75 percent of families with multiple
than nonindustrialized countries (7). affected members show concordance for disease

675
. Gastrointestinal Diseases

Genetic Luminal bacterial


factors antigens/products
Figure 15-1
INFLAMMATORY
BOWEL DISEASE
Inflammatory bowel disease
(IBD) likely results from a com-
bination of genetic predisposi-
tion, cellular alterations, and
altered immunity. The genetic
influences affect both the pre-
disposition to injury and the
nature of the response to the
injury.
Level and Duration
of cytokine production
Ti~"" ioj\
Degree of Resistance to normal

7~g"IWioo
Effectiveness of

type (i.e., all affected family members have CD that Nod proteins may play a similar role in
or all have UC). In the remaining 25 percent, mammals (30).
some members have CD while others~ have UC NOD2 protein is expressed in monocytes (31,
(16). This finding suggests that UC and CD 41), intestinal epithelial cells, and intestinal
may have some common, as well as distinct, Paneth cells (27,33). The protein recognizes
susceptibility genes. Twin studies show that and binds bacterial peptidoglycan, resulting in
monozygotic twin concordance for CD ranges activation of the pro inflammatory cytokine, NF-
from 42 to 58 percent (51-53). Monozygotic KB (23). It is the LRR region of the protein that
twin concordance for UC is significantly lower, functions in peptidoglycan recognition. Human
ranging from 6 to 17 percent. These findings mutations in NOD2 occur in both the LRR region
suggest that although there is a strohg genetic and in the central nucleotide-binding domain.
component that determines susceptibility to Three major mutations have been described in
IBD, environmental factors also play an impor- the LRR region, all of which are associated with
tant role in disease development. CD (13,19,21,24,28,57,58). Interestingly, these
Genetic linkage studies have identified a mutations occur predominantly in Caucasian
number of potential genetic susceptibility loci populations and are extremely rare in Asian and
for IBD. These are listed in Table 15-1. African-American populations (18,32,34,59).
IBDl . The IBDl locus is located in the peri- Mutations in the nucleotide-binding domain
centromeric region of chromosome 16, and was result in Blau's syndrome, a rare disease charac-
originally described by Hugot et al. (29). This locus terized by early-onset granulomatous arthritis,
is linked only to CD, not UC. The locus contains uveitis, and skin rash (36).
the gene NOD2/CARD15, which has now been Patients who have one defective copy of
definitively identified as responsible for disease NOD2 have a 2- to 4-fold increased risk for the
linkage to this chromosomal region (39). development of CD, while homozygous mutants
The family of Nod proteins includes NOD2/ show a 20- to 40-fold increased risk (21, 28,55).
' ··
CARD15 as well as several additional regulatory Approximately 8 to 17 percent of CD patients
proteins. The Nod proteins contain a central carry two mutant NOD2 alleles. NOD2 mutations
nucleotide-binding domain and anN-terminal are associated with disease located in the small
caspase recruitment domain (30). In addition, intestine, as well as stricturing and fistulizing
they possess a C-terminal leucine-rich repeat forms of the disease (12,13,21,26,35, 44,57,58).
(LRR) region that has a high degree of homol- CD-associated mutations in the LRR of NOD2 re-
ogy with plant genes known to be involved in sult in inactivation of the protein and a resultant
disease resistance (14,54). This finding suggests defect in the cellular response to peptidoglycan

676
Inflammat07y Bowel Disease

Table 15-1 IBD3. Several studies have linked the IBD3 lo-
M AJOR SUSCEPTIBILITY LOCI FOR
cus, located on chromosome 6, to both UC and CD
INFLAMMATORY BOWEL DISEASE (15,25,45,49,60). This region contains the major
histocompatability complex (MHC), as well as the
Locus Chromo-
Desig- soma! tumor necrosis factor (TNF) gene. Several human
nation Location IBD"Type Candidate Genes leukocyte antigen (HLA) associations with IBD
IBDI 16ql2 CD NOD2 are well known. Among Caucasians, susceptibil-
ity to UC has been convincingly linked to the
IBD2 12ql3 uc VDR, IFN-yb
HLADRB1 *0103 allele. In addition, this allele is
IBD3 6pl3 CD,UC MHC I, MHC 2, TNF-a
associated with severe colitis and extraintestinal
IBD4 14qll CD TCR a/y complex manifestations of UC (20,41). In Japanese and
IBDS Sq31-33 CD IL3, IL4, ILS, IL13, CSF-2 Jewish populations, susceptibility to UC has been
IBD6 19pl3 CD, UC TCAM-1 , C3, TBXA2R, linked to the HLADRB1 *1052 allele. Polymor-
LTB4H phisms in TNF-a and their relationship to the risk
Other lp36 CD, UC TNF-R family, CASP9 of CD are also under current investigation (38).
Other 3p CD, UC HGFR, EGFR, GNAI2 IBDS. The IBDSlocus resides on chromosome
Other 7q CD,UC MUC-3 Sq31-q33. It was identified by a genome-wide
"lBD = Inflammatory bowel disease; CD = Crohn's disease;
scan of Canadian families with early onset CD .
UC = ulcerative colitis . Heterozygous carriage of the risk alleles in-
bVDR = vitamin D receptor; IFN-y = interferon-gamma; creased the risk for developing CD 2-fold, while
MHC =major histocompatibility complex; TNF-a = tumor homozygous carriage increases this risk 6-fold
necrosis factor-alpha; TCR = T-cell receptor; IL = interleukin; (46). The specific causative gene has not yet
CSF =colony-stimulating factor; !CAM= intercellular adhe-
sion molecule; HGFR =hepatocyte growth factor receptor;
been identified. This region does, however, con-
EGFR = epidermal growth factor recepto.r. tain a number of genes that encode immune-
regulatory cytokines including interleukins
(IL)3, IL4, ILS, and IL14. This locus also contains
(18). This abnormality in monocytes could result genes for colony-stimulating factor isoform 2
in an inability of the innate immune system to and interferon regulatory factor isoform 1 (17).
recognize bacterial products, and a subsequent
Environmental Factors
overreaction to bacteria by the adaptive immune
system (40) . In addition, defective NOD2 protein Numerous data suggest that environmental
function in intestinal epithelial and Paneth factors play a role in the development and
cells may result in an abnormal immunologic progression of both forms of IBD. Susceptibil-
response to normal commensal bacteria within ity genes for IBD demonstrate only incomplete
the gastrointestinal tract. penetrance, and, as noted earlier, concordance
A genetic test for NOD2/CARD15 is not avail- rates for monozygotic twins are 48 to 52 per-
able commercially at this time. Testing family cent for CD and only 6 to 17 percent for UC
members of patients with CD for alterations in (96a,101a,102a) . Factors other than genotype
this gene is not recommended given the overall must be involved in the pathogenesis of IBD. In
prevalence of the disease, and therefore, the addition, the incidence of IBD has increased in
probability of an asymptomatic, gene-positive the developed parts of the world over that last
individual developing the disease. A lack of SO years, and is now becoming increasingly com-
interventional strategies for gene-positive pa- mon in less-developed countries as they become
tients also argues against gene testing at the more industrialized and the standard of living
present time. improves. Environmental changes that might
IBD2. The IBD2 gene locus lies on chromo- affect the development of the mucosal immune
some 12, and appears to be more closely linked system or the indigenous enteric flora include
to the development ofUC than CD (15). Anum- improved hygiene, consumption of sterile or at
ber of possible candidate genes are located in least noncontaminated foods, childhood vac-
this region, but investigation of several of these cinations, and increased age at first exposure to
has yielded negative results (50,56). a variety of intestinal pathogens (95) .

677
Gastrointestinal Diseases

Food Antigens. Numerous studies have are hyperreactive to bacterial antigens, a fac-
demonstrated that exposure to food-associated tor that suggests that local bacterial tolerance
antigens plays an important role in the gastro- mech~misms are abnormal in these individuals
intestinal inflammation that occurs in patients (91). Patients with both UC and CD show higher
with CD. Patients treated with simplified or el- numbers of bacteria attached to their intestinal
emental diets containing proteins in the form of mucosa than do unaffected individuals (100) .
amino acids or small peptide fragments improve In addition, bacterial invasion of the mucosa
syrnptomatically and show decreased inflamma- has been reported in both UC and CD patients
tion as determined endoscopically and through (78). IBD patients also have increased mucosal
serum marker studies (72,86). In one study, production of immunoglobulin (Ig)G antibod-
rectal exposure of CD patients to a series of food ies directed against a wide range of commensal
antigens resulted in increased rectal blood flow organisms (83). The clinical observation that, in
and lymphocyte proliferation in comparison to some patients, disease flares may be ameliorated
control patients (103), a finding that suggests by antibiotic administration is supportive of a
patients with CD show gut-specific sensitization bacterial role. Finally, recent evidence suggests
to food antigens. Reactions were seen with anti- that the NOD2 CD susceptibility gene is involved
gens to yeast and to citrus, although il)dividual in regulation of host responses to bacterial organ-
patients also reacted to other antigen groups. isms (73a). Overall, many view IBD as a disease
Although it is possible that sensitivity to food initiated by a general loss of tolerance for the
antigens is merely a reflection of exposure to an- commensal bacteria of the gastrointestinal tract.
tigens through mucosal defects, the absence of Tobacco Use and Exposure. The association
similar sensitivities in patients with .UC makes between tobacco use and the development of
this possibility unlikely. IBD is well established. Smoking decreases the
It is not likely, however, that expo?ure to risk for the development of UC, but exacerbates
food-associated antigens represents the primary and aggravates CD (62,63,65,76,99,102). Former
abnormality in patients with CD. Instead, ex- smokers have a lower risk of UC than do those
posure to food in the proximal gastrointestinal who never smoked. Exposure to passive smoke
tract may lead to sensitization and stimulation also appears to confer a lessened risk of devel-
of the immune system in genetically.susceptible oping UC relative to nonexposed nonsmokers
individuals. (94). Interestingly, nicotine has been shown to
Infectious Agents. For many yea'!'s investiga- have an inhibitory effect on Th2 lymphocyte
tors have been suspicious that IBD may have an function, the type of cell most implicated in
infectious etiology. These suspicions are based UC (85). Indeed, nicotine-based enemas have
on several observations. First, CD patients have been shown to be beneficial in patients with
an increased incidence of childhood infections milder forms of distal colitis. Nicotine has no
including pharyngitis, tonsilitis, and rhinitis effect on the Th1 cells characteristic of the CD
(104, 106). In addition, gastroenteritis in early inflammatory response.
infancy has been linked to later development of Other Environmental Factors. Epidemio-
CD (90). Studies have shown that patients with logic data suggest that use of nonsteroidal anti-
CD tend to have increased serum levels of anti- inflammatory drugs (NSAIDs) can exacerbate
bodies directed against nonpathogenic as well existing UC, and may even induce it de novo
as pathogenic enteric organisms (61,75). Many (70) . This effect was initially attributed to the
studies have attempted to link IBD to infections cyclooxygenase (COX) -1 inhibitory effect of
'· with Mycobacteria, Yersinia, and several viruses the drugs, but recent reports suggest that even
(66-69,71,79,81,93,97,98); however, no defini- COX-2-specific inhibitors demonstrate this ef-
tive link with any one infectious agent has ever fect (87). Possible mechanisms by which NSAIDs
been made (64,73,77,82,88,89,92,105) . exert these effects include inhibition of protec-
Current evidence, instead, suggests that the tive mucosal prostaglandin production and
resident bacterial flora of the gut may be a factor increased leukocyte migration and adherence.
in initiating and propagating the inflammation It has been estimated that NSAID use increases
in IBD (96). In CD patients, T lymphocytes the risk of IBD by as much as 30 percent.

678
Inflammatmy Bowel Disease

As many as 40 percent of UC patients report immune system through the production and
that psychological stress represents a trigger for secretion of a variety of cytokines. In recent
their disease (80, 101). There is evidence to link years, two functionally different populations
psychological stress with increased susceptibility of CD4-positive T cells have been recognized.
to infection and illness through stress-related im- The T-helper 1 (T 1_11) subset orchestrates cell-
pairment ofthe immune system (74). Some ani- mediated immune responses, and synthesizes
mal models suggest that stress may play a role in and secretes IL2, IL12, and interferon-gamma
the development of colitis. Cotton-top tamarins, (IFN-y). T-helper 2 (T H2) cells mediate humoral
primates that spontaneously develop colitis and responses, and produce IL4, IL5, ILlO, and
serve as a model for human IBD, develop colitis IL13. These two subsets of CD4-positive T cells
only during long-term captivity (84). regulate each other reciprocally through key
cytokines. For example, IFN-y, secreted by THl
Host Factors
cells, suppresses the development of the TI-12
Intestinal Permeability. Increased intestinal response, while IL4, ILIO, and IL13 secreted by
permeability may play a role in the pathogenesis T11 2 cells, inhibits TI-Il (122,123a).
of CD. Increased permeability not only occurs in CD is associated with TI-I 1 cytokine produc-
the intestines of patients affected by the disease, tion (134, 136). UC, on the other hand, does not
but also in their unaffected first-degree relatives fit clearly into either the T11 1 or TH2 category,
(111). It has been suggested that this increased although a modified TH2 response seems to oc-
permeability may represent a predisposing fac- cur in established UC (123-124). Although the
tor to the development of CD because a leaky types of cytokines produced in UC and CD dif-
intestinal barrier intensifies antigen absorption, fer somewhat, both diseases are associated with
leading to exaggerated systemic immune stimu- abnormal immune responses to nonpathogenic
lation (110). commensal bacteria within the gut. Cross-reac-
Appendectomy. Appendectomy early in life tivity of peripheral blood and colonic lamina
(before the age of 20) has been shown in several propria CD4-positive T cells with indigenous
studies to decrease the risk of developing UC flora in patients with UC and CD suggests that
(107, 112, 113). Interestingly, the risk for UC abnormal T-cell-specific immune responses to
is reduced only in patients who undergo ap- the normal flora of the host are important in
pendectomy for acute appendicitis, and not in the pathogenesis of both diseases (120).
those whose appendices are removed because of Activated T lymphocytes are regulated by
nonspecific abdominal pain or incidentally dur- both effector and regulator T-cell subpopula-
ing surgery for other causes (107). This finding tions in healthy gut mucosa. Effector T cells are
suggests that the appendicitis that results in ap- capable of inducing intestinal inflammation,
pendectomy, rather than appendectomy itself, while regulator T cells are able to control or
is protective. Alternatively, there may be other prevent inflammation. The immunosuppres-
factors among patients destined to develop UC sive function of the regulator cells is mediated
that prevent those individuals from developing through the production of ILIO and transform-
appendicitis (109). A recent report suggests that ing growth factor-beta (TGF-~). These regula-
the risk for CD may also be decreased in patients tor cells are thought to play pivotal roles in
who have undergone appendectomy (108). mediating tolerance toward luminal antigens
(125, 129). Genetically engineered ILIO deficient
Immunologic Factors
mice develop severe transmural inflammation
Both CD and UC are, at least in part, disorders of the small and large intestine, reminiscent of
of immunity. It is currently believed that the CD (128). Studies suggest that defects in the
main abnormality responsible for the develop- ILlO and TGF-~ regulatory signaling pathways
ment of inflammation in these disorders is an may exist in humans with UC (131,135).
exaggerated T-cell response to commensal bacte- Activation of effector cytotoxic T cells and
ria or other pathogens (123, 143). CD4-positive T release of cytokines result in the generation
lymphocytes act as immune regulators, control- of activated matrix metalloproteinases, en-
ling the activities of other components of the zymes that are mediators of tissue destruction.

679
Gastrointestinal Diseases

Cytokines act directly on the microvasculature, CROHN'S DISEASE


upregulate adhesion molecules, and enhance re- Definition. Crohn's disease is an idiopathic
cruitment of additional effector cells including chronic inflammatory disease that most com-
neutrophils and macrophages; the latter amplify monly affects the terminal ileum and cecal
and perpetuate the inflammatory response and region, but may affect any portion of the gas-
contribute to additional tissue injury. trointestinal tract from the mouth to the anus.
Autoantibodies. Numbers of mucosal B cells Diseased segments are frequently separated by
and plasma cells increase in UC, a finding that intervening "skip areas" of essentially endoscop-
initially suggested that the disease was antibody ically normal gut. Inflammation in CD may be
mediated and complement dependent (126). transmural, resulting in stenosis, peri-intestinal
Patients with UC also have circulating autoanti- abscesses, or fistulas. Dividing CD into inflam-
bodies, including those directed against human matory, stricturing, and perforating subtypes
intestinal tropomyosin isoform (130,138) as has provided a useful classification to predict
well as anticolonocyte antibodies (132). The response to interventions and outcomes.
production of antiself antibodies is now thought Demography. As noted previously, there has
to represent a phenomenon that is a secondary been a steady rise in the incidence and preva-
protective response aimed at clearing apoptotic lence of CD in Western Europe, Canada, and
cells (133). the United States over the past several decades
Patients with UC commonly have circulat- (152,171a,174,191,192). The incidence of CD
ing antineutrophil antibodies (ANCAs) (119, ranges from 3.4 to 14.6/100,000 in differing
130,132,137,140,148). ANCAs wei·e initially Western countries (152,171a,174,198, 199). CD
described as sensitive and specific markers for affects all ages and both sexes, but its incidence
active Wegener's granulomatosis but are now peaks in the 2nd and 3rd decades of life. A sec-
known to occur in a wide range of diseases. The ond minor peak in incidence occurs in the 4th
prevalence of a positive perinuclear (p) ANCA and 5th decades. CD is more common among
in UC patients ranges from 49 to 86 percent Caucasians than other racial groups (169a,
(121,139). The pANCA pattern is 93 to 97 per- 176a), and is more common in Jewish than
cent specific (146,148), but only 46 to 60 percent non-Jewish populations (186a).
sensitive for the diagnosis (118). pANCAs are also Clinical Features. The signs and symptoms
found in up to 25 percent of pati~ts with CD of CD are often subtle, frequently resulting in a
(121,141,144,145). The titers of these antibodies, delay in diagnosis until months, or sometimes,
however, do not correlate with the degree of se- years after symptom onset. The presentation of
verity of the associated colitis, and although they a patient with CD depends in large part on the
may serve as a convenient clinical marker for UC, location, extent, and severity of the gastrointes-
their role in the pathogenesis of the disease is tinal involvement. CD most frequently affects
unclear (114,142). A recent report suggests that the ileocecal region, followed (in decreasing
pANCA in UC may represent a cross-reacting order of frequency) by the terminal ileum alone,
antibody to an antigenic target on Escherichia diffuse involvement of the small bowel, and
coli and Bacteroides bacterial strains (117). isolated colonic disease (166).
Apoptosis. In normal mucosa, the inflam- Patients with ileocolonic disease experience
matory response is terminated by induction of intermittent episodes of crampy, often post-
apoptosis in activated T cells once the pathogen prandial, abdominal pain. Pain may be referred
has been eliminated. In CD, however, mucosal to the periumbilical region, especially in chil-
T lymphocytes are resistant to apoptosis, lead- dren (166). The abdominal discomfort may be
ing to their accumulation and the persistence accompanied by loose stools. Stools are small,
of the inflammatory response (115,127). In UC frequent at night, loose to watery, but not usu-
patients, T cells are more susceptible to Pas-me- ally overtly bloody. Such symptoms are often
diated apoptosis (116). The Fas ligand is strongly attributed to dietary factors or irritable bowel
expressed by T cells in active UC, but not in CD, disease. The past history commonly includes
suggesting that Fas-Fas ligand-induced apoptosis perirectal or perianal abscesses and fistulas.
contributes to mucosal damage in UC (147,149). Physical examination may localize tenderness

680
Inflammatory Bowel Disease

to the right lower quadrant. Occasionally, an typically involves the distal stomach, and results
inflammatory mass is palpable. in thickening and sometimes granulomatous
Patients with diffuse, small intestinal CD inflammation of the gastric wall. In some pa-
present with diffuse abdominal pain, diarrhea, tients, this distal inflammation results in pyloric
anorexia, and weight loss. Malabsorption may obstruction. Patients With gastric CD often have
also occur. These patients demonstrate diffuse concomitant duodenal involvement. Gastric CD
abdominal tenderness on physical examination. may, however, antedate small bowel involve-
Colonic CD may mimic UC. Patients com- ment, and some of the reported cases of isolated
plain of diarrhea often containing blood and/ granulomatous gastritis may actually represent
m mucus, and crampy lower abdominal pain early gastric CD. Patients with gastroduodenal
that may be relieved with defecation. involvement present with early satiety, nausea,
Growth retardation occurs in many pediatric vomiting, and epigastric pain.
patients with CD (167,173), and may occur A sudden worsening of clinical symptoms
before other signs or symptoms develop. The or an unusual disease presentation should alert
growth failure and malnutrition result from one to the possibility of ischemia or viral infec-
inadequate dietary intake, malabsorption, in- tion superimposed on preexisting CD. Ischemia
creased nutritional requirements, and in treated may develop secondarily to vasculitis, or may
patients, from drug therapy, particularly corti- occur because of endothelialitis resulting from
costeroid use. infection with cytomegalovirus, particularly if
Progressive transmural inflammation with immunosuppressive therapy has been utilized.
scarring and deep ulceration may ultimately Gross Findings. CD classically involves the
lead to symptoms associated with intestinal distal15 to 25 cm of the terminal ileum, often in
obstruction, perforation, bleeding, or fistula for- association with disease involving the right colon,
mation. When obstruction develops, it usually but any part of the gastrointestinal tract may be
does so in the distal ileum. Extensive mucosal involved. Transition from involved to uninvolved
ulceration predisposes the patient to bacterial areas is usually abrupt in the small bowel, but is
translocation with all of its complications (170), less well defined in the large intestine.
including a predisposition to bacterial endo- The external surface of the involved bowel
carditis (169). There is altered small intestinal appears hyperemic and may be covered with
motility with abnormal receptor-mediated small a serosal exudate (fig. 15-2). Areas of serositis
intestinal contraction (202). Deep linear ulcers are rough and nodular, and may coexist with
or fistulas sometimes give rise to profound lower dense fibrous adhesions between bowel loops
gastrointestinal bleeding (15 1, 177). or between the bowel and other abdominal or
Anorectal complications are common in pa- pelvic organs or the abdominal wall. Fat encircles
tients with CD, and in some, may be the most the antimesenteric serosal surface, producing a
troubling aspect of their disease. Approximately pattern known as "creeping fat" (fig. 15-3). Mili-
one quarter of patients with CD involving the ary serosal lesions, the macroscopic equivalent of
small bowel and three quarters of individu- granulomas, may be seen. The miliary lesions are
als with colonic CD will have an anal lesion multiple, minute, whitish nodules on the serosal
sometime during the course of their disease surface. They are usually distributed along the
(193). Anorectal complications are more likely serosallymphatics and seen on the surface of the
to occur during severe attacks, when the colon adjacent mesente1y and peritoneum. They grossly
is extensively involved. Perianal involvement resemble peritoneal seeding by carcinoma or sero-
may predate, postdate, or develop concurrently sal involvement by miliary tuberculosis.
with primary intestinal CD. Lesions in this area Initially, the intestinal wall remains pliable,
consist of perianal abscesses, ulcers, fissures, even though it may appear slightly thickened,
fistulas, and strictures of the anal canal. but with disease progression, the bowel becomes
Esophageal involvement occurs in as many increasingly fibrotic and rigid. Eventually, a
as 6 percent of CD patients (171). Esophageal stricture may develop, resulting in obstruction
lesions include esophagitis, aphthous ulcers, (fig. 15-4). This usually occurs in the area of
strictures, and granulomas (189). Gastric CD the distal ileum near the ileocecal valve. Large

681
Gastrointestinal Diseases

Figure 15-3
CREEPING FAT IN A PATIENT
WITH CROHN'S DISEASE
The overlying serosa appears dull and fibrous adhesions
can be seen. (Courtesy of the Division of Gastrointestinal
Pathology, Armed Forces Institute of Pathology, Washing-
ton, DC.)

Figure 15-2
SEROSAL SURFACE APPEARANCE
IN CROHN'S DISEASE
The marked acute serositis corresponds to the portions
of the serosal surface covered by exudate.

inflammatory pseudotumors may ·form at this


site, simulating carcinoma. Granulomas within
the lymph nodes may be grossly visible as tiny
gray-white specks.
The earliest grossly visible mucosal change
is the formation of an aphthous ulcer. As these Figure 15-4
ulcers enlarge, they may develop a hemorrhagic CROHN'S STRICTURE
rim, which makes them visible. In their early The terminal ileum is markedly narrowed just proximal
stages, aphthous ulcers. are most easily seen in to the ileocecal valve. The mucosa is extensively ulcerated,
the colon because villi tend to obscure their showing a cobblestone pattern.
presence in the small intestine. Aphthous ulcers
are not specific for CD, but also occur in other
conditions including infectious enterocolitis. the development of more flagrant changes of
... In addition, aphthous type ulcers may be tran- CD by weeks or years .
siently found following use of phosphate-based Aphthous ulcers eventually enlarge into
bowel preparations. In some patients, these discontinuous, serpiginous or linear ulcers. At
tiny ulcers are the only or predominant sign of this stage, the mucosa appears reddened and
the disease, whereas in other patients, they are swollen. Islands of nonulcerated mucosa are
associated with more severe changes elsewhere interspersed among ulcerated areas, producing
in the bowel. Recognition of discrete ulcers in a cobblestoned appearance (fig. 15-5). Interven-
areas of otherwise normal mucosa may precede ing "normal" bowel separates diseased bowel

682
Inflammatmy Bowel Disease

Figure 15-6
CROHN'S DISEASE
There are areas of colonic mucosal flattening, ulceration,
and cobblestoning. More normal-appearing colonic mucosa
intervene between areas that are actively inflamed and
ulcerated .

former consist of inflamed mucosa, whereas the


latter are residual mucosal islands between areas
of ulceration. Inflammatory polyps may on oc-
casion become quite large, measuring several
centimeters in maximum dimension; however,
they are rarely large enough to precipitate bowel
obstruction. In addition to the presence of bulky,
lobulated polyps, narrow, tall, filiform post-
Figure 15-5 inflammatory polyps may be seen, the result
MUCOSAL COBBLESTONING IN CROHN'S DISEASE of abnormally healed mucosal remnants after
Top: Endoscopic view of the ileal mucosa shows narrow
ulceration. Inflammatory polyps may bleed, and
ulcers running in different directions, giving the mucosal may also aggravate colonic protein loss.
surface a cobblestone-like appearance. Fistulas and adhesions occur less commonly
Bottom: Numerous linear ulcers criss-cross the mucosa in patients with colonic involvement than in
of the terminal ileum, giving it a cobblestone appearance.
those with small intestinal disease. Fistulas
often develop spontaneously, but occur more
frequently in patients who have had previous
segments, creating skip areas (fig. 15-6). This surgery and who have residual diseased bowel. If
patchy pattern of inflammation contrasts with the process remains localized, an abscess forms .
the continuous pattern of inflammation and Perforation of the intestine is uncommon,
prominent rectal involvement seen in UC. affecting 1.5 percent of CD patients (164) . The
When the linear ulcers heal, long "railroad reason for this is that penetration of the tissues
track" scars remain. With disease progression, by the inflammatory process occurs slowly,
the cut surface of the bowel demonstrates full- causing loops of inflamed bowel to adhere
thickness inflammation, scarring, and fibrosis of to one another, thereby walling off any free
the submucosa, muscularis propria, and serosa. perforation that might occur. Occasionally,
The mucosa may ultimately become atrophic in a mass may be palpable as a consequence.
long-standing disease. Perforations result from deep penetration of
Inflammatory polyps and pseudopolyps fissures or fistulas through the bowel wall, or
develop in association with CD (fig. 15-7). The from complicating ischemia.

683
. Gastrointestinal Diseases

Figure 15·7
FILIFORM POLYPS IN CROHN'S DISEASE
Above: Endoscopic view of a long fingei-like post·in·
flammatory polyp in a strictured area of the ileum.
Right: Low· power view shows the mucosa thrown into
elongated, finger·like, filiform polyps.

CD is frequently complicated by strictures


in the small and large intestine. These stric- range of changes, depending on whether or
tures lead to partial, intermittent obstruction. not the tissues are examined early or late in the
Strictures and fistulas are more common with course of the disease and whether the tissues
ileitis, ileocolitis, and perianal disease than with come from more normal or more diseased parts
disease predominating in the colcm. Strictures of the bowel. The epithelium ranges from com-
may be multiple. They result from transmural pletely normal, to acutely damaged, chronically
inflammation, fibrosis, scarring, and fibromus- damaged, or regenerative. In areas affected by ac-
cular proliferation. Malignant change may also tive disease, the normal architecture of crypts and
lead to strictures and bowel obstruction. villi is distorted (fig. 15-8). This architectural dis-
Microscopic Findings. The ease of making tortion is characterized by glandular irregularity
the diagnosis of CD depends on whether a biop- and branching as well as glandular shortening in
sy or resection specimen is examined. Resection which the bases of the crypts no longer reach the
specimens are more likely to exhibit all of the muscularis mucosae. These architectural changes
classic changes of CD, especially those that typi- are appreciated best in sections of crypts cut in a
cally affect the deeper layers of the bowel wall. plane perpendicular to the muscularis mucosae.
The biopsy diagnosis of CD remains more prob- In tangentially cut sections, the distorted crypts
lematic because all the characteristic histologic are recognized by the presence of cross sections
features, including granulomas, are nonspecific, of glands that show variable diameters (fig. 15-9).
especially when only the mucosa and superficial The epithelium lining the distorted glands often
submucosa are available for examination. The appears hyperplastic. In the small intestine, villi
pattern and distribution of changes in biopsies become distorted or atrophic. Pyloric metaplasia
are frequently characteristic enough to suggest is frequently seen (see below). The presence of
that CD is present or to enable the exclusion distorted villi and/or crypts, areas of pyloric
of other entities in the differential diagnosis. metaplasia, or increased numbers of Paneth
Architectural Changes. The patchy distribution cells, especially in the left colon, indicates that
of CD results in an epithelium that exhibits a the disease is chronic.

684
Inflammatory Bowel Disease

'
' ~ '' .' ··-~',.1!:~ '"\\
Figure 15-8
ARCH ITECTURAL ALTERATIONS IN CROHN'S DISEASE
A: In the ileum, the villi appear blunted and irregular. The crypts are elongated and branched in many areas. The glands
no longer rest on the muscularis mucosae, but are separated from it by fibrous tissue.
B: Some architectural abnormalities are present even in areas of inactive disease. This photograph shows a branched
colonic crypt, but no significant inflammation.
C: The colonic crypts are elongated and irregular, but the architecture is not as severely altered as is often seen in ulcerative
colitis.

Mucosal In{lammat01y Infiltrate. Early in the lymphatics and blood vessels where they pene-
course of CD, increased numbers of mucosal trate the muscularis propria. Denser lymphocytic
plasma cells, lymphocytes, macrophages, mast aggregates also lie in the submucosa away from
cells, eosinophils, and neutrophils can be seen the lymphatics or are scattered throughout all
in nearly all layers of the bowel wall. A basal layers of the bowel wall (fig. 15-12).
lymphoplasmacytic infiltrate occupies the lower An early but nonspecific finding of CD is an
part ofthe mucosa (fig. 15-10). In active disease, increased number of eosinophils and macro-
neutrophils emigrate from the circulation into phages in the lamina propria beneath the
the mucosa, infiltrating the intestinal epithe- surface epithelium (fig. 15-13). Mucosal and
lium, and forming the lesion known as cryptitis submucosal mast cell hyperplasia and degranu-
(fig. 15-11). Collections of neutrophils within the lation are constant features of both UC and CD.
crypt lumens are called crypt abscesses (fig. 15- Dendritic cells lie adjacent to granulomas and
11). Variable edema or fibrosis is present, depend- fissures. They are arranged in band-like zones at
ing on the stage of the disease. The inflammatory the bottom of ulcers or fissures, perhaps play-
infiltr·ate often surrounds submucosal and serosal ing a scavenging role directed against microbial

685
Gastrointestinal Diseases

Figure 15-9 Figure 15-10


ACTIVE CROHN' S COLITIS CROHN'S DISEASE
Architectural distortion is present in this tangential The lamina propria contains a dense mixed inflam-
section. The crypts are no longer evenly spaced, nor are matory infiltrate composed of lymphocytes, plasma cells,
they of similar size and shape. Crypt abscesses are present, and numerous eosinophils. No active inflammation is
an indicator of active disease. present in this microscopic field.

Figure 15-11
ACTIVE INFLAMMATION IN CROHN'S DISEASE
Left: The lamina propria contains a dense infiltrate of chronic inflammatory cells. In addition, focal cryptitis is present
in which neutrophils infiltrate the colonic epithelium individually and in small groups.
Right: A cluster of neutrophils forms a crypt abscess with rupture as neutrophils spill into the surrounding lamina propria.

agents or dietary substances penetrating the lesion develops even before inflammatory cells
gastrointestinal wall through the mucosal de- diffusely infiltrate the lamina propria.
fects. Aggregates of macrophages lead to the Aphthous ulcers initially develop in areas
formation of noncaseating granulomas. overlying lymphoid follicles (fig. 15-14). Anti-
Aphthous and Other Ulcers. Two distinctive gen entry into M cells located in these areas may
types of ulceration affect the small and large in- lead to the proliferation of antigen-sensitized
testines in CD. The first is the histologic equiva- cells and granuloma formation. As the lesion
lent of the grossly evident aphthous ulcer. This progresses, it superficially ulcerates, obliterating

686
Inflammatmy Bowel Disease

Figure 15-12
LYMPHOID AGGREGATES IN CROHN'S DISEASE
Left: Many round lymphoid aggregates are in the colonic wall.
Right: In some foci, germinal centers are within the nodular mural collections of lymphocytes.

Figure 15-13
EOSINOPHILIA IN CROHN'S DISEASE
A: The inflammatory infiltrate in an area involved by
mildly active Crohn's disease contains numerous eosinophils.
B: Eosinophils are numerous in areas uninvolved by
active disease, as in this noninflamed ileum in a patient
with CD .
C: Eosinophils in uninvolved colon .

687
. Gastrointestinal Diseases

Figure 1 5-14
EARLY APHTHOUS ULCER FORMATION
Left: There is neutrophilic infiltration of the surface epithelium overlying this lymphoid aggregate and superficial erosion
of the epithelium. Scattered crypts showed evidence of cryptitis.
Right: Higher-power view of the edge of the ulcer overlying the lymphoid follicle has scattered neutrophils admixed
with lymphocytes.

its associated lymphoid follicle. A thin stream grees of necrosis. Ulcer healing may also entrap
of mucus, neutrophils, and inflammatory de- glandular epithelium within the submucosa or
bris enters from the ulcer mouth and empties deeper tissues, a finding sometimes referred to
into the bowel lumen. The ulcers progressively as enteritis cystica profunda. These glands can
enlarge, forming a continuum with the larger sometimes be difficult to differentiate from
ulcers normally seen in CD. invasive carcinoma (see below).
Knife-like, fissuring ulcers are typical of CD. Mucosal Metaplasia. Patients with chronic dis-
They are deep, narrow, and oriented at right ease often develop pyloric metaplasia, especially
angles to the long axis of the bowel.(fig. 15-15). in the ileum (fig. 15-17). These metaplastic cells
Deep fissures may extend through the bowel are sometimes also referred to as "ulcer-associ-
wall and are the basis for fistula formation. ated cell lineage cells." The pyloric-like glands
Fissures contain acute inflammatory cells and usually occur singly or in clusters in the mucosa
a granulation tissue lining with conspicuous adjacent to ulcer margins. They are also found
pale, plump histiocytic cells. The latter resemble in areas of healed ulceration, away from actively
the epithelioid histiocytes seen in granulomas. inflamed mucosa. Metaplastic cells share many
Giant cells may also be present. features of pyloric and Brunner glands, although
Healed ulcers result in architectural distor- they do not extend deeper than the muscularis
tion and a thickened or duplicated muscularis mucosae, a feature that distinguishes them
mucosae often associated with marked dense from Brunner glands. The cells appear clear or
submucosal fibrosis (fig. 15-16). As a result, it is pale-staining and have a columnar shape. Their
often impossible to distinguish the muscularis cytoplasm contains indistinct neutral mucin
mucosae from the submucosa or underlying granules. The nuclei are round to oval and are

muscularis propria. These structures fuse with located near the base of the cell.
one another and may be replaced with dense These pyloric-like glands develop from the
fibrous tissue. The areas of fibrosis show prolif- base of intestinal crypts where they extrude and
eration of fibroblasts and myofibroblasts, usu- proliferate downward, ramifying in the lamina
ally with accompanying chronic inflammatory propria to form a new gland. The gland then
cells. Fibrosis extends from the bowel wall to generates a duct that penetrates the surface,
involve adjacent structures and traps within it where it carries out secretions and also supplies
lobules of fat that may demonstrate variable de- cells to cover the surface (186).

688
Inflammatory Bowel Disease

Figure 15-15
FISSURE IN CROHN'S DISEASE
Left: Low-power view of transmural inflammation in the
terminal ileum. A deep knife-like fissure extends through
the submucosa into the underlying muscularis propria. To
the left, an abscess is forming.
Above: A mucosal fissure in another CD patient. The ulcer
is deep and miented perpendicular to the muscularis mucosae.

Figure 15-16
CROHN'S DISEASE
Left: There is poor distinction between the muscularis mucosae and the underlying submucosa.
Right: Higher-power view demonstrates marked thickening, duplication, and fragmentation of the muscularis mucosae.

689
Gastrointestinal Diseases

Figure 15-17
PYLORIC METAPLASIA
Left: Low-power view of the terminal ileum ~n a patient with active CD. The gland in the center appears more eosinophilic
than its neighbors on either side.
Right: Higher-power view shows replacement of the normal enterocytes and goblet cells by cells with eosinophilic,
vacuolated cytoplasm, resembling those seen in pyloric glands of the stomach. In addition, a few eosinophilic Paneth cells
lie scattered in the crypt bases.

Figure 15-18
PANETH CELL METAPLASIA
Left: Paneth cells are present in the bases of the glands in this section taken from the sigmoid colon of a patient with
!BD. Paneth cells are not normally present on the left side of the colon, and should therefore be regarded as metaplastic,
and an indicator of chronic injury.
Right: Paneth cells with coarse eosinophilic granules.

Paneth cell metaplasia often develops in specific for CD, but can be seen in any chronic
the large intestine of patients with CD (fig. 15- ulcerating disease process involving the colon.
18). The number of Paneth cells in the small Lymphoid Aggregates. Lymphoid aggregates,
bowel may increase; however, these cells do not which may contain germinal centers, generally
represent a form of metaplasia since Paneth cells lie at the mucosal-submucosal junction as well
are normally present in this location. It is impor- as within deeper layers of the bowel wall, includ-
tant to note that Paneth cell metaplasia is not ing the subserosa! adipose tissue layer (see fig.

690
Inflammatory Bowel Disease

15-13). Lymphoid aggregates form even in the Table 15-2


absence of granulomas, and may be more help- CONDITIONS ASSOCIATED
ful than granulomas in establishing the diagno- WITH INTESTINAL GRANULOMAS
sis of CD. Lymphoid aggregates are not specific Infection
for CD since they can also be found in patients Bacterial infection
with UC. Their presence in the submucosa or Mycobacterium
deeper portions of the bowel wall, however, Yersinia
Campylobacter
separated from the muscularis mucosae, and Salmonella
associated with submucosal edema or fibrosis in Shigella
the presence of an intact mucosa, suggests the Escherichia coli
diagnosis of CD. Lymphoid hyperplasia within Neisseria gonorrhoeae
Clostridium clifficile
the terminal ileum in CD patients may addition- Treponema pallidum
ally present as multiple lymphoid polyps. Fungal infection
Granulomas. The presence of small, compact, Chlamydia! infection
sarcoid-like granulomas is the sine qua non Parasitic infection
for the diagnosis of CD and, when present, Diversion Colitis
is a reliable histopathologic criterion for dif- Sarcoidosis
ferentiating CD from UC. Granulomas assume Foreign Bodies
particular diagnostic significance only when Chronic Granulomatous Disease of Childhood
they are seen in tissues remote from areas of
Diverticular Disease-Associated Colitis
ulceration in situations where foreign body
or mucin granulomas are unlikely. Although
the presence of granulomas represents a useful
diagnostic feature for CD, they can be seen in The granulomas consist of small, localized,
numerous other conditions (Table 15-2). well-formed, loose or more compact aggregates
The reported frequency with which granu- of epithelioid histiocytes, with or without Lang-
lomas are identified in CD varies markedly erhans giant cells, and are often surrounded by
between studies. Possible explanations for this a cuff of lymphocytes (fig. 15-19). Older lesions
include the criteria used to diagnose granulomas; may show varying degrees of hyalinization and
whether or not isolated giant cells are included fibrosis. Granulomas that have definite foci of
among granulomas; the number of biopsies ob- necrosis or suppuration, or are restricted to the
tained; and the number of sections examined. edges of ruptured crypts, are not specific for
Granulomas are found in the bowel wall in SO to CD (159,183). In addition, isolated pericryptal
87 percent of colectomy specimens (187,195) and clusters of histiocytes as well as Langerhans
in 15 to 36 percent of colonoscopic biopsies (179, type giant cells may be seen in patients with UC
180). Upper gastrointestinal biopsies may also (172), most likely as a result of crypt rupture or
show granulomas in a small percentage of cases herniation (fig. 15-20).
(205) . Granulomas may additionally be found Vascular Lesions. Vascular lesions affect ap-
in regional lymph nodes, usually in association proximately 5 percent of CD patients. Oblit-
with granulomas elsewhere in the bowel wall. erative changes include intimal proliferation,
Fewer granulomas occur in the ileum than subintimal fibrosis, medial hypertrophy, medial
in the colon in patients with CD. Granulomas fibrosis, and adventitial fibrosis, all without a
progressively increase in number from the ileum significant inflammatory cell component. De-
to a maximum number in the rectum (155). generative arterial lesions may narrow the vas-
Granulomas also occur in various other tissues cular lumen due to duplication of the internal
and organs, including lymph nodes, pancreas, elastic lamina with medial hypertrophy. Venous
mesentery, peritoneum, liver, lung, kidney, and, lesions feature an irregular vascular sclerosis
occasionally, bones, joints, and skeletal muscle. with thickening of the wall due to hyperplasia
The presence of granulomas does not indicate of fibrous, elastic, and muscular tissues. Inflam-
disease activity, nor does it affect the postopera- matory vascular lesions consist of perivascular
tive recurrence rate (184) . inflammation and chronic inflammatory and/

691
. Gastrointestinal Diseases

Figure 15-19
GRANULOMAS IN CROHN'S DISEASE.
Above: A small compact granuloma in the upper portion
of the mucosa is not associated with a damaged crypt.
Right: Higher-power view shows a compact collection
of histiocytes without evidence of necrosis.

Figure 15-20
GRANULOMA ASSOCIATED WITH CRYPT RUPTURE
Left: A cluster of histiocytes (center) forms a small granuloma.
Right: On higher power, this focus of granulomatous inflammation is clearly associated with a partially destroyed colonic
crypt. This biopsy was taken from a patient with UC, not CD.

or granulomatous cell infiltrates associated with tinal tract. When primary vasculitis affects a
an obliterative vasculopathy (fig. 15-21). Lym- patient with CD, extraintestinal manifestations
phocytes and plasma cells infiltrate one or more of the disorder are usually evident.
layers of small arteries or arterioles, interrupting Another notable feature of CD is submucosal
the internal elastic fibers. The vascular changes lymphatic dilatation, which commonly coexists
seen in CD must be distinguished from primary with edema and lymphoid hyperplasia (fig. 15-
systemic vasculitis involving the gastrointes- 22). Plasma cells, eosinophils, and neutrophils

692
In(lammat01y Bowel Disease

Figure 15-21
VASCULITIS IN CROHN'S DISEASE
A: A markedly inflamed submucosal vessel.
B: Higher-power view shows infiltration of the vessel wall by inflammatory cells with thrombosis. In some areas, the wall
of the vessel demonstrates fibrinoid necrosis.
C: Higher-power view of the inflamed, necrotic vessel wall.
D: A Verhoeff stain shows the damage to the wall of another vessel. There is prominent intimal fibrosis with near complete
occlusion of the vascular lumen.

may infiltrate along the dilated vessels. In more Displaced Epithelium. It is not uncommon to
advanced stages of the disease, fibrous tissue encounter displaced epithelium in resection
replaces the edema. specimens from CD patients (fig. 15-24). This is
Neural Changes. The autonomic neural plex- referred to as enteritis cystica profunda and colitis
uses often appear hypertrophic in CD (fig. 15-23). cystica profunda when it affects the small bowel
Large, irregular, fusiform nerve bundles are pres- and colon, respectively. Displaced epithelium
ent throughout the submucosa and muscularis results from epithelial implantation into the
propria. These often contain increased numbers submucosa, muscularis propria, or serosa fol-
of ganglion cells. Occasionally, striking plexiform lowing mucosal ulceration or the formation of
neuromatous proliferations are seen in associa- mucosal microdiverticula, a common event in
tion with tortuous thick-walled arterioles. They CD patients. Mucosal repair following regenera-
express MHC class 11 antigens (163) and thus tion of an ulcer leaves the detached epithelium
the abnormal nerves become infiltrated with buried in the submucosa. It eventually becomes
mast cells, lymphocytes, and plasma cells. The covered by intact mucosa. Displaced epithelium
nerves also show evidence of extensive axonal also results from epithelialization of fissures or
and dendritic swelling and degeneration (194). fistulous tracts. The displaced epithelium often

693
Gastrointestinal Diseases

becomes cystically dilated, and contains large


accumulations of mucin.
Grossly, the bowel wall containing displaced
epithelium appears thickened. The cut surface
demonstrates numerous ·cystic submucosal
spaces that may contain mucin. The mucosa
overlying such lesions usually shows histologic
evidence of active or healed CD. Histologically,
mucus-filled cysts are seen in the submucosa,
muscularis propria, and serosa. These are lined
by cuboidal to columnar epithelium containing
numerous goblet cells, enterocytes, and Paneth
cells, all supported by a normal lamina propria.
Sometimes the cyst lining disappears due to
pressure atrophy.
It is sometimes difficult to determine whether
the displaced epithelium represents invasive
mucinous carcinoma or merely displaced epithe-
lium, especially when the lamina propria does
not surround the glands or when the benign
epithelium produces excessive amounts of mu-
cin, resulting in large mucinous cysts containing
scant epithelial elements (fig. 15-25). Features
that help to mle out malignancy include the ab-
sence of desmoplasia, the presence of surround-
Figure 15-22 ing lamina propria, and an absence of t:ytologic
LYMPHANGIECTASIA IN CROHN'S DISEASE
atypia within the displaced glands. In some cases,
however, it is impossible to determine whether one
The submucosal and mucosal lymphatic channels of the
ileum are prominently dilated. is dealing with displaced epithelium or invasive
cancer, especially in cases where the overlying
surface epithelium appears dysplastic.

Figure 15-23
NEURAL HYPERPLASIA
Left: Disordered aggregates of large nerve fibers are in the submucosa.
Right: Hypertrophic nerve fibers are also seen in the myenteric plexus.

694
Inflammatmy Bowel Disease

Figure 15-24

ENTERITIS CYSTICA PROFUNDA


A: Glands are deep within the submucosa of the ileum.
B: Cystically dilated gland within the submucosa.
C: These glandular elements are surrounded by normal-
appearing lamina propria. In addition, the cells are basally
arranged without evidence of cytologic atypia.

695
Gastrointestinal Diseases

·D·
-- ·~
. . . . .. . ,.. ,..,
Figure 15-25
CROHN' S DISEASE, ENTERIT!S CYSTICA PROFUNDA, AND INVASIVE ADENOCARCINOMA
A: Low-power view of an area of enteritis cystica profunda. The glands are surrounded by lamina propria.
B: The surface epithelium in this portioQ...of the ileum shows evidence of dysplasia. The nuclei are large and atypical, and
have lost their normal polarity.
C: Invasive well-differentiated adenocarcinoma: a gland with cytologic atypia, no surrounding lamina propria, and
instead, a desmoplastic type stroma.
D: A few single invading cells lie within the desmoplastic stroma .

Histologic Features ofProximal Gastrointestinal cuboidal, to completely flattened. Some appear


Lesions. The villous architecture in the proximal vacuolated and others are frankly megaloblastic,
small intestine may appear normal or the mu- presumably due to coexisting vitamin deficien-
cosa may be completely flattened and covered cies. Very few intraepithelial lymphocytes are
by an abnormal surface epithelium infiltrated seen, but neutrophils are common. A normal
by large numbers of neutrophils. Such areas of biopsy does not exclude the diagnosis of CD
flattening may lie adjacent to more normal- because duodenal involvement may be patchy.
appearing tissues. In the nonileal small intes- Gastric biopsies show some degree of abnor-
tine, the most severe damage occurs proximal mality in as many as 75 percent of patients with
to the ligament of Treitz. The mucosa may show CD (175,176,205). The most commonly identi-
histologic changes similar to those seen in the fied alteration is focal infiltration of the gastric
ileum (fig. 15-26). Erosions, increased numbers pits and glands by inflammatory cells (fig. 15-27).
of lamina propria plasma cells and neutrophils, These infiltrates may include neutrophils, T lym-
crypt abscesses, and pyloric gland metaplasia, phocytes, and histiocytes in variable numbers.
often in the absence of granulomas, are seen. This focal inflammation affects both the neck re-
Surface epithelial cells vary from normal, to gion and deep aspects of the gastric glands, and

696
Inflammatory Bowel Disease

Figure 15-26
DUODENAL CROHN'S DISEASE
A: The duodenal architecture is distorted, and the lamina
propria is edematous. There is no active inflammation in
this tissue fragment.
B: Another tissue fragment from the same biopsy specimen
shows dense inflammation within the lamina propria.
C: A crypt abscess is present.

697
Gastrointestinal Diseases

is more commonly seen in the antrum than in localize to the neck region of the glands. The
the body of the stomach (17 5,17 6). Granulomas presence of deep active inflammation should
are seen in 9 to 16 percent of patients (fig. 15-28) alert the pathologist to the possibility of CD.
(162,175,176,194,205) . GrEmulomas are almost H. pylori infection should }?e ruled out with the
always associated with focal active gastritis. The use of special stains in all patients with any
major differential diagnosis is with Helicobacter form of chronic active gastritis. It is important
pylori gastritis. H. pylori gastritis may also dem- to note that some patients with CD may have
onstrate chronic active inflammation, but the superimposed H. pylori infection (175,176,205).
infiltrates are almost entirely neutrophilic, and CD may affect the esophagus and when it
does, it may be difficult to distinguish from
other forms of granulomatous esophagitis, espe-
cially if a history of CD is not known. Clinically,
severe forms of esophageal CD may simulate
carcinoma because of the presence of an irregu-
lar, stenotic esophageal segment. Radiographic
studies may demonstrate the presence of one or
more aphthous ulcers, inflammation, fistulas,
and strictures.
Crohn's Disease of the Head and Neck Region.
Lesions may develop on the lips, epiglottis, and
aryepiglottic folds of patients with CD (153,154,
204). Oral vesicular lesions and aphthous ulcers
affect many patients. Typical CD is usually
present in the gastrointestinal tract of these in-
dividuals, but occasionally the diseas~ presents
Figure 15-27 first in the oropharynx. Oral lesions appear
GASTRIC CROHN'S DISEASE grossly nodular and firm. Biopsy demonstrates
The antral biopsy shows patchy inflammation. A cluster the presence of chronic inflammatory cells and
of lymphocytes is in the deep mucosa. Less well-defined granulation tissue. Well-formed, noncaseating
lymphocytic infiltrates are in other areas of the biopsy. granulomas may also be present.

Figure 15-28
GRANULOMATOUS GASTRITIS IN CROHN'S DISEASE
Left: A small cluster of histiocytes is in the lamina propria.
Right: Higher-power view shows a compact aggregate of histiocytes and multinucleated giant cells. This granuloma is
not associated with damaged gastric glands.

698
In(lammat01y Bowel Disease

Differential Diagnosis. The differential that act only on the gastrointestinal mucosa
diagnosis of CD includes UC (see below), other and have fewer systemic effects are also useful,
forms of active enterocolitis, and granulomatous although many patients experience adverse re-
enterocolitis. Differentiating IBD from acute actions. Corticosteroid treatment has not been
infectious enterocolitis is sometimes difficult. demonstrated to maintain remission.
Infectious enterocolitis generally lacks the ar- Antiinflammatory Agents. Antiinflammatory
chitectural distortion and metaplastic changes agents such as sulfasalazine and mesalazine are
commonly seen with IBD. In addition, the in- used to treat mild to moderately active CD, or as
flammation in infectious enterocolitis is often maintenance medication in patients who have
superficial. The inflammation within the lamina achieved remission of their disease through the
propria often contains numerous neutrophils, use of steroids. These medications have signifi-
and edema is prominent in acute self-limited en- cant side effects including headaches, nausea,
terocolitis. The basal plasmacytosis characteristic pancreatitis, anemia, and dermatitis. Prepara-
of IBD is not seen. Cryptitis occurs commonly, tions that are released in the small intestine may
and crypt abscesses are sometimes seen, but are be of value in enteric forms of the disorder. In
not as prominent a feature as they are in IBD. general, patients with CD require higher doses
There are numerous causes of granuloma- of mesalamine than are traditionally used for
tous enterocolitis, all of which enter into the patients with UC.
differential diagnosis of CD. These are listed in Immunosuppressive Agents. Azathioprine and
Table 15-2. The granulomas seen in granuloma- 6-mercaptopurine are indicated in patients with
tous enterocolitis with an infectious etiology steroid-dependent CD, extensive small intesti-
frequently show evidence of necrosis, a find- nal disease, gastroduodenal disease, recurrent
ing that is almost never seen in CD-associated disease following prior bowel resection, and
granulomas. In addition, acid-fast or Grocott perianal fistulas refractory to other therapies.
stains may demonstrate the presence of myco- Methotrexate is used for long-term maintenance
bacterial or fungal organisms. Parasitic organ- in adults with CD who are intolerant of the for-
isms may be identified on routine hematoxylin mer preparations. Cyclosporine use in CD has
and eosin (H&E)-stained sections. Sarcoidosis is been disappointing. Side effects of immunosup-
associated with the presence of compact granu- pressive agents include hypersensitivity reac-
lomas similar to those seen in association with tions, bone marrow suppression, pancreatitis,
CD, but the other inflammatory changes that and infectious complications.
characterize IBD are absent. Antibiotics. The antibiotics metronidazole and
Diverticular disease-associated colitis or ciprofloxacin have been used with some success
isolated sigmoiditis may appear histologically in treating patients with mild to moderate CD,
identical to CD. Differentiation between these especially when the disease involves the colon.
diseases requires knowledge of the distribution Some success has been achieved using these
of the inflammation, and the presence or ab- preparations as maintenance therapies, but
sence of diverticula. established, controlled data are lacking.
Treatment. The medical treatment of CD is Biologic Agents. Infliximab (Remicade), the
individualized based on the severity of symp- first biologic agent effective in the treatment of
toms and sites of involvement in each patient. CD, revolutionized the treatment of this disease.
Treatment options include steroids, anti-in- Infliximab is a monoclonal, chimeric anti-TNF-a
flammatory agents, immunosuppressive agents, antibody that acts both through neutralization of
antibiotics, and the new biologic agents. Other free TNF-a as well as through induction of apop-
forms of therapy include nutritional or dietary tosis by binding membrane-bound TNF-a on
treatment and administration of probiotics. cytotoxic T lymphocytes (197, 200). Infliximab
Corticosteroids. Corticosteroids are effective is effective in treating CD patients with disease
in decreasing disease activity and inducing re- that remains refractory to conventional therapies
mission in most CD patients. Due to systemic (196). It is also effective for the maintenance of
side effects, however, long-term use of steroids remission in these patients (188). This dmg is also
is avoided. Newer agents, such as budesonide, used to treat fistulizing forms of CD (150,182).

699
Gastrointestinal Diseases

Infliximab appears to be safe for short-term medically intractable disease. Many patients
therapy; the effects of its long-term use are not experience recurrence of their disease (181),
yet known. Patients treated with infliximab may but many also report an overall improvement
develop human antichimeric antibodies directed in their quality of life following surgery (156).
against the anti-TNF-a antibody itself, or may de- Prognosis. CD is a chronic illness, with the
velop autoantibodies including antinuclear anti- majority of patients experiencing recurrent
bodies and antidouble stranded DNA antibodies disease. Nearly all patients have a recurrence
(157,201). Some patients develop drug-induced within 10 years of their initial diagnosis. Re-
lupus erythematosus (160). The formation of currence occurs more often in patients with
autoantibodies can be prevented by simultane- ileocecal disease (53 percent) than with isolated
ous administration of immunosuppressive agents colonic disease (45 percent) or isolated small
(190). Patients also have infusion reactions and bowel disease (44 percent) (203). Patients who
increased infections, especially those of the up- have undergone surgical procedures are also
per respiratory tract. An additional complication prone to disease recurrence (178).
of infliximab treatment is reactivation of latent Patients with CD may develop numerous
tuberculosis. Therefore, it is recommended that complications of their disease, some of which im-
patients be tuberculin tested prior t® the start pact patient survival (Table 15-3). Patient survival
of treatment. There is concern that long-term is not influenced by disease extent at the time of
therapy with the drug could increase the risk diagnosis. Community- and population-based
for immunoproliferative disorders, but this has studies demonstrate that the survival rate of pa-
not yet been established. tients with CD is similar to, or slightly less than,
Nutritional Therapy. Complete bowel rest and that observed in the non-IBD population. There
concomitant parenteral nutrition can result in are more severe forms of the disease that tend to be
clinical remission in many patients with CD, included in statistics from tertiary referral centers
including those with steroid refractory disease where morbidity, surgical rates, and mo;:tality are
(161). Subsequent studies have demonstrated greater. Patients with CD die of their underlying
that similar results may be achieved with el- IBD, as well as from associated diseases, including
emental diets, oligomeric and other predigested gastrointestinal cancer, respiratory diseases, and
feeds, as well as polymeric liquid formula diets, other gastrointestinal diseases (158).
especially in pediatric patients with short seg-
ment ileal disease (165,168,185):' Nutritional ULCERATIVE COLITIS
intervention is especially important in the Definition. Ulcerative colitis is a chronic IBD in
treatment of pediatric CD patients in whom which the inflammation remains confined to the
growth retardation is a major problem. Aggres- colon. The rectum is involved in 95 percent of
sive nutritional support is indicated in patients patients. The more proximal portions of the co-
with malabsorption, blind loops, and short bowel lon demonstrate variable degrees of involvement.
syndrome since numerous vitamin and trace el- The inflammation is diffuse and continuous, and
ement deficiencies may occur in these patients. is for the most part, confined to the mucosa.
Surgery. The majority of patients with CD Demography. In recent decades, the inci-
require surgery at some time during their lives. dence of UC in the United States, Canada, and
In general, radical resection does not decrease Europe has risen (219a,250a,267,277a). This
the recurrence rate of the disease, and repeated increase in UC incidence may be related to im-
resections place patients at risk for the develop- proved diagnosis due mainly to the increased
ment of short bowel syndrome (181). There- use of sigmoidoscopy and fecal occult blood
fore, conservative surgical techniques have testing in the community. UC mostly affects
evolved in recent times to treat patients with young white people, but there is an increasing
CD-associated complications not amenable or recognition that the disease affects many ages
responsive to medical therapy. Surgery in CD and many ethnic groups (219a,242). The inci-
patients is indicated for treatment of abdominal dence of UC inversely correlates with smoking,
abscesses, internal or external fistulas, bleeding, and clinical relapses have been associated with
bowel obstruction secondary to strictures, and smoking cessation (243,273).

700
In{lammat01y Bowel Disease

Table 15-3 bleeding, fulminant disease, and toxic megaco-


COMPLICATIONS OF CROHN'S DISEASE
lon. Acute and massive rectal bleeding affects
up to 3 percent of patients (220). The bleeding
Local Gastrointestinal
Perforation
originates from widespread ulceration of the
Hemorrhage mucosa overlying telangiectatic vessels of the
Fistulas to adjacent bowel lamina propria.
Fistulas to urinary bladder Characteristically, UC is a chronic mucosal
Fistulas to vagina
Intestinal obstruction
disease with relapses and spontaneous remis-
Enterolith production sions. Relapses are relatively unpredictable
Malabsorption except that the disease activity in foregoing
Lactose deficiency years indicates a 70 to 80 percent probability
Zinc deficiency
Psoas abscesses
that the disease will continue the following year
(242). UC progresses to a more serious form in
Extraintestinal Manifestations
Bronchitis approximately 54 percent of patients. Factors
Emphysema associated with disease progression include
Asthma the extent of disease at diagnosis, the presence
Amyloidosis of joint symptoms, younger age at diagnosis,
Neoplasms and severe bleeding (220). Various infections
Small bowel carcinoma (cytomegalovirus, Salmonella, and Clostridium
Large intestinal carcinoma
Cholangiocarcinoma difficile), medications, and intervening ischemic
Lymphoma disease may also complicate or exacerbate UC.
Squamous cell carcinomas, anus and vagina Gross Findings. Disease extent and in-
volvement vary with the clinical severity. The
distal bowel is always involved, with variable
proximal continuous extension (fig. 15-29).
Some patients show evidence of pancolitis
Clinical Features. There is a wide range of with diffuse involvement of the entire colon.
clinical features affecting all age groups. Diar- The ileum is generally not involved except to
rhea and urgency of defecation, bloody diarrhea, a minor degree by "backwash ileitis." In rare
attacks of crampy abdominal pain, and perianal instances, the rectum is spared. This occurs
soreness are common in the early stages of the mainly in patients who have been treated prior
disease. The most consistent feature of UC is the to resection or biopsy with enema preparations
presence of blood and mucus in the stool. Pa- (210,236,237,255).
tients complain of crampy abdominal pain that is Since UC is primarily characterized by inflam-
worst at the time of defecation. Abdominal pain mation that remains limited to the mucosa,
is usually less severe than in CD. The location of the external surface of the colon usually ap-
pain within the abdomen depends on the extent pears normal, except that in chronic UC, the
of the disease. Patients with left-sided colitis overall length of the colon may be shortened.
complain of lower abdominal discomfort, while This is not true in cases in which carcinoma or
pancolitis is associated with diffuse abdominal toxic megacolon have developed. In the case of
pain. In children, growth failure, characterized toxic megacolon, the colon appears massively
by decreased linear growth and delayed sexual dilated and the wall is paper-thin (fig. 15-30).
maturation, may occur, although less commonly Frequently, fibrinous or fibrinopurulent exu-
than in CD patients (265). dates are seen on the peritoneal surfaces. The
Approximately 30 percent of patients have an descending and sigmoid colon usually show
abrupt onset of disease, occasionally mimicking the most severe involvement. Edema widely
an infectious or dysenteric illness. The disease separates the fibers of the muscularis propria,
may be explosive, with the sudden onset of sometimes leading to perforation.
bloody diarrhea, continuous abdominal pain, Typically, when one opens a colon resected
anorexia, weight loss, iron deficiency anemia, for active UC, blood oozes diffusely from the
and persistent fever. Acute problems include congested vasculature of the mucosal surface.

701
Gastrointestinal Diseases

Figure 15-30
FULMINANT ULCERATIVE COLITIS
The colonic mucosa appears ulcerated and diffusely
hemorrhagic.

The disease usually involves the rectum and


extends for a variable distance proximally in
a continuous fashion. The transition from dis-
eased to uninvolved mucosa is often abrupt.
Variations in the intensity of inflammation may
give a false impression of discontinu0us focal
or skip lesions, particularly in acute UC with
patchy full-thickness mucosal loss. Ulcerated
areas may have intervening mucosa that looks
macroscopically normal. Additionally, treat-
ment with steroid enemas and mucosal heal-
ing may lead to the gross impression of rectal
sparing. Grossly apparent skip areas or areas of
rectal sparing, however, generally show histo-
logic evidence of the architectural abnormalities
characteristic of healed colitis.
In active UC, the mucosa acquires a diffuse,
uniformly granular and erythematous, hemor-
rhagic appearance. Ulcers undermine adjacent
intact mucosa to form polypoid mucosal tags or
pseudopolyps (figs. 15-31, 15-32). Inflammatory
polyps are discrete areas of mucosal inflamma-
Figure 15-29
tion and regeneration. These polyps do not
correlate with disease severity, although they
GROSS APPEARANCE OF THE occur most commonly in patients with severe
COLON IN ULCERATIVE COLITIS
chronic disease. Their distribution depends on
A: The distal two thirds of the colon shows extensive
ulceration and pseudopolyp formation. Note the diffuse, the extent of the colitis. Both localized and
continuous involvement of the diseased segment of colon. diffuse forms of inflammatory polyposis com-
The proximal one third is essentially normal in appearance. plicate UC; however, polyps are numerous only
B: The transition from the inflamed colon to normal- in a minority of cases. Inflammatory polyps are
appearing colon is abrupt.
C: Endoscopically, the mucosa is markedly erythematous
typically short, measuring less than 1.5 cm in
with foci of erosion and ulceration. height. There are also unusual inflammatory

702
Inflammatory Bowel Disease

Figure 15-32
ULCERATIVE COLITIS
There is widespread ulceration of the colon. The
remaining nonulcerated mucosa appears as multiple
pseudopolyps.

polyps that attain a large size or have a bizarre


architecture. Such large postinflammatory
polyps may produce acute intestinal obstruc-
tion (224) and intussusception (223), or mimic
carcinomas (228). In addition, they may bleed
or aggravate protein loss from the colon.
Once formed, postinflammatory polyps tend
to persist and may serve as an indicator of previ-
ous episodes of colitis. They are more prominent
in the colon than in the rectum and can com-
pletely spare the distallarge bowel. Fused polyps
create a labyrinthine appearance and mucosal
bridging. Polyp fusion results from the approxi-
mation of two adjacent polyps that become su-
perficially ulcerated. Fibroblasts grow into the
granulation tissue between the polyp surfaces.
The presence of broad areas of superficial
ulceration that are covered by an overlying
mucopurulent exudate results in partial or
complete loss of the mucosa in some areas. The
ulcers exhibit a linear distribution, particularly
in relation to the attachment of the taeniae
coli. Deep ulceration, with exposure of the
Figure 15-31 underlying muscularis propria or penetration
PSEUDOPOLYPS IN ULCERATIVE COLITIS of it, is seen only in fulminant UC. Extensive
A: Large ulcers have intervening areas of mucosal longitudinal ulcers, especially if connected by
regeneration. These regenerative islands appear as polyps transverse ulcers, are not a feature of UC but are
raised above the ulcerated areas. more characteristic of CD.
B: Endoscopic view of scattered pseudopolyps. The terminal ileum becomes involved only
C: Low-power photomicrograph shows an area of
undermining ulceration flanked by polypoid regenerative in continuity with active pancolitis. This oc-
islands of mucosa. curs in 10 to 20 percent of patients. The ileal

703
Gastrointestinal Diseases

Figure 15-33
MUCOSAL ATROPHY IN LONG-STANDING ULCERATIVE COLITIS
Left: The distal three quarters of the colon shows diffuse loss of the normal pattern of folding. The uninvolved proximal
colon appears essentially normal.
Right: Higher-power view shows a flattened, thinned mucosa.

inflammation, known as backwa~ ileitis, is mucosae. Metaplastic changes such as Paneth


thought to result from incompetence of the cell metaplasia are also common.
ileocecal valve and reflux of intestinal contents Active Colitis. The hallmark of activity in
across it. Grossly, the ileal mucosa appears dif- UC is the presence of neutrophils, with the
fusely abnormal, contrasting with the aphthous level of activity more or less correlating with
ulcers and discontinuous and serpiginous ulcer- the number of acute inflammatory cells in
ations of CD. The involved ileum shows inflam- the lamina propria. In active UC, there is an
mation, erosions, and sometimes ulcerations. intense inflammatory cell infiltrate within the
The ileitis usually resolves following colectomy. lamina propria, neutrophilic infiltration of the
In chronic quiescent UC, the mycosa appears glandular epithelium, mucin depletion, and
granular, with or without postinflammatory pol- surface ulceration. The term chronic active colitis
yps, and the hemorrhagic component is muted indicates the presence of such acute inflamma-
or absent. When UC goes into remission it is tory activity superimposed on a background of
possible for the mucosa to return to a normal chronic damage. The degree of activity can be
gross appearance, or appear smooth and atrophic further characterized by subjective estimations
with a loss of the normal pattern of folding (fig. of the amount of inflammation, such as mild,
15-33). Sometimes the most striking gross feature moderate, or severe.
is intestinal shortening with loss of the haustral An early feature of active colitis is the forma-
folds, which produces •an appearance of a con- tion of cryptitis, which evolves to the formation
tracted, stiff, thickened bowel. This shortening of crypt abscesses and crypt ulcers (fig. 15-35).
results from muscular abnormalities and is best As in CD, cryptitis reflects the migration of
seen in the distal colon and rectum. neutrophils into the crypt epithelium. A collec-
Microscopic Findings. UC is characterized tion of neutrophils in the crypt lumen is a crypt
by inflammation restricted primarily to the abscess. Although crypt abscesses are character-
mucosa, but sometimes involving the sub- istic of active UC, basing the diagnosis of this
mucosa (fig. 15-34). Varying degrees of active disease on their identification is probably not
(neutrophilic) inflammation are superimposed prudent since crypt abscesses occur as part of
on chronic changes. The chronic changes in- acute inflammation associated with many disor-
clude architectural abnormalities such as crypt ders, including CD and acute self-limited colitis.
branching and widening of the distance be- Crypt ulcers are areas of crypt destruction from
tween the bases of the glands and the muscularis the inflammation. Once the crypt ruptures, a

704
In(lammat01y Bowel Disease

Figure 15-34
ULCERATIVE COLITIS
Left: Dense chronic active inflammation in the colon of a patient with pan colitis. The inflammation is limited to the mucosa.
Right: Higher-power view of a dense chronic inflammatory infiltrate within the lamina propria. Scattered foci of active
inflammation are present. The inflammation does not bridge the muscularis mucosae.

Figure 15-35
ACTIVE INFLAMMATION IN ULCERATIVE COLITIS
A: The crypt in the middle of the photograph contains
infiltrating neutrophils. The epithelium is regenerative
in appearance. The adjacent crypt on the right has more
extensive inflammation with formation of a crypt abscess.
B: Neutrophils are present within the lumens of the
two crypts in the center. Such collections are referred to as
crypt abscesses.
C: Neutrophils have accumulated in the crypt lumen,
and the epithelium has been damaged to the extent that
the crypt is partially destroyed. Neutrophils spill out into
the surrounding lamina propria.

705
Gastrointestinal Diseases

Figure 15-36 Figure 15-37


SEVERELY ACTIVE ULCERATIVE COL!TIS BASAL PLASMACYTOSIS IN ULCERATIVE COLITIS
An area of deep ulceration is present in this case of Examination of the deep aspect of the lamina propria in a
fulminant UC. The inflammation in this area extends to colon involved by UC shows a dense infiltr·ate of plasma cells
the muscularis propria. extending down to the muscularis mucosae. This distribution
of inflammation is referred to as basal plasmacytosis.

process sometimes referred to as crypt hernia- 15-37). Hyperplastic mucosal lymphoid follicles
tion, the luminal contents and mucus· escape may be quite prominent, especially in the rec-
into the surrounding lamina propria, sometimes tum. The inflammation remains superfrcial and
eliciting a histiocytic response. Such histiocytic primarily mucosal. Occasionally, this inflam-
collections may simulate the granulomas seen mation extends into the superficial submucosa.
in CD. The presence of acute inflammation, The lamina propria contains a dense infiltrate of
primarily based in the epithelium rather than lymphocytes and plasma cells. Eosinophils may
the lamina propria, distinguishes U<; from acute be present in variable numbers. As the intensity
self-limited colitis. of inflammation increases, the mucosa becomes
Crypt abscesses play a role in the generation extensively superficially ulcerated.
of areas of mucosal ulceration because, when Resolving Colitis. Active disease resolves sponta-
they lead to crypt rupture, the inflammation neously or in response to therapy. Initially, there
spreads laterally beneath the mucosa, causing is a reduction in vascular dilatation and disap-
it to slough and leaving an ulcer. Ulcers may pearance of the acute inflammation. During the
also spread into the submucosa and undermine healing phase, the epithelium actively regenerates,
adjacent, relatively intact mucosa. The ulcers epithelial continuity is restored, and the inflam-
associated with UC tend to be small and gener- matory infiltrate and abscesses begin to resolve.
ally shallow, but in severe UC, they may extend Epithelial regeneration extends from the base of
to the muscularis propria (fig. 15-36). Deep the crypts and from the edge of the ulcers. As the
penetration of the muscular layer or serosa, cells regenerate, they may show a syncytial-like
however, only occurs in toxic megacolon. appearance with large amounts of cytoplasm
The acute inflammatory changes of active (fig. 15-38). They may appear flattened at first,
UC are superimposed on chronic inflammatory but gradually increase in height, first becoming
changes within the colonic mucosa. Basal ac- cuboidal and then eventually columnar in shape.
cumulations of lymphocytes and plasma cells During this regeneration, the epithelium appears
(referred to as basal lymphoplasmacytosis), mucin depleted (fig. 15-38). As it matures and the
together with hyperplasia of lymphoid tissue, inflammation subsides, however, the epithelial
probably represent an early immunologic mani- mucin content is restored. The regenerated
festation of the underlying disease process (fig. crypts may appear branched (fig. 15-38).

706
Inflammatmy Bowel Disease

"'

Figure 15-38
EPITHELIAL REGENERATION IN ULCERATIVE COLITIS
A: The cells attempting to reepithelialize this area of ulceration have enlarged nuclei, prominent nucleoli, and abundant
eosinophilic cytoplasm. The cell borders are indistinct, giving them a syncytial appearance.
B: Reepithelialized ulcer with regenerative, cuboidal epithelial cells.
C: These regenerative glands have evidence of mucin depletion. Only a few goblet cells are seen in the crypts.
D: Regeneration may result in branching of the glands and other architectural abnormalities, as seen here.

Lymphocytes and plasma cells decrease in These represent useful histologically identifiable
number and tend to become more focal as signs of former active disease.
the inflammation subsides. Variable numbers Fulminant Colitis. Patients with fulminant
of acute and chronic inflammatory cells and colitis usually have pancolitis. Microscopic
Paneth cells are present during this phase. examination shows mucosal denudation and
Resolution of the chronic inflammation may replacement by highly vascular granulation tis-
produce a patchy infiltrate that can resemble sue. There is intense infiltration of the mucosa
CD in biopsy specimens. by histiocytes, plasma cells, lymphocytes, and
It takes weeks to months for active disease to neutrophils. Marked submucosal edema may ac-
become quiescent. If the resolution is complete company the inflammation. The inflammatory
and if the initial damage was minimal, com- changes in fulminant colitis may extend to the
plete architectural restoration can occur. More circular and longitudinal layers of the muscu-
commonly, however, permanent architectural laris propria, with varying degrees of muscle
abnormalities, such as distorted crypts, persist. degeneration and necrosis. Often, individual

707
. Gastrointestinal Diseases

Figure 15-40
ULCERATIVE COLITIS
ARCHITECTURAL ABNORMALITIES
In addition to branched and irregular crypts, crypt
shortening occurs in UC. In this example, the glands do
not rest on the muscularis mucosae as occurs in the normal
colon. The intervening lamina propria is mildly fibrotic
and contains an inflammatory infiltrate composed of
lymphocytes, plasma cells, and eosinophils.

Quiescent Colitis. In quiescent UC, the mucosa


may appear normal or diffusely atrophic with
architectural changes resulting from the damage
that occurred during active disease (fig. 15-39).
Mucosal atrophy takes the form of loss of crypt
parallelism with branching or a severe reduction
in the number of crypts per unit area. The crypts
characteristically shorten and the space between
the base of the crypts and the muscularis mu-
cosae widens (gland shortfall) (fig. 15-40). The
muscularis mucosae may appear thickened and
frayed due to previous ulceration and muscular
Figure 15-39 regeneration. Paneth cell metaplasia distal to
QUIESCENT ULCERATIVE COLITIS the hepatic flexure, pyloric metaplasia, and
Top: There is mild residual architectural distortion of the endocrine cell hyperplasia often indicate a long
crypts, but th e lamina propria is normocellular. history of colitis.
Bottom: Normal cellularity of the lamina propria is Ileitis. Backwash ileitis affects a proportion of
associated with an essentially normal glandular epithelium. patients with severe pancolitis. Inflammation
No active inflammation is present.
of the distal ileum is thought to occur in these
patients secondary to reflux of colonic contents
muscle fibers appear shortened and rounded; into the ileum through an incompetent ileoce-
aggregates of eosinophilic-staining cytoplasm cal valve. Histologically, the ileal mucosa shows
are within the myofibrils. The bowel wall, evidence of active inflammation (fig. 15-41).
however, lacks the fibrosis or the prominent Neutrophilic infiltrates are present, sometimes
lymphocytic aggregates seen in CD. Prominent including crypt abscesses. Features of chronic
lymphoid follicles are present in the submucosa injury, such as architectural distortion or pyloric
in fulminant UC but they should not be present metaplasia, should not be seen, and when pres-
in areas away from the ulceration. ent, should raise the possibility of CD.

708
Inflammat07y Bowel Disease

Figure 15-41
BACKWASH ILEITIS
A: The ileal mucosal architecture is relatively preserved,
and does not show the chronic changes seen in CD. The
lamina propria contains scattered neutrophils, and a crypt
abscess is present.
B: Higher-power view demonstrates ileal crypt abscesses
associated with backwash ileitis.
C: The colon shows diffuse pan colitis. The inflammation
is limited to the mucosa, and has the diffuse distribution
characteristic of UC.

Ulcerative Appendicitis. Ulcerative appendicitis, part of the continuous inflammatory process


the appendiceal counterpart of UC, is present in that characterizes UC (fig. 15-42). Appendiceal
the majority of colectomy specimens from pa- involvement, however, may also be seen in a
tients with pancolitis; it presumably represents proportion of patients without pancolitis (214,

709
Gastrointestinal Diseases

Figure 15-42
!)LCERATIVE APPENDICITIS
Left: Patchy ulceration of the appendiceal mucosa.
Right: On higher power, features typical of UC elsewhere in the colon are present. There is distortion of the crypt
architecture, and areas of active inflammation with crypt abscess formation.

227,230,240). Additionally, some patients dem- Sometimes strictures form on an ischemic


onstrate patchy cecal inflammation or appen- basis in patients with UC. Ischemic strictures
diceal orifice inflammation associated with left- show extensive fibrosis, and the mucosa and
sided colitis (215,256,281). Studies suggest that submucosa become replaced by gram!!lation
such "skip lesions" are of no clinical significance, tissue. Ischemia often complicates concurrent
and should not be misinterpreted as features of infection with cytomegalovirus (fig. 15-43).
CD in patients with otherwise typical UC. When fibrosis does develop in the setting of UC,
Upper Gastrointestinal Involvement. ·Rare cases it never develops to the same extent as seen in
of chronic active duodenal or gasg·ic inflam- CD, even when there is deep ulceration with
mation have been reported in association with destruction of the muscularis mucosae. The
UC (250,271,278). It is as yet unclear whether diagnosis of a complicating malignancy must
these cases represent an unusual manifestation be seriously entertained in patients with long-
of UC or a separate associated disorder. Longer standing UC who have a colon stricture.
follow-up of the reported cases is required before Differential Diagnosis. Approximately 5
such a determination can be made. percent of IBD patients exhibit overlapping fea-
Strictures. Disagreement exists concerning tures of both UC and CD, and thus fall into the
the frequency of benign strictures in chronic category of "indeterminate" colitis (221,248,254,
UC. Strictures develop as a result of muscular 282). The term indeterminate colitis is used be-
hypertrophy and thickening of the muscularis cause of inadequate clinical information on the
mucosae and muscularis propria rather than extent and distribution of the disease, or because
from fibrosis as occurs in CD . The hypertrophic of inadequate information from radiographic or
muscle remains in a spastic or contracted state, endoscopic studies. Indeterminate colitis does
resulting in intestinal hypomotility. In addi- not represent a disease entity itself, and should
tion, there are secondary changes that occur in only be used as a provisional diagnosis pending
. the muscle that lead to motility abnormalities, the availability of additional information. In
shortening and contraction of the large intes- most cases, a definitive diagnosis of either UC
tine, and loss of the haustral folds (238,274). or CD can be made within a few years of the
These changes are thought to occur secondary initial diagnosis of indeterminate colitis (249).
to the long-standing effects of cytokines on the Establishing the diagnosis of IBD is often
colonic smooth muscle cells (279). not difficult in endoscopic biopsy material, but

710
Inflammatmy Bowel Disease

Figure 15-43
CYTOMEGALOVIRUS INFECTION IN ULCERATIVE COLITIS
A: There is widespread ulceration, typical of active UC. Edema and hemorrhage are present in the proximal colon; these
represent ischemia superimposed on the patient's underlying UC.
B: Low-power view of apparent active IBD with extensive ulceration. A submucosal vessel contains a fibrin thrombus.
C: Higher-power view of the thrombosed submucosal vessel.
D: A typical cytomegalovirus inclusion in an endothelial cell underlying an area of ulceration.

differentiating between UC and CD often is. IBD crypt branching or atrophy, a villiform structure,
is best distinguished from the other forms of Paneth cell or pyloric metaplasia, lymphoid
colitis by the use a systematic approach when follicles, or prominent plasma cells above the
evaluating biopsy material (Table 15-4). Such muscularis mucosae. The diagnosis of different
a systematic approach involves evaluation of forms of colitis does not rely solely on the his-
several parameters, including epithelial altera- tologic features that are present. Knowledge of
tions (whether acute or chronic), changes in the the endoscopic appearance, the clinical features,
lamina propria, vascular changes, and changes and the disease distribution are essential. Such a
in the muscularis mucosae. Signs of chronicity diagnostic approach facilitates the distinction of
include architectural alterations with prominent UC from the diseases that mimic it (Table 15-5).

711
- Gastrointestinal Diseases

Table 15-4 Table 15-5


FEATURES TO BE EVALUATED IN BIOPSIES DISEASES THAT MAY MIMIC
FOR INFLAMMATORY BOWEL DISEASE INFLAMMATORY BOWEL DISEASE CLINICALLY
Architectural Changes Bacterial Infection
Crypt orientation (distortion) Escherichia coli 0157
Crypt length Salmonella
Distance of crypt bases from muscularis mucosae Shigella
Intercryptal distance Tuberculosis
Crypt branching Clostridium
Villiform transformation of crypt surface Carnpylobacter
Staphylococcal enteritis
Epithelial Changes
Yersinia
Mucus content
Presence of Paneth or pyloric cells Other Infections
Presence or absence of intraepithelial lymphocytes or Lymphogranuloma venereum
eosin ophils Histoplasmosis
Cryptitis Chlamydia! colitis-proctitis
Lamina Propria Changes Cytomegalovirus colitis
Presence or absence of inflammation Amebiasis
Nature of inflammation: acute or chronic • Schistosomiasis
Anisakiasis
Distribution of Inflammatory Changes
Focal or diffuse Ischemic Colitis
Superficial or basal Eosinophilic Gastroenteritis
Within crypts or in lamina propria Behcet's Disease
Mucosal or extension beyond mucosa
Urernic Colitis
Other Features
Presence or absen ce of specific microorganisms Radiation Colitis
Presence or absence of fibrosis Diverticulitis
Presence or absence of granulomas
Drug-Induced Colitis
Colitis in Graft Versus Host Disease

Table 15-6
GROSS FEATURES OF CROHN'S DISEASE VERSUS ULCERATIVE COLITIS

Feature Crohn's Disease Ulcerative Colitis


Distribution Segmental, 50% have normal rectum Diffuse, circumferential continuous with
rectum"
Terminal il eum Often thickened, ulcerated and stenosed, creeping Involved lOo/o, short segment, backwash
mesenteric fat, terminal 15-25 cm ileitis
Colonic involvement Predominantly right-sided, granulomas Usually left-sided and continuous to right
Rectal involvement + +++
Anal disease +++ +
Mucosal surface Aphthous ulcers, linear ulcers, cobblestone Granular, ulcers
appearance, fissures
Mucosal atrophy Minimal Marked
Serosa Inflamed, creeping fat, adhesions Usually normal
Colon shortening Due to fibrosis Due to muscle hypertrophy
Strictures Common Rare
Fistulas 10% with enteroenteric or enterocutaneous Rare
Free perforation Very rare Occurs with toxic megacolon
Pseudopolyps Occur Common
"The appendix may be involved in the absence of right-sided disease.

712
Inflammatmy Bowel Disease

Table 15-7
MICROSCOPIC FEATURES OF CROHN'S COLITIS VERSUS ULCERATIVE COLITIS

Feature Crohn's Colitis Ulcerative Colitis


Distributi.on of the Skip lesions, transmural Diffuse, mucosal and submucosal,
inflammation transmural in toxic megacolon
Crypt architectural distortion Minimal Marked
Paneth cell metaplasia Occurs Common
Cytoplasmic mucin Slightly reduced Mucin depleted, greatly reduced
Vascular telangiectasia Seldom prominent Prominent
Edema Marked Minimal
Lymphoid hyperplasia Common, separated from muscularis mucosae, Rare, mucosa and submucosa, not
transmural and pericolonic tissue, associated associated with edema and
with submucosal edema, fibrosis fibrosis
Crypt abscesses Present, often few in number Common
Granulomas (sarcoid-like) Common Absent
Aphthous ulcers Common Rare
Fissures and sinuses Common Absent
Submucosa Normal, inflamed or reduced width Normal or reduced width
Focal lymphoid aggregates Presence suggests CD' especially when deep Usually absent
in submucosa
Neural hyperplasia Common Rare
Inflammatory and pseudopolyps Less common than in UC Common
Filiform polyposis, giant polyps, Occurs Occurs
postinflammatory polyps
Ileal inflammation Common Minimal, not more than 10 cm
involved
Anal involvement Granulomas Nonspecific
Lymph nodes Granulomas Reactive hyperplasia
'CD = Crohn's disease; UC = ulcerative colitis.

Patients with UC and CD share many simi- of stomal dysfunction and recurrent ileitis. A
larities, but there are also significant differences misdiagnosis is particularly hazardous to the
that create the need to distinguish between patient with CD who undergoes a colectomy
them (Tables 15-6 and 15-7). Different surgi- with construction of an ileal pouch reservoir
cal approaches are used to treat IBD patients because a significant number of these patients
depending on the nature of the underlying develop recurrent CD in the pouch, resulting
disease. Surgical techniques for continent ileos- in chronic inflammation and pouch failure
tomy or ileoanal anastomosis with construction (235,239). As a result, pathologists are under
of a pouch reservoir allows one to avoid an great pressure to distinguish UC from CD on
ileostomy following colectomy. The operation biopsies before the patient undergoes surgical
is designed to improve the quality of life in UC intervention.
patients by preserving fecal continence. This When the diseases are well developed, UC
procedure, however, is generally not used to and CD have unique and distinguishing fea-
treat CD patients (218). Total proctocolectomy tures that allow their separation. Since no single
in a UC patient with backwash ileitis allows feature is invariably present, however, and be-
the ileum to heal, but the same operation in a cause all of the features change with time, all
patient with CD ileocolitis may leave residual of the pathologic features need to be assessed
disease or may be followed by a high incidence in aggregate.

713
_ Gastrointestinal Diseases

The presence of a villous mucosal surface, (206,213,276). Large, long-term studies are still
basal lymphoid aggregates, crypt atrophy, and needed for a complete assessment of the efficacy
surface erosions all favor the diagnosis of UC, and safety of this drug in patients with UC.
whereas the presence of graimlomas favors the A recent report suggests. that topical treat-
diagnosis of CD. Because CD is a focal disease, ment of the rectal mucosa with epidermal
a patient with CD may have biopsy specimens growth factor may be an effective treatment
that show a completely normal mucosa, focal for left-sided UC. Epidermal growth factor is a
or diffuse colitis, or granulomas. potent mitogenic peptide that has been shown
Preservation of colonic mucin is a common to stimulate healing when applied topically
feature of CD, but it may only represent a mani- to skin wounds (211), and is beneficial in the
festation of an essentially focal disorder, and treatment of necrotizing enterocolitis in new-
it may not distinguish CD from UC. Its main barns (2 77).
value is to distinguish a normal biopsy from Probiotics. The use of probiotics has been suc-
specimens showing IBD. The presence of any cessful in the treatment of some patients with
significant ileal disease establishes the diagnosis UC (241,264). Probiotics are live microbial food
of CD rather than UC with backwash ileitis. Il- ingredients that alter the enteric flora and are
eocecal valve incompetence in UC can produce thought to have a favorable effect on health.
ileal changes (backwash ileitis), but the involved Probiotic activity has most commonly been
ileal segment should be short and the bowel associated with lactobacilli and bifidobacteria,
should lack other characteristic features of CD. but other nonpathogenic bacterial strains,
Treatment. Antiintzammat01y Agents. Antiin- including certain Escherichia coli and entero-
flammatory agents such as sulfasalazine, as well cocci, as well as nonbacterial organisms such
as the newer 5-aminosalicylic acid medications, as Saccharomyces boulardii have been used. The
are a mainstay in treating patients with mild to mechanisms by which these probiotics function
moderate UC. These agents are useful for both include production of antimicrobia!~, com-
inducing disease remission and for maintenance petitive metabolic interaction with proinflam-
therapy. They may be administered orally, or in matory organisms, and inhibition of adherence
patients with disease limited to the left colon, and translocation of pathogens (209,219,272).
administered topically in enema preparations. Probiotics may also influence mucosal defenses
Corticosteroids. Intravenous corticosteroids of the mucosal immune system and epithelial
may be required in the treatmenf""of patients function through their impact on intercellular
with moderate or severe UC. Topical steroid en- signaling (229,232,272).
emas are used in patients with left-sided colitis, Effects ofTherapy on Histology. Various thera-
or to "cool down" the rectum of patients with pies used to treat IBD, whether local instilla-
more extensive disease prior to surgery. Corti- tion of corticosteroid enemas or systemically
costeroids have no role in maintenance once administered anti-inflammatory agents, may
remission has been achieved. suppress some of the more classic gross or his-
Immunosuppressive Therapy. Azathioprine and tologic features associated with the diagnosis
6-mercaptopurine are u~ed in the treatment of of UC. Suppression of rectal inflammation can
UC due to their steroid-sparing effects. These lead to the false impression of rectal sparing.
drugs have a delayed onset of action, however, Therapy may also predispose the intestine to
and are therefore not useful for treating acute develop secondary complicating features, such
fulminant disease. Cyclosporine and tacrolimus as cytomegalovirus infection, with or without
. have also been used to treat patients with steroid secondary endothelialitis, and ischemia. In
refractory UC (216) and have a more rapid onset addition, C. difficile infection may occur in
of action than other immunosuppressive agents. patients on immunosuppression.
Biological Agents. The anti-TNF-a antibody, in- Surge1y. Surgical therapy for UC is used ei-
fliximab, is extremely useful for treating patients ther for emergencies or as elective treatment.
with CD. Several reports, mainly uncontrolled Indications for urgent surgery, in decreasing
data, suggest that this agent may also be of ben- order of frequency, include failed medical
efit in the treatment of patients with severe UC treatment in patients with acute severe colitis,

714
Inflammatmy Bowel Disease

toxic megacolon, perforation, or severe bleeding friability, bleeding, loss of the vascular pattern,
(252). There are essentially three indications for and the presence of a mucus exudate and small
elective colectomy for UC. These include failed superficial areas of ulceration (figs. 15-44, 15-45)
medical treatment, growth retardation in a child (217,247). Generally, a significant relationship
with UC, and the development, or concern for, exists between the endoscopic and the histo-
neoplastic transformation in a patient with logic features.
long-standing disease. Failed medical treat- Bacterial overgrowth resulting from stasis is
ment includes chronic disease, recurrent acute thought to play a major role in the develop-
exacerbations, severe symptoms in an otherwise ment ofpouchitis (251,268). Anaerobic bacterial
systemically well patient, suboptimal quality concentrations in ileal pouchitis correlate with
of life, steroid dependence, or extraintestinal the presence of nonspecific histologic changes,
manifestations of the disease. including villous atrophy and chronic inflam-
In patients undergoing emergency surgery, mation. Fecal stasis and aerobic and anaerobic
the most common procedure is colectomy with bacterial overgrowth may contribute to the
ileostomy and preservation of the rectosigmoid development of colonic metaplasia (266). Other
stump. Under the conditions of elective sur- factors that may play a role in the development
gery, several surgical options exist including of pouchitis include the presence of volatile
conventional proctocolectomy, colectomy with fatty acids, fecal bile acids, oxygen free radicals,
ileorectal anastomosis, and restorative procto- ischemia, platelet-activating factor, and hor-
colectomy with ileal reservoir (253). monal factors (208,212,226,244,245,251,268).
Histologic Features of the Ileal Pouch. Patients with pouchitis have a pattern of
Three basic patterns of mucosal change may mucosal inflammation similar to that seen in
be seen in pelvic ileal pouches: 1) normal UC (figs. 15-46, 15-47). Early changes consist
mucosa or mild villous atrophy with absent or of neutrophilic and eosinophilic inflammation
mild inflammation; 2) transient atrophy with with architectural distortion, Paneth cell meta-
temporary moderate or severe villous atrophy, plasia, a partial transition to the colonic muci-
followed by normalization of architecture; and nous phenotype, and an increased proliferative
3) constant atrophy with permanent subtotal or index (207). Refractory chronic pouchitis may
total villous atrophy and severe pouchitis (see resemble CD. Review of the colectomy speci-
below) (fig. 15-44). The pouch develops colonic men usually shows unequivocal UC, however,
metaplasia; pouchitis most commonly affects and the patients do not have any other clinical,
those in whom metaplasia has developed (246). radiologic, or pathologic evidence to support
Pouchitis. Restorative proctocolectomy with a diagnosis of CD. Because of the histologic
ileal pouch-anal anastomosis has become the resemblance to CD, the presence of transmural
surgical treatment of choice for most patients inflammation, granulomas, fibrosis, or strictures
with medically refractory UC. This procedure in areas distant from the anastomosis should
removes all of the diseased mucosa while be excluded. Review of previous biopsy mate-
maintaining fecal continence and transanal rial also proves helpful in delineating the true
defecation. The most common long-term nature of the inflammatory process.
complication of this procedure is nonspecific Prognosis. Since the introduction of effective
inflammation of the ileal reservoir, commonly medical and surgical treatments in the early
known as pouchitis (231,245,257,263,269). This 1960s, patients with UC have a surprisingly
complication affects 14 to 47 percent of pa- low mortality rate. Patients have a normal life
tients (225, 245,253,257,259,270) and becomes expectancy compared with persons in the gen-
chronic in 5 percent (246). eral population (219a,222,258,262,275). Severe
Clinical symptoms of pouchitis include acute attacks, usually occurring during the first
diarrhea, rectal bleeding, abdominal cramps, 2 years of disease, are the major killer, especially
urgency, tenesmus, and malaise. In severe cases, in patients over 50 years of age (280). Patients
these symptoms are accompanied by incon- with long-standing extensive disease have an
tinence and fever (270). Endoscopic findings increased risk for the development of dysplasia
include edema, mucosal erythema, granularity, or colorectal carcinoma (260).

715
Gastrointestinal Diseases

,. Figure 15-44
HISTOLOGIC CHANGES IN THE ILEAL POUCH
A: The ileum leading into the ileal pouch is essentially normal in appearance. The villi are long and slender. No inflammatory
infiltrates are present.
B: Mild architectural changes in an ileal pouch. The villi are somewhat blunted and the crypts are irregular. The lamina
propria contains an increased number of inflammatory cells.
C: Higher-power view of the lamina propria infiltrate shows occasional neutrophils.
D: Ileal pouch with more extensive architectural alterations. The villi are completely flattened and the mucosa now
resembles that of the colon .

Animal Models. Numerous animal models normal immune systems; 3) adoptive transfer
exist for the study of IBD (reviewed in 233,234, models in immunocompromised animals; and
261). These animal models may be divided into 4) genetically engineered models. The most
four basic categories: 1) spontaneous colitis commonly studied animal models for IBD are
models; 2) inducible colitis models in mice with summarized in Table 15-8.

716
Inflammatory Bowel Disease

Figure 15-46
POUCHITIS
Shallow linear ulcerations along an anastomotic line
within an ileoanal ]-pouch.

Figure 15-45
POUCHITIS
Severe diffuse pouchitis with an edematous, granular,
ulcerated mucosa that is friable and bleeds spontaneously.
The appearance is identical to that of active IBD.

Figure 15-47
POUCHITIS
A: The mucosa of the ileal pouch has crypt architectural
distortion and dense chronic inflammation. A crypt abscess
is present in the lower right.
B: A focus of active cryptitis. The histologic features in
this case are indistinguishable from IBD. The diagnosis of
pouchitis relies on the review of the previous colectomy
specimen as well as evaluation of biopsies from the ileum
leading into the pouch.
C: Low-power view of the ileum shows no features
suggestive of IBD. The villi are long and slender and there
is no increase in inflammation within the lamina propria.

717
- Gastrointestinal Diseases

Table 15-8
ANIMAL MODELS OF INFLAMMATORY BOWEL DISEASE
Spontaneous Colitis Models Genetically Engineered Models
Cotton-topped tamarin IL2 knockout/IL2 R knockout mice
C3H/HeJBir mice ILlO knockout mice
SAMP/Yit mice STAT3 knockout mice
T-cell receptor mutant mice
Inducible Colitis Models TNF-3' UTR knockout mice
Trinitrobenzene sulfonic acid-induced colitis Trefoil factor-deficient mice
Oxazolone colitis IL7 transgenic mice
Dextran sulfate sodium colitis STAT-4 transgenic mice
Carrageenan colitis HLA B27 transgenic rats
Peptidoglycan-polysaccharide colitis

Adoptive Transfer Models


CD4+/CD45Rb111 &" T-cell transfer colitis
Colitis induced by transfer of hsp60-specific CD8 T cells

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213. Chey W. Infliximab fpr patients with refractory in ulcerative colitis compared with familial
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257. Oresland T, Fasth S, Nordgren S, Hulte L. The anal anastomosis: a pouchitis disease activity
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ton ]H, Phillips SF. Pouchitis after ileal pouch-

728
NON -NEOPLASTIC
16 POLYPOSIS SYNDROMES

The inherited non-neoplastic (hamartoma) history of P]S, or 3) characteristic prominent


syndromes have gastrointestinal polyposis as a mucocutaneous pigmentation with a family
component feature, but the extent and type of history ofP]S, or 4) any number ofPeutz-Jeghers
polyps vary significantly from one syndrome polyps and characteristic prominent mucocuta-
to the next. Hamartomatous gastrointestinal neous pigmentation (4).
polyps are found in Bannayan-Riley-Ruvalcaba Demography. PJS has an estimated incidence
syndrome, Cowden's syndrome, juvenile pol- of I/120,000 births (27). Approximately SO per-
yposis syndrome, and Peutz-J eghers syndrome. cent of cases are familial and SO percent are spo-
Patients may develop multiple gastrointestinal radicwith new mutations. Based on the number
mucosal polyps, as well as numerous extrain- of families registered in the Finnish Polyposis
testinallesions. Registry, the incidence of P]S is roughly one tenth
The most common polyposis syndromes in- that of familial adenomatous polyposis (4). PJS
volve neoplastic intestinal adenomas; these are has been diagnosed in an individual as young as
covered in the Fascicle on intestinal neoplasms IS days; males and females are equally affected.
(3). The less common non-neoplastic (hamar- Etiology. Germline mutations or loss of het-
tomatous) polyposis syndromes are described erozygosity (LOH) in the STKll gene located at
in this chapter. Patients with these syndromes I9p13.3 accounts for most P]S cases (7,13,I6,
are at increased risk for tumor development. A 20). P]S kindreds inherit mutations in the STKll
knowledge of the number of polyps present, gene as a single hit on one allele, correspond-
their location, the patient age, the family his- ing to the autosomal dominant inheritance
tory, the presence of extraintestinal manifesta- pattern. The second hit then occurs in affected
tions, and the underlying genetic alterations P]S tissues (9,I0,23). Germline mutations are
helps classify the specific syndrome (Table I6-I). usually truncating, but missense mutations also
PTEN mutations are found in 80 percent of pa- occur (9,IS,I7,20). Approximately 70 percent
tients with Cowden's syndrome and 60 percent of familial PJS patients have STKll mutations
of patients with Bannayan-Riley-Ruvalcaba syn- and 30 to 70 percent of patients with sporadic
drome (I,2). Because PTEN mutations underlie disease also have these mutations (23).
the changes in both diseases, some suggest that STKll, which encodes a novel serine-threo-
they belong to a single genetic entity termed nine kinase, consists of nine exons and is ubiq-
the PTEN-hamartoma tumor syndrome (I,2). uitously expressed in adults (9,10,13,IS,I7).
Codons S0-33 7 encode the catalytic kinase
PEUTZ-JEGHERS SYNDROME
Definition. Peutz-Jeghers syndrome (P]S) is
an autosomal dominant disorder characterized Table 16-1
by: I) mucocutaneous melanin pigmentation; NON-NEOPLASTIC POLYPOSIS SYNDROMES
2) hamartomatous intestinal polyposis prefer-
Hereditary Syndromes
entially affecting the small intestine; and 3) Peutz-]eghers syndrome (STKll mutation)
an elevated risk for the development of malig- Juvenile polyposis (SMAD4 or BMPRIA mutation)
nancies. Associated extraintestinal neoplasms Cowden's disease (PTEN mutation)
include ovarian, cervical, testicular, pancreatic, Bannayan-Riley-Ruvalcaba syndrom e (PTEN mutation)
Familial hyperplastic gastric polyposis
and breast tumors. The following criteria are
used to diagnose PJS: I) three or more histologi- Nonhereditary Syndromes
Cronkhite-Canada syndrome
cally confirmed Peutz-]eghers polyps, or 2) any Lymphoid polyposis
number of Peutz-Jeghers polyps with a family

729
Gastrointestinal Diseases

domain of the gene. The STK11 gene product Because rectal polyps occur in less than one
localizes to both the nucleus and the cytoplasm third .of patients, sigmoidoscopy is generally
(18) and is a substrate of the cyclic adenosine less useful for screening than it is in familial
monophosphate (AMP)-dependent protein adenomatous polyposis.
kinase (7). Identification of the PJS gene makes Radiologic Findings. Radiologic examination
genetic screening possible for affected families. using ultrasound, computerized tomography
Mutation testing is done by utilizing full gene (CT) scan, upper gastrointestinal examination,
sequencing of the 23-Kb gene containing the and barium enema detects polyps in various
nine exons. Patients with neoplastic transforma- regions ofthe gastrointestinal tract (21). The dis-
tion of their hamartomas exhibit LOH on 19p in tribution of the lesions suggests the diagnosis.
addition to ~-catenin gene mutations, or muta- Gross Findings. The polyps of P]S arise
tions or LOH at the p53 locus. These findings throughout the gastrointestinal tract to affect
suggest that mutations of the ~-catenin gene or the jejunum, ileum, colon, stomach, duode-
p53 may help convert hamartomatous polyps num, and appendix in decreasing order of
into adenomas and carcinomas (16). frequency. Rare polyps develop in the esopha-
Clinical Features. Most patients present gus, nasopharynx, and urinary tract. Gastric
with mucosal pigmentation and intestinal pol- P]S polyps occur less commonly in Western
yposis (12). Polyps may occasionally be absent; populations than in the Japanese (16,18). Large
conversely, some patients have only intestinal sessile polyps may develop in the stomach;
polyps. The hyperpigmentation commonly gastric polyps are usually larger than the polyps
emerges in infancy or in childhood and consists seen in juvenile polyposis, Canada-Cronkhite
of greenish black to brown melanin deposits on syndrome, and Cowden's disease. Most gastric
the lips, buccal mucosa, periorbital area, nose, lesions arise in the antrum (19).
hands, feet, and occasionally, the genital or Intestinal polyps usually number in the
perianal skin (14). Over 95 percent of patients dozens. They are sessile or pedunculated, with
have melanin spots, most commonly on lips (95 coarsely lobulated, dark heads resembling ad-
percent) and buccal mucosa (66 to 83 percent). enomas (fig. 16-1). They range in size from a
Pigmented lesions of the lips and oral cavity few millimeters to over 7 cm; most measure 0.5
generally develop by 2 years of age: Pigmented to 3.0 cm in diameter. Grossly, they resemble
lesions tend to fade by puberty, except for the other gastrointestinal polyps. Clusters of polyps
buccal lesions (25). "' lying adjacent to one another can resemble one
Most PJS patients develop gastrointestinal large polyp (fig. 16-2). When epithelial islands
symptoms during adolescence or young adult- lie deep in the intestinal wall or on the serosa,
hood. A third of the patients have symptoms intramural nodules may be present.
before age 10; half have symptoms before age Microscopic Findings. PJS polyps have a
20 (24). Diffuse gastrointestinal polyposis causes distinctive histologic appearance. They consist
intussusception (28) or obstruction presenting of gastrointestinal epithelium indigenous to the
as recurrent attacks of crampy abdominal pain site of origin arranged on an arborizing mus-
(24). The polyps preferentially develop in the cular framework. The muscle fibers extend out
small intestine (64 to 67 percent of cases), espe- from the center of the lesion like the branches
cially in the jejunum, although they may arise of a tree, becoming progressively thinner as they
throughout the entire gastrointestinal tract. Polyps reach the polyp surface (fig. 16-3). These muscle
that autoamputate, twist, intussuscept, or prolapse bundles appear relatively hypovascular. Even
become ischemic and cause bleeding, anernia, or when intussusception occurs with secondary
massive hemorrhage. The polyposis may progress, infarction of the polyp, ghosts of the prominent
with intermittent polyp growth and the appear- muscle fibers remain visible (fig. 16-4).
ance of new "crops" of polyps that may appear In the small intestine, cells of the normal
simultaneously in different parts of the bowel. small bowel mucosa, including goblet, absorp-
P]S polyps should be removed because they tive, endocrine, and Paneth cells, line the crypts
are prone to mechanical injury and they may and villi (fig. 16-3). The goblet cells may appear
contain areas of dysplasia or invasive cancer. hypermucinous. Duodenal lesions may contain

730
Non-neoplastic Polyposis Syndromes

Figure 16-2

Figure 16-1 PEUTZ-JEGHERS POLYP


Clusters of Peutz-]egh ers polyps in the small intestine
PEUTZ-JEGHERS POLYP
appear as one large polyp.
The polypoid appearance and the central muscular core
are seen in a bisected polyp.

Figure 16-3
HISTOLOGIC FEATURES OF PEUTZ-JEGHERS POLYPS
A,B: Low- and higher-magnification views of the prominent muscular component which lines the various fronds of the
polyp. It is covered on both sides by mucosa.
C: The prominent muscular bands separate intestinal mucosa.
D: There are numerous goblet cells and lamina propria covering the muscular core.

731
- Gastrointestinal Diseases

Figure 16-4
INFARCTED PEUTZ-JEGHERS POLYP
The polyp was at the lead point of an intu~usception
in a 10-year-old. Much of the epithelium is degenerated
and necrotic. The prominent smooth muscle bands remain.

Brunner glands. The epithelial cells usually re-


tain their normal relationship with one another:
columnar and goblet cells may predominate
in the surface portion whereas Paneth and en-
docrine cells lie at the crypt bases next- to the
muscular framework.
PJS polyps in the colon contain colonic mu-
cosa. The replication zone at the crypt base is Figure 16-5
usually relatively short, and mature cells line EPITHELIAL DISPLACEMENT IN
the elongated, often branched glands. The A PEUTZ-JEGHERS POLYP
epithelium includes absorptive and-goblet cells, Numerous glands are displaced into the submucosa and
with goblet cells predominating in most cases. even onto the serosal surface. At low power they appear as
The surface may have a villous architecture. mucinous pools. Higher magnification of the lesion dis-
closed that they were benign.
Colonic PJS polyps contain arborizing bands of
smooth muscle, but these may be less promi-
nent than the smooth muscle bands found in regenerative cells may line elongated crypts and
small intestinal polyps; the muscle bands may glands. The regenerative epithelium appears im-
be absent in small colonic polyps. Unlike juve- mature and contains numerous mitoses. Some
nile polyps, the lamina propria of PJS polyps glands become cystically dilated. Hyperplastic
appears normal. ' areas show intraluminal papillary projections,
Gastric polyps show prominent foveolar hy- producing a serrated pattern reminiscent of that
perplasia, pit epithelium, and variable numbers found in hyperplastic polyps or serrated adeno-
of deep glands. The most diagnostic feature of mas. PJS polyps lack the prominent edematous
gastric polyps is a central core of finely arboriz- stroma seen in juvenile polyps. Inflammation
ing smooth muscle branches originating from is usually not prominent. Hemosiderin deposits
the muscularis mucosae. Gastric PJS polyps indicate previous mucosal erosion (22).
frequently lack the smooth muscle bundles, Benign glands and mucinous cysts may lie in
however, and resemble the more common gas- the submucosa (fig. 16-5), muscularis propria,
tric hyperplastic polyps. or even in the serosa in 10 percent of polyps
The surfaces of polyps often become su- involving the small intestine (22). This finding
perficially eroded and acutely inflamed. As a is unusual in gastric or large intestinal lesions
result, abnormally long rows of darkly staining (22). The cysts result from one of two processes:

732
Non-neoplastic Polyposis Syndromes

as a part of hamartomatous intestinal lesions ischemia and epithelial sloughing. The sloughed
or from glandular entrapment secondary to epithelial cells assume a rounded shape and
trauma, intussusception, or surface erosion. signet ring-like appearance; however, they lack
Sometimes the deep glands connect with the the usual cytologic features necessary to make a
superficial glands; in other cases they lack diagnosis of signet ring cell carcinoma. In addi-
continuity with the overlying mucosa. Rarely, tion, these cells are usually E-cadherin positive,
glands are found deep in the bowel wall or in the while true signet rings cells are not.
serosa, in the absence of a surface polyp. Such Treatment and Prognosis. It is recommend-
lesions have prominent intramural mucinous ed that individuals suspected of having PJS un-
cysts partially or totally lined by normal goblet dergo regular upper gastrointestinal endoscopy,
cells, absorptive cells, endocrine cells, and/or colonoscopy, and small bowel studies, since
Paneth cells. Infoldings of columnar epithelium intestinal, gastric, and colonic lesions are found
and dystrophic calcification are seen in the in 88 to 100 percent, 24 to 49 percent, and 60
mucinous pools. The benign appearance of the percent of patients, respectively. These polyps,
displaced epithelium differentiates these areas especially when they occur in the jejunum and
from invasive mucinous carcinoma (22). Deep ileum, can lead to intussusception (26).
mucinous cysts may lack an epithelial lining. Carcinoma of the intestinal tract is a frequent
Microscopic Variants. Rare polyps contain complication of PJS. There are well-documented
areas of osseous metaplasia (17). reports of carcinoma arising in PJS and in some
Differential Diagnosis. Two major differen- cases, associated adenomatous or dysplastic
tial diagnostic problems exist with respect to changes are observed within the hamartoma-
PJS polyps: 1) the polyp type and 2) whether or tous polyp (5,8, 11, 14). For these reasons, PJS is
not the lesion contains invasive cancer. Because also now considered to be among the gastroin-
gastric PJS polyps often resemble the more com- testinal cancer syndromes. The carcinoma risk
mon gastric hyperplastic pol)Tps, as well as the is 15 times greater for patients with PJS than
polyps occurring in the stomach of patients for the general population. The frequency of
with juvenile polyposis or Cronkhite-Canada neoplasia ranges between 3 and 6 percent.
syndrome, it is important to correlate the biopsy When neoplasms develop, 73 percent arise in
findings with the clinical history and other the gastrointestinal tract, and include large
features characteristic of each syndrome in intestinal, gastric, pancreatic, small intestinal,
order to establish the correct diagnosis. Gastric and gallbladder carcinomas (figs. 16-6, 16-7), as
hyperplastic polyps seldom, if ever, contain the well as gastrointestinal stromal tumors. Adeno-
arborizing smooth muscle bundles characteristic carcinoma is most common in the duodenum
of classic PJS polyps. In the colon, PJS polyps and stomach, occurring in up to 3 percent of
with extensive hyperplasia may superficially patients. Cancer usually doesn't develop until
resemble a large hyperplastic polyp. The latter, after age 30, with a mean age of 43 years. By
however, typically contains large numbers of age 65, there is a 93 percent rate of developing
glands and lacks arborizing muscle bundles. cancer, whether it is gastrointestinal or extra-
Juvenile polyps contain numerous small cysts gastrointestinal in location (6). An excess of ex-
filled with mucus and inflammatory cells, and tragastrointestinal malignancies (breast, cervix,
contain a disproportionately large amount of ovarian, testicular) also occurs.
stroma when corp.pared with the glands. Because of the increased risk for cancer, it is
It is also possible to over-read epithelial recommended that patients undergo screening.
misplacement as invasive malignancy. Cells ap- The screening recommendations for gastro-
pearing histologically and cytologically benign, intestinal malignancies include colonoscopy
with a brush border and lack of cellular atypia, beginning with symptoms or in the late teens
help distinguish PJS polyps from carcinoma. if no symptoms occur. The interval between
Circumscribed foci of signet ring cells may occur examinations is determined by the number of
in PJS polyps as a result of gland degeneration polyps, but it should be at least every 3 years
from intestinal intussusception, polyp stretch- once it begins. Screening for pancreatic cancer
ing, or torsion. These events cause focal mucosal involves endoscopic or abdominal ultrasound

733
- Gastrointestinal Diseases

Nodular gaiter
Thyroid adenoma carcinoma
Thyroid cancer

Pancreatic
neoplasms
Liver hamartomas Bronchial
Benign and adenomas
malignant Lung carcinoma
gallbladder and bile carcinoma
duct neoplasms
Bile duct cysts Ovarian neoplasms
Adrenal cortical
Testicular Sertoli
hyperplasia
cell turners in men
Gastric cancer
Endometrial
Small intestinal - - - r-f-r--:...:!..J adenoma taus Polyps of renal
cancer pelvis
polyps
Colon cancer Endocervical Polyps of
carcinoma urinary bladder

1\
Figure 16-6
DIAGRAMMATIC REPRESENTATION OF THE NEOPLASMS ASSOCIATED WITH PEUTZ-JEGHERS SYNDROME

every 1 to 2 years after age 30. Screening for


gastric neoplasia consists of upper gastrointes-
tinal endoscopy every 2 years starting at age 10.
Screening for small bowel neoplasms occurs via
annual hemoglobin and small bowel X ray every
2 years beginning at age 10. Screening for breast
carcinoma involves an annual breast exam and
mammography every 2 to 3 years beginning at
age 25. Screening for gynecologic neoplasms
involves annual pelvic exam with Papanicolaou
(PAP) smear beginning around age 20. Screening
for testicular tumors begins at age 10.
JUVENILE POLYPOSIS SYNDROME
Definition. Juvenile polyposis syndrome GPS) is
Figure 16-7
an autosomal dominant syndrome characterized
INTRAEPITHELIAL NEOPLASIA DEVELOPING by multiple gastrointestinal hamartomatous
IN A PEUTZ-JEGHERS POLYP polyps in the absence of the extraintestinal fea-
The cells lining the glands of this polyp have been tures classic for other hamartomatous polyposis
replaced by cells with an increased nuclear to cytoplasmic
ratio and cytologic atypia. syndromes, such as Bannayan-Riley-Ruvalcaba
syndrome and Cowden's disease. The following

734
Non-neoplastic Polyposis Syndromes

diagnostic criteria have been established for the hypokalemia, cachexia, anemia, malnutrition,
diagnosis of]PS: 1) five or more juvenile polyps and abdominal pain (52). Bleeding affects 84
of the colorectum, or 2) extracolonic juvenile to 95 percent of patients (51) and occurs more
polyps, or 3) any number of juvenile polyps in commonly in children; intussusception tends to
a patient with a family history of ]PS (29,54). affect infants. Autoamputation, resulting in the
There are many other terms for ]PS: generalized passage of tissue, also occurs (51) . The number
juvenile polyposis, juvenile polyposis coli, juvenile of new polyps decreases as the patient ages (42).
polyposis of infancy, gastric juvenile polyposis, Gastric polyps affect the antrum and extend to
juvenile polyposis of the stomach, familial juve- the fundus, eventually becoming more numer-
nile polyposis, hamartomatous gastrointestinal ous, larger, and pedunculated. Gastric polyps are
polyposis, hype1plastic inflammatmy polyps, and present either as part of a generalized polyposis
retention polyps. syndrome or as part of familial gastric polyposis,
Demography. ]PS is 10 times less common and are associated with gastric hyperplastic and
than familial adenomatous polyposis (46), with adenomatous polyps.
an incidence of 0.6 to 1.0 cases/100,000 in West- Radiologic Findings. Radiographic examina-
ern populations. Juvenile polyps, however, are tion delineates the distribution of the polyps
the most common pediatric polyps, affecting an as follows: colorectal, 98 percent; gastric, 3.6
estimated 1 percent of children and adolescents percent; duodenal, 2.3 percent; and jejunal and
(49). ]PS occurs in both sporadic and familial ileal, 6.3 percent (35).
forms (58); approximately 20 to SO percent of Gross Findings. Patients with ]PS usually
suspected individuals have the familial form. The have 10 to hundreds of polyps (46). Most polyps
age of onset, number of polyps, polyp location, are located in the rectosigmoid. Juvenile polyps
and the development of further polyps vary. Pa- are usually small, round, smooth-surfaced le-
tients range in age from 10 to 63 years, however, sions, ranging in size from less than 1 mm to 5
patients in the first two decades of life (mean age cm; most measure from less than 1 to 2 cm in
at diagnosis of 18.5 years) are most commonly diameter (figs. 16-8-16-10). Patients presenting
affected. The disorder affects both sexes (35). in late childhood or adulthood usually have
Etiology. ]PS is an autosomal dominant completely normal-appearing intervening mu-
disorder with mutations in either the SMAD4 cosa. Larger polyps tend to be pedunculated,
tumor suppressor gene (36,43-45,50,53) located with a short stalk; only about 25 percent are
at 18q21.1 or in the bone morphogenic protein sessile. Larger lesions are grayish pink-red,
receptor lA (BMPRlA) gene. Both of these genes spherical, mushroom-like, cerebriform, often
are involved in transforming growth factor-beta ulcerated, and covered by an inflammatory
(TGF-~) signaling (48,61a,62,63). Genetic test- exudate. The cut surface displays variably sized
ing is available for both of these known genetic mucus-containing cysts embedded in a gray
mutations. fibrous stroma. Pedunculated polyps may twist,
Juvenile polyps have been described in the causing ischemia and hemorrhage, and result-
stomach, small bowel, and colon in infants and ing in autoamputation.
an autosomal recessive inheritance has been Microscopic Findings. Typical juvenile pol-
suggested for some kindreds (56). yps consist of gastrointestinal glands indigenous
Clinical Features. The clinical course de- to the site of origin, surrounded by an increased
pends on patient age, polyp number, polyp amount of edematous, often inflamed stroma.
location, and the form of ]PS present. Most The stromal-epithelial ratio is disproportion-
patients present in childhood; only 15 percent ately larger than normal. Stroma widely sepa-
present as adults (35). Infants withJPS are likely rates branched, sometimes cystic, variably sized
to have more severe symptoms and complica- tortuous glands. The polyps often appear more
tions (51) than older individuals. Patients with disorderly than other polyps due to the cysti-
]PS of infancy develop diarrhea, protein-losing cally dilated glands and large stromal content
enteropathy, intussusception, gastrointestinal (fig. 16-11). The glands are lined by columnar,
bleeding, and rectal prolapse (35). Other clinical cuboidal, or flattened epithelium. The lining
manifestations of ]PS include polyp prolapse, may appear hyperplastic, with a serrated pattern

735
- Gastrointestinal Diseases

Figure 16-8
JUVENILE POLYPOSIS SYNDROME
Left: Endoscopic appearance of an irregular polyp within the mucosa.
Right: Higher-magnification view.

cause stromal hemorrhage, surface ulceration,


and inflammation. Eroded polyps develop a
granulation tissue cap. Regenerative atypia is
common below eroded areas and may simulate
dysplasia.
The stroma often contains dilated vessels, ar-
eas of hemorrhage or hemosiderin, and variable
numbers of lymphocytes, plasma cells, neutro-
phils, and eosinophils (fig. 16-11). Neutrophils
surround eroded or ulcerated areas. The stroma
may also contain prominent lymphoid follicles.
Smooth muscle fibers are usually absent except
in the center of pedunculated polyps. These are
Figure 16-9 arranged less densely than in PJS polyps.
Disease Variants. Several variants of ]PS ex-
JUVENILE POLYPOSIS SYNDROME
ist: 1) infantile juvenile polyposis, transmitted as a
Resected specimen shows the presence of multiple
pedunculated, reddish , ju,ve nile polyp s distributed
non-sex-linked recessive trait, with a tendency
throughout the large bowel. toward death before age 2 years (37); 2) familial
juvenile polyposis coli (51), the most common
form, which remains limited to the colon and is
resembling that seen in hyperplastic polyps inherited as an autosomal dominant trait with
or serrated adenomas. Polyp surfaces are cov- high penetrance (38,56); 3) familial juvenile gas-
. erect by a single layer of cuboidal or columnar tric polyposis; and 4) generalized juvenile polyposis,
epithelial cells, often with interspersed goblet characterized by the development of numerous
cells (fig. 16-11). The cysts contain either mu- juvenile polyps in the stomach, small intestine,
cus or inflammatory debris (fig. 16-11). When colon, and rectum, in various combinations
the glands rupture, mucus, inflammatory cells, (29-32,40,45,48).
and cellular debris extend into the surrounding Generalized gastrointestinal ]PS affects all
lamina propria. Sometimes the epithelial lining ages; a positive family history is present in 20 to
completely disappears. Repeated torsion may 50 percent of patients (35). Several families with

736
Non-neoplastic Polyposis Syndromes

. .-
....
Figure 16-10
JUVENILE POLYPOSIS SYNDROME
Left : Whole mount section shows a juvenile polyp with a central stalk containing normal mucosa and submucosa . The
head of the polyp consists of a proliferation of glands and a disproportionate amount of stroma.
Right: A different lesion shows a large amount of edematous stroma.

autosomal dominantJPS display extraintestinal The histologic features of ]PS vary widely and
manifestations, including pulmonary and/or are mimicked by a number of other disorders
cerebral arteriovenous malformations, cutane- (see Differential Diagnosis).
ous telangiectasia, subarachnoid hemorrhage, Atypical Juvenile Polyps. Atypical juvenile
hypertrophic pulmonary osteoarthropathy, and polyps have the characteristic gross appearance
digital clubbing (30,34,38). Such patients often of a multilobulated mass containing a number
present in childhood and adolescence with of closely packed polyps attached to a single
polyps occurring in the large and small bowel, stalk. Such lesions contain less stroma and more
sometimes associated with grossly visible foci epithelium than the typical juvenile polyp, and
of lymphoid hyperplasia (30,32, 33,5 7). It is they often acquire a villous or papillary archi-
currently unclear whether this form of disease tecture. Atypical juvenile polyps account for
is due to a single gene abnormality distinct approximately 16 percent of all juvenile polyps,
from juvenile polyposis or represents cases of and may be more prone to dysplasia than are
coincidental juvenile intestinal polyposis and the usual juvenile polyps.
Osler-Rendu-Weber disease. This entity has been Osseous Metaplasia in Juvenile Polyps. Rare
described under OMIM entry 17 5050 and also juvenile polyps contain areas of osseous meta-
as hereditary hemorrhagic telangiectasia with plasia. These areas are usually located superfi-
juvenile polyposis coli (55). cially in the polyps and presumably result from

737
Gastrointestinal Diseases

Figure 16-11
HISTOLOGIC FEATURES OF JUVENILE POLYPS
A: Portion of a juvenile polyp shows regeneration within the colonic glands.
B: The large cystic spaces within juvenile polyps often contain inspissated debris and mucus, as shown here.
C: Dilated vessels and stromal hemosiderin are indicative of previous erosion.
D: Erosion of the surface of the polyp leads to chronic inflammation and congestion of the lamina propria.

738
Non-neoplastic Polyposis Syndromes

metaplasia of reparative lesions, perhaps in the


area of previous surface granulation tissue caps
(fig. 16-12).
Differential Diagnosis. Some juvenile polyps
consist of very hyperplastic glands resembling
the more common hyperplastic polyps or even
adenomas, but the edematous stroma with
inflammatory cells serves to differentiate these
entities. Juvenile polyps also closely resemble
the polyps seen in the Cronkhite-Canada syn-
drome. On a histologic basis, it is difficult, if not
impossible, to differentiate juvenile polyps from
hyperplastic polyps or polyps of the Cronkhite-
Figure 16-12
Canada syndrome. Knowledge of the patient's
age and symptoms, and the distribution and JUVENILE POLYP WITH OSSEOUS METAPLASIA
number of polyps is required. A focus of bone formation is in this polyp . This likely
represents a reaction to previous erosion or ulceration.
Treatment and Prognosis. Patients with
large polyps tend to develop local mechanical
problems. Those with a particularly extensive Most malignancies arose in the distal colon and
polyp burden may have anemia and malnutri- rectum, with isolated cancers in the stomach
tion secondary to diarrhea and protein loss. Re- or duodenum. Tumor stage at diagnosis was
peated colonoscopic clearance of polyps reverses usually advanced, with poor patient survival.
the malnutrition and growth retardation seen in The screening of families includes a careful
severe cases. Large polyps with broad stalks may clinical history, colonoscopy of potentially af-
be difficult to remove endoscopically because fected members, and surveillance colonoscopy
they contain prominent vasculature and require of members in whom polyps have been identi-
greater degrees of electrocautery for their excision fied and removed. Once removed, the polyps
(49). Surgery may be required for patients with must be examined for the presence of adeno-
uncontrolled symptoms, malignancy, or when matous foci.
endoscopic clearance is not possible. Despite a Animal Models. SMAD4 knockout mice
report of the possible benefit from omeprazole develop a syndrome resembling]PS (60). Tram-
therapy (52), in general, the results of pharma- genic expression of noggin inhibits BMP signal-
cologic treatments have been disappointing. ing, which leads to a condition mimicking ]PS
]PS patients have an increased risk for tumor in the transgenic mice (41).
development in the colon, stomach, duodenum,
biliary tree, and pancreas, ranging from 20 to 70 COWDEN'S SYNDROME
percent. Cancer risk increases with age, not with (MULTIPLE HAMARTOMA SYNDROME)
polyp size and number (31,32,35,46,59,61). Definition. Cowden's syndrome (CS) is an
Dysplasia and carcinoma develop within both autosomal dominant, multiple hamartoma
gastric and colonic juvenile polyps (fig. 16-13) syndrome characterized by a high risk of breast,
(39). The dysplasia is usually graded as low thyroid, and endometrial cancers. It is caused by
grade, although occasionally it is more severe germline mutations in PTEN, which is a tumor
(61). Recently, Coburn (31) summarized reports suppressor gene located on 10q23 (75). The
in the English literature on the occurrence and International Cowden Consortium developed
prognosis of gastrointestinal carcinomas de- a set of consensus diagnostic criteria (Table
veloping in patients with ]PS. Of 218 patients 16-2) (65).
with]PS who developed cancer, a family history Demography. The estimated incidence of CS
of polyps was present in 50 percent, and 15 is 1/200,000 (74-76); 10 to 50 percent of cases are
percent had associated congenital malforma- familial (73). More than 90 percent of individu-
tions. The mean age at diagnosis of carcinoma als affected by CS are believed to manifest the
was 35.5 years, with a range of 4 to 60 years. phenotype by age 20 (71). By age 30, 99 percent

739
- Gastrointestinal Diseases

Hypertrophic
osteoarthritis

Figure 16-13
DIAGRAM MATI C Idiopathic hypertrophic
REPRESENTATION OF subaortic stenosis
SOM E OF THE LESIONS
Coarctation of the aorta
ASSOCIATED W ITH
JUVENILE POLYPOSIS
Tetralogy of Fallot
SYNDROME
Small intestinal Gastric polyps
polyps Gastric cancer
Colon polyps
Colon ca.ncer
Mesenteric
lympha ngioma
Intestinal mal rotation

1\
Table 16-2
INTERNATI ONAL COWDEN' S SYNDRO M E CONSORTIUM OPERATIONAL
CRITERIA FOR TH E DIAGNOSIS OF COWDEN'S SYNDROME

Path ognomonic Crit eria Lipomas


Mucocutaneous lesions : Fibromas
Facial tricholemmomas Genitourinary tumors (renal cell carcinoma or uterine
Acral keratoses fibroids) or malformations
Papillomatous papules
Mucosal lesions Operational Diagnosis in an Individual
Mucocutaneous lesions alone if: there are ;, 6 facial
Major Criteria papules, of which 3 or more m ust be trid1.ilemmoma,
Breast carcinoma or cutaneous facial papules and oral mucosal
Thyroid carcinoma, especially follicular thyroid papillomatosis, or oral mucosal papillomatosis and
carcinoma acral keratoses, or palmoplantar keratoses, ;, 6
Macrocephaly (megalencephaly)(95%) Two major criteria but one must include macrocephaly
Lhermitte-Duclos disease or Lhermitte-Duclos disease
Endometrial carcinoma One major and three minor criteria
Four minor criteria
Minor Criteria
Other thyroid lesions (e.g., adenoma or multinodular Operational Diagnosis in a Family Where One
go iter) Individual is Diagnostic for Cowden's Syndrome
Mental retardation (IQ ,; 75) The pathognomonic criterion
Gastrointestinal hamartomas Any one major criterion with or without minor criteria
Fibrocystic disease of the breast Two minor criteria

740
Non-neoplastic Polyposis Syndromes

develop at least the mucocutaneous signs of the fibrocystic disease, and adenocarcinoma) (fig.
syndrome, although any of the other clinical 16-14) (77, 83), gastrointestinal hamartomas
features can also be present. The most common (60 to 80 percent), macrocephaly (40 percent),
manifestations are mucocutaneous lesions, thy- and genitourinary abnormalities, including
roid abnormalities, fibrocystic disease and carci- endometrial cancers (40 to 50 percent) and
noma of the breast, multiple early-onset uterine uterine leiomyomas (65). Patients present with
leiomyomas, and macrocephaly (69, 7la, 72,79). a number of facial abnormalities including a
CS is associated with Lhermitte-Duclos disease beaked nose; mandibular, maxillary, and soft
(craniomegaly, choroidal hamartoma, and palate hypoplasia; and a high arched palate.
conjunctival papilloma); males and females are They also have cafe-au-lait spots, papillomatosis
equally affected. Patients range in age from 4 to of the lips and oropharynx, multiple ocular le-
75 years, with a median of 39 years. sions including retinal gliomas (66), odontitis,
Etiology. CS results from PTEN gene muta- dental caries, adenoid facies, kyphoscoliosis,
tions. PTEN encodes a dual specificity phospha- pectus excavatum, and mental retardation (79).
tase, a substrate of which is phosphatidylino- Some patients develop parathyroid adenomas.
sitol3,4,5,5-triphosphate, a phospholipid in the Skeletal abnormalities, including bone cysts,
phosphatidylinositol-3-kinase pathway. PTEN syndactyly, and other digit abnormalities, affect
affects apoptosis and inhibits cell spreading via 33 percent of patients (66).
the focal adhesion kinase pathway. Mutations Up to 80 percent of patients who undergo
include missense and nonsense point muta- endoscopy have gastrointestinal polyps (fig. 16-
tions, deletions, insertions, and splice site muta- 15) (68,71). Polyps develop in the esophagus,
tions. They are scattered over the entire length stomach, duodenum, terminal ileum, distal
of the PTEN gene, with the exception of the first, colon, and rectum; patients may develop gastric
fourth, and last exons (82). Approximately two carcinoma (72). The polyps usually do not cause
thirds of mutations are found in exons 5, 7, and symptoms. The most common gastrointestinal
8; 40 percent lie in exon 5. Mutations within lesions are esophageal glycogen acanthosis (fig.
the phosphatase core motif of the gene and 5' 16-16), numerous gastric hyperplastic polyps,
of it appear to be associated with the involve- and multiple hamartomatous polyps in the
ment of five or more organs. Identification of rectosigmoid (69,81). Patients may also have
such mutations represents a surrogate marker coexisting intestinal ganglioneuromatosis (71).
for the severity of disease (72). Polymorphisms CS and Bannayan-Riley-Ruvalcaba syndrome
are also found in the gene (82). share overlapping features (Table 16-3). Because
Some CS patients may also have a duplication the clinical literature on CS consists mostly of
of 15qll-ql3 (80). This chromosomal locus is reports of the most florid cases, and unusual
deleted in the Prader-Willi/ Angelman syndrome family or individual case reports, the entire
and is a hot spot of chromosomal duplication spectrum of the component manifestations may
(80). Additionally, CS patients sometimes have be unknown (65).
associated neurofibromatosis. Gross Findings. The distallarge intestine is
It is unclear whether a mutation in the preferentially affected in CS. Grossly, the lesions
BMPRlA gene, which encodes a bone morpho- resemble hyperplastic polyps. The lesions are
genic protein receptor belonging to the TGF- usually small (less than or equal to 6 mm in
~-receptor superfamily, is a rare susceptibility diameter) and not well visualized on barium en-
gene for CS (83a). BMPRlA is also a susceptibility ema studies but are easily seen endoscopically.
gene for ]PS. The majority lie distal to the hepatic flexure.
Clinical Features. Facial tricholemmomas Glycogen acanthosis is seen in the esophagus.
are considered to be a pathognomonic feature Polyps are seen in the stomach and duodenum
of the syndrome (65). Other common mani- as well. Here they tend to be sessile lesions mea-
festations include papillomatous papules, acral suring a few millimeters in diameter.
keratoses, thyroid abnormalities (50 to 70 per- Microscopic Findings. Hamartomas involve
cent; gaiter, adenoma, and carcinoma), breast organs derived from all three germ layers. The
lesions (75 to 100 percent; fibroadenomas, classic hamartoma associated with CS is the

741
Gastrointestinal Diseases

Craniomegaly High arched Merkel cell


palate carcinoma
Eye changes
Oropharyngeal Cafe-au-la it
Facial spots
tricholemmomas papillomatosis
Vitiligo
Adenoid facies
Dermal
Beaked nose Thyroid adenoma fibromas
Thyroid cancer Skin tags
Thyroid goiter Angiomas
Lymphoma

Palmar and
plantar
keratosis
Breast cancer
Renal cell Syndactyly
Ganglioneuromas carcinoma
Lipomas Scoliosis
Hamartomatous Ovarian cysts Pectus
polyps Ovarian cancer excavatum
Ileal lymphoid Uterine cancer
polyps Cervical cancer
Adenomas
Carcinoma
Stromal tumors 1\
Figure 16-14
DIAGRAMMATIC REPRESENTATION OF MAJOR LESIONS DEVELOPING IN COWDEN'S SYNDROME

Table 16-3 tricholemmoma which affects 99 percent of CS


COMPARISON OF COWDEN'S SYNDROME (CS) AND patients. Patients develop mucocutaneous le-
BANNAYAN-RILEY-RUVALCABA SYNDROME (BRRS) sions (facial tricholemmomas, oral papillomas,
CS BRRS
and acral keratoses), breast lesions (fibrocystic
disease and carcinoma), thyroid abnormalities
PTEN mutations + + (multinodular gaiter and carcinoma), and gas-
Multiple lipomas + + trointestinal abnormalities (65,67).
Macrocephaly + + Histologically, a diverse group of polypoid le-
Mucocutaneous lesions + sions can develop anywhere in the gastrointesti-
Breast lesions + nal tract. Colonic polyps include inflammatory
Thyroid lesions + +
polyps, lipomas, adenomas, hamartomatous
Gastrointestinal lesions
polyps, juvenile polyps, hyperplastic polyps (fig.
+ +
16-17), fibromas, nodular lymphoid hyperplasia,
Brain lesions + ganglioneuromas (fig. 16-18), lymphoid polyps,
Facial abnormalities + and epithelioid leiomyomas (64,66, 70,71,77).
Skeletal abnormalities + + There may be a mixture of cell types, including
Mental retardation + + fibroblasts and adipose tissue. The usual CS
Penile pigmented macules + colonic polyp contains an elongated, irregular,
Delayed motor development + regenerative-appearing crypt epithelium with
Cancer development + ?
cystic dilatation, mild edema, inflammation,
and variable fibrosis. Cellular pleomorphism

742
Non-neoplastic Polyposis Syndromes

Figure 16-15 Figure 16-16


COWDEN'S SYNDROME GLYCOGEN ACANTHOSIS IN COWDEN'S SYNDROME
Gastrointestinal endoscopy shows the presence of The esophagus is lined by numerous spherical nodules
numerous gastrointestinal polyps. (Figs. 16-15-16-18 are that represent hyperglycogenated epithelium.
from the same patient.)

and atypia are absent. The collagen table under-


lying the luminal surface may be thickened as
is seen in patients with hyperplastic polyps or
collagenous colitis. Biopsies of the polyps may
show only mild glandular architectural distor-
tion with variable fibrosis and inflammation of
the lamina propria, predominantly consisting of
plasma cells, lymphocytes, and eosinophils (fig.
16-18). Fat cells may be present in the lamina
propria. Dysplasia and adenomas are rare.
Most gastric polyps are hyperplastic, with
elongated, cystically dilated, foveolar epithe-
lium; lamina propria edema; and inflammation Figure 16-17
similar to that seen in sporadic hyperplastic
HYPERPLASTIC POLYP IN COWDEN'S SYNDROME
polyps. The polyps may contain neural ele-
ments (fig. 16-19). The surface epithelium usu- If the full history of the patient was not known it might
be difficult to recognize this as being part of Cowden's
ally appears completely normal, unless erosion disease.
with regeneration has occurred. Patients also
develop duodenal lymphangiectasia, duodenal
lymphoid polyps, or jejunallymphangiomas. including neurofibromatosis, basal cell nevus
Differential Diagnosis. The diagnosis is made syndrome, proteus syndrome, and the Bannayan-
when there are appropriate clinical features, in- Riley-Ruvalcaba syndrome. There may also be
cluding multiple tricholemmomas or a history overlap between these syndromes. PJS is initially
of thyroid or breast abnormalities. Without this considered in the differential diagnosis but pig-
clinical information, the disorder is difficult to mentation of the perioral region, pathognomonic
differentiate from other polyposis syndromes, for P]S, is absent. Additionally, PJS hamartomas

743
Gastrointestinal Diseases

Figure 16-18
• COWDEN'S SYNDROME
Left: The histologic features of the colonic polyps differ but generally show regenerative mucosa.
Right: A careful search disclosed a proliferation of spindle cells within the lamina propria, which also contained ganglion cells.

~
>.·

Figure 16-19
COWDEN'S SYNDROME: GASTRIC BIOPSY
Left: At low-power magnification, a portion of the gastric mucosa from one of the numerous polyps present within the
stomach shows glandular distortion, which at first glance appears to be the result of mucosal fibrosis . Immunostains for
neural markers were positive.
Right: At higher magnific&tion, the spindle cell proliferation is seen partly destroying the glands. Reactive changes are
present in the superficial gastric mucosa.

occur more often in the small intestine and propria. Ganglion cells are found in patients
. show a well-organized, tree-like, smooth muscle with ganglioneuromas, multiple endocrine
architecture supporting normal-appearing epi- neoplasia, and neurofibromatosis.
thelium. ]PS can be considered, particularly in Treatment and Prognosis. Patients with CS
patients with predominantly colorectal polyps. do not appear to have a significantly increased
Juvenile polyps, however, typically have an risk of developing gastrointestinal cancer and
inflammatory appearance and patients lack many believe that gastrointestinal examina-
the clinical stigmata of CS. The differential di- tions are unnecessary unless gastrointestinal
agnosis also includes those disorders in which symptoms are present. Screening strategies for
ganglion cells are present within the lamina extraintestinal tumors are more appropriate.

744
Non-neoplastic Polyposis Syndromes

Seventy-four percent of patients develop ex- it has been proposed that CS and ERRS belong
traintestinal malignant disease; the majority are to a single genetic entity termed the PTEN 11

invasive ductal breast carcinomas and thyroid hammtoma tumor syndrome" (8Sa). In ERRS, 60
tumors. The risk for breast cancer is estimated percent of PTEN mutations occur within exons
to range from 2S to SO percent (69,71,79) . The 6 to 9 contrasting with CS in which 6S percent
mean age of diagnosis is likely to be 10 years of PTEN mutations occur in the first five exons
earlier than for breast cancer occurring in the or the promoter regions. Some ERRS patients
general population. Men also develop breast have PTEN gene deletions (90b,90c).
cancer. The risk of thyroid cancer (predomi- Clinical Features . ERRS is noted at birth
nantly follicular carcinoma) may be as high or shortly thereafter and is characterized by
as 10 percent (78,79). The malignancies often delayed psychomotor development, ileal and
cause patient death. Patients also have an in- colonic juvenile polyps, lingual lesions, subcu-
creased risk of endometrial cancer. taneous and visceral lipomas and hemangiomas,
Other tumors that develop in patients with multiple variable congenital anomalies, mac-
CS include glioblastoma multiforme, cerebellar rocephaly, mental retardation, central nervous
dysplastic gangliocytoma, mucocutaneous l;:>asal system vascular malformations, ocular abnor-
cell and squamous cell carcinomas, malignant malities, skeletal abnormalities including lipid
melanoma, lymphoma, Merkel cell carcinoma, storage myopathy (86), thyroid tumors, and
nonsmall cell lung cancer, uterine and ovarian pigmented penile macules. Patients may also
cancers, renal cell carcinoma, urothelial carci- exhibit widespread verrucous changes of the
nomas of the bladder, osteosarcomas, and, more lips (86) and Hashimoto's disease (90).
rarely, several gastrointestinal cancers, includ- Microscopic Findings. The intestinal polyps
ing gastric (79), colorectal, hepatocellular, and are histologically identical to juvenile polyps.
pancreatic carcinomas. Treatment and Prognosis. Due to the over-
Animal Models. Heterozygous PTEN knock- lapping features of ERRS and CS, it is unclear
out mice show pathologic characteristics similar whether there is an increased incidence of
to those in human CS and its related syndromes. gastrointestinal cancer. Some recommend that
affected patients undergo screening similar to
BANNAYAN-RILEY-RUVALCABA SYNDROME that performed for patients with CS (88) .
Definition. Bannayan-Riley-Ruvalcaba syn-
drome (ERRS) is a rare autosomal dominant con- CRONKHITE-CANADA SYNDROME
genital disorder characterized by macrocephaly, Definition. Cronkhite-Canada syndrome (CCS) is
lipomatosis, hemangiomatosis, and speckled pe- a nonhereditary, adult gastrointestinal polyposis
nis (87). Synonyms include Riley-Smith syndrome, syndrome associated with alopecia, skin hyper-
Bannayan-Zonana syndrome, Soto's syndrome, pigmentation, onychodystrophy, patchy vitiligo,
Ruvalcaba-Myhre-Smith syndrome, macrocephaly, marked edema, tetany, glossitis, cataracts, and
multiple lipomas, and hemangiomata syndrome. intestinal polyposis (fig. 16-20) (93,9S,96).
Demography. This rare syndrome (8S,90) is Demography. The disorder occurs worldwide
inherited as an autosomal dominant disorder and affects both sexes equally. Patients range
(90) and mainly affects men. By 1988, 12 patients in age from 31 to 83 years, contrasting with
with the syndrome had been identified (89a). ]PS in which patients range in age from 7 to 28
Etiology. Patients with the ERRS share a dis- years (99) . Eighty percent of patients present
ease susceptibility locus with CS: 60 percent of after age SO.
ERRS patients have germline PTEN mutations Etiology. All cases are sporadic and CCS is
(89,89a,90,90a,91,92). A significant difference not a genetic disease. Proposed etiologic theo-
in mutation status is found in familial versus ries include nutritional deficiency states, an ac-
sporadic cases of BRRS (88a). In contrast to CS, quired disaccharidase deficiency accompanied
none of the mutations are in the phosphatase by a bacterial overgrowth disorder, an infectious
core motif. Since CS and ERRS share overlap- disorder, a disturbance in intestinal mucin secre-
ping clinical features, including hamartomas, tion, or a nonspecific immune disorder (92,93,
lipomatosis, and overlapping PTEN mutations, 9S,96). Others suggest that epithelial damage,

74S
_ Gastrointestinal Diseases

occurs spontaneously, despite active disease.


When new nail growth occurs, the distal end of
the new nail continues to exhibit an irregular,
ragged appearance. CronkhHe and Canada (93)
Glossitis interpreted the nail changes as resulting from vi-
Hypogeusia -----"r--
tamin deficiencies secondary to malabsorption,
whereas]arnum and]ensen (97) believe them to
be an inherent part of the syndrome. Hair loss
is rapid, occurring in the first few weeks, and it
affects the entire body.
Laboratory findings include hypoprotein-
emia, particularly hypoalbuminemia, anemia,
Esophageal
l-- - - r - polyps blood in the stool, and deficiencies in electro-
lytes (K+ and Ca++), vitamins (vitamin B12), and
Hyperplastic
polyps minerals (zinc and magnesium).
Diarrhea Radiologic Findings. Radiographic studies of
Hematochezia the gastrointestinal tract show multiple nodular
Inflammatory
polyps or polypoid filling defects in the stomach and
Colonic colon. Intestinal lesions range from a few mil-
adenomas
and cancer
limeters to 3 cm in diameter. Gastric lesions
are seen on a background of thickened rugal
folds. Small intestinal radiographs show diffuse

1\ coarsening of the mucosal pattern (94).


Gross Findings. Multiple (5 to 10) polyps de-
velop in the stomach, small intestine, co~pn, and
Figure 16-20 rectum, sometimes occupying the entire mucosal
DIAGRAMMATIC SUMMARY OF SOME surface of these sites. Polyp density is greatest in
OF THE LESIONS ASSOCIATED WITH the stomach and colon, followed by the duode-
CRONKHITE-CANADA SYNDROME num, ileum, and jejunum (93,95). The polyps vary
in color from red to bluish, sometimes demonsb:at-
ing areas of surface ulceration and hemorrhage.
followed by a secondary failure to synthesize Most polyps are sessile although they may be
or release growth factors, plays a role in the pedunculated. The gross appearance of the polyps
development of the lesions (93,97). varies from diffuse mucosal rnicronodularity or
Clinical Features. The usual manifesta- granularity, to gelatinous-appearing pedunculated
tions are chronic diarrhea, protein-losing polyps. Gastric polyps tend to grow in the antrum
enteropathy, weight loss, abdominal pain, and form hyperplastic gastric folds, mimicking
anorexia, weakness, hematochezia, vomiting, Menetrier's disease. Gastric and intestinal le-
paresthesias, and xero.stomia. The diarrhea sions can spontaneously regress.
usually consists of loose, watery bowel move- Microscopic Findings. Polyp morphology
ments occurring 5 to 7 times per day. These reflects the site of origin. The gastric mucosa
may be grossly bloody and the blood loss may undergoes a transformation that results in alter-
be significant enough to require transfusions. nating relatively atrophic and polypoid areas .
. The malabsorption syndrome that invariably The multiple, sessile, broad-based polyps consist
develops in these patients is attributable to dif- of dilated, irregular foveolar glands and mucin-
fuse small intestinal mucosal injury. filled cysts lined by simple mucinous epithelium
Characteristic physical findings include nail without evidence of metaplasia or atypia. The
changes (dystrophy, thinning, splitting), hair lamina propria becomes edematous and is fo-
loss, and dermal hyperpigmentation. Complete cally infiltrated by plasma cells, eosinophils,
loss of all fingernails and toenails occurs in some and neutrophils. Smooth muscle fibers extend
patients. Partial or total regeneration of nails up into the mucosa. The lesions resemble

746
Non-neoplastic Polyposis Syndromes

Figure 16-21
CRONKHITE-CANADA SYNDROME
Left: The colonic mucosa appears polypoid and the lamina propria is edematous.
Right: Marked lamina propria edema distorts the mucosal architecture. There is minimal associated inflammation. (Fig.
2-48 from Atlas of Tumor Pathology, Fascicle 32, Third Series.)

gastric hyperplastic polyps. The nonpolypoid only areas of edema and inflammation may be
intervening mucosa contains cystically dilated seen. With superficial biopsies, CCS may be indis-
glands, in contrast to the normal intervening tinguishable from inflammatory polyps. Biopsies
mucosa seen in ]PS. There may be glandular may also demonstrate what appears to be an area
atrophy with pseudopyloric metaplasia in the of gastritis. Gastric lesions share features with ]PS
body. The glands develop a corkscrew shape, and Menetrier's disease (92). In this situation, the
become cystic, and are lined by hypertrophic, diagnosis is only possible if one is aware of the
bizarre mucous cells. A secondary histiocytic other features of the clinical syndrome. The only
infiltrate may surround glands that rupture. reliable distinction between CCS and colonic ]PS
Cysts may also occur in the submucosa. There is the pedunculated growth of the polyps in the
may be a relationship with Menetrier's disease, latter. Pedunculation is not always present in ju-
since both disorders share clinical and histologic venile polyps; however, CCS tends to affect older
similarities and both are reversible. Adenoma- individuals as compared with ]PS . In CCS, the
taus changes can be present, as can coexisting nonpolypoid intervening mucosa may contain
colorectal carcinomas (98). cystically dilated glands, a feature lacking in ]PS .
Intestinal lesions are essentially similar to Treatment and Prognosis . Symptom onset
those arising in the stomach, appearing as ir- maybe acute and the course rapidly progressive.
regular nodules and foci of mucosal atrophy. The major clinical problem is protein loss from
Both the polyps and the intervening mucosa the damaged mucosa and variable malabsorp-
may show prominent edema, variable inflam- tion. Profound malnutrition may occur and
mation, and dilated cysts (fig. 16-21) . The degree is a major cause of morbidity and mortality.
of inflammation and edema tends to be greater Aggressive supportive therapy with nutritional
than in the stomach and the lesions tend to in- supplementation, fluid and electrolyte replace-
volve the entire thickness of the bowel wall. Villi ment, and transfusion of blood components is
and crypts decrease in number. Goblet cells in- warranted to correct the existing or impending
crease in the remaining crypts. The epithelium deficiencies. The use of total parenteral nutri-
may appear normal, atrophic, degenerative, or tion is successful in some patients. The mortality
regenerative (93). rate is 50 to 60 percent.
Differential Diagnosis. The differential diag- While spontaneous remissions occur, sur-
nosis often includes gastrointestinal inflammatmy vival beyond 2 years for symptomatic patients
conditions. In biopsy specimens of CCS polyps, is uncommon . Other therapies have included

747
(}astrointestinal Diseases

corticosteroids, antibiotics, and surgery, but


results are unpredictable. Since as many as 20
percent of CCS patients develop adenoma or
carcinoma, colonoscopic surveillance is indi-
cated (99-101). The neoplasms develop primar-
ily in the colon and less often in the stomach
(99-101). Colon lesions tend to be proximally
located. Surgery is recommended when compli-
cations such as bleeding, intussusception, bowel
obstruction, malignancy, or prolapse develop.
FAMILIAL HYPERPLASTIC
GASTRIC POLYPOSIS
Definition. The term familial hype1plastic Figure 16-22
gastric polyposis is applied to patients who have LYMPHOID POLYPOSIS
more than 50 genetically acquired gastric hy- Typical lymphoid polyps have prominent lymphoid
perplastic polyps (102,103). tissue with discernible germinal centers surrounded by a
Demography. To date, only a single large collar of normal small lymphocytes.
kindred has been studied.
Etiology. Familial hyperplastic gastric pol-
yposis may represent a new syndrome with
an autosomal dominant mode of inheritance Treatment and Prognosis. Patients have an
(102,103). Gastric polyps develop in 34 to 60 increased incidence of gastric cancer, which is
percent of affected patients. both intestinal and diffuse in type. The foveolar
Clinical Features. Psoriasis affects a third of hyperplasia and hyperplastic polyps play ,g key
the family members (102, 103). The polyps tend role in the development of diffuse carcinoma
to remain asymptomatic and there is a slightly in patients with familial hyperplastic gastric
increased risk for the development of gastric polyposis syndrome (102,103). The foveolar
cancer over that seen in the general population. cells in some patients display prominent glo-
Gross Findings. The polyps average 1 cm in boid features.
size, and most are smaller than 1.5 ctn. They
generally are uniform in shape and size, are scat- LYMPHOID POLYPOSIS
tered throughout the gastric fundus and body, Definition. Lymphoid polyposis, also known
and are less frequent in the cardia and antrum. as nodular lymphoid hype1plasia, is characterized
Microscopic Findings. Histologically, the by the presence of multiple lymphoid polyps.
polyps resemble ordinary hyperplastic polyps. Demography. There are three forms of
The hyperplastic foveolar epithelium lining the lymphoid polyposis: idiopathic, reactive, and
polyps develops a papillary or villous configura- associated with hypogammaglobulinemia.
tion, sometimes with atypJa. Chronic gastritis The idiopathic type is the most common and
is seen in the surrounding mucosa. involves lesions in the small intestine or co-
Differential Diagnosis. The differential di- lon. This form occurs in children usually as
agnosis includes isolated hyperplastic polyps, an incidental finding, as well as in individuals
juvenile polyposis, and the CCS. These dis- undergoing resection for appendicitis, inflam-
•. orders can be separated from one another by matory bowel disease, and familial polyposis.
knowledge of the clinical features of the patient. In the latter condition, the lymphoid polyps
Familial hyperplastic gastric polyposis differs grossly resemble small adenomas. Some patients
from the other syndromes in that the patients with hypogammaglobulinemia and lymphoid
have familial aggregation, the disorder affects polyposis have coexisting giardiasis.
young individuals of several generations, and Clinical Features. Lymphoid polyposis is
the patients exhibit marked foveolar hyperplasia usually an incidental finding at endoscopy or
(102,103). during examination of resected specimens.

748
Non-neoplastic Polyposis Syndromes

Gross Findings. Lymphoid polyposis appears yposis. The major distinction between the two
as several round, pale nodules measuring 3 to lesions is that one is histologically benign and
5 mm. It affects any part of the intestine but is the other is malignant. The usual techniques
particularly common in the ileum. that separate benign from malignant lymphoid
Microscopic Findings. Histologically, lym- proliferations can be used to separate histologi-
phoid polyps consist of normal lymphoid tis- cally equivocal cases.
sue with prominent germinal centers located Treatment and Prognosis. Lymphoid pol-
mainly at the junction of the mucosa and the yposis is a self-limited condition with no serious
submucosa (fig. 16-22). consequences.
Differential Diagnosis. The major entity in
the differential diagnosis is lymphomatous pol-

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79. Starink TM, van der Veen]P, Arwert F, et al. The tion spectrum and genotype-phenotype correla-
Cowden syndrome: a clinical and genetic study tions in Bannayan-Riley-Ruvalcaba s~mdrome
in 21 patients. Clin Genet 1986;29:222-33. suggest a single entity with Cowden syndrome.
80. Suzuki T, Ichinose M, Matsubara Y, et al. Cow- Hum Mol Genet 1999;8:1461-72.
den's disease with a defined genetic altera- 90. Ruvalcaba RH, Myhre S, Smith DW. Sotos syn-
tion-chromosomal duplication at 15q11-q13. drome with intestinal polyposis and pigmentary
J Gastroenterol1997;32:696-9. · changes of the genitalia. Clin Genet 1980;18:
81. Taylor AJ, Dodds WJ, Stewart ET. Alimentary 413-6.
tract lesions in Cowden's diseas~ Br J Radiol 90a. Starink TM, van der Veen JP, Arwert F, et al. The
1989;62:890-2. Cowden syndrome: a clinical and genetic study
82. Tsou HC, Ping XL, Xie XX, et al. The genetic in 21 patients. Clin Genet 1986;29:222-33.
basis of Cowden's syndrome: three novel muta- 90b. Zhou XP, Waite KA, Pilarski R, et al. Germline
tions in PTEN/MMAC1/TEP1. Hum Genet 1998; PTEN promoter mutations and deletions in
102:467-73. Cowden/Bannayan-Riley-Ruvalcaba syndrome
83. Tsubosa Y, Fukutomi T, Tsuda H, et al. Breast result in aberrant PTEN protein and dys-
cancer in Cowden's disease: a case report regulation of the phosphoinositol-3-kinase/ Akt
pathway. Am] Hum Genet 2003;73 :404-11.
with review of the literature. Jpn J Clin Oncol 90c. Zhou XP, Woodford-Richens K, Lehtonen R, et
1998;28:42-6 . al. Germline mutations in BMPR1A/ALK3 cause
83a. Zhou XP, Woodford-Richens K, Lehtonen R, et a subset of cases of juvenile polyposis syndrome
al. Germline mutations in BMPR1A/ALK3 cause and of Cowden and Bannayan-Riley-Ruvalcaba
a subset of cases of juvenile polyposis syndrome syndromes. Am] Hum Genet 2001;69:704-11.
and of Cowden and Bannayan-Riley-Ruvalcaba 91. Zigman AF, Lavine JE, ]ones MC, Boland CR,
syndromes. Am] Hum Genet 2001;69:704-11. Carethers JM. Localization of the Bannayan-
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Bannayan-Riley-Ruvalcaba Syndrome 10q23. Gastroenterology 1997;113:1433-7.
84. Arch EM, Goodman BK, Van Wesep RA, et al.
Deletion of PTEN in a patient with Bannayan-
Riley-Ruvalcaba syndrome suggests allel-
ism with Cowden disease. Am J Med Genet
1997;71:489-93 .

752
Non-neoplastic Polyposis Syndromes

Cronkhite-Canada Syndrome 99. Katayama Y, Kimura M, Konn M. Cronkhite-


92. Burke A, Sobin L. The pathology of Cronkhite- Canada syndrome associated with a rectal
Canada polyps. A comparison to juvenile pol- cancer and adenomatous changes in colonic
yposis. Am] Surg Pathol 1989;13:940-6. polyps. Am J Surg Pathol 1985;9:65-71.
93 . Cronkhite LW, Canada W]. Generalized gastro- 100. Nonomura A, Ohta G, Ibata T, et al. Cronkhite-
intestinal polyposis. An unusual syndrome of Canada syndrome associated with sigmoid
polyposis, pigmentation, alopecia and onycho- cancer. Case report and review of 54 cases with
trophia. N Engl] Med 1955;252:1011-15. the syndrome. Acta Pathol]pn 1980;30:825-45.
94. Dachman AH, Buck JL, Burke AP, Sobin LH. 101. Yokoyama S, Yamashita H, Moriuchi A, et al.
Cronkhite-Canada syndrome: radiologic fea- Cronkhite-Canada syndrome associated with
tures. Gastrointest Radial 1989;14:285-90. adenosquamous carcinoma in gastric polyps.
95. Daniel ES, Ludwig SL, Lewin KJ, et al. The Report of an autopsy case. Stomach Intest
Cronkhite-Canada syndrome: an analysis of 1983;18:981-90.
clinical and pathologic features and therapy in
55 patients. Medicine 1982;61:293-309. Gastric Hyperplastic Polyposis
96. Finan MC, Ray MK. Gastrointestinal polyposis
syndromes: Cronkhite Canada syndrome. Der- 102. Carneiro F, David L, Seruca L, Castedo S, Nesland
matol Clin 1989;7:419-34. ]M, Sobrinho-Simoes M. Hyperplastic polyposis
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polyposis with ectodermal changes. A case with of a family. Cancer 1993;72:323-9.
severe malabsorption and enteric loss of plasma 103. Seruca R, Carneiro F, Castedo S, David L, Lopes
proteins and electrolytes. Gastroenterology C, Sobrinho-Simoes M. Familial gastric polypo-
1966;50:107-13. sis revisited. Autosomal dominant inheritance
98. Johnson GK, Soergel KH, Hensley GT, Dodds confirmed. Cancer Genet Cytogenet 1991;53:
WJ, Hogan WJ. Cronkhite-Canada syndrome: 97-100.
gastrointestinal pathology and morphology.
Gastroenterology 1972;63:140-5 1.

753
17 MOTILITY DISORDERS

INTRODUCTION
Normal gastrointestinal motility depends on rectum describe visceral enlargement of each of
intact neuromuscular function. Extrinsic control these anatomic sites. There is no agreement on
of peristalsis includes the sympathetic (thoraco-
lumbar) and parasympathetic (vagal) innervation
Table 17-1
in the ganglionated plexuses. Intrinsic control
includes the enteric nervous system, smooth GASTROINTESTINAL NEUROMUSCULAR DISORDERS
muscle cells, and interstitial cells of Cajal, with Neural Disorders
the latter serving both as pacemaker cells and Neural developmental abnormalities
as intermediaries of enteric innervation (1-3,6). Hirschsprung's disease and its variants
Gastrointestinal motility diseases constitute a Intes tinal internal sphin cter achalasia
Maturational arrest
complex array of clinical and pathologic disor- Intestinal neuronal dysplasia
ders. They result from neural, muscular, or neu- Megacystis-microcolon and intestinal hypoperistalsis
romuscular diseases (Table 17-1), and they occur Severe idiopathic constipation
at any age. The diseases may be primary motility Absent ent eric nervous system
Visceral neuropathies
disorders or they may complicate systemic dis- Sporadic
eases. Primary motility diseases more typically Familial
affect children than adults. Conversely, second- Paraneoplastic pseudoobstruction
ary conditions, such as scleroderma-associated Infectio ns
Herpes zoster
myopathy, diabetic neuropathy, drug-induced Cytomegalovirus
damage, or viral infections more frequently affect Epstein-Barr virus
adults. Primary motility disorders may be familial Bacterial
or sporadic. They may remain limited to the gut, Chagas' disease
Idiopathic ganglionitis
as in Hirschsprung's disease, or they may be part Autoimmune autonomic neuropa thies
of a generalized peripheral autonomic neuropa- Achalasia
thy, as in familial visceral neuropathy. Familial Allgrove's syndrome
disorders are inherited as both autosomal reces- Slow tra n sit constipation
Complications of systemic neurologic disorders
sive and autosomal dominant diseases. Parkinson's disease
The clinical and pathologic findings of gas- Wallenberg's syndrome
trointestinal motility disorders may be subtle AmyotTophic lateral sclerosis
or dramatic. They can present as dysphagia, Muscle Disorders
gastroparesis, intestinal pseudoobstruction, Visceral myopathies
constipation, or intestinal diverticulosis. A con- Sporadic
Familial
sensus group of pediatric and adult gastroenter- Mitochondrial myopathies
ologists defined intestinal pseudoobstruction as Autoimmune enteralleiomyositis
"a rare, severe disabling disorder characterized Diffuse leiomyomatosis
by repetitive episodes or continuous symptoms Neuromuscular Disorders
and signs of bowel obstruction, including ra- Infiltrative diseases
Scleroderma
diographic documentation of a dilated bowel Amyloidosis
with air-fluid levels in the absence of a fixed, Diabetic neuropathy
lumen-occluding lesion" (5) . Ogilvie's syndrome Toxic n euromuscular disorde rs
is a term used synonymously with acute colonic Drug induced
Radiation induced
pseudoobstruction. Megaesophagus, megaduo- Amanita poisoning
denum, megajejunum, megacolon, and mega-

755
Gastrointestinal Diseases

the criteria for the minimum diameters of the disorders, who have histologic abnormalities
dilated gastrointestinal segments. that have not been well described or placed into
specific syndromes.
General Clinical. Features
Histologic examination using conventional
Patients present with a wide array of poorly hematoxylin and eosin (H&E) stains may have
defined gastrointestinal complaints, including limited usefulness in evaluating many neuro-
abdominal distension, nausea, vomiting, con- muscular disorders. Special stains or ultrastruc-
stipation, diffuse esophageal spasm, delayed tural examination, techniques not typically
gastric emptying, and early satiety. Small in- used in the evaluation of other gastrointestinal
testinal pseudoobstruction leads to diarrhea, disorders, may be required. These include sil-
malabsorption, and steatorrhea secondary to ver stains, assessment of acetylcholinesterase
slowed intestinal transit times, which also al- activity, and immunohistochemical staining
lows for secondary bacterial overgrowth. Some for c-kit, neurofilament protein, PGP 9.5, S-100
patients become malnourished with extreme protein, glial fibrillary acidic protein (GFAP),
weight loss. Recurrent postprandial upper ab- neural cell adhesion molecule (NCAM), and
dominal pain, associated with bloating, nausea, ret or nerve growth factor receptor (NGFR).
and vomiting, indicates that combil!ed gastric Whole mount preparations can also be very
and small intestinal disease is present. helpful because they allow the visualization of
Extraintestinal manifestations depend on the two-dimensional plexuses lying within the
the nature of the underlying disease; these help layers of the intestinal wall. They can be used to
define some syndromes. Features .suggesting define the number of ganglion cells and neurons
autonomic dysfunction include postural diz- per surface area. This approach is most typically
ziness, difficulties in visual accommodation to used for research purposes rather than for clini-
bright light, and sweating abnormalitie~. Recur- cal diagnosis (7). Some histologic changes are so
rent urinary infections and difficulty emptying subtle that they require neuronal co~pting to
the urinary bladder suggest a general visceral document their presence. This is fraught with
neuromyopathic disorder. Patients should be problems since the number of nerves and ganglia
questioned about drug use. Patients bedridden vary with age and with other disease processes.
for prolonged periods of time, such as those Diagnostic Workup. Multiple modali-
with dementia, stroke, and spinal cord injuries, ties are used to diagnose motility disorders.
are particularly prone to developing megacolon They are clinically diagnosed using specific
and chronic pseudoobstruction. physiologic measurements of gastrointesti-
nal motor function, including scintigraphy,
Pathologic Features
gastroduodenojejunal manometry, and surface
Radiologic Findings. Radiologic examina- electrogastrography. The clinician should seek
tion may show ileus, massive bowel dilatation, the pathologist's assistance to rule out the pres-
and slowed gastrointestinal transit times. Poor ence of infiltrative lesions, such as amyloidosis
peristalsis leads to stasis with air-fluid levels. A or connective tissue diseases, or to document
microcolon may develop. Other radiologic fea- the presence of neuromuscular abnormalities.
tures include esophageal dilatation with aper-
Treatment
istalsis, gastric dilatation and delayed emptying,
megaduodenum with segmental dilatation of Treatment of motility disorders ranges from
the jejunum and ileum, and diverticulosis. dietary changes to surgery to intestinal trans-
Microscopic Findings. Even though the plantation in severe cases. Dietary measures,
clinical or gross findings may be dramatic, the including frequent small meals low in fat and
histologic features are often inconspicuous, and fiber, help some patients with gastroparesis. Pro-
they also overlap with the nonspecific neural kinetic drugs such as cisapride, metoclopramide,
or muscular histologic abnormalities accompa- erythromycin, domperidone, leuprolide, miso-
nying other conditions, such as carcinoma or prostol, and octreotide acetate are beneficial in
previous surgery. Additionally, there are patients some cases. Octreotide exerts its effects mainly
who present with clinically evident motility on the small bowel, and is particularly helpful

756
Motility Disorders

in scleroderma. Patients who have acute colonic and sacral regions (10) . A dual developmental
pseudoobstruction, such as following surgery or gradient leads to a cranial-caudal migration in
severe illness, may benefit from treatment with the preumbilical gut and a caudal-cranial migra-
neostigmine, which rapidly decompresses the tion in the postumbilical gut (12) as shown by
colon (4). In patients with irreversibly dilated the fact that colonic and gastric ganglia appear
bowels, no drug improves motility. before ileal ganglia. The neural crest-derived
Bowel decompression through gastrostomy precursors migrate along defined pathways to
and jejunostomy may be beneficial in patients colonize the bowel wall.
with pseudoobstruction. Small bowel transplan- Enteric neuronal migration and differentia-
tation is the only definitive cure for patients tion involve a complex interaction of lineage-
with chronic pseudoobstruction. Candidates determined micro environmental elements,
for transplantation include those receiving total including a number of transcription factors,
parenteral nutrition with frequent episodes of tyrosine kinase receptors and their ligands, the
sepsis, limited intravenous access to nutritional extracellular matrix, and specific adhesion mol-
support, or impending liver failure. Small bowel ecules (12-17,21). The transgenic and knockout
transplantation tends to be challenging in this technologies that allow genetic manipulation
clinical setting. of the mouse embryo have led to the identifi-
cation of a number of genes that are critical to
DEVELOPMENT OF THE the development of the enteric nervous system
ENTERIC NERVOUS SYSTEM (9,12-15,17,19). Table 17-2 lists some of the
The enteric nervous system, a distinct divi- known factors controlling neuronal develop-
sion of the autonomic nervous system, is rela- ment and differentiation.
tively independent of the central nervous sys- By birth, normal enteric ganglia contain
tem (18). It consists of a collection of autonomic both mature and immature neurons. Premature
ganglion-associated neural connections within infants have more immature neurons than
the bowel wall. The intrinsic innervation of the term infants. Mature neurons are larger than
gut wall consists of two interconnected gangli- immature neurons and have a distinct cell mem-
onated nerve plexuses, the myenteric plexus brane, a vesicular nucleus, and a large amount
located between the longitudinal and circular of basophilic cytoplasm. Immature neurons
muscle coats and the submucosal plexus. These are small cells with dark nuclei, clumped chro-
plexuses extend in an uninterrupted fashion matin, and scant cytoplasm (fig. 17-1). Neural
from the esophagus to the anus. The intrinsic stains highlight immature neurons. The normal
plexuses collectively innervate the gastrointes- mature colon contains 7.0 ganglion cells/mm
tinal mucosa, muscle layers, and blood vessels, of myenteric plexus, 3.6/mm in the jejunum,
and they contain reflex pathways that mediate and 4.3/mm in the ileum in 3-pm sections (20).
activities such as peristalsis. The extrinsic inner- Ganglion cells lie approximately 1 mm apart;
vation consists of parasympathetic and sensory they may occur in clusters of from 1 to 5 cells
nerves; disruption of this system produces little in normal adults (8). Normal neonates often
or no functional motor impairment (11,16,18). have plentiful, prominent ganglion cells, but
Enteric neurons originate from the neural they appear small when they are immature (20).
crest (16) in the dorsal neural tube. Here, the
neural crest stem cells divide, giving rise to NEURAL DISORDERS
multipotential ·progenitors that divide further Developmental gastrointestinal neural ab-
to give rise to differentiated cells. The differ- normalities result from failed neural migration
entiation process is influenced by: 1) the site or failed neural differentiation. Developmental
of origin in the neural tube; 2) the environ- neural diseases occur alone or they coexist
ment into which the multipotential stem cells with systemic disorders such as neurofibro-
migrate; and 3) the responsivity of multiple matosis . Most congenital myenteric plexus
lineages of precursor cells to the neurotrophic abnormalities fall into one of five categories:
factors. Enteric neural crest cells originate from aganglionosis, hypoganglionosis, hypergan-
two distinct levels of the neural tube: the vagal glionosis, ganglionic immaturity, and poorly

757
Gastrointestinal Diseases

Table 17-2
FACTORS INVOLVED IN THE DEVELOPMENT OF THE ENTERIC NERVOUS SYSTEM

Gene Defect after Genetic Manipulation


RET/GDNF/GFRDl Knockout leads to complete failure of enteric neurons
Encodes ret, a receptor tyrosine kinase expressed by neural and glia to develop in the entire bowel below the
crest-derived cells that colonize the gut. Ret is the foregut
functional receptor for GDNP
Mash I Knockout leads to aganglionosis of the esophagus and
Encodes a transcription factor required for development of gastric ·cardia; absence of early lineage of enteric
the autonomic nervous system neurons in the rest of the bowel
SoxlO Sox transgenics develop distal intestinal aganglionosis
Encodes a transcription factor expressed by ENSb precursors and die shortly after birth
before and after colonization of gut mesenchyme
Phox2 Phox2 knockout mice die in utero; there is an absence
Homeodomain-containing transcription factor expressed of foregut and midgut ENS
by neural crest cells as they invade foregut mesenchyme
EDNRB (endothelin receptor B) Neural crest cells in EDNRB knockouts fail to colonize the
Growth factor receptor hindgut
NCXl Homozygous targeted disruption animals show neural
Homeobox transcription factor expressed by ENS after hyperplasia and hyperganglionosis
midgestation in the distal gut

HOX4 Transgenic animals show abnormal ganglia in colon


Homeobox transcription factor expressed in foregut and short segment hypoganglionosis in distal colon
'GDNF =glial cell-derived neurolmpic factor.
bENS = enteric nervous system.

Hirschsprung's Disease
Definition. Hirschsprung's disease (HO) is a
congenital disorder characterized by intestinal
megacolon, neural hyperplasia, and absent
gastrointestinal ganglia. Several forms of HO are
defined below. The disorder previously known
as ultrashort HO is now referred to as achalasia
of the internal sphincter; it is discussed in a
later section.
Classic HD. The aganglionic segment begins
in the distal colorectum and extends proximally
Figure 17-1 for variable distances into the adjoining proxi-
MYENTERIC PLEXUS OF A PREMATURE BABY
mally dilated bowel.
Immature ganglion cells are lined up along the edge of
Short Segment HD. The aganglionic segment
the myenteric plexus. These cells are small and dark, and involves several centimeters of the rectum and
recognized with difficulty by those unfamiliar with their rectosigmoid.
appearance. Long Segment HD. The aganglionic segment
involves most or all of the large bowel and it
may extend into the small bowel (43).
classified abnormalities. The pathogenesis of Zonal Colonic Aganglionosis (Skip Segment HD).
developmental disorders of the enteric nervous A short bowel segment is involved in this form
system results from genetic defects, anoxia, or of HO. Ganglion cells are present both proximal
inflammation. and distal to the aganglionic segment.

758
Motility Disorders

Aganglionic megacolon, congenital megacolon, an intracellular tyrosine kinase domain (77,80).


and aganglionosis are synonyms of HD. Point mutations in the RET gene give rise to HD,
Demography. HD affects 1/5,000 to 30,000 multiple endocrine neoplasia (MEN) types 2A
live births; 80 percent of patients are male (70). and 2B, and familial medullary thyroid carci-
Approximately 4 to 6 percent of cases are famil - noma (Table 17 -4) (72). In the case of MEN2, the
ial (70,73) . The disease is likely to be familial RETmutations are activating, i.e., they enhance
when the megacolon extends to the cecum. the function of the encoded protein, whereas
Mothers with HD are more likely to have af- in HD, the mutations are inactivating and lead
fected children than are fathers with HD. Five to loss of function (41).
percent of patients have an affected sibling (73). Evidence pointing to the role of RET in the
Nine percent of patients have total colonic causation of some cases of HD include: 1) gross
aganglionosis (70) . Zonal segmental aganglio- deletions encompassing the region of the RET
nosis is rare (76,89). gene in patients with HD (44,61); 2) genetic
Etiology; HD is a heterogeneous genetic analyses of familial HD demonstrating linkage
disorder with autosomal dominant, autosomal to the chromosomal region containing RET
recessive, and polygenic forms of inheritance. (26, 62); 3) RET expression in enteric ganglia
Current etiologic hypotheses revolve around and their precursors in fetal mice (67); and 4)
two schools of thought: arrested neuroblast mice with knockout of the RET gene developing
migration and intestinal microenvironmental HD (78). More than 50 mutations, including
abnormalities causing failed neuronal differ- missense, nonsense, deletion, and insertion
entiation. This condition is linked to specific
genetic mutations in about 50 percent of cases.
There are four susceptibility genes for HD : Table 17-3
the RET protooncogene on 10qll (23-25,39, MUTATIONS IN HIRSCHSPRUNG'S DISEASE
40,50,72); its ligand, the glial cell line-derived Mutated Gene Function Disease
neurotropic factor (GDNF) gene family; the
RET (intracellular Tyrosine kinase Short segment HD'
endothelin B receptor (EDNRB) gene on 13q22 tyrosine kinase receptor Long segment HD
(35); and its ligand, the endothelin 3 (EDN3) domain)
gene (46,60) or neurturin, a RET ligand (Table RET (ex tracellular Tyrosine kinase Long segment HD
17-3) (38). An as yet unidentified gene located domain) receptor
on chromosome 21q22 may also be involved EDNRB Growth factor Short segment HD
(66). Modifier genes may also play a role in the receptor
pathogenesis of familial HD (75). EDN3 Ligand for EDNRB Shah-Waardenburg
The ret protein is a tyrosine kinase receptor syndrome
with extracellular cadherin-like and cysteine- "HD = Hirschsprung's disease.
rich domains, a transmembrane domain, and

Table 17-4
DISEASE-RELATED RET GENE MUTATIONS
HD" PTC MEN2A FMTC MEN2B Sporadic MTC
Mutations Various Gene Missense Missense A missense A missense
mutations rearrange- mutations at mutations at mutation at mutation at
through ments cysteine cysteine cod on codon
the gene residues: residues:
(see text) RET/PTCl 609 609 918 (Met -· Thr) 918 (Met - Thr)
RET/PTC2 611 611
RET/PTC3 618 618
620 620
634 (most common)
' HD = Hirschsprung's disease; PTC =papillary thyroid carcinoma; MEN =multiple endocrine neoplasia; FMTC = familial
medullary thyroid carcinoma.

759
Gastrointestinal Diseases

mutations, have been described in HD. These to support peristalsis. There is constant internal
mutations occur throughout the gene, without sphincter muscular contraction. Carbon mon-
any mutational hot spots (28,88). The mutations oxide-producing neurons may also be abnormal
can be placed loosely into tWo groups: frame shift in these patients (30).
or missense mutations that disrupt the structure The pathogenesis of the enterocolitis, which
of the intracellular tyrosine kinase domains (64), affects some patients, is not well understood.
or missense mutations in exons 2, 3, 5, or 6 of Enterocolitis is likely a consequence of the
the extracellular domain (40) . Patients with mu- toxemia resulting from stasis and bacterial
tations of the intracellular domain have either proliferation in the dilated colonic lumen. Pa-
short segment or long segment HD, whereas tients who develop enterocolitis have abnormal
those with mutations in the extracellular domain mucosal immune defenses (27,51). Risk factors
of RET have long segment HD. RET mutations for enterocolitis include a delayed diagnosis of
are more common in familial cases (SO percent) HD, long segment disease, family history of HD,
than in sporadic cases (15 to 33 percent) (28,72). female gender, and trisomy 21 (81).
EDNRB mutations are associated with short Clinical Features. HD is the most common
segment HD (69). Homozygosity for EDN3 muta- form of congenital intestinal obstruction. It
tions causes the Shah-Waardenburg s-yndrome, often presents within the first 24 to 48 hours
a combination of HD with Waardenburg's syn- of life in infants who cannot spontaneously
drome. Several genes may modify severity of pass meconium. As many as 80 percent of cases
the HD phenotype in patients with or without are diagnosed during the first year of life. Most
coexisting intestinal neuronal dyspl&sia type B. of the remaining 20 percent are diagnosed in
The first is illustrated by a large Mennonite HD early childhood; about 10 percent of HD cases
pedigree that showed a segregated missense mu- present in adults.
tation in the EDNRB gene (69). This family had Some patients appear perfectly normal at
marker alleles at21q22 that were highly suggestive birth but they develop abdominal distension,
of an HD genetic modifier linked to this chromo- vomiting, and obstipation during the first day
somal region (4 7). This mutation may account for or two of life. The lack of propulsive movements
the prevalence of HD among trisomy 21 patients and of inhibitory reflexes in an intestinal seg-
(4 7). Another HD modifier is exemplified by genes ment leads to severe constipation and marked
encoding glial cell derived neurotrophic factor dilatation of the proximal ganglionic segment.
(GDNF) (74,75,84) and more recentfy, neurturin Patients develop abdominal distension, repeated
(34), two highly homologous naturalligands of intestinal obstructions, enterocolitis, and meco-
the ret tyrosine kinase receptor. nium plug syndrome. Infants with obstruction
The finding of cytomegalovirus (CMV) ge- but without megacolon should be suspected of
netic material in 8.8 percent of cases of HD having HD involving the entire colon.
suggests a role for antenatal CMV infection as The diagnosis of HD usually requires a com-
an etiologic factor in some patients (80). Zonal bination of presenting clinical symptoms, radio-
HD is thought to have an ischemic etiology. logic findings, rectal manometry, and histologic
Pathophysiology. Alterations in intrinsic or histochemical features . Failure of the internal
gastrointestinal innervation contribute to the sphincter to relax following intrarectal balloon
clinical and pathologic features of HD. Vasoac- distension highly suggests the diagnosis.
tive intestinal polypeptide and nitric oxide (59), In young children, vomiting and progres-
components of the nonadrenergic, noncho- sive abdominal distension develop secondarily
linergic system (85) that relaxes smooth muscle to dilatation and hypertrophy of the colon
and forms part of the inhibitory component of proximal to the narrowed segment. Constipa-
the peristaltic reflex, are absent (57). Extrinsic tion may alternate with diarrhea. Reduced food
parasympathetic, cholinergic, and sympathetic intake and malabsorption result in failure to
adrenergic innervations persist, however. As a thrive . As the nutritional status deteriorates,
result, the distal aganglionic bowel is under infections may worsen the underlying motil-
constant, unopposed extramural stimulation so ity problem. Some patients develop a mucosal
that it becomes narrowed, spastic, and unable prolapse at the junction of the ganglionic and

760
Motility Disorders

Table 17-5
ABNORMALITIES ASSOCIATED
WITH HIRSCHSPRUNG'S DISEASE

Genetic Abnormalities
Down's syndrome
Tetrasomy 9p
Tetrasomy 9q
Congenital Abnormalities
Deafness
Intestinal malrotation
Esophageal and intestinal atresia
Hypothalamic hamartoblastoma
Cartilage-hair hypoplasia
Dandy-Walker cysts
Brachydactyly
Tetraamelic postaxial polydactyly
Congenital hypoventilation (Ondine's curse)
Bilateral discolored irides
Holoprosencephaly
Polydactyly
Imperforate anus
Congenital muscular dystrophy
Infantile osteopetrosis
Tumors
Neuroblastoma
Neurofibromatosis
Medullary carcinoma of the thyroid
Pheochromocytoma
Other Syndromes Figure 17-2
Jaw winking syndrome
Hadad's syndrome HIRSCHSPRUNG'S DISEASE
Goldberg-Shprintzen syndrome Barium enema in an infant with Hirschsprung's disease
Achalasia shows massive proximal dilatation of the large intestine.
The distallarge bowel appears stenotic.

aganglionic bowel due to different luminal Gross Findings. The widely dilated, fluid-
pressures in these bowel segments. Mucosal filled, hypertrophic colon empties into a funnel-
prolapse is more prominent in older patients shaped transitional zone that extends to the
and correlates with disease duration (31). anus (figs. 17-2, 17-3). Plain abdominal films
HD patients may also present in the neo- may show air-fluid levels. In adults, an abrupt,
natal period with perforation due to coexist- smooth rectal transition zone with proximal
ing necrotizing enterocolitis or volvulus (79). colonic dilatation, in the setting of an appropri-
Enterocolitis, a major source of morbidity and ate clinical history, suggests the diagnosis (65).
mortality, both before and after definitive surgi- The anal canal and rectum are small and empty,
cal treatment, is preventable by early diagnosis and the anal sphincter is tight.
and colostomy (58) . Major presenting features Microscopic Findings. The typical features
of enterocolitis include abdominal distension, of HD include an absence of ganglion cells (fig.
explosive diarrhea, vomiting, fever, lethargy, 17 -4) and increased numbers of hypertrophic,
rectal bleeding, sepsis, toxemia, mucosal ulcer- nonmyelinated, cholinergic nerves (part of the
ation, and colonic perforation. extrinsic parasympathetic innervation) in the
Associated congenital anomalies or other dis- submucosa and myenteric plexus (fig. 17-4). A
eases are seen in 10 to 15 percent of patients (Table good correlation exists between the density of
17-5) (33,37,42,45,52-55,64,68,71). Ten percent of cholinergic innervation and the severity of the
patients have Down's syndrome; 5 percent have clinical symptoms. Normally, ganglion cells
other serious neurologic abnormalities (29). are distributed at intervals of approximately 1

761
Gastrointestinal Diseases

Figure 17-3
HIRSCHSPRUNG'S DISEASE
Left: Unopened bowel has a proximal area of dilatation tapering into an area of narrowing.
Right: Opened bowel shows its. internal features.

Figure 17-4
HIRSCHSPRUNG'S DISEASE
Left: There is an absence of ganglion cells in the myenteric plexus.
Right: Large hypertrophic nerve trunks are evident.

mm with clusters of 1 to 5 cells and a density smooth muscle cells, and Schwann cells. Gan-
of 17 cells/mm 2 • In HD, ganglion cells are ab- glia can be stained with special stains to high-
sent from both plexuses· in the distal narrowed light their presence (see Special Techniques) .
bowel segment and are decreased in number in Patients with HD have an abnormal synapse
the first few centimeters of the funnel-shaped distribution. There are fewer synaptophysin-posi-
transitional region. tive synapses within the circular and longitudinal
Determining whether ganglion cells are pres- muscle layers in the transitional segments and
ent in premature infants may be difficult due to in aganglionic segments (56) . The adrenergic in-
the sparse cytoplasm and inconspicuous nuclei nervation of an aganglionic gut is also abnormal:
of immature ganglion cells (fig. 17-1). Immature there are alterations in numbers of adrenergic
ganglion cells form rosette-like structures ar- and peptidergic nerves (vasoactive intestinal
ranged around a central neuropil-type matrix, polypeptide, substance P, serotonin, calcitonin
producing a horseshoe-like structure. Because gene-related peptide, and neuropeptide Y-con-
immature ganglia are less distinctive than taining nerve fibers). Patients with HD also have
mature ones, they may mimic macrophages, a relative loss of interstitial cells of Cajal (86,87) .

762
Motility Disorders

Figure 17-5
HIRSCHSPRUNG'S DISEASE WITH PNEUMATOSIS INTESTINALIS
Left: Low-power magnification of a mucosa l biopsy. The most
prominent changes are in the muscularis mucosae, which appears
hypertrophic, and in the submucosa, which appears abnormal.
Above: Higher magnification of the submucosa shows inflammation
and air spaces surrounded by histiocytes and giant cells. The patient is
a 1-yea r-old boy with symptoms from birth .

Increased numbers of mast cells are seen in ascertained, if this was not done intraopera-
all of the bowel layers in the aganglionic por- tively. A progressive increase in the number of
tions of HD. These produce nerve growth factor, ganglion cells occurs as one progresses proxi-
which stimulates neural growth. Sometimes the mally in the funnel-shaped transitional zone
mast cells are in direct contact with the hyper- located between the aganglionic and normally
trophic nerves. innervated bowel. The transitional zone usually
The bowel wall proximal to the aganglionic seg- occurs over a short distance in which ganglia ap-
ment is often biopsied for frozen section analysis pear almost simultaneously in both the myen-
during surgical resections to ensure that the pro xi- teric and submucosal plexuses. The transitional
mal resection margin is normal. Submucosal nerve zone may contain abnormally shaped ganglia.
trunks over 40 pm in diameter strongly correlate Some patients have longer transitional zones
with abnormal innervation and aganglionosis (fig. than others; prominent nerve trunks may be
17-4) (66). Ganglionated segments never show present for several centimeters. Some transition
nerve hunks larger than this. If hype1trophic nerve zones show features of colonic neuronal dys-
trunks or abnormal ganglion cells are present in plasia (see below). Patients who develop post-
frozen sections, the surgeon should extend the re- operative symptoms may have either a retained
section proximally and monitor it with additional portion of the transitional zone with neuronal
frozen sections to identify a region that contains dysplasia or an aganglionic segment, or they
completely normal neural structures. This helps may have developed an acquired hypoganglio-
prevent recurrent disease. nosis (34) secondary to postoperative ischemia
While it may be commonplace to use frozen or infection.
sections in the context of monitoring resection If enterocolitis develops, the histology may
margins, they have also been used to make the include crypt dilatation with mucin depletion,
initial diagnosis. This practice is not recom- cryptitis, crypt abscesses, mucosal ulcers, trans-
mended because there is a high rate of incorrect mucosal necrosis, and perforation. Enterocolitis
frozen diagnoses (63). affects both ganglionic and aganglionic intes-
Once resection specimens are received, the tinal segments, and resembles other forms of
extent of the aganglionosis should be deter- enterocolitis. Pneumatosis intestinalis may be
mined and the status of the proximal margin present (fig. 17-5).

763
Gastrointestinal Diseases

. ;:- ·..
,.
·C
~
~---~
· CL.:,~.

Figure 17-6
HIRSCHSPRUNG'S DISEf\SE SPECIMEN STAINED FOR ACETYLCHOLINESTERASE
A: Staining of the aganglionic segment shows the presence of very thick nerve trunks and thick cholinergic nerve twigs.
B: These thickened, irregular cholinergi<;,nerve fibers are also seen in the area of the muscularis mucosae.
C: In the transitional zone of the same resection specimen, the large neural trunks and the finer cholinergic nerve fibers
around the muscularis mucosae are absent.
D: Higher magnification of the thin fibers in the muscularis mucosae.

Histologic Variants. There are several his- onstrates an increased network of coarse, thick-
tologic variants of HD. One is associated with ened, irregular cholinergic nerve fibers within
intestinal neuronal dysplasia (IND). Generally, the muscularis mucosae and lower mucosa. The
there is a hypoganglionic transitional zone at lamina propria fibers travel in a plane parallel to
the cranial end of the aganglionic segment but the mucosal smiace. Increased ACE nerve fibers are
hyperganglionic segments can also be found consistently present in short and long segment HD
and qualify for diagnosis of HD-associated IND. but they may be absent in total colonic agangli-
Total colonic aganglionosis can be divided into onosis, as noted above. ACE staining patterns are
. two groups based on the histologic findings. less dramatic in neonates than in older individuals,
Some cases are histologically similar to short possibly leading to a false negative diagnosis (32) .
segment and long segment disease, whereas in Antibodies to PGP 9.5, S-100 protein, nemo-
others, the bowel is aganglionic, but there is peptide Y, neuron specific enolase (NSE), nemo-
little or no neural hyperplasia. The latter finding filament protein (40,49,63), or the microtubule-
can lead to a false negative diagnosis. associated protein (MAP)S, all highlight nerve
Special Techniques. Acetylcholinesterase (ACE) fibers. NSE or ret antibodies (fig. 17 -7) intensely
enzymatic staining is a very reliable method for stain ganglion cells, facilitating recognition of
diagnosing HD (fig. 17-6). This technique dem- small immature ganglion cells.

764
Motility Disorders

Differential Diagnosis. A number of con- tions have been explored. Common themes
genital disorders are associated with megacolon embraced by these newer approaches include
(Table 17-6). Disorders in the differential diag- definitive surgery without the need for stomas,
nosis of neural hyperplasia include neurofibro- operative correction in the newborn period, the
matosis, MEN2b, Crohn's disease, and neuronal
dysplasia.
Treatment and Prognosis. Surgery is invari-
ably necessary for the treatment of symptomatic
/
,.
-
'I
.1'
.
·~ ., I
HD. Operations vary, depending on the extent r: t ~ • I rt

of the aganglionosis. Surgery is also used to ~ ' ,


.. . '·' I
treat the enterocolitis, especially in the face .... ,. /,,. !'l'
of an impending perforation. The traditional .' "
management of HD involves the creation of
,'.1'

,.,
I

a proximal diverting ostomy. This is followed ~


~~ ~
..
.~
. '. ;\ '
.If . ~ -
.
;,

by a second operation in which a definitive "~


"' ' . ~
'":.::.. ,. ~
J
pull-through procedure is performed after the ' -.:
intestine has decompressed and the infant has ...........
.y"'

" . , 't
' J.
had a chance to grow. With the advent of im-
proved perioperative patient care, laparoscopy, Figure 17-7
and managed care-directed pressure to reduce
RET IMMUNOSTAINING OF A NORMAL GANGLION
hospital costs, other surgical management op-
The ganglion cells are clearly stained.

Table 17-6
CONGENITAL CONDITIONS ASSOCIATED WITH MEGACOLON

Condition Prominent Features Inheritance


Cartilage-hair hypoplasia Short stature with metaphyseal dysplasia, sparse and fine hair, ARb
immunodeficiency; HD' is uncommon
Down's syndrome Short stature, brachycephaly, upward-slanting palpebral fissures, Trisomy 21
small mouth, heart defects, joint hypennobility, mental retardation
Hirschsprung brachydactyly Broad distal phalanges, nail hypoplasia of thumbs and halluces ? XLR
Hirschsprung cleft palate Microcephaly, prominent nose with hypertelorism, synophrys, sub- ? AR
mucous cleft palate, sparse hair, mental retardation
Hirschsprung coloboma Microcephaly, iris colobomas, hypertelorism, bulbous nose, mental AR
retardation
Hirschsprung digit hypoplasia Upward-slanting palpebral fissures, micrognathia, hypoplastic distal AR
digits and nails, growth and mental retardation
Lesch-Nyhan syndrome Mental retardation, self-mutilation, choreoathetosis, hyperuricemia; XLR
HD is uncommon
Multiple endocrine neoplasia, Marfanoid habitus, thick lips, nodules of tongue and lips, endocrine AD
type3 neoplasms
Pallister-Hall syndrome Prenatal growth deficiency, hypothalamic hamartoblastoma, laryngeal Sporadic
cleft, postaxial polydactyly, imperforate anus, heart defects, lethal
(similar to severe Smith-Lemli-Opitz syndrome)
Riley-Day syndrome Absent tearing, corneal ulceration, decreased pain sensation, smooth AR
tongue with decreased taste, vomiting, fever, mental impairment
Smith-Lemli-Opitz syndrome Microcephaly, bitemporal narrowing, ptosis, nostril anteversion, hypo- AR
tonia, incomplete genital development in males, mental retardation
Waardenburg-Shah syndrome Telecanthus, white forelock or piebaldism, deafness; HD uncommon AD
'HD = Hirschsprung's disease.
bAR= autosomal recessive; XLR = X-linked recessive; AD= autosomal dominant.

765
_ Gastrointestinal Diseases

use of laparoscopy to make smaller incisions Table 17-7


(48), and the avoidance of an incision alto- CAUSES OF ACQUIRED INTESTINAL
gether, using a complete transanal colon resec- NEURONAL DYSPLASIA TYPE A
tion (22). One-stage procedures are especially
Infections
attractive in infants without enterocolitis (82);
however, a single stage operation may carry with Drugs
it a higher risk of enterocolitis than a two-stage Inflammatory bowel disease
operation (82). Other intestinal inflammatory conditions
Patients who have associated IND tend to Necrotizing enterocoliti s
have delayed restoration of normal defecation Status postsurgery
following treatment. Persistent constipation Status postradiotherapy
is the most important long-term problem in
Prenatal ischemic events
patients operated on for BD. Inadequate resec-
tion, anastomotic strictures, coexisting IND,
and achalasia of the internal anal sphincter also
cause persistent constipation (53). Constipation sometimes called the hypogenetic type of dysgan-
persists in 10 to 27 percent of patient~ and in glionosis (134), may also be a form of IND type A.
up to 40 percent of patients with disseminated Demography. IND type A is relatively rare,
IND associated with BD. As many as 79 percent and probably accounts for only 5 percent of
of patients may have associated IND (50). congenital gastrointestinal neuronal defects.
Animal Models. Animal models have played The frequency of isolated IND type B varies
an important role in unraveling the neural from 0.3 to 40 percent of all rectal suction bi-
abnormalities present in HD. Hox-4 transgenic opsies (132). IND occurs as an isolated disorder
mice and RETknockout mice develop congeni- (135) or it coexists with neurofibromatosis,
tal megacolon. The latter develop total gastro- MEN2b, BD, intestinal malrotation (102), or
intestinal aganglionosis (69,78) . Mutations of short bowel syndrome. Some suggest that 25
the EDNRB gene produce megacolon, spotty to 79 percent of patients with BD have associ-
coat color, and aganglionosis confined to the ated IND type B (132). Others, however, rarely
rectosigmoid in piebald lethal mice: This sug- encounter l-ID-associated IND. These incidence
gests different functions for RET-mediated and differences result from variable diagnostic cri-
EDNRB-mediated signaling pathwa ys in the teria, biopsy procedures, staining techniques,
establishment of the enteric nervous system. and patient age. In HD, IND lies within, or just
C-erbB2 knockout mice also develop megacolon proximal to, the aganglionic transitional zone
(36). BD animal models are described in detail (100,108,129,130,135,137). Patients have also
in references 35, 54, and 83. been described with aganglionosis involving the
entire colon and terminal ileum, and coexist-
Intestinal Neuronal Dysplasia
ing jejunal and gastric IND. IND accounts for
Definition. Patients with IND have defective residual symptoms in BD patients following
gastrointestinal neuromuscular ilmervation. IND pull-through operations (109). IND affects both
occurs in two forms: type A is characterized by children and adults (114-117,119).
decreased gastrointestinal sympathetic innerva- Etiology. IND is both a congenital and an ac-
tion, and type B is characterized by increased quired disease. IND type A may result from a de-
numbers of ganglion cells, a dysplastic submu- velopmental hypoplasia of the myenteric plexus
cosal plexus, and defective neuronal nerve fiber (134), possibly due to abnormal expression of
differentiation (97,108). These diseases are very neurotrophic factors. Table 17-7 lists causes of
controversial and poorly understood, and con- acquired IND type A. Pediatric patients with
sensus definitions for each entity are not avail- MEN2b and IND type B have symptoms suggest-
able. This group of diseases requires more study. ing that both disorders result from mutations
IND type A is also known as hypoganglionosis. in the same domain of the RET protooncogene.
IND type B is also known as hype1ganglionosis. The In some cases, IND and neurofibromatosis are
entity known as oligoneuronal disease, which is familial and associated with tandem duplication

766
Motility Disorders

Table 17-8 tension causes intermittent colicky pain, often


CONDITIONS ASSOCIATED WITH
relieved by massive flatulence. Some children
INTESTINAL NEURONAL DYSPLASIA experience overflow discharge of stool. The
diagnosis of IND type A is usually difficult to
Tumors establish. X-ray studies, determination of transit
Carcinoid tumors
Familial gastTointestinal stromal tumors times, and anorectal manometry are not reliable
Lipoblastomatosis indicators of the disease (135). IND type A is
Medullary carcinoma of the thyroid encountered in three forms: 1) an isolated form
Neurofibromatosis occurring as a segmental or even disseminated
Pheochromocytoma
disease; 2) hypoganglionosis of variable length
Paraneoplastic Syndromes
adjacent to aganglionic HO; and 3) hypogan-
Cystic Fibrosis glionosis in combination with IND type B in a
Other Gastrointestinal Abnormalities proximal segment.
Anal atresia IND type B also clinically both mimics and
Choledochal cyst
Congenital hyperplasia of the interstitial cells of Cajal complicates HO. HD-associated IND is a dis-
Esophageal atresia seminated process in one third of patients and
Hirschsprung's disease localized in the remaining. Patients present
Intestinal duplication with constipation, intestinal obstruction, in-
Microvillous atrophy
Persistent urachus tussusception, or volvulus (112,120) . Gastro-
Pyloric stenosis intestinal symptoms include nausea/vomiting,
Rectal or sigmoid sten osis diarrhea, constipation, and fecal incontinence.
Extraabdominal Malformations Symptoms develop insidiously, with progressive
Aortic stenosis development of severe constipation that results
Congenital diaphragmatic hernia
Vertebral body malformations
in overflow incontinence (132). The mean age at
diagnosis is 1.5 years . Many patients eventually
spontaneously develop normal colonic motility
(132). IND type B is thought to have an unfavor-
in the NFl gene and a reciprocal translocation able course if the condition is associated with
(t15;16)(q26.3;q12.1) (91). IND may also be ganglionic heterotopia in the mucosa or if there
one component of a complex malformation are large numbers of immature ganglia.
pattern, since it can coexist with extraintestinal A significant number of patients develop se-
and nonobstructive intestinal malformations vere intraabdominal complications during the
(Table 17-8) (92,98,103,105,121,122,130,131). perinatal period, including necrotizing entero-
IND is also associated with intestinal microvillus colitis, meconium ileus, or bowel perforation
atrophy (130) and lipoblastomatosis. especially in premature neonates. Conditions
Pathophysiology. Patients with IND type associated with IND are listed in Table 17-8.
A lack the normal number of ganglion cells, Gross Findings. IND can be diffuse, involv-
leading to motility abnormalities. IND type ing both the small and large intestine, or it may
B is characterized by a malformation of the remain confined to a single intestinal segment.
parasympathetic submucosal plexus. Disturbed Extensive disease may involve the stomach and
innervation of the nonadrenergic, noncholin- esophagus (125,131,138). The bowel grossly ap-
ergic excitatory nerves contribute to abnormal pears either normal or variably dilated.
motility patterns· (119). Microscopic Findings. IND Type A . Muco-
Clinical Features. The symptoms caused sal biopsies with histochemical analyses are
by IND type A resemble those seen in HO. In usually not helpful in diagnosing IND type A
newborns, there may be delayed meconium because the disease is only reliably detected in
discharge; infants and small children show rare the parasympathetic system of the myenteric
bowel evacuations that respond to enemas. plexus. Therefore, full-thickness biopsies are
With increasing age, fecal masses can be pal- essential for the diagnosis (132) . Patients with
pated through the abdominal wall. The colon IND type A have a reduced number of myenteric
becomes dilated and contains fecalomas. Dis- ganglia and m yenteric plexus neurons, no or

767
Gastrointestinal Diseases

Figure 17-8
INTESTINAL NEURONAL DYSPLASIA TYPE A
A: Small submucosal and myenteric ganglia with immature neuroblast-like cells .
B: Higher magnifica tion of one of the ganglia shows the immature, small, shriveled ganglion cells and swelling of the
surrounding neural structures. ""
C: The swollen nerves are seen passing through the muscularis propria.
D: S-100 protein immunostain of the muscularis propria highlights the swollen nerve fibers.

low colonic mucosal ACE levels, and hypertro- bowel is diagnostic. The distance between the
phy of the muscularis mucosae and the circular ganglia in IND type A is nearly double that of
muscle of the muscularis propria (120, 128). the normal bowel; the average cell size is slightly
Absent or small submucosal and myenteric greater than normal (135).
ganglia containing only. one or two ganglion IND Type B. Controversy also exists over the
cells and immature neuroblast-like cells extend diagnostic criteria for IND type B. Criteria for
throughout the affected parts of the gastroin- IND B include: 1) hyperplasia of the parasym-
testinal tract (fig. 17 -8) (96,119). Patients with pathetic myenteric and submucosal plexuses
IND type A may also have a reduction in the characterized by increased numbers of neurons
r.,.
interstitial cells of Cajal, perhaps contributing to and ganglia (fig. 17-9) (93,110); 2) giant submu-
the dysmotility. Some patients have irreversible cosal ganglia containing 7 to 15 ganglion cells
neuronal degeneration (fig. 17-8). (93,113,116,117); 3) hypertrophic nerve bundles
There is no consensus as to how few ganglion containing an increased number of thickened,
cells there should be to make a diagnosis of IND beaded and disorganized axons (fig. 17-10); 4) in-
type A. Meier-Ruge (117) suggests that a 10-fold creased ACE activity in the nerves of the mucosa,
decrease in the number of ganglion cells per submucosa, and arterial adventitia (93,116);
centimeter of bowel as compared to normal and 5) a proliferation of fine nerve fibers in the

768
Motility Disorders

..- ,

- -.......
I~
-
~ .. . ... _,
. ---
-.
-.. .... .
'
~· .,
.., ,. \ ,
:0

... -- .., .... .. .. ~

,
,.

.,
11 - _ ...
--......
" ,... ...
"
.
1
,"/"

Figure 17-9
INTESTINAL NEURONAL DYSPLASIA TYPE B
Left: A large collection of ganglion cells is evident in the mucosa. The distance from the base of the crypts to the muscularis
mucosae is widened and contains numerous ganglion cells.
Right: The myenteric plexus shows unusually large collections of ganglion cells.

lamina propria and circular muscle (133). The


diagnostic controversy is best exemplified by a
study in which three pathologists agreed on the
diagnosis in only 14 percent of children without
aganglionosis (112). Smith (136) also found that
according to the criteria described by Borchard,
only 11 percent of patients with megacolon
had the obligatory criteria (hyperplasia of the
submucosal plexus, an increase in ACE-positive
nerve fibers around submucosal blood vessels,
and ACE activity in the lamina propria).
These discrepancies reflect the fact that cases
diagnosed as IND may be heterogeneous in nature,
and the fact that there are no accepted criteria Figure 17-10
that cover all the histologic features that are seen.
INTESTINAL NEURONAL DYSPLASIA TYPE B
Fmthermore, the suggested criteria are not uni-
S-100 protein immunostain highlights the thickened
versally accepted. The diagnosis of IND type B is nerves in the superficial submucosa.
fmther complicated by the fact that the density of
ganglion cells in the myenteric plexus decreases
significantly with age during the first 3 to 4 years giant ganglia, hyperganglionosis, and increased
of life. Finally, estimates of nerve cell density are numbers of nerves are demonstrable in the mus-
influenced by section thickness (139). cularis propria and the myenteric plexus (the
In some of cases of IND type B, there are in- motor division of the enteric nervous system)
creased nerve cells per ganglion (approximately as well as in the mucosa and submucosal plexus
10 cells per ganglion versus 4 per ganglion in (secretory and sensory division) (95,112,135).
normal children). The individual nerve cells are The diagnostic criteria relating to nerve cell
reduced in size (20 percent smaller) when com- density may overlap with age-related changes
pared with normal mature ganglion cells. These (116). The morphology of the myenteric plexus
nerves show an increase in the number of ACE- also varies at different levels of the gut. The
positive nerve fibers and an absence of NCAM density of the neural meshwork increases in the
and nicotinamide adenine dinucleated phos- distal direction and is highest in the sigmoid
phate (NADPH) diaphorase activity (106). The colon and proximal rectum. In the lower pa1ts of

769
Gastrointestinal Diseases

the rectum, the meshwork is less compact, and Individuals with IND type B often have sec-
small ganglia and fibers extend in longitudinal ondary changes in the muscularis propria. There
directions. Many neurons contain bizarre nuclei may be areas of significant muscle atrophy in
and a poorly defined cytoplasm. one or another layer of th~ muscularis propria;
Giant ganglia are thought to result from the alternatively, there may be hyperplasia of either
premature expression of laminin and other the circular or longitudinal layer of the muscu-
trophic factors during embryologic life, block- laris propria; or these two changes may both be
ing neuroblast migration into the submucosa present. These secondary changes undoubtedly
and myenteric plexus (123,124,125,133). Only reflect abnormal innervation of the muscle lay-
about 5 percent of the ganglia in IND are giant ers and the neuromuscular junction (107).
ganglia (115). The specificity of giant ganglia as Overall, it would be desirable to have better
a marker for IND type B has been questioned, quantitative diagnostic criteria for IND type B
since occasional giant ganglia can be found in to distinguish normal variants from pathologic
individuals without a history of constipation. conditions, particularly in very young children.
Furthermore, the presence of giant ganglia may Moore et al. (118) introduced a morphologic
be age independent, whereas hyperplasia of the scoring system based on the finding of hypergan-
submucosal plexus and increases in ACE activity glionosis, giant ganglia, neuronal maturity, het-
in the nerve fibers of the lamina propria appear erotopic neuronal cells, and ACE activity in the
to be age-dependent findings that disappear lamina propria, muscularis mucosae, or adven-
with maturation of the enteric nervous system titia of submucosal blood vessels. Hyperganglio-
(115). Therefore, neural hyperplasi.a is signifi- nosis and increased ACE activity of nerve fibers
cantly more common in neonates than in older in the lamina propria had major importance in
individuals (95). this scoring system. The best diagnostic indicator
Patients with IND type B may also l}ave hy- of IND in adults may be the detection of 6 to 10
perplasia of the interstitial cells of Cajal. This giant ganglia with more than seven nerxe cells in
can be visible grossly as a thick, white, fibrous 15 biopsy sections (90) . Some suggest that to make
band between the inner circular and outer longi- a reliable diagnosis of IND type B, at least 30 serial
tudinal muscle layers throughout the full length sections must be examined and that they need to
of the resected bowel. Microscopically, this contain a minimum of four giant ganglion cross
band-like layer consists of haphazardly arranged sections (117). It is further suggested that the nerve
spindle- to oval-shaped cells. The nuclei are cell profiles be stained by an enzyme histochemical
long and oval, with slightly tapered ends, and reaction specific for nerves (117).
possess hyperchromatic or clumped chromatin Given all the confusion surrounding the
and occasional small nucleoli. The cells have a diagnosis of IND type B, the question arises
moderate amount of eosinophilic cytoplasm; how to best diagnose the changes present. Our
mitotic figures are rare. The muscle layers are current practice is to be descriptive. We state
partially replaced by these hyperplastic spindle that hyperganglionosis is present and state
cells and focally the full thickness of the inner the number of ganglion cells/ganglia. We also
muscular layer can be involved. Residual my- state whether neuronal hyperplasia is present
enteric plexus can be identified in the midst of or not. If tissue was received for ACE staining,
the hyperplastic cells. we describe whether ACE staining in nerves is
Patients with IND type B often have large increased and whether there is neural hyper-
numbers of mast cells in the bowel wall com- plasia on the H&E or other stained sections. We
pared to normal. Mast cells produce nerve also describe whether the neurons and ganglion
growth factors that support the development cells appear histologically normal. If only large
and functional maintenance of the sympathetic ganglia are present, we suggest that the change
and cholinergic neurons, and they may be im- may be age-related and may resolve with time,
portant in the neuronal hyperplasia seen in this requiring no therapy.
condition (111). We have also seen endocrine Histologic Variants. A variant of IND affects
cell hyperplasia associated with hyperganglio- older patients who present with chronic diar-
nosis in the neonate. rhea, pseudoobstruction, and multiple polyps,

770
Motility Disorders

which contain prominent ganglioneuromatous protein, smooth muscle actin, desmin, nemo-
proliferations within the lamina propria. The filament, and NSE.
submucosal ganglia and myenteric plexus be- Differential Diagnosis. Clinically, IND mim-
come infiltrated with chronic inflammatory cells. ics HO but the histologic features distinguish
Special Techniques . ACE histochemistry the two disorders, except in those situations
is a widely accepted technique for diagnosing where IND coexists with HO. The presence of
enteric neuronal disorders, particularly HO and giant ganglia, immature ganglia, and hetero-
IND type B. The rapid ACE technique may be of topic nerve cells aids in the diagnosis of IND.
great value in determining the extent of IND in- The lesions differ from the neurofibromas of
traoperatively. A slight or moderate increase in neurofibromatosis by the diffuse exaggeration
ACE activity in the parasympathetic nerve fibers of normal neural tissue, contrasting with the
in the lamina propria and around submucosal tumor formation seen in neurofibromas (94,
vessels is present in approximately 60 percent 137) . Overlap may exist between the two con-
of cases (111). The number of NCAM-positive ditions. IND type A can also be seen in other
nerve growth factor receptor (NGFR) fibers in settings (see Table 17 -7).
the lamina propria and muscularis mucosae Treatment and Prognosis. Some patients,
is also markedly decreased in IND (111). This especially those with IND type B, outgrow their
finding is considered to be helpful, especially in disease as the enteric nervous system matures .
diagnosing IND in neonatal cases where hyper- Patients with persistent symptoms are managed
ganglionosis may be a normal finding. Newer medically with prokinetic agents, colonic irriga-
neuronal markers, such as NADPH diaphorase tions, and cathartics. If bowel symptoms persist
histochemistry and immunohistochemistry, lac- after 6 months of conservative treatment, inter-
tate dehydrogenase (LDH) histochemistry, and nal sphincter myotomy should be considered
succinate dehydrogenase histochemistry may (134). Resection and pull-through operations
be used (93,101,115,129). An increased number may be indicated for extensive IND (127). The
of giant ganglia with more than seven LOB- decision to treat with surgery is usually based
positive nerve cells is suggested to be typical on the patient's clinical symptoms. Individuals
for IND type B. Abnormal neural proliferations who develop ileus may require resection (138).
can be highlighted by silver stains or antibodies Patients with both aganglionosis and IND have
to S-100 protein, NSE, PGP 9.5, neuropeptide Y, a worse prognosis than those with only one or
or neurofilament protein. Recently, Cuprolinic the other disease.
blue has been proposed as the method that Animal Models. HoxllLl is a homeobox
stains the largest number of ganglion cells . This gene involved in peripheral nervous system
stain only stains cell bodies and not the axons, development as confirmed by knockout mice
which makes distinguishing individual cells exhibiting megacolon. This gene localizes to
relatively easy. We have also used ret immuno- human chromosome 2pl3 .1->p12 at a 14cr
stains to highlight the ganglion cells. interval between WI5987 (D2ST088N) and
Hutson et al. (104) performed immunofluo- GCT1B4 (B2S4797) (126).
rescence for the presence of neurotransmitters
Neuronal Maturational Arrest
associated with excitatory nerves (substance P
[SP]) and those associated with inhibitory nerves Definition. Neuronal maturational arrest syn-
(vasoactive intestinal polypeptide [VIP]) (104). dromes are characterized by the failure of neural
These two peptides represent functional markers elements to mature properly. Synonyms include
for the colonic contraction (SP) and relaxation neuronal immaturity and ganglionic immaturity.
(VIP) necessary for forward propulsion (99) . The Etiology. The underlying cause(s) of failed
authors found two variants of IND: one with neuronal maturation is unknown. Pathogenetic
an isolated deficiency of SP labeling in colonic mechanisms may include: 1) failure of normal
nerves and a second group with deficient stain- numbers of neural crest cells to migrate into the
ing for both SP and VIP (104) . Interstitial cells gut; 2) inadequate neural proliferation in the
of Cajal are diffusely immunoreactive for c-kit, gut; or 3) death of nemo blasts once they arrive
CD34, and vimentin but nomeactive for S-100 in the gut. The lesion may result from failure of

771
Gastrointestinal Diseases

the local microenvironment to support normal Pathophysiology. Achalasia results from


neuronal development during fetal life. There abnormal innervation of the internal anal
have also been reports of delayed maturation sphincter. Normal relaxation of the internal
of the interstitial cells of Cajal, contributing to anal sphincter occurs by the activation of intra-
pseudoobstruction in neonates. mural nonadrenergic, nonch.o linergic (NANC)
Clinical Features. Children present with poorly nerves (146-148) via nitric oxide (NO), the
defined motility disorders, including intestinal transmitter in NANC signaling (140). In achala-
pseudoobstruction or chronic constipation. sia, there are abnormalities in NO synthase and
Microscopic Findings. The histologic fea- NAOPH diaphorase. The latter mediates intemal
tures differ depending on the stage at which anal sphincter relaxation in the absence of NO
myenteric plexus development ceased. Patients synthase innervation.
exhibit several major histologic abnormalities: Clinical Features. Anal achalasia is a disorder
1) no myenteric plexus seen in either H&E- that only affects the internal anal sphincter. This
stained or specially stained sections; 2) small disorder presents in a manner similar to that of
numbers of neuronal structures (ganglia and HO, but there are ganglion cells on rectal biopsy
nerve trunks) are present; however, the neurons (141). Anorectal manometry demonstrates the
are small and have only one or two prpcesses, absence of rectosphincteric reflex during rectal
and the ganglia lack the nerve tracts and mesh- balloon inflation (143).
like structures that characterize the normal Microscopic Findings. Rectal biopsies have
myenteric plexus; or 3) an apparently normal ganglion cells and normal ACE activity (142,
myenteric plexus is seen on H&E-stained sec- 144,145).
tions but there is a deficiency of neurons as Treatment. Patients are treated by intemal
seen by silver or immunohistochemical stain- sphincter myotomy.
ing. These neurons lack neurofilaments, fl:lrther
Absent Enteric Nervous System
confirming their immaturity. The ganglion cells
may also line up at the periphery of the ganglia Definition. An absent enteric nervous 'system
as occurs in premature infants (see fig. 17-1). means an absence of nerves and ganglia from
There is no inflammation or neural degenera- the stomach to the colon.
tion. These findings contrast with tho.se seen in Clinical Features. A unique case report de-
patients with HO or INO type B in that there is scribed a full-term infant who developed severe
no neural hyperplasia. "" perinatal pseudoobstruction in the absence of
Special Techniques, Silver stains, enzymatic gastrointestinal neurons and ganglia (149).
stains, or immunostains facilitate the diagnosis. Microscopic Findings. In the above case, no
We utilize immunostaining for the ret protein nerves or ganglia were present in the Auerbach
in order to highlight the presence of ganglion plexus, within the muscularis propria or myen-
cells, which may be small, to distinguish them teric plexus area. S-100 protein and ACE stain-
from the nerve-supporting enteric glia. Anum- ing confirmed the absence of neural structures.
ber of immunostains can be used to highlight Sporadic PGP 9.5 positivity identified extrinsic
the neurons. nerves associated with the submucosal blood
Differential Diagnosis . Other motility vessels and within the area of the Auerbach
disorders. plexus. Electron microscopy failed to show en-
Treatment. Neuronal immaturity often spon- teric nerve fibers and neuronal cell bodies and
taneously improves with conservative therapy their associated Schwann cells within Auerbach
and the normal development of the child. plexus. Extrinsic nerve fibers were sparse. Inter-
stitial cells of Cajal in Auerbach plexus (ICC-AP)
Internal Anal Sphincter Achalasia
were quite prominent in the area between the
Definition. Internal anal sphincter achalasia is circular and longitudinal muscle layers and their
the failure of relaxation of the intemal anal sphinc- distribution resembled that seen in normal hu-
ter in the presence of ganglion cells as seen in rectal man tissues. The ICC-AP processes were in close
suction biopsies (142,144,145). This abnormality apposition with each other and with nearby
is also known as the utrashmt form of HD. smooth muscle cells, but no gap junctions were

772
Motility Disorders

found. No close contacts were found between


the ICC-AP and extrinsic nerves.
In the inner third of the circular muscles, no
normal interstitial cells of Cajal were detected.
Interstitial cells of Cajal of the deep muscle
plexus, located between the inner and outer
division of the circular muscle layers in the
zone of connective tissue, were in various stages
of injury. They were characterized by partial
or complete destruction of their organellar
contents. Their long thin processes frequently
contacted adjacent circular muscle cells. The
normal distribution of the ICC-AP and their
normal close contacts with smooth muscle cells Figure 17-11
appeared to be sufficient for the generation of MEGACOLON
regular rhythmic slow wave activities, even in The body of this patient with intestinal pseudoob-
the absence of interstitial cells of Cajal in the struction has been opened and the dilated stomach and
deep muscle plexus. colon bulge out of the abdominal cavity. A feature such as
Treatment and Prognosis. The child received this can be seen in patients with primary neuropathies or
primary myopathies.
enteral feedings, but the infant's feeding toler-
ance was limited by his impaired gastric empty-
ing and he eventually died of hepatic failure. neuronal autoantibodies that cross-react with
neural tissues, destroying them (151,152,158).
Familial Visceral Neuropathies
Demography. Patients with small cell car-
Definition. Hereditary familial visceral neu- cinoma of the lung (150), carcinoid tumors,
ropathies are a group of genetic diseases char- medulloblastomas, and oligodendrogliomas
acterized by pseudoobstruction (fig. 17-11), (150,155) develop the disease.
myenteric plexus abnormalities, variable inheri- Pathophysiology. Some patients with neural
tance patterns, and characteristic extraintestinal and neuroendocrine tumors develop distinctive
manifestations (Table 17 -9). antineuronal autoantibodies (151,154,158),
Demography. These diseases are rare. including type 1 antineuronal nuclear antibod-
Clinical Features. The clinical findings of ies, also defined as anti-anti Hu on the basis
each syndrome are listed in Table 17-9. of their molecular target, type 2 antineuronal
Microscopic Findings. These are listed in nuclear antibodies (or anti-Ri), anti-Purkinje
Table 17-9. The nerves often appear vacuolated cell cytoplasmic antibodies (anti-yo), N-type
(fig. 17 -12). Silver stains or immunostains high- voltage-gated calcium channel antibodies, P/Q
light both the number and the shape of the neu- type calcium channel antibodies, and ganglionic
rons and nerve fibers of the myenteric plexus. and muscle type nicotinic acetylcholine receptor
Special Studies. Ultrastructural examination antibodies (156,159,160). The most commonly
of the autosomal recessive visceral neuropathy identified antineuronal antibody is anti-HU,
with intranuclear inclusions form of the disease an immunoglobulin G. It recognizes a group of
shows intranuclear neuronal inclusions con- proteins with molecular weights in the range of
sisting of a random array of straight or slightly 35 to 40 kDa that are expressed by both neurons
curving filaments. These filaments have a charac- and neoplastic cells. Hu antigens include four
teristic beaded pattern with a periodicity of 15 to nervous system-specific RNA-binding proteins
30 nm. They measure 17 to 2 7 nm in diameter. (identified as HuD, HuC, HuR, and Hel-N1).
These share sequence homology with the em-
Paraneoplastic Pseudoobstruction
bryonic lethal abnormal vision-binding protein
Definition. Paraneoplastic pseudoobstruction of Drosophila. The anti-HuD antibodies evoke
develops in patients with neuroendocrine or neuronal apoptosis that may contribute to im-
neural neoplasms caused by the production of pairment of the enteric nervous system (153).

773
Gastrointestinal Diseases

Table 17-9
FINDINGS IN VISCERAL NEUROPATHIES

Disease
and Genetic Clinical Gastroin testinal Microscopic Extraintestinal
Tr_a nsmission Findings Lesions Lesions Silver Stains Lesions
Familial Forms
Autosomal CliP' Megaduodenum, Atrophy of Argyrophilic Extensive
recessive Mental generalized dila- smooth neurons decrease focal calci flea-
with mental retardation tion of small muscle in all in number, tion of basal
retardation, intestine, redun- gastrointestinal remaining ganglia and
basal ganglia dant colon tissues neurons appear subcortical
calciftcation misshapen and white
pyknotic matter
Autosomal CliP Dilation and non- Reduction and Decreased Neural
recessive Diffuse neurologic peristaltic hypo- degeneration of neurons in inclusions in
neuronal abnormalities, mild activity involving myenteric plexus myenteric plexus, central and
intranuclear autonomic insuffi- the esophagus, neurons, remaining peripheral
inclusion ciency, denervation stoma<;h, and eosinophilic argyrophilic nervous
disease hypersensitivity of small intestine; neuroftlament neurons are systems
pupillary and esopha- extensive colonic containing intra- misshapen with
geal smooth muscle, diverticulosis nuclear inclusions only a few
progressive spasticity, in myenteric and processes
ataxia, absent deep submucosal plexus
tendon reflexes, dys- neurons
arthria, gastroparesis,
neurogenic bladder
Autosomal Predominantly Abnormai gastric Hypertrophy of Decreased number None
dominant present with intes- emptying, dom- smooth muscle, of degenerated
visceral tinal pseudoob- inant segmental reduction and neurons with
neuropathy struction, symptom dilation of jejun- degeneration of poorly deftned
onset at any age, urn and ileum, myenteric plexus, cell borders and
postprandial small intestinal argyrophilic decreased silver
abdominal pain, diverticulosis, neurons staining, some
distension, diarrhea, proximal small neurons appear
constipation int131ltine always vacuolated
involved or beaded
Autosomal Symptoms start Hypertrophic Neural abnormal- Deficiency of CNS malfor-
recessive in infancy pyloric stenosis, ities, neuroblasts argyrophilic mations with
visceral short dilated small present, hyper- cells, no heterotopia
neuropathy intestine, intestin- trophy of muscu- visible intrinsic and absence
type II al malrotation Jaris propria, no neurons or of operculum
muscle processes temporale,
degeneration patent ductus
arteriosus
Sporadic Visceral Neuropathy
Type I Similar to other Affects both the Reduced myenteric Neuronal swelling, None
sporadic forms of CliP large and small neurons, no inflam- fragmentation
intestine mation, neuronal and dropout,
swelling, gliosis, eventually neu-
no inclusions rons disappear
Type Il Similar to other Affects both th e Degenerated argyphil- Axonal No ne
sporadic forms of CliP large and small ic and argyrophobic disorganization
intestine neurons, loss of and
antral staining pro- degeneration
ducing signet ring
cell appearance,
no inflammation
' CliP = chronic idiopathic intestinal pseudoobstruction; CNS = central nervous system.

774
Motility Disorders

Figure 17-12
PRIMARY NEUROPATHY
This patient had massive dilation of the colon.
A: Medium magnification shows an area of the myenteric
plexus that appears vacuolated.
B: Abnormal-looking ganglia are present.
C: An antibody to S-100 protein highlights the vacuo-
lization of the nerves .

., \'' ·.r
,. ~, f ' ;
' J ' ( )
•.'
' j
f' ) I I

.'
/
} ' " · >: ••
~

,. ..•.;
... .. ,J ... .:""'
J
./ .. ~·

c . ..."'
':·
.. ' ..

Clinical Features. Patients present with leads to gliosis, sometimes completely replacing
gastrointestinal dysmotility and autonomic dys- the nerve tracts. Only a few normal-appearing
function, often before the underlying malignan- neurons remain. The key finding suggesting
cy is diagnosed. They experience weight loss, the diagnosis is the presence of lymphoid cells
pseudoobstruction, constipation, gastroparesis, and plasma cells within the myenteric plexus.
gastroesophageal reflux, esophageal dysmotility Special Techniques. Serologic testing for the
suggestive of spasm or achalasia, intractable Hu antibody offers a simple means of distin-
dysphagia, postprandial fullness, nausea, vomit- guishing those patients with paraneoplastic gas-
ing, diarrhea, fecal incontinence, and bloating trointestinal tract dysmotility syndromes (15 1).
(150,154,158). They also develop associated Rarer autoantibodies can also be evaluated.
peripheral, sensory, and motor neuropathies; Differential Diagnosis. The differential diag-
neurogenic bladders; ataxia; encephalopathy; nosis includes toxic neural damage from drugs,
orthostatic hypotension; and decreased deep infection, or an autoimmune neuropathy, as
tendon reflexes (150,154,156,15 7), giving a clue well as aganglionosis in the absence of a tumor.
to the likely etiology of this motility disorder. Treatment and Prognosis. The treatment
Gross Findings: Pseudoobstruction results in of the underlying tumor may not necessarily
dilatation of the stomach, small intestine, and colon. reverse the intestinal manifestations, which
Microscopic Findings. Myenteric neurons, require symptomatic and supportive therapy.
from the esophagus to the colon, are reduced in
number and the myenteric plexus is infiltrated INFECTIOUS CAUSES OF
with plasma cells, lymphocytes, and eosinophils MOTILITY DISORDERS
(fig. 17-13). Remaining neurons appear vacu- Demography. Some patients with viral infec-
olated and display cytoplasmic irregularities tions and many patients with Chagas' disease
and decreased cellular processes. Axons swell, develop gastrointestinal motility disorders. Her-
become fragmented, and drop out. The damage pes zoster and cytomegalovirus (CMV) damage

775
Gastrointestinal Diseases

Figure 17-13
PARANEOPLASTIC PSEUDOOBSTRUCTION
The patient had a carcinoid tumor of the ovary.
Left: ~ematoxylin and eosin (H&E) stain highlights the increased cellularity of the myenteric plexus.
R1ght. Many of the cells are smalllymphocytes (leukocyte common antigen immunostain).

the myenteric plexus, leading to the develqpment esophagus to the rectum. The gastrointestinal
of pseudoobstruction in immunocompromised tract may also show any of the features seen
patients. Some bacterial infections also result in with any other pseudoobstruction syndrome.
motility disorders or irritable bowel syndrome. Microscopic Findings. Patients with infec-
Etiology. Secondary gastrointestinal neuropa- tious causes of motility disorders may show any
thies can be caused by neurotropic vimses, includ- of the features discussed in chapter 10. Here,
ing herpes zoster (162), Epstein-Barr (EBV) vims the focus is on those that relate to the motility
(169) and CMV (161). Other infections result in disorders. In CMV or HSV infection, viral inclu-
autoimmune attacks on neural sbuctures due to sions may be identified, or not. The diagnosis
the presence of cross-reacting antigens, such as can be made by demonstrating CMV or HSV
those present in some Campylobacter iniections. intranuclear inclusions in the myenteric plexus
Chagas' disease is discussed in chapter 10. neurons or in the muscle fibers. The typical
Clinical Features. Delayed gastric emptying mucosal effects of viral gastroenteritis may also
occurs as a consequence of acute viral gastroen- be present, or the patient may have healed viral
teritis, due to CMV (163,164,166,168), rotavims gastroenteritis with little inflammatory injury to
(161), or Norwalk or Hawaii vims infections the gastrointestinal mucosa. In patients without
(167). Generally, if there is a delay in gastric obvious inclusions, the enteric nerves may har-
emptying, it is transient and returns to normal bor either latent virus or residual inflammation
after the patient recovers from the viral infec- without significant mucosal alterations.
tion (161,165). Patients may 'also develop tachy- Special Techniques. Gastrointestinal motil-
gastria (an accelerated gastric rhythm), causing ity abnormalities may be documented utilizing
nausea and vomiting (168) . In some patients, gastric emptying scintiscans to demonstrate
symptoms persist following treatment (166). delayed gastric or intestinal transit. Bacteria
.Some patients present with pseudoobstruc- or vimses can often be cultured directly from
tion and abdominal pain (167). Autonomic the tissues (166). In patients without obvious
neuropathies may also be seen in patients with inclusions, ultrastructural examination, im-
neurotropic viral infections (170). munohistochemistry, or in situ hybridization
Gross Findings. In patients with viral infec- demonstrates the presence of the virus.
tions, especially CMV and, to a lesser extent, Differential Diagnosis. Other causes of gas-
herpes simplex vims (HSV), the various gastro- trointestinal motility disorder.
intestinal surfaces may appear normal or there Treatment. The beginning of this chapter
may be erosion or ulcers anywhere from the discusses general approaches to the treatment

776
Motility Disorders

of motility disorders. Treatment of specific infec- Differential Diagnosis. The differential diag-
tions is discussed in chapter 10. nosis includes paraneoplastic ganglionitis and
Chagas' disease (172,174) .
IDIOPATHIC GANGLIONITIS
Definition. Idiopathic ganglionitis is a motility ACHALASIA
disorder associated with chronic inflammation Definition. Achalasia is a rare disorder of
that affects the ganglia, in the absence of a unknown etiology associated with neuronal
known cause for the inflammation. Synonyms degeneration that results in esophageal aperi-
include acquired intestinal aganglionosis and ac- stalsis, impaired esophageal motility, and failed
quired megacolon-megarectum. relaxation of the lower esophageal sphincter.
Demography. The disorder often affects young Achalasia is also known as cardiospasm and
women of an average age of 25 years (171) . megaesophagus.
Etiology. The etiology of idiopathic gangli- Demography. Achalasia affects about 7 to
onitis is poorly understood. Most cases are due 13/100,000 in Europe and the United States (196,
to autoimmune circulating enteric neuronal 205). The disorder typically affects adults between
antibodies in the absence of cancer (173,175) . the ages of 21 and 60 years (180,185), affecting
Pathophysiology. In some patients, the de- both sexes equally. Approximately one third of
velopment of idiopathic ganglionitis correlates patients are newly diagnosed after age 60 (192).
with abnormalities in the concentration of The disease is rare in children (179,222,224).
enteric neurotransmitters and enzyme activity. Some cases are sporadic; others are familial (188,
There is a significant decrease in VIP concen- 209,210,221), with the latter often inherited as
tration and ACE activity in the nerves of the an autosomal recessive h"ait (204,220). Familial
muscularis propria and in the nerve cell bodies forms of the disease occur alone or in the pres-
in the myenteric plexus. ence of multisystem disease. One form of familial
Clinical Features. Patients present with severe disease combines achalasia and adrenocortico-
constipation and abdominal pain late in child- tropin unresponsiveness (206) . Another consists
hood. Some have associated mental retardation of microcephaly, optic atrophy, ataxia, mental
or psychiatric disorders. Initially, the motility retardation or developmental delay, and achalasia
disorder remains limited to the colon; later it in- (195,207,221). Familial cases account for less than
volves the entire gastrointestinal tract. There may 2 percent of the total (187,224).
be abdominal pain, nausea, vomiting, malnutri- Etiology. Achalasia probably results from
tion, diarrhea, and weight loss due to extreme a combination of genetic, autoimmune, and
inanition and hypergammaglobulinemia (173) . infectious factors (176). Familial achalasia may
Gross Findings. The rectum tends to be full result from a common exposure to an infection
of stool; fecal impaction is not unusual. A rectal or environmental toxin or it may represent
diameter over 6.5 cm at the pelvic brim on lat- a genetically transmitted disease. Implicated
eral radiographic view is common, as is a cecal environmental factors include bacteria, viruses
diameter in excess of 12 cm. (184,202,213), toxic agents such as combat
Microscopic Findings. Patients without cancer gas, and esophageal trauma; fetal ischemic
and without central nervous system involve- esophageal damage results from gastrointestinal
ment may show extensive ganglionitis with malrotations (177,181).
nemonal vacuolization and loss. A diffuse lympho- An autoimmune etiology is suspected be-
plasmacytic infiltrate may affect all layers of the cause of the association of achalasia with the
intestinal wall. The infiltr·ate also extensively dam- class II human leukocyte antigen (HLA) DQw1,
ages the submucosal and myenteric nerve plexus- and evidence of circulating antibodies against
es, resulting in a marked reduction in the number the myenteric plexus (200). A significant asso-
of myenteric nerve fibers. CD3- and CD4-positive ciation exists between idiopathic achalasia and
T lymphocytes surround the altered nerves. The the DQB1 *0602 allele and the DRB1 *15 allele in
histology of the musculature varies, appearing white patients. In blacks, there is no association
hypertrophic or atrophic, probably secondary between these two alleles and achalasia but a
to the neural abnormalities (173,175) . trend is present with DRB1*12, suggesting that

777
Gastrointestinal Diseases

0 Viruses Bacteria T cell-mediated


auto immune
0~ • injury
\::J • ••

Figure 17-14
DIAGRAM OF THE
PATHOGENESIS
OF ACHALASIA

Myenteric
plexus injury

idiopathic achalasia is associated with HLA a hypertonic lower esophageal sphincter due to
alleles in a race-specific manner (223): The its failure to fully relax.
expression of HLA antigens on ganglion cells Clinical Features. Since the esophagus'never
could initiate their autoimmune destruction by completely empties, a column of swallowed
T lymphocytes (198). The ganglia of 80 percent food builds up within it (193). This presents
of achalasia patients express one of th_ese histo- clinically as recurrent, progressive dysphagia,
compatibility antigens. pain, regurgitation, dyspepsia, retrosternal
Some postulate that an unknown factor trig- fullness, aspiration syndromes, and weight loss
gers the expression of the DQw1 class II HLA (178, 183). Aspiration pneumonia occurs when
antigen on myenteric ganglia. This antigen is the retained esophageal contents harbor bacte-
then recognized as foreign by T lymphocytes, ria (203). As the esophagus dilates, it may com-
which initiate an autoimmune process, destroy- press the bronchi. Although most patients are
ing neurons and ganglion cells (217,222). symptomatic for years before seeking medical
A final theory suggests that achalasia com- attention, some severely symptomatic patients
plicates neurologic and psychiatric diseases, present early. Regurgitation may cause noctur-
including Parkinson's disease, depression (215), nal coughing and aspiration. Erosive esophagitis
hereditary cerebellar ataxia, and neurofibro- complicates achalasia when acid reflux devel-
matosis (208,212). The various theories are ops, but may also occur secondary to bacterial
combined in figure 17-14. fermentation in a stagnant esophageal pool.
Pathophysiology. Achalasia is the best- Radiologic Findings. Chest radiographs
characterized esophageal motility disorder. show a dilated esophagus with an air-fluid
Patients with achalasia exhibit defective in- level due to retained food and saliva. Early, the
trinsic and extrinsic esophageal innervation esophagus appears minimally to moderately
. (194). The degenerative process preferentially dilated and the lower esophageal sphincter
affects NO- producing inhibitory neurons that remains contracted. Over time, the esophagus
affect the relaxation of the esophageal smooth progressively dilates and all esophageal motil-
muscle. There is also loss of inhibitory, non- ity ceases. The sphincter remains closed except
adrenergic, noncholinergic vagal nerve fibers for occasional brief periods of relaxation, and
and VIP-containing nerve fibers that results in acquires a "bird's beak" appearance due to the

778
Motility Disorders

Figure 17-15
ACHALASIA
The characteristic "birds-beak" pattern of achalasia is
seen on upper gastrointestinal examination.

presence of a shortened, angulated, narrowed


distal esophagus (fig. 17-15).
Gross Findings. The characteristic gross
features of achalasia consist of an enormously
dilated, lengthened esophagus that tapers into
a shortened narrowed tube at the esophagogas-
tric junction (fig. 17 -16). In advanced disease,
diverticula form, sometimes attaining a diam- Figure 17-16
eter of 10 cm or more. Some patients develop GROSS APPEARANCE OF THE
esophagobronchial fistulas. ESOPHAGUS IN ACHALASIA
Microscopic Findings. Histologic abnormali- The distal esophagus is dilated in comparison with the
ties affect the esophageal myenteric plexus, dor- more proximal esophagus.
sal vagal nucleus, and vagal trunks. The earliest
changes consist of myenteric inflammation with cells increase in number and may be difficult to
injury to, and subsequent loss of, neurons and distinguish from the lymphocytes (214). Lewy
ganglia and subsequent fibrosis of the myenteric bodies, identical to those seen in Parkinson's
plexus (186,189,198,199). Ganglionitis develops disease, may be found in the ganglion cells in
consisting of a mixture of lymphocytes and eo- the myenteric plexus.
sinophils with a less conspicuous population of Patients with disease severe enough to ne-
plasma cells and mast cells. The majority of the cessitate esophageal resection may completely
myenteric lymphocytes are CD3-, COS-positive lack myenteric ganglia, especially in the dilated
T cells. The lymphocytes express T-cell intracy- segment (199). Some patients have residual
toplasmic antigen (TIA-1), indicating that they ganglion cells in the proximal esophagus and a
are either resting or activated cytotoxic T cells. few randomly distributed ganglion cells in the
The TIA-1 cells appear to decrease in number as mid- and distal esophagus. There may also be
the disease progresses (190). reduced numbers of ganglion cells in the proxi-
In late-stage disease, the infiltrate becomes mal stomach. In most severe cases, an almost
more patchy and localized in and around my- total loss of the myenteric ganglion cells affects
enteric nerves (fig. 17 -17). Occasionally, there is the distal third of the esophagus. The remaining
marked eosinophilia of the muscularis propria. ganglion cells appear degenerated. The muscula-
Auerbach plexus widens as scar tissue and small ris propria appears atrophic, hypertrophic (182,
infiltrating inflammatory cells replace dying 199), or normal depending on disease severity;
neurons (fig. 17-18) (191,199,214). Satellite the changes tend to preferentially involve the

779
Gastrointestinal Diseases

Figure 17-17
ACHALASIA
Medium- (left) and high-power (right) views of a patchy infiltrate that surrounds the nerves and myenteric ganglia.

Figure 17-18
ACHALASIA
The area of the myenteric plexus (left) widens due to the presence of fibrosis . Inflammation is also present (right).

inner circular layer, especially distally (197). normalities (200) . Resting lower esophageal
These changes are secondary to the neural and sphincter pressure is elevated in 90 percent of
ganglionic alterations. patients. In achalasia, the sphincter relaxes by
Nonspecific mucosal abnormalities include only 30 percent, contrasting with 100 percent
diffuse squamous hyperplasia and lympho- relaxation in normal individuals (193) .
cytic esophagitis. The lymphocytes infiltrate Differential Diagnosis. The clinical features
the lamina propria and submucosa surrounding are mimicked by Chagas' disease and by diffuse
submucosal ducts and glands and form promi- esophageal leiomyomatosis. The histologic
nent germinal centers. With the passage of time, features are mimicked by Chagas' disease, au-
chronic inflammation and ulceration result in toimmune ganglionitis, and paraneoplastic
fibrosis and stricture formation. pseudoobstruction.
Special Techniques. Manometry is often the Treatment and Prognosis. No therapy can
diagnostic modality used to diagnose achalasia, reverse or halt the enteric neuronal degen-
particularly in patients with early stage disease eration. Therefore, treatment of the disease is
with minimal endoscopic or radiographic ab- aimed at decreasing the resting pressure in the

780
Motility Disorders

Figure 17-19
BARRETT ESOPHAGUS
The patient developed Barrett esophagus after treatment by sphincterotomy for achalasia.
Left: Low-power magnification.
Right: Area of Barrett esophagus. Dysplasia is present as well.

lower esophageal sphincter by pharmacologi- Other experimental therapies have been pro-
cal or mechanical means to the point that the posed for the treatment of achalasia, including
sphincter no longer poses a substantial bar- endoscopic myotomy of the lower esophageal
rier to the passage of ingested material. Esoph- sphincter or endoscopic injection of ethanol-
agomyotomy and pneumatic dilatation remain amine into the sphincter (206).
the major treatment modalities (216). Patients Carcinomas may develop in long-standing
who are poor operative risks can be given a achalasia. This risk is estimated to be 33-fold
trial of medical therapy with nitrates or calcium normal in patients who have had the disease
channel blockers (201). These agents have been for decades (205,217) . The tumors, which are
used with variable success (186,218,219). Intra- usually squamous cell in type, can arise at all
sphincteric injection with botulinum toxin levels of the esophagus but they are most com-
is gaining widespread use, particularly in the mon in its middle third (210).
elderly (201). The botulinum toxin induces im- Patients who have undergone a previous
mediate symptomatic improvement that lasts for esophagomyotomy and who experience esopha-
approximately 6 months in approximately two geal reflux show all the changes and complica-
thirds of patients. Most patients need repeated tions associated with reflux disease (see chapter
injections to maintain remission. Unfortunately, 3), including Barrett esophagus (fi.g. 17 -19) and
botulinum toxin therapy is expensive (189). adenocarcinomas (198, 199).

781
Gastrointestinal Diseases

ACHALASIA OF THE CARDIA accommodation, and a fixed heart rate. Many


IN ALLGROVE'S SYNDROME patients have gastrointestinal dysmotility and
Definition. Allgrove's syndrome, which fea- present with anorexia, early satiety, abdominal
tures achalasia, addisonianism (adrenocortico- pain, vomiting after eating, and constipation or
tropin hormone [ACTH] insensitivity), and diarrhea. Motor and sensory neural abnormali-
alacrima (lack of tears), is an autosomal recessive ties are minimal or absent.
disorder recently associated with the AAAS gene Pathophysiology. As in myasthenia gravis,
encoding the Aladin protein. autoantibodies specific for neuronal nicotinic
Demography. Achalasia of the cardia assodated acetylcholine receptors in autonomic ganglia
with Allgrove's syndrome is a rare disorder in chil- (ganglionic receptors) may disrupt cholinergic
dren characterized by defective relaxation of the synaptic transmission and lead to autonomic
cardia and aperistalsis in the esophageal body. failure.
Etiology. The gene for Allgrove's syndrome Clinical Features. Panautonomic failure
has been linked to chromosome 12q13. Muta- develops in a subacute manner (over a period
tions of the AAAS gene lead to a presumptive of days or weeks) (225,226). The course of the
lack of function of the encoded protein known disease is generally slow and recovery is incom-
as Aladin or Adracalin. • plete (225). The clinical findings are listed above
Clinical Features. Pediatric achalasia devel- in the disease definition.
ops in the first 6 months of life and differs from Gross Findings. The gross features are similar
the adult form of the disease in that the achala- to those of many pseudoobstruction syndromes.
sia is part of a multisystemic disorde{ Children Microscopic Findings. The histologic fea-
often present with vomiting undigested food, tures are identical to those seen in paraneo-
failure to thrive, and recurrent chest infections. plastic neuropathy.
They also present with heaviness and pain in Special Techniques . Serologic studies to
the chest, progressive dysphagia, nocturnal detect ganglionic receptor antibodies establish
regurgitation, and weight loss. Associated ab- the diagnosis.
normalities include alacrima, autonomic and Differential Diagnosis. An identical syn-
motor neuropathy, short stature, microcephaly, drome develops in patients with paraneoplastic
and nerve deafness. · neuropathy.
Pathologic Findings. All patienj:s with All-
grove's syndrome show a striking widening of CHRONIC SEVERE
the myenteric plexus between the circular and IDIOPATHIC CONSTIPATION
longitudinal layer due to fibrosis. The fibrosis Definition. Chronic severe idiopathic constipa-
and necrosis of the muscle sometimes seen in tion in adults is a distinctive clinical syndrome
esophageal achalasia are components of this without an obvious cause, but with subtle neu-
disorder. Myenteric ganglia are absent or mark- ral abnormalities. Synonyms include idiopathic
edly decreased. Numerous CD3-positive lym- chronic constipation, colonic inertia, and slow
phocytes surround the myenteric ganglia. The transit constipation.
nerves fail to stain for neuronal NO synthase; Demography. The disease typically affects two
however, thick inducible nitric oxide synthase major groups of patients: adult women who have
(iNOS) nerve bundles are present in the inter- severe chronic constipation and children with a
muscular plane in all cases. similar presentation. Children range in age from
0.25 to 10 years, with a mean of 4.5 years.
AUTOIMMUNE Etiology. The etiology of idiopathic consti-
AUTONOMIC NEUROPATHY pation is poorly understood. Many adults use
Definition. Idiopathic autonomic neuropathy antidepressants and narcotics for abdominal
results in severe panautonomic failure. Sym- pain and related disorders, making it unclear
pathetic failure manifests as severe orthostatic whether the disease is a primary myenteric
hypotension and anhidrosis. Parasympathetic plexus disorder or the result of long-term ca-
failure includes dry mouth, sexual dysfunc- thartic, antidepressant, or narcotic use (abuse)
tion, impaired pupillary response to light and (227). If there is any history of the use of these

782
Motility Disorders

drugs, the case should be classified as a drug-


induced motility disorder and not an idiopathic
disorder. Some postulate that the abnormalities
are developmental in origin, rather than an
acquired destructive lesion, since frank axonal
degeneration, Schwann cell hyperplasia, and
inflammation are absent (227).
Pathophysiology. The pathogenetic mecha-
nisms are poorly understood and believed to be
multifactorial in nature (228). Abnormalities
of the enteric nervous system or the interstitial
cells of Cajal are thought to cause the disease
(232,233).
Clinical Features. Patients present with Figure 17-20
chronic constipation. Symptoms vary in their GLIOSIS IN A PATIENT WITH
severity. Adults with severe disease may have CHRONIC CONSTIPATION
no more than one bowel movement per week, Many dendritically-shaped glial cells are in the myenteric
despite laxative use. Patients may also develop plexus (glial fibrillary acidic protein [GFAP] immunostain).
abdominal pain, bloating, and nausea, and may
require manual disimpaction. Rarely, marked S-1 00 protein. There are also increased numbers
ileus and large intestinal pseudoobstruction of PGP 9.5-immunoreactive nerve fibers in
develop (227). Other complications include the muscularis propria (227). The ratio of the
stercoral ulceration, intestinal ischemia, gas- thickness of the circular to longitudinal muscle
trointestinal bleeding, bowel perforation, and is significantly lower in the left colon of consti-
peritonitis. Patients may also exhibit abnormal pated subjects than in normal individuals (229).
gastric emptying and gastroparesis. Melanosis coli is frequently present.
Gross Findings. Despite the fact that patients The topographic organization of the inter-
experience severe constipation, the degree of in- stitial cells of Cajal resembles that of control
testinal dilatation is seldom sufficient to warrant populations, but there can be a significant
a diagnosis of megacolon or megarectum. If the reduction of these cells in all layers except for
bowel is resected, the intestinal wall may appear the outer longitudinal muscle layer.
contracted, thickened, and markedly stenotic. Differential Diagnosis. Other motility disorders.
Alternatively, the bowel may appear dilated Prognosis and Treatment. Surgical interven-
and thinned. Stercoral ulcers may be present. tion is considered a therapeutic option (230).
Polyps may appear to be present, however, they
represent areas of mucosal prolapse. MUSCLE DISORDERS
Microscopic Findings. The histologic fea- Intestinal muscle diseases occur either as a
tures of this entity are usually not seen unless prima1y disorder or secondary to muscular dystro-
the pseudoobstruction or stercoral ulcers are phy, progressive systemic sclerosis, Ehlers-Danlos
severe enough to warrant a resection. Myenteric syndrome, dermatomyositis, and systemic lupus
plexus abnormalities are usually present. These erythematosus. Adults commonly have systemic
include decreased, small, irregular neurons; manifestations of the underlying disease; few
decreased neuronal processes; and clusters of patients have only gastrointestinal disease. In con-
variably sized intraganglionic nuclei, which trast, children rarely have gastrointestinal smooth
represent glia (fig. 17 -20), Schwann cells, or muscle disease as part of a systemic disorder.
immature neurons (227,231-233) . There is also
a notable decrease in ganglionic density and Megacystis-Microcolon and
size. The changes are significantly greater in Intestinal Hypoperistalsis Syndrome
the ascending and descending colon. In other Definition. Megacystis-microcolon and intesti-
patients, there may be an increase in neuronal nal hypoperistalsis syndrome (MMIHS) is a rare,
supporting tissues demonstrable by staining for generally fatal, congenital disorder affecting

783
Gastrointestinal Diseases

newboms. It is characterized by intestinal and Table 17-10


urinary bladder distension; an atonic, short, MEGACYSTIS-MICROCOLON-ASSOCIATED CONDITIONS
dilated small intestine; a displaced or malrotated
microcolon; and widespread gastrointestinal Gastrointestinal Abnormalities
Anal atresia
hypoperistalsis, hydronephrosis, and hydro-
Colonic atresia
ureters (237,240,242). The entity is also known Esophageal atresia
as neonatal small left colon syndrome, adynamic Imperforate anus
bowel disease, non-Hirschsprung's megacolon, and Intestinal malrotation
neonatal hollow visceral myopathy. Prune belly Intestinal stenosis
Mesenteric anomalies
syndrome may be the male equivalent. Omphalocele
Demography. Less than 100 cases have been Pyloric hypertrophy
reported. MMIHS predominantly affects girls Neural Changes
(female to male ratio, 4 to 1) (237,240,242). An Abnormal motor development
autosomal recessive mode of inheritance is pres- Blindness
Failed spontaneous respiration at birth
ent (236,237). More than SO percent of patients Mental retardation
are born to diabetic mothers. Partial deafness
Etiology. Although it has been suggested Seizures
that this condition may result from neuronal Genitourinary Abnormalities
maturational arrest (242) or a primary cellular Cryptorchidism
defect of contractile fiber synthesis (236), more Distended cloaca-bladder
Hydronephrosis
recent evidence suggests that it results f.rom the Hydro ureter
absence of the alpha-3 nicotinic acetylcholine Hydrourethra
receptor subunit (241). Megacystis
Clinical Features. MMIHS invariably pres- Penile hypoplasia
Renal dysplasia
ents during the first week of infancy. All patients Urachal remnant
develop vomiting and abdominal distension
Other Changes
due to intestinal pseudoobstruction, as well Cardiomyopathy
as distended urinary bladder due to bladder Cleft palate
pseudoobstruction. Other features include lax Limb malformations
abdominal musculature, incomplete intesti- Syndromic facies
nal rotation, a short bowel, microcolon and
microileum, and decreased or absent intestinal
muscle fibers. There is also vacuolization and
peristalsis. Patients often have associated central
degeneration of the smooth muscle cells of the
and peripheral neurologic disturbances. A mega-
bowel and bladder (234,240). Ultrastructurally,
esophagus resembling achalasia may develop.
the smooth muscle cells show disorganization
Other changes are listed in Table 17-10 (23 7).
of the myofilaments, degeneration of the cyto-
Gross Findings. Prenatal sonography at 18 to
plasmic central core, and abundant prolifera-
20 weeks shows the characteristic changes. After
tion of interstitial connective tissue. Excessive
the bilth, the most commqn gross abnormalities
intracytoplasmic smooth muscle cell glycogen
are megacystis, bilateral hydronephrosis, mega-
displaces contractile fibers to the cellular periph-
ureters, short bowel, microileum, microcolon,
ery, suggesting a fundamental defect of glycogen
and intestinal malrotation with malfixation
energy utilization (236). These changes affect
(235). Plain films show either dilated small
the smooth muscle of the intestine and blad-
bowel loops or a gasless abdomen with an evi-
der (240). Most cases fail to show any neural or
dent gastric bubble. A large urinary bladder is
ganglionic abnormalities (234).
present in all patients. Ganglioneuromas may
Special Studies. Ultr·ashuctural studies show
· be found in the uterus.
the vacuolar degeneration of smooth muscle cells,
Microscopic Findings. The major pathologic
abundant connective tissue between the muscle
abnormalities involve the intestinal muscula-
cells, and myofiber disorganization (238,240).
ture. The longitudinal muscle coat is thinned,
Treatment and Prognosis. Patient progno-
and abundant connective tissue lies between the
sis is generally poor. Most patients die in the

784
Motility Disorders

Table 17-11
CLASSIFICATION OF FAMILIAL VISCERAL MYOPATHIES

Type I Type 11 Type Ill Type IV


Genetic Autosomal dominant Autosomal recessive Autosomal recessive Autosomal recessive?
tran smission Consanguineous m arriage
Age at onset After first decade of life Teenagers Middle age Childhood
Percent <50o/o >75o/o lOOo/o Unknown
symptom atic
Symptoms Varies from dysphagia Severe abdominal pain, Intestinal Intestinal
and con stipation to int estinal pseudo- pseudoobstru ction pseudoobstruction
in testin al pseudo- obstruction
obstruction
Extragastro- Megacystis, uterine Ptosis and external Non e Unknown
intestin al in ertia, mydriasis ophthalmoplegia,
m anifestations mild degen eration of
striated muscle
Gross find in gs Esophageal dilation, Gastric dilation , slight Marked dilation of th e Gastropares is, tubular SI
m egaduodenum, redun- dilation of entire SI,' en tire Gl tract from the without diverticula,
dant colon, and mega- SI diverticulosis esophagus to the normal colon , n ormal
locystis rectum esophagus
Microscopic Degeneration and Resembles type I Resembles type I Severe vacuolar degener-
findin gs fibrosis of both muscle ation and atrophy of the
layers of digestive tract Sllongitudinal muscle,
marked hyp ertrophy of
the circular muscle
"SI= sm all intestine; GI = gastrointestin al.

first few days of life from intestinal pseudo- relationship with glycogenosis type IV (25 7) or
obstruction and sepsis (239); occasional patients polysaccharidosis (250,251).
live up to 4 years. Those patients who survive Clinical Features. Symptoms often appear in
usually need to be maintained on total paren- the second decade of life, usually after menarche,
teral nutrition. They may also require renal and persist with recurrences of varying intensity
transplantation for renal failure . Some cases and chronicity (244,245,253) . Other forms only
are diagnosed in utero and mothers may elect become evident in middle age. Many patients
to terminate these pregnancies. with sporadic visceral myopathy go unrecog-
Animal Models. Transgenic mice lacking nized clinically. Symptoms include dysphagia,
nicotinic acetylcholine receptors show some of heartburn, bloating, postprandial right upper
the phenotypic features of MMIHS. quadrant abdominal pain, distension, nausea,
vomiting, constipation, and alternating diarrhea
Hollow Visceral Myopathies
and constipation. Patients are usually short, under-
Definition. Hollow visceral myopathies are weight, and malnourished, and have postprandial
muscle disorders that affect all the hollow vis- abdominal pain, leading to decreased food intake.
cera, including the entire gastrointestinal tract, Sigmoid or cecal volvulus results from a redundant
urinary tract, and gallbladder. colon (246). Patients with bacterial overgrowth in
Demography. Hollow visceral myopathies a dilated duodenum develop malabsorption and
affect both children and adults, and are the most diarrhea. Antibiotics may improve the diarrhea
common causes of chronic primary intestinal (243) . Severe constipation may occur during preg-
pseudoobstruction (252-259). Seventy-five nancy. In some women, spontaneous labor does
percent of symptomatic patients are females. not occur and may need to be induced. Mydriasis
Etiology. The genetic mode of transmission affects 50 percent of patients but it does not affect
differs (Table 17-11) (246). Some cases are spo- vision. Dysplastic nevus syndrome may be associ-
radic, others are familial. Other cases have a ated with the disorder (249).

785
Gastrointestinal Diseases

Figure 17-21
PRIMARY MYOPATHY
A: Low-power view of the small intestine shows irregular staining in the outer layer of the muscularis propria.
B: Higher m agnification shows atrophic muscle fibers surrounded by fibrous tissue.
C: The muscle has a moth-eaten appearance. (Figures C and Dare from a different patient.)
D: Higher magnification shows the smudgy, atrophic smooth muscle cells.
..,.

Intestinal pseudoobstruction develops in most vary considerably in length. Megaduodenum is


symptomatic cases. It is characterized by gastric particularly common. Multiple diverticula are
and small intestinal dilatation and diffuse small usually seen (256) .
intestinal diverticulosis (253,254). Perforation of Microscopic Findings. The morphologic
small intestinal diverticula, with peritonitis and abnormalities in all of the familial myopathies
intraabdominal abscesses can occur (244,252). resemble one another. The myopathic changes
Extragastrointestinal manifestations include may be more pronounced in either the longitu-
megacystis and microscopic hematuria. dinal or circular layer of the muscularis propria
Gross Findings. Typically, patients develop (256,257) . Some patients have abnormalities
an atonic dilated esophagus, megaduodenum, in both layers (243,260). Changes may also be
redundant colon, and megacystis. Megaduo- present in smooth muscle cells in the muscularis
denum is usually detected during early teenage mucosae and in the blood vessels. The charac-
years. The stomach and distal small intestine teristic lesions involve muscle cell degeneration,
usually appear normal, although the jejunum muscle cell loss, and fibrosis of the muscularis
may become distended. Pathologists examine propria. Many smooth muscle fibers appear
the gastrointestinal tract either following sur- swollen, with clear cytoplasm (figs. 17-21,
gical resection or at autopsy. Typically what is 17 -22). The cytoplasm of smooth muscle cells
seen is segmental dilatation and thinning of commonly appears rarified or vacuolated and
the alimentary tract with gradual tapering into the cells may have indistinct boundaries. Many
a more normal diameter. Areas of dilatation muscle fibers appear densely eosinophilic and

786
Motility Disorders

Figure 17-22
SPORADIC VISCERAL MYOPATHY
A: This area of the bowel shows prominent vacuolization
but not much inflammation.
B: Prominent vacuolization of the smooth muscle fibers
is highlighted by the red trichrome stain. Some fibrosis is
present, as shown by the blue staining.
C: There is prominent cytoplasmic vacuolization of the
smooth muscle fibers.

others appear fragmented and thread-like. The


muscle cells may have a smudgy appearance,
with indistinct cell boundaries, fragmentation,
and cellular dropout. This creates spaces appar-
ently containing cellular debris.
The muscle cells of the muscularis propria and
muscularis mucosae may contain numerous ovoid,
translucent gray, cytoplasmic inclusions (248),
which may be easily visualized in routine H&E-
stained sections, but are enhanced by their strong
positivityforperiodic acid-Schiff (PAS) (248). Some
inclusions stain at the periphe1y with antibodies
to muscle-specific actin (fig. 17-23).
Ultrastructurally, the muscle cells appear very Figure 17-23
abnormal (fig. 17 -24). The muscularis propria VISCERAL MYOPATHY
may show marked nuclear enlargement and Alpha-actin stain shows the presence of prominent
hyperchromasia. Muscle hypertrophy may "peripheralization." The central portion of the muscle fibers
occur in early stages of familial visceral my- is relatively devoid of staining.
opathy. The hypertrophy is most marked in
the muscularis mucosae and may represent a chrome stains. Collagen is sometimes deposited
compensatory response to the degeneration of around degenerating muscle cells, producing a
the muscularis propria. honeycombed appearance. In the most advanced
In late-stage disease, a severe reduction in cell stages, the muscle layers are completely replaced
numbers is accompanied by extensive patchy by collagen and the intestinal wall is extremely
fibrosis, a change easily highlighted with tri- thinned (246,247,249). The myenteric plexus,

787
Gastrointestinal Diseases

Figure 17-24 Figure 17-25


ULTRASTRUCTURAL APPEARANCE OF THE PRIMARY MYOPATHY
MUSCLE CELLS IN PRIMARY MYOPATHY The architecture of the bowel wall is distinctly abnormal.
The individual cells appear abnormal, with the dense The mucosa is thrown up into long polypoid structures.
bodies and actin filaments arranged in a haphazard The "polyps" are extensions of the submucosa covered by
architectural pattern. normal-appearing mucosa. The muscle abnormalities are
not visible at this power.

Nonfamilial Primary Myopathies


neurons, nerve processes, and nerve terminals
all appear normal. No acute inflammatory cells, Definition. Nonfamilial myopathies are gastro-
lymphocytes, or plasma cells are seen in the intestinal myopathies that affect patients--who
muscle layer. Vasculitis is absent. do not have a family history of the disease.
Patients with a malabsorption syndrome due Etiology. Unknown.
to luminal stasis develop a chronic mucosal in- Clinical Features. Patients present at all ages.
flammatory cell infiltrate in the superficial lamina Infants in the first few months of life present
propria, which tends to be patchy (256). A myo- with pseudoobstruction and total gastrointesti-
pathy may be suspected when the bowel "' appears nal involvement. Adults experience recurrent or
polypoid due to mucosal prolapse (fig. 17-25). persistent bowel obstruction, dysphagia, nausea,
Differential Diagnosis. The clinical dif- vomiting, postprandial abdominal pain, and
ferential diagnosis includes other causes of bloating. Bowel habits are erratic and alternate
megacolon, including metabolic causes such between constipation and diarrhea. Less severe
as hypothyroidism and hypercalcemia, and sys- symptoms are vague and nonspecific. Some-
temic disorders such as amyloidosis, progressive times the diagnosis is not made until a compli-
systemic sclerosis, and diabetes. In late-stage cation, such as pseudoobstruction, volvulus,
disease, the muscle lesions mimic those seen in stercoral ulceration, or perforation, results. The
scleroderma or diabetes, but these two disorders perforation usually results from ischemia sec-
can be distinguished clinically. ondary to vascular obstruction during volvulus,
Treatment. Mild to moderate constipation is torsion, or intussusception.
managed by milk of magnesia or bulk-forming Gross Findings. The gross features resemble
laxatives. Malabsorption from bacterial over- those of other forms of chronic intestinal pseu-
growth in diverticula is treated with antibiotics. doobstruction.
?evere diverticulosis may need to be resected. Microscopic Findings. The histologic abnor-
Patients who present with postprandial pain, malities primarily involve the smooth muscle.
distension, and weight loss due to a megaduo- The changes are most severe in the muscularis
denum may benefit from an end-to-side duode- propria but similar abnormalities affect the
nojejunostomy. Sigmoid or cecal volvulus may muscularis mucosae and vascular smooth
require emergency resection. muscles. Changes include smooth muscle

788
Motility Disorders

Table 17-12
MITOCHONDRIAL MYOPATHIES

Kearns-Sayre syndrome
OGlMD syndrome (oculo-gastrointestinal muscular
dystrophy)
MNGIE syndrome (mitochondrial neurogastrointestinal
encephalomyopathy)
MELAS syndrome (mitochondrial myopathy, enceph-
alomyopathy, lactic acidosis, stroke-like episodes)
MEPOPL syndrome (mitochondrial encephalopathy,
sensorimotor polyneuropathy, ophthalmoplegia,
pseudoobstruction)
POLIP syndrome (polyneuropathy, ophthalmoplegia,
Figure 17-26
leukoencephalopathy, intestinal pseudoobstruction)
PRIMARY MYOPATHY Myoclonic epilepsy with ragged red fibers
Primary myopathies usually involve the smooth muscle
of the intestinal wall. There may be a variable diffuse, mixed
acute and chronic inflammatory cell infiltrate with inter-
stitial fibrosis and perinuclear cytoplasmic vacuolization.
Etiology. Mitochondrial myopathies are a
heterogeneous group of disorders resulting from
edema, fragmentation, and fiber degeneration structural, biochemical, or genetic mitochon-
involving both layers of the muscularis propria. drial derangements. Mitochondria contain DNA
The changes may be associated with a vari- known as mitochondrial DNA, or mtDNA (267),
able, diffuse, mixed acute and chronic inflam- which contains 37 genes (263). It differs from
matory cell infiltrate; marked nuclear enlarge- nuclear DNA in that it is maternally inherited,
ment and irregularity; interstitial fibrosis; and demonstrates DNA heteroplasmy and mitotic
perinuclear cytoplasmic vacuolization (fig. segregation, and is more susceptible to mutation
17-26). The inflammation is scattered through- than nuclear DNA (263,270,281). (Heteroplasmy
out both muscle layers. Fibrosis replaces the refers to the fact that cells and tissue harbor both
muscularis propria in advanced stages, causing wild type and mutant mtDNA.) Point mutations
thinning of the intestinal wall. Focal secondary in mitochondrial structural genes result in im-
smooth muscle hypertrophy leads to increased paired mitochondrial protein synthesis (262)
thickness of the muscle layers. The presence and disruption of oxidative phosphorylation
of the inflammatory infiltrate and the lack of and the respiratory chain (272,27 4). There is
a family history distinguish this disorder from no relationship between the site of mutation
the familial visceral myopathies (fig. 17 -26). and the clinical phenotype (263). Additionally,
The mucosa sometimes exhibits the polypoid the presence of heteroplasmy allows different
projections typical of the redundant mucosal tissues harboring the same mtDNA mutation to
folds that can be present in any motility disorder. be affected to different degrees, thus resulting
These folds consist of upward submucosal exten- in tremendous symptom variation.
sions covered by an essentially normal mucosa. Mitochondrial neurogastrointestinal enceph-
Treatment. The treatment is the same as for alomyopathy (MNGIE) is an autosomal recessive
the familial form of the disease. disease associated with multiple deletions of
mtDNA. Some patients have homozygous or
Mitochondrial Myopathies
compound heterozygous mutations in the gene
Definition. Mitochondrial myopathies are a encoding thymidine phosphorylase (TP) located
group of diseases characterized by the presence on chromosome 22q13.32-qter, which results in
of defective mitochondrial DNA and various a markedly increased concentration of thymine
neuromuscular abnormalities. The mitochon- in the blood (276). Thymidine phosphorylase
drial encephalomyopathy syndromes are shown is not a mitochondrial protein, but it appears
in Table 17-12 (265,266,275,278). to have a selective effect on the mitochondrial

789
Gastrointestinal Diseases

nucleotide pools required for maintaining the and refractile, and demonstrable in rectal suc-
integrity and abundance of mtDNA. tion biopsies (2 77). Microvesicular steatosis
Keams-Sayre syndrome is a sporadic condition affects the liver, skeletal and gastrointestinal
almost invariably associated with large-scale smooth muscle, and Schwann cells of the
rearrangements (deletions and more rarely du- peripheral nerves. Skeletal muscle fi.bers may
plications) in the mitochondrial genome (264). show a massive mitochondrial proliferation,
A deletion of 4,977 base pairs flanked by a 13- resulting in ragged red fibers histologically
bp direct repeat is the usual molecular defect (261,263,269,279).
in Kearns-Sayer syndrome (273). Other large Special Studies. Mitochondrial myopathies
deletions may be identified as well. can be diagnosed based on biochemical respira-
Clinical Features. Mitochondrial myopathies tory chain analysis or by mitochondrial DNA
should always be considered when there is an un- analysis. Ultrastructural examination of the
explained association of neuromuscular, gastro- eosinophilic inclusions discloses the megamito-
intestinal, and non-neuromuscular symptoms. chondria. There are increased numbers of
These disorders are usually maternally inherited. mitochondria within endothelial and vascular
Several mitochondrial myopathies have charac- smooth muscle cells (268,280). Mitochondrial
teristic gastrointestinal as well as multjsystem enzyme analysis of fresh frozen skeletal muscle
alterations: gastrointestinal dysmotility with reveals a respiratory chain defect.
pseudoobstruction, abdominal pain and persis- Differential Diagnosis. The differential diag-
tent vomiting, gastric and duodenal dilatation, nosis includes other gastrointestinal neuromus-
duodenal diverticulosis (277), ophthalmoparesis cular disorders. The clinical features distinguish
(271), ptosis, peripheral neuropathy, lactic acido- this group of lesions from other neuromuscular
sis, leukodystrophy as determined by magnetic disorders. Biochemical, ultrastructural, and ge-
resonance imaging of the brain, increas~d ce- netic studies document the mitochondrial my-
rebrospinal fluid protein, and muscle wasting; opathy. The consistent and early involvement of
esophageal motility is variably affected. the gastrointestinal tract distinguishes MNGIE
The gastrointestinal and hepatic manifesta- from other mitochondrial disorders with ragged
tions of mitochondrial myopathies present at red fi.bers, such as Kearns-Sayre syndrome.
any age: in the neonate with hepatomegaly or Treatment and Prognosis. Therapy is largely
hepatic failure, in infancy with failure to thrive supportive, including total parenteral nutrition
and diarrhea, and in childhood and early adult- and treatment of complications, including per-
hood with hepatic failure and chronic intestinal forated diverticula and bacterial overgrowth.
pseudoobstruction. Patients may appear chroni- The prognosis of patients with MNGIE is poor
cally malnourished and exhibit severe growth and prior to the availability of long-term par-
failure. There may be obvious muscle wasting enteral nutrition, the average patient died at
and patients may complain of severe burning around age 30 (269). General recommendations
pain and paresthesias of the feet (277). Some include avoidance of extremes in temperatures,
of the mitochondrial myopathies, particularly prompt treatment of fever and infections, and
those with oculogastrointestinal muscular dys- avoidance of overexercise. Drugs known to
trophy, which includes ptosis, diplopia, and interfere with mitochondrial function, such as
intestinal pseudoobstruction, are sometimes phenytoin, chloramphenicol, and tetracycline,
included under the familial visceral myopathies are to be avoided. Therapy with coenzyme ~
type II (chronic intestinal pseudoobstruction riboflavin, and other vitamins, cofactors, and
with ophthalmoplegia). oxygen scavengers maybe useful (266,272,274,
Microscopic Findings. The external layer 278). They are used with the aim of mitigating,
of the muscularis propria becomes atrophic, postponing, or preventing damage to the respi-
· and there are increased numbers of abnormal- ratory chain (263).
appearing mitochondria in ganglia and smooth
Autoimmune Enteric Myositis
muscle cells. Megamitochondria manifest as
cytoplasmic inclusions in submucosal ganglion Definition. Autoimmune enteric myositis
cells. They are round, brightly eosinophilic, combines intestinal pseudoobstruction with a

790
Motility Disorders

diffuse transmural lymphoid infiltrate in the and CD4-positive cells and occasional B cells.
absence of neural damage. Smooth muscle actin immunoreactivity is lost
Demography. Autoimmune enteric myositis in the inner circular muscle.
is very rare (283-287). As the disease progresses, myonecrosis occurs
Etiology. The disorder may follow a typical in the circular muscle layer. Lymphoid cells infil-
attack of acute gastroenteritis (287). One pa- trate the lamina propria, submucosa, muscularis
tient had a history of chronic active hepatitis. propria, and serosa of the ileum and colon.
This is of interest because immune responses to Although there are scattered lymphocytes in
hepatitis viruses may result in the production of the myenteric plexus, there are no neural abnor-
smooth muscle antibodies through molecular malities. Both layers of the muscularis propria
mimicry (282). Hepatitis B virus shows sequence become thickened secondary to muscular hyper-
homology with myosin and caldesmon and plasia, hypertrophy, and collagen deposition.
hepatitis C virus shares sequence homologies Following treatment with immunosuppressive
with vimentin and myosin, but to a different agents, the infiltrates decrease, although some
sequence of myosin than hepatitis B virus. Thus lymphocytic infiltrates may remain.
different viruses induce autoimmune reactivity Treatment and Prognosis. Treatment with
to different smooth muscle proteins and to dif- immunosuppressive drugs may alleviate the
ferent parts of the same protein. pseudoobstruction. Some patients, however,
Pathophysiology. Autoantibodies can be require parenteral nutrition (287).
detected in patients with the disorder. These
Diffuse Leiomyomatosis
include antineutrophil cytoplasmic antibody
(ANCA), antinuclear antibodies, anti-DNA anti- Definition. Diffuse (esophageal) leiomyoma-
bodies, and antismooth muscle antibodies, sup- tosis is benign pseudomuscular hypertrophy of
porting an autoimmune etiology. The myositis the esophageal wall, predominantly involving
results in a severe T-cell-mediated inflammatory its lower third (288,289).
disorder involving the intestinal muscularis Demography. Diffuse leiomyomatosis is a
propria. The autoimmune injury appears to be rare condition with approximately only 40 cases
clinically limited to the muscularis propria, par- reported to date.
ticularly the circular muscle layer. Other sites, Etiology. Sporadic and hereditary cases have
such as the bladder, are not involved, as is seen been described. Genetic analyses have demon-
in visceral myopathies (287). The lymphoid in- strated a relationship with a large deletion in
filtrate causes myonecrosis and smooth muscle the COL-A4, AS, A6locus, which includes genes
cell dropout. The lymphocytes also secrete cyto- encoding the a V and a VI chains of collagen
kines that inhibit smooth muscle contractility. IV. (288,289,293,294). Close segregation of
Clinical Features. Patients present in the diffuse leiomyomatosis and sex-linked Alport's
same way as other patients with chronic intes- syndrome has been documented in most males
tinal pseudoobstruction due to other causes. with the disease (288,289).
Gross Findings. The gross features of the Clinical Features. Initial symptoms usually
bowel resemble those of other causes of pseu- appear during childhood or adolescence. The
doobstruction. usual age of onset is 6 years in males and 10
Microscopic Findings. The ileum and colon years in females. Clinical manifestations include
have normal architecture and normal enteric dysphagia, postprandial vomiting, and subster-
ganglia. There is a modest increase in the cel- nal or epigastric pain. Patients with rectal in-
lularity of the lamina propria and a profound volvement may develop symptoms resembling
and florid lymphocytic infiltrate involving the Hirschsprung's disease, with chronic constipa-
muscularis propria. This infiltrate is especially tion and rectal dilatation as well as the lack of
dense around blood vessels and the circular a rectal anal inhibitory reflex during repeated
muscle. The infiltration of the muscularis pro- anorectal manometries.
pria can be intense enough to obscure the cir- Gross Findings. Leiomyomatosis involves the
cular muscle coat. The infiltrate is largely CD3- esophagus as well as extraesophageal organs such
and COS-positive with some CD3-negative the female genital tract and the tracheobronchial

791
Gastrointestinal Diseases

tract (290,295,297). It can also involve the peri- Demography. Scleroderma has a worldwide
urethral and perirectal areas, and the clitoris distribution. It occurs four to six times more
and vulva. If rectal involvement is present, the frequently in women than in men, usually
walls of the rectum and anal canal are markedly affecting women in the 3rd to 5th decades.
thickened and the rectum markedly dilated Scleroderma is the most common systemic
(29 1,292,297). The involved tissue contains a disease causing generalized gastrointestinal
thickened muscular wall. Examination of the dysmotility. Ethnic origin plays a role in disease
esophagus shows dilatation of the proximal lu- susceptibility. The disease is significantly more
men and variable degrees of segmental stenosis likely in black than white women.
at the lower end (296,297). These features may Etiology. Scleroderma is an autoimmune
lead to a mistaken diagnosis of achalasia, espe- connective tissue disorder that is associated
cially since esophageal manometry may show with an increased frequency of class I and
similar abnormalities (296a). class II MHC alleles. Autoantibody associations
Microscopic Findings. Biopsies of the thick- divide patients into two groups: those with
ened muscular layer usually show diffuse benign anticentromere antibodies (ACA) have limited
muscular hypertrophy that infiltrates the en- scleroderma, and those with antitopoisomer-
teric plexuses. There is extensive replacement of ase-1 (SCL-70) antibodies have the diffuse form
the normal fiber pattern by irregular plexiform of the disease. In some patients, antibodies
fibers in the thickened esophageal muscular specifically inhibiting M3-muscarinic receptor-
layer. The process may affect either one or both mediated enteric cholinergic neurotransmis-
of the circular and longitudinal muscl~ layers, sion may provide a pathogenetic mechanism
but the muscularis mucosae is minimally in- for the gastrointestinal dysfunction seen with
volved. Usually only minimal atypia without this disease.
mitoses is seen (288,289) . The muscular hyper- Pathophysiology. The pathogenesis of
trophy predominates in the lower third of the scleroderma involves vascular, immunologic,
esophagus, but it may involve the entire length and fibrotic processes. Progressive fibrosis of
of the organ as well as the adjacent proximal various internal organs, including the gastro-
stomach. The nerve strands are thin and only intestinal tract, is the pathologic hallmark of
rare ganglion cells are seen. The esophageal scleroderma, and the extent and rate of progres-
mucosa is typically normal, but there may be sion of the fibrosing process are major factors
associated esophagitis or Barrett esophagus, or in determining the course and prognosis in
even complications of Banett esophagus. patients with this disorder (fig. 17-27). This
Treatment and Prognosis. Because of the se- fibrosing process results in disruption of the
vere pain, patients with diffuse leiomyomatosis normal architecture of the affected organs, ulti-
undergo partial or subtotal esophagectomy with mately leading to their dysfunction and failure.
proximal gastrectomy (290, 291,295). Fibrosis of the walls of medium-sized and small
arterioles also plays a critical role in causing
MOTILITY DISORDERS ACCOMPANYING many manifestations of the disease.
CONNECTIVE TISS,UE DISEASES Mast cells and eosinophils may also play
a critical role in these fibrosing processes.
Scleroderma
Heparin-binding growth factors may provide
Definition. Scleroderma is a generalized the link between activation of both endothelial
autoimmune connective tissue disorder char- cells and fibroblasts. Endothelial cells are tar-
acterized by fibrosis and degenerative changes gets of the immune activity, but they may also
of the skin and multiple internal organs, in- act as immune co-stimulators. The cytokines
. eluding the gastrointestinal tract. By definition, produced by many cells are bound, protected,
esophageal scleroderma is part of the CREST and enhanced by heparin, which is produced
syndrome (calcinosis cutis, Raynaud's phenom- by activated mast cells. These factors may cause
enon, esophageal sclerosis, sclerodactyly, and endothelial cell proliferation and excess col-
telangiectasia). Scleroderma is also known as lagen production by fibroblasts. The microvas-
progressive systemic sclerosis. cular system is one of the first targets involved

792
Motility Disorders

t Endothelin I
t NO

Figure 17-27
DIAGRAM OF THE
PATHOGENESIS OF
THE CHANGES PRESENT
IN SCLERODERMA

Vasoconstriction Neural atrophy


Ischemia

(312,313), resulting in damage to the capillaries (300,313,317,319). Gastrointestinal symptoms


and the induction of perivascular infiltrates. include heartburn, nausea, vomiting, dyspha-
The excessive tissue fibrosis is due to expan- gia, diarrhea, constipation, and fecal inconti-
sion of fibrogenic clones of tissue fibroblasts. nence. There is a particularly high incidence
Persistent activation of genes encoding multiple of esophageal involvement in patients with
extracellular matrix proteins in scleroderma fi- Raynaud's phenomenon.
broblasts distinguishes the controlled repair that Smooth muscle atrophy leads to loss of
occurs during normal wound healing from the esophageal peristalsis, dysphagia, and a defec-
uncontrolled connective tissue deposition that tive lower esophageal sphincter. These changes
results in the fibrosis characteristic of sclero- predispose the patient to develop heartburn,
derma (306). Subpopulations of fibroblasts also nocturnal cough, recurrent pulmonary infec-
demonstrate disturbed regulation of collagen tions, and asthma secondary to severe reflux
turnover by transforming growth factor-beta esophagitis. Patients with scleroderma also
(TGF-~) and collagen receptors (305). develop dysphagia from lower esophageal
Vasoconstriction secondary to increased rings. The rings develop at the esophagogastric
levels of the vasoconstrictor endothelin 1 junction, generally affecting patients over age
and decreased NO results in ischemia (298). 30 (309). All of the complications of gastro-
Neural and muscular dysfunction follow esophageal reflux disease discussed in chapter
(301,315,319). Neural dysfunction due to 3 affect scleroderma patients.
neural atrophy and collagen deposition occurs Gastric dysmotility and delayed gastric emp-
before smooth muscle con tractility is impaired tying affect more than 50 percent of patients
(316). Complete denervation releases the in- (319) . Gastroparesis and antral distension cause
testinal smooth muscle from its customary dyspepsia. Gastric involvement may cause
inhibitory factors, resulting in loss of normal bleeding secondary to the development of
peristalsis. Motility disturbances develop prior vascular abnormalities, including gastric antral
to histologic evidence of smooth muscle atro- vascular ectasia (31 0).
phy. In the next stage, smooth muscle atrophy Patients may also have severe intestinal mo-
and fibrosis are superimposed on the preexist- tility disturbances and pseudoobstruction. Forty
ing neural damage. percent of patients with generalized scleroderma
Clinical Features. Visceral disease often develop intestinal symptoms in the 4th to 6th
dominates the clinical picture, sometimes pre- decades of life (317). Small intestinal and co-
ceding the development of skin changes. The lonic involvement may lead to life-threatening
esophagus, small intestine, colon, and stomach complications. Patients with small intestinal in-
are affected in decreasing order of frequency volvement have anorexia, early satiety, halitosis,

793
Gastrointestinal Diseases

fixed and symmetrical, rneasuring 2 to 4 mm in


width. Other radiographic studies show small
or large intestinal diverticulosis (303), absent
peristalsis, or dilatation of any portion of the
gastrointestinal tract. The small intestines may
acquire a typical "hide-bound" appearance of
closely packed valvulae conniventes.
Gross Findings. The gross features vary,
depending on disease stage and the type of
specimen examined. Anatomic studies show
esophageal erosions or gastroesophageal reflux
disease in 53 percent, strictures in 29 percent,
and Barrett esophagus in 16 percent of patients.
The esophagus appears variably dilated, often
with concomitant distal esophagitis. Some
Figure 17-28 patients develop gastric antral vascular ectasia
SCLERODERMA or gastric thickening. Megaduodenum, small
The small bowel appears dilated and the valvulae bowel dilatation, or diverticula are present in
conniventes are especially prominent. (Courtesy of Dr. Joel 42 percent and pneumatosis intestinalis in 8
Lichtenstein, Seattle, WA.) percent. Eight percent of patients also have
colonic dilatation or wide mouthed diverticula.
The diseased intestines appear thickened, flac-
nausea, vomiting, intestinal pseudoobstruction cid, atonic, and focally constricted, with loss of
and distension, abdominal pain, weight loss, the colonic haustral pattern.
impaired motility, malabsorption, steatorrhea, Microscopic Findings. The early· changes
diarrhea, constipation, and intestinal perfo- of well-developed scleroderma are seldom seen
ration (299,302,304,307). They also develop because tissue is not removed until complica-
multiple diverticula, which may contribute to tions develop. Prominent but patchy smooth
the malabsorption (312). muscle atrophy affects the muscularis propria,
Colonic involvement affects 10 to 50 percent particularly the inner circular layer (fig. 17 -29).
of patients (300) . Patients with large intestinal These changes are superimposed on neural
disease develop colonic or rectal diverticula, damage. The muscle fibers appear fragmented
pseudoobstruction, constipation, diarrhea, and fibrotic, often disappearing completely
fecal incontinence, rectal prolapse, spontane- (figs. 17-29, 17-30). The submucosa and mus-
ous perforation, and infarction. Anorectal in- cularis propria become progressively atrophic
volvement is almost as common as esophageal and are replaced by fibrous tissue (315,318).
involvement. Disordered anorectal function Ceroid pigment granules may be deposited in
occurs early in scleroderma, leading to fecal degenerating muscle cells. Blood vessels may be
incontinence or rectal.prolapse (308,317) . markedly thickened with perivascular collagen
The extragastrointestinal features of sclero- deposition (fig. 17-31). Serosal fibrosis (where
derma are associated with prominent, and often serosa is present) and submucosal fibrosis de-
severe, microvascular alterations, frequently velop throughout the gut. Degranulating mast
involving the hands and fingers. cells, macrophages, and activated lymphocytes
Radiologic Findings. More than 50 percent infiltrate the perivascular tissue.
of patients have radiologic evidence of dysmo- In uncomplicated cases, the mucosa appears
tility (fig. 17 -28) (300). Ultrasonographic hyper- normal. At most, there may be edema and a mild
echoic regions corresponding to fibrosis of the chronic inflammatory infiltrate in the lamina
submucosa or muscularis propria predict esoph- propria (307). Mucosal erosions and ulcerations
ageal functional abnormalities (311). There may may also develop, especially in patients with
also be associated esophagitis, mucosal rings, reflux esophagitis (fig. 17-32). Gastric altera-
and stricture formation. The mucosal rings are tions include gastric mucosal atrophy. Duodenal

794
Motility Disorders

Figure 17-29
SCLERODERMA
A: Low magnification of the esophageal wall shows all
of the layers. There is prominent submucosal fibrosis and
atrophy of the muscularis propria.
B: Higher magnification shows the patchy myofiber
dropout. It involves both the inner and outer muscular
layers.
C: There is almost complete loss of the muscle fibers,
with only occasional residual longitudinal muscle fibers
evident.

~ ...-:- . : ,,; .,.__ .


~ If" . I
. . .. ~
• '• o .._ :'

.., ,·
r
.f

..,..
,-.

Figure 17-30 ..
SCLERODERMA AFFECTING THE COLON
A: Low magnification of submucosal fibrosis. There is
a serosal inflammatory infiltrate because diverticula were
present, one of which ruptured.
B: Area of myofiber dropout.
C: Another area with muscle fiber degeneration,
inflammation, and early fibrosis.

795
Gastrointestinal Diseases

Figure 17-31
SCLERODERMA
A submucosal vessel is thickened and surrounded by a
mild inflammatory infiltrate.

Brunner glands may develop periglandular


fibrosis (314). There may be a nonspecific in-
crease in the mononuclear cells in the lamina
propria of the intestine (fig. 17 -33). This is often
a manifestation of the decreased motility_and a
change in the bacterial flora. The fibrosis may
Figure 17-32
mimic amyloidosis.
Patients with scleroderma may also develop SCLERODERMA
eosinophilic gastroenteritis. The eosinophilic Many patients with scleroderma develop severe reflux
infiltrate often localizes in the basal mucosa and esophagitis, as is seen in this biopsy.
Top: Strips of esophageal mucosa with inflammatory
the muscularis propria, resulting in myonecrosis exudates indicate the presence of erosions.
(fig. 17 -34). "' Bottom: Higher magnification shows the changes often
Special Studies. Specific serologic tests help present with reflux, including areas of fibtinopmulent exudate.
identify the exact collagen vascular disease that
is present. Antinuclear antibody (ANA) profiles
are particularly helpful. ANAs are usually positive primary myopathy and scleroderma based solely
in scleroderma patients. Nuclear ribonucleopro- on histologic examination. The clinical features,
tein (RNP) and centromere antibodies are more however, serve to separate the two disorders, as
specific, but not as sensitive, markers. Patients does serologic testing.
with CREST have ANA restricted to the centro- Treatment and Prognosis. Since there is no
meric DNA. ANA with anti-SS-A/Ro specificity effective treatment for scleroderma, therapy is
is associated with vasculitis and nephritis and directed toward supportive symptomatic relief.
ANA with anti-SS-dLA and anti-nRNP specificity Antireflux measures, including lifestyle changes
is associated with milder clinical disease (304) . and use of antacids, H2-receptor antagonists,
Differential Diagnosis. Early scleroderma and prokinetic agents, help alleviate the symp-
can usually be differentiated from a visceral toms of reflux esophagitis and are important in
myopathy by the presence of fibrosis of the preventing its complications, including peptic
intestinal smooth muscle and the absence of a strictures and Barrett esophagus.
vacuolated honeycombed appearance. Remain- Early muscle dysfunction is partially revers-
ing muscle cells appear normal or atrophic. The ible with prokinetic drugs. Prokinetic drugs
changes in scleroderma are patchier than those also decrease the acidity of the refluxate, in-
found in primary myopathies. In severe disease, crease lower esophageal sphincter pressure, and
it may be impossible to distinguish between a increase gastric emptying. Prokinetic agents

796
Motility Disorders

Figure 17-33 /

SCLERODERMA
Small intestinal biopsies sometimes show changes mimicking those found in amyloidosis due to the presence of marked
submucosal fibrosis. These biopsies are not deep enough to indicate the muscular changes.
A: Low magnification view of such a biopsy.
B: Higher magnification shows the presence of acellular deposits involving the mucosa and submucosa. The deposits are
negative with Congo red stains and blue with trichrome stains. The tissue is not as eosinophilic as in amyloidosis.
C: Vascular changes are sometimes seen in such biopsies.
D: There is a modest increase in the number of mononuclear cells in the lamina propria of the small intestine. Occasionally,
regenerative features are seen in such tissues.

(metoclopramide, domperidone, cisapride, oc- synthesis and deposition as well as mononuclear


treotide, and erythromycin) are also effective cell infiltrates.
in treating pseudoobstruction.
Diabetes Mellitus
Patients with end-stage disease characterized
by severe muscle fibrosis are not amenable to Definition. Diabetic neuropathies encompass a
pharmacologic functional restoration. The main group of clinical syndromes affecting both somatic
therapeutic options for bacterial overgrowth are and autonomic peripheral nerves (321). The term
antibiotics and nutritional supplementation. diabetic gastroenteropathy describes a generalized
Placement of enterostomy tubes for decompres- gastrointestinal motility defect in the setting of
sion and nutritional support may prove neces- diabetes. Gastroparesis is defined as delayed gas-
sary in selected cases (317). Approximately 19 tric emptying of either solids or liquids occurring
percent of patients require total parenteral or in the absence of mechanical obstruction (331).
enteral nutrition. Diabetic gastropathy is a term that encompasses a
Animal Models. Several animal models help number of neuromuscular dysfunctions of the
elucidate the pathogenesis of scleroderma. stomach, including abnormalities of gastric con-
A tight skin-2 mouse seems to be a promis- tractility and emptying, tone, and myoelectric
ing model, since it shows enhanced collagen activity in patients with diabetes.

797
Gastrointestinal Diseases

Figure 17-34
EOSINOPHILIA IN SCLERODERMA
A: The muscle in the area of the ileocecal valve appears
fibrotic and is infiltrated by numerous eosinophils.
B: Similar changes are seen in the lower mucosa. The
degree of eosinophilia in the muscle fibers can be quite
striking.
C: Area of myonecrosis of the muscularis propria
secondary to the eosinophilic infiltration.

Demography. Diabetes is the most common denum. The delay results from food retention
cause of chronic gastroparesis (322). It ajfects as in the proximal stomach due to decreased mo-
many as 20 to 50 percent of diabetics, especially tor activity and resulting in late antral filling.
those with long-standing, poorly controlled Hyperglycemia also delays gastric emptying,
disease. induces antral hypermotility, promotes pyloric
Pathophysiology. Gastrointestinal diabetes- contractions and gastric electrical dysrhythmias,
related alterations occur via six mechanisms: 1) and modulates esophageal and small intestinal
a visceral neuropathy involving the parasympa- motility (331). Diabetic gastroparesis may also
thetic or sympathetic nervous system; 2) a mi- contribute to inadequate glycemic control and
croangiopathy; 3) abnormal plasma glucose and impaired absorption of orally administered anti-
electrolyte levels; 4) increas~d susceptibility to diabetic drugs. The predisposition to accelerated
infections and bacterial overgrowth; 5) altered atherosclerosis is a risk factor for developing
production of insulin, motilin, pancreatic poly- mesenteric ischemia and intestinal infarction.
peptide, somatostatin, gastrin, and glucagon; Clinical Features. The gastrointestinal ef-
and 6) the effects of localized ischemia (330). fects of diabetes are not commonly appreciated.
The most important underlying condition ap- Many diabetics, especially patients with type
pears to be the visceral autonomic neuropathy, I diabetes, develop gastrointestinal problems,
which causes decreased motility, hypotonia, including gastroparesis, diarrhea, constipation,
and possibly diminished secretions. Damage to delayed esophageal and intestinal transit, mega-
enteric neurons or the interstitial cells of Cajal colon, chronic nausea, weight loss, and fecal
or subtle dysfunctions in these cells may also be incontinence (322,324,328,329,333). Thirty to
responsible for the diabetic gastropathy (326). 50 percent of randomly selected patients with
Diabetic gastroparesis is characterized by long-standing type I or type II diabetes exhibit
difficulty in emptying solid foods into the duo- delayed gastric emptying (322,323,325,332). An

798
Motility Disorders

lmed. 30 min. 45 min.

60 min. 90 min.

Figure 17-35
DIABETIC GASTROPARESIS
Left: The classic features of diabetic gastroparesis are seen. The stomach is enlarged and filled with a large amount of
retained food.
Right: Technetium study shows retention of the gastric contents over time.

association exists between the onset of gastro- terns. The radiologic criteria for gastroparesis
paresis and other evidence of autonomic failure, are: 1) diminished gastric peristalsis with reten-
including peripheral autonomic neuropathy, tion of barium contrast media at 30 minutes,
retinopathy, and nephropathy. Most com- without evidence of mechanical obstruction; 2)
monly, gastroparesis manifests as postprandial significant solid residue after an overnight fast;
fullness, vague epigastric pain, nausea, vomit- 3) elongated sausage-like configuration of the
ing, heartburn, bloating, early satiety, excessive stomach, with only mild dilatation and with-
eructation, and anorexia. Symptom onset is usu- out an air level; and 4) a dilated and/or atonic
ally insidious. Bezoar formation and pulmonary duodenal bulb.
aspiration syndromes may be complications. Microscopic Findings. Glycosylation ab-
Diabetic ketoacidosis and intragastric bezoars normalities result in abnormal collagen de-
may cause severe pain. posits, with resultant diffuse basement mem-
Constipation affects approximately 60 per- brane thickening affecting vessels and nerves
cent of diabetics, alternating with diarrhea throughout the gastrointestinal tract. Capillary
and mimicking irritable bowel syndrome. Ad- basement membranes become widened by
ditionally, small intestinal stasis and bacterial a homogeneous, multilayered, eosinophilic
overgrowth result in bile salt deconjugation, substance. This thickening is most evident in
defective micelle formation, fat malabsorption, the loose submucosal tissues. The mesenteric
steatorrhea, and diarrhea. Incontinence affects vessels develop accelerated atherosclerosis. The
up to 24 percent of diabetics. The diarrhea and underlying vasculopathy causes variable degrees
fecal incontinence mainly result from anorectal of ischemia. Similar basement membrane wid-
sphincter dysfunction, abnormal rectal sensa- ening affects small nerve twigs (fig. 17-36). In
tion, rapid transit from uncoordinated small end-stage disease, scattered necrobiotic smooth
bowel motor activity, or absent myoelectric muscle cells appear as homogeneous, round
responses (331). Symptoms most commonly eosinophilic bodies scattered among areas of
affect patients with poorly controlled disease. smooth muscle atrophy and fibrosis (327).
Gross and Radiologic Findings. The stom- Special Techniques. A practical approach to
ach often appears massively dilated and the diagnosing diabetic gastropathies in patients
duodenal bulb may be dilated and atonic (fig. with dyspepsia is to start with noninvasive
17-35) (320). Other X-ray findings include pro- gastric motility tests and to use invasive tests if
longed gastrointestinal transit time, localized further information is desired. The solid phase
dilatation, and abnormal intestinal fold pat- gastric emptying test and electrogastrography

799
Gastrointestinal Diseases

.
'..
.. " •
I
1 "'\
~

Figure 17-36
DIABETIC COLOPATHY
A: The muscularis mucosae is markedly thickened.
B: Higher magnification shows fibrosis bet~en the muscle fibers.
C: Some of the changes center around the vessels.
D: The vessels in patients with diabetes often show other changes, including fibrinoid necrosis, as illustrated here.

reveal abnormalities in overall emptying and early satiety and fullness as well as improvement
gastric myoelectric abnormalities, respectively in glycemic controL Normoglycemic control of
(326) . If further insights into gastric duodenal the diabetes and prokinetic therapy, especially
function are needed, then gastric ultrasound, with cisapride, dramatically improves both the
antroduodenal manometry, and Barostat studies clinical and functional activity of patients with
can be obtained (326) . · diabetic gastroparesis. Other useful prokinetic
Differential Diagnosis. Gastroparesis com- drugs include erythromycin and clonidine. In
plicates other neuromuscular conditions besides the most severe cases of diabetic gastroparesis, a
diabetes. Acute gastroparesis may occur as part gastrostomy may be indicated to vent the stom-
of acute gastroenteritis or secondary to drug ach and to prevent recurrent vomiting. (326).
administration. Metabolic disorders, includ- Rarely, invasive methods to provide nutritional
ing uremia, hypercalcemia, and hypokalemia, support (jejunostomy) may be necessary if se-
· may also retard gastric emptying. The intestinal vere weight loss has occurred. Gastric emptying
features of diabetes resemble other motility procedures are used (e.g., gastro-jejunostomy),
disorders, especially scleroderma. but are seldom successful long term. Newer
Treatment and Prognosis. Treatment goals treatments try to augment NO signaling. There
include reduction in upper gastrointestinal may also be a role for gastric pacing procedures.
symptoms of nausea, vomiting, bloating, and There is no evidence that either gastroparesis or

800
Motility Disorders

Table 17-13
GASTROINTESTINAL AMYLOIDOSIS

Protein Associated Disease Forms of Amyloidosis


Immunoglobulin Multiple myelo- Primary amyloidosis: systemic disease associated with plasma cell
light chain (AL) ma and other dyscrasia (deposits in heart, kidney, gut, liver, and spleen), especially
monoclonal B-cell around blood vessels and sometimes between muscle fibers; massive
and plasma cell submucosal gastrointestinal involvement is common
proliferations
Serum amyloid-asso- Associated with Secondary amyloidosis: systemic chronic disease; amyloid deposits in blood
ciated protein (AA) chronic disease vessels and in the mucosa; lamina propria deposits cause mucosal nodularity
Transthyretin, AA Hereditary amy- Hereditary familial amyloidosis: small intestine commonly involved;
prealbumin (AF) loidosis perireticular deposition throughout muscle fibers and in neural plexuses;
single organ amyloid deposition
~2-microglobulin Chronic renal disease

delayed esophageal transit has any negative im- Intestinal pseudoobstruction develops as the
pact on the prognosis of patients with diabetes. result of either a myopathy or a neuropathy.
Intestinal amyloid neuropathy leads to diarrhea,
Amyloidosis
steatorrhea, or constipation (334,335).
Definition. Amyloidosis consists of acellular Gastric amyloidosis presents as hematemesis
eosinophilic proteinaceous tissue deposits. or prolonged nausea and vomiting associated
These proteins have a characteristic ~-pleated with weight loss, gastroparesis, gastric amy-
structure, ultrastructural appearance, and tinc- loid tumors, or gastric outlet obstruction. The
torial qualities. chemical type of amyloid often determines the
Demography. The prevalence of amyloid dominant clinical features (Table 17-13) (337).
deposits increases with age. In one autopsied Gross Findings. Grossly, the bowel may ap-
patient population, amyloid was found in 36 pear normal. Alternatively, intramural amyloid
percent (336). deposits cause mural rigidity. Bowels with A~2M
Etiology. All known types of amyloid affect amyloid deposits exhibit a distinctive rippled
the gastrointestinal tract, including amyloid A serosal appearance. Amyloid tumors produce
(AA), amyloid of lambda or kappa light chain firm, bulky, intramural masses. Endoscopic
origin, transthyretin amyloid (ATTR), and ~2- ultrasound may demonstrate thickening of the
microglobulin (A~2M) (Table 17-13). gastrointestinal wall with loss of the normal
Pathophysiology. Two mechanisms explain layered structure of the mucosa and submucosa.
the intestinal motor dysfunction present in Microscopic Findings. Eosinophilic, homo-
patients with amyloidosis: 1) amyloid deposi- geneous, hyaline amyloid is deposited around
tion in gastrointestinal smooth muscle, and the muscle fi.bers and blood vessels in the lamina
2) amyloid-induced damage to intrinsic or propria and the myenteric plexus (fig. 17-3 7).
extrinsic nerves. The primary site of deposition varies with
Clinical Features. Patients with primary and the type of amyloid present. Amyloid of light
secondary amyloidosis.have gastrointestinal in- chains and A~2M are deposited throughout
volvement anywhere from the esophagus to the the gastrointestinal tract, especially the small
anus (334). In the esophagus, amyloid deposits intestine. A~2M preferentially deposits in the
in both striated and smooth muscles, lead- muscularis propria. The outline of the muscle
ing to a weakening of both the proximal and layers is preserved but most muscle fi.bers are
distal esophageal sphincters (334). Esophageal encircled by the amyloid deposits. They then
involvement mimics achalasia. Patients with become atrophic and disappear. Because the
esophageal amyloidosis also develop esophageal changes affect the deeper layers of the intestinal
aperistalsis due to muscular atrophy and neural wall, they are hard to demonstrate on biopsy.
abnormalities. The esophagus is less involved than the rest of

801
Gastrointestinal Diseases

Figure 17-37
AMYLOIDOSIS
Left: Dense amyloid deposits involve the lower mucosa and muscularis mucosae as well as other layers of the gastric wall.
Right: Higher magnification of the dense eosinophilic acellular deposits within the gastrointestinal wall.

the gastrointestinal tract in this form of amyloi- patients with plasma cell dyscrasias. Other impor-
dosis. AA protein preferentially deposits in the tant therapeutic interventions include intensive
myenteric plexus, without appreciable ·muscle nutritional support for malnourished patients,
infiltration. Patients with familial amyloidosis motility-enhancing drugs, octreotide therapy for
show a severe reduction in the number of gan- motility disorders, and correction of clotting dis-
glion cells or degeneration of ganglion cells orders in bleeding patients. The prognosis depends
without extensive deposition of amyloid in the on the amyloid type, the nature of the underly-
enteric plexus. ing chronic inflammatory disorder (in secondary
Special Techniques. Amyloidosis is usually forms), and the status of other involved major
diagnosed on H&E-stained sections. lts pres- organs, such as the hemt or kidneys.
ence is confirmed with a Congo red ~ain and
the presence of a characteristic apple-green DRUG-INDUCED MOTILITY DISORDERS
birefringence when examined under polarized A number of drugs are well known to af-
light. It can also be confirmed ultrastructurally, fect gastrointestinal motility. Constipation
in which case the amyloid fibers exhibit their secondary to drug ingestion occurs relatively
characteristic periodicity. The different forms of frequently and must always be taken into ac-
amyloid are distinguished using immunostains count in evaluating patients for this complaint.
for the specific protein. Drug-induced constipation is also a well-known
Treatment and Prognosis. Therapy that phenomenon accompanying the use of an-
reduces the supply of amyloid fiber precursor tidepressants. Sometimes these drugs lead to
proteins improves patient prognosis; colchicine persistent constipation with frequent fecaloma
and chemotherapeutic modalities are used to treat formation . This is discussed in chapter 8.

802
Motility Disorders

REFERENCES

General References Development of the Enteric Nervous System


Anuras S, Shaw A, Christensen ]. The familial syn- 8. Aldridge RT, Campbell PE. Ganglion cell distri-
dromes of intestinal pseudoobstruction. Am] Hum bution in the normal rectum and anal canal. A
Genet 1981;33:584-91. basis for the diagnosis of Hirschsprung's disease
Fenoglio-Preiser CM, Noffsinger AE, Stemmermann by anorectal biopsy.] Pediatr Surg 1968;3:475-
GN, Lantz PE, Listrom MB, Rilke FO. Motility 90.
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Mitochondrial neurogastrointestinal enceph- rectal involvement mimicking Hirschsprung
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303. Govoni M, Muccinelli M, Panicali P, et al. 321. Greene DA, Sima AA, Albers JW, Pfeifer M.
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tients with diabetic neuropathy. Gastroenterol- 335 . Menke D, Kyle R, Fleming R, et al. Symp-
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329. Murray L, Lombard M, Aske ], et al. Esopha- primary systemic amyloidosis. Mayo Clin Proc
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1987;82:840-3. consecutive autopsical patients and 98 retro-
330. Nilsson PH. Diabetic gastroparesis: a review. J spective bioptic specimens. Pathol Res Pract
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814
Index*

Microsporidiwn infection, 566, 568, 569


A
Mycobacterium avium complex, 550, 551, 552
Abetalipoproteinemia, 607, 609 Mycobacterium tuberculosis infection, 553
Abdominal wall defects, 41 Pneumocystis carinii infection, 562
Absent enteric nervous system, 772 Strongyloides infection, 5 71
Acanthosis, 95
Toxoplasma infection, 569
Acanthosis nigricans, esophagus, 116 Acquired intestinal aganglionosis, 777
Achalasia, 777 Acquired megacolon-megarectum, 777
Allgrove's syndrome, see Allgrove's syndrome Actinomyces infections, 430, 431
Clinical features, 778 Appendicitis, 629
Definition, 777 Actinomycosis, see Actinomyces infections
Demography, 777 Active gastritis, 127
Differential diagnosis, 780 Acute atrophic gastritis, 376
Etiology, 777, 778 Acute gastritis, 127, 127-131
Gross findings, 779, 779
Acute hemorrhagic gastritis, 127
Internal anal sphincter, 772 Acute intestinal ischemia, see Acute mesenteric
Microscopic findings, 779, 780
ischemia
Pathophysiology, 778 Acute mesenteric ischemia, 261
Radiologic findings, 778, 779 Clinical features, 263
Special techniques for diagnosis, 780 Definition, 261
Treatment and prognosis, 780 Demography, 261
Acid secretion and peptic ulcers, 177 Etiology/pathophysiology, 261, 262
Acrodermatitis enteropathica, 613 Radiologic findings, 263
Acquired hypogammaglobulinemia, 605 Treatment and prognosis, 264
Acquired immunodeficiency syndrome (AIDS),
Acute radiation gastritis, 376
539, 539, see also Human immuno-
Acute radiation syndrome, 368, 368
deficiency virus infection Acute segmental obstructive enteritis, 273
Adenovirus infection, 560 Acute ulcer, 376
AIDS-related motility disorder, 543
Addison's disease and malabsorption, 603
Anorectal disease, 549 Adenocarcinoma, small bowel, 602
Arteriopathy, 547 Adenovirus infections, 452, 453
Candida infection, 561, 562 In immunocompromised patients, 560
Clyptosporidiwn infection, 563, 563, 564 Adult-onset hypogammaglobulinemia, 605
Cytomegalovirus infection, 555, 556-559 Adventitia, normal, 7, 7
Enteropathy, 543, 546, 547 Aeromonas infections, 419
Esophagitis, 548 Alcohol duodenitis, 304
Gastropathy, 543, 549
Alcohol gastritis, 304
Graft versus host disease, 571, 572-574 Alcohol-induced gastrointestinal injury, 304
Herpesvirus infection, 559, 560
Clinical features, 305
Histoplasma infection, 562 Gross findings, 306, 306
Isospora belli infection, 565 Microscopic findings, 306, 306, 307
Kaposi's sarcoma, 549
Pathophysiology, 304, 305
Malabsorption syndromes, 602
Alkaline reflux, esophagus, 91

*Numbers in boldface indicate table and figure pages.

815
Gastrointestinal Diseases

Alkaline reflux gastropathy, 139 Appendiceal congenital anomalies, 621


Allergic esophagitis, 102 Appendice·al diverticula, 198, 621, 622
Allergic proctocolitis, 644, 645 Appendiceal drug effects, 634
Allgrove's syndrome, 782 Appendiceal foreign bodies, 634
Amebiasis, 466 Appendiceal intussusception, 622, 623
Ameboma, 467 Appendiceal septa, 623
American trypanosomiasis, 476 Appendicitis, 624
Amoeba infections, 466, 468 Associated organisms, 625, 625
In immunocompromised patients, 5 71 Clinical features, 625
Amyand hernia, 623 Demography, 624
Amyloidosis, 801, 802, 803 Endoscopic findings, 626
Esophagus, 114, 115 Gross findings, 626, 626
Malabsorption, 607 Microscopic findings, 626, 627, 628
Anal atresia, 77 Pathophysiology, 624, 624, 625
Anal fissure, 221 Specific types, 628
Anal fistula, 222, 223 Actinomycosis appendicitis, 629
Anaphylactoid purpura, 276 Campylobacter appendicitis, 628
Anastomotic ulcer, 229 Enterobius ve1micularis appendicitis, 630, 630
Ancylostoma caninum, 480 Fungal appendicitis, 629
Ancylostoma duodenale, 480 Parasitic appendicitis, 631
Anderson's disease, 609 Schistosoma appendicitis, 630, 631
Angiodysplasia, 232, 234 Tuberculosis appendicitis, 628
Angiostrongylus infections, 496 Viral appendicitis, 629, 630
Anisakidosis, see Anisakis infections Yersinia enterocolitica appendicitis, 628, 6Z9
Anisakis infections, 154, 486, 487, 488 Appendix, normal, 23, 24, 25
Annular pancreas, 66 Apple peel atresia, 47, SS
Anorectal agenesis, 79 Arteriovenous malformation, 232
Anorectal congenital anomalies, 75, 76-78 Ascariasis, see Ascaris infections
Classification, 75, 76 "" Ascaris infections, 478, 479, 480
High (supralevator) abnormalities, 79 Aspergillosis, see Aspergillus infections
Intermediate abnormalities, 79 Aspergillus
Low abnormalities, 76 Appendicitis, 629
Anorectal cysts, 80, 82 Esophagitis, 108, 109
Anorectal anomalies/malformations, 75, 76-78 Other infections, 446
Anorectal disease in immunocompromised patients, Astrovirus infections, 454
549 In immunocompromised patients, 560
Anorexia nervosa, 232 Atresia, 47, 48, 49, 51, 53, 54
Anthrax, 435 Esophageal, 48
Antibiotic-associated drug injury, see Antimicro- Gastric, 48
bial-associated drug injury Intestinal, 48
Anticoagulant-induced gastrointestinal injury, 338, Multiple, 48
340 Atrophic gastritis, 142
~ntimicrobial drug gastrointestinal injury, 312 Autoimmune diseases, esophagus, 115
Associated Clostridium difficile colitis, 312 Autoimmune enteric myositis, 791
Antineutrophil cytoplasmic antibody, 275, 278 Autoimmune enteropathy, 607, 653, 654
Anus, normal, 25, 26 Autoimmune gastritis, 141
Aortoenteric fistula, 221 Clinical features, 142
Aphthous ulcers, 682, 686, 688, 689 Definition, 141

816
Index

Demography, 141 Barium-induced gastrointestinal injury, 320, 321,


Differential diagnosis, 144, 145 322
Etiology, 141 Barrett esophagus, 98
Gross findings, 142 And achalasia, 781, 781
Microscopic findings, 142, 143, 144 Biopsy evaluation, 99
Pathophysiology, 141 Clinical features, 99
Treatment and prognosis, 144, 145 Definition, 98
Autoimmune neuropathy, 682 Demography, 98
Differential diagnosis, 102, 102
8 Etiology, 98
Bacillus anthracis infections, 435 Gross and endoscopic findings, 99, 99
Bacterial esophagitis, 104, 104 Microscopic findings, 100, 100-102
Bacterial gastrointestinal infections, 395 Pathophysiology, 99
Actinomyces, 430, 431 Treatment and prognosis, 102
Aeromonas, 419 Bassen-Kornzweig syndrome, 607
Anthrax, 435 Behcet's disease, 282
Bacterial infections in immunocompromised Benign mucous membrane pemphigoid, esoph-
patients, 550, 551, 552, 554 agus, 116
Bacterial overgrowth syndrome, 438, 438 Binge eating disorder, 232
Campylobacte1; 407 And laxative-induced injury, 315
Chancroid, 429 Biopsy evaluation, gastric, 124, 125
Chlamydia, 433, 435 Bisphosphonate-induced gastrointestinal injury, 328
Clostridium difficile, 408, 410 Blastocystis infections, 478
Clostridiumperfringens and C. welchii, 414,416 Blastomyces infections, 447
Clostridium septicum, 413 Boerhaave's syndrome, 112, 225, 385
Escherichia coli, 395, 396, 398, 399 Bouveret's syndrome, 221
Granuloma inguinale, 429 Bowel infarction, in dialysis patients, 27 4
Listeria, 436 Bronchopulmonary malformations, 56, 58
Mycobacterium tuberculosis, 422, 423, 424 Brown bowel, 611, 612
Neisseria gonorrhoeae, 425 Brunner gland heterotopia, 170
Plesiomonas, 419 Brunner gland hyperplasia and peptic ulcer
Salmonella, 400, 401, 403 disease, 185, 186
Shigella, 404 Buerger's disease, 280
Staphylococcus, 406 Bulimia nervosa, 232
Treponema, 427, 428 And laxative-induced injury, 315
Trophe1yma, 431, 432, 433 Bullous pemphigoid, esophagus, 116
Tropical sprue, 437, 438
Vibrio, 417
c
Yersinia, 420, 421 Caliber-persistent artery, 235
Bacterial overgrowth syndromes, 438, 438 Calymmatobacterium granulomatosis infections, 429
Causing malabsorption, 602 Campylobacter infections, 407
Balantidiasis, see Balantidium infections Appendicitis, 628
Balantidium infections, 469, 470 Candida infections
Bannayan-Riley-Ruvalcaba syndrome, 745 Esophagitis, 107, 108, 109, 440, 442, 562
Differentiation from Cowden's syndrome, 741, Gastric ulcer disease, 182
742 In immunocompromised patients, 561, 562
Bannayan-Zonana syndrome, 745 Other infections, 440, 441, 442
Barium granuloma, 156, 320, 322, 651 Candidiasis, see Candida infections

817
Gastrointestinal Diseases

Capillaria philippinensis infections, 497 Pathophysiology, 308


Cardiospasm, see Achalasia Treatment and prognosis, 311
Cathartic colon, 315, 317 Chlamydia infections, 433
Caudal dysplasia, 80 Lymphogranuloma venereum, 433, 435 ·
Celiac disease, 589 Cholera, 418
Associated diseases, 591, 591-593 Cholesterol ester storage disease, 661
Classification, 597 Chronic antral gastritis, 144, 146
Clinical features, 592, 594 Chronic atrophic gastritis, 146, 147, 148
Definition, 589 Chronic erosive gastritis, 127, 151
Endoscopic findings, 595, 595 Chronic gastritis, 140
Epidemiology, 589 Antral, 144, 146
Microscopic findings, 595, 596-599 Autoimmune, 141, see Autoimmune gastritis
Pathophysiology, 589, 590 Atrophic, 146, 147, 148
Radiologic findings, 595 Classification, 141
Related disorders, 599 Metaplasia, 147, see also Metaplasia, in chronic
Collagenous sprue, 600, 601 gastritis
Enteropathy-associated T-celllymphoma, 601 Chronic granulomatous disease and malabsorp-
Refractory sprue, 599 tion, 607
Small bowel adenocarcinoma, 602 Chronic intestinal ischemia, see Chronic mesen-
Ulcerative jejunoileitis, 600, 601 teric ischemia
Serologic and other laboratory tests, 594 Chronic mesenteric ischemia, 264
Treatment and prognosis, 599 Classification, 266
Types, 592 Clinical features, 264
Atypical celiac disease, 592 Complications, 271, 272
Latent celiac disease, 592 Definition, 264
Potential celiac disease, 593 Demography, 264
Refractory celiac disease, 593 Differential diagnosis, 270
Silent celiac disease, 593 Endoscopic findings, 264
Typical celiac disease, 592 Gross findings, 264, 265, 266
Celiac sprue, 589, see also Celiac disease Microscopic findings, 266, 267-271
Chagas' disease, 476, 477 Chronic renal disease and gastrointestinal injury,
Causing motility disorders, 775 341, 342
Chancroid, 429 Chronic severe idiopathic constipation, 782, 783
Chemical gastropathy, 138, 140 Churg-Strauss syndrome, 278, 279
Chemical-induced injury, 293 Chylomicron retention disease, 609
Clinical features, 293 Ciliated cell metaplasia, 148
Demography, 293 Cirsoid aneurysm, 235
Etiology, 293, 293 Clofazimine-induced crystal-storing histiocytosis,
Pathologic findings, 294 344
Chemically induced eosinophilia, 339, 340 Clostridium difficile
Chemically induced gastric injury, 347, 347-351 And antimicrobial-associated injury, 312
~hemically induced intestinal injury, 349, 352 And chemotherapy-induced injury, 308
Chemotherapy-induced gastrointestinal injury, 307 And ischemia, 256
Clinical features, 308 Infections, 408, see also Clostridium difficile
Differential diagnosis, 311 infections
Etiology, 307 Clostridium difficile infections, 408
Gross findings, 308 Clinical features, 409
Microscopic findings, 309, 309-312 Demography, 408

818
Index

Differential diagnosis, 412 Anorectal cysts, 80, 82


Etiology and pathophysiology, 409 Atresia and stenosis, 4 7, 48-51
Gross findings, 410 Bronchopulmonary malformations, 56
Microscopic findings, 410 Caudal dysplasia, 80
Pseudomembranous colitis, 410, 410, 411 Diaphragmatic hernia, 46
Special techniques for diagnosis, 411 Diverticula, 62, 63, 64
Treatment and prognosis, 412 Duplications, 58, 58-61, see also Duplications of
Clostridium perfringens infections, 414, 416 gastrointestinal tract, congenital
Clostridium septicum infections, 413, 4 14-416 Enterogenous cysts, 58
Clostridium welchii infections, 414 Heterotopias, 68
Cocaine-induced gastrointestinal injury, 335, 337 Mesocolic hernia, 46
Coccidioides infections Microgastria, 74, 75
Esophagitis, 109 Miillerian/mesonephric duct remnants, 74
Other infections, 450 Omphalomesenteric remnants, 64
Colchicine-induced gastrointestinal injury, 332, Peritoneal encapsulation, 67
332 Positional abnormalities, 39, 40
Colitis Thymic-renal-anal-lung dysplasia, 80
Diverticular disease associated, 204, 205 Tracheoesophageal fistula, 47
Colitis cystica profunda, 218, 220 Congenital microvillus atrophy, 661
Collagenous colitis, 656, 656-658 Connective tissue motility disorders, 793
Collagenous gastritis, 159 Corrosive colitis, 322
Collagenous sprue, 600, 601 Corrosive esophagitis, 110, 110, 322, 324, 325
Colon, normal, 19, 22-24 Corrosive gastritis, 322, 324
Lamina propria, 23, 24 Corrosive-induced gastrointestinal injury, 322,
Colonic diverticula, 199 324-326
Clinical features, 200 Corrosive proctitis, 322
Definition, 199 Cow's milk intolerance, 644, 644
Demography, 200 Cowden's syndrome, 739, 740-743
Differential diagnosis, 205 Associated abnormalities, 741, 741
Diverticular disease-associated colitis, 204, 205 Differentiation from Bannayan-Riley-Ruvalcaba
Etiology, 200 syndrome, 741, 742
Gross findings, 201, 202, 203 Crescentic colitis, 204
Microscopic findings, 203, 203, 204 Crohn's disease, 680
Treatment and prognosis, 207 Aphthous and other ulcers, 682, 686, 688, 689
Colonic inertia, 782 Appendiceal disease, 634, 635
Colonic ischemia, see Chronic mesenteric ischemia Clinical features, 680
Common variable immunodeficiency, 605, 606, 607 Definition, 680
Communicating bronchopulmonary foregut Demography, 680
malformations; 56 Differential diagnosis, 699
Complex atresia, 47 Differentiation from diverticular disease, 207
Condyloma acuminatum, 462 Differentiation from Helicobacter pylori gastritis,
Congenital appendiceal abnormalities, 621 698
Congenital diaphragmatic hernia, 46 Differentiation from ulcerative colitis, 711, 712,
Congenital gastrointestinal abnormalities, 33 713
Abdominal wall defects, 41 Enteritis/colitis cystica profunda, 693, 695, 696
Annular pancreas, 66 Gastric, 155, 156
Anorectal anomalies, 75 Granulomas, 691, 691, 692
Appendix, 621 Gross findings, 681, 682-684

819
Gastrointestinal Diseases

Lymphoid aggregates, 690 Diffuse leiomyomatosis, 791


Microscopic findings, 684, 684-698 Diphyllobothriasis, see Diphyllobothrium infections
Mucosal metaplasia, 688, 690 Diphyllobothrium infections, 498
Neural changes, 693, 694 Disruptions, 385
Paneth cell metaplasia, 688, 690 Disseminated intravascular coagulation, 284
Prognosis, 700 Diverticula, 62, 195
Pyloric metaplasia, 688, 690 Appendiceal, 198, 621, 622
Treatment, 699 Colonic, 199, see also Colonic diverticula
Vascular lesions, 691, 693, 694 Congenital, 62, 63, 64
Cronkhite-Canada syndrome, 745, 746, 747 Esophageal, 19 5, see also Esophageal diverticula
Crypt hyperplasia, 586, 587, 597, 599 Gastric, 197, see also Gastric diverticula
Cryptococcus infections, 449 Small intestinal, 197, 198, 199
Cryptosporidiosis, see Clyptosporiwn infections Diverticular disease, 200
Clyptosporidiwn infections, 470, 471, 472, 474 Diverticulitis, 201, 206
Causing malabsorption, 602 Diverticulosis, 195, see also Colonic diverticula
In immunocompromised patients, 563, 563, 564 Donovanosis, 429
Curling ulcers, 382, 383 Drug-associated esophagitis, 111, 112, 344, 345, 346
Cushing ulcers, 127 Drug-induced gastric injury, 347, see also Chem-
Cyclospora infections, 473, 474 ical-induced gastric injury
Cysticercosis, 498 Drug-induced gastrointestinal dysmotility, 343, 803
Cystic fibrosis Duodenal peptic diseases, 184
Appendix, 637, 638 Genetics, 185
Esophagus, 115 Peptic duodenal ulcers, 184, 187, 187
Cystic hamartomatous epithelial polyp, 168 Peptic duodenitis, 184, 185, 185, 186
Cytomegalovirus Duplications of gastrointestinal tract, congenital, 58
And ischemia, 256 58-61
And ulcerative colitis, 710, 711 Associated findings, 59
Causing motility disorders, 776 Clinical features, 59
Esophagitis, 106, 106, 107, 459, 461 Definition, 58
In immunocompromised patients, 555, 556-559 Demography, 58
Other infections, 458, 460, 461 Differential diagnosis, 62
Etiology, 59
Gross findings, 59, 60
Davidson's syndrome, 661 Microscopic findings, 61, 61
Decidual nodules, appendix, 637, 637 Treatment and prognosis, 62
Dextrogastria, 39 Dysgammaglobulinemia, 605
Diabetes mellitus, 799
Causing malabsorption, 603
Diabetic colopathy, 799, 800 Ectopia, see Heterotopia
Diabetic gastroenteropathy, 797 Ectopic gastric mucosa, 68
Diabetic gastropathy, 797 Ehlers-Danlos syndrome, 281
Esophageal disease, 114 Electrical gastrointestinal injury, 384, 384
Gastroparesis, 797, 799 Embryology, normal, 33, 34
Diabetic gastroenteropathy, 797 Distal colon, rectum, anus, 38, 38
Diabetic gastropathy, 797 Esophagus, 33, 35, 36
Diaphragmatic hernia, 46 Intestine, 36, 37
Diarrheic shellfish poisoning, 342 Stomach and duodenum, 34
Dieulafoy lesion, 235 Emphysematous gastritis, 138

820
Index

Endocrine system of gastrointestinal tract, 8, 9, 10 Microscopic findings, 196


Endometriosis, appendix, 636 Pulsion type, 195
Endosalpingiosis, appendix, 636 Traction type, 195, 196
Enema-induced gastrointestinal injury, 319 Treatment and prognosis, 197
Kayexalate-sorbitol enema, 320 Zenker diverticulum, 196, 196
Entamoeba infections, 466, 468 Esophageal fistula, 222
Enteric nervous system, 757, 758 Esophageal inlet pouch, 68, 68, 69
Absent, 772 Esophageallung, 56
Enteritis cystica profunda, 218, 220 Esophageal varices, 236, 238, 239
And Crohn's disease, 688, 693, 695, 696 Esophagitis
Enterobius vennicularis infections, 488, 489, 490 Bacterial, 104, 104
Appendicitis, 630, 630 Corrosive esophagitis, 110, 110
Enterochromaffin-like (ECL) cell hyperplasia, 142 Drug-associated, 111, 112, 344, 345, 346
Enterocolitis necroticans, 2 7 3 Fungal, 107
Enterocutaneous fistula, 221 Aspergillus, 108, 109
Enterocytozoon organisms, 566 Candida, 107, 108, 109
Enteroenteric fistula, 221 Coccidioides, 109
Enterogenous cysts, 58 Histoplasma, 108
Enteropathy-associated T-celllymphoma, 601 Mucor, 108
Eosinophilia, chemically induced 339, 340 Radiation, 111, 111
Eosinophilic esophagitis, 102, 103, 644 Tuberculosis, 104, 105
Distinction from gastroesophageal reflux Viral, 105, 105
disease, 103, 103 Cytomegalovirus, 106, 106, 107
Eosinophilic gastroenteritis, 646, 647, 648 Herpes, 105, 105, 106
Eosinophils, normal, 5, 5 Esophagitis desiccans superficialis, 325
Epidermolysis bullosa acquisita, esophagus, 116 Esophagus, normal, 10, 11, 12
Epidermolysis bullosa dystrophia, esophagus, 116 Estrogen-induced gastrointestinal injury, 334, 335
Epstein-Barr virus, and motility disorders, 776 Exomphalocele, 43
Erosive gastritis, 127, 129-131 Exomphalos, 43
Erythema multiforme, esophagus, 116
Escherichia coli infections, 395, 396
And ischemia, 256 Fabry's disease, 661
Differential diagnosis, 400 Factor V Leiden mutation, 284
Enteroaggregative E. coli, 396 Familial hypobetalipoproteinemia, 608
Enterohemorrhagic E. coli, 396, 398 Familial hyperplastic gastric polyposis, 748
Enteroinvasive E. coli, 399 Familial juvenile polyposis, 736
Enteropathogenic E. coli, 395 Familial microvillus atrophy, 661
Enterotoxigenic E. coli, 399, 399 Familial polyposis coli, 736
Techniques for identification, 400 Familial visceral neuropathies, 773, 774, 775
Esophageal atresia, 48, 51 Fecalith, appendix, 634
Esophageal bronchus, 56 Fetal stomach, 74
Esophageal diseases, 91 Fibromuscular hamartoma, esophagus, 117
In immunocompromised patients, 548 Fibrosing colonopathy, 333, 334
Esophageal diverticula, 195 Fistulas, 221, 222-224, 386
Clinical features, 196 Focal hyperplasia, gastric, 165, 165
Demography, 195 Folate deficiency, 611
Etiology, 195 Follicular gastritis, 136, 136
Gross findings, 196 Food allergy, 643, 643

821
Gastrointestinal Diseases

Food granuloma, 156, 157 Gastric surgery, and malabsorption, 602


Foreign body granuloma, 156 Gastric syphilis, 428
Fundic gastritis, 141, see also Autoimmune gastritis Gastric xanthoma, 169, 170
Fundic gland polyp, 168, 169 Gastritis, 126
Fungal appendicitis, 629 Acute gastritis, 127, 127-131
Fungal esophagitis, 107, 108, 109 Autoimmune gastritis, 141
Fungal gastrointestinal infections, 440, 446 Chemical-induced gastritis, 347, 34 7-351
Aspe1gillus, 446 Chronic gastritis, 140
Blastomyces, 447 Antral gastritis, 144
Candida, 440, 441, 442 Atrophic gastritis, 146
Coccidioides, 450 Classification, 141
Clyptococcus, 449 Granulomatous gastritis, 153, 154, see also
Histoplasma, 443, 444, 445 Granulomatous gastritis
Paracoccidioides, 447 Helicobacter heilmannii gastritis, 13 7, 138
Zygomycetes, 448 Helicobacterpylori gastritis, 129, see also
Helicobacter pylori gastritis
G Lymphocytic gastritis, 151, 152, 153
Gangliosidoses, 660 Suppurative gastritis, 138
Adult GM1 gangliosidosis, 660 Gastritis cystica profunda, 218, 220
Sandhoff's disease, 661 Gastritis polyposa, 166
Tay-Sachs disease, 660 Gastrocutaneous fistula, 221
Ganglionic immaturity, 771 Gastroenteritis, eosinophilic, 646, 647, 648
Gastric antral vascular ectasia, 241, 243, 244 Gastroesophageal reflux, see Reflux esophagitis
Gastric atresia, 48, 53 Gastroesophageal reflux disease, 91, see also
Gastric diseases, 123 Reflux esophagitis
Gastric biopsy evaluation, 124, 125 Distinction from eosinophilic esophagitis, 103,
In immunocompromised patients, 549 103
Mucosal barrier repair, 123, 124 Gastrojejunal ulcer, 229
Mucosal barrier structure, 123, 123 Gastroparesis, 797, 799
Surgical specimens, 126 Gastroschisis, 41, 42
Gastric diverticula, 197 Generalized juvenile polyposis, 735
Pulsion type, 197 Giardia infections, 463, 464, 465
Traction type, 197 Causing malabsorption, 602
Gastric hypoplasia, 74 In immunocompromised patients, 571
Gastric juvenile polyposis, 735 Giardiasis, see Giardia infections
Gastric peptic ulcer disease, 189 Gluten-sensitive enteropathy, 589, see also Celiac
Clinical features, 180, 180 disease
Definition, 180 Glycogen acanthosis, 114, 114
Differential diagnosis, 183 Glycogen storage diseases, 659
Etiology, 180 Graft versus host disease, esophagus, 117
Gross findings, 180, 181 In immunocompromised patients, 571, 572-574
Microscopic findings, 181, 182, 183 Granuloma inguinale, 429
G.astric polyps, 165 Granulomas, 650, 650
Differential diagnosis, 166 And Crohn's disease, 691, 691, 692
Fundic gland polyp, 168, 169 Barium, 156, 320, 322, 651
Hyperplastic polyp, 166, 166, 167 Sutur~ 15~ 15~ 651, 651
Isolated hamartomatous polyp, 169 Talc, 651
Polyposis syndromes, 169 Granulomatous diseases, 650, 650

822
Index

Granulomatous gastritis, 153, 154 Causing motility disorders, 776


Associated with malignancy, 157, 158 Esophagitis, 105, 105, 106, 455, 456
Isolated idiopathic, 158, 158 In immunocompromised patients, 559, 560
Gut-associated lymphoid tissue, 2 Other infections, 454, 456
Heterotopias, 68
H Heterotopic Brunner glands, 71, 73
Haemophilus ducreyi infections, 429 Heterotopic gastric mucosa, 69, 70, 71
Chancroid, 429 Heterotopic pancreas, 71, 72
Hamartomatous gastrointestinal polyposis, 735 Heterotopic prostate, 74
Heavy metal-induced gastrointestinal injury, 329 Heterotopic salivary glands, 73
Ferrous sulfate, 329 Heterotopic sebaceous glands, 73, 74
Gold, 330, 330, 331 Heterotopic thyroid gland, 74
Iron, 331, 332 Hirschsprung's disease, 758
Mercury, 330, 330 Associated abnormalities, 760, 761
Helicobacter heilmannii gastritis, 137, 138 Clinical features, 760
Helicobacter pylori, 66 Definition, 758
And gastritis, 129, see also Helicobacter pylori Demography, 759
gastritis Differential diagnosis, 765, 766
And hypertrophic gastropathy, 164 Etiology, 759, 759
And injury from alcohol, 304 Gross findings, 761, 761, 762
And injury from nonsteroidal antiinflammatory Intestinal neuronal dysplasia, 764
drugs, 295 Microscopic findings, 761, 762, 764
And peptic ulcers, 175, 188 Pathophysiology, 760
And reflux esophagitis, 92 Special techniques for diagnosis, 764, 765
Differentiation from Crohn's disease, 698 Total colonic aganglionosis, 764
Helicobacter pylori-associated hypertrophic Treatment and prognosis, 765
gastropathy, 164 Histoplasma infections
Helicobacterpylori gastritis, 129, 176, 176, 177 Appendicitis, 629
Clinical 'features, 133 Esophagitis, 108
Definition, 129 In immunocompromised patients, 562
Demography, 129 Other infections, 443, 444, 445
Differential diagnosis, 136 Histoplasmosis, see Histoplasma infections
Gross findings, 133 HIV enteropathy, 546, 546, 547
Microscopic findings, 133, 134-136 Hollow visceral myopathies, 785, 786-789
Pathophysiology, 131, 132, 133 Homocystinuria, 284
Treatment and prognosis, 136 Homozygous hypobetalipoproteinemia, 608
Hemangiomata syndrome, 745 Hookworm infections, 480, 481, 482, see also
Hematomas, 225, 385, 387 Ancylostoma and Necator species
Hemolytic uremic sypdrome, 284 Human immunodeficiency virus infection (HIV), 539
Hemorrhoids, 235, 235, 236 Anorectal disease, 549
Henoch-Schonlein purpura, 276, 277 Clinical features, 543, 544
Hereditary familial visceral neuropathies, 773, Demography, 539
774, 775 Esophageal disease, 548
Hernias Etiology, 540, 540-542
Congenital diaphragmatic, 46 Gastric disease, 549
Mesocolic, 46, see also Mesocolic hernias HIV enteropathy, 546, 546, 547
Umbilical, 45 Pathophysiology, 542, 542
Herpesvirus Special techniques for diagnosis, 545

823
Gastrointestinal Diseases

Treatment and prognosis, 545 Bacterial infections, 395, see also Bacterial
Human papilloma virus infections, 462, 463 gastrointestinal infections
Condyloma acuminatum, 462 Diagnosis, 393, 394
Hunter's syndrome, 659 Epidemiology, 393, 393
Hurler's syndrome, 659 Fungal infections, 440, see also Fungal gasti·o-
Hyperganglionosis, see Intestinal neuronal dyspla- intestinal infections
sia type B Parasitic infections, 463, see also Parasitic
Hyperplasiogenic polyp, gastric, 166 gastrointestinal infections
Hyperplastic inflammatory polyps, 735 Pathologic features, 394
Hyperplastic polyps, Viral infections, 450, see also Viral gastro-
Appendix, 63 7 intestinal infections
Stomach, 166, 166, 167 Inflammatory bowel disease, 675
Hypersecretory hypergastrinemia with protein Appendiceal disease, 634
loss, 162 Crohn's disease, see Crohn's disease
Hyperthyroidism and malabsorption, 603 Demography, 675
Hypertrophic gastropathies, 159, 159 Differentiation from diverticulosis-associated
Hypertrophic hypersecretory gastropathy, 164 colitis, 205
Hypertrophic hypersecretory gastropathy with Esophagus, 115
protein loss, 164 Etiology, 675, 676
Hypoganglionosis, see Intestinal neuronal dzsplasia Genetics, 675, 676
type A Ulcerative colitis, see Ulcerative colitis
Hypogenetic type of dysganglionosis, 766 Inflammatory cap polyp, 217
Hypoparathyroidism and malabsorption, 603 Inflammatory cloacogenic polyp, 217, 217
Hypothyroidism and malabsorption, 603 Inflammatory fibroid polyp, 648, 649, 650
Esophagus, 117
Internal anal sphincter achalasia, 772
Idiopathic autonomic neuropathy, 782 Intestinal atresia, 48, 51, 53-SS
Idiopathic chronic constipation, 782 Intestinal epithelial dysplasia, 662
Idiopathic eosinophilic esophagitis, 102 Intestinal metaplasia, 148, 149, 150
Idiopathic ganglionitis, 777 Intestinal neuronal dysplasia (IND), 764, 766
Idiopathic granulomatous gastritis, 158, 158 And Hirschsprung's disease, 763
Idiopathic myointimal hyperplasia of the mesen- Clinical features, 767
teric vein, 283 Definition, 766
Ileal pouch, 715 Demography, 766
Pouchitis, 715, 716, 717 Differential diagnosis, 771
Ileitis, 708, 709 Etiology, 766
Imerslund syndrome, 610 Gross findings, 767
Immunocompromised patients and gastrointestinal Histologic variants, 770
diseases, 539 IND type A, 767, 768
Bacterial infections, 550, SS 1, 552, 554 IND type B, 768, 769
Viral infections, 555, 556-560 Microscopic findings, 767
Immunosuppressive agent-induced gastrointestinal Pathophysiology, 767
injury, 313, 315, 316 Special techniques for diagnosis, 771
Imperforate anus, 75, 78 Treatment and prognosis, 771
Infantile hypertrophic pyloric stenosis, 47 Intestinal neuronal dysplasia type A, 767, 768
Infantile juvenile polyposis, 736 Intestinal neuronal dysplasia type B, 768, 769
Infection-induced motility disorders, 775 Intraepitheliallymphocytosis, 587, 588
Infections of the gastrointestinal tract, 393

824
Index

Intussusception, 207 L
Definition, 207
Demography, 207 Lacerations, 225, 385, 386
Etiology, 207, 208 Laxative-induced gastrointestinal injury, 315
Clinical features, 208 Clinical features, 316
Gross findings, 208, 209 Demography, 315
Microscopic findings, 209, 210 Differential diagnosis, 319
Radiologic findings, 208 Etiology, 316
Treatment and prognosis, 210 Gross findings, 317, 317
Intussusception, appendiceal, 622, 623 Microscopic findings, 318, 318, 320
Ischemia, gastrointestinal, 255 Pathophysiology, 316
Acute mesenteric ischemia, 261, see also Acute Treatment and prognosis, 319
mesenteric ischemia Leishmania infections, 474, 475
Chronic mesenteric ischemia, 264, see also Leishmaniasis, see Leishmania infections
Chronic mesenteric ischemia Lichen planus, esophagus, 116
Demography, 255 Lipid islands, gastric, 169
Drugs and chemicals inducing ischemia, 336, 337 Lipid malabsorption, 607, 608
Etiology, 255, 256, 257 Listeria infections, 436
Pathophysiology, 257, 258 Littre hernia, 65
Isolated hamartomatous polyp, 169 Lupus erythematosus and malabsorption, 605
Isolated idiopathic granulomatous gastritis, 158, 158 Lymphocytic colitis, 654, 655
Isolated sigmoiditis, 204 And celiac disease, 592, 592, 593
Isospora belli infection Lymphocytic gastritis, 127, 151, 152, 153
Causing malabsorption, 602 Lymphocytic phlebitis, 283
In immunocompromised patients, 565 Lymphogranuloma venereum, 433, 435
Lymphoid polyposis, 748, 748
Lysosomal acid esterase deficiency, 661
Jejuna! ulcer, 229 Lysosomal storage diseases, 659
Juvenile polyposis coli, 735
Juvenile polyposis of infancy, 735 M
Juvenile polyposis of stomach, 735 Macrocephaly, 7 45
Juvenile polyposis syndrome, 734, 736-738 Magnesium deficiency, 613
Associated abnormalities, 740 Malabsorption syndromes, 583
Atypical juvenile polyps, 737 Biopsy specimens, 583
Familial juvenile gastric polyposis, 736 Celiac disease, see Celiac disease
Familial polyposis coli, 736 Crypt hyperplasia, 586, 587
Generalized juvenile polyposis, 736 Demography, 583
Infantile juvenile polyposis, 736 Drug-induced, 610
Osseous metapla~ia, 737, 739 Etiopathogenesis, 583, 584, 585
Juvenile polyps, appendix, 637 Histology, 585, 586-588
Crypt hyperplasia, 586, 587
K Intraepitheliallymphocytosis, 587, 588
Katayama fever, 484 Villous atrophy, 586, 587
Kawasaki's disease, 279 Immunologic, 603
Kearns-Sayre syndrome, 790 Infections, 602
Kohlmeier-Degos disease, 280 Lipid malabsorption, 607
Kwashiorkor, 610 Malnutrition, 610
Postoperative, 602

825
Gastrointestinal Diseases

Systemic, 602 Microscopic; polyangiitis, 276, 277


Vitamin deficiency, 610 Microsporidiosis, see Microsporidia infections
Malakoplakia, 651, 6S2, 6S3 Microsporidia infections
Malignant atrophic papulosis, 280 Causing malabsorption, 602
Mallory-Weiss syndrome, 112, 225, 227 In immunocompromised patients, 566, S68, S69
Mallory-Weiss tear, 227, 385 Microvillus inclusion disease, 661 , 662
Malnutrition, 610 Mitochondrial myopathies, 789, 789
Kwashiorkor, 610 Kearns-Sayre syndrome, 790
Malrotation/nonrotation, congenital, 40, 41 Mitochondrial neurogastrointestinal encepha-
Marfan's syndrome, 281 lomyopathy, 789
Mast cells, normal, 3, 4 Oculogastrointestinal muscular dystrophy, 790
Meckel diverticulum, 65, 6S -67 Mitochondrial neurogastrointestinal encephalomy-
Medication-induced esophageal injury, 344, 34S, opathy, 789
346 Molluscum contagiosum, 463, 464
Megacolon, 76S, 773 Motility disorders, 755, 7SS
Megacystis-microcolon and intestinal hypo- Autoimmune neuropathy, 782
peristalsis syndrome, 784, 78S Clinical features, 756
Megaesophagus, see Achalasia Connective tissue disorders, 792
Melanosis, esophageal, 113, 113 Drug-induced, 802
Melanosis coli, 315, 317, 318, see also Laxativ~ ­ Enteric nervous system, 757, 7S8
induced gastrointestinal injury Infectious disorders, 775
Menetrier's disease, 159 Muscle disorders, 783
Clinical features, 159 Neural disorders, 757
Definition, 159 Pathologic features, 756
Demography, 159 Treatment, 756
Differential diagnosis, 162 Mucocele, appendix, 637, 638
Etiology, 159 Mucopolysaccharidoses, 659
Gross findings, 160, 160, 161 Hunter's syndrome, 659
Microscopic findings, 161, 161 Hurler's syndrome, 6,59
Treatment and prognosis, 162 Mucor infections, 449, 4SO
Mesenteric inflammatory venoocclusive disease, 283 Appendicitis, 629
Mesenteric ischemia, see Chronic mesenteric Esophagitis, 108
ischemia Mucormycosis, see Mucor infections
Mesenteric phlebosclerosis, 283 Mucosa, normal, 2, 2, 3
Mesenteric venous thrombosis, 262, 262 Lamina propria, 2, 3-S
Mesocolic hernias, 46 Mucosal barrier, 123, 123
Mesentericoparietal, 46 Muscularis mucosae, 2, 2
Paraduodenal, 46 Mucosal regeneration, 123, 124
Transmesocolic/omentomesenteric parietal, 46 Mucosal stress ulcers, 382
,Mesonephric duct remnants, 74 Mullerian duct remnants, 74
Metaplasia, in chronic gastritis, 14 7 Multiple hamartoma syndrome, see Cowden's
Ciliated cell metaplasia, 148 syndrome
· Intestinal metaplasia, 148, 149, ISO Multiple lipomas, 745
Pancreatic metaplasia, 150, I SI Muscle motility disorders, 783
Pyloric metaplasia, 148, 149 Muscularis propria, 6 , 6
Squamous metaplasia, 147 Mycobacterium avium complex, in immunocompro-
Microgastria, 74, 7S mised patients, 550, SS 1, SS2
Microscopic colitis, 654

826
Index

Mycobacterium tuberculosis infections, 522 And chemical gastropathy, 139, 140


Clinical features, 422 And diverticulitis, 201
Demography, 422 And ischemia, 256
Differential diagnosis, 425 And peptic ulcers, 177, 179, 188
Gross findings, 423, 423 Injury to gastrointestinal tract, 294
Immunocompromised patients, 553 Norwalk-like virus infections, 452
Microscopic findings, 424, 424 Norwalk virus infections, 452
Pathophysiology, 422 In immunocompromised patients, 560
Special techniques for diagnosis, 425
Treatment and prognosis, 425 0
Myopathies, 784 Oculogastrointestinal muscular dystrophy, 790
Myxoglobulosis, 633, 633 OIES complex, 40, 43, 43, 49
Oligoneuronal disease, 766
N
Omphalocele, 43, 43-45
Necator americanus infections, 480 Omphalomesenteric cyst, 66
Neisseria gonorrhoeae infections, 425 Omphalomesenteric remnants, 64
Neonatal enteropathies, 661 Oxygen free radicals and ischemia, 258, 258
Neonatal necrotizing enterocolitis, 271, 273, 274
Nerves, normal, 7 p
Neural gastrointestinal disorders, 757 Pancreatic enzyme supplements and gastrointesti-
Neurogenic appendicitis, 632 nal injury, 333, 333
Neurogenic appendicopathy, 632 And fibrosing colonopathy, 333, 334
Neuroimmune appendicitis, 632 Pancreatic metaplasia, 150, 151
Neuromuscular disorders, drug induced, 343, 343 Paneth cell metaplasia, 688, 690
Neuronal immaturity, 771 Paracoccidioides infections, 447, 448
Neuronal maturational arrest, 771 Paraneoplastic pseudoobstruction, 773, 776
Neutrophils and ischemia, 259 Parasitic gastrointestinal infections, 463
Nevus, esophageal, 113 Amoeba, 466, 468
Niemann-Pick disease, 660, 660 Angiostrongylus, 496
Nodular lymphoid hyperplasia, 748 Anisakis, 486, 487, 488
Nonfamilial myopathies, 788, 789 Ascaris, 478, 479, 480
Non-neoplastic polyposis syndromes, 729 Balantidium, 469
Nonspecific jejunitis, 273 Blastocystis, 478
Nonsteroidal antiinflammatory drug enteropathy, Capillaria philippinensis, 497
294 Chagas' disease, 476, 477
Nonsteroidal antiinflammatory drug gastritis, 294 Clyptosporidium, 470, 471, 472
Nonsteroidal antiinflammatory drug injury, 294, Cyclospora, 473
295 Enterobius vermicularis, 488, 489, 490
And inflammatory bowel disease, 678 Giardia, 463, 465, 466
Clinical features, 296 Hookworm, 480, 481, 482
Demography, 294 Leishmania, 474, 475
Differential diagnosis, 303 Schistosoma, 483, 484, 485
Etiology, 295 Strongyloides, 492, 493-495
Gross findings, 297, 297, 298 Tapeworm, 498
Microscopic findings, 298, 299-304 Trematode, 500
Pathophysiology, 295, 296 Trichuris, 490, 491, 492
Treatment and prognosis, 303, 305 Paroxysmal nocturnal hematuria, 284
Nonsteroidal antiinflammatory drugs Pemphigus, esophagus, 115

827
Gastrointestinal Diseases

Peptic ulcer disease, 17 5 Pseudoepitheliomatous hyperplasia, 95


Demography, 179 Pseudomembranous colitis, 410, 410, 411
Duodenal peptic ulcer disease, Sf!e Duodenal Pseudoobstruction
peptic diseases Drugs and chemicals causing, 343
Gastric defense mechanisms, 175 Radiation induced, 3 70
Gastric peptic ulcer disease, see Gastric peptic Pseudo-Zollinger-Ellison syndrome, 164
ulcer disease Pulmonary sequestrations, 57
Pathogenesis, 175 Pyloric metaplasia, 148, 149
Treatment and prognosis, 188 Pyloric stenosis, 48, SO
Perforations, 225, 226, 385
Periappendicitis, 631, 632
Peritoneal encapsulation, 67 Radiation colitis, 365
Peutz-]eghers polyps, appendix, 637 Radiation enteritis, 365
Peutz-]eghers syndrome, 729 Chronic irradiation enteritis, 378
Clinical features, 730 Radiation enteropathy, 365
Definition, 729 Radiation esophagitis, 111,111, 365, 371
Demography, 729 Radiation-induced carcinogenesis, 367, 367
Differential diagnosis, 733 Radiation-induced gastrointestinal injury, 365, 365
Etiology, 729 Acute radiation syndrome, 368, 368
Gross findings, 730, 731 Carcinogenesis, 367, 367
Microscopic findings, 731, 732, 733 Clinical features , 367, 368
Radiologic findings, 730 Definition, 365
Treatment and prognosis, 733, 734 Demography, 365
Peyer patch, 2, 3 Differential diagnosis, 379, 381
Picornavirus, 560 Etiology, 365, 366
Pigbel, 273, 415 Gross findings, 370, 370-372
Pill esophagitis, 344, 346 Microscopic findings, 372, 373-379
Platelets and ischemia, 259 Pathophysiology, 366
Plesiomonas infections, 419 Treatment and prognosis, 380
Pneumocystis carinii infection, 562 Types, 365, 365
Polyarteritis nodosa, 275, 275 Vascular injury, 372, 374, 377, 380, 381
Polyposis syndromes, 169 Radiation gastritis, 365
Polyps, gastric, 165, see also Gastric polyps Acute atrophic gastritis, 376
Portal colopathy, 239 Acute radiation gastritis, 376
Portal hypertensive colopathy/enteropathy/vascu- Acute ulcer, 3 76
lopathy/intestinal vasculopathy, 239, 240 Radiation proctitis, 365, 372, 379, 380
Portal hypertensive gastropathy, 240, 241 Radiation sickness, 368
Postoperative ·malabsorption syndromes, 602 Reactive gastropathy, 139, 140
Pouchitis, ileal, 715, 716, 717 Rectal prolapse, 213
Prediverticular disease, 200 Classification, 214
. Procidentia, 214 Clinical features, 215
Proctocolitis, allergic, 644, 645 Definition, 213
Progesterone-induced gastrointestinal injury, 334, Demography, 214
335, 336 Differential diagnosis, 218
Progressive fibrous occlusion, 633, 634 Etiology/pathophysiology, 214, 214
Prostaglandin-induced gastrointestinal injury, 327, Gross findings, 215
328 Microscopic findings, 215, 216
Prostaglandins and ischemia, 260 Treatment and prognosis, 218

828
Index

Variants, 217 Etiology, 792


Colitis/proctitis cystica profunda, 218 Gross findings, 794
Inflammatory cap polyp, 217 Microscopic findings, 794, 795-798
Inflammatory cloacogenic polyp, 217, 217 Pathophysiology, 792, 793
Solitary rectal ulcer syndrome, 217 Radiologic findings, 794, 794
Reflux esophagitis, 91 Special studies for diagnosis, 796
Clinical features, 92 Treatment and prognosis, 796
Definition, 91 Segmental arterial mediolysis, 281
Demography, 91 Segmental mediolytic arteritis, 281
Differential diagnosis, 97, 97 Segmental necrotizing enteritis, 273
Gross and endoscopic findings, 93, 93 Segmental obstructing acute jejunitis, 273
Microscopic findings, 93, 94-96 Selective IgA deficiency, 603
Pathophysiology, 91, 92 Selenium deficiency, 613
Treatment and prognosis, 98 Serosa, normal, 7, 7
Refractory sprue, 599 Severe combined immunodeficiency and malab-
Retention polyp, 735 sorption, 607
Gastric, 166 Shigella infections, 404
Rheumatoid arthritis, 282, 283 Short bowel syndrome, 229
Riley-Smith syndrome, 745 Sidney classification system, 140, 141
Rotavirus infections, 450 Sinuses, 221
Rotavirus-like virus infections, 451 Situs inversus, 39
Ruvalcaba-Myhre-Smith syndrome, 745 Slow transit constipation, 782
Small intestine, normal, 13, 14-21
Ampulla of Vater, 19, 21
Salmonella infections, 400 Brunner glands, 18, 19, 20
Clinical features, 401 Laminapropria,17,19
Demography, 400 Lymphoid tissue, 16, 18
Differential diagnosis, 404 Small intestinal diverticula, 197, 198, 199
Etiology, 400 Small intestinal fistula, 222
Gross findings, 402 Small intestinal resection, 602
Microscopic findings, 402, 403 Solitary rectal ulcer syndrome, 217
Pathophysiology, 401, 401 Soto's syndrome, 745
Special techniques for diagnosis, 404 South American blastomycosis, 447
Treatment and prognosis, 404 Spirochetosis, 429
Salmonellosis, see Salmonella infections In immunocompromised patients, 553, 554
Sandhoff's disease, 661 Squamous metaplasia, 147
Sapporo virus infections, 452 Staphylococcal infections, 406
Sapporo-like virus infections, 452 Stenosis, 47, 49-51
Sarcoidosis, 650 Stevens-Johnson syndrome, 116
Schistosoma infections, 483, 484, 485 Stomach diseases, see Gastric diseases
Appendicitis, 630, 631 Stomach, normal, 12, 13, 14
Schistosomiasis, see Schistosoma infections Stomal ulcer, 229
Scleroderma, 792 Storage diseases, 659
And malabsorption, 603 Stress gastritis, 127
Clinical features, 793 Strictures, 228, 229, 230
Definition, 792 Radiation induced, 370, 373
Demography, 792 Strongyloides infections, 492, 493-495
Differential diagnosis, 796 In immunocompromised patients, 571

829
Gastrointestinal Diseases

Strongyloidiasis, see Strongyloides infections Tuberculous esophagitis, 104, 105


Submucosa, normal, 5, 5 Tubular stomach, 74
Submucosal heterotopia of gastric glands, 169 Tufting enteropathy, 662
Suppurative gastritis, 138 Type A gastritis, 141, see also Autoimmune gastritis
Suture granuloma, 156, 157, 651, 651 Typhoid fever, 400
Syphilis, 427, 428
Systemic calciphylaxis, 341 u
Systemic lupus erythematosus, 281 Ulcerative appendicitis, 636, 636, 709, 710
Systemic mastocytosis, 602, 604 Ulcerative colitis, 700
Active colitis, 704, 705, 706
T Appendiceal disease (ulcerative appendicitis),
Taenia infections, 498 636, 636, 709, 710
Taeniasis, see Taenia infections Clinical features, 701
Talc granuloma, 651 Cytomegalovirus involvement, 710, 711
Tapeworm infections, 498 Definition, 700
Cysticercosis, 498 Demography, 700
Diphyllobothriasis, 498 Differential diagnosis, 710, 712
Taeniasis, 498 Differentiation from Crohn's disease, 711, 712,
Tay-Sachs disease, 660 713
Telangiectasia, mucosal, 242, 243, 244 Fulminant colitis, 707
Thermal injury, 382 Gastric/duodenal disease, 710
Thromboangiitis obliterans, 280, 280 Gross findings, 701, 702-704
Thrombotic thrombocytopenic purpura, 284 Ileal pouch and complications, 714, 715
Thymic-renal-anal-lung dysplasia, 80 Ileitis, 708, 709
Total colonic aganglionosis, 764 Microscopic findings, 704, 705-710
Toxoplasma infections, 569 Prognosis, 715
In immunocompromised patients, 569 Quiescent colitis, 708, 708
Toxoplasmosis, see Toxoplasma infections "' Resolving colitis, 706, 707
Tracheobronchial chondroepithelial hamartoma, 57 Strictures, 710
Tracheoesophageal fistula, 47 Treatment, 714
Transplantation, 663 Ulcerative gastritis, 127
Small intestine, 663, 664-666 Ulcerative jejunoileitis, 600, 601
Trematode infections, 500 Ultrashort form of Hirschsprung's disease, 772
Fasciolopsis, 500 Umbilical fistula, 64
Heterophyes, 500 Umbilical hernia, 45
Treponema! infections, 427 Uremia-induced gastrointestinal injury, 139, 341
Syphilis, 427, 428
Trichuriasis, see Trichuris infections V
Trichuris dysentery syndrome, 491 VACTERL syndrome, 47, 49
Trichuris infections, 490, 491, 492 Varicella virus infections, 458, 458
Tropheryma infections, 431 Varices, 236, 238, 239
Whipple's disease, 431 Varioliform gastritis, 127, 151
Tropical necrotizing enterocolitis, 273, 274 Vasculature, normal, 7, 7
Tropical sprue, 437, 438 VATER syndrome, 47, 49
Trypanosoma cruzi, 476 Vibrio infections, 417
Tuberculosis, see Mycobacterium tuberwlosis infec- Cholera, 418
tions Villous atrophy, 586, 586, 587, 597, 598
Tuberculous appendicitis, 628

830
Index

Villous hyperplasia, 586


Viral appendicitis, 629
w
Watermelon stomach, 241, 242
Viral esophagitis, 105, 105-107
Wegener's granulomatosis,. 278
Viral gastrointestinal infections, 450, 457
Whipple's disease, 431, 432, 433, 602
Adenovirus, 452, 453
Wolman's disease, 661
Astrovirus, 454
Cytomegalovirus, 458, 460, 461
X
Herpesvirus, 454, 456
Human papilloma virus, 462, 463 Xanthelasma, 169
Molluscum contagiosum, 463 Xanthoma, gastric, 169, 170
Norwalk and Norwalk-like virus, 452 Xanthomatosis, 651, 652
Rotavirus and rotavirus-like particles, 450 Xanthomatous diseases, 650
Sapporo and Sapporo-like virus, 452
y
Varicella zoster virus, 458, 458
Viral infections in immunocompromised patients, Yersinia infections, 420, 421
555, 556-560 Appendicitis, 628, 629
Visceral neuropathies, see Familial visceral Yersiniosis, see Yersinia infections
neuropathies
Vitamin A deficiency, 611 z
Vitamin B12 deficiency, 610
Zenker diverticulum, 196
Imerslund syndrome, 610
Zinc deficiency, 613
Malabsorption, 610
Acrodermatitis enteropathica, 613
Vitamin E deficiency, 611
Zollinger-Ellison syndrome, 162, 163, 188, 189
Brown bowel, 611, 612
Zygomycosis, 448
Volvulus, 211
Colonic, 212, 213
Gastric, 211
Small intestinal, 211

831

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