Gyn&obs&pat&zhe&fad&qui&she&guo&vol 2&1 ST

Wenxin Zheng
Oluwole Fadare
Charles Matthew Quick
Danhua Shen
Donghui Guo
Editors
Gynecologic and Obstetric

Pathology, Volume 2
123
Gynecologic and Obstetric Pathology, Volume 2
Wenxin Zheng
Oluwole Fadare
Danhua Shen
Donghui Guo
Editors
Gynecologic and Obstetric

Pathology, Volume 2
Editors
Wenxin Zheng Oluwole Fadare
Department of Pathology Department of Pathology
Department of Obstetrics and Gynecology University of California San Diego
University of Texas Southwestern Medical Center San Diego, CA
Dallas, TX USA
USA
Danhua Shen
Charles Matthew Quick Department of Pathology
Department of Pathology, College of Medicine Peking University People’s Hospital
University of Arkansas for Medical Sciences Beijing
Little Rock, AR China
USA
Donghui Guo
Department of Obstetrics and Gynecology
Tianjin Gynecologic and Obstetrics Central
Hospital
Tianjin
China
ISBN 978-981-13-3018-6 ISBN 978-981-13-3019-3 (eBook)

https://doi.org/10.1007/978-981-13-3019-3
© Science Press & Springer Nature Singapore Pte Ltd. 2019

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Foreword
The field of gynecologic and obstetric pathology is at a cross-roads. In the past decade we have
begun to witness the departure of venerated contributors to this discipline and now we are
being inundated with new information about pathogenesis that informs diagnostic expectations
and patient outcome. The old model in which the next generation sits at the knee of the learned
and patiently awaits their turn at the helm is rapidly fading. Succession is now not simply
achieved by learning the old language but by speaking a new one.
The textbook Gynecologic and Obstetrics Pathology, edited by Drs. Zheng, Fadare, and
Quick is emblematic of the sea change. We’ve all heard the joke about resorting to one’s grand-
child to solve a computer conundrum. How many of us turn to our younger colleagues to
interpret emerging genomic information in the management of gynecologic cancer? An appre-
ciation of such talent is crucial to our evolution as well as that of our discipline.
The senior editor in this project, Dr. Wenxin Zheng, has a long track record of innovation.
With this has come a facility to recognize the most talented young clinician-investigators and
to recruit them into this new textbook. Drs. Fadare and Quick as well as the younger chapter
authors are well on their way, having already put us on notice that by their dedication, creativ-
ity and their role in discovery. Their input is what will keep this and subsequent editions at the
forefront of pathology texts dedicated to women’s health.
Energy and intellect drive discovery but experience is essential to provide a needed perspec-
tive when this information is transmitted to the practicing pathologist. The editors wisely bal-
ance the list of talented newcomers with recognized experts in the field. Together they provide
the finer details of diagnosis and differential diagnosis while eliciting the nuances relevant to
clinical management.
In the current world, where discoveries and their impact on practice can become global
almost instantaneously, one does not need to travel far to realize that expertise in obstetric and
gynecologic pathology is intercontinental. In recognizing this, Zheng et al. will also provide an
edition written in Chinese, bringing this message to pathologists (and their patients) in coun-
tries where the language is read and spoken. To my knowledge, this book will be the first of its
kind to accomplish this, creating a truly international presence that will place this first edition
among the leading texts in the field. The editors and authors are to be commended for their
contribution and I look forward to their success in opening a new chapter (and book!) in the
history of the pathology of the female reproductive tract.
Christopher P. Crum
Division of Women’s and Perinatal Pathology
Harvard Medical School, Brigham and Women’s Hospital
Boston, MA, USA
v
Preface
Pathology of the female genital tract is complex, and encompasses a wide spectrum of neoplas-
tic and non-neoplastic diseases of the gonads, reproductive ducts, secondary müllerian system,
and external genitalia. Clinical practitioners in this discipline must therefore familiarize them-
selves with a broad spectrum of pathology, including skin-like diseases of the vulva, a myriad
of peritoneal diseases, as well as conventional diseases of other female genital tract organs.
This field progresses in a vibrant and dynamic academic environment in which diagnostic
concepts continually evolve as our understanding of various disease processes improves over
time. The contemporary gynecologic pathologist is in a unique position to recognize and define
morphologic correlates to newly defined genomic profiles and individual gene mutations,
assess whether they are likely to have diagnostic or prognostic significance for a given patient
and/or her family, and broadly participate in the push towards increasingly personalized cancer
care. These exciting trends notwithstanding, it remains true that definitive pathologic classifi-
cation of gynecologic disease is still primarily based on the traditional pillars of surgical
pathology, including gross pathology, morphologic assessment buttressed by immunopheno-
typic analysis where needed, and careful clinicopathologic correlation.
This book is envisioned as a “bridge” that acknowledges both of the aforementioned reali-
ties. It is designed to provide a broad coverage of diagnostic gynecologic and obstetric pathol-
ogy, inclusive of both neoplastic and non-neoplastic diseases. The book is neither a dense and
comprehensive treatise on every disease process nor is it a dry listing of relevant “facts” about
each entity. Rather, it is best conceptualized as a large scale aggregation of the most up to date
information in gynecologic pathology, all presented in a concise and narrative manner that is
designed to be easily accessible to the general practitioner, specialist and student alike. An
overt effort has been made to discuss each topic in a way that is maximally relevant to the
diagnostic surgical pathologist, such that by reading any section should substantially increase
the reader’s confidence that the most germane clinicopathologic information on that entity has
been reviewed before a diagnostic decision is made.
The material is organized into 36 chapters, representing the full spectrum of diagnostic
gynecologic pathology. In addition to chapters on traditional topics in gynecologic pathology,
there are individual chapters on site-specific carcinogenesis, gynecologic cytology, intra-
operative consultation, endometriosis and development/maldevelopment of the female repro-
ductive system, among others. Additionally, in a departure from most current texts, there are
stand-alone chapters to provide intensive coverage of some traditionally under-covered topics,
including melanocytic lesions of the female genital tract, non-neoplastic diseases of the endo-
metrium, and vulvovaginal soft tissue lesions. Entities with a significant diagnostic component
are presented, where feasible, divided into the following subsections: Clinical features, Gross
findings, Microscopic findings, Differential diagnosis, Biomarkers, and Genetic features. As
expected, not all entities or chapters lend themselves to this specific format, but most chapters
are broadly structured based on these general themes. Microscopic findings are lavishly illus-
trated, and numerous tables help summarize pertinent points for easy reference. The overall
objective of each chapter is to integrate traditional pathologic features, clinical features, where
applicable, and current paradigms in disease classification into a format that can be readily
applied in routine practice. These chapters are authored by over 50 physicians, most of whom
vii
viii Preface
are experienced subspecialty practitioners of clinical gynecologic pathology from around the
world, and without whose expertise, dedication, and diligence this work would not have been
possible. It is the sincere hope of the editors that all of those who are interested in gynecologic
pathology—diagnostic pathologists, students, residents and investigators—will find this book
tremendously useful.
The understanding of gynecologic disease involves pathologists and researchers from
across oceans and all over the world, and to that end an exciting feature of this book is that it
is written with a direct linkage to the second edition of the book “Gynecologic and Obstetric
Pathology”. The latter book is in Chinese, and is published by Science Press, Beijing, China.
The current text is published in both English and Chinese, representing a collaborative effort
by both publishers: Springer and Science Press. Although the titles and the number of chapters
are identical in the two books, the authors of the chapters are different. Additionally, while the
chapter outlines and some of the contents overlap, the two books do not represent a direct
translation from one to the other. Rather, they are best considered complementary “sister”
books. This results from Dr. Wenxin Zheng serving as the first editor-in-chief for both books.
Considering this special and close relationship, the co-editors for the Chinese book, Drs.
Danhua Shen and Donghui Guo, are listed as co-editors of the English version of this book,
while Drs. Fadare and Quick are also listed as co-editors on the second edition of the Chinese
book.
Dallas, TX Wenxin Zheng

San Diego, CA Oluwole Fadare
Little Rock, AR Charles Matthew Quick
Acknowledgments
To my dear wife Wenda and my beloved family (Yuxin, Genfu, and Deshun) for their constant
love and endless support! In memory of my parents Maoguan Zheng and Jinxian Wang as well
as my ultimate mentor Dr. Stuart C. Lauchlan.
Wenxin Zheng
To my wife Abby for her love, encouragement, and inspiration, and to our beloved children
Nathaniel, Darrell and Olivia for (mostly) putting up with the occasional absences that were
required to do this.
Oluwole Fadare
To my everything, Shelly, and my wonderful children Dexter, Bernice, and Alice.

To my beloved family members for their continuous support and care, and to all my colleagues
who participated in editing this outstanding book. I am honored to be an editor for this presti-
gious book.
Danhua Shen
To my beloved family members for their constant support and care, and to Drs. Zhaoai Kong
and Song Lin whose past instruction and training have been and continues to be invaluable.
Donghui Guo
The Editors would like to sincerely thank Dr. Christopher P. Crum, M.D. for serving as a senior
consulting adviser for this book. Dr. Crum has made significant contributions to the field of
gynecologic pathology and has trained innumerable residents and fellows, including many
who have served as an author for this book. The quality of this work is in part attributable to
his years of dedicated teaching and research in the field of gynecologic pathology.
ix
Contents
1 Uterine Mesenchymal Lesions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Brooke E. Howitt and Marisa R. Nucci
2 Fallopian Tube. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
David L. Kolin and Brooke E. Howitt
3 Benign Diseases of the Ovary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
David Suster, Martina Z. Liu, and Douglas I. Lin
4 Ovarian Epithelial Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Jing Zhang, Elvio G. Silva, Anil K. Sood, and Jinsong Liu
5 Serous Neoplasms of the Ovary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Preetha Ramalingam
6 Ovarian Endometrioid and Clear-Cell Tumors. . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Jennifer Katzenberg and Andres A. Roma
7 Ovarian Mucinous, Brenner Tumors, and Other Epithelial Tumors. . . . . . . . . . 203
Cathleen Matrai, Taylor M. Jenkins, Esther Baranov,
and Lauren E. Schwartz
8 Germ Cell Tumors and Mixed Germ Cell-Sex Cord-Stromal
Tumors of the Ovary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
Hao Chen, Charles Matthew Quick, Oluwole Fadare, and Wenxin Zheng
9 Sex Cord-Stromal Tumors of the Ovary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
Mohamed Mokhtar Desouki
10 Secondary Tumors of the Ovary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
Kelley Carrick and Wenxin Zheng
11 Peritoneum and Broad Ligament . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
M. Ruhul Quddus, Sharon Liang, Wenxin Zheng, and C. James Sung
12 Endometriosis and Endometriosis-Associated Tumors. . . . . . . . . . . . . . . . . . . . . 405
Rosalia C. M. Simmen, Charles Matthew Quick,
Angela S. Kelley, and Wenxin Zheng
13 Complications of Early Pregnancy and Gestational
Trophoblastic Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
Philip P. C. Ip, Yan Wang, and Annie N. Y. Cheung
14 Overview of Placenta Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
John Paul B. Govindavari and Anna R. Laury
15 Placenta and Pregnancy-Related Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493
Erica Schollenberg, Anna F. Lee, Jefferson Terry, and Mary Kinloch
xi
xii Contents
16 Principles and Practical Guidelines of Intraoperative Consultation. . . . . . . . . . 541

Hannah Goyne, Emily Paull Acheson, and Charles Matthew Quick
17 Gynecologic Cytology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571
Uma Krishnamurti, Marina Mosunjac, Georgios Deftereos,
and Krisztina Z. Hanley
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631
About the Editors
Oluwole Fadare Dr. Oluwole Fadare is a Professor of

Pathology at the University of California San Diego School of
Medicine (UCSD, San Diego, CA, USA), where he also serves
as the Chief of Anatomic Pathology for the UCSD Health
System and Director of the Gynecologic/Breast Pathology fel-
lowship. Dr. Fadare completed a fellowship in breast and gyne-
cologic pathology at the Yale University School of Medicine
(New Haven, CT, USA) in 2005, and has spent his subsequent
academic career focused on the pathologic aspects of women’s
health. Dr. Fadare has been the recipient of numerous presti-
gious awards, including most recently the 2018 Arthur Purdy
Stout Prize from the Arthur Purdy Stout Society of Surgical
Pathologists in recognition of “significant career achievements
in Surgical Pathology by a Surgical Pathologist (less than 45
years old) whose publications have had a major impact on
diagnostic pathology”, a 2018 Stowell-Orbison Certificate of
Merit from the United States and Canadian Academy of
Pathologists (USCAP), and a 2017 Excellence in Mentoring
Award from UCSD Health Sciences International “in recogni-
tion of a sustained commitment to helping create a cadre of
global leaders in innovative academic medicine”. Dr. Fadare
has published more than 200 peer-reviewed articles in high
impact scientific journals, predominantly centered on gyneco-
logic pathology. Previous books edited or co-written include
Diagnosis of Neoplasia in Endometrial Biopsies: A Pattern-
Based and Algorithmic Approach (Cambridge University
Press, 2014) and Precancerous Lesions of the Gynecologic
Tract: Diagnostic and Molecular Genetic Pathology (Springer
2015). Dr. Fadare has served in various editorial capacities for
over 80 journals, and is currently an editorial board member
for the International Journal of Gynecological Pathology,
Human Pathology, Advances in Anatomic Pathology, Archives
of Pathology and Laboratory Medicine, Archives of Medical
Research, and Diagnostic Pathology, among others. He is also
active in various professional societies, and currently serves on
the education committee for the International Society of
Gynecologic Pathologists and on the membership committee
for USCAP. Dr. Fadare’s research has been clinical based, and
has focused on integrating morphological, immunohistochem-
ical and molecular aspects of gynecologic tract neoplasms to
optimize diagnostic, prognostic and predictive patient care.
xiii
xiv About the Editors
Donghui Guo Dr. Guo graduated from the Fourth Military

Medical University of China in 1974, and is one of the top
gynecologic pathologists in China. Mentored by Professor
Song Lin in the early part of her career, Dr. Guo has practiced
gynecologic pathology for more than 30 years. Dr. Guo served
as Chairman in the Department of Pathology, Tianjin Central
Hospital of Obstetrics and Gynecology for 10 years. She has
mentored many graduate students, residents, and fellows with
an interest in gynecologic pathology. Dr. Guo has served as a
committee member as well as a well-recognized expert in
gynecologic pathology for many professional societies in
China. Dr. Guo has completed 4 major scientific achievements
(please provide the details here) with multiple awards in
Tianjin, China. Dr. Guo has authored and co-edited 5 pathol-
ogy books and has published more than 30 peer-reviewed
articles.
Charles Matthew Quick Dr. Charles “Matt”hew Quick is an

associate professor and clinical educator in the Department of
Pathology at UAMS in Little Rock, Arkansas. He completed
fellowships in surgical pathology at UAMS and Women’s &
Perinatal pathology at Harvard Medical School, Brigham &
Women’s Hospital. Dr. Quick serves as the Director of
Anatomic Pathology Sub-Specialty Practice, Gynecologic
Pathology, and the Surgical Pathology Fellowship.
He has published numerous research publications and
review articles, and has authored and co-edited multiple text-
books, including “High-Yield Pathology: Gynecologic and
Obstetric Pathology.” He loves all things teaching and gyne-
cologic pathology related and has won numerous teaching
awards for his medical student and resident education efforts,
including UAMS’s campus-wide “Chancellor’s Award for
Teaching Excellence.” Dr. Quick is dedicated to expanding
pathology education in medical school and has started numer-
ous programs at UAMS to effect this change including the
UAMS pathology interest group: SCOPE, a summer pathol-
ogy preceptorship, and the integration of autopsy pathology
into the first year gross anatomy course, earning him an
Education Innovation award in 2015. His efforts have led to a
dramatic increase in medical students choosing pathology as a
career in the state of Arkansas.
Dr. Quick serves as an Ambassador for the United States
and Canadian Academy of Pathology, and has taught numer-
ous interactive microscopy courses for the USCAP at both
annual meetings and the new teaching complex located in
Palm Springs, California. He serves as the Gynecologic
Pathology Course Director for the USCAP Interactive
Microscopy Center. Dr. Quick’s research interests include the
study of endometrial precancers, vulvar squamous carcino-
genesis and the impact of epithelial-mesenchymal transition
on tumor behavior.
About the Editors xv
Danhua Shen Dr. Danhua Shen, Associate Professor of

Pathology, is the Chairman of the Department of Pathology,
People’s Hospital of Peking University, China. Dr. Shen is
one of the top gynecologic pathologists in China. In addi-
tion to her dedication to pathology diagnosis, Dr. Shen has
participated in many research projects of National Natural
Science Foundation of China. She is the head of the Female
Reproductive Diseases Group of the Pathology Branch of the
Chinese Medical Association, and serves as an executive com-
mittee member for many prestigious professional societies
including the Chinese Gynecologic Oncology Group, Chinese
Society of Obstetrics and Gynecology, and Chinese Society of
Colposcopy and Cervical Pathology, etc. Dr. Shen is also an
editorial board member for the Journal of Chinese Pathology
and the Chinese Journal of Obstetrics and Gynecology, and
the Journal of Diagnostic Pathology.
Dr. Shen has published more than 100 peer reviewed arti-
cles, and has been involved in seven clinical and pathological
related monographs/books or book chapters either as an
editor-in-chief or deputy editor-in-chief. Dr. Shen has also
participated in many book translations in the field of Pathology
and Obstetrics and Gynecology.
Wenxin Zheng Dr. Zheng is a tenured Professor in the

Department of Pathology and the Department of Obstetrics
and Gynecology at the University of Texas Southwestern
Medical Center (UTSW). An internationally recognized gyne-
cologic pathologist as well as active physician scientist, he
specializes in all aspects of gynecologic pathology and holds
the Mark and Jane Gibson Distinguished Professorship in
Cancer Research. Dr. Zheng also serves as the Director of
Gynecologic Pathology service and the Director of
Gynecologic Pathology Fellowship at the UTSW Medical
Center.
Dr. Zheng earned his medical degree at Shanghai Medical
College Fudan University. He completed a residency in obstet-
rics and gynecology at the Hospital of Obstetrics and
Gynecology in Shanghai and, later, a residency in anatomic
and clinical pathology at New York Hospital-Cornell Medical
Center. He received advanced training through a gynecologic
pathology fellowship at Women & Infants Hospital of Rhode
Island and a research fellowship in molecular reproductive
medicine at Columbia University College of Physicians and
Surgeons (New York).
Dr. Zheng runs an active consultation practice that receives
material world wide. Dr. Zheng has published more than 180
peer-reviewed articles in high impact scientific journals,
mostly in the field of gynecologic pathology. He has served in
various editorial capacities for over 50 journals, and is cur-
rently an editorial board member for multiple journals in the
biomedical sciences. His main research contributions include
endometrial serous carcinogenesis and precancerous lesion
endometrial glandular dysplasia, cell origin of low-grade
xvi About the Editors
ovarian serous carcinoma, molecular mechanism of progestin

resistance in endometrial cancer and its precancers, hormonal
etiology of ovarian epithelial cancers, and tubal contribution
of ovarian endometriosis and its associated ovarian cancers. In
addition, Dr. Zheng has created a novel approach called one-
stop cervical care (OSCC) to diagnose and treat cervical pre-
cancers. Dr. Zheng Loves teaching gynecologic pathology to
residents and fellows and have taught numerous gynecologic
pathology courses nationally and internationally.
Contributors
Emily Paull Acheson Department of Pathology, College of Medicine, University of Arkansas

for Medical Sciences, Little Rock, AR, USA
Esther Baranov Penn Medicine, University of Pennsylvania Heath System, Philadelphia, PA,
USA
Kelley Carrick Departments of Pathology, Obstetrics and Gynecology, University of Texas
Southwestern Medical Center, Dallas, TX, USA
Hao Chen Department of Pathology, UTSouthwestern Medical Center, Dallas, TX, USA
Annie N. Y. Cheung Department of Pathology, The University of Hong Kong, Queen Mary
Hospital, Hong Kong, SAR, China
Department of Pathology, HKU-Shenzhen Hospital, Shenzhen, China
Georgios Deftereos University of Utah School of Medicine, Salt Lake City, UT, USA
Mohamed Mokhtar Desouki Department of Pathology, Microbiology and Immunology,
Vanderbilt University School of Medicine, Nashville, TN, USA
Oluwole Fadare Department of Pathology, University of California San Diego, San Diego,
CA, USA
John Paul B. Govindavari Department of Pathology and Laboratory Medicine, Cedars-Sinai
Medical Center, Los Angeles, CA, USA
Hannah Goyne Department of Pathology, College of Medicine, University of Arkansas for
Medical Sciences, Little Rock, AR, USA
Krisztina Z. Hanley Emory University Hospital, Atlanta, GA, USA
Brooke E. Howitt Department of Pathology, Stanford University Medical Center, Stanford,
CA, USA
Philip P. C. Ip Department of Pathology, The University of Hong Kong, Queen Mary Hospital,
Hong Kong, SAR, China
C. James Sung The Warren Alpert Medical School of Brown University, Women & Infants
Hospital, Providence, RI, USA
Taylor M. Jenkins Penn Medicine, University of Pennsylvania Heath System, Philadelphia,
PA, USA
Jennifer Katzenberg Department of Pathology, University of California San Diego, San
Diego, CA, USA
Angela S. Kelley Department of Obstetrics and Gynecology, University of Michigan Health
Systems, Ann Arbor, MI, USA
xvii
xviii Contributors
Mary Kinloch Saskatoon City Hospital, Saskatoon, SK, Canada

University of Saskatchewan, Saskatoon, SK, Canada
David L. Kolin Department of Pathology, Brigham and Women’s Hospital, Boston, MA,
USA
Uma Krishnamurti Emory University Hospital, Atlanta, GA, USA
Anna R. Laury Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical
Center, Los Angeles, CA, USA
Anna F. Lee Children’s and Women’s Health Centre of British Columbia, Vancouver, BC,
Canada
University of British Columbia, Vancouver, BC, Canada
Sharon Liang Department of Pathology and Laboratory Medicine, Allegheny Health Network
West Penn Hospital, Drexel University College of Medicine, and Temple University School of
Medicine, Pittsburgh, PA, USA
Douglas I. Lin Foundation Medicine, Inc., Cambridge, MA, USA
Martina Z. Liu Brigham and Women’s Hospital, Boston, MA, USA
Jinsong Liu Department of Pathology, The University of Texas MD Anderson Cancer Center,
Houston, TX, USA
Cathleen Matrai Weill Cornell Medical College, Cornell University and New York-
Presbyterian Hospital, New York, NY, USA
Marina Mosunjac Emory University Hospital, Atlanta, GA, USA
Marisa R. Nucci Division of Women’s and Perinatal Pathology, Department of Pathology,
Brigham and Women’s Hospital, Boston, MA, USA
Charles Matthew Quick Department of Pathology, College of Medicine, University of
Arkansas for Medical Sciences, Little Rock, AR, USA
Preetha Ramalingam Department of Pathology and Laboratory Medicine, MD Anderson
Cancer Center, University of Texas, Houston, TX, USA
Andres A. Roma Department of Pathology, University of California San Diego, San Diego,
CA, USA
M. Ruhul Quddus The Warren Alpert Medical School of Brown University, Women &
Infants Hospital, Providence, RI, USA
Erica Schollenberg IWK Health Centre, Halifax, NS, Canada
Dalhousie University, Halifax, NS, Canada
Lauren E. Schwartz Penn Medicine, University of Pennsylvania Heath System, Philadelphia,
PA, USA
Elvio G. Silva Department of Pathology, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA
Rosalia C. M. Simmen Department of Physiology and Biophysics, University of Arkansas
for Medical Sciences, Little Rock, AR, USA
Anil K. Sood Gynecologic Oncology and Reproductive Medicine, The University of Texas
MD Anderson Cancer Center, Houston, TX, USA
David Suster Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA,
USA
Contributors xix
Jefferson Terry Children’s and Women’s Health Centre of British Columbia, Vancouver, BC,
Canada
University of British Columbia, Vancouver, BC, Canada
Yan Wang Department of Pathology, HKU-Shenzhen Hospital, Shenzhen, China
Jing Zhang Department of Pathology, Xijing Hospital, The Fourth Military Medical
University, Shaanxi, People’s Republic of China
Wenxin Zheng Departments of Pathology, Obstetrics and Gynecology, University of Texas
Southwestern Medical Center, Dallas, TX, USA
Uterine Mesenchymal Lesions
1
Brooke E. Howitt and Marisa R. Nucci
Abstract esenchymal tumors that may be encountered in the uterus.

m
This chapter will cover the pathology of uterine mesen- The salient histopathologic, immunophenotypic, as well as
chymal tumors, including endometrial stromal neoplasms, molecular findings that help separate these different tumor
undifferentiated uterine sarcomas, uterine tumors resem- types will be discussed.
bling ovarian sex cord-stromal tumors (UTROSCT),
smooth muscle tumors, perivascular epithelioid cell tumor
(PEComa), Mullerian adenosarcoma, and inflammatory 1.2 Endometrial Stromal Tumors (ESTs)
myofibroblastic tumor, as well as some less common
mesenchymal tumors that may be encountered in the Currently, the World Health Organization (WHO) recognizes
uterus. The salient histopathologic, immunophenotypic, four main categories of endometrial stromal tumors: (1)
as well as molecular findings that help separate these dif- endometrial stromal nodule, (2) low-grade endometrial stro-
ferent tumor types will be discussed. mal sarcoma, (3) high-grade endometrial stromal sarcoma,
and (4) undifferentiated uterine sarcoma. High-grade endo-
Keywords metrial stromal sarcoma is now recognized as a distinct
Leiomyoma · Leiomyosarcoma · Endometrial stromal entity largely due to its unique histology, clinical behavior,
tumor · Endometrial stromal sarcoma · PEComa · and underlying molecular alterations [1, 2]. Additional
Inflammatory myofibroblastic tumor · Adenosarcoma · molecularly defined “high-grade uterine sarcomas” with
Uterine tumor resembling ovarian sex cord-stromal tumor alterations in the gene BCOR have more recently been
described and thus have not been formally adopted into the
WHO categorization of endometrial stromal tumors and
therefore will be discussed separately.
1.1 Introduction
This chapter will cover the pathology of uterine mesenchy- 1.2.1 Endometrial Stromal Nodule
mal tumors, including endometrial stromal neoplasms,
undifferentiated uterine sarcomas, uterine tumors resem- 1.2.1.1 Definition
bling ovarian sex cord-stromal tumors (UTROSCT), smooth Endometrial stromal nodule (ESN) is defined as an endome-
muscle tumors, perivascular epithelioid cell tumor trial stromal neoplasm with no or minimal myometrial inva-
(PEComa), Mullerian adenosarcoma, and inflammatory sion and no vascular invasion.
myofibroblastic tumor, as well as some less common
1.2.1.2 Clinical Features
Endometrial stromal nodules (ESN) are benign neoplasms
B. E. Howitt that occur across a very wide age range but are most fre-
Department of Pathology, Stanford University Medical Center, quently encountered in women in their fifth to sixth decades
Stanford, CA, USA
[3–6].
e-mail: [email protected]
M. R. Nucci (*)
1.2.1.3 Gross Findings
Division of Women’s and Perinatal Pathology, Department of
Pathology, Brigham and Women’s Hospital, Boston, MA, USA ESN may be located at the submucosal layer of the uterine
e-mail: [email protected] wall, project into the endometrial cavity as an exophytic
© Science Press & Springer Nature Singapore Pte Ltd. 2019 1

W. Zheng et al. (eds.), Gynecologic and Obstetric Pathology, Volume 2, https://doi.org/10.1007/978-981-13-3019-3_1
2 B. E. Howitt and M. R. Nucci
Fig. 1.2 Endometrial stromal nodule. This is an example of an endo-

metrial stromal nodule, composed of cells with bland fusiform nuclei,
often forming whorls around small arteriole-like vessels. These high-
power cytologic features are indistinguishable from a low-grade endo-
Fig. 1.1 Endometrial stromal nodule. Endometrial stromal nodules are metrial stromal sarcoma
well circumscribed, and typically soft in consistency and yellow to tan
in coloration. This example also shows some cystic change
mass, or occur deep within the myometrium with no appar-

ent connection to the endometrium. On gross examination,
they are well circumscribed and may be mistaken for a leio-
myoma; however, ESNs are usually softer in consistency and
less rubbery without a bulging cut surface. Additionally,
ESNs tend to be more yellow in coloration (Fig. 1.1).
Hemorrhage and cystic degeneration may be seen.
Endometrial stromal nodules can vary in size but are usually
<10 cm, though larger tumors have been described [3, 5, 7,
8]. It is important to note that the border of ESN with the
surrounding myometrium must be entirely submitted for his-
tologic examination to exclude microscopic infiltration.
1.2.1.4 Microscopic Findings Fig. 1.3 Endometrial stromal nodule. Microscopically, endometrial
Histologically, ESN are well-circumscribed but unencapsu- stromal nodules typically are sharply demarcated from the surrounding
myometrium without infiltrative borders
lated tumors resembling the nonneoplastic stroma of prolif-
erative endometrium, composed of cells with uniform round
to ovoid/fusiform nuclei that have scant to moderate amounts ESN no vascular invasion is present, and any irregular foci at
of eosinophilic to amphophilic cytoplasm. These cells appear the myometrial interface must be <3 in number, and each of
to whorl around a prominent vascular component, which these foci should extend <3 mm from the main mass [3].
resembles spiral arterioles of nonneoplastic endometrium ESN may demonstrate variant morphology, including smooth
(Fig. 1.2). The vessels are typically evenly spaced and uni- muscle and sex cord-like differentiation, making the diagno-
form in caliber throughout the neoplasm. In a minority of sis more challenging [6, 9, 10] (discussed in more detail in
cases, larger, thick-walled vessels may be focally present and the low-grade endometrial stromal sarcoma (LGESS) variant
are usually located at the periphery. ESN is characterized by morphology section).
sharp circumscription between the tumor nodule and sur- Occasionally, some endometrial stromal tumors are pre-
rounding tissue (endometrium or myometrium) (Fig. 1.3). dominantly well-circumscribed but exhibit greater than
Sometimes there may be some slight irregularity to the bor- 3 mm extension into the surrounding myometrium yet also
der in the form of small lobulated or fingerlike extensions lack the typical overt myometrial permeation seen in endo-
into the surrounding myometrium (Fig. 1.4) [3]. However in metrial stromal sarcoma. The term “endometrial stromal
1 Uterine Mesenchymal Lesions 3
endometrial stromal neoplasms. Similarly, HCL like other

smooth muscle neoplasms frequently have prominent cleft-
like spaces that are not a feature of ESN/LGESS. It is impor-
tant to be aware that while immunohistochemistry may be
helpful in this distinction by the finding of strong diffuse
caldesmon and desmin positivity and CD10 negativity, many
examples of HCL may be CD10 positive and also have less
strong/diffuse staining for caldesmon/desmin than conven-
tional leiomyomas [12]. Furthermore, endometrial stromal
tumors may have morphologic and immunophenotypic evi-
dence of smooth muscle differentiation so correlation of the
immunohistochemical findings with the morphology is criti-
cal. Regarding the concept of stromomyoma or endometrial
stromal lesion with smooth muscle differentiation, please
refer to the section of LGESS below.
Fig. 1.4 Endometrial stromal tumor with limited infiltration. Some
endometrial stromal neoplasms have predominantly well-circumscribed
borders but may show a limited amount of permeative, fingerlike pro- 1.2.1.7 Genetic Profile
jection into the myometrium. When these measure >3 mm from the The genetic profile of ESN is nearly identical to that in
main mass and are >3 in number, these tumors are classified as endome- LGESS and thus will be discussed below under
trial stromal tumors with limited infiltration
LGESS. Briefly, ESN is characterized by frequent transloca-
tions involving JAZF1.
tumor with limited infiltration” has been proposed for such
tumors [6]. Given that very few cases have been described 1.2.1.8 Management and Outcome
and all have been treated by hysterectomy, the long-term bio- Most women with ESN have been treated by hysterectomy,
logic potential and natural history is not known [6]. In prac- in part because they may be an incidental finding in hysterec-
tice, we recommend diagnosing these as “endometrial tomy specimens but also due to the difficulty in distinguish-
stromal sarcoma with limited infiltration” or “endometrial ing between ESN and LGESS in biopsy or curettage
stromal neoplasm with limited infiltration” with a comment samplings which often triggers hysterectomy. If fertility
suggesting that the tumor may pursue a benign clinical preservation is desired, this might be possible with resection
course but clinical follow-up is nevertheless recommended. of the nodule to include the mass and a rim of myometrium
to assess for invasion but is dependent on tumor size or loca-
1.2.1.5 Biomarkers tion within the uterus. Although few women with ESN have
Similar to nonneoplastic endometrial stroma, ESNs are virtu- been treated conservatively (i.e., local excision without com-
ally always positive for CD10 and PR by immunohistochem- plete hysterectomy), none of the reported patients have
istry and are otherwise nearly identical immunophenotypically recurred [3, 6].
to LGESS.
1.2.1.6 Differential Diagnosis 1.2.2 E

ndometrial Stromal Sarcoma
One of the most important considerations in the differential (Low-Grade)
diagnosis of ESN is that of LGESS, which is a malignant
tumor. ESN and LGESS are distinguished entirely by histo- 1.2.2.1 Definition
logic features, specifically pattern of growth/border with A malignant tumor composed of cells resembling nonneo-
myometrium and presence or absence of lymphovascular plastic endometrial stroma, with invasion into surrounding
invasion [2, 6, 11]. In some cases, there may be limited infil- myometrium and/or vascular invasion
tration of the myometrium, comprising a gray area diagnosti-
cally. As discussed above, such tumors are classified as 1.2.2.2 Clinical Features
“endometrial stromal neoplasm with limited infiltration.” Of LGESS occur over a wide age range but are most commonly
note, ESN cannot be distinguished from LGESS by immuno- encountered in the perimenopausal and postmenopausal
histochemical or molecular methods. period, with a mean age at presentation of 52 years [13].
Another entity that may be confused with ESN is highly Though ESS comprise <1% of all uterine malignancies, they
cellular leiomyoma (HCL). HCL is characterized by a dense, are the second most common uterine sarcoma [14]. Typically,
hypercellular spindled stroma but contains characteristic patients with LGESS present with abnormal uterine bleed-
intratumoral thick-walled vessels which are not common in ing, postmenopausal bleeding, or pain; less commonly a
mass or uterine enlargement may be palpated. In about one lymphovascular invasion, in contrast to ESN (Fig. 1.6).
third of cases, clinical presentation may be related to signs or Hyaline bands and plaques are commonly encountered in
symptoms related to metastatic disease. LGESS but are not a specific finding (Fig. 1.7a). Foamy his-
tiocytes, either singly or in clusters, may be seen in LGESS
1.2.2.3 Gross Findings (Fig. 1.7b). Less commonly encountered morphologic fea-
LGESS may present as an intracavitary or intramural uterine tures include extensive myxoid change and a prominent
mass and can appear well-circumscribed or with overt myo- fibrous stroma.
metrial infiltration with tonguelike extensions and wormlike
intravascular tumor plugs (Fig. 1.5) [7]. The cut surface is 1.2.2.5 Biomarkers
generally tan to yellow and hemorrhage may be apparent. CD10 was recognized as a potential marker of endometrial
Necrosis is less commonly identified grossly. stromal differentiation based on its high expression in LGESS
[15–18]. It is now well known that CD10 is expressed in
1.2.2.4 Microscopic Findings and Histologic endometrial stromal cells including those in eutopic endome-
Grading trium, adenomyosis, and endometriosis in addition to ESN
Histologically, the tumor cells resemble nonneoplastic and LGESS [18, 19]. CD10 is typically strongly and diffusely
proliferative-phase endometrial stroma and appear virtually positive in nonneoplastic and neoplastic endometrial stroma
identical to ESN. However, LGESS by definition exhibits (Fig. 1.8a); however, some endometrial stromal tumors may
prominent fingerlike penetration of the myometrium and/or be negative for this marker [20–22]. Another marker of
Fig. 1.5 Low-grade endometrial stromal sarcoma, gross appearance. Fig. 1.6 Low-grade endometrial stromal sarcoma. From low-power
Endometrial stromal sarcoma is a tan to yellow mass with nodular microscopic examination, the permeative fingerlike pattern of infiltra-
“wormlike” growth through the myometrium tion into the myometrium is apparent
a b
Fig. 1.7 Low-grade endometrial stromal sarcoma histologic features. also be present in small numbers or large aggregates in endometrial
(a) Endometrial stromal neoplasms frequently have hyaline plaques or stromal neoplasms
bands, but this is not specific to this entity. (b) Foamy histiocytes may
a b
Fig. 1.8 Low-grade endometrial stromal sarcoma immunohistochem- plasms. (c) Desmin is typically negative in endometrial stromal neo-
istry. (a) CD10 is almost always positive in LGESS (as well as ESN). plasms; however, it may be positive in areas of smooth muscle
(b) The hormone receptors estrogen receptor and progesterone receptor differentiation
are typically strongly positive in low-grade endometrial stromal neo-
e ndometrial stromal differentiation is the novel marker inter- Other less common variant features include epithelioid mor-
feron-induced transmembrane protein 1 (IFITM1) which has phology, clear or granular cytoplasm, bizarre atypia, pseudo-
shown to be a sensitive and specific marker for endometrial papillary growth, ossification, osteoclast-like giant cells, and
stromal tumors and is also highly expressed in nonneoplastic adipocytic metaplasia [27–32].
endometrial stroma [23]. Endometrial stromal tumors are
generally positive for ER and PR (Fig. 1.8b) and negative for 1.2.2.7 Endometrial Stromal Tumor
smooth muscle markers (Fig. 1.8c); however desmin positiv- with Endometrioid Glands
ity has been documented in otherwise conventional appearing Uncommonly, LGESS may have foci of endometrioid glandu-
ESTs, while caldesmon appears to be specific for smooth lar differentiation [30, 33]. Although divergent differentiation
muscle differentiation. p53 is generally wild type in is the most likely explanation for their presence, some exam-
LGESS. Nuclear beta-catenin is frequently expressed in both ples may represent entrapped nonneoplastic endometrial glands
ESN and LGESS [24]. (Fig. 1.9). In general, this type of differentiation in LGESS is
focal and the main differential diagnosis is the distinction from
1.2.2.6 Variants of Endometrial Stromal Tumors adenomyosis, particularly gland-poor adenomyosis, which
Both ESN and LGESS may exhibit a wide range of altered only rarely forms a distinct grossly apparent mass [34].
differentiation, including smooth muscle, sex cord-like, and
epithelial (endometrioid-type glands); very rarely skeletal 1.2.2.8 Endometrial Stromal Tumor with Smooth
muscle differentiation may be seen [4, 9, 10, 25–27]. Muscle Differentiation
Extensive stromal hyalinization secondary to increased col- ESN/LGESS with smooth muscle differentiation are not
lagenous matrix production may impart a fibroblastic appear- common but are a source of confusion in the recognition and
ance. However, in general, other areas with typical diagnosis of endometrial stromal tumors [10, 26]. If the
endometrial stromal morphology are usually present. In smooth muscle component comprises more than 30% of the
addition, the characteristic vascular component and arrange- tumor, then they are considered by some to be mixed endo-
ment of the tumor cells around them are maintained [28, 29]. metrial stromal-smooth muscle tumors [10]; however, many
prefer to use the terminology ESN with smooth muscle dif- 1.2.2.9 Endometrial Stromal Tumor with Sex
ferentiation or LGESS with smooth muscle differentiation. Cord-Like Elements
Historically these tumors may have been called “stromomy- LGESS/ESN may contain variable amounts of sex cord-like
oma.” Histologic features of smooth muscle differentiation elements, typically resembling ovarian granulosa cell or
include typical smooth muscle morphology reminiscent of Sertoli cell tumors (Fig. 1.11a, b). This finding is seen in up
that seen in leiomyomata (Fig. 1.10a), nodules with central
prominent hyalinization, or irregular islands that can be
either discrete or merge imperceptibly with the areas charac- a
teristic of stromal differentiation (Fig. 1.10b). These tumors
have been shown to be of endometrial stromal derivation by
molecular analyses; therefore, determination of benign ver-
sus malignant should be made using the criteria for endome-
trial stromal tumors [10]. Immunohistochemically, areas of
smooth muscle differentiation within an endometrial stromal
tumor will stain identically to smooth muscle tumors, while
areas of conventional endometrial stromal appearance should
be negative for caldesmon but may be variably positive for
desmin. CD10 is not entirely specific and may be expressed
in the smooth muscle component.
Fig. 1.10 Endometrial stromal tumors with smooth muscle differentia-

Fig. 1.9 Low-grade endometrial stromal sarcoma with endometrioid tion. Both endometrial stromal nodule (a) and low-grade endometrial
glands. The infiltrative pattern of this tumor is apparent, and focally stromal sarcoma (b) may demonstrate varying amounts of smooth mus-
there is a benign-appearing endometrioid gland within the LGESS cle differentiation
a b
Fig. 1.11 Low-grade endometrial stromal sarcoma with sex cord differentiation. Endometrial stromal tumors may have variant sex cord differen-
tiation (a). Typically, this is in the form of cords and trabeculae resembling granulosa cell or Sertoli cell tumor (b)
to 60% of endometrial stromal tumors and may coexist with be confused with uterine smooth muscle tumors [10, 20, 27,
smooth muscle differentiation. The presence of sex cord-like 28, 51]. Conversely, uterine smooth muscle tumors may
differentiation in ESN and LGESS does not appear to have mimic endometrial stromal tumors, particularly when the
an impact on clinical behavior. Histopathologic criteria for former is markedly cellular (e.g., highly cellular leiomyoma)
the distinction between a stromal nodule and stromal sar- or has prominent vascular invasion (e.g., intravascular leio-
coma, as outlined previously, are applied regardless of the myomatosis, IVL) [8, 52–55]. In general, the morphologic
presence of sex cord-like elements. Immunohistochemically, appearance of tumor cells and the growth pattern within the
the sex cord-like elements will stain for typical sex cord myometrium can distinguish LGESS from leiomyosarcoma.
markers (e.g., inhibin, calretinin, CD99) only in the areas of In contrast to leiomyosarcoma, areas of smooth muscle dif-
sex cord differentiation. The background endometrial stro- ferentiation in LGESS tend to be bland and will not exhibit
mal tumor will typically not be positive for these markers. the degree of cellularity and nuclear pleomorphism that is
frequently encountered in leiomyosarcoma. In cases in
1.2.2.10 Genetic Profile which there is prominent lymphatic or vascular permeation
Chromosomal rearrangements involving chromosomes 6, 7, by leiomyosarcoma, morphologic features such as the pres-
and 17 are the most frequent cytogenetic abnormalities that ence of fascicular growth even in the intravascular compo-
have been reported in both LGESS and ESN, with JAZF1- nent help facilitate its recognition as a malignant smooth
SUZ12 being the most common gene fusion identified muscle tumor. In addition, a panel of antibodies including
(reported frequency ranges from 25% to >90% depending on caldesmon, desmin, and CD10 may be helpful in difficult
the study design and tumor morphology) [32, 35–41]. This cases, provided one is aware of the potential pitfalls. ESN/
gene fusion reflects the chromosomal translocation t(7;17) LGESS are at most only focally positive for smooth muscle
(p15;q21) or related variant translocations frequently actin and desmin in most cases; however, a subset of mor-
observed in LGESS via conventional cytogenetics or phologically typical cases may show more extensive expres-
FISH. In ESN, one study has demonstrated that the non- sion of these markers [9, 10, 28, 56–58]. In contrast,
rearranged JAZF1 allele is transcriptionally active in ESN, caldesmon is a more specific marker of smooth muscle dif-
but in ESS it appears to be silenced [42], suggesting that epi- ferentiation than desmin and may be useful in this differen-
genetic changes play a role in LGESS pathogenesis. Another tial [56, 59]. In the distinction between intravenous
translocation involving JAZF1, t(6;7)(p21;p15), resulting in leiomyomatosis and LGESS, the histologic features sugges-
a JAZF1-PHF1 gene fusion, is present in up to 28% of ESS tive of smooth muscle in the former including vasculature
[41, 43–45]. LGESS with PHF1 rearrangement is enriched and clefting may be helpful. Additionally, the nuclei of
for sex cord-like differentiation [43, 45] but also may show smooth muscle tumors tend to be blunted (“cigar-shaped”)
myxoid morphology, smooth muscle differentiation, or typi- rather than delicately ovoid or fusiform as in endometrial
cal morphology [46]. In tumors lacking JAZF1 abnormali- stromal tumors. One pitfall to keep in mind is that caldesmon
ties, PHF1 has been also been found to be recurrently may, in some cases of highly cellular smooth muscle neo-
involved in another chromosomal translocation and resultant plasms, including cellular IVL, only show patchy or focal
gene fusion with MEAF6 [47, 48]. Other partners of PHF1 positivity [56]. One study has shown that IFITM1 may be a
described in LGESS include EPC1, BRD8, and EPC2 [49]. more specific marker of endometrial stromal differentiation
A subset of LGESS with conventional karyotyping have no in the distinction from smooth muscle tumors [60]. Similarly,
evidence of chromosomal rearrangements as well as no evi- nuclear beta-catenin staining is supportive of EST diagnosis
dence of JAZF1 or PHF1 gene fusions by RT-PCR or FISH, over a smooth muscle tumor in one study [24]. If there is a
suggesting that some of the molecular alterations in these question diagnostically, FISH for JAZF1 rearrangement may
tumors have not yet been discovered or may be too small to be performed.
detect with these methods. In addition, FISH studies of Endometrial stromal tumors with sex cord-like differen-
mixed endometrial stromal-smooth muscle tumors show evi- tiation must be distinguished from uterine tumors resem-
dence for the JAZF1 gene rearrangement in both the endo- bling ovarian sex cord tumor (UTROSCT). In the initial
metrial stromal component and smooth muscle component, description of UTROSCT, all endometrial stromal tumors
supporting the concept that these tumors are of endometrial with sex cord elements were divided into group I or group II
stromal derivation [38, 40]. Rarely, LGESS can show MDM2 based on the percent of sex cord elements present in the
amplification by FISH as well as MDM2 protein expression tumor, with group I containing only focal sex cord elements
by immunohistochemistry [50]. and group II a predominance [61]. Since that time, it has
been recognized that group I represents endometrial stromal
1.2.2.11 Differential Diagnosis tumors with sex cord-like elements while group II represents
Endometrial stromal tumors with smooth muscle differentia- UTROSCT (see later section). The finding of conventional
tion or those that have a fibrous or myxoid appearance may endometrial stromal neoplasia is the distinguishing feature
of LGESS/ESN, but may not be present or be difficult to

identify in biopsy or curettage specimens.
Consideration of the differential diagnosis of LGESS ver-
sus HGESS is discussed in the HGESS section.
1.2.2.12 Management and Outcomes

Patients with LGESS are treated by hysterectomy and bilat-
eral salpingo-oophorectomy. Patients with tumors confined
to the uterus (stage I) have an excellent prognosis, with a
5-year survival rate over 90% [7, 62]. However, recurrence
may occur in up to 25% of patients with stage I disease [7,
63]. Poor prognostic indicators within stage I disease include
older patient age and tumor size [62]. Unfortunately, there
are no histopathologic or molecular parameters to predict
which patients with tumors confined to the uterus are at risk
for recurrence. Distant metastases, frequently involving the Fig. 1.12 High-grade endometrial stromal sarcoma, gross appearance.
lung, may occur and may occur late, nearly a decade follow- High-grade endometrial stromal sarcoma may appear very similar to
ing initial diagnosis [64]. Tumors that are high stage at pre- low-grade stromal sarcoma on macroscopic examination, with a soft,
fleshy consistency, yellow to tan color, and “wormlike” infiltration of
sentation (stage III/IV) have a significantly worse prognosis, the myometrium
with only 50% 5-year survival [65]. After surgery, adjuvant
treatment options include local radiation therapy. There is no
evidence that chemotherapy or radiotherapy has any impact 1.2.3.4 Microscopic Findings and Histologic
on long-term survival [63]. Given that LGESS is typically Grading
positive for PR, hormonal therapy is an option that may be HGESS have high-grade, but uniform, cytologic atypia and
considered in patients who present with advanced-stage distend to lack the typical morphology of LGESS in that they do
ease or have recurrences. not closely resemble nonneoplastic endometrium. In some
cases HGESS may be associated with more typical appear-
ing areas of LGESS [69, 70] and, in very rare cases, may be
1.2.3 H
igh-Grade Endometrial Stromal composed of low-grade morphology entirely [68, 71].
Sarcoma (HGESS) HGESS typically has a nodular permeative growth within the
myometrium; however, destructive myometrial infiltration
1.2.3.1 Definition may also be seen (Fig. 1.13a). Moreover, the background
The discovery of YWHAE-NUTM2A/B gene fusions in a sub- vascular pattern is different; HGESS has numerous delicate
set of endometrial stromal sarcomas, which are associated and arborizing vessels as opposed to the spiral arteriolar-like
with a clinical outcome intermediate between that of LGESS vascular network of LGESS (Fig. 1.13b). In the high-grade
and undifferentiated uterine sarcoma, has led to the reintro- areas, the tumor cells are epithelioid with moderate to scant
duction of HGESS in the most recent WHO classification [2, amount of variably eosinophilic cytoplasm and rounded
66, 67]. HGESS is a malignant tumor of endometrial stromal nuclei with conspicuous nucleoli. Mitotic activity is fre-
derivation, with variable morphology but typically contain- quently brisk, >10 per 10 HPFs and tumor necrosis is not
ing at least a focal characteristic round cell component. uncommon. The low-grade components, when present, may
have typical LGESS morphology but is also highly enriched
1.2.3.2 Clinical Features for the fibromyxoid variant.
Patients often present with similar symptoms to other uterine
sarcomas, with abnormal uterine bleeding and/or a palpable 1.2.3.5 Biomarkers
uterine mass; however, unlike LGESS, patients with HGESS HGESS has a distinctly different immunohistochemical pro-
typically present with advanced-stage disease (stages III– file from that seen in LGESS, typically with a CD10−/cyclin
IV >> stage I) [68]. D1+ (>70% of tumor nuclei)/ER−/PR− pattern in the mor-
phologically high-grade areas [70]. In cases with both histo-
1.2.3.3 Gross Findings logic low- and high-grade components, different patterns of
HGESS grossly may appear very similar to LGESS, with staining may be seen in the morphologically low-grade ver-
either an intracavitary or intramural fleshy tan to yellow sus high-grade component, with the low-grade component
mass (Fig. 1.12); however, necrosis and/or hemorrhage is showing positivity for CD10, ER, and PR and only patchy
more common. positivity (usually weak and focal) for cyclin D1 [70]. In
a b
Fig. 1.13 High-grade endometrial stromal sarcoma, microscopic fea- stromal neoplasms, the vasculature in high-grade endometrial stromal
tures. (a) Though permeative fingerlike infiltration is often seen, sarcoma is characterized by thin-walled, delicate arborizing vessels.
destructive myometrial invasion (pictured here) may also be identified Additionally the tumor cells are epithelioid with vesicular nuclei
in high-grade stromal sarcoma. (b) In contrast to low-grade endometrial
a b
Fig. 1.14 High-grade endometrial sarcoma (YWHAE-rearranged) is strongly and diffusely positive for cyclin D1 (a) and BCOR (b)
contrast, the high-grade component is typically negative for worth noting that other biologically related genomic altera-
CD10, ER, and PR and shows strong and diffuse positivity tions have been recently discovered in high-grade uterine
(>70% tumor cell nuclei) for cyclin D1 (Fig. 1.14a), which sarcomas (see BCOR-altered sarcomas below). Although
may be used as a marker for YWHAE rearrangement [32, 70, most HGESS are positive for CD117 (c-kit), they lack hot
72], although this is not entirely sensitive or specific [73, 74]. spot mutations in CKIT [75].
Additionally, CD117 (c-kit) and BCOR (Fig. 1.14b) may be
positive in HGESS [75, 76]. 1.2.3.7 Differential Diagnosis
Given that HGESS has an epithelioid appearance, it may be
1.2.3.6 Genetic Profile confused with an undifferentiated carcinoma, particularly in
HGESS has the characteristic karyotypic abnormality limited sampling such as a biopsy or curettage. One pitfall to
t(10;17)(q22;p13) associated with a YWHAE-NUTM2A/B keep in mind is that endometrial undifferentiated carcinoma
fusion [67, 68]. YWHAE rearrangements have not been found can also show strong and diffuse positivity for cyclin D1;
in other gynecologic tumors, and FISH or RT-PCR studies however, they will usually show focal positivity for EMA, a
may serve as a useful adjunct to the histologic diagnosis [72, broad-spectrum cytokeratin. Undifferentiated carcinomas
77]. FISH analysis on FFPE tissue for the YWHAE- may also be positive for CD10 [73]. Identification of a well-
NUTM2A/B rearrangement is becoming more widely avail- differentiated adenocarcinoma component is helpful in
able and is feasible to use in routine clinical practice. It is establishing a diagnosis of undifferentiated carcinoma
(“dedifferentiated carcinoma”) rather than HGESS. In cases 1.2.4 U

terine Stromal Sarcoma with BCOR
lacking a well-differentiated adenocarcinoma component or Alterations
significant EMA/cytokeratin expression, molecular studies
may be necessary (YWHAE FISH). Recently, new genomic subtypes of uterine sarcomas have
HGESS must also be distinguished from LGESS, which been described, which appear to be high grade in morphol-
in cases where the dominant morphology is low-grade may ogy and clinical behavior and are associated with distinct
be difficult. Adequate sampling and attention to identifying genetic alterations in the gene BCOR. The first involves the
the high-grade areas is key to distinguishing HGESS from gene fusion ZC3H7B-BCOR (or the reverse fusion BCOR-
LGESS. Features that should raise suspicion for a HGESS ZC3H7B) and the second, internal tandem duplications
include high disease stage at presentation, destructive myo- (ITD) of BCOR [74, 79–81].
metrial invasion, and a large epithelioid cell population
arranged in nests or cords among an arborizing delicate vas- 1.2.4.1 Clinical Features
cular network. The correct block must be selected to stain Patient with ZC3H7B-BCOR uterine sarcomas have a mean
immunohistochemically, as the morphologically low-grade age of presentation of 54 years (range 28–71) [79]. In tumors
areas in HGESS can stain identically to LGESS. However, with BCOR ITD, patients appear to be younger (mean age
molecular studies such as FISH may be performed on any 24 years) [74].
tumor block as even the low-grade areas will harbor the
YWHAE translocation. 1.2.4.2 Gross Findings
HGESS may also be confused with undifferentiated uter- The gross findings are not well-known for this new group of
ine sarcoma (UUS), particularly in a limited biopsy. UUS tumors but appear to be similar to other uterine sarcomas
can be positive for cyclin D1, but the finding of co-expression (Fig. 1.15a).
of strong and diffuse CD10 is helpful in excluding
HGESS. Conversely, identification of a low-grade compo- 1.2.4.3 Microscopic Findings and Histologic
nent is helpful to support a diagnosis of HGESS rather than Grading
UUS. In many cases molecular studies will be required to In tumors with ZC3H7B-BCOR fusions, the tumors predomi-
make a definitive diagnosis. nantly involved the endometrium with tonguelike myome-
A diagnosis of leiomyosarcoma (LMS) may also be con- trial invasion similar to that seen in LGESS (Fig. 1.15b).
sidered in the differential of HGESS, particularly when the Histologically, the tumor cells are spindled with mild to
dominant LMS morphology is epithelioid. In contrast to moderate nuclear atypia and set in a prominent myxoid
HGESS which typically has a very uniform morphology stroma in the majority of cases (Fig. 1.15c). Collagen plaques
and may include areas of low-grade ESS morphology, LMS may also be seen. Mitoses are conspicuous. No cases
often has more prominent pleomorphism and lacks the described to date have associated conventional LGESS mor-
prominent vasculature resulting in the characteristic nested phology [79, 80]. In uterine sarcomas with BCOR ITD,
growth pattern of HGESS. Immunohistochemistry will tumors have a similar morphologic appearance to those har-
generally be very helpful in this regard; SMA, desmin, and/ boring BCOR gene fusions, with uniform spindle and round
or caldesmon will be positive in LMS while generally nega- cells with abundant mitotic figures, frequently in a myxoid
tive in HGESS, and conversely cyclin D1 diffuse positivity stroma with a prominent vascular network [74].
is seen in HGESS but only focal staining, if any, is present Lymphovascular invasion is common.
in LMS.
1.2.4.4 Biomarkers
1.2.3.8 Management and Outcomes All tumors with ZC3H7B-BCOR fusions express CD10
Patients with HGESS frequently have recurrences, usually (Fig. 1.16a) while displaying negative or limited reactivity
within a few years of initial diagnosis [68]. The 5-year sur- with smooth muscle markers (SMA, desmin, and
vival is ~33%, much worse than that seen in LGESS [62]. h-caldesmon) [79]. ER/PR positivity may be seen in a
Treatment is primarily surgical, with hysterectomy and bilat- minority of cases, but not diffuse strong positivity. Cyclin D1
eral salpingo-oophorectomy and tumor debulking. Although is positive in the majority of cases (Fig. 1.16b) [79]. BCOR
experience is limited, both adjuvant chemotherapy and radi- IHC is positive in half of cases, suggesting that IHC is not a
ation therapy appear to have some benefit in HGESS [62], sensitive marker for this tumor [79]. Uterine sarcomas with
particularly anthracycline-based chemotherapy [78]. BCOR ITD have diffuse cyclin D1 and BCOR immunohisto-
Hormonal therapy is likely ineffective as HGESS is typically chemical expression and only focal or negative CD10 expres-
negative for estrogen and progesterone receptor. sion and were negative for muscle markers [74].
a b
Fig. 1.15 BCOR-altered sarcoma. (a) The gross appearance of a BCOR- frequently demonstrate a permeative, fingerlike pattern of myometrial inva-
fusion sarcoma is similar to other uterine sarcomas with a fleshy, heteroge- sion. (c) Histologically, a myxoid stroma is typically prominent in sarco-
neous cut surface and foci of hemorrhage and necrosis. (b) These sarcomas mas with BCOR ITD, with hyperchromatic spindled tumor cells
a b
Fig. 1.16 BCOR-altered sarcoma, immunohistochemistry. (a) CD10 is be negative or only weakly focally positive for CD10. (b) Cyclin D1 is
strongly and diffusely positive in BCOR-fusion sarcomas as pictured strongly and diffusely positive in BCOR-altered sarcomas
here; however, those with internal tandem duplications of BCOR tend to
1.2.4.5 Differential Diagnosis 1.2.5.3 Gross Findings

The primary diagnostic considerations for BCOR-altered UUS typically presents as a large tan-yellow to gray, fleshy
uterine sarcomas include undifferentiated uterine sarcoma intracavitary polypoid mass or masses. Hemorrhage and
with uniform morphology, high-grade endometrial stromal necrosis are common.
sarcoma (YWHAE-altered), and myxoid leiomyosarcoma.
The distinction of BCOR-altered sarcomas from HGESS and 1.2.5.4 Microscopic Findings and Histologic
UUS may be difficult on morphologic and immunohisto- Grading
chemical grounds as there can be significant overlap; how- UUS is a sarcoma composed of cells that, unlike LGESS, do
ever, the high-grade component of BCOR-fusion sarcomas not resemble proliferative-phase endometrial stroma and, in
are typically CD10 positive which is in contrast to YWHAE- contrast to LGESS, usually shows destructive infiltration of
related HGESS. Myxoid leiomyosarcoma typically has the myometrium. Histologically, there are two subgroups of
hyperchromatic spindled nuclei and shows positivity for UUS, the pleomorphic type (Fig. 1.17), in which the neo-
smooth muscle markers. In difficult cases, molecular testing plastic cells show variable but frequently marked cytologic
may be needed. pleomorphism and numerous mitoses, including atypical
forms, without evidence of differentiation toward any tissue
1.2.4.6 Genetic Profile type both cytologically and architecturally by pattern of
ZC3H7B-BCOR gene fusions or BCOR ITD identified by growth within the myometrium. [83]. In contrast, UUS with
either targeted sequencing or FISH are the hallmark feature uniform morphology is characterized by atypical but fairly
of these tumors [74, 79, 80]. Of note, one ESS had previ- monomorphic epithelioid tumor cells which overlap mor-
ously been reported to have this genomic alteration, but a phologically with tumors we now classify as HGESS with
detailed histopathologic review was not performed in this YWHAE translocations or high-grade uterine sarcomas with
case [82]. BCOR alterations as described previously. In practice, the
diagnosis of UUS should only be made after extensive sam-
1.2.4.7 Management and Outcomes pling of tumor, to exclude a recognizable line of differentia-
Limited clinical data suggest that patients with ZC3H7B- tion within the tumor, and after HGESS with YWHAE
BCOR sarcomas present at higher stage and have worse translocation or BCOR alterations have been excluded,
prognosis compared with LGESS and may include lung, which might require molecular studies.
bone, and skin metastases and progressive peritoneal disease
after chemotherapy [79, 80]. 1.2.5.5 Biomarkers
Long-term follow-up in two of three patients with BCOR UUS has no well-defined immunohistochemical marker but
ITD revealed one patient to be alive without evidence of dis- often demonstrates positivity for both CD10 and cyclin D1.
ease 22 years after diagnosis and the other to be dead of dis- Additionally, UUS (particularly the pleomorphic type)
ease 8 years after diagnosis, suggesting that the clinical
course of uterine sarcomas with BCOR ITD is more indolent
than those with BCOR gene fusion [74].
1.2.5 Undifferentiated Uterine Sarcoma
1.2.5.1 Definition
Undifferentiated uterine sarcoma (UUS) is a heterogeneous
group of tumors and likely represents dedifferentiated forms
of specific uterine sarcomas (adenosarcoma, endometrial
stromal sarcoma, carcinosarcoma, leiomyosarcoma, etc.).
Some consider this entity as “undifferentiated endometrial
sarcoma”; however, we prefer the term UUS, as some of these
tumors are likely not of endometrial stromal derivation.

UUS are rare tumors encountered in postmenopausal women
Fig. 1.17 Undifferentiated uterine sarcoma, pleomorphic type. These
who present with postmenopausal bleeding, symptoms tumors demonstrate marked pleomorphism and abundant mitoses
related to the uterine mass, or symptoms related to metastatic including abnormal forms and have no specific line of differentiation by
disease. either morphology or immunohistochemistry
f requently have abnormal overexpression of p53 in contrast are subgroups of UUS with varying prognoses [88].
to HGESS [84]. Treatment options include complete debulking surgery as
well as consideration of radiation therapy for local control
1.2.5.6 Differential Diagnosis and chemotherapy for systemic control.
The diagnosis of UUS is essentially a diagnosis of exclusion
and should only be considered after excluding an undifferen-
tiated carcinoma, carcinosarcoma, leiomyosarcoma, and 1.2.6 Diagnostic Considerations
high-grade endometrial sarcoma; all of which may have from Curettage Specimens
areas of morphologic overlap. A diagnosis of UUS should
only be made on a complete excision specimen, as biopsies A suspected endometrial stromal neoplasm identified in a
may lack the diagnostic features of other uterine sarcomas/ curettage or biopsy specimen must be distinguished from
carcinomas. Extensive tumor sampling, immunohistochemi- potential mimics, including nonneoplastic aglandular func-
cal staining, and in some cases molecular testing are required tionalis, endometrial basalis, as well as benign neoplasms
to confidently diagnose UUS. such as endometrial polyp and malignant neoplasms most
UUS can be distinguished from undifferentiated carci- notably adenosarcoma. Multiple fragments of aglandular
noma and carcinosarcoma by identifying areas diagnostic of cellular endometrial-type stroma containing spiral arteriole-
an epithelial component, either morphologically or immuno- like vessels are suggestive of a stromal neoplasm (Fig. 1.18);
histochemically (EMA and/or cytokeratin positivity). in one study, curettage of a stromal neoplasm typically pro-
Similarly, leiomyosarcoma (LMS) may demonstrate a vari- duces fragments of aglandular stroma measuring ≥5 mm
ety of patterns and identifying a better differentiated area of [89]. Distinction of endometrial stromal neoplasms from
the tumor is key – LMS should contain, at least focally, fragments of basalis is made by virtue of the presence of an
strong positivity for one or more smooth muscle markers orderly component of glands in the latter. Strips of aglandu-
(SMA, desmin, caldesmon). The distinction of UUS from lar functionalis, usually associated with submucosal leio-
HGESS was discussed previously in the HGESS section. In myomata (Fig. 1.19) or occasionally progestin therapy, tend
all of these cases, adequate sampling and careful evaluation to be less cellular and show features of compression or reac-
of all tumor morphologies is necessary in making a diagnosis tive surface changes when related to submucosal leiomy-
of UUS. As molecular studies are more widely available, oma. Fragments of cellular endometrial polyps usually
these should be considered to exclude known translocation- exhibit other features of polyp, including large thick-walled
associated entities including YWHAE, JAZF1, and BCOR vessels and abnormal glandular architecture. Adenosarcoma
FISH as well as examining for BCOR internal tandem also may exhibit a cellular stroma that is CD10 positive but
duplications. typically has an epithelial component with glandular cuff-
ing, albeit sometimes subtle. Appreciation of a more spin-
1.2.5.7 Genetic Profile dled atypical stroma without the characteristic vascular
UUS tend to be cytogenetically complex, particularly when network facilitates this distinction.
histologically pleomorphic [85]. As mentioned above, previ-
ously termed “UUS with uniform morphology” likely repre-
sent various forms of HGESS and rarely may harbor JAZF1
translocation [83]. TP53 mutations are not uncommon in
UUS, in contrast to endometrial stromal neoplasms [83],
suggesting that those UUS with TP53 mutation may have no
relationship with ESS or that they have acquired a secondary
TP53 mutation. One study interrogated for KIT, EGFR, and
PDGFR hot spot mutations as well as amplification of EGFR
in UUS; none of the tumors included in their study had any
molecular aberration in these genes [86]. In an array CGH
study on endometrial sarcomas, a large number of copy num-
ber alterations in UUS are described, including gain of 7p in
a subset [85].
1.2.5.8 Management and Outcomes Fig. 1.18 Recognizing endometrial stromal neoplasia in an endome-
trial curettage. Multiple large fragments or thick strips of pure endome-
UUS is an aggressive tumor with a dismal prognosis. The trial stromal tissue without any glands is concerning for an endometrial
mean overall survival is less than 2 years [87]. In one study, stromal neoplasm. The finding of sex cord elements, as demonstrated
one third of patients did survive >5 years, suggesting there here, is additionally supportive of a neoplasm
while type 2 represents what we currently consider to be

“UTROSCT” [61].

UTROSCT occurs across a wide age range in reproductive-
and postmenopausal-aged women, with a mean age of
52 years at diagnosis [93]. Patients most often present with
abnormal uterine or postmenopausal bleeding [92, 93].

Upon gross examination, UTROSCT is generally a well-
circumscribed, firm to fleshy, tan, yellow, or gray mass that
may be found anywhere within the endomyometrium and
rarely in the cervix. Tumor size is generally small (mean
~6 cm) but may be >20 cm [61, 91–93]. Areas of hemorrhage
may be appreciated but necrosis is typically absent.
Fig. 1.19 Aglandular functionalis may raise concern for an endome-
trial stromal neoplasm; however, the strips are usually thin and lined by 1.2.7.4 Microscopic Findings
endometrial surface epithelium and may show reactive surface changes
Though typically recognized as a well-circumscribed mass
grossly, UTROSCT may demonstrate infiltration of the myo-
If an endometrial stromal neoplasm is suspected upon his- metrium upon histologic examination. Morphologically, it is
tologic evaluation, the next step in interpretation is to deter- purely or predominantly composed of epithelial-like cells
mine whether it is benign or malignant. Unfortunately, this arranged in one or more architectural patterns consistent
distinction is based on whether or not there is myometrial with ovarian sex cord-stromal tumors, most commonly gran-
infiltration or lymphovascular invasion, two criteria that gen- ulosa cell tumor (adult type) or Sertoli cell tumors, including
erally cannot be assessed on biopsy or curettage material. the retiform pattern (Fig. 1.20a). Leydig cells are generally
Performing immunohistochemistry can aid in confirming not encountered in UTROSCT. The variety of architectural
endometrial stromal differentiation, and if a JAZF1 translo- patterns includes solid, nested, trabeculae, cords, glandular,
cation is identified, the proliferation can be classified as an and retiform though nests, trabeculae, and cords are the most
endometrial stromal neoplasm, but these ancillary studies common growth patterns. Cytologically, atypia is minimal
cannot aid in determining benign versus malignant. One and mitoses are generally low (<1 per 10 HPFs) [94]. We
could raise the possibility of sarcoma if some fragments of have seen exceedingly rare examples of UTROSCT with
tissue contain myometrium infiltrated by stromal tumor or worrisome histologic features including necrosis, infiltrative
definite lymphovascular invasion is identified; however, as growth, conspicuous cytologic atypia, and brisk mitotic rate
this is highly uncommon to see in a biopsy specimen, pru- (Fig. 1.20b, c).
dent clinical and radiologic correlation is critical. In general,
diagnosis of an endometrial stromal neoplasm with a com- 1.2.7.5 Biomarkers
ment explaining the inability to reliably distinguish between UTROSCT are variably positive for a wide variety of immu-
a stromal nodule and LGESS in a biopsy or curettage speci- nohistochemical markers, including smooth muscle markers
men is appropriate. (SMA, desmin, caldesmon), the endometrial stromal marker
CD10, sex cord differentiation markers (inhibin, calretinin,
CD99, MelanA, CD56, FOXL2, and SF-1) (Fig. 1.21a, b),
1.2.7 U
terine Tumor Resembling Ovarian Sex and epithelial markers (cytokeratins, EMA). UTROSCT are
Cord Tumor (UTROSCT) also frequently positive for WT-1, CD117, and ER/PR
[90–99]. HMB45 is generally negative [90]. Although none
1.2.7.1 Definition of these markers are sensitive or specific to UTROSCT,
UTROSCT is a rare tumor in the uterus that morphologically immunohistochemical “polyphenotypic” positivity for mul-
resembles various forms of sex cord-stromal differentiation tiple of the aforementioned markers can be helpful in the
typically seen in the ovary [61, 90–92], including Sertoli diagnosis.
cell, granulosa cell, and Leydig cell differentiation. In the
original description, “UTROSCT” included type 1 and type 1.2.7.6 Differential Diagnosis
2; however, it is now generally accepted that type 1 refers to Diagnostic difficulty typically involves distinguishing
endometrial stromal tumors with sex cord-like elements, UTROSCT from other mesenchymal tumors of the uterus
a b
Fig. 1.20 Histologic features of uterine tumor resembling ovarian sex grooves. (b) Though usually well-circumscribed, UTROSCT can also
cord tumor (UTROSCT). (a) The granulosa cell-like pattern is com- have infiltrative borders. (c) Rarely, brisk mitotic activity may be
mon, with trabeculae and nests of uniform ovoid cells with nuclear appreciated
a b
Fig. 1.21 Immunohistochemical markers in uterine tumor resembling fusely positive in UTROSCT, similar to sex cord tumors of the ovary.
ovarian sex cord tumor (UTROSCT). (a) Steroidogenic factor 1 (SF-1) (b) Calretinin is typically strongly positive in UTROSCT but is a less
is a specific marker for sex cord differentiation and is strongly and dif- specific marker of sex cord differentiation
displaying sex cord differentiation, most notably endometrial Treatment is surgical, most commonly hysterectomy, but in
stromal neoplasms and less commonly adenosarcoma [100]. cases where fertility preservation is desired, a more conser-
The most important distinction is from LGESS, which is vative approach has been advocated with successful out-
malignant and associated with a much higher recurrence rate comes [105, 106]. In the rare examples of UTROSCT with
than UTROSCT. worrisome histologic features such as necrosis and brisk
ESN and LGESS may exhibit morphologic features of mitotic rate, we favor regarding these tumors as having a
ovarian sex cord-stromal tumors (discussed in the endome- higher likelihood for malignant behavior, though no studies
trial stromal tumors section). These elements may be present have established histologic criteria for malignancy in
focally, most often in the form of inter-anastomosing trabec- UTROSCT. As such, they are uniformly regarded as neo-
ulae, cords, and less commonly tubules. Uncommonly, they plasms with uncertain malignant potential.
may also be the predominant pattern in which the stromal
element is less conspicuous, particularly in a biopsy speci-
men. Whether UTROSCT also represent a form of endome- 1.3 Uterine Smooth Muscle Tumors
trial stromal neoplasia is a subject of debate although recent
molecular evidence suggests they may not be of endometrial Overview
stromal derivation (see genetic profile section below). Other Smooth muscle tumors are the most common uterine neo-
frequent entities considered in the differential diagnosis with plasms and include benign leiomyoma and variants, intrave-
UTROSCT are an epithelioid smooth muscle tumor and nous leiomyomatosis, smooth muscle tumors of uncertain
PEComa. Immunohistochemistry should be helpful in distin- malignant potential, and leiomyosarcoma.
guishing an epithelioid smooth muscle tumor from
UTROSCT, as smooth muscle tumors are positive for SMA
and desmin, and occasionally cytokeratins, but should be 1.3.1 Leiomyoma
negative for sex cord markers (inhibin, SF1, CD99, WT1,
melanA, etc.). PEComa demonstrates dual positivity for 1.3.1.1 Definition
smooth muscle and melanocytic markers (MelanA, HMB45) Leiomyoma is a benign smooth muscle tumor.
but should be negative for SF-1, WT1, and CD99. As indi-
vidual examples of UTROSCT are not always positive for all 1.3.1.2 Clinical Features
of these markers, a large panel of immunohistochemical Although more than 75% of women have leiomyoma(s) in
stains may be helpful in making the diagnosis. Less likely to their uterus, only about 25% are symptomatic [107–109].
be confused with UTROSCT is an endometrioid carcinoma Symptoms related to uterine leiomyoma include abnormal
with extensive sex cord-like differentiation, either primary in uterine bleeding, pelvic pain or pressure, and infertility or
the endometrium or metastatic from the ovary. Identifying recurrent pregnancy loss [108, 110, 111]. The type and sever-
typical adenocarcinoma morphology is helpful in this dis- ity of symptoms associated with leiomyomata is broadly
tinction, as well as the lack of smooth muscle marker and sex related to tumor size and location within the uterine wall
cord marker positivity in endometrioid carcinoma. [108]. The myometrium can conceptually be divided into
three zones: submucosal, intramural, and subserosal.
1.2.7.7 Genetic Profile Submucosal leiomyomata, as well as larger intramural
UTROSCT have been thought to represent endometrial stro- tumors that distort the endometrial cavity, may cause abnor-
mal neoplasms which show predominantly or entirely sex mal uterine bleeding and reproductive problems. Subserosal
cord differentiation; however, they do not harbor JAZF1 or or deeper leiomyomata are less likely to cause uterine bleed-
PHF1 rearrangements [101, 102]. Thus, many now believe ing but are more likely to be associated with pelvic pain or
that these may not represent endometrial stromal neoplasms. pressure.
Similarly, they do not harbor FOXL2 or DICER1 mutations
characteristic of the ovarian sex cord-stromal tumors, adult- 1.3.1.3 Gross Findings
type granulosa cell tumor and Sertoli-Leydig cell tumor, Leiomyomas may be essentially microscopic or very large
respectively [96, 103]. No recurrent or specific molecular (>20 cm) and solitary or numerous. The usual leiomyoma is
alterations have been described in UTROSCT, however the grossly well circumscribed and has a firm, rubbery texture
karyotype of one case has been reported, which revealed two (Fig. 1.22). Leiomyoma typically bulges out upon sectioning
balanced translocations t(X;6)(p22.3,q23.2) and t(4;18) because of increased intratumoral pressure. The cut surfaces
(q21.1;q21.3) [104]. are white or slightly pink and the bands of neoplastic smooth
muscle are often whorled, giving the impression that the
1.2.7.8 Management and Outcomes smooth muscle bundles are wrapped around a central core.
UTROSCT is generally a benign tumor with excellent prog- Lastly, there should be minimal variation in the appearance
nosis, but rare cases have been reported to recur [61, 91, 93]. of the cut surface. Minute foci of hemorrhage may be seen,
varying degrees, particularly in the luteal phase of reproduc-

tive women [112, 113]. Atypical mitotic figures, however,
are worrisome and should prompt further examination and
exclusion of malignancy. Within leiomyoma, one may see
varying numbers of mast cells and occasionally even promi-
nent infiltrates of other chronic inflammatory cells [114,
115]. Occasionally, dense lymphocytic infiltrates rarely may
simulate lymphoma [116, 117]. There is a wide variation in
the amount of collagenous extracellular matrix within leio-
myoma. Similar to their gross appearance, usual leiomyoma
is well circumscribed microscopically.
1.3.1.5 Secondary and Iatrogenic Changes

in Leiomyoma
Degenerative changes in leiomyomata, including myxoid/
gelatinous change, hyalinization, and calcification, are com-
Fig. 1.22 Gross appearance of typical uterine leiomyoma. Leiomyomas mon but usually easily appreciated as such. When hemor-
are characterized by being well-circumscribed, white to tan with a bulg-
ing rubbery cut surface
rhage or necrosis is present as a form of degenerative change
(Fig. 1.24), it tends to have a grossly uniform appearance,
resulting in an even pink or red cut surface. Histologically,
the interface between the viable and nonviable tissue has a
uniform arc with a transition zone composed of fibroblasts,
viable and nonviable smooth muscle cells, and scattered
inflammatory cells typical of ischemic infarction, in contrast
to the abrupt, sharply defined necrosis seen in tumor cell
(coagulative) necrosis. From time to time, thrombosis may
be seen in tumor vessels, suggesting that ischemia is the
principal cause of benign degeneration. Other clinical situa-
tions in which rapid degeneration may be noted include
pregnancy and other iatrogenic hormonal stimuli (i.e., oral
contraceptives or clomiphene), as well as torsion of a pedun-
culated subserosal or submucosal tumor. Over time, hyalin-
ization, mummification, or even dystrophic calcification may
Fig. 1.23 Histologic features of leiomyoma (typical). Leiomyomas
contain fascicular bundles of spindle cells with abundant pink cyto- become prominent.
plasm and blunt-ended nuclei which have a relatively uniform shape
and size
but large hemorrhagic areas are not characteristic. Similarly,

necrosis is not identified grossly, although areas of myxoid
degeneration may be appreciated as having a more gelati-
nous appearance. Any significant variation or deviation from
this appearance should warrant additional sampling and con-
sideration by the pathologist.
1.3.1.4 Microscopic Findings

Histologic examination of a typical leiomyoma shows fasci-
cles of bland spindled smooth muscle cells, which are virtu-
ally indistinguishable from their normal counterparts.
Specifically, the cells are long and tapered, have abundant
pink cytoplasm, and contain spindle-shaped nuclei with
blunt ends which have a relatively uniform shape and size
(Fig. 1.23). The chromatin is pale, finely textured, and uni-
Fig. 1.24 Leiomyoma with degeneration and hemorrhage. Hemorrhage
formly dispersed. Nucleoli may be noted but if present are and myxoid degeneration may be seen in leiomyoma and may be related
small and inconspicuous. Mitotic figures may be present to to an iatrogenic process
a b
Fig. 1.25 Histologic features of leiomyoma with hydropic change. (a) more difficult. (b) From low-power magnification, alternating hyper-
Prominent edema is present in hydropic leiomyoma, which may mimic and hypocellular regions may be apparent
myxoid stroma, and make the recognition of a smooth muscle neoplasm
Hydropic foci may be microscopic and patchy (Fig. 1.25a). sound energy transfer results in microscopically bland coag-
Microscopic foci of hydropic degeneration may be worri- ulative necrosis lacking atypical ghost cells.
some at lower magnifications because they often have more
irregular contours and may have sharp borders (Fig. 1.25b). 1.3.1.6 Genetic Features of Leiomyoma
Careful attention at higher magnification often resolves this Leiomyoma is characterized by recurrent point mutations
by noting the fluid-filled intercellular spaces and the absence and small deletions as well as characteristic chromosomal
of truly necrotic cells. When more extensive, the wet, slip- translocations. The karyotype of leiomyoma is either normal
pery cut surface of hydropic degeneration may often be (60%) or noncomplex with one or more chromosomal trans-
described as “myxoid.” Such tumors should be histologically locations (40%) [119–124]. The gene most commonly
examined to exclude a myxoid leiomyosarcoma by recogniz- mutated in leiomyoma is MED12, with heterozygous MED12
ing their edematous nature and lack of other malignant fea- mutations found in up to 70–80% of uterine leiomyomas
tures. In contrast to myxoid leiomyosarcoma, hydropic [125–130]. The vast majority of these are located in exon 2
leiomyomata do not infiltrate into the fascicles of adjacent at the codon 44 position. There is no evidence to date that
myometrium. germline MED12 mutations play a role in the development
In addition to the naturally occurring patterns of degen- of leiomyoma. HMGA1 or HMGA2 overexpression is com-
eration, we now frequently encounter iatrogenic necrosis and mon in leiomyoma, reflecting chromosomal translocations
other changes related to attempted conservative (nonsurgi- involving 6p21 (HMGA1) and 12q14 (HMGA2). HMGA2
cal) management of uterine fibroids. A number of new thera- overexpression is found in 10–25% of uterine leiomyomas
peutic strategies to noninvasively ablate uterine leiomyomata and tends to be mutually exclusive with MED12 mutations
have been devised. The most widespread of these new proce- [127]. When considering uterine leiomyomas lacking
dures is uterine artery embolization [118]. In this technique, MED12 mutation, HMGA2 overexpression is found in ~40%
a catheter is threaded into the uterine artery and spheres of of tumors. Other recurrent molecular aberrations in leiomy-
synthetic polymer are injected. Because the blood supply to oma include COL4A5/6 deletions, which are mutually exclu-
leiomyomata is larger than to the surrounding myometrium, sive with MED12, HMGA2, and FH alterations [131].
the tumors tend to be more vulnerable to ischemia. Of note, Leiomyomas lack TP53 mutations [128, 131].
embolization material can frequently be seen distending and Recurrent chromosomal aberrations in leiomyoma
occluding vessels within and near the tumor. Another nonin- include (in addition to HMGA2/HMGA1 as described above)
vasive therapy for uterine leiomyomata is MRI-guided ther- 13q, 1p36, 10q22, 7q deletion, trisomy 12, 1p deletion, and
mal ablation by focused application of ultrasound energy. Of monosomy 22 [122, 132–137]. Interestingly, 7q deletions
interest to pathologists, the gross appearance of a leiomyoma have been identified in both MED12-mutated and HMGA2-
early after this type of treatment has some features grossly altered leiomyoma, suggesting that loss of 7q may be impor-
concerning for malignancy. Specifically, the borders of soni- tant for progression rather than initiation of tumorigenesis.
cated and nonsonicated tissues may be geographic and well-
defined, and sonicated tissues may be variegated in color and 1.3.1.7 Clinical Management and Outcome
show extensive hemorrhage. In distinction to geographic Leiomyomata are the most common indication for hysterec-
tumor necrosis, thermal effect resulting from focused ultra- tomy [108, 138]. However, leiomyomata may be managed
expectantly if associated with no or minimal symptoms. mitoses per 10 high-power fields; such tumors are classified
Myomectomy (resection with uterine conservation) is the as “leiomyomata with increased mitotic activity” [2, 149–
most widely employed hysterectomy alternative for women 152]. This diagnostic term is useful in denoting the special
who wish to preserve fertility [139]. Tumor size and location nature of these tumors, as well as communicating the absence
play an important role in determining which technique is most of other worrisome features. Ki-67 is a proliferation marker
appropriate. When compared with hysterectomy, the alterna- that may be helpful in the diagnosis of leiomyoma with
tives are associated with several unique risks, namely, the risks increased mitotic activity. One way in which Ki-67 immuno-
of tumor “recurrence” and uterine rupture during pregnancy histochemistry might be useful is in excluding pyknotic
following myomectomy [108]. The risk of symptomatic recur- nuclei as a mimic of mitoses. It should be noted that prolif-
rence is more likely due to the growth of a second crop of erative “hot spots” may be seen beneath eroded and attenu-
leiomyomata and requires a second operation in a subset of ated mucosal surfaces of submucosal leiomyoma or adjacent
cases [108]. Morcellation with powered devices may result in to ischemic changes. Mitotically active leiomyoma is not
peritoneal dissemination of benign and malignant smooth known to have any clinical significance with regard to recur-
muscle tumors [140, 141]. In fact, studies have shown that the rence or progression to malignancy. Similarly, there are no
rate of unexpected sarcoma after a laparoscopic morcellation known molecular or cytogenetic alterations specific to mitot-
procedure may be far higher than once thought and that dis- ically active leiomyoma. Atypical mitotic figures reflect
semination of leiomyosarcoma by morcellation occurs in genomic instability and as such should be considered a wor-
nearly two thirds of cases, some resulting in mortality [141]. risome finding. Detection of atypical mitoses in a smooth
Uterine artery embolization as described previously muscle tumor that would otherwise be classified as a leio-
results in symptomatic improvement for most patients, but myoma with increased mitotic activity should raise suspi-
this technique has been associated with adverse outcomes cion for a more ominous diagnosis as these are rarely if ever
ranging from postprocedure fevers to amenorrhea, uterine encountered in benign leiomyomata. Mitotically active leio-
rupture, endomyometritis, and fatal sepsis [142–144]. myomas appear to have similar molecular features as con-
Uterine artery embolization also has been implicated as a ventional leiomyoma, with frequent MED12 mutations, but
factor delaying the diagnosis of uterine sarcomas [145]. infrequent abnormal expression of HMGA2 or FH [128,
Medical therapy, in the form of androgenic steroids, 153].
gonadotropin-releasing hormone (GnRH) agonists, or selec-
tive estrogen receptor modulators, may also be attempted in 1.3.2.2 Cellular Leiomyoma
the clinical management of symptomatic fibroids, with vari- Leiomyomata are often more cellular than their surrounding
able success rates [146, 147]. myometrium. The term cellular leiomyoma is reserved for
notably cellular tumors. Although hypercellularity is neces-
sary to classify a tumor as this benign variant, it is quite
1.3.2 Variants of Leiomyoma subjective and difficult to quantitate just how cellular a tumor
must be to make a diagnosis of cellular leiomyoma. On
According to the 2014 WHO classification, there are a num- inspection of tissue sections without the microscope, the
ber of distinct morphologic variants of leiomyoma, including heavy hematoxylin staining of a cellular leiomyoma often
cellular leiomyoma, leiomyoma with bizarre nuclei, mitoti- will stand out, reflecting the increased number of nuclei as
cally active leiomyoma, hydropic leiomyoma, apoplectic well as the relative lack of extracellular matrix deposition.
leiomyoma, epithelioid leiomyoma, myxoid leiomyoma, and One practical approach is to classify only those tumors with
dissecting (cotyledonoid) leiomyoma, some with specific an extreme or eye-catching degree of cellularity as cellular
genetic alterations. Additionally, there are leiomyomas with leiomyoma. Another approach is to reserve the term “cellular
other cellular elements such as lipoleiomyoma and angi- leiomyoma” for cases in which an endometrial stromal neo-
oleiomyoma (or “vascular leiomyoma”). Each of these will plasm was at least considered in the microscopic differential
be discussed below with relevant clinicopathologic and diagnosis. Few studies have examined the molecular altera-
genetic information included with each variant. tions specifically in cellular leiomyoma. From the published
data available for review, they lack TP53 mutations [128],
1.3.2.1 Mitotically Active Leiomyoma only 6% have PTEN deletions, and only 9–14% have MED12
Both nonneoplastic myometrium and leiomyoma demon- mutations [128, 154], suggesting the pathogenesis of cellular
strate variation in mitotic rate depending on the phase of leiomyoma may differ from conventional leiomyoma. 1p
menstrual cycle [113]. Some investigators have noted that deletion was present in 23% of cellular leiomyomas in one
exogenous progesterone increases the mitotic rate in leio- study [155] and a subset have been reported to have 10q22
myomata [148]. Occasionally, leiomyomas may be histolog- rearrangements, which have also been described in conven-
ically unremarkable but demonstrate mitotic activity up to 15 tional leiomyoma [156].
1.3.2.3 Highly Cellular Leiomyoma

a
Highly cellular leiomyoma is a markedly cellular variant of
leiomyoma that frequently has an irregular border, which in
combination with its marked cellularity may mimic a low-
grade endometrial stromal sarcoma. Highly cellular leiomy-
oma can be recognized based on its characteristic histologic
features which include the presence of fascicular areas at
least focally, large thick-walled blood vessels within the
tumor, and cleft-like spaces [8]. In problematic cases, immu-
nohistochemistry may be useful. Highly cellular leiomyo-
mata are often positive with markers of smooth muscle
differentiation (SMA, desmin, and caldesmon), though nota-
bly some cases show decreased staining with caldesmon. It is
important to note that highly cellular leiomyoma may be dif- b
fusely positive for CD10; therefore, this marker alone is
often not useful in distinction from endometrial stromal
tumors [20].
1.3.2.4 Epithelioid Leiomyoma

One of the most frequent alternative patterns of differentia-
tion has an epithelioid appearance, which is also referred to
as being “plexiform.” However, epithelioid and plexiform
leiomyomas likely represent distinct leiomyoma variants as
molecular studies have shown that the gene expression pro-
files of plexiform leiomyomas are distinct from leiomyomata
with “true” epithelioid morphology [157]. In plexiform leio-
myoma, there is abundant extracellular matrix that results in
small ribbons or islands of rounded smooth muscle cells
(Fig. 1.26a, b), giving it a pseudo-epithelioid appearance, Fig. 1.26 Histologic features of plexiform leiomyoma. (a) From low-
which is not an uncommon finding in otherwise conventional power magnification, ribbons and cords of cells are apparent, with
abundant collagenous stroma. (b) High-power examination reveals
leiomyoma. They may sometimes have an infiltrative pattern small pseudo-epithelioid-shaped cells without cytologic atypia or mito-
and consequently mimic endometrial stromal sarcoma [158, ses set in a collagenous stroma
159]. In contrast, “true” epithelioid leiomyomas are uncom-
mon and composed of rounded cells with abundant eosino-
philic cytoplasm. The clinical features of women with high-power fields), and lacked severe nuclear atypia and
epithelioid leiomyomata are similar to those with leiomyo- tumor necrosis. Even with these studies, classification of epi-
mata showing conventional spindle cell morphology. thelioid smooth muscle tumors remains problematic.
Specifically, these tumors present in the latter reproductive Only a small number of epithelioid leiomyomata have
years but can occur at any age beginning in the third decade been analyzed cytogenetically to date. In a series of five
[160]. Epithelioid leiomyomata may have an unusual macro- tumors, most had simple karyotypic abnormalities similar to
scopic appearance, including a yellow to tan color and softer those seen in leiomyomata of the usual histologic type [162].
consistency, which is not specific but should prompt addi- The similarity between the cytogenetics of typical and epi-
tional sampling. thelioid leiomyomata suggest that they share a common
The prognosis of epithelioid leiomyoma is somewhat pathogenesis. The greater complexity of cytogenetics aberra-
uncertain. This unpredictability has led some to regard all tions and rearrangements involving 17q21 in two epithelioid
epithelioid smooth muscle neoplasms as tumors of uncertain tumors, however, may distinguish epithelioid and conven-
malignant potential [161]. In one of the largest series (n = 18) tional smooth muscle tumors [162].
studied to date, Prayson et al. retrospectively correlated
pathologic features with clinical outcome [160]. Similar to 1.3.2.5 Myxoid Leiomyoma
non-epithelioid smooth muscle tumors, no one histologic Myxoid leiomyoma is a smooth muscle tumor characterized
feature was predictive of metastatic potential. In general, by abundant myxoid material separating the muscle bundles
benign epithelioid smooth muscle tumors were smaller which correlates to a gelatinous, soft tan to gray cut surface
(<6 cm), had low mitotic rates (up to 3 mitoses per 10 on gross examination. This leiomyoma variant should be
similarly well circumscribed, without significant cytologic there is some molecular evidence suggesting other mecha-
atypia or necrosis. Mitoses should number <2 per 10 high- nisms. For example, rearrangements of 12q15 and aberrant
power fields and lack atypical forms. As the amount of myx- expression of HMGA2 have been described, which are simi-
oid matrix may vary, conventional areas of leiomyoma are lar genetic aberrations that have been described in lipoma,
often seen. The principal differential diagnostic consider- suggesting a common mechanism for adipocytic differentia-
ations include distinction from myxoid leiomyosarcoma, tion [168, 169]. Rare examples of liposarcoma arising from
inflammatory myofibroblastic tumor, and myxoid change lipoleiomyoma have been described; in these cases, the
associated with degeneration. The diagnosis of myxoid leio- tumors showed features of liposarcoma including pleomor-
myosarcoma should be considered in any myxoid smooth phic hypercellular areas and lipoblasts [170].
muscle tumor with cytologic atypia, infiltrative margins,
and/or a mitotic rate of >2 per 10 high-power fields (see 1.3.2.8 Leiomyoma with Other Cellular
myxoid leiomyosarcoma discussion below). Inflammatory Components: Angioleiomyoma
myofibroblastic tumor can also have a myxoid matrix but is (“Vascular” Leiomyoma)
distinguished from myxoid leiomyoma by more often having Leiomyomas may sometimes have increased numbers of
an irregular interface with the myometrium, its often promi- vascular channels and these have been variably described as
nent lymphoplasmacytic infiltrate, and its characteristic “tis- “vascular” leiomyoma or angioleiomyoma [171, 172]. The
sue culture”-like appearance with cells having open vesicular vascular component can be composed of large-caliber ves-
nuclei. In addition, inflammatory myofibroblastic tumor sels (“venous”-like) or numerous smaller vessels with peri-
typically shows diffuse positivity for ALK corresponding to vascular concentric smooth muscle proliferations
ALK rearrangements. Alk immunohistochemistry should be (“myopericytoma”-like). When the tumor has large-caliber
considered before rendering a diagnosis of myxoid leiomy- vessels, the main distinction is from an arteriovenous malfor-
oma, as it has been reportedly misdiagnosed in the literature mation, which would not be well circumscribed. When the
[163]. A more frequent diagnostic consideration is the dis- vasculature is myopericytic-like, an endometrial stromal
tinction from leiomyoma with degenerative changes. In this tumor may be entertained; however, an angioleiomyoma
scenario, the myxoid change is typically focal or multifocal would show positivity for smooth muscle markers, including
and tends to occur immediately adjacent to ischemic necro- desmin and caldesmon.
sis or around blood vessels. Appreciating the association
with degenerative changes is helpful in this distinction. 1.3.2.9 Leiomyoma with Special Growth
Patterns: Diffuse Leiomyomatosis
1.3.2.6 Dissecting (“Cotyledonoid”) Leiomyoma Diffuse leiomyomatosis, also known as intrauterine leiomy-
Dissecting leiomyoma is an uncommon lesion which also omatosis, is an unusual entity characterized by a large num-
has been referred to as “cotyledonoid” due to its gross resem- ber (typically >100) of leiomyomata which are confined to
blance to placental tissue when the tumor shows extrauterine the uterus [173]. Typically, on gross examination, there are
extension. This unusual entity typically occurs in innumerable masses which enlarge and distort the uterus and
reproductive-aged women and is characterized by tongues of often appear confluent on cut section. Microscopically, the
benign-appearing smooth muscle neoplasia, with varying tumors tend to be more cellular than conventional leiomy-
degrees of hydropic change, dissecting the surrounding myo- oma and show indistinct borders with merging of the adja-
metrium with occasional involvement of the broad ligament cent tumor masses. Nuclear atypia, necrosis, and vascular
and pelvis [164–166]. There is no cytologic atypia, necrosis, involvement are absent. This is a clinically benign entity of
or significant mitotic activity. When there is intravascular uncertain etiology although molecular studies have shown
extension, this tumor overlaps with intravenous leiomyoma- the tumorous masses to be polyclonal suggesting that patients
tosis (see below). with this disease are prone to leiomyoma development [174].
1.3.2.7 Leiomyoma with Other Cellular 1.3.2.10 Intravenous Leiomyomatosis

Components: Lipoleiomyoma Intravenous leiomyomatosis (IVL) is a condition in which a
Lipoleiomyoma is a leiomyoma variant in which adipocytic smooth muscle tumor is morphologically indistinguishable
differentiation is present [167]. The number of adipocytes from conventional leiomyoma yet invades vascular spaces
varies, although usually it is a minor component, and the and in dramatic cases may track along the vena cava and
amount correlates with the gross appearance. As the fat con- extend into the right heart [52–54, 175, 176]. It affects pri-
tent increases, the tumor can have a yellow cut surface. In marily women in their late reproductive ages but has been
dramatic examples in which the fat content predominates, reported as early as 21 years of age [177]. The presenting
the tumor can grossly mimic a lipoma. Although some have symptoms often depend on the extent of growth. If IVL is
speculated that adipocytic differentiation is degenerative, associated with a large leiomyoma of the uterus, pelvic pain
or bleeding typically predominates. If extension into the vena aggressive biologic property. Despite this malignant charac-
cava is significant, symptoms such as syncope and dyspnea teristic, the intravascular growth is usually indolent. In most
may be prominent. Upon gross examination, wormlike tumor cases, surgical intervention is sufficient treatment.
projections may be seen in the parametria of hysterectomy Gonadotropin-releasing hormone agonist (e.g., leuprolide)
specimens (Fig. 1.27a). This pattern of intravascular growth may be used as short-term therapy. Molecularly, IVL appears
also may be seen in endometrial stromal sarcoma as well as to have similar cytogenetic alterations commonly seen in con-
uterine leiomyosarcoma [55]; however, the appearance of ventional leiomyoma such as t(12;14). Regional losses on
IVL is otherwise identical to that of typical leiomyoma, with chromosomes 22q and 1p and gains on chromosomes 12q
a firm, white to tan rubbery cut surface. Similarly, the micro- were the most common alterations in one study [179]. MED12
scopic appearance in most cases of IVL is that of a typical mutations have not been documented in IVL [179].
uterine leiomyoma but uncommonly may exhibit the same Karyotypes of two cases of IVL have shown the presence of
spectrum of benign variant morphologies as seen in leiomy- a derivative chromosome, der(14)t(12;14)(q15;q24), which is
oma [52] (Fig. 1.27b). Atypical histology and adhesion to the also frequently found in typical uterine leiomyomata [180].
vessel wall may be associated with a more aggressive clinical Presumably, the ability of IVL to grow within venous spaces
course [178]. Intravenous extension might be considered an reflects some additional unknown genetic alterations.
1.3.2.11 Benign Metastasizing Leiomyoma

Benign metastasizing leiomyoma (BML) is a somewhat con-
a
troversial entity characterized by bland-appearing smooth
muscle tumors in the lung or lymph nodes and is thought to
represent “metastasis” from a histologically unremarkable
uterine leiomyoma, a theory that has molecular support of
common origin [181–183]. The typical clinical scenario is
the presentation of one or several small masses in the lung or
abdominopelvic lymph nodes in women with a history of
hysterectomy in which one or more typical leiomyomata
were present in the hysterectomy specimen. The histologic
appearance of the extrauterine tumors consists of bland
smooth muscle cells, indistinguishable from that seen in con-
ventional benign leiomyoma. As its name suggests, the clini-
cal course is benign. BML are characterized by 19q and 22q
terminal deletions as well as loss of 3q and 11q in one study
b
[181, 184], which are alterations not commonly found in
typical leiomyomata, suggesting that benign metastasizing
and typical uterine leiomyomata do not share a common ori-
gin. While BML is thought to be unrelated to conventional
benign leiomyoma, some have proposed a relationship
between BML and IVL based on histopathologic and molec-
ular genetic studies [185, 186].
1.3.2.12 Disseminated Peritoneal

Leiomyomatosis
Disseminated peritoneal leiomyomatosis (DPL) is a disorder
in which smooth muscle tumorlets are scattered across peri-
toneal and omental surfaces [187–189]. It is rare and occurs
generally in women of reproductive age but occasionally in
postmenopausal women. The tumorlets can range from
Fig. 1.27 Intravenous leiomyomatosis (IVL). (a) The gross appear- microscopic to 25 mm in size and number from less than five
ance of IVL may mimic an endometrial stromal sarcoma, with exten- to several hundred. The striking peritoneal involvement may
sive “wormlike” tumor projections within the myometrium and initially clinically mimic an aggressive ovarian neoplasm;
parametrium. (b) IVL are usually histologically indistinguishable from
leiomyoma and often demonstrate plexiform-like morphology.
however, the correct diagnosis is made by recognizing that
Intravascular foci may be seen adjacent to a larger leiomyoma, as each tumorlet is a small leiomyoma. The cut surfaces of the
shown here larger lesions have the white to tan, bulging whorled
appearance of typical uterine leiomyoma. Similarly, the

microscopic appearances of the tumorlets also are identical
to typical uterine leiomyomata. Occasionally, they may be
associated with foci of endometriosis imparting an
adenomyoma-like appearance. DPL generally has a benign
clinical course. The leiomyomatous nodules may even per-
sist or recur over many years [187]. Clonality analysis of
these tumorlets, however, demonstrates that each nodule is
clonal [187]. Moreover, these studies found that all the
tumorlets have an identical pattern of X chromosome inacti-
vation, strongly suggesting that all the nodules arose from a
common clonal origin via a single transformation event.
Thus, these disseminated tumor nodules are truly “meta-
static.” In some cases, the mechanism of dissemination
appears to be iatrogenic, as this disorder has been reported to
follow morcellation procedures, and it is unclear if the biol-
ogy of iatrogenic BML is different from that of non-
iatrogenic BML [141, 190, 191]. Regardless, the molecular Fig. 1.28 Leiomyosarcoma, gross appearance. Leiomyosarcoma is
mechanisms that permit intraperitoneal dissemination and/or typically a large, heterogeneous appearing mass with irregular borders.
Abundant necrosis and hemorrhage is evident in this example
growth of otherwise benign-appearing smooth muscle
tumors on peritoneal surfaces have yet to be elucidated.
1.3.3 Leiomyosarcoma
1.3.3.1 Definition (Conventional

Leiomyosarcoma)
Malignant tumors of smooth muscle origin with predomi-
nantly spindle cell, fascicular growth patterns are considered
to represent typical or conventional leiomyosarcoma.

Leiomyosarcoma (LMS) is the most common malignant uter-
ine mesenchymal tumor, comprising over one half of malig-
nant uterine mesenchymal tumors and 1–2% of all uterine
malignancies, and generally occurs in late reproductive-aged
Fig. 1.29 Conventional leiomyosarcoma, microscopic appearance.
or postmenopausal women [14]. The typical clinical presen- Histologically, leiomyosarcoma is composed of fascicles of spindled
tation is abnormal uterine bleeding/postmenopausal bleeding cells with abundant eosinophilic cytoplasm and moderate to severe
followed by palpation of a mass or pelvic pain [192]. In some nuclear atypia. In this case there are conspicuous mitotic figures
cases, leiomyosarcoma develops after pelvic radiation.
Although LMS are generally considered to arise de novo, 1.3.3.4 Microscopic Findings
there is limited molecular evidence for LMS arising from a Conventional leiomyosarcomas are characterized histologi-
pre-existing leiomyoma in a minority of cases [193, 194]. cally by hypercellular bundles of hyperchromatic atypical
Approximately one third of women with LMS present spindled tumor cells growing in fascicles, with appreciable
with extrauterine disease [192]. eosinophilic cytoplasm (Fig. 1.29). The interface of LMS
with the surrounding myometrium is frequently destructively
1.3.3.3 Gross Findings infiltrative (Fig. 1.30) although some tumors appear grossly
LMS is generally encountered as a large, often solitary myo- and microscopically well-circumscribed. The tumor nuclei,
metrial mass (mean diameter 10 cm) [2]. In contrast to leio- similar to benign smooth muscle cells, are often described as
myoma, the cut surface of LMS is gray, yellow, or tan and “cigar-shaped” due to the blunted or rounded ends of the
soft, frequently with visibly necrotic and/or hemorrhagic nucleus. A minor component of variant morphology such as
foci, and demonstrates irregular infiltration of the surround- epithelioid cells may be present. The degree of nuclear atypia
ing myometrium (Fig. 1.28). may vary throughout the tumor though most cases
Fig. 1.30 Conventional leiomyosarcoma, microscopic appearance.

Leiomyosarcoma typically shows destructive infiltrative invasion into Fig. 1.32 Leiomyosarcoma, tumor cell necrosis. Tumor cell necrosis
surrounding nonneoplastic myometrium has a very sharp border between viable and nonviable tumor tissue,
without areas of fibrosis, hyalinization, or significant inflammation
that do not meet these diagnostic thresholds may be catego-

rized as smooth muscle tumors of uncertain malignant poten-
tial or atypical leiomyoma (see pertinent sections below).
Histologic grading of leiomyosarcoma is somewhat contro-
versial and is not currently accepted as a prognostic indicator
in uterine LMS [196]. However, there may be value in
assigning a “morphologic” grade, particularly for review of
and correlation with future tumor recurrences or metastasis.
1.3.3.5 Biomarkers
Immunohistochemically, LMS are usually positive for smooth
muscle markers including smooth muscle actin (SMA), des-
min, and caldesmon; however, it is not unusual to lose expres-
sion for one or more of these, particularly in morphologically
Fig. 1.31 Conventional leiomyosarcoma, microscopic appearance. high-grade or poorly differentiated tumors. Of note, LMS may
Leiomyosarcoma often has at least focally marked pleomorphism and demonstrate keratin and/or EMA positivity [20, 197, 198].
multinucleated tumor giant cells Once the line of smooth muscle differentiation is established,
additional stains have been proposed to aid in classification of
demonstrate diffuse cytologic atypia that is moderate to the smooth muscle tumor, including p16, p53, ER, PR, ki67,
severe. Multinucleated tumor cells are present in over half of stathmin, fascin, and IMP-3. p16 and p53 are overexpressed in
cases (Fig. 1.31). Tumor cell necrosis is defined as an abrupt most LMS, and proliferation as indicated by ki67 index is also
transition between viable tumor and necrotic areas, without significantly higher in LMS [199–205]. Complete absence of
an intervening area of hyalinization/inflammation or other p16 staining may also be seen in LMS [206]. Stathmin is not a
ischemia-related histopathology (Fig. 1.32). Tumor cell specific marker for LMS, but the presence of only weak stath-
necrosis and abundant mitotic activity is usually, but not min staining in a smooth muscle tumor should prompt special
always, present. If tumor cell necrosis is present in a smooth consideration for a benign variant as all LMS were diffusely
muscle neoplasm with at least diffusely moderate nuclear strongly positive for stathmin in one study [207]. Fascin and
atypia, then the mitotic index is not critical for the diagnosis IMP-3 are two additional markers showing increased expres-
of leiomyosarcoma. If, however, tumor cell necrosis is sion in LMS and STUMP compared to leiomyoma [208, 209].
absent, then both significant diffuse moderate to severe Approximately one third of LMS express ER/PR, which may
nuclear atypia as well as mitoses numbering at least 10 per have prognostic and/or therapeutic implications (see
10 HPFs is required for the diagnosis of LMS [195]. Tumors “Management and Outcomes” section below).
1.3.3.6 Genetic Profile including STUMP and atypical leiomyoma (“leiomyoma

LMS have markedly complex karyotypes, which makes it with bizarre nuclei”). This is based on mitotic counts, assess-
difficult to identify alterations specific to LMS. Some of the ment of nuclear atypia, and presence of coagulative tumor
recurring chromosomal arm-level alterations described in cell necrosis. There are significant interobserver differences
LMS include gains of 1q, 17p, and Xp, and loss of heterozy- in the interpretation of tumor cell necrosis [228] as well as
gosity for 10q (including in the PTEN gene locus) and 13q subjectivity in determining what constitutes “at least moder-
(containing the gene RB1) is present in >50% of LMS [134, ate” cytologic atypia. Additionally, assessment of mitotic
210–213]. TP53 mutations are common in LMS, reported in index may be difficult as pyknotic and apoptotic nuclei may
up to 65% of cases [128, 212, 214–217]. MED12 mutations mimic mitoses but should not be included in the mitotic
are found in ~10% of LMS [127, 128, 218] although reports count. Moreover, mitotic rates may vary throughout the
range from 2 to 20% [129, 130, 218–222]; however, most of tumor; thus examination of mitotic index on multiple differ-
the MED12 mutations present in LMS are not the typical hot ent sections of tumor is required. Immunohistochemistry has
spot mutations seen in leiomyoma and rather represent com- proven to be variably useful in this distinction, with panels
plex or truncating mutations [128]. HMGA2 overexpression including p16, p53, ER, PR, and ki-67/mib-1 [201, 205,
is seen in ~35% of LMS and appears to be mutually exclu- 229]. However, no immunohistochemical stain or panel of
sive with MED12 mutation [127], similar to leiomyoma. stains is definitive for distinction of LMS from other smooth
HMGA1 rearrangements have been described in only two muscle tumors, and these should only be considered in the
LMS [223]. α-Thalassemia/mental retardation syndrome context of tumor morphology.
X-linked (ATRX) and death domain-associated (DAXX) are PEComa may also be considered in the differential diag-
two genes frequently mutated in LMS and are associated nosis with LMS; however, this is more commonly encoun-
with the alterative lengthening of telomere (ALT) phenotype tered in the epithelioid variant of LMS. Given that
contributing to the pathogenesis of uterine leiomyosarcoma conventional LMS can have epithelioid areas and PEComa
in up to 78% of cases [213, 215, 217, 219, 224, 225]. More may have a significant spindled component, there may be
recent molecular studies on LMS have identified additional morphologic overlap. Immunohistochemistry is helpful in
genes that are upregulated or downregulated with correlation this distinction; while PEComa may be positive for both
with clinical outcome and response to therapeutic treatment. SMA and desmin, it is generally negative for caldesmon.
Briefly, one study analyzed three independent cohorts of Conversely, LMS may have limited HMB-45 positivity (but
sequenced LMS data to identify key genes upregulated in again this is more frequent in the epithelioid variant) but
LMS including CCNE1, MMP9, APOE, and SDC1 [226]. should not be MelanA positive.
Another study also found upregulation of CCNE1 frequently Endometrial stromal sarcoma may be considered, particu-
in LMS and, in addition to finding frequent PTEN deletions, larly when the pattern of invasion is not destructive, and the
also described a possible novel tumor suppressor gene, tumor is highly cellular imparting a “blue” appearance from
VIPR2, which is a negative regulator of smooth muscle pro- low power. The tumor cytomorphology and morphology of
liferation, as the most frequent gene altered in LMS in their intratumoral vasculature will aid in the diagnosis (as previ-
study [212]. Deletion of VIPR2 was also associated with ously discussed in the endometrial stromal tumors section).
poorer clinical outcome. Another study divided LMS into Additionally, endometrial stromal tumors with smooth mus-
two molecular subgroups based on differing gene expression cle differentiation do not typically have the severe cytologic
profiles and found that one type had an expression profile atypia present in most LMS. Confirmatory immunohisto-
more closely resembling nonneoplastic smooth muscle and chemistry including a panel of SMA, desmin, caldesmon,
the other type had upregulation of genes known to be and CD10 may also prove useful.
involved in common tumorigenesis pathways [227]. This Carcinosarcoma with a predominance of the sarcomatous
group also showed that response to chemotherapy differed component may be confused with LMS, particularly in lim-
between the two molecular subtypes; however, the histologic ited sampling. Recognizing an epithelial component is key to
features were also likely different between these two groups diagnosing carcinosarcoma; and extensive leiomyosarcoma-
as the type I tumors were characterized as “low-grade,” while tous differentiation is not typical of carcinosarcoma.
the type II tumors were high grade with invasive and ana- Poorly differentiated and dedifferentiated LMS should be
plastic morphology. Thus it is unclear if the molecular fea- distinguished from undifferentiated uterine sarcoma. Indeed,
tures are superior to histologic features in determining some cases of UUS may in fact represent dedifferentiated
prognosis and chemotherapeutic response in LMS. LMS without any residual morphologic or immunopheno-
typic evidence of smooth muscle differentiation. The pres-
1.3.3.7 Differential Diagnosis ence of fascicular growth should prompt consideration of
One of the most challenging diagnostic considerations is the LMS. Additionally, extensive sampling of large tumors is
distinction of LMS from other uterine smooth muscle tumors needed before a diagnosis of UUS should be made.
Immunohistochemistry should be performed selectively on [245–247]. Ovarian preservation has been considered in pre-
the blocks of tumor containing fascicular growth as staining menopausal patients with early-stage leiomyosarcoma but
more poorly differentiated/undifferentiated tumor foci will appears to yield little benefit [192, 241]. Intraperitoneal mor-
be of little use. cellation of an unsuspected LMS results in increased risk of
Inflammatory myofibroblastic tumor (IMT) may be con- recurrence and shorter time to recurrence [248]. Most studies
sidered in the differential diagnosis of LMS, though more have found that adjuvant chemotherapy or radiotherapy has
commonly in myxoid variants and LMS with less severe minimal, if any, effect on survival [192, 237, 240] though
cytologic atypia as well as smooth muscle tumors of uncer- some recent studies have shown benefit of chemotherapy in
tain malignant potential (STUMP; discussed later). The pres- metastatic LMS [192, 247]. Aromatase inhibitors may pro-
ence of a prominent lymphoplasmacytic inflammatory cell long progression-free survival for some patients with
component and myxoid stroma should prompt consideration ER-positive leiomyosarcoma [249–251]. mTOR inhibition
of IMT. Positive Alk immunohistochemistry and/or break- has been proposed in uterine LMS as activated AKT/mTOR
apart FISH can confirm the diagnosis [230]. pathway proteins are highly expressed [252–254]. With the
Gastrointestinal stromal tumor/sarcoma may rarely be advent of widely available next-generation sequencing and
encountered in the uterus and as there may be significant other molecular testing on tumor specimens, it is likely that
morphologic overlap with smooth muscle tumors including a personalized approach to the treatment of LMS may prove
LMS, a panel of desmin, CD34, c-kit (CD117), and DOG-1 more beneficial than standard chemotherapy. One recent
will aid in classification. Of note, both DOG-1 and c-kit may example of this is palbociclib, a CDK4/6 inhibitor, which has
be expressed strongly in LMS, but without associated KIT been shown to be effective for LMS harboring CDKN2A
mutation [231–233]. alterations, which is encountered in LMS in up to 20% of
Rhabdomyosarcoma, particularly those with predomi- cases [255].
nantly spindled morphology, may be confused with LMS,
although the latter is overwhelmingly more common in the 1.3.3.9 Variants of Leiomyosarcoma:
uterus [234]. Morphologic features to raise concern for rhab- Diagnostic Considerations
domyosarcoma include densely eosinophilic cytoplasm and and Molecular Features
presence of cross-striations. Immunohistochemistry for
caldesmon and myogenin or other skeletal muscle-specific Epithelioid Leiomyosarcoma
marker will distinguish between smooth muscle and skeletal Epithelioid leiomyosarcoma (Fig. 1.33) shows epithelioid
muscle differentiation. differentiation in the form of round to polygonal cells with
ample eosinophilic cytoplasm (Fig. 1.34); conventional spin-
1.3.3.8 Management and Outcomes dled areas may be seen, and in these cases, a leiomyosar-
LMS is an aggressive tumor, with high rates of both local coma, mixed epithelioid and spindle types, can be considered.
recurrence and distant metastasis. The 5-year survival rate Similar to conventional spindled leiomyosarcoma, features
for LMS is 25–50%, albeit a bit higher in stage I disease indicative of malignancy include large tumor size, nuclear
[235–237]. No study has shown a definite prognostic impor-
tance of the morphologic grade once the diagnostic threshold
for leiomyosarcoma is met. Factors that affect outcome
include patient age and stage at presentation, and within the
early-stage cohort, vascular invasion, mitotic count, and
tumor circumscription have also been shown to have prog-
nostic significance in some studies [238–241]. Progesterone
receptor (PR) expression appears to be a favorable prognos-
tic indicator in low-stage LMS [242]. Similarly, androgen
receptor (AR) expression may also be a positive prognostic
indicator, particularly when co-expressed with ER and/or PR
[243]. High levels of IMP-3 expression in LMS may be asso-
ciated with worse disease-specific survival [244].
The treatment of choice for leiomyosarcoma is total
abdominal hysterectomy and bilateral salpingo-
oophorectomy. The likelihood of nodal disease is quite low
in the absence of more obvious disease, suggesting that
Fig. 1.33 Epithelioid leiomyosarcoma, gross appearance. Similar to
upfront lymph node dissection has little prognostic or other uterine sarcomas, epithelioid leiomyosarcoma has a fleshy, multi-
therapeutic role in the management of leiomyosarcoma nodular appearance with hemorrhage and necrosis

diagnosis of epithelioid LMS is broad and includes other

tumors with epithelioid cytomorphology. Epithelioid leio-
myoma can be rendered if the tumor is well circumscribed
and lacks cytologic atypia and the mitotic rate is <5 per 10
high-power fields; whenever this differential is being consid-
ered, it is important to extensively sample the tumor, particu-
larly the border to assess for the possibility of invasion. If
any infiltration is present, then the tumor should be consid-
ered of at least uncertain malignant potential. Epithelioid
angiosarcoma will show a greater degree of associated hem-
orrhage and will be positive for endothelial markers such as
CD34, CD31, and/or ERG. Epithelioid trophoblastic tumors
are typically well circumscribed and composed of a rela-
tively uniform population of cells that are typically arranged
in nests and cords and associated with eosinophilic hyaline-
Fig. 1.34 Epithelioid leiomyosarcoma, microscopic appearance.
Epithelioid leiomyosarcoma is composed of small nests and cords of
like material; they are also typically positive for p63 and
atypical polygonal cells, with eosinophilic cytoplasm and mitoses GATA 3. Melanoma can show significant morphologic over-
lap but is typically negative for smooth muscle markers and
is positive for S100 and SOX 10.
Myxoid Leiomyosarcoma
Similar to conventional LMS, myxoid LMS occurs in late
reproductive or postmenopausal women and most present
with abnormal uterine bleeding or pain and stage I disease;
however it differs from conventional LMS in its gross and
microscopic characteristics [258, 259]. Grossly, the cut sur-
face is typically gelatinous and myxoid, although it may also
have deceptively well-circumscribed borders with the sur-
rounding myometrium similar to conventional LMS. Necrosis
and hemorrhage may be seen. Histologically, the tumor cells
show diffuse or fascicular growth, but the low-power appear-
ance may be hypocellular in comparison to the surrounding
myometrium due to the abundant myxoid matrix separating
the neoplastic cells. The tumor cells are spindled to stellate
Fig. 1.35 Epithelioid leiomyosarcoma, immunohistochemistry. and have variable amounts of eosinophilic cytoplasm with
Smooth muscle actin (SMA) (shown here) is positive in epithelioid
leiomyosarcoma, as is desmin and caldesmon; however, the extent and variably sized but typically hyperchromatic nuclei (Fig. 1.36).
intensity of positivity can be variable The mitotic rate is variable and is sometimes low which may
in part be due to the abundant myxoid matrix and associated
hypocellularity. As such, the diagnostic criteria for malig-
atypia, necrosis, mitotic rate, and vascular invasion. Tumors nancy in myxoid LMS differ from conventional LMS in that
with significant cytologic atypia and a mitotic rate ≥5 per 10 the threshold for the mitotic rate is much lower at 2 per 10
high-power fields are classified as malignant [160]. high-power fields. Thus, in a tumor with moderate to marked
Epithelioid leiomyosarcomas are typically positive for cytologic atypia, the mitotic rate needs only reach 2 per 10
smooth muscle markers, including smooth muscle actin, des- high-power fields in order to diagnose the tumor as malig-
min, and h-caldesmon, although the expression can be vari- nant. In one study, all myxoid LMS had infiltrative borders,
able (Fig. 1.35). Of note, some may show focal HMB-45 most commonly in the form of a markedly irregular and
expression, and in these instances, the possibility of a angulated interface; though in a minority of cases, tongue-
PEComa should be considered [256]; other characteristic like permeative growth or only focal destructive myometrial
areas of PEComatous differentiation should be identified and invasion was seen [258]. Immunohistochemically, these
co-expression of other melanocytic markers such as melanA tumors are typically positive for smooth muscle markers
and cathepsin K (which should be diffuse in PEComa) should although the degree of expression may be less than that of
be evaluated [257]. No studies have specifically evaluated tumors of the conventional type. They typically are negative
the molecular features of epithelioid LMS. The differential for ALK and approximately half show loss of p16 and
typically show normal p53 and p16 staining. Perhaps even

more challenging is the distinction of myxoid LMS from
BCOR-altered high-grade sarcoma as both can have a fas-
cicular growth pattern and myxoid matrix; however, the lat-
ter typically lacks the hyperchromatic elongated nuclei of
myxoid LMS, shows minimal to no muscle marker positiv-
ity, and is diffusely positive for cyclin D1 and in 50% of
tumors, BCOR, although this marker is less sensitive and
may be negative.
1.3.4 S
mooth Muscle Tumors of Uncertain
Malignant Potential
Fig. 1.36 Myxoid leiomyosarcoma, microscopic appearance. Myxoid Smooth muscle tumors of uncertain malignant potential
leiomyosarcoma is composed of hyperchromatic spindled to stellate (STUMP) are not well defined secondary to poor reproduc-
tumor cells set in a myxoid stroma imparting a somewhat hypocellular
appearance. Mitotic activity is present
ibility agreement on histomorphologic classification, but
with this caveat in mind, one study found that 11% of
STUMPs harbor MED12 mutations, similar to the fre-
a bnormal p53 staining patterns which correlate with TP53 quency in LMS [128]. Likewise, approximately one third
mutations or deletions [206]. No studies to date have specifi- of STUMPs have PTEN deletions [128]. STUMPs with any
cally evaluated the molecular features of myxoid LMS. degree of myxoid features should be stained immunohisto-
Distinction of myxoid LMS from conventional LMS is chemically for Alk or examined with FISH analysis for ALK
somewhat subjective; the finding of a grossly gelatinous rearrangement, given that a recent study found that a sig-
mass or a tumor in which >50% shows a prominent myxoid nificant minority of STUMPs were reclassified as
matrix is considered sufficient in diagnosing a leiomyosar- inflammatory myofibroblastic tumor (IMT) after Alk

coma as of the myxoid rather than the conventional subtype immunohistochemical staining [260]. Our practical
[258]. The differential diagnosis also includes myxoid leio- approach to the consideration of whether a tumor should be
myoma, hydropic leiomyoma, inflammatory myofibroblas- considered of uncertain malignant potential (or of uncertain
tic tumor, and BCOR-altered high-grade sarcoma. Myxoid biologic behavior) is the following. Tumors with significant
leiomyoma is a very uncommon tumor and should only be cytologic atypia and a mitotic rate that is near the threshold
diagnosed when a myxoid smooth muscle tumor is well cir- (i.e., 8 or 9 mitoses per 10 high-power fields) should be
cumscribed, lacks cytologic atypia, and shows no or only considered of uncertain malignant potential as it seems
rare mitoses. Hydropic leiomyoma typically has a watery unlikely there is significant biologic difference in tumors
rather than gelatinous cut surface which corresponds micro- with such close mitotic rates; as a practical point, in any
scopically to edema fluid which appears “pink” rather than situation in which the mitotic rate is close to the threshold,
“bluish”; in addition, it is well circumscribed, lacks atypia, extensive sampling and exhaustive mitotic counts should be
and usually shows minimal to no mitoses. The distinction performed (every block of tissue; at least 100 high-power
from inflammatory myofibroblastic tumor is more chal- fields counted). In some cases, a proliferation marker can
lenging as both can be myxoid and have infiltrative mar- be used to identify “hot spots.” A stand-alone diagnosis of
gins, and indeed these tumors have been misclassified as “STUMP” should not be used in a biopsy/curettage as the
myxoid LMS in the past [258], most likely because they fragments may not be large enough to provide a formal
can have leiomyoma-like areas as well as these only being mitotic count; in this scenario, “atypical smooth muscle
relatively recently recognized as occurring in the gyneco- tumor representing at least STUMP” can be rendered.
logic tract. They tend to have a “fasciitis-like” appearance STUMP can also be considered in epithelioid or myxoid
being composed of cells with enlarged nuclei, vesicular tumors in which the mitotic rate is also near the threshold.
chromatin, and prominent nucleoli. This appearance in Recently, additional histologic parameters for the diagnosis
combination with the finding a lymphoplasmacytic infil- of STUMP have been proposed which include atypical
trate sprinkled throughout and aggregating at the periphery mitoses, infiltrative margins, and vascular involvement
of the mass are clues to the diagnosis. Inflammatory myofi- [261]. In this study, the risk of adverse outcome was higher
broblastic tumors can be positive for desmin and SMA but (36.4%) than in previously published reports (range
also are positive in most cases for ALK, which corresponds 7–26.7%) suggesting that use of more stringent criteria can
to rearrangements of the ALK gene. In addition, they exclude some patients from further follow-up.
1.3.5 A
typical Leiomyoma (“Leiomyoma One subtype of atypical leiomyoma that deserves specific
with Bizarre Nuclei”) mention is FH-deficient atypical leiomyoma, a finding which
is not uncommon; in one study ~38% of atypical leiomyoma
Atypical leiomyoma is characterized by significant cyto- were FH deficient [264]. Hereditary leiomyomatosis and
logic atypia (readily seen from 4× objective) (Fig. 1.37a) renal cell carcinoma syndrome (HLRCC; formerly known as
but lacks both tumor cell necrosis and significant mitotic “Reed syndrome”) is characterized by numerous uterine and/
activity [195]. Nuclear atypia in atypical leiomyoma or cutaneous leiomyomata, often presenting at very young
comprises some combination of nuclear enlargement, mul- ages, as well as renal cell carcinoma [265]. It has also been
tinucleation, hyperchromasia, coarse chromatin, or promi- suggested that HLRCC is associated with uterine LMS; how-
nent nucleoli (Fig. 1.37b). The atypia may be focal or ever, some of these “leiomyosarcomas” may actually repre-
diffuse. Though in the past these tumors have variably sent atypical leiomyoma. There is only one large study from
been named atypical leiomyoma, symplastic leiomyoma, Finland that reports LMS occurring in the setting of FH
and pleomorphic leiomyoma, it has been proposed that germline mutation [266], and this did not include pathology
these be termed “leiomyoma with bizarre nuclei,” in the review.
most recent WHO [2]; however, many of the molecular Histologically, FH-deficient atypical leiomyomata are
alterations present in these tumors overlap with those characterized by diffuse nuclear atypia (in contrast to atypi-
found in LMS. Specifically, 12% have TP53 mutations, cal leiomyomas with focal or scattered foci of severe nuclear
10% have MED12 mutations, and 24% have PTEN dele- atypia), epithelioid nuclei with very prominent nucleoli
tion [128]. Additionally, the miRNA profile of atypical (characteristically cherry red or “orangeophilic”) with peri-
leiomyoma was more similar to LMS/STUMP than to con- nucleolar clearing, intracellular and extracellular aggregates
ventional leiomyoma or cellular leiomyoma [128]. of eosinophilic material (Fig. 1.38a), as well as staghorn-
Histologically, the distinction of atypical leiomyoma from shaped intratumoral vasculature (Fig. 1.38b) [264, 267–270];
LMS is the absolute absence of tumor cell necrosis and a however, these features are not specific nor sensitive for
mitotic index no higher than ordinary leiomyomata. Bell HLRCC-associated or FH-deficient atypical leiomyomata
et al. have suggested that atypical leiomyoma have no [264, 271, 272]. Patients with HLRCC have germline muta-
more than 10 mitotic figures per 10 HPFs [195]. While one tions in the fumarate hydratase gene, FH, located on 1q42.1,
study has shown no evidence of recurrence [262], another and the tumors from these patients have accumulated a sec-
has shown that atypical leiomyomas have a low risk (<2%) ondary somatic inactivation of FH, resulting in complete loss
of extrauterine/intraabdominal recurrence [263]. of protein function and expression, which can be demon-
Therefore, careful follow-up is required or consideration strated with FH immunohistochemical staining (loss of
of hysterectomy for a diagnosis of atypical leiomyoma in staining in tumor cells) (Fig. 1.38c) [267]. Of note, loss of
which there was incomplete excision. FH can also be found in non-syndromic leiomyomata [268,
a b
Fig. 1.37 Atypical leiomyoma (“leiomyoma with bizarre nuclei”). (a) significant mitotic activity. (b) The nuclear atypia in atypical leiomy-
Atypical leiomyoma is characterized by fascicular growth of spindled oma is characterized by nuclear enlargement, hyperchromasia, and
cells with abundant eosinophilic cytoplasm and nuclear atypia that is multinucleation
readily identifiable from low power, but without tumor cell necrosis or
a c
Fig. 1.38 FH-deficient leiomyoma. (a) Histologic features of vasculature is thought to be one of the more specific histologic features
FH-deficient leiomyoma include large eosinophilic or orangeophilic of these tumors. (c) Loss of FH protein expression by immunohisto-
nucleoli and prominent perinucleolar clearing and extracellular and/or chemistry is seen in the majority. Note the vessels serving as positive
intracellular aggregates of eosinophilic material. (b) Staghorn-shaped internal controls with retained cytoplasmic expression of FH
271, 273, 274]. FH inactivation is thought to account for less FH immunohistochemistry. It is now recognized that loss of
than 2% of all uterine leiomyomas and is mutually exclusive FH by immunohistochemistry is not entirely specific for the
with both MED12 and HMGA2 alterations [153, 274]. germline FH mutation (HLRCC). Likewise, it is also possi-
Recognition of this FH-deficient leiomyomata is important ble that the mutated protein may be nonfunctional but stable
because they may indicate that the patient has and thus detectable by immunohistochemistry. In summary,
HLRCC. Clinical recognition of HLRCC may facilitate can- recognition of an atypical leiomyoma with the distinctive
cer screening, especially for an aggressive form of renal cell morphologic features suggestive of FH-deficiency should
carcinoma. Immunohistochemistry may be helpful in rein- prompt confirmation of FH loss by immunohistochemistry, if
forcing the diagnosis of an atypical leiomyoma with available. In addition, it is reasonable to recommend referral
FH-deficiency. Specifically, immunohistochemistry for to a medical geneticist in the appropriate clinical setting.
fumarate hydratase (FH) reveals staining loss in the majority
of HLRCC-associated tumors. FH staining is normally dif-
fusely cytoplasmic in a granular pattern but tumors with FH 1.4 Mixed Epithelial and Stromal Tumors
loss have essentially absent staining. Adjacent myometrium
and endothelial cells serve as useful internal controls. Thus, Overview
presence of staining is a “negative” or normal result while Mixed epithelial-stromal tumors of the uterus encountered in
lack of staining is an abnormal result, which supports con- practice include primarily adenosarcoma. Even though they
cern for the diagnosis of HLRCC in atypical leiomyomas. are classified as a mixed tumor, uterine adenosarcoma has
There is a risk of both false negative and positive results with been shown to represent a mesenchymal neoplasm as the
epithelial component does not harbor clonal somatic altera- 1.4.2.3 Gross Findings
tions [275]. Given this information, true mixed epithelial and Adenosarcomas are typically bulky, soft, polypoid masses
stromal tumors may not exist in the uterus. Adenofibroma that fill the endometrial cavity (Fig. 1.39) and may prolapse
and carcinofibroma exist in theory yet rarely (if ever) occur through the cervical os. Papillary projections on broad stalks
in practice. Carcinosarcoma, which is composed of malig- may be seen within cystic spaces. They most commonly
nant epithelial and stromal components, is not an uncom- involve the uterine fundus but may also occasionally arise in
monly encountered tumor but is now understood to represent the lower uterine segment or cervix.
a form of metaplastic epithelial malignancy rather than a true
mixed epithelial-stromal tumor and thus is discussed in detail 1.4.2.4 Microscopic Features
in Chap. 18 (Vol. 1). Histologically, adenosarcoma is characterized by phyllodi-
form architecture in the form of dilated, cleft-like glands
with intraglandular polypoid projections (Fig. 1.40). The
1.4.1 Adenofibroma glandular component is lined by benign epithelium, which
may show a range of appearances from bland to atypical,
Adenofibroma is by definition a mixed tumor with both with metaplasia frequently present, particularly squamous
benign epithelial and stromal components. Histologically it or tubal metaplasia (Fig. 1.41a, b). Additional characteris-
is characterized by phyllodes-like architecture but lacks tic histologic features include periglandular cuffing by
any evidence of periglandular cuffing and stromal cytologic hypercellular stroma, stromal mitotic activity (at least 1–2
atypia, and mitotic activity should be <2 per 10 HPFs [276]. mitoses per 10 high-power fields), and stromal atypia
Adenofibroma of the uterus is exceedingly rare, and the (Fig. 1.42a, b). Mitotic activity and stromal atypia can be
diagnosis should be made with extreme caution as many quite variable in adenosarcoma, with some cases exhibiting
(including these authors) believe these represent especially little of either, which likely leads to both its under-recogni-
low-grade forms of adenosarcoma; indeed some “adenofi- tion as well as its overdiagnosis [277, 287]. The mesenchy-
bromas” with low mitotic counts and lacking significant mal component of uterine adenosarcoma is more commonly
stromal cytologic atypia have been reported to be associ- homologous (with a stromal or fibrous appearance); how-
ated with tumor recurrence and/or metastasis [277]. In ever, heterologous differentiation, most commonly in the
practice this diagnosis should never be made in biopsy or
curettage specimens.
1.4.2 Mullerian Adenosarcoma
1.4.2.1 Definition
Adenosarcoma is a biphasic tumor composed of a benign
Mullerian glandular (epithelial) component and a malignant
stromal (mesenchymal) component.

Mullerian adenosarcoma is an uncommon form of uterine
sarcoma, representing 5–10% of uterine sarcomas and
<0.5% of all uterine malignancies [278–282].
Adenosarcoma is most common among postmenopausal
women; however, there is a wide age range, and up to 30%
of reported cases occur in premenopausal women [277,
278, 283, 284]. The most common symptoms and clinical
findings at presentation include abnormal vaginal bleed-
ing, an enlarged uterus, a pelvic mass, or a polyp/tissue
protruding through the os [278, 283, 285]. A history of
recurrent polyps is not uncommon [278]. Prior pelvic radi-
ation and prolonged estrogen exposure, whether endoge-
nous or exogenous (including selective estrogen receptor
Fig. 1.39 Adenosarcoma, gross appearance. Adenosarcoma is typi-
modulators such as tamoxifen), is thought to be associated
cally a polypoid, exophytic mass with heterogeneous tan to yellow cut
with a mild risk of development of adenosarcoma in some surface. Cystic spaces with intracystic papillary projections may also be
cases [278, 281, 286]. identified (though not represented in this example)
Fig. 1.40 Adenosarcoma, low-power histologic appearance. Low-

grade adenosarcoma is characterized by broad, leaf-life papillary pro-
jections filling cystic cavities b
Fig. 1.42 Adenosarcoma, microscopic appearance. (a) Periglandular

stromal cuffing is a consistent feature of adenosarcoma and is often
appreciated at low power. (b) Stromal atypia in adenosarcoma is vari-
b able but is usually present. In this example the tumor cells are small but
markedly hyperchromatic with a primitive appearance
>25% of the tumor. Sex cord-like differentiation may also

be identified, and its presence should not be considered in
the assessment of sarcomatous overgrowth [288, 289].
1.4.2.5 Biomarkers
Currently there is no specific immunohistochemical bio-
marker for adenosarcoma. CD10, ER, and PR are commonly
positive, particularly in morphologically low-grade adeno-
sarcomas and those lacking sarcomatous overgrowth [22,
290–294]. WT-1 is another marker frequently positive in
adenosarcoma; however, in contrast to CD10, ER, and PR,
Fig. 1.41 Adenosarcoma, epithelial component. (a) The epithelial WT-1 is also often positive in areas of sarcomatous over-
component of adenosarcoma is typically bland but may also show some growth [294]. However, in most instances, immunohisto-
atypia. (b) Epithelial metaplasia, commonly in the form of squamous
differentiation, is a typical finding in adenosarcoma chemistry is not necessary to establish the diagnosis of
adenosarcoma, and only in occasional circumstances is
immunohistochemistry helpful in the differential diagnosis.
form of rhabdomyosarcomatous differentiation, also may Of note, though most adenosarcomas demonstrate normal
be seen, but most commonly in the setting of sarcomatous (wild-type) p53 staining in the form of patchy or weak
overgrowth. Sarcomatous overgrowth is defined as having a expression, occasional cases of adenosarcoma, usually those
pure sarcoma without any epithelial elements present in with a morphologically high-grade sarcomatous component,
may display strong diffuse or completely absent (null) abnor- diagnosis of adenosarcoma, it is our opinion that these
mal p53 expression [277, 295–297]. lesions should be classified as “endometrial polyp with
unusual features” with a comment stating that although diag-
1.4.2.6 Molecular Features nostic features of adenosarcoma are not identified, close
Few studies have examined the molecular features of adeno- clinical follow-up with sampling of any “recurrent” polyps is
sarcoma, but TP53 mutations are uncommon and when pres- recommended [287].
ent are almost always associated with sarcomatous Carcinosarcoma can be distinguished from adenosarcoma
overgrowth, a poor prognostic indicator [275, 295, 297, 298]. by the presence of a malignant epithelial component in addi-
High-level copy number gains of MYBL1 are seen in a subset tion to the malignant mesenchymal component.
of adenosarcomas, most often associated with sarcomatous Carcinosarcoma usually lacks the typical architectural fea-
overgrowth. Low-level amplification of MDM2 has also been tures of adenosarcoma, though occasionally carcinosarco-
described, seemingly unrelated to the presence of sarcoma- mas with adenosarcoma-like growth have been encountered
tous overgrowth. ATRX mutations were identified in a subset in our practice. Examining the epithelium at high magnifica-
of adenosarcoma, which may be associated with loss of tion is helpful. Additionally, a collision tumor (adenosar-
expression of ATRX by IHC. DICER1 mutations have been coma and carcinoma) could be considered.
identified in MA with rhabdomyosarcomatous differentia- Occasionally LGESS may contain benign-appearing
tion [275]. Few gene fusions have been described in MA, but endometrioid glands [30, 33]; usually the glandular elements
small numbers of cases with NCOA2/3-expressed gene are focal, but they may occasionally be more extensively
fusions have been reported [275]. Cytogenetically, one series present. Morphologic features including the lack of periglan-
evaluated the karyotypes obtained on adenosarcomas both dular stromal cuffing, subepithelial condensation, and
with and without sarcomatous overgrowth and found that characteristic leaflike glandular contours will aid in this dis-
markedly complex karyotypes were only seen in adenosar- tinction. Immunohistochemistry is of little value as both
coma with sarcomatous overgrowth and metastatic tumors LGESS and adenosarcoma are typically positive for CD10,
[299]. Additionally, abnormalities of chromosome 8 were ER, and PR. Molecular analysis may be useful as most
present in the majority of cases (71%), characterized by LGESS harbor abnormalities of JAZF1 on chromosome 7.
either gaining an extra copy of chromosome 8 or by rear- Similar to LGESS, other uterine sarcomas (typically high
rangement at 8q13 [299]. grade) may demonstrate infiltration through or around pre-
existing benign endometrial glands, which can also pose a
1.4.2.7 Differential Diagnosis diagnostic challenge. Identifying typical areas of low-grade
The differential diagnosis of adenosarcoma varies widely, adenosarcoma without sarcomatous overgrowth will aid in
with some adenosarcomas being difficult to distinguish from making the diagnosis of adenosarcoma. Extensive sampling
benign uterine polyps, uterine polyps with unusual features, of the tumor is often helpful. In the case of a high-grade sar-
and so-called adenofibroma, while at the other end of the coma with focal intratumoral benign-appearing glands, but
spectrum, clearly malignant adenosarcomas must be distin- lacking phyllodes-like or broad papillary leaflike architec-
guished from other types of uterine malignancies including ture and/or periglandular stromal cuffing, the diagnosis of
carcinosarcoma and other uterine sarcomas with a glandular adenosarcoma cannot be confirmed.
component or infiltrative growth through pre-existing glands.
At the very low-grade end of the spectrum of adenosar- 1.4.2.8 Clinical Management and Outcome
coma morphologies, it can be challenging to distinguish Patients with uterine adenosarcoma typically present with
from a benign endometrial polyp, which can exhibit unusual disease confined to the uterus, with less than 5% of cases
features including highly cellular stroma, stromal atypia, and associated with metastasis at the time of diagnosis [282].
some architectural features of adenosarcoma [287, 300]. Adenosarcoma is associated with better survival in compari-
Endometrial polyps with stromal cell atypia in the form of son to other types of uterine sarcoma, particularly carcinosar-
multinucleation, symplastic, or degenerative hyperchroma- coma and leiomyosarcoma; however, the presence of
sia can occur, similar to stromal polyps seen at other sites in sarcomatous overgrowth is associated with a poor prognosis
the female genital tract [300]; however, mitotic activity similar to other high-grade uterine malignancies [301].
should be absent in the atypical cells. In these instances, a Similarly, once there is a recurrence, the overall prognosis is
diagnosis of endometrial polyp can be made without further poor [283]. In the largest clinicopathologic series of Mullerian
qualification. However, in polyps with unusual architecture adenosarcoma, recurrence occurred in approximately one
(including subtle phyllodes-like glandular appearance and fourth of patients, most commonly in the vagina, pelvis, or
intraglandular polypoid projections of stroma), subepithelial abdomen [278]; however, smaller studies have found recur-
stromal condensation reminiscent of what is seen in adeno- rence rates as high as 45% [280, 281, 297, 302]. The 5-year
sarcoma, yet overall the features are insufficient for the survival rates for early-stage disease range from 60 to 87%,
and the variation is likely related to innate differences in study may be found in the fundus or upper endocervix and may be
cohorts, follow-up times, and size of studies. When consider- associated with subsequent development of, or co-existence
ing stage III–IV, 5-year survival rates are much lower (15– of, endometrioid intraepithelial neoplasia and low-grade
48%) [284, 303]. Histologic features that are repeatedly endometrioid adenocarcinoma.
associated with poor prognosis include the presence of sarco- Grossly, APAs may present as sessile polyps or be exophytic and
matous overgrowth and deep myometrial invasion in the pri- pedunculated; less commonly they can be endophytic extending
mary tumor [278, 283, 285]. Clinical features associated with deep into the myometrium. Microscopically, APA is composed of
adverse outcome include increased patient age (i.e., post- varying amounts of myomatous or “myofibromatous” stroma as
menopausal status) [282]. Patients with uterine adenosar- well as a glandular component; the glands appear loosely clustered
coma are treated by hysterectomy, typically with bilateral imparting a lobulated appearance from low-power microscopic
salpingo-oophorectomy. Lymphadenectomy is not indicated examination and have haphazard, irregular branching [304]. The
in the absence of specific clinical suspicion as the rate of glands display an irregular distribution within the stroma and exhibit
lymph node metastasis is extremely low. Although the epithe- mild to moderate cytologic atypia. A characteristic finding is (often
lial and stromal component of Mullerian adenosarcoma can extensive) morular metaplasia (Fig. 1.43). On occasion, the architec-
be positive for estrogen and progesterone receptor (suggest- tural glandular complexity may parallel that seen in low-grade endo-
ing tumoral hormonal sensitivity) [293], the impact of bilat- metrioid adenocarcinoma, and indeed the degree of architectural
eral oophorectomy on outcome, particularly in women who complexity in APA correlates with recurrence risk as well as myoin-
wish to maintain their fertility, is not clear. Radiotherapy or vasive carcinoma in follow-up. Immunohistochemically, the myofi-
chemotherapy is also considered in patients with inoperable bromatous stroma is usually positive for SMA and/or desmin.
or metastatic disease [283]. Radiation therapy has not been Recent studies have demonstrated abnormalities in PTEN, CTNNB1
shown to have significant benefit in patients with uterine ade- (beta-catenin), HNF-1B, mTOR, and mismatch repair proteins that
nosarcoma. Interestingly, one large study found that adjuvant are similar to those seen in endometrioid adenocarcinoma [305]. As
radiotherapy was associated with decreased overall survival a result, recent recommendations suggest treating these lesions simi-
[282]. The possible benefit of chemotherapy is unknown, as larly to endometrioid intraepithelial neoplasia/atypical hyperplasia
many of the large studies either excluded adenosarcoma or [306]. In general, hysterectomy is advised; however, conservative
had such small numbers of patients with adenosarcoma that excision has been performed with preservation of fertility [307].
no conclusion could be made although independent case The differential diagnosis of APA includes endometrioid
reports of response to various chemotherapeutic agents exist. intraepithelial neoplasia/atypical hyperplasia, myoinvasion
in well-differentiated adenocarcinoma, adenomyoma, and
adenomyomatous polyp. In curettage specimens, the diagno-
1.4.3 Carcinofibroma sis is more challenging; APAs may be confused with endo-
metrial polyps with fibrotic stroma or even endometrial
Carcinofibroma exists in theory, composed of a malignant carcinoma with myoinvasion [308]. Myoinvasion in low-
epithelial component and a benign (but neoplastic) stromal grade adenocarcinoma may be extremely difficult to distin-
component. However, in practice these are virtually never guish from APA, and unfortunately, immunohistochemistry
encountered or diagnosed.
1.4.4 Carcinosarcoma
Although this tumor is composed of a malignant epithelial

and mesenchymal component, it is now widely accepted
(based on morphologic, clinicopathologic, and molecular
data) that these tumors represent metaplastic carcinomas and
thus are discussed in the endometrial carcinoma chapter.
1.4.5 Atypical Polypoid Adenomyoma
Although not truly a mixed stromal and epithelial neoplasm,

atypical polypoid adenomyoma (APA) will be considered in
Fig. 1.43 Atypical polypoid adenomyoma, microscopic appearance.
this section as it often is considered to be a biphasic uterine
Atypical polypoid adenomyoma is characterized by a fibromyomatous
lesion. APAs are rare neoplasms that occur primarily in pre- stroma that is distinct from the surrounding endometrial stroma (at
menopausal women, most commonly in the fourth decade. right). The glands are endometrioid with moderate architectural atypia
They typically arise in the lower uterine segment but also and most cases have conspicuous squamous morular metaplasia
will not generally aid in this distinction [308]; however, if

caldesmon staining is absent, APA may be favored as myo-
metrium is strongly positive for caldesmon. Of note, the
diagnosis of myoinvasion should be approached with caution
in a biopsy/curettage specimen; indeed, the lack of typical
noninvasive endometrioid carcinoma should raise the possi-
bility that an APA is being overinterpreted as myoinvasive
carcinoma. One morphologic feature that may be helpful is
in EIN and endometrial confined adenocarcinomas typically
do not exhibit distinctive myofibromatous stroma; myome-
trium is composed of long fascicles of smooth muscle,
whereas the fascicular stroma in an APA is intersecting and
short. In the consideration of APA versus benign endometrial
polyps with myomatous stroma (“adenomyomatous polyps”)
and adenomyoma, the presence of endometrial-type stroma
immediately adjacent to the glandular component, which is Fig. 1.44 Perivascular epithelioid cell tumor (PEComa), gross appear-
then surrounded by the myomatous stroma, is strongly sup- ance. PEComas can have a variable gross appearance but may show a
portive of an adenomyomatous polyp or adenomyoma as pale yellow to tan and solid cut surface, with multinodular infiltration of
the myometrium
APA does not have an endometrial-type stroma component.

1.5 Other Mesenchymal Tumors Histologically, PEComas are characterized by plump epitheli-
oid cells with abundant granular pale to eosinophilic cyto-
Additional tumors discussed herein are not specific to the uterus, plasm and a centrally placed nucleus containing a prominent
and in fact most occur in higher numbers outside the uterus, but nucleolus and sometimes nuclear pseudo-inclusions.
are not uncommonly encountered in uterine pathology; these Multinucleate tumor cells, spider cell-like giant cells, and
include PEComa, inflammatory myofibroblastic tumor, solitary lipid-laden cells may also be seen. Occasionally uterine
fibrous tumor, and adenomatoid tumor, among others. PEComas display a predominant spindle cell morphology, but
most often there is a combination of epithelioid and spindled
cells. The tumor cells are usually nested and may exhibit a
1.5.1 U
terine Perivascular Epithelioid Cell perivascular distribution [257, 309, 310]. Uterine PEComas
Tumor (PEComa) have been described as having at least two morphologic sub-
types, which correlate with slightly different immunopheno-
1.5.1.1 Definition typic profiles [309]. One subtype can mimic the growth pattern
The WHO defines PEComa as “a tumor composed of histologi- of LGESS with fingerlike permeation of the uterine wall and
cally and immunohistochemically distinctive perivascular epi- is composed of cells with abundant eosinophilic, clear, or
thelioid cell,” of which there is no known normal counterpart [2]. granular cytoplasm (Fig. 1.45a, b); these tumors exhibit sig-
nificant HMB-45 and MelanA expression with only focal
1.5.1.2 Clinical Features smooth muscle marker positivity. The other subtype is com-
PEComa may occur in the setting of tuberous sclerosis composed of epithelioid cells that have less abundant clear cyto-
plex, but are more common in the sporadic setting, particularly plasm, less HMB-45 expression, and more extensive muscle
so in the uterus. Age at time of presentation varies widely (25– marker positivity. The relationship of uterine PEComa to epi-
75 years), though most commonly patients present in the peri- thelioid smooth muscle tumors is unclear; however, it appears
menopausal setting. In women with a germline TSC1/2 that they may be part of a morphologic spectrum [256, 309].
mutation, the age at presentation is much earlier (third to fourth Because of this spectrum, use of the term “PEComa” for uter-
decade). Symptoms are similar to other uterine tumors and ine tumors exhibiting this morphology has been admonished
include primarily abnormal uterine or postmenopausal bleeding by some because uterine PEComa does not appear yet to be a
followed by pain and other symptoms related to a pelvic mass. clinically homogeneous, rigorously defined tumor type [256].
Nevertheless, immunohistochemistry (see Biomarkers section
1.5.1.3 Gross Findings below) should be considered in all cases of uterine mesenchy-
Grossly, PEComas have a similar appearance to smooth muscle mal tumors with prominent epithelioid cytomorphology, not
tumors. They are seen as solitary myometrial masses with either only to further define the concept of uterine PEComa but also
well-circumscribed or infiltrative borders and can range in size because some patients with tumors having a uterine PEComa-
from <1 to >30 cm (mean ~5 cm). The cut s urface is fleshy and like morphology should be investigated for the possibility of
soft, with variably present hemorrhage and/or necrosis (Fig. 1.44). tuberous sclerosis or lymphangioleiomyomatosis [309].
a b
Fig. 1.45 PEComa, microscopic features. (a) Low-power magnifica- lioid and spindle cells with clear to granular cytoplasm, pleomorphism,
tion of PEComa demonstrating an ESS-like pattern of invasion and and scattered intranuclear pseudo-inclusions
lymphovascular invasion. (b) Higher-power magnificent reveals epithe-
a b
c d
Fig. 1.46 PEComa, immunohistochemistry. (a) This PEComa is predominantly epithelioid in morphology. (b) Desmin is strongly positive. (c)
HMB-45 demonstrates multifocal, patchy positivity. (d) MelanA is multifocally positive
1.5.1.5 Biomarkers factor (MiTF)) markers but are negative for PAX8 and kera-
PEComas express both smooth muscle (such as SMA, des- tins [257, 309] (Fig. 1.46a–d). Importantly, the degree of
min, and caldesmon) and melanocytic (HMB-45, MelanA, positivity for either the smooth muscle markers or melano-
CathepsinK, and microphthalmia-associated transcription cytic markers can vary greatly, and even focal positivity
should be interpreted as a positive result. PEComas harbor- Other translocations have also been recently reported in
ing TFE3 rearrangements have a slightly different morphol- small numbers in PEComa (one case each: HTR4-ST3GAL1
ogy, with typically purely epithelioid cells with cleared and RASSF1-PDZRN3) [315]. Array comparative genomic
cytoplasm and nested architecture, and have diminished hybridization studies have identified a number of recurrent
expression of SMA and desmin [311]. losses/gains, most notably loss of chromosomes 19, 16p,
17p, 1p, and 18p and gains of X, 12q, 3q, 5, and 2q [320].
1.5.1.6 Genetic Profile
Most studies interrogating the molecular alterations in 1.5.1.7 Differential Diagnosis
PEComa include tumors from various anatomic sites, Perhaps the most common, and arguably one of the most
including the uterus, so the molecular features discussed challenging, differential diagnostic considerations for
are not specific only to uterine PEComas, but rather PEComa is that of smooth muscle tumors, particularly the
PEComas of any anatomic site. The most well-character- epithelioid variants and when clear cell morphology is pres-
ized alterations are those resulting in inactivation of TSC2 ent, as they may have overlapping immunoprofiles [51, 256,
(16p13.3) or less commonly TSC1 (9q34) due to the asso- 309, 321–329]. While HMB45 may be positive in some epi-
ciation of PEC tumors (angiomyolipoma and lymphangi- thelioid smooth muscle tumors, MelanA positivity is more
oleiomyomatosis) with the genetic disease tuberous specific for PEComa and may be helpful in this differential
sclerosis complex. TSC1/2 are involved in many cell cycle diagnosis.
regulatory pathways, including the mTOR pathway. Loss Uterine tumor resembling ovarian sex cord tumor
of TSC1/2 results in increased activation of mTOR [312]; (UTROSCT) may also be considered in the differential diag-
thus many have proposed using mTOR inhibitors in these nosis with PEComa. As discussed in the UTROSCT section,
tumors. While any inactivating genetic hit in TSC1/2 (muta- both tumors are commonly positive for smooth muscle and
tion, deletion, copy number loss) may contribute to the melanocytic markers; however, sex cord markers SF-1 and
pathogenesis, not all PEComas have inactivation of TSC1/2. WT-1 are generally negative in PEComa.
As some PEComas lack inactivation of TSC2 and the resul- Occasionally, LGESS may exhibit an epithelioid cyto-
tant activation of the mTOR pathway, some have suggested morphology [27], which may raise the possibility of
that mTOR pathway activation be confirmed before treating PEComa; however, the latter has more prominent thick-
a PEComa patient with an mTOR inhibitor [310]. TFE3, a walled vessels and lacks the characteristic spiral arteriolar
member of the MIT/TFE family of transcription factors, is vessels of LGESS. Immunohistochemistry for HMB-45 and
rearranged in a small subset of PEComas and appears to be CD10 will help in this distinction; however, HMB-45 posi-
mutually exclusive with TSC1/2 altered PEComa [311, tivity alone does not equate with the diagnosis of PEComa,
313, 314]. PEComas harboring TFE3 rearrangements have as it also been reported in several cases of uterine leiomyo-
a slightly different morphology, with purely epithelioid sarcoma with both conventional and clear cell areas, leading
cells with cleared cytoplasm and nested architecture, and some to question the veracity of PEComa as an entity in the
immunohistochemically show no or minimal expression of uterus [94, 323].
SMA and desmin [311]. TFE3-rearranged PEComas lack Alveolar soft part sarcoma (ASPS) only rarely involves
TSC2 inactivation, suggesting that this subset of PEComa the gynecologic tract including the uterus [330] but may also
has an alternate pathogenesis and may not be amenable to be considered in the differential diagnosis with PEComa
mTOR inhibition therapy [315, 316]. One PEComa has given the similarity in morphologic growth patterns, as ASPS
been reported to have TFE3 amplification rather than rear- is composed of nests of epithelioid cells with abundant
rangement [317]. The TFE3 translocation partners docu- eosinophilic cytoplasm and large nuclei with prominent
mented in alveolar soft part sarcoma and Xp11 translocation nucleoli (Fig. 1.47). Immunohistochemically, ASPS is TFE3
renal cell carcinoma have not been found in PEComa to positive, reflecting the characteristic ASPSCR1-TFE3 gene
date. Recently, multiple groups have identified PSF as the fusion, but is typically negative for SMA, desmin, HMB-45,
most frequent translocation partner resulting in a SFPQ/ and MelanA.
PSF-TFE3 gene fusion and one case harbored a DVL2-
TFE3 gene fusion [315, 318, 319]. 1.5.1.8 Management and Outcomes
RAD51B (14q24) translocations (resulting in RAD51B- Histologic parameters shown to be useful in predicting malig-
RRAGB or RAD51B-OPHN1 gene fusions) have also been nant behavior include tumor size >5 cm, high-grade nuclear
identified in a small minority (8%) of uterine PEComas in atypia, infiltrative borders, tumor cell necrosis, lymphovascu-
one study [315]. In one of these cases, TSC2 and TP53 muta- lar invasion, and mitotic activity. In one study by Folpe et al.
tions were also identified, suggesting that these PEComas, that included PEComas from all anatomic sites, they con-
unlike the TFE3-associated PEComas, likely have a shared cluded that having any two of these morphologic criteria
pathogenesis with the TSC2-inactivated PEComas. qualified the PEComa to be “malignant” [331]. A subsequent
Interestingly, it was reported that the RAD51B translocation study by Schoolmeester et al. looking specifically at prognos-
PEComas were initially diagnosed as leiomyosarcoma. tic histologic parameters for uterine PEComa found that

Inflammatory myofibroblastic tumor (IMT) is more com-
monly seen in extrauterine sites, but has been described in
the uterus and in fact may be under-recognized in this ana-
tomic location [230, 338–340]. IMTs were initially thought
to represent a reactive, “pseudo-neoplastic” process, but
have since been shown to be not only neoplastic but also with
potential for aggressive clinical behavior. IMTs may occur at
any age, although they have a predilection for children and
adolescents. Of the 29 cases that have been described in the
uterus in the three largest series, the patients’ ages ranged
from 6 to 73 years. The most common symptoms of patients
with uterine IMT are menorrhagia and abdominal pain; how-
ever, some tumors are identified incidentally, and in a minor-
ity of cases (primarily extrauterine sites), patients can present
Fig. 1.47 Alveolar soft part sarcoma, microscopic features. Alveolar
soft part sarcoma may mimic PEComa morphologically with polygonal
with constitutional symptoms including fever, weight loss,
to epithelioid cells with abundant eosinophilic cytoplasm arranged in and malaise [2, 25, 245].
nests, but immunohistochemically can be distinguished by lack of
SMA, desmin, HMB-45, and MelanA expression 1.5.2.3 Gross Findings
Uterine IMTs typically occur as a polyp extending from the
increasing the threshold to four morphologic c riteria for diag- uterine wall or as a circumscribed myometrial mass. Upon
nosing malignant PEComa was more specific for predicting gross examination, IMTs may appear fibrous, fleshy, or
malignant behavior [257]. More recently, a review article on gelatinous. Uterine IMTs range in size from 1 to 20 (mean
uterine PEComa summarized the data on 78 cases reported in 5–7) cm; this mean size at presentation is similar to extra-
the literature and applied both the Folpe and Schoolmeester uterine IMTs. Spread beyond the uterus at the time of diag-
criteria to all of these cases and found that while the Folpe nosis is extremely uncommon.
criteria was most sensitive, the Schoolmeester criteria was
more specific and furthermore identified those PEComas at 1.5.2.4 Microscopic Findings
highest risk for early recurrence [310]. The authors of this IMT is a variably cellular, fascicular myofibroblastic/fibro-
meta-analysis review article suggest using a modified Folpe blastic neoplasm with a frequently myxoid to collagenous
criteria, including either the presence of any two worrisome stroma and associated prominent lymphoplasmacytic infil-
features or tumor cell necrosis alone, with subsequent appli- trate [338]. IMT can have a variety of morphologic patterns
cation of the Schoolmeester criteria to identify those patients including the myxoid/vascular pattern, a compact spindle
most at risk for early recurrence. cell pattern, and fibromatosis-like pattern (Fig. 1.48a–d)
As touched upon in earlier sections, mTOR therapy is [338]. The myxoid/vascular pattern is composed of plump
considered in many patients with PEComa, with promising spindle cells in an edematous to myxoid matrix, having an
results in small studies [332–337]. TFE3-rearranged appearance akin to nodular fasciitis. The compact spindle
PEComas lack TSC inactivation, suggesting that this subset cell pattern typically has spindle cells arranged in a fascicu-
of PEComa has an alternate pathogenesis and may not be lar or storiform pattern set in a more collagenous-appearing
amenable to mTOR inhibition therapy [315, 316, 335]. stroma. The fibromatosis-like pattern is hypocellular with a
Because some PEComas lack inactivation of TSC2 and thus densely collagenous to sclerotic, hyalinized matrix contain-
activation of the mTOR pathway, some have suggested that ing elongate (and less plump) spindle cells. Virtually all
mTOR pathway activation be confirmed before treating a IMTs have myxoid areas, at least focally though it may com-
PEComa patient with an mTOR inhibitor [310]. prise 10% or less of the tumor. Uterine IMTs typically have
rounded pushing borders with the myometrium, but they
may also have focally irregular borders; two of six cases
1.5.2 Inflammatory Myofibroblastic Tumor from the series of Rabban et al. infiltrated the endometrium
and entrapped benign glands [339]; in the series by Parra-
1.5.2.1 Definition Herran et al., five of nine informative cases demonstrated
A neoplasm composed of myofibroblastic cells with infiltrative borders [230]; and from Bennet et al., all cases
admixed inflammatory cells, most notably plasma cells and demonstrated either infiltrative (75%) or focally irregular
lymphocytes. (25%) borders [340]. Cytologic atypia is typically mild to
a b
c d
Fig. 1.48 Inflammatory myofibroblastic tumor (IMT), microscopic most notably lymphocytes and plasma cells, at least focally, are identi-
appearance. (a) The characteristic morphology and one that is most fied in the vast majority. (c) The fasciitis-like pattern is also a common
readily identifiable as IMT is the myxoid pattern with abundant myxoid morphologic finding in IMT. (d) Collagenous stroma may also be
stroma imparting a hypocellular appearance. (b) Inflammatory cells, present
moderate, but occasionally may be severe [340]. Mitotic rate immunohistochemistry, in part due to the morphologic over-
can vary, from <1 to >20 per 10 HPFs in the largest series of lap and inability to reliably distinguish IMT from the much
uterine IMT [230, 340]. more common uterine smooth muscle tumors [341].
1.5.2.5 Biomarkers 1.5.2.6 Genetic Profile

IMTs are often positive for smooth muscle markers. The Cytogenetic and molecular genetic analyses have shown that
molecular alteration most characteristic for IMT is rear- 50–70% of IMTs (of all anatomic sites) have rearrangements
rangement of the ALK gene at 2p23. This results in overex- involving the ALK gene on chromosome 2p23.453 [342].
pression of ALK which may be detected These abnormalities are more common in pediatric patients
immunohistochemically Fig. 1.49 [341]. Additionally, IMTs and have been described in tumors at both pulmonary and
frequently express SMA and desmin, with more limited extrapulmonary sites, including uterine. ALK gene rear-
expression of caldesmon that is typically restricted to the rangement results in overexpression of ALK protein, which
more compact fascicular areas. CD10 is also frequently can be diagnostically useful as mentioned above [343].
expressed in IMT [230, 340]. Although ALK-negative IMT Various gene fusion partners have been identified in uterine
are readily accepted outside the uterus, the vast majority of IMT, including IGFBP5, THBS1, FN1, TPM3, DES, SEC31,
uterine IMTs described to date are positive for ALK by or TIMP3 [163, 340]. Rarely, uterine IMTs may harbor gene
have a fascicular growth pattern and myxoid appearance,

myxoid leiomyoma may be considered in the differential
diagnosis. On gross examination, this extremely uncommon
variant of leiomyoma typically appears gray and gelatinous,
although this feature depends on the extent of myxoid
change within the tumor. Histologically, an abundant pale
blue myxoid matrix separates the bland-appearing smooth
muscle bundle fibers. Features helpful in the recognition of
IMT versus a myxoid leiomyoma is the presence of a fasci-
itis-like growth pattern, a storiform growth pattern, a lym-
phoplasmacytic infiltrate, and positive staining for ALK by
immunohistochemistry. Other immunohistochemical stains
including smooth muscle markers are not as useful because
IMT often express desmin, while myxoid LMS may have
reduced expression of muscle markers. A recent study has
Fig. 1.49 Inflammatory myofibroblastic tumor, immunohistochemis- shown some promise in the use of p53 and p16 immunohis-
try. Inflammatory myofibroblastic tumor is positive for ALK immuno- tochemistry in distinguishing IMT from myxoid LMS; in
histochemistry in most cases. Note the prominent granular cytoplasmic that study no IMT had abnormal p53 or p16 expression,
staining in the spindled tumor cells while >50% of myxoid and conventional LMS had abnor-
mal p53 or p16 [206]. The STUMP category of uterine
fusions not involving ALK, similar to extrauterine IMT, most smooth muscle tumors has also been shown to include mis-
notably the ETV6-NTRK3 fusion [342, 344, 345]. ROS1- diagnosed (i.e., underdiagnosed) cases of IMT, in up to 14%
rearranged IMT have been described in other viscera/soft tis- of cases [260, 348].
sue but have yet to be documented in the uterus [346, 347]. Similar to IMT, the myxoid variant of endometrial stro-
mal tumors [28, 50] also may present as a polypoid endome-
1.5.2.7 Differential Diagnosis trial mass; however, LGESS has a characteristic multinodular
There can be significant morphologic overlap for IMT with or tonguelike pattern of myometrial infiltration, and at least
myxoid LMS and other smooth muscle neoplasms. Thus, focally there is an appearance of typical endometrial stromal
the differential diagnosis includes myxoid leiomyosarcoma, neoplasia with its characteristic growth pattern and promi-
myxoid leiomyoma, and the myxoid variant of endometrial nent (arteriolar) vascular component. Immunohistochemistry
stromal sarcoma. When evaluating myxoid uterine tumors, for CD10 is unlikely to be helpful as many IMTs demon-
the diagnosis of IMT should be considered, particularly as strate CD10 positivity; however, LGESS is negative for ALK
IMTs with larger size, higher proportions of myxoid stroma, immunohistochemistry.
and higher mitotic activity may have a higher propensity for
more aggressive behavior [230, 340]. Similar to the conven- 1.5.2.8 Management and Outcomes
tional spindle cell type of uterine leiomyosarcoma, myxoid Uterine IMT only rarely recurs, and histologic parameters
leiomyosarcoma also typically affects women in their sixth that may be associated with more aggressive behavior
decade who may present with abnormal vaginal bleeding, include tumor cell necrosis, large tumor size (≥8 cm), high
pelvic pain, or a pelvic mass. However, in contrast, myxoid mitotic activity (≥7 per 10 HPFs), a predominantly myxoid
leiomyosarcoma usually will have a more gelatinous gross pattern, lymphovascular invasion, and infiltrative borders
appearance with a glistening cut surface, although this may [230, 340]. However no definitive criteria for “malignancy”
vary in extent depending on the amount of extracellular exist in uterine IMT as the total number of cases reported is
myxoid matrix deposition. The tumor cells may be spindled small and many with limited clinical and follow-up data. The
or stellate and the degree of (Alcian blue positive) extracel- epithelioid variant, which is associated with a distinctive
lular matrix deposition may obscure the tumors fascicular nuclear membrane or perinuclear pattern of Alk staining and
architecture. Although the majority of IMTs may have a an aggressive clinical course, has not been described in the
bland cytomorphologic appearance, tumor cells typically uterus to date [349]. Although surgery is the mainstay of
exhibit at least focal moderate atypia. IMT can be distin- therapeutic management of IMT, tyrosine kinase inhibitor
guished from myxoid leiomyosarcoma by its typically (but therapy may be considered in patients with recurrence or
not always) pushing border without vascular invasion, the with metastatic disease. The presence of ALK rearrangement
presence of a prominent lymphoplasmacytic infiltrate, and makes IMTs amenable to tyrosine kinase inhibition similar
immunohistochemical expression of ALK. Because uterine to other ALK-rearranged tumors [350], with promising pre-
IMTs typically have a rounded, pushing border and may liminary results in small studies [351].
1.5.3 Adenomatoid Tumor gous component) most commonly Mullerian adenosarcoma and
carsinosarcoma and are not included in this discussion. In gen-
Adenomatoid tumors are tumors of mesothelial origin that eral, rhabdomyosarcoma is separated into three histologic
typically involve the serosal surfaces of uterus or (more com- types – embryonal, alveolar, and pleomorphic. In the female
monly) the fallopian tube. In addition to their characteristic genital tract, embryonal rhabdomyosarcoma (ERMS) is uncom-
anatomic location, the gross appearance of adenomatoid mon and most frequently occurs in the uterine cervix but has also
tumors are firm, rubbery tumors with white or gray cut sur- been reported in the uterine corpus [234, 354–359]. When pri-
faces. The border with the adjacent myometrium may not bulge mary in the cervix, it typically occurs in children or young
out or be as defined as typical leiomyomata. Microscopically, women and often presents as a polypoid, grape-like mass; in this
the mesothelial proliferation forms gland-like spaces nestled scenario it is referred to as “botryoid rhabdomyosarcoma” which
between smooth muscle fascicles (Fig. 1.50), but the mesothe- just refers to the subset of ERMS that occur at a mucosal site and
lial cells are not infrequently inconspicuous. Consequently, the grow in this distinctive fashion. ERMS of the uterine corpus
gland-like spaces may look more like venules or even adipose occurs over a wide age range, but patients are typically older than
or signet ring cells. The mesothelial origin of these cells can be those presenting with cervical primaries. Patients typically pres-
confirmed by their expression of cytokeratins, WT-1 [352], ent with vaginal bleeding or abdominal distension or pain. On
D2-40, and calretinin, but not of CD-31 or CD-34 [353]. It is gross examination, the tumor also typically projects into endo-
presumed that the mesothelial cells are neoplastic and the metrial cavity with a “grape-like” appearance and has a gray-
smooth muscle cells are hyperplastic. As adenomatoid tumors white fleshy to glistening cut surface (“botryoid subtype”) but
are usually benign, under 2 cm in size, and an incidental finding can also be an intramural mass. Necrosis and hemorrhage may
in women in the years before menopause, they have no clinical be seen. Histologically, uterine ERMS has similar features to that
impact apart from their mimicry of leiomyomata and other of soft tissue and other sites; namely, a tumor composed of small,
benign tumors. Distinction from malignant mesothelioma is round to spindle-shaped “undifferentiated” blue cells intermin-
not a common diagnostic dilemma as mesothelioma demon- gled with variable numbers of rhabdomyoblasts with brightly
strates a highly infiltrative growth pattern. eosinophilic cytoplasmic processes that may contain cross-stria-
tions (also termed “tadpole” or strap cells). The botryoid subtype
typically shows alternating hypocellular and hypercellular
1.5.4 Rhabdomyosarcoma primitive-appearing spindled cells (Fig. 1.51a) that frequently
condense underneath surface epithelium to form a “cambium”
Rhabdomyosarcomas are malignant tumors showing skeletal layer (Fig. 1.51b, c). Tumor cells may also demonstrate striation
muscle differentiation by morphology and immunohistochemi- (“strap” cells) and islands of cartilaginous differentiation may be
cal expression; of note, rhabdomyosarcomatous differentiation present (Fig. 1.50d). Immunohistochemistry shows positivity for
can be seen as a component of other tumor types (as a heterolo- skeletal muscle markers, although it may be patchy. This tumor
may be difficult to recognize, particularly in older women, and
there can be morphologic overlap with adenosarcoma as well as
a poorly sampled carcinosarcoma, both of which may com-
monly have rhabdomyosarcomatous differentiation. The only
well-characterized molecular alteration in ERMS is DICER1
mutation, which may occur as either germline or somatic inacti-
vation [359–364]. DICER1 is involved in miRNA processing
and its inactivation is likely a key step in the pathogenesis of
ERMS. No studies to date have evaluated for the presence of
DICER1 mutations in other tumors demonstrating rhabdomyo-
sarcomatous differentiation aside from the aforementioned ade-
nosarcoma [275]. ERMS in adults, even if of the botryoid
subtype, appears behave more aggressively with a worse overall
survival [355].
Alveolar and pleomorphic rhabdomyosarcoma are rare in
the uterus [355, 365–369]. The former is characterized by
rounded undifferentiated cells growing in a nested/alveolar
pattern surrounded by fibrous septa and admixed with vari-
Fig. 1.50 Adenomatoid tumor. Adenomatoid tumor is characterized by
attenuated flattened to cuboidal mesothelial cells forming cyst-like
able numbers of wreath-like multinucleate cells and rhabdo-
spaces within myometrium. In this example, the mesothelial compo- myoblasts. Most alveolar rhabdomyosarcomas express
nent is conspicuous PAX3-FKHR or PAX7-FKHR gene fusions with the latter
a b
c d
Fig. 1.51 Rhabdomyosarcoma, embryonal type. (a) Embryonal rhab- underneath nonneoplastic surface epithelium. (c) In some cases, the
domyosarcoma with alternating hypocellular and hypercellular areas, cambium layer can be very subtle, particularly in areas of hemorrhage.
with hyperchromatic, primitive-appearing spindled cells in the hyper- (d) Cartilaginous differentiation, as shown here, may be seen in embry-
cellular foci. (b) The classic histologic feature of embryonal rhabdo- onal rhabdomyosarcoma
myosarcoma is the “cambium” layer in which the tumor cells condense
possibly associated with a more favorable prognosis [370]. present at a wide age range (34–81 years). Tumors range in
Pleomorphic rhabdomyosarcoma is a high-grade sarcoma size from 3.5 to 12.5 cm and grossly appear as a well-
composed of pleomorphic cells which may show features of circumscribed firm yellow-tan nodule. Histologic appear-
ERMS or alveolar subtype elsewhere and may best be con- ance is similar to SFT described elsewhere with bland spindle
sidered “anaplastic” rhabdomyosarcoma in this context. cells arranged in a “patternless pattern” and alternating
hypo- and hypercellular areas, as well as the characteristic
staghorn or hemangiopericytoma-like thin-walled branching
1.5.5 Solitary Fibrous Tumor (SFT) vasculature. An adipocytic component or myxoid change
may be present in a minority. Also similar to SFTs reported
Solitary fibrous tumor rarely occurs in the uterus, but is elsewhere, histologic features are not entirely helpful in
worth mentioning as the clinical and imaging impression is determining malignant potential; indeed at least one case in
often that of leiomyoma, and thus pathologic recognition of the largest series that metastasized to the lung demonstrated
this entity is essential as SFT are considered tumors of uncer- low mitotic activity, nuclear atypia, or necrosis, although the
tain malignant potential, even when no worrisome histologic tumor size was 10 cm [371, 372]. Immunohistochemically,
features are present. Within the female genital tract, the uter- SFT are positive for CD34 and STAT6 but negative for the
ine corpus is the most common location [371] and patients smooth muscle markers SMA, desmin, and caldesmon.
1.5.6 Angiosarcoma Features that are helpful in distinguishing between an

adenomyosis-related process and an endometrial stromal sar-
Angiosarcoma of the uterus is exceedingly rare as a pure, coma include the presence of obvious adenomyosis elsewhere,
primary tumor as the largest case series to date comprises a thickening or hypertrophy of the surrounding myometrium,
four cases [373]; however, within the female genital tract, it and lack of a grossly evident mass. The presence of variant
is the second most common site after the ovary. Clinically morphologic features (such as sex cord differentiation, hyaline
patients present in the perimenopausal or postmenopausal bands or plaques, and foamy histiocytes) should raise high
years. These are aggressive tumors similar to angiosarcoma suspicion for LGESS and warrants molecular investigation for
of soft tissue, with most patients dying of disease, often JAZF1 rearrangement.
within a year of diagnosis [373, 374]. Likewise, immunohis-
tochemistry for uterine angiosarcoma reveals CD31 and
CD34 positivity; presumably ERG would also be positive in References
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Fallopian Tube
2
David L. Kolin and Brooke E. Howitt
Abstract Keywords
The fallopian tube contains a muscular wall and plicae Fallopian tube · Serous carcinoma · Serous tubal
lined by ciliated, tubal-type epithelium. While primary intraepithelial carcinoma · Ectopic pregnancy · Pelvic
tumors of the fallopian tube are unusual, benign, border- inflammatory disease
line, and malignant tumors occur, many of which have
similar counterparts in the endometrium and ovary. Over
the past two decades, there has been a realization that the
fimbriae are the source of many (and some believe all) 2.1 Introduction
cases of “ovarian” high-grade serous carcinoma. The spec-
trum of serous tubal neoplasia includes p53 signatures, The fallopian tube has garnered increased attention over the
serous tubal intraepithelial carcinoma, and high- grade past 15 years as it has become implicated as the site of origin
serous carcinoma. These entities have unique morphologic, of many pelvic high-grade serous carcinomas. High-grade
immunophenotypic, and genetic features, with varied clini- serous carcinoma of the fallopian tube was likely underap-
cal significance. The fallopian tube is a frequent site of preciated in the past, as a result of under-sampling of the
metastatic disease from not only the ovary and uterus but fallopian tube and lack of recognition of in situ lesions. Now
may also contain metastases from distant sites (most often that serous tubal intraepithelial carcinoma (STIC) is recog-
the gastrointestinal tract and breast). Metastases may be nized as the precursor of many, if not all, high-grade serous
located within the serosa, mucosa, muscular wall, or intra- carcinomas, more tumors are being classified as fallopian
vascular spaces. The fallopian tube can manifest several tube primaries. With the introduction of the Sectioning and
metaplasias, such as mucinous and transitional, as well as Extensively Examining the Fimbria (SEE-FIM) protocol for
reactive phenomena, including pseudocarcinomatous grossing fallopian tubes, the ability to detect small intramu-
hyperplasia. Sexually transmitted diseases are the most cosal lesions in the fimbria has increased significantly. Since
common causes of infectious salpingitis, which may result the fallopian tube is now accepted to be the site of origin of
in pelvic inflammatory disease and ectopic pregnancy. many BRCA1- and BRCA2-related “ovarian” malignancies,
Because the fimbriae are a site of serous carcinogenesis, the the frequency of prophylactic salpingectomies has increased
SEE-FIM grossing protocol was developed to extensively significantly in recent years. It therefore behooves the pathol-
sample the fimbria in risk-reducing salpingectomies and is ogist to familiarize themselves with the spectrum of intraepi-
now applied in many specimens containing salpingecto- thelial lesions which are commonly encountered in routine
mies, including those from low-risk women. At a mini- salpingectomy specimens.
mum, entirely submitting and examining the distal fallopian This chapter begins with a review of fallopian tube anat-
tube are generally advised. omy and histology. Tubal neoplasias are described, with an
emphasis on both benign and malignant tumors which are
unique to the fallopian tube. Nonneoplastic disorders are
D. L. Kolin then addressed, including inflammatory conditions and vari-
Department of Pathology, Brigham and Women’s Hospital,
ous metaplasias which may be observed and are important to
Boston, MA, USA
recognize as they may mimic neoplastic processes. Special
B. E. Howitt (*)
attention is given to tubal ectopic pregnancies. Finally, sug-
Department of Pathology, Stanford University Medical Center,
Stanford, CA, USA gested grossing protocols are given for the most commonly
e-mail: [email protected] encountered tubal specimens.

54 D. L. Kolin and B. E. Howitt
2.2 Fallopian Tube Anatomy

and Histology
The fallopian tubes traverse from the uterus to the ovary

through the broad ligament and have a length of 7–12 cm
[1]. Anatomically, the fallopian tube is comprised of four
regions: the infundibulum and its fimbriated end, closest to
the ovary; the ampulla, the longest portion of the tube; the
isthmus, a narrow portion of the tube nearest the uterus;
and a short intramural (or interstitial) portion of the tube
which is within the uterine corpus. The infundibulum is
funnel-shaped and has attached to its end approximately 25
finger-like folds comprising the fimbriae, which are imme-
diately adjacent to the ovary and help to capture the egg
during ovulation [2]. A band of smooth muscle, the fimbria Fig. 2.2 Pigmented macrophages in the tubal lamina propria are
ovarica, attaches the fimbriated end of the fallopian tube to termed melanosis tubae or pseudoxanthomatous salpingiosis and are
the ovary. The fallopian tube mesentery, the mesosalpinx, is associated with endometriosis
the region of the broad ligament between the ovary and the
fallopian tube. The cells lining the plicae vary as a function of the men-
Blood supplies the fallopian tube via the tubal branches of strual cycle. At ovulation, the fraction of ciliated cells and
the ovarian and uterine arteries [1]. Lymphatic drainage of cell height are highest [4]. During the luteal stage, when
the fallopian tube either follows the ovarian vessels to para- serum progesterone levels are high, the percent of ciliated
aortic lymph nodes or the uterine vessels to internal iliac cells and the height of fimbrial cells both decrease [4, 5].
nodes [3]. These changes are exaggerated further during pregnancy,
Histologically, a cross section of the tube shows the outer when progesterone levels are higher [5].
serosal layer, middle muscular layer (myosalpinx), and an There are variations of normal histology which may be
inner mucosal layer (endosalpinx). The myosalpinx is com- encountered routinely in fallopian tubes. Plical fibrosis is
posed of an inner circular and outer longitudinal layer. present in 35% of salpingectomy specimens, and its sever-
Invaginations of the tubal mucosa, termed plicae, become ity increases with patient age [6]. Intramuscular edema of
increasingly complex from the interstitium to the fimbria. the wall may be seen and is associated with recent preg-
The plicae are lined by three different cell types: secretory, nancy [6]. Pigmented macrophages containing hemosiderin
ciliated, and intercalated (peg) cells (Fig. 2.1). The ciliated and/or lipofuscin are occasionally seen in the lamina pro-
cells are crucial for enabling tubal transport of ova. pria of the fallopian tube (Fig. 2.2) [7]. This phenomenon
occurs in 5% of salpingectomies and is called melanosis
tubae, pseudoxanthomatous salpingiosis, or pigmentosis
tubae and is associated with endometriosis, infertility, and
hydrosalpinx [6–8].
2.3 elationship with Pelvic Serous

R
Tumors
2.3.1 Overview
Interest in the fallopian tube as a possible source of “ovar-

ian” carcinoma started after reports in 2001 showed an
increase in tubal dysplasia and early carcinoma in women
with BRCA1 mutations [9–13]. Since then, a spectrum of
tubal serous neoplasia has been described, including p53 sig-
natures and serous tubal intraepithelial carcinoma (STIC,
Fig. 2.1 Normal fallopian tube plicae are lined by secretory (blue), Table 2.1). Clinical, pathologic, and molecular evidence now
ciliated (red), and peg cells (black), which are variants of secretory cells shows that most so-called ovarian high-grade serous
2 Fallopian Tube 55
Table 2.1 Terminology for serous tubal intraepithelial proliferations

Lesion Diagnostic criteria Significance
p53 signature • Secretory cell No increased risk
outgrowth of serous
• Abnormal p53 carcinoma
staining by IHC
Benign serous tubal • Abnormal p53 No increased risk
epithelial staining by IHC of serous
proliferation/lesion • Mild nuclear carcinoma
enlargement
Serous tubal • Abnormal p53 Unknown risk of
epithelial staining by IHC future HGSC, but
proliferation/lesion • Nuclear enlargement probably very low
of uncertain • Increased N:C ratio Perform deeper
significance • Preserved polarity levels to rule out
• Increased Ki-67 STIC
proliferative index
Serous tubal • Abnormal p53 Risk of later
intraepithelial staining by IHC developing HGSC: Fig. 2.3 p53 signatures are characterized by a secretory cell outgrowth
carcinoma (STIC) • Nuclear enlargement 4–11% and abnormal p53 staining pattern (diffuse overexpression or null)
• Increased N:C ratio Consider germline
• Lost polarity testing for
• Increased Ki-67 BRCA1/2
proliferative index mutations low Ki-67 proliferation index (Fig. 2.3) [17, 18]. They are
Adapted from ref. [15] thought to be early precursors of serous carcinoma because
they are often found adjacent to a STIC, and they share both
identical TP53 mutations with concomitant STICs and risk
carcinoma (HGSC) originates from tubal epithelium. The factors with ovarian carcinoma, such as lower parity and
introduction of a protocol to extensively examine the tubal older age at first childbirth [17, 18].
fimbria (SEE-FIM, described in detail later) has facilitated In diagnosing serous carcinoma precursors of the fallo-
detection of precursor lesions [14]. As risk-reducing (pro- pian tube, p53 immunohistochemistry is often used as a sur-
phylactic) salpingo-oophorectomies become more common, rogate for TP53 mutations [10]. Lesions with wild-type
pathologists will encounter these tubal lesions with increas- TP53 show a wild-type or patchy pattern of p53 staining,
ing frequency. while tumors with TP53 mutations display an abnormal pat-
tern of p53 expression characterized by either diffuse over-
expression (>75%) or a null pattern (complete absence) of
2.3.2 Terminology of Tubal Serous Neoplasia staining.
Li-Fraumeni syndrome, in which patients have germ-
2.3.2.1 Secretory Cell Expansion and Outgrowths line mutations in one allele of TP53, serves as an interest-
Tubal secretory cell expansion (SCE) and outgrowths ing model for the carcinogenesis of the distal tube.
(SCOUTs) are benign proliferations of either serous/ciliated Patients with Li-Fraumeni have abundant p53 signatures
(type I) or endometrioid (type II) cytomorphology. A SCE is (up to 20 in each section of fimbria), indicating frequent
defined as more than 10 secretory cells in a row, while a biallelic inactivation of TP53 [19]. The high frequency of
SCOUT contains more than 30 secretory cells in a row [15, loss of heterozygosity in these patients demonstrates that
16]. The main differential diagnoses include a p53 signature the fimbria is prone to TP53 mutations. The fimbrial
and serous tubal intraepithelial carcinoma (STIC). Both SCE mucosa has been postulated to be especially vulnerable to
and SCOUTs have minimal cytologic atypia, wild-type p53 mutations because of its proximity to inflammatory medi-
staining, and a low Ki-67 proliferation index. For clinical ators and oxidative stress secondary to ovulation [20].
purposes, these terms are considered “benign tubal epithelial However, there is no increased risk of ovarian carcinoma
proliferations” and do not need to be mentioned in a pathol- in Li-Fraumeni syndrome [19]. This suggests that muta-
ogy report. tions in TP53 are necessary, but not sufficient, for the
development of high-grade serous carcinoma and that
2.3.2.2 p53 Signature additional mutations (e.g., in BRCA1/2) are required for
p53 signatures are non-obligate precursors of serous carci- carcinogenesis. Conversely, p53 signatures are not more
noma. They occur most frequently in the fimbria and are common in BRCA1/2 carriers than in controls, despite the
characterized by a segment of at least 12 consecutive secre- fact that BRCA1/2 carriers are at high risk for serous
tory cells with abnormal p53 immunohistochemistry and a carcinoma [18].
2.3.2.3 Serous Tubal Intraepithelial Carcinoma proliferation index (Fig. 2.4b, c) [11]. There is no accepted
(STIC) or validated Ki-67 cutoff for STIC lesions, although most
Serous tubal intraepithelial carcinoma (STIC) is a precursor STICs show greater than 75% staining [11]. Positive staining
lesion of high-grade serous carcinoma found in the fallopian with stathmin 1 and p16 (strong and diffuse) is also support-
tube. Approximately 90% of STICs are located within the ive of STIC (Fig. 2.4d).
fimbria and with the remainder in the more proximal tube STIC is by definition intraepithelial and thus “noninva-
[11, 21]. STICs are seen in 5–8% of risk-reducing salpingo- sive”; however, similar to serous endometrial intraepithelial
oophorectomy specimens [10, 22]. They are also identified carcinoma, it may disseminate in the peritoneum or less
in the setting of a tubal or ovarian HGSC: 61% of ovarian, commonly metastasize to lymph nodes before progressing to
67% of tubal, and 22–50% of so-called primary peritoneal an invasive tubal carcinoma [26]. Given this metastatic
HGSC are associated with a STIC [21, 23]. It is uncommon potential, STIC is usually staged as Tla (AJCC) or IA
to detect a STIC incidentally (i.e., in non-BRCA1/2 carriers (FIGO), even in the absence of invasion [27].
without HGSC) in a salpingectomy specimen (0.1–0.8%) One may encounter serous tubal intraepithelial prolifera-
[24, 25]. tions that do not fully satisfy criteria for a STIC. Occasionally,
STICs are characterized by increased nuclear-to- one is seen adjacent to a high-grade serous carcinoma with-
cytoplasmic ratio, loss of polarity, mitotic activity, and epi- out an identified STIC [28]. This suggests that invasion may
thelial stratification (Fig. 2.4a). Immunohistochemically, have occurred directly from the intraepithelial proliferation
they show abnormal p53 staining and increased Ki-67 or that the carcinoma overgrew a pre-existing STIC.
a b
c d
Fig. 2.4 Serous tubal intraepithelial carcinoma (STIC) is characterized tubal epithelium STIC shows increased Ki-67 proliferative activity (b),
by increased nuclear-to-cytoplasmic ratio, mitotic activity, loss of abnormal p53 staining pattern (c), and diffuse positivity for p16 (d)
polarity, and prominent nucleoli (a). Compared to the adjacent benign
2 Fallopian Tube 57
There is little evidence to guide treatment of patients carcinoma, while delaying premature menopause. It has
diagnosed with a STIC in the absence of an invasive malig- been speculated that cells from a STIC may exfoliate or
nancy. A small but significant fraction of these patients detach from the fallopian tube and later result in advanced
(4–11%) will go on to develop so-called “primary perito- pelvic carcinoma (“precursor escape”) [28]. This mecha-
neal” serous carcinoma at a later time [22, 29, 30]. Peritoneal nism has been postulated to explain some cases of pelvic
washings may be positive in up to 15% of patients with an high-grade serous carcinoma that arise following prophy-
incidentally detected STIC [31], but the prognostic signifi- lactic salpingo-oophorectomies.
cance of positive washings is unclear. Given the potential for
extratubal metastases, patients are usually observed with
serial serum CA-125 and pelvic ultrasounds, with consider- 2.3.4 D
efinition of Primary Organ Site
ation of BRCA1/2 germline testing if not already performed of Cancers Involving Tube, Ovary,
[30, 32]. Some have advocated for staging, including lymph- and Peritoneum
adenectomy, following a STIC diagnosis [26, 30]. The role
for prophylactic chemotherapy, if any, is unclear [29]. There is some controversy regarding how to assign a pri-
mary site to high-grade serous carcinomas that involve the
tube, ovary, and/or peritoneum. Traditional clinicopatho-
2.3.3 T
ubal Fimbria as the Main Source logic parameters which have been used to differentiate pri-
of Pelvic Serous Carcinoma mary ovarian carcinoma from metastatic disease, such as
bilaterality and surface involvement, are less useful in
Historically, the ovarian surface epithelium or cortical inclu- determining the site of origin of serous carcinoma [21].
sion cysts were thought to be the site of origin of ovarian Features which favor a tubal primary include unilateral
high-grade serous carcinoma. A new paradigm emerged tubal disease, a spectrum of neoplasia in the tube including
when examination of risk-reducing salpingo-oophorectomy STIC, and the absence of advanced (e.g., omental) disease
specimens in BRCA1 and BRCA2 mutation carriers identi- spread [28].
fied early tubal carcinomas, and it was postulated that the Recent consensus guidelines have suggested an algorithm
fallopian tube may be the source of ovarian serous carcinoma for assigning the primary site of serous carcinoma (Table 2.2).
[9–13]. Incidentally discovered STICs in patients without They state that when the tube is involved by carcinoma (by
disease in the ovary added additional evidence that HGSC STIC and/or invasive carcinoma), the primary organ site
arises in the tube [33–35]. Next-generation sequencing of should be specified as the fallopian tube, even if there is a
synchronous STICs and ovarian HGSC have found identical greater burden of disease present in one of the ovaries [27,
mutations in TP53, further bolstering the evidence for STICs 40]. Furthermore, high-grade serous carcinoma should only
as HGSC precursors [36].
There has been some debate about whether all pelvic (i.e.,
Table 2.2 Guidelines for assigning a primary site for carcinomas
tubal, ovarian, and peritoneal) HGSC arises from the fallo- involving the tube, ovary, and peritoneum
pian tube or if there may be a second, fallopian tube-
Primary site Criteria
independent, pathway. For example, STIC is seen less
Fallopian STIC present, with or without ovarian or peritoneal
frequently in BRCA1/2 carriers with HGSC than those with- tube disease OR
out germline mutations, raising the possibility of two differ- Invasive mucosal carcinoma in tube, with or without
ent mechanisms for oncogenesis in these populations [37]. ovarian or peritoneal disease OR
Fallopian tube incorporated in tubo-ovarian mass
Integrated genomic analyses of cases of HGSC both with
Ovary Ovarian carcinoma (even microscopic), in the absence
and without identified STICs have shown similar copy num- of a STIC or tubal mucosal carcinoma AND
ber alterations and mRNA expression profiles between the Tubes must be fully evaluated with SEE-FIM to
two groups, providing evidence that both share a common exclude a tubal primary
origin (putatively the fallopian tube) [38]. Details of the cell Primary No STIC or invasive carcinoma in tubes or ovaries,
peritoneal after examining with SEE-FIM and submitting
of origin of ovarian serous carcinomas are described in Chap.
ovaries in toto
4 of this book. N.B. Do not diagnose “primary peritoneal” in the
Given the high lifetime risk of ovarian carcinoma, pro- setting of neo-adjuvant chemotherapy; these cases
phylactic bilateral salpingo-oophorectomies are recom- should be assigned a site of origin of “tubo-ovarian,”
even if there is no residual disease at these sites
mended for BRCA1/2 carriers. Since the fimbria is now
Tubo- HGSC diagnosed on cytology or omental biopsy OR
recognized as the site of origin for the majority of “ovar- ovarian Tumors treated with neo-adjuvant chemotherapy in
ian” carcinoma, prophylactic salpingectomies are some- which there is peritoneal disease, but no remaining
times performed first, with delayed oophorectomies [39]. tumor in the tubes or ovaries
This gives some of the benefits of risk reduction for ovarian Adapted from ref. [27]
be assigned a primary site of the ovary if both tubes have Table 2.3 WHO classification of fallopian tube tumors
been examined using the SEE-FIM protocol and tubal neo- Epithelial tumors and cysts
plasia has been excluded. Primary peritoneal serous carci- Hydatid cyst
noma should only be diagnosed when the tubes and ovaries Benign epithelial tumors
have been examined microscopically and are disease-free. Papilloma
Serous adenofibroma
Neoadjuvant therapy for HGSC is common and can greatly
Epithelial precursor lesion: serous tubal intraepithelial carcinoma
reduce tumor burden and may obscure the site of origin.
Epithelial borderline lesion: serous borderline tumor
Consequently, in the setting of treated disease, a tubo-ovarian Malignant epithelial tumors
primary should be assumed even if no residual disease Low-grade serous carcinoma
remains in the tubes or ovaries. High-grade serous carcinoma
The stage-adjusted outcomes of tubal, ovarian, and pri- Endometrioid carcinoma
mary peritoneal high-grade serous carcinoma are similar, Undifferentiated carcinoma
suggesting that these diagnoses could be grouped together as Mucinous carcinoma
“tubo-ovarian” or “pelvic” high-grade serous carcinoma Transitional carcinoma
[41]. Others argue that because the ovaries are frequently Clear cell carcinoma
Tumor-like lesions
involved by disease, the terminology “HGSC of ovary”
Tubal hyperplasia
should be retained [42]. The incidence of fallopian tube car-
Tubo-ovarian abscess
cinoma will likely increase as cases that may have previously Salpingitis isthmica nodosa
been classified as primary ovarian carcinoma are now recog- Metaplastic papillary tumor
nized to have likely originated from the f allopian tube. Placental site nodule
Mucinous metaplasia
Endometriosis
2.4 Tumors of the Fallopian Tube Endosalpingiosis
Mixed epithelial-mesenchymal tumors
2.4.1 Overview Adenosarcoma
Carcinosarcoma
Mesenchymal tumors
The tube is a site of a wide variety of neoplasia, including
Leiomyoma
benign and malignant epithelial and mesenchymal tumors. Leiomyosarcoma
Historically, the fallopian tube was viewed as an unusual site Mesothelial tumors
for neoplasia in the female genital tract. However, with the Adenomatoid tumor
recognition that many so-called ovarian carcinomas arise Germ cell tumors
from the fimbria, the relative incidence in tubal carcinoma Mature teratoma
has increased. In this chapter, attention will be given to those Immature teratoma
lesions which are common or unique to the tube. The WHO Lymphoid and myeloid tumors
classification of fallopian tube tumors is presented in Modified slightly from ref. [40]
Table 2.3. Many tumors that occur in the fallopian tube have
more common, histologically identical, counterparts in the 2.4.2.2 Borderline Tumors
ovary and endometrium; those lesions are discussed in the Serous borderline tumors of the fallopian tube are rare and
relevant chapters. have a morphologic appearance similar to those of the ovary
[45, 46]. They usually present with abdominal pain and can
range in size from 2 to 23 cm [45]. Most are treated conser-
2.4.2 Epithelial Tumors vatively, with excellent outcomes [45, 46]. Both endometri-
oid and mucinous borderline tumors of the fallopian tube
2.4.2.1 Benign Tumors have also been reported [47, 48].
Papillomas 2.4.2.3 Malignant Tumors

Papillomas of the fallopian tube are rare neoplasms composed The vast majority of malignant tumors of the fallopian tube
of branching papillary cores lined by bland, non-ciliated, are high-grade serous carcinomas. It is not entirely clear why
non-metaplastic, epithelium [43]. Papillomas may represent a we do not encounter low-grade serous carcinoma of the fal-
variation of papillary tubal hyperplasia; a localized, mass- lopian tube. It may be that the cell of origin for low-grade
forming process favors a papilloma, while hyperplasia often serous neoplasia is not of fallopian tube origin, but no studies
affects the entire tube. Papillomas may cause tubal obstruc- to our knowledge have evaluated this directly. The lack of
tion, resulting in hydrosalpinx or infertility [43, 44]. frequent precursor lesions in the fallopian tubes in cases of
2 Fallopian Tube 59
ovarian low-grade serous carcinoma, in stark contrast to

a
high-grade serous carcinoma, lends indirect support to this
possibility. FIGO staging of fallopian tube carcinomas is
incorporated into the staging system for ovarian and perito-
neal carcinoma [49]. Given the pathogenic link between fal-
lopian tube and high-grade ovarian carcinoma described
earlier, it is not surprising that some of the risk factors, such
as nulliparity, are shared for tubal and ovarian carcinoma
[50]. Combined estrogen-progestin postmenopausal hor-
mone replacement also appears to increase the risk of tubal
carcinoma [51].
Clinically, fallopian tube carcinomas classically present
with the Latzko triad of pelvic mass, abdominal pain, and b
vaginal discharge caused by a sudden release of fluid from a
hydrosalpinx (“hydrops tubae profluens”). However, these
symptoms are only found in 15% of patients with tubal car-
cinoma [36]. The average age of fallopian tube carcinomas is
55 years [52]. They often present at a high stage when dis-
ease has disseminated elsewhere in the abdomen.
High-Grade Serous Carcinoma

The histology and immunophenotype of tubal high-grade
serous carcinoma are the same as in the ovary, which is
described in Chap. 5. Grossly, the lumen may be distended,
and the tumor often involves the fimbria (Fig. 2.5).
Architecturally, HGSC may be papillary, pseudoglandular,
or composed of sheets of tumor cells with slit-like spaces
(Fig. 2.6a). Cytologically, the nuclei are pleomorphic with
prominent nucleoli. Mitotic activity is usually abundant
(>12/10 HPFs). Immunohistochemically, they are positive
for CK7, PAX-8, WT-1, and p16, with an aberrant pattern of Fig. 2.5 Tubal high-grade serous carcinoma may protrude from the
p53 staining (Fig. 2.6b–d). One interesting biomarker is ostium (a) and distend the lumen (b)
estrogen receptor, which is expressed in >50% of tumor cells
in about 60% of HGSCs [53]. The differential diagnosis of
high-grade serous carcinoma includes low-grade serous car- Tubal HGSC may spread to the ovaries, uterine serosa,
cinoma, high-grade endometrioid carcinoma, and a metasta- and peritoneum. Lymphatic spread, while less common,
sis from an endometrial serous carcinoma or a most frequently results in metastases to the para-aortic and
non-gynecologic site. The two-tiered grading of serous car- pelvic lymph nodes. The surgical management and
cinoma in the ovary, using nuclear atypia and mitotic activ- chemotherapeutic regimens for primary fallopian tube carci-
ity, can also be applied to tubal serous carcinoma [54]. In noma are the same as in the ovary.
cases with ambiguous histomorphology, WT-1 is an excel-
lent marker of serous lineage in the tube, and abnormal p53 Carcinosarcoma
staining is helpful when the differential diagnosis is between Carcinosarcomas, also called malignant mixed Müllerian
high- and low-grade serous carcinoma. The presence of tumors, are biphasic tumors composed of both malignant
squamous differentiation, endometriosis, or an adenofibro- stroma (sarcoma) and epithelium (carcinoma) (Fig. 2.7).
matous component would favor an endometrioid tumor. They have a poor prognosis [56]. Their histology is the same
Metastatic serous carcinoma from the endometrium is usu- as those which arise elsewhere in female genital tract,
ally negative for WT-1 [55]. A previous history of a malig- although they occur much less frequently in the fallopian
nancy elsewhere is most helpful to suggest a metastasis from tube than in the endometrium and ovary. The histotype of the
a non-gynecologic site. In cases where the tumor morphol- epithelial component may be difficult to subclassify as a
ogy does not seem compatible with a Müllerian primary, an single Müllerian histotype, and it is not necessary to do so.
appropriate immunohistochemical panel, often including Heterologous differentiation (e.g., rhabdomyosarcomatous
PAX-8, can be used to work up possible metastatic disease. or chondrosarcomatous differentiation) is associated with a
a b
c d
Fig. 2.6 (a) High-grade serous carcinoma is composed of nests of sion of p16 (b), and abnormal p53 staining pattern (c). In contrast to
pleomorphic, hyperchromatic cells. Mitotic activity is abundant, and endometrial serous carcinoma, which is usually WT-1 negative, tubo-
calcifications may be present. (b) The tumor shows diffuse overexpres- ovarian serous carcinoma is positive for WT-1 (d)
a b
Fig. 2.7 Carcinosarcoma is a biphasic malignant tumor. (a) A malignant epithelial proliferation involves the tubal fimbria. (b) Elsewhere, there is
a malignant stromal component (chondrosarcoma, in this case)
2 Fallopian Tube 61
worse prognosis and should be reported if present. There is 2.4.4 Other Tubal Tumors
no minimum amount of sarcomatous differentiation required
to qualify as a carcinosarcoma, and the combination of any 2.4.4.1 Benign Mesenchymal Tumors
amount of sarcoma with a carcinoma should be diagnosed as Leiomyomas are uncommon in the fallopian tube, but are the
a carcinosarcoma. most common mesenchymal tumor of this site. They are
identical histologically to those that arise in the myome-
Other Tumors trium. Rare cases of cavernous and capillary hemangiomas
Primary fallopian tube mucinous, endometrioid, and of the fallopian tube have been described [62, 63].
clear cell carcinomas have been reported but are extremely
rare [57–59]. Gestational trophoblastic disease (partial 2.4.4.2 Malignant Mesenchymal Tumors
mole, complete mole, and gestational choriocarcinoma), Primary sarcomas of the fallopian tube are extremely rare
identical to intrauterine disease, rarely arises in ectopic [64]. Leiomyosarcomas of the tube have a morphology and
pregnancies [60]. immunophenotype which mimics those of uterine
leiomyosarcomas. Criteria for malignancy are the same as in
the uterus. Their prognosis is generally poor [65, 66]. There
2.4.3 M
ixed Epithelial and Mesenchymal are single case reports describing biphasic synovial sarcoma
Tumors [67], well-differentiated liposarcoma [68], and chondrosar-
coma [69] of the fallopian tube. Embryonal, alveolar, and
2.4.3.1 Serous Adenofibroma pleomorphic rhabdomyosarcomas of the fallopian tube, not
Serous adenofibromas of the tube are benign biphasic tumors arising in an adenosarcoma or carcinosarcoma, have also
composed tubal epithelium overlying a fibromatous stromal been reported [70–72].
nodule (Fig. 2.8). They are small and often incidentally
found during examination of salpingectomies for other indi- 2.4.4.3 Adenomatoid Tumor
cations. They are seen in 10% of women with either BRCA1/2 Adenomatoid tumors are the most common benign tumor of
mutations or a strong family history of breast/ovarian carci- the fallopian tube. They are mesothelial-derived prolifera-
noma but only in 2.5% of non-high-risk women [25]. tions that may occur in the uterus, tube, and ovary. Grossly,
they are solid tan-white nodules, usually smaller than 2 cm.
2.4.3.2 Adenosarcoma In the fallopian tube, they are well-circumscribed and usu-
Adenosarcomas are malignant neoplasms composed of ally lack the infiltrative border seen in other organs [73].
benign epithelium and sarcomatous stroma. Primary fallo- Histologically, they may show a variety of architectures
pian tube adenosarcomas are extremely rare and share the including angiomatoid, tubular, or solid (Fig. 2.9).
same morphology with leaf-like architecture and periglan- A lipoblast-like or signet-ring cell morphology is frequently
dular stromal condensation as those in the endometrium or identified [73]. Cytologic atypia in the form of bizarre or
cervix [61]. symplastic-type atypia (i.e., enlarged, hyperchromatic nuclei
a b
Fig. 2.8 (a) Serous adenofibromas may form small nodules on the fallopian tube, typically on the fimbria. (b) They are benign biphasic tumors
composed of a fibromatous stromal component and serous epithelial component
a b
Fig. 2.9 (a, b) Adenomatoid tumors of the tube form well-circumscribed nodules and are often composed of small tubules
with smudgy chromatin) may be seen in adenomatoid tumors tube often show an aberrant expression, which can mimic
and does not affect the excellent prognosis. They display a the staining pattern of a STIC [77]. Recent phylogenetic
mesothelial immunophenotype and are positive for pankera- analysis of cases of synchronous STICs and ovarian high-
tin, calretinin, WT-1, and D2-40 [73, 74]. They are more grade serous carcinoma have shown that the STIC, usually
likely to occur in immunosuppressed patients post-renal presumed to be the precursor lesion, in some cases actually
transplant, but the mechanism for this phenomenon is unclear represents an intramucosal metastases from the ovarian
[75]. The differential diagnosis includes mesothelioma, sal- tumor [80].
pingitis isthmica nodosa, and metastatic adenocarcinoma.
Mesothelioma is larger, is often symptomatic, and, by defini-
tion, has infiltrative growth with invasion into adipose tissue 2.5 Nonneoplastic Disorders
or adjacent organs. Salpingitis isthmica nodosa is lined by of the Fallopian Tube
tubal epithelium and is negative for mesothelial-specific
markers such as D2-40 and calretinin. 2.5.1 T
ubal Epithelial Metaplasia
and Hyperplasia
2.4.4.4 Metastatic Tumors
The fallopian tube is an uncommon site of metastatic dis- 2.5.1.1 Mucinous Metaplasia
ease. In one series of 287 fallopian tubes from 145 patients Mucinous metaplasia is found in approximately 3% of fal-
removed for various reasons, metastatic carcinoma was lopian tubes [25]. Although rare, it is significant because it
identified in 1.4% of tubes [6]. Metastatic tumors in the tube may accompany mucinous lesions elsewhere in the female
may be present in lymphovascular spaces or in intraluminal, genital tract and be associated with Peutz-Jeghers syndrome.
mucosal, submucosal, muscular, or serosal compartments of Mucinous metaplasia of the tube is associated with muci-
the tube (Fig. 2.10) [76–78]. By far the most common type nous cystadenomas, mucinous ovarian tumors of low malig-
of metastatic malignancy is adenocarcinoma (87%), nant potential, and lobular endocervical glandular hyperplasia
although lymphoma, neuroendocrine tumors, and mesothe- [81, 82]. In patients with Peutz-Jeghers syndrome, the muci-
lioma may also metastasize to the tube [77]. Excluding the nous epithelium is positive for MUC6 by immunohistochem-
uterus and ovary, the most common primary sites of meta- istry, suggesting pyloric gland differentiation [81].
static carcinoma are the appendix, colon, stomach, biliary Metastases to the tubal epithelium may occasionally show
system, and breast [76, 77]. Metastatic mucosal disease may mucinous differentiation with bland cytology, so care should
histologically mimic a STIC, so care should be taken when be taken when diagnosing mucinous metaplasia in a patient
diagnosing these lesions in patients with a synchronous pri- with a history of adenocarcinoma elsewhere [77].
mary or history of a previous malignancy [36, 77]. Of note,
tubal mucosal metastases from both endometrioid and 2.5.1.2 Transitional Metaplasia and Walthard
serous endometrial carcinoma can histologically mimic Cell Rest
STICs [36, 79]. Immunohistochemistry for p53, p16, and Walthard cell rests are small, solid, or cystic nests of transi-
WT-1 may be helpful, depending on the context. Caution tional epithelium (Fig. 2.11). They are seen in 5% of salpin-
should be used with p53 and p16, since metastases to the gectomy specimens and are of no significance [6].
2 Fallopian Tube 63
a b
c d
Fig. 2.10 (a, b) Metastatic breast carcinoma NOS to the fallopian tube nantly in lymphovascular spaces. (d) Metastatic lobular carcinoma of
forms a mural nodule composted of epithelioid cells. (c) In this meta- the breast is composed of inconspicuous signet-ring cells
static gastric carcinoma to the fallopian tube, tumor is present predomi-
a b
Fig. 2.11 Walthard cell rests may be solid or cystic (a) and are composed of benign transitional epithelium (b)
2.5.1.3 Metaplastic Papillary Tumor clusters from papillary tubal hyperplasia may shed from the
Metaplastic papillary tumor is a rare lesion of the fallopian tube and seed the ovarian or peritoneal surface, where they
tube. Twelve cases have been reported to date, and it is become cortical inclusion cysts or endosalpingiosis [61].
almost always found during pregnancy or in the immediate These deposits may then acquire KRAS or BRAF mutations
postpartum period [83, 84]. It is usually not grossly visible. and develop into borderline serous tumors. Others have not
Microscopically, the tumor shows papillary architecture with found an association between papillary hyperplasia and bor-
edematous papillary cores with sparse lymphocytic inflam- derline tumors [85]. The lack of diagnostic criteria and inter-
mation. Cytologically, the cells are columnar and non- observer variability complicate this diagnosis.
ciliated, with enlarged nuclei and occasional prominent
nucleoli. Epithelial budding and pseudostratification can be 2.5.1.7 Pseudocarcinomatous Hyperplasia
seen. Very infrequent mitotic activity is permitted [83, 84]. It
is uncertain if the tumor represents a metaplasia or is a true Definition
neoplasm. The differential diagnoses include other papillary Pseudocarcinomatous hyperplasia is an exuberant prolifera-
lesions of the tube, including a papilloma, papillary hyper- tion of the tubal epithelium which may be mistaken patho-
plasia, and a borderline tumor. logically for carcinoma. It usually occurs between the ages
of 17–40 (mean 29 years), much younger than most serous
2.5.1.4 Other Metaplasias carcinomas. It may either present as an adnexal mass or be
Oncocytic (eosinophilic) metaplasia is incidental and seen in discovered incidentally [86]. Half of cases are seen in asso-
4% of fallopian tubes [6]. Clear intraepithelial vacuoles, ciation with pelvic inflammatory disease [86].
which are PAS and mucicarmine negative, are thought to
represent a degenerative change seen in older patients [6]. Pathological Findings
Grossly, the tube may be enlarged with a thickened wall.
2.5.1.5 Tubal Mucosal (Epithelial) Hyperplasia Pyosalpinx, a tubo-ovarian abscess, or hydrosalpinx may
Inflammatory conditions of the tube can induce a florid also be present. Microscopically, plical fusion results in the
hyperplasia of the tubal epithelium, with complex architec- epithelium forming cribriform and pseudoglandular struc-
ture which may mimic a neoplasm. Hyperplasia can be dif- tures (Fig. 2.13). Invagination of the epithelium into the
ferentiated from neoplasia based on the lack of significant stroma may induce a stromal response which resembles des-
atypia and mitotic activity and the presence of an inflamma- moplasia [86]. Cytologically, the cells may show moderate
tory infiltrate. nuclear atypia, including prominent nucleoli and focal loss
of polarity [86]. However, there is usually only infrequent
2.5.1.6 Papillary Tubal Hyperplasia mitotic activity, with no atypical forms, and cells often main-
Papillary tubal hyperplasia refers to a specific form of epi- tain a normal nuclear-to-cytoplasmic ratio. Marked chronic
thelial hyperplasia, in which the epithelium forms papillary inflammation, occasionally associated with an acute infil-
tufts with detached papillae within the lumen (Fig. 2.12). It trate, is always present. Psammoma bodies are often seen, as
is often, but not always, associated with psammoma bodies is overlying mesothelial hyperplasia. Papillary structures
or chronic salpingitis. It has been suggested that epithelial may even be present in tubal lymphatics [86].
a b
Fig. 2.12 (a, b) Papillary tubal hyperplasia is characterized by abundant detached papillae within the tubal lumen
2 Fallopian Tube 65
Fig. 2.14 In salpingitis isthmica nodosa, tubal diverticula protrude

into the wall of the tube and are surrounded by fibrosis or smooth mus-
cle hypertrophy, without inflammation
Grossly, salpingitis isthmica nodosa forms nodules rang-

ing from millimeters to 2 cm in size [88]. Histologically,
bland tubal epithelium forms diverticula into the wall. There
is often smooth muscle hypertrophy surrounding the epithe-
lium (Fig. 2.14).
2.6.2 Tubo-ovarian Abscess

Fig. 2.13 (a, b) Pseudocarcinomatous hyperplasia may show complex
cribriforming and pseudoglandular architecture
Tubo-ovarian abscesses are most frequently sequelae of sal-
pingitis from an ascending sexually transmitted disease. Risk
Differential Diagnosis factors include infection with a sexually transmitted disease,
The most important differential diagnosis is malignancy, multiple sexual partners, HIV infection, and age between 15
most likely high-grade serous carcinoma. Given the associ- and 25 [89]. Tubo-ovarian abscesses are most commonly
ated inflammatory infiltrate, infections should also be con- caused by Chlamydia trachomatis or Neisseria gonorrhoeae.
sidered. Mitotic activity may be the most helpful feature to Rarer causes include tuberculosis, actinomyces, and leprosy.
differentiate pseudocarcinomatous hyperplasia from malig- Abscesses may also form secondary to ruptured appendicitis
nancy, as the former can show both architectural and cyto- or inflammatory bowel disease.
logic features suggestive of carcinoma [86]. A wild-type
pattern of p53 immunohistochemistry would also be reassur- 2.6.2.1 Pathological Changes
ing. Areas of solid growth and atypical mitoses should not be Salpingitis leads to blockage of the tube with subsequent
observed in pseudoepitheliomatous hyperplasia, but are abscess formation and necrosis. As it resolves, tubo-ovarian
common in high-grade serous carcinoma. adhesions may form.
2.6.2.2 Granulomatous Salpingitis

2.6 Inflammatory Disorders Rarer causes of salpingitis include mycobacteria, actinomy-
ces, and leprosy, all of which manifest as granulomatous
2.6.1 Salpingitis Isthmica Nodosa inflammation (Fig. 2.15). Mycobacterial infection can be
confirmed with a Ziehl-Neelsen stain or PCR which can be
Salpingitis isthmica nodosa is seen in 3–5% of fallopian performed on formalin-fixed paraffin-embedded tissue.
tubes and is strongly associated with ectopic pregnancy, Actinomyces israelii salpingitis is associated with IUDs and
where is it present in 25–50% of cases [25, 87]. It has also also presents with granulomatous inflammation [90]. Tubal
been associated with infertility [88]. schistosomiasis is a cause of ectopic pregnancies in the
developing world but is rarely seen in North America [57]. It Pelvic Inflammatory Disease
can induce an extensive inflammatory infiltrate with fibrosis, Xanthogranulomatous salpingitis may occur after longstand-
granulomatous reaction, and destruction of normal tubal ing PID and is characterized by foamy macrophages in the
architecture (Fig. 2.16). wall of the tube (Fig. 2.18). Pelvic tuberculosis may clini-
Noninfectious causes of granulomatous salpingitis cally present as pelvic inflammatory disease and should be
include Crohn disease, sarcoidosis, and foreign body reac- considered in immunocompromised patients [85]. Rare cases
tions (Fig. 2.17). It may be difficult to determine a specific of salpingitis can also be caused by Enterobius vermicularis
etiology without adequate history. and pelvic coccidioidomycosis [91, 92].
2.6.2.3 Evolution and Outcomes Pyosalpinx

Even with prompt treatment, resolving pelvic inflammatory In acute salpingitis, an inflammatory infiltrate composed pre-
disease and tubo-ovarian abscesses may result in tubo- dominantly of neutrophils may involve the tubal lumen and
ovarian adhesions and fibrosis. These can result in long-term lamina propria (Fig. 2.19). In severe cases, the tubal lumen
sequelae of infertility, ectopic pregnancy, pelvic pain, and may become distended with an acute inflammatory infiltrate
recurrent episodes of PID [89]. with necrotic debris, grossly visible as pus, and is termed
Fig. 2.15 Tuberculosis infection of the tube shows non-necrotizing Fig. 2.16 Fibrous tissue surrounds calcified Schistosoma eggs in the
granulomatous inflammation fallopian tube
a b
Fig. 2.17 (a) Foreign bodies may elicit a giant cell reaction. (b) The foreign material can often be visualized with polarization
2 Fallopian Tube 67
a b
Fig. 2.18 (a, b) Xanthogranulomatous salpingitis is associated with PID and is characterized by a mixed inflammatory infiltrate, including foamy
macrophages
Fig. 2.19 Neutrophils fill the tubal lumen and infiltrate the lamina pro- Fig. 2.20 Acute salpingitis may eventually result in plical fusion,
pria in acute salpingitis termed follicular salpingitis
pyosalpinx. As the acute salpingitis resolves, the plicae may 2.6.3 Tubal Ectopic Pregnancy
become fused and lamina propria fibrotic, called follicular
salpingitis (Fig. 2.20). Ectopic pregnancies are those in which the embryo implants
outside the endometrium. The vast majority (~95%) occur in
Hydrosalpinx the fallopian tube and less frequently in the cervix, ovary,
As salpingitis resolves, the fimbria may fuse. The tube and abdominal cavity [93]. It occurs in 1% of natural preg-
secondarily becomes distended with clear serous fluid, a nancies and 2–3% of pregnancies which are a result of assis-
condition termed hydrosalpinx. It commonly mimics a tive reproductive technologies [94]. Most tubal ectopics are
serous cystadenoma both clinically and grossly. in the ampulla (80%), and less commonly in the isthmus
Microscopically, however, smooth muscle bundles are (12%), infundibulum, fimbria, or cornua [93].
present in the cystic wall in a hydrosalpinx, which differ-
entiate it from a cystadenoma (Fig. 2.21). The tubal-type 2.6.3.1 Etiology
epithelial lining is the same in both a hydrosalpinx and Tubal ectopic pregnancies are caused by pathologic processes
serous cystadenoma. which obstruct the tubal lumen and interfere with the transport
a b
Fig. 2.21 (a) A hydrosalpinx cystically distends the fallopian tube lumen. (b) The hydrosalpinx is lined by tubal-type epithelium, with a mus-
cular wall
of the ovum or embryo. Three-quarters of cases have an identi-

fied risk factor [94]. The factors most strongly associated with
ectopic pregnancies are previous ectopic, previous tubal sur-
gery, and salpingitis isthmica nodosa [87, 95]. Historically, in
utero diethylstilbestrol exposure was also strongly linked to
ectopic pregnancy [95]. However, it was banned for use in
pregnancy by the Food and Drug Administration in 1971, so a
history of exposure is now rarely found in women of child-
bearing age. Other risk factors less strongly associated with
ectopic pregnancy are previous infection with gonorrhea or
chlamydia, pelvic inflammatory disease, infertility, more than
one lifetime sexual partner, history of pelvic or abdominal sur-
gery, smoking, and age of first intercourse less than 18 [95]. In
salpingitis secondary to gonorrhea or chlamydia, the tubal Fig. 2.22 A tubal ectopic pregnancy causes distension of the tube with
lumen can be distended with suppurative inflammation, and serosal congestion
cilia can be lost, both of which impede transport of the fertil-
ized egg and increase the likelihood of an ectopic pregnancy. suggestive of an ectopic pregnancy. Management can be
Although pregnancy is much less common when a progestin- medical (with methotrexate), surgical, or expectant. In terms
secreting intrauterine device or oral contraceptive pill is used, of surgical options, salpingotomy is usually preferred as it
when a pregnancy does occur in these settings, it is much more maintains the possibility of fertility on the ipsilateral side.
likely to result in an ectopic pregnancy [96], presumably However, salpingectomy may be performed if the tube has
because progestins inhibit ciliary activity and increase the extensive damage and is not salvageable.
probability of tubal implantation.
2.6.3.3 Pathological Findings
2.6.3.2 Development and Outcome Grossly, the fallopian tube may be distended with blood
The most common presenting symptoms are abdominal pain (Fig. 2.22). Villi or an embryo may be visible within the
and vaginal bleeding [94]. Rupture of the tube can cause lumen (Fig. 2.23). The wall of the tube is perforated in some
tachycardia, syncope, shock, and ultimately death if treat- cases. Adhesions on the fallopian tube may reflect previous
ment is delayed. Diagnosis is usually based on physical infection or abdominal surgery. Histologically, an ectopic
examination, serum β-HCG, and ultrasound findings, such as pregnancy can be documented by the presence of villi in the
absence of a gestation in the uterus. In cases with equivocal fallopian tube, often accompanied by significant hemorrhage
findings, a diagnostic laparoscopy may be performed. An (Fig. 2.24). Implantation site and embryo may also be visual-
endometrial biopsy may also be performed; an absence of ized. It may resemble a partial hydatidiform mole, because
villi in the setting of a persistently elevated β-HCG is highly of the trophoblastic proliferation and hydropic villi, which
2 Fallopian Tube 69
can be caused by methotrexate. Chronic salpingitis and sal-

pingitis isthmica nodosa are also frequently seen (in 88%
and 43% of cases, respectively) [97].
2.6.3.4 Secondary Disorders Associated

with Tubal Ectopic Pregnancy
Previous ectopic pregnancy is the strongest risk factor for a
future ectopic pregnancy. In cases treated with salpingotomy,
persistent trophoblast in the fallopian tube occurs in 8% of
cases and is treated with methotrexate [94]. Rarely interme-
diate trophoblast lesions, such as placental site nodules and
placental site trophoblastic tumors, may occur in the tube
following an ectopic gestation [98].
Fig. 2.23 An embryo and chorionic villi from a tubal ectopic
pregnancy
2.6.4 Tubal Sterilization
a Tubal sterilization is often performed during a caesarian sec-

tion, and the tubes may show pregnancy-related changes such
as deciduosis (see below). Interestingly, a large study involv-
ing 4489 patients with endometrial cancer showed that previ-
ous tubal ligation was associated with fewer cases of stage III
and IV disease, and decreased mortality [99]. This suggests
that tubal ligation prevents peritoneal disease by eliminating
transtubal spread as a possible mechanism of dissemination.
2.6.5 Pregnancy-Related Changes
Ectopic decidua (deciduosis) is identified in about 10% of

the postpartum tubal ligation specimens, although the mech-
anism is unclear. It may be present in either the plicae or
subserosal tissue in specimens from pregnant or postpartum
patients (Fig. 2.25) [6]. Deciduosis can also be seen in
Fig. 2.24 (a) At low power, the tube is distended with hemorrhage. (b) Fig. 2.25 Cells with abundant eosinophilic cytoplasm in tubal decidu-
Higher power shows chorionic villi with trophoblast adherent to the tube osis resemble the stromal cells in gestational endometrium
patients taking high-dose progestins. The high levels of pro- such as paratubal cysts or hydrosalpinx [103]. Grossly, the
gesterone during pregnancy also cause physiologic shifts in tube appears congested, with possible ischemic necrosis.
the histology of the tubal epithelium, as described earlier. Microscopically, tubal blood vessels may be dilated and
associated with hemorrhage and necrosis. Treatment options
include laparoscopic reduction of the torsion or salpingec-
2.6.6 Endometriosis tomy. In resected specimens, the tubes may show congestion
and ischemic changes. Untreated cases may progress to
There is tubal involvement in 6% of patients with endome- peritonitis.
triosis [100]. Clinically, it may cause infertility if the
endometriosis is mass-forming and occludes the tubal
2.6.7.2 Tubal Prolapse
lumen. Histologically, the diagnosis is made if two of the Prolapse of the fallopian tube through the vaginal vault may
following three features are noted: Müllerian glands (usu- occur after either vaginal or abdominal hysterectomies. Most
ally endometrioid), endometrial-type stroma, and hemosid- cases present symptomatically with vaginal discharge, pelvic
erin-laden macrophages (Fig. 2.26). If only glands are pain, or postcoital bleeding [104]. Predisposing factors are
present, endosalpingiosis should be considered. In a preg- those which impede healing of the vault, such as infection or
nant patient, deciduosis manifests as only decidualized vaginal cuff hematoma [104]. It is more common in premeno-
endometrial stroma without glands. Salpingitis is present in pausal women and can occur at any time post-hysterectomy
66% of patients with endometriosis and may be seen even if (reports range from the immediate postoperative period to
the fallopian tube itself is not involved with endometriosis 32 years after surgery) [104]. Instead of involving the vaginal
[101]. Pseudoxanthomatous salpingiosis is frequently seen vault, the tube may rarely prolapse through an abdominal cae-
with tubal endometriosis (Fig. 2.2). In so-called polypoid sarian section wound [105].
endometriosis, the endometriosis forms a mass and may be Histologically, prolapsed tube shows distortions from its
clinically mistaken for a neoplasm. usual appearance, with a polypoid shape, tubal epithelium,
Occasionally the proximal fallopian tube mucosa is colo- and an increase in stroma (Fig. 2.27). Clinically, the pro-
nized by endometrial glands and stroma, a process termed lapsed tube resembles granulation tissue under colposcopy
endometrialization [102]. This process is associated with and may be misdiagnosed as “adenocarcinoma” pathologi-
tubal ligation. cally as well if tubal epithelium is not appreciated [106]. On
cervical cytology, prolapsed fallopian tube shows columnar
cells which may be mistaken for malignancy if with signifi-
2.6.7 Other Nonneoplastic Disorders cant reactive atypia [107].
2.6.7.1 Torsion of the Tube 2.6.7.3 Paratubal Cyst

Torsion of the fallopian tube is an uncommon cause of pelvic Paratubal cysts are common, benign simple cysts found adja-
pain in adolescent and middle-aged women. It is often asso- cent to the tube and lined by tubal-type epithelium. They are
ciated with other pathology which distorts the tubal anatomy, also known as hydatid cysts of Morgagni, despite being
a b
Fig. 2.26 (a, b) Endometriosis involving the tubal serosa

2 Fallopian Tube 71
n oninfectious in origin. They are often small lesions inciden- identical to those found in the ovary and testis (Fig. 2.28)
tally noted in resection specimens, but they may also present [109, 110]. Hilus cell heterotopia in the tube can be associ-
as a mass. Similar to hydrosalpinx, paratubal cysts com- ated with ipsilateral hilus cell hyperplasia [110]. They
monly contain smooth muscle fibers in the cystic wall. occasionally show brown lipofuscin pigment or Reinke
crystals [109]. Most cases form discrete, circumscribed
2.6.7.4 Tubal Submucosal Hilus Cells nodules; however, others may display an infiltrative, single-
Heterotopic hilus cells, or Leydig cell hyperplasia, are seen file morphology which mimics metastatic lobular breast
in less than 1% of fallopian tubes and may involve the carcinoma [110].
endosalpinx or mesosalpinx [108]. Clinically, they may be
associated with androgenic manifestations. Microscopically, 2.6.7.5 Salpingoliths
they are composed of epithelioid cells with abundant, Salpingoliths are calcifications of the fallopian tube that may
eosinophilic cytoplasm and prominent nucleoli and are
be intraluminal, epithelial, or in the lamina propria, with an
associated overlying epithelial proliferation (Fig. 2.29)
[101]. Salpingoliths occur in about a third of tubes with acute
or chronic salpingitis or in cases with ovarian serous neopla-
sia, but in only 5% of cases without tumors or salpingitis
Fig. 2.27 Prolapsed fallopian tube may show fimbria lined by tubal-
type epithelium, as well as areas resembling granulation tissue. Fig. 2.28 Hilus cell hyperplasia in the tube is composed of cells identi-
Photomicrograph courtesy of Dr. C. Crum (Brigham and Women’s cal to ovarian hilus cells, with large, epithelioid cells with abundant
Hospital, Boston, MA) eosinophilic cytoplasm
a b
Fig. 2.29 Salpingoliths are calcifications in the tube and may be intraluminal (a) or within the tubal stroma (b)
[101]. There is conflicting evidence on a possible association 2.7.3 T

ubal Specimens from High-Risk
between salpingoliths and serous borderline tumors of the Patients
ovary [101, 111].
Patients with known germline mutations in BRCA1/2, a per-
sonal history of breast cancer, or a family history suspicious
2.7 rossing Methods for Tubal
G for BRCA1/2, have an increased risk of tubal neoplasia.
Specimens Salpingectomies performed for prophylaxis in these patients
should be sectioned following the Sectioning and Extensively
2.7.1 Tubal Segments from Tubal Ligation Examining the FIMbria (SEE-FIM) protocol, which maxi-
mizes the amount of fimbria examined microscopically
The length and diameter of the tubal segment should be mea- (Fig. 2.30) [11, 14]. In SEE-FIM, the fimbriae are ampu-
sured. The presence (or absence) of fimbria should be docu- tated, longitudinally sectioned at 2–3 mm intervals, and sub-
mented because it may have relevance to the planning and mitted in toto. The remainder of the tube is also sectioned
success of a future reversal procedure. The tubal serosal sur- and submitted in toto. There is mixed evidence regarding the
face is examined for exudates, adhesions, and paratubal cysts. utility of routine deeper levels to increase the STIC detection
A probe can be used to assess for patency. Representative rate [113, 114]. This protocol for high-risk patients should be
cross sections of the tubal segment are submitted and embed- considered for all patients with a history of prior malignancy,
ded so that an entire cross section can be visualized micro- as thorough sampling can increase the detection rate of
scopically to ensure sterilization has taken place. occult metastases [78].
2.7.2 Uterus with Attached Bilateral Tubes 2.7.4 T

ubal Specimens Containing “Essure”
Devices
The length and diameter of the fallopian tubes should be
measured. The presence and state of fimbria should be The Essure system, developed by Bayer, is an alternative to
noted, and the surface examined for exudates, adhesions, tubal ligation for permanent sterilization. It involves the
and paratubal cysts. A probe can be used to assess for placement of a metal coil in each fallopian tube, which
patency. For hysterectomies performed for benign condi- induces tubal fibrosis and prevents pregnancy. Since it was
tions (e.g., leiomyomata, prolapse), the fimbria should be introduced in 2002, there have been reports of pelvic pain,
amputated and submitted in toto. The remained of the tube tubal perforations, and pregnancies [115]. Essure devices
is cross-sectioned at 5 mm intervals. Any luminal contents may be received either in salpingectomy specimens or as part
such as hemorrhage or purulent exudate should be noted. of a hysterectomy. Given their potential medicolegal signifi-
Representative sections of the midportion and cornual por- cance, they should be given special care in the grossing
tion of the tube are submitted. The recommendation for room.
complete sampling of the fimbria in all cases arises because Specimens containing Essure coils are weighed, measured,
an incidental STIC is found in approximately 1% of salpin- and photographed. Radiographs should also be obtained
gectomies performed for benign indications [34]. For hys- (Fig. 2.31a). The tubal serosal surface is examined for areas of
terectomies performed for malignancies, including ovarian possible disruption or perforation. The tube should be pinned
and endometrial carcinoma, the fallopian tubes including and fixed prior to opening. The tubes can be opened longitudi-
fimbriated ends should be submitted in toto according to the nally. Photographs and radiographs are repeated before remov-
SEE-FIM protocol (see next section). Increased sampling is ing the coils (Fig. 2.31b). The size of the coil and its position
warranted because of the potential for microscopic meta- in the tube is documented. After the coil is removed, the region
static deposits which may upstage a patient. In one series, of the fallopian tube in contact with the coil is submitted in
metastatic deposits were found in 1.6% of cases endometrial toto. The fimbria should also be submitted in toto, as well as
carcinoma with grossly normal tubes [112]. SEE-FIM representative sections of the remaining tube. (This Essure
should also be used in cases in which the patient has a per- protocol was adapted from a version created by Dr. Bradley
sonal history of breast cancer, or a family history of breast Quade, Dr. Carolyn Glass, and Delia Liepins, Department of
and/or ovarian cancer. Pathology, Brigham and Women’s Hospital.)
2 Fallopian Tube 73
Fig. 2.30 In the SEE-FIM

protocol, the fimbriae are
amputated and longitudinally
sectioned to maximize the
surface area of the fimbrial
mucosa examined
microscopically. The
remainder of the tube is
cross-sectioned and submitted
in toto. Adapted from ref. [14]
a b
Fig. 2.31 (a) Radiograph of fallopian tube containing metal contraceptive coil (“Essure”). (b) Fallopian tube containing coil after opening
longitudinally
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Benign Diseases of the Ovary
3
David Suster, Martina Z. Liu, and Douglas I. Lin
Abstract 3.1 natomy, Histology, and Function

A
In surgical pathology, an understanding of the normal ovar- of the Ovary
ian anatomy and the range of nonneoplastic lesions of the
ovary is essential during the examination of gynecological 3.1.1 Cortex, Medulla, and Hilus
specimens. Pathologists routinely evaluate nonneoplastic
adult ovaries as components of (1) hysterectomy proce- 3.1.1.1 Gross Ovarian Anatomy
dures for uterine leiomyomata, uterine prolapse, vaginal The ovaries are paired pelvic reproductive organs that are
bleeding, or gynecological cancer and (2) risk-reducing grossly located posterior to both the broad ligament and the
prophylactic salpingo-oophorectomy, with the primary ipsilateral fallopian tube, which is helpful in determining the
goals of excluding ovarian malignancy and/or determining laterality of a specimen. Grossly, the ovaries are ovoid in
whether the ovary is the source of hormone production shape, but size and surface appearance vary according to age.
driving uterine cancer. In these scenarios, with the excep- In general, ovaries from reproductive-age women are larger
tion of endometriosis, ovarian infection, or a hormone-pro- (up to 5 cm) with smoother outer surface, compared to post-
ducing lesion, any incidental nonneoplastic lesion menopausal ovaries, which can typically shrink in size and
encountered in the ovary is likely not of clinical signifi- acquire more convoluted, cerebriform surface (Fig. 3.1).
cance. However, another frequently encountered scenario Three ill-defined ovarian components can be grossly identi-
is examination of the ovary via biopsy, cystectomy, or exci- fied the outer cortex, the inner medulla, and the hilus [1].
sion for a specific purpose, including ovarian enlargement,
cyst formation, masses, torsion, infection, infertility, or 3.1.1.2 Histology of Cortex, Medulla, and Hilus
ectopic pregnancy, in which the ovary is submitted for eval- Microscopically, the ovarian surface is lined by the ovarian
uation for a clinical or radiological reason. Each of these surface epithelium (OSE), which is composed of a single
settings requires the pathologist to have knowledge of the layer of modified peritoneal mesothelial cells. The morphol-
normal ovarian anatomy, the histology, and the range of ogy of OSE ranges from flat to cuboidal to columnar with a
nonneoplastic lesions of the ovary in order to guide the low nuclear-to-cytoplasmic ratio and inconspicuous nuclei.
obstetrician-gynecologist or gynecologic oncologist to the OSE is separated from the underlying cortex by a basement
appropriate treatment and follow-up. membrane (Fig. 3.2). OSE is thought to be derived from
embryonic coelomic epithelium, which becomes the meso-
Keywords thelium lining the serous body cavities and the surface epi-
Ovary · Benign · Nonneoplastic · Anatomy · Histology thelium covering the ovary [2]. For this reason, by
immunohistochemistry, OSE cells are positive for cytokera-
tin, WT1, calretinin, estrogen and progesterone receptor,
and Ber-EP4. In addition, several studies have shown that
D. Suster
OSE is typically negative for both Pax2 and Pax8, reflecting
Department of Pathology, Beth Israel Deaconess Medical Center,
Boston, MA, USA the specific Müllerian lineage-determinant nature of these
latter transcription factors. The presence of occasional
M. Z. Liu
Brigham and Women’s Hospital, Boston, MA, USA PAX2-positive and PAX8-positive Müllerian-like epithelial
cells on the ovarian surface may represent the transfer of
D. I. Lin (*)
Foundation Medicine, Inc., Cambridge, MA, USA fallopian tubal epithelial cells to the ovary because of their
e-mail: [email protected] anatomic proximity, physiological contact, or adhesion [2].

80 D. Suster et al.
a trophies and corpora albicantia and large vessels remain in

the medulla.
The proximal medulla merges with the hilus, which con-
tains large blood vessels derived from ovarian artery and
vein, large lymphatic trunks and plexuses, fibroconnective
tissue, and nerve fibers (Fig. 3.3). The ovarian hilus attaches
to the broad ligament, and unique cell subtypes may be
identified in the hilar region. The first cell type is the ovar-
ian hilus cells, which are characterized by eosinophilic
cytoplasm, round nuclei, and prominent nucleoli and are
morphologically similar to testicular Leydig cells (Fig. 3.4)
[6]. Reinke crystals, lipid vacuoles, and golden-brown pig-
ment may be present, and they are positive for inhibin and
calretinin by immunohistochemistry. The hilus cell popula-
tion secretes steroid hormones and may undergo expansion
Fig. 3.1 Gross ovary [7], which is described later in the hilus cell (Leydig)
hyperplasia section.
Fig. 3.2 Ovarian surface epithelium and cortical stroma

Fig. 3.3 Ovarian hilus
Alternatively, a metaplasia or differentiation process from

OSE to Müllerian-type or fallopian tube-like epithelium has
also been proposed to account for areas of PAX2-positive
and PAX8-positive OSE [3].
The ovarian cortex is composed of ovarian stromal cells,
which are spindle-shaped with scant cytoplasm, and is
arranged in a storiform growth pattern with variable amount
of collagen (Fig. 3.2). The border between the cortex and
medulla is subtle and ill-defined as cortical and medullary
stromal cells have similar morphology. Ovarian stromal
cells can respond to pituitary and pregnancy hormones, and
they are capable of producing steroid hormones, including
androstenedione, testosterone, estradiol, and estrone [4, 5].
By immunohistochemistry, ovarian stromal cells stain for
smooth muscle actin, desmin, estrogen receptor, and pro-
gesterone receptor. The medulla is more easily identifiable
during menopause or postmenopause, when the cortex Fig. 3.4 Hilus cells
3 Benign Diseases of the Ovary 81
Fig. 3.5 Rete ovarii Fig. 3.7 Walthard’s nest
Fig. 3.6 Wolffian remnants (epoophoron) Fig. 3.8 Multiple primordial follicles in neonatal ovary
A second cell population that can be identified in the hilus become atretic if not selected for ovulation. At birth,
is the epithelial lining constituting the rete ovarii, which thousands of primordial follicles are present in the neo-
resembles the male rete testis counterpart. Morphologically, natal ovary (Fig. 3.8); and, throughout life, their numbers
this cell population ranges from cuboidal to columnar and is steadily decrease through folliculogenesis and atresia. In
arranged in a network of clefts, tubules, and small papilla the reproductive age ovary, primordial, primary, and sec-
(Fig. 3.5). The rete ovarii stains positively for EMA, cyto- ondary follicles are found in the superficial ovarian cor-
keratin, and Pax8 and is negative for Pax2 and Gata3 [8, 9]. tex (Fig. 3.9). Primordial follicles are characterized by a
The rete ovarii may be in close proximity to mesonephric primary oocyte surrounded by a single layer of flattened,
tubule remnants (i.e., epoophoron) (Fig. 3.6) and Walthard’s mitotically inactive, granulosa cells (Fig. 3.10). In the
nests (i.e., transitional cell metaplasia) (Fig. 3.7). first stage of maturation from primordial to primary fol-
licle, the flattened, mitotically inert granulosa layer
assumes a cuboidal to columnar shape, becomes mitoti-
3.1.2 Follicular Development and Atresia cally active, and increases in size (Fig. 3.11). Proliferation
of the granulosa cells results in their stratification with
Follicular development (folliculogenesis) is a continuous up to five concentric layers of granulosa cells around the
process wherein primordial follicles are either selected oocyte and progression to a secondary or pre-antral
and undergo maturation in preparation for ovulation or follicle (Fig. 3.12).
82 D. Suster et al.
Fig. 3.9 Primordial, primary, and secondary follicles in the cortex Fig. 3.12 Secondary (pre-antral) follicle
Fig. 3.10 Primordial follicles in reproductive age ovary Fig. 3.13 Mature (Graafian) follicle. From left to right: antrum, granu-
losa cell layer, theca cell layers, and ovarian cortical stroma
Secondary (pre-antral) follicles subsequently mature into

Graafian (mature) follicles as they increase in size and
migrate deeper into the ovarian cortex. At this point, the
surrounding stroma differentiates into layers of theca interna
and theca external cells (Fig. 3.13). Simultaneously, a large
cavity or antrum is formed within the Graafian or mature
follicle that is filled with interstitial fluid and is lined by
granulosa cells (Fig. 3.13). At the same time, the oocyte
migrates to an eccentric position at one pole of the follicle
within the cumulus oophorus, which projects into the antrum
(Fig. 3.14). During each ovulatory cycle, typically only one
mature Graafian follicle will progress to a preovulatory fol-
licle, in which the oocyte and a surrounding layer of granu-
losa cells (corona radiate) float freely in antrum fluid
(Fig. 3.15). Physiologically, preovulatory follicles may reach
Fig. 3.11 Primary follicle up to 2–3 cm in diameter. Following ovulation, the ovulatory
follicle devoid of the oocyte develops into a corpus luteum

(Fig. 3.16a, b). In the absence of fertilization, the corpus
luteum degenerates (Fig. 3.17a–c), and the regressed corpus
luteum is converted to a scar, the corpus albicans (Fig. 3.18).
Developing follicles that do not progress to ovulation
undergo atresia, which is a continuous process from birth to
the end of reproductive life. Molecular mechanisms that
induce follicular atresia are not completely known [10, 11];
however a morphologic spectrum of atretic follicles may be
seen during the routine histological examination of the ovary
(Fig. 3.19a–c).
3.1.3 H
ormones and Peptides Secreted
by the Ovary
Fig. 3.14 Mature (Graafian) follicle
The ovary produces a variety of hormones and peptides that
are secreted into the blood in both physiologic and patho-
logical conditions. We will focus on hormones and peptides
that are produced by the benign ovary and that are physio-
logically and clinically useful. Factors that are associated
with neoplasia, such as elevated CA125 and germ cell tumor
markers, are discussed elsewhere in the book. Briefly,
regarding CA125, in addition to a variety of cancers, a num-
ber of benign ovarian or gynecological conditions may be
associated with CA125 elevation, such as endometriosis,
fibroids, pelvic inflammatory disease, menses, pregnancy,
and peritonitis [12].
The ovary is a site of steroid hormone production in both
physiological and pathological conditions. Numerous stud-
ies have demonstrated the extra-adrenal steroidogenic poten-
tial and gonadotropin responsiveness of ovarian sex cord
stromal cells. During ovulatory cycles, there is an intimate
Fig. 3.15 Preovulatory follicle. Oocyte with surrounding zona pellu- physiologic interrelationship between the hypothalamo-
cida and layer of granulosa cells floating in antrum fluid pituitary-ovarian-endometrial axis. The interplay of rising
a b
Fig. 3.16 Corpus luteum low (a) and high (b) power
84 D. Suster et al.
a b
Fig. 3.17 Morphological changes of degenerating corpus luteum (a–c)
and progesterone, produced by the follicular granulosa theca

cells and by the corpus luteum, respectively, induce cyclic
endometrial alterations to provide an appropriate environ-
ment for implanting the fertilized embryo [13]. Progesterone
production by corpus luteum is controlled by placental
human chorionic gonadotropin (HCG) and is also required
for maintenance of early pregnancy until the placenta takes
over this function.
In addition to estrogen production, the ovary is also a
source of small amounts of extra-adrenal androgen produc-
tion, such as testosterone and androstenedione. This andro-
genic, steroidogenic activity by ovarian stromal cells is
accentuated during menopause with complete follicular
atresia and depletion of follicles. Both androgenic and
Fig. 3.18 Corpus albicans estrogenic activity may also be seen with benign or neo-
plastic proliferations of sex cord stromal cells, including
pituitary follicle-stimulating hormone (FSH) and luteinizing stromal hyperplasia, hyperthecosis, or sex cord stromal
hormone (LH) levels regulates late stages of follicular matu- tumors. This excess hormone production in turn may play a
ration, ovulation, and cyclic steroid hormone production by role in the development of virilization symptoms and endo-
follicular granulosa and theca cells. The ovarian estrogens metrial neoplasia.
a b
Fig. 3.19 Morphologic spectrum of atretic follicles (a–c)
The ovarian sex cord stromal cells also produce nonste- early follicular phase inhibin B levels, are all correlated
roidal hormones, such as glycoproteins, inhibin A and B, with ovarian reserve and are predictive of reproductive
which are secreted into the bloodstream and negatively regu- potential [17]. AMH is produced by the granulosa cells of
late FSH synthesis by the pituitary [14]. The main cellular small growing follicles. During follicular maturation, AMH
sources of inhibin B are the growing follicle granulosa cells physiologically inhibits initial follicle recruitment and sub-
and granulosa cell tumors, while inhibin A is mainly pro- sequent FSH-dependent selection and growth of pre-antral
duced by the corpus luteum and the placenta [15]. For this and small antral follicles. As follicles mature, AMH remains
reason, in infertile women who are undergoing assisted highly expressed in cumulus cells [18]. For these reasons,
reproduction therapies, inhibin B may be a useful marker of AMH levels reflect the number of antral and pre-antral fol-
ovarian reserve, a term that describes the remaining pool of licles present in the ovaries, and the levels of circulating
oocytes or a woman’s reproductive potential [16], since low AMH in blood have been used in various clinical scenarios
inhibin B levels have been shown to predict a poor ovulatory and applications. For instance, circulating AMH levels
response [15]. In addition, serum inhibin B levels are helpful have been suggested to predict the ovarian response to
in the diagnosis and management of granulosa cells tumors. hyperstimulation of the ovaries for in vitro fertilization
Both adult and juvenile types of granulosa cells tumors may (IVF) and egg/oocyte retrieval and the timing of meno-
present with elevation of serum inhibin B in either a primary pause. Low AMH levels have also been proposed to indi-
or a recurrent tumor setting. cate iatrogenic damage to the ovarian oocyte reserve, and
Besides inhibin B, another marker of ovarian reserve is AMH has also been used as a surrogate marker for antral
the anti-Müllerian hormone (AMH). AMH levels, as well follicle count in the diagnosis of polycystic ovary syndrome
as chronologic age, early follicular phase FSH levels, and (PCOS) [19].
86 D. Suster et al.
Finally, a number of other ovarian growth factors

involved in cell cycle or apoptosis, together with gonado-
tropins and estrogens, have been proposed to regulate fol-
licular development and follicular atresia. During follicle
development, local ovarian growth factors, such as IGF-I,
EGF/TGF-alpha, basic FGF, and cytokines, including inter-
leukin-1 beta, activate different intracellular cell cycles and
anti-apoptotic pathways to prevent follicles from undergo-
ing atresia and apoptotic demise [10]. IGF-I and estrogen
induce the proliferation of granulosa cells via activation of
the mitotic cell cycle and promote granulosa cell survival
via anti-apoptotic signals. The main cell cycle and anti-
apoptotic molecular pathway induced by IGF-I and estro-
gen appear to be via activation of phosphatidylinositol
3-kinase and its downstream target, protein kinase B/Akt
[11]. In contrast, other signaling factors have been impli- Fig. 3.20 Corpus luteum of pregnancy, low power, undulating
cated in promoting follicle atresia, such as androgens, architecture
TNF-alpha, and Fas ligand, the latter two presumably by
acting through receptors with a death domain. These diverse
hormonal, growth, and signaling factors may then converge
on selective intracellular pathways to regulate follicle cell
growth, proliferation, survival and apoptosis during follicu-
lar development, and atresia [10].
3.2 Pregnancy-Associated Findings
3.2.1 Corpus Luteum of Pregnancy

Secretion of progesterone by corpus luteum is critical to
secretory differentiation of the endometrium in preparation
for embryo implantation and for the maintenance of preg-
nancy in the first 8 weeks of gestation. As the placenta devel-
ops, the corpus luteum gradually regresses during pregnancy. Fig. 3.21 Corpus luteum of pregnancy, medium power, invaginations
However, the corpus luteum may persist in later gestation,
and it can present as a benign ovarian lesion during preg-
nancy [20].
3.2.1.2 Pathology
Grossly, the corpus luteum of pregnancy is a single, yellow,
cerebriform nodule, often with hemorrhagic center.
Microscopically, wedge-shaped invaginations imparting a
cerebriform, undulating architecture are seen at low power
magnification (Figs. 3.20 and 3.21). The surrounding ovarian
stroma may undergo deciduosis or ectopic decidua (Fig. 3.21,
top). On high power, the lesion is composed of luteinized
granulosa cells with eosinophilic cytoplasm and central
nuclei with prominent nucleoli (Fig. 3.22). In contrast to the
nonpregnant corpus luteum, pink hyaline globules and calci-
fications are features specific of the corpus luteum of preg-
nancy (Fig. 3.22). The main differential diagnosis includes
pregnancy luteoma [21]. Features favoring corpus luteum of Fig. 3.22 Corpus luteum of pregnancy, high power hyaline globules
pregnancy over pregnancy luteoma include occurrence in

early pregnancy, yellow gross color, cerebriform architec-
ture, and presence of hyaline globules and calcifications.
3.2.2 P
regnancy Luteoma (Theca-Lutein
Hyperplasia of Pregnancy)

Pregnancy luteoma (also known as theca-lutein hyperplasia
of pregnancy) is a rare, tumor-like lesion that may be inci-
dentally discovered during pregnancy. It more frequently
occurs in multiparous African-American women, and these
lesions are thought to arise from theca-lutein cells ( luteinized
theca interna cells of the follicle) or from stroma-lutein cells
(luteinized stromal cells) [22]. Therefore, pregnancy luteoma Fig. 3.24 Luteoma of pregnancy, low power: diffuse, solid, sheet-like
may secrete androgens, including testosterone, which may architecture
cause hirsutism or virilization of mothers and their female
infants [23]. Luteoma of pregnancy can simulate a tumor and
present as an adnexal mass. By imaging, they can appear
solid but may have a cystic component [24]. These lesions
are benign and are likely under the influence of human cho-
rionic gonadotropin, as they undergo spontaneous regression
and serum androgen levels normalize after delivery [25].
Due to their benign nature, conservative management is rec-
ommended with preservation of the ovary unless the lesion
persists in the postpartum period.
3.2.2.2 Pathology
Grossly, pregnancy luteomas are discrete or multinodular
brown or red/hemorrhagic solid nodules ranging from 1.0 cm
up to 20 cm that replace the ovarian parenchyma (Fig. 3.23).
They may be bilateral in up to a third of cases [22, 23].
Microscopically, the nodules are typically composed of a
Fig. 3.25 Luteoma of pregnancy, high power: solid growth of eosino-
philic cells with round nuclei, prominent nucleoli, and delicate blood
vessels
solid proliferation of luteinized stromal cells with eosino-

philic cytoplasm (Fig. 3.24) and central nuclei with small to
prominent nucleoli (Fig. 3.25). Mitotic activity may be brisk,
up to 7/10 per high power fields. Necrosis, cystic changes, or
follicle-like spaces containing eosinophilic (colloid-like)
secretion may be seen (Fig. 3.26) [21]. In the postpartum
period, degenerative changes, frothy/pale rather than eosino-
philic cytoplasm, and fibrosis can be present. By immunohis-
tochemistry, lesional cells are positive for inhibin, calretinin,
and Melan A and are negative for keratins and other mela-
noma markers.
3.2.2.3 Differential Diagnosis

Fig. 3.23 Luteoma of pregnancy gross: Tan brown and red solid nod- The main differential diagnosis includes other sex cord stro-
ule with foci of hemorrhage mal tumors such as steroid cell tumor, luteinized thecoma or
88 D. Suster et al.
anomalies and preeclampsia with its sequelae [27].

Virilization of the pregnant woman due to elevated andro-
gens is observed in less than half of cases but only rarely
observed in female fetuses. As this is a benign condition
which regresses after delivery, management should be con-
servative to preserve future fertility. Surgical intervention
is warranted only in the setting of ovarian torsion or
rupture.
3.2.3.2 Pathology
Hyperreactio luteinalis is characterized by bilateral ovarian
enlargement up to 15 cm or more in greatest dimension. The
ovarian surface is lobulated, and sectioning reveals numer-
ous cysts ranging from 1 to 3 cm in size (Fig. 3.27) that are
remarkable for a smooth, yellow lining. The cyst content is
Fig. 3.26 Luteoma of pregnancy, high power: typical follicle-like clear watery to hemorrhagic. Morphologically, the cysts are
spaces containing colloid-like secretory secretion lined by luteinized granulosa and theca interna cells often
with edema or features of torsion of the cyst wall and ovarian
stroma (Fig. 3.28).
luteinized granulosa cell tumor, Leydig cell tumor, and meta-
static carcinoma or melanoma.
3.2.3 Hyperreactio Luteinalis

Hyperreactio luteinalis is a rare condition characterized by
bilateral massive, cystic enlargement of the ovaries during
pregnancy. It occurs more commonly in primiparous
women and is most frequently associated with singleton
pregnancies [26]. Hyperreactio luteinalis is characterized
by the formation of numerous, large theca-lutein cysts; this
occurs in response to abnormally high levels of human cho-
rionic gonadotropin (HCG) or, in rare cases, to increased Fig. 3.27 Hyperreactio luteinalis, low power, associated with torsion
sensitivity of the ovarian stroma to HCG. Elevated HCG
during gestation has been observed secondary to conditions
resulting in a large placenta, such as multiple gestation,
diabetes mellitus, and Rh sensitization; however, most
cases of hyperreactio luteinalis are observed in normal sin-
gleton gestations. Additionally, similar effects on the ova-
ries are seen in molar pregnancies, trophoblastic disease,
and choriocarcinoma [26]. Presenting signs and symptoms
are related to maternal virilization secondary to increased
circulating androgens produced by the ovaries or abdomi-
nal pain due to ovarian enlargement, torsion, or rupture. A
significant proportion of cases are discovered incidentally
on routine imaging or occasionally at the time of cesarean
section. Ultrasound typically shows bilateral enlarged ova-
ries with numerous cystic structures, and these findings
should not be mistaken for malignancy [26]. Although
hyperreactio luteinalis is a benign process, it has been asso-
ciated with adverse effects on the pregnancy secondary to Fig. 3.28 Hyperreactio luteinalis cyst lining, high power, associated
elevated hCG, including the slightly increased risk of fetal with torsion

The histological differential diagnosis includes luteinized
follicular cyst, luteoma of pregnancy, and cystic granulosa
cell tumor. The gross examination and clinical history, in
particular with regard to bilateral ovarian enlargement due to
numerous luteinized follicular cysts, are essential in differ-
entiating these entities.
3.2.4 L
arge Solitary Luteinized Follicular Cyst
of Pregnancy

Large solitary luteinized follicle cyst is a rare, unilateral
tumor-like ovarian lesion with less than 15 cases having been
reported in the literature as of 2017. It is typically discovered Fig. 3.29 Large solitary luteinized follicle cyst of pregnancy: lining
during mid- to late pregnancy or puerperium, and although composed of luteinized cells with clear and eosinophilic cytoplasm and
its pathogenesis is unknown, a role of abnormal response to small uniform round nuclei
hCG has been postulated [28, 29]. Due to its enormous size,
patients typically present with signs and symptoms of a large
ovarian or adnexal mass with or without torsion or rupture
[30]. Endocrine manifestations are typically absent [28].
Following excision, no recurrences have been reported high-
lighting a benign biological behavior.
3.2.4.2 Pathology
The gross appearance is of a large unilocular cyst, up to 55 cm
in size (average diameter of 25 cm), filled with either serous
or mucoid fluid [28]. The cyst wall is typically thin, measur-
ing less than 0.5 cm [31], which, upon histological examina-
tion, is composed of up to ten layers of luteinized cells with
eosinophilic to vacuolated cytoplasm lining the cyst wall.
Distinct granulosa and theca layers are typically not seen.
Instead, the luteinized cells lining the cyst wall are uniform
with small, round nuclei, smooth nuclear contours, and small
Fig. 3.30 Large solitary luteinized follicle cyst of pregnancy with
nucleoli (Fig. 3.29). However, foci of scattered cells may focal nuclear atypia
show marked nuclear enlargement, hyperchromasia, and
bizarre and pleomorphic nuclei (Fig. 3.30) [28]. Importantly,
hyaline bodies or calcified foci that are frequently seen in cor- 3.2.5 Ectopic Decidua (Deciduosis)
pus luteum of pregnancy are not present. Mitosis, apoptosis,
and necrosis are typically absent. Nests of luteinized cells, 3.2.5.1 Clinical Features
similar in appearance to those lining the cyst, can be identi- The development of ectopic decidua is considered a physi-
fied within the stroma of the cyst wall, which should not be ologic phenomenon of pregnancy and has been reported in
mistaken for invasion. A reticulin stain can highlight scattered almost all ovaries at term [32]. During pregnancy, ectopic
fibrils surrounding the nests of luteinized cells [29]. decidua may also be encountered in diverse locations such
as endocervical stroma, uterine serosa, fallopian tubes,
3.2.4.3 Differential Diagnosis omentum, appendix, small and large intestine, and urinary
The major malignant differential diagnoses that should be bladder [33]. Involvement of the appendix may give rise to
excluded include unilocular cystic granulosa cell tumors of signs and symptoms of acute appendicitis during pregnancy
either adult or juvenile types. Other benign differential diag- [34]. Ectopic decidua may also occur in early gestation, as
noses include corpus luteum of pregnancy, pregnancy lute- well as in nonpregnant women with progestin treatment,
oma, and hyperreactio luteinalis, which can be distinguished with trophoblastic disease, and with a hormone-producing
based on the gross and histological features. ovarian or extra-ovarian lesion [33]. Deciduosis is a benign
90 D. Suster et al.
process that regresses in the postpartum period without any 3.2.5.3 Differential Diagnosis
major complications. The differential diagnosis includes a luteinized sex cord stro-
mal tumor or a metastatic neoplasm (melanoma, deciduoid
3.2.5.2 Pathology mesothelioma, carcinoma), especially when encountered in
Gross lesions are often not seen but, if present, may mimic non-gynecological sites such as the omentum [36].
a neoplasm as gray to white nodules, polyps, or sheets on
the ovarian surface or extra-ovarian sites [32].
Microscopically, ectopic decidua typically involves the 3.2.6 Pregnancy-Associated Granulosa
ovarian cortex or areas of periovarian adhesions (Fig. 3.31). Cell Proliferation
Morphologically, deciduosis resembles the decidualized
endometrial stroma counterpart of the gestational endome- 3.2.6.1 Clinical Features
trium, and it is characterized by epithelioid cells with abun- Pregnancy-associated granulosa cell proliferations are
dant clear to pink cytoplasm and bland, round nuclei benign, incidental findings in ovaries removed during preg-
(Fig. 3.32). Mitotic activity is absent, but focal nuclear nancy. They are thought to occur due to the FSH-like activity
pleomorphism, hyperchromasia, prominent nucleoli, and of HCG and the hormonal milieu of pregnancy. Follow-up
necrosis may be seen [35]. data on these lesions is scant, with only ten reported cases in
the literature; however they are considered benign nonneo-
plastic lesions of the ovary [37, 38].
3.2.6.2 Pathology
Because they are incidental findings, gross appearance has
not been described. Microscopically, they are characterized
by multifocal, microscopic foci of solid, non-cystic, intrafol-
licular granulosa cell proliferation, typically measuring
<1 mm in diameter, but have been reported to be up to 5 mm
in greatest dimension. They are spatially located within the
center of atretic ovarian follicles and are surrounded by a
theca layer. The classic architecture and cytological features
of granulosa cells are seen, including solid, insular, microfol-
licular, or trabecular patterns, high nuclear-cytoplasmic ratio,
and oval nuclei with nuclear grooves. Two other patterns of
proliferation have also been reported: (1) microscopic,
<5 mm, nodules of luteinized granulosa cells with round,
Fig. 3.31 Ectopic decidua involving the ovarian cortex
non-grooved nuclei, and (2) a sertoliform tubular pattern with
vacuolated cytoplasm, mimicking testicular sertoli tubules.

The main differential diagnoses are adult granulosa cell
tumor or Sertoli cell tumor [37]. Clinical history of preg-
nancy, small size, and presence of the surrounding theca
layer are helpful in classifying these lesions as benign
proliferations.
3.2.7 Ovarian Ectopic Pregnancy

Primary ovarian ectopic pregnancy, i.e., the implantation of
the embryo in the ovary, is one of the rarest forms of ectopic
pregnancy with an incidence of approximately 3% of all natu-
rally conceived ectopic pregnancies. This incidence is signifi-
Fig. 3.32 Ectopic decidua, high power: epithelioid cells with abundant cantly lower than primary ectopic pregnancies occurring in the
clear to pink cytoplasm, bland, round nuclei fallopian tube (approximately 95% of all ectopic pregnancies)
and slightly higher than the incidence of abdominal ectopic

pregnancies (approximately 1–2% of ectopic pregnancies)
[39]. In contrast to tubal gestation, which is associated with
traditional risk factors, such as pelvic inflammatory disease
and prior pelvic surgical procedure, the causes of primary
ovarian pregnancy are unknown. However, the following
hypotheses have been proposed: (1) secondary reflux of the
fertilized oocyte to the ovary, (2) interference in the release of
the ovum from the ruptured follicle, (3) malfunction of the
tubes, and (4) inflammatory thickening of the tunica albuginea
[40]. In addition, use of intrauterine contraceptive device
appears to be a risk factor that is significantly and specifically
associated with ovarian ectopic pregnancy compared to tubal
pregnancy, as an intrauterine contraceptive device is found in
up to 90% of patients with primary ovarian pregnancy com-
pared to up to 30% in patients with non-ovarian extrauterine Fig. 3.33 Ovarian ectopic pregnancy with implantation site
pregnancy [40–42]. The signs and symptoms of ovarian preg- trophoblasts
nancy are similar to tubal pregnancy, including severe pain
and hemoperitoneum. Ovarian pregnancy is typically detected
in emergency settings when surgical treatment is the gold stan-
dard [40]. Little data is available in the literature regarding
treatment with methotrexate; however, if diagnosed early, pri-
mary management may include conservative surgical resec-
tion to preserve fertility and methotrexate medical treatment.
Compared with tubal pregnancy, ovarian ectopic pregnancy
that may have a higher incidence of intra-abdominal hemor-
rhage [40], which is a life-threatening complication, is likely
due to the fact that the ovary is a solid organ and has a more
robust blood supply than the fallopian tube [43]. Therefore,
proper awareness of ovarian ectopic pregnancy, in the clinical
setting of an ovarian mass and elevated serum β-hCG levels,
may guide the timely initiation of appropriate therapies [43].
3.2.7.2 Pathology
Similar to tubal ectopic pregnancy, pathological diagnosis of Fig. 3.34 Ovarian ectopic pregnancy with placental chorionic villi
primary ovarian pregnancy requires gross or histological evi-
dence of embryonic implantation in the ovary. Grossly, ovar- products of conception including chorionic villus, implanta-
ian pregnancy may appear as a hemorrhagic cyst or mass that tion site, isolated trophoblast, and embryonic sac with or
may mimic a neoplasm. Gross identification of a gestational without fetal tissue [43]. When the morphologic evidence is
sac, placental villi, or an embryo may be possible depending equivocal in the ovary, ancillary immunohistochemistry for
on the gestational age. Microscopically, identification of staining β-hCG, human placental lactogen, and inhibin to
implantation site trophoblasts (Fig. 3.33), immature placen- highlight trophoblasts can be used to aid the diagnosis [43].
tal chorionic villi (Fig. 3.34), or embryonic tissue within
ovarian parenchyma is required for the diagnosis.
3.3 varian Disorders Associated
O
3.2.7.3 Differential Diagnosis with Infertility
The differential diagnosis includes hemorrhagic cysts, such
as the corpus luteum, a luteinized follicular cyst, a germ cell 3.3.1 P
remature Ovarian Failure
tumor, and a ruptured tubal ectopic pregnancy. Distinction with Accelerated Follicle Depletion
from a fallopian tube pregnancy requires that the ipsilateral
fallopian tube is intact or with no evidence of pregnancy 3.3.1.1 Clinical Features
after extensive histologic examination and in addition to the Premature ovarian failure (POF) or primary ovarian
identification, within the affected ovary, of any evidence of insufficiency (POI) is defined as at least 4 months of

92 D. Suster et al.
a menorrhea and FSH levels of >40 mIU/mL on two sepa- thus limiting the accuracy of the test. A patient with dimin-
rate occasions, at least 1 month apart, in a woman under ished ovarian reserve may have few to no follicles present
40 years old. Presenting symptoms include irregular men- by biopsy, but these findings are known to have a poor cor-
ses, which may precede definitive diagnosis by several relation with the presence of follicles elsewhere in the
years. In addition, patients may suffer from infertility or ovary owing to heterogeneous distribution. In addition, the
menopausal-type symptoms secondary to low estrogen procedure is invasive, and rarely, pregnancy has occurred in
levels. The most common causes of POF are chemotherapy the absence of follicles on biopsy. Therefore ovarian biopsy
and radiotherapy treatments for malignancy; however, is not necessary or recommended as a means of diagnosing
most cases of POF with accelerated follicle depletion and POF [16].
diminished ovarian follicle reserve have no known etiol-
ogy [44]. A small proportion of cases may be attributed to
an underlying genetic or autoimmune (discussed elsewhere 3.3.2 Autoimmune Oophoritis
in this chapter) disorder. Among the known genetic altera-
tions that have been linked to POF, those related to the X 3.3.2.1 Clinical Features
chromosome are the most common, with a smaller propor- Autoimmune oophoritis is a rare cause of premature ovar-
tion attributed to somatic genes. Variations in the X chro- ian failure (POF) with accelerated follicle depletion.
mosome include Turner syndrome (mosaic or complete Patients affected by autoimmune oophoritis present in early
monosomy), trisomy X syndrome, fragile X syndrome, stages with menstrual irregularities and decreased fertility,
and deletions in either the long or short arm of the X chro- ultimately leading to sustained amenorrhea before the age
mosome. Somatic genetic alterations include galactose- of 40 with associated high FSH and low estrogen levels
mia, 17-alpha-hydroxylase deficiency, and mutations in [47]. Autoimmune oophoritis is most commonly associated
the FSH receptor, LH receptor, inhibin, and FOXL2 genes. with autoimmune Addison’s disease in the setting of auto-
Other known causes of POF include tobacco smoking, immune polyendocrine syndromes (APS) type 1 and type
infectious oophoritis, and pelvic surgery for benign dis- 2. Outside of this association, autoimmune POF may be
ease. Diagnostic testing should include FSH, LH, prolac- seen with autoimmune thyroiditis or type 1 diabetes melli-
tin, estradiol levels, and markers of ovarian follicle reserve tus most commonly and, rarely, with other non-endocrine
such as inhibin B and/or anti-Müllerian hormone (AMH) autoimmune disorders. Autoimmune POF has been attrib-
levels [45]. Pregnancy and autoimmune oophoritis should uted to steroid-cell autoantibodies, also termed ovary and
be excluded, and karyotyping or other genetic testing adrenal autoantibodies, which are directed against
should be considered, especially if there is a familial his- steroidogenic enzymes: 17 alpha-hydroxylase and cyto-

tory of POF (present in approximately 20–30% of cases). chrome P450-side chain cleavage enzymes [48].
Noninvasive testing to determine ovarian reserve include Immunofluorescence studies show that these autoantibod-
clomiphene citrate challenge, FSH, inhibin B, AMH lev- ies localize to the theca cells of antral (secondary and ter-
els, ovarian volume, and antral follicle count [45]. tiary) follicles but spare granulosa cells and the primary
Management of premature ovarian failure includes hor- follicles. These autoantibodies incite an immune response
mone replacement therapy and fertility treatments to leading to the destruction of theca cells and a decrease in
induce ovarian hyperstimulation for egg retrieval in cases estrogen secondary to lack of substrate. Thus, FSH and LH
of diminished ovarian reserve or utilizing donor oocytes levels increase, stimulating production of inhibin B by the
when there is complete follicle depletion. remaining granulosa cells. This pattern of concurrent
increase in FSH and inhibin B is specific for autoimmune
3.3.1.2 Pathology oophoritis and is not seen in other causes of POF. Serologic
Grossly, the ovaries of patients diagnosed with POF may detection of steroid-cell autoantibodies is the preferred
appear unremarkable or be distorted by cystic follicles or method of diagnosis [49]. Ultrasound may show ovarian
corpora lutea. Ovarian biopsy has been suggested as a enlargement or multiple cystic follicles but is nonspecific.
method for determining ovarian reserve by documenting Biopsy is rarely performed because the expected inflamma-
the number and type of follicles present. Histological eval- tory infiltrate is almost never seen in the absence of sero-
uation of the cortical tissue by ovarian biopsy should logic evidence of autoimmune POF. Management includes
include quantification of all follicles in various states of hormone replacement and fertility treatments utilizing
maturation including corpora lutea and atretic forms [46]. donor oocytes. A safe and effective immunosuppressive
However, ovarian biopsy is no longer recommended as a regimen has not been developed or validated for use early
means of determining the ovarian reserve because follicle in the course of autoimmune oophoritis to theoretically
distribution within the ovarian cortex is heterogeneous, restore ovarian function.
3.3.2.2 Pathology
Ovaries affected by autoimmune oophoritis may appear
grossly unremarkable or may be mildly enlarged. Rarely, the
ovary may be markedly enlarged with numerous cystic
follicles [50]. Histological features include a dense mono-
nuclear infiltrate composed of T and B lymphocytes and
plasma cells involving the theca interna of antral follicles,
while primary follicles and granulosa cells are spared
(Figs. 3.35, 3.36, 3.37, and 3.38) [51]. Rarely, an eosino-
philic infiltrate accompanies the mononuclear cells in the
destruction of the antral follicles (Fig. 3.39) [52]. Later in
disease progression, diminished numbers of follicles remain.
As with any inflammatory process, oophoritis secondary to
infection must be ruled out. Correlation between the histo-
logical and clinical serologic findings is essential in the diag-
nosis of autoimmune oophoritis. Fig. 3.37 Autoimmune oophoritis with destruction of theca layer
Fig. 3.35 Autoimmune oophoritis, low power Fig. 3.38 Autoimmune oophoritis with CD3 immunostain highlight-
ing T cells in theca layer
Fig. 3.36 Autoimmune oophoritis with mixed inflammatory cells

involving theca layer Fig. 3.39 Autoimmune oophoritis with prominent eosinophils
94 D. Suster et al.
3.3.3 P
rimary Ovarian Insufficiency Without
Follicle Depletion (Resistant Ovarian
Syndrome)

Primary ovarian insufficiency without follicle depletion or
resistant ovarian syndrome (also known as Savage syndrome
or gonadotrophin-insensitivity syndrome) accounts for
10–20% of infertility cases due to premature ovarian failure.
It is characterized by primary or secondary amenorrhea with
resistance to endogenous and exogenous gonadotropins. The
resistance is thought to be secondary to intrinsic follicular
FSH and LH receptor dysfunction, a post-receptor defect, a
block of receptors by circulating antigonadotropin antibod-
ies (anti-FSH and anti-LH), steroidogenic enzyme defects
(i.e., StAR, CYP17, NR5A1), or Gs alpha-subunit gene
mutations [53–55]. Clinically, patients with resistant ovary Fig. 3.41 Resistant ovarian syndrome with fibrotic replacement of
syndrome are characterized by normal female sex character- ovarian stroma
istics, regular female karyotype, and primary or secondary
amenorrhea [56]. High circulating levels of endogenous cific replacement of ovarian stroma (Fig. 3.41). Focal antral
gonadotropins with normal ovarian follicle counts, normal follicles may be present. In addition, rare cases of stromal
anti-Müllerian hormone level, and low estradiol are present. luteinization and hilar cell hyperplasia have been described,
No standardized treatment guidelines exist for resistant presumably secondary to high levels of LH.
ovary syndrome, and patients often fail to respond to high
levels of exogenous hormones for endogenous oocyte 3.3.3.3 Differential Diagnosis
retrieval [57]. However, fertility treatment with donor The differential diagnosis for resistant ovary syndrome
oocytes and surrogate gestation are options. includes other conditions which may cause a similar histo-
logical patterns including premature ovarian failure with
3.3.3.2 Pathology accelerated follicle depletion, hypogonadotropic ovarian
Grossly, the ovaries of patients with resistant ovary syndrome failure secondary to hypothalamic-pituitary dysfunction,
have a normal appearance, regardless of whether the patient is Cushing syndrome, and morbid obesity. Differentiating
prepubertal or an adult. Microscopically, the ovary is charac- these different entities often requires clinical-pathological
terized by appropriate numbers of primordial follicles, which correlation [58, 59].
appear normal and may display clustering as in unaffected
ovaries (Fig. 3.40). The background ovarian cortical stroma is
homogenous and cellular and resembles the normal ovarian 3.3.4 Polycystic Ovarian Syndrome
stroma. Cortical stromal hyalinization and fibrosis may be
present in some cases, with or without hyaline/fibrotic/cal- 3.3.4.1 Clinical Features
Polycystic ovary syndrome (PCOS), also known as Stein-
Leventhal syndrome, is the most common endocrine disorder
in women of reproductive age with a reported incidence of
between 6 and 15% in premenopausal women, depending on
the population and diagnostic criteria used. The mechanism
of PCOS is thought to be related to insulin resistance and to
dysfunction of the hypothalamic-pituitary axis. The associa-
tion with type 2 diabetes mellitus has been well characterized.
Insulin resistance leads to hyperinsulinemia which results in
overstimulation of theca cells and increased androgen secre-
tion. Obesity tends to exacerbate the insulin resistance, and
patients with PCOS most often have increased central obesity
[60–62]. A hereditary role is thought to play a part in PCOS,
Fig. 3.40 Resistant ovarian syndrome with follicle clustering with some studies demonstrating familial clustering [63].
In addition, multiple studies propose a genetic role in the

development of PCOS: mRNA studies have revealed that the
theca cells of PCOS patients have increased expression of
genes, such as CYP11A, 3BHSD2, CYP19, and YP17, which
encode essential enzymes in androgen biosynthesis path-
ways. Linkage and association studies have suggested that the
candidate genes responsible for PCOS may be located some-
where in the region of chromosome 19p13.3 [61, 63].
Therefore, environmental, hereditary, and genetic factors may
all play a role in the development of PCOS.
PCOS is a diagnosis of exclusion and is most commonly
defined by the Rotterdam criteria, in which two of the three
following criteria are met: (1) oligo- and/or anovulation, (2)
clinical and/or biochemical signs of hyperandrogenism, and
(3) polycystic ovaries with antral follicle excess (>10–12) by
ultrasound. In addition, most patients with PCOS will have a
variety of laboratory abnormalities. High levels of LH are
commonly encountered and are likely the driving force
behind theca cell growth. Patients tend to have normal or Fig. 3.42 PCOS, low power, multiple cystic follicles
slightly higher levels of FSH and will usually present with a
LH:FSH ratio of greater than 2 [60–62]. Levels of anti-
Müllerian hormone and prolactin tend to be increased as well
[18]. Most patients have increased androgen production with
raised levels of total testosterone (as well as circulating free
testosterone due to low levels of sex hormone-binding pro-
tein), androstenedione, DHEA, and DHEA-s.
Clinically, patients present with symptoms of hyperan-
drogenism (hirsutism, menstrual irregularities, etc.), infertil-
ity (secondary to anovulation), abdominal pain, hepatic
steatosis, abnormal uterine bleeding, and polycystic ovaries,
among others. Pharmacologic therapy with oral contracep-
tives for managing hyperandrogenism and menstrual dys-
function, combined with weight-loss strategies, is the
first-line therapy for PCOS [60]. Metformin may also play a Fig. 3.43 PCOS, high power, luteinized stromal cells (hyperthecosis)
role in restoring normal metabolic functions and ovulation;
however, for women desiring pregnancy, clomiphene is now outer cortical linear array of multiple small cysts.
a treatment of choice [64]. Surgery is no longer commonly Microscopically, multiple cystic follicles of a relatively uni-
used in the treatment of PCOS; however, it may still be use- form size are seen (Fig. 3.42). Due to anovulation, corpus
ful for specific patients [65–67]. The clinical differential luteum and corpus albicans are usually not present. Theca
diagnosis for PCOS is broad and includes congenital adrenal cell hyperplasia occurs in follicles and may also be identified
hyperplasia, thyroid disease, and hyperprolactinemia as well as islands or isolated theca cells in the cortical stroma (stro-
as other causes of androgen excess including ovarian tumors, mal hyperthecosis) (Fig. 3.43). Atretic and involuted follicles
adrenal tumors, and ovarian hyperthecosis. In these other may be present combined with some increased stromal
entities, there is a primary well-defined cause leading to the fibrosis.
PCOS phenotype with underlying androgen overproduction,
and the potential complete recovery of the hyperandrogen- 3.3.4.3 Differential Diagnosis
emic state as well as the remission of the PCOS phenotype The microscopic differential diagnosis includes hyperreactio
should follow the removal of the underlying cause [68]. luteinalis and ovarian hyperstimulation syndrome. Similar
microscopic findings mimicking PCOS may also be seen in
3.3.4.2 Pathology oophorectomy specimens of transgender patients following
Grossly, the ovaries in PCOS are symmetrically enlarged and androgen treatment and sex-reassignment female-to-male
usually have a thick capsule. On cut sections, there is an surgical procedure.
96 D. Suster et al.
3.3.5 Ovarian Endometriosis
Ovarian endometriosis is a leading cause of infertility in

reproductive age women with a prevalence of 0.5–5% in fer-
tile and 25–40% in infertile women [69]. In contrast, there
appears to be no significant link between endosalpingiosis
and infertility, suggesting endometriosis and endosalpingio-
sis are two different clinical disease processes with different
presentations [70]. The clinicopathological characteristics of
ovarian endometriosis and endosalpingiosis are described in
full elsewhere in the book (see Chap. 12 and endosalpingio-
sis section below in this chapter, respectively).
3.4 varian Findings in Perimenopausal

O
and Postmenopausal Women Fig. 3.45 Atrophy, low power
3.4.1 Ovarian Atrophy

Typically, the ovaries gradually decrease in volume with each
decade of life from age 30 to age 70, and the mean volume in
premenopausal women is significantly greater than in post-
menopausal women [71]. Atrophy is the extreme reduction of
ovarian volume and function in postmenopausal women.
3.4.1.2 Pathology
Grossly, ovaries are small and shrunken in size, typically
<2 cm, with smooth or gyriform surface (Fig. 3.44), and they
may be difficult to identify if adhesions are present.
Microscopically, there is cortical stromal atrophy, which is
characterized by a thin cortex and minimal amounts of
medullary stroma (Figs. 3.45 and 3.46). In the medulla and
hilar junction, multiple corpora albicantia and vessels may Fig. 3.46 Atrophy, medium power
be prominent.
3.4.2 Stromal Hyperplasia and Hyperthecosis

At the other extreme from atrophy, proliferations of the
ovarian stroma may also be seen in perimenopause and
menopause. Stromal hyperplasia and hyperthecosis are
typically incidental findings in perimenopausal and post-
menopausal women; however a subset of patients may
present with endocrine manifestations, either androgenic
or estrogenic [72]. Stromal hyperthecosis may more often
present in reproductive age women. Stromal hyperplasia
and hyperthecosis may represent components of a morpho-
logic spectrum of benign proliferation of ovarian stromal
cells [1].
3.4.2.2 Pathology
Macroscopically, both ovaries may be normal in size or
enlarged, and a grossly identifiable mass is typically absent.
Fig. 3.44 Atrophic ovary, gross When enlarged, the cortex and/or medulla may be expanded
by ill-defined nodules or by a diffuse stromal proliferation

[1]. Microscopically, in stromal hyperplasia, there is a dif-
fuse or nodular proliferation of spindle-shaped, non-
luteinized ovarian stromal cells with scant cytoplasm that
are identical to cells that comprise the normal ovarian cortex
(Figs. 3.47 and 3.48). In stromal hyperplasia, luteinized
stromal cells are not present in the cortex, and if they are
found, a diagnosis of stromal hyperthecosis is warranted. In
stromal hyperthecosis, a hyperplastic ovarian stroma is
accompanied by single clusters or, rarely, microscopic nod-
ules (<1 cm) of luteinized cells with abundant clear cyto-
plasm, round nuclei, and prominent nucleoli (Figs. 3.49 and
3.50). Therefore, identification of luteinized cells is critical
in the distinction between stromal hyperplasia and hyper-
thecosis, whereas the presence of a grossly visible mass is
important in the distinction between stromal hyperthecosis Fig. 3.49 Stromal hyperthecosis: single, clusters or rarely microscopic
and a stromal luteoma or other luteinized sex cord stromal nodules (<1 cm) of luteinized cells with abundant clear cytoplasm and
tumors. Both stromal hyperplasia and stromal hyperthecosis round nuclei
may be associated with hilus cell hyperplasia. Hormone
Fig. 3.50 Stromal hyperthecosis, high power

Fig. 3.47 Stromal hyperplasia, low power
production by these benign lesions may induce proliferation
of the endometrium, atypical hyperplasia, and well-differ-
entiated endometrioid adenocarcinoma [73, 74].
3.4.3 Hilus Cell (Leydig) Hyperplasia

Expansion of the hilus (Leydig) cell population is frequent
during perimenopause, during postmenopause, or during
pregnancy. The hilus cells presumably respond to elevated
serum hCG or LH, and they may secrete androgens and
estrogens [7]. As a result, patients can exhibit androgenic or
estrogenic manifestations.
3.4.3.2 Pathology
Macroscopically, by definition, a lesion is not grossly
Fig. 3.48 Stromal hyperplasia, high power visible. Microscopically, there are ill-defined clusters or
98 D. Suster et al.
nodules of pink cells often closely associated with nerves

and vascular and lymphatic spaces (Fig. 3.51). On higher
power, the hyperplastic cells are polygonal eosinophilic
cells with round nuclei and prominent nucleoli, similar to
the native hilus cells (Fig. 3.52). Lipofuscin pigment,
Reinke crystals (Fig. 3.53), associated stromal hyperpla-
sia, and stromal hyperthecosis may be seen. In addition to
the hilus, occasionally microscopic nodules, nests, and
clusters of hilus cells can be located in the mesovarium, in
the mesosalpinx, and in the medulla and cortical regions
of the ovaries, wherein they may be associated with
peripheral nerve fibers [6]. By immunohistochemistry,
lesional cells are positive for inhibin and calretinin
(Figs. 3.54 and 3.55) [6].
Fig. 3.53 Hilus (Leydig) cell hyperplasia with Reinke crystals
Fig. 3.51 Hilus (Leydig) cell hyperplasia, low power Fig. 3.54 Hilus (Leydig) cell hyperplasia, inhibin immunostain
Fig. 3.52 Hilus (Leydig) cell hyperplasia, high power Fig. 3.55 Hilus (Leydig) cell hyperplasia, calretinin immunostain
3.4.3.3 Differential Diagnosis adhesions. Microscopically, areas of abundant acute and

The main differential diagnosis includes hilus cell tumor, chronic inflammation, composed of neutrophils and lympho-
which is distinguished by the presence of a grossly visible cytes (Figs. 3.56 and 3.57), are seen in association with
tumor, or a metastatic tumor (melanoma, breast lobular or necrosis and fibrinous exudates, which are typical of a pyo-
gastric carcinoma) [75]. Clinical history of prior malignancy genic abscess (Figs. 3.58 and 3.59). Possible sequelae of a
is a helpful clue to distinguishing hilus cell hyperplasia from healed ovarian infection include para-ovarian and tubo-
a metastatic tumor. Morphologically, metastasis to the ovary ovarian adhesions, a tubo-ovarian cyst, and scarring of the
may exhibit mild atypia or abundant foamy vacuolated cyto- fallopian tube leading to infertility or ectopic pregnancy.
plasm due to neoadjuvant chemotherapy or well-developed Rarely, an untreated tubo-ovarian infection may progress to
malignant cytologic features in chemotherapy-naïve cases a chronic xanthogranulomatous abscess, which may mimic
[75]. In addition, a panel of immunostains may be helpful in malignancy by imaging [78, 79]. Similar to other sites, a
confirming metastasis (carcinoma: EMA+/inhibin−/cal- xanthogranulomatous abscess in the ovary is characterized
retinin−, melanoma: S100+/Sox10+/inhibin−/calretinin−). by the presence of a prominent number of foamy histiocytes,
Caution should be used with cytokeratins as they may be fre- associated with giant cells, plasma cells, and neutrophils
quently positive in ovarian sex cord stromal cells. (Figs. 3.60 and 3.61).
3.5 Ovarian Infection
3.5.1 I nfectious Oophoritis and Tubo-

Ovarian Abscess Due to Acute
and Subclinical Pelvic Inflammatory
Disease

Acute and chronic oophoritis and tubo-ovarian abscess are
typically manifestations of infection-induced pelvic inflam-
matory disease of the upper reproductive tract and perito-
neum. Presenting signs and symptoms may be subtle;
however, pelvic tenderness is a common hallmark presenting
symptom [76]. Other signs and symptoms include fever and
cervical or vaginal mucopurulent discharge. In addition, clin-
ically silent spread of infection to the upper genital tract may Fig. 3.56 Acute oophoritis
also occur, thereby resulting in subclinical pelvic inflamma-
tory disease and infertility [77]. The majority (approximately
85%) of infectious oophoritis and pelvic inflammatory dis-
ease cases are caused by sexually transmitted pathogens, such
as Chlamydia trachomatis and Neisseria gonorrhea, or bacte-
rial vaginosis-associated pathogens, while fewer than 15% of
acute cases are associated with enteric or respiratory patho-
gens [76]. Risk factors include young age and history of sex-
ual activity and/or multiple partners. Non-sexually transmitted
infectious oophoritis may also be due to secondary direct or
lymphatic spread of intestinal infection (i.e., diverticulitis,
appendicitis, or complication of Crohn’s disease). Treatment
includes specific antimicrobial therapy or surgery for a rup-
tured or antibiotic-resistant abscess.
3.5.1.2 Pathology
Grossly, an ovarian abscess is characterized by a cystic mass
with central areas of necrosis and hemorrhage and areas of Fig. 3.57 Acute oophoritis
100 D. Suster et al.
Fig. 3.58 Acute oophoritis with abscess formation, low power Fig. 3.61 Xanthogranulomatous oophoritis, high power

The differential diagnosis includes an ovarian neoplasm or
unusual causes of tubo-ovarian abscess, such as actinomyco-
sis and tuberculosis. These are rare but specific causes of
tubo-ovarian abscess and frequently are initially mistaken
for ovarian malignancies due to their clinical presentation
and unusual radiological appearances. Unlike acute and sub-
clinical pelvic inflammatory disease related to sexually
transmitted pathogens, the disease is considered chronic
when caused by Mycobacterium tuberculosis or actinomy-
ces. These forms of pelvic inflammatory disease are defined
as chronic upper reproductive tract infections when lasting
>30 days in duration [76]. In patients with infertility, clinical
differential diagnosis also includes endometriosis and auto-
immune oophoritis.
Fig. 3.59 Acute oophoritis with abscess formation, high power
3.5.2 Actinomycosis
Female genital tract actinomycosis most often occurs in the

endometrium, usually but not always as a complication of an
intrauterine device. An untreated endometrial actinomycotic
infection may lead to pelvic inflammatory disease, tubo-
ovarian abscess, and ovarian actinomycosis [80]. Clinically,
the presenting signs and symptoms may be indistinguishable
from other forms of pelvic inflammatory disease [81]. By
imaging, tubo-ovarian actinomycosis can be nonspecific, but
a predominantly solid appearance, with a linear, solid, well-
enhancing lesion extending directly from the mass, has been
reported [79]. Grossly, the ovaries may be enlarged with
areas of necrotic cavities. Microscopically, there is a tubo-
ovarian abscess formation composed of neutrophils, histio-
cytes, lymphocytes, and plasma cells. Identification of
Fig. 3.60 Xanthogranulomatous oophoritis, low power basophilic granules composed of gram-positive and
Fig. 3.64 Actinomycosis granules, silver stain
Fig. 3.62 Actinomycosis granules
Fig. 3.65 Necrotizing granulomas of ovarian tuberculosis, low power
is now considered extremely rare in developed countries.

Compared to the fallopian tube and the endometrium,
which are involved in 100% and 79% cases of female gen-
Fig. 3.63 Actinomycosis granules, gram stain ital tract tuberculosis, the ovaries are involved in only
approximately 11% of cases [83]. The presenting signs of
silver-
positive, branching filamentous-like bacteria is tubo-ovarian tuberculosis include a pelvic mass, ascites,
required for the diagnosis. These are similar in appearance to vague abdominal distention, weight loss, and infertility
their endometrial counterpart (Figs. 3.62, 3.63, and 3.64). In [83, 84]. By imaging, a tubo-ovarian abscess due to tuber-
addition, co-occurrence of both true actinomycotic and culosis usually mimics peritoneal carcinomatosis derived
gram- and silver- negative pseudo-actinomycotic radiate from ovarian cancer [79]. Grossly, the ovary may be
granules has been reported in both endometrial and tubo- enlarged, and necrosis may not be grossly seen.
ovarian specimens [82]. Treatment includes antibiotics, such Microscopically, similar to other sites, noncaseating or
as penicillin, surgery in cases of large tubo-ovarian abscesses caseating necrotizing granulomas are present (Figs. 3.65,
or inability to rule out neoplasm, and removal of intrauterine 3.66, and 3.67). Acid fast stains may be negative for
device [81]. organisms on paraffin-embedded sections. For this reason,
triaging a portion of the specimen during intraoperative
frozen section, if applicable, to microbiology cultures
3.5.3 Tuberculosis may aid in the diagnosis [85]. Alternatively, molecular
methods such as polymerase chain reaction are emerging
The incidence of ovarian tuberculosis has declined due supplementary diagnostic tools for female genital tract
antituberculosis campaign and specific treatments, and it tuberculosis [86].
much more difficult to diagnose in women than is orchitis in

men, and there have been only a few cases of viral infection
of the ovaries that were documented histologically in women.
Cytomegalovirus oophoritis in three autopsy patients was
characterized by focal ovarian cortical necrosis with numer-
ous cytomegalic cells with viral cytopathic effect and a vari-
able but usually severe inflammatory reaction [88].
3.6 enign Cysts of Epithelial or Follicular

B
Origin
3.6.1 E
ndosalpingiosis, Cortical Inclusion
Cysts, and Simple Cysts
Fig. 3.66 TB necrotizing granuloma of ovary, medium power

Endosalpingiosis and cortical inclusion cysts are common
incidental findings within the ovarian cortex that are observed
in both pre- and postmenopausal women. The incidence
increases with age with predilection for postmenopausal
women [70]. Both endosalpingiosis and cortical inclusion
cysts typically present as small, simple, cystic structures
within the ovarian cortex which may be multiple and, if
detected by imaging, are innocuous in appearance [89].
More commonly, the cystic structures are noted at the time of
specimen examination or by microscopy. Rare cases of
mass-forming aggregates of cystic endosalpingiosis have
been reported [90]. Cortical inclusion cysts are likely to orig-
inate from ovarian surface epithelium, whereas endosalpin-
giosis is thought to be derived from misplaced fallopian tube
epithelium implanted onto the surface of the ovary by way of
injury, adhesions, or intraovarian endosalpingiosis [91, 92].
Supporting this notion, there appears to be two sources of
Fig. 3.67 TB necrotizing granuloma of ovary, high power ovarian epithelial inclusions that are morphologically and
immunophenotypically different: (1) fallopian tube cells
(Pax8+/calretinin−) and (2) ovarian surface epithelium
3.5.4 Other Infectious Disorders (Pax8−/calretinin+), with fallopian tube cells being the most
predominant source [91]. An alternative hypothesis is that
In addition to ovarian infections due to bacterial sexually endosalpingiosis is the result of metaplasia of multipotent
transmitted or non-sexually transmitted organisms, other par- peritoneal cells. With the recent discovery of a serous precur-
asitic, fungal, and viral infections involving the ovaries have sor in the fallopian tube epithelium giving rise to high-grade
also been rarely reported in the literature. The following para- serous carcinomas, it has been theorized that endosalpingio-
sitic or fungal pathogens may rarely cause ovarian infections sis of the ovary may represent a possible site of origin for
often due to secondary involvement in a systemic disease: either high-grade or low-grade serous carcinoma of the
schistosomiasis, enterobiasis, echinococcosis, blastomyces, ovary. The concept is based on studies showing that endosal-
coccidiomycosis, and aspergillus. Clues to the diagnosis pingiosis in the ovary displays the same immunohistochemi-
include a high index of suspicion, history of travel to endemic cal staining pattern shared by normal fallopian tube
area, and clinical history such as an immunocompromised epithelium [91, 93]. Cortical inclusion cysts, however, do not
state. Diagnosis requires histological identification of patho- typically share this association with fallopian tube epithe-
genic parasites or fungal forms. lium and have been shown to be mesothelial in origin. Both
Furthermore, extremely rare cases of acute oophoritis due cortical inclusion cysts and endosalpingiosis are benign,
to viruses such as from mumps and cytomegalovirus have incidental findings and, if detected clinically, should be man-
also been reported [87, 88]. However, acute oophoritis is aged conservatively with repeat imaging.
3.6.1.2 Pathology
Endosalpingiosis and cortical inclusion cysts are grossly
recognizable as cystic spaces within the ovarian cortex that
range in size from microscopic to up to 1 cm. The cyst con-
tent is watery, and the lining is smooth. Histologically, the
cyst lining of endosalpingiosis consists of a single layer of
fallopian tube-like epithelium, which is remarkable for cili-
ated, secretory, and intercalated cells (Figs. 3.68 and 3.69)
that are either Pax8 (secretory cells) or tubulin positive (cili-
ated cells) and calretinin negative by immunohistochemis-
try. In contrast, cortical inclusion cysts display a flattened
lining composed of mesothelial-like ovarian surface epithe-
lial cells (Fig. 3.70) that are positive for calretinin and nega-
tive for Pax8 [91]. Papillary projections of the epithelium
and associated fibromatous stroma are absent from both cyst
types. Rare cases of mass-forming endosalpingiosis have Fig. 3.70 Cortical inclusion simple cyst
been reported and consist of aggregates of thin-walled,
ultiloculated cysts lined by flat fallopian tube-like epithe-

m
lium with no associated solid component. By immunohisto-
chemistry, the lining cells of endosalpingiosis are also
positive for phospho-Smad2, BCL2 and FOXJ1, and WT1,
and those of cortical inclusion cysts are positive for WT1
and calretinin [93].

The main differential diagnosis includes serous cystade-
noma, serous cystadenofibroma, and endometriosis. Lack of
endometrial-type stroma and hemosiderin-laden macro-
phages would be helpful in the distinction from endometrio-
sis. Care should be taken to differentiate the flattened lining
of a serous cystadenoma from the mesothelial lining of a
cortical inclusion cyst. Cysts that are grossly greater than
1 cm and are lined by either fallopian tube-type cells or
Fig. 3.68 Cystic endosalpingiosis ovarian surface, flat to cuboidal, epithelial-type cells are
arbitrarily designated as serous cystadenoma or simple

(mesothelial) cysts, respectively.
3.6.2 Cystadenoma and Cystadenofibroma
Cystadenomas are cystic, ovarian mass lesions that are >1 cm

and that can be detected by imaging and clinically raise sus-
picion for malignancy. Grossly, cystadenomas may be uni-
locular and multilocular and contain papillary projections.
The outer ovarian surface is typically smooth. Cyst fluid may
be serous or mucinous. Similarly to endosalpingiosis or corti-
cal inclusion cysts described above, the cyst lining of serous
cystadenoma consists of a single layer of fallopian tube-like
epithelium, with ciliated, secretory, and/or intercalated cells.
Papillary projections of the stroma and/or associated fibroma-
tous stroma may be seen in serous cystadenofibromas. In con-
Fig. 3.69 Endosalpingiosis, high power trast, cyst lining of mucinous cystadenoma consists of a single
layer of mucinous epithelium with bland, basally located atretic follicular cysts, which are cysts derived from follicles
nuclei. By definition, significant cytological nuclear atypia or prior to ovulation. Alternatively, commonly encountered
architectural complexity is absent in cystadenomas. For addi- cysts are derived from corpus luteum after ovulation, such as
tional details regarding epithelial ovarian lesions and distinc- hemorrhagic corpus luteum, corpus luteal cysts, and corpus
tion between cystadenoma with borderline tumors, see also albicans cysts.
Chaps. 5–7.
3.6.4.2 Non-luteinized Follicle Cyst
3.6.3 Endometriotic Cyst (Endometrioma) Clinical Features

By definition, follicular cysts are greater than 3 cm in size.
The clinical and pathological features of endometriosis are These cystic changes may develop during the follicular
described elsewhere in the book (see also Chap. 12). Briefly, growth phase or in follicles undergoing atresia, usually sec-
an endometrioma is defined as a cystic lesion arising from ondary to endogenous follicle-stimulating hormone or exog-
endometriosis in the ovary. Endometriomas are estrogen- enous hormonal effect. These types of cysts are functional as
dependent and may be associated with chronic pelvic pain, they most often produce estradiol and they may involute
dysmenorrhea, dyspareunia, and/or infertility [94]. Grossly, spontaneously. An association between follicular cysts and
endometriomas are red to dark brown, hemorrhagic unilocu- tamoxifen use has also been reported [95]. Clinically, non-
lar cysts. Microscopically, the cyst lining is composed of luteinized cysts may have variable pre- and postpubertal pre-
endometrial-type tissue in the form of (1) endometrial-type sentations. Common presenting signs include lower
glands, (2) endometrial-type stroma, and/or (3) stromal abdominal pain, gastrointestinal-type or ovarian torsion-type
hemosiderin-laden macrophages. The presence of at least symptoms, or dysfunctional uterine bleeding due to estradiol
two out of the three components is required for the definitive production [96]. Treatment is typically a conservative man-
diagnosis. In the absence of the latter two components, the agement to preserve ovarian function.
epithelial lining of endometriosis should be differentiated
from the lining of endosalpingiosis or a serous cystadenoma, Pathology
since these are different diseases that have different clinical Grossly, follicle cysts are 3–10 cm in diameter with a smooth
presentations [70] and treatments [94]. For additional details thin lining surrounding a central cavity filled with serous-
regarding endometriosis, see Chap.12. proteinaceous material. Microscopically, these cysts resem-
ble the normal growing follicle with an inner granulosa cell
layer and outer theca cell layers (Fig. 3.71). The granulosa
3.6.4 Follicular Cyst cells are mainly small, with regular nuclei and an indistinct
rim of cytoplasm, while the theca cells are rounded to
3.6.4.1 Preovulatory Physiological Cystic spindled, sometimes with a prominent nucleus/nucleolus and
Follicles
During ovulation, physiological follicular development from
primordial to secondary, tertiary, and mature Graafian folli-
cle has been previously described in the beginning of this
chapter. Briefly, between days 1 and 7 of the follicular phase
of the menstrual cycle, primordial follicles develop into pri-
mary and secondary follicles. Of these follicles, a single
dominant tertiary follicle is selected to continue developing,
while the remaining primary follicles undergo atresia.
Between days 8 and 14 of the follicular phase, the dominant
tertiary follicle begins to undergo enlargement of the ovum,
with formation of the zona pellucida and proliferation of
granulosa cells and the formation of a central cavity. The
mature follicle immediately prior to ovulation is known as a
Graafian follicle and physiologically may reach up to
approximately 3.0 cm prior to ovulation. However, under the
influence of disordered function of the pituitary-ovarian axis,
preovulatory follicles may often undergo pathologic cystic Fig. 3.71 Non-luteinized follicular cyst: low power view of large
changes and develop into non-luteinized, luteinized, or dilated cystic cavity lined by a regular layer of granulosa cells
influence of human chorionic gonadotropin (hCG) during

pregnancy, thus giving rise to the so-called large solitary
luteinized follicle cyst of pregnancy and puerperium,
which has been described in detail earlier in the chapter
[28]. However, luteinized follicular cysts may also
develop in nonpregnant women de novo or as a result of
gonadotropin administration [97]. They present as a pal-
pable abdominal mass, vaginal bleeding, discomfort, and
abdominal pain. Additionally patients with large cysts
may mimic malignancy and are at risk for torsion [30].
Surgery may be necessary to remove large or persistent
cysts.
Pathology
Fig. 3.72 Non-luteinized follicular cyst: high power view demon- Luteinized cysts may be divided into granulosa-lutein cysts
strates normal granular cell layer four to five cells thick with surround- and theca-lutein cysts and are characterized by prominent
ing theca cell layer luteinization of the granulosa cell layer, the theca cell layer,
or sometimes both. The luteinization appears as larger cells
with increased amounts of eosinophilic cytoplasm; these
changes mimic those seen in the corpus luteum. Grossly,
these cysts are composed of large unilocular or multilocular
smooth-walled cysts that can grow in size up to 30 cm.
Granulosa-lutein cysts show luteinization of the granulosa
cell layer where the granulosa cells are characterized by an
increased amount of eosinophilic cytoplasm (Figs. 3.74 and
3.75). The distinction between granulosa and theca cell lay-
ers in these cases may be difficult to identify. Theca-lutein
cysts may also show an expansion of the theca cell layer,
characterized by large eosinophilic theca cells with a rela-
tively normal appearing overlying granulosa cell layer
(Fig. 3.76). The differential diagnosis includes other types
of ovarian cysts, such as endometriotic cysts and cystic
ovarian neoplasms.
Fig. 3.73 Non-luteinized follicular cyst: shedding of granulosa cells

into the center of the central cavity
an ample rim of eosinophilic to clear cytoplasm (Fig. 3.72).

The cyst walls are usually smooth and flattened without the
involutions present in luteal cysts. As these cysts involute,
the lining may become attenuated making it difficult to dis-
tinguish them from simple cysts. Shedding of granulosa cells
within the central cavity may be present as well depending
on the stage of the cyst (Fig. 3.73). The differential diagnosis
includes luteal-type cysts and other functional preovulatory
cysts as well as cystic granulosa cell tumors.
3.6.4.3 Luteinized Follicle Cyst
Clinical Features
Variable degrees of luteinization may be seen in follicular Fig. 3.74 Luteinized follicular cyst: prominent eosinophilic, granular
cysts. Luteinized follicular cysts may develop under the cell layer
Pathology
Grossly, these cysts may resemble their follicular counter-
parts. Microscopically, atretic cysts are characterized by
absence or degeneration of the granulosa cell layer and are
lined by an attenuated/degenerating cyst wall lining or nor-
mal ovarian stroma (Figs. 3.77 and 3.78). Within this stroma,
single or small groups of luteinized theca cells may be iden-
tified. The central cavity is often either compressed or
replaced by a central zone of loose connective tissue
(Fig. 3.79). Atretic cysts may histologically be indistinguish-
able from involuting follicles or small follicular cysts.
Fig. 3.75 Luteinized follicular cyst lining
Fig. 3.77 Early follicle with loss of antrum and early degenerative
changes
Fig. 3.76 Luteinized follicular cyst: expansion of luteinized theca cell

layer with prominent eosinophilic cytoplasm
3.6.4.4 Atretic Follicular Cyst
Clinical
Atretic follicular cysts may be found incidentally on oopho-
rectomy specimens and clinically are not associated with any
significant pathology. Atresia refers to the process of granu-
losa cell apoptosis under the influence of hormonal control
by multiple ligand-receptor pathways including the tumor
necrosis factor alpha, Fas, and other pathways. Both un-
luteinized and luteinized follicular cysts may undergo atretic Fig. 3.78 Atretic follicle cyst with loss of granular cell layers and
changes [10, 11]. attenuation of wall lining
Pathology
Grossly, the hemorrhagic corpus luteum is as a unilocular
cystic structure within the ovarian cortical parenchyma with
a yellow-orange cyst wall lining and contains a dark red cav-
ity composed of hemorrhagic material (Fig. 3.80). These
cysts may be multiple and, like the corpus luteum, may vary
in size. Microscopically, the cyst wall lining appears as a
convoluted layer of luteinized granulosa cells with an outer
layer of theca cells. The central cystic cavity is often filled
with red blood cells which may extravasate into the cyst wall
(Figs. 3.81 and 3.82). Small thin-walled vessels may
Fig. 3.79 Atretic follicles with degenerative changes and replacement

of central cavity by a myxoid fibrous stroma
3.6.5 Cysts Derived from Corpus Luteum
3.6.5.1 Hemorrhagic Corpus Luteum
Clinical Features
Following ovulation and prior to the formation of the true
corpus luteum, the corpus hemorrhagicum (“bleeding cor-
pus luteum”) may be formed when blood vessels supplying
the mature follicle rupture. The hemorrhagic corpus luteum
is composed of a cyst-like space with a central area of hem- Fig. 3.80 Hemorrhagic corpus luteum, gross
orrhage [98]. Corpus hemorrhagicum cysts are one of the
most commonly encountered types of ovarian cysts. They
are more often unilateral than bilateral and are encountered
in patients just after the ovulation period. These cysts can
be seen with increased frequency in patients undergoing
ovulation therapy for pregnancy, in various bleeding disor-
ders, or in patients who are on anticoagulation therapy [99,
100]. Clinically, patients with these cysts have variable pre-
sentations, often being asymptomatic or presenting with
abdominal pain [101]. In some cases, rupture of the cysts
can present as hemoperitoneum with signs of acute abdo-
men [102]. The differential diagnosis includes other com-
mon causes of abdominal pain in a female such as ovarian
torsion, ovarian cyst rupture, acute appendicitis, ectopic
pregnancy, infection, and malignancy. Most corpus hemor-
rhagicum cysts will spontaneously regress; however, some
cysts may require treatment. Excision is usually curative;
however, in some cases, an oophorectomy is required to Fig. 3.81 Hemorrhagic corpus luteal cyst showing large central cavity
stop the bleeding [103]. with blood and red blood cell extravasation into cyst wall
lutea, corpus luteum cysts produce progesterone and may

cause menstrual cycle irregularities if persistent. These
cysts may rarely cause hemoperitoneum if they rupture
when they are filled with blood (see hemorrhagic corpus
luteal cyst) [104].
Pathology
Grossly, corpus luteum cysts may range in size from 3 cm to
greater than 10 cm and contain clear fluid or blood. The cyst
wall lining is usually thin, convoluted, and yellow in color.
Microscopically, corpus luteum cysts resemble the normal
corpus luteum with increased convolutions of the cyst wall
which is composed of luteinized granulosa cells and theca
cells (Figs. 3.84 and 3.85). A small zone of vessels may also
Fig. 3.82 Hemorrhagic corpus luteal cyst: convoluted luteinized cyst be identified within the cyst wall (Fig. 3.85). The granulosa
wall lining involved by prominent hemorrhage cells are fully luteinized and are present singly or in clusters
depending on the stage of the cyst (Figs. 3.85 and 3.86).
Smaller peripheral clusters of theca-lutein cells may be iden-
tified residing within the cyst wall. Evidence of fresh hemor-
rhage, fibrin deposition, and sometimes organizing blood
Fig. 3.83 Hemorrhagic corpus luteal cyst showing a thin band of

fibrous tissue overlying the cyst wall lining at the interface with the Fig. 3.84 Low power view of corpus luteum cyst with focal area of
hemorrhagic cyst compartment hemorrhage
s ometimes be seen in association with the cyst lining. The

interface between the granulosa/theca cell layer and area of
hemorrhage is often sharply demarcated and may include a
thin lining of fibrous tissue at the cyst wall-blood interface
(Fig. 3.83).
3.6.5.2 Corpus Luteum Cysts
Clinical
Corpus luteum cysts are derived from corpora lutea which
form in the postovulatory period of the menstrual cycle.
Corpus luteum cysts will typically involute spontaneously
if fertilization does not occur but may sometimes persist if
Fig. 3.85 Corpus luteum cyst, medium power: Convoluted luteinized
they become filled with fluid or blood. Clinically they are cyst wall lining with focal areas of red blood cell extravasation and
nearly all asymptomatic. Similar to the normal corpora small vessels visible within the cyst wall
Fig. 3.86 Corpus luteum cyst, high power: fully luteinized cyst wall
lining
Fig. 3.87 Corpora albicans cyst with a hyalinized convoluted cyst wall
collections may be identified in association with a fibrous and central edematous cystic cavity
tissue reaction and hemosiderin-laden macrophages. The
cyst wall linings may become attenuated or obscured, and
the convolutions of the cyst wall may be lost when there is a
large amount of hemorrhage or fluid. The differential diag-
nosis includes luteinized follicular cysts as well as endome-
triotic cysts.
3.6.5.3 Corpora Albicans Cyst
Clinical
If pregnancy does not occur following the rupture of a mature
follicle during ovulation, the corpus luteum undergoes invo-
lution to create the corpora albicans. The corpora albicans
essentially represents an avascular scar, which is the remnant
of the reabsorbed mature ovarian follicle. The corpora albi-
cans is a solid, hyalinized structure; however, in some cases,
Fig. 3.88 Corpora albicans with cystic degeneration of the central
it may undergo cystic change with a central cavity filled with portion
clear fluid. Unlike follicular cysts, luteinized cysts, and cor-
pus luteal cysts, corpora albicans cysts tend to be small and
remain less than 1 cm in size. Clinically, these are nonfunc-
tional cysts, with few to no clinical signs or associated
pathology.
Pathology
Microscopically, corpora albicans cysts have a convo-
luted cyst wall lining composed of a thick band of acel-
lular hyalinized material similar to the normal corpora
albicans (Fig. 3.87). The cyst wall may have a thin layer
of fibrous tissue, a remnant of the degenerated corpus
luteum. The central cavity is often cystically dilated and
may be empty or filled with a faintly opaque edematous
liquid (Figs. 3.88 and 3.89). While calcifications may be
present in association with the corpora albicans, they are
less likely to appear in association with a corpora albi- Fig. 3.89 Corpora albicans cyst. High power view shows a hyalinized
cans cyst [105]. corpora albicans cyst wall lining with edematous clear liquid filling the
central cavity
3.7 Nonneoplastic Ovarian Enlargement
3.7.1 Massive Ovarian Edema

Massive ovarian edema represents a tumor-like condition in
which there is gross enlargement of one or both ovaries by
massive edematous fluid. The condition is thought to be
caused by partial or intermittent torsion of the ovary which
does not induce necrosis but compromises the lymphatic
drainage enough to produce the accumulation of fluid. Most
cases occur in 20–30-year-old women, although several
cases have been reported in young prepubertal girls [106– Fig. 3.90 Massive ovarian edema. Lower power shows the cortex of
the ovary with a myxoid appearance due to massive edema and a
110]. Clinically, patients present with a palpable abdominal peripheral rim of residual normal ovarian cortex
mass and abdominal pain. Less frequently, patients present
with menstrual disorders or with androgenic manifestations,
such as virilization and hirsutism. Massive ovarian edema
coexisting with polycystic ovarian syndrome, acute appendi-
citis, and leiomyomata has been reported in the literature
[106, 111]. A close association with ovarian fibromatosis has
been described as well, suggesting that massive ovarian
edema and fibromatosis may represent a spectrum of
response pattern to ovarian tissue injury (torsion or prior pro-
cedures) [108, 112]. A single case report of a combined
edematous/fibromatous lesion reported an association with a
CHOP gene translocation on chromosome 12q13-15 [112].
Radiological examination can show an enlarged ovary with
preservation of blood flow and peripherally placed follicles
and may be useful prior to surgery to help guide management Fig. 3.91 Massive ovarian edema. The peripheral ovarian cortex
[108]. Treatment of massive ovarian edema most often con- appears to have increased cellularity due to the edematous nature of the
sists of salpingo-oophorectomy. Intraoperative wedge resec- central cortex
tion combined with frozen section diagnosis (to exclude
neoplasia), detorsion/transfixation, and drainage of the ovary
may also be considered to conserve reproductive function in
younger women [110].
3.7.1.2 Pathology
Grossly, the ovaries are often enlarged to a size of 8–12 cm;
however they can grow to as large as 35 cm [106, 107, 109,
110]. The enlarged ovarian mass may exhibit a tan-white col-
oration and a tense external surface. On cut sections, the
stroma is white-gray in color with a weeping clear protein-
aceous fluid infiltrating the ovarian stroma. Microscopically,
the ovarian stroma becomes hypocellular and is replaced by
edematous clear fluid imparting a myxoid appearance. This
edema is more often located within the inner cortex, while the
periphery of the ovary tends to be more cellular (Figs. 3.90
and 3.91). The edematous fluid displays apart normal struc-
tures which may still be identified within the area of edema Fig. 3.92 Massive ovarian edema. Residual corpora albicans within
(Fig. 3.92). The vasculature and lymphatic vessels are often edematous changes
3.7.2 Ovarian Torsion and Infarction

Adnexal torsion is a gynecological surgical emergency
that can occur in the pediatric and adult population.
Although the presenting symptoms can be vague, the clini-
cal signs of ovarian torsion include acute lower abdominal
pain, nausea, vomiting, pelvic pain, or tenderness with or
without a palpable or adnexal mass [113, 114]. In the adult
population, ovarian or adnexal torsion typically results
from a complication of an ovarian or adnexal lesion, most
often a benign cyst or tumor and less likely a malignant
neoplasm [115]. The choice of the appropriate surgical
approach is challenging, as it is patient and age specific
Fig. 3.93 Massive ovarian edema. Edematous ovarian stroma and and includes possible detorsion with early presentation or
prominent lymphovascular channels surgical excision [114, 116].
3.7.2.2 Pathology
The underlying pathophysiology of ovarian torsion involves
torsion of the ovarian pedicle leading to reduced venous
return, stromal edema, internal hemorrhage, and infarction.
For this reason, grossly, the ovary may appear enlarged,
swollen, and replaced by a hemorrhagic or infarcted mass
Fig. 3.94 Massive ovarian edema. Edematous ovarian stroma showing

prominent lymphovascular channels
prominent, and there may be areas of intermixed normal ovar-

ian stroma (Figs. 3.93 and 3.94). Mixed chronic inflammatory
cells may be present within the edematous areas as well as
focal luteinized stromal cells. The ovarian stroma within the
edematous areas consists of widely spaced bland appearing
spindle to stellate cells with little to no mitotic activity [106].
The differential diagnosis of these lesions includes, but is not
limited to, ovarian fibromatosis, ovarian fibroma and fibroth-
ecoma, ovarian cystic lesions, stromal tumors, ovarian myxo-
mas, and other lesions with myxoid changes [107, 110]. Fig. 3.95 Ovarian torsion, gross outside surface
Fig. 3.96 Ovarian torsion, gross hemorrhagic cut surface
Fig. 3.98 Ovarian torsion with hemorrhagic infarction of follicular

cyst wall
Fig. 3.97 Ovarian torsion, intermittent or partial with hemorrhage

separating non-infarcted cortico-medullary stroma
(Figs. 3.95 and 3.96). Microscopically, partial or intermit- Fig. 3.99 Calcified foreign embolization material for uterine fibroids
in ovarian hilar vessels
tent ovarian torsion may result in massive ovarian edema,
which was previously described above in this chapter, or
hemorrhage separating non-infarcted normal structures 3.8 Incidental Findings
(Fig. 3.97). Alternatively, full torsion ultimately results in
hemorrhagic infarction of the ovary and of the underlying 3.8.1 Cortical Fibromatosis
cyst or neoplasm, if one is present (Fig. 3.98). Due to exten-
sive infarction, a definitive pathological diagnosis and clas- Prominent areas of cortical fibrosis, which are character-
sification of cyst or neoplasm may not always be possible; ized by replacement of ovarian cortical stroma by areas of
however, they are most often benign. The differential diag- abundant collagen deposition, can be seen in peri- and post-
nosis of torsion includes ovarian abscess and necrosis due menopausal ovaries as part of aging-related changes [1].
to ovarian vein thrombosis or due to ovarian artery occlu- Focal areas of cortical fibromatosis may also be seen in
sion following uterine artery embolization for leiomyomata reproductive age ovaries in the setting of polycystic ova-
[117–119]. Identification of thrombosis or foreign emboli- ries, cortical fibromas, or massive edema [120]. Cortical
zation material is required to make the latter diagnosis fibromatosis may morphologically resemble a small
(Fig. 3.99). fibroma (Figs. 3.100 and 3.101); however, the distinction
Fig. 3.100 Cortical fibromatosis, low power Fig. 3.102 Benign mesothelial proliferation within ovarian surface
adhesions and hemosiderin deposition
Fig. 3.101 Cortical fibromatosis, high power

Fig. 3.103 Benign mesothelial proliferation with papillary
architecture
from an ovarian fibroma is made by the presence of a >1 cm

grossly or radiologically visible, well-circumscribed mass (Fig. 3.102), similar to the spectrum of florid mesothelial
in patients with a fibroma. proliferations of the testicular tunica vaginalis [121]. In
addition, another common pattern of mesothelial prolifera-
tion is composed of surface micropapillary projections com-
3.8.2 Mesothelial Proliferation prised of stromal or fibrotic cores and lined by
mesothelial-like ovarian surface epithelium (Fig. 3.103).
Similar to other mesothelial-lined surfaces, the ovarian sur- Factors that may predispose to mesothelial hyperplasia
face and/or periovarian adhesions may exhibit a reactive include pelvic inflammation, a large primary ovarian mass,
mesothelial hyperplasia, in some cases florid, which may torsion or infarction, ascites, and endometriosis [122]. The
mimic neoplasia. These benign mesothelial proliferations differential diagnosis of a benign mesothelial proliferation
are characterized by small nests, cords, and gland-like, includes invasive or metastatic ovarian tumor and cystic or
sheet-like, or nest-like arrangements of mesothelial cells papillary mesothelioma.
3.8.3 Artifacts of Granulosa Cells 3.9 Other Rare Disorders
Benign granulosa cells may cause diagnostic confusion 3.9.1 R

esidual Ovarian Syndrome (Ovarian
and mimic malignancy in two scenarios: (1) artifactual Remnant Syndrome)
displacement of granulosa cells in ovarian lymphovascu-
lar channels and/or fallopian tubes and (2) tangentially 3.9.1.1 Clinical Features
sectioning of a developing and maturing cystic follicle. In Residual ovarian syndrome, also known as ovarian remnant
the first scenario, artifactual vascular displacement of syndrome, refers to a condition occurring in women who
granulosa cells within the ovary is thought to be second- have persistent ovarian tissue that was unintentionally left
arily related to surgical procedure, to specimen manipula- behind in the patient after a bilateral oophorectomy. As a
tion in the pathology laboratory, or to ovulation. In this result of this residual ovarian tissue, patients most frequently
situation, cohesive groups of benign inhibin- or calretinin- present with pelvic pain and/or a pelvic mass, possibly many
positive, mitotically active granulosa cells can be identi- years after bilateral oophorectomy [126]. Risk factors for
fied in either ovarian lymphovascular spaces or within residual ovarian syndrome include a history of endometrio-
fallopian tube lumen and stroma [123–125]. The displaced sis, pelvic inflammatory disease, multiple previous surgeries,
granulosa cells may mimic an adult granulosa cell tumor, and pelvic adhesive disease, all of which may be associated
a high-grade carcinoma such as small cell carcinoma or an with incomplete removal of an ovary during initial oophorec-
immature teratoma. Premenopausal age, the presence of tomy [127]. The recommended treatment for residual ovar-
an associated follicle with similar cells, and absence of ian syndrome is surgical excision of residual ovarian tissue
mass lesion to suggest a tumor are helpful in confirming and/or pelvic mass.
the artifactual lymphovascular displacement of benign
granulosa cells. 3.9.1.2 Pathology
In the second scenario, tangential sectioning of a develop- Definitive criteria for diagnosis of residual ovarian syndrome
ing follicle in the ovary may mimic a small adult granulosa include a history of bilateral oophorectomy with histological
cell tumor, either during intraoperative frozen section con- documentation of ovarian tissue obtained during subsequent
sultation or on permanent sections. In this situation, a solid surgical excision. Pathological examination may reveal
or cystic population of granulosa cells with bland nuclear ovarian-type stroma, follicles, corpus luteum, or an ovarian-
features may be seen in the ovarian stroma (Fig. 3.104). The type tumor (Figs. 3.105 and 3.106), with or without associ-
presence of a surrounding theca cell population and obtain- ated endometriosis or fibrous adhesions. If a pelvic mass is
ing additional tissue levels may be helpful in confirming the present, care should be taken to exclude possible malignant
diagnosis of a developing cystic follicle instead of an adult transformation of residual ovarian tissue and/or associated
granulosa cell tumor. endometriosis.
Fig. 3.105 Ovarian remnant syndrome. Ovarian-type fibroma present-

ing as a pelvic mass in a patient 12 years after a total hysterectomy and
Fig. 3.104 Tangentially sectioned follicle bilateral salpingo-oophorectomy
Fig. 3.106 Ovarian remnant syndrome. Cortical-type stroma identi-

fied within pelvic mass of same patient
Fig. 3.107 Uterus-like adnexal mass, low power
3.9.2 Uterus-Like Adnexal Mass

Uterus-like adnexal mass is a rare condition that typically
presents as an ovarian or adnexal mass that is discovered
incidentally or in the setting of abdominal pain. Rarely, it
has been associated with elevated CA-125, raising clinical
suspicion for ovarian malignancy; however, increased
CA-125 may occur in the setting of similar benign processes
such as endometriosis [128]. Imaging typically shows a
well-defined, thick-walled, cystic mass associated with the
ovary or adjacent adnexal structures. The cyst may be mul-
tiloculated or have a solid component [129]. The origin of
uterus-like adnexal mass is controversial with two coexist-
ing theories. The first is that uterus-like adnexal mass repre-
sents a congenital anomaly of the Müllerian tract, as it has Fig. 3.108 Uterus-like adnexal mass, medium power
been described in association with genitourinary anomalies
and malformation of the uterus [130, 131]. The second is the mass should be well circumscribed with a thick muscu-
that uterus-like adnexal mass is derived from metaplasia of lar wall surrounding cystic spaces lined by rough, hemor-
the ovarian surface in association with foci of endometrio- rhagic tissue like that lining the endometrial cavity. The
sis. This theory is supported by the presence of myofibro- cyst may be complex with septations or solid portions. Cyst
blasts within the ovarian stroma, which have been shown to content is thick and brown as is seen in an endometriotic
undergo smooth muscle metaplasia [132]. In addition, the cyst. Residual ovarian stroma may be present. Histologically,
majority of cases have been diagnosed in the absence of the cyst wall is composed of bundles of smooth muscle
associated congenital anomalies of the Müllerian and geni- with associated fibroconnective tissue and large muscular
tourinary tract. Proponents of this model prefer the term blood vessels as seen in native myometrium. The cyst cav-
“endomyometriois” rather than uterus-like adnexal mass to ity is lined by endometrial tissue including endometrial
describe this entity. stroma and glands associated with a prominent smooth
muscle component (Figs. 3.107, 3.108, and 3.109). The
3.9.2.2 Pathology smooth muscle component is positive for smooth muscle
Uterus-like adnexal mass has been reported to range in size actin, desmin, and vimentin. The endometrial glands are
from 4 to 13 cm in greatest dimension. By gross e xamination, positive for cytokeratin and epithelial membrane antigen,
Fig. 3.109 Uterus-like adnexal mass, high power
Fig. 3.110 Ovary with non-necrotizing granuloma. A giant cell with

and the endometrial-type stroma is positive for CD10. Both asteroid body suggestive of sarcoidosis is present on the right side
the smooth muscle and endometrial lining are positive for
estrogen and progesterone receptors.

The differential diagnosis includes extrauterine adenomy-
oma and smooth muscle metaplasia of ovarian endometrio-
sis. Extrauterine adenomyoma is mass forming with a
prominent smooth muscle component, but it does not show
uterus-like organization that is seen in uterus-like adnexal
mass. Smooth muscle metaplasia is a relatively common
finding in ovarian endometriosis (up to 17% of endometrio-
sis cases in one study), but this process is typically focal and
not mass forming [132].
3.9.3 S
econdary Ovarian Involvement
by Systemic Disorders
Fig. 3.111 Ovary with non-necrotizing granuloma due to polarizable
Rarely, the ovary is a site of secondary involvement by sys- foreign material. The patient had a history of abdominal myomectomy
years prior to oophorectomy
temic disorders, and ovarian involvement is usually an inci-
dental finding in women with systemic disease. For
instance, systemic inflammatory disorders such as sarcoid- scleroderma; or (3) amyloid deposition in the ovaries with
osis, Crohn’s disease, or vasculitis have been reported in systemic amyloidosis [137, 139, 140]. Clinical history and
the literature to secondarily involve the ovary [133–137]. In pathological correlation are helpful in identifying second-
addition, systemic amyloidosis and systemic storage disor- ary involvement by these disorders. The main differential
ders involving the ovary have also been reported [138, diagnosis of non-necrotizing granulomas in the ovary is a
139]. Patients may present with a tumor-like ovarian mass, foreign body reaction to exogenous material (Figs. 3.110
uterine bleeding, and constitutional symptoms such as and 3.111), often suture material introduced from a previ-
fever. Microscopically, features in the ovary are similar to ous operative procedure, to keratin from a teratoma or to
morphological changes seen in other organ systems. This is refractile crystalline material of uncertain origin [140]. In
illustrated by the presence of non-necrotizing granulomas the differential of ovarian necrotizing granulomas due to
in the ovary in cases of secondary involvement by either systemic disease, an infectious oophoritis process with
(1) systemic sarcoidosis or Crohn’s disease; (2) vasculitis abscess formation and necrotic pseudoxanthomatous nodu-
involving ovarian hilar or adnexal vessels in cases of lar inflammation due to endometriosis must also be
systemic giant cell arteritis, polyarteritis nodosa, and
excluded [141].
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Ovarian Epithelial Carcinogenesis
4
Jing Zhang, Elvio G. Silva, Anil K. Sood, and Jinsong Liu
Abstract · ovarian inclusion cyst · p53 signature · polyploid giant

The mortality rate of epithelial ovarian carcinoma (EOC) cancer cells (PGCCs) · secretory cell expansion · seromu-
ranks the highest in all gynecological malignancies, cinous carcinoma · serous tubal intraepithelial carcinoma
although it is the third common cancer in the female · somatic blastomere · the dualistic model of ovarian car-
reproductive system. In spite of the progress in reductive cinogenesis · the secondary Müllerian system · the somatic
surgery and the extensive applications of platinum and blastomere model · TP53 mutation · tumor progression ·
paclitaxel and the other first-line chemotherapeutic drugs, undifferentiated carcinoma · Walthard cell nests
the 5-year survival rate of EOC patient is improved merely
from 36% in 1975 to 46% in 2011 [1]. The reason is that
the definitions and carcinogenetic mechanisms closely The mortality rate of epithelial ovarian carcinoma (EOC)
related to EOC remain poorly understood. For over a ranks the highest in all gynecological malignancies, although
decade, the rapid development of molecular genetics pro- it is the third common cancer in the female reproductive sys-
vides a new foundation for our understanding of ovarian tem. In spite of the progress in reductive surgery and the exten-
epithelial carcinogenesis. In the current chapter, we will sive applications of platinum and paclitaxel and the other
focus on the cell origin, pathogenesis, molecular genetics, first-line chemotherapeutic drugs, the 5-year survival rate of
and clinical applications of different EOC histological sub- EOC patient is improved merely from 36% in 1975 to 46% in
types to improve our understanding of this deadly disease. 2011 [1]. The reason is that the definitions and carcinogenetic
mechanisms closely related to EOC remain poorly under-
Keywords stood. For over a decade, the rapid development of molecular
Brenner tumors · cancer stem cell · carcinogenesis · clear genetics provides a new foundation for our understanding of
cell carcinoma · endoreplication · endocycle · endometri- ovarian epithelial carcinogenesis. In the current chapter, we
oid carcinoma · endometriosis · endomitosis · epithelial will focus on the cell origin, pathogenesis, molecular genetics,
ovarian carcinoma · epithelial-mesenchymal transition and clinical applications of different EOC histological sub-
(EMT) · fere ex nihilo model · high-grade serous carci- types to improve our understanding of this deadly disease.
noma · immune checkpoint · intraepithelial carcinoma ·
low-grade serous carcinoma · malignant mixed Müllerian
tumors (MMMT) · mesenchymal-epithelial transition 4.1 he Models of Ovarian
T
(MET) · mucinous carcinoma · ovarian epithelial inclusion Carcinogenesis
J. Zhang Several theories have been proffered on the origins of ovarian

Department of Pathology, Xijing Hospital, The Fourth Military cancer. Most intriguing are the theories on ovarian surface epi-
Medical University, Shaanxi, People’s Republic of China thelial metaplasia, the secondary Müllerian system, the dualistic
E. G. Silva · J. Liu (*) model of ovarian carcinogenesis, the fere ex nihilo model, and
Department of Pathology, The University of Texas MD Anderson the recently described role of polyploid cells in tumor initiation
Cancer Center, Houston, TX, USA
and progression. Ovarian epithelial metaplasia is a classic the-
ory of EOC, but it is difficult to find the transformation between
A. K. Sood
ovarian surface epithelium (OSE) and carcinoma. Analogously,
Gynecologic Oncology and Reproductive Medicine,
The University of Texas MD Anderson Cancer Center, although the second Müllerian system theory is well-known, the
Houston, TX, USA progression process of EOC also cannot be confirmed.
122 J. Zhang et al.
Therefore, these two theories have become less popular in 3. The unknown origin of OEI: Some epithelial cells in OEI
recent years. On the other hand, the dualistic model of ovarian exhibit the differentiation toward fallopian tube epithe-
carcinogenesis is among most discussed model in past decade. lium, rather than OSE.
However, ovarian cancer can be potentially have multiple cell 4. Different histomorphology: There are no obvious histo-
origins, and the malignant transformation may be achieved via logical transitions between mesothelial cells and
formation of tetraploidy or polyploidy as an intermediate stage Müllerian epithelium.
and followed by amitosis rather mitosis to generate genetically
aberrant stem cells for cancer initiation. In order to better under- In addition, the histological observations on the ovaries
stand the overall landscape of ovarian carcinogenesis, we will from the carriers with hereditary BRCA mutation or contra-
discuss each of cell origins and mechanisms involved in tumor lateral normal ovary of sporadic EOC reveal that the mor-
progression in light of the most recent research progress. phological changes (hyperplastic papillae on the ovarian
surface, the increase and dilatation of cortical inclusion
cysts, and mild cell atypia) are not sufficient to achieve the
4.1.1 The Ovarian Surface Epithelial Cells diagnostic criteria for precancerous lesions. For all of the
abovementioned reasons, this theory has become less popu-
This theory is based on the speculation that all ovarian epithe- lar in the past two decades.
lial tumors originate from OSE. The OSE represents mesothe-
lial-like cells and is configured as a single layer of stable
epithelium without prominent differentiated characteristics in 4.1.2 The Secondary Müllerian System
the general state. They possess two potentials that differentiate
into mesenchymal cells or epithelial cells, called epithelial- At the early stage of embryogenesis, the somatic epithe-
mesenchymal transition (EMT) or reversal of this process lium and its subepithelial mesenchyme are derived from
named mesenchymal-epithelial transition (MET). As one of the Müllerian ducts. During the embryonic development,
the normal physiological functions, EMT/MET plays a vital the distal parts of the two Müllerian ducts (also known as
role in regulating the OSE repair process after ovarian ovula- the primary Müllerian system) fuse to form the uterus, cer-
tion [2]. The imbalance of EMT/MET is suggested to be a vix, and proximal one third of the vagina, while the proxi-
possible mechanism in the initiation of EOC. In this hypothe- mal Müllerian ducts remain separated to become the two
sis, ovarian epithelial inclusion (OEI)/inclusion cyst (OIC) is fallopian tubes [5]. The mucosal epithelium lining on those
formed via OSE invagination. These OEIs may transform into sites is called the Müllerian epithelium. Indeed, the ovaries
Müllerian epithelial cells via metaplasia and give rise to differ- do not belong to the Müllerian system because the gonads
ent histological types (e.g., serous, endometrioid, clear cell, and reproductive tract are developed separately in embry-
mucinous and transitional cells) under the influence of local onic stage.
factors (such as steroid hormones). Their morphologies are In view of the similarity between ovarian epithelial tumors
parallel to the mucosa of fallopian tube, endometrium, gastro- and Müllerian epithelium, Lauchlan [6] put forward the sec-
intestinal tract or endocervix, and bladder, respectively. These ond Müllerian system theory in 1972, which is that the coe-
OEIs with Müllerian phenotype further gain the ability for lothelium has an ability to transform into the Müllerian
malignant transformation and to progress to corresponding epithelium. Taking this ability into consideration, he further
EOCs (serous carcinoma, endometrioid carcinoma, mucinous suggested that OSE, OEI, and all extraovarian Müllerian-
carcinoma, or other subtype) with lineage infidelity via an type epithelial tissues adjacent to fallopian tube and pelvic
abnormal regulation of homeobox (HOX) gene [3]. In this cavity are part of the second Müllerian system. The second
process of tumor transformation, both OEIs and cancer cells Müllerian system includes endometriosis, endosalpingiosis,
show the changes that cells gradually lose the characteristics and endocervicosis, which are collectively referred to as
of mesenchymal cells and obtain different Müllerian epithelial Müllerianosis. With his comprehensive understanding of the
differentiated features, including the expression of specific morphologic features of these lesions, Dr. Lauchlan thought
epithelial marker (E-cadherin) in the differentiated stage [4]. that these three lesions can change into each other through
However, the theory has been challenged in the several metaplasia and thus that all epithelial tumors in the ovary and
aspects: pelvic cavity can be potentially derived from the second
Müllerian system.
1. Different cells of origin: OSE belongs to the coelothelium Similar to OSE metaplasia theory described above, the
(mesothelial cells), rather than Müllerian epithelium. The secondary Müllerian system theory cannot entirely account
histotypes of EOCs primarily show differentiation toward for other observations on ovarian carcinogenesis and accord-
Müllerian, rather than mesothelial cells. ingly has become less popular in recent years. However, it
2. Discrepancy in immunophenotype: OSE does not express remains a potential cell of origin for extraovarian or pelvic
common EOC markers (such as PAX-8), but highly Müllerian epithelial tumors, especially low-grade lesions
express calretinin and the other mesothelial markers. (type I) as described below.
4 Ovarian Epithelial Carcinogenesis 123
4.1.3 The Dualistic Model Table 4.1 The comparison between type I and type II epithelial ovar-
ian carcinomas [9]
In recent years, data have accumulated on the histological Type I epithelial ovarian Type II epithelial
carcinomas ovarian carcinomas
observation and molecular genetic levels demonstrated that
Histologic features
EOCs are heterogeneous diseases with several histological
Histological Low-grade serous High-grade serous
subtypes with different cells of origin, pathogenesis, and types carcinoma, carcinoma,
clinical biological features. Kurman and colleagues pro- endometrioid undifferentiated
posed the “dualistic model” of ovarian carcinogenesis, i.e., carcinoma, clear cell carcinoma, malignant
carcinoma, mixed Müllerian
EOC could be classified as type I and type II tumors based on
seromucinous tumors
their distinct set of clinicopathologic features [7–9]. carcinoma, mucinous
Type I EOCs include low-grade serous carcinoma, endo- carcinoma, malignant
metrioid carcinoma, clear cell carcinoma, seromucinous car- Brenner tumors
cinoma, mucinous carcinoma, and malignant Brenner Tumor grade Low-grade (except High-grade
clear cell carcinoma)
tumors. In the genesis, these carcinomas often follow a
Proliferation Usually low Usually high
sequential pattern of evolution from benign to borderline to activity
malignant tumors. Clinically, these tumors grow slowly and Clinical features
most of them have an indolent biological behavior; most are FIGO stage Usually early stage Usually advanced
confined to one ovary at presentation. All histological sub- (FIGO I) stage (FIGO III and
types of type I EOCs are low-grade tumors, and the progno- FIGO IV)
Clinical process Slow and indolent Rapid and aggressive
sis is relatively good, with the exception of clear cell
Response to General Good (but late
carcinoma. The mortality rate accounts for only 10% of all chemotherapy recurrence)
EOCs. The tumor genomes are relatively stable at the molec- Progress course Benign to borderline to Mostly from serous
ular genetic level, although there are different genotypes in malignant tumors tubal intraepithelial
different histological types (see Table 4.1) [9]. carcinoma
Type II EOCs include high-grade serous carcinoma, Early screening Feasible Difficult
Prognosis Relatively good Relatively poor
undifferentiated carcinoma, and malignant mixed Müllerian
Genetic features
tumors (MMMT, also called carcinosarcoma). Clinically,
Chromosomal Low High
these tumors are highly aggressive and rapidly progressive. instability
All histological subtypes of type II EOCs belong to high- Common gene KRAS, BRAF, PTEN, TP53, BRCA1/2
grade tumors. More than 75% of cases are diagnosed at mutation ARID1A, PIK3CA,
advanced stage (FIGO III and IV) with extensive dissemina- CTNNB1, ERBB2,
PPP2R1A
tion. The prognosis is poor and the mortality rate accounts
Deficiency of Rare Common
for 90% of all EOCs. In the molecular genetics, these tumors homologous
have highly unstable genomes and prone to have the amplifi- recombination
cation or deletion of DNA copy numbers. Among them, repair proteins
TP53 gene mutation is most common (>95% of high-grade
serous carcinoma) (Table 4.1) [9].
could be the origin of high-grade serous carcinoma, and both
stromal-epithelial interaction and steroid hormones play critical
4.1.4 The Fere Ex Nihilo Model roles in tumorigenesis and progression [11].
The stem cells are defined as a subgroup of cells with dif-
The dualistic model of ovarian carcinogenesis helps in our ferentiation potential and the ability for self-renewal. Under
understanding of EOCs and may even provide a frame work to certain conditions, these cells can differentiate into a variety of
guide clinical decision-making. However, this model may be functional cells. It has been reported that both OSE and ovar-
too simplified for such a highly heterogeneous group of dis- ian cancer cell are capable of expressing stem cell markers
eases. For example, even among high-grade serous carcinomas, such as SOX2 [12], CD133 [13], and NANOG [14]. The small
the tumors have different clinical biological behaviors [10]. In populations of stem cells, which possess the features of stem
particular, Silva raised several questions that argue against fal- cell or mimic stem cells, are predominantly located in hilar
lopian tube theory for pelvic serous carcinoma (see Sect. OSE in mouse model. The hilum OSE are cycling slowly and
4.2.1.2). Toward this end, Silva put forward the fere ex nihilo express stem cell markers ALDH1, LGR5, LEF1, CD133, and
model (or out of nothing) from unremarkable primitive or early CK6B [15]. Therefore, those OSE cells or other stromal cell
epithelial or mesenchymal stem cells: this model hypothesizes types that express stem cell markers can potentially be the cell
that uncommitted or stem cells from the mesenchyme could be of origin of benign and malignant ovarian tumors [16, 17].
a potential source of transformation for both benign and malig- Evidence supporting this view includes the development
nant tumors. During this process, stromal fibroblasts, via MET, of benign epithelial neoplasms of the ovaries from guinea
124 J. Zhang et al.
pigs following treatment of testosterone and estrogenic hor- of mitotic spindle. There are two kinds of endoreplication.
mones [18, 19]. Inflammation is a well-known risk factor for The first form is called the endocycle, which consists of
ovarian cancer, as may occur in ovulation, which causes the alternating DNA synthesis (S) phases and gap (G) phases
rupture of OSE and a repair process, resulting in pelvic foci of without chromosome segregation during a mitotic (M) phase
inflammatory microenvironment. Using SV40 T/t antigen to or cell division (cytokinesis). The developmentally con-
disable to ovarian surface epithelial cells together with onco- trolled endocycle results in cells with a single polyploid
gene RAS, Liu’s laboratory has successfully been able to nucleus and no feature of mitosis to support specific need of
transform the normal ovarian epithelial cells into high-grade development [35–39]. Another form of endoreplication is
Müllerian carcinoma, which is associated with massive known as endomitosis, in which cells execute an abortive
upregulation of inflammatory cytokine (e.g., interleukin-1β, mitosis that does not result in fully separate sister chromatids
interleukin-6, and interleukin-8) [20]. Through the chemo- or cell division, followed by subsequent re-entering of S
kines and cytokines secreted by cancer cells, for example, phase to generate multinucleated cells [36–39]. Endocycle
Gro-1 can induce stromal fibroblast senescence [21]. CXCR2 and endomitosis can be mixed, and the distinction between
and interleukin-1β promote tumor cell proliferation [22, 23]. the two forms may be context development depending on
The close interaction among tumor cells, stromal cells, and specific type of development.
inflammatory tumor microenvironment provides a favorable Polyploid giant cancer cells (PGCCs), characterized by a
condition for tumor cell recruitment, adhesion, migration, sur- single, giant nucleus or multinucleated cells, are commonly
vival, and colonization [24, 25]. The fact that OSE can be trans- found in tumor tissues with high-grade carcinoma or after
formed into high-grade Müllerian carcinoma provides further treatment (such as chemotherapy, radiotherapy, or targeted
support that the OSEs can be also the potential cells of origin for therapy) [40–42]. PGCCs have a distinct advantage over regu-
high-grade carcinoma. lar cancer cells in dealing with stresses (e.g., hypoxia, starva-
tion, temperature, pH, and diet conditions in physiologic
stresses; drugs and radiation in pathologic stresses) and repro-
4.1.5 Somatic Blastomere Model duction [35–39]. Increasing DNA content by endoreplication
is a widely utilized effective mechanism to sustain the mass
The above theories described the cell of origin for ovarian production of proteins and high metabolic activity necessary
cancer. However, it remains unknown how the cells are transfor tumor growth. Following endoreplication, cancer cells
formed into carcinoma. The most accepted paradigm in car- may thus arrest the mitotic cell cycle and allow the cell to sur-
cinogenesis is an accumulation of genetic mutations or vive during mitotic catastrophe or genotoxic stresses and enter
aneuploidy [26, 27]. However, these theories at the individ- endoreplication cell cycle to form PGCCs [30, 43–45].
ual gene or individual chromosomal levels cannot entirely Accumulating evidence suggests that PGCCs may have
account for enormous genomic and epigenetic changes played a fundamental role in tumor initiation. They may have
detected by The Cancer Genome Atlas (TCGA) projects in hijacked normal embryonic developmental program to facili-
high-grade carcinomas [28]; it has been argued that somatic tate the generation of new diploid cancer initiating cells in
mutation theory may be wrong for most cancer [29]. In addi- response to oncogenic and therapeutic stress [30, 45]. Our
tion, all of the four models described above fail to consider laboratory has provided the first experimental evidence that
the level of differentiation as reflected in the level of malig- normal ovarian or fallopian tubal epithelial cells and cancer
nancy in different histotypes. Recently, we have proposed a cells can undergo endoreplication [42, 46]. This process can
unified somatic blastomere model to explain the origin of all lead to genomic instability and dedifferentiation into more
cancers and disease relapse [30]. This model is based on primitive state, to facilitate the reprogramming and emer-
long-term and puzzling observation that early blastomere gence of new cancer initiating cells. We have shown that this
stage embryo is highly chaotic [31] with high frequency of multistep reprogramming process includes four distinct but
polyploidy [32, 33]. The endoreplication and cell fusion are overlapping process including initiation, self-renewal, termi-
required for development from blastomere to compaction/ nation, and stability and facilitating normal or cancer cells to
morula stage embryo, which is required for the first differen- be reprogrammed to cancer cells or resistant cancer cells
tiation event to become trophoblasts and inner cell mass fol- [45]. The mitotic apparatus for well-known mitotic division
lowing fertilization [34]. Unlike the mitotic cell cycle, which is shut down with activation of senescence program in the
involves several distinct phases including DNA synthesis (S) giant cell cycle; emergence of new tumor initiating cells is
and distribution of replicated DNAs to two identical daugh- largely from amitotic separation from giant mother cells
ter cells via mitosis (M) with the intervening gap phase (G), including budding, splitting, and branching, the more primi-
endoreplication represents a specific process in which tive mode of cell division used in fungi [42, 45]. Unexpectedly,
nuclear membrane does not break down while the genome is endoreplication of ovarian cancer cells recapitulates the divi-
replicated twice or multiple times without cell division and sion and growth pattern of blastomere stage embryo to form
subsequently separated into daughter cells without formation compaction and morulae-like embryonic cell types, which is
associated with massive mitotic and cytokinesis failure and tumor). The closer toward the embryonic stage, the higher
genomic instability [30]. Moreover, the endoreplicating cells developmental potential to allow the tumor to behave in
recapitulate the morphology and spatial and time-dependent malignant manner [30]. Thus, it is possible that high-grade
activation of embryonic reprogramming factor OCT4/ serous carcinoma or the other EOCs, particularly those can-
NANOG/SOX2, capable of differentiation into three germ cers with marked nuclear atypia, may be achieved via the
layers and develop into malignant germ cell tumors [30]. giant cell cycle-mediated reprogramming following the re-
Formation of tetraploidy or polyploidy is a common feature differentiation and followed by developmental arrest [30, 42,
at the border of normal epithelial cells and mesenchymal and 45]. This model also offers a sensible explanation why high-
high grade carcinoma, which is associated with activation of grade serous carcinoma is usually detected in late stage with
senescence and dedifferentiation program and stem cell acti- wide dissemination in the peritoneal cavity. The schematic
vation, supporting the generality of our model to other types diagram on how epithelial or mesenchymal cell is trans-
of cancer [47]. Further, formation of polyploidy appears to formed into cancer cells via the giant cell cycle is shown in
be a major mechanism in response to starvation or mitotic Fig. 4.1. The details on the role of the PGCCs and the giant
insult in Drosophila [48]. Subsequent generation of intestinal cell cycle in tumor initiation and disease relapse can be found
stem cells from polyploidy cells is associated amitosis, a in recent review by Liu [47].
primitive form of cell division without using mitotic spindle
[48]. Taken together, the above data together provide a previ-
ously appreciated mechanism via formation of polyploid 4.2 he Cell Origin and Molecular Genetic
T
cells for generating genetically altered daughter stem cells in Profiles
response to acute or chronic insults using primitive mode of
cell division for cancer initiation [47]. During the past decade, it has become clear that some high-
Our model also explains the level of differentiation grade serous carcinomas arise from the mucosal epithelium
observed in the ovarian cancer. Depending on the level of of fallopian tube fimbria [49–51]. In addition, significant
stem cell arrested at the specific developmental hierarchy progress has also been made in the cell origin of the other
during organ development, the tumors could behave in subtypes of EOCs. These progresses will help out our under-
benign or low-grade type of malignancy such as cystade- standing on the origin of EOC and offer a new potential strat-
noma or borderline tumor or high-grade carcinoma (type II egy for treatment and early screening.
a b1 b2 c d
Initiation Self-renewal Termination Stability

(mitosis/ (Enreplication/ (Endomitosis)
cytokinesis Endocycle)
failure)
Fig. 4.1 A schematic diagram of somatic blastomere-like model for facilitate the genomic reorganization and reprogramming. With the ter-
how normal fallopian tubal and ovarian epithelial cells are transformed mination of the giant cell cycle via endomitosis to form early tumor
into high-grade serous carcinoma. Normal fallopian tubal cells (or ovar- papillae (c), multiple tumor papilla with different genetic and epigenetic
ian epithelial cells or stromal fibroblasts) (a) the nucleus starts endorep- changes together generated via amitotic endoreplication division. In this
lication due to mitotic/cytokinesis failure; (b) endoreplicating cells grow process, the clone(s) with advantageous p53 mutations achieve the sta-
autonomously (self-renewal, b1 and b2) and lead to genomic chaos and ble tumor expansion and develop into high-grade serous carcinoma (d)
126 J. Zhang et al.
4.2.1 Ovarian Serous Carcinoma directly detach and adhere to the ovarian surface, it is possible
that the tubal OEIs may be formed via the shedding and
Serous carcinoma is the most common histological subtype invagination of tubal mucosal epithelium into the ovarian cor-
of ovarian epithelial tumors. It represents a heterogeneous tex. Interestingly, the different proportional distribution of
group of tumors at both morphology and molecular genetics mixed ciliated and secretory cells has been found in the tubal
and exhibits a typical dualistic model of ovarian carcinogen- OSEs, tube OEIs, serous cystadenomas, and borderline
esis. In 2004, based on the systematic analysis of histology tumors, with a remarkably increasing secretory/ciliated cell
and clinical behavior with more than 10-year follow-up, ratio in the low-grade serous carcinoma, suggesting that tubal
Malpica et al. [40] at MD Anderson Cancer Center first epithelial cells could be the potential origin of these tumors.
proposed a two-tier system for grading ovarian serous carci- In the 2014 WHO classification, ovarian borderline serous
noma. Namely, ovarian serous carcinoma is classified as tumors are further divided into two types, namely, serous
low-grade and high-grade. This grading system is currently borderline tumor/atypical proliferative serous tumor and
widely used and is accepted by the WHO classification of borderline serous tumor-micropapillary variant/noninvasive
gynecological tumors [52, 53]. Although they are in the same low-grade serous carcinoma. Both of them have the same
category of serous carcinoma, low-grade serous carcinoma is KRAS mutation rate (about 50% of cases); however, there is
significantly different from high-grade serous carcinoma in a more analogous genetic profile between borderline serous
morphology, genotyping, and biological behavior. tumor-micropapillary variants and low-grade serous carci-
noma in comparison with serous borderline tumor, which
4.2.1.1 Low-Grade Serous Carcinoma suggests that borderline serous tumor-micropapillary variant
Low-grade serous carcinoma has typical features of type I may be an intermediate lesion in the development of border-
EOCs. The progression from benign to borderline to malig- line serous tumor to low-grade serous carcinoma [52]. On
nant process can be observed histologically. The epithelial the other hand, development of low-grade serous carcinoma
cells lining on the serous cystadenoma have the same histo- from serous borderline tumor, regardless conventional type
logical and immunophenotype as OEI cells. The areas of or micropapillary variants, is time-dependent [56]. With
benign serous components present in almost all borderline increasing follow-up time, conventional serous borderline
tumors. Likewise, the transition from borderline to malig- tumor will also develop into low-grade serous carcinoma. It
nant components also exists in the majority of low-grade remains to be determined whether such further subclassifica-
serous carcinoma. As the precursor lesion represents an tion is clinically meaningful or potentially misleading as the
important clue for tumor origin, the abovementioned patho- term of atypical proliferative tumor neglects the low malig-
logical findings suggest that the ovarian serous cystadenoma, nant potential of conventional serous borderline tumor.
borderline tumor, or low-grade carcinoma may develop via a Genetic and genomic profiles: The most common molecular
sequential progression process from OEIs. genetic alterations in low-grade serous carcinoma are KRAS,
Cells of origin: While it is well-known that the fallopian BRAF, or ERBB2 mutations. These three gene mutations can
tube can serve as a precursor lesion for high-grade serous promote the transduction of growth signals into the nucleus,
carcinoma, recent evidence suggests that these epithelial resulting in uncontrollable cell proliferation and malignant
cells can be also potential source of low-grade lesions includ- transformation via sustained activation of the downstream
ing cystadenoma, serous borderline tumor, and low-grade MAPK kinase signaling pathway [57, 58]. Accumulating evi-
serous carcinoma. Due to close anatomic relationship dence points toward that there are mutually exclusive relation-
between the fallopian tubal fimbria and ovaries, ovarian rup- ships among KRAS, BRAF, or ERBB2 mutations with only one
ture caused by periodic ovulation may provide an opportu- gene mutation exists at an individual tumor in most cases. The
nity for implantation of the epithelial cells of fallopian tube mutation rate accounts for about 2/3 of the borderline tumors
on the ovary. Through morphological and immunohisto- and low-grade serous carcinoma, of which 33.3% of the bor-
chemical comparisons among OSEs, OEIs, tubal epithelium, derline tumors and low-grade serous carcinomas have KRAS
serous cystadenomas, serous borderline tumors, and low- mutations at codon 12 and 13, 33.3% of serous borderline
grade serous carcinomas, Zheng and Kong et al. [23, 54, 55] tumors and a small number of low-grade serous carcinomas
found two types of OEIs including mesothelial type (cal- show BRAF mutation at codon 600, whereas ERBB2 mutation
retinin+/PAX8−/tubulin–) and tubal type (calretinin–/ is less than 5% of entire tumors. KRAS or BRAF mutation is
PAX8+/tubulin+). The tubal OEIs account to 78% of all OEIs considered to be an early event in low-grade serous carcinomas
and have a significantly higher proliferative index, which may because they also exist in serous cystadenomas adjacent to bor-
further proliferate and progress to ovarian serous cystade- derline serous tumors [59]. Compared with BRAF mutation,
noma or borderline tumors. Conversely, mesothelial OEIs serous borderline tumors with KRAS mutation have a greater
may not develop to tumor because of its low proliferative rate. potential to progress to low-grade serous carcinoma. In fact,
As the mucosal epithelium of fallopian tubal fimbria can BRAF mutation in advanced low-grade serous carcinoma is
KRAS / BRAF / ERBB2 mutation
Tubal mucosal epithelium
a b c d f
1p, 5q, 8p, 18q, 22q

and Xp allelic imbalance
Fig. 4.2 The illustration of progression of ovarian low-grade serous grade serous carcinoma (f), with/without the stage of borderline serous
carcinoma and associated changes in molecular genetics. The mucosal tumor-micropapillary variants/noninvasive low-grade serous carcinoma
epithelial cells (a) of fallopian tubal fimbria may shed and adhere to the (e). During the period of tumorigenesis and progression, the KRAS/
ovarian surface and then form the tubal OEIs (b, yellow arrow). The BRAF/ERBB2 mutation rate gradually increases. And the multiple chro-
progression process is from serous cystadenoma (c) to borderline serous mosomal allelic imbalances also promote the formation of low-grade
tumor/atypical proliferative serous tumor (d) and eventually to low- serous carcinoma simultaneously
very rare [60]. In addition, the low-grade serous carcinomas are ing evidence accumulated in the literatures that provide the
more likely to have an allele imbalance of 1p, 5q, 8p, 18q, 22q, support for the origin of high-grade serous carcinoma. (1) In
and Xp chromosomes than borderline tumors [61]. The hetero- the specimens of prophylactic bilateral salpingectomy from
zygosity deletion of ch1p36 and the heterozygosity/homozy- the patients with hereditary BRCA1/2 mutation carriers,
gous deletion of ch9p21 often are found in low-grade serous there are the occult precancerous lesions that are p53 signa-
carcinoma. Given that there are tumor suppressor genes (such ture and STICs, but no malignant ovarian tumors. The p53
as miR-34a) in ch1p36 region and CDKN2A/B (encoding signature is arbitrarily defined as more than 12 successive
tumor suppressor protein p14, p16, and p15) in ch9p21 region, secretory cells with benign morphological features exhibit-
these deletions may lead to the uncontrollable cell growth in ing strongly positive expression of p53 immunohistochemi-
borderline tumors and eventually progress to low-grade serous cal staining and less than 10% of Ki-67 cell proliferation
carcinomas [62] (Fig. 4.2). index [65]. As for STIC, its cytological features are enlarged,
polymorphic, and hyperchromatic nuclei with nucleoli and
4.2.1.2 High-Grade Serous Carcinoma mitotic figures, high ratio of nucleus to cytoplasm, multi-
High-grade serous carcinoma is the most common EOC. Its layered cells, or the lack of cellular polarity. The immunohis-
incidence is about 60–80% of all EOCs. More than 75% of tochemical staining of p53 exhibits strongly positive or
tumors are in advance stage with extensive abdominopelvic totally negative expression, and Ki-67 cell proliferation
dissemination at the diagnosis [63]. However, there are usu- index is more than 10% [51]. (2) There are tubal p53 signa-
ally no morphologically recognizable precursor lesions in ture and/or STICs in 50–60% of cases with the sporadic
ovarian tissues. Recent studies showed that some ovarian ovarian and/or peritoneal high-grade serous carcinoma [62].
high-grade serous carcinomas may not originate in ovarian (3) Similar to ovarian high-grade serous carcinomas, there
tissues but in the seeding from serous epithelial tumor cells are the overexpression of p53 protein and the mutation of
in the mucosal epithelium of fallopian tubal fimbria as sec- TP53 gene both in p53 signature and STICs. The TP53 muta-
ondary tumors. The spectrum of tumorigenesis and progres- tion rate gradually increases with the process of tumor pro-
sion is from tubal secretory cell expansion [64] or secretory gression from p53 signature to STICs to high-grade serous
cell outgrowths to tubal p53 signature, to tubal serous tubal carcinoma. (4) The evidence that there is the same TP53
intraepithelial carcinoma (STIC)/noninvasive high-grade mutation site in concurrent p53 signature, STICs, and ovar-
serous carcinoma, to shedding and implantation on the ovary, ian high-grade serous carcinoma supports the notion that
and eventually to ovarian high-grade serous carcinoma. high-grade serous carcinoma arises from the clonal prolifer-
Evidence supporting the fallopian tubal epithelial origin ation of p53 signature cells [66, 67]. (5) The genetic profile
as the main source of pelvic serous carcinoma: The follow- of high-grade serous carcinoma is close to tubal epithelial
128 J. Zhang et al.
cells [68]. (6) STICs have shorter telomeres compare with 5. No STICs in the fallopian tube are identified in 50%
concurrent ovarian high-grade serous carcinoma, while telo- serous carcinoma; it will be very difficult to unify a the-
mere shortening is known to be an early molecular event of ory while no precursor lesions are identified in 50% of
tumorigenesis [69]. (7) In the models of genetically modified cases of the same cancer.
mice, the secretory cells in the mucous of fallopian tube can 6. The main molecular evidence of clonality of the same
transform to malignant lesion due to Tp53, Pten, and Brca TP53 mutation should be treated with caution as it has
mutations, resulting in STIC and ovarian high-grade serous been shown to be an unreliable indicator of metastasis in
carcinoma [70, 71]. (8) A recent study confirmed that the many other tumors.
salpingectomy is an effective method to reduce EOC risk in
the general population based on the analysis of large clinical Ovarian serous carcinoma as multicellular cells of origin:
database between 1973 and 2009 [72]. As mentioned above, there are approximately half of the
Based on above data, the secretory cells in the mucosa of cases of ovarian high-grade serous carcinoma without con-
fallopian tube have been proposed to be the cell origin of current STIC, suggesting that these tumors may be derived
high-grade serous carcinoma via the following process [73]: from other cell origins [75, 76]. One possible source of cell
the secretory cells have DNA damages that cannot be nor- origin is the OEIs within ovarian cortex; some OEIs may be
mally repaired due to the stimulation of a variety of DNA formed by direct shedding and implantation of normal fal-
toxicity factors, resulting in the accumulation of DNA dam- lopian tubal epithelial cells into the ovarian cortex [55, 77],
ages. Because of the pressure of survival, there are a series of which undergo a series of molecular genetics and morpho-
molecular genetic alterations in the damaged cells, such as logical change including TP53 mutations, and eventually
adaptive TP53 mutations, which lead to uncontrollable cell develop into high-grade serous carcinomas [78]. In addition,
growth, over-proliferation, secretory cell outgrowths, and it is documented that a small number of low-grade ovarian
then p53 signature. Some cells with p53 signature can serous carcinoma can progress into high-grade serous carci-
develop to STIC directly or through tubal dysplasia to form noma or that borderline serous tumors can progress to high-
STIC [65, 74]. Due to the close contact between the fallopian grade serous carcinoma after tumor recurrence. The incidence
tubal fimbria and the ovarian surface, and the loose adhesion by this pathway is likely to be low, since less than 3% of
between STIC cells, it is possible the tumor cells shed and high-grade serous carcinomas show concurrent serous bor-
implant on the ovarian surface and ultimately form “ovarian” derline tumor, low-grade carcinoma, and high-grade compo-
high-grade serous carcinoma, a possibility that is more plau- nents in same tumor. These low-grade serous carcinomas
sible than ovarian metastasis via lymphovascular invasion. may progress to high-grade carcinoma possibly via TP53
Recent studies that there are tumor cells in the intraperito- mutations [79]. In addition, some high-grade serous carci-
neal washings in some patients with STIC also provide a noma has been observed to arise from adenofibroma; and the
direct evidence for this disseminated implantation [51]. fibroma components cannot be explained by tubal implanta-
Evidence against fallopian tubal epithelial cells as main tion theory. Based on the clinical and pathologic observation
source of pelvic serous carcinoma: Despite of prevalent view and arguable evidence for fallopian tube theory, in his alter-
of fimbria of fallopian tube as a major source of high-grade native view article, Silva proposed that the fere ex nihilo
serous carcinoma discussed above, there are several impor- model including the multicentric cell origin under the influ-
tant clinical and pathological observations of pelvic serous ence of environmental factors (such as hormones) may be the
carcinoma that cannot be clearly explained by fallopian tube responsible for development of various ovarian carcinomas
origin [11]: (see Sect. 1.1.4). However, regardless of the cells of origin,
the transformation process can be achieved via the giant cell
1. Most of high-grade serous carcinomas are at stages III cycle described above (Fig. 4.1).
and IV, while 70% the fallopian tubal carcinoma are stage Subclassification of high-grade serous carcinoma.
I or II. Through the morphological analysis of high-grade serous
2. There is no direct evidence that the cells from small tubal carcinoma-associated BRCA1/2 mutation, Soslow et al. [80]
intraepithelial carcinoma can travel all the way against found that these tumors usually present with solid pattern,
gravity to the abdomen rather to the pelvis, which is endometrioid carcinoma- and transitional cell carcinoma-
against the law of gravity. like feature, which is characterized by “SET” (solid, pseudo
3. Most STICs are noninvasive, while most high-grade
endometrioid, transitional cell carcinoma-like). BRCA1-
serous carcinomas are highly invasive; it is difficult to associated cancer is associated with highly cellular prolifera-
rationalize that the noninvasive precursor carcinomas tive activity, tumor-infiltrating lymphocytes, and geographic
give rise to 70% invasive carcinoma in peritoneal cavity. or comedo necrosis. Compared with the classic high-grade
4. Many high-grade serous carcinomas are located intra- serous carcinoma whose histological patterns are papillary,
ovarian stromal, not on the surface. glandular, cribriform, and solid area with slit-like space, the
SET subtype is more common in younger women, and the ular genetic alterations also participate in the transformation
tumor cells are more sensitive to chemotherapy due to defi- process. Norquist et al. [88] found that the loss of BRCA1/2
ciencies of homologous recombination. Moreover, the allele exists in STICs, but not in p53 signature, suggesting
patients have better prognosis [80, 81]. In view of the above- that both TP53 mutation and BRCA1/2 deletion are the key
mentioned different clinicopathological characteristics, it is events in early carcinogenesis. Kim et al. [71] reported that
suggested that high-grade serous carcinoma should be ovarian/fallopian tubal high-grade serous carcinoma cannot
divided into classic subtype and SET subtype [9]. be directly induced by Tp53 mutation alone but by both Tp53
Based on the results of TCGA genome analysis, in 2013 and Pten mutation. Drapkin and Dinulescu et al. [70] also
Verhaak et al. [82] presented a molecular subtype of high- confirmed that the combination of Brca1/2, Tp53, and Pten
grade serous carcinoma associated with the prognosis of mutations in tubal epithelial cells leads to STIC and high-
patients. That is classification of ovarian cancer (CLOVAR). grade serous carcinoma, whereas only Tp53 mutation cannot
The tumors were classified into differentiated, proliferative, induce tumor formation. The simultaneous loss of functions
immunoreactive, and mesenchymal type. Among these sub- leads to a decrease in cell genome stability, a series of onco-
types, the prognosis of patients with immunoreactive type is gene activation and/or tumor suppressor gene inactivation,
the best, and the prognosis is the worst in patients with mes- and leads to multiple chromosomal breaks and deletions and
enchymal type. In 2016 Murakami et al. [83] further associ- the formation of aneuploidy or polyploidy, which is condu-
ated the molecular typing with tumor morphology: the cive to avoiding immune surveillance, over-proliferation, and
mesenchymal type often presents a significant desmoplastic the progression to high-grade serous carcinoma from STIC.
reaction; the immunoreactive type usually manifests as The prevalent view of carcinogenesis of high-grade serous
plenty of lymphocyte infiltration in the tumor tissues; the carcinoma and its main molecular genetic alterations is
proliferative type frequently has the solid growth pattern; shown in Fig. 4.3. Because of conflicting evidence and dif-
and the differentiation type generally exhibits the papillary ferent views that is for or against the tubal theory, we ask
pattern. However, this molecular subtype needs be further readers of this chapter to take the views from different
confirmed by more studies before used clinically. authors with great caution and make your own observation
Common genetic and genomic alterations: The most during the daily practice and decide which theory will best fit
prominent genetic features of high-grade serous carcinoma with what you observe, rather than blindly believe what are
are genomic instability (the abnormalities of many DNA described by a particular author, journal, or academic group.
copy number and structure) and TP53 mutations. According We want to point out that health discussion and expression of
to genomic TCGA project, TP53 mutation is found in almost different opinions should greatly help us to clarify controver-
all tumors tissues (96%) through a sequenced genomic anal- sial points and move field to next level. As Einstein puts it,
ysis on 489 cases of high-grade serous carcinoma [28]. The “blind belief in authority is the greatest enemy of truth.”
TP53 mutation rate is as high as 57% even in precancerous
lesions, p53 signature [84]. TP53 mutation is not only an
initial event of high-grade serous carcinogenesis but also 4.2.2 T
he Other Ovarian Epithelial
involved in tumor progression. In addition, nearly half of the Carcinomas
high-grade serous carcinomas display BRCA1 (17q21.31)
and BRCA2 (13q13.1) inactivating mutations (including 4.2.2.1 Endometrioid Carcinoma, Clear Cell
germline mutation, somatic mutation, or promoter methyla- Carcinoma, and Seromucinous Carcinoma
tion). Further, common amplification of CCNE1, NOTCH3, Ovarian endometrioid and clear cell carcinoma account for
PIKCA3, and AKT, and the inactivation of RB and NF1 has about 25% of all EOCs, which are the most common tumors
also been observed in some tumors [28, 85]. Alterations in after serous carcinoma. Seromucinous carcinoma (also
DNA copy number have been observed in early lesions like known as endocervical-type mucinous or mixed epithelial
STICs [86]. High-grade serous carcinoma with BRCA1/2 carcinomas of Müllerian type) is very rare. It is composed
mutation is characterized by numerous alterations in DNA predominately of serous and endocervical-type mucinous
copy number but without CCNE1 amplification, a very com- epithelium, foci of clear cells, and uncommon area of endo-
mon event in primary and refractory tumors [81]. The minor- metrioid and squamous differentiation. All of three tumors
ity of high-grade serous carcinomas with inherited mutations belong to type I EOCs and are believed that at least 1/3 of the
also has germline deletion mutations in BARD1, BRIP1, cases originate in endometriosis [89, 90]. These tumors usu-
MRE11, NBN, RAD51C, RAD51, and PALB2 genes involved ally have endometriosis, endometrial benign, and/or border-
in the signaling pathway of Fanconi anemia [87]. line tumors in the background lesions.
Although TP53 mutation is a common event in high-grade Most endometrial carcinomas are low-grade (FIGO grade
serous carcinoma, the mutation alone in TP53 is not sufficient 1), whose clinical manifestations are consistent with the fea-
to induce malignant transformation, suggesting other molec- tures of type I EOCs. Only a few endometrial carcinomas
130 J. Zhang et al.
a
most cases <3% cases KRAS,
TP53 BRAF,
mutation
Tubal epithelim ERBB2
b g
mutation
?
f
1p, 5q, 8p,
BRCA1/2 18q, 22q and
inactivation
Xp allelic
c h imbalances
few cases?
DNA copy
number
e
amplification
or deletion TP53 mutation
d
Fig. 4.3 The progression of high-serous serous carcinoma and asso- (f). Few ovarian high-grade serous carcinomas may be derived from
ciated molecular genetic alterations. The normal mucosa epithelium the OEIs. The TP53 and BRCA1/2 mutations and numerous amplifica-
of fallopian tubal fimbria (a) undergoes p53 signature (b), serous tions and deletions of DNA copy number involve in above two path-
tubal intraepithelial carcinoma (c), serous tubal invasive carcinoma ways. Less than 3% of high-grade serous carcinomas are originate in
(d), and ovarian high-grade serous carcinoma via the shedding and direct progression of low-grade serous carcinoma (h) or the recur-
implantation in ovary (e). The normal tubal epithelium may seed on rence of borderline serous tumor (g). This process may also be related
the ovarian surface during ovulation process and form the tubal OEIs to TP53 mutations
belong to intermediate-grade or high-grade (FIGO grade 2 or OEI cells exhibit the endometrioid morphological changes. In
3). In these tumors, it is frequently found the component of combination of the recent views that some OEIs are derive
low-grade carcinoma or the presence of some molecular from the seeding of tubal epithelial cells [54, 90], it is possi-
genetic alterations similar to concurrent low-grade carci- ble that fallopian tube may contribute the histogenesis of
noma, which suggests that these intermediate-grade or high- ovarian endometriosis. Lately, Yuan et al. [94] found that 18
grade components may be transformed via dedifferentiation cases (56%) showed a high level of FMO3 and a low level of
of low-grade carcinoma [52]. Few high-grade endometrioid DMBT1 expression in 32 ovarian endometriosis cases by a
carcinomas have the same clinical features and genetic alter- gene differential array analysis, which is similar to fallopian
ations (such as TP53 mutation) as those of high-grade serous tubal profile. This result suggests that approximately 60% of
carcinomas. Recent evidence supports the notion that these the ovarian endometriosis may be derived from the fallopian
tumors are more suitable for being classified to a variant of tube, whereas about 40% of the cases may be of endometrial
high-grade serous carcinomas [80, 90, 91]. origin. Using a fallopian tube- specific promoter OVGP1
Endometriosis is an estrogen-dependent inflammatory dis- gene, Wu et al. [95] developed an animal model with specifi-
ease. Ovary is the most common organ involved by endome- cally biallelic inactivation of Apc and Pten in oviductal or
triosis. Thus far its origin is still in dispute. Its major theory is ovarian epithelium using Ovgp1-iCreERT2 mice and found
the reflux menstruation and the coelomic metaplasia [92]. In that there was the formation of endometrioid carcinoma-like
2005, Zheng et al. [93] found the earliest morphological malignant epithelial tumors in the fallopian tubes or ovaries,
changes of endometriosis and named it “initial endometrio- respectively. On the basis of the morphology and global
sis.” Its histological feature is a transition from minimal to genetic profiles, the oviduct- derived tumors more closely
mature endometriosis in normal ovarian tissue. This change resemble human ovarian endometrioid carcinomas than do
presents both in the ovarian epithelium and in the cortical OSE-derived poorly differentiated ovarian carcinoma. The
OEI, and the latter is most common. That is, some ovarian abovementioned results provide strongly experimental evi-
dence that tubal epithelial cells may be one of the potential homolog 1) or hMSH2 (human mutS homolog 2) protein.
origins of ovarian endometrioid carcinoma. KRAS and BRAF mutations are rare, with an incidence of
Recent data suggest that clear cell carcinoma may arise less than 7% [9, 52].
from ciliated cells in the endometrium (both eutopic endo- Compared with endometrioid carcinomas, clear cell car-
metrium and endometriosis) and fallopian tubes, whereas cinomas rarely have abnormal Wnt/β-catenin signaling path-
endometrioid carcinoma may arise from secretory cells way. The most common genetic alteration is ARID1A
rather than histotype-specific mutations. The cystathionine inactivation mutation. It is documented that the expression
gamma-lyase (CTH) and methylenetetrahydrofolate dehy- status of the SWI/SNF complex serves as an independent
drogenase 1 (MTHFD1) can serve as specific markers for prognostic factor. The loss of one or multiple SWI/SNF com-
ciliated and secretory cells, respectively [96]. plex subunits demonstrates aggressive behaviors and poor
Common genetic and genomic alterations: At the genetic prognosis [83]. Clear cell carcinoma also has a high PIK3CA-
level, several unique genes have been found in the endome- activated mutation (40%) and PTEN deletion mutation
trioid carcinoma. The most frequently mutated gene is (10%). More than 70% PIK3CA mutation occurs simultane-
ARID1A tumor suppressor gene. Its encoded protein ously with ARID1A mutation [52]. Clear cell carcinoma
BAF250a can bind to the AT-rich DNA sequence and is a key shows similar frequency of MSI [104, 105] as endometrioid
component of the switch/sucrose non-fermentable (SWI/ adenocarcinoma except that MSI is mainly manifested as
SNF) chromosome remodeling complex. The function of hMSH2 germline mutation. Furthermore, clear cell carci-
this complex is to mobilize nucleosomes, regulate gene noma has a unique epigenetic alteration, which involves in
expression and chromosome kinetics, and participate in the the methylation of multiple gene promoters in α-estrogen
regulation of a variety of cell processes (e.g., development, receptor alpha (ERα) and hepatocyte nuclear factor 1 (HNF-
differentiation, proliferation, DNA repair, and tumor sup- 1) signal pathways [106]. The changes in cell metabolism
pression). Mutations in ARID1A have been detected in induced by HNF-1β expression are conducive to tumorigen-
46–57% of cases of clear cell carcinoma, 30% in cases of esis and cell survival [107].
endometrioid carcinoma, and 33% in cases of seromucinous Seromucinous tumors are very rare. Morphologically, sero-
carcinoma; on other hand, there are no detected ARID1A mucinous tumors in addition to serous and endocervical-type
mutations or deletions in serous and mucinous carcinoma mucinous epithelium contain endometrioid, undifferentiated,
and malignant Brenner tumor, suggesting that these muta- and squamous-type epithelium with frequent expression of ER
tions are histotype-specific. Interestingly, and unexpectedly, and PR, lack of expression of CK20 and CDX2, and infre-
while it is widely believed that endometriosis is a precursor quent expression of WT1. This tumor is also frequently asso-
lesion of endometrioid, clear cell, and seromucinous carci- ciated with endometriosis-like endometrioid or clear cell
noma. These mutations are also found in endometriosis tissues carcinoma. Although seromucinous carcinomas were intro-
adjacent to cancer tissues [97], suggesting that these com- duced as a new entity in 2014 WHO classification, it has been
monly believed cancer-causing mutations are actually not the argued that its name may have a serious flaws that obscure that
drivers of malignant transformation. ARID1A may be an early nature of neoplasms [90]. Due to its rarity, there are few reports
event of endometriosis progression to cancer [98–100]. In about its molecular genetics except ARID1A inactivation
addition to ARID1A gene, endometrioid, clear cell, and sero- mutation. In 2017, through the study of 32 tumors diagnosed
mucinous carcinomas have other special genetic alterations. It as seromucinous carcinomas from 2 medical centers, the
is now clear that sole ARID1A inactivation is not sufficient to authors found that these tumors had KRAS (70%), PIK3CA
induce tumorigenesis. The deletion of both Arid1a and Pten (37%), PTEN (19%), and ARID1A (16%) mutations. 30% of
leads to endometrioid and undifferentiated carcinoma in vivo cases harbored concurrent KRAS and PIK3CA mutation [108].
studies [101]. And the combinations of deletions of ARID1A The immunophenotype and molecular genetics of seromuci-
and PIK3CA can cause clear cell-like tumors via the activating nous carcinoma overlapped predominantly with endometrioid
inflammation signaling pathways [102, 103]. and low-grade serous carcinoma. After integrating morphol-
The genetic alterations in the endometrioid carcinoma ogy, immunophenotype, and genotyping, 32 cases of seromu-
appear to be different from that of clear cell carcinoma. cinous carcinomas were reclassify to endometrioid (23 cases),
Mutations in PI3K/PTEN and Wnt/β-catenin signaling path- low-grade serous (8 cases), and mucinous carcinoma (1 case).
ways are frequently detected, including CTNNB1 (15–40%), It has been proposed to reclassify this group of tumors as
PIK3CA (20%) and PTEN (14–21%). CTNNB1 mutation is “mixed Müllerian tumors” which can be subcategorized as
associated with squamous differentiation, low-grade tumors, “mixed Müllerian cystadenomas,” “mixed Müllerian atypical
and good prognosis. PIK3CA and PTEN mutations can occur proliferative (borderline) tumors,” and “mixed Müllerian car-
simultaneously. 13–20% cases of endometrial carcinoma cinomas.” Therefore, seromucinous carcinoma may be due to
possess microsatellite instability (MSI), which usually mani- the heterogeneity and lineage infidelity of different histotypes
fest as the deletion expression of hMLH1 (human mutL and may not be a real distinct subtype of EOCs [108].
132 J. Zhang et al.
4.2.2.2 Mucinous Carcinoma and Malignant mucinous tumor may develop from a Brenner tumor in
Brenner Tumor which the component of Brenner tumor is compressed and
According to the 2014 WHO classification, ovarian muci- obliterated by an expanding mucinous neoplasm. The tran-
nous carcinoma refers to the gastrointestinal-type. With fur- sitional cell nests in Brenner tumors frequently contain
ther studies on clinical pathology and molecular genetics, it mucinous cells, prompting that the overgrowth of these
is clear that the vast majority (more than 90%) of ovarian mucinous epithelial cells eventually lead to the occurrence
mucinous carcinoma (especially advanced tumors) are sec- of mucinous tumors.
ondary, mostly from the gastrointestinal tract (especially col- Mucinous carcinomas commonly possess the activation
orectum and appendix). The other common metastatic sites of RAS/MEK signaling pathways. More than 90% of cases
include pancreas, bile duct, gallbladder, endocervix, bladder, present KRAS, BRAF, and/or ERRB2 mutation. Among
etc. The real primary mucinous carcinomas are less than 5% them the most common is KRAS-activated somatic cell
of EOCs [7, 109]. mutation (64.5%) [116]. The amplification of ERRB2 is
The size of primary ovarian mucinous carcinoma is often about 15% to 20%. KRAS mutation is thought to be an early
large (more than 10 cm). Histologically, there are significant event of mucinous carcinogenesis because KRAS mutation
heterogeneity changes in tumor tissue, such as the presence of is found in mucinous cystadenomas and borderline tumors
components of benign mucinous cystadenoma/adenofibroma, adjacent to cancer tissues [52]. Moreover, TP53 mutation
borderline tumor, and carcinoma. The vast majority of tumors rates in mucinous carcinomas and borderline tumors are
are low-grade, which fully reflects the tumorigenesis of type 56.8% and 11.5%, respectively [116]. About 21% cases of
I EOCs. Clinically, the patients with stage I ovarian mucinous mucinous carcinomas had an inactivated mutation of RNF3
tumors (borderline with/without intraepithelial carcinoma or tumor suppressor gene, similar to pancreatic mucinous
microinvasion, and invasive carcinoma) have excellent prog- tumors [117].
nosis, whose 5-year survival rate is more than 90%. Advanced Brenner tumors are composed of urethral/transitional epithe-
ovarian mucinous carcinomas are uncommon and have a poor lium nested around with fibromatous stroma. The vast majority
prognosis. The overall survival rate of these patients is the of tumors are benign. The malignant tumors are very rare, and
same as that of metastatic adenocarcinoma [110]. around 80% of tumors are confined to the ovary (FIGO stage I),
Compared with metastatic mucinous carcinoma, most pri- with a typical progression process of type I EOCs, i.e., from
mary tumors are confined to unilateral ovaries, suggesting that benign to borderline to malignant Brenner tumors.
its precursor lesions should be located in the ovaries. Its origin is still unknown because the morphology of
Accumulating molecular genetic evidence suggests that at Brenner tumors is totally different from Müllerian epithe-
least a subset of mucinous tumors (including mucinous cyst- lium and lacks the expression of Müllerian immunohisto-
adenomas, borderline tumors, and mucinous carcinomas) may chemical markers (PAX-8 and PAX-2). Some scholars
arise from mucous epithelium within mature cystic teratomas believe that its origin is independent of ovarian OEI [8].
(germ cell origin) and Brenner tumor (non-germ cell origin). Many tissue or cell types, including transitional cell metapla-
The cell origin of teratomas is believed to be postmeiotic sia from OSE, mesonephric remnant, the rete ovarii, muci-
ovarian germ cells [111]. There are mucinous tumors in nous tumor, fallopian tube, and teratoma, have been presumed
about 2–11% of ovarian mature cystic teratoma. Around to be the origin of Brenner tumor [113].
3–8% mucinous tumors are associated with teratomas. Using Walthard cell nests consist of transitional epithelium and
short tandem repeat analysis, genotypical concordance usually exist at/near the tuboperitoneal junction and fre-
between the teratomas and coexisting mucinous tumors are quently coexist with Brenner tumors. It has long been con-
found, which provide the evidence that the cell origin of sidered the origin of Brenner tumors because they display
some mucinous tumors is germ cells [111, 112]. epithelia with the same morphology and immunophenotype
Mucinous tumors are often associated with Brenner (e.g., GATA3 and p63 positive, germline marker SALL4
tumors. Seidman et al. [113] found that 20% of mucinous negative) as Brenner tumors [8, 118]. Roma et al. [118]
tumors have Brenner tumor components and 16% of found that 43% of patients with Brenner tumors had Walthard
Brenner tumors contain concurrent mucinous tumors. In cell nests in the soft tissue surround fallopian tubes/ovaries.
the molecular genetics, there is 12q14-21 amplification Through a morphologic and immunohistochemical analysis
both in ovarian mucinous carcinoma and coexistence of in Brenner tumors, Kuhn et al. [119] found that tubal secre-
Brenner tumors using an analysis of comparative genomic tory cells, transitional metaplasia, Walthard cell nests, and
hybridization [114]. It is also reported that all two compo- the epithelial component of Brenner tumors shared a similar
nents in most mixed Brenner and mucinous tumors have a immunophenotype, consistently expressing AKR1C3 (an
concordant X-chromosome inactivation pattern via a enzyme involved in androgen biosynthesis) and androgen
human androgen receptor gene assay [115]. These results receptor, but not calretinin. The stromal cells that closely
confirm that the components of Brenner and mucinous surrounded the epithelial nests showed strong expression of
tumors share a same clonal relationship. Some mucinous calretinin, inhibin, and steroidogenic factor 1 (markers of
tumors originate from the Brenner tumor and the pure steroidogenic cells) in the majority of tumors. There were
small groups of cilia in transitional metaplasia and Walthard half of the cases have deficiencies of mismatch repair proteins.
cell nests, multifocal stretches of cilia and/or ciliated vacu- It is not clear whether the tumor is an independent histological
oles in benign tumors, and well-developed cilia in atypical subtype or a poorly differentiated variant of high-grade serous
proliferative tumors. These findings suggest a tubal origin of or endometrioid carcinoma. MMMTs have significant biphasic
Brenner tumors via transitional metaplasia and Walthard cell differentiation of high-grade carcinoma and sarcoma elements.
nests under the effect of androgenic stimulation. It is believe that these tumors belong to high-grade carcinoma
Malignant Brenner tumors are low-grade EOCs with the with sarcomatoid differentiation due to the same clonality of
activation of PI3K/AKT signaling pathway. PIK3CA mutation these two elements. Its most common molecular genetics alter-
has been reported in an individual case [120]. In benign Brenner ations are TP53 mutation and CDKN2A amplification [9].
tumors, the positive rate of p16 immunohistochemistry is 92%, In summary, many of EOCs come from extraovarian tis-
while completely negative expression of p16 is found in the sues, and the ovaries could be secondary involvement; a sig-
borderline/atypical proliferative Brenner tumor. The data from nificant number of ovarian cancer may also arise from
fluorescence in situ hybridization confirm that there is loss of multifocal origin of different type of Müllerian epithelial
heterozygosity of CDKN2A gene (encoding p16 protein), sug- cells. Recent studies have provided increasing evidence that
gesting that CDKN2A deletion may play a role in progression a number of EOCs may arise directly or indirectly from tubal
from benign to borderline Brenner tumor [9]. epithelial cells except that a part of mucinous carcinoma and
endometriosis-associated EOCs (endometrioid, clear cell,
4.2.2.3 Undifferentiated Carcinoma and seromucinous carcinoma) derive from ovarian germ
and Malignant Mixed Müllerian Tumor cells and glandular epithelial cells of endometriosis, respec-
Both of these histotypes are rare high-grade and aggressive tively (Fig. 4.4). However, readers should consider these
malignant tumors. Undifferentiated carcinomas lack the fea- models only as hypotheses. As more evidence accumulates
tures of high-grade serous or endometrioid carcinoma. Nearly in the future, these models will be revisited and updated.
Fig. 4.4 The proposed models of ovarian epithelial carcinogenesis. them are derived from OEIs. And less than 3% of cases are from the
Normal mucosa epithelial cells of fallopian tubal fimbria shed and progression of low-grade serous carcinomas or the recurrence of bor-
implant on the ovarian surface. The OEIs are formed via the epithelial derline serous tumors. Malignant Brenner tumors progress from benign
invagination during ovulation process and then undergo metaplasia. Brenner tumors that may derive from the Walthard cell nests, although
Endometrioid, clear cell, and seromucinous carcinoma originate in the cell origin of Walthard cell nests is unclear. Mucinous carcinomas
endometriotic glands and OEIs. Low-grade serous carcinoma arises originate in mucosal epithelium within the mature cystic teratomas and
from OEIs. High-grade serous carcinoma mostly comes from the seed- benign Brenner tumors
ing of serous tubal epithelial carcinoma (STIC). A very small number of
134 J. Zhang et al.
4.3 ewly Clinical Applications Based

N is particularly important for these high-risk groups to be
on Ovarian Epithelial Carcinogenesis taken into consideration of close follow-up and early screen-
Models ing. Although diagnostic value for high-risk patients with
asymptomatic tumor in early stage by ultrasound examina-
These above new models on carcinogenesis and the mecha- tion is very limited [124], other imaging techniques, such
nisms of molecular genetics suggest that diagnosis, preven- as multispectral fluorescence imaging and magnetic reso-
tion, and treatment of the patients with EOCs should be nance imaging (MRI) diffusion-weighted imaging, could
determined by new strategy. help to improve the detection rate of small-volume tumors
[125, 126].
In conclusion, the decreases in mortality of EOCs should
4.3.1 The Adjustments in Early Screening focus on the detecting small volume of type II EOCs and
identify high-sensitivity molecular markers or genetic altera-
Traditional strategy in early screening of EOC is “the tri- tions in this type of tumors. The morphology, molecular
ple methods” worldwide, which includes gynecological genetics, and biological behavior in STICs are similar to
examination, transvaginal ultrasound, and serum CA125 high-grade serous carcinoma, which are different from the
detection. This screening strategy is based on the tradi- precancerous lesion of type I EOCs because most of them
tional concept that EOC form mass in the early stage. In existed as benign and borderline tumors. Even though the
fact, only a small number of patients with type I EOCs are lesions are confined to the epithelium of tubal mucosa, the
diagnosed at the early stage due to the mass formation. cells in STICs have markedly decreased adhesion and easily
The majority of type II EOCs, the most common type of shedded and implanted into pelvic cavity. Tumor mutation-
EOCs, is often missed because there may not form mass at specific DNAs can be detected in ovarian cystic fluid [127],
the early stage. given their biological characteristics; it may be possible to
In addition, the prognosis of patients with EOCs detect these lesions using detection of cytology in combina-
depends not only on tumor staging but also on the biologi- tion with genetic probes or a highly sensitive molecular
cal behaviors of specific histological subtypes of tumors. imaging technology in the fallopian tube, although it is
In general, type II EOCs show more rapid growth, more unlikely to detect all of high-grade serous carcinoma due to
aggressive clinical behaviors, and higher lethality rate alternative multicentric origins for these tumors.
compared with type I EOCs. Therefore, it is unlikely to
achieve early diagnosis only by conventional screening
method in type II EOCs. A published literature from the 4.3.2 The Changes in Prevention Strategy
large-scale clinical trial result has exhibited the ineffec-
tiveness of this screening method and provides further sup- As the significant number of EOCs is secondary to extra-
port for this view [121]. ovarian tissue, especially the significant number of high-
In view that there is no obvious mass formed in some type grade serous carcinoma arising from the mucosa of fallopian
II EOCs in the ovary and/or pelvic cavity at early stage [122], tube fimbria, it is not surprising that prophylactic bilateral
the concept of early diagnosis for EOC has changed to a new salpingo-oophorectomy can effectively reduce the EOC risk
idea by trying to find a small and/or tiny ovarian tumors in in women with BRCA gene mutation or the family history of
pelvic cavity. Based on the theory that the fallopian tube fim- EOCs. In addition, bilateral salpingo-oophorectomy has
bria is also an important source of EOCs, not only ovaries been gradually replaced by bilateral salpingectomy so that
but also fallopian tubes should be checked in order to find the female fertility and endocrine function can be maintained
STIC, a precursor of high-grade serous carcinoma, which as well as decreased risk in cardiovascular diseases caused
will also affect FIGO staging in high-grade serous carcino- associated with removal of ovary [128]. Toward this end, the
mas. The standardized sampling, Sectional and Extensively Gynecologic Oncology Group (GOG) underwent the clinical
Examining the FIMbria (SEE-FIM) proposed by Crum et al. trials that bilateral salpingo-oophorectomy was replaced by
[123], has been widely adopted in pathological examination bilateral salpingectomy to prevent hereditary EOCs. In 2015,
of fallopian tube and greatly increase the detection rate of Falconer et al. [72] analyzed data from the Swedish Cancer
STIC. However, it must be emphasized that approximately Registry on women with previous surgery on benign indica-
50% of pelvic serous carcinomas have no defined STIC; the tion (sterilization, salpingectomy, hysterectomy, and bilat-
pathologic examination of the fallopian tube along is unlikely eral salpingo-oophorectomy; n = 251,465) compared with
to find all of precursor lesions for all pelvic serous carcinoma. the unexposed population (n = 5,449,119) between 1973 and
In patients with EOCs with familial genetic defect (such 2009 using Cox regression models. They found that there
as BRCA1/2 mutation and Lynch syndrome-related MSI), it was a statistically significantly lower risk for ovarian cancer
among women with previous salpingectomy (HR = 0.65, 4.3.3 T

he Improvements in Therapeutic
95% CI = 0.52 to 0.81) when compared with the unexposed Methods
population. Bilateral salpingectomy was associated with a
50% decrease in risk of EOC compared with the unilateral Today, ovarian cancer remains one of the most challenging
procedure (HR = 0.35, 95% CI = 0.17 to 0.73, and 0.71, 95% diseases on treatment. Since EOCs are comprised of a het-
CI = 0.56 to 0.91, respectively). These data support that sal- erogeneous group of diseases, the different histological sub-
pingectomy by itself, or in combination with other benign types have different pathogenesis patterns, cell origin, and
surgery, is an effective method to reduce EOC risk in the molecular genetic alterations. Therefore, it is necessary for
general population. patients to receive individualized therapy according to the
The most direct and effective preventive method is that specific histologic and molecular features of tumors.
the patients with benign diseases undergo prophylactic The majority of type I EOCs is confined to the ovary
removal of bilateral fallopian tubes (so-called opportunistic (FIGO stage IA). All of them are classified as low-grade car-
salpingectomy) and keep their ovaries when they need hys- cinomas, with the exception of clear cell carcinoma. For
terectomy surgery, because there is no physiological signifi- FIGO IA tumor, the main clinical therapeutic strategy is sur-
cance for the fallopian tubes after hysterectomy. In addition, gical resection, including tumor and ipsilateral ovary with/
for women who are willing to have sterilization surgery, the without pelvic lymphadenectomy. For advanced tumors with
application that traditional tubal ligation is replaced by bilat- extraovarian dissemination, the patients must undergo adju-
eral salpingectomy may have a good preventive effect on vant chemotherapy. However, due to an indolent biological
EOCs that originate in fallopian tubes and endometrium. behavior, tumor cells are often not sensitive to chemotherapy
However, as mentioned above, in our opinions, the evidence and easy to develop drug resistance. In consideration of con-
that majority of pelvic serous carcinoma is still a hypothesis stitutive activation of MAPK signaling pathway induced by
and likely to be multicentric origins. Great caution should be KRAS, BRAF, or ERBB2 mutation, it is possible for MAPK
excised in clinical practice as not all of normal physiologic inhibitor-based therapy to become an effective adjuvant ther-
functions are known in the ovarian and other organs in apeutic approach. Indeed, this sort of treatment has showed
women. efficacy for advanced and/or recurrent type I EOCs in the
Mounting evidence has shown a close correlation among clinical trials [133, 134]. In addition, in view of the correla-
EOCs, ovulation, inflammation caused by the process of tion between some type I EOCs (e.g., endometrioid and clear
ovulation, and the release of sex hormones. The decrease of cell carcinoma) and the deficiency of mismatch repair pro-
ovulation (such as oral contraceptives, multiple pregnancies, teins and a large number of tumor-infiltrating lymphocytes
breastfeeding, delayed menarche, etc.) can effectively reduce within the tumor stroma, the patients may benefit from the
the incidence of EOCs [129, 130]. It is reported that oral current anti-PD-1 (programmed death 1) inhibitors in
contraceptives can reduce the incidence of ovarian cancer by immune checkpoint therapy. For those type I EOCs with
50%. The longer duration women have used oral contracep- ARID1A mutation (such as endometrioid, clear cell, and
tives, the greater reduction is in the EOC risk. However, the seromucinous carcinoma), it is interesting to note that tumor
incidence of mucinous tumors seems little affected by oral cells exhibit sensitivities to EZH2 inhibitors [135, 136] and
contraceptives [131]. Unfortunately, long-term use of oral poly (ADP-ribose) polymerase (PARP) inhibitors [137]
contraceptives has multiple potential side effects. Because in vitro. Additional work is needed to determine if these
the rupture of ovarian follicle releasing the ovum and follicu- inhibitors can be explored for clinical application in the
lar fluid is a prostaglandin-mediated inflammatory process future.
that can be stopped by nonsteroidal anti-inflammatory drugs The vast majority of type II EOCs is advanced stage at
(e.g., aspirin) and lead to pharmacologic production of a presentation. The main strategy of clinical treatment is
luteinized unruptured follicle, which mimics a normal non- reductive surgery in combination with chemotherapy. The
conception cycle with unaltered steroid patterns/levels and tumor cells are prone to have secondary drug resistance,
cycle length, it is suggested that non-hormonal periodic although they are sensitive to drugs in the initial phase of
interruption of incessant ovulation could be recommended chemotherapy [81]. In patients with high-grade serous carci-
for women who are at high EOC risk. Recent data clearly noma, nearly 50% of cases have the deficiency of homolo-
reveal that the usage of low doses of aspirin can lessen the gous recombination proteins and about 20% of patients
risk of ovarian cancer [132]. Considerable further research is having BRCA1 or BRCA2 mutations (16% of cases are germ-
required to validate the potential of this approach. In short, as line mutations; 4% of cases are somatic mutations). Since
knowledge accumulation on the ovarian epithelial carcino- the European Medicines Agency and the US Food and Drug
genesis, more and more drugs with low side effects are being Administration approved the development of PARP inhibi-
developed for the prevention of EOCs. tors (olaparib) for cisplatin-sensitive, recurrent, or advanced
136 J. Zhang et al.
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tors are also at the various stages of clinical trials [138]. The identifies two groups of ovarian high-grade serous carcinomas
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[139]. On the other hand, current immunotherapies have region Y-box 2 expression predicts poor prognosis in human ovar-
been largely ineffective in advanced and current ovarian cancer ian carcinoma. Hum Pathol. 2012;43:1405–12.
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tumor in patients with serous ovarian carcinoma using immuno-
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Serous Neoplasms of the Ovary
5
Preetha Ramalingam
Abstract 5.1 Overview

Serous neoplasms of the ovary are composed of tumors
where the epithelial cell type resembles that of the fallo- 5.1.1 D
evelopment of Ovarian Serous
pian tube. These tumors range from benign, borderline to Tumors
frankly malignant. Our understanding of borderline and
malignant serous neoplasms has evolved in the past few The origin of ovarian cancer continues to be controversial.
decades. SBTs, though uncommon, are encountered in Historically these tumors were thought to arise from the
routine practice and have been the subject of several con- ovarian surface epithelium and inclusion cysts/glands in the
troversies regarding terminology and diagnostic criteria, parenchyma; however, a definitive precursor lesion has not
which will be addressed. Our understanding of the patho- been identified thus far. More recently there have been sev-
genesis of ovarian cancer has advanced significantly, but eral studies to suggest that the precursor lesion for ovarian
controversy still exists regarding its origin, and recent carcinoma is present in the fallopian tube, i.e., serous tubal
studies have suggested the possibility of origin in the fal- intraepithelial carcinoma (STIC). Even earlier changes such
lopian tube at least in a subset of cases. Approximately as “p53 signature” have been identified in patients with
10% of ovarian cancers are hereditary due to mutations in BRCA germline mutations, who have had risk-reducing
the BRCA1 or BRCA2 genes, which not only poses one of salpingo-oophorectomy. p53 signature lesions are composed
the strongest risk factors but also has implications for of short stretches of benign appearing non-ciliated tubal epi-
patients and family members in terms of risk-reducing thelium that demonstrate overexpression of p53 but no cor-
surgery options. From a practical standpoint, familiarity responding increase in proliferation marker Ki-67. These
with the diagnostic criteria of high- and low-grade serous lesions are typically seen in the fimbriated end of the fallo-
carcinoma is necessary for pathologists. This chapter pian tube, and in one study, almost 60% had TP53 mutations.
addresses the pathologic features, relevant immunohisto- Some of the reasons to support a tubal origin for ovarian can-
chemistry, molecular genetics, and challenges associated cer include the identification of STIC in patients with BRCA
with the diagnosis of ovarian serous neoplasms. gene mutations who have had prophylactic BSO, rather than
early carcinomas in the ovary. STICs are typically identified
Keywords in the fimbrial end of the fallopian tube that is in close prox-
Ovary · Fallopian tube · Peritoneal · Serous · Borderline · imity to the ovary, permitting cell deposition in the latter dur-
Low grade · High grade · Seromucinous · ing ovulation. From a molecular standpoint, identical TP53
Clinicopathologic · Immunohistochemistry · Molecular mutations have been identified in STIC and synchronous
ovarian/peritoneal cancers, and STICs have different telo-
mere lengths than paired ovarian/peritoneal tumors (they
would be identical if they represented metastasis). On the
contrary, the incidence of STIC in patients with high-grade
serous carcinoma (HGSC) has been variable ranging from
18.8% to 47% [1, 2] serial sectioning and complete submis-
sion of the fimbrial end of the fallopian tube, suggesting that
not all ovarian carcinomas are associated with STIC, and in
P. Ramalingam (*) some cases, the origin of the tumor is still not known.
Department of Pathology and Laboratory Medicine, MD Anderson Low-grade serous carcinoma (LGSC) is thought to arise
Cancer Center, University of Texas, Houston, TX, USA
in a stepwise fashion from cystadenoma and serous border-
142 P. Ramalingam
line tumors (SBT) [3]. The majority of LGSCs are associ- formed. Malignant serous tumors must be graded in all
ated with SBTs, and both have BRAF and KRAS mutations cases unless there are limitations that preclude accurate
[4–6]. Serous cystadenomas and borderline tumors are grading. The two-tier grading system proposed by Malpica
thought to arise from inclusion cysts in the ovarian paren- et al. is recommended, and tumors must be classified as
chyma as they are histologically and immunophenotypically either LGSC or HGSC [6, 13].
similar, and cystadenomas are distinguished from inclusion
cysts based on an arbitrary 1.0 cm cutoff. Inclusion cysts
from ovaries of patients with SBT have been shown to have 5.2 Benign Serous Tumors
higher levels of epithelial cell aneusomy when compared to
those from ovaries without neoplastic disease [7]. It is now 5.2.1 General Features
known that the inclusion cysts in the ovarian parenchyma,
i.e., endosalpingiosis, are derived from fallopian tube epi- Benign serous tumors typically occur in women from 40 to
thelium and are immunophenotypically different than the 60 years of age. Patients may either be asymptomatic or
ovarian surface epithelium. Inclusion cysts are positive for present with abdominal pain secondary to a large mass or
PAX-8 and negative for calretinin, while the converse is true torsion. Benign serous tumors can range in size from
for ovarian surface epithelium which is mesothelial derived 1.0 cm to up to 30.0 cm but are usually <15.0 cm. Cysts
and positive for calretinin and negative for PAX-8 [3, 8]. A less than 1.0 cm are best reported as inclusion cysts, which
study using tubulin to label ciliated cells showed a progres- are also called as endosalpingiosis. The outer surface is
sive decrease in ciliated cells from normal tubal epithelium, smooth and typically no papillary excrescences are identi-
ovarian inclusion cysts, and SBT to complete absence in fied in the inner wall. Cystadenofibromas may have some
LGSC [8]. HGSC arising from the fallopian tube is thought papillary areas which are more polypoid and edematous/
to be derived from a clonal expansion of tubal secretory fibrotic rather than truly papillary as seen in borderline
cells [9]. Similarly LGSC may represent a clonal expansion tumors (Fig. 5.1).
of secretory cells which acquire BRAF and KRAS rather
than p53 mutations [8].
Serous neoplasms comprise approximately 30% of all
ovarian tumors [10, 11]. About 60–65% are benign, 10% are
borderline tumors, and the remainder are malignant tumors
(25–30%) [10, 11]. The epithelium of the benign tumors
closely resembles that of the fallopian tube, but with border-
line and malignant tumors, the papillary nature, hierarchical
tufting, and psammoma bodies assist with the diagnosis.
Benign serous tumors are termed cystadenoma, adenofi-
broma, or cystadenofibroma depending on the extent of cys-
tic and fibrous component present in the tumor. Tumors that
have epithelial proliferation greater than that expected in
benign serous tumors are classified as SBTs. The 2014
WHO classification of tumors of female reproductive organs
recommends using this terminology for tumors that show
>10% of hierarchical tufting. In our institution, cases with
typical features of borderline tumor, even if less than 10%,
are called focal SBT, especially in postmenopausal women
who can have associated peritoneal implants [12]. Using
this terminology requires careful discussion with the sur-
Fig. 5.1 Gross image of serous cystadenofibroma with papillary areas
geon to ensure that the peritoneal cavity is examined at the that are smooth and polypoid unlike in borderline tumors which have
time of frozen section and limited staging biopsies per- papillary fronds and excrescences
5 Serous Neoplasms of the Ovary 143
5.3 Pathologic Features
5.3.1 Gross Findings
The cysts may be unilocular or multilocular with none to

variable amount of fibrous/solid component. The contents of
the cyst are frequently watery and clear though sometimes it
can have a mucinous consistency. Hence distinction of a
serous from mucinous cystadenoma is best done on histo-
logic examination rather than based on the consistency of the
contents.
5.3.2 Histologic Features
Serous cystadenomas are lined by ciliated tubal-type epithe-

lium (Fig. 5.2a, b). There is no hierarchical papillary tufting, Fig. 5.3 Serous cystadenofibroma showing glands and fibrotic stroma
and occasionally the epithelium may appear stratified sec-
ondary to tangential sectioning. In some cases the epithelium
is flattened secondary to pressure atrophy, and the cilia may
not be readily identified. In some cases cysts may have a
mixture of serous and mucinous epithelium. When the
fibrous component is admixed with cystic component, a
diagnosis of serous cystadenofibroma is appropriate
(Fig. 5.3). In such cases several small glands may be seen
embedded within the fibrotic stroma. When the cystic com-
ponent is virtually absent, a diagnosis of serous adenofi-
broma is made, and when the lesion is present on the ovarian
surface, it is called a serous surface papilloma (Fig. 5.4).
While some amount of papillary proliferation is allowed, if
hierarchical tufting is present, a diagnosis of borderline
tumor must be considered, even if less than 10%, due to the
risk of possible peritoneal involvement (Fig. 5.5a). If the
papillary tufting is <10% and entirely intracystic (Fig. 5.5b),
a diagnosis of serous cystadenoma/cystadenofibroma with Fig. 5.4 Serous surface papilloma showing large edematous papillae
without hierarchical tufting involving the ovarian surface
a b
Fig. 5.2 (a) Serous cystadenoma showing a fibrous cyst wall lined by a single layer of epithelium without epithelial proliferation or tufting.
(b) Higher-power image showing cuboidal cells with no cytologic atypia and cilia (arrows)
144 P. Ramalingam
a b
Fig. 5.5 (a) Serous cystadenoma with epithelial proliferation on the cystadenofibroma with intracystic proliferation comprising <10%
ovarian surface best designated as serous borderline tumor even though which can be called either focal serous borderline tumor or serous cyst-
it comprises <10% due to the risk of peritoneal involvement. (b) Serous adenofibroma with epithelial proliferation
eration. Serous cystadenomas can mimic rete cystadenoma;

however, the latter is characterized by a hilar location and
cyst wall lined by cuboidal or flattened epithelium with
undulations (Fig. 5.6). In some cases normal rete ovarii is
present in the cyst wall, which can also have fibromuscular
stroma and hilus cells.
Benign serous tumors are managed by surgical removal.
Those patients with surface epithelial proliferation may ben-
efit from closer follow-up.
5.4 Serous Borderline Tumors
5.4.1 General Features
SBTs are considered to be precursors of LGSC. Per the

Fig. 5.6 Rete cystadenoma showing flattened epithelium with undula- 2014 World Health Organization (WHO) classification of
tions, located in the ovarian hilum tumors of female reproductive organs, these tumors have
epithelial proliferation and atypia greater than benign serous
epithelial proliferation is reasonable as majority of these tumors such as cystadenoma/cystadenofibroma but less than
patients have an uneventful clinical course. At our institution that of LGSC [14]. Another important distinction from
we call such tumors focal SBT. If we encounter such lesions LGSC is the histologic absence of frank invasive carcinoma.
at the time of frozen section, the surgeon is alerted to thor- SBTs comprise approximately 5–10% of ovarian serous
oughly examine the peritoneal cavity and perform limited neoplasms and occur in a wide age range, with a mean age
sampling. However, it must be noted that such tumors in of 42 years [15–19]. These tumors are less frequent than
most other institutions will likely fall in the cystadenofi- HGSC and are not associated with BRCA 1/2 gene muta-
broma with epithelial proliferation. tions. The majority of these tumors (70%) are confined to
the ovary at the time of diagnosis, and the remainder present
with extraovarian disease, either involving the pelvis (stage
5.3.3 Differential Diagnosis II) or the upper abdomen (stage III). A third of SBTs are
bilateral [14, 16, 18, 20]. There has been controversy regard-
Serous cystadenoma is distinguished from inclusion cysts by ing the terminology of SBTs. Serous tumor of low malig-
a size greater than 1.0 cm. Similarly, surface papillomas nant potential and atypical proliferative serous tumors have
<1.0 cm are designated as surface papillary stromal prolif- been alternative terms used for these tumors. The 2014
WHO classification of tumors of female reproductive organs variable involvement by papillary excrescences. The papillae
recommends use of either SBTs or atypical proliferative are grossly tan-yellow soft, friable, and edematous
serous tumors but not serous tumor of low malignant poten- (Fig. 5.7b). The cyst contents are typically serous; however,
tial (SLMP). However, several experts in the field do not mucinous fluid can also be present. Solid fibromatous areas
recommend the use of atypical proliferative serous tumors. may be present within the cyst wall which may grossly have
The concern with use of this terminology is that it may not the appearance of cystadenoma but microscopically could
effectively communicate to the clinician the malignant show areas consistent with borderline tumor; hence sampling
potential for these tumors, albeit in a small proportion of of these areas, in the absence of typical papillary excres-
cases [19, 21]. A recent population-based study has shown cences, is important.
that tumors designated as atypical proliferative serous
tumors have a 5-year absolute serous carcinoma risk of
0.9% but at 20 years was 3.7%. The authors also found that 5.5.2 Histologic Features
the risk of LGSC was significantly higher in patients with
APST than in the general population [22]. The latter finding The histologic appearance of SBT is characteristic with the
reiterates findings of prior reports that patients with APST presence of complex arborizing papillary that show hierar-
do not always have a “benign course” and the term SBT is chical tufting. The papillary emanating from the large edem-
more reflective of the biological behavior of these tumors atous/fibrotic papillae become progressively smaller
[21, 23–25]. Considering atypical proliferative serous resulting in detached papillary epithelial tufts (Fig. 5.8a).
tumors as benign tumors could potentially give a false The lining is either low cuboidal or stratified with at least
understanding of the clinical course of these tumors, which focal presence of ciliated cells (Fig. 5.8b). Cells with abun-
is time dependent, as shown by the proponents of this termi- dant eosinophilic cytoplasm can be seen in a subset of
nology and others [21, 22, 26]. We and many others recom- SBT. Intracytoplasmic mucin may be present in an otherwise
mend the use of SBT. typical SBT, and its focal presence does not warrant a diag-
nosis of a seromucinous borderline tumor. The lining epithe-
lium shows only mild to moderate atypia, and the presence
5.5 Pathological Findings of marked atypia is inconsistent with a diagnosis of
SBT. Tumors with a low-power appearance of SBT that is
5.5.1 Gross Findings intracystic without evidence of “invasion” that have marked
cytologic atypia must be designated as HGSC (Fig. 5.9a, b).
Grossly the tumors can range from 1.0 cm to 35.0 cm with an Therefore, high-power examination of these tumors to be
average size of 11.0 cm. The tumors may be intracystic with certain that the nuclei do not show atypia beyond what is
or without surface involvement or be purely surface tumors expected for SBT is recommended for all cases. Also of note
(Fig. 5.7a). The cyst may be unilocular or multilocular with is that focal HGSC can be present in an otherwise typical
a b
Fig. 5.7 (a) Serous borderline tumor involving surface and parenchyma of both ovaries displaying numerous papillary excrescences. (b) Cut
surface of ovary involved by serous borderline tumor showing delicate edematous papillae without evidence of hemorrhage or necrosis
146 P. Ramalingam
a b
Fig. 5.8 (a) Typical serous borderline tumor showing prominent epithelial proliferation arising from larger fibrotic papillae with hierarchical tuft-
ing. (b) High power of papillae showing cuboidal to columnar cells with minimal cytologic atypia and cilia
a b
Fig. 5.9 (a) Serous tumor resembling serous borderline tumor on low power showing characteristic hierarchical tufting and no invasion. (b)
Higher-power image of the tumor cells with marked atypia consistent with high-grade serous carcinoma
SBT, and careful examination must be performed to exclude 5.5.4 Differential Diagnosis
this possibility [27].
The differential diagnosis for SBTs includes serous cystad-
enofibroma with epithelial proliferation and HGSC, both of
5.5.3 Biomarkers which have been discussed earlier in this chapter. Another
consideration is clear cell carcinoma (CCC), as SBT can
Immunohistochemical stains are rarely necessary to make a show cytoplasmic clearing. The presence of papillary, solid,
diagnosis of SBT. However, they are positive for CK7, and tubulocystic patterns, hobnailing, and marked cytologic
MOC-31, PAX-8, WT-1, and ER/PR [28–31]. In cases where atypia would favor CCC. SBT will be positive for WT-1 and
a HGSC is to be excluded, diffuse staining for p53 and p16 CCC for napsin-A and HNF-1β, if further confirmation is
would favor this diagnosis over SBT [32]. necessary.
5.6 pecific Issues of Serous Borderline

S tions of this diagnosis must be taken into consideration.
Tumors While SBT-MP when confined to the ovary has the potential
to recur, there is no indication for adjuvant therapy for these
5.6.1 M
icropapillary and Cribriform Growth patients. Using the term noninvasive carcinoma may trigger
Patterns clinicians to give unnecessary adjuvant therapy for patients
who would otherwise only require observation, of course in
A subset of SBTs is characterized by the so-called micropap- the absence of invasive peritoneal disease. For these afore-
illary pattern (SBT-MP), and these tumors are also the sub- mentioned reasons, the term SBT-MP is recommended at
ject of much controversy with respect to terminology. These least at our institution.
tumors comprise 5–15% of SBTs in various series [33–35]. SBT-MP is characterized by small slender papillae that
Tumors with this pattern are more likely to be bilateral and are five times as long as they are wide, devoid of fibrovascu-
have surface involvement, higher-stage disease, and worse lar cores, and emanate from the base of large fibrotic papillae
prognosis prompting some authors to call them noninvasive (Fig. 5.10a, b). This pattern has been likened to a Medusa
LGSC [19, 25, 33–35]. There has been considerable debate head and must measure at least ≥5.0 mm in order to qualify
on whether the worse outcome in these patients, when com- for a diagnosis of SBT-MP. When compared to typical SBT,
pared to typical SBT, is related to the stage and type of peri- these tumors have a nonhierarchical branching pattern. The
toneal disease (i.e., invasive implants), rather than the papillae are lined by predominantly non-ciliated cells that,
histologic pattern. Most authors favor using the term SBT-MP similar to typical SBT, have only mild-moderate cytologic
rather than noninvasive LGSC as several studies have shown atypia and scant mitoses. Cribriform pattern of SBT is
that the prognosis is largely dependent on the stage and type thought to result from fusion of these micropapillae, at least
of implant [17, 19, 25, 33]. However, it must be noted that in some cases, and hence it is included in the SBT-MP cate-
noninvasive LGSC is the accepted terminology for these gory of tumors (Fig. 5.11). The extent of cribriform pattern is
tumors in the 2014 WHO classification of tumors of female variable and can range from <25% to greater than 25% and
reproductive organs. In a recent population-based study in is not infrequently admixed with the micropapillary pattern
Denmark, clinicopathologic features of atypical proliferative [17]. The MP and cribriform patterns may be admixed with
serous tumor, i.e., typical SBT, were compared with nonin- typical SBT. The 2014 WHO classification of tumors of
vasive LGSC, i.e., SBT-MP [22, 26]. Briefly, the study female reproductive organs states that tumors with at least
showed that patients with stage I “noninvasive LGSC had a 5.0 mm of MP/cribriform pattern but with “less atypia” than
worse outcome than patients with “APST”.” However, that accepted for SBT can be classified as SBT with MP fea-
patients in both groups with advanced-stage disease had a tures. Discerning subtle differences in the degree of atypia in
similar outcome. The use of the term noninvasive LGSC is SBT-MP and noninvasive LGSC is likely to be highly sub-
not currently widely accepted, and the therapeutic implica- jective and non-reproducible. SBT-MP can have areas with
a b
Fig. 5.10 (a) Micropapillary serous borderline tumor showing slender typically five times long as they are wide, lined by cells with mild to
papillae lacking fibrovascular cores arising from larger edematous moderate atypia and the absence of prominent hierarchical tufting
papillae, imparting a “Medusa head” appearance. (b) The papillae are
148 P. Ramalingam
5.6.2 Serous Borderline Tumor

with Intraepithelial Carcinoma
SBT with intraepithelial carcinoma is a dubious entity. This

concept is better defined in mucinous borderline tumors. By
extrapolation it would refer to tumors in which there is mark-
edly increased cytologic atypia without invasion. In serous
neoplasms, this atypia likely is a manifestation of HGSC
arising in the background of a SBT. However, in some
tumors, the atypia is intermediate between HGSC and typi-
cal SBT, i.e., resembling the nuclei of LGSC. More studies
are needed to evaluate this feature to determine if it repre-
sents a distinct entity.
5.6.3 Serous Borderline Tumor

Fig. 5.11 Serous borderline tumor with cribriform pattern showing with Microinvasion
coalescence of glands with low-grade cytology. This pattern is typically
seen in association with micropapillary pattern
About 10–15% of SBT demonstrate stromal invasion, but
unlike most other tumors, they do no elicit a stromal reac-
tion. The size limit that distinguishes microinvasion from
LGSC has varied in different reports from 3.0 mm to 5.0 mm
to 10 mm2, and the 2014 WHO classification of tumors of
female reproductive organs uses the 5.0 mm cutoff.
Microinvasion refers to the presence of isolated single cells
or clusters of cells with abundant eosinophilic cytoplasm,
small micropapillae, or nests of cells with cribriform pattern
surrounded by clear spaces (Fig. 5.13a, b). An uncommon
pattern is the presence of macropapillae surrounded by a
cleft/clear space (Fig. 5.14). Some of the micropapillae
within clear spaces may represent involvement of lymphatic
spaces. D2-40 staining has shown the presence of tumor
within lymphatics in up to 60% of SBTs with microinvasion;
however, this does not correlate with an increased incidence
of lymph node involvement [36]. The tumor cells in the
stroma are cytologically similar to the cells lining the papil-
Fig. 5.12 Serous borderline tumor with micropapillary pattern show- lae of the borderline tumor. The tumor cells with abundant
ing mild to moderate atypia and prominent cherry red nucleoli eosinophilic cytoplasm likely represent degenerating or
senescent tumor cells, and they have been shown to have
increased nuclear atypia and small cherry red nucleoli lower expression of both estrogen and progesterone recep-
(Fig. 5.12); hence, relying on the architectural criterion is tors as well as Ki-67 [37]. Microinvasion has been reported
recommended. If the focus of MP/cribriform pattern is to have a higher incidence in pregnant women but, however,
<5.0 mm, these tumors can be signed out as either “SBT with has no prognostic implications in these patients [15, 38].
focal MP features,” or the presence of these patterns can be Most reports on SBT with microinvasion have shown no
mentioned in a comment. SBT-MP is currently managed adverse effect on prognosis even in nonpregnant patients [15,
similar to typical SBT. For pathologists the most important 19, 37, 39, 40]. However, a single study has shown that
requisite is to sample these tumors thoroughly to rule out microinvasion may be an adverse prognostic indicator inde-
invasive carcinoma. At our institution, when micropapillary pendent of stage and type of SBT [38]. In the absence of
pattern is identified, we submit two sections per centimeter extraovarian disease and no areas diagnostic of LGSC, the
of the largest tumor dimension. management of these patients should be similar to SBT with-
a b
Fig. 5.13 (a) Serous borderline tumor with microinvasion. The glands (arrowhead). (b) Microinvasion showing both single cells and small
are lined by cells with abundant eosinophilic cytoplasm (arrow), and papillae surrounded by clear spaces with no stromal reaction. The foci
similar cells are seen in the stroma without associated stromal reaction are small and measure <5.0mm
they infiltrate the underlying tissue or are present on the peri-

toneal surface [23, 41, 44–46]. The 2014 WHO classification
of tumors of female reproductive organs has abandoned
these terms and recommends that invasive implants be desig-
nated a LGSC, as they have similar behavior and outcome,
and all other implants be termed “implants” [14]. For
purposes of understanding the microscopic features of the
implants, the traditional terminology will be used in this
chapter; however, since there is no prognostic significance
for the subtypes of noninvasive implants, they may be
reported as “implants” in the diagnostic report. Alternatively
using the traditional terminology is also accepted as they are
ingrained in the literature and also add another level of
description and clarity that is beneficial to the clinician.
Noninvasive implants are typically present on the perito-
neal surface or in peritoneal invaginations. Noninvasive
Fig. 5.14 Serous borderline tumor with macropapillary pattern of implants are further subdivided into epithelial and desmo-
microinvasion showing large edematous papillae surrounded by clear
plastic implants [45, 46]. The former is composed, as the
spaces (arrows)
name suggests, primarily of epithelial proliferation composed
of hierarchical branching papillae with fibrovascular cores
out microinvasion. It is recommended that the presence and that are usually present within a cystically lined space
focality of microinvasion be included in the final diagnosis. (Fig. 5.15). These epithelial proliferations do not elicit a stro-
From a practical standpoint, the presence of multiple foci of mal response and do not invade the underlying adipose tissue;
microinvasion should prompt additional sampling to exclude hence, they may not be grossly identified in the omentum. At
LGSC. our institution we submit one section for every 2 centimeters
of the resected omentum, to increase the chance of capturing
them microscopically. For example, a 30.0 cm omentum
5.6.4 Serous Borderline Tumor with Implants would get 15 sections with focused sampling of fibrous or
thickened areas. Desmoplastic noninvasive implants are com-
Peritoneal implants are present in about a third of all SBTs posed predominantly of fibrous tissue with a granulation tis-
[23, 24, 34, 35, 41–43]. They have been traditionally classi- sue-like appearance within which the epithelium is embedded
fied as noninvasive and invasive implants based on whether (Fig. 5.16a, b). Hemorrhage, inflammation, fibrin, and
150 P. Ramalingam
p sammoma bodies may be present in the stroma. Isolated with desmoplastic stromal reaction invading the surrounding
single cells with clear spaces may be present and does not fibrous/adipose tissue (Fig. 5.18). While the criteria seem to
warrant a diagnosis of invasive implant (Fig. 5.17). As a rule, be well established, their application can be quite challeng-
the epithelial stromal ratio is quite low in desmoplastic nonin- ing. There is much variation in interpretation of equivocal
vasive implants. Desmoplastic implants appear as firm implants in which either the epithelium is composed of papil-
plaques or nodules that have a stuck on appearance on the lae surrounded by clear spaces without clear invasion into the
omental surface or in the invagination of the fat lobules. surrounding adipose tissue (Fig. 5.19a) or when the epithelial
Invasive implants have been shown to behave like LGSC, stromal ratio is high within an otherwise desmoplastic nonin-
and the 2014 WHO classification of tumors of female repro- vasive implant (Fig. 5.19b). The former used to be termed
ductive organs recommends using the latter terminology [14]. early invasion, but this terminology has fallen out of favor
Invasive implants are characterized by small micropapillae [41]. Based on some studies, it appears that peritoneal
surrounded by clear spaces or irregular haphazard glands implants that have characteristic features of invasive implants,
especially micropapillary or cribriform pattern, that do not
invade the adjacent adipose tissue (Fig. 5.20) behave similar
to invasive implants/LGSC and should be designated as such
[46]. Review of cases from several small and large academic
centers and community pathologists, as part of our clinical
practice, has shown that these criteria are not uniformly
applied and there is significant interobserver variability in the
classification of implants even among experts [19, 46, 47].
This is particularly the case for implants that are “picked” off
the surface of peritoneal surfaces in which there is no associ-
ated adipose tissue to evaluate the presence or absence of
invasion. It may be impossible to classify an implant as inva-
sive or noninvasive, and “indeterminate for invasion” may be
used in select cases. In these challenging cases, especially, if
this finding is isolated in a well-staged patient, a conservative
approach is recommended. This brings up another issue on
whether the extent/quantity of invasive implant/LGSC involv-
ing the peritoneal cavity at the time of original diagnosis has
Fig. 5.15 Noninvasive peritoneal implant showing epithelial prolifera-
an impact outcome. There is no established data on this issue
tion resembling serous borderline tumor within cystically lined space and this merits further investigation.
a b
Fig. 5.16 (a) Desmoplastic noninvasive implant showing a prolifera- reactive stromal cells with scattered epithelial nests (arrows). The gland
tion of stromal cells with a granulation tissue-like appearance that is to stroma ratio is low
stuck on the omental surface. (b) Higher power shows hemorrhage and
Fig. 5.17 Desmoplastic noninvasive implants with isolated nests sur- Fig. 5.18 Invasive peritoneal implant showing marked proliferation of
rounded by clear spaces (arrows) with overall low gland to stroma ratio, papillae surrounded by halos with associated desmoplastic stromal
which does not warrant a diagnosis of invasive implant reaction and infiltration into the adjacent adipose tissue
a b
Fig. 5.19 (a) Implant with small nests surrounded by clear spaces reaction present within an adhesion. The degree of epithelial prolifera-
(arrows) within an adhesion and no invasion into adjacent adipose tis- tion may be considered sufficient for a diagnosis of invasive implant
sue. (b) Implant with marked epithelial proliferation with focal stroma
In some cases the ovarian tumor, despite adequate sam- 5.6.5 S

erous Borderline Tumor Involving
pling, only reveals a SBT but peritoneal sampling reveals Lymph Nodes
invasive implants/LGSC. In such cases, the ovarian tumor is
considered the primary site, despite the absence of invasive About a third of SBTs have regional lymph node involve-
tumor. The College of American Pathologists recommends ment [48]. Involvement by SBT must be distinguished from
documenting the presence and type of implants in the synop- endosalpingiosis but can also coexist with each other. There
tic report and the cases are staged as pT3. is speculation that at least a subset of SBTs in lymph nodes
152 P. Ramalingam
arise from preexisting endosalpingiosis and do not represent desmoplastic reaction. When single or clusters of epithelial
involvement by the ovarian tumor. Involvement of lymph cells with abundant eosinophilic cytoplasm that resemble cells
nodes by SBT is not an independent adverse prognostic indi- seen in microinvasion (Fig. 5.22) are present, they can mimic
cator and hence is reported as “involvement” rather than intranodal mesothelial cells. Using a limited panel of immu-
“metastatic carcinoma” [42, 48, 49]. nostains including calretinin for mesothelial cells and MOC-
Histologically the tumor can form small clusters of epithe- 31 or BER-EP4, PAX-8, and ER for SBTs can allow the
lial cells surrounded by clear spaces, micropapillae within cys- distinction. The only pattern of significance is that of a non-
tic spaces, or foci with cribriform architecture, usually within intracystic aggregate of tumor cells with or without micropap-
the lymph node sinuses or in the parenchyma (Fig. 5.21a, b). illary pattern that measures >1.0 mm, with associated
The nuclei show mild to moderate atypia, and there is often no desmoplasia (Fig. 5.23), which is consistent with LGSC. This
Fig. 5.20 Implants with a micropapillary pattern present in fibrous Fig. 5.22 Serous borderline tumor resembling single cell pattern
septae within adipose tissue without invasion of the underlying tissue. (arrows) of microinvasion resembling mesothelial cells
Some studies have shown that these lesions behave similar to unequivocal
invasive implants and should be considered as such
a b
Fig. 5.21 (a) Serous borderline tumor involving lymph node paren- line tumor in lymph node sinuses (arrows) with associated calcification
chyma showing epithelial proliferation and tufting that is in excess of and adjacent endosalpingiosis
that acceptable for endosalpingiosis. (b) Minute foci of serous border-
implants and only 5% of noninvasive implants [50]. In this

study KRAS mutations were more frequent in advanced-
stage disease and a predictor of higher recurrence rate. The
question of whether peritoneal implants represent ovarian
tumor-related lesions, i.e., monoclonal versus multifocal dis-
ease arising independently in the peritoneum, is still debated.
Testing for loss of heterozygosity and X-chromosome inacti-
vation have shown variable results with some investigators
reporting concordant patterns and others demonstrating dis-
cordant patterns, supporting monoclonal and multifocal ori-
gin, respectively. This likely represents the variability in the
origin of implants encompassing both possibilities. SBTs
also have very low DNA copy number suggesting a relatively
stable genome.
Fig. 5.23 Metastatic low-grade serous carcinoma in a lymph node 5.6.7 Management and Outcome
showing a focus of tumor with haphazard glands eliciting a desmoplas-
tic stromal reaction (arrow). Adjacent focus of serous borderline tumor
is present (asterisk) Early reports on survival of patients with stage I of SBTs
reported 99–100% survival rates, but the follow-up was
short. As our understanding of the disease course of SBTs
can be seen in the lymph node in association with ovarian SBT has evolved, these tumors could recur several years or some-
or LGSC. Distinction of SBT from endosalpingiosis is impor- times decades after initial diagnosis. Hence later reports
tant. Endosalpingiosis can have intraglandular papillae, usu- included much longer follow-up, and while the survival is
ally with a fibrovascular core; however, hierarchical tufting is still excellent, it is estimated to be approximately 95–98%.
absent. This is discussed in further detail in the peritoneal Recurrences occur in about 10% of cases and can either
serous tumors section, later in this chapter. recur as SBT or LGSC. However, a minority of patients who
recur as LGSC may have an adverse outcome, resulting in
disease-related death; hence, long-term follow-up is essen-
5.6.6 Genetic Studies tial for these patients. Given the long interval between diag-
nosis and recurrence, these tumors could represent
The pathogenesis of SBT, serous cystadenofibroma, and independent primaries or disease progression.
LGSC has been studied extensively, and there is sufficient Patients with stage II and III disease with noninvasive
evidence that this represents a spectrum of the same disease, implants are at increased risk for recurrence on long-term
both histologically and molecularly. Serous cystadenofibro- follow-up. Earlier reports of excellent overall survival were
mas are not infrequently seen in the background of SBT, and based on a 5-year follow-up which is too short for these
the latter is seen in almost two-thirds of LGSC. Studies have tumors. Regardless, the relapse rate (20–50%) is still much
shown that SBT has BRAF mutations in 23–48% and KRAS less than for patients with invasive implants (>50%).
mutations in 17–39.5% of cases. Interestingly in all the cases The treatment of SBT, especially in young women who
studied, KRAS and BRAF mutations were mutually exclu- want fertility preservation, is surgical resection with surgical
sive. BRAF mutations have been reported only in serous staging including pelvic washing, omentectomy, and perito-
cystadenofibroma associated with SBT. neal biopsies being recommended. There is some debate on
KRAS, BRAF, and ERBB2 are upstream regulators of the the merits of complete staging including pelvic lymphade-
mitogen-activated protein kinase (MAPK) pathway, and nectomy. Earlier studies have shown that lymph node
mutations in these genes result in tumor proliferation. The involvement is the only site of recurrence in about 20% of
incidence of BRAF mutations in SBT is much lower when patients with SBT emphasizing the importance of surgical
compared to LGSC; however, KRAS mutations seem to have staging [51]. Recent study compared the outcomes of patients
a similar incidence in both tumors. These findings seem to with complete staging versus patients without any surgical
suggest that unlike KRAS, BRAF mutations are rarely staging. Only 6% of patients in the first group had lymph
involved in progression of SBT to LGSC. Furthermore, node involvement, and the relapse rates were not signifi-
BRAF mutations have been identified in nonrecurrent SBTs cantly different in the two groups. Hence, currently routine
suggesting a protective role for this gene. In a recent study, lymphadenectomy is not recommended for patients with
KRAS mutations have been identified in 60% of invasive SBT, except in cases with lymphadenopathy [52].
154 P. Ramalingam
5.7 Serous Carcinoma Several risk factors have been postulated for HGSC such as
late age of menarche, parity, and early menopause; however,
5.7.1 Overview the most important risk factor is a family history of ovarian
cancer [70]. Patients with HGSCs are typically postmeno-
Serous carcinomas, particularly HGSC, comprise the majority pausal (mean age of 63 years) and present with symptoms
of all epithelial ovarian cancers [53]. Several studies have now related to disseminated peritoneal disease such as nausea,
shown that HGSC and LGSC represent two distinctly different vomiting, abdominal pain and bloating, constipation, and uri-
disease entities based on clinical, morphologic, immunopheno- nary frequency; however, their non-specific nature delays
typic, and molecular characteristics [54–57]. Though a small diagnosis in some patients [71]. Laboratory testing typically
subset of LGSC may be associated with or “progress” to shows an elevated serum CA-125 usually >500 U/mL; how-
HGSC, the majority develop through a distinct pathway that is ever, this marker is fairly non-specific. Radiologic examina-
different than HGSC. LGSC has been shown to arise in a step- tion shows either unilateral or frequently bilateral complex
wise fashion from inclusion cysts to serous cystadenoma to ovarian masses, with omental and peritoneal lesions.
SBT [8]. However, the precursor for HGSC in the ovary has
been a subject of controversy. Traditionally it was thought to
arise from the ovarian surface mesothelium which presumably 5.8.2 Pathologic Features
underwent tubal-type metaplasia; however, no putative precur-
sor lesion has been identified. An alternative theory that has 5.8.2.1 Gross Features
emerged is that majority of ovarian HGSCs arise from the tubal The gross appearance of HGSC is variable. The tumor may
epithelium of the fimbrial end of the fallopian tube [58–62]. In have solid, hemorrhagic, and necrotic appearance (Fig. 5.24)
asymptomatic BRCA-positive patients who have undergone as well as cystic and papillary components. The tumor size is
risk-reducing bilateral salpingo-oophorectomy, early serous highly variable and ranges from small papillary tumors
carcinoma has been more frequently identified in the fallopian involving the surface to large tumors with parenchymal and
tube than in the ovary. Majority (80%) of these early fallopian surface involvement; mean size is 8.0 cm.
tube cancers are associated with serous tubal intraepithelial
carcinoma (STIC). Furthermore, STIC has been reported to be 5.8.2.2 Histologic Features
present in up to 40–60% of patients with advanced-stage ovar- Histologically, these are serous neoplasms that can have
ian cancer [63, 64]. STIC is cytologically similar to HGSC but varying architectural patterns including papillary, microcys-
is limited to the tubal epithelium without invasion and harbors tic, micropapillary, glandular, and solid patterns but are char-
TP53 mutations [65]. Studies have shown that in disseminated acterized by marked nuclear atypia (Fig. 5.25a–d).
ovarian cancer associated with STIC, both lesions show identi- In some cases HGSC can mimic either endometrioid carci-
cal TP53 mutations supporting a clonal relationship [61, 65]. noma or clear cell carcinoma. The glandular lumen, unlike in
Telomere studies in matched STIC and HGSC have shown endometrioid carcinoma, is slit like with irregular rather than
shorter telomeres in majority of STIC when compared to both smooth borders. A subset of HGSC can have large papillary
normal tubal epithelium and HGSC [66]. These findings sug- fronds mimicking urothelial carcinoma (Fig. 5.26). These
gest that STIC is likely an earlier lesion than HGSC [66].
However, in about 15–30% of HGSC, no lesion is identified in
the fallopian tube, despite extensive sampling using the SEE-
FIM protocol [2, 59, 67]. A recent multicenter study performed
genomic analysis of advanced-stage HGSC with and without
STICs and found no significant differences in the RNA
sequence and miRNA data between the two cohorts suggesting
a common origin for all HGSCs [68]. Having said that, the pos-
sibility of multifocal disease arising in a background of meta-
plasia to tubal-type epithelium must also be considered [2].
5.8 High-Grade Serous Carcinoma
As mentioned earlier, HGSC is the most common ovarian epi-

thelial carcinoma (80–90%) and affects the western popula- Fig. 5.24 Gross image of high-grade serous carcinoma showing a uni-
tion and Caucasian women more frequently than others [69]. locular cyst with papillary (asterisk) and solid tumor (arrow)
a b
c d
Fig. 5.25 High-grade serous carcinoma with varying histologic patterns. (a) Papillary pattern. (b) Microcystic and cribriform pattern. (c)
Micropapillary pattern. (d) Glandular pattern
“transitional cell carcinomas” were initially thought to be a dis-

tinct entity, but immunohistochemical stains have shown that
their immunophenotype is similar to HGSC, and are now con-
sidered to be a variant of this tumor in most cases [72]. Rare
tumors are composed entirely of transitional cell pattern, and
most show at least focal areas of typical HGSC. The tumor
cells have variable amounts of cytoplasm which can sometime
be clear. The nuclei are usually pleomorphic though in some
cases tumor heterogeneity is present and the nuclei are rela-
tively uniform with fine chromatin. In the latter, the presence of
numerous mitotic figures and immunohistochemical evidence
of serous differentiation will facilitate the diagnosis. While
destructive stromal invasion is a necessary feature to make a
diagnosis of LGSC, it is not essential for a diagnosis of HGSC.
“Noninvasive” tumors with a predominantly intracystic papil-
lary appearance, reminiscent of SBT, are still considered to be
Fig. 5.26 High-grade serous carcinoma with transitional pattern char-
HGSC if the cytologic features are present. Psammoma bodies
acterized by large papillae lined by sheets of tumor cells that resemble
are present usually focally and in some cases extensively, urothelial carcinoma. Occasional intraepithelial punched-out spaces are
though the latter is more characteristic of LGSC. seen which is typical
156 P. Ramalingam
5.8.3 Pathologic Grading equivocal, the case may be signed out as “serous carcinoma”
with a comment detailing the challenge with grading.
Ovarian serous carcinomas were traditionally graded as well,
moderate and poorly differentiated carcinomas. In 2004 Malpica
and colleagues proposed a two-tier grading system to distinguish 5.8.4 Biomarkers
LGSC from HGSC. Cytologic features including marked nuclear
atypia, pleomorphism, hyperchromasia, and prominent nucleoli, HGSC is positive for epithelial markers such as MOC-31,
with concurrent increase in mitotic activity, >12/10 hpfs, are BER-EP4, and CK7. These tumors are positive for PAX-8,
characteristic of HGSC [6, 13]. This grading system has been WT-1, and hormone receptors ER and PR and are usually dif-
found to be highly reproducible and is recommended by the fusely positive for p16 (Fig. 5.27a–d). Majority of HGSC show
2014 WHO classification of tumors of the female reproductive diffuse staining for ER/PR; particularly ER tends to be consis-
organs. The mitotic activity is the secondary criterion and is par- tently expressed in these tumors. This is in contrast to ER/PR
ticularly not reliable in patients who have had prior chemother- expression in uterine serous carcinoma which is quite low
apy, as it can be quite low. Similarly nuclear atypia can be quite when compared to endometrial endometrioid adenocarcinoma
prominent in patients who have had prior therapy; however, [73]. p53 can show two patterns of staining (Fig. 5.28a, b), one
marked pleomorphism with bizarre atypical cells is more typical in which the tumor cells show diffuse, strong nuclear staining
of HGSC. Of note, an attempt must be made to grade all serous in >60–75% of the tumor cells (mutant phenotype) and the
carcinomas, which is usually possible in most cases. In small other in which there is complete loss of p53 expression (null
core biopsies and post therapy, if grading is challenging, immu- phenotype). The former corresponds to a missense mutation in
nohistochemical stains for p53 and Ki-67 may be used (specifics TP53 while the latter to a nonsense mutation that results in a
discussed later). In rare cases where the histologic findings are truncated version of the protein which is not detected by the
a b
c d
Fig. 5.27 (a) High-grade serous carcinoma positive for MOC31; (b) PAX-8, (c) WT-1, (d) estrogen receptor
p53 antibody. In the null phenotype pattern, close examination study that were reported to be negative were histologically
to ensure that the internal control is working is necessary to not compatible with a diagnosis of HGSC based on review by
definitively conclude that there is complete loss of expression seven gynecologic pathologists. In cases that lack TP53 muta-
of p53. Another pattern of staining described in a recent study tion, p53 dysfunction is associated with a copy number gain
of HGSC is that of diffuse cytoplasmic staining in the tumor in MDM2 or MDM4.This results in the typical immunohisto-
cells in the absence of strong nuclear staining [74]. In this chemical pattern described above. Almost 50% of HGSC are
study, four cases of HGSC that showed diffuse cytoplasmic associated with either germline or somatic mutations of
staining were associated with loss-of-function (either indel or BRCA1 and BRCA2 genes. Another characteristic feature is
splicing) mutations of TP53. Loss-of-function mutations are the presence of numerous DNA copy number changes.
typically associated with complete absence of p53 expression,
the so-called null phenotype, and in this small cohort, it appears
that cytoplasmic staining may be another manifestation of this 5.8.6 Management and Outcome
type of mutation. Caution must be use when interpreting com-
plete absence or cytoplasmic staining in tumors with morpho- The standard approach for management of patients with
logic features of HGSC. The immunophenotype of common HGSC typically includes primary surgery followed by adju-
epithelial tumors and mesothelioma is summarized in Table 5.1. vant chemotherapy with platinum-based drug carboplatin
and taxane such as paclitaxcel (Taxol). The extent of residual
disease after primary surgery correlates with response to
5.8.5 Genetic Profile subsequent therapy [76]. In patients who cannot be optimally
debulked, neoadjuvant chemotherapy is recommended fol-
HGSC is associated with TP53 mutations in 96% of HGSCs, lowed by interval debulking after three cycles. In such
per the Cancer Genome Atlas [75]. Recent studies have shown patients preoperative laparoscopic examination to evaluate if
that the majority (71%) of cases in the Cancer Genome Atlas they can be optimally cytoreduced (no tumor nodules
a b
Fig. 5.28 (a) High-grade serous carcinoma showing diffuse strong staining for p53 (mutated phenotype) (b) and complete absence of p53 staining
(null phenotype)
Table 5.1 Immunohistochemical expression of ovarian epithelial neoplasms and mesothelioma

MOC31 PAX8 WT-1 ER/PR HNF-1β Napsin-A Calretinin p16 p53
Low-grade serous carcinoma + + + + − − −/+ Patchy Patchy
High-grade serous carcinoma + + + + − − −/+ Diffuse Diffuse
Endometrioid adenocarcinoma + + − + − − − Patchy Patchy/rarely diffuse
Clear cell carcinoma + + − −/+ + + − Patchy Patchy or diffuse
Seromucinous carcinoma + + +/− + − − − Patchy Patchy
Mesothelioma − −/+ + −/+ − − + Patchy Patchy or diffuse
ER estrogen receptor, PR progesterone receptor
158 P. Ramalingam
>1.0 cm) by p rimary surgery is typically performed with

subsequent treatment planning based on this assessment
[77–79]. In these cases, omental biopsies are obtained prior
to therapy, and on such biopsies confirmation of gynecologic
origin and grading of tumor must be provided by the
pathologist.
The prognosis of HGSC is variable. The 5-year survival is
about 30–40% [80]. Initial response to chemotherapy is typi-
cally good in most patients; however, 20–30% of patients
relapse within 6 months of treatment.
5.9 Low-Grade Serous Carcinoma

Fig. 5.29 Low grade serous carcinoma with haphazardly infiltrative
LGSC is much less common than HGSC with a reported papillary pattern. Numerous psammoma bodies are present (right field)
incidence of 3–5% [81]. LGSC is associated with serous
cystadenoma or SBT in majority of cases and likely arise
from these tumors. LGSC can be associated with SBT in up
to 60% of cases [82]. Patients with LGSC present almost a
decade earlier than HGSC. The presentation is variable, and
patients may be symptomatic from bulky disease, or the
diagnosis may be made incidentally, in patients with low-
stage disease. Ascites, abdominal distention, and pain can be
seen in patients with advanced-stage disease.
5.9.2 Pathologic Characteristics
5.9.2.1 Gross Features

The tumors are often bilateral, and grossly they can have a
gritty appearance due to extensive calcification. The average
size of the tumors is about 8.0 cm. Fig. 5.30 Low grade serous carcinoma with micropapillary (upper
left) and cribriform (lower right) patterns of invasion; background
serous borderline tumor is present
5.9.2.2 Histologic Features
Histologically the most typical appearance of LGSC is that
of epithelial nests and small papillae surrounded by clear admixture of micropapillary, glandular, and single cell
halos haphazardly infiltrating the stroma, associated with patterns.
numerous psammoma bodies (Fig. 5.29). In the ovary, there From a cytologic point of view, LGSC can show mild to
is frequently an associated serous borderline tumor compo- moderate nuclear atypia and small nucleoli (Figs. 5.33
nent (Fig. 5.30). In some cases, a predominantly glandular and 5.34). The distinction from HGSC serous carcinoma is
pattern may be seen, and the glands are embedded in the based on nuclear pleomorphism rather than just nuclear
stroma without the typical clear spaces around them atypia. Especially post therapy, diffuse moderate atypia and
(Fig. 5.31). The main difference between the glandular pat- prominent nucleoli can be seen. Mitotic activity is typically
tern of LGSC and tangentially sectioned SBT in the stroma low (<12/10hpfs) in these tumors. Cases with either increased
is the presence of desmoplastic stromal reaction. Another nuclear atypia or mitoses may pose a challenge to distinguish
pattern that can be challenging to recognize is the inverted from HGSC, and in these cases, immunostains may be used
macropapillary pattern that is characterized by large edema- to differentiate the two tumors (discussed below).
tous papillae surrounded by clear spaces that can mimic tan- Though uncommon, a few patients with SBT/LGSC can
gentially sectioned edematous papillae of SBT (Fig. 5.32). A have admixed high-grade areas (Fig. 5.35) or can recur as
subset of cases may show cribriform pattern in the invasive HGSC; hence, careful examination of the entire tumor is
component. Frequently in high-volume tumors, there is an necessary [27].
Fig. 5.31 Low grade serous carcinoma with a glandular pattern of

invasion Fig. 5.33 Low grade serous carcinoma with banal cytology
Fig. 5.32 Macropapillary pattern of low-grade serous carcinoma Fig. 5.34 Low grade serous carcinoma with low grade cytology and
showing numerous large edematous papillae surrounded by clear numerous psammoma bodies
spaces. When not so prominent, they can be mistaken for tangential
sectioning of the serous borderline tumor component
Therefore correlation with morphology and p53 staining is
more important.
5.9.3 Biomarkers
Similar to HGSC, LGSCs are positive for PAX-8, WT-1, 5.9.4 Genetic Studies
estrogen receptor (ER), and progesterone receptor (PR).
When distinction of LGSC from HGSC is morphologically LGSC is typically associated with either KRAS or BRAF
challenging, immunohistochemical stains for p16, p53, and mutations in about 35% and 33% of cases, respectively,
Ki-67 may be used. LGSCs show patchy staining for p16, which are also seen in SBTs [86, 87]. KRAS mutations at
wild-type staining for p53 (Fig. 5.36a, b), and low Ki-67 codons 12 and 13 and BRAF mutations at codon 599 are
proliferation index, while HGSCs show diffuse staining for mutually exclusive in that only one of the two mutations is
p16 and p53 and elevated Ki-67 proliferation index [83–85]. present in a given tumor [87]. LGSCs have a fewer number
These markers are also helpful in detecting focal HGSC in of somatic mutations [88], and methylation profiling shows
an otherwise predominantly LGSC. In some cases p16 that they are more closely related to SBT than HGSC [89].
staining may show aberrant overexpression in LGSC Subsequent studies have shown that BRAF mutations are
(Fig. 5.37a, b) or patchy expression in HGSC (Fig. 5.37c, d). much less frequent in advanced-stage LGSC (2–6%) [4, 90].
160 P. Ramalingam
patients with inoperable disease or significant comorbidities,

neoadjuvant chemotherapy followed by interval debulking
may be considered [92]. Patients with advanced-stage dis-
ease have ~70% 5-year and ~50% 10-year survival rates
[81]. Patients with LGSC do not respond very well to che-
motherapy, but lack of other evidence-based therapeutic
alternatives still makes it the mainstay of treatment. Recent
studies have shown that hormonal maintenance therapy fol-
lowing primary surgery and platinum-based chemotherapy
was associated with lower risk of disease progression when
compared to observation only [93]. However, there was no
effect on overall survival in this single retrospective study
[93]. Hormonal therapy has also shown to have moderate
antitumor activity in patients with recurrent LGSC especially
when they are platinum sensitive and the tumor is positive
for both ER and PR expressions [94]. Clinical trial using
Fig. 5.35 An example of serous borderline tumor on the left showing selumetinib, a mitogen-activated protein kinase kinase
low-grade cytology adjacent to an area of high-grade serous carcinoma (MEK) inhibitor, has shown either complete or partial
with prominent cytologic atypia. There was differential staining for p16
and p53 in the two components (not shown) response in 15% of recurrent LGSC [95]. Additional studies
are needed to find alternative therapies for this uncommon
The authors suggested that these LGSCs likely arose from chemotherapy-resistant tumor.
SBTs without BRAF mutations, explaining the lower fre-
quency in the study [90]. Similar findings were identified in
a subsequent study [4] suggesting that BRAF mutations in 5.10 D
ifferential Diagnosis of Low-Grade
SBT may somehow have a protective effect on the future and High-Grade Serous Carcinoma
development of LGSC [91].
5.10.1 High-Grade Serous Carcinoma Versus
Low-Grade Serous Carcinoma
5.9.5 Management and Outcome
Distinguishing LGSC from HGSC is of utmost importance,
Treatment options for LGSC include primary surgical resec- and an attempt must be made to grade all serous neoplasms.
tion with adequate surgical staging for early-stage disease The morphologic differences such as nuclear pleomorphism
and optimal cytoreductive surgery for advanced-stage dis- and mitotic activity assist in distinguishing HGSC from
ease followed by adjuvant chemotherapy [81, 91, 92]. In LGSC. Some cases of HGSC may have a “micropapillary”
a b
Fig. 5.36 Low grade serous carcinoma, with patchy staining for (a) p16, and (b) wild-type staining for p53
a b
c d
Fig. 5.37 (a) Example of low-grade serous carcinoma with banal cytology showing (b) aberrant overexpression of p16. (c) Case of high grade
serous carcinoma with marked cytologic atypia showing (d) patchy staining for p16
appearance with numerous psammoma bodies mimicking squamous differentiation, lack of WT-1 expression, and
LGSC from low power; however, atypia and mitotic activity wild-type staining for p53 favor endometrioid adenocarci-
are usually apparent on high power; hence careful examina- noma, though a small subset of high-grade endometrioid
tion is necessary in all cases. Additionally immunohisto- adenocarcinoma can be diffusely p53 positive [96].
chemical stains for p16, p53, and Ki-67 may be employed in
this differential as these markers are overexpressed in
HGSC, while they show patchy or wild-type expression in 5.10.3 Clear Cell Carcinoma
LGSC. In some cases especially core biopsies, the distinc-
tion may be challenging to make and must be stated as such Clear cell carcinoma can closely mimic HGSC especially
in the report. since both tumors can have papillary pattern and cytoplasmic
clearing (Fig. 5.38a–d). The presence of tubulocystic pattern,
papillae with hyalinized fibrovascular cores, and hobnailing
5.10.2 Endometrioid Adenocarcinoma support a diagnosis of CCC over HGSC. In challenging cases,
use of immunostains such as ER, WT-1, HNF-1β, and napsin-
Endometrioid adenocarcinoma typically lacks the degree of A can be helpful in the differential diagnosis. CCC is typically
nuclear atypia seen in HGSC. The glands do not have intrag- positive for HNF-1β and napsin-A and negative for ER and
landular tufting and papillae seen in HGSC. The presence of WT-1, while HGSC shows the opposite staining pattern [97].
162 P. Ramalingam
a b
c d
Fig 5.38 (a) High-grade serous carcinoma showing cytoplasmic clearing and (b) hobnailing mimicking clear cell carcinoma. Tumor cells are
positive for WT-1 (c) and negative for napsin-A (d)
5.10.4 Malignant Mesothelioma to be negative in majority of mesotheliomas [28]; however,

positive staining has been reported, and we have encountered
Malignant mesothelioma can mimic both HGSC and it in routine practice (Fig. 5.41).
LGSC. The tubular and papillary patterns of MM can resem-
ble LGSC and HGSC (Fig. 5.39a, b). The atypia in MM is
usually mild to moderate though rare cases may show marked 5.10.5 Metastatic Tumors
atypia. Histologic features that should raise concern for MM
include monomorphic cells with abundant pink cytoplasm Both HGSC and LGSC can mimic metastatic breast cancer,
frequently invading the stroma as single cells, lack of promi- particularly since all these tumors can have a micropapillary
nent stratification of the nuclei, and low mitotic activity. The pattern. Especially in patients with BRCA gene mutations
histologic overlap, particularly with LGSC, can really con- who are at a higher risk for both breast and ovarian tumors,
found the diagnosis. Immunostains that support epithelial this can be a real diagnostic challenge. Invasive ductal car-
and mesothelial cells must be employed as a panel. Markers cinomas of the breast can have significant nuclear atypia in
of epithelial differentiation include MOC-31 and BER-EP4, the metastatic site mimicking ovarian HGSC. An immuno-
and those of mesothelial differentiation include WT-1, cal- histochemical panel to include markers of breast cancer
retinin, D2-40, and thrombomodulin (Fig. 5.40a–c). ER and such as GATA3, gross cystic disease fluid protein-15, and
PR are typically negative (Fig. 5.40d) in mesothelioma, mammaglobin and those of HGSC such as PAX-8 and WT-1
though focal staining can be seen. PAX-8 has been reported may be used to facilitate the distinction. However, it must be
a b
Fig. 5.39 Malignant mesothelioma mimicking serous carcinoma
a b
c d
Fig. 5.40 (a and b) Malignant mesothelioma showing positive staining for (a) WT1 and (b) calretinin and negative staining for (c) MOC31 and
(d) estrogen receptor
164 P. Ramalingam
tumor and mixed epithelial borderline tumors. Since the pre-

dominant cell types were serous and endocervical mucinous
epithelium and the tumor had papillary architecture similar
to SBT, the authors designated them as seromucinous tumors.
Seromucinous carcinomas are uncommon tumors, and there
is some controversy regarding its existence as a distinct
entity, and its diagnostic reproducibility is questionable.
Molecular studies have shown that both seromucinous bor-
derline tumors and carcinomas have ARID1A mutations sim-
ilar to endometrioid and clear cell tumors. This finding along
with the morphologic heterogeneity of these tumors, i.e., the
presence of epithelium besides serous and mucinous types,
suggests that mixed epithelial tumor, rather than seromuci-
nous, may be a better designation for this group of neo-
plasms. The clinicopathologic and molecular features of
Fig. 5.41 Diffuse PAX8 staining can be seen in a small subset of these tumors are described in detail below.
mesotheliomas
noted that both GCDFP-15 and mammaglobin are not very 5.11.2 Seromucinous Cystadenoma/
sensitive markers and a negative staining does not exclude a Adenofibroma
breast primary. On the other hand, both these markers can
show staining in a small subset of ovarian carcinomas [98]. Seromucinous cystadenoma/adenofibromas are benign
GATA3 is currently the most sensitive and specific marker tumors that are composed of a mixture of epithelial cells
for breast carcinomas and should be included in the immu- which comprises at least 10% of the lesion. They present
nohistochemical panel when a breast primary is in the dif- in women in the reproductive age group and are detected
ferential diagnosis. PAX-8 is expressed in most HGSC; either incidentally or due to symptoms related to an ovar-
however, we have encountered a few cases of breast carci- ian mass. The tumors are usually unilocular and grossly
noma that express this marker; therefore, using a panel of indistinguishable from typical serous cystadenomas. The
stains rather than reliance on any one marker is cyst may contain serous or mucinous fluid. Histologically,
recommended. the epithelial components are primarily serous and muci-
Other tumors with a well-described micropapillary pat- nous; however, endometrioid, transitional-like, and squa-
tern such as lung and bladder carcinomas can mimic either mous cells may be present. In adenofibromas, the stroma
HGSC or LGSC. For lung adenocarcinomas, the use of PAX- is bland and fibrous. They are treated with unilateral
8, WT-1, ER, and TTF-1 may facilitate the distinction. salpingo-oophorectomy.
Aberrant TTF-1 staining has been reported in a small subset
of ovarian serous carcinomas; hence, a panel of markers
must be employed in this differential diagnosis. Metastatic 5.11.3 Seromucinous Borderline Tumor
urothelial carcinoma with micropapillary pattern can be dis-
tinguished from serous carcinomas using CK7, CK20, These tumors are noninvasive proliferative tumors that
GATA3, ER, and WT-1. were previously considered to be a subtype of mucinous
tumors and were designated as endocervical-type mucinous
borderline tumor [99–101]. In the 2014 WHO classification
5.11 Seromucinous Tumors of tumors of female reproductive organs, they are catego-
rized as a separate group of tumors [14]. The patients are
5.11.1 Overview typically in the reproductive age group and present with
non-specific symptoms related to an ovarian mass. They are
Seromucinous tumors are a new category of tumors in the associated with endometriosis in a third of the cases.
2014 WHO classification of tumors of female reproductive Majority of cases are unilateral; however, up to 30% can be
organs [14]. They are divided into benign, borderline and bilateral [99]. The tumors have an average size of 8–10 cm.
carcinomas, similar to other epithelial tumors of the ovary. The cysts are invariably unilocular with intracystic papil-
The term seromucinous tumor was first coined by Shappell lary excrescences. The cyst wall may contain hemorrhage,
in 2002 [99]. In their series, there was no clinical difference and histologically these usually represent areas of
between cases of endocervical-like mucinous borderline endometriosis.
Histologically the tumor resembles a typical SBT with com-

plex papillary architecture and hierarchical tufting (Fig. 5.42).
The epithelial lining is composed primarily of endocervical-type
mucinous and serous epithelium; however, endometrioid, transi-
tional-like, and squamous epithelium can be present (Fig. 5.43a,
b) [99]. Cells with abundant eosinophilic cytoplasm also called
“indifferent cells” may be interspersed usually at the tip of the
papillae and tufts (Fig. 5.43c). Goblet cells are not identified.
Nuclear atypia is minimal and mitotic activity is low. There is
usually an acute inflammatory infiltrate present within the epi-
thelial lining (Fig. 5.43d). Intraepithelial carcinoma, microinva-
sion, and occasionally micropapillary pattern may be present, but
these features do not seem to have an adverse effect on prognosis
[99, 102, 103]. Stromal invasion is absent by definition.
The tumors are positive for PAX-8, ER, and PR and either
negative or focally positive for WT-1. They are negative for
CK20 and CDX-2. Fig. 5.42 Seromucinous borderline tumor with low-power features of
typical serous borderline tumor
a b
c d
Fig. 5.43 (a) Seromucinous borderline tumor showing areas with dant cytoplasm, i.e., indifferent cells (arrow) and squamous differentia-
prominent cytoplasmic mucin resembling endocervical glands. (b) tion (asterisk), are present. (d) Intracellular neutrophilic infiltrate is
Other areas show distinct tubal-type morphology. (c) Cells with abun- frequently seen
166 P. Ramalingam
Molecularly the tumors demonstrate mutations in ARID1A 5.11.6 Differential Diagnosis

and consequent loss of BAF-250a expression in tumor cells.
These findings support the notion that these tumors are more The differential diagnosis is based on the predominant cell
closely related to endometrioid and clear cell carcinomas, type present in an individual tumor. The most common con-
which show similar ARID1A mutations. siderations include endometrioid adenocarcinoma with
mucinous differentiation and LGSC. Distinguishing endo-
metrioid adenocarcinoma with mucinous differentiation
5.11.4 Seromucinous Carcinoma from seromucinous carcinoma is somewhat arbitrary as there
is significant histologic and immunophenotypic overlap
Seromucinous carcinomas are described in the 2014 WHO between the two tumors.
classification of tumors of female reproductive organs as Distinguishing LGSC from seromucinous carcinoma is
tumors composed predominantly of serous- and endocervical- based on the absence of different cell types, lack of associ-
type mucinous epithelium, but endometrioid, clear cell, and ated endometriosis, and strong diffuse WT-1 positivity in the
squamous differentiation may be present [14]. In the largest former.
series reported, the tumors presented in women of reproduc- Molecular studies have shown that KRAS mutations are
tive age group with over half the women being less than most common followed by PIK3CA, PTEN, and ARID1A.
40 years of age [104]. The majority were unilateral though BRAF mutations are less common and when present are not
about one sixth were bilateral. associated with concurrent KRAS mutations [105].
The histologic appearance is characterized by the pres- The 2014 WHO classification of tumors of the female
ence of a mixture of cell types primarily endocervical-like reproductive organs and the initial largest series of 19 tumors
mucinous, serous, endometrioid, and eosinophilic “indiffer- reported by McCluggage et al. supported retaining seromuci-
ent cells,” but hobnail cells, squamous cells, clear cells, and nous carcinoma as a distinct entity [104]. However, more recent
signet-ring cells may also be present (Fig. 5.44a, b). The study on a larger number of seromucinous carcinomas suggests
tumors typically show expansile pattern of invasion similar that these tumors can be classified as either endometrioid or
to mucinous and endometrioid tumors, and infiltrative inva- serous carcinomas in majority of cases using immunohisto-
sion is less common. chemical and molecular studies [105]. The diffuse staining for
hormone receptors and the presence of KRAS and PTEN muta-
tions in majority of cases suggest that most tumors are likely a
5.11.5 Biomarkers variant of endometrioid adenocarcinoma. The authors suggest
that the immunomolecular findings do not support a category
Seromucinous carcinomas are positive for CK7, PAX-8, ER, of ovarian seromucinous carcinoma. Given the small number
and PR and are negative for CK20 and CDX2. Majority of of reported cases in the literature, our understanding of these
the reported tumors are either negative or very focally posi- tumors is still evolving, and additional studies are needed to
tive for WT-1. determine if it represents a distinct entity or not.
a b
Fig. 5.44 (a) Seromucinous carcinoma with endocervical-type (arrow) and squamous differentiation (asterisk). (b) Another example showing
tubal and mucinous differentiation. The tumor was WT-1 positive (not shown) and best classified as low-grade serous carcinoma
The prognosis of these tumors in the few reported studies sis with miliary granular appearance or cyst-like lesions with
has been favorable with most patients presenting with stage I psammomatous calcification [108]. As mentioned previ-
disease. Advanced-stage disease has been associated with ously, by definition, the ovaries are either uninvolved or
worse prognosis. show only minimal surface involvement. Grossly the omen-
tum shows adhesions, plaques, and granular lesions.
Histologically, the tumors are similar to noninvasive epithe-
5.11.7 Management and Outcome lial (Fig. 5.45) and desmoplastic implants. Endosalpingiosis
is usually present and can have some intraglandular prolif-
The majority of the tumors both borderline and carcinoma eration (Fig. 5.46a); however, hierarchical tufting when pres-
are stage I; however, peritoneal implants, usually desmoplas- ent warrants a diagnosis of SBT (Fig. 5.46b). The lesions
tic noninvasive, and lymph node involvement can be seen in may be present in the fibrous septae separating adipose tissue
a minority of cases (~10%). The treatment is similar to SBTs nodules; however, no invasion is identified. Adequate sam-
and consists of unilateral or bilateral salpingo-oophorectomy pling of the omental tissue is recommended to rule out areas
with staging biopsies. The prognosis of seromucinous bor- of LGSC.
derline tumors is excellent in the reported cases thus far, even
in the presence of peritoneal implants [99].
5.12 Peritoneal Serous Neoplasms
5.12.1 Peritoneal Serous Borderline Tumor
The peritoneum is usually involved by implants of SBT as

discussed previously. Rarely peritoneal borderline tumors
with minimal or no involvement of the ovaries can occur and
were formerly referred to as primary peritoneal serous
micropapillomatosis [106]. These tumors likely arise from
peritoneal endosalpingiosis which is present in majority of
cases (~70–80%) [106, 107]. The patients are usually in the
reproductive age group (mean 32 years) and present with
abdominal pain or infertility [107]. Some patients are asymp-
tomatic, and the diagnosis is made either on atypical findings
Fig. 5.45 Abdominal wall lesion showing florid endosalpingiosis
in a Pap smear, or radiologic examination/ surgery for other (arrows) and areas with epithelial proliferation consistent with perito-
complaints [107]. The typical finding is diffuse carcinomato- neal serous borderline tumor (arrowhead)
a b
Fig. 5.46 (a) Areas of endosalpingiosis with intraluminal papillae without epithelial tufting, which is not sufficient for a diagnosis of serous
borderline tumor. (b) Serous borderline tumor partially involving a gland of endosalpingiosis (arrow)
168 P. Ramalingam
5.12.2 Management and Outcome 5.12.5 Differential Diagnosis
The prognosis for patients with peritoneal SBT is favorable The assessment of peritoneal serous tumors should include
similar to patients with ovarian SBT with noninvasive distinction of LGSC from HGSC using criteria and immuno-
implants. However, similar to their ovarian counterparts, histochemical stains previously described. Other entities
there is a small risk for progression to LGSC; hence, long- such as peritoneal mesothelioma should also be excluded
term follow-up is recommended for these patients. (previously discussed).
5.12.3 Peritoneal Serous Carcinoma 5.12.6 Genetic Profile
The Gynecologic Oncology Group (GOG) established crite- The genetic profile of primary peritoneal HGSC is similar to
ria to distinguish ovarian serous from primary peritoneal other pelvic HGSCs with predominance of TP53 mutations
serous carcinoma in 1993 [109]. Per the GOG criteria, (1) [68, 112]. KRAS and BRAF mutations have been identified in
both ovaries should be normal in size or enlarged by a benign peritoneal LGSC similar to ovarian primaries [87, 113].
process; (2) involvement of extraovarian sites should be
larger than that involving the surface of both ovaries; and (3)
the tumor in the ovarian surface and superficial cortical 5.12.7 Management and Outcome
stroma or within the ovarian parenchyma must measure
5 × 5 mm. Per the College of American Pathologists, a diag- The management and outcome for peritoneal serous carci-
nosis of primary peritoneal serous carcinoma is made in the noma are similar to advanced-stage ovarian carcinoma,
presence of normal bilateral ovaries and fallopian tubes by either HGSC or LGSC. If the patients can be optimally deb-
gross and microscopic examination or when they are enlarged ulked, then surgery followed by adjuvant therapy is the
by benign disease. Hence both ovaries and fallopian tubes mainstay of treatment. In patients who are not surgical can-
must be entirely submitted for histologic evaluation. The didates, neoadjuvant therapy with platinum-based drug car-
presence of either serous tubal intraepithelial carcinoma or boplatin and taxane such as paclitaxcel (Taxol), as used for
tubal mucosal serous carcinoma, regardless of the size, is ovarian serous carcinoma, is recommended.
consistent with a fallopian tube primary. The presence of
serous carcinoma in the fimbrial end, rather than the ovary, in
patients with BRCA mutations and demonstration of clonal
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Ovarian Endometrioid and Clear-Cell
Tumors 6
Jennifer Katzenberg and Andres A. Roma
Abstract 6.1 Introduction

Clear-cell and endometrioid tumors are subtypes of
Müllerian epithelial tumors that can arise in the uterus as Ovarian epithelial tumors are a heterogeneous group of neo-
well as the ovary. These subtypes of primary ovarian tumors plasms that are classified predominantly by cell type. Two of
include benign, borderline, and malignant counterparts as these histotypes—clear cell and endometrioid carcinoma—
opposed to other Müllerian sites where these tumors usu- have been shown to display a strong association with endo-
ally present as malignant neoplasms (carcinomas). A strong metriosis, and the latter appears to be the disease process that
association with endometriosis has been reported with the is most central to their development [1–9] (Figs. 6.1a–c).
histogenesis of these tumors. This chapter covers the clini- Endometriosis is diagnosed in about 10% of reproductive-
copathologic features of these endometriosis-associated age women and reaches a prevalence of 30–50% of women
histotypes of ovarian carcinoma. with infertility or other clinical symptoms [3–6]. The origin
and pathogenesis of endometriosis are comprehensively
Keywords addressed in Chap. 31. This chapter covers the clinicopatho-
Endometrioid carcinoma · Clear-cell carcinoma · logic features of the aforementioned two endometriosis-
Endometriosis · Adenofibroma associated histotypes of ovarian carcinoma.
a b
Fig. 6.1 (a) Medium magnification of endometrioma composed of almost devoid of endometrial type stroma, but with persistent vessels
endometrial type epithelium and focal superficial dense stroma with and hemosiderin deposits. (d) Endometriosis with atypia consistent
vessels. (b) High power of endometriosis. (c) Area of endometriosis with atypical endometriosis
J. Katzenberg · A. A. Roma (*)

Department of Pathology, University of California San Diego,
San Diego, CA, USA
174 J. Katzenberg and A. A. Roma
c d
Fig. 6.1 (continued)
6.2 Ovarian Endometrioid Tumors a
6.2.1 Benign Endometrioid Tumors
Although most ovarian endometrioid and clear-cell tumors

are carcinomas, benign and borderline counterparts also
exist [10, 11]. The most common benign endometrioid tumor
is endometrioid adenofibroma/cystadenofibroma. While
endometrioma is considered a pseudotumor, representing
cystic endometriosis instead of a tumor, recent studies have 2 cm
shown that ARID1A and PIK3CA mutations appeared consis-
tently in concurrent endometriosis-associated clear-cell car- b
cinomas [12].
6.2.1.1 Endometrioid Cystadenoma/

Adenofibroma/Cystadenofibroma
These are uncommon ovarian tumors composed of different
amounts of cystic elements, benign fibromatous-type stroma,
and glands lined by endometrioid-type epithelium (Fig. 6.2a,
b). If both cystic and fibrous elements are present, the tumor
is labeled cystadenofibroma. Rarely, endometrioid cystade-
nomas have been described and represent unilocular tumors
with minimal to no fibromatous stroma [10]. Incidence of
benign endometrioid tumors is relatively uncommon when
compared to benign serous and mucinous tumors.
The first series of 12 endometrioid adenofibromas was
reported by Kao and collaborators; 2 years later, Roth et al. Fig. 6.2 (a) Gross image on endometrioid cystadenoma; note areas of
remote hemorrhage that are suggestive of endometriosis (arrows) (cour-
reported ten additional cases and subclassified them as tesy Dr. Wenxin Zheng). (b) Endometrioid adenofibroma composed of
benign, proliferating, and adenocarcinoma [13, 14]. an exophytic polypoid structure lined by endometrial epithelium with
abundant fibromatous stroma and occasional entrapped glands
Clinical Features
Risk factors for these tumors include previous tamoxifen effects, may cause proliferative and, in rare instances, malig-
therapy; while the origin as mentioned has been linked to nant changes in endometriosis [15]. Most patients are post-
endometriosis. Tamoxifen, as a result of its estrogenic menopausal, with an average age of 57 years. Tumors are
6 Ovarian Endometrioid and Clear-Cell Tumors 175
a b
Fig. 6.3 (a) Frozen section of an endometrioid adenofibroma composed of thick fibrotic, polypoid, bulbous papillary structures lined by cuboidal
epithelium. (b) Adjacent area with an abundance of endometrioid-type glands within a polypoid papillary structure
often unilateral with nonspecific symptoms; pain can result triosis, the main differential diagnosis is with a borderline
from torsion or bleeding [11, 13, 14]. tumor or even carcinoma. Endometriosis lacks the dense
fibromatous stroma, has more cellular endometrial type
Pathologic Findings stroma, and evidence of recent or remote hemorrhage.
Grossly, these tumors display substantial variability in size, Benign serous or mucinous cysts have a different epithe-
and may exceed 15 cm in greatest dimension in some cases. lial lining, displaying ciliated epithelium and intracyto-
Adenofibromas have a solid, white, firm cut surface and are plasmic mucin, respectively. Clear-cell and mucinous
usually unilateral; they may display a smooth fibroma-like cystadenofibromas are rare [10, 11]. Borderline tumors,
external surface or show a cauliflower-like appearance with described later, have more epithelial proliferation and
papillary excrescences [10, 11]. Papillary structures are thick atypia, while carcinomas have definitive features of
and fibrotic, which can be used to differentiate these tumors malignancy, including invasion, glandular crowding, and
from serous borderline tumors, which often have more significant atypia. In particular, serous borderline tumors
edematous papillae (Fig. 6.3a). Tumors have a predominance can be confused with endometrioid cystadenofibromas
of fibrous stroma and widely spaced glands within the with papillary features; however, the papillae are more
stroma, which is hypocellular in comparison to normal endo- fibrotic in endometrioid cystadenofibromas and serous
metrium (Fig. 6.3b), and can be associated with an endome- borderline tumors harbor abundant epithelial prolifera-
triotic cyst or endometriosis. Alternatively, they may form a tion, mild atypia, and cell detachment (i.e., detached pap-
nodule within the wall of an otherwise cystic/multicystic illary fragments devoid of stroma).
lesion. Stromal cells are typically spindled with scant cyto-
plasm and tapering nuclei. The stromal component domi- Management and Outcomes
nates in adenofibroma while the cystic component is more These are benign tumors and the prognosis is excellent; most
conspicuous in cystadenofibroma. The epithelial component tumors are treated with simple resection without staging [10,
is characterized by endometrial type epithelium, sometimes 11].
simple, cuboidal, or cylindrical, but most frequently strati-
fied inactive or proliferative-type endometrium [10, 11].
Other endometrial phases can be present, such as secretory 6.2.2 Borderline Endometrioid Tumors
patterns, or may be atrophic or metaplastic. There is usually
mild to absent atypia or mitosis, and no periglandular stro- The category of borderline tumor is well defined for serous
mal cuffing. Dystrophic stromal calcifications can be and mucinous tumors; however, there is less agreement in
present. the specific criteria that determine an endometrioid tumor to
be borderline [10]. Borderline ovarian tumors have more epi-
Differential Diagnosis thelial proliferation than is seen in their benign counterparts,
While it is important to differentiate from other benign and display variable nuclear atypia; however, in contrast to
ovarian adenofibromatous or cystic lesions and endome- carcinomas, there are no definitive features of malignancy,
a b
Fig. 6.4 (a) Low power of endometrioid tumor with clustered, yet mildly atypical, endometrioid glands within a fibromatous stroma, features of
borderline tumor (courtesy Dr. Wenxin Zheng). (b) High-power magnification demonstrating mild atypia (courtesy Dr. Wenxin Zheng)
including destructive stromal invasion, and their prognosis is 6.2.2.4 Management and Outcomes
much better than that of carcinomas [16]. Endometrioid borderline ovarian tumors carry a good prog-
nosis. Most tumors are stage I; therefore surgical staging is
6.2.2.1 Clinical Features not necessary in most cases; however, in most series,
While endometrioid carcinomas are common ovarian tumors, patients were treated with total abdominal hysterectomy
borderline or atypical proliferative tumors (as they are also and bilateral salpingo-oophorectomy. Rare recurrences
known) are rare [17]. In one of the largest studies to date, were recorded, but malignant behavior has yet to be
Bell et al. reported 33 tumors. Patient age ranged from 24 to reported [11, 17, 18].
85 years with a mean of 46 years [17]. Presentation included
a mass in half the patients, pain in few, and incidental finding
in the remaining patients. Most tumors were unilateral, solid, 6.2.3 Ovarian Endometrioid Carcinomas
and cystic. More than 60% are associated with endometriosis
[10, 11, 17]. These tumors are malignant epithelial tumors that resemble
endometrioid carcinoma of the uterine corpus at the morpho-
6.2.2.2 Pathologic Findings logic level.
Tumors may display a predominant fibromatous back-
ground or may show an intracystic component. Predominant 6.2.3.1 Clinical Features
glandular and papillary patterns have also been described Ovarian endometrioid carcinoma accounts for less than 5%
[17]. of all ovarian tumors, and between 10 and 20% of all ovarian
Similarly to adenofibromas, the majority of these carcinomas [10, 11, 19]. They primarily present in post-
tumors contain abundant glands surrounded by a dense menopausal women with average age of 56 years. Most are
fibromatous stroma (Fig. 6.4a, b). The glands in these low grade and/or present at early stage, and more than 60%
tumors demonstrate moderate architectural complexity of cases arise from endometriotic cysts or have evidence of
and are more closely packed. As reported previously, most endometriosis elsewhere in the patient [10, 11, 19].
cases display grade 1 nuclei, while a third contain grade 2
nuclei [17]. The presence of extensive necrosis was found 6.2.3.2 Pathologic Findings
in one-third of cases, but predominantly the ischemic or The majority of tumors are cystic or multicystic, with varying
infarct type [17]. degrees of solid growth, either interposed between cysts or
The category of borderline or atypical proliferative projecting into cysts [17, 20]. Some tumors can be completely
tumor with intraepithelial carcinoma was described in solid with hemorrhage and necrosis. Other tumors can arise
tumors with diffuse, marked, cytologic atypia evidenced from an endometriotic cyst and might include areas of atypi-
by nuclear enlargement and pleomorphism with large, cal endometriosis (Fig. 6.5a, b); intracystic tumors can pres-
prominent nucleoli [17]. Its significance is uncertain ent as a polypoid nodule projecting into the lumen of a
since none of these patients have recurred or died of thick-walled endometriotic “chocolate” cyst (Fig. 6.6). Size is
disease. variable with a mean tumor size of 14–15 cm (range, 4–30 cm)
and tumors are uncommonly bilateral [17, 20]. Necrosis and
6.2.2.3 Differential Diagnosis hemorrhage are seen in less than half of the cases.
The main differential diagnosis is endometrioid adenocarci- The diagnosis of carcinoma is based on one of the two
noma, which is further detailed in the following section. morphologic features. When the tumor displays destructive,
a b
Fig. 6.5 (a, b) Low, medium, and high power of endometriotic cyst with an atypical lining. Note the simple lining of cells with large, pleomorphic
nuclei and hobnail features. These findings are not sufficient for a diagnosis of carcinoma
Fig. 6.6 Gross image of endometrioid carcinoma arising in endome-

trioma. Note yellow central tumor within cyst harboring focal greenish
lining
b
infiltrative growth the diagnosis is evident; these tumors har-
bor irregular, and in some cases incomplete or fragmented,
glands within a desmoplastic stroma (Fig. 6.7a, b).
Additionally, as reported by Bell et al., tumors with conflu-
ent glandular growth exceeding 5 mm in dimension are also
designated as carcinomas. This is the most common pattern
seen, at least in one series (Fig. 6.8a, b) [17, 20]. The glandu-
lar proliferation consists of crowded, back-to-back
endometrioid glands with moderate-to-severe cytologic

atypia, often with stratified epithelium, as well as glands
with extensive branching and budding, with concomitant
exclusion of intervening stroma or glands with substantial
internal complexity (bridging and cribriform growth pattern)
(Fig. 6.9a–h) [17, 20]. Nearly all tumors in one series dem-
onstrated background areas of borderline tumor (noninvasive Fig. 6.7 (a, b) Areas of stromal invasion with desmoplastic stroma and
component) or an adenofibromatous background [20]. incomplete glands
a b
Fig. 6.8 (a) Adenocarcinoma composed of endometrioid glands with growth smaller than 5 mm; in isolation this focus would be insufficient
confluent growth and minimal intervening stroma exceeding 5 mm in to warrant a diagnosis of carcinoma
dimension. (b) An image from the same tumor showing confluent
a b
c d
Fig. 6.9 (a, b) Endometrioid adenocarcinoma composed of clustered carcinoma. Notice the lack of high-grade atypia associated with
glands and solid growth. (c–f) Complex glands with intraglandular pap- clear-cell or high-grade serous carcinoma
illary features and necrosis. (g–h) solid growth in endometrioid adeno-
e f
g h
Several variant growth patterns have been described. A

villoglandular pattern is common and contains villous papil-
lae projecting into a cystic lumen [10]. Secretory changes
can also be seen represented by vacuolated cells resembling
secretory-type endometrium. Squamous differentiation is
common. Mucinous change, ciliated cells (Fig. 6.10), and an
oxyphilic variant, composed of large polygonal tumor cells
with eosinophilic cytoplasm, have been described. Lastly, an
unusual but important-to-recognize variant is composed of
solid growth punctuated by tubular or small rosette-like
glands (microglandular pattern) resembling sex cord ele-
ments and has been termed “endometrioid carcinoma resem-
bling sex-cord stromal tumor” or the sertoliform variant
(Fig. 6.11a–c) [10, 11]. Endometrioid carcinomas should be
graded using the FIGO grading system that is applicable to
their endometrial counterparts.
Fig. 6.10 High power of endometrioid carcinoma with ciliated cells.
Notice cilia within apical border of gland
a b
Fig. 6.11 (a–c) “Endometrioid carcinoma resembling sex cord stromal tumor” or the “sertoliform variant” composed of tubules that are fused in
areas. This growth pattern resembles that seen in a Sertoli cell tumor
6.2.3.3 Biomarkers involved in the regulation of several important cellular

Similarly to other Müllerian carcinomas, endometrioid ovar- processes; β-catenin is a key effector in this pathway.
ian tumors express vimentin, cytokeratin 7, and PAX8 and β-Catenin-mediated signaling is deregulated in ovarian
usually lack cytokeratin 20 (Fig. 6.12a–d); these tumors endometrioid carcinomas, usually on the basis of activat-
express estrogen and progesterone receptors in varied pro- ing mutations of CTNNB1; CTNNB1 mutations are very
portions based on grade or degree of differentiation [16, 21, uncommon in other major types of ovarian carcinoma
22]. WT1 is rarely expressed in ovarian (and uterine) endo- [27]. CTNNB1 mutation has been associated with squa-
metrioid carcinoma and can be used in its distinction from mous differentiation, low tumor grade, and a favorable
other ovarian carcinomas, especially serous carcinoma. outcome [25, 26]. PIK3CA and PTEN mutations also co-
occur in a subset of ovarian endometrioid carcinomas in
6.2.3.4 Genetic Profile both the ovary and the endometrium; PIK3CA mutations
Whole-genome or targeted sequencing has shown that are associated with an adverse prognosis [27]. Activating
mutations in PTEN (14–20%), CTNNB1 (16–53.3%), and mutations in KRAS and BRAF have been reported in ovar-
KRAS are most commonly associated with ovarian endo- ian endometrioid carcinomas, but the frequency of muta-
metrioid cancer [23–26]. The canonical Wnt (i.e., Wnt/β- tions in these genes is rather low [27]. Loss of
catenin/Tcf, hereafter Wnt/β-cat) signaling pathway is heterozygosity (LOH) is common in endometriosis and
a b
c d
Fig. 6.12 (a) High-power detail of endometrioid adenocarcinoma. (b) PAX8 is positive in tumor cell nuclei. (c) Cytokeratin 7 is positive in tumor
cell cytoplasm. (d) Cytokeratin 20 is negative in tumor cell cytoplasm
synchronous ovarian carcinomas, and may involve altera- risk is much smaller than for uterine cancer [34]. In one study,
tions in TP53 [28, 29]. loss of MMR protein function is more common in endometrio-
Similar molecular genetic profiles have been described in sis-associated carcinomas (10%) when compared to high-grade
endometriosis, endometrial borderline/atypical proliferative serous carcinomas (1%) [33]. Specifically, MMR function was
tumor, and ovarian endometrioid carcinoma, which supports lost in endometrioid (2/29 cases), clear-cell (1/27 cases),
endometriosis as a precursor lesion [23–31]. Mutations of undifferentiated (1/8 cases), and mixed carcinomas with an
the tumor-suppressor gene AT-rich interactive domain- endometrioid, clear cell, and/or undifferentiated component
containing protein 1A (ARID1A) are common to endometri- (3/5 cases) [33]. As expected tumors with abnormal MMR sta-
oid and clear-cell ovarian carcinomas; Wiegand et al. tus demonstrated MSI using a polymerase chain reaction-
reported mutations in ARID1A in 30% of endometrioid car- based assay evaluating five mononucleotide repeat markers
cinomas and none of the studied 76 high-grade serous ovar- [34]. The following features, commonly seen in endometrial
ian carcinomas [32]. carcinomas with abnormal MMR expression, were not seen in
Finally, microsatellite instability (MSI), or DNA mismatch ovarian tumors: tumor-infiltrating lymphocytes, peritumoral
repair (MMR) protein loss, in these tumors has been described lymphocytes, or variable morphology. Among seven patients
[33, 34]. Ovarian cancer, particularly endometrioid adenocar- with tumors with abnormal MMR/MSI, five (71%) were alive
cinoma, is also associated with Lynch syndrome, although the without disease at the conclusion of the study [33].
6.2.3.5 Differential Diagnosis gastrointestinal carcinoma, in particular colorectal

Correct interpretation of tumor type, as well as not overcall- (Fig. 6.13a–c) (Table 6.1). Unfortunately, in a quarter of
ing a borderline endometrioid tumor as carcinoma, is a key cases, the metastatic tumor can be the primary manifestation
differential diagnostic consideration. Additionally, determin- of disease. Features commonly ascribed to metastatic tumors
ing if the tumor is primary to the ovary or a metastasis from include bilateral involvement, younger age at presentation
another gynecological or extra-gynecologic site is also (47 years vs. 63 years of age), and morphologic features such
important, and will be discussed. as a “garland growth pattern” and “dirty” necrosis [35, 36].
As previously noted, a diagnosis of ovarian endometrioid Another classic feature common to metastatic tumors is the
carcinoma requires either destructive invasion, typically presence of multinodular or multifocal involvement within
composed of incomplete glands and detached single cells in the ovary. Metastatic tumors can have a smooth outer surface
a desmoplastic stoma, or confluent growth. The latter is more and occasionally may be unilateral and small [35].
challenging to recognize, and requires at least 5 mm of back-
to-back glands or a cribriform growth pattern [17, 20]. Table 6.1 Features suggestive of metastatic spread to ovary rather
Frequently, ovarian endometrioid carcinomas coexist than primary ovarian endometrioid carcinoma
with endometrial endometrioid carcinomas and determining Bilateral > unilateral
if the tumors represent synchronous primaries versus metas- Multinodular configuration
tasis is challenging and will be addressed subsequently. Surface involvement
Finally, metastatic carcinomas can mimic primary ovar- Ovarian tumor <10 or 12 cm
ian tumors, with the most common mimic being primary Lymphovascular invasion
a b
Fig. 6.13 Frozen section slides of an ovarian tumor in a patient with a tures of colorectal carcinoma. (c) Garland pattern of invasion composed
history of colorectal carcinoma. (a) Low power showing two distinct of large cysts with cribriform architecture and dirty necrosis
patterns of metastasis. (b) Destructive invasive pattern with classic fea-
6.2.3.6 Management and Outcomes presence of associated endometrial hyperplasia

Ovarian endometrioid carcinoma has a favorable prognosis, (Fig. 6.14a–d). Synchronous ovarian carcinoma is usually
although their lower grade and lower stage probably account unilateral with no surface involvement, demonstrates a
for much of this [22]. A recent Canadian study showed that background of endometriosis and/or adenofibroma, lacks
the 5-year and 10-year overall survival rates for women with vascular invasion, and is not found in other organs or sites
endometrioid ovarian cancer were 80.6% and 68.4%, respec- [11, 38]. Bilateral involvement and/or multinodular growth
tively; after adjusting for confounders, excluding stage, there in ovarian tumors are characteristics of metastases
was a significantly lower risk of death from endometrioid (Fig. 6.15a–d) [11].
cancer compared to serous ovarian cancer [37]. In this study, Clonality analysis using LOH and gene mutation analysis
almost all (98%) patients with endometrioid cancer under- has been shown to be useful in discriminating metastatic
went primary surgery; neoadjuvant chemotherapy was sel- from independent primary carcinomas [39]. Molecular diag-
dom used for patients with endometrioid cancer (7.1%) [37]. nostic techniques have shown that metastatic carcinomas
contain identical mutation profiles [40].
6.2.4 S
pecific Issues Associated with Ovarian 6.2.4.2 Endometrioid Carcinoma Arising
Endometrioid Tumors in Endometriosis
Sampson first described the association between endometri-
6.2.4.1 Endometrioid Carcinoma Involving Both osis and endometrial carcinoma in the 1920s and since then
Ovary and Endometrium most studies have shown increased risks for ovarian cancer
Coincidence of both primary ovarian and endometrial carci- in women with endometriosis [8, 41–44]. In a systematic
noma is a relatively common event occurring in about 5–10% review, the relative risk for clear-cell or endometrioid ovar-
of cases; both tumors are of endometrioid type in the majority ian carcinomas was approximately twofold for women with
of cases [11, 38]. Usually, the tumors are well differentiated a history of endometriosis [45]. According to a recent
and have similar morphologic features. Often it is quite dif- population-based study in Denmark, women with endome-
ficult to determine if the tumors represent synchronous pri- triosis had statistically significantly increased risk for ovar-
maries or metastasis based on clinical or morphologic ian (standardized incidence ratios (SIR) 1.55; 95% confidence
features alone. Accurate diagnosis as independent primaries interval (CI): 1.35–1.77) and endometrial cancer (SIR 2.13;
or metastases is necessary for appropriate staging and treat- 95% CI: 1.77–2.55) [46]. For ovarian cancer, statistically
ment as there is a substantial change in grade between the significantly increased risk were observed after 1–4 years
two scenarios. (SIR 1.51; 95% CI: 1.00–2.18) and 5–9 years of follow-up
Synchronous tumors are diagnosed if most of the fol- (SIR 1.78; 95% CI: 1.30–2.37) but not ≥10 years after the
lowing features are present: histological dissimilarity of first diagnosis of endometriosis [46]. Also, for ovarian can-
tumor type, absent or only superficial myoinvasion of the cer, increased risk were observed only for endometrioid (SIR
endometrial tumor, absence of vascular invasion, and/or 1.64; 95% CI: 1.09–2.37) and clear-cell (SIR 3.21; 95% CI:
a b
Fig. 6.14 (a, b) Endometrial endometrioid tumor with pushing borders, cystic ovarian endometrioid tumor with divergent papillary and glandu-
confined to the endometrium. (b) Note the presence of benign endome- lar morphology indicative of synchronous primary
trial glands at the base of the endometrial tumor. (c, d) A concurrent
c d
a b
c d
Fig. 6.15 (a) Invasive endometrial adenocarcinoma with lymphovascular invasion. (b, c) Ovarian tumor with similar morphologic features, albeit
with areas of necrosis. (d) The tumor also invaded the fallopian tube indicative of metastatic spread
a b
c d
Fig. 6.16 (a, b) Well-differentiated polypoid endometrioid adenocarcinoma arising from areas of endometriosis. (c, d) High-grade carcinoma
arising from endometriosis; other foci showed classic features of clear-cell carcinoma
2.01–4.85) tumors [46]. An increased risk for endometrioid 6.3 Ovarian Tumors with a Sarcomatous
tumors was observed ≥10 years after a diagnosis of endome- Component
triosis. For clear-cell tumors, statistically significantly
increased risk was observed 5–9 years and ≥10 years after a 6.3.1 Adenosarcoma
diagnosis of endometriosis [46].
While there are few clinical signs that can be concerning Müllerian adenosarcoma of the ovary is rare [11]. It has simi-
for malignant transformation, there is no definitive way to lar morphologic features to uterine adenosarcoma. In one of
risk stratify patients [47]. the largest series, Eichhorn and collaborators reported 40
In their analysis of benign ovarian endometrioid tumors cases [48]. Mean age at presentation was 54 years (range
and well-differentiated endometrioid carcinomas, Bell and 30–84 years). All patients underwent oophorectomy and in
Kurman found frequent coexistence of endometriosis, benign 85% hysterectomy as well. Contralateral oophorectomy was
endometrioid neoplasms such as endometrioid adenofibroma performed in 28% of patients; all but one patient had unilat-
or endometrioid tumor of borderline or low malignant poten- eral disease [48]. Grossly, most tumors were predominantly
tial, and well-differentiated endometrioid carcinoma solid with numerous small cysts. Microscopically, tumors
(Fig. 6.16a–d) [17]. These findings, and other similar molecu- were composed of benign-appearing, and occasionally
lar abnormalities seen in endometrioid tumors and adjacent malignant-appearing, glands set in sarcomatous stroma; sar-
endometriosis, support a process of endometriosis-carcinoma comatous overgrowth was seen in 25% of cases [48]. Most
progression. glands displayed endometrioid epithelium, while squamous,
a b
Fig. 6.17 (a) Adenosarcoma with a classic phyllodes pattern of growth and dense, cellular stroma. (b) High power showing dense stroma and
benign epithelium; note the presence of stromal mitosis
a b
Fig. 6.18 (a, b) Adenosarcoma with areas of stromal nuclear pleomorphism
tubal, hobnail, clear-cell, or even mucinous-type epithelium Abnormal uterine bleeding was not as common as in
was also seen [48]. Cystic dilatation of the glands was com- endometrial tumors, and ovarian adenosarcomas more likely
mon and accounted for some of the cysts seen on gross presented with a pelvic mass [48]. Ovarian adenosarcoma
examination; leaflike stromal projections were common demonstrated a poorer prognosis when compared to the
(Fig. 6.17a, b). In most cases, the stromal component resem- endometrial subtype [48].
bled endometrial stroma, but could also be fibromatous or an
admixture of both. Periglandular cuffing was identified in all
tumors (Fig. 6.18a, b) [48]. 6.3.2 Endometrioid Stromal Sarcoma
Twenty of the 32 patients with available follow-up
recurred between 3 months and 6.6 years after diagnosis Endometrial stromal sarcoma is a mesenchymal, spindle-cell
(mean 2.6 years). Three patients developed lung metastases, neoplasm that predominantly arises from the endometrium
and two died of disease [48]. [49]. Extrauterine tumors are quite rare [49, 50]. Intrauterine
Compared with data from endometrial adenosarcoma, and extrauterine tumors share similar morphologic features,
ovarian tumors appear to present at younger age, with about including bland, uniform spindle cells resembling
half of patients presenting at or before 50 years of age. proliferative-type endometrial stroma with admixed spiral,
a b
Fig. 6.19 (a, b) Endometrial stromal sarcoma composed of bland, uniform, spindled cells resembling proliferative-type endometrium and
admixed spiral, arteriole-like vessels
arteriole-like vessels (Fig. 6.19a, b) [49]. In addition, cases 6.4 Carcinosarcoma

can harbor variable histologic features including sex cord,
smooth muscle, fibromyxoid, and glandular differentiation Primary ovarian carcinosarcoma, previously known as
[49, 50]. malignant mixed Müllerian tumor, is a rare malignancy
In one of the largest series, Oliva and collaborators accounting for 1–3% of all ovarian tumors. It is more com-
described 27 primary ovarian endometrioid stromal sarco- mon in the uterus, where it represents around 5% of malig-
mas [50]. The mean age at presentation was 56 years (range nant tumors [10, 11, 54–57]. Ovarian carcinosarcoma,
38–76 years). All patients underwent oophorectomy, and similarly to their uterine counterpart, occurs in postmeno-
60% of them, in addition, hysterectomy. Contralateral pausal women at a median age of 65 years [54].
oophorectomy was performed in 70%; 20 patients had uni- Carcinosarcoma, by definition, is a biphasic tumor com-
lateral disease [50]. Grossly, most tumors were predomi- posed of high-grade epithelial and mesenchymal components
nantly solid, while a smaller proportion was predominantly (Fig. 6.20a–f) [10, 11, 54]. These tumors are typically large
cystic. with conspicuous areas of hemorrhage and necrosis [54]. The
On microscopic examination, a diffuse growth of uniform epithelial component is typically composed of grade 3 endo-
cells with scant cytoplasm predominated; a nodular growth metrioid, serous or undifferentiated carcinoma; clear-cell,
pattern was present in some tumors, as well as a fibromatous mucinous, squamous, or undifferentiated components can also
morphology [50]. These tumors usually express CD10 and be seen. The mesenchymal component can be homologous
variable amounts of SMA, and in general lack desmin and (high-grade undifferentiated, round-cell or spindle-cell sar-
h-caldesmon [49]. coma, similar to endometrial stromal sarcoma, fibrosarcoma
Several cytogenetic abnormalities have been reported in or rarely leiomyosarcomas) or heterologous (rhabdomyosar-
uterine ESS, the most common involving a nonrandom t coma, chondrosarcoma, osteosarcoma, or liposarcoma) [10,
(7;17)(p15;q21), which results in the fusion of the first 3 11, 54, 55]. Rarely other components such as melanocytic or
exons of JAZF1 (at 7p17) to the last 15 exons of JJAZ1 [49]. neuroectodermal differentiation have been reported [55].
In a small series, only one of the six reported extrauterine TP53 mutations (23%) and/or p53 protein overexpression
endometrial stromal sarcoma contained JAZF1-JJAZ1 fusion (60%) are the most frequent molecular abnormalities [56].
transcripts detected by reverse transcriptase–polymerase PI3KCA mutations (19%) and KRAS mutations (24%) have
chain reaction [49]. been reported [57].
Ovarian endometrioid stromal sarcomas are frequently Carcinosarcomas of the gynecologic tract have a very
associated with extraovarian spread at the time of diagnosis. poor prognosis, with an overall 5-year survival of less than
Oliva et al. reported that the majority of patients had stage II 30%, the worst of which are ovarian primaries [54, 58]. In a
disease or higher (20/27) [50]. recent single-institution case series, most patients presented
As expected, many cases of extrauterine endometrial with stage III or IV ovarian carcinosarcoma with a median
stromal sarcoma are associated with endometriosis progression-free survival and overall survival of 10 and
[50–53]. 21 months, respectively [59].
a b
c d
e f
Fig. 6.20 (a) Biphasic neoplasm with malignant glands and spindled stroma. (b, c) Rhabdomyosarcomatous component of carcinosarcoma; note
the prominent rhabdomyoblastic differentiation. (d–f) Chondrosarcomatous component in carcinosarcoma
6.5 Ovarian Clear-Cell Tumors tal finding, a palpable pelvic mass, or with nonspecific symp-
toms such as vaginal bleeding [10, 62, 65–67]. While the
6.5.1 Overview pathogenic relationship between adenofibromas and clear-
cell carcinoma is unclear, there is some histomorphologic and
A model of ovarian carcinogenesis has been proposed that molecular evidence that suggests an adenofibroma-carcinoma
divides these diverse tumors into two groups designated, type sequence [65, 66, 68–70]. Studies have also suggested that
I and type II [60, 61]. The prototypic type I tumor is low- there is an alternate pathogenic mechanism in endometriosis-
grade serous carcinoma; type I tumors are generally confined associated clear-cell carcinoma compared to those with an
to the ovary at diagnosis (stage I) and develop in a stepwise adenofibromatous background [68–71]. Some adenofibromas
fashion from a well-established precursor lesion, such as a are associated with endometriosis, so it is difficult to defi-
borderline tumor [60, 61]. In addition to low-grade serous nitely claim that there are two different tumorigenic path-
carcinomas, endometrioid and mucinous carcinomas are con- ways; nevertheless, no study to date has shown malignant
sidered type I tumors. Molecular genetic alterations that are behavior in clear-cell adenofibromas which are considered
commonly encountered in type I tumors are KRAS, BRAF, benign [11].
PTEN, and/or CTNNB1 and/or microsatellite instability. Type
II tumors, on the other hand, are highly aggressive, have a 6.6.1.2 Pathological Findings
high frequency of TP53 mutations, and do not arise from pre- Clear-cell cystadenomas/adenofibromas are generally
cursor lesions. In other words, they arise de novo. The patho- smooth, lobulated, solid masses raging in size from 3 to
genesis of ovarian clear-cell carcinoma, however, does not fit 16 cm; the cut surface is gray-white with small, closely
neatly into one of these two categories [60–62]. In terms of packed cysts imparting a spongelike appearance [11, 65–67].
the precursor lesions, histologic and epidemiologic analyses Microscopically, they consist of orderly, widely spaced
have shown a close relationship between endometriosis and glands of various sizes lined by 1–2 layers of flat, cuboidal to
ovarian clear-cell carcinoma [63, 64]. While the current 2014 columnar epithelium. This epithelium is typically lined with
WHO subdivides all ovarian clear-cell tumors into benign, clear cells with or without cytoplasmic hobnailing and rarely
borderline, and malignant types, the criteria for distinguish- eosinophilic cells embedded in a fibromatous stroma
ing these categories are not well established, and their bio- (Fig. 6.21a–c). The stroma is composed of bundles of
logic behavior remains uncertain [11, 65–67]. spindle-shaped cells with plump elongated nuclei, resem-
bling ovarian stroma. There is little to no nuclear atypia, and
mitotic figures are rare. Because of the rarity of these tumors,
6.6 Benign Clear-Cell Tumors it is recommended that they be sampled extensively, or sub-
mitted entirely, to exclude areas of atypia or invasive carci-
6.6.1 Clear-Cell Cystadenoma/Adenofibroma noma [65].
6.6.1.1 Clinical Features 6.6.1.3 Differential Diagnosis

These tumors are extremely rare with an average age range of It is important to differentiate these benign lesions from
40–61 years at diagnosis. They usually present as an inciden- clear-cell carcinoma, and extensive sampling is recom-
a b
Fig. 6.21 (a–c) Different magnifications of a clear-cell adenofibroma, composed of a tubular epithelial proliferation of cuboidal epithelium with
clear cytoplasm devoid of cytologic atypia set in a dense stroma
which then develops into borderline adenofibroma and

c
finally clear-cell carcinoma [62].

Similar to adenofibroma, the tumor’s cut surface is predomi-
nately solid, but small cysts containing clear, watery fluid
can be seen [66]. Histologically, these tumors are noninva-
sive and have a background appearance that is similar to
clear-cell adenofibroma but with greater variation in gland
size and shape and increased glandular crowding; the stroma
does not differ from that of adenofibroma [10, 65–67]. The
epithelium is composed of clear, hobnail, or eosinophilic
cells with mild-to-moderate nuclear atypia typified by varia-
tion in size, chromatin clumping, irregular nuclear contours,
and prominent nucleoli (Fig. 6.22a–c) [11, 65–67]. Cellular
Fig. 6.21 (continued) stratification may be seen. There is no substantial architec-
tural complexity, and minimal to no intraglandular cribri-
forming, solid, or papillary growth; the mitotic count is
mended. This diagnostic consideration is discussed further in typically less than one per ten high-power fields [10,
subsequent sections. 65–67].
Occasionally, rare tumors have been associated with
6.6.1.4 Management and Outcomes focal areas of invasion, or microinvasion, consisting of
While considered benign, studies have demonstrated a glands, epithelial islands, or single cells with malignant
genetic linkage between clear-cell adenofibromas and clear- nuclear features scattered haphazardly in normal or desmo-
cell carcinomas, specifically loss of heterozygosity on 5q, plastic stroma. The clinical significance of microinvasion is
10q, and 2q in both lesions, suggesting that adenofibromas unclear [65].
could represent a clonal precursor for ovarian clear-cell car-
cinoma [70]; otherwise, the prognosis is excellent [10]. 6.7.1.3 Genetic Profile
Studies by Weigand et al. demonstrated that the ARID1A
gene is frequently disrupted in ovarian clear-cell and endo-
6.7 Borderline Clear-Cell Tumors metrioid carcinomas [72]. When there is a component of bor-
derline clear-cell adenofibroma within the clear-cell
6.7.1 Clear-Cell Borderline Tumor/Atypical adenocarcinoma, they can share genetic abnormalities such
Proliferative Clear-Cell Tumor as loss of heterozygosity and mutations of ARID1A with sub-
sequent loss of BAF250a protein expression. Of note, loss of
6.7.1.1 Clinical Features BAF250a is seen more commonly in clear-cell carcinoma
Clear-cell borderline tumors, also referred to as “atypical arising from endometriosis rather than from borderline ade-
proliferative tumors,” comprise less than 1% of all ovarian nofibromas [73].
borderline tumors, and 5–8% of all clear-cell neoplasms [10,
65]. The average age at diagnosis is 59–68 years but increases 6.7.1.4 Differential Diagnosis
to 72 years for borderline tumors with microinvasion [65– The main differential diagnostic consideration is clear-cell
67]. These tumors typically present with abdominal enlarge- carcinoma (Fig. 6.23a, b). As opposed to the homogenous,
ment or a mass. The majority are unilateral, and 10–20% are solid cut surface of a borderline clear-cell lesions, clear-cell
associated with endometriosis confined to the ovary or pelvis carcinomas tend to have a fleshy cut surface with areas of hem-
on the ipsilateral side [10]. orrhage, necrosis, and a predominantly polypoid or papillary
Zhao et al. studied the progression of precursor lesions, growth pattern. Microscopically, clear-cell carcinoma is
such as endometriosis and borderline adenofibromas, into more architecturally complex and composed of tubulocystic,
clear-cell carcinoma and proposed an endometriosis- solid, and/or papillary growth set in a fibromatous to desmo-
carcinoma sequence with two different pathways. The first plastic stroma.
pathway begins with epithelial atypia arising in an endome- A less common diagnostic consideration includes yolk
triotic cyst that evolves into clear-cell carcinoma. In the other sac tumor with a predominant polyvesicular viteline pattern
pathway, non-cystic endometriosis induces a fibromatous (Fig. 6.24a–d) [74–76]. Compared to clear-cell lesions, yolk
reaction, which results in the formation of an adenofibroma, sac tumors are generally restricted to younger patients.
a b
Fig. 6.22 (a–c) Clear-cell borderline tumor composed of a tubular proliferation of cuboidal epithelium with clear cytoplasm and larger cells with
prominent nucleoli set in a fibromatous stroma. Notably absent is the presence of destructive invasion
a b
Fig. 6.23 (a, b) A clear-cell proliferation with prominent atypia that was seen adjacent to classic areas of clear-cell carcinoma that raises the pos-
sibility of a borderline tumor transitioning into carcinoma
a b
c d
Fig. 6.24 (a–d) Yolk sac tumor with an endodermal sinus and microcystic pattern of growth resembling Müllerian clear-cell carcinoma
Histologically, yolk sac tumors are often heterogeneous, and diagnosis is 53–55 years (range 19–82). The presentation
extensive sampling will often reveal more classic features, is similar to borderline adenofibroma with abdominal
such as Schiller-Duval bodies or hyaline globules. They are swelling, a pelvic mass, symptoms of endometriosis,
positive for alpha-fetoprotein, glypican-3, and SALL-4, and symptoms related to paraneoplastic syndromes, or non-
CK7 and EMA are negative [11, 76]. specific symptoms [10, 11, 65, 66, 71, 79, 80]. Ovarian
clear-cell carcinomas are associated with several paraneo-
6.7.1.5 Management and Outcomes plastic syndromes including hypercalcemia, venous
Since these tumors are rare, their behavior is not well under- thromboembolism, subacute cerebellar degeneration, and
stood. They are thought to carry a good prognosis, unless bilateral diffuse uveal melanocytic proliferation [79–81].
associated with areas of malignant transformation [10, 11]. A study by Matsuura et al. demonstrated that a thrombo-
embolic event was noted in 27.3% of patients with clear-
cell carcinoma, compared to 6.8% of patients with other
6.8 Ovarian Clear-Cell Adenocarcinoma epithelial ovarian cancers [81]. As previously mentioned,
50–70% of these tumors are associated with endometrio-
6.8.1 Clinical Features sis, but a small percentage can arise from borderline/atyp-
ical proliferative clear-cell tumors [68–71]. Additionally,
Ovarian clear-cell carcinoma comprises 5–25% of all they have also been associated with Lynch syndrome
ovarian carcinomas [10, 11, 77, 78]. The average age at [82–85].
6.8.2 Pathological Findings as a protruding nodule in an endometriotic cyst or as vari-

ably solid and cystic masses with a tan to yellow, hemor-
Macroscopically, clear-cell carcinomas are typically unilat- rhagic and necrotic cut surface [10, 11, 78]. Microscopically,
eral with an average size of 13 cm, but significant variation the architecture is quite diverse with tubulocystic, papil-
(range <1 to 35 cm) [78] (Fig. 6.25a, b). They can present lary, and solid growth patterns (Fig. 6.26a, d). The papillary
pattern, one of the most common patterns, is composed of
small and rounded papillary structures, with hyalinized,
a edematous, or “empty” fibrovascular cores; the papillae
lack hierarchical branching and tufting (Fig. 6.26a) [78].
The tubulocystic pattern is composed of small to large cys-
tic structures lined by tumor cells with luminal eosinophilic
material imparting a “targetoid” appearance. The solid
component consists primarily of contiguous tightly packed
nests of varying sizes rather than diffuse sheets (Fig. 6.26d)
[78]. The neoplastic cells can be clear, hobnail, flattened, or
cuboidal with clear, pale, or eosinophilic cytoplasm; sig-
net-ring-like cells have also been described (Fig. 6.27a–d)
[78]. The nuclei are hyperchromatic and eccentric, and
b have conspicuous nucleoli; most tumors show moderate-to-
severe atypia (Fig. 6.27e, f). Interestingly, mitoses are rela-
tively uncommon when compared to other high-grade
tumors, with most tumors showing 6 or less per 10 high-
power fields [78]. The cytoplasm is rich in glycogen that is
PAS positive and diastase sensitive. Some intracellular
lipid is present and intracellular mucin may rarely be seen,
which when present imparts a signet-ring appearance.
Psammoma bodies and eosinophilic hyaline bodies can be
seen in the papillary stroma. The associated stroma is most
often fibroblastic and hyalinized, but myxoid and edema-
tous changes have been described [78]. Most clear-cell car-
cinomas demonstrate no appreciable inflammation, but
when present the most common type is lymphoplasmacytic
[78]. There is no grading system as all are considered high
Fig. 6.25 (a, b) Gross images of two examples of clear-cell carcino- grade [11].
mas (courtesy Dr. Wenxin Zheng)
a b
Fig. 6.26 (a–d) Low power of clear-cell carcinoma with papillary (a), tubulocystic (b, c), and solid patterns (d)
c d
a b
c d
Fig. 6.27 (a–f) High-power magnification showing clear-cell morphology, nuclear atypia and pleomorphism, hobnail features, and eosinophilic/
oncocytic change in clear-cell carcinoma
e f
By immunohistochemistry, clear-cell carcinomas are pos- PTEN, another tumor-suppressor gene located at chromo-
itive for CK7, EMA, PAX-8, napsin A, and HNF-1β; estrogen some 10q23.3, has been implicated in the sequential progres-
and progesterone receptors are usually negative but can be sion from endometrial cysts to clear-cell carcinoma [89].
focally positive. WT1 is negative and most tumors are P53 PTEN encodes a phosphatase that dephosphorylates
wild type [11, 76, 86, 87]. phosphatidylinositol-3,4,5-triphosphate (PIP3), a phospho-
lipid that promotes cell growth and survival; its inactivation
leads to phosphorylation and activation of PIP3. In a study
6.8.3 Genetic Profile by Sato et al., somatic mutations in PTEN were seen in
approximately 8% of ovarian clear-cell carcinomas [89].
Ovarian clear-cell carcinomas share features of both type Studies have shown that one-third of ovarian clear-cell
I and type II tumors. Like type I tumors, most are diag- carcinomas have PIK3CA-activating mutations [72, 88, 90].
nosed at a low stage and are associated with precursor While this gene is mutated in other tumor types, ovarian
lesions including endometriosis, clear-cell adenofibro- clear-cell carcinoma has the highest frequency of PIK3CA
mas, and clear-cell borderline tumors [60–64, 66, 68–71]. mutations. From a therapeutic perspective, this finding is sig-
Studies by Fukunaga et al. and Ogawa et al. have shown nificant because new PI3K-targeting drugs are being devel-
that clear-cell carcinoma arises from endometriosis in oped. Most PIK3CA mutations occur in ARID1A-deficient
50–70% of cases [63, 64]. Like type II tumors, they tend carcinomas, suggesting that they might work together to pro-
to be high grade and behave aggressively when diagnosed mote tumorigenesis [72, 88, 90].
at a higher stage [62]. The carcinogenesis of ovarian Lynch syndrome is associated with ovarian clear-cell car-
clear-cell carcinoma has been hypothesized to be com- cinoma [82–84, 91]. In one of the largest studies, abnormal
prised of two different pathways: the adenofibroma- MMR expression by immunohistochemistry was identified in
carcinoma sequence and an endometriosis-carcinoma 6% of tumors and included deficiencies in MSH2/MSH6 (3),
sequence [60–62]. MLH1/PMS2 (1), MSH6 (1), and PMS2 (1) [84]. Patients
ARID1A, a tumor-suppressor gene, is commonly mutated were younger, with a mean age of 40 (range 31–48), which
in ovarian clear-cell carcinomas (46–57%) resulting in loss contrasted with a mean of 53.2 years (range 28–82) for the
of its protein product, BAF250a [72]. Studies have shown overall cohort of 109 tumors [84]. Tumors with diffuse intra-
that the BAF250a loss is seen more often in the endometriosis- tumoral stromal inflammation and peritumoral lymphocytes
carcinoma sequence. Additionally, mutations in ARID1A are were more frequently associated with MMR loss [84].
also seen in adjacent endometriotic lesions and in adjacent Unlike high-grade serous carcinoma, ovarian clear-cell
proliferative/atypical clear-cell adenofibromas, supporting a carcinomas have a lower frequency of BRCA1 and BRCA2
causal relationship [72, 88]. mutation [92, 93].
6.8.4 Differential Diagnosis Endometrioid carcinomas typically display a glandular

architecture with occasional solid growth. Eosinophilic cyto-
As previously mentioned, determining if a clear-cell tumor is plasm and cytoplasmic clearing are not usual, except in cases
benign, borderline, or malignant is the first step in analyzing with secretory change (please see endometrioid carcinoma
these lesions. In short, borderline tumors show more cytologic section) [97].
atypia than adenofibromas, but they lack convincing features of Germ cell tumors with clear changes include dysgermi-
malignancy; however, due to the limiting number of borderline noma as well as yolk sac tumors. Both of these tumors usu-
tumors reported, it is possible that borderline tumors are not a ally present in young women, as opposed to clear-cell
biologic category. These tumors share many molecular features carcinoma which occurs in postmenopausal or perimeno-
with carcinoma, and it could be our inability to differentiate pausal women [11, 12, 98]. Dysgerminomas are solid, white,
between the adenofibromas with more nuclear “atypia” from fleshy tumors with a diffuse or nodular growth pattern.
carcinomas. We cannot exclude the possibility that some Histologically, they are composed of solid sheets or nests/
tumors are progressing from adenofibromas to carcinomas and cords of polygonal tumor cells with clear cytoplasm and
are examined at a “borderline” point in progression. atypical, centrally placed nuclei with prominent nucleoli
The differential diagnosis of clear-cell carcinoma includes (Fig. 6.29a–d). The stroma is composed of fibrous bands
distinction from many other types of carcinomas, germ cell infiltrated predominantly by lymphocytes [10, 11, 98]. If the
tumors, sex cord stromal tumors, and metastasis. Ovarian clinical presentation and morphology are not sufficient to
high-grade serous carcinomas share a similar degree of cyto- differentiate between the two tumors, immunostains are
logic atypia, and while the architecture can be predominantly quite helpful. Dysgerminomas are positive for OCT3/4,
papillary or solid, as in clear-cell tumors, the presence of SALL4, PLAP, and CD117 while negative for cytokeratins
cytoplasmic clear-cell change is generally not as pronounced. while the opposite is true for clear-cell tumors [99, 100].
An exception to this is in cases of serous carcinoma with Yolk sac tumors present in young patients with a range of
neoadjuvant treatment where clear-cell change can be more <1 year to 46 years [101]. They harbor a multitude of morpho-
prominent (Fig. 6.28a, b) [94]. logical patterns, including microcystic or reticular, endoder-
Also, less frequently, serous borderline tumors can dismal sinus, solid, alveolar-glandular, polyvesicular vitelline,
play features resembling clear-cell carcinoma; features most myxomatous, papillary, macrocystic, hepatoid, and glandular
helpful in diagnosing clear-cell carcinoma with predominant (see differential diagnosis of borderline clear-cell tumors;
papillary features included unilaterality, nonhierarchical Fig. 6.24a–d) [11, 12, 101]. Some of these patterns, especially
branching, a monomorphous cell population, presence of the papillary and glandular patterns, can be commonly con-
more typical patterns of clear-cell carcinoma elsewhere in fused with clear-cell carcinomas. Yolk sac tumors express
the tumor, and presence of endometriosis [95]. In addition, germ cell tumor markers including SALL4, and additional
WT1 and estrogen receptor immunomarkers are usually not ancillary immunostains such as AFP, glypican-3, CK7, and
expressed in clear-cell carcinoma but are in serous tumors EMA have been used to facilitate this differential diagnosis
[95, 96]. [100–102]. Yolk sac tumors can express AFP; however, this
a b
Fig. 6.28 (a, b) Cystic high-grade serous carcinoma with micropapillary structures and significant cytologic atypia devoid of clear-cell change
marker has low sensitivity and specificity [101]. Glypican-3 is carcinomas (Fig. 6.30a–d). Metastatic clear-cell renal carcino-
expressed in the ample majority of yolk sac tumors (94–100%) mas are typically positive for CA-IX, CD10, and renal cell
but less frequently in clear-cell carcinomas (17%) [101]. CK7 carcinoma antigen, whereas ovarian clear-cell tumors express
expression in yolk sac tumors is variable (0–82%) but has Napsin A, CK7, and p504S; PAX8 and HNF1β do not help
been reported universally in clear-cell carcinomas [101, 102] distinguish between these tumors [103].
while EMA has been reported negative in yolk sac tumors and
widely expressed in carcinomas [102].
Lastly, metastatic tumors with clear cells can mimic pri- 6.8.5 Management and Outcomes
mary Müllerian carcinomas. In a recent study, Fadare and col-
laborators reviewed a large series of clear-cell renal carcinomas Ovarian clear-cell carcinomas are more likely to be detected
metastatic to the gynecological tract [103]. Although clear-cell at an early stage than other high-grade ovarian cancers, and
renal carcinomas and primary Müllerian clear-cell carcinomas if confined to the ovary have a good prognosis [104]. When
displayed extensive morphologic overlap, an increased mitotic presenting as advanced stage, the prognosis is very poor, and
index and prominent alveolar pattern were more frequently the tumors are usually resistant to standard treatment [104].
seen in metastatic tumors. Diffuse hobnail cells, hyaline glob- Cytoreductive surgery is recommended for patients with
ules, predominant tubulocystic pattern, or presence of a papil- advanced-stage (II or above) disease; hence, development of
lary growth pattern were more frequently seen in ovarian novel treatments based on molecular characteristics is
a b
c d
Fig. 6.29 (a, b) Dysgerminoma composed of large, clear cells, grow- (d) Placental alkaline phosphatase immunostain showing diffuse cyto-
ing in sheets, nests, and cords, separated by thick fibrous bands. (c) plasmic expression
Large cells with prominent nucleoli, characteristic of dysgerminoma.
a b
c d
Fig. 6.30 (a–d) Clear-cell renal cell carcinoma composed of cystic and solid patterns composed of clear cells devoid of significant atypia
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authors have none to declare.
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Ovarian Mucinous, Brenner Tumors,
and Other Epithelial Tumors 7
Cathleen Matrai, Taylor M. Jenkins, Esther Baranov,
and Lauren E. Schwartz
Abstract malignant or borderline histology, with borderline tumors

In this chapter we cover a wide variety of ovarian lesions. being more common [1, 2]. Given that findings of malignancy
While the majority of the chapter focuses on mucinous in these tumors may be focal, thorough gross inspection and
neoplasms of the ovary, we also discuss Brenner tumors sampling are essential, with two sections per centimeter of
and cover a wide range of rare ovarian neoplasms tumor being the recommended practice.
that every pathologist should be familiar with. This chap- Mucinous ovarian tumors have historically been difficult
ter emphasizes the differential diagnosis of these entities to classify, and the earlier literature must be regarded with
and keys to case workup and diagnosis. scrutiny in terms of prognosis and therapeutic response, as
many prior cohorts may have included tumors of extraovar-
Keywords ian origin. It has been extensively demonstrated over the
Mucinous · Brenner · Borderline · Carcinoma · Wolffian · years that, as with serous tumors, mucinous neoplasms fit
Small Cell into three main categories: benign (cystadenoma), borderline
(atypical proliferative mucinous tumors (APMT), and malig-
nant (carcinoma). Of note, the category of “seromucinous”
tumors of the ovary as introduced in the 2014 WHO includes
7.1 Ovarian Mucinous Tumors ovarian tumors previously categorized as endocervical/
Mullerian subtype of ovarian mucinous tumors. They will be
Epithelial ovarian neoplasms account for the majority of ovar- discussed separately in Chap. 24.
ian tumors, both benign and malignant. Mucinous tumors are The origin of mucinous tumors of the ovary has long been
the second most common type of ovarian neoplasm, exceeded debated. Based on molecular profiling, it is thought that pri-
only by tumors of serous origin. Mucinous tumors of ovarian mary mucinous neoplasms are more closely related to
origin are less likely to be malignant than their serous counter- endometriosis- related tumors, such as endometrioid neo-
parts, with benign tumors accounting for the vast majority, or plasms and clear-cell neoplasms, as well as low-grade serous
around 80% of mucinous neoplasms of the ovary. The remain- carcinoma, rather than to high-grade serous carcinoma.
ing 20% of mucinous tumors of ovarian origin are of either Some believe that primary mucinous neoplasms of the ovary
are to be considered non-Mullerian-derived neoplasms; how-
ever, many have been shown to express PAX8, a Mullerian
marker. Other suggested origins include germ cell and devel-
opment from Brenner tumors [3].
There is no single clinical or histologic feature, diagnostic
test, or immunohistochemical marker that definitively distin-
guishes between primary and metastatic mucinous neo-
C. Matrai
plasms of the ovary. However, when using all criteria in
Weill Cornell Medical College, Cornell University and New York-
Presbyterian Hospital, New York, NY, USA concert, confident determination can be attained in approxi-
e-mail: [email protected] mately 85% of these tumors. Features that favor metastatic
T. M. Jenkins · E. Baranov · L. E. Schwartz (*) disease include small size, bilaterality, multinodular growth
Penn Medicine, University of Pennsylvania Heath System, and/or surface involvement, and of course extraovarian dis-
Philadelphia, PA, USA ease or pseudomyxoma peritonei (PMP) [4].
e-mail: [email protected];
[email protected]
204 C. Matrai et al.
a b
c d
Fig. 7.1 Mucinous cystadenoma. (a) The tumors are typically large in Microscopically, the tumor is typically composed of glands and cysts
size with a smooth external capsule. (b) Cysts may be unilocular or lined by a simple, non-stratified epithelium. (d) On high power, the
multilocular, with thick viscous contents and a glistening surface. (c) cells are bland, with basally located nuclei and abundant apical mucin
7.2 Benign Mucinous Tumors/Mucinous in size from a few centimeters to greater than 30 cm, with rare
Cystadenomas reports up to 70 kg [9]. On gross examination, the external
surface of the tumor is typically smooth, with a thick tan-white
7.2.1 Clinical Features capsule. Mucinous cystadenomas are usually multicystic, and
typically have multiple smooth-walled cysts of varying sizes
Mucinous cystadenomas comprise 10–15% of all benign with thick, viscous contents (Fig. 7.1). These features can help
ovarian neoplasms and approximately 80% of mucinous distinguish them from serous tumors grossly, which tend to be
ovarian neoplasms [1, 2, 5]. The vast majority, >95%, are smaller and generally less complex, though this is not uni-
unilateral. While these tumors occur in women of all ages, formly the case. Any papillary or solid areas should be sam-
they are most common in women in the third to fifth decades pled thoroughly, as these features are more common in
of life [1, 6]. borderline/APMT and mucinous carcinoma as well as some
special categories of mucinous tumors (i.e., mural nodules).

7.2.3 Microscopic Findings
Mucinous cystadenomas typically have a large, multilocular
gross appearance, with an average reported size ranging from Histologically, mucinous cystadenomas typically display
10 to 18 cm [2, 7, 8]. Of note, cystadenomas can range widely either a gastric-foveolar type epithelium or intestinal type
7 Ovarian Mucinous, Brenner Tumors, and Other Epithelial Tumors 205
epithelium with scattered goblet cells, though this latter fea-

ture is more voluminous in borderline and malignant muci-
nous tumors, as well as tumors of extraovarian origin [5].
The lining is usually single celled, and consists of columnar,
non-ciliated epithelial cells with apical mucin and basal
nuclei. Architecturally, the cells form glands and cysts with
mucinous contents. Cytologically, there is minimal to no
significant atypia, though focal mitotic activity and/or reac-
tive atypia may be encountered at the periphery of the cysts,
which should not be mistaken for true cytologic atypia.
Areas of degenerative calcification and muciphages are
common, and in some cases luteinized stromal cells may be
seen. Dissection of acellular mucin has been described in up
to 10% of cases and should not be mistaken for invasive
disease [10].
Stratification, tufting, and papillary architecture are typ-
Fig. 7.2 Mucinous cystadenoma with associated Brenner tumor. A
ically absent (Fig. 7.1), though if present should comprise
transitional cell component can be seen admixed with bland mucinous
<10% of the epithelial volume. These latter tumors are glands
termed “mucinous cystadenoma with focal epithelial pro-
liferation,” a descriptive intermediate entity falling between
that of a classic cystadenoma and a borderline tumor, anala- unclear and the exact pathogenesis is unknown, though it is
gous to that seen in serous tumors (Table 7.1) [21]. In our postulated that the intimately admixed tumors may be due to
experience, the proliferation in these tumors is typically a metaplastic phenomenon [15]. Brenner tumors will be fur-
quite focal and is not usually a cause for diagnostic ther discussed below.
dilemma. However, when areas of proliferation are encoun- In the past, mucinous tumors including cystadenomas
tered, they should always be thoroughly sampled and care- have historically fallen into two main categories based on
fully evaluated microscopically. Mucinous cystadenomas their histologic appearance: intestinal type and endocervical/
with focal epithelial proliferation have been shown to Mullerian type, with intestinal type being far more common
behave well. (85%). According to the 2014 WHO, tumors of the endocer-
While mucinous cystadenomas of the ovary are relatively vical/Mullerian type are now recognized as histologically
common tumors, mucinous adenofibromas and cystadenofi- distinct tumors, officially referred to “seromucinous” tumors,
bromas are less so. These entities are histologically charac- which have their benign, intermediate, and malignant cate-
terized by their prominent fibrous stromal component in gories akin to their pure mucinous and serous counterparts.
addition to their epithelial derivation [11]. Adenofibromas These neoplasms will be discussed at greater length in Chap.
are predominantly solid tumors whereas cystadenofibromas, 24. Of note, this new designation remains somewhat contro-
as their namesake implies, have a predominant or partial cys- versial and a few recent papers have called into question the
tic component with variable amounts of fibrous stroma. true validity of this third category [17].
Mucinous adenofibromas and cystadenofibromas are less
common than their serous counterparts [12, 13]. Because
cystadenofibromas may appear radiologically as a cystic 7.2.4 Molecular Features
mass with solid components, they can mimic malignancy
and it is therefore important to keep these entities in the dif- Kras mutation has been reported in mucinous cystadeno-
ferential diagnosis [14]. mas, though not to the rates seen in borderline mucinous
A significant percentage of mucinous cystadenomas are tumors or mucinous carcinomas, with percentages ranging
associated with a minor transitional cell/Brenner component, from 0 to 58% [18–20]. Notably, though percentages vary
with reported figures most commonly in the 15–17% range, between studies, the trend is the same in that these muta-
though smaller studies have reported numbers as high as tions are more common in borderline and carcinoma cases.
30% [15, 16] (Fig. 7.2). This component may be present as a One of the same studies also showed that while a signifi-
discrete nodule or may be intimately admixed with the muci- cant proportion of mucinous borderline tumors and an
nous component of the tumor, and hence may be referred to even higher percentage of mucinous carcinomas show
as a concurrent Brenner tumor or a mixed tumor, respec- increased expression of c-myc on immunohistochemical
tively. Rare cases with prominent microcystic change have staining, mucinous cystadenomas did not show increased
been noted [15]. The significance of this association is expression [18].
Table 7.1 Primary ovarian mucinous neoplasms

Entity Clinical features Gross features Histopathologic features
Mucinous Unilateral (95%), mean age Mean size 10–18 cm, usually Multiple cysts lined by simple
cystadenoma 40–50 years, present with multilocular cyst (may be unilocular) mucinous epithelium without atypia
abdominal/pelvic pain or mass, with a smooth surface
rarely estrogenic symptoms
Mucinous As above As above <10% of the cyst is involved by
cystadenoma with epithelial stratification and tufting
focal epithelial
proliferation
Mucinous borderline Unilateral (>90%), mean age Mean size 17–22 cm, multilocular cystic Lined by intestinal type epithelium
tumor (and variants) 40–50 years, abdominal mass neoplasm which may contain solid foci; with greater than 10% showing
sampling at least 1 cm, increased to 2 cm proliferation; may show intraepithelial
if large in size or atypical features carcinoma and/or microinvasion
Mucinous carcinoma Reported age ranges varies, Similar to borderline tumors, tend to be Must contain one or both of the
most patients in their 40s unilateral and large with solid and cystic invasive patterns: confluent glandular/
components expansile and/or destructive stromal
7.2.5 Differential Diagnosis worse prognosis [23]. Occasionally, these tumors may cause
obstructive symptoms, usually due to large size [2, 9, 25].
The differential diagnosis of benign mucinous tumors
includes:
7.3 Mucinous Borderline Tumors/Atypical
• Other cystic ovarian lesions: Proliferative Mucinous Tumors
–– Serous lesions, benign and borderline
–– Endometrioid lesions, benign and borderline 7.3.1 Clinical Features
• Metastatic mucinous tumors
Mucinous borderline tumors (MBT) comprise approximately
The main differential for mucinous cystadenomas is other 35–45% of tumors in the intermediate epithelial category [4,
cystic lesions and their borderline counterparts, especially 21]. They are less commonly bilateral than their serous coun-
those of serous and endometrioid type. The possibility of a terparts, with only approximately 7% showing involvement of
metastatic mucinous tumor from outside the ovary mimick- both ovaries [26]. While bilaterality does occur, one should be
ing a mucinous cystadenoma should always be considered prudent in confirming the site of origin, as this is a more com-
since some metastatic adenocarcinoma glandular epithelia mon feature observed in extraovarian primaries. MBT can
may have a bland-looking appearance, but this would be far occur in patients of all ages, though they are most common
less likely in the case of an otherwise unremarkable muci- between the fourth and sixth decades of life [16, 27, 28]. These
nous cystadenoma lacking in clinical concern for metastasis. tumors comprise approximately 67% of mucinous tumors that
Differentiating primary mucinous tumors from metastatic do not fall into the “benign” category [2]. In the past, MBT
lesions to the ovary will be discussed below with the differ- have also been referred to as “mucinous tumors of low malig-
ential diagnosis of mucinous carcinomas, given its higher nant potential,” though this term has fallen out of favor in recent
level of relevance to these tumors. Extensive sampling, two years. Many of the tumors initially placed in this group were
sections per cm of tumor, is recommended for mucinous characterized based upon the criteria that have now been estab-
tumors in order to accurately differentiate a mucinous cyst- lished to be associated with non-ovarian primaries, and recent
adenoma from other primary mucinous neoplasms. work has been extremely valuable in further establishing
their diagnostic features as well as prognostic implications.
7.2.6 Management and Outcomes

Invariably, mucinous cystadenomas are benign tumors. As
with the vast majority of ovarian masses, the standard of treat- Like cystadenomas, on gross examination borderline muci-
ment is removal of the involved adnexae, though it is quite nous tumors are typically large, unilateral, and multicystic,
common to see cystectomy alone, particularly in women who with multiple cysts of varying sizes. The average size has
wish to preserve fertility [2, 22]. However, very rarely, these been reported to range between 17 and 22 cm [8, 29].
tumors may recur, particularly if incompletely excised [23, Generally, the cyst lining is smooth, though some areas may
24]. Tumor rupture has not been associated with recurrence or have a velvety appearance and/or grossly evident papillae.
Solid or firm areas can be seen, which may represent a minor growth, they are best placed in the borderline category. In
fibromatous component, densely packed small cysts, or reac- order to make this diagnosis, proliferation should involve at
tive stroma, though these areas should always be thoroughly least 10% of the tumor.
sampled to rule out malignancy [29]. Grossly, they tend to Microscopically, MBTs show a higher degree of prolifer-
have fewer loculations than seromucinous tumors, and may ation than their cystadenomatous counterparts as seen in the
contain intracystic papillae [30]. form of papillary proliferation, epithelial stratification, tuft-
ing, and villoglandular formation observed in at least 10% of
the tumor epithelial volume (Fig. 7.3). It is not uncommon to
7.3.3 Microscopic Findings find areas of associated cystadenoma [29]. Many tumors
show epithelial stratification within the range of 1–3 layers,
As with their serous counterparts, when mucinous tumors though a significant number contain foci with beyond three
show increased epithelial proliferation and mild nuclear layers of stratification. Epithelial stratification beyond even
atypia but lack destructive stromal invasion or expansile one layer should trigger close evaluation for a borderline
a b
c d
Fig. 7.3 Mucinous borderline tumor. (a) Mucinous borderline tumor extensive epithelial proliferation within glandular and cystic spaces
with background cystadenoma. Epithelial proliferation as seen in the with no associated destructive or infiltrative growth. The epithelium
center of the image comprising >10% of the tumor epithelial volume in shows papillary proliferation and stratification of the epithelium. (c)
this case. Typical mucinous cystadenomatous areas can be seen in the Mucinous borderline tumor. There is mild cytologic atypia and promi-
upper and lower portions of the image. If areas of proliferation amount nent epithelial stratification with fusion of papillae and few detached
to less than 10%, the tumor is classified as mucinous cystadenoma with cell clusters. (d) Mucinous borderline tumor with fusion of papillae and
focal epithelial proliferation. (b) Mucinous borderline tumor. There is focal cribriforming. There are few, scattered mitotic figures
component. Papillary structures may be single or branched, most common abnormality as illustrated by targeted deep
with thin fibrous cores or cores lacking in stroma. It is not sequencing rates of up to 92% [32, 33]. PIK3CA, p53 muta-
uncommon to see fusion of papillae and/or detached cell tion, and ERBB2 amplification have also been noted, though
clusters, the former of which may impart the appearance of these latter two categories to a lesser extent than seen in
small cribriform foci, not to be confused with the expansile mucinous carcinomas (11.5% vs. 56.8% and 6.2% vs. 18.8%,
growth pattern of carcinoma (Fig. 7.3). These findings may respectively) [32, 34]. MBT show lower rates of coding
be focal or multifocal, and are typically concentrated toward mutations than carcinoma and slightly higher rates of coding
the tips of papillae and centers of glandular structures. mutations than cystadenomas [34].
Tangential sectioning may further emphasize the architec-
tural complexity (Fig. 7.3).
The nuclei in MBTs are generally larger than those seen 7.3.6 Differential Diagnosis
in cystadenoma and atypia is usually mild to moderate. The
proliferative rate is typically low, and shows predominantly The differential diagnosis of borderline mucinous tumors
basal staining with Ki67 immunohistochemical stains, with includes:
decreasing staining seen toward the tips of papillae [4].
However, this diagnosis is predominantly made on histology, • Other cystic ovarian lesions:
and Ki67 staining is not routinely employed to discriminate –– Serous lesions: Benign, borderline, and malignant
between borderline tumors and its mimics. While some –– Endometrioid lesions: Benign, borderline, and
mitotic activity is typically present, numerous mitotic figures malignant
should prompt the observer to search for a more nefarious • Metastatic mucinous tumors
lesion, including intraepithelial carcinoma. Microscopic foci • Sex cord stromal tumors
of invasion may be seen (see Special Issues below), but by
definition there is no destructive stromal invasion in The main differential for mucinous borderline tumors is
MBT. Pools of acellular mucin (pseudomyxoma ovarii) are other cystic lesions and their borderline counterparts espe-
not uncommon, and frequently show associated mucin gran- cially those of serous and endometrioid type. Further, the
ulomas, findings which may mimic invasive disease. These possibility of a metastatic mucinous tumor from outside the
foci may be devoid of epithelium or there may be fragmented ovary mimicking a mucinous borderline tumor must be
free-floating epithelium suspended within mucin pools. The considered. Differentiating primary mucinous tumors from
ruptured gland may be visible in the adjacent tissue. In our metastatic lesions to the ovary will be discussed below in
experience, this and the presence of associated inflamma- the part of the chapter discussing the differential diagnosis
tion, foreign-body reaction, and edema can be helpful in dis- of mucinous carcinomas. Extensive sampling, two sections
tinguishing gland rupture and mucin granuloma from per cm of tumor, is recommended of mucinous borderline
microinvasion. tumors to rule out a carcinoma component and to better
evaluate for the possibility of a metastatic process
(Table 7.1).
7.3.4 Biomarkers
Immunohistochemically, these tumors have typically been 7.3.7 Management and Outcomes

regarded as lacking a Mullerian phenotype, with minimal
staining for WT-1, ER, and PR. However, more recent stud- True borderline tumors have an overwhelmingly benign
ies have also shown that PAX8 may be positive in approxi- course following surgery when stringent criteria regarding
mately 60% of cases [4]. They are usually positive for CK7, diagnosis are applied [35]. Many of the tumors previously
show patchy co-expression of CK20, and typically show no referred to as advanced-stage mucinous borderline tumors
staining or weak staining with CDX2 [31]. are now thought to represent undiagnosed extraovarian pri-
maries, in part due to more recent studies showing survival
rates approaching 100% in true ovarian borderline mucinous
7.3.5 Molecular Features tumors, but also due to the high association of advanced
stage disease with PMP, which is now known to be nearly
The most common mutations in mucinous tumors are found uniformly associated with metastasis from the gastrointesti-
in the mitogen-activated protein kinase pathway (MAPK). nal tract, with few exceptions. Other metastatic sites are
Mutations in KRAS, CDKN2A, and BRAF are among those favored for the remainder of poorly behaved tumors, includ-
most frequently observed, with KRAS mutations being the ing pancreatobiliary and endocervical.
While the gold standard for treating MBT patients 7.4.2 Mucinous Borderline Tumor
includes resection with comprehensive staging, in actual- with Microinvasion
ity, the procedure performed strongly factors in patient
age, reproductive status, and desire to preserve fertility. As mentioned above, mucinous borderline tumors may be
While these tumors historically have recognized potential associated with microinvasion, which according to current
for spread, more recent studies have shown them to be classification criteria is defined as an area (or areas) of stro-
quite well behaved, with very low rates of extraovarian mal invasion measuring less than 5 mm in greatest linear
disease [36, 37]. In fact, most studies have shown that extent [21]. Multiple proposals have been put forth regarding
patients who underwent conservative surgery without standardized criteria for microinvasive foci, including 3 mm
complete staging did not have higher rates of recurrence in linear extent or 10mm2 in area, and there has generally
[38]. There has been a report of fertility-sparing surgery been no agreed-upon definition over the last years. However,
which showed higher rates of invasive recurrence than tumors with less than 5 mm of invasion have demonstrated
serous tumors, though this was only in one single-center an excellent prognosis, and this is the current cutoff as rec-
study and requires follow-up confirmatory studies [39]. ommended by the 2014 WHO [21]. Multiple foci of microin-
Microinvasion in these tumors typically does not portend vasive carcinoma may be seen but no single focus should
a worse prognosis [4, 21, 40]. However, there remain measure greater than 5 mm in order to qualify for this diag-
areas in need of further studies, such as whether or not the nosis. There is no limit to the number of foci identified in a
number of microinvasive foci or the cytology of the micro- single tumor, and geographically distinct foci should not be
invasive foci (low- or high-grade nuclei) has particular combined for an additive measurement. Microinvasive foci
significance [40]. are comprised of single cells, clusters, and/or small foci of
confluent or cribriform glandular growth within the stroma
(Fig. 7.5) [4, 21]. Most studies suggest that the rate of micro-
7.4 pecial Issues with Mucinous
S invasion falls in the 10–18% range, though figures up to 29%
Borderline Tumors have been described [4, 21, 40, 42]. Mucin granulomas with
associated epithelium may be a diagnostic pitfall in these
7.4.1 Mucinous Borderline Tumor cases, and may likely be the source of these higher reported
with Intraepithelial Carcinoma rates in the literature [40, 43].
While a great deal is now known about these tumors,
While epithelial stratification and architectural complexity there is still much that remains to be elucidated, includ-
are frequent features of typical MBT, marked nuclear atypia ing whether the presence of microinvasive disease in
is not. Intraepithelial carcinoma (IEC), as defined by the mucinous tumors with concurrent IEC has special signifi-
presence of high-grade nuclear atypia which differs from the cance [40]. Some authors have referred to mucinous
background epithelium, has been reported in up to 40–55% tumors with IEC and microinvasion as “microinvasive
of mucinous borderline tumors [4]. Historically, the defini- intraepithelial mucinous carcinoma” [40]. For prognosti-
tion of intraepithelial carcinoma in mucinous tumors has cation purposes, a cutoff of 10% tumor involvement has
been variable and has included the presence of both nuclear been proposed [40].
atypia and architectural complexity [40]. However, recent
proposals have suggested only grade 3 nuclear atypia or
frankly malignant cells be considered diagnostic for intraepi- 7.4.3 Mucinous Borderline Tumor
thelial carcinoma, and some follow-up studies have shown with Pseudomyxoma Peritonei
recurrence rates to be higher in this group while no differ-
ence was detected based upon architectural complexity [40]. Pseudomyxoma peritonei (PMP) is a rare clinical entity
These areas are typically cytologically distinct from the characterized by mucinous ascites and/or mucin deposits
background (a very helpful feature), with pleomorphism, within the peritoneal cavity. It was initially thought to
hyperchromasia, loss of polarity, and often increased mitotic represent the mucinous parallel of tumor implants associated
activity (Fig. 7.4). with serous borderline tumors. PMP typically has a pro-
Overall, most studies have not shown decreased survival tracted clinical course with multiple recurrences and obstruc-
based upon the presence of intraepithelial carcinoma, and the tive symptoms, with progressive disease and death being
prognosis is generally regarded as excellent [41]. MBT with seen in up to half of patients [44, 45]. It has been reported as
intraepithelial carcinoma is more commonly reported at fre- an incidental finding in approximately 2 of every 10,000
quencies of 30–40% [41], though it has been reported in up laparotomies [46]. Histologically, mucoid deposits may con-
to 40–55% of mucinous borderline tumors [40]. tain variable amounts of typically low-grade or cytologically
a b
Fig. 7.4 Mucinous borderline tumor with intraepithelial carcinoma. can be seen. (b) There is cytologic atypia and notably increased mitotic
(a) Both architectural complexity and high-grade nuclear atypia (right activity. (c). Marked cytologic atypia is seen
side of image) distinct from non-atypical epithelium (left side of image)
bland mucinous epithelium. While this entity has historically 7.4.4 Mucinous Tumors with Mural Nodules
been controversial in terms of its origin, numerous clinico-
pathologic and molecular studies have now concluded that Mural nodules are rare nodules that occur singly or multiply
the vast majority of PMP cases have an extraovarian origin, in mucinous ovarian tumors of all types, with the first series
most commonly the appendix. The majority of these tumors reported by Prat and Scully in 1979 [51]. There are three
are now termed “low-grade appendiceal mucinous neo- main types: (1) those composed of reactive sarcoma-like tis-
plasms” [45, 47, 48]. The high rates of bilateral ovarian sue, termed sarcoma-like mural nodule (SLMN); (2) true
involvement, concurrent appendiceal neoplasm with similar sarcoma; and (3) anaplastic carcinoma [51–53]. These nod-
histologic features, and progressive molecular derangements ules vary widely in size and may be sharply demarcated from
including identical KRAS mutations and loss of heterozy- the surrounding tissue in the cases of SLMN and less well
gosity in ovarian as compared to appendiceal tumors favor circumscribed in the latter two categories. Patients with
this conclusion [45, 49]. The rare cases of PMP of true ovar- SLMNs are typically younger than those with sarcoma/ana-
ian origin are most commonly seen in association with tumor plastic carcinoma, with a mean age of approximately
rupture, specifically in cases of mucinous tumors arising in 36 years [53]. The origin of SLMNs is unclear, and it is not
mature cystic teratomas. These tumors are morphologically known whether this entity represents a reactive or neoplastic
and immunohistochemically similar to primary gastrointesti- process.
nal tumors and very likely arise from gut elements of the Microscopically, the histologic appearance of SLMNs is
teratoma [50]. varied and tumors may consist of multinucleated osteoclast-
a b
Fig. 7.5 Mucinous borderline tumor with microinvasion. (a) There is a derline tumors with microinvasion. The invasive cells show cytologic
haphazard arrangement of infiltrative small glands, cell clusters, and atypia and are arranged as single cells and nests within reactive stroma.
single cells with areas of associated extracellular mucin within the (c) Haphazard arrangement of angulated glands underlying noninvasive
stroma. The invasive foci measure less than 5 mm. (b) Mucinous bor- tumor. There is surrounding desmoplastic response
and epulis-like giant cells, pleomorphic spindle cells, and/or upon this component. While early studies illustrated the poor
histiocytes/inflammation. They may contain conspicuous behavior of tumors with malignant nodules with fatality rates
mitoses but do not show invasion into the surrounding tissue approaching 50%, few recent studies have shown that if a
or capillary lymphatic spaces. Sarcomatous nodules are most tumor is stage 1a, there may not be an adverse effect on the
commonly composed of undifferentiated sarcoma, though outcome [53]. However, given the limited information avail-
many types have been reported including fibrosarcoma, able, these tumors should be regarded with caution when
rhabdosarcoma, and more recently osteosarcoma [54]. encountered in clinical practice.
Anaplastic carcinomatous nodules show large atypical cells
with irregular nuclei and prominent nucleoli that are positive
for cytokeratins and EMA, a feature which can be very help- 7.5 Mucinous Carcinoma
ful in distinguishing more challenging cases from SLMNs.
The growth pattern may be rhabdoid, spindled, and/or Primary mucinous carcinoma of the ovary is very rare, repre-
pleomorphic. senting <5% of all primary ovarian carcinomas [55].
Thorough sampling and accurate diagnosis are crucial, as Although primary mucinous carcinoma of the ovary is rare,
SLMNs do not have an adverse effect on prognosis [21]. metastatic adenocarcinomas that often mimic primary ovar-
When an anaplastic carcinomatous or true sarcomatous com- ian mucinous carcinoma are common, and differentiating
ponent is identified, the tumor should be classified based these entities is of the utmost importance to the practice of
gynecologic pathology. In this part of the chapter, primary 7.5.3 Pathological Findings
mucinous carcinoma is discussed with an emphasis on dif-
ferentiating this neoplasm from the various metastatic ade- For the diagnosis of carcinoma to be rendered for a primary
nocarcinomas that have been reported to involve the ovary. mucinous neoplasm of the ovary one of the two, or both,
invasive patterns must be noted. The two invasive patterns
described in mucinous carcinoma are the confluent glandular
7.5.1 Clinical Features or expansile pattern and the destructive stromal invasive pat-
tern. The confluent glandular/expansile pattern denotes
Patients with primary mucinous carcinoma of the ovary architecturally complex glandular formations with minimal
tend to present at a younger age than those with serous to no intervening stroma (Fig. 7.6) [59, 60]. In other words,
tumors. The mean ages reported in the literature vary, but differentiating a borderline mucinous neoplasm from a muci-
generally note the majority of patients to be in their 40s nous carcinoma with confluent glandular/expansile invasion
[56, 57]. Patients generally present with increasing abdom- is similar to differentiating atypical endometrioid hyperpla-
inal girth, as is common for the other mucinous neoplasms sia from endometrioid carcinoma. In contrast to the glandu-
of the ovary [57]. The majority of patients diagnosed with lar/expansile pattern of invasion, destructive stromal invasion
primary mucinous carcinoma of the ovary are found to be is characterized by altered glands infiltrating altered stroma
of low stage with advance-stage disease noted in only very often leading to an inflammatory response. The malignant
rare cases [58]. glands noted in destructive invasion often exhibit altered
cytologic and architectural features compared to adjacent
noninvasive components of the same neoplasm (Fig. 7.7).
7.5.2 Gross Findings The altered features may include rounded glandular contours
with stroma now evident between glands and single cells and
At gross inspection mucinous carcinomas appear similar to cytologic changes including increasing cytoplasmic eosino-
borderline mucinous tumors, in that they tend to be large, philia combined with decreased intracellular mucin [60].
unilateral, and multicystic. The surface of the ovary should
be examined in detail and any nodules noted, as surface
involvement will affect staging. Often the surface of the neo- 7.5.4 Biomarkers
plasm will be smooth with the neoplasm confined to the
ovary. Rupture should also be noted. On cut section the neo- Limited studies are available discussing the role of biomark-
plasm is usually solid and cystic. Mucinous material should ers in the diagnosis and management of primary mucinous
be exuded from the neoplasm similar to other mucinous neo- carcinoma. In a study of patients diagnosed with mucinous
plasms. Microscopic examination, rather than gross exami- ovarian lesions preoperative CA19.9 and CA125 levels were
nation, is critical to determine a mucinous borderline tumor shown to be elevated in patients with carcinoma as compared
from a mucinous carcinoma. to patients found to have benign mucinous neoplasms at the
Fig. 7.6 Mucinous carcinoma with confluent glandular/expansile inva-

sion. Note the lack of stroma between glandular structures and the crib- Fig. 7.7 Mucinous carcinoma showing the infiltrative pattern of inva-
riform architecture (on the right of the image) sion. Note the stromal response clusters of carcinoma
time of resection [61]. Further, in patients with normal The main differential diagnosis of primary mucinous
CA125, CA19.9 has been shown to be elevated in patients ovarian carcinoma is a borderline mucinous ovarian tumor as
with borderline and malignant mucinous ovarian neoplasms described above and metastatic carcinoma involving the
as compared to benign neoplasms [62]. Another tumor ovary. Metastatic lesions from a variety of organs have been
marker that is often elevated in patients with mucinous ovar- reported to involve the ovary and mimic primary ovarian
ian carcinoma is carcinoembryonic antigen (CEA) [2]. All mucinous neoplasms. The most commonly reported meta-
three markers CA19.9, CA125, and CEA can be used to fol- static carcinomas to the ovary are of gastrointestinal origin.
low patients postoperatively; however, none have proven These include carcinomas from the colon, stomach, small
effective as a screening test for primary mucinous ovarian bowel, and pancreaticobiliary tract. Further, extraovarian
carcinoma. gynecologic primaries, such as those from the endocervix,
have also been noted to metastasize to the ovary and mimic
primary ovarian mucinous carcinoma [59] (Table 7.2).
7.5.5 Molecular Features In the workup of a mucinous carcinoma involving the
ovary clinical, morphologic, and immunohistochemical fea-
A variety of molecular alterations have been reported in pri- tures of the neoplasm are important to consider when deter-
mary ovarian mucinous carcinomas, with mutations in KRAS mining if the neoplasm is primary to the ovary or metastatic.
being the most common [33, 63]. Other reported molecular A series of algorithms described in the literature conclude
alterations include HER2 amplification, aberrant signaling that a good place to start when evaluating mucinous neo-
involving the WNT pathway, and TP53 mutations [63, 64]. plasms is considering size and laterality. A general rule sug-
KRAS mutations and HER2 amplification have been found to gests that bilateral small tumors (<10–13 cm) are highly
be nearly mutually exclusive [64], while TP53 mutations suspicious for metastasis while unilateral large (>10–13 cm)
may occur in the context of other molecular alterations [63]. tumors are more suggestive of primary ovarian lesions [59,
65]. Important to note is that metastatic colorectal carcinomas
as well as metastatic endocervical carcinomas have been
7.5.6 Differential Diagnosis noted to not follow these general rules [59].
A series of studies have described a variety of immuno-
The differential diagnosis for mucinous carcinomas of the histochemical markers (Table 7.3) that can be helpful in dis-
ovary is relatively broad and includes: criminating primary mucinous carcinomas of the ovary from
metastatic lesions. The two most discussed cytokeratin stains
• Metastatic carcinoma involving ovary: used in the workup of mucinous lesions of the ovary are CK7
–– Upper and lower tract gastrointestinal primaries: and CK20 [31]. In general, CK7 diffuse positivity suggests a
∘∘ Colonic carcinoma primary ovarian lesion, but must be interpreted with caution
∘∘ Pancreatic carcinoma as metastatic lesions from the upper gastrointestinal prima-
–– Endocervical carcinoma ries can also show diffuse positivity. As far as CK20, diffuse
• Borderline mucinous ovarian tumors positivity suggests a lower gastrointestinal primary, but can
Table 7.2 Primary ovarian mucinous neoplasms versus metastatic lesions involving the ovary
Entity Gross features Histopathologic features Immunohistochemistry
Primary ovarian Tend to be unilateral Often identified within the stroma of the ovary with CK 7 expression greater than CK 20
mucinous and large with mean well-differentiated mucinous epithelium with variable expression, occasionally PAX8
neoplasm size >20 cm atypia. Carcinomas show two patterns of invasion positive
(confluent/expansile and destructive stromal). Often lack
surface involvement of the ovary
Metastatic Tend to be bilateral Can be noted to involve the surface of the ovary, Appendix/Lower GI : CK20 positive,
carcinomas and smaller superficial cortex, and stroma CK7 negative, SATB2 positive
involving the (<10–13 cm) Upper GI: CK7>CD20 expression,
ovary PAX8 negative
Pancreas: CK7>CK20, Can see loss
of DPC4
Endocervix: p16 diffuse and
HPV-ISH positive if HPV related,
Non-HPV related lesions difficult to
determine by IHC
Note: Important to consider all features together including clinical history as this is a very difficult differential diagnosis in many instances
Table 7.3 Immunohistochemical stains to consider in the workup of mary ovarian carcinomas tend to overlap. An
mucinous lesions involving the ovary
immunohistochemical stain for DPC4 has been shown to be
CK7 Compare with CK20 expression CK7>CK20 → Favor helpful. DPC4 staining is lost in many pancreatic and biliary
primary ovarian over upper GI tract
tract adenocarcinomas, whereas expression is retained in
CK20 Compare with CK7 expression CK20 > CK7 → Favor
ovarian primaries and metastases from other sites [68].
lower GI tract over primary ovarian
PAX8 Positivity favors primary ovarian Additional immunohistochemical stains that have been
CDX2 Not very helpful, positivity supports mucinous type explored in the workup of ovarian mucinous neoplasms are
SATB2 Positivity suggests lower GI tract estrogen receptor (ER) and progesterone receptor (PR).
DPC4 Loss of staining suggests pancreatic primary Unfortunately, these markers have proved for the most part
p16 Diffuse positivity suggests possible HPV-related cervical unhelpful since all primary mucinous carcinomas and the
carcinoma primary strong majority of metastatic mucinous carcinomas were
found to be negative for both markers. The only exception
be seen in some primary ovarian mucinous tumors [31]. was borderline seromucinous tumors, which were noted to
Critical to the interpretation of these markers is the compari- variably express ER [69]. ER and PR are helpful if an endo-
son of CK7 and CK20 expression. metrioid ovarian primary or metastasis is in the differential
PAX8, a commonly used Mullerian marker, is of some as these types of tumors should express ER and PR.
use in the workup of mucinous neoplasms of the ovary. Lastly, if a metastatic lesion from the cervix is under con-
Although positivity is found in the minority of primary ovar- sideration, p16 staining may be helpful. P16 expression should
ian mucinous neoplasms, when present, PAX8 positivity is be strong and diffuse in metastatic usual-type endocervical
strongly suggestive of a primary ovarian neoplasm, espe- adenocarcinomas to the ovary as these are invariably HPV
cially if metastasis from other Mullerian organs has been related [70]. When p16 is equivocal, HPV in situ hybridization
eliminated [66]. can be used to aid the diagnosis. Non-HPV-related endocervi-
CDX2, a transcription factor involved in intestinal differen- cal carcinomas can be extremely difficult to differentiate from
tiation, has been suggested as a helpful marker in distinguishing primary ovarian mucinous neoplasms. For this differential the
primary mucinous ovarian carcinoma from metastasis given size and laterality algorithm is of great importance, as well as
that CDX2 is positive in a large majority of colorectal carcino- correlation with history and examination of the cervix.
mas; however, expression has also been shown in ovarian muci- In summary, a variety of factors should be considered
nous carcinomas as well as appendiceal, pancreaticobiliary, and when differentiating a primary mucinous ovarian carcinoma
gastric carcinomas. As a result, it is important to interpret CDX2 or other mucinous neoplasms from a metastasis. The most
staining in the context of CK7 and CK20 staining realizing that important factors are size of the lesion(s) and laterality as
its expression or lack thereof may not be any more helpful than well as clinical history. Immunohistochemistry may prove
the comparison of CK7 to CK20 expression [31]. helpful in various situations, but should be interpreted with
SATB2 is a relatively new marker of lower intestinal dif- caution as the patterns of expression often overlap in the pri-
ferentiation that has been shown to be helpful in discriminat- mary and metastatic lesions (Table 7.1).
ing primary ovarian mucinous carcinomas from metastatic
lower gastrointestinal primaries. Like CDX2, it is suggested
that SATB2 staining be interpreted in the context of CK7 and 7.5.7 Management and Outcomes
CK20 staining. Unlike CDX2, SATB2 has been shown to be
negative in cervical metastasis and pancreaticobiliary metas- Surgery is the mainstay of treatment for primary ovarian car-
tases. Further, in a recent study SATB2 was noted to be nega- cinomas of the ovary [57]. Fortunately, the majority of muci-
tive in all primary mucinous carcinomas of the ovary except nous ovarian carcinomas are found to be confined to the
for those arising from a teratoma, further supporting its use ovary at diagnosis and can be removed in their entirety.
in the workup of mucinous lesions of the ovary [67]. Patients with successful surgery often have an excellent
The differential diagnosis of a metastatic pancreaticobili- prognosis with greater than 90% being disease free at 5 years
ary carcinoma to the ovary versus a primary ovarian muci- [57]. Mucinous carcinomas tend to be less responsive to che-
nous carcinoma can be especially challenging, although motherapy, especially platinum-based therapies, than other
applying the algorithm of size and laterality can be extremely ovarian epithelial neoplasms and as a result patients with
helpful. Many pancreaticobiliary metastases simulate bor- advanced disease often have a poor prognosis [57]. Currently
derline neoplasms and cystadenomas as they tend to have a there is not a specific primary chemotherapy regime recom-
simplistic architecture [68]. Further, many of these metasta- mended for primary mucinous ovarian carcinoma. The use of
ses may present at the same time if not before the main pan- gastrointestinal regimes is being explored and future studies
creaticobiliary primary. Many of the immunohistochemical may reveal an ideal regimen [57]. Further, futures studies
stains discussed above, CK7, CK20, and CDX2, are of lim- may also reveal the benefits of more targeted therapy in the
ited value as the patterns seen in pancreaticobiliary and pri- emerging era of personalized medicine.
Table 7.4 Brenner tumors

Entity Clinical features Gross features Histopathologic features Genetic profile
Benign 5th–7th decades. <2 cm, white-tan, solid, Round to ovoid nests of bland Few molecular alterations
Brenner Incidental finding firm, rubbery cut surface transitional cells within a fibrous identified. KRAS mutations
tumor stroma. Nuclei are elongated with open and MYC amplification have
chromatin, nuclear grooves, and small been described
nucleoli. Minimal atypia, no/rare
mitoses, and no necrosis
Borderline 5th–7th decades. Avg. 18 cm. Large cystic, Exuberant papillary projections with KRAS and PIK3CA
Brenner Enlarging pelvic/ white-tan tumor with true fibrovascular cores and variable mutations in ~30% of cases.
tumor abdominal mass papillary projections and cellular atypia; large irregular nests of Homozygous deletion of
solid rubbery areas tumor cells within fibrous stroma; no CDKN2A
stromal invasion
Malignant 5th–7th decades. 16–20 cm. Large, cystic, Exuberant papillary proliferation with EGFR, RAS, MAPK, p16
Brenner Enlarging pelvic and solid masses with atypia, high mitotic rate, and stromal LOH, and exon 9 PIK3CA
tumor abdominal mass. May papillary projections, invasion. Solid, irregular nests invade mutations have been
rarely present with necrosis, and gritty into the surrounding stroma. Necrosis described. Negative for TERT
abnormal vaginal texture representing and calcifications are often prominent. promoter mutations
bleeding. Up to 12% numerous calcifications Glandular or mucinous components (mutations seen in urothelial
are bilateral may be present carcinoma)
is thought to be a “hotspot” for carcinogenesis [74]. However,

it remains a hypothesis since there is no scientific evidence to
support.
Brenner cell tumors were previously classified as transi-
tional cell tumors and included the separate entity “transi-
tional cell carcinoma.” Many of these tumors, which are
malignant, were subsequently found to be histologic variants
of high-grade ovarian serous carcinoma and have been
reclassified as transitional-like carcinoma of high-grade
serous type, and are a distinct entity from the malignant
Brenner tumor [75].
Fig. 7.8 Walthard cell nest associated with fallopian tube at the tubo- 7.7 Benign Brenner Tumors
peritoneal junction
7.7.1 Clinical Features
7.6 Ovarian Brenner Tumors Benign Brenner tumors represent 5% of all benign ovarian
tumors and typically arise in adults in the fifth to seventh
Brenner tumors of the ovary represent approximately 2% of decades (mean age 50 years), but can occur in patients
all primary surface epithelial ovarian tumors [71]. Brenner younger than 30 or older than 80 [72]. Most patients are
tumors are further classified as benign, borderline, and asymptomatic and the tumors are found incidentally. If the
malignant, depending on the degree of architectural com- tumors become large the patient may experience abdominal
plexity, cellular proliferation, nuclear atypia, and stromal discomfort or distension. Brenner tumors may rarely have
invasion. Brenner tumors are predominantly benign (>90%) functioning stroma resulting in endocrine symptoms [21].
with rare transformation to borderline or malignant Brenner
tumors (<10%). Borderline Brenner tumors present at an
older age (mean age 60 years), are large, and are often symp- 7.7.2 Gross Findings
tomatic related to the size of the tumor. Malignant Brenner
tumors occur during the fifth to sixth decades (mean age Most benign Brenner tumors (>50%) are <2 cm but can rarely
55 years) with similar symptoms to borderline tumors [72] reach up to 10 cm or greater (<10%) [76]. They are frequently
(Table 7.4). diagnosed incidentally in ovaries removed for another reason.
Brenner tumors are thought to arise from Walthard cell Grossly they are solid, white-tan to yellow with a firm, rubbery,
nests which develop in the setting of transitional metaplasia homogenous cut surface, similar to a fibroma. Calcifications
at the tubo-peritoneal junction (Fig. 7.8) [73]. This junction and small cysts filled with mucinous material may be seen.
a b
Fig. 7.9 Benign Brenner tumor. (a) Lower power showing nests of bland transitional type epithelial cells in a background of paucicellular fibro-
matous stroma. (b) Higher power of nest within benign Brenner tumor highlighting the cytologic features of the neoplasm
Table 7.5 Immunohistochemistry for the differential diagnosis of Brenner tumors

Diagnosis CK7 CK20 Uroplakin Thrombomodulin
Walthard cell rests Positive Negative Negative Negative
Benign Brenner tumor Positive Negative Positive Positive
Borderline Brenner tumor Positive Negative Positive Positive
Malignant Brenner tumor Positive Negative Positive Positive
Metastatic urothelial carcinoma Positive Positive Positive Positive
Transitional-like HGSC Positive Negative Rare Rare
Rarely the tumor may be predominantly cystic. Approximately nous component is PAX8 negative, suggesting that these
25% of benign Brenner tumors are associated with other tumors do not arise from Mullerian epithelium.
tumors, most commonly mucinous ovarian neoplasms [77].
Less than 10% of Brenner tumors are bilateral [72].
7.7.4 Biomarkers
7.7.3 Microscopic Findings Brenner tumors are positive for cytokeratins, EMA, WT1,
p63, S100, GATA3, uroplakin, and thrombomodulin [16,
Brenner tumors of the ovary have epithelial elements resem- 21]. Most exhibit CK7 positivity and CK20 negativity, simi-
bling urothelial transitional cell epithelium. They are composed lar to other ovarian primary surface epithelial tumors. In con-
of oval to irregular nests of bland transitional type epithelial trast, transitional cell tumors of the urinary tract (urothelial
cells in a background of paucicellular fibromatous stroma carcinomas) in most instances exhibit both CK7 and CK20
(Fig. 7.9). The nests are usually solid but may also contain positivity. Brenner tumors exhibit evidence of urothelial dif-
mucinous or eosinophilic material within a central cavity. ferentiation with GATA3, uroplakin, and thrombomodulin
Usually the cells have moderate to abundant amounts of ampho- expression. Benign Brenner tumors may have an endocrine
philic to clear cytoplasm. The nuclei are oval with fine chroma- cell component and are often immunopositive for chromo-
tin and characteristic nuclear grooves (“coffee bean” nuclei). granin A, serotonin, and neuron-specific enolase (NSE) [82]
Small nucleoli may be present. Epithelial atypia and mitoses are (Table 7.5).
rare. Focal or extensive calcification may be present (Fig. 7.9).
Approximately 25% of Brenner tumors are seen in asso-
ciation with other benign tumors of the ovary, such as muci- 7.7.5 Molecular Features
nous cystadenomas (most common), teratomas, and struma
ovarii. In cases with struma ovarii association, the Brenner Few molecular alterations have been described in benign
component may stain with thyroglobulin [78–80]. A recent Brenner tumors. KRAS mutations at codon 12 were identified
study showed that clonality analysis of combined Brenner in one study [83]. There has been one reported case of a
and mucinous tumors of the ovary demonstrated that these 12q14-21 amplification [84]. Benign Brenner tumors associ-
two morphologies share a monoclonal origin [81]. In the ated with mucinous cystadenomas have been reported to
combined Brenner and mucinous cystadenomas, the muci- have MYC amplification in both components [80].
7.7.6 Differential Diagnosis enlarging pelvic mass and the tumors are usually unilateral
and confined to the ovary [74]. Borderline Brenner tumors
The differential diagnosis of benign Brenner tumors includes: are thought to arise from their benign counterparts [89].
• Walthard cell nests

• Transitional cell metaplasia 7.8.2 Gross Findings
• Sex cord-stromal tumors
• Leiomyomas Grossly, borderline Brenner tumors are large solid and cystic
• Metastatic urothelial carcinoma tumors, averaging 18 cm (range 10–28 cm). The solid areas
are grossly homogenous and white-tan.
A few benign entities can mimic benign Brenner tumors
including Walthard cell nests, transitional cell metaplasia, sex
cord-stromal tumors, and leiomyomas. Walthard cell nests are 7.8.3 Microscopic Findings
commonly an incidental finding seen on routine sections of fal-
lopian tubes. Walthard cell nests are CK7+, CK20−, and uropla- Microscopically, these tumors have an architectural com-
kin− [21, 74, 85]. Transitional cell metaplasia, which usually plexity demonstrated by exuberantly proliferative papillary
occurs in the same location as Walthard cell rests at the tubo- projections with true fibrovascular cores or polypoid projec-
peritoneal junction, or at the ovarian hilum or tubal fimbriae, tions (hence the name “atypical proliferative”). In addition,
can also mimic benign Brenner tumors [86, 87]. In addition, there are large, irregularly shaped nests of transitional cells
sometimes sex cord-stromal tumors may histologically mimic surrounded by dense fibrous stroma (Fig. 7.10). There is
benign Brenner tumors; however, fibromas are composed of variable cellular atypia with no evidence of invasion of the
more spindled cells and are arranged in a storiform pattern and surrounding fibrous stroma. These tumors are morphologi-
thecomas have more abundant, pale, vacuolated cytoplasm. cally similar to noninvasive low-grade papillary urothelial
Finally, uterine leiomyomas may mimic benign Brenner tumors carcinomas. If high-grade cytologic features are noted in the
when adherent to the uterus [88]. They have bland, cigar-shaped absence of stromal invasion, these tumors can be diagnosed
nuclei with moderate eosinophilic cytoplasm and are organized as borderline Brenner tumors with intraepithelial
in a more swirling pattern than Brenner tumors. carcinoma.
Immunohistochemical stains will help differentiate these tumors
as leiomyomas are SMA+, desmin+, and uroplakin−.
Metastatic urothelial carcinoma can also mimic Brenner 7.8.4 Biomarkers
tumors as the metastatic deposits may appear nest-like and
dispersed throughout the ovarian stroma. These lesions The immunohistochemical profile of borderline Brenner
should have more cellular atypia, mitotic figures, and per- tumors is almost identical to that of benign Brenner tumors.
haps necrosis which would distinguish them from a benign Diffuse staining in CK7, CA125, thrombomodulin, and
Brenner tumor, although borderline and malignant Brenner EMA is as in all subtypes of Brenner tumors, benign and
tumors would still be on the differential. GATA3 positivity malignant [90]. In addition, GATA3 is positive, p63 is posi-
may be misleading; however, CK20 should not be strongly tive, EGFR is positive, and cyclin D1 and Ras may have
positive in Brenner tumors as it is in urothelial cell tumors. weak-to-moderate staining. These tumors are negative for
Benign Brenner tumors have a benign clinical course. Complete

excision (unilateral or bilateral oophorectomy) is curative.
7.8 orderline Brenner Tumor (Atypical

B
Proliferative Brenner Tumor)
Borderline Brenner tumors are rare and comprise only 3–5%

of Brenner tumors. The average age of presentation is Fig. 7.10 Borderline Brenner tumor showing features of both benign
59 years. Patients usually present with symptoms of an and borderline glandular components
a b
Fig. 7.11 Borderline Brenner tumor in combination with borderline mucinous tumor. (a) Low power showing the various components of the
tumor. (b) Higher power highlighting the transition between the borderline Brenner component and mucinous component
p16, Rb, and p53. P16 is usually negative in the epithelial pools of acellular mucin. Serous carcinomas usually have
component of borderline Brenner tumors despite being posi- more atypia, higher nuclear to cytoplasmic ratios, and hob-
tive in the majority (92%) of benign Brenner tumors [89]. nailing. Immunohistochemical stains will help differentiate
This may be associated with promoter hypermethylation and these lesions. It is important to keep in mind that borderline
a homozygous deletion in CDKN2A, the gene encoding p16 Brenner tumors commonly occur simultaneously with muci-
[89] (Table 7.5). nous or serous ovarian neoplasms (Fig. 7.11). Whenever a
borderline Brenner tumor is identified, a malignant Brenner
tumor must be excluded by ruling out stromal invasion.
7.8.5 Molecular Features Finally, adult granulosa cell tumors can frequently mimic
many other ovarian neoplasms, including Brenner tumors.
Homozygous deletions of CDKN2A (p16-encoding gene) They can both have elongated nuclei with nuclear grooves,
have been identified in the epithelial component of border- moderate amounts of cytoplasm, and solid growth patterns.
line Brenner tumors (retained in benign). PIK3CA somatic Patients with granulosa cell tumors frequently present with
mutations have been detected in the stromal component in hyperestrogenism and endometrial hyperplasia.
5% of benign Brenner tumors. Somatic mutations in KRAS Immunohistochemically, granulosa cell tumors are positive
and PIK3CA are identified in 29% of borderline Brenner for inhibin, calretinin, CD99, SMA, and keratins (dot-like
tumors. Loss of CDKN2A and to a lesser extent KRAS and positivity) and are negative for EMA and uroplakin [21, 91,
PIK3CA somatic mutations may play a role in the transition 92].
of a benign to a borderline Brenner tumor [80, 89].

7.8.6 Differential Diagnosis
These tumors typically have a benign clinical course and sur-
The differential diagnosis of borderline Brenner tumors gical resection is curative, although, rarely, there have been
includes: reports of local recurrence. There have been no reported
cases of malignant behavior including metastases or death
• Mucinous borderline tumors from a borderline Brenner tumor [89].
• Serous borderline tumors
• Metastatic urothelial carcinoma
• Malignant Brenner tumor 7.9 Malignant Brenner Tumor
• Granulosa cell tumor
Surface epithelial ovarian tumors are frequently cystic,
with papillary or micropapillary projections, and have a vari- Malignant Brenner tumors are quite rare, comprising approxi-
ety of morphologies. Mucinous tumors can be distinguished mately 1% of Brenner tumors [71]. The median age of presen-
by the intestinal or foveolar type columnar epithelium with tation in a large study of 207 patients was 65 years [93]. They
mucin, and mucinous secretions into the cystic lumens or are usually unilateral but are bilateral in 12% of cases.
Approximately 80–90% of patients present with stage I disease 7.9.5 Molecular Features
with a 90% survival and the remaining 10–20% present with
stage II–IV disease [93, 94]. These patients usually present EGFR-RAS-MAPK mutations, Exon 9 PIK3CA mutations,
with abdominal pain or an enlarging abdominal mass. Rarely, P16 LOH [20], and Ras driver mutations have all been
abnormal vaginal bleeding may be the initial presentation [94]. described [7]. Although malignant Brenner tumors may mor-
phologically resemble urothelial carcinoma, the pathogene-
sis is distinct. TERT promoter mutations, commonly present
7.9.2 Gross Findings in urothelial carcinoma, have not been identified in benign or
malignant Brenner tumors [21].
Malignant Brenner tumors are 16–20 cm in greatest dimen-
sion on average [94]. They are cystic and solid with papillary
or polypoid components. A gritty texture on cut surface may 7.9.6 Differential Diagnosis
represent prominent calcifications.
The differential diagnosis of malignant Brenner tumors
includes:
7.9.3 Microscopic Findings
• Transitional-like high-grade serous carcinoma
Microscopically, malignant Brenner tumors have an exuber- • Serous ovarian cancer
antly proliferative transitional epithelium with cellular atypia • Metastatic urothelial carcinoma
and unequivocal stromal invasion in association with a • Metastatic squamous cell carcinoma
benign or borderline Brenner tumor component. The malig-
nant component consists of large, closely packed irregular Transitional-like high-grade serous carcinoma (TLHGSC)
nests of transitional epithelial cells infiltrating into the sur- is a variant of high-grade serous carcinoma of the ovary. This
rounding stroma. A desmoplastic stromal reaction will help entity was previously classified under the same umbrella as
identify the areas of invasion (Fig. 7.12). The epithelial cells Brenner tumors (transitional cell tumors of the ovary) and
demonstrate nuclear pleomorphism with hyperchromasia was called transitional cell carcinoma. These malignant
and numerous mitoses. Foci of necrosis are commonly seen. tumors have since been found to be related to high-grade
Calcifications are often prominent and squamous differentia- ovarian serous carcinoma and have been reclassified as such.
tion has been reported [21, 95]. TLHGSC is a distinct entity from the malignant Brenner
tumor [2, 20]. Histologically this tumor resembles a malig-
nant urothelial neoplasm but does not have a benign or bor-
7.9.4 Biomarkers derline Brenner tumor component. They frequently have a
papillary architecture with a multilayered transitional cell
Malignant Brenner tumors have a similar immunoprofile as epithelium and smooth luminal borders. A nested pattern
benign/borderline Brenner tumors; however, there is variable similar to that seen in malignant Brenner tumors can be seen
expression in the invasive components (Table 7.5). and may be a diagnostic pitfall. TLHGSC is usually strongly
a b
Fig. 7.12 Malignant Brenner tumor. (a) Low power highlighting the infiltrative nature of the glandular component of the tumor. (b) Higher power
highlighting the cytologic atypia associated with the malignant nature of this tumor
positive for p16, PAX8, and WT1 and shows p53 staining clinical importance, especially in benign and borderline
consistent with a p53 mutation, and is negative for EGFR, lesions. In the cases of mixed carcinoma, it may become
cyclin D1, and Ras. This staining pattern is the opposite for important to note and describe the component that composes
borderline and malignant Brenner tumors [21]. the minority of the carcinoma, especially if the carcinoma
Metastatic urothelial or metastatic squamous cell carcino- that composes the minority of the specimen is of higher
mas may mimic malignant Brenner tumors and immunohis- grade than the other component(s) or if metastases are identi-
tochemistry may be necessary for definitive diagnosis. In the fied that appear similar histologically to the minority compo-
setting of exuberant calcification, ovarian serous carcinoma/ nent. Immunohistochemical stains can be especially helpful
psammocarcinoma may also be a diagnostic pitfall; however, to better classify the components of mixed lesions; however,
immunohistochemistry can easily distinguish these entities stains must be interpreted with caution as the staining pat-
[96]. terns of many high-grade ovarian epithelial carcinomas over-
lap. It is our practice to note mixed histology and to describe
histologic and immunohistochemical findings. We find that
7.9.7 Management and Outcomes open communication with our clinicians in these particular
cases is of the utmost importance as this often assists the
Patients with malignant Brenner tumors most commonly oncologists in determining the best course of therapy.
present with stage I disease (55.4%). 14.4% of patients pres-
ent with stage II disease, 18% with stage III, and 12.2% with
stage IV disease [21, 93]. Approximately 5% of patients have 7.10.3 Undifferentiated Carcinoma
positive lymph nodes at diagnosis. Five-year disease-specific and Unclassified Adenocarcinoma
survival (DSS) of tumors confined to the ovary is 94.5%
compared to 51.3% for those with extraovarian spread [93]. In extremely rare circumstances a diagnosis of unclassified
Regional lymphatic spread is uncommon and thus regional adenocarcinoma may be rendered. This term should only be
lymphadenectomy as part of staging is unnecessary and does used in the extremely rare case that exhibits no clear charac-
not confer any improvement on survival. One case report teristics of any type of ovarian malignancy, but expresses
demonstrated transformation of a malignant Brenner tumor epithelial markers. Further, we feel that this diagnosis should
into a trabecular carcinoid [97]. not be rendered unless extensive sampling, an extensive
immunohistochemical workup, as well as extensive consul-
tation with experts in the field have been performed. It is
7.10 Other Epithelial Tumors especially important to consider metastatic lesions and non-
epithelial ovarian lesions as many of these may focally
7.10.1 Squamous Cell Carcinoma express epithelial stains. Hopefully, as ancillary studies con-
tinue to develop and become more common, the term unclas-
Very few pure squamous cell carcinomas (pSCC) primary to sified adenocarcinoma will disappear.
the ovary have been reported in the literature [98, 99]. The
majority of squamous cell carcinomas noted to involve the
ovary arise in association with teratomas, Brenner tumors, or 7.11 Other Rare Tumors
endometriosis, or represent metastatic disease [99]. It is very
important that all of these possible associations are elimi- 7.11.1 Small-Cell Carcinoma of the Ovary,
nated before a diagnosis of pSCC is considered. The origin Hypercalcemic Type (SCCOHT)
of pSCC is believed to be metaplasia of the surface lining of
the ovary [99]. Given the rarity of pSCC treatment guidelines Small-cell carcinoma of the ovary, hypercalcemic type
do not exist. Based on various case reports, it is believed that (SCCOHT), is a rare highly aggressive malignancy first
pSCC is very aggressive and should be managed aggres- described in 1979 by Robert E. Scully, and currently defined
sively [98, 100]. by deleterious genetic mutations in SMARCA4 and loss of
nuclear immunostaining for SMARCA4 (BRG1) [101].
SCCOHT was originally speculated to represent poorly dif-
7.10.2 Mixed Epithelial Tumors ferentiated carcinoma, although sex cord-stromal, germ cell,
and neuroendocrine origins have also been suggested [102,
Mixed epithelial tumors of the ovary are defined as ovarian 103]. While still characterized as a miscellaneous ovarian
tumors composed of two or more distinct epithelial compo- neoplasm, recent data suggests either a primitive germ cell or
nents, each representing >10% of the tumor. Fortunately, in mesenchymal origin for SCCOHT [104, 105]. Some have
most circumstances, the mixed nature of the lesion has no even suggested a change in nomenclature from SCCOHT to
malignant rhabdoid tumor of the ovary (MRTO), given the contain characteristic follicle-like structures with eosino-
clinical, morphologic, and molecular similarities to malig- philic (rarely basophilic) fluid [106]. Roughly half of tumors
nant rhabdoid tumors [105]. contain foci or diffuse areas of neoplastic cells with moder-
Small-cell carcinoma of the ovary, hypercalcemic type ate to abundant eosinophilic cytoplasm, large pale nuclei,
(SCCOHT), affects primarily adolescent and young women, prominent nucleoli, and occasionally cytoplasmic hyaline
with a peak incidence in the second and third decades of life, globules. Cases with exclusively or predominantly such
although the age at diagnosis reported in the literature ranges tumor morphology are designated “large cell variant” of
between 14 months and 71 years of age [106, 107]. Patients SCCOHT [106]. Additional, but far more infrequent, mor-
most often present with abdominal pain or distention, but phologies include spindle cell or clear-cell components, mul-
may also present with a palpable mass, weight loss, nausea, tinucleate cells, or cystic glandular spaces lined by benign or
vomiting, and/or constipation [107]. Paraneoplastic hyper- malignant-appearing mucinous epithelium [106].
calcemia (elevated preoperative calcium) is present in The utility of immunohistochemistry in diagnosing
approximately 60% of cases, though the majority of these SCCOHT was revolutionized by the recent discovery of
patients are not symptomatic [106, 107]. Importantly, famil- disease-driving SMARCA4 mutations and the development
ial cases have been described with germline mutations in of an antibody against SMARCA4 (BRG1) [101]. Complete
SMARCA4 and autosomal dominant patterns of inheritance loss of nuclear staining with the SMARCA4 antibody is
[101, 108]. Patients with germline SMARCA4 mutations are found in greater than 95% of SCCOHT cases [105]. Most
often diagnosed at a younger age than patients with somatic cases also reveal diffuse nuclear immunoreactivity to WT1,
mutations [101]. with an antibody against the N-terminus of WT1 [103].
Gross examination typically reveals these tumors to be Other historically utilized immunostains include cytokera-
large (diameter 14.7 cm, range 6–30 cm), solid, fleshy, tins (focally positive, cytoplasmic), EMA (focally positive,
cream-colored masses with foci of hemorrhage, necrosis, membranous), calretinin (focally positive), CD10 (focally
and cystic degeneration, closely resembling ovarian lympho- positive), α-inhibin (negative), desmin (negative), and S100
mas or dysgerminomas [106, 107]. While typically unilat- (negative) [102, 103]. Interestingly, cases have been report-
eral, these tumors can rarely be bilateral, particularly in edly immunoreactive for parathyroid hormone-related pro-
familial cases with germline mutations in SMARCA4 [108]. tein (PTHRP), irrespective of preoperative calcium levels,
Microscopically, these tumors are predominantly com- but almost always negative for parathyroid hormone (PTH)
posed of diffuse sheets, or less commonly trabeculae, of [106].
monotonous small round blue cells with scant cytoplasm, SCCOHT is characterized by deleterious somatic or
ovoid to round hyperchromatic nuclei, and brisk mitotic germline mutations in the SMARCA4 gene [101]. SMARCA4
activity [106] (Fig. 7.13). There is often minimal tumor encodes the SMARCA4 (BRG1) protein, an enzymatic com-
stroma, though infrequently the stroma may be myxoid, ponent of the SWI/SNF chromatin-remodeling complex,
fibrous, or edematous [106]. Approximately 80% of tumors which is responsible for the control of downstream gene
expression [105]. Mutations in both gene alleles or loss of
heterozygosity is required for tumor formation [101].
Deleterious mutations in SMARCA4 have also been impli-
cated in rhabdoid tumor predisposition syndrome type 2
(RTPS2), a syndrome that predisposes patients to developing
malignant rhabdoid tumors [101]. In one study, approxi-
mately 50% of patients with known SCCOHT that were
tested for a germline mutation in SMARCA4 were found to
have a mutation, regardless of positive or negative family
history of disease [101]. This suggests a prominent role for
genetic testing and counseling in all patients with known or
suspected SCCOHT [105].
The differential diagnosis for poorly differentiated tumors
such as small-cell carcinoma of the ovary, hypercalcemic
type (SCCOHT), is broad, and includes adult or juvenile
granulosa cell tumors [105, 106]. Juvenile granulosa cell
tumors are also characterized by follicle-like spaces with
Fig. 7.13 Small-cell carcinoma of the ovary, hypercalcemic type.
Tumor composed of diffuse sheets and trabeculae, of monotonous small
eosinophilic material, but are not associated with hypercal-
round blue cells with scant cytoplasm and ovoid to round, hyperchro- cemia. Additionally, juvenile granulosa cell tumors are often
matic nuclei more pleomorphic appearing and will be negative for WT-1
and EMA, and positive for α-inhibin, and will have retained Among the reported cases of primary ovarian NSCNEC
SMARCA4 nuclear staining. Other malignancies on the dif- in the literature, age at diagnosis ranges between 18 and
ferential for SCCOHT include desmoplastic small round-cell 77 years of age with an average of 51 years of age [113, 114].
tumor (DSRCT), pulmonary-type small-cell carcinoma of Patients most commonly present with abdominal pain,
the ovary, endometrial stromal sarcoma (ESS), peripheral abdominal distention, ascites, and a palpable abdominal or
neuroectodermal tumor, neuroblastoma, rhabdomyosarcoma pelvic mass [112]. Most cases of primary ovarian NSCNEC
(RMS), and metastatic melanoma, lymphoma, or small-cell are associated with elevated CA-125 and/or CEA [111]. To
carcinoma of the lung [105]. Importantly, all other tumors on date, there are no known molecular mechanisms or genetic
the vast differential for SCCOHT should have retained profiles for primary ovarian NSCNEC.
nuclear positivity for the SMARCA4 antibody [105]. It Grossly, tumors are typically unilateral, partially cystic,
should be noted, however, that there are rare cases in the lit- and large, ranging in size from 5 to 30 cm, with an average
erature of SCCOHT with SMARCA4 gene mutations causing size of 15.3 cm [112]. Microscopically, NSCNEC are com-
retained SMARCA4 protein [101]. posed of intermediate to large atypical cells, with moderate
Clinically, SCCOHT is a highly aggressive neoplasm to abundant eosinophilic or granular cytoplasm, and round to
with a dismal prognosis [107, 109]. The long-term survival oval vesicular nuclei with coarsely stippled chromatin or
rate is 10–20% overall with a mean overall survival of prominent nucleoli, arranged in trabeculae, nests, or solid
14.9 months [109]. Slightly over half of patients are found to sheets [112]. Areas of confluent geographic necrosis and
have extraovarian disease in the abdomen and pelvis at diag- central comedo-like necrosis are common. Mitotic activity is
nosis [107]. The most important prognostic factor is tumor brisk with atypical mitoses present. Immunohistochemistry
stage at diagnosis, with a long-term survival rate of 33% and often reveals tumor cells positive for synaptophysin, chro-
a mean survival of 35.3 months for patients with early-stage mogranin A, neuron-specific enolase (NSE), CD56, EMA,
disease [109]. In the largest clinical analysis of patients to and pancytokeratin [113].
date, 33% of patients with stage IA disease were disease free Primary ovarian NSCNEC must be differentiated from
for an average of 5.7 years (range 1–13 years) postsurgery metastatic neuroendocrine carcinoma, primary or metastatic
[106]. Comparatively, no patients with stage IC disease were carcinoid tumor, small-cell carcinoma of pulmonary or
disease free at follow-up and 90% had died of disease within hypercalcemic type, and other non-neuroendocrine tumors
2 years postsurgery [106]. Factors associated with improved with neuroendocrine differentiation (such as sex cord-
prognosis include older age at diagnosis, normal preopera- stromal or germ cell tumors) [113]. Primary ovarian
tive serum calcium, lack of large-cell variant histology, NSCNEC can be distinguished from metastatic neuroendo-
tumor size less than 10 cm, and administration of adjuvant crine carcinoma as it is almost always unilateral and most
radiotherapy [106, 109]. Current management typically often associated with ovarian surface epithelial tumors, a
involves surgical resection, followed by chemotherapy or clue to its primary ovarian origin. Additionally, CA-125 is
radiotherapy [109]. More recent studies suggest that high- often elevated, pointing to an ovarian origin [111]. Primary
dose chemotherapy with autologous stem cell rescue (HDC- or metastatic carcinoid tumors involving the ovary are distin-
aSCR) offers the best chance at long-term survival [110]. guished by their smaller cell size, low mitotic rate, decreased
cellular atypia, and absence of necrosis. Small-cell carci-
noma of hypercalcemic type can be easily differentiated
7.11.2 Non-small, Neuroendocrine Carcinoma from NSCNEC with several immunostains including an
immunostain for SMARCA4 (see previous section).
Originally described by Collins et al. in 1991, primary ovar- Approximately two-thirds of patients with primary ovar-
ian non-small-cell neuroendocrine carcinoma (NSCNEC) of ian NSCNEC present with stage I disease, although out-
the ovary, also referred to as large-cell neuroendocrine carci- comes are variable [113]. Patients may survive up to 5.5 years
noma (LCNEC, LCNC) or undifferentiated carcinoma of with no evidence of disease or die of disease in as little as
non-small-cell neuroendocrine type, is an exceedingly rare 4 months despite aggressive treatment [112]. The remaining
diagnosis with less than 50 cases reported in the literature third of patients who present with stage III or IV disease
thus far [111]. The vast majority of primary ovarian NSCNEC often die of disease within months, although some have been
are admixed with a smaller component of ovarian surface epi- reported to survive up to 3 years with no evidence of disease
thelial neoplasms (benign, borderline, or malignant) or less [112, 113]. The majority of recent cases are treated with total
commonly a germ cell neoplasm, helping to differentiate abdominal hysterectomy (TAH) and bilateral salpingo-
these primary ovarian neuroendocrine carcinomas from meta- oophorectomy (BSO) with adjuvant chemotherapy [112].
static neuroendocrine carcinoma [112]. Even less commonly, Reported chemotherapy regimens are extremely variable,
NSCNEC may have pure neuroendocrine differentiation with although most documented regimens include platinum-based
no associated epithelial component [113]. chemotherapy [112]. Given the rarity of cases there is no
accepted standard therapy; however, the best outcomes

reported to date are in patients who underwent TAH-BSO
and at least six cycles of adjuvant cisplatinum-based chemo-
therapy regardless of the stage at presentation [112].
7.11.3 Hepatoid Carcinoma
Hepatoid carcinoma of the ovary is extremely rare with less

than 50 cases reported in the literature [115, 116]. These
cases tend to be highly aggressive and morphologically
mimic hepatocellular carcinomas. While these lesions are
more common in postmenopausal patients, they have been
reported in younger women with an age range of 35–78 years
[115]. Patients may present with bilateral or unilateral ovar-
ian masses and tend to have an elevated alpha-fetoprotein Fig. 7.14 Cystically dilated rete ovarii lined by cuboidal, non-ciliated
and an elevated CA-125 [115]. Histologically hepatoid car- bland cells
cinomas of the ovary are composed of mostly sheets of
monotonous cells with distinct borders, abundant eosino-
philic cytoplasm, and centrally placed nuclei with prominent tions similar to adenomas. A case of rete ovarii adenocarci-
nucleoli [116, 117]. Mitoses are generally conspicuous. In noma was reported and redescribed in the literature many
addition, PAS-positive diastase-resistant hyaline globules years ago, with no recently reported cases [123]. Given the
can be seen and glycogen can be demonstrated within the long interval of time in the reporting of a case of rete ovarii
cytoplasm of the tumor cells. Immunohistochemically these adenocarcinoma and the fact that the carcinoma reported was
tumors are usually positive for AFP, cytokeratins, and reported before the development of many modern ancillary
HepPar1 [118]. In addition they can be positive for albumin, studies, we feel that it is unclear if this entity does exist and
alpha1-antitrypsin, and alpha1-antichymotrypsin [118]. look forward to reading more studies on the subject in the
Importantly, the differential diagnosis of hepatoid carcinoma future.
of the ovary should include yolk sac tumor with a hepatoid The differential diagnosis for rete ovarii lesions is broad
pattern and metastasis. Unlike other entities in the differen- with the most common mimics being lesions of serous ori-
tial diagnosis, hepatoid carcinoma usually appears in its pure gin, sex cord-stromal tumors, including Sertoli-Leydig cell
form, though it has been reported to occur in conjunction tumors, and female adnexal tumors of Wolffian origin
with other types of ovarian surface epithelial and stromal (FATWO). Morphology in combination with immunohisto-
tumors [119–122]. chemistry should be used to distinguish rete ovarii lesions
from other entities when clinically indicated. Of note, rete
ovarii lesions are uniformly positive for PAX8 and SF-1
7.11.4 Tumors Associated with Rete Ovarii (weak) immunostains and negative for PAX-2 and GATA3
immunostains [126].
The rete ovarii are structures of mesonephric origin that are
often identified within the periadnexal soft tissue. The rete
ovarii are similar to the rete testis in men. Various lesions 7.11.5 Adenomatoid Tumor
including cysts, cystadenoma, adenomas, adenomatous
hyperplasias, and adenocarcinomas have been noted to arise Historically described by many terms (lymphangioma,
from the rete ovarii [123–125]. Of these lesions the most mixed leiomyoma, adenoma, adenomyoma, benign meso-
common are rete cysts and rete cystadenomas. The only dis- thelioma, and angiomatoid formation), and eventually
tinction between a rete cyst and a rete cystadenoma is size, descriptively termed “adenomatoid tumor” by Golden and
with cystadenomas being larger than 1 cm. The epithelial lin- Ash in 1945, adenomatoid tumors of the ovary are extremely
ing of both of these benign entities is similar to that of the rare, often incidental, benign neoplasms of mesothelial ori-
rete ovarii—simple, non-ciliated, and bland with irregular gin [127]. While adenomatoid tumors in general occur with
infoldings (Fig. 7.14). Adenomas of the rete ovarii are well- relative frequency in the male and female genital tracts (epi-
circumscribed proliferations of crowded tumors and papillae didymis, fallopian tubes, and uterus), they rarely appear in
cytologically similar to surrounding rete ovarii. Adenomatous the ovary and can pose a diagnostic challenge by mimicking
hyperplasias of the rete ovarii are uncircumscribed prolifera- other ovarian neoplasms such as yolk sac tumors [128].
Ovarian adenomatoid tumors, much like their counter- [128]. Tumor cells are classically positive for mesothelial
parts in the male and female genital tracts, are often found markers such as calretinin, CK5/6, and WT-1; however, recent
incidentally during autopsy or when the ovaries are removed studies have shown that adenomatoid tumors are most often
for other reasons; however, several cases in the literature positive for CAM5.2, calretinin, D2-40, and WT-1, with only
reportedly presented with symptoms [128]. The age at pre- a small percentage positive for CK5/6 [127].
sentation is wide, ranging from 23 to 79 years, with an aver- Until very recently, there have been no studies revealing a
age of 54 years of age [128]. Importantly, these benign molecular pathogenesis for ovarian adenomatoid tumors. One
mesothelial tumors are not associated with asbestos expo- recent study, however, performed next-generation sequencing
sure, while primary ovarian malignant mesotheliomas may on 31 adenomatoid tumors of the male and female genital
or may not be associated with asbestos exposure [129]. No tracts (7 epididymal tumors, 7 fallopian tube tumors, 17 uter-
clinical biomarkers have been associated with ovarian ade- ine tumors) and found a single heterozygous somatic mis-
nomatoid tumors or other adenomatoid tumors of the female sense mutation in the TRAF7 gene in all tumors [130]. These
genital tract to date [127]. somatic missense mutations were all clustered into one of the
On gross examination, these tumors are unilateral, pre- five locations at the C-terminus of the protein, with the most
dominantly located in the ovarian hilum and often quite common mutation of the female genital tract located at
small (ranging between 1 and 16 mm in size, average of p.S561R followed by p.H521R. A member of the tumor
7 mm), though sizes up to 8 cm have been reported [127, necrosis factor receptor-associated factor (TRAF) family, the
128]. Grossly, these lesions typically appear well circum- TRAF7 gene encodes an E3 ubiquitin ligase known to play a
scribed, solid, white to yellow, and firm [128]. role in regulating nuclear factor-kappa B (NF-kB). This study
Microscopically, adenomatoid tumors are often well cir- further revealed that mutations in TRAF7 drive aberrant acti-
cumscribed, though infiltrative patterns are reported [127, vation of the NF-kB signaling pathway in vitro, leading to
128]. A variety of architectural patterns have been described upregulation of L1 cell adhesion molecule (L1CAM), a
in the literature (adenoid, angiomatoid, glandular, microcys- known transcriptional target of NF-kB. While this study did
tic, trabecular, oncocytic, and solid), but all are distinctive for not include an ovarian adenomatoid tumor, the results suggest
oval, elongated, or slit-like tubules lined by flat to columnar that somatic missense mutations in TRAF7 may be a geneti-
cells with threadlike bridging strands that cross these tubular cally defining event for all adenomatoid tumors of the male
spaces [128] (Fig. 7.15). Tubules may be focally cystically and female genital tracts [130].
dilated and, while often empty, rarely may contain basophilic Ovarian adenomatoid tumors, due to their rarity, may
fluid [128]. Stroma may be scant to moderate. Tumor cells cause more diagnostic confusion than their tubal and uterine
often contain abundant dense eosinophilic cytoplasm to pale counterparts [128]. Architectural variants, particularly adeno-
vacuolated cytoplasm with bland nuclei, which lack cytologic matoid tumors with hyaline bodies, can mimic the reticular or
atypia and mitotic activity. Tumor cells often at least focally liposarcoma-like pattern of yolk sac tumor. While hyaline
contain small to large intracytoplasmic vacuoles, mimicking bodies are a characteristic finding in yolk sac tumors they are
signet-ring cells or lipoblast-like cells [127, 128]. Rarely, nonspecific and can occur in a variety of ovarian tumors
cells may contain PAS-positive eosinophilic hyaline bodies [128]. Adenomatoid tumors can be differentiated from yolk
sac tumors by their bland nuclei lacking primitive cytology.
The multicystic pattern of adenomatoid tumor can mimic a
multilocular peritoneal inclusion cyst (benign cystic mesothe-
lioma), though this would occur as an ill-defined collection of
cysts on the ovarian serosa rather than a well-circumscribed
mass in the ovarian hilum. The vacuolar pattern of adenoma-
toid tumor could mimic foci of a female adnexal tumor of
Wolffian origin (FATWO), although adenomatoid-like areas
of FATWOs are typically admixed with other architectural
patterns, allowing for distinction between the two.
Additionally, epithelioid hemangiomas and lymphangiomas
may be on the differential, though these could be distin-
guished with immunohistochemical stains [127, 128].
Adenomatoid tumors of the ovary, as well as those of the
male and female genital tract, display a benign clinical
course requiring no additional therapy after resection [130].
In fact, the majority of patients with ovarian adenomatoid
Fig. 7.15 Adenomatoid tumor tumors are found to harbor these neoplasms following resec-
tion of the ovary for other reasons. Several recent studies carcinoma [137]. While there are no specific biomarkers
have revealed that long-term follow-up (on average 8 years) associated with DSRCT, serum CA-125 levels are often ele-
for adenomatoid tumors of the female genital tract, including vated in primary ovarian DSRCT [140]. Elevated inhibin has
those in the ovary, reveals no evidence of recurrence follow- been reported in rare cases [137]. Imaging and laparoscopy
ing resection [127]. typically reveal widespread intraperitoneal involvement with
one to several large masses and numerous smaller peritoneal
tumor deposits [136]. Ovarian involvement may be unilateral
7.11.6 Ovarian Mesothelioma or bilateral (approximately 50% are bilateral), and the most
common metastatic sites are liver, lymph nodes, lung, and
Mesothelioma arising within the peritoneal cavity to involve bone marrow [140].
the ovary and mimic a primary ovarian neoplasm is rare, but Gross examination reveals tumors to be large, with an
has been reported and usually affects middle-age and elderly average size of 11 cm (range 5–20 cm) [137]. Multiple large
patients [129, 131, 132]. Rare mesotheliomas confined to the tumor nodules are often present with multifocal hemorrhage
ovary have also been reported [129]. Morphologically meso- and necrosis. Microscopic examination reveals nests or
theliomas involving the ovary tend to be of the epithelioid sheets of monotonous, round to ovoid, small round blue cells
type, but some can contain a sarcomatous component [129]. with scant cytoplasm in an abundant desmoplastic stroma
Mesothelioma should be considered in the differential diag- [141]. Architectural variants include rosette-like, tubular,
nosis of a variety of ovarian neoplasms including low-grade glandular, or trabecular architecture [142]. Nuclei are hyper-
serous carcinoma or borderline serous tumors with implants. chromatic with inconspicuous nucleoli, brisk mitotic activ-
Of utmost importance is the consideration of the distribution ity, and focal necrosis. Additionally, tumor cells may be
of the lesion and immunohistochemical profile. markedly pleomorphic, appear spindled, contain abundant
Recommended immunohistochemical profiles to evaluate eosinophilic cytoplasm (rhabdoid appearance), or exhibit
for mesothelioma involve a variety of markers. Calretinin clear-cell or signet-ring features [141, 142].
and D2-40 are especially recommended given that they are DSRCT is classically defined by co-expression of epithe-
usually negative in ovarian epithelial neoplasms, while posi- lial, mesenchymal, and neural immunohistochemical mark-
tive in mesothelioma. While WT-1 is often used to evaluate ers; however, no single stain is specific or sensitive for
for mesothelioma in the pleural cavity, WT-1 is unhelpful DSRCT and thus immunostains must be interpreted with
when considering an ovarian neoplasm as WT-1 is positive in caution. Characteristically positive immunostains include
the majority of ovarian epithelial primaries. Additional stains cytokeratins (CAM 5.2, AE1–3, PanCK, but not CK5/6 or
to consider include PAX8, estrogen, and progesterone recep- CK20), EMA (membranous staining pattern), desmin (peri-
tors, which are usually negative in mesothelioma; however, nuclear dot-like staining pattern), and neuron-specific eno-
one must interpret these stains with caution given recent lase (NSE) [142]. Positive immunostaining for WT-1 (with
reports of positivity in rare cases of mesothelioma [133, an antibody directed against the C terminus) is seen in over
134]. A recent study has described the usefulness of the two-thirds of cases and INI1 expression is typically retained
marker BAP-1 in the differential diagnosis of mesothelioma [142]. Few cases may exhibit positive staining for CD99,
and serous carcinoma as loss of BAP-1 staining strongly smooth muscle actin (SMA), muscle-specific actin, chromo-
supports the diagnosis of mesothelioma [135]. granin, synaptophysin, CD56, neurofilament, and S100
[142]. Immunostains for myogenin, MyoD1, myoglobin,
glial fibrillary acidic protein (GFAP), and HMB-45 are clas-
7.11.7 Desmoplastic Small Round-Cell Tumor sically negative [142].
DSRCTs are genetically characterized by a t(11;22)
Desmoplastic small round-cell tumor (DSRCT) is a rare, (p13;q12) gene translocation leading to an EWS-WT1 gene
highly aggressive, intra-abdominal neoplasm with a strong fusion product [142]. This translocation fuses the Ewing sar-
male predominance (male-to-female ratio of 4:1) [136]. Of coma (EWS, also referred to as EWSR1) gene with the Wilms’
the approximately 850 cases described thus far in the litera- tumor-suppressor (WT1) gene, creating a functional chimeric
ture, less than 20 have been reported to arise in the ovary and fusion protein that is thought to act as a transcriptional acti-
involve the peritoneal cavity of adolescent women [137, vator on several downstream targets. Fluorescent in situ
138]. Primary ovarian DSRCT presents in the second and hybridization (FISH) with break apart probes for EWS is
third decades of life, with a reported age at presentation diagnostic of DSRCT; however, an EWS-WT1 gene fusion is
ranging from 6 to 31 years of age [137, 139]. not always present, and EWS gene rearrangements are pos-
Patients typically present with abdominal distention, sible [142].
intractable abdominal and pelvic pain, nausea, vomiting, Making a definitive diagnosis of DSRCT based on mor-
constipation, and weight loss, mimicking epithelial ovarian phologic features alone is not typically possible given the
expansive differential diagnosis for “small round blue cell” there is no known molecular mechanism characterizing
tumors. This differential includes undifferentiated or poorly FATWOs to date [143].
differentiated carcinoma, small-cell carcinoma of hypercal- On gross examination, FATWOs are unilateral, well cir-
cemic type, immature teratoma, poorly differentiated Sertoli- cumscribed, or encapsulated, solid to partially cystic masses
Leydig cell tumor, juvenile granulosa cell tumors, ranging from 0.8 to 25 cm in greatest diameter [145]. The cut
neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, primi- surface is typically rubbery, tan-yellow to gray, and focally
tive neuroectodermal tumor, lymphoma, neuroblastoma, and hemorrhagic or necrotic. They occur throughout the broad
hepatoblastoma [141, 142]. ligament, often sparing the ovaries, but can rarely present as
The reported life expectancy after a diagnosis of ovarian ovarian tumors [145]. Rare bilateral ovarian FATWOs are
DSRCT ranges from 4 to 42 months [140]. The current stan- documented in the literature [146].
dard of care is aggressive surgical resection and adjuvant Histologically, FATWOs present with a variety of archi-
high-dose chemotherapy, followed by either whole abdomi- tectural patterns mimicking both surface epithelial tumors
nopelvic intensity-modulated radiation therapy or hyperther- and sex cord-stromal tumors. FATWOs are composed of epi-
mic intraperitoneal chemotherapy (HIPEC) [142]. Currently, thelial cells growing in tubular, sievelike (retiform), multi-
the most widely accepted adjuvant chemotherapy for DRSCT cystic, or diffuse (solid) patterns with variable amounts of
is the “P6 protocol,” which consists of four cycles of cyclo- fibrous stroma, often with a single architectural pattern pre-
phosphamide, doxorubicin, and vincristine (CDV), with dominating (Fig. 7.16) [144, 145]. The tubular pattern of
alternating ifosfamide and etoposide in between cycles architecture is characterized by closely packed hollow
[137]. Patients with chemoresponsive disease and optimal tubules with compressed lumens lined by cuboidal to colum-
surgical cytoreduction appear to have the best long-term out- nar epithelial cells. The sievelike (retiform) pattern is charac-
comes and improved survival. Overall, despite often respond- terized by solid areas separated by various-sized cysts filled
ing well to chemotherapy, tumors recur rapidly and long-term with eosinophilic secretions and lined by low cuboidal, occa-
survival is dismal [140]. sionally hobnailed, epithelial cells. The diffuse (solid) pat-
tern is characterized by sheets of oval to spindle-shaped cells
with scant eosinophilic cytoplasm. Tumor cells are typically
7.11.8 Female Adnexal Tumors of Wolffian cytologically bland, with fine even chromatin, inconspicuous
Origin nucleoli, and low mitotic activity (<1/10 high-power fields)
[144, 145].
First reported in 1973 by Kariminejad and Scully, female Immunohistochemistry can be confusing due to lack of
adnexal tumors of probable Wolffian origin (FATWO) are specificity or sensitivity of any one immunostain, including
rare epithelial ovarian tumors with fewer than 100 cases doc- those that have been shown to be positive in mesonephric
umented in the literature thus far [143]. Previously called remnants [126, 144]. More recently, studies have shown
“Wolffian adnexal tumor” and “retiform Wolffian adenoma,” PAX8 to be negative in virtually all cases of FATWO, which
FATWOs are thought to be derived from mesonephric
(Wolffian) duct remnants [144]. During male embryogene-
sis, mesonephric ducts and tubules form the vas deferens and
other male reproductive structures. In female embryogene-
sis, the mesonephric ducts and tubules degenerate, leaving
remnant mesonephric inclusions throughout the broad liga-
ment, extending from the hilum of the ovary along the meso-
salpinx to the lateral uterus and lateral walls of the vagina
(Gartner’s ducts) [145]. FATWOs exclusively arise in these
locations and share histologic and immunologic characteris-
tics with mesonephric remnants, leading to the hypothesis
that these tumors are of mesonephric (Wolffian) origin [144].
FATWOs either present with abdominal swelling and
pain, pelvic pain, and vaginal bleeding or are incidentally
discovered during pelvic examination or laparotomy in
approximately half of patients [145]. Age at presentation
ranges from 15 to 87 years of age, with a median age of
50 years old [145, 146]. No biomarkers are reported to be
Fig. 7.16 Female adnexal tumor of Wolffian origin composed of epi-
associated with FATWOs, and elevated serum CA-125 has thelial cells growing in tubular, sievelike (retiform), and diffuse (solid)
not been documented in the literature [145]. In addition, patterns with a minimal amount of intervening stroma
may emerge as a useful immunohistochemical stain for diag- 3. Kurman RJ, Shih Ie M. The dualistic model of ovarian car-
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currently determined by clinical behavior (recurrence or 15. Roma AA, Masand RP. Different staining patterns of ovarian
metastases) rather than by pathological features, although Brenner tumor and the associated mucinous tumor. Ann Diagn
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Germ Cell Tumors and Mixed Germ
Cell-Sex Cord-Stromal Tumors 8
of the Ovary
Hao Chen, Charles Matthew Quick, Oluwole Fadare,

and Wenxin Zheng
Abstract Keywords
Ovarian germ cell tumors (OGCTs) account for approxi- Mature cystic teratoma · Mature solid teratoma · Immature
mately 30% of all primary ovarian neoplasia, secondary teratoma · Homunculus (fetiform teratoma) · Teratoma
only to epithelial ovarian tumors. OGCTs occur mostly in with malignant transformation · Struma ovarii · Carcinoid
younger women and account for approximately 60% of Neuroectodermal type tumors · Sebaceous tumors ·
all ovarian tumors in women under 21 years of age. Most Dysgerminoma · Yolk sac tumor · Embryonal carcinoma ·
OGCTs are pure, and about 10% of OGCTs contain more Non-gestational choriocarcinoma · Polyembryoma ·
than one component. For these mixed tumors, the behav- Mixed malignant germ cell tumors · Gonadoblastoma ·
ior and prognosis are largely determined by the most Germ cell-sex cord-stromal tumor, unclassified
malignant component; therefore, thorough examination
and extensive specimen sampling are critical for identify-
ing and quantifying all components of the tumor. Germ
cell tumors generally mimic various stages of normal 8.1 Introduction
embryogenesis and have the potential to develop into any
normal tissue type; however, the haphazard distributions Ovarian germ cell tumors (OGCTs), which are believed to
and composition of various tissue types can be diagnosti- arise from primordial germ cells, account for approximately
cally challenging. Achieving the correct diagnosis 30% of all primary ovarian neoplasia, secondary only to epi-
depends on familiarity with this potentially haphazard thelial ovarian tumors. The vast majority of OGCTs (approx-
pattern of various tissue types, correct identification of all imately 95%) are mature cystic teratoma [1, 2]. OGCTs
tissue components, and recognition of foci of possible occur mostly in younger women and account for approxi-
malignant transformation. This chapter focuses on the mately 60% of all ovarian tumors in women under 21 years
clinicopathologic features of OGCTs and also briefly cov- of age, of which one-third are malignant germ cell tumors
ers mixed germ cell and sex cord-stromal tumors. [3]. In contrast, OGCTs account for only 6% of ovarian
tumors in postmenopausal women. Most OGCTs are pure
and only about 10% of OGCTs contain more than one com-
ponent. For these mixed tumors, the behavior and prognosis
of the tumor are largely determined by the most malignant
H. Chen
Department of Pathology, UTSouthwestern Medical Center, component; therefore, thorough examination and extensive
Dallas, TX, USA specimen sampling are critical for identifying and quantify-
C. M. Quick ing all components of tumor.
Department of Pathology, College of Medicine, University of Based on the anatomical location, age of unset, precursor
Arkansas for Medical Sciences, Little Rock, AR, USA lesions (cells of origin, genetic characteristics), and chromo-
O. Fadare somal makeup, human germ cell tumors can be roughly sub-
Department of Pathology, University of California San Diego, classified into the following groups [4]: type I, neonatal and
San Diego, CA, USA
infantile teratoma and yolk sac tumor; type II, dysgermi-
W. Zheng (*) noma and other germ cell tumors (occur mostly in adoles-
Departments of Pathology, Obstetrics and Gynecology,
University of Texas Southwestern Medical Center,
cents and young adults); type III, spermatocytic seminoma
Dallas, TX, USA (typically occurs in testis of elderly males); type IV, dermoid
e-mail: [email protected] cyst; and type V, hydatidiform mole of childbearing-age
232 H. Chen et al.
women. The pathogenesis of OGCTs is not yet fully under- patients can present with abdominal pain, bloating, and
stood. Mature cystic teratomas (MCT) contain diploid chro- abnormal vaginal bleeding, especially in larger and/or
mosomes with a normal 46, XX karyotype, and are believed ruptured tumors. Ovarian torsion occurs in 3–16% of
to originate from germ cells immediately after the first cell cases. Around 10% of cases are discovered during preg-
division of meiosis. Therefore, it is classified as a type IV nancy. These tumors can occasionally present with hir-
germ cell tumor using a previously described scheme [5]. sutism, which is associated with ovarian interstitial
However, recent studies demonstrate that MCTs may vary in luteinization. Teratoma-associated encephalitis is a rare
cell origin, with most MCTs originating from germ cells yet potentially fatal paraneoplastic syndrome that occurs
post-first cell division of meiosis., A minority of MCTs arise in young women, and is caused by antibodies to the
from primordial germ cells before meiosis occurs. In con- N-methyl-d-aspartic acid receptor (NMDAR). Tumors
trast to MCTs, neonatal and infantile yolk sac tumors, as causing this syndrome may display specific morphologi-
well as immature teratomas, likely originate from pluripotent cal features [8].
embryonic stem cells. OGCTs in elderly women can occur
synchronously with somatic type tumors, and are believed to 8.2.1.3 Macroscopic Features
originate from tumor stem cells. Overall, the pathogenesis of Mature teratomas are usually unilateral, but may be bilat-
OGCTs is different from that of male testicular germ cell eral in 10–15% cases. They are generally oval in shape
tumors which are mostly malignant and aneuploid, and are with a smooth external surface. They may be peduncu-
believed to originate mostly from primordial germ cells lated. The size of mature teratomas ranges from micro-
before meiosis. scopic up to 40 cm, with an average diameter of 8 cm [9].
Germ cell tumors generally mimic various stages of nor- On sectioning, the tumors are typically unilocular; how-
mal embryogenesis and have the potential to develop into ever, they may occasionally be multilocular. The cysts are
any normal tissue types; however, the haphazard distribu- usually filled with sebaceous material, hair, and occasion-
tions and composition of various tissue types can be diagnos- ally mucinous or serous fluid (Figs. 8.1 and 8.2). The cyst
tically challenging. Achieving the correct diagnosis depends is lined with skin, mucosa, or dark membranous tissue.
on the following three factors: (1) familiarity with this hap- The cyst wall varies in thickness, often with focal thicken-
hazard pattern of various tissue types; (2) correct identifica- ing or a nodular appearance. A solid nodule composed of
tion of all tissue components; and (3) correct identification of adipose tissue, teeth, and bone, protruding into the cyst
malignant transformation of benign/mature components. lumen, is colloquially called “Rokitansky’s protuberance.”
This chapter focuses on the clinicopathologic features of Other tissues such as gastrointestinal mucosa, white or
OGCTs and also briefly covers mixed germ cell and sex gray matter of the brain, and thyroid may be seen within
cord-stromal tumors. the large protuberance. The protuberance and areas of
thickened cyst wall are most likely to contain various
mature and immature tissues; the grossing of the specimen
8.2 Teratoma should focus on those areas.
8.2.1 Mature Cystic Teratomas
8.2.1.1 Definition
This is a tumor composed exclusively of mature tissue
derived from two or three germ cell layers. These tumors are
usually cystic, but rarely can be solid. If the lining of cyst is
solely composed of mature skin and associated adnexal
structures, it may also be called a dermoid cyst.

The mature cystic teratoma is the most common type of
ovarian tumor, accounting for approximately one-fourth
of all ovarian tumors, and usually occurs in reproduc-
tive-age women [6, 7]. While teratomas in adults are pre-
2 cm
dominantly mature, the ratio of mature to immature
teratomas is approximately 2:1 in pediatric patients.
Fig. 8.1 Mature cystic teratoma. There is sebaceous material and a
Most patients are asymptomatic, and the tumors are usu- solid Rokitansky protuberance (arrow) in the capsule. Red-brown thy-
ally incidental findings in routine examination; however, roid tissue is present within left capsule with a colloid-like appearance
8 Germ Cell Tumors and Mixed Germ Cell-Sex Cord-Stromal Tumors of the Ovary 233
8.2.1.4 Microscopic Features
Mature Cystic Teratoma, Classic Type

Classic mature cystic teratomas usually contain mature tis-
sues from two or three embryonic layers. Almost all cases
contain ectodermal elements (skin and associated adnexal
structures such as sweat glands, sebaceous glands, hair and
hair follicles) and/or mesodermal elements (adipose tissue,
smooth muscle, bone and cartilage, etc.); endodermal ele-
ments such as respiratory epithelia, gastrointestinal epithe-
lia, thyroid, neural/glial tissue, neurons, and choroid
plexus may also be present (Fig. 8.3). With the exception
of adrenal tissue and gonads, all tissue types have been
described in mature teratoma. These various tissue types
are usually haphazardly organized within the tumor. The
frequency of various tissue types in teratoma is listed in
Fig. 8.2 Mature cystic teratoma. There is a Rokitansky protuberance Table 8.1.
with hair and teeth (arrow) within the capsular wall
a b
c d
Fig. 8.3 Mature cystic teratoma. The more common mature tissues include epidermis, sebaceous glands, hair follicles, and adipose tissue (a);
sweat glands and cartilage (b); mature glial tissue (c); and epithelium of the gastrointestinal and respiratory tracts (d)
234 H. Chen et al.
Table 8.1 Frequency of various tissue types identified in mature cystic adnexa. In contrast, mature cystic teratomas contain tis-
teratomas
sues derived from two or three embryonic layers; how-
Frequency Percentage Cell/tissue types ever, some use these terms interchangeably.
Common >66 Skin, hair, sebaceous glands, white fat, 2. Immature teratomas
brain tissue (children)
The diagnosis of an immature teratoma depends on the
Relatively 33–66 Sweat glands, brain tissue (adult),
common smooth muscle, peripheral neural tissue, identification of immature mesenchyme, which is almost
cartilage, bone, respiratory epithelia always composed of immature neuroectoderm. Extensive
Occasional 5–33 Teeth, gastrointestinal epithelia, sampling of the specimen, particularly the solid areas, is
thyroid, ependymal tissue, melanocytes required to rule out immature teratomas.
Rare <5 Prostatic gland, retina, mammary tissue,
3 . Homunculus (fetiform teratomas)
pituitary glands, choroid plexus,
ganglion, lung, liver, kidney, This rare form of mature teratoma contains mature tissue
cardiomyocytes, thymus, cerebellum, derived from three embryonic layers, and demonstrates
skeletal muscle, brown fat more defined organization causing it to resemble mal-
formed organs, and, rarely, a fetus.
Mature Cystic Teratoma with Rare, Microscopic Foci 8.2.1.6 Treatment and Prognosis

of Immature Neural Tissue Mature cystic teratomas have an excellent prognosis.
The presence of rare, microscopic foci of immature neural Surgical removal is the treatment of choice. Ovarian cystec-
tissue is associated with an excellent outcome. Therefore, in tomy, if possible, is adequate treatment in children and young
the WHO classification of germ cell tumors, this type of tera- women. As 10–15% of cases involve both ovaries, careful
toma is still classified as mature [10]. It has been proposed examination of the contralateral ovary is warranted. When
that less than five foci of immature neural tissue, with single necessary, frozen section evaluation can be performed to
focus less than 21 mm, is used as the diagnostic criteria for guide clinical decision-making. If thyroid tissue is identified
this type of mature teratoma [11]. Considering that this des- within tumor, it should be mentioned within the pathology
ignation may have significant overlap with previously report as postsurgical hypothyroidism can occur and hinder
described grade I immature teratoma, we recommend use of wound healing.
the phrase “mature cystic teratoma with microscopic foci of
immature neural tissue” as the diagnosis. In addition, pathol-
ogists should also mention the size of the immature neural 8.2.2 Mature Solid Teratomas
foci and recommend close follow-up in a diagnostic com-
ment. It is worth noting that rare tubules lined with a single 8.2.2.1 Clinical Presentation
layer of benign, cuboidal cells can be found in mature neural This rare tumor mainly occurs in children and young adults
glial tissue. These tubules may represent ependymal epithe- 10–20 years of age [12, 13]. It has a similar clinical presenta-
lia, not primitive neuroepithelia. tion profile as their cystic counterparts, but notably can be
associated with glial implants (gliomatosis peritonei).
Teratomas Associated with Encephalitis
This rare variant of mature teratoma displays prominent lym- 8.2.2.2 Macroscopic Features
phoplasmacytic infiltration which is most pronounced within Solid teratomas are often larger than 10 cm. The tumor is
the neuroglial matrix and adjacent tissue. This contrasts with completely solid, with occasional microcystic areas and
teratomas not associated with encephalitis, wherein the often contains brain, cartilage, and bone. Grossly it can be
inflammatory cells are mainly seen in epithelial components differentiated from immature teratomas, which often display
(most commonly squamous and respiratory epithelia). The necrosis and hemorrhage. Gliomatosis peritonei may be
characteristic features of this type of teratoma include reac- associated with these tumors and present as disseminated,
tive germinal centers and diffuse lymphoplasmacytic infil- small, gray-tan, firm nodules on the peritoneal surfaces, sim-
trates within the neuroglial matrix, with accompanying ilar to the nodules of peritoneal miliary tuberculosis. The
degenerative neuronal changes [8]. extent of this finding may vary and may involve the pelvic
and/or abdominal cavities.
1. Dermoid cyst 8.2.2.3 Microscopic Features
Strictly speaking, dermoid cysts contain only ectodermal Solid teratomas usually contain mature tissues from three
elements. They are usually filled with gray-tan, greasy embryonic layers, which often maintain the architecture of
pilosebaceous contents. Microscopically, the cyst wall is an organ. Well-differentiated neuroglia is often identified, in
lined by keratinizing squamous epithelium with skin which mitotic figures are usually absent or rare. Unlike
mature cystic teratoma, in which presence of microscopic taining mucus or blood. The solid areas are gray-tan to pink,
foci of immature neural components is acceptable, this tumor soft, fleshy, and often hemorrhagic and necrotic (Fig. 8.4).
should be designated immature if microscopic, rare, primi- Patchy calcification is frequently seen. Gross analysis and
tive neuroectodermal components are present. As a result, sectioning should focus on the gray-tan, soft, fleshy areas,
extensive sampling of the specimen is required to rule out with special attention to areas of hemorrhage and necrosis,
immature teratomas. Gliomatosis peritonei usually consists as these are the areas in which immature tissue is most likely
of deposits of mature neuroglial tissue. Occasionally, other to be identified.
tissue types such as squamous epithelia or cartilage can be
seen within these foci. 8.2.3.4 Microscopic Features
Most of the tumors consist of a mixture of mature and immature
8.2.2.4 Differential Diagnosis embryonic components. Identification of immature embryonic
Grade 1 immature teratoma is the most important differential elements within tumors is the key for the diagnosis of immature
diagnosis. Identification of immature neuroectoderm within teratoma. The immature embryonic type tissue is usually neuro-
the tumor is the key. ectodermal and composed predominantly of small blue neuro-
blasts, primitive neuroepithelial rosettes, and tubules (Fig. 8.5).
8.2.2.5 Treatment and Prognosis The primitive neuroepithelial tubules and rosettes are lined by
Similar to mature cystic teratoma, these tumors have an
excellent prognosis; however, gliomatosis peritonei tends to
recur. Treatment consists of salpingo-oophorectomy with
complete resection of peritoneal glial implants.
8.2.3 Immature Teratoma
8.2.3.1 Definition
This is a teratoma containing variable amounts of immature
(typically primitive neuroectodermal) tissue.

Immature teratomas are most commonly seen in children
and young adults (less than 20 years of age) [14–16]. Most
immature teratomas have a 46 XX karyotype, with rare cases 2 cm
of bilateral immature teratomas being associated with an
abnormal Y chromosome [17]. A palpable abdominal mass Fig. 8.4 Immature teratoma. The cut surface of the tumor is predomi-
and pelvic or abdominal pain, occasionally with nausea, nantly solid, soft, and fleshy. Hemorrhage and necrosis as well as large
vomiting, diarrhea, and fever, are the most common clinical cysts are present
presentations. Rarely patients can present with an acute
abdomen due to ovarian torsion or tumor rupture.
Spontaneous rupture can cause diffuse pelvic or abdominal
implants as well as adhesion formation. Serum AFP can be
elevated in patients with immature teratoma, but the level
rarely exceeds 1000 ng/mL. Serum AFP level can also be
elevated, and <10% patients have an elevated level of
β-hCG. The majority (70%) of cases are stage IA disease,
while 30% are stage II or above.
8.2.3.3 Macroscopic Features

Immature teratomas are typically round or oval adnexal
mass, and are commonly unilateral; however, the contralat-
eral ovary may contain a mature teratoma in 10–15% of
cases. The tumor is usually large, ranging from 6 to 42 cm in
diameter, with average of 18.5 cm [14]. Upon sectioning, the Fig. 8.5 Immature teratoma. Neuroectodermal tubules (lower left) and
tumors are predominately solid, with small microcysts con- cartilage (upper right)
236 H. Chen et al.
a crowded cells with a high N:C ratio and frequent mitotic figures
and apoptotic bodies. These foci may be pigmented. The lumi-
nal surface of the tubules displays a smooth membrane, which
is a helpful feature used to distinguish it from other nonneural
tubules (especially renal tubules). The relative amount of the
primitive neuroepithelial component is a critical factor in grad-
ing and determining the prognosis. In poorly differentiated, or
grade 3, immature teratoma, more primitive neuroepithelium is
present, which typically demonstrates increased nuclear atypia
and mitotic activity, as well as epithelial stratification of the epi-
thelial rosettes (Fig. 8.6). Islands of immature cartilage, bone,
skeletal muscle, and glandular structures set in a myxoid stroma
are often seen. Other embryonic endodermal elements such as
hepatic tissue, intestinal epithelium, and glomeruli (rare) may
b
also be present. The presence of the abovementioned immature
components alone is not sufficient for the diagnosis of immature
teratoma. In addition, one must not confuse retinal tissue, cere-
bellar tissue, or thymic tissue as primitive neuroepithelium.
Occasionally immature teratoma can be seen admixed with
other types of germ cell tumor, such as yolk sac tumor, chorio-
carcinoma, or embryonal carcinoma, with yolk sac tumor being
the most common (Fig. 8.7). If the largest focus of other germ
cell tumor types is less than 2 mm in diameter, they are found to
have no effect on the overall prognosis of the tumor [18].
Markedly elevated serum AFP level should alert the pathologist
to the presence of a yolk sac component, and if absent in the
Fig. 8.6 Immature teratoma. The neuroectodermal tubules are lined by
multiple layers of cells (a) with basophilic cytoplasm and overlapping initial sections additional tissue should be submitted. Of note,
nuclei. Mitotic activity is typically brisk (b) the presence of immature intestinal glandular tissue and liver
parenchyma may lead to increased levels of AFP in the absence
of a yolk sac component.
Fig. 8.7 Immature teratoma

a b
with yolk sac tumor (*). This
tumor demonstrates a focal
component of yolk sac tumor
within an immature teratoma
(a); The yolk sac tumor cells
show strong nuclear positivity
for SALL4 while immature
neuroectodermal cells are
relatively weak (b)
*
*
Table 8.2 Grading of ovarian immature teratomas (three-tiered Rare examples have been reported in which ovarian carci-
system)
nosarcoma may display mesenchymal components that
Grade Histological features resemble primitive neuroectodermal tissue or immature
1 Rare foci of immature neural tissue, less than 1 low-power tubules seen in an immature teratoma [21–24]. The term
field (4X) per slide
“teratoid carcinosarcoma” has been applied for these
2 Moderate foci of immature neural tissue, more than 1 but
less than 4 low-power fields per slide cases. The key to correctly identifying these unusual com-
3 Abundant foci of immature neural tissue, more than 4 lower binations is to sample the tumor well, and to characterize
power fields per slide (Fig. 8.8) each component accurately.
3. Mixed malignant germ cell tumor
Adequate sampling and careful histologic examination
8.2.3.5 Grading of Immature Teratomas can help to correctly identify other germ cell tumor types,
The grading of immature teratomas is based on the relative which is the key in making an accurate diagnosis and thus
quantities of the immature neural tissue. Norris et al. [16] determining the prognosis for the patient. Careful chart
first proposed a three-tiered system to grade immature tera- review may disclose clinical findings, such as elevated
tomas (shown in Table 8.2). This system has been further tumor markers like AFP that can serve as a clue to the
simplified into a two-tiered system: low grade (previously presence of altered differentiation.
grade 1) and high grade (previously grades 2 and 3). 4 . Mature cystic teratoma with rare, microscopic foci of
immature neural tissue
8.2.3.6 Immunohistochemistry Rare, microscopic foci of immature neural tissue (where
Neuroectodermal tissue is typically positive for NSE, S-100, the largest focus is less than 2 mm in diameter, and less
NF, synaptophysin, NGFR, and GFAP; immature neural tis- than four foci per tumor) are within the acceptable diag-
sue can express SALL4, LIN28, SOX2, and glypican-3, but nostic spectrum of a mature cystic teratoma. The presence
is usually weaker when compared with other germ cell of rare, microscopic immature neural tissue has no effect
tumors [19, 20]. Immature endodermal tissues such as intes- on prognosis. Yanai-Inbar and Scully studied 11 such
tinal type glands and hepatic tissue can express AFP, which cases, and found no recurrence of tumor [11]; however,
can lead to an elevated serum APF level. The Ki67 (MIB-1) extensive sampling of the tumor is the key to making the
proliferative index is usually high in primitive neuroepithe- correct diagnosis.
lial tubules or rosettes.
8.2.3.9 Treatment and Prognosis
8.2.3.7 Genetics Approximately one-third of patients have extra-ovarian
Immature teratomas typically exhibit fewer DNA changes spread of tumor at the time of diagnosis. Overall, the grade
than other germ cell tumors. No gain of 12p or i(12p) has and FIGO stage of the tumor determine treatment planning
been identified [10]. Grade 1–2 immature teratomas are usu- and clinical outcome. For patients with low-grade, low-stage
ally diploid, whereas most grade 3 tumors are aneuploid. (stage I–II) tumors, fertility-preserving surgical procedures
and close follow-up are recommended. Extra attention
8.2.3.8 Differential Diagnosis should be given to the contralateral ovary at the time of sur-
1. Malignant transformation of mature cystic teratoma gery, since approximately 10–15% of patients may have a
Mature cystic teratomas harboring malignancy are typi- mature teratoma in the contralateral ovary. For high-grade,
cally cystic, with a thickened cyst wall, or intraluminal low-stage (stage I–II) tumors, any stage III tumor, or recur-
protuberance, and filled with greasy sebaceous material rent tumor, adjuvant chemotherapy may be attempted. This
and hair. Microscopically, various patterns of squamous tumor is usually unresponsive to radiotherapy.
cell carcinoma or adenocarcinoma are present; however, It has been reported that surgical removal can lead to a
these lack the primitive neuroepithelial components seen cure in most children and adolescents regardless of tumor
in an immature teratoma. It is worth noting that malignant grade, and that chemotherapy can be given in recurrent cases
neuroendocrine carcinoma can have neuroepithelial [25]. In most recurrent cases in children, foci of yolk sac
tubule-like structures; therefore, the overall clinicopatho- tumor are typically present [15] as opposed to immature neu-
logical features of the tumor should be considered in ral tissue; therefore, identifying other germ cell components
order to make the correct diagnosis. is far more important than the pathological staging of tumor.
2. Carcinosarcoma of ovary (malignant mixed Müllerian Moreover, the following exceptions should be noted:
tumor)
These tumors characteristically contain both Müllerian- 1 . Extra-ovarian spread of immature teratomas, including
type adenocarcinoma, and a homogenous or heterogenous lymphovascular metastasis and peritoneal implants, has
sarcoma, such as rhabdomyosarcoma or chondrosarcoma. poor prognosis.
238 H. Chen et al.
2. Post-chemotherapy peritoneal glial implants and residual implants and separate grading of individual implants are
tumor are usually benign due to the elimination of the recommended. The following example diagnosis may be
immature tumor components by chemotherapy. Most utilized in these cases “Ovarian immature teratoma (grade
studies have shown that these tissues have no adverse 1), with peritoneal non-invasive implants (grade 0).”
effect on the overall prognosis of the patient.
3. Growing teratoma syndrome is defined by persistent

growth of tumor even after chemotherapy; however, 8.2.4 Homunculus (Fetiform Teratoma)
serum AFP levels may remain normal. Microscopically,
these tumors have a benign appearance. Since they are 8.2.4.1 Definition
resistant to chemotherapy, surgical removal is required. Fetiform teratoma (homunculus) is a term that has been
Complete removal of such tumors generally results in a given to a rare form of ovarian teratoma that resembles a
good long-term prognosis; however, rare cases of recur- malformed fetus, containing well-developed mature tissues
rence with other germ cell tumor types (such as yolk sac and malformed organ structures.
tumor) have been reported.
4. Gliomatosis peritonei is composed of peritoneal implants 8.2.4.2 Clinical Features
of mature glial tissue. It can occur de novo with the pri- It occurs in young females, around 20–35 years of age. It is
mary tumor or postsurgically. It is the most common type usually asymptomatic, occasionally presenting as a pelvic
of pelvic spread of immature teratoma, and occasionally mass. X-ray studies can show partially developed skull, man-
may be seen in patients with mature cystic or solid terato- dible, vertebral bodies and/or attached ribs, and pelvic bones.
mas [26]. In extremely rare situations, it can be seen in The pubic bone is the most common pelvic bone found in a
patients with no known history of a germ cell tumor under- homunculus. Rarely complete pelvic structures including a
going treatment with a ventricular peritoneal shunt [27]. In tailbone and femur can be seen.
addition to the peritoneal implants (Figs. 8.9 and 8.10),
lymphovascular, and even hematogenous spread can be 8.2.4.3 Macroscopic Features
seen in rare cases. Spontaneous or post-chemotherapeutic Typically this tumor is a large oval cystic adnexal mass, com-
maturation of the disseminated tumors occurs in approxi- monly containing fetus-like structures, recognizable skull
mately one-third of patients, leading to noninvasive (which may include cerebral and cerebellar tissue) facial bones,
implants. The exact pathogenesis of gliomatosis peritonei tissues resembling eyeballs, and a mandible with attached
is still unclear. Two theories have been proposed to explain teeth. The skull can be covered with skin and hair. A rudimen-
this phenomenon: direct seeding of teratoma or stem cell- tary torso including a rib cage which may contain pulmonary
derived peritoneal metaplasia. These glial cells are typi- tissue may be present. Other organs such as the intestines, and
cally positive for GFAP and SOX2. Glial implants are poorly formed upper or lower extremities, can also be seen.
considered grade 0, or noninvasive implants, and have Like a mature cystic teratoma, the cystic p ortion of this tumor
benign biological behavior [26]. Extensive sampling of can also be filled with greasy sebaceous material and hair.
Fig. 8.8 Immature teratoma, grade 3. There are many foci of immature Fig. 8.9 Immature teratoma, gliomatosis peritonei. There are innumer-
neuroepithelial tissue including many foci of neuroectodermal tubules able, military, gray nodules of glial implants on the congested perito-
(circled) neal surface
Fig. 8.10 Immature
teratoma, gliomatosis a b
peritonei. Typical peritoneal
glial implants (a). GFAP is
positive (b)
8.2.4.4 Microscopic Features 8.2.5.2 Clinical Features

Various malformed organs or organ-like structures are pres- Malignant transformation occurs in approximately 2% of all
ent and resemble their corresponding well-developed organ mature cystic teratomas, with squamous cell carcinoma account-
counterparts. Hematopoiesis can be seen in the marrow of ing for about 80% of cases. Adenocarcinoma and sarcomas each
the malformed bone. Neural tissues of both central and accounts for 7% of cases, respectively [28]. Other rare malig-
peripheral neural system can be seen. nancies include neuroendocrine carcinoma (carcinoid, small-
cell, and large-cell carcinoma) [29–31], malignant melanoma,
8.2.4.5 Differential Diagnosis skin adnexal tumors, and neurogenic tumors. Unlike other
Primary ovarian pregnancy: Primary ovarian pregnancies malignant germ cell tumors, malignant transformation occurs
most commonly present as rupture of the ovary within the mostly in postmenopausal women, although sarcomas usually
first trimester. Spontaneous abortion is common. The diag- occur in younger patients than other tumor types. The clinical
nosis is dependent on the identification of normal chorionic presentation is similar to that of a mature cystic teratoma or
villi, trophoblasts, and implantation site within the ovarian other forms of ovarian cancer depending on the stage of the
parenchyma; tubal and uterine pregnancy should be tumor. Patients with malignant teratomas are, on average, older
excluded. than their counterparts with benign teratomas [32].
8.2.4.6 Prognosis and Treatment 8.2.5.3 Macroscopic Features

As with all mature teratomas the prognosis is excellent. Malignant teratomas are almost always unilateral, large
Unilateral oophorectomy is curative. ovarian masses, ranging in 10–20 cm in diameter. About half
of the cases show surface adhesion or capsular rupture.
Malignant transformation occurs mostly at the protuberance,
8.2.5 Teratoma with Malignant presenting as a nodular or polypoid mass that may partially
Transformation or completely fill the cyst lumen. On sectioning, tumor is
soft, friable, and often hemorrhagic and necrotic.
8.2.5.1 Definition
Also known as a malignant teratoma, this term specifically 8.2.5.4 Microscopic Features
refers to malignancies arising within a mature cystic tera- In addition to the typical components of a mature cystic tera-
toma. Malignancies arising from monodermal teratomas toma, a malignant component is present (Fig. 8.11). Most
(such as thyroid carcinoma and carcinoid tumor), and malig- studies have reported that squamous cell carcinomas are the
nant germ cell tumors (such as choriocarcinomas), are not most common somatic type malignancies arising from MCT;
included in this entity. however, in one large-scale cohort, mucinous and serous bor-
240 H. Chen et al.
a b
Fig. 8.11 Teratoma with malignant transformation. Well-differentiated squamous cell carcinoma (a) and moderately differentiated adenocarci-
noma (b)
derline tumors were more common than squamous cell 8.3.1.2 Clinical Features
carcinoma [32]. Half of the squamous cell carcinomas are well Although only accounting for 2.5–5% of all ovarian tera-
differentiated. Squamous cell carcinoma can arise from the toma, struma ovarii is the most common type of monodermal
lining squamous epithelium or from squamous metaplasia of teratoma. Most patients are in their fifth decade [35]. Patients
the glandular epithelium (transition between squamous epican present with a pelvic mass or bloating, ascites (up to one-
thelium and glandular epithelium is commonly seen in mature third of patients), hyperthyroidism (5–15%), thyroid gland
cystic teratomas). Adenocarcinomas can arise from various hyperplasia or postsurgery compensatory thyroid gland
tissue types. Other rare types of malignancy include adeno- hyperplasia (5–15%), Meigs syndrome (triad of ascites,
squamous carcinoma, mucoepidermoid carcinoma, basal cell pleural effusion, and ovarian tumor), and peritoneal implants.
carcinoma, melanoma, and undifferentiated carcinoma. Significant elevation of the serum thyroglobulin level can be
Mucinous tumors arising from a teratoma can cause pseudo- seen in patients with a malignant struma ovarii [36]. A pre-
myxoma peritonei [33]. Sarcomas, including angiosarcoma, operational I131 abdominal imaging study or radionuclide
leiomyosarcoma, rhabdomyosarcoma, fibrosarcoma, osteo- angiography can help to identify the ovarian thyroid tissue.
sarcoma, chondrosarcoma, undifferentiated pleomorphic sar-
coma, among others have been described as well [34]. 8.3.1.3 Macroscopic Features
Struma ovarii are usually unilateral and usually range in size
8.2.5.5 Treatment and Prognosis from 0.5 to 10 cm (may be up to 20 cm). Grossly, it appears
The overall prognosis is poor and the outcome depends on similar to a goiter, with smooth or nodular outer surface. The
the tumor type and stage. The 5-year survival of FIGO stage cut surface is solid, gelatinous, and dark brown to beefy red
I–IV patients is 56%, 25%, 12%, and 0%, respectively. Of in color, often with multiple small cysts filled with gelati-
note, tumors with sebaceous differentiation usually have a nous or mucinous material. Some tumors can be predomi-
better prognosis, although this possibility requires more nately or entirely cystic, containing bluish gelatinous
extensive validation. Total hysterectomy and bilateral material (Fig. 8.12). Malignant struma ovarii is usually more
salpingo-oophorectomy is the first choice of treatment. than 10 cm in size, and associated with adhesion formation
and ascites.
8.3 onodermal Teratomas and Somatic

M 8.3.1.4 Microscopic Features
Type Tumors Arising from Dermoid Cyst Struma ovarii is typically composed of acini filled with dense
pink colloid that resembles normal or goiterous thyroid tis-
8.3.1 Struma Ovarii sue. All morphologic variants of thyroid goiter can also be
seen in the setting of struma ovarii, including macrocystic,
8.3.1.1 Definition microcystic (Fig. 8.13a), embryonal, and mixed type.
A mature teratoma composed of either exclusively or pre- Oxyphilic, clear cell, and solid tubular variants can also be
dominantly of thyroid tissue (more than 50% of tumor vol- seen [36–38]. Features of thyroid goiters such as hemorrhage
ume). It includes both benign struma ovarii and rare thyroid and cystic change are often present. Tumors are positive for
carcinomas (malignant struma ovarii). thyroid-specific markers such as thyroglobulin (Fig. 8.13b)
and TTF-1. Cystic struma ovarii presents as dilated cysts Three to 10% of all struma ovarii are malignant [37] and
with thin fibrous septa. The cysts are lined with flat or low most are papillary carcinoma, followed by follicular carci-
cuboidal epithelium. Occasional tumors may demonstrate noma. Insular carcinoma (poorly differentiated), medullary
focal or diffuse adenomatous hyperplasia [37]. Follicular carcinoma, and undifferentiated carcinoma are rare [40]. The
adenomatous (crowded microfollicles/trabeculae and solid same diagnostic criteria of thyroid based papillary carcinoma
areas) or papillary hyperplastic changes that lack of nuclear are used in the diagnosis of ovarian papillary carcinoma,
features of papillary carcinoma are sometimes referred to as including clear nuclei (or ground glass nuclei), nuclear
hyperplastic struma ovarii, and are believed by some authors grooves, nuclear crowding, and nuclear pseudo-inclusions
to have malignant potential [39]. (Figs. 8.14 and 8.15). The diagnosis of follicular carcinoma
is difficult as the tumor lacks a capsule and is irregular in
shape. The capsular infiltration criteria often used in diagno-
sis of thyroid follicular carcinoma cannot be applied to the
ovarian variant of follicular carcinoma. The most reliable
finding used to make a diagnosis of ovarian follicular carci-
noma is lymphovascular invasion (Fig. 8.16) [37].
It is controversial whether the same diagnostic criteria for
thyroid carcinoma should be applied to the diagnosis of
malignant struma ovarii. This is complicated by the fact that
some morphologically benign strumas demonstrate
malignant behavior, such as extra-ovarian spread and recur-
rence. Robboy et al. [41] reported 27 cases of struma ovarii
with malignant behavior. Interestingly, only 12 cases met the
histologic criteria of thyroid carcinoma, while 15 cases
demonstrated benign morphology (13 cases of adenomatous
changes, 2 cases of benign thyroid tissue). The “benign”-
2 cm appearing tumors have been designated “highly differenti-
ated follicular carcinoma” [42]. This diagnosis can only be
made when extra-ovarian spread or metastasis is present. In
Fig. 8.12 Struma ovarii. The tumor has a capsule with multifocal cys-
tic and solid areas. There is dark brown and blue-green colloid material
rare cases, the spread or distant metastasis can occur as late
within the cysts as 17 years after treatment [43].
Fig. 8.13 Struma ovarii. The

tumor is composed of thyroid
a b
follicles of varying sizes.
There is eosinophilic colloid
material in the lumen (a) and
thyroglobulin staining is
positive (b)
242 H. Chen et al.
a b
Fig. 8.14 Ovarian thyroid papillary carcinoma, classical type. The cut surface is predominantly solid (a). The tumor shows a papillary growth
pattern (b), characteristic ground glass nuclei, nuclear grooves, and nuclear overlap (c)
Fig. 8.15 Ovarian thyroid

papillary carcinoma, follicular
a b
type. The tumor is composed
entirely of the follicular
pattern (a), but the tumor cells
have characteristic ground
glass nuclei, nuclear grooves,
and nuclear overlap (b)
Fig. 8.16 Ovarian thyroid a b

follicular carcinoma. The
tumor cells infiltrate into the
serosa of the fallopian tube
(a). There is a tumor embolus
within a blood vessel (b)
8.3.1.5 Genetic Profile ovarian disease as completely as is possible. I131 treatment

Like thyroid papillary carcinoma, ovarian papillary carci- has shown success in the treatment of extra-ovarian disease
noma can also have a BRAF V600E mutation, however at in some cases. Clinical indications that are suggestive of
much less frequency (only 6%). Other BRAF mutations such malignant struma ovarii include tumor adhesion to adjacent
as T1779A and K601E have also been reported [37, 44, 45]. structures, more than 1 L of ascites and peritoneal spread.
RET/PTC rearrangement can be seen in rare follicular vari- Morphological features suggesting a poor prognosis include
ants of papillary carcinomas [46]. the following: if the tumor is larger than 10 cm, composition
of the mass consisting of more than 80% tumor, necrosis,
8.3.1.6 Differential Diagnosis and ≥5mitotic figures per 10 high-power fields. Long-term
1. Ovarian mature cystic teratoma follow-up is recommended for all struma ovarii measuring
Thyroid tissue is often present in a mature cystic tera- >5 cm in diameter [48].
toma; however, it should be less than 50% of the tumor. Fukunaga et al. studied 105 cases of malignant struma
Diligent sampling of tumor is critical to make the correct ovarii, and found that highly differentiated follicular carci-
diagnosis. nomas had the best prognosis (no patients died of tumor),
2. Ovarian metastasis from carcinoma of the thyroid and that follicular carcinoma had a worse prognosis (14%
gland dead of disease) when compared to papillary carcinoma (7%
Metastasis from a thyroid primary is extremely rare, but dead of disease). Tumor with even a focal component of
has been reported [37, 47]. The correct diagnosis depends poorly differentiated carcinoma had a poor prognosis [40].
on obtaining additional clinical data.
3. Adult granulosa cell tumor
Occasionally, granulosa cell tumors may show pseudo- 8.3.2 Carcinoid
papillary structure, and need to be distinguished from papil-
8.3.2.1 Definition
lary carcinoma. Granulosa cell tumors should lack nuclear
features, and will typically display areas of classic histol-
Carcinoid tumors are well-differentiated neuroendocrine neo-
ogy. Immunohistochemical staining with inhibin, calretinin,
plasms that resemble carcinoids of the gastrointestinal tract.
thyroglobulin, and TTF-1 can also facilitate the diagnosis.
Ovarian primary carcinoid can be subcategorized into five
subtypes: insular type; trabecular type; strumal carcinoid
8.3.1.7 Treatment and Prognosis (consisting of insular or trabecular carcinoid and thyroid
Most struma ovarii are clinically benign and oophorectomy glands); goblet cell carcinoid resembling that of appendix;
is considered curative. Patients with malignant struma ovarii and mixed types. In addition, carcinoid can be present in
should be treated by oophorectomy and resection of extra- Sertoli-Leydig cell tumor as a heterogeneous component.
244 H. Chen et al.
8.3.2.2 Clinical Features nar cells are present at the periphery of islands, while tri-
Primary ovarian carcinoid is extremely rare. Insular carci- angular-shaped cells are located in the center. Tumor cells
noid is the most common type (26–53%), followed by may also form acinar, cribriform, and pseudo- rosette
strumal carcinoid (26–44%), with trabecular carcinoid as the structures. The acinar lumens contain eosinophilic secre-
third most common (23–29%). Mucinous (goblet cell) carci- tions, which may be condensed and calcified. Tumor cells
noid is exceptionally rare (1.5%) [49, 50]. The average age have abundant cytoplasm and many eosinophilic gran-
of patients is 53 (range 14–79) [49, 51, 52]. Most patients ules, which are more prominent at the periphery of the
present with an ovarian mass. Carcinoid syndrome can be islands. The cells have uniform, round nuclei with coarse
seen in up to 30% of insular carcinoid cases, 13% of trabecu- chromatin granules (salt and pepper nuclei), and conspic-
lar carcinoid cases, and 3.2% of strumal carcinoid cases. uous nucleoli. Mitotic figures are rare or absent.
25% of trabecular carcinoids produce YY polypeptides [53], 2. Trabecular carcinoid
which in turn can inhibit bowel movement and cause severe Trabecular variants resemble carcinoids of foregut or
constipation. The presence of elevated levels of serum sero- hindgut origin. The cords are composed of columnar cells
tonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid which have abundant cytoplasm, oval nuclei, and argyro-
(5-HIAA) can be diagnostically useful. philic granules at both poles of the nucleus. Tumor cells
form parallel cords, trabeculae, or ribbons separated by
8.3.2.3 Macroscopic Features thin fibrous stroma. The elongated nuclei of tumor cells
Ovarian carcinoid is typically a unilateral tumor, and the are organized perpendicular to the long axis of cords or
mass is typically firm, yellow-tan, and solid. Hemorrhage ribbons (Fig. 8.19).
and necrosis are rare. Occasionally the tumor may present as 3 . Strumal carcinoid
a small firm nodule (usually less than 4 cm) protruding into Strumal carcinoid is composed of carcinoid tumor and
the lumen of a mature cystic teratoma or a mucinous cystic thyroid tissues in various proportions (Fig. 8.20).
tumor. Insular carcinoid usually has smooth capsule with an Approximately 50% of cases are trabecular carcinoids.
average size of 10 cm (3–28 cm). Grossly, carcinoid and Other types of carcinoid such as insular and mucinous
struma components may be separately recognized. carcinoid may also be seen. The thyroid component
resembles normal thyroid tissue or a follicular adenoma.
8.3.2.4 Microscopic Features Neuroendocrine cells can replace the original lining of the
1. Insular carcinoid thyroid-type follicles. Similar to thyroid medullary carci-
This tumor resembles a midgut carcinoid and is character- noma, various amounts of amyloid deposition in the
ized by nests or islands of tumor cells separated by fibrous stroma can be seen. One-third of cases show stromal
stroma (Figs. 8.17 and 8.18). Typically, palisading colum- luteinization.
Fig. 8.17 Insular carcinoid. The cells are arranged in acini (a) and have round nuclei and small eosinophilic granules in cytoplasm (b)
Fig. 8.18 Insular carcinoid. This tumor originates from a mature teratoma (mature teratoma marked by *) (a). The tumor cells are arranged in
acini and have round nuclei (b); synaptophysin (c) and chromogranin (d) are positive.
4. Mucinous (goblet cell) carcinoid

Mucinous or goblet cell carcinoids are believed to origi-
nate from the appendiceal tissue within a teratoma [49–
51]. Based on the morphology, Baker et al. [51] proposed
subdividing this tumor into three groups: well-
differentiated, atypical, and carcinomatous types. The
tumor cells of well-differentiated tumors are cuboidal to
columnar, some of which contain cup-shaped (goblet cell)
or round intracytoplasmic mucin (signet ring cells)
(Fig. 8.21). The tumor is composed of small nests or
glands, which may be floating in a sea of lightly staining
amorphous mucin. The mucin pool is often surrounded by
connective tissue bands in which signet ring cell infiltra-
tion can be present. Atypical mucinous carcinoid is com-
posed of single, fused, or cribriform glands. The nuclei of
the tumor cells are crowed, enlarged, and hyperchromatic
with mild-to-moderate nuclear atypia. Tumors with a car-
Fig. 8.19 Trabecular carcinoid. The tumor cells are arranged in long,
wavy ribbons with their longitudinal axis perpendicular to the ribbons.
cinomatous component contain large, solid areas of tumor
The nuclei are small, round to oval growth, crowded glands, and isolated signet ring cells.
246 H. Chen et al.
a b
Fig. 8.20 Strumal carcinoid. The cells show an infiltrative pattern within the tumor stroma (a); benign thyroid tissue (b)
usually positive. Trabecular and insular carcinoids are typ-

ically CK7 positive, and negative for CK20, while muci-
nous carcinoids are atypically CK7 negative and diffusely
positive for CK20. Ovarian primary carcinoids are usually
TTF-1 negative, with exception if tumors arising from the
bronchial tissue within teratoma [54]; it is worth noting
that the carcinomatous components do not express TTF-1
[55, 56].

1. Ovarian metastatic carcinoid (including Krukenberg
tumors)
Metastatic carcinoid tumors are almost exclusively from
the gastrointestinal tract, with rare cases from other organ
systems such as the lung or kidney. The vast majority
(88%) of ovarian metastatic carcinoids involve bilateral
Fig. 8.21 Mucinous carcinoid. Tumor cells with a large amount of
cytoplasmic mucin float within a pool of mucin
ovaries, often with extra-ovarian metastasis present. In
contrast, primary ovarian carcinoids are unilateral, some
with associated teratomas or other epithelial tumors [54].
These tumor cells usually demonstrate severe nuclear The vast majority of ovarian metastatic carcinoids are
atypia and numerous mitotic figures. Focal necrosis can positive for CDX-2 (19/20 cases studied) [55, 56]. On the
be seen. In general, areas of carcinomatous differentiation other hand, CDX 2 expression in primary ovarian carci-
are relatively mucin poor when compared to the carcinoid noids varies among tumor types: insular and mucinous
component. are the types mostly positive, while the trabecular type is
5 . Carcinoids with mixed patterns typically negative. Morphologically, metastatic tumors
Carcinoid tumors may be mixed and contain two or more from the stomach are similar to atypical ovarian primary
of the aforementioned subtypes. Most commonly, it is a carcinoids, while metastatic tumors from the appendix are
mixture of insular and trabecular carcinoids; however any mostly goblet cell carcinoids and occasionally signet ring
combination may theoretically occur. Associated tera- carcinoid. As a result of the overlapping histologic and
tomatous elements are often present. immunohistochemical features it is challenging to sepa-
rate metastatic from primary tumors.
8.3.2.5 Immunohistochemistry Recently, SATB2 has been shown to distinguish meta-
These tumors express at least one or more neuroendocrine static gastric carcinoid from metastatic appendiceal carci-
markers, including synaptophysin (Fig. 8.18c), chromo- noid, with a reasonable degree of success. SATB2 is
granin (Fig. 8.18d), CD56, and Leu7(CD57). CDX-2 is diffusely and strongly positive in appendiceal carcinoid,
and negative or weakly positive in gastric carcinoid [57]. 8.3.3.3 Macroscopic Features
Currently, the expression pattern of SATB2 in primary Tumors are usually unilateral, measuring 4–20 cm in diam-
appendiceal goblet cell carcinoid is still not well studied eter (average 14 cm) [58]. The cut surface is red-tan, fleshy,
due to the extreme rarity of the disease. and solid. Occasional tumors may also be cystic, with intra-
2. Sex cord-stromal tumor luminal papillary excrescences [60]. Hemorrhage and necro-
When associated teratomatous components are absent, sis may be prominent.
trabecular carcinoids need to be distinguished from sex
cord-stromal tumors. The Sertoli tubules in a well- 8.3.3.4 Microscopic Features
differentiated Sertoli-Leydig cell tumor can be some- Neuroectodermal tumors are morphologically identical to
times mistaken as trabecular carcinoid. A panel of their counterparts in the central or peripheral nervous sys-
immunostains can help in the diagnosis. Carcinoid cells tem. These tumors can be further subcategorized into three
express at least one neuroendocrine tumor marker groups: differentiated, primitive, and anaplastic [57, 59, 61,
(synaptophysin、chromogranin, Leu7); however, it is 62]. The differentiated group includes ependymoma, astro-
worth noting that both carcinoid and sex cord-stromal cytoma, and oligodendroglioma; the primitive group includes
tumors express CD56. In addition, sex cord-stromal Ewing sarcoma/PNET, neuroblastoma, ependymoblastoma,
tumors also express inhibin, WT-1, SF-1, and medulloblastoma, and medulloepithelioma; finally, the ana-
calretinin. plastic group is composed of glioblastoma multiforme
3 . Struma ovarii (Fig. 8.22) and anaplastic ependymoma (Fig. 8.23).
Typical struma may form trabecular structures, and often Ependymoma is occasionally associated with astrocytoma,
will coexist with strumal carcinoid. Immunostains can aid but only rarely associated with a teratoma, which is in con-
in the diagnosis. Strumal tissue expresses TTF-1 and thy- trast to the other types of differentiated tumors, which are
roglobulin, as opposed to carcinoid tumors which do not usually associated with mature and immature teratomas.
express either marker.
8.3.3.5 Immunohistochemistry
8.3.2.7 Treatment and Prognosis Ependymoma and astrocytoma are GFAP positive, whereas
Almost all ovarian primary trabecular and strumal carcinoids Ewing sarcoma/PNET is diffusely and strongly positive for
are stage I, and have an excellent prognosis. The 5-year sur- CD99. Oligodendroglioma can sometimes be confused with a
vival rate of insular carcinoid is 95%, and the 10-year sur- central neurocytoma; however, it is GFAP positive and synap-
vival rate is 88%. Total hysterectomy and bilateral tophysin negative, whereas central neurocytoma demonstrates
salpingo-oophorectomy is the first line of treatment. For the opposite staining pattern. The immunophenotypic com-
young patients who desire to preserve fertility, or patients parison between ovarian/peritoneal ependymoma and central
with trabecular carcinoid, unilateral salpingo-oophorectomy ependymoma is summarized in Table 8.3 [63]. Moreover,
and close follow-up can be offered. For patients with extraovarian/peritoneal ependymomas do not contain IDH1/2
ovarian disease, surgical resection of extra-ovarian tumor as mutations [59]. Taken together, the genetic and immunophe-
much as technically feasible, as well as chemotherapy,
should be considered.
8.3.3 Neuroectodermal Type Tumors
8.3.3.1 Definition
These tumors are entirely, or predominantly, composed of
neuroectodermal tissue with similar morphology and differ-
entiation as neuroectodermal tumors of the central nervous
system. Less often these tumors may resemble peripheral
type neuroectodermal tumors such as Ewing sarcoma/primi-
tive neuroectodermal tumor.

Neuroectodermal tumors are incredibly rare. Most occur in
young adults although there is a large age range (6–69 years).
Most patients present with pelvic or abdominal pain and a Fig. 8.22 Glioblastomas. The tumor cells are atypical; there is brisk
pelvic mass [58, 59]. mitotic activity and pseudopalisading necrosis
248 H. Chen et al.
a b
c d
Fig. 8.23 Anaplastic ependymoma. The tumor exhibits perivascular pseudorosettes (a), papillary (b), and solid growth with remarkable cellular
atypia (c). GFAP staining is diffusely positive (d)
Table 8.3 Immunophenotypical difference between ovarian/perito- tumors have a relatively good prognosis. When extra-ovarian
neal and central ependymomas spread occurs, the prognosis is poor.
Biomarkers Ovarian/peritoneal ependymoma Central ependymoma
CAM5.2 60%+ 10%+
CK18 100%+ 20%+ 8.3.4 Sebaceous Tumors
CK7 80%+ 10%+
34βE12 60%+ – 8.3.4.1 Definition
ER 100%+ 10%+ Sebaceous tumors are neoplasms that resemble cutaneous
PR 80%+ 20%+
sebaceous gland tumors, including sebaceous adenoma,
basal cell carcinoma with sebaceous differentiation, and
notypic evidence suggests that although these two tumors are sebaceous carcinoma. They may arise from dermoid cyst.
histologically similar, their pathogenesis may be divergent.
8.3.3.6 Genetic Profiles Sebaceous tumors within a dermoid cyst are exceedingly
Ewing sarcoma/PNET may contain t(11;22)(q24;q12) [10]. rare, and typical occur in middle-aged to elderly women.
When they occur, they usually present as pelvic mass.
Tumors in the differentiated group have a better prognosis 8.3.4.3 Macroscopic Features
than tumors in other groups; that being said when confined These tumors are predominantly cystic and are usually asso-
within the ovarian capsule, even primitive and anaplastic ciated with a mature cystic teratoma.
8.3.4.4 Microscopic Features 3. Retinal anlage tumors

The tumors are morphologically identical to their cutaneous Also known as a melanotic neuroectodermal tumor of infancy,
counterparts. In general, the tumor cells have foamy or bub- this tumor is extremely rare [6]. Generally, this tumor is
bly cytoplasm that stains with Oil Red O [64]. biphasic and composed of tubular or alveolar patterns. Large
melanin-containing cells with abundant cytoplasm and pale
nuclei and surrounding nests of smaller neuroblast-like cells
8.3.5 Other Tumor Types possessing scant or fibrillar cytoplasm are typically seen.
Minimal mitotic activity and no atypia should be present;
1. Pituitary adenoma however these tumors are usually aggressive.
Pituitary adenoma is an exceptionally rare finding that
may originate from ectopic pituitary tissue within a
mature cystic teratoma. The tumor cells can be functional 8.4 Primitive Germ Cell Tumors
and produce any pituitary hormone, most notably ACTH
and prolactin, and cause Cushing syndrome or 8.4.1 Dysgerminoma
amenorrhea-lactation syndrome. It is a benign tumor, and
surgical removal is curative [65–67]. 8.4.1.1 Definition
2. Melanocytic tumors Dysgerminoma originates from premeiotic diploid germ
Malignant melanoma arising from teratoma is exceed- cells and lacks a specific pattern of differentiation. It is mor-
ingly rare, and so far less than 50 cases have been reported phologically identical to testicular seminoma.
[68, 69]. Melanocytic nevi have been reported to arise
within dermoid cysts [70] (Fig. 8.24). 8.4.1.2 Clinical Features
Dysgerminoma accounts for 1% of all ovarian germ cell
tumors, and approximately half of all malignant germ cell
tumors. The vast majority (90%) occur in patients less than
30 years old (average age 22 years) [71]. Patients may present
with abdominal pain or a mass, bloating, and occasionally
ascites. Almost all patients with dysgerminoma have elevated
serum LDH (1 and 2 fractions) at presentation. Approximately
5% of cases show mild elevation of serum β-hCG. Pure dys-
germinoma is negative for AFP; therefore, elevation of serum
AFP level suggests mixed germ cell tumor.
8.4.1.3 Macroscopic Features

Ninety percent of dysgerminomas involve a unilateral ovary;
however, when the tumor is large, microscopic foci of tumor
may be present in the contralateral ovary even if it is grossly
normal. The tumors are solid and encapsulated with an aver-
Fig. 8.24 Malignant melanoma originating from a teratoma. The age diameter of 15 cm (range 3–50 cm). Their cut surfaces
tumor cells have large nuclei with prominent nucleoli and conspicuous are gray-tan, soft, fleshy, and lobulated (Fig. 8.25a). Areas of
pigmentation coagulative necrosis, hemorrhage, and calcification may be
Fig. 8.25 Dysgerminoma.
The surface of the tumor is
a b
smooth and has a conspicuous
capsule. The position of
surgeon’s finger shows the
fallopian tube (a). The cut
surface is solid, fleshy, and
lobulated with focal
hemorrhage (b)
2 cm
250 H. Chen et al.
present (Fig. 8.25b). Such areas should be sampled exten- tumor cells are organized in insular, corded, diffuse, and
sively to identify other malignant germ cell tumor compo- pseudoglandular patterns. Nests of cells are intersected by
nents, which may have significant implications in the fibrous septa (alveolar pattern), typically containing lympho-
prognosis and treatment of the tumor. Of note, the presence cytes. Epithelioid histiocytes/granulomas with m ultinucleated
of small grainy calcifications may suggest the concurrent giant cells are present in approximately 20% of cases
presence of an underlying gonadoblastoma. The tumor may (Fig. 8.27). Syncytiotrophoblasts are present in 3–5% of
contain trophoblastic tissue, particularly in the areas of tumors (Fig. 8.28) [72], which may result in elevated serum
hemorrhage. β-hCG level. Mitotic figures are frequently seen. Necrosis
and hemorrhage are common. Atrophic calcification is occa-
8.4.1.4 Microscopic Features sionally seen in some tumors along with fibrotic and hyaline
Morphologically, dysgerminoma is identical to the semi- degeneration. Dysgerminoma is usually a pure disease; how-
noma of testis and germinoma of the thoracic region. The ever, it may occasionally be associated with gonadoblastoma
tumor is composed of a monotonous cell population. The or other germ cell tumors.
tumor cells are round or polygonal with abundant pale to
eosinophilic cytoplasm and discrete cell membranes. Tumor 8.4.1.5 Immunohistochemistry
cells have one large, rounded to squared-off nuclei with one Tumor cells composing a dysgerminoma are strongly posi-
or more prominent nucleoli. Monotonicity of cells and nuclei tive for PLAP, CD117/c-kit (Fig. 8.29a), and D2–40.
is a characteristic feature of dysgerminoma (Fig. 8.26). The Although CD117 membrane positivity is a characteristic fea-
a b
c d
Fig. 8.26 Dysgerminoma. Nests (a), cords (b), and microcysts (c) are separated by lymphocyte-rich fibrous connective tissue. The tumor cells are
round or polygonal, have abundant cytoplasm, and large, centered nuclei with prominent nucleoli (d)
a b
Fig. 8.27 Dysgerminoma. There are a large number of granulomatous changes in this tumor, essentially causing the tumor cells to become invis-
ible (a). SALL4 staining helps to demonstrate the scattered tumor cells (b)
Fig. 8.28 Dysgerminoma.
Syncytiotrophoblastic giant
a b
cells (a) that are positive for
β-hCG (b) are obvious in this
tumor
ture of dysgerminoma, it can also be seen in some yolk sac 8.4.1.6 Genetic Profiles
tumors (especially the solid variant) [73]. Tumor cell nuclei Approximately 25–50% of dysgerminomas contain c-KIT
are positive for OCT4 (Fig. 8.29b) and SALL4 (Fig. 8.29c) mutations, most commonly in exon 17, but not the exon 11,
[74–76]. LIN28 is another sensitive marker for dysgermi- which confers the susceptibility to imatinib therapy [10, 77].
noma (Fig. 8.29d) [20]. All three markers are also positive in Approximately 60% of tumors contain isochromosome 12p
embryonal carcinoma, and SALL4 and LIN28 are positive in and/or 12p overrepresentation [78].
yolk sac tumor as well. Syncytiotrophoblasts in dysgermi-
noma are strongly positive for β-hCG and CAM5.2, while 8.4.1.7 Differential Diagnosis
AE1/AE3 and CK7 are often focal and weakly positive. 1. Small-cell carcinoma, hypercalcemic type
CK20, EMA, HMWK, and CD30 should be negative. The gross appearance of the tumor and the age of patients
Commonly used immunohistochemical markers helpful in of hypercalcemic small-cell carcinoma are similar to
the workup of ovarian germ cell tumors are summarized in those of dysgerminoma. In addition, dysgerminoma may
Table 8.4. occasionally have the microcystic spaces similar to the
252 H. Chen et al.
a b
c d
Fig. 8.29 Dysgerminoma: common immunohistochemical markers. CD117 is positive along the cell membrane (a); OCT4 (b) and SALL4 (c) are
positive in the nuclei (b); and LIN28 is positive within the cytoplasm (d)
Table 8.4 Immunohistochemical markers for ovarian germ cell tumors and other ovarian malignancies
Biomarkers Dysgerminoma Embryonal carcinoma Yolk sac tumor Lymphoma Granulosa cell tumor Melanoma
CK −/+ + + − − −
SALL4 + + + −/+a −/+ −
LIN28 + + + − − −
OCT4 + + − −/+b − −
AFP − − +/− − − −
Glypican-3 − −/+ +/− − − −
CD117 + − −/+ − + −
CD30 − + − +/− − −
S-100 − − − − − +
LCA − − − + + −
MPO − − − − + −
Lymphoblastic lymphoma can be SALL4 positive
a
diffuse large B-cell lymphoma is occasionally OCT3/4 positive

b
pseudofollicular spaces commonly seen in hypercalcemic composed of relatively large cells; when this occurs, the
small-cell carcinoma; however, small-cell carcinoma of cytoplasm is typically eosinophilic with or without rhab-
the hypercalcemic type is composed of small round cells doid inclusions. In contrast, the tumor cells of dysgermi-
with scant cytoplasm, hyperchromatic nuclei, and small noma have a centrally located round nucleus, with coarse
nucleoli. Occasionally, small-cell carcinoma may be chromatin, discrete nuclear membrane, and one or more
Table 8.5 The clinicopathological features of dysgerminoma and ever, lymphoma is frequently bilateral and can involve
embryonal carcinoma
both ovaries in approximately half of patients. Germ cell
Dysgerminoma Embryonal carcinoma (such as PLAP, D2-40, SALL4) and lymphoid markers
Clinical 10–15% cases are Unilateral can help to make the correct diagnosis (Table 8.3). It is
features bilateral
worth noting that the germ cell marker OCT4 can be
Rare endocrine Abnormal endocrine
manifestations manifestations in 60% of expressed in some large B-cell lymphomas [79].
cases 6. Gonadoblastoma
Histological Even distributed Severe atypia, variation in Gonadoblastomas contain germ cell as well as sex cord-
features monotonous nuclei nuclear size, and crowding stromal components. Calcification may be prominent.
of nuclei
More than 50% are associated with malignant germ cell
Monotonous cells Prominent pleomorphic cells
Lymphocytic Stromal edema, occasional
tumors, most commonly a dysgerminoma. Careful mor-
infiltration in the small spindled fibroblasts phologic assessment, as well as judicious use of immu-
fibrous stroma nostains, can help to identify the minor sex cord-stromal
Histocytic granulomas No granulomas should be components, if present. Moreover, other features such as
are often seen present heterogeneity of cells, deposition of basement membrane-
Syncytiotrophoblastic Syncytiotrophoblastic giant
giant cells are present cells often seen
like eosinophilic material, and distinctive clinical sce-
in only 5% of cases nario seen with gonadoblastomas can aid in the diagnosis
[80, 81].
7 . Ovarian trophoblastic disease or neoplasia
prominent nucleoli. A panel of immunostains can help. Because of the elevated β-hCG level, trophoblastic dis-
Small-cell carcinoma, hypercalcemic type, lacks expres- ease often enters into the differential diagnosis with dys-
sion of germ cell markers such as OCT4, SALL4, PLAP, germinoma with syncytiotrophoblastic differentiation.
CD117, and D2-40. The presence of a gestational sac and chorionic villi can
2. Embryonal carcinoma essentially rule out dysgerminoma (and choriocarci-
The clinicopathological features of both dysgerminoma noma). Choriocarcinoma is comprised of a dual-cell pop-
and embryonal carcinoma are summarized in Table 8.5. ulation (cytotrophoblasts and syncytiotrophoblasts), as
Both tumors are diffusely positive for SALL4, OCT4, and described elsewhere.
LIN28. Dysgerminoma is positive for CD117 and D2-40,
but negative for CD30. In contrast, embryonal carcinoma 8.4.1.8 Treatment and Prognosis
usually shows the opposite staining pattern, with the Surgical resection of the tumor and complete staging is the
exception of papillary and glandular variants which may first line of treatment of dysgerminoma. Because the tumor
be positive for D2-40. is sensitive to chemoradiation, conservative unilateral
3. Yolk sac tumor salpingo-oophorectomy can be offered to young patients to
Yolk sac tumor can have clear cytoplasm and be positive preserve fertility if no capsular involvement or extra-ovarian
for CD117. Unlike the prominent monotonicity of cells spread is present. Chemotherapy is usually offered to higher
and nuclei commonly seen in dysgerminoma, yolk sac stage patients. Recurrence occurs in 25–35% of patients,
tumor exhibits greater cellular and nuclear variation. It usually within 2 years of diagnosis. Dysgerminoma has an
often contains hyaline bodies, and lacks lymphocytic excellent prognosis, with a >90% 5-year survival rate. The
infiltration and granuloma formation. A panel of immu- most prognostic factor is the size of the tumor (<10 cm).
nostains including OCT4, AFP, and glypican-3 can help Interestingly, nuclear atypia and mitotic figure count have no
to facilitate the diagnosis (Table 8.3). effect on the overall prognosis. For patients with an abnor-
4. Clear-cell carcinoma mal hormonal presentation, total hysterectomy and bilateral
Similar to dysgerminoma, clear-cell carcinoma also has salpingo-oophorectomy are recommended.
clear cytoplasm, and exhibits a solid or nested growth pat-
tern; however, it typically occurs in older patients.
Morphologically, it usually shows a characteristic tubulo- 8.4.2 Yolk Sac Tumor
cystic and papillary growth pattern, as well as endome-
triosis or an adenofibromatous background. Clear-cell 8.4.2.1 Definition
carcinoma is PAX-8, EMA, napsin A, and HNF-1-β posi- Yolk sac tumors have various distinctive morphologic pat-
tive, but is negative for germ cell tumor markers such as terns, which can differentiate into several endodermal struc-
PLAP, CD117, D2-40, OCT4, and SALL4. tures including primitive gut and mesenchyme, derivatives of
5. Lymphoma extra-embryonal tissue (secondary yolk sac and allantois),
Diffuse large B-cell lymphoma should be distinguished and embryonal somatic tissues (intestine and liver).
from dysgerminoma as both can form nest or cords; how- Historically, it has been called “endodermal sinus tumor,”
254 H. Chen et al.
which is not recommend anymore. The majority of yolk sac sac tumors are stage I. Elevated serum AFP can be found in
tumors originate from undifferentiated or pluripotent germ almost all cases, and readings may reach 1000 ng/mL or
cells. A minority of tumors may originate from somatic epi- more; therefore, an elevated serum AFP level should alert
thelial neoplasia through a process of neometaplasia/retrodif pathologists and clinicians to the possibility of this tumor.
ferentiation [82]. Rare cases may derive from
gonadoblastoma. 8.4.2.3 Macroscopic Features
Almost all yolk sac tumors are unilateral, most commonly
8.4.2.2 Clinical Features within the right ovary. Indeed, if both ovaries are involved, it
Yolk sac tumors account for approximately 20% of malig- is strongly suggestive of metastasis. The tumor is usually
nant germ cell tumors, secondary only to dysgerminoma. large, with an average diameter of 15 cm (range 5–35 cm)
The majority of tumors occur in children, adolescents, and [83], and is frequently encapsulated. The cut surface is grey-
young women. About half of these tumors occur after men- yellow, soft, solid, and fleshy with frequent necrosis and
arche, with an average age of 18 years [82]. Patients often hemorrhage (Fig. 8.30). Occasionally, the tumor can be cys-
present with abdominal pain and a pelvic mass; torsion and tic with a honeycomb-like appearance [12, 84]. It is not
rupture occur in approximately 10% of cases. 70% of yolk unusual for the contralateral ovary to contain a mature cystic
teratoma [85].

Yolk sac tumor can exhibit various histological or growth
patterns. Two or more patterns often coexist within the same
tumor. The common growth patterns are listed as follows:
1. Microcystic or reticular pattern

The microcystic, or reticular pattern, is the most com-
mon pattern. These tumors are often composed of micro-
cysts, labyrinthine channels, and scattered pockets of
myxoid stroma (Fig. 8.31). The microcysts and channels
are lined by flat or polygonal epithelial cells which have
large vesicular nuclei and prominent nucleoli.
2. Macrocystic pattern
Fig. 8.30 Yolk sac tumor. The tumor has a smooth surface and a con- Similar to the microcystic pattern; however, larger cysts
spicuous capsule. The cut surface is solid and cystic and shows hemor-
rhagic and necrotic areas
are present.
Fig. 8.31 Yolk sac tumor:

a b
microcystic or reticular
pattern. The microcystic
pattern (a) is prominent in
this tumor. The tumor cells
are diffusely positive for
SALL4 (b)
3. Endodermal sinus pattern myxoid stroma are characteristic of this pattern. It can
The presence of Schiller-Duval (S-D) bodies is charac- be further subdivided into two groups: endometrioid-
teristic of this pattern. Classic S-D bodies are papillae like glands, often with prominent sub-nuclear vacuoles
with a fibro-vascular center which is mantled by cuboi- (Figs. 8.34 and 8.35), and glands similar to primitive
dal, or low columnar, hobnailing tumor cells (Fig. 8.32a,
b). Although S-D bodies are diagnostic for yolk sac
tumor, they are only present in about one third of tumors.
Sometimes anastomosing channels and tubules can form
labyrinth-like structures, which is also known as the fes-
tooning variant of a S-D body (Fig. 8.32c, d). It is impor-
tant to recognize the festooned variant of an S-D body,
especially when classic S-D bodies are not present.
4. Myxoid pattern
This pattern is composed of tumor cells arranged in
glands and cords which are scattered within large
amount of myxoid material (Fig. 8.33).
5. Alveolar-glandular pattern
This pattern contains variable amounts of glandular or
alveolar structures lined by flat or cuboidal tumor cells,
surrounded by myxoid stroma.
6. Glandular pattern
Fig. 8.33 Yolk sac tumor: myxoid pattern. This tumor demonstrates a
The glandular pattern can be seen in approximately one prominent glandular pattern and a large amount of myxoid material in
third of yolk sac tumors. Scattered, simple glands within the tumor stroma
a b
c d
Fig. 8.32 Yolk sac tumor: endodermal sinus pattern. Classical S-D bodies (a, b) and variants of S-D bodies (c, d)
256 H. Chen et al.
intestinal glands, consisting of single or fused glands,

occasionally forming cribriform structures. These
glands are typically surrounded by a myxoid stroma.
7. Polyvesicular pattern
The polyvescular pattern is rare. It is composed of cystic
structures of various size, lined by flat or columnar epi-
thelium. Pear or gourd shaped cysts are similar to those
seen in the primitive yolk sac, and surrounded by loose
or dense fibrous stroma (Fig. 8.36). These cysts are lined
by mesothelial-like epithelium, and filled with PAS pos-
itive material [60].
8. Papillary pattern
The papillae composing the papillary pattern are usually
lined by cells with severe nuclear atypia (Fig. 8.37).
9. Parietal pattern
This pattern contains tumor cells, or glands, which are
Fig. 8.34 Yolk sac tumor: endometrioid pattern. These glands mimic
endometrioid carcinoma with secretory change denoted by conspicuous
scattered in sea of brightly eosinophilic basement mem-
subnuclear vacuoles brane like material (PAS positive) (Fig. 8.38).
a b
c d
Fig. 8.35 Yolk sac tumor. The tumor is composed of microcystic (lower) and endometrioid (upper) patterns (a). AFP is focally positive (b).
Glypican-3 is negative (c). SALL4 is diffusely positive (d)
a b
Fig. 8.36 Yolk sac tumor: polyvesicular pattern. This tumor has cysts, or vesicles, of varying sizes (a). SALL4 is diffusely positive (b)
Fig. 8.37 Yolk sac tumor: papillary pattern. This tumor has prominent
fibrovascular stalks covered by atypical cells b
10. Other rare patterns

The solid and hepatic patterns are other well described,
yet uncommon patterns of growth that may be seen in a
yolk sac tumor. The solid pattern is composed of three
tumor cell types:embryonal, clear cell (Fig. 8.39), and
hepatoid cells. Other features that may be seen in any
pattern that are helpful in the diagnosis include S-D
bodies (Fig. 8.32), basement membrane like material
(Fig. 8.38), and hyaline bodies [86, 87]. Hyaline bodies
can be present intracellularly or within the stroma.
These hyaline bodies are PAS and PAS-D positive, as
well as AFP and ɑ1-antitrypsin positive (Fig. 8.40).
Fig. 8.38 Yolk sac tumor: parietal pattern. There is a large number of
extracellular amorphous eosinophilic basement membrane-like depos-
Yolk sac tumors are AFP, glypican-3, SALL4, and LIN28 its around tumor cells and nests of tumor cells
positive (Fig. 8.41). AFP positivity is characteristic of yolk
sac tumor; however its sensitivity is relatively low (only
258 H. Chen et al.
83%), and often it is only focally positive [19]. Tumor cells (28%), and be focally positive for CK7 and EMA. Thus, a
that compose the parietal pattern are usually AFP negative. panel including AFP, glypican-3, CK7, and EMA has
Glypican-3 is positive in 70% of cases. SALL4 and LIN28 only a limited utility in separating yolk sac tumor and
are positive in almost 100% of yolk sac tumors [19, 20], and clear-cell carcinoma. For this purpose the best markers
OCT4 and D2-40 are usually negative. Tumor, especially the are SALL4 and LIN28 [19, 20]. Although clear-cell carci-
solid pattern, can express CD117 [73]. Pan-cytokeratin is noma can be occasionally positive for SALL4 and LIN4,
usually diffusely positive. CK7 and EMA are usually nega- the positivity is usually focal (<10% cells).
tive or only focally positive (i.e., only expressed in <5% 2. Embryonal carcinoma
cells). Tumors deriving from a somatic epithelial tumor are Yolk sac tumor and embryonal carcinoma often coexist.
positive for CK7 and EMA [82]. Embryonal carcinoma can be solid and have clear cyto-
plasm; the tumor cells have larger nuclei, prominent
8.4.2.6 Differential Diagnosis nucleoli, and severe nuclear atypia. No Schiller-Duval
1. Clear-cell carcinoma bodies, hyaline bodies, basement membrane-like mate-
The clinicopathological features of yolk sac tumor and rial, hepatoid cells, or intestinal differentiation is seen in
clear-cell carcinoma are summarized in Table 8.6. Clear- embryonal carcinoma. Embryonal carcinoma is positive
cell carcinoma can express AFP (35%) and glypican-3 for OCT4 and CD30, whereas yolk sac tumor shows the
opposite staining pattern. Unlike yolk sac tumor, embryo-
nal carcinoma is negative for AFP and is rarely glypican-3
positive. SALL4 and LIN28 are strongly positive in both
tumors.
3. Dysgerminoma
Monotonous cells and nuclei are characteristic of dysger-
minoma. Dysgerminoma usually lacks papillae, and hya-
line bodies are rarely seen. OCT4 and CD117 are
positive.
4. Other tumors
Other tumors including endometrioid carcinoma,
juvenile-type granulosa cell tumor, hepatoid adenocarci-
noma, and polyembryoma may have histologic features
that can overlap with those seen in yolk sac tumor.
Fortunately, these features are often focal, and careful
examination of these tumors often reveals more character-
istic histology. In difficult cases application of immunos-
Fig. 8.39 Yolk sac tumor: solid pattern. This tumor shows demon-
strates a solid growth pattern. The tumor cell cytoplasm is clear tains can help to resolve these differential diagnoses.
a b
Fig. 8.40 Yolk sac tumor: hyaline globules. Hyaline globules (a, arrow) are conspicuous both within the cytoplasm and stroma. They are positive
for PAS-D (b)
a b
c d
Fig. 8.41 Yolk sac tumor: alveolar-glandular pattern. (a) Immunohistochemical staining is positive for AFP (b), SALL4 (c), and LIN28 (d)
Table 8.6 Clinicopathological features of yolk sac tumor and clear- 8.4.2.7 Treatment and Prognosis
cell carcinoma
Yolk sac tumor is a highly aggressive tumor. Local spread or
Yolk sac tumor Clear-cell carcinoma distant metastasis may occur even at early stage. At the time
Clinical Most cases occur in Older women, of diagnosis, local invasion or peritoneal spread is present in
features women <30 years. Only mostly in their 50s
rarely occurs in patients (40–70 years) approximately 30% of patients. Even when tumor is grossly
older than 40 or in confined to the ovary, occult metastasis can often be seen.
postmenopausal women Lymphatic metastasis is often seen in pelvic and periaortic
Macroscopic Grey-yellow, solid with Solid or cystic with lymph nodes. Hematogenous dissemination to lung and liver
features areas of necrosis and yellow, yellow-tan,
is the most common form of metastatic spread. This tumor is
hemorrhage, and areas of or brown papillary
myxoid (gelatinous) excrescences. sensitive to chemotherapy, and overall survival is more than
change Evidence of 80%. Tumors with a parietal, hepatoid, or glandular (mainly
endometriosis may intestinal) pattern are less sensitive to chemotherapy, and
be present
have a relatively poor prognosis. Yolk sac tumor is resistant
Characteristic Schiller-Duval bodies; Broad-based
morphologic hobnail cells; solid areas papillae lined by to radiation therapy.
features often composed of small hobnail cells with
primitive cells with clear cytoplasm;
frequent mitosis rare mitotic figures; 8.4.3 Embryonal Carcinoma
Polyvesicular areas cysts are lined by
composed of various clear or hobnail
shaped cysts; cysts are lined cells 8.4.3.1 Definition
by mesothelial-like Embryonal carcinoma is a rare type of germ cell tumor,
epithelium, and filled with exhibiting rudimentary epithelial differentiation. This tumor
PAS-positive material
is morphologically identical to its testicular counterpart.
260 H. Chen et al.
8.4.3.2 Clinical Features 8.4.3.5 Immunohistochemistry

Embryonal carcinoma occurs almost exclusively in children Embryonal carcinoma is cytokeratin positive but EMA nega-
and young women (i.e., <30 years), with an average age of tive. It is also positive for SALL4, LIN28, CD30 (Fig. 8.44a),
15 years. Patients often present with an abdominal or pelvic OCT4 (Fig. 8.44b), NANOG, and SOX2. It is negative for
mass. Menstrual abnormalities are common in adult women. CD117. SOX2 is negative in dysgerminoma and yolk sac
Precocious pseudo-puberty, amenorrhea, and hirsutism can tumor; therefore, a panel including CD117, SOX2, and
be seen in children. Serum β-hCG levels are often elevated. CD30 can be used to distinguish between embryonal carci-
noma and dysgerminoma. Similarly, a panel including AFP,
8.4.3.3 Macroscopic Features glypican-3, OCT4, and CD30 can be used to distinguish
This tumor is usually a large, unilateral tumor with average between embryonal carcinoma and yolk sac tumor.
diameter of 17 cm. The surface of the tumor is usually
smooth and glistening; however it is not unusual for capsular 8.4.3.6 Genetic Profiles
thinning or rupture to occur. The cut surface is soft and fleshy Most tumors have an isochromosome i12p [10].
and typically composed of cysts of variable sizes and colors.
The cysts may be filled with mucinous material. Solid areas 8.4.3.7 Differential Diagnosis
are firm and often demonstrate prominent areas of hemor- 1. High-grade serous carcinoma (HGSC)
rhage and necrosis. Serous carcinoma is composed of high-grade tumor cells
which may be cytologically similar to those seen in
8.4.3.4 Microscopic Features embryonal carcinoma, but embryonal carcinoma usually
Pure embryonal carcinoma of the ovary is rare, and it is most coexists with other germ cell tumor histotypes, which can
often found as a component of a mixed malignant germ cell be a useful feature used to distinguish these two tumors.
tumor. Morphologically, it is identical to its testicular coun- In addition, embryonal carcinoma is positive for germ cell
terpart. It is usually composed of large primitive cells form- markers, such as SALL4, LIN28, and OCT4, whereas
ing nests, gland-like spaces (Fig. 8.42), and papillae, often HGSC is usually negative or only focally positive, with
with central necrosis [88, 89]. Loose edematous or dense LIN28 being the most common to be found partially
sarcomatous areas (mesenchymal transformation) may also positive.
be present. The polygonal tumor cells have an ill-defined 2. Yolk sac tumor
membrane and abundant amphiphilic or clear cytoplasm. Yolk sac tumor and embryonal carcinoma often coexist.
The nuclei are large and vesicular, with coarse chromatin and Schiller-Duval bodies, hyaline bodies, basement mem-
one or two prominent nucleoli (Fig. 8.43). Mitotic figures are brane-like material, hepatoid cells, and intestinal differen-
numerous. Syncytiotrophoblasts and/or intermediate tropho- tiation are characteristic features of yolk sac tumor, and
blasts are present in most cases. are usually absent in embryonal carcinoma. Embryonal
Fig. 8.42 Embryonal carcinoma. The tumor has distinct “epithelial” Fig. 8.43 Embryonal carcinoma. The primitive tumor cells in this
appearance with irregular silt-like glands lined with primitive tumor example are growing a solid pattern and have characteristic large vesic-
cells ular nuclei with prominent nucleoli
a b
Fig. 8.44 Embryonic carcinoma. The tumor cells are positive for CD30 in a membranous pattern (a) and OCT4 in the nuclei (b)
carcinoma is positive for OCT4 and CD30, whereas yolk is composed of a mixture of embryonal carcinoma and
sac tumor is negative for both. Unlike yolk sac tumor, yolk sac tumor.
embryonal carcinoma is negative for AFP and is rarely
glypican-3 positive. SALL4 and LIN28 are strongly posi- 8.4.3.8 Treatment and Prognosis
tive in both tumors. Embryonal carcinoma is a highly aggressive cancer, and is
3. Dysgerminoma usually treated with surgical removal and chemotherapy.
Monotonicity of nuclei and cells is a characteristic feature Fortunately, this tumor is sensitive to chemotherapy; how-
of dysgerminoma. Other characteristic histologic fea- ever it is resistant to radiation therapy. Patients with extra-
tures, such as fibrous septa, lymphocytic infiltrates, and ovarian spread have a poor prognosis.
histiocytic granuloma, are usually absent in embryonal
carcinoma. In addition, dysgerminoma generally lacks
papillary or glandular structures, which are commonly 8.4.4 Non-gestational Choriocarcinoma
seen in embryonal carcinoma. A panel of immunostains
including CD117 (negative in embryonal), SOX2, and 8.4.4.1 Definition
CD30 (both positive in embryonal) can help to make the A malignant neoplasm of germ cell origin composed of cyto-
correct diagnosis. trophoblastic and syncytiotrophoblastic cells.
4 . Choriocarcinoma
Choriocarcinoma should be distinguished from embryo- 8.4.4.2 Clinical Features
nal carcinoma with a prominent syncytiotrophoblastic Pure, non-gestational choriocarcinoma is an exceedingly
component. OCT4 and CD30 are diffusely positive in rare and highly aggressive tumor accounting for only 1% of
embryonal carcinoma, and are negative in the cytotropho- malignant germ cell tumors [90]. Pure tumors are most com-
blast/intermediate trophoblastic components of chorio- mon in children or young women before puberty, but occa-
carcinoma. In addition, SALL4 and LIN28 are diffusely sionally may occur in postmenopausal women. Rare cases
positive in embryonal carcinoma, and negative, or only are associated with gonadal dysplasia (46XY, 45XO/46XY)
weakly positive, in the cytotrophoblast/intermediate tro- [91, 92]. Much more commonly seen than the pure form, this
phoblastic components of choriocarcinoma. tumor is frequently a component of a mixed malignant germ
5 . Polyembryoma cell tumor. Most patients present with pseudo-puberty, vagi-
Polyembryoma is a tumor that contains innumerable nal bleeding, or signs mimicking an ectopic pregnancy
embryoid bodies composed of two cavities separated by (young women). Elevated serum or urine β-hCG is almost
embryonic germ disc. The embryonic disc is composed of always present [93].
a band of primitive cells similar to those seen in embryo-
nal carcinoma along with a smaller band composed of 8.4.4.3 Macroscopic Features
flattened yolk sac-type cells that lie underneath. This Choriocarcinoma is usually a large (often >6 cm), unilateral
tumor is considered a special type of germ cell tumor that tumor. The cut surface is grey-tan, solid, or solid and cystic,
262 H. Chen et al.
and displays abundant hemorrhage and necrosis. Luteinized a previous pregnancy. Features such as bilateral ovarian
nodules or cysts may be seen in the adjacent ovarian tissue. involvement and multi-organ metastasis are helpful and
may provide a hint to the correct diagnosis.
8.4.4.4 Microscopic Features 3 . Primary ovarian pregnancy-associated choriocarcinoma
Morphologically, non-gestational choriocarcinoma is identi- In the extraordinarily uncommon setting of a choriocarci-
cal to gestational choriocarcinoma. The tumor is composed of noma arising in an ovarian pregnancy, the history of a pre-
an intimate combination of cytotrophoblast and syncytiotro- vious ovarian pregnancy may be the only clue to the
phoblast (Fig. 8.45). The cytotrophoblast and syncytiotropho- origin of the malignancy.
blasts are admixed in a distinctive plexiform pattern, with the
latter located at the periphery, surrounding clusters of cytotro- 8.4.4.7 Treatment and Prognosis
phoblasts. Cytotrophoblastic cells are mononucleated with Non-gestational, pure, choriocarcinoma has a poor prognosis,
vesicular nuclei, abundant clear cytoplasm, and well-defined which is often worse than seen in gestational choriocarcinoma.
cell borders. Syncytiotrophoblast cells are multinucleated with Unilateral salpingo-oophorectomy combined with cisplatin-
dark nuclei and abundant, vacuolated, amphophilic cytoplasm. based multi-reagent chemotherapy has shown promising
Hemorrhage and necrosis are often prominent (Fig. 8.46). results.
Syncytiotrophoblastic cells are positive for β-hCG, whereas 8.4.5 Polyembryomas
cytotrophoblast cells are negative. The tumor cells are posi-
tive for cytokeratin, but negative for EMA. SALL4 and 8.4.5.1 Definition
LIN28 may be focally positive. Polyembryoma is an exceedingly rare malignant germ cell
tumor composed entirely (or predominantly) of embryoid bod-
8.4.4.6 Differential Diagnosis ies resembling an embryo at 15–16 days of gestation [94, 95].
1. Other germ cell tumors (such as dysgerminoma, So far, no pure polyembryoma has been reported as all reported
embryonal carcinoma) with syncytiotrophoblastic cases have consisted of polyembryoma as the dominant compo-
component nent or have been found coexisting with other germ cell tumors
Other germ cell tumors may contain syncytiotrophoblas- (mainly immature teratoma, occasionally embryonal carci-
tic cells; however, they lack cytotrophoblastic cells. noma, yolk sac tumor, dysgerminoma, choriocarcinoma, etc.)
Furthermore, when germ cell tumors contain syncytiotro- [96, 97]. In the 2014 WHO classification of ovarian germ cell
phoblasts they are usually scattered and not present in the tumors, it is classified as a variant of immature teratoma.
same quantity as those seen in choriocarcinoma.
2. Ovarian metastatic gestational choriocarcinoma 8.4.5.2 Clinical Features
On occasion a primary tumor of the uterus may metasta- Most of these tumors have occurred in children and young
size to the ovary. In this case there is usually a history of women. Reported patients commonly present with a pelvic
Fig. 8.45 Choriocarcinoma. These tumors are defined by their admix- Fig. 8.46 Choriocarcinoma. Large areas of hemorrhagic necrosis are
ture of conspicuous cytotrophoblastic and syncytiotrophoblastic cells common
mass and occasional endocrine abnormalities, such as pre- 8.4.5.4 Microscopic Features
cocious puberty in children. Some of these tumors can The defining histologic feature of this tumor is the presence
secrete AFP [98], which may be indicative of a YST of numerous embryoid bodies (Fig. 8.48). Well-developed
component. embryoid bodies are composed of two cavities (recapitulat-
ing amniotic and yolk sac cavities) separated by embryonic
8.4.5.3 Macroscopic Features germ disc. Less developed embryoid bodies may only con-
Polyembryoma is usually a unilateral, large (commonly tain a poorly formed bilayer of germ discs. The embryoid
diameter >10 cm), encapsulated mass with a smooth or nod- bodies are surrounded by an abundant edematous to myxoid
ular surface. The cut surface is grey-tan and solid with stroma with prominent blood vessels. Minor teratomatous
honeycomb-like cystic areas (Fig. 8.47). Areas of hemor- components are almost always present, although they typi-
rhage and necrosis are common. cally occupy <10% of the tumor volume. Scattered syncytio-
trophoblasts may be seen.

1. Ovarian germ cell tumors with occasional embryoid
bodies
Other germ cell tumors may contain occasional embryoid
bodies; however, in those tumors, the embryoid bodies are
the minor component.
2. Yolk sac tumor
Schiller-Duval bodies, especially glomeruloid-type
Schiller-Duval bodies, can be mistaken for an embryoid
body; however, Schiller-Duval bodies lack the character-
istic dual cavity seen in polyembryoma.

Polyembryoma is a highly aggressive tumor that is often
found with metastasis at the time of presentation. Historically,
it has a very poor prognosis, with most patients being dead of
disease within 1 year; however, chemotherapeutic regimens
Fig. 8.47 Polyembryoma. This tumor is large and demonstrates a solid have significantly improved patient outcomes. Currently, the
and honeycomb-like cut surface prognosis of polyembryoma is similar to that of other mixed
Yolk sac cavity
Embryonic Amniotic
germ disc cavity
a b
Fig. 8.48 Polyembryoma. The tumor has multiple embryoid bodies (a). A well-differentiated embryoid body contains blastoderm, and an amni-
otic and primitive yolk sac cavity (b)
264 H. Chen et al.
malignant germ cell tumors. Surgery combined with chemo- ous tumor components. Extensive sampling of these
therapy is the recommended treatment. tumors, focusing on grossly heterogeneous areas of the
tumor, is critical in order to identify all of the tumor
components.
8.4.6 Mixed Malignant Germ Cell Tumors
8.4.6.1 Definition The morphologic features of each individual component are
Mixed malignant germ cell tumors (MGCTs) are defined by identical to those seen in their respective pure forms. The
the presence of two or more types of malignant germ cell most common components include dysgerminoma, yolk sac
components within a tumor. The most common combination tumor, and immature teratoma. Embryonal carcinoma and
is dysgerminoma and yolk sac tumor [99]. Mature teratoma choriocarcinoma are relatively rare. The most common
with one malignant germ cell component, malignant transfor- combination is dysgerminoma and yolk sac tumor
mation of mature teratoma, gonadoblastoma, and mixed germ (Fig. 8.49); other common combinations include dysgermi-
cell-sex cord-stromal tumors are not included in this entity. noma and embryonal carcinoma (Fig. 8.50), yolk sac tumor
and embryonal carcinoma (Fig. 8.51), and immature tera-
8.4.6.2 Clinical Features toma and yolk sac tumor. The various components may be
MGCTs account for 8–20% of all ovarian malignant germ intimately admixed or form relatively discrete zones within
cell tumors [88]. They occur mostly in adolescents (average each tumor.
age of 16 years), and very rarely in postmenopausal women
[100]. Patients may present with abdominal pain, a pelvic/ 8.4.6.5 Treatment and Prognosis
abdominal mass, or bloating. Some patients manifest symp- The size and composition of the tumor are the most impor-
toms of endocrine abnormalities. tant prognostic factors. When the tumor is <10 cm, the prog-
nosis is usually good [101]. Surgery combined with
8.4.6.3 Macroscopic Features chemotherapy is the recommended treatment. The choice of
MGCTs are usually large (average diameter 15 cm) and chemotherapy depends on the relative composition of the
unilateral. The cut surface varies depending on the vari- malignant components of the tumor.
2 cm
Fig. 8.49 Mixed germ cell tumor. Different areas of differentiation are
grossly identifiable. In this case, the upper left area contains yolk sac
tumor and the lower right area is composed of dysgerminoma
Fig. 8.50 Mixed germ cell tumor (dysgerminoma and embryonal car-
cinoma). The left area is composed of dysgerminoma, and the right area
is embryonal carcinoma which displays significant nuclear atypia
a b
c d
Fig. 8.51 Mixed germ cell tumor (yolk sac tumor and embryonal car- large nuclei and prominent nucleoli (a, b). Immunohistochemical stain-
cinoma). In this example the yolk sac tumor is composed of cells with ing exhibits OCT4 expression in the embryonal carcinoma (c), and
small nuclei, microcystic change, and myxoid stroma, while the embry- SALL4 expression in the yolk sac tumor and embryonal carcinoma (d)
onal carcinoma component has a glandular architecture and cells with
8.5 Germ Cell-Sex Cord-Stromal Tumors considered to be clinically benign, and is often considered as
an “in situ” malignant germ cell tumor due to its high rate
Germ cell-sex cord-stromal tumors are composed of germ (60%) of associated malignant transformation.
cell and sex cord components, and can be subcategorized
into two groups: (1) gonadoblastoma, including gonadoblas- 8.5.1.2 Clinical Features
toma with a malignant germ cell tumor, and (2) germ cell-sex Gonadoblastomas occur mostly in patients <15 years of age
cord-stromal tumors, unclassified. Tumors of the first group (average age 18 years, range 1–38). They arise almost exclu-
arise almost exclusively in dysgenic gonads, whereas tumors sively in the setting of dysgenetic gonads. Clinical presenta-
of second group are not associated with dysgenic gonads. tions include amenorrhea or gynecologic tract developmental
abnormalities. Virilization of a phenotypic female is the most
common presentation (45%), followed by hypospadias in
8.5.1 Gonadoblastoma, Including phenotypic male (20%) [102]. Abdominal swelling or pain
Gonadoblastoma/Malignant Germ Cell may be present, and is usually due to malignant transforma-
Tumor tion of tumor.
8.5.1.1 Definition 8.5.1.3 Macroscopic Features

Gonadoblastoma is composed of a mixture of immature sex 40% of gonadoblastomas involve bilateral gonads. They typ-
cord and primitive germ cells. A pure gonadoblastoma is ically arise from indeterminate gonads, dysgenetic testis, or
266 H. Chen et al.
streak gonads. The tumors are usually small (<3 cm). The cut toma” [80]; however, this terminology is controversial [81].
surface is solid, tan to yellow, soft to firm, and sometimes In fact, this diffuse growth pattern can be seen in most
gritty. When associated with malignant germ cell tumor, the gonadoblastomas in variable quantities. These tumors can be
tumor is usually larger with grossly appreciable areas of further subdivided into three patterns: (1) the solid or expans-
divergent differentiation. ile pattern, in which germ cells form large solid nests; (2) the
anastomosing pattern composed of aggregates of small nests;
8.5.1.4 Microscopic Features (3) and the corded, or trabecular, pattern. Sex cord-stromal
cells may be conspicuous in a diffuse-type tumor; however,
Classic-Type Gonadoblastoma immunostains may be needed to identify a component of sex
Gonadoblastoma is usually composed of discrete nests of cord-stromal tumor, and distinguish it from a dysgerminoma.
cells separated by fibrous stroma (Fig. 8.52). The nests con- The majority of gonadoblastomas with a (46 XY) genotype
tain primitive germ cells and sex cord cells, with the latter have a malignant germ cell tumor component, most com-
typically located at the periphery of the nest or around small monly dysgerminoma (57%), followed by yolk sac tumor
acini. The primitive germ cells are similar to the tumor cells (4%) and embryonal carcinoma (4%). A recent series of
that comprise dysgerminoma, with abundant, clear to fine gonadoblastoma demonstrated that the majority (12/14) of
granular cytoplasm, round vesicular nuclei and prominent gonadoblastomas with (46, XX) contained a malignant germ
nucleoli. Mitotic figures may be present (and may even be cell tumor as well (Fig. 8.53) [103].
brisk). Sex cord cells are usually located at the periphery of
the germ cell nest or around individual or clustered germ 8.5.1.5 Immunohistochemistry
cells. Small acini, or cysts, filled with amorphous eosino- Gonadoblastoma is composed of two cell types (Fig. 8.54a),
philic PAS-positive material (similar to Call-Exner bodies) including primitive germ cells that are positive for SALL4
may form. Variable amounts of basement membrane-like (Fig. 8.54b), LIN28, OCT4 (Fig. 8.54c), PLAP, CD117, and
material are present within the nests. Calcifications are com- D2–40 [19] and sex cord-stromal cells that are positive for
mon, ranging from small flecks to large mulberry-like aggre- WT-1 (Fig. 8.54d), inhibin, calretinin, SF-1, FOXL2, and
gates. Luteinized cells or Leydig-like cells are present in SOX9 [80]. Immunohistochemical stains may be helpful in
two-thirds of tumors; however, unlike Leydig cells, these differentiating these comingling components.
cells lack Reinke crystals. Tumor regression is common, and
presents as a decrease in cell mass and a relative increase in 8.5.1.6 Genetic Profiles
basement membrane-like material and calcification. Half of patients with this tumor have a 46,XY karyotype; 1/4
Occasionally, calcifications are the only histologic finding. of patients have a 45, XO/46, XY mosaic karyotype; other
less common karyotypes include 46,XX, 45,XO/46,XY, and
Diffuse-Type Gonadoblastoma 45,XO (Turner syndrome) [102]. The testis-specific protein
Occasionally, a gonadoblastoma may grow in a diffuse man- Y-encoded 1 (TSPY1)gene increases the susceptibility to
ner, in which it has been termed “dissecting gonadoblas- gonadoblastoma in patients with dysgenetic gonads [104].
a b
Fig. 8.52 Gonadoblastoma. This tumor is arranged in small round lumens with amorphous hyaline material (a) and tubules (b). The dysgermi-
noma- or seminoma-like cells are present within the tubules (a, right). There are conspicuous psammoma-like calcifications (a)

1. Dysgerminoma
Dysgerminomas are devoid of sex cord-stromal compo-
nents, and calcifications are rarely present. Indeed, when
calcification is present in a case of putative dysgermi-
noma, additional sections and careful examination are
warranted to identify possible underlying
gonadoblastoma.
2. Ovarian sex cord-stromal tumors with annular
tubules
Patients with this tumor have a normal karyotype and
developmentally normal gonads. Germ cells are absent in
tumor cell nests.
3. Ovarian gynandroblastoma
These uncommon tumors are composed of granulosa-
theca cells and Sertoli-Leydig cells, but lack the germ
Fig. 8.53 Ovarian germ cell tumor resembling testicular spermato- cells seen in gonadoblastoma.
cytic tumors. There are three cell types in these tumors: small cells with 4. Mixed germ cell and sex cord-stromal tumors,
hyperchromatism and scanty cytoplasm which mimic lymphocytes;
medium-sized cells (the most common) with round nuclei and granular
unclassified
to filamentous chromatin; and large cells (uncommon) with granular These tumors may enter the differential diagnosis as they
chromatin. This tumor is mixed with dysgerminoma, both of which are composed of a mixture of germ cells and sex cord-
originated from a gonadoblastoma stromal tumor; however, these tumors lack the distinctive
a b
c d
Fig. 8.54 Gonadoblastoma. These tumors consist of two cell types (a). The germ cells are positive for SALL4 (b) and OCT4 (c), while the sex
cord-stromal cells are positive for WT-1 (d)
268 H. Chen et al.
nested architecture, deposition of basement membrane- OCT4 and SALL4, whereas the sex cord-stromal component
like material, and calcification. Unlike gonadoblastoma, is usually negative for these markers, but positive for SF-1,
these mixed tumors are typically unilateral, and the inhibin, and calretinin [108].
patient will have a normal karyotype and developmentally
normal gonads. 8.5.2.5 Differential Diagnosis
1. Gonadoblastoma
8.5.1.8 Treatment and Prognosis These tumors display a distinct nested architecture, depo-
Gonadoblastoma is a clinically benign tumor when it is unas- sition of basement membrane-like material, and extensive
sociated with an overt malignancy; however, patients do mulberry-like calcifications. These features are character-
need a karyotype analysis. Most patients should undergo a istic of gonadoblastoma and are absent in unclassified
prophylactic bilateral gonadectomy to prevent the develop- mixed germ cell and sex cord-stromal tumors. In addition,
ment of a malignant germ cell tumor. The treatment and patients with gonadoblastoma have dysgenetic gonads
prognosis of a tumor with malignant transformation depend and abnormal karyotypes (Table 8.7).
on the type, size, and stage of the malignant components. 2. Dysgerminoma
When germ cells are the predominant component of the
tumor, mixed germ cell and sex cord-stromal tumors need to
8.5.2 M
ixed Germ Cell and Sex Cord-Stromal be distinguished from dysgerminomas. Careful examina-
Tumor, Unclassified tion, additional sections, and immunohistochemical stain-
ing may help to identify sex cord-stromal components.
8.5.2.1 Definition
Mixed germ cell and sex cord-stromal tumors are composed 8.5.2.6 Treatment and Prognosis
of a mixture of germ cells and sex cord-stroma components, Although these tumors are mostly benign, they do have
but they lack the distinctive features of a gonadoblastoma. malignant potential. Malignant transformation or metastasis
Namely, unlike their counterparts with gonadoblastoma, the may occur, but the risk is significantly lower than that
patients with these tumors are genetically and phenotypi- ascribed to gonadoblastoma. Conservative unilateral oopho-
cally normal. rectomy is the recommended treatment, and metastatic
tumors are sensitive to chemotherapy.
Table 8.7 Comparison between gonadoblastoma and mixed germ cell
This is a rare tumor that most commonly occurs in infants and sex cord-stromal tumor, unclassified
and children younger than 10 years of age; however, rare
Mixed germ cell and
cases have been reported in postmenopausal women [105– sex cord-stromal
107]. Abdominal pain is the most common clinical presenta- Gonadoblastoma tumor, unclassified
tion. Some patients can present with an abdominal mass, and Clinical Most commonly occur in Almost all patients
a quarter of the patients can have precocious features young women 10–30 years are children
of age; majority of patients <10 years of age;
pseudo-puberty. have abnormal karyotypes, normal 46, XX
symptoms of virilization, karyotype; normal
8.5.2.3 Macroscopic Features amenorrhea, and other female phenotype
Mixed germ cell and sex cord-stromal tumors are typically endocrine abnormalities
unilateral, large tumors (diameter 7–18 cm). The cut surface Macroscopic Small tumor (usually <3 cm) Large tumor
features Bilateral in 40% of patients Almost always
is usually solid or solid and cystic, grey-tan to grey-yellow, Calcifications present in unilateral
and devoid of necrosis and calcification. 45% of tumors Calcification absent
Microscopic Distinct nested architecture Variable
8.5.2.4 Microscopic Features features Hyaline bodies and speckled architecture;
calcification common however there is a
These tumors are definitionally composed of a mixture of
Stromal luteinization is lack of nested
germ cells and sex cord-stromal components, but lack the common architecture
distinctive features of gonadoblastoma. As such, it is some- 60% tumors contain Hyaline bodies and
what of a diagnosis of exclusion. Germ cells may form cords, dysgerminoma or other speckled
malignant germ cell calcification
trabeculae, solid or hollow tubules (sometimes, similar to sex
components Rare stromal
cord tumor with annular tubules), cysts, or haphazard struc-
luteinization may
tures. Any or all of the abovementioned patterns can be seen be present
within one tumor. Nested architecture, deposition of base- Not associated with
ment membrane-like material, and calcification are typically malignant germ cell
absent. The germ cell component is typically positive for tumors
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Sex Cord-Stromal Tumors of the Ovary
9
Mohamed Mokhtar Desouki
Abstract Keywords
Sex cord-stromal tumors (SCSTs) are rare neoplasms Sex cord stromal tumors · Granulosa cell tumors ·
derived from, or display differentiation towards primi- Sertoli-leydig cell tumors
tive sex cords or stromal cells. The tumors in this cate-
gory exhibit a great diversity of patterns with a long
array of mimickers, and accordingly may pose a diag-
nostic challenge. Some of the derivative cells are Abbreviations
involved in hormone production under physiologic con-
ditions; therefore, many tumors under this category pro- AGCT Adult granulosa cell tumor
duce excess hormones, which may lead to the EMA Epithelial membrane antigen
development of hormone- mediated syndromes. There FATWO Female adnexal tumor of probable Wolffian
are clear age-related differences in the incidence of sev- origin
eral tumors in this category, with juvenile granulosa cell GIST Gastrointestinal stromal tumor
tumors, for example, occurring primarily in the <20- GST Glutathione S-transferase
year age group, Sertoli-Leydig cell tumors predominat- JGCT Juvenile granulosa cell tumor
ing between menarche and 25 years, and adult granulosa LTSP Luteinized thecoma associated with sclerosing
cell tumors most commonly occurring between ages peritonitis
25–50 years. The correct diagnosis of an ovarian tumor MST Microcystic stromal tumor
is important in all patients, but is arguably particularly NOS Not otherwise specified
so for this category, since young patients represent a sig- PJS Peutz-Jeghers syndrome
nificant proportion of patients, and issues of fertility SCCHT Small cell carcinoma of hypercalcemic type
preservation abound. This makes awareness of the diag- SCST Sex cord-stromal tumor
nostic criteria and the differential diagnosis of the SCTAT Sex cord tumor with annular tubules
SCSTs an important task. The 2014 World Health SF-1 Steroidogenic factor 1
Organization classification of SCSTs categorized this SLCT Sertoli–Leydig cell tumor
group under three main categories: pure stromal tumors, SRST Signet ring stromal tumor
pure sex cord tumors, and mixed SCSTs. This chapter SST Sclerosing stromal tumor
highlights all SCSTs, with an emphasis on the clinico- WHO World Health Organization
pathologic characteristics and advances in molecular YST Yolk sac tumor
features of each entity, as well as a detailed discussion of
differential diagnostic considerations, and the utility and
limitations of immunohistochemical markers and ancil-
lary studies in their diagnostic work-up. 9.1 Histogenesis
Sex cord-stromal tumors (SCSTs) are heterogeneous group

of neoplasms derived from, or display differentiation towards
M. M. Desouki (*)
primitive sex cords or stromal cells. The former include
Department of Pathology, Microbiology and Immunology,
Vanderbilt University School of Medicine, Nashville, TN, USA granulosa cells and Sertoli cells of the ovarian cortex while
e-mail: [email protected] the latter include theca cells, fibroblasts and Leydig cells [1].
274 M. M. Desouki
During embryogenesis, the primitive cells form subcoelomic androgenic symptoms. However, overlap does occur and
mesenchyme condensations that differentiate to the mature nonfunctioning tumors are common among this group as
cortical supporting stroma and the granulosa theca cells of well [1].
the developing follicles. The primitive cells have the ability
to differentiate towards the Sertoli and the Leydig cells of the
testis and the hilus of the ovary. 9.2 Incidence and Clinical Significance
Due to the wide range of differentiation, the tumors
develop from these cells are diverse and complex and contain Apart from fibroma, all other ovarian SCSTs are uncommon
mixture of more than one cell type in most instances. More neoplasms that are known to have a wide morphologic spec-
recently, it has been hypothesized that during development trum and which accordingly may be diagnostically challeng-
of the surface epithelium, some of the epithelial cell precur- ing. SCSTs constitute <10% of all ovarian tumors of which
sors (Gonadal Ridge Epithelial-Like) penetrate into the ovar- benign tumors e.g. fibromas and thecomas account for
ian stroma to form the granulosa cells surrounding the approximately 85% of all SCSTs. On the other hand, adult
follicles. The authors concluded that the ovarian surface epi- granulosa cell tumor (AGCT), Sertoli–Leydig cell tumor
thelial cells do penetrate into the ovary to form the granulosa (SLCT) and sclerosing stromal tumor (SST) account for
cells of follicles [2]. This may explain the morphologic simi- approximately 15% of SCSTs. The remaining tumors col-
larity between many tumors in this category and the more lectively are very rare, and constitute <1% of the SCSTs [3].
common epithelial tumors. Clinical information, including endocrine manifestations
As some of the mentioned cells are involved in hor- and the patient age are important parameters to clinically
mone production under physiologic conditions (e.g., investigate and communicate to the pathologist. The patient
estrogen, progesterone, androgen and corticosteroids), a age is especially significant since there are clear age-related
fraction of SCSTs are expected to produce hormones differences in the incidence of several tumors in this cate-
leading to the development of hormone mediated syn- gory: (a) Juvenile GCTs (JGCTs) occur primarily in the <20
dromes or isolated hormone production which may be the age group, (b) SLCTs predominate between menarche and
initial presenting symptom. Tumors derived from the 25 years, (c) fibrothecomas and AGCTs are most commonly
ovarian cells e.g., granulosa cells and theca cells produce occurring between 25–50-year age group, and (d) fibromas,
estrogenic symptoms and hormones developed from tes- steroid cell tumors and fibrosarcomas commonly emerge
ticular cell types e.g. Sertoli or Leydig cells produce after menopause [4–8] (Table 9.1).
Table 9.1 Clinical characteristics of sex cord stromal tumors

Tumor Frequency Mean age (y) Main symptoms Prognosis Associations
Fibroma 70 48 Mass Benign Meigs’ syndrome,
Gorlin’s syndrome
Fibrosarcoma <1 50 Mass/abdominal pain Malignant
Thecoma 15 59 Abnormal vaginal bleeding Benign Trisomy 12,EH and EC
Sclerosing ST 2 24 Abnormal vaginal bleeding Benign Trisomy 12
Signet ring ST <1 37 Mass/abdominal pain Benign
Steroid cell tumor <1 43 Virilization 34% Malignant
Leydig cell tumor <1 58 Virilization Benign
Microcystic ST <1 45 Pelvic mass Benign
AGCT 7 55 Abnormal bleeding/mass Malignant FOXL2 mutation
EH and EC
JGCT <1 13 Isosexual precocity/abnormal Malignant Ollier’s diseaseMaffucci’s
bleeding syndrome
FOXL2 mutation (10%)
SCT <1 30 Incidental finding Benign PJS
SCTAT <1 27–34 PJS: Asymptomatic PJS: Benign PJS: Adenoma malignum
Sporadic: Mass, abnormal Sporadic:15%
bleeding malignant
SLCT 3 25 Virilization, abnormal bleeding Malignant DICR1 mutation
SCST, NOS <1 49 Mass Malignant
Data from multiple sources (see the references for each tumor in the text)
AGCT adult granulosa cell tumor, EC endometrial carcinoma, EH endometrial hyperplasia, JGCT Juvenile granulosa cell tumor, NOS not other-
wise specified, PJS Peutz-Jeghers syndrome, SCT Sertoli cell tumor, SLCT Sertoli–Leydig cell tumor, SCTAT, Sex cord tumor with annular
tubules, and ST Stromal tumor
9 Sex Cord-Stromal Tumors of the Ovary 275
Patients are either asymptomatic with the tumor discovered Table 9.2 Classification of ovarian sex cord-stromal tumors [3, 10]
incidentally on routine clinical examination or on pathologic I. Pure stromal tumors
examination for surgery performed for unrelated disease, or • Fibroma, cellular Fibroma and fibrosarcoma
present with abdominal pain, pelvic or abdominal mass, or • Thecoma (typical and luteinized associated with sclerosing
peritonitis)
endocrine related symptoms due to hyperestrinism (e.g., iso-
• Sclerosing stromal tumor
sexual precocity, abnormal uterine bleeding and endometrial
• Signet ring stromal tumor
hyperplasia or carcinoma) and hyperandrogenism (e.g., hirsut- • Microcystic stromal tumor
ism, acne, hoarse voice, irregular menstrual periods, male-pat- • Stromal tumor with minor sex cord elementsa
tern scalp hair and loss of normal female fat distribution) [3]. • Leydig cell tumor
A small subset of SCSTs have known associations with • Steroid cell tumor
specific syndromes, including Gorlin’s (fibroma), Meigs’ II. Pure sex cord tumors
(fibroma), Ollier’s disease (JGCT), DICER1 (SLCT, and • Adult granulosa cell tumor
JGCT), Maffucci’s (JGCT), and Peutz–Jeghers (sex cord • Juvenile granulosa cell tumor
tumor with annular tubules [SCTATs] and Sertoli cell tumor • Sertoli cell tumor
• Sex cord-stromal tumors with annular tubules
[SCT]) [5, 9] and therefore the initial presentation may be of
III. Mixed sex cord-stromal tumors
the extraovarian symptoms related to a particular syndrome
• Sertoli-Leydig cell tumors
(Table 9.1). • Sex cord-stromal tumors, not otherwise specified
The clinical behavior for SCSTs (Table 9.1) vary tremen- Not included in the 2014 WHO classification of SCSTs of the ovary
a
dously and are largely histotype-dependent. Even within a

single diagnostic category or within single entity e.g., SLCTs
and steroid cell tumors, patient outcomes may vary signifi- 9.4 Overall Application
cantly. Diagnostic issues are compounded by the rarity of sev- of Immunohistochemistry
eral entities. The keys to accurately diagnosing the tumors in to Aid Diagnosis
this group are to recognize the full pathologic spectrum of
every constituent entity, and to consider the possibility for Several immunohistochemical (IHC) antibodies have proven to
each ovarian/metastatic neoplasm that is in the differential be helpful in diagnosing SCSTs. Notably, α-inhibin and cal-
diagnosis. The differential diagnosis for a given case typically retinin, which are positive in most of the tumors in this category
includes many other SCSTs. Similarly, SCST is frequently in [11–15], are diagnostically useful (Fig. 9.1 and Table 9.3). On
the differential diagnosis for a wide variety of non-SCSTs. the other hand, epithelial membrane antigen (EMA) is negative
in almost all tumors in this category [1]. α-Inhibin is more spe-
cific (less sensitive) and calretinin is more sensitive (less specific)
9.3 Classification and General Features among the IHC markers. The intensity for α-inhibin and cal-
retinin is variable and may be focal or patchy [15]. Steroidogenic
The most recent World Health Organization (WHO) classifi- factor 1 (SF-1), WT1 (Fig. 9.2), CD56, CD99 and CD10 are
cation of SCSTs categorized these tumors according to the other positive markers with different localization to the cellular
following clinicopathologic entities: pure stromal, pure sex compartments in most SCSTs [13, 15–18] (Table 9.3). Leydig
cord, and mixed SCSTs [3]. The “pure stromal tumors” is and steroid cell tumors are positive for Melan-A (MART1) [19]
comprised of the fibroma-thecoma, as well as the steroid cell (Fig. 9.3). These markers have varying performances and some
tumors. Despite the fact that stromal tumor with minor sex are more useful than the others for a particular entity [15]
cord elements, previously included in the 2003 WHO clas- (Table 9.4). However, a judiciously selected panel of markers can
sification [10], is not included in the 2014 WHO classifica- provide ample diagnostic information.
tion, for completeness sake, the tumor will be included in FOXL2 is a newly introduced nuclear IHC marker that is
this chapter. Luteinized thecoma should be categorized as a expressed in many ovarian SCSTs regardless of the FOXL2
separate entity if it is associated with sclerosing peritonitis. gene mutation status (Table 9.4 and Fig. 9.4). In contrast to
The “pure sex cord tumors” comprises AGCTs, JGCTs, the relatively specific FOXL2 gene mutation in AGCTs (see
SCTs, and SCTATs. The “mixed SCSTs” category comprises AGCTs section below), FOXL2 expression by IHC is seen in
SLCTs with different differentiation as well as SCSTs not almost all cases of adult and juvenile GCTs, fibromas, SSTs,
otherwise specified (NOS) (Table 9.2). Gynandroblastoma is fibrosarcomas and SCTATs and in 50% SLCTs, 60% theco-
not included in the 2014 WHO classification and as recom- mas, 9% steroid cell tumors and 75% of SCST NOS while
mended by others [1] we prefer the term “SCST of mixed negative in Leydig cell component of SLCTs, retiform SLCT,
forms” then specify the patterns and the percent of each Leydig cell tumors and stromal luteomas. Of the non-SCSTs
component. Therefore, gynandroblastoma will not be tested, only 3 of 3 cases of Female adnexal tumor of probable
included as separate entity in this chapter. Wolffian origin (FATWO) expressed the FOXL2 IHC marker
276 M. M. Desouki
a b
Fig. 9.1 Alpha Inhibin and calretinin immunohistochemical stains in usually positive in most cases of sex cord stromal tumors with α-inhibin
an adult granulosa cell tumor. α-Inhibin (a) is a cytoplasmic marker is more specific and calretinin is more sensitive among the IHC
while calretinin (b) is a cytoplasmic/cell membrane marker. Both are markers
Table 9.3 Commonly used immunohistochemistry markers in ovarian

sex cord stromal tumors and pattern of expression
Antibody Pattern
Inhibin Cytoplasmic
Calretinin Cytoplasmic/nuclear
SF-1 Nuclear
FOXL2 Nuclear
WT1 Nuclear
PR Nuclear
CD56 Cytoplasmic
CD99 Cytoplasmic/membrane
CD10 Cytoplasmic/membrane
Melan-A Cytoplasmic
Fig. 9.3 MART-1 (Melan A) immunohistochemical marker in a ste-

roid cell tumor. MART-1 is a cytoplasmic marker that is positive in
~96% of steroid and leydig cell tumors
a b
Fig. 9.2 Steroidogenic factor 1 (SF-1) and WT1 immunohistochemical stains in representative cases of sex cord stromal tumors. Signet ring stromal
tumor (a) and adult granulosa cell tumor (b). Both markers are nuclear and are usually positive in most cases of sex cord stromal tumors
Table 9.4 Positivity rate of commonly used immunohistochemistry t hecomatous differentiation (fibrothecomas) constitute ~85%
markers in selected sex cord stromal tumors of SCSTs. Cellular fibromas constitute ~10% of this cate-
Tumor Inhibin Calretinin SF-1 WT1 CD99 FOXL2 CD10 gory [24]. Fibromas commonly affect women in the fifth
Fibroma 70 100 100 100 0 100 0 decade with a mean age of 48-years (range of 17–79 years).
Thecoma 100 100 100 100 0 60 70 The average age of women with cellular fibroma is 46-years
GCT 94 81 100 78 88 98 90
(range of 14–93 years). The most common presenting symp-
SCT 100 100 100 0 32 0 44
toms are pelvic mass and abdominal pain and occasionally
SLCT 100 89 100 100 50 50 44
SCST, 86 80 99 82 68 74 – symptoms related to urinary dysfunction (frequency, dysuria
NOS and nocturia), abnormal uterine bleeding, dyspareunia,
Numbers are the percent of positive cases pooled from different studies increasing abdominal girth and elevated CA-125 on routine
(see text for references) blood work [8, 23].
GCT granulosa cell tumor, SCT Sertoli cell tumor, SLCT Sertoli–Leydig
cell tumor, SCST NOS Sex cord stromal tumor not otherwise specified
Fibromas are typically unilateral (9% bilateral) and range in
size from <1 cm to 16 cm (average of 3.8 cm). They typically
have smooth, sometimes lobulated outer surfaces, solid to
rubbery consistency and white to tan cut surfaces. Edema
and calcification are common gross findings. Infarction and
hemorrhage occasionally present. Fibromas associated with
Gorlin syndrome are usually (~75%) bilateral and more
commonly multinodular rather than smooth [9]. Cellular
fibromas usually reach large size compared to conventional
fibromas with an average size of 9 cm (range of 1–19 cm).
The outer surface may be smooth (34–36%), pedunculated/
polypoid (6–22%), solid, white-yellow or tan with cystic
areas [7, 8, 24].

Fibromas are composed of uniformly distributed, bland
Fig. 9.4 FOXL2 in adult granulosa cell tumor. FOXL2 is a nuclear spindle-shaped cells, which usually arrange in a swirling
marker that is positive in most cases of sex cord stromal tumors (image (storiform) pattern with abundant collagen matrix interven-
is courtesy of Katja Gwin, UT Southwestern Medical Center)
ing between the fibroblasts (Fig. 9.5). Hyaline globules may
be present and sometimes are heavy but are non-specific
[20]. FOXL2 by IHC appears to be more sensitive with stron-
ger staining for SCSTs than α-inhibin and calretinin.
Therefore, despite FOXL2 IHC has limited differentiating
ability among SCSTs, in a panel of α-inhibin and calretinin,
FOXL2 is relatively a sensitive marker for labeling most of
the tumors in this category [20–22].
9.5 Pure Stromal Tumors
9.5.1 Fibromas and Cellular Fibromas
9.5.1.1 Definition
Fibroma is a benign neoplasm composed of proliferation of
a pure population of fibroblasts that produce collagen.
Cellular fibroma is a fibroma with increased cellularity [23].
9.5.1.2 Clinical Presentations Fig. 9.5 Ovarian fibroma. Representative case of fibroma composed of
Fibromas represent 70% of all SCSTs (4% of all ovarian uniformly distributed, bland spindle-shaped cells arranged in a swirling
neoplasms), and in combination with tumors showing pattern with abundant intervening collagen matrix
278 M. M. Desouki
Fig. 9.6 Ovarian fibroma. The tumor is composed of uniform spindle- Fig. 9.8 Ovarian cellular fibroma. The tumor exhibits increased cellu-
shaped cells containing elongated nuclei with tapered ends. No cyto- larity with haphazard rather than the storiform growth pattern of con-
logical atypia or increased mitotic figures ventional fibroma with scant collagen matrix
Fig. 9.7 Ovarian fibroma. The tumor is composed of uniform bland Fig. 9.9 Ovarian cellular fibroma. The cells arrange in a herringbone
spindle cells with intervening collagen bundles in a swirling pattern pattern. The nuclei are bland, oval, with smooth nuclear contours, even
chromatin, and indistinct nucleoli with no atypia or increased mitotic
activity
findings [25]. The nuclei are elongated with tapered ends and
inconspicuous nucleoli. No cytological atypia is present, and 5%, foamy histiocytes in up to 3%, bizarre nuclei in up to 3%
mitotic figures are usually infrequent (Figs. 9.6 and 9.7). and calcifications in up to 6% of cases [8]. Cells arranged in
Calcification, intercellular edema, sex cord–like elements a herringbone pattern with prominent Verocay-like areas
and hyaline fibrosis may be focally present. The cellularity is were occasionally seen in cellular fibroma. The nuclei are
typically mild to moderate [7]. bland, oval, with smooth nuclear contours, even chromatin,
Cellular fibromas as the name implies tend to have and indistinct nucleoli with no more than mild atypia (mod-
increased cellularity. No consensus on how much cellularity erate atypia may be seen focally around areas of necrosis)
is reasonable to consider the fibroma a cellular rather than [8]. Mitotic figures varies with a mean of 1.5/10 HPF with
conventional one. It is our personal experience that when the most cases have 0–3 mitotic figures/10 HPF (Fig. 9.9).
fibroblasts are haphazardly arranged and there is no/minimal Mitotically active cellular fibroma is a tumor that exhibits
collagen matrix or edema, the term cellular fibroma is used high mitotic count (≥4/10 HPFs) with no more than mild
(Fig. 9.8). Necrosis with sharp demarcation from the adja- nuclear atypia at most. In these tumors the average mitotic
cent viable tumor tissue may be seen in up to 30%, minor sex count /10HPF is 6.7 (range of 4–19). The average age of the
cord-like elements in up to 9%, focal luteinized cells in up to patients is 41 years. The clinical presentation, gross and
microscopic findings and clinical outcome are similar to that

of cellular fibroma with <4 mitoses/10 HPF [8, 24].
9.5.1.5 Biomarkers
Fibromas, fibrosarcomas and fibrothecomas are infrequently
positive for α-inhibin (50–70%, variable intensity), calretinin
(25–100%, variable intensity), CD56 (100%, cytoplasmic
rather than membranous), WT1 (80–100%, weak and
patchy), SF-1 and FOXL2 (100%) and cytokeratin (20%,
weak). CD99, CK5/6, CD10, EMA and MART1 have been
reported as negative [13, 15, 16, 20] (Table 9.4).
9.5.1.6 Genetic Association

Fibromas may be associated with ascites and pleural effusion
(Meigs’ syndrome) and in association with nevoid basal cell
syndrome (Gorlin’s syndrome). The latter is an autosomal Fig. 9.10 Ovarian leiomyoma: The smooth muscle fibers are bland
dominant syndrome described with ovarian fibroma and with abundant eosinophilic cytoplasm morphologically resembling a
cutaneous basal cell carcinomas and the patients usually fibroma. However, the spindle cells in leiomyoma have blunt ended
have a mutated PTCH gene located at 9q22.3 [9]. Trisomy 12 nuclei and less extracellular collagen
has been reported in a subset of fibromas [26]. Fibromas,
including cellular ones, have shown loss of heterozygosity the former, and the presence of entrapped follicular
(LOH) at 9q22.3 [27]. derivatives with surrounding fibrous tissue in the latter [30].
The status of fibromatosis as a distinct clinicopathologic
9.5.1.7 Differential Diagnosis entity is unclear.
All ovarian neoplasms and non-neoplastic lesions com- Leiomyoma: Ovarian leiomyoma is rare, unilateral and
posed entirely or focally of spindle cells are in the differ- is morphologically similar to their uterine counterpart. The
ential diagnosis of ovarian fibroma. SCSTs with spindle fascicular arrangement of smooth muscle fibers can mor-
cells include fibroma, fibrosarcoma, thecoma, luteinized phologically resemble a fibroma. The spindle cells in leio-
thecoma with sclerosing peritonitis (LTSP), diffuse and myoma are bland with abundant eosinophilic cytoplasm,
sarcomatoid GCT, poorly differentiated SLCT, signet blunt ended nuclei with infrequent mitosis and the extra-
ring-stromal tumor (SRST) and SST. The list of other neo- cellular collagen is usually less abundant than that of
plastic and nonneoplastic lesions with spindle cells fibroma [31] (Fig. 9.10). In contrast, fibromas have scant
include smooth muscle neoplasms, endometrioid stromal cytoplasm and wavy nuclei. Most leiomyoma variants,
sarcoma, gastrointestinal stromal tumor (GIST), endome- including leiomyoma with bizarre nuclei, mitotically
trioid carcinoma with spindle cells, undifferentiated car- active, cellular, myxoid and epithelioid may develop in the
cinoma, undifferentiated sarcoma, adenosarcoma, ovary. IHC markers can facilitate this differential, since
carcinosarcoma, mesothelioma, FATWO, massive ovarian smooth muscle tumors diffusely express desmin and
edema, fibromatosis, stromal hyperplasia and hypertheco- h-caldesmon in contrast to the negative/focally weak posi-
sis [28]. Because the list is extensive, the characteristics tive staining that is typical in fibroma. SMA will not help
of the SCSTs with spindle cells will be discussed in detail in that differential where fibromas and leiomyomas are
in the corresponding section of the specific SCST in this usually positive for it [28].
chapter. A brief mention of the salient differentiating fea- Gastrointestinal stromal tumor: GIST may exhibit a pure
tures will be discussed in the differential diagnosis sec- spindle or a mixed spindle and epithelioid morphology
tions. To avoid repetition, non-SCSTs/non neoplastic (Fig. 9.11). The nuclei exhibit mild to moderate nuclear
lesions will be discussed in the differential diagnosis sec- atypia with mitotic rates that range from <1 to 6 /10 HPFs.
tion of each SCST. GISTs exhibit diffuse c-kit (CD117) and DOG1 positivity,
Fibromatosis: Fibromas are easily diagnosed lesions, and are negative for sex cord stromal markers. H-caldesmon
however, small incidental tumors may be confused with cel- and SMA may be positive in GIST. Concurrent GIST of the
lular cortex (fibromatosis). The latter is typically seen in GI is helpful [32].
children, adolescents, and young women and may be related
to massive ovarian edema [29]. The distinction between 9.5.1.8 Prognosis
fibroma and fibromatosis is based on the presence of a mass Fibromas including mitotically active ones behave in benign
lesion, which is delineated from the background stroma in fashion while cellular fibromas manifest by rare (1%) local
280 M. M. Desouki
9.5.2 Fibrosarcomas
9.5.2.1 Definition
A malignant fibroblastic tumor of the ovary [24].
9.5.2.2 Clinical Presentations

Ovarian fibrosarcomas are rare (<1% of all ovarian tumors),
however, it is relatively a common primary ovarian sarcoma.
It occurs predominantly in the fifth decade (mean age of
50.3 years, range of 8–73). Patients are usually symptomatic
with palpable mass and pelvic pain. Tumors present equally
at stage I and stage III with recurrence in all reported cases
[24]. However, there is no universally accepted staging sys-
tem for gynecologic sarcomas. The tumor usually develop do
novo; however, malignant change in an ovarian fibrothecoma
Fig. 9.11 Gastrointestinal stromal tumor: This tumor exhibits a pure
with minor sex cord elements has been reported [33]. There
spindle cell morphology similar to ovarian fibroma or leiomyoma. is no report suggesting a potential risk of pelvic radiation
Positive c-kit (CD117) and DOG1 in GIST, negative sex cord stromal with ovarian fibrosarcomas.
markers and concurrent GIST of the GI are helpful to differentiate
between these mimickers in most cases
Fibrosarcomas are unilateral tumors, which usually reach
large size. The tumors usually have softer consistency and a
recurrence in the pelvis or abdomen. Therefore, simple tan to yellow color compared to the firm and gray white con-
excision is curable in almost all cases of fibromas [8, 24]. ventional fibromas. Solid to cystic heterogeneous consis-
However, if cellular fibroma is associated with ovarian sur- tency and associated hemorrhage and necrosis are common
face adhesion, rupture or extraovarian involvement, local gross findings [7, 24] (Fig. 9.12).
recurrence increases [8].
Fibrosarcoma, like those of other organs, is composed of
spindle cell proliferation with a storiform or herringbone
growth pattern with moderate to severe nuclear atypia. The
Key Diagnostic Points tumor may contain luteinized stromal cells or minor sex-cord
Fibroma elements. High mitotic count is usually encountered in fibro-
Gross sarcomas, but is not by itself a conclusive indication of
• Unilateral (91%), small (average size of 3.8 cm), malignancy [8, 24] (Fig. 9.13).
white, smooth or lobulated.
• Calcification is common.
Microscopic
• Mild to moderate cellularity.
• Bland spindle fibroblasts arrange in a swirling
pattern.
• Abundant collagen matrix between the fibroblasts.
• Elongated nuclei with tapered ends, no cytologic
atypia and infrequent mitosis.
• Calcification and edema are common.
Markers
• Positive: Inhibin (70%), calretinin (100%), CD56
(100%), WT1 (100%), SF-1 (100%), FOXL2
(100%).
• Negative: CD99, CK5/6, CD10, and EMA. Fig. 9.12 Ovarian Fibrosarcoma. Gross photograph of large mass with
gray white cut surfaces with extensive hemorrhage and gross necrosis
Fig. 9.13 Primary ovarian fibrosarcoma. High power (×40) showing Fig. 9.14 Leiomyosarcoma. The tumor exhibits marked nuclear
increased, cellularity, moderate to severe atypia and prominent mitotic atypia, increased mitotic count and coagulative tumor necrosis.
figures Immunohistochemical markers with positive smooth muscle markers in
leiomyosarcomas and negative stains in fibrosarcoma are helpful in this
differential
9.5.2.5 Biomarkers
The diagnosis is based on morphology and exclusion of
other entities with specific lineage derivation and no specific
IHC panel for fibrosarcoma is recommended. Fibrosarcoma
has been reported positive for vimentin, while negative for
actin and desmin with 30–40% Ki-67 labeling index (a case
report) [34]. One of 8 cases has been reported weak positive
for CD10 [18] and 3 of 3 cases has been reported positive for
FOXL2 [20].
9.5.2.6 Genetic Association

Fibrosarcomas have been reported in association with
Maffucci’s syndrome and the nevoid basal cell carcinoma
syndrome [35, 36].

Cellular and mitotically active fibroma: It is the moderate to
severe nuclear atypia rather than the mitotic count as opposed Fig. 9.15 Low-grade endometrial stromal sarcoma. The tumor exhib-
to the original publication by Prat and Scully [24] that label its diffuse proliferation of small cells with infiltrative borders and lym-
the tumor as fibrosarcoma [8]. Tsuji et al. concluded that the phovascular invasion
MIB-1 (Ki-67) labeling index and the proliferative index by
DNA flow cytometry are higher in fibrosarcomas and could of small arterioles. The borders are infiltrative and vascular
be used to sort out this differential diagnosis [37]. invasion is a common finding (Fig. 9.15). The cytoplasm is
Leiomyosarcoma: Leiomyosarcoma usually exhibits scant and the nuclei of LGESS are ovoid to spindle. Foci of
marked nuclear atypia with or without increase in the mitotic glandular differentiation, sex cord-like elements, smooth
count (Fig. 9.14). Primary ovarian myxoid variants have muscle differentiation, and fibrous areas are not uncommon
been reported. However, excluding metastatic leiomyosar- findings in ovarian LGESS [38]. Endometriosis is a common
coma before diagnosing a primary ovarian one is essential. association with primary ovarian LGESS. CD10 IHC is typi-
Leiomyosarcomas mostly express smooth muscle markers, cally diffusely and strongly positive in LGESS in contrast to
e.g. desmin and h-caldesmon [31, 38]. the negative staining in fibrous tumors [15]. Most LGESS
Low grade endometrial stromal sarcoma: Primary and are negative for α-inhibin and CD99. Of note, uterine LGESS
metastatic LGESS exhibits a constellation of findings, which may be calretinin positive [39].
include diffuse proliferation of small cells resembling the Poorly differentiated (sarcomatoid) Sertoli-Leydig cell
cells of proliferative phase endometrial stroma and a network tumors: Occur in younger age, no herringbone pattern, and
282 M. M. Desouki
may contain heterologous differentiation (see SLCT section cases [6] especially the tumors previously categorized as
below). luteinized thecomas, which are reportedly more likely to
Diffuse adult granulosa cell tumor: AGCT exhibits be associated with androgenic rather than estrogenic
grooved nuclei and most probably will have other conven- manifestations [40].
tional GCT patterns (see GCT section below). LTSP occur in young patients (mean of 36 and median:
27 years) with wide age range from 10 months to 85 years.
9.5.2.8 Prognosis The lesions typically present with abdominal distension,
Fibrosarcoma has poor prognosis and all reported cases acute abdomen, ascites, bowel obstruction, nausea and vom-
died of disease [24]. Excision with or without postoperative iting [41].
chemo and radiotherapy are the current management
options. 9.5.3.3 Gross Findings
Thecomas are mostly (95%) unilateral tumors with firm,
smooth-surfaces and homogeneous yellow and lobulated cut
surfaces. The tumor may reach up to 22 cm with an average
Key Diagnostic Points dimension of 5 cm [6]. Most LTSPs are bilateral, polypoid,
Fibrosarcoma lobulated, or cerebriform with tan, gray, or pink, homoge-
Gross neous, cut surfaces with occasional hemorrhage [41].
• Unilateral, large, soft, tan-yellow, solid to cystic
with heterogeneous consistency. 9.5.3.4 Microscopic Findings
• Hemorrhage and necrosis are common. The neoplastic cells are fusiform and grow in a diffuse
pattern with alternating hyaline plaques or rarely in a nod-
Microscopic ular pattern. The cells have ill-defined membranes and
• Increased cellularity. pale gray cytoplasm. Calcifications and keloid-like scle-
• Spindle cells with storiform or herringbone growth rosis are common findings. Vesicular nuclei with delicate
pattern. membranes are usually appreciated with no nuclear atypia
• Moderate to severe atypia. and infrequent mitoses [6] (Figs. 9.16 and 9.17).
• Increased mitotic activity. Calcifications and bizarre nuclei resembling those in sym-
plastic leiomyoma do occur with smudgy chromatin and
Markers no increase in mitotic activity [42]. Pure forms composed
• Only useful in excluding other high grade malig- of theca cells only with no admixture of fibroblasts
nancies with spindle cells. (fibrothecomas) or granulosa cells (granulosa-theca cell
tumors) are extremely rare. The granulosa cell component
if any should not exceed 10% [40].
9.5.3 Thecomas and Luteinized Thecomas

Associated with Sclerosing Peritonitis
9.5.3.1 Definition
Thecomas are a group of pure ovarian stromal tumors origi-
nating from and resembling theca cells of the developing
ovarian follicles. If associated with sclerosing peritonitis, the
term luteinized thecoma is applicable [3].

Thecomas are rare neoplasms accounting for <1% of ovar-
ian tumors. However, thecomas represent about 15% of the
tumors in the category of SCSTs (Table 9.1). Thecomas
occur typically in postmenopausal women with an average
age of 59 years and only rare (10%) occurrence before the
age of 30 years. Approximately half of the cases present
with manifestations of hyperestrinism e.g. abnormal uterine
bleeding, endometrial hyperplasia and endometrial adeno- Fig. 9.16 Ovarian thecoma. The tumor is composed of plump to spin-
carcinoma while androgenic symptoms present in 10% of dle cells with central nuclei
a b
c d
Fig. 9.17 Ovarian thecoma. Low (a) and high (b) power captions of a tumor that is composed of plump to spindle cells with abundant pale cyto-
plasm and central nuclei. The tumor is positive of inhibin (c) and calretinin (d)
LTSP exhibit single or clusters of lutein cells which are

ovoid cells containing abundant cytoplasm interspersed between
the neoplastic spindle cells in the ovarian cortex with spared
medulla. The tumors are usually hypercellular with frequent
stromal edema resembling MST. The cells are spindle or rarely
round/oval with pale cytoplasm (Fig. 9.18). In contrast to con-
ventional thecoma, the mitotic index is high (Fig. 9.19). Due to
sparing of the existing follicles and predominance of the lesions
in the ovarian cortex, some authors suggested a non-neoplastic
process and the term “thecomatosis“may be used [41].
The peritoneal lesions are numerous brown to white lobu-
lated or nodular indurated fibrous adhesions. Morphologically,
the lesions consisted of fascicular growth pattern of mitoti-
cally active but cytologically bland fibroblasts with variably
fibrillary and pink cytoplasm, elongated nuclei and admixed
inflammatory cells [6, 43]. Involvement of the septa between
Fig. 9.18 Ovarian luteinized thecoma. The tumor is composed of fas-
the fat lobules give the lesion the described lobulated pattern cicles of spindled cells with abundant eosinophilic cytoplasm. Clusters
separated by intercellular myxoid or edematous collagen of luteinized cells containing vacuolated cytoplasm are interspersed
with infiltrating chronic inflammatory cells [41]. between the tumor cells
284 M. M. Desouki
a b
c d
Fig. 9.19 Mitotically active ovarian thecoma. Low (a) and high (b) increased mitotic activity (arrow). The tumor cells are positive of
power captions of a mitotically active thecoma that is composed of inhibin (c) and calretinin (d)
plump to spindle cells with abundant cytoplasm and central nuclei with
9.5.3.5 Biomarkers 9.5.3.7 Differential Diagnosis

Thecomas are positive in both spindle cells and luteinized Fibroma: Thecoma typically has a nodular growth pattern
cells for α-inhibin (90–100%, strong staining), calretinin and the cells have abundant pale to vacuolated cytoplasm. In
(100%, strong staining), CD56 (100%) FOXL2 (100%), contrast, fibroma does not show strong α-inhibin expression
SF-1 (100%) and CD10 (70%). The spindle cells of luteinized and are mostly CD10 negative. Morphologic overlap between
thecoma are rarely positive for AE1/AE3, α-SMA, desmin, fibroma and thecoma exists and the term of fibrothecoma
c-kit, estrogen receptors (ER) and progesterone receptors may be used in lesions with overlapping features [7].
(PR) and negative for α-inhibin, calretinin (Fig. 9.20), CD56, Granulosa cell tumor: GCTs especially with diffuse
EMA, beta-catenin, TGF-b and CD34 [11, 16–18, 20, 44] growth pattern do not display the pale, eosinophilic cyto-
(Table 9.4). The extraovarian sclerosing lesions are positive plasm unless they are luteinized. Reticulin stain usually sur-
with Cytokeratin AE1/AE3 and are rarely positive for ER rounds individual cells in thecoma/fibroma and surrounds
and PR [44]. clusters of cells in GCTs (Fig. 9.21) [6].
Sclerosing stromal tumor: Both SST and thecoma may
9.5.3.6 Genetic Association have a lobulated architecture and an epithelioid cellular
Trisomy 12 has been reported in a subset of thecomas, component especially at low power examination. Clinically,
fibrothecomas, fibromas and GCTs [26, 45]. SST typically occurs in women younger than 30 years and
a b
c d
Fig. 9.20 Ovarian luteinized thecoma. The tumor is composed of fascicles of spindled cells with abundant eosinophilic cytoplasm (a). The tumor
cells are positive of inhibin (b), calretinin (c) and reticulin histochemical stain surrounds individual cells (d)
a b
Fig. 9.21 Reticulin histochemical stain in fibrothecoma and adult granulosa cell tumor. A reticulin stain surround individual cells in fibrothecoma
(a) and nests of cells in adult granulosa cell tumor (b)
286 M. M. Desouki
mostly is not associated with hormonal manifestations. No

hemangiopericytoma-like vascular pattern that characterize
SST in luteinized thecoma.
Massive ovarian edema: Typically occur in children, ado-
lescents, and young women, with an average age of 21 years.
Massive edema is usually unilateral with ovarian torsion as a
common complication in 50% of cases. Grossly, the ovaries
have an edematous appearance and fluid may exude from cut
surfaces. Microscopically, the ovaries are diffusely hypocel-
lular with entrapped follicles within the edematous stroma (a
feature that is not seen in fibroma and thecoma) [29].
Stromal hyperplasia and hyperthecosis: These non-
neoplastic conditions are almost always bilateral. Excess
androgen is usually produced by hyperthecosis while estrogen
or androgen is typically produced by stromal hyperplasia with
clinical manifestation reflecting the deranged hormone pro- Fig. 9.23 Ovarian stromal hyperthecosis. The non-neoplastic lesion is
duction. Despite the fact that these lesions are diffuse, they composed of nodular proliferation of stromal cells with intervening
sometimes form masses up to 8 cm in size. Stromal hyperpla- small nests of luteinized stromal cells
sia is characterized by a diffuse or nodular proliferation of
stromal cells with scant cytoplasm with intervening single
cells and small nests of luteinized stromal cells (Fig. 9.22). If
forming nodules, the term stromal hyperthecosis is used which
is usually associated with stromal hyperplasia [28] (Fig. 9.23). Key Diagnostic Points
The same differential apply for LTSP, however, the asso- Thecoma
ciated peritoneal lesions are characteristics of LTPS and a Gross
must by the 2014 WHO to render the diagnosis. Additionally, Thecoma
the brisk mitotic figures is a feature of LTSP [3]. • Unilateral (95%), small (average of 5 cm), firm,
smooth, homogeneous yellow and lobulated.
9.5.3.8 Prognosis
Thecomas are benign tumors and rare malignant cases have Lutenized thecoma associated with sclerosing
been described which may be a misdiagnosed fibrosarcomas peritonitis
or GCT variant. Therefore, surgical excision is curative in • Bilateral, polypoid, lobulated/cerebriform, tan,
most cases [46]. Despite the high mitotic count, LTSPs are gray, or pink, associated peritoneal fibrosis.
benign tumors with no reported recurrences; however,
patients may die of intestinal obstruction [41]. Microscopic
Thecoma
• Increased cellularity.
• Fusiform cells alternating with hyaline plaques.
• Diffuse or rarely nodular pattern.
• Cells with ill-defined membranes and pale
cytoplasm.
• Vesicular nuclei with delicate membranes.
• No nuclear atypia and infrequent mitosis.
• Calcifications and keloid-like sclerosis are common.
Lutenized thecoma associated with sclerosing
peritonitis
• Spindle cells with interspersed ovoid lutein cells
with abundant cytoplasm.
• Hypercellular with frequent edema.
• High mitotic count.
• Ovarian cortex with spared medulla.
Fig. 9.22 Ovarian stromal hyperplasia. The ovarian stroma is hyper-
cellular with diffuse proliferation of stromal cells
second and third decades (average of 24 years). The tumors

Markers are usually hormonally inactive. In the rare event of active
Thecoma tumors, androgen production, most frequently during
• Positive: Inhibin (100%), calretinin (100%), CD56 pregnancy, is the main hormone secreted. The patient may
(100%), WT1 (100%), SF-1 (100%), FOXL2 present with menstrual irregularity, pelvic pain, abdominal
(100%) (both spindle and luteinized cells) and distension and/or abdominopelvic mass [48, 49].
CD10 (70%).
• Negative: CD99, EMA, beta-catenin, MART-1, and 9.5.4.3 Gross Findings
CD34. SSTs are encapsulated masses ranging in size from 5 to
• Reticulin stain surrounds individual cells. 24 cm (average of 10.5 cm) with lobulated outer surface and,
solid, smooth cut surfaces with frequent cysts and infrequent
Lutenized thecoma associated with sclerosing calcifications (Fig. 9.24) [49].
peritonitis
• Positive: Inhibin, calretinin and CD56 (positive in 9.5.4.4 Microscopic Findings
luteinized cells and negative in spindle cells). SSTs show a pseudolobular pattern with hypercellular
• Peritoneal lesions are positive for AE1/AE3 and areas separated by edematous collagenous hypocellular
rarely positive for ER and PR. areas and poorly defined vascular network of capillaries
exhibiting hemangiopericytoma-like pattern. The cells are
spindle, round to oval with moderate amount of eosino-
philic cytoplasm and vesicular nuclei with no nuclear
9.5.4 Sclerosing Stromal Tumors atypia and infrequent mitosis (Figs. 9.25 and 9.26).
Sometimes, the nuclei are eccentrically located giving
9.5.4.1 Definition signet ring like appearance [48].
SSTs are rare benign tumors arising from the ovarian stroma
first described by Chalvardjian and Scully in 1973 [47]. The 9.5.4.5 Biomarkers
pluripotent immature ovarian stromal cells were claimed to Vimentin, SMA, glutathione S-transferase (GST) and calretinin
be the source of these neoplasms or from a population of are positive in almost all cases of SSTs, α-inhibin is positive in
muscle-specific actin-positive cells of theca externa origin 90% (Fig. 9.27), CD10 is positive in 90% and muscle specific
(perifollicular myoid stromal cells) [48]. antigen (MSA) is positive in 50% of cases while S100, desmin,
and CD34 are negative in almost all cases [18, 50].
SSTs are rare accounting for 2–6% of ovarian stromal 9.5.4.6 Genetic Association
tumors. Most tumors (>80%) occur in young adults in the Trisomy 12 has been reported in a subset of cases [49].
a b
Fig. 9.24 ovarian sclerosing stromal tumor: Gross photograph of a sizable, circumscribed mass with lobulated outer surface (a) and solid and
smooth cut surfaces with gross calcifications (b)
288 M. M. Desouki
a b
Fig. 9.25 Ovarian sclerosing stromal tumor: The tumor is composed of alternating hypercellular areas separated by edematous and collagenous
hypocellular areas
a b
Fig. 9.26 Ovarian sclerosing stromal tumor: The tumor is composed amount of eosinophilic cytoplasm and vesicular nuclei with no nuclear
of alternating nodules of hypercellular areas separated by collagenous atypia and infrequent mitosis (b)
hypocellular areas (a). The cells are round to oval with moderate
a b
Fig. 9.27 Immunohistochemical markers in sclerosing stromal tumor: The same case depicted in Fig. 9.26. The lesional cells are positive for
inhibin (a), calretinin (b) and smooth muscle actin (c)
c IHC
• Positive: Vimentin (100%), SMA (100%), glutathi-
one S-transferase (100%) calretinin (100%), inhibin
(90%) and CD10 (90%).
• Negative: S100, Desmin, and CD34.
9.5.5 Signet Ring Stromal Tumors
9.5.5.1 Definition
SRSTs are benign ovarian stromal neoplasms with prolifera-
tion of signet ring cells and variable amount of spindle-
shaped stromal cells [51, 52].
Fig. 9.27 (continued) 9.5.5.2 Clinical Presentations

Very rare tumors occurring mainly in the fourth decade
(mean of 37, range of 34–41 years). The patients usually
present with pelvic mass, abdominal pain and rarely weight
9.5.4.7 Differential Diagnosis loss [51–53].
Thecoma: SSTs are morphologically similar to, and as sug-
gested by Tiltman and Haffajee [50] are probably closely 9.5.5.3 Gross Findings
related tumors with antigenic determinants like SMA and Grossly the tumors range in size from 3.5 to 13.0 cm (mean
vimentin (see thecoma section above and the differential of 9.8 cm). The outer surface is smooth and the cut surface is
diagnosis of MST below). solid, gray, tan, or yellow with or without cyst formation.
Fibroma: GST IHC stain is positive in the cytoplasm of Rarely the tumors are nodular with focal hemorrhage and
all SSTs and negative in the cytoplasm of fibromas (both gross necrosis [51].
lesions have nuclear staining for GST) (see fibroma section
above). 9.5.5.4 Microscopic Findings
SRSTs exhibit diffuse growth pattern of bland spindle
9.5.4.8 Prognosis cells which merge with vacuolated cells with indented
These tumors are benign and surgical enucleation or oopho- eccentric nuclei pushed against one pole of the cell simu-
rectomy are curative. lating signet rings. The signet ring cells are present either
diffusely or in a portion of the neoplasm and contain a
single large vacuole per cell. The nuclei of the signet-ring
cells are bland with no to mild atypia at most. Mitotic fig-
ures are usually sparse and occasionally the signet ring
Key Diagnostic Points
cells have high mitotic figures (up to 16/10HPF) (Fig. 9.28).
Sclerosing Stromal Tumor No epithelial proliferation such as glands or cords, no des-
Gross moplasia or tumor necrosis. Intra- and extracellular hya-
• Encapsulated, medium sized (average of 10.5 cm), line globules are occasionally present [51]. Ultrastructurally
smooth, lobulated and solid. the vacuoles in SRSTs are cytoplasmic edema, mitochon-
• Frequent cysts. drial swelling, or pseudoinclusions of an edematous extra-
cellular matrix [53].
Microscopic
• Pseudolobular pattern with hypercellular and edem- 9.5.5.5 Biomarkers
atous hypocellular areas. The signet ring component of these tumors are positive for
• Hemangiopericytoma-like vascular network. vimentin and CD10 while negative for α-inhibin, WT1 cal-
• Spindle, round to oval cells with vesicular nuclei retinin, EMA, carcinoembryonic antigen (CEA), desmin,
and eosinophilic cytoplasm. and S-100 IHC markers, AE1/AE3, CK7, and CK20
• No cytologic atypia and infrequent mitosis. (Fig. 9.29). The tumor cells are negative for PAS, mucicar-
mine, alcian blue histochemical stains (Fig. 9.30) [51, 53].
290 M. M. Desouki
a b
Fig. 9.28 Ovarian signet ring stromal tumor: SRSTs usually exhibit cells with indented eccentric nuclei pushed against one pole of the cell
diffuse growth pattern. However, in this case, the tumor exhibits nodu- simulating signet rings (b). The nuclei are bland with no atypia or
lar growth pattern (a). The cells are bland which merge with vacuolated mitotic figures
a b
c d
Fig. 9.29 Immunohistochemical markers in signet ring stromal tumor: The same case (Fig. 9.28). The signet ring cells are positive for vimentin
(a) and CD 10 (b) while negative for inhibin (c) and WT1 (d)
Fig. 9.30 Mucicarmine stain in signet ring stromal tumor: The same Fig. 9.31 Signet ring carcinoma (Krukenberg tumor) metastatic to the
case (Fig. 9.28). The signet ring cells are negative for the mucicarmine ovary: sheets as well as individual cells dissecting through the hypercel-
histochemical stain lular stroma. The nuclei have mild atypia with no increase in mitotic
activity

Signet ring carcinoma (Krukenberg tumor): Differentiating
an SRST from metastatic Krukenberg tumor of primary GI
or of primary ovarian origin is the most clinically significant
differential. Krukenberg tumors are usually bilateral with
frequent gross hemorrhage and necrosis. On microscopic
examination, the tumor cells in Krukenberg tumors show dif-
fuse growth pattern either in sheets or individual cells dis-
secting through the hypercellular to edematous stroma
(Fig. 9.31). In contrast to SRSTs, epithelial proliferation
such as glands, nests, or cords may be identified in
Krukenberg tumors. Lymphovascular space and perineural
invasion could be identified in Krukenberg tumors. Relying
on nuclear atypia or mitotic count is not helpful in this dif-
ferential. The nuclei in Krukenberg tumors usually have no
atypia and occasionally have mild or moderate atypia. Fig. 9.32 Mucinous (goblet) cell carcinoid metastatic to the ovary:
Mitotic figures are usually absent or sparse in Krukenberg The malignant cells form variable sized acini and single cells dissecting
tumors [51, 54]. Histochemical and immunohistochemical through the stroma
stains are helpful in this differential with positive PAS-D in
Krukenberg tumors while negative staining in SRSTs. markers e.g. CK20 (Fig. 9.33) are positive in mucinous car-
Additionally, Krukenberg tumors are usually positive for cinoid and negative in SRSTs.
epithelial markers such as pankeratin, CK7 and CK20 while Sclerosing stromal tumor: An SST may contain luteinized
negative for vimentin, α-inhibin, and calretinin. A recom- cells that may have a signet-ring appearance. SST can be rec-
mended staining panel for this differential includes PAS-D, ognized by its pseudolobular and nodular architecture, hypo-
vimentin, and pan-cytokeratin [51]. cellular fibrous areas, staghorn vessels, and the admixture of
Mucinous (goblet) cell carcinoid: Mucinous carcinoid spindle cells with the luteinized cells in the cellular areas
tumors may contain signet-ring cells, which are PAS-D posi- (see SST section above).
tive. Mucinous carcinoids are often bilateral and associated
with extraovarian disease. Microscopically, mucinous carci- 9.5.5.7 Prognosis
noids have epithelial proliferation as acini, and glands and These tumors are benign and surgical enucleation or oopho-
express neuroendocrine markers [55] (Fig. 9.32). Epithelial rectomy are curative with no reported recurrence [51].
292 M. M. Desouki

This group of tumors are rare constituting less than 1.0% of
all SCSTs. Traditionally, the group includes hilus cell tumor,
stromal luteoma, Leydig cell tumor and pregnancy luteoma
beside others [56]. The 2014 WHO classification included
steroid cell tumor, malignant steroid cell tumor, and Leydig
cell tumor as three separate entities under pure stromal
tumors category [3]. The pregnancy luteoma is considered
by some as an exaggerated hyperplasia of theca-lutein during
pregnancy rather than a neoplasm and has been dropped
from the 2014 WHO classification [3, 57].
The age range of patients with steroid cell tumors is very
wide (2.5–80 years) with a mean age of 43 years. While 50%
of steroid cell tumors present with androgenic symptoms e.g.
hirsutism and virilization, stromal luteoma presents with
Fig. 9.33 Cytokeratin-20 in mucinous (goblet) cell carcinoid meta- estrogenic symptoms mainly vaginal bleeding. The patients
static to the ovary: in contrast to signet ring stromal tumor, the malig- may be asymptomatic and the tumor is discovered during rou-
nant cells of mucinous carcinoid are positive for CK20 stain tine exam or incidentally on adnexal examination for surgical
specimen performed for other reason or rarely present with
abdominal distension, abdominal pain or amenorrhea [58].
In addition to multiple deranged urine and serum hor-
mone levels, elevated 24-h urinary 17-ketosteroids in 70% of
Key Diagnostic Points patients with androgenic manifestations has been reported
Signet Ring Stromal Tumor [58]. The plasma testosterone and androstenedione levels
Gross were elevated in all patients with androgenic symptoms.
Plasma cortisol level was found to be elevated in all patients
• Unilateral, medium sized (average of 9.8 cm),
with Cushing syndrome like manifestations [58].
smooth, solid, gray, tan, or yellow with or without
cyst formation.
• May exhibit gelatinous appearance.
These tumors are yellow to dark brown, unilateral (94%),
Microscopic well circumscribed or “encapsulated” with a mean diameter
of 8 cm (range of 1.2–45 cm) The tumors may be lobulated
• Bland spindle cells which merge with vacuolated
or multinodular with hemorrhage, cyst formation and necro-
cells in a diffuse growth pattern.
sis as common gross findings (Figs. 9.34 and 9.35). Small
• Signet ring cells present either diffusely or in a por-
tumors (<1 cm) confined to the ovarian parenchyma is for-
tion of the neoplasm.
merly designated as stromal luteoma.
• Signet cells contain a single large vacuole per cell.
• Bland nuclei with no atypia and sparse mitotic figures.
• No epithelial proliferation.
• No desmoplasia or tumor necrosis.
Markers
• Positive: Vimentin (100%) and CD10.
• Negative: Calretinin, inhibin, EMA, CEA, desmin,
AE1/AE3, CK7, CK20, S-100, PAS, mucicarmine,
and alcian blue.
9.5.6 Steroid Cell Tumors
9.5.6.1 Definition
A tumor that composed entirely of steroid secreting cells
(lutein, adrenal cortical and Leydig cells) with absent crys- Fig. 9.34 Ovarian steroid cell tumor: Gross photograph showing well-
tals of Reinke [56]. circumscribed yellow mass
Fig. 9.36 Ovarian steroid cell tumor: The tumor composed of a uni-
form cell population with finely granular eosinophilic cytoplasm and
centrally located nuclei with prominent nucleoli. The cells are sepa-
Fig. 9.35 Ovarian steroid cell tumor: Gross photograph showing lobu- rated by thin fibrous septa rich in vasculature
lated, solid gray-yellow cut surfaces

The cells form diffuse aggregates in linear or circular pat-
tern separated by thin fibrous septae rich in vasculature.
Thick fibrous septa, calcifications and psammoma body for-
mation are rare findings. The most common type of cells are
polygonal which varied in size from medium to large and
contains abundant eosinophilic granular or vacuolated cyto-
plasm. No crystals of Reinke should be present by defini-
tion. The cells have distinct cell borders and the nuclei are
centrally placed, monotonous with prominent nucleoli and
minimal atypia (Figs. 9.36, 9.37 and 9.38) [58]. Cell degen-
eration creating pseudo-acini, fat droplets pushing the nuclei
to one side (signet ring appearance) are rare findings.
Lipochrome granules are common cytoplasmic inclusions.
Ovarian hyperthecosis is a common association with steroid Fig. 9.37 Ovarian steroid cell tumor: The tumor is composed of a uni-
cell tumors (Fig. 9.23). Malignant features include large form cell population with vacuolated cytoplasm separated by thin
size (>7 cm), high mitotic index (>2 per 10 HPFs), necrosis, fibrous septa
hemorrhage, significant nuclear atypia and usually present
at an advanced age [58]. cell tumor and makes Leydig cell tumor a straightforward
diagnosis [59].
9.5.6.5 Biomarkers Stromal luteoma: A special subtype of the steroid cell
The tumors are positive for α-inhibin, calretinin, SF-1, tumor category and is characterized by small size (<1 cm). It
melan-A in almost all cases. The tumors are also positive for is located within the ovarian stroma and it is commonly asso-
CD99 (32%), vimentin (75%, diffuse), CAM5.2 (46%), ciated with ovarian stromal hyperthecosis.
AE1/AE3 (37%, focal, paranuclear, and globoid), CD10 Pregnancy luteoma: Considered to be a non-neoplastic
(70%) and SMA (29%, diffuse). The tumors are rarely posi- proliferation probably related to the secretion of chorionic
tive for CD68, desmin, EMA, neuron-specific enolase and gonadotropin during pregnancy [57]. Pregnancy luteoma is
S-100 while negative for FOXL2, WT1, chromogranin A, usually multiple (50%), bilateral (33%) and contains brisk
CD15 (Leu-M1), myoglobin, neurofilament, alpha-mitotic figures with absent nuclear atypia. Therefore,
fetoprotein, CEA, and HMB-45 (Fig. 9.39) [13, 18, 19, 56]. diagnosing steroid cell tumor in pregnancy may be
challenging.
9.5.6.6 Differential Diagnosis Luteinized thecoma: Characterized by the presence of
Leydig cell tumor: Demonstrating crystals of Reinke in the predominant spindle cell background (see thecoma section
cytoplasm of the neoplastic cells essentially excludes steroid above).
294 M. M. Desouki
a b
Fig. 9.38 Ovarian steroid cell tumor: The tumor cells form nodules (a) separated by thin fibrous septa rich in vasculature (b)
a b
Fig. 9.39 Immunohistochemical markers in ovarian steroid cell tumor: The tumor cells are positive for inhibin (a), calretinin (b) and negative for
epithelial membrane antigen (c)
stage I and have favorable with benign behavior [59]. On

the other hand, the behavior of steroid cell tumors, NOS
have a guarded prognosis especially in older patients
(above 51 years) with a reported rate of 34% malignant
behavior [58].

Steroid Cell Tumor
Gross
• Unilateral (94%), medium-sized (average of 8 cm),
well circumscribed.
• Lobulated or multinodular with hemorrhage, cyst
formation and gross necrosis.
Fig. 9.40 Ovarian clear cell carcinoma: The tumor is composed of
highly atypical clear cells with eccentric nuclei in contrast to the cen- Microscopic
trally located nuclei of steroid cell tumors
• Diffuse aggregates of cells separated by thin fibrous
septa rich in vasculature.
• Variable sized polygonal cells with eosinophilic
granular cytoplasm.
• Distinct cell borders, centrally placed monotonous
nuclei, prominent nucleoli with minimal atypia.
• No crystals of Reinke.
• Malignant features: Large size (>7 cm), high mitotic
index (>2 per 10 HPFs), necrosis, hemorrhage, sig-
nificant nuclear atypia and advanced stage.
Markers
• Positive: Inhibin (100%), calretinin (100%), SF-1
(100%), MART-1 (96%), CD99 (32%), vimentin
(75%), CAM5.2 (46%, focal), AE1/AE3 (37%,
focal), CD10 (70%) and SMA (29%, diffuse).
• Negative: FOXL2, WT1, chromogranin-A and
Fig. 9.41 Metastatic renal cell carcinoma to the ovary: This tumor is
HMB-45.
composed of atypical eosinophilic cells with eccentric nuclei in con-
trast to the centrally located nuclei of steroid cell tumors
9.5.7 Leydig Cell Tumors

Clear cell carcinoma: An exclusively solid clear cell car-
cinoma is distinctly uncommon. In eosinophilic variant of 9.5.7.1 Definition
clear cell carcinoma, conventional clear cell carcinoma mor- Leydig cell tumor is composed of Leydig cells as proven by
phology most probably will be identified in most cases. The the presence of cytoplasmic/nuclear crystals of Reinke under
neoplastic cells in clear cell carcinoma are atypical and sepa- microscopic examination [60].
rated by fibrous stroma [58] (Fig. 9.40).
Metastatic renal cell carcinoma is characterized by clear 9.5.7.2 Clinical Presentations
cells filled with glycogen with no clinical manifestation of Leydig cell tumors occur predominantly in the sixth and sev-
endocrine effects [58] (Fig. 9.41). enth decades (average of 58 years, range of 32–75 years)
with symptoms related to hormone production mainly testos-
9.5.6.7 Prognosis terone in most cases in the form of hirsutism, clitoromegally,
Surgical excision with or without chemotherapy and baldness and deepening of the voice. Abdominal distension
radiotherapy are the main therapeutic approaches to these due to ascites, symptoms of intestinal obstruction and amen-
tumors. Most patients with steroid cell tumors present at orrhea are other rare presentations [59, 60].
296 M. M. Desouki
9.5.7.3 Gross Findings 9.5.7.6 Differential Diagnosis

The tumors are typically unilateral and relatively small in Steroid cell tumor: Crystals of Reinke is the differentiating
size (range of 1.3–5 cm, average 2.4 cm) with solid cut sur- finding. The term “steroid cell tumor, probably Leydig cell
faces (rare hemorrhage). The tumors are yellow, red-brown tumor” may be used if the tumor is located in the hilus with
or black and mainly located in the ovarian hilus or rarely in no identifiable crystals of Reinke [60]. The same differential
the parenchyma (non-hilar tumors) [60]. diagnosis for steroid cell tumors described above apply for
Leydig cell tumors.
9.5.7.4 Microscopic Findings Leydig cell Hyperplasia: These are multiple (rarely sin-
Leydig cell tumors are well-circumscribed, unencapsulated gle) nodules or clusters of Leydig cells most probably in
tumors that exhibit lobular aggregates of eosinophilic to vacu- the ovarian hilus and rarely in extraovarian site e.g. fallo-
olated cell nests separated by delicate septa with vasculariza- pian tubes. The nodules are small in size with no gross
tion. The cells contain abundant, granular cytoplasm, which mass and no organ distortion [62]. Leydig cell hyperplasia
may contain cytoplasmic lipochrome pigments and hyaline is immune-phenotypically like that of leydig cell tumor
eosinophilic spheres. The crystals of Reinke are rod or spheri- (Fig. 9.43).
cal cytoplasmic or rarely nuclear eosinophilic structures,
which should be identified to qualify the tumor as Leydig cell. 9.5.7.7 Prognosis
The nuclei are centrally located, rounded or angulated and These tumors are mostly benign and excision is curative.
contain single small nucleoli. The nuclei are hyperchromatic
with occasional multinucleation (Fig. 9.42). Invagination of
the cytoplasm inside the nuclei creating empty spaces may be
seen. Clustering of nuclei in a perivascular arrangement lead Key Diagnostic Points
to pools of amorphous eosinophilic material is characteristic. Leydig Cell Tumor
Nuclear atypia in the form of enlarged, bizarre nuclei is not Gross
uncommon and does not correlate with the biologic behavior. • Unilateral, small (average of 2.4 cm), solid and well
Mitoses is rare to absent. Fibrinoid necrosis of the wall of circumscribed.
blood vessels may be seen [59]. • Located in the hilus of the ovary.
9.5.7.5 Biomarkers Microscopic

Same as steroid cell tumor (see above) with the following • As that of steroid cell tumor with crystals of Reinke.
differences: FOXL2 by IHC is negative in all six cases tested • Crystals of Reinke are rod or spherical cytoplasmic
compared to positive staining in 1 of 1 case of steroid cell or nuclear eosinophilic structures.
tumor NOS [20]. AE1/AE3 pancytokeratin was negative in
Markers
the 2 cases of Leydig cell tumor compared to positive stain-
ing in 3 of 5 (60%) cases of steroid cell tumor NOS in the • Mostly as that of steroid cell tumor.
same study [61].
9.5.8 Microcystic Stromal Tumors
9.5.8.1 Definition
Microcystic stromal tumor (MST) of the ovary is a benign
tumor of probable stromal origin with distinctive conspicu-
ous microcystic change first described by Irving and Young
on 2009 [63]. Subsequent work has shown that they consis-
tently display alterations in in beta-catenin-APC pathway
and accordingly may represent a manifestation of Familial
Adenomatous Polyposis syndrome [64, 65].

Very rare tumors occurring in women with mean age of
45 years (range of 26 to 63 years). The patients usually
Fig. 9.42 Ovarian Leydig cell tumor. Aggregates of eosinophilic cells present with a pelvic mass and rarely with hormonal mani-
with centrally located nuclei and abundant cytoplasm festations [63].
a b
c d
Fig. 9.43 Leydig cell hyperplasia of the fallopian tube. The lesion is composed of small nodules with no organ distortion. The morphology is
identical to that of steroid/leydig cell tumors (a, b). The lesion is positive for inhibin (c) and calretinin (d)
9.5.8.3 Gross Findings bland, round, oval or spindle-shaped with fine chromatin and
The tumors are usually unilateral with a mean size of 8.7 cm indistinct nucleoli. Bizarre nuclei with smudgy chromatin
(range of 2–27 cm) and localized to the ovary. The tumors may be focally present. Mitotic rate is low (range of 0–2
are usually solid with cystic degenerations however; pure mitoses/10 HPFs) [63]. The diagnosis of MST is mainly by
solid or cystic tumors are rarely exist. The solid component exclusion of other known entities with the following features
are firm and tan or yellow in color. Small foci of hemorrhage (1) a predominant microcystic pattern with lobulated cellular
and/or necrosis may be present [63]. masses which are intervened with hyalinized fibrous stroma,
(2) absence of epithelial component, (3) absence of tera-
9.5.8.4 Microscopic Findings tomatous or other germ cell elements and (4) characteristic
The tumors consist of three main components; microcysts, IHC staining pattern (see below).
solid cellular regions, and fibrous stroma with variable
amount of each component. The microcysts predominate in 9.5.8.5 Biomarkers
most cases and are characterized by small round to oval The tumors are positive in all cases for beta-catenin (nuclear),
empty spaces sometimes coalesce to form large irregular cyclin D1, CD10, WT1, FOXL2, and vimentin and positive
spaces. Intracytoplasmic vacuoles are common findings. The in 60% of cases for SF-1, focally positive for cytokeratin in
solid areas are usually intersected by fibrous bands and hya- 25% of cases while negative for α-inhibin (very rarely posi-
line plaques simulating thecomas. The cytoplasm of the cells tive), calretinin (very rarely positive) and EMA by IHC
is finely granular, lightly eosinophilic and the nuclei are [63–65].
298 M. M. Desouki
9.5.8.6 Molecular Findings with clear vacuolated cells and eccentric nuclei, interspersed
Somatic missense point mutations of the CTNNB1 gene have with fibroblasts and lutein cells. α-Inhibin and calretinin are
been reported in 57% of ovarian MSTs. The mutations are typically positive [47].
heterozygous in exon 3, which will result in amino acid sub- Signet ring stromal tumor: Another tumor, which shares
stitutions at codons 32, 34, 35, and 37. The aberrant nuclear similarity with MST (see above). SRST is typically a unilat-
β-catenin expression by IHC detected in all cases may be the eral solid or solid-cystic tumor occurring in adult women
result of stabilizing CTNNB1 mutations in 57% of cases. without hormonal manifestations. Microscopically, the bland
Additionally, the dysregulation of the Wnt/B-catenin signet-ring cells are admixed with a diffuse fibroblastic
pathway may be involved in the tumorigenesis of MSTs and proliferation [51].
may be involved in activation of the β-catenin leading to Another tumors in the differential of MST include SLCT,
upregulation of cyclin D1 which has been reported positive JGCT, yolk sac tumor, monodermal teratomas (struma
in all cases tested by IHC [64, 65]. ovarii), carcinomas, Brenner tumor and FATWO [63]. These
tumors are discussed under different topics in this chapter.
Thecoma: women with MSTs are 2 decades younger than 9.5.8.8 Prognosis
those with thecomas [40]. Prominent hyaline plaques in a These tumors are thought to be benign based on limited evi-
tumor with microcysts prompted a diagnosis of thecoma. dence. Patients that have treated with simple excisions have
Estrogenic manifestations are common in thecomas. Grossly, shown with no evidence of disease at a mean of 4.3 years
the majority of MSTs are solid-cystic, whereas thecomas are follow up [63].
usually solid and yellow. Microscopically, both tumors con-
sist of bland cells with round to elongate nuclei and infre-
quent mitotic figures. However, thecomas are characterized
by conspicuous population of polygonal to fusiform cells Key Diagnostic Points
(rather than round) with pale cytoplasm. Bizarre nuclei are Microcystic Stromal Tumor
common in MSTs [66]. CD10 staining is faint weak to mod- Gross
erate in thecomas in contrast to the strong and diffuse stain- • Unilateral, medium sized (average of 8.7 cm), solid
ing in MST [18]. α-Inhibin and calretinin are usually negative with cystic formation, firm, tan or yellow.
in MSTs compared to positive pattern in thecomas [14].
Lutenized thecoma associated with sclerosing peritonitis: Microscopic
LTSP may show microcystic pattern. It occurs in young • Three components: Microcysts, solid cellular
women and is bilateral, composed of cellular proliferations regions and fibrous stroma.
of non-luteinized spindle cells, with numerous aggregates of • Microcysts predominate with lobulated solid cellu-
luteinized cells. The cells are diffusely positive for α-inhibin, lar masses, which are intervened with hyalinized
calretinin, and CD56 and the tumor is associated with scle- fibrous stroma.
rosing peritonitis [43]. • Microcysts are small round/oval empty spaces.
Steroid cell tumor with oxyphil cells: In contrast to MST, ste- • Intracytoplasmic vacuoles are common.
roid cell tumors have a frequent manifestation with hormonal • Finely granular, eosinophilic cytoplasm.
manifestations, especially androgenic. Occasionally MST may • Bland, round/oval or spindled nuclei with fine chro-
exhibit yellow cut surfaces on gross examination. matin and indistinct nucleoli.
Microscopically, steroid cell tumors often exhibit a diffuse pat- • Low mitotic rate.
tern with minimal to absent stroma in most cases. However, • No epithelial, teratomatous or germ cell elements.
NOS tumors consist of aggregates of cells interspersed among • Exclusion of other known entities with microcysts
fibrous and edematous stroma. The tumor cells in steroid cell should be performed.
tumors have rounded contour with moderately abundant eosino-
Markers
philic cytoplasm resembling cells of the MST, but in the former,
the nuclei are central with prominent nucleoli. CD10 is usually • Positive: CD10 (100%), vimentin (100%), cyclin
positive in steroid cell tumors, but unlike the MST, α-inhibin D1 (100%), WT1 (100%), FOXL2 (100%) nuclear
and calretinin are positive in most steroid cell tumors [18, 43]. beta-catenin (100%), SF-1 (80%) and cytokeratin
Sclerosing stromal tumor: Like that of MST, an SST is (25%, focal).
characteristically unilateral, solid, white or yellow often with • CTNNB1 gene somatic mutations (57%).
edema and cyst formation. Microcysts are not a striking fea- • Negative: EMA, inhibin (weak positive in 6% of
ture of SST while staghorn, thin-walled vessels are promi- cases), calretinin (weak positive in 6% of cases).
nent. The neoplastic cells of the SST are rounded to polygonal
9.5.9 Stromal Tumors with a Minor cigar shaped with inconspicuous nucleoli and no/rare
Sex-Cord Element mitotic figures [42].
9.5.9.1 Definition 9.5.9.5 Biomarkers

These are sex cord stromal tumors mainly fibromatous or Reticulin stain highlights individual cells in the spindle cell
thecomatous cell tumors with minor component of sex cord component and groups of cells in the minor sex cord element
elements of granulosa or Sertoli cell types [42]. component (Fig. 9.21). Fat stains may be positive in either
component [42]. The minor sex cord elements are positive
9.5.9.2 Clinical Presentations for α-inhibin, calretinin, CD99 and CD56 [67].
The average age of the patients is 48 years (range
16–65 years). The most presenting complaint is adnexal 9.5.9.6 Differential Diagnosis
mass. Abnormal uterine bleeding, abdominal pain or discov- Granulosa cell tumor and Sertoli-Leydig cell tumor: The
ered incidentally in the work up for another disease are other minor component of the sex cord element in stromal tumor
presentations. The tumors may be hormonally active with with a minor sex-cord element is the key. Additionally, the
estrogen or androgen production with associated endome- stroma of stromal tumor with a minor sex-cord element is
trial hyperplasia or carcinoma in few cases [42]. predominantly fibrous with abundant collagen production in
comparison to the thecomatous type stroma in GCT while
9.5.9.3 Gross Findings the stroma of SLCT contains immature mesenchymal cells
The tumors look alike fibromas or thecomas with smooth and Leydig cells in most cases.
outer surface. Cut surfaces are solid, firm, white, yellow or Brenner tumor: The minor sex cord element may resem-
pink with no hemorrhage or necrosis [42]. ble Brenner tumor on low power examination. In Brenner
tumor, the epithelial cells contain transitional or mucinous
9.5.9.4 Microscopic Findings cells or combination and sometimes with central lumens
By definition, the sex cord element should be minor (up to contain eosinophilic or mucinous material.
10%) with granulosa cell exhibiting nuclear grooves, solid Adenofibroma: The glands in adenofibromas are usually
structures resembling immature testicular tubules or indif- abundant, large and of variable size and shape compared to
ferent elements constituting the main sex cord element in the monotonous Sertoli tubules in stromal tumor with a minor
most cases. The cells of the sex cord elements have rounded sex-cord element. endometriosis and mucinous changes are
nuclei with prominent nucleoli and occasional crystals of common association with endometrioid adenofibromas [42].
Reinke. The sex cord elements may be scattered in small Metastatic carcinoid: metastatic carcinoid may form
groups throughout the tumor or localized in one or few foci. widely scattered small aggregates of epithelial cells in a
In most cases, the sex cord elements are sharply demar- fibromatous background resembling stromal tumor with a
cated from the stromal component or rarely merged imper- minor sex-cord element. However, under high power exami-
ceptibly. The stromal component is that of fibroma/thecoma nation, carcinoid nuclei are uniform, rounded with coarse
morphology with intersecting fascicles traversed by colla- chromatin. IHC is useful with positive synaptophysin, chro-
gen and hyalinized material. The nuclei are elongated and mogranin and CD56 in carcinoids (Fig. 9.44). In contrast to
a b
Fig. 9.44 Metastatic carcinoid tumor to the ovary: The tumor is composed of scattered small aggregates of cells in a fibromatous background
resembling sex-cord elements (a). The tumor is positive for chromogranin by immunohistochemistry (b)
300 M. M. Desouki
stromal tumor with a minor sex-cord element, carcinoids are SCSTs after fibromas. The tumor predominates in perimeno-
usually bilateral and present elsewhere (e.g. small intestine) pausal or early postmenopausal women with a median age of
[5] (see the differential diagnosis section under SCT below). 50–55 years [1, 4, 69]. The tumor may produce estrogen or
Stromal hyperplasia and hyperthecosis: see the differen- androgen with clinical effects including abnormal uterine
tial diagnosis section under thecoma above. bleeding due to hyperplasia. Associated endometrial carci-
noma have been reported to be ~ 5% of cases with AGCTs.
9.5.9.7 Prognosis The most common presenting symptom is postmenopausal
Surgical excision is curative. bleeding due to endometrial hyperplasia or adenocarcinoma
secondary to estrogen production by the AGCT [69]. Initial
presentation in perimenopausal women include menstrual
irregularity, menorrhagia, amenorrhea, infertility, virilizing
Key Diagnostic Points features or hirsutism, abdominal/pelvic pain which could be
Stromal Tumor with a Minor Sex-Cord Element severe (acute abdomen) due to tumor rupture or torsion and
Gross abdominal distention [68, 69].
• Similar to fibroma and thecoma with smooth outer 9.6.1.3 Gross Findings
surface. AGCTs are unilateral in 90% of cases. The tumor size
• Solid, firm, white, yellow or pink. ranges from microscopic incidental finding to a large tumor
• No hemorrhage or necrosis. filling the whole pelvis (average of 12.7 cm) [69]. The
Microscopic tumors are solid with variable cystic spaces and hemorrhage
(Figs. 9.45 and 9.46). Tumors with prominent theca ele-
• The stromal component is that of fibroma/thecoma ments are often yellow and firm. Rupture at the time of sur-
morphology (see above). gery is not uncommon [4].
• The sex cord element should not exceed 10% (gran-
ulosa cells or setoliform tubules or indifferent 9.6.1.4 Microscopic Findings
elements). AGCTs are composed of organoid or diffuse architecture
• The sex cord elements have rounded nuclei with with epithelioid and spindle cell components. Multiple pat-
prominent nucleoli and occasional crystals of terns are usually seen in a single tumor. The patterns include;
Reinke. diffuse, trabecular, insular, gland-like, corded, microfollicu-
• Sex cord elements may be scattered or localized in lar, macrofollicular, “watered silk”, pseudopapillary
few foci. (Fig. 9.47), nodular, sarcomatoid and systic [1].
Markers In the diffuse pattern, which is one of the most common
patterns, the cells arrange in sheets with scant cytoplasm
• Reticulin highlights individual cells in the spindle ‘small blue cell tumor’ (Figs. 9.48 and 9.49). Careful
cell component and groups of cells in the sex cord
component.
• The sex cord elements are positive for inhibin, cal-
retinin, CD99 and CD56.
9.6 Pure Sex Cord Tumors
9.6.1 Adult Granulosa Cell Tumors
9.6.1.1 Definition
AGCTs are ovarian tumors, which are derived from granu-
losa cells of the ovarian stroma that under physiologic condi-
tions produce estrogen [68].

AGCTs are rare tumors constituting 2% to 5% of all ovarian Fig. 9.45 Ovarian adult granulosa cell tumor: Gross photo of an adult
tumors. Despite its rarity, GCTs are the second most c ommon granulosa cell tumor showing solid and lobulated large mass
examination most probably will reveal foci of epithelial

proliferation especially at the periphery. In the insular pat-
tern, the nests usually are surrounded by a conspicuous
stroma with thick trabeculae or thin cords. In nodular pat-
tern, the cells grow in nodules in which each nodule has
smooth contour and diffuse arrangement of neoplastic cells
within the nodules. The rare microfollicular pattern with
Call–Exner bodies is the most described pattern in the text-
books. In this pattern, Call-Exner bodies are characteristic
structures in which granulosa cells arrange around spaces
filled with eosinophilic or rarely basophilic material,
degenerating nuclei, or hyalinized basement membrane
material (Figs. 9.50 and 9.51). The macrofollicular pattern
is much less common. In sarcomatoid pattern, the cells are
fusiform to spindled simulating ovarian fibroma. When
Fig. 9.46 Ovarian adult granulosa cell tumor: The cut surface of this excised in late pregnancy, AGCT exhibits massive edema or
histologically proven adult granulosa cell tumor is gray, solid with cyst luteinization altering the morphology and making the diag-
formation and gross hemorrhage nosis challenging [70].
Fig. 9.47 Adult granulosa cell tumor of the ovary. The characteristic Fig. 9.48 Adult granulosa cell tumor of the ovary. The tumor is com-
tumor cells form pseudo-papillary growth pattern (image courtesy of posed of diffuse growth pattern of small blue round cells with scant
Dr. Oluwole Fadare) cytoplasm
a b
Fig. 9.49 Adult granulosa cell tumor of the ovary. The tumor is composed of diffuse architecture with nuclear grooves (a). The tumor cells are
positive for inhibin (b)
302 M. M. Desouki
Fig. 9.50 Adult granulosa cell tumor of the ovary. Microfollicular pat- Fig. 9.51 Adult granulosa cell tumor of the ovary. Microfollicular pat-
tern with Call–Exner bodies characterized by arrangement of the granu- tern with vaguely formed Call–Exner bodies
losa cells around spaces filled with eosinophilic material with
degenerating nuclei
a b
Fig. 9.52 Ovarian adult granulosa cell tumor of the ovary. The tumor oval, haphazardly arranged nuclei with evenly dispersed chromatin and
is composed of diffuse architecture with micro and macro follicles (a). nuclear grooves (b)
The cells are monotonous with scant cytoplasm and uniform angular to
The cells in AGCT have scant cytoplasm, pale, uniform, inimal to exuberant. The stroma may be vascular, fibrous or
m
angular to oval, haphazardly arranged nuclei with evenly dis- edematous to hypercellular with o ccasional luteinized and
persed chromatin and nuclear grooves (Figs. 9.49 and 9.52). vacuolated cells. Leydig cells with crystals of Reinke and
Scattered atypical (bizarre) nuclei is rare and is independently hepatoid stroma could also occur in AGCTs [1, 71].
correlated with the biologic behavior of the tumor [66]. The
presence of the most famous feature (nuclear grooves), varies 9.6.1.5 Biomarkers
from tumor to tumor and may be inconspicuous. Mitotic rate AGCTs are positive for α-inhibin (94%), calretinin (81%)
also varies from tumor to tumor but usually low and most (Figs. 9.1, 9.2 and 9.49), WT1 (78%), SF-1 (100%), CD56
tumors exhibit low-grade features. Sometimes the cells are (100%), FOXL2 (98%) (Fig. 9.4), CD10 (90%), PR (100%)
luteinized with ample cytoplasm, which is pale or eosino- and CD99 (88%) by IHC [11–13, 18, 20] (Table 9.4).
philic simulating thecoma [1]. SLCT component may be Reticulin histochemical stain usually surrounds nests of cells
present in AGCT. The volume of the stroma varies from (Figs. 9.21 and 9.53).
FOXL2 is a potential driver in the pathogenesis of AGCTs

and makes testing FOXL2 mutation in the tumor or patient’
serum for circulating tumor cells [78] of valuable diagnostic
application for AGCT especially those with overlapping
morphologic features and/or negative conventional IHC
markers [75, 76]. Contrary to the mutational status, a
FOXL2-positive immunophenotype is not specific for AGCT
with expression in a wide variety of SCSTS endometrial-
type stromal neoplasms, and rare others.
In contrast to the somatic mutation described in AGCTs,
germline mutation in FOXL2 is associated with blepharophi-
mosis, ptosis and epicanthus inversus syndrome with or
without early ovarian failure [79].

Fig. 9.53 Reticulin stain in adult granulosa cell tumor. The stain sur-
Thecoma: AGCT with luteinized cells in the stroma with
rounds nests, rather than individual cells paucity of epithelial proliferation is morphologically similar
to thecoma. A reticulin stain with its characteristic staining
pattern where it surrounds individual cells in thecoma and
9.6.1.6 Chromosomal Aberrations invests nests of cells in AGCT is of great aid in this differen-
Trisomy 12 has been described in few cases of AGCTs [26, tial (See thecoma section above) (Fig. 9.21).
45]. Unlike high-grade serous carcinoma, there is no known Cellular fibroma: Another tumor similar to AGCT espe-
inherited predisposition for AGCT. BRCA1 and BRCA2 cially tumor with sarcomatoid pattern. Reticulin stain is of
germline mutations have not been associated with high risk great aid and FOXL2 molecular testing may solve the buzzle
of developing AGCT [72]. with positive mutation in AGCT and wild type in fibroma
(see fibroma section above).
9.6.1.7 FOXL2 Gene Mutation Sertoli-Leydig cell tumor: Another tumor with features,
Forkhead box L2 (FOXL2) is a 2.7 kb single-exon gene which may overlap with AGCT. Tubular differentiation in
encoding a 376 amino acid transcription factor required for AGCT may simulate tubules of SLCT and sometimes the
granulosa-cell development. It has been postulated from tumor contains both AGCT and SLCT patterns “the so called
in vitro studies that the FOXL2 mutation may affect cell gynandroblastoma”. Our approach is to call such neoplasm a
cycle progression, steroidogenesis, apoptosis and DNA dam- SCST of mixed form and indicate the patterns and percent of
age repair in follicular cells. FOXL2 is a marker of ovarian each component (see SLCT below).
differentiation and plays an important role in the normal Endometrioid carcinoma: Endometrioid carcinoma may
development of granulosa cells [73]. Additionally, FOXL2 have sex cord stromal pattern or grows in a sarcomatoid pat-
has been implicated in the regulation of apoptosis, oxidative tern, which sometimes may be extensive simulating AGCT. In
stress and cell proliferation [74]. contrast to AGCT, carcinoma usually exhibits a higher nuclear
Somatic missense mutation in codon 134 (402C > G) in grade, more mitotically active, lacks nuclear grooves and
FOXL2 has been identified in the majority (97–100%) of lacks IHC sex cord stromal markers and are positive for EMA
AGCTs. The mutation leads to substitution of a cysteine by and other epithelial markers (Figs. 9.54 and 9.55). Bilaterality,
tryptophan (C134W) which appears not to affect the location endometriosis, foci of conventional endometrioid carcinoma
or the function of the protein. This mutation affects only one (Fig. 9.56), luminal mucin, squamous morules and an adeno-
allele (heterozygous state) in most tumors. The exact mecha- fibromatous component point out to carcinoma rather than a
nism of the mutation to AGCT tumorigenesis remains AGCT [80]. PAX-8 stains 90% of endometrioid carcinomas
unknown [73, 75]. while 11% of GCT show focal weak positivity [81]. PR stains
A somatic mutation in the FOXL2 gene appears to be almost all cases of GCTs and 71% of endometrioid carcino-
relatively specific to AGCT with reported mutation in only mas [82]. An immunoprofile with CK7+/inhibin−/calretinin–
15–21% thecomas (some of which has been reclassified as and WT1–points out to carcinoma.
AGCTs) [76], 10–13% JGCTs, 11% SLCTs and none of the Insular carcinoid tumor: It is usually associated with tera-
other types of ovarian SCSTs (fibromas, SCTATs, SSTs, toma component, the nuclear chromatin is granular “salt and
MSTs and steroid cell tumors), germ cell tumors or epithelial pepper” and the cells are positive for neuroendocrine mark-
ovarian tumors [22, 75, 77]. This concludes that mutant ers and negative for sex cord stromal markers.
304 M. M. Desouki
a b
Fig. 9.54 Endometrioid adenocarcinoma with sarcomatoid growth and lacks nuclear grooves (a). The tumor cells are positive for the low
pattern. In contrast to adult granulosa cell tumor with sarcomatoid pat- molecular weight CAM5.2 (b)
tern, this tumor exhibits a higher nuclear grade, more mitotically active
a b
Fig. 9.55 Poorly differentiated ovarian endometrioid adenocarcinoma. In contrast to adult granulosa cell tumor, this tumor exhibits a higher
nuclear grade and lacks nuclear grooves (a, b)
Struma ovarii: The rounded structures may simulate the Metastatic breast carcinoma: Lobular and invasive mam-
microfollicles—Call–Exner bodies of the AGCT. However, mary carcinoma of no special types typically are bilateral
acini of struma usually contain colloid-like material and the and is EMA and GATA3 positive and α-inhibin and WT1
diversity of patterns in struma ovarii e.g. trabecular patterns negative [1] (Fig. 9.58).
is remarkable (Fig. 9.57). Immunostaining for thyroglobulin Metastatic malignant melanoma: History of an extraovarian
will aid to sort out this differential [83]. melanoma, bilateral ovarian involvement, melanin pigment,
Small cell carcinoma of the hypercalcemic type (SCCH): and positivity for melanoma markers will aid to segregate this
The presence of follicles in SCCHT and the small blue round devastating neoplasm from AGCT [1] (Fig. 9.59).
cells with scant cytoplasm characteristic of this high-grade Table 9.5 lists the utilization of commonly used IHC
tumor are similar to those of AGCT. The cells in AGCTs markers in the differential diagnosis of GCTs with few enti-
have regular arrangement and grooved nuclei and always ties mentioned above.
lack highly malignant features and mitotic rate compared to
SCCHTs [84]. α-inhibin stain is positive in AGCT and nega- 9.6.1.9 Prognosis
tive in SCCHT. (See the differential diagnosis section under Most patients (up to 91%) present at an early stage. However,
JGCTs below). recurrence tends to occur often many year after the initial
Fig. 9.56 Ovarian endometrioid adenocarcinoma. Conventional mor- Fig. 9.57 Struma ovarii: The rounded structures may simulate the
phology of endometrioid carcinoma present in poorly differentiated microfollicles of adult granulosa cell tumor. The acini of struma contain
cases of endometrioid carcinoma (this is another field in for the same colloid-like material
cases depicted in Fig. 9.55)
a b
Fig. 9.58 Metastatic breast carcinoma to the ovary: Invasive mammary carcinoma of no special type to the ovary (lower field) and coincidental
high-grade serous carcinoma (upper field) (a). The breast carcinoma is negative for WT-1 while the serous carcinoma is positive for the marker (b)
diagnosis in many cases (Fig. 9.60). The staging system used d ebulking, large tumor size (>15 cm), grossly solid tumors,
for AGCT is the same for ovarian epithelial tumors (FIGO reduced β-catenin expression, high mitotic rate, capsular
staging) [85]. Surgery is the main line of management for invasion with extraovarian spread and lymphovascular space
patients with AGCT. Staging usually includes an omentec- invasion [22, 69].
tomy, lymph node dissection, peritoneal biopsies and obtain- FOXL2 mutated tumors especially those with homozy-
ing peritoneal washings for cytological evaluation. For gous mutations have been reported to have significantly
postmenopausal women, a total hysterectomy and bilateral higher relapse rates and worse disease-free and overall sur-
salpingo-oophorectomy is the operation of choice and a vival than tumors with the wild-type FOXL2 gene [21]. The
more conservative approach is reasonable for younger high frequency of FOXL2 mutation in AGCTs encouraged
women with early stage disease to preserve fertility [46, 68]. scientists to suggest that it could be a therapeutic target in
Clinico-pathologic factors that have been reported to be this tumor. However, studies are still in its early stages and
associated with worse outcome include advanced stage at therapeutics designed to target FOXL2 may adversely affect
presentation, older age (>40 years), patients with abdominal regulatory activities of other important FOX transcription
symptoms, clinically palpable mass, incomplete tumor factors [86].
306 M. M. Desouki
a b
Fig. 9.59 Metastatic malignant melanoma to the ovary: The tumor cells look like an adult granulosa cell tumor (a). History of an extraovarian
melanoma, bilateral ovarian involvement, melanin pigment, and positivity for MART1 (b) will aid to solve this differential
Table 9.5 Utilization of immunohistochemistry in the differential diagnosis of granulosa cell tumors
Inhibin PR EMA Chromogranin EpCAM PAX8 FOXL2
Diagnosis (cytoplasm) (nucleus) (cytoplasm) (cytoplasm) (membrane) (nucleus) (nucleus)
Granulosa cell 94 100 1% 0 0 11 98
tumor
Endometrial 0 71 95% 0 97 90 0
carcinoma
Carcinoid 1 2 21% 90 93 20 0
Small cell 0 0 40 33 0 0 0
carcinoma
The numbers are the reported frequency of positive cases from multiple studies (see text for references)
a b
Fig. 9.60 Recurrent adult granulosa cell tumor in the peritoneal cavity. The patient has a history of primary ovarian AGCT 15 years prior to this
lesion. The tumor is composed of diffuse growth pattern (a). The tumor cells are positive for inhibin (b).

Key Diagnostic Points JGCTs are similar to that described in AGCT (see above)
Adult Granulosa Cell Tumor with size range from 5 to 15 cm and >95% are unilateral. The
Gross tumors may be cystic with intracystic papillary, friable pro-
• Unilateral (90%), large (average of 12.7 cm), solid jections. The pseudo papillae may represent projections of
with variable cystic spaces and hemorrhage. neoplastic cells with necrosis [1].
• Tumors with prominent theca elements are yellow
and firm. 9.6.2.4 Microscopic Findings
• Rupture at the time of surgery is not uncommon. The morphology of JGCT is characterized by a nodular
• Worrisome features: Large size (>15 cm), solid or diffuse proliferation of neoplastic cells in a myxoid
tumors. and edematous background separated by variable sized
follicles. The follicle-like spaces contain proteinaceous
Microscopic material and lined by granulosa cells, occasionally with
• Patterns: Diffuse, trabecular, insular, gland-like, an outer layer of theca cells with rare/no Call-Exner bod-
corded, microfollicular, macrofollicular, “watered ies (Fig. 9.61). Occasionally, hobnail-type cells are pres-
silk”, pseudopapillary, nodular, sarcomatoid and ent lining follicles. In contrast to AGCTs, the cells
systic. contain abundant eosinophilic or vacuolated cytoplasm,
• Mild to moderate cellularity. the nuclei are non-grooved, larger, rounded, hyperchro-
• Organoid or diffuse architecture with epithelioid matic with minimal to severe nuclear atypia [4]. JGCTs
and spindle cell components. are known to display a notably higher mitotic index than
• Scant, pale, uniform cytoplasm. AGCTs. Foci of atypical nuclei with smudgy chromatin
• Oval nuclei, evenly dispersed chromatin, nuclear may be present extensively in a given tumor (Fig. 9.62).
grooves and usually low mitotic rate. Small foci of AGCT, a fibrothecomatous stromal compo-
• Call–Exner bodies (microfollicular pattern): nent and areas of sclerosis will not argue against the
Granulosa cells arranged around spaces filled with diagnosis of JGCT [1].
eosinophilic material.
• The stroma may be vascular, fibrous or edematous. 9.6.2.5 Biomarkers
• Worrisome features: High mitotic rate, capsular and Like AGCTs, JGCT are positive for α-inhibin, calretinin
lymphovascular invasion. and other markers by IHC and reticulin stain surrounds
nests of cells (Fig. 9.62) [11, 12, 18, 20]. All reported cases
Markers are positive for Fli-1 and CD99 by IHC. However, none of
• Positive: inhibin (94%), calretinin (81%), WT1 the tested cases demonstrated rearrangement in EWSR1
(78%), SF-1 (100%), CD56 (100%), FOXL2 (98%), gene [87].
CD10 (90%) and CD99 (88%).
• FOXL2 somatic gene mutation (97%).
• Negative: MATR-1.
9.6.2 Juvenile Granulosa Cell Tumors
9.6.2.1 Definition
JGCTs are ovarian tumors derived from the granulosa cells
of the ovarian stroma which occur predominantly at young
age group [1, 72].

As the name implies with exceptions, JGCT occurs predomi-
nantly at younger age (average of 13 years). JGCTs are rare
(less than 5% of GCTs) and commonly associated with
hyperestrinism resulting in isosexual pseudoprecocity in
pre-pubertal girls. Adnexal mass and acute abdomen when Fig. 9.61 Juvenile granulosa cell tumor of the ovary. Diffuse prolifera-
tumor ruptures are other presentations [1, 4, 72]. tion of tumor cells among follicle-like spaces of different size and shape
308 M. M. Desouki
a b
Fig. 9.62 Juvenile granulosa cell tumor of the ovary. Foci of atypical nuclei with smudgy chromatin are present in this case (a). Diffuse prolifera-
tion of tumor cells among follicle-like spaces of different sizes and shapes. Reticulin stain surrounds nests of cells (b)
9.6.2.6 Molecular Features and Genetic

Susceptibility
Unlike the predominance of FOXL2 somatic mutation in
AGCT, FOXL2 mutation is present in only up to 13% of
JGCT [75, 77]. Two activating mutations of the alpha subunit
of the trimeric G protein (Gαs) have been reported in 30% of
JGCTs. The mutations are located at position 201 (R201C
and R201H) and have been proposed to inhibit the GTPase
activity, therefore, maintaining Gαs in its active form which
will lead to abnormal proliferation and tumor invasion [88].
In-frame duplications of exon 3 of the AKT1 gene as well as
different point mutations resulting in alteration of the highly
conserved residues of the AKT1 gene have been reported in a
subset of JGCTs [89]. Somatic DICER1 mutations have been
reported in up to 25% of JGCTs [77, 90]. However, this
mutation has not been identified in 4 JGCTs tested in another
Fig. 9.63 Ovarian yolk sac tumor: YST sometimes is confused with
report [91]. Rarely JGCT is associated with enchondromato- JGCT because of the similarity between the follicles and the cysts in
sis (Ollier’s disease), Mafucci syndrome, and abnormal YST. Positive germ cell markers e.g. SALL4 and glypican 3 and
karyotype [92]. negative sex cord markers e.g. α-inhibin and calretinin are characteris-
tics for a YST
Adult GCT: AGCTs contain more regular follicles than that
in JGCTs, less luteinized cells, grooved nuclei and less follicles lined by hobnail-like cells, nuclear pleomorphism
mitotic count. and pseudopapillae simulating that in JGCT. Clinical sce-
Yolk sac and other germ cell tumors: A YST sometimes is nario with carcinomas being rare in the young, lack of true
confused with JGCT because there may be similarity follicles, lack positivity for α-inhibin and calretinin will help
between the follicles and the cysts in YST (Fig. 9.63). Other to reach the right diagnosis (see differential diagnosis section
germ cell elements (e.g., dermoid cyst), Schiller–Duval bod- under AGCT above).
ies, a reticular pattern, positivity for AFP, SALL4 or glypican Pregnancy luteoma: The follicle-like spaces of preg-
3 and negativity for α-inhibin and calretinin are characteris- nancy luteoma may simulate the follicles in JGCT. The
tics for YST [93]. abundant eosinophilic cytoplasm is characteristic of preg-
Carcinomas: Epithelial tumors as clear cell, undifferenti- nancy luteoma. Additionally, pregnancy luteoma tend to be
ated and transitional cell carcinomas may contain cystic bilateral, multiple and have more homogenous patterns
a b
Fig. 9.64 Small cell carcinoma of the hypercalcemic type: Low (a) and high (b) power captions of small cell carcinoma of the hypercalcemic
type. The tumor lacks the nodular growth pattern of JGCTs and the cells are frankly primitive
(see the differential diagnosis section under steroid cell stage [95]. In contrast to AGCTs, JGCTs are less likely to
tumor above) [57]. recur and if recurrence does occur, this usually happen within
Small cell carcinoma of the hypercalcemic type (SCCH): 3 years of initial diagnosis [4, 96].
Hypercalcemia (in 60% of SCCH) and the lack of estrogenic
manifestations may help in differentiating this tumor from
GCTs. Grossly, most cases of SCCH are bilateral and
advanced stage, as compared with GCTs, which are typically Key Diagnostic Points
confined to one ovary. Morphologically, SCCH and JGCT Juvenile Granulosa Cell Tumor
may both have high mitotic activity, and both may display Gross
follicles. However, the constituent cells of SCCH are notably • Similar to AGCT (see above).
primitive and lack abundant cytoplasm (with the exception
of the large cell variant) (Fig. 9.64). A subset of SCCH show Microscopic
mucinous glands, which would be uncharacteristic in • Nodular or diffuse proliferation in a myxoid and
JGCT. Furthermore, SCCHT lacks the nodular growth pat- edematous background separated by follicles.
tern of JGCTs. The cells of SCCH lack α-inhibin positivity • The follicle-like spaces contain proteinaceous
and have as a defining feature a loss of expression of material and lined by granulosa cells.
SMARCA4 (BRG1); the latter distinguishes SCCH from all • Rare/no call-Exner bodies.
histologic mimics [94]. • Abundant eosinophilic or vacuolated cytoplasm.
• Non-grooved large, round, hyperchromatic nuclei
9.6.2.8 Prognosis with variable atypia (minimal to severe).
The presence of gsp mutation may carry worse prognosis • High mitotic count.
since this mutation is usually associated with advanced stage
at initial presentation [88]. Other factors, which may indicate Markers
poor outcome include advanced stage at presentation and • As that of AGCT (see above) and positive for Fli-1
strong FOXL2 protein expression. Of note, the presence of by IHC.
cytological atypia or high mitotic rate does not affect the • Activating mutations of the trimeric G protein
clinical outcome. The overall survival for patients with stage (30%).
I is 97% [4, 21]. Excision is usually adequate for early stage • FOXL2 somatic gene mutation in only 10% of
disease and adjuvant chemotherapy may be considered for cases.
patients with recurrence or those who present at advanced
310 M. M. Desouki
9.6.3 Sertoli Cell Tumors c ollection of Leydig or granulosa cells could be identified and
is not a background to consider mixed SCST diagnosis.
9.6.3.1 Definition Malignant criteria include large tumors (>5 cm), >5
A tumor composed exclusively of Sertoli cells [97]. mitosis/10HPF, nuclear atypia and necrosis [97].
9.6.3.2 Clinical Presentations 9.6.3.5 Biomarkers

Less than 5% of tumors with Sertoli component are pure SCTs. As the case with SLCTs, these tumors are typically positive
The mean age of patients is 30 years (range of 2–76 years). In for α-inhibin (82%), calretinin (50%), CD99 (86%), WT1
contrast to SLCTs (see below), the pure ones are typically hor- (100%), SF-1 (100%), vimentin (94%), AE1/AE3 (65%),
monally inert and a minority produces estrogen or androgen CD10 (44%) and CAM5.2 (65%) while negative for EMA,
with isosexual pseudoprecocity and abnormal uterine bleeding chromogranin, and CK-7 (Table 9.4). SMA is positive in
as presenting symptoms. Incidental finding on routine exami- 22%, neuron specific enolase in 50% and S100 in 10% of
nation is common, however, abdominal mass/swelling, pain, or cases. Fat stain is positive in most cases [13, 18, 97].
menstrual irregularities are other presentations [97].
9.6.3.6 Molecular Features and Genetic
9.6.3.3 Gross Findings Association
SCTs are typically unilateral, solid or lobulated, and yellow, Rare cases have been seen in patients with Peutz-Jeghers
tan or brown with an average size of 9 cm (range of 0.8– syndrome (PJS) [99]. DICER1 somatic mutations has been
30 cm, mostly in the range of 4–12 cm). Unlike SLCTs, reported in 63% of cases (For more information on DICER1
cystic change is uncommon in SCTs. Gross hemorrhage and mutation, refer to SLCTs section below) [100].
necrosis may be seen [97].
9.6.3.4 Microscopic Findings Sertoli-Leydig cell tumor: SCT is differentiated from SLCT
SCTs are well-demarcated from the surrounding ovarian tis- by the presence of more than rare Leydig cells in the latter. A
sue and composed of well-formed hollow or solid (simulat- retiform pattern and the presence of heterologous elements
ing prepubertal testis) tubules which may be focal. The favor SLCT (see SLCT below) [101].
tubules may simulate endometrioid carcinoma, has complex Adult granulosa cell tumor: A SCT may grow in cords
branches, or cystically dilated. Few cases may have eosino- and trabeculae similar to AGCT even with grooved nuclei
philic or basophilic fluid in the lumens of the tubules with [98]. The presence of well-formed solid or hollow tubules
rare histiocytes. Other patterns e.g. alveolar, pseudo- favor SCT (see AGCT above).
papillary, trabecular, spindled and diffuse could also be Endometrioid carcinoma: Endometroid carcinoma some-
encountered. The cords and trabeculae are present in ~50% times is composed of closely packed tubules simulating SCT
of cases with 1–3 cells thick short and anastomosing pattern. “Sertoliform endometrioid carcinoma”. The older age, squa-
Rarely, the cords and trabeculae are long and ran parallel to mous morules, identifying typical areas of endometroid car-
each other. Diffuse pattern where no tubular differentiation is cinoma merging with the Sertoli-like areas, background of
appreciated in ~40% of cases. In alveolar pattern, the islands adenofibroma or endometriosis, positive EMA and negative
of tumor cells are separated by delicate fibrous septae [97]. α-inhibin support the diagnosis of carcinoma [80] (see the
The glands are lined by cuboidal to columnar cells with differential diagnosis section under AGCT above).
moderate amount of eosinophilic, pale or luteinized cytoplasm Carcinoid tumor: A carcinoid tumor grows in cords and
and basally located round nuclei with occasional grooves. The trabeculae and acini, which may be morphologically similar
cytoplasm may be deeply eosinophilic (oxyphilic cells), or to well-differentiated Sertoli tubules. The cells in carcinoids
contain vacuoles that sometimes push the nucleus against the have a brush border, contain prominent neuroendocrine
cell periphery. Mild cytologic atypia and few mitoses are the granules, and the nuclei have the characteristic morphology
characteristic features in most cases [98]. Bizarre nuclei with with “salt and pepper” chromatin, and cytoplasmic granules.
large mononucleate or multinucleated cells with smudgy chro- The stroma of carcinoid is often more prominent with exten-
matin may be seen in few cases with no increase in mitotic sive fibrosis. Ovarian carcinoids are typically associated with
activity and was considered degenerative change. Moderate to a teratoma, mucinous tumor or strumal component [102].
severe cytologic atypia, which include vesicular nuclei with Positive neuroendocrine markers and negative α-inhibin will
coarse chromatin, prominent nucleoli, may be seen in a small aid to sort out this differential in most cases.
fraction of cases. Tumor necrosis is rarely seen in these tumors. Female adnexal tumor of probable Wolffian origin:
In cases with abundant lipid-rich cytoplasm the term “lipid- FATWO is frequently seen in the broad ligament but rarely in
rich” SCT is used. The background stroma is variable the ovary [103]. Solid tubules with elongated cells with oval
and occasionally sclerotic with rare calcifications. Minor nuclei seen in FATWO may be similar to SCTs. However, the
a b
c d
Fig. 9.65 Dysgerminoma: The tumor cells grow in a diffuse pattern and traversed by fibrous septa containing lymphocytes (a). The tumor cells
usually are positive for CD117 (b), SALL4 (c) and OCT 3/4 (d) stains
FATWO is characterized by an admixture of many histologic 9.6.3.8 Prognosis

patterns, such as cysts with a sieve-like appearance. Most cases are benign and presented at an early stage (local-
Immunostains may be helpful in the differential with positive ized to the ovary) and surgical excision is curative.
CK7, CK19 and GST mu in FATWO [104]. Of note, FOXL2
protein has been reported positive by IHC in the three cases
tested in one study. However, none of the three cases har-
bored FOXL2 gene mutation [20].
Steroid cell tumor: Steroid cell tumor may simulate a
SCT composed predominantly of cells with abundant lipid Sertoli Cell Tumor
rich cytoplasm. Tubule formation is not seen in steroid cell Gross
tumors and lipochrome pigment in the neoplastic cells is • Unilateral, medium sized (average of 9 cm), solid or
present in 40% of steroid cell tumor in contrast to an absence lobulated, yellow, tan or brown.
in SCTs (see steroid cell tumor above).
Microscopic
Dysgerminoma: Bi-laterality is slightly common in dys-
germinoma and dysgerminoma is relatively more common • Well-formed hollow or solid tubules simulating
than SCTs. All dysgerminomas have a conspicuous diffuse prepubertal testis.
pattern traversed by fibrous septae containing lymphocytes • Other patterns include alveolar, pseudo-papillary,
and the tumor cells usually are positive for CD117, OCT 3/4 trabecular, spindled and diffuse.
and SALL4 by IHC [93] (Fig. 9.65).
312 M. M. Desouki
Table 9.6 Characteristics of Sex cord tumors with annular tubules in

• Cords and trabeculae present in ~50% of cases with patients with and without Peutz-Jeghers syndrome (PJS)
1–3 cells thick, short and anastomosing pattern. Patients without
• Diffuse pattern where no tubular differentiation in Finding Patients with PJS PJS
~40% of cases. Age (years) Range of 4–57 6–76 (mean,
(mean, 27) 34)
• Cuboidal to columnar cells with eosinophilic, pale
Abdominal mass Rare Common
or luteinized cytoplasm. Gross tumor Uncommon Common
• Basally located round nuclei with occasional Bilateral tumors Common Rare
grooves. Tumor size Small Large
• Mild cytologic atypia and few mitoses. Malignant behavior Very rare Common
• Variable stroma with rare calcifications. Multifocal Common Rare
• Minor component of Leydig or granulosa cells may Calcifications Common Rare
be present (not a reason to consider mixed SCST Adenoma malignum of Common Not reported
cervix
diagnosis).
Solid nests (granulosa cell Rare Common
• Malignant criteria: Large tumors (>5 cm), increased differentiation)
mistosis (>5 mitosis/10HPF), nuclear atypia and Elongated tubules Rare Common
necrosis. (Sertoliform)
Markers
• Positive: Inhibin (82%), calretinin (50%), CD99 9.6.4.4 Microscopic Findings
(86%), WT1 (100%), SF-1 (100%), vimentin Patients with PJS: The SCTAT is bilateral in more than 50%
(94%), AE1/AE3 (65%), CAM5.2 (65%) and CD10 of cases. The tumors are characterized by sharply circum-
(44%). scribed, rounded nests with ring-shaped tubules containing
• Negative: EMA, chromogranin, and CK-7. hyalinized basement membrane-like material. The tubules
are distributed singly or in clusters in simple or communi-
cating architecture within the cortical or medullary stroma.
The nuclei are located at the periphery of the tubules and
9.6.4 Sex Cord Tumors with Annular Tubules around the hyaline material (Fig. 9.66). Calcification is
common in the ovarian stroma. The cells may contain large
9.6.4.1 Definition lipid vacuoles.
A rare SCST with a distinctive pattern of simple and com- Patients without PJS: The appearance of the tumor is
plex annular tubules [105]. similar to that in patients with the PJS. SCT pattern with
elongated tubules and pale cytoplasm occupying the central
9.6.4.2 Clinical Presentations portions is common. The neoplastic cells are columnar with
Patients with PJS present at an earlier age (mean of 27 years) ample pale cytoplasm. The nuclei are basally located, round
compared to a mean age of 34 years in patients without to oval with occasional grooves and single nucleoli. Nuclear
PJS. Most patients with PJS have gastrointestinal polyposis pleomorphism and mitotic figures are very rare even in
and muco-cutaneous melanin pigmentation with incidental cases with malignant behavior [106]. Moderate increase in
SCTAT on microscopic examination of the ovaries [105, mitotic count (7–10/10 HPF) has been reported in a malig-
106]. In contrast to tumors associated with PJS, abdominal/ nant case [107].
pelvic masses are palpable in ~50% of patients without PJS
[106]. Table 9.6 summarizes the characteristics of SCTAT in 9.6.4.5 Biomarkers
patients with and without PJS. Like most other SCSTs, SCTAT are positive for α-inhibin
(100%), calretinin (100%), WT1 (100%) and CD56 (100%).
9.6.4.3 Gross Findings AE1/AE3 has been reported positive in 67% of cases. CD10,
The SCTAT in patients with PJS may be seen grossly in only EMA, CK5/6 and Melan-A/MART-1 are negative in all
28% of cases as single or multiple small nodules. The tumors reported cases [15, 17–19].
are grossly yellow and relatively small (up to 3 cm). Ovarian
cysts and tumors other than the SCTAT are present in 25% of 9.6.4.6 Differential Diagnosis
cases. The SCTAT in patients without PJS are unilateral and The SCTAT has a specific morphology and usually is a
range in size from microscopic to 20 cm. Gross hemorrhage straightforward diagnosis if the pathologist is familiar with
and necrosis are rarely seen (Table 9.6) [105]. the entity.
a b
Fig. 9.66 Sex cord tumor with annular tubules: Low (a) and high (b) characteristic of SCTAT. The nuclei are located at the periphery of the
power captions of sharply circumscribed, rounded nests with ring- tubules and around the hyaline material
shaped tubules containing hyalinized basement membrane-like material
9.6.4.7 Prognosis
SCTAT in patients with PJS is benign with rare malignant • Elongated tubules and pale cytoplasm.
cases have been reported [108]. The patients may die of asso- • Columnar cells with ample pale cytoplasm.
ciated cervical adenoma malignum, which does metastasize. • Basally located round to oval nuclei with occasional
SCTAT is clinically malignant in ~15% of cases without PJS grooves and single nucleoli.
with half of them died of disease [106]. • Rare atypia and low mitotic count.
Markers
Key Diagnostic Points • Positive: Inhibin (100%), calretinin (100%), WT1
Sex Cord Tumor with Annular Tubules (100%), CD56 (100%) and AE1/AE3 (67%).
Gross • Negative: CD10, EMA, CK5/6 and MART-1.
Patients with PJS:
• Bilateral (>50%), multiple, small (up to 3 cm), yel-
low nodules.
9.7 Mixed Sex Cord-Stromal Tumors
Patients without PJS:
• Unilateral, large (up to 20 cm). 9.7.1 Sertoli–Leydig Cell Tumors
Microscopic 9.7.1.1 Definition
Patients with PJS: SLCTs are mixed SCSTs with formation of Sertoli cells,
• Circumscribed, round nests with ring-shaped Leydig cells and sometimes primitive gonadal stroma and
tubules containing hyalinized basement membrane- heterologous elements [109].
like material.
• The tubules are distributed singly or in clusters. 9.7.1.2 Clinical Presentations
• In the ovarian cortex or medulla. SLCTs predominate (75%) of patients younger than 30 years
• The nuclei are located at the periphery of the tubules and only 10% are >50 years with and average age of 25 years
and around the hyaline material. [110]. The retiform tumors occur at a young age (mean of
• Calcification is common in the ovarian stroma. 15 years) [111]. Androgenic symptoms e.g. virilism,
amenorrhea, deepening of voice, and clitoromegaly are the
Patients without PJS: main symptoms in approximately half of patients especially
• Similar to that in patients with the PJS. in well-differentiated tumors and less commonly in retiform
and tumors with heterologous elements. Other symptoms
314 M. M. Desouki
include abdominal swelling or pain [109]. In association perpendicular to the basement membranes with occasional
with cervical embryonal rhabdomyosarcoma, SCLTs have bizarre forms [99]. The Leydig cells are present throughout
been reported in 4 cases [112]. the tumor with variable density in a single or cluster pattern
(Figs. 9.68 and 9.69) [110]. Well-differentiated tumors are
9.7.1.3 Gross Findings almost always without heterologous or retiform elements
SLCT are usually (98.5%) unilateral tumors that range in [113].
size from microscopic to 51 cm (average 13.5 cm). SLCTs
tend to be solid, lobulated and yellow in color with or with- 9.7.1.6 Moderately Differentiated
out cyst formation. Some tumors are completely cystic espe- The characteristic morphology is the presence of alternating
cially those with retiform component with or without cellular areas separated by hypocellular edematous stroma in
papillary or polypoid excrescences resembling serous lobulated pattern. The neoplastic cells grow as sheets,
tumors. Higher-grade lesions especially those with mesen- tubules, nests, cords or microcysts. The cells arrange in an
chymal heterologous elements show gross hemorrhage and alveolar pattern with scant cytoplasm and small, round nuclei
necrosis [5] (Fig. 9.67). Tumors with mucinous heterologous which are sometimes bizarre [66]. Cysts with luminal eosin-
elements may be multicystic with mucinous contents similar
to mucinous tumors. SLCTs usually present at an early stage
[101, 109].

SLCTs are classified according to tumor differentiation and
clinical behavior into well-differentiated (11% of cases, clin-
ically benign), moderately (intermediately) differentiated
(54% of cases, 11% malignancy rate), poorly differentiated
(11% of cases, 59% malignancy rare), SLCT with retiform
pattern (15%) and SLCT with heterologous elements [109].
9.7.1.5 Well-Differentiated
These tumors are composed predominantly of tubules form-
ing either [1] compact lobules of round or oval small tubules,
which may be cystically dilated or [2] tubules, which infil-
trate between the intervening collagen bundles. The tubules
Fig. 9.68 Well-differentiated Sertoli-Leydig cell tumor. The neoplas-
usually have open lumina and rarely are solid with incon-
tic cells form tubules with elongated nuclei, which arrange perpendicu-
spicuous lumens. The tubules are lined by cells with lipid lar to the basement membranes. The Leydig cells are present throughout
rich or oxyphilic cytoplasm and elongated nuclei arranged the tumor (image courtesy of Dr. Oluwole Fadare)
a b
Fig. 9.67 Sertoli-Leydig cell tumor: Gross photo of an SLCT showing large, yellow tumor with smooth outer surface (a) and nodular cut surfaces
with areas of gross hemorrhage and necrosis (b)
a b
Fig. 9.69 Well-differentiated Sertoli-Leydig cell tumor with bizarre nuclei. The neoplastic nuclei are enlarged, hyperchromatic with smudgy
chromatin. However, no increase in mitotic activity. The Leydig cells are present throughout the tumor (a, b)
Fig. 9.70 Moderately differentiated sertoli-Leydig cell tumor. The Fig. 9.71 Moderately differentiated sertoli-Leydig cell tumor. Leydig
characteristic morphology is shown in this photomicrograph with alter- cells are present at the periphery of the hypercellular areas
nating cellular areas separated by hypocellular stroma in a lobulated
pattern. The cells have small, round nuclei and scant cytoplasm. Leydig
cells are scattered in the hypocellular areas
rate with rare to absent Leydig cells [1, 109] (Figs. 9.72
and 9.73).
ophilic material simulating struma ovarii and follicles may
9.7.1.8 Sertoli-Leydig Cell Tumor with Retiform
be present [1]. Leydig cells are usually rimming the nodules
and populating the hypocellular areas (Figs. 9.70 and 9.71). Pattern
The stroma may be fibrous or cellular and sometimes simu- These tumors represent 15% of the moderately and poorly
lating sarcoma with frequent edema containing Leydig cells differentiated SLCTs and as the name implies are character-
[109]. ized by growth pattern simulating the rete testis. The reti-
form pattern may be the pure pattern or more commonly
9.7.1.7 Poorly Differentiated occur within otherwise typical moderately and poorly dif-
These tumors are characterized by sarcomatoid growth ferentiated SLCTs with or without heterologous elements.
pattern with focal pattern of conventional SLCTs. They are Morphologically these tumors exhibit irregularly branched,
formed of solid sheets of poorly differentiated cells that elongated, narrow, tubules that include poorly formed tubules
range from spindle cells mimicking sarcoma to epithelial- and cysts with intraluminal polypoid projections lined by
like with high nuclear grade and invariably high mitotic epithelial cells with varying degrees of stratification and
316 M. M. Desouki
Fig. 9.72 Poorly Differentiated Sertoli-Leydig cell tumor. The tumor Fig. 9.74 Sertoli-Leydig cell tumor with heterologous mucinous element.
cells exhibit sarcomatoid growth pattern. They are formed of spindle The tumor exhibits the morphology of moderately differentiated tumor
cells mimicking sarcoma with high nuclear grade and absent tubule with alternating hypercellular and hypocellular stroma in a lobulated pat-
formation tern. Notice the presence of bland gastrointestinal mucinous element
a nuclear atypia. Immature Sertoli cells forming columns or

ribbons are frequently present. The polypoid projections are
of three types (1) small and rounded or blunt which are often
hyalinized, (2) large and bulbous, often with edematous
cores and (3) delicate and branching and lined by stratified
cells and cellular buds, simulating serous tumor. The stroma
are either hyalinized or edematous with moderate to dense
cellular proliferation [1].
9.7.1.9 Sertoli-Leydig Cell Tumor

with Heterologous Elements
Twenty-two percent of SLCTs display heterologous
elements in the form of gastrointestinal-type mucinous

epithelium (Fig. 9.74), skeletal muscles, bone, fetal-type
cartilage (Fig. 9.75) and other mesenchymal structures.
b Mucinous epithelium is the most common, constituting
~90% of the heterologous differentiation and may exhibit
benign, borderline or low-grade mucinous adenocarcinoma
features (Fig. 9.74). Insular or mucinous-goblet cell carci-
noids are occasionally present within the mucinous ele-
ment. Apart from the associated heterologous elements,
these tumors are morphologically similar to moderately or
poorly differentiated ones [109].
9.7.1.10 Biomarkers
SLCTs stain strongly for α-inhibin (100%), calretinin (89%),
WT1 (100%), AE1/AE3 (100%), vimentin, CD56 (100%),
SF-1 (100%), CD99 (Sertoli component only; 50% of cases),
FOXL2 (Sertoli component only; 50%) and CD10 (44%)
while negative for CK5/6 and EMA [13, 15, 17, 18, 20].
Fig. 9.73 Poorly Differentiated Sertoli-Leydig cell tumor. The same SLCTs may exhibit focal staining for alpha fetoprotein [1]
tumor exhibits sarcomatoid (a) and epithelioid (b) growth patterns (Table 9.4).
ultinodular goiter, cystic nephroma and pleuropulmonary

m
blastoma [115]. Patients with DICER1 syndrome are also at
an increased risk for developing cervical embryonal rhabdo-
myosarcoma, medulloepithelioma, pituitary blastoma, cervi-
cal neuroectodermal tumor, intestinal hamartomatous polyps
and Wilms tumor [116]. In contrast to the missense somatic
DICER1 mutations, the germline defects are mainly truncat-
ing mutations. Interestingly, patients with SLCTs with germ-
line DICER1 mutations also harbor somatic DICER1 defects,
which advocates for genetic testing of all patients with
SLCTs [90]. SLCTs in patients with germline DICER1
mutation tend to occur at a younger age and the tumors
exhibit JGCT morphology and heterologous elements [115].

Fig. 9.75 Sertoli-Leydig cell tumor with heterologous cartilaginous
Endometrioid carcinoma: Endometrioid carcinoma may
element. The tumor exhibits the morphology of moderately differenti- have cords and sex cord stromal pattern (corded and hyalin-
ated tumor with cartilaginous element ized pattern) simulating SLCT (Figs. 9.76 and 9.77). This
clinically important differential has been discussed in AGCT
above.
9.7.1.11 DICER1 Mutation Krukenberg tumor: Refer to the differential diagnosis sec-
DICER1 encodes an RNase III endoribonuclease that cleaves tion under SRST above. Special emphasis on the differential
precursor miRNAs, small non-coding RNAs that regulate diagnosis of SLCT from tubular Krukenberg tumor will be
translation of genes, into mature miRNAs. The mutations in discussed in this section. The designation of tubular
the miRNA processing pathways will result in dysregulation Krukenberg tumor implies the similar feature with SLCT,
of their target mRNA. It has been reported that miRNAs are which is the tubule formation. The clinical presentation may
downregulated in most cancers and the reduced expression be overlapping especially that metastatic tubular Krukenberg
of DICER has been associated with poor outcome in differ- tumor to the ovary often occur in young patients. Sometimes
ent cancer types [22, 114]. tubular Krukenberg tumor grow in nodular pattern with stro-
Most (60–98%) of SLCTs had a somatic DICER missense mal lutein cells that simulate Leydig cells [1]. Features of
‘hotspots’ mutations that adversely affect encoding the Krukenberg rather than SLCT include bilaterality, marked
metal-binding sites within the RNase IIIb catalytic centers. nuclear atypia, signet-ring cells, staining for EMA but not
The most common reported mutations include p.D1709N for sex cord markers. Of note, luteinized stromal cells in
(c.5125G > A) and p.E1705K (c.5113G > A) of DICER1- Krukenberg tumors stain for sex cord markers [54].
mutant tumors [90, 100]. Well-differentiated SLCTs do not
harbor DICER1 mutations in contrast to moderately and
poorly differentiated ones. No apparent association between
DICER1 mutation and the presence of heterologous ele-
ments [22, 77, 100].
It appears that DICER1 mutations are non-specific for
SLCTs with reports of mutations in JCGTs, SCSTs NOS,
YSTs, mixed germ cell tumors, dysgerminona, cervical
rhabdomyosarcoma and testicular germ cell tumors [22, 77,
90, 100]. In contrast to ovarian SLCTs, no reports of DICER1
mutations in tested cases of testicular SCTs [100]. No
DICER1 mutations have been reported in AGCTs and
DICER1 and FOXL2 mutations appear to be mutually exclu-
sive in ovarian SCSTs even those with mixed GCT and
SLCT morphology (what has been known as gynandroblas-
tomas) [90, 100].
In addition to the somatic mutation described above, a
Fig. 9.76 Endometrioid carcinoma with corded and hyalinized pat-
germline mutation does occur in the familial DICER1 syn- tern. The carcinoma mimics Sertoli Leydig cell tumor. However, con-
drome. In addition to SLCTs, the patients may develop ventional adenocarcinoma component is seen (upper field)
318 M. M. Desouki
Fig. 9.77 Endometrioid carcinoma with corded and hyalinized pat- Fig. 9.78 Carcinosarcoma. The growth pattern of the epithelial and
tern. The tumor mimics Sertoli Leydig cell tumor with no conventional mesenchymal components mimics sertoli-Leydig cell tumor
adenocarcinoma component in this field
Mucinous tumors: Because of the different patterns of elements have no specific prognostic significance whereas
SLCT and the relatively common association with mucinous the significance of mesenchymal elements is generally more
heterologous elements, mucinous tumors lend themselves in unfavorable. In general, tumor rupture, the presence of mes-
this differential. On microscopic examination, most heterol- enchymal heterologous elements and high stage at presenta-
ogous tumors contain classic foci of Sertoli cells between the tion carry a worse outcome [5, 101].
mucinous component. This emphasizes the requirement of
adequately sampling grossly mucinous neoplasms.
Serous tumors: SLCT with retiform pattern may be misdi- Key Diagnostic Points
agnosed as serous carcinoma. Clinical information including Sertoli Leydig Cell Tumor
the patient age is relevant to the differential diagnosis Gross
between SLCT and a serous neoplasm or even a malignant
mixed mesodermal tumor (carcinosarcoma). The latter usu- • Unilateral (98.5%), large (average of 13.5 cm),
ally occur at a different age range with very rare exceptions. solid, lobulated and yellow with or without cyst
Germ cell tumor: Differentiating a SLCT from a germ formation.
cell tumor including embryonal carcinoma or reticular- • Retiform tumors tend to be cystic.
microcystic pattern of YST rely on the presence of regions • High-grade tumors have gross hemorrhage and
diagnostic in one direction or the other [1, 93]. necrosis.
Ovarian edema: The presence of typical nodular pattern • Tumors with mucinous heterologous elements may
with cellular growth “blue nodules” separated by edematous be multicystic with mucinous contents.
stroma in SLCT is usually present (see the differential diag- Microscopic
nosis section under thecoma above).
Sarcomas and poorly differentiated carcinomas including • Types: Well-differentiated, moderately differenti-
carcinosarcoma: Important differential diagnostic consider- ated, poorly differentiated, retiform pattern and
ations especially to poorly differentiated SLCT that have with heterologous elements.
been discussed under the differential diagnosis sections of Well-differentiated:
other tumors above (Fig. 9.78).
• Small tubules with open lumina lined by uniform
lipid rich or oxyphilic cells.
9.7.1.13 Prognosis
• Elongated nuclei arranged perpendicular to the
The grade of SLCT drives the prognosis but overall the prog-
basement membranes.
nosis is favorable. Well-differentiated tumors have 100%
• Leydig cells are present throughout the tumor.
survival. Moderately differentiated tumors have 10% malig-
• No heterologous or retiform elements.
nant behavior. Retiform and poorly differentiated tumors
carry a worse outcome with recurrence within 2 years Moderately-differentiated:
especially in the peritoneal cavity. Mucinous heterologous
SLCT. Mixed patterns seen in different tumors as fibrotheco-

• Alternating cellular and hypocellular areas in lobu- mas, GCTs and SLCTs may also qualify for the term unclas-
lated pattern. sified [117].
• Sheets, tubules, nests, cords or microcysts.
• Scant cytoplasm and small round nuclei. 9.7.2.2 Clinical Presentations
• Leydig cells rimming the nodules and populating A fraction (5 to 20%) of SCSTs fall into this category.
the hypocellular areas. Clinical situation as pregnancy may cause difficulty in clas-
• Heterologous elements may be present. sifying SCSTs due to prominent edema, increased luteiniza-
Poorly-differentiated: tion in GCTs and prominent Leydig cells in SLCTs [70]. The
mean patient age is 49 years (range of 12–83 years) and the
• Sheets of poorly differentiated cells ranging from tumors may be non-functioning or produce estrogen or
Sarcomatoid to epithelial-like. androgen. Other presentations include abdominal or pelvic
• Focal pattern of conventional SLCT. pain, abdominal fullness, abnormal uterine bleeding, and
• High nuclear grade and high mitotic rate. weight loss or gain. Most of the tumors in this category pres-
• Rare to absent Leydig cells. ent at stage I [117].
• Heterologous elements may be present.
Heterologous elements: 9.7.2.3 Gross Findings
• Gastrointestinal-type mucinous epithelium is the

most common. All tumors are unilateral. The mean tumor size is
• Mucinous element could be benign, borderline or 16 cm (range of 0.3–30 cm). The surfaces are smooth,
invasive mucinous carcinoma. yellow to tan or red, with a firm, solid or rarely cystic
• Skeletal muscles, bone, cartilage and other mesen- consistency. Few tumors contain foci of hemorrhage
chymal structures are rare. and necrosis with capsule rupture [117].
Retiform pattern:
• Irregularly branched, elongated, narrow tubules. 9.7.2.4 Microscopic Findings
• Intraluminal polypoid projections lined by epithe- The tumors exhibit nodular growth pattern with hypercellu-
lial cells. lar and hypocellular myxoid or edematous areas, partial cyst
• Varying degree of stratification and nuclear atypia. formation and smooth pushing borders. The tumors are com-
• The polypoid projections are either (1) small, round posed of spindle cells with storiform or fascicular growth
or blunt (often hyalinized), (2) large and bulbous patterns. The nuclei are spindled and sometimes oval or
(often edematous) and (3) delicate and branching round with rare bizarre forms and variable mitotic rate (mean
(lined by stratified cells). of 5/10 HPF; range of 0 to 24). Granulosa and Sertoli pat-
• The stroma are either hyalinized, edematous or terns with foci of trabeculae, cords, Sertoliform tubules,
densely cellular. fibrothecomatous and retiform architecture may be present.
Markers Foci of hemorrhage and necrosis may be rarely seen [117].
• Positive: Inhibin (100%), calretinin (89%), WT1 9.7.2.5 Molecular Features

(100%), AE1/AE3 (100%), CD56 (100%), SF-1 Somatic DICER1 mutation has been reported in 1 of 12 and
(100%), CD99 (Sertoli component only; 50% of 1 of 7 cases of SCSTs, NOS in 2 studies [77, 91].
cases), FOXL2 (Sertoli component only; 50%) and
CD10 (44%). 9.7.2.6 Prognosis
• Negative: CK5/6 and EMA. Similar to that of AGCT and SLCT with 92% 5-year
• DICER1 somatic gene mutation in 60–98% of cases. survival [117].
9.7.2 S
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Secondary Tumors of the Ovary
10
Kelley Carrick and Wenxin Zheng
Abstract present the pathologist with little differential diagnostic

Secondary tumors of the ovary (STO) are tumors from dilemma in some cases, while in other cases there may be sig-
extraovarian sites. Determining the primary versus sec- nificant diagnostic challenge due to similarities in the gross,
ondary nature of an ovarian neoplasm is an exercise that microscopic, and clinical features of some primary and second-
may range from simple to essentially impossible due to ary ovarian tumors. Adding to the diagnostic difficulty pre-
similarities in gross, microscopic, and clinical features of sented by the frequent overlap in morphologic and clinical
some primary and secondary ovarian tumors. Adding to features is the fact that, in some cases, the pathologist (and cli-
the difficulty is the fact that, in some cases, the patholo- nician) may be unaware of a synchronous or historical extra-
gist (and clinician) may be unaware of a synchronous or ovarian primary neoplasm. As misdiagnosis impacts the
historical extraovarian primary neoplasm. As misdiagno- expected prognosis of the tumor and may have an adverse
sis impacts prognosis and treatment, it is important that effect on treatment, it is important that the pathologist have an
the pathologist have an appropriate index of suspicion of appropriate index of suspicion regarding the possibility of
metastasis, and a grasp of the possible gross, microscopic, metastasis, and a grasp of the possible gross, microscopic, clin-
clinical, and immunohistochemical staining features of ical, and immunohistochemical staining features of secondary
secondary ovarian tumors. Tumors metastatic to the ovary ovarian tumors. Tumor metastatic to the ovary may originate
may originate from almost any primary site, especially in from almost any primary site, especially in young females, in
young females, in whom the rich vascularization of the whom the rich vascularization of the ovaries may render them
ovaries may render them more susceptible to metastasis. more susceptible to metastasis. As ovarian metastasis has been
As ovarian metastasis has been documented to appear documented to appear many years after diagnosis of primary
many years after diagnosis, it is emphasized that a history tumor originating from various extraovarian sites, it is empha-
of neoplasia of any type, even if remote, may be signifi- sized that a history of neoplasia of any type, even if that history
cant in the evaluation of an ovarian tumor with morpho- is remote, may be significant in the evaluation of an ovarian
logic features unusual for a primary ovarian neoplasm. tumor with morphologic features unusual for an ovarian pri-
mary neoplasm.
Keywords
Krukenberg tumor · Metastasis · Ovarian malignancies ·
Secondary tumors of the ovary 10.2 Epidemiology
Available data regarding the frequency of STOs varies across

different studies, a finding which may be explained by sev-
10.1 Overview eral factors including the geographic region under study,
study methodology (inclusion of autopsy versus surgical
Secondary tumors of the ovary (STO) are those neoplasms that cases, inclusion of only those tumors presenting clinically as
spread to the ovary from extraovarian sites. Determining the an abdominopelvic mass versus asymptomatic/incidentally
primary versus secondary nature of an ovarian neoplasm may discovered tumors, etc.), thoroughness of pathologic exami-
nation of the ovaries, and pathologist experience [1, 2].
K. Carrick (*) · W. Zheng Given the caveat that available data are somewhat uneven,
Departments of Pathology, Obstetrics and Gynecology, University the proportion of tumors metastatic to the ovaries is esti-
of Texas Southwestern Medical Center, Dallas, TX, USA
mated to vary from approximately 3–17% in Western nations
324 K. Carrick and W. Zheng
[3–5] to approximately 21–30% in Eastern nations [6, 7]. metastasize to the ovary via blood vessels or lymphatics, as
The proportion of STOs and the relative frequency of pri- evidenced by the notable intravascular tumor identified in
mary sites of origin vary across different geographic regions many cases of STO. Direct spread is a frequent pathway for
due to geographic differences in the prevalence of various carcinomas of the fallopian tube and uterus to involve the
extraovarian primary neoplasms and their relative tendency ovary, for some colorectal and appendiceal carcinomas, and
to metastasize to the ovaries [1]. While gastric cancer, which for the rare mesothelioma [2, 12]. Tumor may also reach the
has a relatively high rate of ovarian spread, accounts for ovary through the fallopian tube lumen, a route deemed to
23.4% and 30.4% of tumors metastatic to the ovary in Japan account for spread of some carcinomas from the uterine cor-
and Korea, respectively, it is found in a reported 4.5% of pus and cervix [13, 14]. Transperitoneal spread, another
STOs in the Netherlands, which reflects its incidence in route of ovarian involvement, is typically accompanied by
those countries [7–9]. In several series examining secondary ovarian surface implantation, involvement of the superficial
ovarian malignancies in Europe and the USA, tumors of ovarian cortex, and general peritoneal spread. A good exam-
colorectal, breast, endometrial, and appendiceal origin have ple of this kind of spread is from high-grade serous carci-
been demonstrated to be the most common [4, 5, 9]. Patient noma of the fallopian tube.
age at diagnosis of a STO appears to be associated with the
origin and typical age distribution of the primary tumor [1].
For some of the most common types of metastatic tumors 10.5 G
eneral Pathologic Findings
(intestinal, gastric, and breast), the average age of patients and Clinical Correlation
presenting with ovarian involvement is lower than the aver-
age age of those without ovarian spread, which suggests that STOs may have considerable morphologic overlap with
the increased vascularization of ovaries in young women ovarian primary neoplasms, presenting diagnostic challenge
renders them more receptive to metastasis [2]. in many cases. The most challenging issues in differential
diagnosis typically involve mucinous tumors, endometrioid,
and endometrioid-like tumors. Over the years, several gross
10.3 Clinical Presentations and microscopic features have been proposed in the litera-
ture to aid in the distinction of primary versus secondary
Clinically, ovarian metastasis may be symptomatic or asymp- ovarian tumors, the most important of these being laterality
tomatic, and may present synchronously or metachronously and size of the ovarian tumor. Several studies have shown
with the extraovarian primary tumor. Ovarian metastatic that an algorithm using tumor size and laterality can accu-
tumor tends to remain asymptomatic until it reaches a certain rately distinguish a substantial majority of primary and met-
size. Presenting symptoms, found in a reported 70% of astatic tumors (bilateral tumors of any size, or unilateral
patients, are nonspecific and do not clearly differ from those tumor less than 10 cm more likely to be metastatic; unilat-
related to primary ovarian neoplasia [10]. Symptoms related eral tumor greater than or equal to 10 cm more likely an
to an ovarian mass and to an advanced stage of disease can ovarian primary neoplasm) [15, 16]. A 2008 study examin-
include abdominal pain, weight loss, and increasing abdomi- ing 194 primary and metastatic ovarian tumors demon-
nal girth [4]. As STOs, like primary tumors of the ovary, can strated that adjusting the size criterion of the algorithm to
induce ovarian stromal luteinization with consequent hor- 13 cm rather than 10 cm optimized performance of the algo-
mone production (“functioning stroma”), the patient may rithm, correctly classifying 87% of tumors overall, includ-
also experience consequences of increased estrogen, proges- ing 98% of primary tumors and 82% of metastatic tumors
terone, or androgens including abnormal uterine bleeding, [17]. Tumor size and laterality are helpful guidelines, espe-
virilization, and hirsutism [11]. Importantly, the ovarian cially in the operative setting. Exceptions are common,
metastasis may be the presenting sign of disease from a however, particularly among cases of colorectal and endo-
small, clinically occult non-ovarian primary tumor (for cervical adenocarcinomas [15, 17]; thus, laterality and
example, a small gastric carcinoma). In some cases, the pri- tumor size alone are not sufficient for determination of pri-
mary tumor may not be discovered until years after discov- mary site. In fact, there is a growing body of evidence to
ery of the ovarian metastasis or until autopsy. The primary indicate that a significant proportion of STOs are unilateral
tumor may remain unknown in up to 15–20% of cases [4, 9]. and relatively large [18]. A recent study from the Netherlands
including 2312 cases of tumor metastatic to the ovary from
various primary sites demonstrated that STOs from all sites
10.4 R
outes of Tumor Metastasis taken together were bilateral in the majority (46.3%) of
to the Ovary cases, with 63.9% of breast, 62.9% of gastric, and 58.9% of
appendiceal primaries generating bilateral metastases. In
Tumor may secondarily involve the ovary via any of several contrast, a minority (40.2%) of colorectal cancers had bilat-
routes of spread, which accounts for some of the more typi- eral metastases in this study [9]. Another study including 19
cal gross and microscopic features of STO. Tumor may tumors metastatic from the lower and upper gastrointestinal
10 Secondary Tumors of the Ovary 325
tract demonstrated that over 80% of these tumors were 7. Tubules and follicle-like spaces can be seen in metastases
greater than 10 cm [19]. from various sites and can mimic ovarian primary tumors,
Based on the above understanding and our own experi- particularly sex cord-stromal tumors [12].
ence, we summarize general gross features which are sug- 8. Ovarian stromal luteinization and resulting hormonal

gestive of metastasis to the ovary as follows: manifestations (“functioning stroma”) are nonspecific
and can appear in association with primary or metastatic
1. Bilateral ovarian involvement (notable exception: tubo- tumors.
ovarian serous carcinoma, which is often bilateral). As
metastatic tumor may be small and not enlarge the ovary, As noted above, STOs and primary ovarian neoplasms
adequate sampling is needed to rule out metastasis. may have overlapping morphologic and clinical features that
2. Tumor size less than 10–12 cm. confound diagnosis. Thus, in addition to careful gross and
3. A multinodular growth pattern. microscopic examination of the tumor, consideration of met-
4. Presence of tumor on the ovarian surface and/or in the astatic disease and clinical correlation are necessary when
superficial cortex. the diagnosis is not clear. This assessment may require intra-
operative and/or postoperative evaluation for an extraovarian
As with gross features, microscopic features of STOs may primary neoplasm if pathologic examination suggests the
bear similarity to microscopic features of primary ovarian possibility of a metastasis, or if the pattern of tumor spread is
tumors, particularly in mucinous and endometrioid/ unusual for an ovarian primary neoplasm. A directed panel
endometrioid- like tumors. Microscopic features favoring of immunohistochemical stains is useful in many cases and
metastasis include the following [2, 12, 20]: should be undertaken in any case in which the primary ver-
sus secondary nature of the ovarian tumor is uncertain. As
1. Presence of signet ring cells primary and secondary ovarian tumors often have overlap-
2. Infiltrative growth pattern with stromal desmoplasia ping immunohistochemical staining patterns (particularly in
3. Notable variation in growth pattern from one area to another the case of mucinous ovarian tumors arising in association
4. Histomorphology unusual for an ovarian primary with a teratoma, which have an intestinal immunophenotype
5. Multinodular growth pattern indistinguishable from metastatic tumor of gastrointestinal
6. Involvement of the ovarian surface and superficial cortex origin), a panel of immunostains should be employed and
7.
Hilar and/or extraovarian lymphovascular space correlated with gross, microscopic, and clinical findings. It is
involvement also important to note that metastatic tumors may have an
immunohistochemical staining pattern that deviates from the
Other pearls that can be useful in determining the primary usual, expected pattern. For typical immunohistochemical
versus secondary nature of an ovarian tumor include the staining features of primary and secondary ovarian tumors
following: with mucinous and endometrioid/endometrioid-like mor-
phology, see Table 10.1. Additional information regarding
1. A history of an extraovarian primary tumor should raise the use of immunohistochemical stains is provided in subse-
suspicion of metastasis, even if this history is remote. quent sections.
2. Metastatic tumors may be unusually large with thin-

walled cysts mimicking a primary ovarian neoplasm,
even if cysts are not a feature of the extraovarian primary 10.6 Secondary Ovarian Tumors
tumor [2, 12]. from the Gastrointestinal Tract
3. If tumor is bilateral and morphology is mucinous or endo-
metrioid/endometrioid-like, the probability of metastasis 10.6.1 Krukenberg Tumor
increases, as bilateral mucinous and endometrioid ovar-
ian primaries are relatively rare. Definition: The term “Krukenberg tumor” has not been con-
4. A carcinoma with mucinous morphology and either sistently defined over the years but has historically referred

advanced stage or association with pseudomyxoma peri- to tumors metastatic to the ovary that have a significant com-
tonei is likely to be metastatic. ponent of mucin-containing signet ring cells. A recent source
5. For endometrioid/endometrioid-like tumors, an adenofi- defines “Krukenberg tumor” as a metastatic adenocarcinoma
bromatous background or presence of endometriosis in which signet ring cells comprise at least 10% of the neo-
favors a primary ovarian origin. plasm [2]. The stomach, most often the pylorus, is the most
6. The presence of foci of histologically benign-appearing common source for these tumors, representing the primary
and low-grade proliferative mucinous epithelium (border- site in greater than 60% of cases [11]. Other possible primary
line/atypical proliferative features) that might suggest an sites include colon, rectum, breast, gallbladder, bile ducts,
ovarian origin is nonspecific and does appear in meta- appendix, and less commonly the small intestine, pancreas,
static tumors. urinary bladder, renal pelvis, and cervix [11 24]. Rare
Table 10.1 Typical immunohistochemical staining features of primary and secondary tumors with mucinous and endometrioid/endometrioid-like morphology [19, 21–23]
326
Primary site of
origin CK7 CK20 PAX8 ER PR SATB2 CDX2 DPC4/SMAD4 P16
Ovarian Endometrioid: Endometrioid: Endometrioid: Endometrioid: Endometrioid: Endometrioid: Endometrioid: Endometrioid: Endometrioid:
Positive Negative Positive Usually positive Usually positive Negative Negativef Positive Negative to
Mucinous: Mucinous: Mucinous: Mucinous: Mucinous: Mucinous: Mucinous: often Mucinous: Positive patchy positive
Positivea,b Variable positive positive/ usually usually Negativea,e positivef Mucinous:
to negativea,b negativec negatived negatived Negative to
patchy positive
Colorectal Negative Positive Negative Negative Negative Positive Positive Positive (approx. Negative to
(75–90% of (CK20>CK7) 90% of cases) patchy positive
cases negative)g
Appendiceal Negative (70% Positive Negative Negative Negative Positive Positive Positive Negative to focal
of cases)h (CK20>CK7) positive
Gastric Positive/negative Positive/negative Negative Negatived Negatived Negative or Signet ring Positive Negative/positive
positive type: variable
staining
Intestinal type:
positive
Pancreatobiliary Positive Negative/ Negative Negative Negative Negative Negative/ Negative (approx. Negative to focal
positivei positivej 50% of pancreatic positive
carcinomas
negative)
Endocervical Positive Negative Positive/ Negativek Negativek Negativek Negative/ Positive Strong diffuse
negativek positivek positivel
a
Primary ovarian epithelial tumors are typically CK7+/CK20−; thus a CK7−/CK20+ immunophenotype suggests a metastasis. Notable exception: The subset of ovarian mucinous tumors of intes-
tinal phenotype arising in association with a teratoma has an immunohistochemical staining profile indistinguishable from that of metastatic tumors of intestinal origin (CK7−/CK20+/SATB2+/
CDX2+/ER−/PR−/PAX8−)
b
Ovarian primary mucinous tumors of intestinal type are typically positive for CK7, often with diffuse strong positivity for this marker; they are often positive for CK20 as well, although with
patchy variable staining. As noted above, the subset of ovarian mucinous tumors of intestinal phenotype arising in association with teratomas have an immunohistochemical staining profile indis-
tinguishable from that of metastatic tumors of intestinal origin (CK7−/CK20+). Ovarian seromucinous tumors, separated from ovarian mucinous tumors in the 2014 WHO Classification of Tumors
of Female Reproductive Organs, typically have a CK7+/CK20−/PAX8+/CDX2− immunophenotype
c
PAX8 staining is variable in ovarian tumors of mucinous type unassociated with a teratoma, negative in ovarian mucinous tumors arising in association with a teratoma, and typically positive in
ovarian seromucinous tumors
d
ER and PR are typically negative in ovarian mucinous tumors (those with and without an associated teratoma) and positive in ovarian seromucinous tumors. Weak ER or PR staining does not rule
out stomach as a primary site
e
SATB2 is typically negative in ovarian mucinous tumors unassociated with a teratoma, positive in ovarian mucinous tumors associated with a teratoma, negative in ovarian seromucinous tumors,
and positive in metastatic tumors of colorectal or appendiceal origin
f
Ovarian mucinous tumors unassociated with teratoma show variable staining for CDX2. CDX2 is typically positive in ovarian mucinous tumors arising in association with a teratoma, and negative
in ovarian seromucinous tumors. Endometrioid adenocarcinoma may have focal positivity for CDX2 in morules and in foci of squamous differentiation
g
Adenocarcinomas of rectal origin may be positive for CK7
h
Approximately one-third of appendiceal mucinous neoplasms are positive for CK7; in contrast, appendiceal adenocarcinomas of usual intestinal type typically have negative to focal positivity for
CK7, like colonic adenocarcinomas
i
Approximately one-third of pancreatic ductal adenocarcinomas are positive for CK20, with focal positivity most common
j
Approximately 30% of pancreatic ductal adenocarcinomas are positive for CDX2
k
PAX8 is positive in the majority of endocervical adenocarcinomas. ER and PR are negative in the majority of endocervical adenocarcinomas. Endocervical adenocarcinomas may infrequently be
positive for SATB2. CDX2 is expressed in endocervical adenocarcinoma of intestinal type and in some nonintestinal types of endocervical adenocarcinoma
l
K. Carrick and W. Zheng
Endocervical adenocarcinoma expresses strong diffuse positivity for p16 in the vast majority of cases related to HPV; HPV-unrelated subtypes are negative for p16
Krukenberg-type tumors have been deemed to be of primary

ovarian origin [11].
Clinical Features: Patients with Krukenberg tumors are
younger than the average patient with tumor metastatic to the
ovary, with an average age of 45 years and an age range of 13
to 84 years in one large series. A significant proportion of
patients (35–45%) in this series were younger than 40 years
of age [11]. This young age can be ascribed to the relatively
high percentage of gastric adenocarcinomas of signet ring
type giving rise to Krukenberg tumors, and the relatively
high frequency of this tumor type in younger females [25].
Patients may be asymptomatic or may present with nonspe-
cific symptoms of abdominal pain or increased abdominal
girth due to the ovarian mass(es) or ascites. Patients may also
present with abnormal uterine bleeding, hirsutism, or viril-
ization related to ovarian stromal luteinization and resultant Fig. 10.1 Krukenberg tumor of gastric origin. The tumor is smooth
hormone production (“functioning stroma”) within those surfaced and bosselated, as is typical of Krukenberg tumors. The cut
metastatic tumors. Symptoms related to involvement of the surface is solid and tan with red discoloration due to hemorrhage
primary site or due to extraovarian spread (lung metastasis,
bone metastasis) may also be encountered. The primary
tumor is most often identified preoperatively, intraopera-
tively, or within a few months of discovery of the Krukenberg
tumor, although the primary site may not be discovered for
several years or until autopsy. Significantly, primary gastric
and breast cancers may be small and difficult to detect
clinically [12].
Pathologic Findings:
Gross: Krukenberg tumors are bilateral in the majority of
cases (63% of cases in one large series) [11]. Krukenberg
tumors have been found in ovaries ranging from the normal
size up to 34 cm, with an average size of 10.4 cm [11, 24]. As
Krukenberg tumors can involve ovaries of normal size, the
above-noted percentage of bilaterality in Krukenberg tumors
is likely artificially low, as tumor may not be detected if a
normal-sized ovary is not removed or adequately sampled.
The involved ovary is generally smooth surfaced and bosse- Fig. 10.2 Krukenberg tumor of gastric origin. The low-power appear-
ance is one of variably defined nodularity, a feature common to second-
lated. The cut surface is typically white to tan to pale yellow ary tumors of the ovary
and may have foci of red, brown, or purple discoloration due
to hemorrhage (Fig. 10.1). The cut surface may be solid and
multinodular, or solid and cystic with cysts ranging from vary as well. The low-power appearance is often one of ill-
small to large enough to suggest an ovarian primary neo- defined nodularity, typical of tumors metastatic to the ovary
plasm. Cysts may contain mucoid, serous, or hemorrhagic (Fig. 10.2). Tumor nodules may coalesce or may be sepa-
fluid. The cut surface may be firm and similar to that of a rated by less cellular areas with edematous or mucoid stroma.
fibroma, or may be relatively soft and edematous, fleshy, or A second low-power appearance commonly seen in
gelatinous. The central portion of the tumor may be softer Krukenberg tumors is that of a more cellular periphery, with
and of a different color and consistency than the periphery of edema and lesser cellularity centrally [11]. Surface involve-
the tumor [11]. ment is seen less commonly than with other metastases of
Microscopic: As Krukenberg tumor is defined as a meta- gastrointestinal origin, possibly due to an increased fre-
static adenocarcinoma with a significant component (at least quency of lymphovascular, rather than transcoelomic, spread
10%) of mucin-containing signet ring cells, a significant of the tumor [24]. Foci of hemorrhage and necrosis may be
component of signet ring cells is required for diagnosis; present. High-power examination often demonstrates vari-
however, a variety of cell types and architectural patterns are ability in both the epithelial and stromal components of the
often present in the tumor, and the stromal component may tumor with different cell types and architectural patterns,
Fig. 10.3 Krukenberg tumor of gastric origin. Classic signet ring Fig. 10.5 Krukenberg tumor of gastric origin. Signet ring cells in an
cells active stroma
Fig. 10.4 Krukenberg tumor of gastric origin. Signet ring cells line Fig. 10.6 Krukenberg tumor of gastric origin. The tumor must have a
tubules significant component of signet ring cells (10%) to be classified as a
Krukenberg tumor, but cell types and architectural patterns may vary,
as in this case. Moderately well-formed small glands are present in a
sometimes with an abrupt transition from one architectural background of conspicuous edema, a feature of many Krukenberg
tumors
pattern to another. Tumor cells may be abundant and obvi-
ous, or inconspicuous and sparsely scattered within a fibrous
stroma. The proportion of signet ring cells often varies mark- may be cellular, may have a storiform architecture, and may
edly in different areas of the tumor, being inconspicuous or be prominently edematous or mucoid. Stromal reactivity/
absent in some areas. Signet ring cells have a variable amount desmoplasia may be present or absent. Stromal luteinization
of eosinophilic or basophilic intracytoplasmic mucin and is often present and may be prominent [11]. Lymphovascular
may be disposed singly or in cords, clusters, sheets, or lining invasion is commonly seen, most often in the ovarian hilum
part or all of a tubule (Figs. 10.3, 10.4, and 10.5). Signet ring and at the tumor periphery.
cells are often accompanied by variably well-formed tumor Biomarkers: Periodic acid-Schiff (PAS), Alcian blue, or
glands of various sizes, including both small and large glands mucicarmine stains may be used to highlight intracytoplas-
and cysts (Figs. 10.6 and 10.7). Hollow and solid sertoliform mic mucin. A directed panel of immunohistochemical stains
tubules may be present. Extracellular mucin may be abun- may be employed to aid in the determination of the primary
dant [11]. Stroma may be fibrous with a fibroma-like appear- site. Typical immunohistochemical staining profiles of the
ance, rendering diagnosis more challenging when tumor more common primary sites generating Krukenberg tumors
cells are few, especially in the intraoperative setting. Stroma are as follows [22, 26, 27]:
quent bilaterality of the neoplasm, prominent

lymphovascular space invasion, and frequent multinodular
growth. The presence of signet ring cells and architectural
patterns not typical of primary ovarian neoplasia are other
helpful clues. For determination of primary site when
metastasis is suspected, clinical correlation and a directed
panel of immunohistochemical stains should be employed
to aid in diagnosis.
Management and Outcome: There are no uniform
guidelines in the treatment of Krukenberg tumors of the
ovary, as these are a heterogeneous group with variable bio-
logic characteristics. Tumors must be treated according to
the site of origin and stage. Treatment remains challenging.
Patients with tumors of gastrointestinal origin may benefit
from metastasectomy, chemotherapy which may include
Fig. 10.7 Krukenberg tumor of gastric origin. This tumor shows a adjuvant chemotherapy and HIPEC (hyperthermic intraperi-
notable variation in growth pattern from one area to another with an toneal chemotherapy), and targeted therapy such as mono-
abrupt transition between different architectural patterns, a feature clonal antibodies against EGFR for colorectal cancer and
common to secondary tumors of the ovary Her2neu for gastric cancer [1, 28, 29].
–– Stomach: Variable staining with CK7 and CK20; CDX2 is

variably expressed, with positivity ranging from 20 to 10.6.2 Gastric Adenocarcinoma,
90% of cases; SATB2 may be negative or positive, more Non-Krukenberg Type
often negative; weak ER and PR expression may be seen;
typically positive for CA 19-9; may be positive for Definition: An adenocarcinoma of gastric origin with an
HepPar1. intestinal phenotype, thought to arise from metaplastic epi-
–– Colon/rectum: Predominantly CK7− (exception: adeno- thelium. As Krukenberg tumors arising from the stomach
carcinomas of rectal origin may be CK7 positive)/CK may have foci of glandular differentiation, intestinal type
20+/CDX2+/SATB2+. tumors of gastric origin may also have signet ring cells,
–– Breast: Predominantly CK7+/CK20−/GATA3+/ER+/ PR+. although signet ring cells may not exceed 10% of the tumor
to qualify for the diagnosis of adenocarcinoma of non-
Differential Diagnosis: The differential diagnosis of Krukenberg type.
Krukenberg tumors includes a relatively long list of potential Clinical Features: These tumors are uncommon relative
primary sites that may give rise to metastatic tumors with to metastatic gastric tumors of diffuse type/signet ring cell
signet ring morphology, including the stomach (most fre- type, and thus data is limited. A 2006 series of four cases [30]
quent primary site), colon, rectum, breast, gallbladder and and a 1982 series of three cases [31] noted a somewhat older
bile ducts, appendix, and less commonly the small intestine, age of patients with metastatic gastric intestinal type carci-
pancreas, urinary bladder, renal pelvis, and cervix. Several noma relative to patients with metastatic signet ring cell car-
primary ovarian neoplasms may also present a differential cinoma (patients with metastatic gastric intestinal type
diagnosis with Krukenberg tumor, including primary ovarian carcinoma are in the sixth decade on average). Tumors are
mucinous carcinoma (although this does not typically have either bilateral or unilateral. In the majority of patients, ovar-
signet ring cells), clear-cell carcinoma, mucinous carcinoid ian metastases are identified after the gastric primary is dis-
tumor with signet ring cells, sclerosing stromal tumor, signet covered, although one reported patient presented initially
ring stromal tumor, small-cell carcinoma of hypercalcemic with a presumed ovarian primary carcinoma. The limited data
type, Sertoli-Leydig cell tumor (if sertoliform tubules are suggest that metastatic adenocarcinoma of gastric origin,
present in the Krukenberg tumor; of note, signet ring cells intestinal type, typically occurs in the setting of widespread
may be seen in Sertoli-Leydig cell tumors of heterologous metastatic disease throughout the abdomen and pelvis [30].
type with small nests of mucinous carcinoid), and fibroma (if Pathologic Findings:
tumor cells are few and stroma has a fibromatous quality). Gross: Ovarian masses in the few cases reported have
Tumor-like lesions such as mucicarminophilic histiocytosis ranged from 4 to 19 cm with an average diameter of 11.5 cm.
may also present a differential diagnosis [12, 24]. The cut surface is typically solid and cystic with a multinodu-
Clues to the diagnosis of Krukenberg tumor include fea- lar appearance to the solid areas. Necrosis is common. Tumors
tures typical of tumors metastatic to the ovary, such as fre- may contain mucinous or hemorrhagic fluid [30, 32].
Microscopic: The microscopic appearance of these tumors Clinical Features: In one 2006 series of 86 cases of
is similar to that of metastatic tumors of intestinal origin. The colorectal adenocarcinoma metastatic to the ovary, patients
tumors are formed of medium-sized to large tubular glands ranged in age from 19 to 85 years with a median age of 51;
with a pseudoendometrioid appearance, characterized by 24% of patients were younger than 40 [18]. A single case in
columnar epithelium with only focal intracytoplasmic mucin. a 12-year-old patient has been documented [32]. The major-
Other microscopic features, commonly shared by metastatic ity of patients have known intestinal carcinoma prior to diag-
tumors of intestinal origin, include segmental necrosis of epi- nosis of the ovarian tumor, while a minority (less than 10%)
thelium lining the neoplastic glands, high-grade nuclear fea- present with an ovarian mass and postoperative workup dis-
tures, variable to brisk mitotic activity, and frequent closes the intestinal primary. Some patients present with
intraluminal “dirty” necrosis. In addition to the moderate to symptoms related to their colorectal mass (rectal bleeding,
well-formed glands typical of tumors of intestinal type, these change in bowel habits, etc.), while others present with
tumors may show papillary, cribriform, trabecular, and nested symptoms related to either the ovarian mass or the stromal
patterns. Some tumors have abundant intracytoplasmic mucin luteinization generated by the tumor (abnormal uterine
with cells ranging from goblet type to foveolar type, raising bleeding, breast tenderness, etc.). Some patients present with
the differential diagnosis of a primary ovarian mucinous carci- nonspecific symptoms such as abdominal or pelvic pain [18
noma, but have the varied histologic patterns and desmoplasia 32]. Importantly, patients with ovarian metastasis from pri-
typical of mucinous neoplasms metastatic to the ovary. mary colorectal adenocarcinoma may have no symptoms
Microscopic features common to metastatic tumors in general related to the primary tumor and may have a unilateral ovar-
include areas of bland, benign-appearing mucinous epithelium ian mass greater than 10 cm [33].
and cysts lined by flattened epithelium, prominent stromal Pathologic Findings:
edema in areas, and notable morphologic variability within a Gross: Metastasis may be unilateral or bilateral. Several
small zone of tumor [30–32]. Signet ring cells, if present, by series have documented a higher percentage of unilateral
definition do not comprise more than 10% of the tumor. than of bilateral metastasis [9, 33, 34], although this has not
Biomarkers: Gastric adenocarcinoma of intestinal type been demonstrated in all series. Tumor size ranges from 2 to
shows variable positivity for CK7 and CK20, like gastric 24 cm and may be greater than 10 cm [18, 33]. Tumors tend
adenocarcinoma of diffuse type. Unlike gastric adenocarci- to have a smooth capsule without gross evidence of surface
noma of diffuse type, CDX2 is typically strongly, diffusely involvement by tumor, and lack the bosselation typical of
expressed. SATB2 may be positive or negative (limited data Krukenberg tumors. A minority are ruptured [33]. The cut
exists on SATB2 staining in gastric adenocarcinomas). There surface may be solid or solid and cystic, and may show large
may be weak staining for ER and/or PR. Tumor may be posi- thin-walled cysts suggesting an ovarian primary neoplasm.
tive for CA 19-9 and/or HepPar1 [21, 22]. Tissue is soft, friable, yellow, red, or gray, and may contain
Differential Diagnosis: The differential diagnosis mucinous or clear fluid, recent or remote hemorrhage, and
includes primary ovarian mucinous and endometrioid adeno- necrosis (Fig. 10.8) [2, 32].
carcinomas, and metastatic adenocarcinomas that may have
a mucinous, endometrioid, or pseudoendometrioid morphol-
ogy (primarily tumors of intestinal or appendiceal origin,
less commonly tumors of gallbladder or biliary tract origin).
Management and Outcomes: Limited data is available
on this infrequently reported ovarian metastasis. Of the four
patients reported in the 2006 series noted above, the three
patients with follow-up information were deceased within 1
year of discovery of the ovarian metastasis [30].
10.6.3 Colorectal Adenocarcinoma
Definition: Adenocarcinoma originating in the colon or rec-

tum. Colorectal adenocarcinoma is one of the most common
sources of metastatic ovarian tumor. One recent series of
STOs including 713 adenocarcinomas of colorectal origin
found that 50% of tumors originated from the rectosigmoid
Fig. 10.8 Metastatic colonic adenocarcinoma. The external surface is
colon, 37% from the ascending colon and cecum, 8% from relatively smooth and uninvolved by tumor. The cut surface in this case
the descending colon, and 5% from the transverse colon [9]. is solid, soft, yellow-tan, and necrotic appearing
Microscopic: Microscopically, tumors often have a pseu- pseudoendometrioid morphology, tumor glands are typically
doendometrioid, mucinous, or mixed pseudoendometrioid of moderate size but may range from small and tubular to
and mucinous character [34]. The pseudoendometrioid large and cystic (Figs. 10.11 and 10.12). Broad areas of
appearance is most typical of metastatic colorectal adenocar- necrosis may be present (Fig. 10.13). Frequently encoun-
cinoma and overall resembles typical primary colorectal tered architectural patterns include a cribriform pattern and a
adenocarcinoma; this pattern features columnar cells with “garland” pattern (neoplastic epithelium draped at the
only focal intracytoplasmic mucin (scattered goblet cells periphery of necrotic material). Intraluminal “dirty” necrosis
may be present) and marked nuclear atypia with nuclear and segmental necrosis of glandular epithelium are common
stratification and brisk mitotic activity (Figs. 10.9 and 10.10). features (Figs. 10.14 and 10.15). A papillary pattern, charac-
A mucinous-type epithelium, with more extensive well- terized by well-formed papillae or micropapillae, is occa-
differentiated mucin-rich cells, is a less commonly encoun- sionally seen [17, 18, 32, 34]. Rarely, a classic pattern of
tered cell type. In tumors characterized by the more common colloid carcinoma with clusters of neoplastic cells floating in
Fig. 10.9 Metastatic colonic adenocarcinoma. Like the majority of Fig. 10.11 Metastatic colonic adenocarcinoma. Tumor glands are
secondary ovarian tumors of colorectal origin, this tumor has pseudoen- most often of moderate size but may range from small and tubular to
dometrioid cytologic features, characterized by columnar cells with large and cystic, as in this case. Large cystic glands may mimic a pri-
only focal intracytoplasmic mucin. This area has a cribriform pattern mary ovarian mucinous neoplasm
Fig. 10.12 Metastatic colonic adenocarcinoma. Malignant epithelium

Fig. 10.10 Metastatic colonic adenocarcinoma. Brisk mitotic activity in the top portion of the photomicrograph lines a large cystic tumor
and marked nuclear atypia, in excess of that typically seen in endome- gland and is cytologically bland (“maturation phenomenon”), poten-
trioid adenocarcinoma with a comparable degree of glandular differentially mimicking the benign or borderline areas of a primary ovarian
tiation, typify these tumors mucinous neoplasm
pools of mucin may be encountered [32]. Occasionally,

metastatic tumors of small bowel or large bowel origin have
cells with clear cytoplasm, which may mimic an ovarian pri-
mary clear-cell carcinoma or secretory variant of endometri-
oid adenocarcinoma (Fig. 10.16). Signet ring cells may be
present in small numbers. No squamous differentiation is
present. Stroma may be desmoplastic, edematous, or mucoid,
and often contains luteinized stromal cells [2].
Lymphovascular space invasion is common [12].
Biomarkers: Typical immunohistochemical staining pro-
files for metastatic colorectal adenocarcinoma and its more
challenging differential diagnostic considerations are as fol-
lows [19, 21–23]:
–– Colorectal adenocarcinoma: Negative for CK7 in approx-

Fig. 10.13 Metastatic colonic adenocarcinoma. Broad areas of necro- imately 75–90% of cases, although adenocarcinomas of
sis, as seen in this tumor, are more common in metastatic tumors than rectal origin may be positive for CK7; typically strongly
in primary ovarian tumors
Fig. 10.14 Metastatic colonic adenocarcinoma. Intraluminal “dirty” Fig. 10.15 Metastatic colonic adenocarcinoma. Segmental necrosis of
necrosis is a common feature glandular epithelium and a “garland pattern” in which the neoplastic
epithelium is draped at the periphery of necrotic material are often seen
Fig. 10.16 Metastatic colonic adenocarcinoma with unusual morpho- mullerian clear-cell adenocarcinoma. Right: Tumor may occasionally
logic patterns. Left: A papillary pattern, with large well-formed papil- have a colloid appearance, with groups of tumor cells floating in abun-
lae. A micropapillary pattern may also be seen. Center: Adenocarcinoma dant dissecting mucin
of small or large bowel origin may have clear cytoplasm, mimicking
Fig. 10.17 Metastatic colonic adenocarcinoma. In contrast to endometrioid adenocarcinoma, tumor is typically immunoreactive for CK 20 (left),
CDX2 (center), and SATB2 (right)
positive for CK20 (80–100% of cases), but may infre- gallbladder, bile ducts, pancreas, uterine cervix, endome-
quently show no or only focal positivity for CK20 trium, or urachus. Adenocarcinoma of breast and lung origin
(decreased CK20 staining is associated with microsatel- may also occasionally mimic endometrioid adenocarcinoma
lite unstable carcinomas); typically positive for SATB2 [32]. Of these, mucinous and endometrioid adenocarcinomas
(96%), CDX2 (72–100%), and DPC4/SMAD4; negative of ovarian origin are the most difficult to exclude when con-
for PAX8, ER, and PR (Fig. 10.17). sidering metastasis from a colorectal primary. Features help-
–– Mucinous tumors of intestinal phenotype, ovarian origin ful in discriminating between the top differential diagnostic
(excluding the subset of ovarian mucinous carcinomas considerations are as follows:
arising in association with a teratoma): Typically positive Features favoring metastatic colon cancer:
for CK7, although infrequently may be negative; CK20
expression variable, sometimes negative but more often • A known colorectal primary.
patchy positive; variable expression of CDX2 and PAX8; • Gross findings of bilaterality, multinodularity of tumor,
typically positive for DPC4/SMAD4; typically negative and ovarian surface involvement.
for SATB2, ER, and PR. • Prominent “dirty” necrosis, segmental necrosis of tumor
–– Mucinous tumors of intestinal phenotype, ovarian origin, epithelium, higher nuclear grade and more mitotic activ-
arising in association with a teratoma: ity than is typical of endometrioid adenocarcinoma with a
Immunohistochemical staining profile is indistinguish- similar degree of glandular differentiation, and lympho-
able from that of metastatic tumors of intestinal origin vascular space invasion.
(CK7−/CK20+/SATB2+/CDX2+/PAX8−/ER−/PR−).
–– Seromucinous tumors of ovarian origin: Typically CK7+/ Features favoring primary ovarian endometrioid
PAX8+/ER+/PR+/CK20-/CDX2−. adenocarcinoma:
–– Endometrioid tumors of ovarian or endometrial origin:
CK7+/ER+/PR+/PAX8+/DPC4/SMAD4+/CK20−; may • Squamous differentiation, an adenofibromatous compo-
focally express CDX2. nent, and/or a background of endometriosis.
• Gross findings of unilaterality of tumor, an often cystic
Immunohistochemical staining may be used in the workup cut surface, and presence of chocolatey material related to
of mucinous and endometrioid/pseudoendometrioid tumors remote hemorrhage and endometriosis.
involving the ovary, although there is overlap in staining pat- • Primary endometrioid adenocarcinoma usually has less
terns between ovarian primary and metastatic neoplasms; thus, prominent necrosis than does metastatic colorectal adeno-
circumspect interpretation and correlation with clinical find- carcinoma; however, it may show the “dirty” and/or seg-
ings are required. Note that CDX2 is not specific for intestinal mental epithelial necrosis more characteristic of colorectal
carcinoma and may be demonstrated in tumors of endometrial, adenocarcinoma [2].
pancreatobiliary, gastric, lung, bladder, and ovarian origin. For
additional information regarding immunohistochemical stain- Features favoring primary ovarian mucinous
ing features of tumors in this differential, please see Table 10.1. adenocarcinoma:
Differential Diagnosis: The differential diagnosis
includes primary ovarian tumors of mucinous and endome- • Presence of a teratoma.
trioid types, and metastatic tumors with similar morphology • Large unilateral tumor (although metastatic colorectal car-
that may arise from the appendix, small bowel, stomach, cinoma may also be unilateral and large) [9, 18, 33, 34].
• Like primary ovarian endometrioid adenocarcinoma, pri- bowel adenocarcinoma accounted for only 1.7% of ovarian
mary ovarian mucinous adenocarcinoma has a lower inci- metastases in one large series [9]. A 2017 case report and
dence of multinodularity and ovarian surface involvement review of the literature detailing 72 cases of adenocarcinoma
than does metastatic colorectal adenocarcinoma. of small bowel origin metastatic to the ovary noted a mean
• Microscopically, small areas of invasive carcinoma with patient age of 46.7 years in the 12 cases well documented
extensive benign-appearing mucinous tumor favor an enough to report, with solitary metastasis to the ovary in the
ovarian primary mucinous tumor, although metastatic majority of these cases and peritoneal dissemination in a sub-
colorectal cancers may also have deceptively bland epi- stantial minority of cases [39]. Although the duodenum is the
thelium and large cysts that mimic a benign or borderline area of the small bowel most frequently involved by adenocar-
primary ovarian tumor (Figs. 10.11, 10.12). cinoma (with most of the tumors arising around the ampulla of
• Primary ovarian mucinous carcinoma does not typically Vater), the jejunum was the most frequently involved section
show the “dirty” necrosis or lymphovascular space inva- of small bowel generating ovarian metastasis in this 2017
sion more characteristic of metastatic colorectal cancer. series, giving rise to 69% of the 12 well-documented cases.
• Ovarian primary mucinous carcinomas have goblet cells Pathologic Findings:
more frequently than do metastatic colonic adenocarcino- Gross: Literature regarding gross findings in metastatic
mas, although metastatic colonic adenocarcinomas may tumors of small bowel origin is limited. Metastatic tumor
have goblet cells as well [2, 12]. may be bilateral or unilateral, and may be cystic or solid and
cystic. In the 2017 series noted above, 51% of the tumors
Metastatic colorectal cancer is the most common primary were bilateral and 49% unilateral. The largest documented
site generating metastatic tumor to the ovary in many series tumor was 26 cm [39].
in Western nations, and has a greater tendency to be unilat- Microscopic: Literature regarding microscopic findings in
eral and greater than 10 cm relative to other primary sites. metastatic tumors of small bowel origin is likewise limited.
This evidence is contradictory to the conventional concept of Microscopically, the tumors most often appear as conventional
metastatic cancer, in which metastatic tumor is more fre- intestinal type adenocarcinoma as would be seen in metastasis
quently bilateral and less than 10 cm in size. Therefore, we from the large bowel, and thus may have a pseudoendometri-
recommend that the threshold should be relatively low for oid or mucinous character. Tumor differentiation varies from
considering the possibility of metastatic colon cancer for well differentiated to moderately to poorly differentiated [39].
tumors with microscopic features suggesting that diagnosis. Adenocarcinoma of small bowel origin may occasionally have
A directed panel of immunohistochemical stains should be an unusual, strikingly clear cytoplasm, which may mimic
employed when the primary site is not clear, although over- ovarian clear-cell carcinoma or the secretory variant of endo-
lap in immunohistochemical staining patterns mandates that metrioid adenocarcinoma. Tumor with this unusual morphol-
caution in interpretation is warranted, and that clinical find- ogy is characterized by glands and cysts lined by cells with
ings must be taken into consideration. abundant clear cytoplasm, including some areas with subnu-
Management and Outcomes: Colorectal adenocarci- clear or supranuclear vacuoles. These cases do typically show
noma metastatic to the ovary qualifies as stage IV disease the “dirty” necrosis characteristic of intestinal type adenocar-
and has had a poor outcome relative to the primary ovarian cinomas. Tumors demonstrating both conventional intestinal
neoplasms in the differential diagnosis. The treatment strat- type adenocarcinoma morphology and the more unusual clear-
egy is not currently well defined. A few studies have sup- cell morphology noted above have been described [35].
ported a higher median overall survival in patients undergoing Biomarkers:
metastasectomy [36, 37].
–– Non-ampullary small intestinal adenocarcinomas tend to
have a CK7+/CK20+ immunophenotype (66%). CK7
10.6.4 Metastasis from Small Intestine expression may be focal or diffuse. Approximately 33%
have a CK7+/CK20− immunophenotype. Both of these
Definition: Adenocarcinoma of small bowel origin meta- staining patterns contrast with that of colorectal adeno-
static to the ovary. carcinoma (usually CK7−/CK20+) [22].
Clinical Features: Most intestinal tumors metastatic to the –– Approximately 60–70% of small intestinal adenocarcino-
ovary are from the large bowel, although occasional tumors mas stain positively for CDX2 [22].
originate from the small intestine. Risk factors for adenocarci- –– A subset (46%) of small intestinal adenocarcinomas stain
noma of the small intestine include Crohn’s disease, celiac positively for SATB2, although staining tends to be less
disease, Peutz-Jeghers syndrome, familial adenomatous pol- strong and diffuse than that seen in colorectal adenocarci-
yposis (FAP), and hereditary nonpolyposis colorectal cancer nomas [40].
syndrome [38]. In accordance with its low incidence, small- –– Tumors are negative for PAX8, ER, and PR.
Differential Diagnosis: 10.6.5 Metastasis from Appendix

Small-bowel adenocarcinoma with conventional intestinal
type differentiation: For small-bowel adenocarcinoma with Definition: Metastasis to the ovary from a primary appendi-
conventional intestinal type differentiation, the differential ceal neoplasm. Diagnostic entities in the appendix with
diagnosis includes primary ovarian mucinous and endometri- capacity to metastasize include low-grade appendiceal muci-
oid tumors, and metastatic tumors with a similar morphology nous neoplasm (LAMN), high-grade appendiceal mucinous
that may arise from the large bowel, appendix, stomach, gall- neoplasm (HAMN, rare), and adenocarcinoma.
bladder, bile ducts, pancreas, uterine cervix, endometrium, or Adenocarcinomas may be of mucinous type, conventional
urachus [2]. Adenocarcinoma of breast or lung origin may intestinal type, or signet ring cell type.
also be included in the differential diagnosis due to their Clinical Features: Ovarian metastasis of appendiceal ori-
occasional resemblance to endometrioid adenocarcinoma gin is less common than metastatic colorectal or breast cancer
[32]. Of these, primary ovarian mucinous and endometrioid in most series [3, 6, 9]. Ovarian spread from a primary appen-
adenocarcinomas are the most challenging to exclude. diceal neoplasm is most common in cases of LAMN of the
Clinical and morphologic features that may aid in this differ- appendix, although ovarian spread may also be seen in cases of
ential diagnosis are as described above in the section on dif- adenocarcinoma of the conventional intestinal and mucinous
ferential diagnosis of metastatic tumors of colorectal origin. types, carcinomas with neuroendocrine differentiation and
Clear cell variant of small-bowel adenocarcinoma: For focal goblet cell carcinoid patterns, colloid and signet ring cell
the clear cell variant of small-bowel adenocarcinoma, the carcinomas, and rarely typical carcinoid tumors [2, 44, 45].
differential diagnosis includes primary ovarian clear-cell LAMN: LAMNs usually present in the sixth decade, and
carcinoma and endometrioid adenocarcinoma, secretory may present as an abdominal mass or as an ovarian metasta-
variant. Importantly, the clear cell variant of small-bowel sis [46, 47]. Other presentations include abdominal pain or
adenocarcinoma does not have the classic morphologic fea- distention, which is often due to pseudomyxoma peritonei
tures diagnostic of mullerian clear-cell adenocarcinoma (see below). Approximately 15–20% of LAMNs are inciden-
(tubulocystic architectural pattern, papillae with hyalinized tal findings in patients undergoing surgery for unrelated con-
fibrovascular cores, hobnailing of cells, etc.); however, papil- ditions [46]. With LAMN, the appendix is usually dilated
lae and micropapillae may be seen in metastatic carcinomas and often has adherent mucin; an obvious associated solid
of intestinal origin [32]. Secretory endometrioid adenocarci- mass is often not detected.
noma is rare and, when seen, may have squamous differen- Appendiceal Adenocarcinoma: Appendiceal adenocar-
tiation, an association with endometriosis, or a component of cinomas are uncommon, with an incidence of 0.082% out of
endometrioid adenofibroma, like conventional endometrioid 50,000 appendectomy specimens. Patients are usually in the
adenocarcinoma. Areas with other morphologies typical of fifth to seventh decades, and usually present with symptoms
mullerian primaries may also be seen and provide a clue to of acute appendicitis [46]. Less common presentations
the diagnosis. include a palpable mass, intestinal obstruction, gastrointesti-
Clinical identification of small-bowel primary tumors can nal bleeding, or symptoms related to metastasis. Patients
be challenging, as they are not revealed on colonoscopy or may also be asymptomatic. One 2007 study including 48
upper endoscopy; thus, if an ovarian tumor with an intestinal patients with primary appendiceal malignant neoplasms of
phenotype is identified and metastasis is suspected, it is rea- various histologic types metastatic to the ovary determined
sonable to consider the small bowel as a source, even when that the most common symptoms were abdominal pain and
endoscopy is negative [38]. bloating [48].
Management and Outcomes: Small-bowel adenocarci- Pseudomyxoma Peritonei: “Pseudomyxoma peritonei”
noma is typically resected when possible. Tumors are most refers to a clinicopathologic syndrome in which the perito-
often diagnosed at an advanced stage. A median survival of neal cavity contains more or less abundant mucinous mate-
39.7 months was demonstrated in one large study of surgi- rial, associated with variable amounts of viable epithelial
cally resected cases [41], whereas median survival has been glandular cells derived from a mucinous neoplasm.
demonstrated to be markedly lower (8 months) in patients Historically, it was stated that the primary lesion could be a
with unresectable tumors [42]. Chemotherapy using fluoro- borderline or malignant mucinous neoplasm of appendiceal,
pyrimidine plus a platinum salt appears to be the most effec- pancreatic, or ovarian origin. More recently, however, stud-
tive treatment regimen in nonrandomized prospective trials ies have led to the conclusion that the appendix is the site of
for advanced small-bowel adenocarcinoma at this time. origin in almost all cases, and that any ovarian involvement
Targeted therapy against EGFR is not yet established but is is metastatic [49, 50]. Most cases of pseudomyxoma perito-
under investigation. Phase I and phase II studies to evaluate nei arise from low-grade appendiceal mucinous tumors,
the safety and efficacy of targeted therapies in small-bowel either LAMN or low-grade adenocarcinoma. Rarely, a
adenocarcinoma treatment are currently underway [43]. primary ovarian mucinous neoplasm of gastrointestinal

Fig. 10.18 Pseudomyxoma peritonei involving the omentum. The Fig. 10.19 Metastatic LAMN. Abundant mucin and neoplastic epithe-
external surface shows the characteristic gelatinous appearance lium involve the ovarian surface
p henotype associated with a teratoma may spread to the peri-

toneum and cause pseudomyxoma peritonei [51].
Gross:
LAMN: Secondary ovarian tumors originating from
LAMNs are bilateral in the majority of cases [52], with a
mean diameter of 15–16 cm. There is often generalized pseu-
domyxoma peritonei (Fig. 10.18), and mucinous material
may conspicuously coat the surface of one or both ovaries.
Tumors are usually multilocular/multicystic and mucoid on
cut surface, although in some cases the tumor may have a
firmer, more solid character due to organization of mucin
with fibrosis [49].
Appendiceal Adenocarcinoma: Secondary ovarian
tumors originating from appendiceal adenocarcinoma are
also bilateral in the majority of cases, and have a mean diam-
Fig. 10.20 Metastatic LAMN. Large neoplastic glands, some incom-
eter of 11 cm. The cut surface is usually solid and firm, but a plete, haphazardly involve the ovarian stroma and are associated with
cystic component may be present, particularly in low-grade dissecting extracellular mucin (pseudomyxoma ovarii)
adenocarcinomas [52]. Ovarian involvement by appendiceal
adenocarcinoma of conventional intestinal type has a gross
appearance similar to that of metastatic intestinal appears to extrude (Fig. 10.21). The glands and cysts are
adenocarcinoma, while ovarian involvement by appendiceal haphazardly distributed in the ovarian stroma, are often
adenocarcinoma of signet ring type has a gross appearance incomplete, may have a scalloped contour, and often exhibit
similar to that of Krukenberg tumor. Moderate- to high-grade retraction from the adjacent stroma resulting in cleft-like
mucinous adenocarcinomas may have nonspecific gross fea- spaces around the neoplastic glands (Fig. 10.22). This retrac-
tures or may have a gelatinous consistency [12]. tion from the adjacent stroma is a characteristic feature of
Microscopic: metastatic LAMN [12, 50, 52]. Overall, there is a remark-
LAMN: Secondary ovarian tumors originating from ably bland appearance to the tumor cells throughout most of
LAMNs usually have mucin on the ovarian surface, which the neoplasm in the majority of cases, although there may be
may or may not be associated with neoplastic epithelium, some mild-to-moderate nuclear atypia [2].
and dissecting extracellular mucin within the ovary (pseudo- Appendiceal Adenocarcinoma: Secondary ovarian
myxoma ovarii) (Figs. 10.19 and 10.20). The neoplastic tumors originating from appendiceal adenocarcinomas may
glands and cysts are lined by tall, well-differentiated, mucin- be of conventional intestinal type, intermediate- to h igh-grade
rich (hypermucinous) epithelium, from which mucin often mucinous type, or signet ring type. Tumors of conventional
Fig. 10.21 Metastatic LAMN. Neoplastic epithelium is tall columnar Fig. 10.23 Adenocarcinoma of appendiceal origin metastatic to the
and bland with mucin-rich cytoplasm ovary. Tumor in this field has nonspecific medium-sized gland mor-
phology and destructive stromal invasion. The tumor showed a diversity
of morphology in other sections, with both gland formation and signet
ring cells
Fig. 10.22 Metastatic LAMN. Neoplastic epithelium has a scalloped

contour and shows retraction from the adjacent stroma, unique features
seen in many cases of metastatic LAMN
Fig. 10.24 Tumor classified as “goblet cell carcinoid,” metastatic to
the ovary. In this area the tumor shows the characteristic neoplastic gob-
intestinal type and mucinous type resemble those of similar let cells, arranged in small tight clusters. In other areas there was a
classic pattern of gland-forming adenocarcinoma with frankly infiltra-
type arising from elsewhere in the GI tract. These tumors
tive growth
have no unique morphologic characteristics, except for the
presence of operative findings suggesting the appendix as the
likely primary site [2]. A diversity of morphology is present adenocarcinomas with neuroendocrine differentiation rather
in some cases, such that the adenocarcinoma may show both than goblet cell “carcinoids” [53]. In this series, the appendi-
gland formation and signet ring cells (Fig. 10.23) [32, 44]. ceal and ovarian tumors showed a variety of architectural
Adenocarcinoma with Neuroendocrine Differentiation: patterns including signet ring cell, glandular, nested, and
The appendix may also give rise to adenocarcinomas with corded patterns with goblet cells. Interestingly, signet ring
neuroendocrine differentiation, which have historically been cells are often a conspicuous feature of this tumor, and
termed “goblet cell carcinoid” (Fig. 10.24). There is limited metastasis from this tumor constitutes one form of
literature on ovarian spread of these tumors. A 2007 series of Krukenberg tumor [2, 32]. The metastatic tumors may have
30 cases of ovarian metastases from tumors of this type noted focal areas with features diagnostic of what has historically
that the overall clinical features and morphologic findings been termed “goblet cell carcinoid,” but the presence of frank
support classification of most of these tumors as metastatic destructive, infiltrative growth merits classification of the
tumor as an adenocarcinoma with neuroendocrine differen- As primary and metastatic tumors to the ovary may have
tiation [53, 54]. Of note, the involved appendix may be firm overlapping immunohistochemical staining patterns, immu-
and thickened but may not have a grossly identifiable dis- nostaining may be of limited value in certain cases; how-
crete mass; thus, the appendiceal primary tumor may be ever, a panel of immunostains should be employed when the
overlooked at operation [53]. Even when an appendiceal pri- source of tumor is uncertain. Positive staining for PAX8,
mary tumor is not identified, a goblet cell carcinoid-like pat- CK7, ER, or PR favors a primary ovarian tumor, although
tern within an ovarian tumor should suggest an appendiceal negative staining for these markers does not exclude an
primary tumor. Appendiceal tumors meeting the criteria for ovarian primary. Rare mucinous primary ovarian tumors
“goblet cell carcinoid,” as strictly defined, rarely metastasize with an intestinal phenotype associated with a teratoma may
to the ovary. Likewise, typical carcinoids of appendiceal ori- generate pseudomyxoma peritonei, a finding almost always
gin rarely metastasize to the ovary [32]. ascribable to an appendiceal primary neoplasm [51]; these
Biomarkers: tumors have an immunophenotype indistinguishable from
metastatic tumors of intestinal origin (CK7−/CK20+/
–– LAMNs and mucinous adenocarcinomas of appendiceal CDX2+/SATB2+/PAX8−).
origin typically express CK20, CDX2, DPC4/SMAD4, Management and Outcomes: Overall, low-grade appen-
and SATB2. Approximately one-third express CK7, with diceal mucinous neoplasms (LAMNs) involving the ovary
approximately 25–75% of cells staining. exhibit more indolent behavior and have a better prognosis
–– Appendiceal adenocarcinomas of conventional intestinal than appendiceal adenocarcinomas [56]. The prognosis and
type are immunophenotypically similar to colorectal treatment of LAMN are dependent on tumor stage. LAMN
adenocarcinomas. pursues a progressive clinical course when it is widely dis-
–– Appendiceal “goblet cell carcinoids” have a mixed immu- seminated in the peritoneum [46]. Currently, complete cyto-
nophenotype that shows both neuroendocrine and glandu- reductive surgery plus hyperthermic intraperitoneal
lar differentiation; most are positive for CK20, up to 70% chemotherapy (HIPEC) is the most commonly employed
are positive for CK7, and staining with neuroendocrine treatment for pseudomyxoma peritonei (PMP).
markers synaptophysin and chromogranin A is focal Regarding appendiceal adenocarcinomas, the reported
rather than diffuse [22]. 5-year survival rates range from 18.7 to 55%. Patients with
mucinous carcinoma have a better prognosis than those with
Differential Diagnosis: non-mucinous carcinoma. Patients with peritoneal carcino-
LAMN: The differential diagnosis of secondary ovarian matosis have a poor prognosis. As with LAMN, treatment
involvement with LAMN is with primary ovarian mucinous depends on disease stage [46].
cystadenoma, mucinous borderline tumor, and mucinous
carcinoma. Metastatic LAMN is favored by the presence of
an appendiceal neoplasm, bilateral ovarian involvement, 10.7 M
etastasis from the Pancreas, Biliary
pseudomyxoma peritonei and/or ovarii, scalloped neoplastic Tract, and Liver
glands, and subepithelial clefting. The presence of a tera-
toma or PAX-8 positivity favors an ovarian primary. 10.7.1 Pancreas
Importantly, a lack of grossly identifiable appendiceal rup-
ture does not rule out that the tumor originated in the appen- Definition: Metastatic adenocarcinoma originating from the
dix, as the rupture site may be small and difficult to identify, pancreas, most often adenocarcinoma of ductal type. Ovarian
or healed over by fibrosis [55]. metastases of pancreatic mucinous cystadenocarcinoma, aci-
Appendiceal adenocarcinoma: The differential diagnosis nar cell carcinoma, neuroendocrine tumors, and solid pseu-
of metastatic appendiceal adenocarcinoma is with primary dopapillary tumor have also been infrequently to rarely
ovarian mucinous and endometrioid adenocarcinomas, and reported.
with metastatic adenocarcinomas of mucinous and endome- Clinical Features: The frequency of pancreatic adeno-
trioid/pseudoendometrioid types originating elsewhere. The carcinoma metastatic to the ovary has varied in recent
distinction of a primary ovarian neoplasm from metastatic Western series, although the pancreas typically represents
tumor of appendiceal or other origin depends to a great the source of fewer than 10% of nongenital tract primary
degree on adequate sampling of the ovarian neoplasm and tumors generating a clinically apparent ovarian metastasis
clinical correlation. General features favoring metastatic car- [4]. Ovarian spread is often part of disseminated disease but
cinoma include a known extraovarian primary tumor, bilater- has been the dominant clinical finding or presenting clinical
ality, multinodular growth pattern, involvement of the finding in some cases [57]. Patients are usually in their mid
ovarian surface, high stage of disease, and histologic features to late years of life, with reported mean ages ranging from 56
unusual for a primary ovarian neoplasm. to 63 years.
Pathologic Findings: Biomarkers:

Gross: Ovarian metastases originating from pancreatic
ductal adenocarcinoma and mucinous cystadenocarcinoma –– Pancreatic ductal adenocarcinoma: Typically CK7 posi-
are typically bilateral and often form solid nodules like other tive. Staining with CK20 is variable, with most tumors
tumors metastatic to ovary; however, the tumors may be being either negative or focally positive. Loss of reactivity
large, unilateral, cystic, or multiloculated, mimicking a pri- for DPC4/SMAD4 specifically suggests a pancreatic pri-
mary ovarian mucinous carcinoma [57]. mary, as approximately 50% of these tumors show loss of
Microscopic: Metastatic pancreatic ductal adenocarci- DPC4/SMAD4; however, positivity for DPC4/SMAD4
noma and mucinous cystadenocarcinoma may form solid does not rule out a pancreatic primary or suggest any
nodules and/or cysts. In tumors with solid nodules, a pattern other primary neoplasm specifically.
of small neoplastic glands haphazardly infiltrating a desmo- –– Pancreatic acinar cell carcinoma: Positive for chymotryp-
plastic stroma is the typical appearance. Single tumor cells sin and trypsin, and negative for neuroendocrine markers
and signet ring cells may be present. In tumors with cyst for- [59].
mation, foci resembling mucinous cystadenoma, mucinous
borderline tumor, and primary ovarian moderately differenti- Differential Diagnosis: The differential diagnosis of pan-
ated to well-differentiated mucinous adenocarcinoma may creatic adenocarcinoma of ductal or mucinous type includes
be present (Fig. 10.25); interestingly, this variation from primary ovarian mucinous neoplasms and similar-appearing
high-grade invasive malignancy to low-grade cystic neopla- metastases from other sites. General features favoring metas-
sia (“maturation phenomenon”) is a distinctive feature of the tasis include bilaterality, a multinodular growth pattern,
tumor which may provide a clue to the diagnosis. Foci of tumor implants on the ovarian surface and in the superficial
frank malignancy are often present but may be focal. Surface cortex, variable histologic patterns, lymphovascular space
tumor implants and lymphovascular invasion may be seen. invasion, and intra-abdominal spread of tumor [2, 12]. The
Rarely, the gross and microscopic appearance is typical of differential diagnosis for the rare pancreatic acinar cell carci-
Krukenberg tumor [2, 57]. noma metastatic to the ovary can include carcinoid tumor
Only a few cases of pancreatic acinar cell carcinoma met- and other neuroendocrine tumors due to the acinar architec-
astatic to the ovary have been reported [58]. Microscopically, ture, although the distinctive eosinophilic granular cytoplasm
tumors are characterized by cells with round nuclei, stippled and nuclear characteristics of acinar cell carcinoma contrast
chromatin, prominent nucleoli, and abundant pale to eosino- with those of usual endocrine neoplasms [2].
philic finely granular cytoplasm, similar to their primary Management and Outcomes: Pancreatic adenocarci-
counterpart in the pancreas. Architectural patterns include noma typically has a poor prognosis due to the early devel-
solid nests and acinar structures of varying sizes ranging up opment of systemic metastatic disease. Currently available
to small cysts, with little intervening stroma. The mitotic rate chemotherapeutic agents show a modest but statistically sig-
is typically brisk, and lymphovascular space invasion is nificant improvement in survival [60].
common.
10.7.2 Tumors of Gallbladder, Extrahepatic

and Intrahepatic Bile Ducts
Definition: Adenocarcinoma of gallbladder or biliary ductal

(extrahepatic or intrahepatic) origin.
Clinical Features: The incidence of biliary tract cancer
metastatic to the ovary varies significantly with geographic
area, reflecting the variable regional incidence of biliary tract
adenocarcinoma. In the United States, few examples have
been reported over the years [61, 62]. Thailand has the high-
est incidence of cholangiocarcinoma worldwide due to infes-
tation with Opisthorchis viverrini, endemic in northern
regions of the country; thus, metastatic biliary neoplasms are
more common there than elsewhere [32]. In a 2006 study of
170 tumors of gynecologic and nongynecologic origin meta-
static to the ovary in Northern Thailand, cancer involving
Fig. 10.25 Pancreatic adenocarcinoma metastatic to the ovary. This intrahepatic bile ducts accounted for 10% of ovarian metas-
particular example features well-differentiated glands of varying sizes tases, while cancer involving extrahepatic biliary ducts and
gallbladder accounted for 7% of ovarian metastases [6].

Patients range in age from the third to the ninth decades, with
a mean age of 59 years. Tumors may present with symptoms
related to the primary tumor (jaundice, pruritis, cholangitis,
etc.), or may present initially as an ovarian mass [62–64].
Gross: Regarding carcinoma of the gallbladder and extra-
hepatic bile ducts metastatic to the ovary, most tumors are
bilateral, with a mean size of 9.4 cm. The cut surfaces are
variable, most often solid and cystic but sometimes solid or
multicystic [63]. Regarding carcinoma of the intrahepatic
bile ducts metastatic to the ovary, about two-thirds of cases
are bilateral, with a mean size of 12 cm. Again, the majority
of reported tumors are solid and cystic, but many are cystic
or uniformly solid [2, 64].
Microscopic: Carcinoma metastatic to the ovary from the Fig. 10.27 Metastatic adenocarcinoma of gallbladder origin. The
gallbladder and extrahepatic or intrahepatic bile ducts often tumor has a mucinous morphology overall, although intracytoplasmic
shows the multinodular growth (obvious or vague), ovarian mucin is not prominent
surface involvement, and varied histologic patterns typical of
metastatic tumor, but may closely mimic a primary ovarian
mucinous neoplasm [61, 62]. Cytologic and architectural
patterns vary and overall are similar to primary ovarian
mucinous tumors and mucinous adenocarcinomas metastatic
from other sites, including colon and, most notably, pan-
creas. Tumors are typically gland forming and may show a
mucinous morphology with or without abundant extracellu-
lar mucin, a pseudoendometrioid morphology, or the non-
specific small- to medium-sized gland morphology typical of
biliary tract adenocarcinomas (Figs. 10.26, 10.27, 10.28, and
10.29). Some tumors have shown substantial signet ring
morphology, qualifying for a diagnosis of Krukenberg tumor
[32, 61, 63, 64]. Tumors may have striking cytologic atypia
Fig. 10.28 Metastatic adenocarcinoma of gallbladder origin. Signet

ring cells are interspersed among columnar cells and line papillae.
Exceptionally, tumors of biliary tract origin may have substantial signet
ring morphology
discordant with the degree of glandular differentiation.

Additionally, like metastatic tumors of pancreatic origin,
tumors may show remarkably bland, benign-appearing areas
mimicking a mucinous cystadenoma or mucinous borderline
tumor (“maturation” phenomenon), although most tumors
are clearly malignant [32, 62].
Biomarkers: Carcinomas of the extrahepatic bile ducts
and gallbladder almost always express CK7 and may also
express CK20. In contrast, intrahepatic cholangiocarcinomas
are positive for CK7 but tend to be negative for CK20. The
Fig. 10.26 Metastatic adenocarcinoma of gallbladder origin. Tumor tumors typically express CA 19.9 and CK19. ER may be
may show a mucinous, pseudoendometrioid, or nonspecific small- to
medium-sized gland morphology typical of biliary tract neoplasms.
detected in a small percentage of cases [59].
This example forms large glands, mimicking a primary ovarian Differential Diagnosis: Adenocarcinomas of gallbladder
neoplasm and intrahepatic or extrahepatic bile duct origin metastatic to
Microscopic findings overall are characteristics of hepato-

cellular carcinoma, although in rare cases cysts may be
prominent. Neoplastic cells show the moderate to abundant
eosinophilic cytoplasm and polygonal cell shape typical of
hepatocellular carcinoma [2, 67, 68].
Biomarkers: Hepatocellular carcinomas are negative for
CK20 and CKAE1/AE3, and are often negative for CK7
(approximately 30% may be positive). They are often positive
for CK8, CK18, and CAM5.2. They are usually positive for
HepPar 1 (80–100% of cases) and may be positive for glypi-
can-3 (50–90% of cases) and AFP (17–70% of cases) [59].
Differential Diagnosis: Given the relatively distinctive
cytomorphologic features of hepatocellular carcinoma, the
differential diagnosis includes primary ovarian hepatoid yolk
sac tumor and hepatoid adenocarcinomas of primary ovarian
Fig. 10.29 Metastatic adenocarcinoma of gallbladder origin. Like and extraovarian origin. Hepatoid yolk sac tumor typically
metastatic tumors from the pancreas and other gastrointestinal sites, occurs at a younger age than hepatocellular carcinoma and
metastatic adenocarcinoma of biliary tract origin may have areas with hepatoid adenocarcinomas, and should show other morpho-
bland cells mimicking the benign or borderline areas of a primary ovar- logic features characteristic of yolk sac tumor and/or other
ian mucinous neoplasm
germ cell elements. Hepatoid adenocarcinomas are rare, and
may originate from the ovary and from various extraovarian
the ovary have no strikingly unique morphologic or immuno- sites including the stomach, gallbladder, colon, lung, and uri-
histochemical staining features and may resemble mucinous nary bladder, among other sites [69]. Hepatoid
and endometrioid or pseudoendometrioid adenocarcinomas adenocarcinomas are often more pleomorphic than hepato-
originating from the ovary and other sites. cellular carcinoma and occur in an older age group [12].
Immunohistochemistry is of limited value in determining Hepatoid adenocarcinomas may also show foci of more typi-
primary site in this instance. If gross and microscopic fea- cal adenocarcinoma, providing a clue to the diagnosis.
tures suggest metastasis but the primary site is not clear, cor- Hepatoid adenocarcinomas often express the hepatocellular
relation with clinical findings, and a directed battery of markers HepPar1, glypican-3, and AFP, limiting their useful-
immunohistochemical stains, is recommended. ness in the differential diagnosis.
Management and Outcomes: Metastatic biliary tract Management and Outcomes: For patients with meta-
cancer overall has a poor prognosis. Currently available sys- static hepatocellular carcinoma, significant challenges exist
temic therapies for advanced/metastatic biliary tract cancers in achieving favorable treatment outcomes with currently
are of limited therapeutic efficacy [65]. Candidate agents for available systemic therapies. Patients with advanced-stage
targeted, “personalized” therapy are emerging [66]. disease have an overall poor prognosis [70].
10.7.3 Metastasis from Liver 10.8 Metastatic Neuroendocrine Tumors
Definition: Tumor of hepatocellular origin metastatic to the Neuroendocrine tumors arise in various organs including the
ovary. gastrointestinal tract, pancreas, thyroid, lung, and skin. The
Clinical Features: Hepatocellular carcinoma metasta- most common type of neuroendocrine tumor giving rise to
sizes to the ovary less commonly than pancreatobiliary ade- ovarian metastasis is the well-differentiated type of neuroen-
nocarcinoma, and only a few such cases have been reported docrine tumor historically referred to as “carcinoid tumor.”
[67, 68]. All patients have been adults. Ovarian metastases They are most often of small bowel origin, although occasion-
have been discovered prior to discovery of the liver tumor, ally of appendiceal, colonic, gastric, pancreatic, or lung origin
synchronously, and after detection of the liver tumor. (of note, the term “carcinoid tumor” is no longer commonly
Pathologic Findings: used in reference to neuroendocrine tumors of the gastrointes-
Gross: Ovarian tumors in the two reported series range tinal tract, and has been replaced by the term “well-differenti-
from 4 to 11 cm. Most tumors have a solid cut surface. A ated neuroendocrine tumor” (NET)). The following discussion
green hue may provide a clue to the diagnosis [2, 67, 68]. focuses on well-differentiated neuroendocrine tumors/carci-
Microscopic: Features typical of metastatic disease, such noid tumor. High-grade neuroendocrine carcinoma, a more
as ovarian surface involvement, are seen in some cases. clinically aggressive and poorly differentiated tumor type
exemplified by, but not restricted to, small-cell carcinoma of white to yellow and may resemble an ovarian fibroma or the-
the lung, metastasizes to the ovary from various organs less coma grossly [2, 32, 71, 72].
often than well-differentiated neuroendocrine tumors, and is Microscopic: Metastatic carcinoid tumor in the ovary
discussed briefly in relevant sections below. shows microscopic features similar to primary carcinoid tumor
Definition: Tumor arising from cells that release hor- in the ovary and other organs. Tumor cells are characteristi-
mones into the bloodstream in response to a signal from the cally uniform with round to ovoid nuclei, finely granular chro-
nervous system. matin, inconspicuous nucleoli, and moderate-to-abundant
Clinical Features: Evaluation of literature related to eosinophilic cytoplasm (Fig. 10.30). Mitoses are infrequent,
well-differentiated neuroendocrine tumor/carcinoid tumor but occasional pleomorphic cells or cells with nucleolar prom-
metastatic to the ovary is complicated by the varied criteria inence may be seen. These classic cytologic features are the
that have been employed over the years for diagnosis of such most frequently encountered, but cells may occasionally have
tumors. If strict diagnostic criteria are applied, tumors meet- clear or oncocytic cytoplasm, or a spindled morphology. Cells
ing the diagnostic criteria for well-differentiated endocrine are typically disposed in one or more architectural patterns
tumor/carcinoid tumor from any source rarely metastasize to common to neuroendocrine neoplasms in general including
the ovary [32]. Two relatively large series of carcinoid tumors insular, trabecular, ribbonlike, acinar, or solid tubular patterns
metastatic to the ovary have been reported [71, 72]. Rare (Fig. 10.31). When the acinar pattern is encountered, acini
cases of pancreatic neuroendocrine neoplasms metastatic to often contain eosinophilic secretions, which may calcify in a
the ovary have also been reported outside of these series psammomatous or nonpsammomatous fashion [2, 32, 71, 72].
[73–75]. In addition to the above-noted common architectural patterns,
Carcinoid tumors account for approximately 2% of larger cysts and follicle-like spaces are sometimes seen
metastases that form detectable ovarian masses [2]. Most (Fig. 10.32) [12]. Metastatic carcinoid tumor often has a
metastatic carcinoid tumors are of ileal origin, although less prominent paucicellular fibrous stroma, which may be exten-
frequently the primary site is the jejunum, appendix, colon, sively hyalinized (Fig. 10.33). Vascular invasion may be seen
stomach, pancreas, or lung [71–79]. In the largest series (35 occasionally [12].
cases) of carcinoid tumors metastatic to the ovary to date, Biomarkers:
patients ranged from 21 to 82 years of age, with a median age
of 57 years. Patients may present with manifestations of the –– Well-differentiated neuroendocrine tumors/carcinoid
carcinoid syndrome (flushing and diarrhea), may have symp- tumors from any primary site typically express selected
toms related to an intestinal or ovarian mass, or may be cytokeratins and a variety of neuroendocrine markers,
asymptomatic. A majority of patients with ovarian metasta- although the immunostaining profile varies somewhat
sis have extraovarian metastasis as well, which contrasts depending on the site of origin.
with the rarity of extraovarian spread of primary ovarian car- –– Well-differentiated neuroendocrine tumors/carcinoid
cinoid tumor. tumors express LMWCKs (CAM5.2) in nearly 100% of
Outside of the two large series of carcinoid tumors meta- cases, and HMWCKs (AE1/AE3) a bit less frequently.
static to the ovary noted above, rare pancreatic neuroendo-
crine neoplasms metastatic to the ovary have been reported
including a VIPoma [73], a glucagonoma [74], and an
ACTH-secreting tumor [75]. Ovarian metastasis was discov-
ered years after diagnosis of the pancreatic primary tumor in
the patients with VIPoma and glucagonoma. In the patient
with metastatic ACTH-secreting pancreatic endocrine tumor,
however, the initial presentation was due to bilateral ovarian
masses, hirsutism, and Cushing’s syndrome; subsequent
workup disclosed the pancreatic neuroendocrine tumor.
Gross: Carcinoid tumor metastatic to the ovary is usually
bilateral, in contrast with primary ovarian carcinoid tumor,
which is almost always unilateral. These tumors are typically
of relatively modest size, ranging from microscopic foci up
to 9.5 cm, and have a smooth or bosselated external surface.
The cut surface is typically solid, but may be solid and cystic
or predominantly cystic, with cysts containing clear, watery
Fig. 10.30 Metastatic well-differentiated neuroendocrine tumor of
fluid. Tumors typically show the discrete to confluent nodu- ileal origin. Tumor cells are uniform with round to ovoid nuclei, incon-
lar architecture often seen in metastatic lesions. The tumor is spicuous nucleoli, and subtly granular eosinophilic cytoplasm
–– Well-differentiated neuroendocrine tumors/carcinoid

tumors of small bowel, appendiceal, colonic, and rectal
origin express synaptophysin. Chromogranin expression
is frequent but not as consistent, and is more often nega-
tive in tumors of rectal origin [22].
–– CDX2 expression in well-differentiated neuroendocrine
tumors/carcinoid tumors likewise varies with the site of
origin. Srivastava and colleagues demonstrated CDX2
positivity in nearly 100% of ileal and appendiceal carci-
noid tumors, but none in gastroduodenal and rectal prima-
ries [80].
–– Pancreatic neuroendocrine tumors: Express CAM5.2 in
greater than 90% of cases and CKAE1/AE3 in approxi-
mately 50% of cases.
–– Pancreatic neuroendocrine tumors almost always express
Fig. 10.31 Metastatic well-differentiated neuroendocrine tumor of at least one marker of neuroendocrine differentiation;
ileal origin, insular architectural pattern NSE and synaptophysin are expressed in greater than
90% of these neoplasms, while chromogranin A, which is
more specific, is detected in 85–90%.
–– Pancreatic endocrine tumors are often multihormonal, and
multiple specific neuroendocrine markers (insulin, gluca-
gon, ACTH, gastrin, VIP, etc.) may be expressed [59].
Differential Diagnosis: ccs that may have an insular,

tubular/acinar, or tubular and cystic architectural pattern
reminiscent of carcinoid tumor, including granulosa cell
tumor of adult type, Sertoli or Sertoli-Leydig cell tumor,
Brenner tumor, and adenocarcinoma of various types, most
notably endometrioid and breast carcinoma. Careful consid-
eration of gross and microscopic features, and immunohisto-
chemical staining when the diagnosis is uncertain, should
resolve the differential diagnosis in most cases. Gross and
microscopic features helpful in the differential diagnosis are
as follows:
ileal origin, insular pattern, and follicle-like space with eosinophilic Primary ovarian carcinoid tumor: Primary ovarian car-
intraluminal secretion cinoid tumor is almost always unilateral, does not typically
show extraovarian spread, and is not typically multinodular
or associated with lymphovascular space invasion like meta-
static carcinoid tumors. Primary ovarian carcinoid tumor is
often associated with a teratoma, mucinous tumor, or struma
ovarii; thus, the presence of any of these features strongly
suggests a primary ovarian carcinoid tumor and essentially
excludes metastatic carcinoid tumor, except for the rare pos-
sibility of a collision tumor. When bilateral ovarian carcinoid
tumors or extraovarian spread of tumor is found, an extra-
ovarian primary tumor is likely [2]. It has been noted that
cystic or follicle-like spaces are more commonly encoun-
tered in metastatic than in primary ovarian carcinoid tumors
(Fig. 10.32). Immunohistochemical staining for CDX2 does
not distinguish between tumors of intestinal origin and pri-
mary ovarian carcinoid, as primary ovarian carcinoid tumors
may express CDX2 [81], and carcinoid tumors of intestinal
origin may fail to express CDX2. Of note, a carcinoid tumor
ileal origin. This neuroendocrine tumor shows the insular pattern and in the small intestine may be small and difficult to locate
prominent fibrous stroma often seen in these neoplasms clinically [2].
Granulosa cell tumor: The Call-Exner bodies of granu- improved the course of disease in these patients. Surgical
losa cell tumor may resemble the acinar structures of carci- resection is recommended when possible. Nonsurgical treat-
noid tumor, although the cytologic features of these tumors ment options for patients with well-differentiated gastroen-
are distinct. Granulosa cell tumor has round, ovoid, or angu- tero-pancreatic neuroendocrine tumors include somatostatin
lated, grooved nuclei and scant indistinct cytoplasm. The analogues, multi-kinase inhibitors, targeted therapy, chemo-
cells are rather haphazardly oriented relative to each other therapy, and radiolabeled somatostatin analogues [82].
and to the lumen of the Call-Exner body. In contrast, carci-
noid tumors typically have round to ovoid nuclei with finely
granular chromatin, no nuclear grooving, more distinct and 10.9 Metastatic Cervical Carcinoma
abundant cytoplasm, and a more orderly polarity around the
acinar spaces. Granulosa cell tumors of adult type typically Definition: Tumor metastatic to the ovary from the uterine
express inhibin, calretinin, CD99, and WT-1, but are nega- cervix. Ovarian metastases from cervical carcinomas of vari-
tive for neuroendocrine markers [23]. ous histologic types, including adenocarcinoma, squamous
Sertoli/Sertoli-Leydig cell tumor: The hollow and solid carcinoma, high-grade neuroendocrine carcinoma/small-cell
tubules of Sertoli/Sertoli-Leydig cell tumor may mimic the carcinoma, mixed high-grade neuroendocrine carcinoma/
acinar and ribbonlike structures of carcinoid tumor, although small-cell carcinoma and adenocarcinoma, adenosquamous
carcinoid tumor usually has longer, thicker ribbons with a carcinoma, glassy cell carcinoma, transitional cell carcinoma,
more orderly architecture. Of note, Sertoli/Sertoli-Leydig and undifferentiated carcinoma, have been reported [83, 84].
cell tumor may have a component of carcinoid tumor, typi- Of these, cervical adenocarcinoma is the most frequent histo-
cally minor in extent and associated with heterologous ele- logic type to develop ovarian metastasis [2, 32, 85].
ments. Sertoli/Sertoli-Leydig cell tumors stain for inhibin, Clinical Features: Ovarian spread of cervical carcinomas
MART-1, and calretinin, which are typically negative in car- of all types has been considered infrequent. A 2006 study of
cinoid tumors [2, 23, 32]. 3471 patients with stage Ib to IIb cervical cancer who under-
Brenner tumor: Brenner tumor, with its fibromatous went radical hysterectomy and bilateral salpingo-
stroma and nests of bland epithelium, may mimic primary or oophorectomy demonstrated ovarian metastasis in 5.31% of
metastatic insular carcinoid tumor. In Brenner tumor, epithe- those with endocervical adenocarcinoma and only 0.79% of
lial nests are of transitional type with ovoid, grooved nuclei. those with cervical squamous cell carcinoma [85]. Patients
Immunohistochemical stains for neuroendocrine markers are have ranged in age from approximately 29 to 73 years, with
negative. a mean age of 49.9 years in one large study [85, 86].
Endometrioid adenocarcinoma: These tumors may also Ovarian metastasis may present synchronously or meta-
have small tubules that resemble the acinar structures of car- chronously in reference to the cervical primary tumor. In
cinoid tumor. Consideration of nuclear and architectural fea- some cases, ovarian metastasis becomes apparent several
tures and immunohistochemical staining should resolve the years after diagnosis of the primary tumor, while in other
differential diagnosis. Squamous elements or morular meta- cases the ovarian metastasis is the presenting sign of a clini-
plasia excludes carcinoid tumor. Endometrioid adenocarci- cally unsuspected cervical tumor [13, 83, 87]. Cervical
noma is typically positive for PAX-8, ER, and PR, which are tumors giving rise to ovarian metastasis are clearly invasive
typically negative in carcinoid tumor. Endometrioid adeno- in most cases, and some are of advanced stage, with extra-
carcinoma and other carcinomas may contain neuroendo- uterine involvement or a bulky primary tumor [83, 86]. In a
crine cells that stain focally for neuroendocrine markers, substantial minority of cases, however, the cervical tumor is
though staining is less diffuse than in carcinoid tumor. Of not clinically evident prior to discovery of the ovarian metas-
note, both endometrioid adenocarcinoma and ovarian carci- tasis, and may demonstrate only small foci of superficial
noid tumor may express CDX2 [23, 81]. invasion or no unequivocal stromal invasion. Extension of
Management and Outcomes: Among the 17 patients cervical tumor into the lower uterine segment or uterine cor-
with carcinoid tumor metastatic to the ovary in the 2007 pus has been identified as a possible risk factor for ovarian
series by Strosberg and colleagues [72], two deaths occurred metastasis, postulated mechanisms including transtubal
in the follow-up interval (range of follow-up 8–146 months), spread of tumor [13, 86].
yielding a projected 5-year survival rate of 94%. All patients Pathologic Findings:
underwent surgical resection of the ovarian masses, and most Gross:
underwent surgical resection of the primary tumor, with or Metastatic endocervical adenocarcinoma: For endocer-
without more extensive debulking. Fifteen patients received vical adenocarcinoma metastatic to the ovary, metastasis
long-term depot-octreotide therapy, and two received strep- may be bilateral or unilateral. Some tumors are unilateral
tozocin-based chemotherapy. It is postulated that cytoreduc- and large (reported tumors have ranged up to 30 cm), mim-
tive surgery and treatment with octreotide substantially icking a primary ovarian mucinous neoplasm. Tumors have a
Fig. 10.34 Large ovarian metastasis from an endocervical adenocarci- Fig. 10.35 Metastatic endocervical adenocarcinoma of usual type.
noma, with a smooth bosselated external surface The tumor has the hybrid endometrioid-mucinous features typical of
endocervical adenocarcinomas of usual type. The cells are columnar
with varied glandular, papillary, and cribriform architecture
smooth or nodular external surface (Fig. 10.34). The cut sur-
face may be predominantly solid or multicystic, sometimes
with solid or papillary areas [13, 86].
Metastatic cervical squamous carcinoma: Squamous
cell carcinoma metastatic to the ovary may be unilateral or
bilateral. Reported tumors have ranged up to 17 cm. Tumors
show a smooth or nodular external surface, and a solid, solid
and cystic, or predominantly cystic cut surface [83, 86, 87].
Microscopic:
Metastatic endocervical adenocarcinoma: Among the
various subtypes of endocervical adenocarcinoma, the usual
(HPV related) type is the most common to exhibit ovarian
metastasis. In the ovary, these tumors show microscopic fea-
tures similar to their primary endocervical counterparts. The
majority of these tumors have a pseudoendometrioid appear-
ance with hybrid endometrioid and mucinous features, char-
acterized by an endometrioid appearance at low magnification
Fig. 10.36 Metastatic endocervical adenocarcinoma of usual type.
but with varying amounts of apical mucin evident at higher Tumor cells are columnar and stratified with apoptosis and apical mito-
magnification. Nuclei are typically hyperchromatic and sis. Apical mucin varies in these tumors and is scant in this case, simu-
elongated, with numerous apical mitoses and frequent apop- lating the appearance of an endometrioid adenocarcinoma primary or
metastatic to the ovary
tosis (Figs. 10.35 and 10.36). In the ovary, the growth
pattern(s) may be borderline-like, confluent glandular, cribri-
form, papillary, or villoglandular, and may not be readily have distinctive clear and/or pale eosinophilic, abundant
recognized as invasive, thus simulating a primary ovarian cytoplasm with distinct cell borders. They may show single-
mucinous borderline tumor or well-differentiated primary cell infiltration and foci of signet ring and intestinal type dif-
ovarian mucinous carcinoma with a confluent invasive pat- ferentiation with goblet cells or Paneth-like neuroendocrine
tern [13]. Of note, a “carpeting” pattern of tumor spread, in cells [88].
which endocervical adenocarcinoma spreads superficially in Metastatic cervical squamous cell carcinoma: With
the endometrium without obvious myometrial invasion or involvement by cervical squamous cell carcinoma, the ova-
lymphovascular invasion, may be seen in endocervical ade- ries show nodules of metastatic tumor replacing normal
nocarcinomas with adnexal involvement [86]. ovarian parenchyma (Figs 10.37 and 10.38) [86]. Microscopic
Endocervical adenocarcinoma of the rarer gastric type features are typical, except that some tumors show striking
(HPV unassociated) has also been reported to metastasize to cyst formation within the squamous nests [83, 87]. Similar to
the ovary, although less commonly. These tumors typically the “carpeting” pattern of tumor spread noted in some cases
of endocervical adenocarcinoma, cervical squamous cell

carcinoma in situ has been documented to extend to involve
the endometrium, fallopian tubes, ovarian surface, and ovar-
ian epithelial inclusion glands, with secondary ovarian stro-
mal involvement [14].
Biomarkers:
–– Endocervical adenocarcinoma of usual (HPV-associated)

type shows HR-HPV infection by in situ hybridization
and PCR, and expresses p16 in a diffuse, strong nuclear
and cytoplasmic pattern (Fig. 10.39). Importantly, p16
can serve as a useful surrogate marker for HPV infection
when direct HPV detection methods are unavailable;
however, direct detection of HPV is more specific than is
immunostaining for p16 due to the occasional strong, dif-
Fig 10.37 Cervical primary squamous cell carcinoma with early stro- fuse p16 positivity seen in some HPV-unrelated adenocar-
mal invasion (stage T1a2), generating ovarian metastasis cinomas that may present a differential diagnosis.
Endocervical adenocarcinoma of usual type generally
does not express vimentin, ER, or PR, or does so only
focally.
–– Endocervical adenocarcinoma of gastric type is usually
HPV unassociated and thus does not demonstrate HR-
HPV infection by PCR or in situ hybridization, and is
negative or shows focal to patchy positivity for p16. p53
is often expressed in endocervical adenocarcinoma of
gastric type, as p53 mutations are often found in these
tumors [23].
–– Squamous carcinomas are almost always associated with
HPV infection and thus show HR-HPV infection by in
situ hybridization and PCR, and express p16 in a diffuse,
strong nuclear and cytoplasmic pattern like HPV-related
endocervical adenocarcinomas.
Differential Diagnosis: Although exceptions arise, gross

and microscopic features common to ovarian metastasis are
often seen in cases of cervical carcinoma metastatic to the
Fig 10.38 Squamous cell carcinoma metastatic to the ovary. The
tumor shows cytomorphologic features that are the usual for squamous
ovary and provide a clue to the diagnosis. Bilateral tumor, a
cell carcinoma. Tumor is disposed in variably sized nests multinodular architecture, surface nodularity, foci of destruc-
Fig 10.39 Metastatic
endocervical adenocarcinoma
of usual type. This HPV-
related neoplasm shows
strong, diffuse positivity for
p16 (left) and HR-HPV
infection by in situ
hybridization (right)
tive stromal invasion, microscopic features uncommon for a 37.5% for stage IIa, and 18.0% for stage IIb, despite admin-
primary ovarian neoplasm, prominent lymphovascular inva- istration of adjuvant therapy (radiotherapy and/or chemo-
sion, and a known cervical primary tumor all suggest metas- therapy) to 92.3% of patients [85].
tasis. Strong, diffuse staining with p16 is likewise strongly
suggestive of a metastatic HPV-related tumor. Identification
of HPV infection by in situ hybridization or molecular meth- 10.10 Metastatic Endometrial Carcinoma
ods confirms the diagnosis. Other points helpful in the dif-
ferential diagnosis are as follows: Definition: Metastasis to the ovary originating from an
Metastatic endocervical adenocarcinoma: The differen- endometrial adenocarcinoma. The most common histologic
tial diagnosis of metastatic endocervical adenocarcinoma type of endometrial adenocarcinoma to secondarily involve
includes ovarian mucinous borderline tumor, primary ovarian the ovary is endometrioid adenocarcinoma. Metastases of
mucinous adenocarcinoma with a confluent invasive pattern, endometrial serous carcinoma, uterine carcinosarcoma, and
and other primary and metastatic carcinomas of mucinous other types of endometrial adenocarcinoma are less
and endometrioid/pseudoendometrioid types (most notably common.
primary and metastatic endometrioid adenocarcinoma, and Clinical Features: Synchronous endometrial and ovarian
adenocarcinomas of intestinal, appendiceal, gastric, and pan- carcinoma is found in approximately 10–15% of patients
creatic origin). The most challenging differential is with pri- with ovarian cancer and 5% of patients with endometrial
mary ovarian mucinous neoplasia, which metastatic cancer [89–91]. When encountered, this finding raises the
endocervical adenocarcinoma may mimic grossly and micro- important question of whether the two lesions represent
scopically; thus, an appropriate index of suspicion for possi- independent primary tumors or whether one lesion is a
ble metastasis is warranted. Clinical correlation and metastasis from the other. When histology is dissimilar the
immunohistochemical staining should be employed when the distinction is relatively easy, but when similar the distinction
diagnosis is uncertain. Clues to an ovarian primary endome- may be challenging. Making this distinction is essential for
trioid adenocarcinoma include squamous morules, endome- prognostication and treatment planning. Patients with syn-
triosis, or an endometrioid adenofibroma. Primary and chronous primary endometrial and ovarian carcinomas tend
metastatic endometrioid adenocarcinomas typically express to be younger, present with early-stage disease, and have a
vimentin, ER, and PR; show only patchy positivity for p16; more favorable overall prognosis than do patients who pres-
and are negative for CEA; in contrast, endocervical adenocar- ent with only an endometrial or ovarian carcinoma at the
cinomas are typically CEA positive, p16 block positive (when same clinical stage [89, 91–94]. Likewise, patients with syn-
HPV related), vimentin negative, and negative to focally posi- chronous, independent primary cancers have a better prog-
tive for ER and PR. Please see Table 10.1 for typical immuno- nosis than do patients with endometrial cancer with ovarian
histochemical staining features of other tumors with mucinous metastasis [95].
and endometrioid/endometrioid-like morphology. Pathologic Findings:
Metastatic cervical squamous cell carcinoma: A squa- Gross: Endometrial tumors secondarily involving the
mous tumor in the ovary may be metastatic or rather a pri- ovary are usually smaller than 5 cm and bilateral. These
mary ovarian tumor associated with a teratoma, endometriotic tumors may be solid or solid and cystic on the cut surface.
cyst, or massive squamous overgrowth in an endometrioid General gross features favoring metastatic tumor include
adenocarcinoma [32]. Adequate gross evaluation and sam- bilaterality, a multinodular growth pattern, and tumor on the
pling are essential to evaluate for associated features. Primary ovarian surface (with the caveat that tumor may develop in
ovarian squamous carcinoma is rare and, before an ovarian the ovary in the context of surface endometriosis; thus, a
primary squamous carcinoma is diagnosed, the possibility of careful search for endometriosis can be helpful).
metastasis from an occult squamous carcinoma in the cervix Microscopic: Endometrial tumors secondarily involving
or elsewhere should be entertained [32]. Ovarian transitional the ovary have microscopic features similar to their endome-
cell carcinoma should also be excluded prior to making the trial counterparts (Figs. 10.40, 10.41, and 10.42). Microscopic
diagnosis of metastatic squamous cell carcinoma, although features favoring metastasis include a multinodular growth
this tumor is rare. pattern, involvement of the ovarian surface (again with the
Management and Outcomes: A 2006 study including 52 caveat that tumor may develop in the ovary in the context of
patients with stage Ib to IIb cervical cancer and ovarian surface endometriosis), and hilar or extraovarian lymphovas-
metastasis who underwent radical hysterectomy, pelvic cular space invasion. An unusual finding occurring occasion-
lymphadenectomy, and bilateral salpingo-oophorectomy ally in the setting of an endometrial endometrioid
demonstrated a poor outcome for these patients, unrelated to adenocarcinoma with squamous differentiation is that of
FIGO stage or histologic type. Five-year survival rates for keratin deposits or degenerated mature squamous cells with
patients with ovarian metastasis were 46.6% for stage Ib, an associated foreign-body giant cell reaction on the surface
Fig. 10.40 Metastatic endometrioid adenocarcinoma of uterine corpus Fig. 10.42 Metastatic endometrioid adenocarcinoma of uterine corpus
origin. These tumors show morphology similar to their uterine counter- origin. Squamous differentiation may be seen in endometrioid adeno-
parts. Papillary, glandular, and cystic patterns may be seen carcinomas primary to the ovary or metastatic from the uterine corpus.
Squamous differentiation is not seen in adenocarcinomas of intestinal,
gastric, or appendiceal origin
and weak to moderate in intensity); however, a mutation

pattern of p53 expression (that is, either intense expression
of p53 in greater than 75% of tumor cell nuclei or near-
complete negativity for p53 consistent with the null phe-
notype) may be noted in a minority of FIGO grade 2 and 3
endometrioid adenocarcinomas. Expression of p16 is typi-
cally patchy, although occasional high-grade endometri-
oid adenocarcinomas express p16 in a strong, diffuse
pattern. Nuclear B-catenin expression, loss of PTEN, and
loss of mismatch repair (MMR) proteins (MLH1, MSH2,
MSH6, and PMS2) may be seen. Unexpected expression
of mammaglobin, CDX2, TTF-1, and GATA3 may also be
encountered. Of note, immunohistochemical staining is
not helpful in the distinction between endometrial and
Fig. 10.41 Metastatic endometrioid adenocarcinoma of uterine corpus
origin. Tumor typically has less cytologic atypia and mitotic activity
ovarian primary endometrioid adenocarcinoma [23].
than the usual metastatic tumor of gastrointestinal origin, which often –– Endometrial serous carcinomas express CK7, CA125,
displays a pseudoendometrioid morphology and sometimes vimentin, while they are usually negative
for CK20. In contrast to endometrioid adenocarcinomas,
of one or both ovaries [96]. If no viable tumor is present, this endometrial serous carcinomas express p16 in a strong,
finding does not appear to worsen the patient’s prognosis, diffuse fashion and show a mutation pattern of p53 stain-
even if keratin granulomas are identified elsewhere in the ing (approximately 90% of endometrial serous carcino-
peritoneum. mas express p53 in a strong, diffuse fashion, while
Biomarkers: Endometrioid adenocarcinoma is the most approximately 10% show near-complete negativity for
common histologic type of endometrial tumor to metastasize p53 consistent with the “null” phenotype). Most have low
to the ovary, with endometrial serous carcinoma being less levels of ER expression and low-to-absent PR expression.
common and other tumor types rare. Typical immunohisto- In contrast to serous carcinomas of ovarian, tubal, or peri-
chemical staining features of endometrioid adenocarcinoma toneal origin, which express WT-1 in about 90% of cases,
and endometrial serous carcinoma are as follows: endometrial serous carcinomas express WT-1 in only
20–30% of cases [23].
–– Endometrioid adenocarcinomas typically express CK7,
CA125, ER, PR, and vimentin, and are usually negative Differential Diagnosis: Differential diagnosis for meta-
for CK20. Staining for p53 is usually wild type (patchy static endometrioid adenocarcinoma includes primary
ovarian endometrioid adenocarcinoma, and other primary Table 10.3 Endometrioid tumors of ovary and endometrium, features
favoring ovarian metastasis from endometrial primary
and metastatic tumors with an endometrioid-like architec-
tural pattern. Differential diagnosis includes some high- 1. Histologic similarity of the tumors
grade serous and clear-cell carcinomas, Sertoli/Sertoli-Leydig 2. Large endometrial tumor, small ovarian tumor(s)
3. Atypical endometrial hyperplasia/endometrial intraepithelial
cell tumor, endometrioid yolk sac tumor, and metastatic
neoplasia (EIN) present
tumors of endocervical, gastrointestinal, and appendiceal 4. Deep myometrial invasion with direct extension into adnexa and/
origin [12]. Helpful features that can be used to resolve the or vascular space invasion in myometrium
differential diagnosis are as follows: 5. Spread elsewhere in typical pattern of endometrial carcinoma
Metastatic endometrioid adenocarcinoma versus pri- 6. Ovarian tumors bilateral and/or multinodular
mary ovarian endometrioid adenocarcinoma: Literature 7. Hilar location, vascular space invasion, surface implants,a or
combination in ovary
over the last 20 years or so has focused on the view that syn-
8. Ovarian endometriosis absentb
chronous tumors of the endometrium and ovary more often
9. Similar molecular genetic or karyotypic abnormalities
represent independent primary tumors. The idea of synchro- in both tumors
nous endometrial and ovarian carcinomas representing two a
Infrequently, primary ovarian endometrioid adenocarcinoma may arise
separate primary tumors in the majority of cases has been from endometriosis involving the ovarian surface
supported by the fact that most synchronous tumors have a b
In addition to ovarian endometriosis, the presence of an endometrioid
favorable overall prognosis, which would be unexpected if adenofibroma in the ovary suggests an ovarian primary tumor
either tumor were metastatic. Most tumors with synchronous
involvement of the endometrium and ovary are of endometri- also be used for tumor types other than endometrioid. In
oid type. When tumors are of the serous type or any other many cases there is strong evidence regarding whether an
histologic type, there is a greater statistical likelihood that ovarian tumor represents a metastasis or an independent pri-
the ovarian tumor is metastatic [32]. mary tumor, but in some cases this distinction is difficult or
Over the years, various studies have delineated histologic impossible.
and genetic criteria to aid in the determination of whether Recently, studies from different research groups using
synchronous endometrial and ovarian tumors with similar different molecular techniques have suggested that tumors
histology represent independent primary tumors or meta- that would be categorized as independent synchronous pri-
static disease [97]. Historic criteria favoring synchronous mary tumors by historic morphologic criteria are often clon-
independent endometrioid primary tumors are presented in ally related and may thus represent dissemination/metastasis
Table 10.2, while features favoring metastasis to the ovary from one site to another [98–100]. They furthermore suggest
are listed in Table 10.3 [97]. Beyond the features listed in that the relatively good prognosis of most of these patients
Table 10.3, another feature suggesting ovarian metastasis is might be explained by isolated ovarian spread of an indolent
the presence of tumor within the fallopian tube lumen. This endometrial tumor, possibly through the fallopian tube
feature, and some of those listed in Tables 10.2 and 10.3, can lumen, without invasion of vascular structures or easy access
to the peritoneal cavity [100]. This evolving concept has not
Table 10.2 Endometrioid tumors of ovary and endometrium, features gained widespread acceptance at this time, and further work
favoring independent primary tumors is required. An alternate explanation that has been proffered
1. Histologic dissimilarity of the tumors for the similar molecular alterations identified in some syn-
2. No or only superficial myometrial invasion of the endometrial chronous endometrial and ovarian endometrioid adenocarci-
tumor nomas is that a common carcinogenic agent acting on
3. No vascular space invasion of the endometrial tumor endometrium and ectopic endometrial tissue within the ovary
4. Atypical endometrial hyperplasia/endometrial intraepithelial could induce similar genetic events in the two locations, sim-
neoplasia (EIN) present
ulating metastasis from one site to another. It is furthermore
5. Absence of other evidence of spread of endometrial tumor
6. Ovarian tumor unilateral (80–90%) of cases
noted that a metastatic lesion may exhibit a different molecu-
7. Ovarian tumor located in parenchyma lar profile from the primary tumor due to tumor heterogene-
8. No vascular space invasion, surface implants,a or predominant ity and progression. Currently, ovarian endometrioid
hilar location in ovary adenocarcinomas are evaluated for their likely primary or
9. Absence of other evidence of spread of ovarian tumor secondary nature according to the morphologic criteria pre-
10. Ovarian endometriosis presentb sented in Tables 10.2 and 10.3.
11. Dissimilar molecular genetic or karyotypic abnormalities Endometrioid adenocarcinoma versus serous carci-
in the tumor
noma: Lower nuclear grade, a more orderly glandular and
a
Infrequently, primary ovarian endometrioid adenocarcinoma may arise
from endometriosis involving the ovarian surface
villous pattern with smooth luminal borders, squamous dif-
b
In addition to ovarian endometriosis, the presence of an endometrioid ferentiation, and a lack of associated serous tubal intraepithe
adenofibroma in the ovary suggests an ovarian primary tumor lial carcinoma (STIC) favor endometrioid adenocarcinoma.
Immunohistochemical staining may be helpful in cases with can-3−/CK7+/EMA+/ER+/PR+ immunostaining profile. Of

ambiguous morphologic features. Serous carcinomas show a note, most yolk sac tumors show staining for AFP, although
mutation pattern of p53 staining, strong diffuse staining with the AFP staining may be focal and weak [23].
p16, and diffuse staining with IMP3. Serous carcinomas of Endometrioid adenocarcinoma versus metastatic
tubo-ovarian or peritoneal origin also stain for WT-1 in the tumor of intestinal, appendiceal, or gastric origin:
majority of cases. Endometrioid adenocarcinomas, in con- Metastatic tumors of intestinal, appendiceal, or gastric origin
trast, tend to show a wild-type pattern of p53 staining, patchy may have a pseudoendometrioid morphology. These tumors
positivity for p16, focal staining for IMP3, and minimal typically show increased nuclear atypia and mitotic activity,
staining with WT-1. intraluminal “dirty” necrosis, segmental necrosis of glandu-
Endometrioid adenocarcinoma versus clear-cell carci- lar epithelium, and disposition of glandular epithelium at the
noma: Endometrioid adenocarcinoma may have areas of periphery of necrotic areas. Squamous differentiation is vir-
cytoplasmic clearing, raising the possibility of clear-cell tually never seen. A CK7+/CK20−/ER+/PR+/PAX8+ immu-
adenocarcinoma. Features favoring a diagnosis of endome- noprofile is consistent with endometrioid adenocarcinoma,
trioid adenocarcinoma with cytoplasmic clearing over clear- whereas a CK7 variable/CK20+/ER−/PR−/PAX8− immu-
cell adenocarcinoma include a lack of the classic cytologic noprofile is consistent with metastatic carcinoma of gastroin-
and architectural features diagnostic of clear-cell carcinoma testinal origin.
(“hobnail” cells, cells with polyhedral as opposed to colum- Management and Outcomes: Patients with endometrial
nar cytology, a tubulocystic architectural pattern, or a papil- adenocarcinoma metastatic to the ovary, as diagnosed by his-
lary pattern with hyalinized vascular cores), and an ER+/ toric morphologic criteria, have a worse prognosis than those
PR+ immunoprofile. Mullerian clear-cell carcinoma typi- patients with independent, synchronous endometrial and
cally shows absent or markedly diminished staining with ER ovarian primary tumors. In a 2016 retrospective review of 72
and PR, which can be quite helpful in this differential diag- patients with simultaneous carcinomas of the endometrium
nosis. Mullerian clear-cell carcinoma also expresses race- and ovary with the same histopathologic subtype, 10-year
mase (p504s) and Napsin A with greater frequency than survival rate for patients with endometrial tumor metastatic
other histologic subtypes of mullerian adenocarcinoma, to the ovary was 36.6%, as opposed to 61.3% for patients
although the practical utility of these stains is limited by their with independent synchronous primary tumors [95].
sensitivity and specificity [101, 102].
Endometrial or ovarian endometrioid adenocarci-
noma versus endocervical adenocarcinoma: Endocervical 10.11 Other Metastatic Tumors from Uterus
adenocarcinoma of usual type often has focal cytoplasmic
mucin and a vaguely endometrioid appearance. Positivity for Definition: Non-carcinomatous tumors of uterine origin sec-
HPV, strong diffuse staining for p16, and focal to negative ondarily involving the ovary, most commonly low-grade
staining with ER and PR are seen in endocervical adenocar- endometrial stromal sarcoma (ESS), and less commonly
cinoma of usual type. leiomyosarcoma (LMS). Rare cases of mullerian adenosar-
Endometrioid adenocarcinoma versus Sertoli/Sertoli- coma [103], uterine choriocarcinoma [104], and placental
Leydig cell tumor: Endometrioid adenocarcinoma may site trophoblastic tumor [105] metastatic to the ovary have
have a sertoliform architectural pattern (hollow or solid also been reported. Discussion will focus on ESS and LMS,
tubules, cords) in areas that mimics primary Sertoli or as these are the most common.
Sertoli-Leydig cell tumor. Features favoring endometrioid Clinical Features: Of the non-carcinomatous uterine
adenocarcinoma include areas with a more classic endome- tumors that have been documented to metastasize to the
trioid architectural pattern, squamous differentiation (rules ovary, ESS metastasizes to the ovary more frequently than
out a sex cord-stromal tumor), and an immunoprofile consis- any other and can present diagnostic challenge [32]. Patients
tent with endometrioid adenocarcinoma (CK7+/EMA+/ are usually perimenopausal or postmenopausal, but occa-
inhibin−/calretinin−/WT1−/FOXL2−). Of note, endometri- sional patients are younger. In a series of 21 uterine and
oid adenocarcinomas can occasionally show inhibin extragenital sarcomas metastatic to the ovary reported by
positivity. Young and Scully in 1990, eight ESS patients ranged in age
Endometrioid adenocarcinoma versus endometrioid from 33 to 79 years, with an average age of 50 [106]. Some
yolk sac tumor: Yolk sac tumor may have an endometrioid patients with ESS metastatic to the ovary have a documented
architectural pattern, suggesting primary or metastatic endo- history of ESS, greatly facilitating diagnosis, while in some
metrioid adenocarcinoma. Features favoring endometrioid cases there is no or incorrect reporting of the uterine primary
adenocarcinoma in this differential include older patient age, tumor (i.e., history of a “fibroid”) [32, 106, 107]. Ovarian
squamous differentiation, lack of any of the architectural pat- metastasis accounts for the clinical presentation in occa-
terns more typical of yolk sac tumor, and a SALL-4−/glypi- sional patients, and symptoms are those attributable to an
ovarian mass. In other patients, the ovarian metastasis is tic challenge [12]. The few reported cases of uterine leio-
diagnosed synchronously with the uterine primary tumor, or myosarcoma metastatic to the ovary with microscopic
years after diagnosis of the uterine primary [32, 106]. In one description available have had the spindled myoid cells with
reported case, ovarian and extraovarian metastases were variable nuclear atypia and increased mitotic activity charac-
reported 17 years after diagnosis of a uterine low-grade teristic of LMS. One tumor showed prominent myxoid
endometrial stromal sarcoma [108]. change [106].
LMS metastasizes to the ovary less frequently than does Biomarkers:
ESS but is probably more common than the rare reports in
the literature suggest, particularly in patients with wide- –– ESS typically expresses CD10, ER, PR, and WT-1, with
spread disease [2, 109]. In the aforementioned 1990 study by varied extent and intensity. Many also express SMA,
Young and Scully, three LMS metastatic to the ovary cytokeratin, or AR in a patchy fashion. Expression of des-
occurred in patients 35, 44, and 49 years of age. In the first min and CD34 is rare. Of note, this immunohistochemical
patient, a large ovarian metastasis became symptomatic staining profile is characteristic of the portion of tumor
14 months after hysterectomy. In the second patient, the resembling proliferative-type endometrium; any meta-
ovarian metastasis occurred in the setting of widespread dis- plastic elements, such as endometrioid glands, sex cord
ease, while in the third, ovarian involvement was micro- elements, or smooth muscle, tend to acquire the immuno-
scopic [106]. phenotype of the corresponding metaplastic element [23].
Pathologic Findings: –– Leiomyosarcomas typically express the smooth muscle
Gross: markers SMA, desmin, and h-caldesmon, although des-
Low-grade ESS: Low-grade ESS metastatic to the ovary min may be negative. Leiomyosarcomas may also express
is more often bilateral, and may vary in size from micro- CD10, ER, and PR. Cytokeratin is frequently expressed in
scopic to greater than 15 cm. Tumors are predominantly a patchy fashion.
solid or solid and cystic, rarely multicystic, and may have
discernible nodularity. The cut surface is white to gray white, Differential Diagnosis: The differential diagnosis of ESS
with or without foci of yellow coloration, hemorrhage, and metastatic to the ovary includes primary ovarian ESS and
necrosis [106]. A wormlike pattern of vascular plugging may primary ovarian sex cord-stromal tumors with similar histol-
rarely be seen on the cut surface [32]. ogy such as fibroma, thecoma, granulosa cell tumor, and
Uterine LMS: Uterine LMS metastatic to the ovary may Sertoli/Sertoli-Leydig cell tumor. Features helpful in the dif-
be bilateral or unilateral and ranges in size from microscopic ferential diagnosis are as follows:
up to 15 cm. Available gross descriptions detail cut surfaces Metastatic ESS versus primary ovarian ESS: Primary
with multiple firm tumor nodules or the lobulated, white-tan, ovarian ESS is rare but does occur [107, 110]. Given the rar-
fleshy appearance typical of LMS [106]. ity of primary ovarian ESS, when ESS is encountered in the
Microscopic: ovary, metastasis must be considered. A clinical history of a
Low-grade ESS: Low-grade ESS metastatic to the ovary primary uterine ESS is of course strongly suggestive of met-
can show all the varied morphologic patterns that may be astatic tumor. Bilaterality of tumor favors metastasis,
seen in primary ESS, such as fibrous or myxoid change, although bilateral ovarian primary ESS has also been docu-
smooth muscle differentiation, endometrioid gland forma- mented [110]. Associated ovarian endometriosis favors an
tion, and epithelioid cells [32, 108]. The diagnostic difficulty ovarian primary neoplasm [32, 106, 107].
presented in some cases is due to a lack of the classic archi- Metastatic ESS versus sex cord-stromal tumors: As the
tectural patterns of ESS. Metastatic tumor typically shows distinctive vascular pattern and “tonguelike” or “wormlike”
the small round to ovoid nuclei characteristic of ESS, infiltration pattern typical of primary uterine ESS may be
although the “tonguelike” pattern of uterine invasion, and the seen only focally in an ovarian metastasis, and as metastatic
characteristic vascular pattern of prominent interspersed ESS may show morphologic features overlapping with some
small arterioles, may be focal or absent. A diffuse pattern is primary ovarian sex cord-stromal tumors, a primary ovarian
the most common architectural pattern [32]. Tumor may also sex cord-stromal tumor may present a plausible differential
have a nested, nodular, clustered, corded, tubular, or single- diagnosis. A diffuse growth pattern in the metastatic ESS
cell pattern. Diagnostic challenge may arise secondary to may suggest a granulosa cell tumor. The presence of paucic-
finding fibrous bands or large pauci- to acellular fibromatous ellular or acellular fibromatous areas may resemble fibroma.
areas suggestive of fibroma, or hyaline plaques suggesting a Areas with hyaline plaques may raise a differential diagnosis
diagnosis of thecoma [32, 106]. with thecoma. Areas of a cord-like or sex cord-like growth
Uterine LMS: Uterine leiomyosarcoma metastatic to the may suggest a granulosa cell tumor or a Sertoli/Sertoli-
ovary is most often seen in the setting of more widespread Leydig cell tumor. Careful microscopic examination should
disease and typically does not present a significant diagnos- demonstrate absence of the nuclear features characteristic of
granulosa cell tumor. The pattern of small arterioles charac- limited benefit. There is some evidence that secondary cyto-
teristic of ESS is often seen at least focally in the ovary and reductive surgery may improve outcome. Targeted therapies
is a significant clue to the diagnosis. Additionally, the are under investigation [115].
“tonguelike,” often intravascular pattern of tumor infiltration
typical of ESS is not usually seen in the ovary, but is often
seen in extraovarian foci of tumor, facilitating diagnosis. 10.12 Metastatic Tumors from the Tubal
Bilaterality and extraovarian spread of tumor are typical of Fimbriated End
metastatic ESS but rare with the sex cord-stromal tumors in
the differential [32, 106]. More thorough sampling to uncover Definition: Tumors originating in the fallopian tube fimbria
areas of more revealing histology, and a directed battery of with secondary involvement of the ovary. Historically, carci-
immunohistochemical stains, may be performed in cases in nomas with predominant ovarian involvement were thought
which there is diagnostic uncertainty. to be derived from the ovarian surface epithelium. Mounting
LMS and other non-carcinomatous uterine tumors: Outside evidence from a number of related studies [116–119], how-
of ESS, other non-carcinomatous uterine tumors metastatic to ever, suggests that a majority of high-grade serous ovarian
the ovary are relatively rare. Uterine LMS metastatic to the carcinomas actually arise in the fimbriae rather than the ovar-
ovary tends to occur in the setting of more widespread disease, ian surface epithelium. Studies have demonstrated that the
and does not typically present much diagnostic difficulty when long-sought-for precursor of ovarian high-grade serous car-
encountered. As with primary ovarian ESS, LMS occurring cinoma appears to develop from an occult intraepithelial car-
primarily in the ovary or periovarian tissue is rare; thus, LMS cinoma in the fimbria designated “serous tubal intraepithelial
encountered in the ovary is more likely representative of carcinoma” (STIC), which may involve the ipsilateral and
metastasis. Ovarian metastasis of uterine choriocarcinoma is contralateral ovarian surfaces and/or peritoneal surfaces sec-
rare and must be distinguished from primary ovarian chorio- ondarily. Another possible mechanism of spread is implanta-
carcinoma of gestational or germ cell origin [12, 104, 111]. If tion of normal fimbrial epithelium on the denuded ovarian
choriocarcinoma is identified in the ovary and is not clearly surface at the site of rupture when ovulation occurs, causing
metastatic from a uterine or tubal gestational choriocarcinoma, the development of cortical inclusion cysts, which may
the ovarian tumor must be adequately sampled to rule out tera- develop neoplastic changes over time [120]. Invasive tumor
tomatous or other germ cell elements. If no teratoma or other involving the distal fallopian tube may also extend directly
germ cell elements are found, it may be impossible to differen- into the ovarian parenchyma, sometimes aided by the pres-
tiate between a primary ovarian choriocarcinoma of either ence of tubo-ovarian adhesions [2].
gestational or germ cell origin and metastasis from a uterine Clinical Features: The clinical presentation of ovarian
choriocarcinoma that has regressed [2]. Ovarian metastasis of carcinoma developing secondarily from the tubal fimbriae is
uterine adenosarcoma has also been documented [103]. Of similar to that of tumors which would historically have been
note, ovarian/adnexal adenosarcoma may represent a primary classified as primary ovarian neoplasia. Patients with symp-
tumor, particularly if it is associated with endometriosis. tomatic tumors are typically postmenopausal, with a mean
Management and Outcomes: Adnexal spread of low- age ranging from 56 to 63 years [121–123]. In symptomatic
grade ESS occurs in approximately 15% of cases [12]. The patients, the most common symptoms include an abdominal/
tumor may behave indolently and patients may have pro- pelvic mass, and abdominal pain and distention due to bulky
longed survival, with recurrence developing more than a tumor or ascites. Abnormal uterine bleeding/discharge is
decade after initial diagnosis [112]. Stage is the most impor- also a relatively common symptom [124]. Some patients will
tant prognostic factor for this tumor. At this time, the optimal have tumor identified in an endometrial biopsy/curettage,
treatment of recurrent or metastatic low-grade endometrial endocervical curettage, or Pap smear. The majority of
stromal sarcoma remains to be determined. Surgical resec- patients are white, non-Hispanic [121]. Patients with BRCA1
tion is the primary treatment and is recommended when pos- or BRCA2 germline mutations are at increased risk for the
sible. The tumors are relatively chemo- and radioresistant. development of serous tubal intraepithelial carcinoma
Hormonal treatment with progestin therapy or aromatase (STIC), with or without tubal invasion and ovarian spread.
inhibitors may be effective in achieving disease control in Among symptomatic patients with fallopian tube carcinoma,
some cases due to the frequent presence of ER and PR, women with BRCA-associated tumors present at a slightly
although further study is required [112, 113]. Targeted thera- younger age than those with sporadic tumors, although avail-
pies are also under investigation [114]. able literature suggests that both patient groups have similar
Uterine LMS is an aggressive neoplasm with a poor out- clinicopathologic features [125, 126].
come regardless of clinical stage. Surgical resection is the Pathologic Findings: The majority of malignant neo-
cornerstone of treatment for early-stage tumor. Advanced- plasms developing in the fallopian tube fimbriae are high-
stage, recurrent, or metastatic LMS is treated with cytotoxic grade serous carcinomas (Figs. 10.43, 10.44, 10.45, 10.46,
chemotherapy, although currently available regimens are of and 10.47), and a smaller percentage are endometrioid
c arcinomas. Other types of carcinoma developing in the fal-

lopian tube fimbriae are rare; few examples of undifferenti-
ated carcinoma and mucinous carcinoma have been
documented [122, 127]. Secondary ovarian involvement
from a fallopian tube primary carcinoma may vary from min-
imal, with only involvement of the ovarian surface epithe-
lium, to massive, such that determination of primary site is
difficult or impossible.
Biomarkers: Immunohistochemistry may be employed
as an adjunctive aid in the determination of tumor type
(serous, endometrioid, mucinous, clear cell, etc.). Biomarkers
are not useful, however, in distinguishing between an ovarian
primary neoplasm and a tumor of tubal origin secondarily
involving the ovary.
Differential Diagnosis: The most common differential
Fig. 10.43 Serous carcinoma, high grade, of tubal fimbrial origin diagnosis for ovarian involvement by a tubal primary is an
involving both ovaries ovarian primary tumor with secondary tubal involvement. As
Fig. 10.44 Serous tubal intraepithelial carcinoma (STIC) involving carcinoma (STIC) shows a mutation pattern of staining with p53
tubal fimbria. Note malignant epithelium of serous type with a high (strong, diffuse staining in this case) (right). Caution is warranted in the
nuclear grade and nuclear disarray, contrasting with that of normal cili- interpretation of tubal intraepithelial carcinoma, as adenocarcinoma
ated benign tubal type epithelium (left). Serous tubal intraepithelial metastatic to the fallopian tube may closely mimic STIC
Fig. 10.45 Serous tubal intraepithelial carcinoma involving tubal fim- denced by strong, diffuse nuclear staining in >75% of the tumor cells.
bria, with underlying mucosal invasion (left). Both the STIC and the In approximately 10% of cases, a p53 mutation is indicated by virtually
invasive carcinoma show a mutation pattern of p53 staining, as is typi- no p53 staining (“null pattern”)
cal of high-grade serous carcinoma. In this case the mutation is evi-
high-grade serous carcinoma advocate that if serous tubal

intraepithelial carcinoma (STIC) or mucosal invasive carci-
noma is identified in the fallopian tube, the fallopian tube
should be designated the primary tumor site, regardless of
the presence or size of ovarian or peritoneal disease; like-
wise, if the fallopian tube is partially or completely incorpo-
rated into a tubo-ovarian mass, the fallopian tube should be
designated the primary site, regardless of the presence or size
of ovarian or peritoneal disease [128]. For patients with
high-grade serous carcinoma, it is recommended that the
tubal fimbriae be carefully examined and entirely submitted.
It should be noted that metastasis to the fallopian tube may
colonize the epithelium and closely mimic serous tubal
intraepithelial carcinoma (STIC); thus, circumspection is
warranted in the interpretation of tubal intraepithelial carci-
Fig. 10.46 Serous carcinoma, high grade, of tubal fimbrial origin sec- noma. Of note, although designation of the primary site for a
ondarily involving the ovary. High-grade serous carcinoma may have a carcinoma involving both the fallopian tube and ovary has
glandular, papillary, or solid architectural pattern. Psammoma bodies implications for cancer epidemiology, registration, and entry
are a frequent finding but are not pathognomonic for serous carcinoma into clinical trials, there is limited therapeutic and prognostic
significance associated with this designation [129].
Management and Outcomes: High-grade serous carci-
noma, the most common type of fallopian tube primary car-
cinoma to secondarily involve the ovary, has a similar
prognosis and treatment whether the primary site is consid-
ered to be fallopian tube or ovary. The most important prog-
nostic factor for high-grade serous carcinoma is stage; by the
time patients become symptomatic, they have advanced-
stage disease in approximately 75–80% of cases, and less
than 25% of patients will be cured by current therapies. The
current mainstay of treatment for almost all patients with
high-grade serous carcinoma is cytotoxic chemotherapy.
Tumors arising in association with BRCA1 and BRCA2
germline mutations have been demonstrated to have a more
favorable prognosis than do sporadic tumors [130]. A series
of new therapeutic drugs that target poly(ADP-ribose) poly-
merase (PARP) is under investigation for treatment of BRCA
Fig. 10.47 Serous carcinoma, high grade. High-grade serous carci- mutation-positive ovarian cancer [131].
noma is characterized by a high nuclear grade and frequent mitotic
activity. In contrast to endometrioid adenocarcinoma, serous carcinoma
more often has crack-like, rather than smooth, glandular luminal bor- 10.13 Metastatic Breast Carcinoma
ders, and more prominent nuclear disarray
Definition: Carcinoma of breast origin metastatic to the

noted previously, the vast majority of fallopian tube primary ovary.
carcinomas are of high-grade serous type, with a smaller per- Clinical Features: Breast carcinoma metastatic to the
centage of endometrioid adenocarcinomas. Given the great ovary is uncommonly identified in surgical specimens but is
rarity of primary fallopian tube clear-cell and mucinous car- relatively common at autopsy [4, 6]. Ovarian metastasis is
cinomas, tubo-ovarian involvement by a tumor of either of found at autopsy in approximately 10–15% of women with
these two types would usually be considered primary to the breast cancer, and in about 1% of risk-reducing salpingo-
ovary [2]. If there is both tubal and ovarian involvement by oophorectomy specimens from BRCA patients [2, 12]. Mean
serous, endometrioid, or undifferentiated carcinoma, a tubal age at diagnosis of ovarian metastasis was 52 in one series
primary is of greater likelihood and should be considered. [132]. Ovarian metastasis was discovered at a median of 5
Current (2018) College of American Pathologists years after the diagnosis of breast cancer in two large series
guidelines for assignment of primary site in tubo-ovarian [132, 133]; rarely, ovarian metastasis is detected before the
breast cancer [134]. Most patients are asymptomatic from

their ovarian metastasis, but a minority of patients are symp-
tomatic (ascites, pelvic pain) and/or present with a relatively
large mass mimicking an ovarian primary neoplasm. A
majority of patients with ovarian metastasis have extraovar-
ian metastasis as well [132, 133]. Patients with breast cancer
are at increased risk of developing ovarian cancer and vice
versa, especially patients with BRCA1 or BRCA2 mutations
[135]. Of note, breast cancer patients presenting with a new
adnexal or pelvic mass have been found to be more likely to
have an independent ovarian or tubal primary malignancy
than metastatic breast cancer by a ratio of 3:1 [136].
Gross: Ovarian metastases are bilateral approximately
two-thirds of the time [134]. Metastases from breast carci-
noma are generally small compared with other metastatic Fig. 10.49 Mammary carcinoma of lobular type metastatic to the
tumors, usually less than 5 cm and as small as 1 mm or less ovary. Metastatic mammary carcinoma with a single file pattern such as
[12, 134]. Infrequently, the metastases may be larger than this one may raise a differential diagnosis of leukemia, lymphoma, or
5 cm and grossly indistinguishable from a variety of primary granulosa cell tumor
and metastatic ovarian tumors [134, 137]. The cut surface is
typically solid and white with discrete to confluent nodules, cinomas may have corded, insular, diffuse, or dispersed
but may rarely be solid and cystic or show prominent cyst patterns, and tumor cells may be sparse and thus easily
formation [12, 134]. missed on H&E (Fig. 10.49). Signet ring cells are usually
Microscopic: Breast carcinoma metastatic to the ovary not a prominent feature but can infrequently be abundant
has the same range of cell types and histologic patterns and generate a tumor meeting the criteria for Krukenberg
characteristic of primary breast cancer [2]. Lobular breast tumor [139]. Tumor cells may involve the theca interna of
cancer metastasizes to the ovary more often than does duc- the Graafian follicle, the granulosa or theca layer of the cor-
tal cancer [12, 132, 138] although, due to the greater fre- pus luteum, or a corpus albicans [12]. The stroma often has
quency of ductal carcinoma, a majority of ovarian no distinctive features and is rarely luteinized, in contrast to
metastases from breast cancer are of the ductal type [12]. that of gastrointestinal tumors metastatic to the ovary.
Ductal carcinomas can show tubular, cribriform, solid, pap- Lymphovascular invasion may be inapparent or multifocal
illary, insular, sheetlike, corded, and signet ring patterns, as [32, 134]. If a patient has received chemotherapy, tumor
well as mixtures of these patterns (Fig. 10.48). Lobular car- cells may be altered with foamy cytoplasm and minimal
cytologic atypia, and reduced to absent mitoses, rendering
diagnosis more challenging. Ovarian surface involvement
may be seen but is generally not as conspicuous as in
tumors metastatic from the gastrointestinal tract and other
intra-abdominal sites [2].
Biomarkers:
–– In general, breast carcinoma is positive for CK7, GATA3,

GCDFP-15, mammaglobin, and ER (Figs. 10.50 and
10.51). It is typically negative for CK20, PAX8, and
WT-1.
–– Up to 30% of breast carcinomas may be negative for
GCDFP-15 and mammaglobin [26].
–– Of note, mammaglobin diffusely stains some endometri-
oid adenocarcinomas, and occasional serous and clear-
cell carcinomas [140].
–– GATA3 stains approximately 90% of mammary ductal
Fig. 10.48 Mammary carcinoma of ductal type metastatic to the ovary.
Tumors with a glandular or cribriform architecture like this one raise a
carcinomas and up to 100% of lobular carcinomas but is
differential diagnosis of endometrioid adenocarcinoma, primary or not specific for breast carcinoma and marks a variety of
metastatic other neoplasms including urothelial carcinoma,
Fig. 10.50 Mammary
carcinoma of ductal type
metastatic to the ovary.
Mammary carcinomas often
express GATA3 (left) and ER
(right). Of note, endometrioid
adenocarcinomas also
infrequently express GATA3.
Expression of PAX-8 and/or
CA125 strongly favors
endometrioid adenocarcinoma
Fig. 10.51 Mammary

carcinoma of ductal type
metastatic to the ovary. This
tumor has a small tubular
architecture (left). Expression
of mammaglobin (right) is
often demonstrated in
mammary carcinomas,
although mammaglobin is not
specific and may diffusely
mark some endometrioid
adenocarcinomas
s quamous cell carcinoma, mesothelioma, and rare endo- Serous carcinoma: Is positive for CK7 and negative for
metrial adenocarcinomas [141]. CK20, and may show positivity for ER and mammaglobin,
–– Use of a directed panel of immunostains is recommended although mutation-type staining for p53 and positivity for
when ancillary testing is needed, as no single marker is PAX8, CA125, and/or WT1 strongly favor serous carcinoma.
adequately informative. Carcinoid tumor: Is positive for synaptophysin in virtu-
ally 100% of cases, and with other neuroendocrine markers
Differential Diagnosis: The differential diagnosis (NSE, PGP9.5, and chromogranin) in many cases.
includes primary ovarian surface epithelial carcinomas (endo- Granulosa cell tumor: Is typically unilateral and shows
metrioid, serous, or undifferentiated carcinoma), other meta- ovoid or angulated small nuclei with scant indistinct cyto-
static carcinomas, granulosa cell tumor, carcinoid tumor, plasm and characteristic nuclear grooves in at least some
desmoplastic small round cell tumor, and hematopoietic neo- cells. These tumors are usually EMA negative but may show
plasms [12]. Metastatic breast tumors with a predominantly patchy or punctate marking for LMWCKs, whereas carcino-
glandular architecture may resemble endometrioid adenocar- mas tend to have strong diffuse marking for EMA and vari-
cinoma, and tumors with an insular pattern may mimic carci- ous cytokeratins. An inhibin+/calretinin+/WT1+/CD99+/
noid tumor. A tumor with a diffuse/dispersed or single file FOXL2+/GATA3−/mammaglobin−/GCDFP− immunophe-
pattern may suggest leukemia or lymphoma. Metastatic notype is consistent with granulosa cell tumor [23].
breast carcinoma may also mimic granulosa cell tumor [2]. Desmoplastic small round cell tumor: Is characterized by
Careful attention to gross and microscopic features will pro- small round uniform cells with hyperchromatic nuclei and
vide a clue to the diagnosis in many cases, but immunostain- scant cytoplasm, and may have tubular or glandular forma-
ing and clinical correlation will be required for some cases. tions or signet ring cells that suggest the possibility of a met-
Features helpful in the differential diagnosis are as follows: astatic breast carcinoma. Although these tumors may occur
Endometrioid adenocarcinoma: Shares the CK7+/ in the elderly, most tumors develop in adolescents or young
CK20−/ER+ immunoprofile typical of breast carcinoma and adults. They show a distinctive immunohistochemical stain-
may also mark with mammaglobin and GATA3 less fre- ing pattern with positivity for epithelial (keratin, EMA),
quently, although positivity for PAX8 and/or CA125 strongly muscular (desmin), and neural (NSE) markers, which con-
favors endometrioid adenocarcinoma. Endometrioid adeno- trasts with that of metastatic breast carcinoma [12, 142].
carcinoma tends to be unilateral and may arise in the setting Hematolymphoid neoplasms: If the metastatic breast car-
of endometriosis or an endometrioid adenofibroma. cinoma has a dispersed, diffuse, or cord-like pattern, the
findings could suggest a hematolymphoid neoplasm. Use of cases, and melanin pigment in approximately 50% of cases.
immunohistochemical stains for keratins and hematolym- Unexpected findings include clear cells, rhabdoid cells, and
phoid antigens is confirmatory of the diagnosis. myxoid stroma. Architecturally, the tumor tends to have a
Management and Outcomes: A 2016 study of 28 patients solid growth pattern. A distinctive architectural feature found
with ovarian metastasis from previously treated breast cancer in many metastatic melanomas is a pattern of discrete
demonstrated a mean survival of 49.5 months (approximately rounded aggregates with a nevoid appearance. Other possi-
4 years) after discovery of the ovarian metastasis. Survival ble patterns include follicle-like spaces and a pseudopapil-
was 120.8 months for patients with an ovarian metastasis lary appearance [32, 145–147]. Melanoma metastatic to the
alone versus 106.9 months for patients with multiple second- ovary may grossly and microscopically mimic an ovarian
ary sites, a difference of nearly 14 months, implying that mul- primary neoplasm but, like other tumors metastatic to the
tifocal metastasis is a poor prognostic feature [132]. A 2010 ovary, metastatic melanoma tends to have a multinodular
study of 29 women with ovarian involvement with metastatic gross and microscopic appearance.
breast cancer compared outcomes between patients who The differential diagnosis for metastatic melanoma
underwent macroscopic resection of metastases versus includes primary ovarian melanoma and, depending on the
patients who did not; data indicated that survival improved cytoarchitectural features of the case, may include granulosa
significantly when optimal debulking surgery was performed, cell tumor of juvenile or adult type, small-cell carcinoma of
even when patients had advanced pelvic disease [133]. hypercalcemic type, undifferentiated carcinoma, lipid-poor
steroid cell tumor, pregnancy luteoma, and sarcoma [32]. A
panel of immunohistochemical stains is very helpful in
10.14 Metastatic Malignant Melanoma establishing the diagnosis of melanoma, especially in cases
where melanin pigment is not identified. S-100 marks at
Autopsy studies have demonstrated ovarian involvement by least 98% of melanomas, regardless of histologic type,
metastatic melanoma in approximately 20% of patients who although S-100 is not a specific marker, and thus is most
died of melanoma, although clinical detection of ovarian helpful as a screen for melanoma. HMB-45 and melan-A are
metastasis is rare [2, 12]. Data from occasional case reports both relatively specific for melanocytic type cells and have a
and three large series of melanoma metastatic to the ovary sensitivity of 60–80%. SOX-10 positivity has also been
indicate that patients may be symptomatic from the ovarian found in the majority of melanomas. Of note, S-100 and
metastasis, with abdominal swelling or pain [143–147]. A melan-A are positive in some ovarian sex cord-stromal
majority of patients with ovarian metastasis also have syn- tumors [23, 150].
chronous extraovarian metastasis. Most of the reported cases Once a diagnosis of melanoma has been established, it
have had an antecedent cutaneous melanoma, prior removal must be determined whether the melanoma is primary or
of a pigmented skin lesion, or rarely an ocular melanoma metastatic. Primary ovarian malignant melanoma is rare but
[144, 148]. The interval may be long (up to 22 years in one may occur in the setting of teratoma, including monodermal
reported case), and in some patients no prior history of ante- teratoma (struma ovarii) [151, 152]; thus, a background of
cedent melanoma is described. In these instances, the pri- teratoma is an important clue to the possible primary nature
mary melanoma may be unknown to the clinician, or may of the neoplasm. In these rare cases, junctional activity at the
have regressed [149]. base of squamous epithelium may be seen. Bilaterality and
Pathologists know that melanoma may show different multinodular growth suggest metastatic tumor, even in the
cytologic features and different architectural patterns, and absence of an identifiable primary tumor. In some cases it
may appear in unexpected locations; thus, the diagnosis may may not be possible to determine whether the melanoma is
be challenging. In the ovaries, metastatic melanoma may be primary or metastatic [32].
bilateral or unilateral, and may be solid, solid and cystic, or
even predominantly cystic. No specific gross features have
been described except for brown or black coloration, which 10.15 M
etastasis from Kidney and Lower
may be focal, in some tumors. Tumors average approxi- Urinary Tract
mately 10 cm but may be as large as 20 cm [145–147].
Microscopically, the most common cell type is a variably Metastasis from kidney: Renal cell carcinoma rarely metas-
pleomorphic, large epithelioid cell with abundant eosino- tasizes to the ovaries. Most reported cases of renal cell carci-
philic cytoplasm. Small cells with scant cytoplasm are also noma metastatic to the ovaries have been of the clear cell
common. Fewer tumors have a spindled cytomorphology. type [153–155], although other types (chromophobe, collect-
Admixed cell types may be seen. Prominent nucleoli, char- ing duct, and unclassified types) have been infrequently
acteristic of melanoma, are seen in approximately 80% of reported [153, 156]. In some cases, the ovarian tumor is dis-
cases, nuclear pseudoinclusions in approximately 25% of covered prior to diagnosis of the renal primary. In other
cases, the ovarian tumor is discovered after diagnosis of the clear-cell carcinoma and lipid-rich ovarian steroid cell
renal primary, with one reported ovarian metastasis present- tumors are as follows:
ing 14 years after discovery of the renal primary.
The differential diagnosis of metastatic clear-cell renal –– Clear-cell renal cell carcinoma: The most useful panel
cell carcinoma involving the ovary includes mullerian clear- of antibodies for distinguishing clear-cell renal cell carci-
cell carcinoma and lipid-rich ovarian steroid cell tumor. noma from mullerian clear-cell carcinoma is CK7, CD10,
Although some morphologic overlap exists between these and RCC, as clear-cell renal cell carcinoma typically
entities (most notably, clear cytoplasm), certain distinctive expresses CD10 and RCC but not CK7, while mullerian
morphologic features and variations in the immunostaining clear-cell carcinoma typically expresses CK7 but not
patterns facilitate diagnosis. Morphologic features helpful in CD10 or RCC. Clear-cell renal cell carcinoma also typi-
the differential diagnosis are as follows: cally expresses CA-IX and vimentin, while mullerian
clear-cell carcinoma often expresses Napsin-A and p504s.
• Metastatic clear-cell renal cell carcinoma: Tends to Of note, both tumors usually express PAX8, and fewer
maintain the expected morphologic pattern. Grossly, than 10% of mullerian clear-cell carcinomas express ER
tumors are solid or solid and cystic, and uniformly or and PR [23, 157].
focally yellow to orange [153–155]. Classic morphologic –– Steroid cell tumors: Are typically inhibin+/calretinin+/
features of clear-cell renal cell carcinoma include a pre- melan-A+/EMA−. Approximately 40–50% stain for
dominance of cells with clear cytoplasm disposed in sheets cytokeratin [23].
or in tubules containing intraluminal blood or eosinophilic
material. The prominent vascular pattern of renal cell car- Metastasis from lower urinary tract: Urothelial carci-
cinoma is also usually present. In contrast to the relatively noma metastatic to the ovary from the urinary bladder, ure-
uniform clear-cell cytology typically shown by metastatic ter, or renal pelvis is rare (Figs. 10.52 and 10.53). This may
clear-cell renal cell carcinoma, mullerian clear-cell carci- mimic a primary tubo-ovarian transitional cell carcinoma,
noma typically has greater cytologic and architectural malignant Brenner tumor, or undifferentiated carcinoma
variation, with a mix of clear, eosinophilic, cuboidal, hob- [32]. A single case of urothelial carcinoma of renal pelvis
nail, and flat cells. The cells may be disposed in various origin and three cases of urothelial carcinoma of bladder ori-
architectural patterns including sheets, papillae, and lining gin with glandular differentiation and signet ring morphol-
cystic spaces, usually with at least focal presence of the ogy are reported to have metastasized to the ovary and
round tubulocystic glands characteristic of mullerian generated Krukenberg tumors [158, 159]. Thorough sam-
clear-cell carcinoma. Luminal mucin, eosinophilic hyaline pling of the ovarian tumor may disclose benign or borderline
globules, and papillae with stromal hyalinization also Brenner elements, or the presence of benign mucinous ele-
favor mullerian clear-cell carcinoma [32, 155]. ments, which provide clues to the diagnosis of a primary
• Ovarian steroid cell tumors of lipid-rich type: Do not malignant Brenner tumor. Most primary ovarian transitional
show the tubular growth pattern with intraluminal blood cell carcinomas are thought to be high-grade serous carci-
or eosinophilic material typical of clear-cell renal cell car- noma with transitional like morphology; these tumors may
cinoma. Careful morphologic examination should pro- have areas of more classic serous-type morphology, or less
vide a clue to the diagnosis. commonly endometrioid morphology, which establish the
primary nature of the tumor. Undifferentiated ovarian carci-
Typical immunohistochemical staining patterns helpful in noma tends to have high-grade cytologic features and may
distinguishing clear-cell renal cell carcinoma from mullerian have pseudopapillae due to necrosis, but lacks the true
Fig. 10.52 Urothelial

carcinoma metastatic to the
ovary. This example is
characterized by nests of
malignant urothelium with
central necrosis, involving a
desmoplastic stroma. The
tumor closely mimics primary
ovarian malignant Brenner
tumor, and may closely
resemble primary ovarian
transitional cell carcinoma
found to have ovarian metastasis at autopsy, although ovar-

ian metastasis discovered during life is less common.
Challenges in the differential diagnosis may arise, especially
if the pulmonary primary is unknown, or if the metastasis
involves an ovary harboring a primary ovarian neoplasm [79,
160]. Ovarian spread of primary pulmonary neoplasms has
received limited attention in the literature, the largest pub-
lished series being a 2005 report of 32 cases [79]. Among
these cases, it was noted that 53% of patients had a known
history of lung cancer, 31% had synchronously discovered
pulmonary and ovarian tumors, and 16% presented first with
an ovarian mass and no known history of lung cancer.
Histologic types in this series included small-cell carcinoma
(44%), adenocarcinoma (34%), large-cell carcinoma (16%),
squamous cell carcinoma (3%), and atypical carcinoid (3%).
Fig. 10.53 Urothelial carcinoma metastatic to the ovary. A different Two cases of pulmonary adenocarcinoma of the fetal type
area from the same tumor depicted in Fig. 10.52 shows a second pattern metastatic to the ovary have also been reported [161, 162]. In
typical of urothelial carcinoma, well-formed papillae lined by malig- the aforementioned 32 case series, the mean ovarian size was
nant urothelium 9.7 cm, and a minority (one-third) of the metastases were
bilateral. Features common to metastatic tumors in general
p apillae with smooth luminal borders characteristic of uro- (such as multinodular growth, prominent necrosis, and
thelial carcinoma and some primary ovarian “transitional extensive lymphovascular invasion) were noted in many of
cell” carcinomas [12]. the tumors. Notation of these features, of any histologic fea-
Immunohistochemical staining features useful in the dif- tures uncommon to ovarian primary neoplasms in general,
ferential diagnosis between urothelial carcinoma and its and of any clinical history available will aid in making the
chief mimics are as follows: correct diagnosis in most cases. Immunohistochemical stain-
ing for TTF-1 may be of adjunctive aid in the diagnosis, as
–– Urothelial carcinoma typically expresses both CK7 and many pulmonary adenocarcinomas, small-cell carcinomas,
CK20, p63, thrombomodulin, GATA3, and uroplakin III and atypical carcinoid tumors express TTF-1. It should be
[157]. noted that TTF-1 expression may be seen in endometrioid
–– Primary tubo-ovarian “transitional” carcinomas typically tumors arising from the uterus or ovary.
have an immunohistochemical staining pattern similar to Metastasis from the mediastinum: Ovarian metastasis
that of ovarian high-grade serous carcinoma and express of mediastinal tumors is less commonly reported than ovar-
CK7, WT1, PAX8, p16, and often ER. A mutation-type ian metastasis of lung tumors. There are rare reported cases
pattern with p53 staining (diffuse or null pattern) is seen of thymoma metastatic to the ovary [163]. A case of a child
in most cases. These tumors are usually negative for with a posterior mediastinal neuroblastoma metastatic to the
CK20, p63, uroplakin, and thrombomodulin, although ovary has also been reported [164].
GATA3 may be expressed [23].
–– Limited data exists regarding the immunohistochemical
staining patterns of malignant Brenner tumors. Benign 10.17 L
ymphoma and Leukemia Involving
Brenner tumors show an immunophenotype similar to the Ovary
urothelium, suggesting true urothelial differentiation in
these tumors, although borderline and malignant Brenner Lymphoma involving the ovary: While as many as 25% of
tumors exhibit urothelial markers less often than their disseminated lymphomas were found to involve one or both
benign counterparts [23]. ovaries at autopsy in a 1972 study [165], lymphoma present-
ing clinically as an ovarian mass is rare. Lymphoma present-
ing as an incidental finding in the ovary is also rare. An
10.16 Metastasis from the Lung exception to the above is ovarian involvement in countries
and Mediastinum where Burkitt lymphoma is endemic; in these nations, the
ovary is a frequent site of involvement, and the patients are
Metastasis from the lung: The clinical presentation of ovar- typically children [166]. Any type of lymphoma may involve
ian metastasis from a primary lung carcinoma is relatively the ovary, and affected patients span all age groups. In most
rare. Approximately 5% of women with lung cancer are cases in which ovarian lymphoma is discovered there is more
disseminated disease with associated abdominal or pelvic leukemia, and 22% of cases of chronic lymphocytic leuke-
lymph node involvement. In a minority of cases, however, mia [177]. The percentage of cases involving the ovary was
there is exclusive involvement of a single ovary, suggesting noted to decrease over the time period of the study, likely
that the ovary is the primary site [167]. reflecting increasing efficacy of treatment.
Ovarian involvement by lymphoma may be a small inci- Leukemic involvement of the ovary infrequently produces
dental finding or a large mass (masses ranging up to 25 cm a symptomatic ovarian mass. In a 1997 study focusing on 11
have been reported). The external surface is typically smooth cases of granulocytic sarcoma of the female genital tract, 7
or bosselated and intact. The cut surface is usually white to cases had ovarian involvement and produced masses ranging
tan, fleshy to firm or rubbery, and solid, with occasional from 5 to 14 cm. Three of the tumors had a green cut surface.
areas of cystic degeneration, hemorrhage, or necrosis [168– Myeloid differentiation was readily recognizable in three of
171]. Most lymphomas involving the ovary are of B-cell the cases, whereas the other cases presented more of a diag-
type, the most common subtypes including diffuse large nostic challenge due to primitive cytologic features without
B-cell type, Burkitt lymphoma, and follicular lymphomas. the classic eosinophilic myelocytes. Sclerosis was present in
Rare tumors are of T-cell type, reported cases including the majority of tumors, and prominent in one tumor [176].
T-cell anaplastic large-cell lymphoma and precursor Microscopic features of leukemia in the ovary are similar to
T-lymphoblastic lymphoma [167–169]. Primary plasmacy- those of lymphoma, although nuclei have paler, finer chro-
toma of the ovary and secondary ovarian involvement by matin than do most lymphomas, and the cytoplasm is more
multiple myeloma have also been rarely reported [172–174]. abundant, pale pink, or deeply eosinophilic. Once leukemia
Cytologically, lymphomas in the ovary are similar to their enters the differential diagnosis, the diagnosis can be con-
counterparts in lymph nodes and extranodal sites, although firmed by staining for chloroacetate esterase or a directed
sclerosis may be more prominent in the ovary, and may battery of immunohistochemical stains. The differential
induce unusual patterns including single file, trabecular, diagnosis includes lymphoma and, as noted above with lym-
insular, and storiform arrangements. Lymphomas may also phoma, other tumors consisting of singly disposed cells such
diffusely involve the ovary, and spare or obliterate physio- as granulosa cell tumor, dysgerminoma, undifferentiated car-
logic structures [12, 175]. cinoma, melanoma, and metastatic carcinomas including
Possibly due to the propensity of these tumors to have breast carcinoma.
associated sclerosis, lymphoma cells in the ovary may appear
more epithelioid or spindled than in extraovarian sites, caus-
ing diagnostic difficulty. The differential diagnosis includes 10.18 Other Rare Metastatic Tumors
other tumors characterized by relatively small cells that may
be singly disposed, including granulosa cell tumor, dysger- Virtually any tumor can metastasize to the ovary, and the list
minoma, small-cell carcinoma of hypercalcemic type, granu- of such tumors is not limited to those reported above. Thus,
locytic sarcoma, undifferentiated carcinoma, melanoma, and it is critical that when one encounters an ovarian tumor with
breast carcinoma. The differential diagnostic considerations cytologic or architectural features uncommon to primary
can be excluded with a directed panel of immunohistochemi- ovarian neoplasia, metastasis is considered.
cal stains [12, 175]. Head and neck tumors of thyroid, salivary gland,
Leukemia involving the ovary: The most substantial esophageal, and sinonasal origin: Head and neck tumors
data regarding leukemic involvement of the ovaries consists have infrequently been the source of ovarian metastasis. The
of autopsy studies and case series reported before 2000, thyroid is a rare source of ovarian metastasis, even in autopsy
which would be expected to reflect treatment efficacy at the series [2]. Few cases of thyroid follicular carcinoma and pap-
time [168, 170, 176–178]. More recent information consists illary thyroid carcinoma have been reported to metastasize to
of one series of 124 leukemic ovarian tumors which focused the ovary, up to 12 years after the initial presentation in the
on survival data [179], and infrequent case reports [180, thyroid [182–184]. In a recent study, anaplastic thyroid car-
181]. Leukemic involvement of the ovary appears to be less cinoma was found to involve the ovary in 2% of 45 cases
common than lymphomatous involvement of the ovary; in examined at autopsy [185]. As thyroid tissue may develop in
studies that have included both leukemias and lymphomas, the ovary as a component of a teratoma or as a monodermal
there were only three cases of ovarian leukemia among a teratoma, malignant thyroid tissue in the ovary raises the dif-
total of 61 cases. In a 1987 autopsy study of 1206 cases of ferential diagnosis of malignant struma ovarii. If other tera-
acute and chronic leukemias gathered between 1958 and tomatous elements are not found on thorough sampling, a
1982, the ovary was involved by leukemia in 11% of the diagnosis of malignant struma ovarii should be made only
cases of acute myelogenous leukemia, 9% of cases of chronic when the possibility of spread from a thyroid neoplasm has
myelogenous leukemia, 21% of cases of acute lymphoblastic been explored and excluded [182].
Rare salivary gland tumors have been documented to References

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Peritoneum and Broad Ligament
11
M. Ruhul Quddus, Sharon Liang, Wenxin Zheng,
and C. James Sung
Abstract tumors identical to those of the Müllerian system commonly

The peritoneum is a site for diverse nonneoplastic and neo- seen within the pelvis and thus extending the territory of
plastic disease processes including those encountered in Müllerian tumors beyond the pelvic brim up to the level of
many other organ systems in the body. Once proposed as the diaphragm. Peritoneal diseases in females include lesions
part of the secondary Müllerian system, its role in the patho- arising from native components of the peritoneum as well as
genesis of primary serous carcinomas has recently been tumors related to the secondary Müllerian system. Therefore,
questioned. It has been postulated that primary Müllerian discussion of peritoneal diseases should include all lesions
peritoneal/omental serous carcinoma is a metastasis from of the female genital system. Accordingly, this chapter first
the similar tumor of the fallopian tubes. This theory, how- addresses the general diseases followed by diseases of the
ever, applies to serous carcinomas only, not tumors of any secondary Müllerian system.
other Müllerian cell types. Far from being a mere receptacle
for metastasis from other organ sites, the notion that the
peritoneum and its derivatives serve as important source of 11.1 S
ection 1: General Diseases
primary peritoneal carcinomas remains a valid concept. of the Peritoneum
Keywords 11.1.1 Anatomy and Histology

Müllerian system · Primary peritoneal carcinoma
Implants · Mesothelioma Similar to the pleura, the peritoneum also has parietal and
visceral layers. The parietal peritoneum covers the posterior
abdominal wall, diaphragm, retroperitoneal cavity, and sur-
faces of the pelvis. The visceral peritoneum covers the ali-
The peritoneum is a site for diverse neoplastic and nonneo- mentary track and the surfaces of intra-abdominal organs.
plastic disease processes including inflammation, reactive The parietal and visceral peritoneum combines at the vascu-
changes, and neoplasms, including benign, borderline, and lar mesentery which is rich in blood vessels, lymphatics,
malignant tumors. It has unique potential to give rise to lymph nodes, and nerves. Unlike the closed peritoneal cavity
in males, the female peritoneal covering is discontinued at
M. Ruhul Quddus · C. James Sung (*) the fimbriated end of fallopian tube creating a natural thor-
The Warren Alpert Medical School of Brown University, Women oughfare along the tube, uterine cavity, vagina, and eventu-
& Infants Hospital, Providence, RI, USA ally to the exterior. This exposes the female peritoneum to
e-mail: [email protected]; [email protected] external (environmental) stimuli [1]. The interrupted perito-
S. Liang neal covering thus forms a unique uterotubal–peritoneal
Department of Pathology and Laboratory Medicine, Allegheny structure. This unique anatomic characteristic fulfills physi-
Health Network West Penn Hospital, Drexel University College of
Medicine, and Temple University School of Medicine, ological functions of reproduction, but serendipitously
Pittsburgh, PA, USA allows ascending movement for physiologic and pathologic
e-mail: [email protected] agents, such as menstrual blood, chemical substances, and
W. Zheng possibly pathogens, resulting in ailments.
Departments of Pathology, Obstetrics and Gynecology, University The peritoneum is derived from the mesoderm but
of Texas Southwestern Medical Center, Dallas, TX, USA expresses both mesenchymal and epithelial cell intermediate
368 M. Ruhul Quddus et al.
filaments. It is covered by a single layer of flat or low

cuboidal mesothelial cells with central nuclei (Fig. 11.1),
sparse or abundant cytoplasm, and distinct cell borders.
The nucleolus is typically inconspicuous. Ultrastructurally,
mesothelial cells have tight junctions, intercellular bridges,
long microvilli, and tonofilaments. The long microvilli on
the cell surface, being most characteristic (Fig. 11.2), help
distinguish it from metastatic adenocarcinoma. By immu-
nohistochemistry, mesothelial cells express different kinds
of cytokeratins as well as other proteins, including cyto-
keratin 5/6, EMA, CEA, and Leu-M1 (CD15). Mesothelial
cells also express special markers including calretinin
(Fig. 11.3), thrombomodulin, and basal laminin. They are
negative for Ber-EP4 and B72.3. These characteristics aid
in differentiating mesothelial lesions from metastatic Fig. 11.3 Mesothelial cells stain strongly with calretinin, both nuclear
and cytoplasmic staining (IHC, 400×)
epithelial lesions.
Fig. 11.4 Acute peritonitis with numerous inflammatory cells infiltrat-

ing omentum (H&E, 200×)
Fig. 11.1 Histology of mesothelial cells (H&E, 400×)

11.1.2 Inflammatory Diseases
11.1.2.1 Acute Peritonitis

Diffuse acute peritonitis may result from infection or irrita-
tion by chemical agents, a common occurrence after rupture
of acute appendicitis or diverticulitis. The disease is charac-
terized by massive infiltration of acute inflammatory cells
and exudates (Fig. 11.4). Fat necrosis may be present.
Children, immunocompromised patients, and adults with cir-
rhosis may develop spontaneous bacterial peritonitis.
Recurrent acute peritonitis is characteristic of Mediterranean
fever, a recessive hereditary disease, more frequently seen in
Sephardic Jews, Armenians, Turkish, and certain Middle
Eastern populations [2, 3]. Localized acute peritonitis is typ-
ically associated with inflammation of pelvic organs.
Fig. 11.2 Ultrastructural image of mesothelial cells showing long 11.1.2.2 Granulomatous Peritonitis
slender microvilli on the surface of the cells. This gives the typical Many infectious and noninfectious agents may inflict a gran-
“window” effect around the mesothelial cells under light microscope ulomatous response in peritoneum. Presence of diffuse
11 Peritoneum and Broad Ligament 369
Fig. 11.6 Foreign-body granuloma composed of inflammatory cells,

Fig. 11.5 Granulomatous peritonitis with a classic necrotizing granu-
multinucleated foreign body-type giant cells, and empty spaces with
loma (tubercle), caseation necrosis, and Langhans-type multinucleated
talc powder (H&E, 200×)
giant cells (H&E, 200×)
g ranulomata in the peritoneum may be misinterpreted as dis- also be encountered. Sometimes histiocytic proliferation
seminated carcinomatosis. Histological examination is may occur around necrotic nodules, known as necrotic
required to confirm the diagnosis. pseudo-xanthomatous tubercles, with or without pigmenta-
Mycobacterial infection is the most common infection in tion. Pigmented histiocytic proliferation is rarely seen, and
the peritoneum (Fig. 11.5), showing an increase in incidence typically is secondary to deposition of melanin pigments, a
in recent years, especially in immunocompromised patients condition known as peritoneal melanosis, usually associated
[4]. The mode of transmission could be via systemic dissemi- with ruptured mature cystic teratoma [6]. These pigment-
nation or direct spread of intraperitoneal infection. Caseating laden histiocytes lack organelles, a differentiating point from
necrosis, epithelioid cells, and Langhans-type giant cells are malignant melanoma.
characteristics of this lesion. Acid-fast stain or immunofluo-
rescence stains may detect mycobacterium; however, they 11.1.2.4 Peritoneal Fibrosis and Adhesions
may also be negative. Molecular testing for mycobacterium, Peritoneal fibrous adhesions and reactive fibrosis often occur
typically via polymerase chain reaction (PCR), can help to after inflammation and abdominal surgery. Severe adhesions
resolve difficult cases. Rare cases of granulomatous peritoni- may result in intestinal obstruction. Patients with cirrhosis,
tis may also be caused by fungal infection. pulmonary tuberculosis, or asbestos exposure may develop
Noninfectious granulomata are caused by non-pathogens localized transparent plaques on the surface of the liver or
such as surgical glove talcum powders, suture materials, con- spleen. Diffuse fibrosis in the abdomen is known as sclerotic
trast medium, and other iatrogenic agents (Fig. 11.6). Fecal or fibrotic peritonitis (Fig. 11.7). This condition is typically
contamination, pancreatic enzymes, digestive secretions, and idiopathic, although occasionally asbestos has been impli-
bile resulting from intestinal perforation or ruptured neo- cated. Sarcoidosis, abdominal peritoneal dialysis, and use of
plasm, such as dermoid cyst or ovarian tumors, may induce beta-anti-adrenergic agents may also be contributory [7].
noninfectious granulomas. Keratin-induced foreign body Sclerosing peritonitis is a rare, often fatal condition of perito-
granulomas may be seen in endometrial or ovarian carcino- neal inflammation secondary to peritoneal dialysis. It may
mas with squamous differentiation, as well as teratomas with follow renal or liver transplantation. The patients are typically
keratin formation. It has been reported that the presence of young females of reproductive age, presenting with abdomi-
keratin granulomata without viable tumor cells does not nal pain, abdominal distention, ascites, intestinal obstruction,
affect prognosis in patients with endometrioid carcinoma [4, and a pelvic tumor. The condition may also be associated
5]. Sarcoidosis and Crohn’s disease may rarely cause granu- with anticonvulsant treatment [8, 9]. Sclerotic peritonitis is
lomatous peritonitis. thought to be a reactive process and it may be confused with
desmoplastic type mesothelioma of the peritoneum.
11.1.2.3 Non-granulomatous Histiocytic
Lesions 11.1.2.5 Rare Subtypes of Peritonitis
Endometriosis can trigger histiocytic response in the perito- Other rare types of peritonitis include eosinophilic peritoni-
neum and omentum. Decidualization, endosalpingiosis, and tis and peritonitis secondary to collagen vascular diseases,
endocervicosis (endocervical mucinous-type epithelia) may including systemic lupus erythematosus.
11.1.3 Tumorlike Diseases
11.1.3.1 Mesothelial Hyperplasia

Mesothelial hyperplasia is usually an incidental finding,
often caused by irritation due to intra-abdominal hemor-
rhage, ascites, and/or inflammation. It is a reactive process
characterized by proliferation of mesothelial cells.
Mesothelial hyperplasia is usually localized and mild, with
solitary small nodules. Microscopically mesothelial hyperpla-
sia may appear as solid sheets, trabeculae, tubules, papillae, or
tubulo-papillary growths (Fig. 11.8a–c). When mesothelial
hyperplasia presents with papillary or tubulo-papillary lesions,
it may mimic serous borderline tumor or metastatic adenocar-
cinoma. Mesothelial hyperplasia may occasionally involve
Fig. 11.7 Sclerotic peritonitis. Lower power view showing submeso- underlying mesenchymal tissue, making it even harder to dif-
thelial fibrosis and inflammatory infiltrates (H&E, 100×) ferentiate from other neoplasms (Fig. 11.9a, b).
a b
Fig. 11.8 Mesothelial hyperplasia, various morphologic types. (a) Mesothelial cells proliferate to become stratified or papillary. (b). Small tubu-
lar growth. (H&E 400) (c) Marked papillary growth (H&E, 100×)
a b
Fig. 11.9 Reactive mesothelial cells may appear sheetlike (a) but the cells appear monotonous or pleomorphic with abundant cytoplasm (H&E,
200×) and (b) without nuclear atypia (H&E, 400×)
The morphologic appearance of reactive mesothelial cells Table 11.1 Differences between marked mesothelial hyperplasia ver-
sus diffuse malignant mesothelioma
varies depending upon the degree of proliferation and com-
plexity of architectural patterns. In mild hyperplasia, the Marked mesothelial Diffuse malignant
hyperplasia mesothelioma
nuclei are small, regular, round, or oval, with centrally placed
Clinical presentations No previous history of Previous history
nucleoli. The cytoplasm may be eosinophilic and vacuolated. asbestos exposure of asbestos
In more severe cases, mesothelial cells may be multinucle- exposure
ated with enlarged nuclei, abundant cytoplasm, and promi- Gross findings Not grossly visible Grossly visible,
nent nucleoli, mimicking adenocarcinoma; however, cells of necrotic
Cytologic morphology Monotonous Pleomorphic
mesothelial hyperplasia are typically uniform in size with
population of small or
abundant cytoplasm. Conversely, adenocarcinoma cells usu- enlarged, distinct cell
ally have pleomorphism, much larger nuclei, increased N/C border
ratios, and frequent mitotic figures. Cytoplasm Abundant eosinophilic Prominent
Florid mesothelial hyperplasia must be differentiated cytoplasm, with vacuolation
occasional vacuoles
from diffuse malignant mesothelioma (DMM). The differ-
Tissue infiltration None or superficial Deeply
ences between the two scenarios are summarized in pseudoinvasion infiltrative
Table 11.1. The presence of grossly visible nodules, necro- Immunohistochemical CK +, vimentin +, p53 +, EMA +
sis, vacuolated cytoplasm, nuclear pleomorphism, and deep staining desmin +
tissue infiltration supports the diagnosis of diffuse malignant
mesothelioma (DMM). Positive immunostaining with p53
and EMA also supports the diagnosis of diffuse malignant 11.1.3.2 Peritoneal Inclusion Cyst
mesothelioma (DMM) [10, 11]. Peritoneal inclusion cysts may have a variety of clinical presenta-
Mesothelial hyperplasia must also be differentiated from tions. It is usually seen in females of reproductive age, often with
serous borderline tumor of the peritoneum or ovary. The dif- a prior history of abdominopelvic surgery, inflammation, or
ferences of ovarian or peritoneal tumors are usually quite endometriosis, which may indicate that inflammation is causal in
apparent. The presence of columnar-type tumor cells, absent this entity [12]. In most cases, peritoneal inclusion cysts are inci-
microvilli (the so-called window around mesothelial cells), dental findings during intra-abdominal surgery. Some patients
crack artifacts around tumor cell nests, seromucinous pro- may present with lower abdominal pain or a pelvic mass. Some
teinaceous materials, and abundant psammoma bodies may evidence suggests that hormonal changes may affect the disease
support a diagnosis of serous tumor. Characteristics of serous process. Therapeutic options include observation or surgical
tumor will be discussed later in this chapter and in other resection. Most cases are benign although recurrences may occur
chapters. in 50% of the cases. Surgery is generally curative.
a b
Fig. 11.10 Multicystic peritoneal inclusion cyst is composed of multiple cysts separated by fibrous septae lined by (a) flat mesothelial cells
(H&E, 100×), with (b) may show occasional squamous metaplasia (H&E, 200×)
Multicystic peritoneal inclusion cysts (MPIC) have also 11.1.3.3 Calcifying Fibrous Pseudotumor
been described as benign cystic mesothelioma, cystic peri- This rare benign soft-tissue lesion is defined as a paucicel-
tonitis, or postsurgical peritoneal inclusions. Use of the term lular collagenous reaction associated with inflammation and
“mesothelioma” often creates unnecessary anxiety among dystrophic calcifications. It possibly represents a reactive
the clinicians and patients, so many have elected to avoid process and often presents as an incidental finding in the vis-
this term in clinical practice. The lesion is composed of mul- ceral peritoneum of the small intestine and the stomach, typi-
tiple thin-walled cysts forming grapelike clusters attached cally in younger patients below 20 years of age. Grossly the
to peritoneal surfaces. The cysts may range from several lesion presents as a well-defined solid tumor up to 20 cm.
millimeters up to 20 cm, containing clear serous fluid.
The cut surfaces are gritty (or sandy). Microscopically dense
Microscopically the cysts are separated by fibrous stroma collagen fibers are arranged in a concentric pattern and
lined by single- or multilayered flat or cuboidal mesothelial admixed with benign-appearing fibroblasts, lymphocytes,
cells with benign-appearing nuclei or slight nuclear pleo- and plasma cells. Focal psammoma bodies or dystrophic cal-
morphism (Fig. 11.10a, b). Focal mesothelial hyperplasia, cifications are present. It can undergo torsion and present as
adenomatous changes, or squamous differentiation may be acute peritonitis [13]. It has been suggested that the lesion
encountered. may be associated with inflammatory myofibroblastic tumor
The differential diagnoses of multicystic peritoneal inclu- [14, 15] or sclerotic phase of inflammatory myofibroblastic
sion cysts include malignant mesothelioma, cystic mesothe- tumor [16, 17] which are discussed later in the chapter.
lioma, cystic lymphangioma, and adenomatoid tumor.
Malignant mesothelioma presents as papillary or tubulo- 11.1.3.4 Splenosis
papillary neoplasm, containing tumor cells with nuclear In splenosis, multiple nodules of ectopic splenic tissue are
pleomorphism and marked proliferative activity. Multicystic present in the abdominal cavity. The condition typically
lymphangioma, another differential diagnosis of mesotheli- occurs as a result of autoimplantation of splenic tissue after
oma, is a congenital condition often seen in children, which traumatic rupture of the spleen and is typically asymptom-
typically occurs in the small intestinal mesentery, omentum, atic. Splenosis is generally an incidental finding many
mesentery of the sigmoid colon, and retroperitoneum. The months or even years after splenectomy during subsequent
cysts are characterized by spongiform spaces lined by endo- intra-abdominal surgery or autopsy. Some female patients
thelial cells. Smooth muscle cells and lymphocytes are often may present with abdominal pain, having symptoms similar
present in the cyst wall of cystic lymphangioma, but not in to those of endometriosis, adnexal tumor, or diffuse perito-
MPIC. Adenomatoid tumors typically are seen in the fallo- neal carcinomatosis [18–20]. The number of the nodules
pian tubes or uterine serosa with a classic gross and micro- may vary from case to case with some cases demonstrating
scopic appearance and generally lack marked inflammatory over 100. The nodules vary in size from several millimeters
infiltrate. The differential diagnosis of multicystic peritoneal to centimeters. The nodules are typically composed of red
inclusion cysts from cystic mesothelioma is discussed later pulp surrounded by a dense collagenous pseudocapsule
in the chapter. devoid of smooth muscle or elastic fibers. Larger splenic
nodules may contain all the components of a normal spleen.

The condition may cause intra-abdominal adhesions, result-
ing in intestinal obstruction.
It is easy to distinguish splenosis from accessory spleen.
The latter is a congenital phenomenon, typically found in the
splenic hilum, near the tail of pancreas or anywhere along the
splenic vessel to the left side of abdomen and measuring from
a few millimeters to 2–3 cm. Accessory spleens typically have
a true capsule and a small splenic hilum, and no history of
adhesions or traumatic injury. It is relevant to recapitulate that
splenic parenchymal involvement by a malignant epithelial
tumor of gynecologic origin is considered stage IV disease.
11.1.3.5 Trophoblastic Implants

Extratubal secondary trophoblastic implants in the abdomen
are a rare complication of laparoscopic procedures for tubal Fig. 11.12 Peritoneal keratin granuloma. Remnants of keratin and
ectopic pregnancy or in vitro fertilization (IVF) [21, 22], squamous cells are surrounded by multinucleated giant cells and
with an estimated incidence of 3.6% [23–25]. It is more inflammatory cells (H&E, 400×)
commonly seen in intra-abdominal laparoscopic surgery as
opposed to open laparotomy, as well as oviduct reanastomo- endometrial–tubal–pelvic routes. Occasionally peritoneal
sis as opposed to salpingectomy. The clinical presentations keratin granulomas may be associated with carcinoma of the
include a rebound of serum or urine hCG levels after surgical uterine cervix or atypical polypoid adenomyoma of the uterus
removal of an ectopic pregnancy, abdominal pain, and/or [4, 26, 27]. The center of the granulomata contains keratinous
abdominal hemorrhage. Trophoblastic cells in decidualized material or remnants of squamous cells, surrounded by
stroma can be seen by microscopic examination (Fig. 11.11). chronic inflammation, foreign-body giant cells, and dense
It may be prevented by a thorough examination of surgical fibrosis (Fig. 11.12). Residual anucleated keratin material
field after removal of ectopic pregnancy. may also be seen after radiation therapy of a malignant tumor.
The granulomata are typically present on the serosal surfaces
11.1.3.6 Peritoneal Keratin Granulomas of the adnexa, uterus, colon, and appendix and may be misinter-
Peritoneal keratin granulomata are formed due to local reac- preted as metastatic tumor. A few studies with small sample size
tion to keratin debris derived from other intraabdominal showed that peritoneal keratin granulomata without viable
sources. The condition is often seen in cases of endometrial tumor cells do not affect patient’s prognosis. Pathological exam-
adenocarcinoma or ovarian carcinoma with squamous ination is mandated to rule out viable tumor in these foci [26].
differentiation or ruptured ovarian mature cystic teratoma
(dermoid cyst). Keratin may reach the abdomen through the 11.1.3.7 Infarcted Appendix Epiploica
Appendix epiploicae are polypoid adipose tissue on the sero-
sal surfaces of large intestine, especially of the transverse
colon and sigmoid colon. They may undergo torsion, infarc-
tion, and calcification. If detached, they float freely in the
abdominal cavity. Microscopically these nodules are com-
posed of central fat necrosis and calcification surrounded by
pseudo-capsule of dense fibrous tissue (Fig. 11.13).
11.1.4 Mesothelioma
11.1.4.1 Benign Mesothelioma
Adenomatoid Tumor
Adenomatoid tumor is a benign mesothelial derived tumor
often seen near the oviducts in females and epididymis in
Fig. 11.11 Focal decidual stromal reaction with rare trophoblastic
cells in peritoneum (patient had a recent history of ectopic pregnancy) males, uterine serosa, broad ligament, and occasionally near
(H&E, 100×) the ovarian hilum and ovary.
By definition, this tumor is noninvasive. It may present as a

diffuse or multifocal entity on peritoneal surfaces within the
abdominal cavity. Approximately 80% of cases have been
reported in females of reproductive age and follow-up of
most of these demonstrates a benign course [31–33]. Often
the tumor is an incidental finding during intra-abdominal
surgery, although some patients may present with abdominal
pain or ascites. According to the literature, most patients
have not been exposed to asbestos [31].
1. Gross examination: Well-differentiated papillary meso-

thelioma may present as a solitarily lesion or multiple
gray or white firm nodules. Occasionally the tumor may
appear papillary, and is typically smaller than 2 cm. The
Fig. 11.13 Infarcted and pseudo-capsulated appendix epiploica of the tumor often involves the omentum and the pelvic perito-
intestine (H&E 40×) neum; however, involvement of the stomach, intestine,
and mesentery has also been reported [31].
2. Microscopic examination: Well-differentiated papillary

mesotheliomas of the peritoneum are composed of broad
fibrovascular cores lined by a single layer of cuboidal to
flat mesothelial cells (Fig. 11.15a). Occasional basal vac-
uoles may be seen. Some fibrovascular cores may show
mucinous change, with prominent fibrosis or hyaliniza-
tion. The tumor cells are uniform in size and shape, lack-
ing mitosis, nucleoli, or tissue necrosis (Fig. 11.15b).
Other rare histological subtypes include tubulo-papillary,
adenomatoid, branching, and solid patterns. Rare cases
may present with multinucleated giant cells and psam-
moma bodies. Histochemical, immunohistochemical, and
ultrastructural characteristics of this tumor support meso-
thelial origin of this tumor.
3. Differential diagnoses: It is important to differentiate

well-differentiated papillary mesothelioma from malig-
Fig. 11.14 Adenomatoid tumor composed of gland-like spaces lined
by cuboidal mesothelial cells (H&E, 100×) nant mesothelioma because they have a vastly different
prognosis. Even though the gross appearance of well-
differentiated papillary mesothelioma is quite different
1. Gross examination: This tumor often demonstrates a
from that of invasive malignant mesothelioma, some fea-
gray-yellow tubercle-like growth pattern, and is typically tures resembling well-differentiated papillary mesotheli-
solitary. Occasional tumors may present with multiple oma may also be present focally in malignant
nodules of variable sizes ranging from several millimeters mesothelioma [32]. Therefore the diagnosis of well-
to multiple centimeters. differentiated papillary mesothelioma must adhere to
2. Microscopic examination: Typically, this tumor forms
strict criteria including both the lack of nuclear pleomor-
irregular, reticular slit-like spaces lined by a single layer phism and tissue infiltration. Tumors showing any evi-
of flat or low cuboidal, epithelial-like cells (Fig. 11.14) dence of invasion must be noted and may represent
with mild nuclear pleomorphism and rare mitoses. Several focally malignant mesothelioma as opposed to well-
rare atypical histological subtypes such as solid, angio- differentiated papillary mesothelioma. Also to remember
matous, and cystic variants have been reported [28]. that well-differentiated mesothelioma with invasive foci
in the papillae is prone to multifocality and recurrence.
11.1.4.2 Malignant Mesothelioma However, they rarely are fatal [33].
The histologic difference between well-differentiated
Well-Differentiated Papillary Mesothelioma papillary mesothelioma and serous borderline tumor is
Well-differentiated papillary mesothelioma of the perito- rather striking as the latter shows irregular feather-like
neum is rare and has an indolent clinical course [29, 30]. cell clusters. The nuclei of serous borderline tumors usu-
ally demonstrate more nuclear pleomorphism when com- exposure remains controversial. One recent study reported
pared to those of a well-differentiated papillary that 29% of 96 male patients had occupational asbestos
mesothelioma; however they may be difficult to distin- exposure while none of the 113 female patients had any
guish in some cases. Scattered ciliated cells in the lining history of asbestos exposure [37]. Some authors also noted
epithelium can help to identify a serous tumor if present. that mesothelioma in female patients may be related to
Immunohistochemical characteristics of serous border- radiation, chronic inflammation, organic chemicals, or non-
line tumor are discussed later in the chapter. asbestos fibers. Approximately 40% of female patients sur-
4. Treatment and prognosis: The treatment of choice for vived more than 4 years, much more than their male
well-differentiated papillary mesothelioma is surgery; counterparts [38].
however, this may not be curative. This tumor typically
presents with an indolent clinical course, with many 1. Clinical characteristics: The clinical presentation of dif-
patients surviving several years or even several fuse malignant mesothelioma is similar to that of ovarian
decades. or other peritoneal malignancies. Patients typically report
abdominal discomfort, abdominal distention, indigestion,
Low-Grade Cystic Mesothelioma and weight loss. Many patients present with ascites.
Most cystic mesothelial lesions appear as a reactive pro- Occasional cases may present with retroperitoneal, intes-
cess, e.g., peritoneal inclusion cysts, but rare cases may tinal, or pelvic tumors; intussusception; deep umbilical
represent a true neoplastic process such as low-grade cystic subcutaneous nodules; or even cervical or inguinal
mesothelioma (Fig. 11.16a) [34]. Unlike peritoneal inclu- lymphadenopathy. The tumor may be confused with a
sion cysts, cystic mesothelioma may be lined by atypical disseminated ovarian tumor when both ovaries are
mesothelial cells. Focally the tumor may show a classic involved. Diagnosis requires a thorough histologic exam-
pattern similar to that seen in malignant mesothelioma. ination, although some cases are diagnosed by cytologic
Under low power, this tumor may be confused with an ade- examination of the ascites fluid [39].
nomatoid tumor (Fig. 11.16b). Cystic mesothelioma typi- 2. Gross examination: Both the visceral and parietal perito-
cally behaves in an indolent fashion, but may infrequently neum will show diffuse thickening with extensive tumor
recur after resection. nodules and plaques. The tumor may encase or infiltrate
visceral organs. In contrast to the behavior of malignant
Diffuse Malignant Mesothelioma (DMM) epithelial tumors, these tumors less frequently show local
Fewer cases of peritoneal diffuse malignant mesothelioma invasion and metastasis.
(DMM) are encountered compared to those occurring in the 3. Microscopic examination: Diffuse malignant mesotheli-
pleura. DMM in peritoneum composes 10–20% of all cases oma of the abdominal and pleural cavities has identical
of malignant mesothelioma and predominantly affects histological features. The tumor may show tubular or pap-
middle-aged or elderly males [35, 36]. The causal relation- illary or tubulo-papillary morphologic features
ship between diffuse malignant mesothelioma and asbestos (Fig. 11.17a, b). Some may present as solid sheets
a b
Fig. 11.15 Well-differentiated papillary mesothelioma. (a) Low-power view shows broad fibrovascular core lined by flat to cuboidal mesothelial
cells (H&E, 200×). (b) Higher power view shows that the mesothelial cells are rather uniform with no mitosis or prominent nucleoli (H&E, 400×)
a b
Fig. 11.16 Low-grade cystic mesothelioma. (a) Gross examination reveals numerous thin-walled cysts. (b) Low-power view may be similar to
adenomatoid tumor (H&E, 100×)
(Fig. 11.17c) and others may appear granulomatous. The Most patients were alive and free of disease on follow-
tumor may occasionally show invasion of sub-peritoneal up between 18 months and 11 years [38].
tissue such as the omentum. Intra-abdominal lymph nodal 4.
Immunohistochemical characteristics: Immuno
involvement may also be identified in some instances. histochemistry is critical to the accurate diagnosis of
The cytology of the tumor cells may vary, but vague api- mesothelioma. Mesotheliomas are frequently positive for
cal cytoplasmic protrusions are commonly seen as well as specific tumor markers, e.g., calretinin, WT-1, CK 5/6,
moderate-to-severe nuclear pleomorphism. Although and mesothelin (Table 11.2). Rarely, rather less specific
there is more nuclear pleomorphism and mitotic activity markers, e.g., D2-40 and h-caldesmon, are positive.
than in benign mesothelial tumors, the nuclear pleomor- Similar to serous tumors, malignant mesothelial cells are
phism and frequency of mitotic figures are much less pro- often positive for pancytokeratins, EMA, CK7, and
nounced than those seen in low-grade serous CA125. In contrast to serous tumors, malignant mesothe-
adenocarcinoma (Fig. 11.18). lial cells do not express CEA, LeuM1, B72.3, Ber-EP4,
Compared to pleural malignant mesothelioma, abdom- ER, and PR. However, some ovarian or peritoneal serous
inal malignant mesothelioma may have the following tumors may not express CEA and LeuM1. Therefore
unusual morphological characteristics: staining with B72.3, Ber-EP4, and other more specific
(a) Decidualization (Fig. 11.19) characterized by solid markers may be a better panel to be used in distinguishing
sheets of polygonal eosinophilic tumor cells with these two entities [41, 42].
abundant cytoplasm, well-demarcated cell borders, 5. Ultrastructure: Mesothelial cells are characterized by

and prominent nucleoli [40]. Two-thirds of this sub- long slender microvilli whereas in adenocarcinoma the
type occurs in females, even as early as in adoles- tumor cells demonstrate short, stout microvilli. Malignant
cence. This rare subtype is associated with a high mesothelial cells may contain cytoplasmic glycogen but
mortality rate. not mucin. Intermediate filaments may be present near
(b) Biphasic differentiation, which is uncommon. the nuclei.
(c) Rare tumors may be associated with marked inflam-
6. Differential diagnosis: Differentiating diffuse malignant
matory infiltrate (Fig. 11.20), often with lymphoid mesothelioma from atypical mesothelial hyperplasia, diffuse
follicles. Others may be entirely replaced by fibrous fibroblastic malignant mesothelioma, and reactive fibrosis is
tissue, resulting in diagnostic challenge. already briefly discussed previously in this chapter.
(d) Localized malignant mesothelioma: These tumors Differentiating diffuse malignant mesothelioma from
should be distinguished from diffuse malignant meso- pelvic high-grade serous adenocarcinoma is the most
thelioma because of their localized presentation and important, yet most difficult, distinction to be made. The
better prognosis. These are localized circumscribed characteristics of these two tumors are summarized in
lesions of the serosal membranes having similar micro- Table 11.2. Features supporting a diagnosis of mesotheli-
scopic appearance to that of diffuse variant. The median oma include prominent tubulo-papillary structures, follicu-
age is 63 with male preponderance (male/female 2:1). lar tumor cells, moderate amount of eosinophilic cytoplasm,
a b
Fig. 11.17 Diffuse malignant mesothelioma. (a–b) Papillary and tubular structures may be present (H&E, 200×). (c) Diffuse solid sheet pattern
(H&E, 200×)
mild-to-moderate nuclear atypia, fewer mitosis, and pres-

ence of acidic mucin (Alcian Blue positive). The most spe-
cific immunohistochemical markers for adenocarcinoma
are B72.3, Ber-Ep4, and MOC-31, while calretinin
(Fig. 11.21) and h-caldesmon are relatively specific for
mesothelial lesions.
The deciduoid pattern of abdominal malignant meso-
thelioma must be differentiated from an abdominal ecto-
pic decidual reaction. Malignant mesothelioma typically
forms masses and displays significant cytologic atypia.
The tumor cells are positive for cytokeratin, whereas
decidual cells are negative (Fig. 11.19).
7. Treatment and prognosis: No effective treatment for dif-
fuse malignant mesothelioma is available to date. Primary
surgical resection with adjuvant chemotherapy is still
Fig. 11.18 Diffuse malignant mesothelioma. The tumor cells may
being studied. The mortality rate is nearly 100%. Most
show moderate nuclear atypia with relatively constant nuclear cytoplas- patients survive less than a year from diagnosis.
mic ratio (H&E, 400×)
Table 11.2 Diffuse malignant mesothelioma versus high-grade serous

adenocarcinoma
Diffuse malignant High-grade serous
Characteristics mesothelioma adenocarcinoma
Clinical
History of asbestos Often None
exposure
Diffuse abdominal Yes Predominantly
tumor ovarian and
pelvic
involvement
Response to No response. Partial response
chemotherapy Typically lethal
Histology
Biphasic differentiation Present Absent
Columnar cells Rare Prominent
Psammoma bodies Rare Often
Nuclei Rounded Oval or elongated
Fig. 11.19 Diffuse malignant mesothelioma. Tumor cells show con- Mucin secretion Acidic Apical neutral
spicuous deciduoid change (HE, 600×) cytoplasmic mucin
mucin
Ultrastructure
Tonofilaments Abundant Rare
Cilia Rare Abundant
Intracytoplasmic Often seen Rarely seen
lumens
Apical snouts Rare Often seen
Immunohistochemistry Ber-Ep4 (−), CA Ber-EP4 (+), CA
19-9 (−), Leu M1 19-9 (+), Leu M1
(−), MOC-31 (−), (+), MOC-31 (+),
calretinin (+), calretinin
h-caldesmon (+), (−), h-caldesmon
WT-1 (+) (−), WT-1 (+)
1. Microscopic examination: The tumor is composed of

small epithelioid cells forming round or irregular islands
tucked in dense fibrous stroma, hence the name
(Fig. 11.22a). Rosettes, glands, and basal palisading pat-
Fig. 11.20 Diffuse malignant mesothelioma. Tumor may be associ- tern may be seen. Under low power, central necrosis and
ated with significant fibrosis and inflammatory infiltrates (H&E, 200×) focal calcifications are frequently present. On high power,
the tumor cells appear morphologically similar, with
11.1.5 Miscellaneous Primary Neoplasms scant cytoplasm and indistinct cell borders (Fig. 11.22b).
Sometimes the tumor cells may appear as striated muscle
11.1.5.1 I ntra-abdominal Desmoplastic Small cells with abundant eosinophilic cytoplasm and eccentric
Round Cell Tumor (DSRCT) nuclei. Abundant mitoses, single-cell necrosis, and lym-
Intra-abdominal desmoplastic small round cell tumor phovascular space invasion are frequently seen.
(DSRCT) is an infrequently encountered undifferentiated 2. Immunohistochemical phenotypes: Immunohistochemical
tumor seen in adolescents and young people. The origin of staining confirms that DSRCT displays a variety of dif-
the tumor, whether or not from primitive mesothelium, ferentiation [44–46]. Almost all tumors express epithe-
remains unclear. Most tumors arise in the abdomen, although lial markers CAM5.2 and AE1/AE3 but they do not
some pleura-based cases have also been reported [43]. express CK20. About 4/5 of the tumors express EMA,
DSRCT is more commonly seen in males (male-to-female NSE, desmin (with perinuclear punctated distribution),
ratio of 4:1). The average age is 25 years. Typical clinical and vimentin. 2/5 to 2/3 of the tumors express Ber-EP4,
symptoms include abdominal distention, pain, and palpable CD57 (Leu-7), CD15 (Leu-M1), and CA125. Another
mass. Some patients may present with ascites. In females, 90% of cases are positive for WT1. WT1 is not helpful
the disease may be confused with primary ovarian tumors in differentiating small-cell carcinoma from juvenile
when limited to the pelvis. granulosa cell tumors. It has been reported that intra-
abdominal desmoplastic round cell tumors react to 4. Differential diagnoses: DSRCT should be differentiated
WT1 (C-terminal) in contrast to serous carcinomas of from several other small round blue cell neoplasms such
the ovaries/fallopian tubes and mesotheliomas which as neuroblastoma, extra-skeletal Ewing sarcoma, primi-
typically react to N-terminal of WT1 [47]. The com- tive neuroectodermal tumor, immature teratoma, lym-
bined immunohistochemical characteristics are helpful phoma, rhabdomyosarcoma, rhabdoid tumor, poorly
in differentiating this tumor from other diagnostic differentiated stromal tumors, adult-type or juvenile gran-
considerations. ulosa cell tumor, and small-cell carcinoma associated
3. Genetics: This tumor frequently contains a translocation with hypercalcemia. In general, the age of the patient,
of t(11;22)(p13;q12) resulting in fusion of EWS1 gene on lack of extra-abdominal primary tumor, tumor distribu-
chromosome 22 with Wilms tumor-suppressor gene tion, and characteristic microscopic and immunohisto-
(WT1) on chromosome 11 [48, 49]. This fused EWS/WT1 chemical staining patterns help support a diagnosis of
may be detected using RT-PCR. This translocation is DSRCT. DSRCT reacts to C-terminal of the WT1 which
unique to this tumor and therefore its detection confirms is helpful to differentiate from some of the tumors dis-
the diagnosis [50]. cussed here as the others react with the N-terminal of
WT1. The EWS/WT1 gene fusion can be detected by RT-
PCR and the presence supports the diagnosis of
DSRCT. The presence of unusual features such as tubu-
lar, glandular, cystic, papillary, anastomosing trabecular,
and single-cell cord-like patterns may contribute to diag-
nostic difficulty. Chromosome analysis usually clinches
the diagnosis.
5. Treatment of prognosis: Patients with DSRCT require
chemotherapy and radiation therapy after surgical resec-
tion. Neoadjuvant chemotherapy has also been adopted.
Some patients may benefit from bone marrow transplan-
tation. Unfortunately more than 90% of patients die of the
disease despite aggressive therapy.
11.1.5.2 Inflammatory Myofibroblastic Tumor

Inflammatory myofibroblastic tumor has had many syn-
onyms in the past, e.g., inflammatory pseudotumor, plasma
Fig. 11.21 Diffuse malignant mesothelioma. Tumor cells are diffusely cell granuloma, fibrous xanthoma, pseudo-sarcoma, lym-
positive for calretinin (IHC, 200×) phoid hamartoma, myxoid hamartoma, inflammatory myo-
a b
Fig. 11.22 Intra-abdominal desmoplastic small round cell tumor (DSRCT). (a) Low-power view shows cluster of small round blue cells separated
by abundant fibrous stroma (H&E, 200×). (b) High-power view shows rather uniform neoplastic cells with scant cytoplasm and inconspicuous cell
border (H&E, 400×)
1. Gross examination: The size of tumor varies from 1 to

20 cm. It is usually solitary and surrounded by fibrous
tissue.
2. Microscopic examination: Solitary fibrous tumor has

been classified into three distinct histological subtypes.
(a) Nonspecific type: This tumor is formed by coarse
sclerotic collagen fibers associated with elongated
slits. The tumor cells are elongated and inconspicu-
ous (Fig. 11.24a).
(b) Vascular tumorlike with branching staghorn blood
vessels.
(c) Cellular type: This type is characterized by benign
spindle cells with varying cellularity organized in a
sheetlike pattern (Fig. 11.24b).
(d) Mixed type: Showing features of both nonspecific
Fig. 11.23 Inflammatory myofibroblastic tumor appears as scar-like and cellular type.
tissue with dark-staining nuclei of myofibroblastic cells (H&E, 200×) 3. Immunohistochemical phenotypes: The tumor cells may
express vimentin, CD34 (Fig. 11.24c), and BCL–2, but
fibrohistiocytic proliferation, and benign myofibroblastoma. are negative for cytokeratin, actin, S100, CD31, and des-
The etiology of this entity is unknown. It may originate in min. These immunohistochemical characteristics help
diverse anatomic sites including the lung, mesentery, omen- differentiate this tumor from mesothelioma. Solitary
tum, and retroperitoneum [51, 52]. Histologically the tumor fibrous tumor should also be differentiated from gastroin-
is composed of spindle-shaped myofibroblastic cells testinal stromal tumor (GIST) with the latter expressing
accompanied by a varying amount of collagen fibers and c-kit (CD117).
inflammatory infiltrate. Inflammatory myofibroblastic
tumor is typically found in females less than 20 years old. 11.1.5.3 O mental Mesenteric Myxoid
Patients may present with fever, general malaise, weight Hamartoma
loss, chronic anemia, thrombocythemia, polyclonal hypo- This rare tumor was first reported in three infants in 1983
gammaglobulinemia, splenomegaly, and a mass in the mes- [60]. In these cases, multiple tumor nodules were found in
entery. There are three histologic patterns: nodular the omentum and mesentery, which were characterized
fasciitis-like, fibrohistiocytic-like, and fibroma (or cicatrix)- histologically by plump mesenchymal cells in a myxoid,
like (Fig. 11.23). well-vascularized stroma. They were initially diagnosed as
The pathogenesis of the disease remains unknown; sarcomas, including liposarcoma, primitive sarcoma, or
however, 50–60% of the cases show a point mutation at leiomyosarcoma; however, long-term follow-up showed no
2p23, involving the ALK gene [53, 54], which may play an evidence of recurrence after surgical removal of the tumor.
important role in the pathogenesis of this tumor. Some This tumor is now classified as a hamartoma or a variant of
authors currently believe that this entity may in reality myofibroblastic tumor [60].
represent a group of diseases with diverse etiology and
pathogenesis, ranging from reactive changes to a low-
grade neoplasm with potential for local recurrence or even 11.1.6 Secondary Neoplasms
metastasis.
The peritoneum may serve as a generous receptacle for sec-
Solitary Fibrous Tumor ondary neoplasms either by direct spread or by metastasis
Solitary fibrous tumor, a primary mesenchymal tumor from intraabdominal or pelvic organs sites, e.g., fallopian
possibly composed of sub-mesothelial fibroblasts, was
tubes, ovaries, breasts, colon, appendix, stomach, and pan-
previously known as fibrous mesothelioma. This benign creas. Metastatic tumors to the peritoneum can be divided
tumor is typically discrete and well demarcated [55–57]. into two major categories: mucinous or serous, with the
The tumor is often seen in the pleura. The clinical presen- former originating from the gastrointestinal tract and latter
tations and immunohistochemical characteristics of perito- generally thought to be from the gynecologic tract. A better
neal and pleural solitary fibrous tumor are similar. understanding of mucinous tumors secondarily involving the
Although rarely infiltrative, most patients are cured after peritoneum has been achieved lately; however, the pathogen-
surgical resection [58], although recurrence has been esis of high-grade serous carcinoma involving peritoneum is
reported in some cases [59]. still evolving (see the segment on Müllerian tumors below).
a b
Fig. 11.24 Solitary fibrous tumor. (a) Nonspecific solitary fibrous tumor is composed of coarse collagen fibers accompanied by elongated slit-like
spaces. The tumor cells are elongated and inconspicuous (H&E, 200×). (b) Cellular type solitary fibrous tumor is composed of highly cellular
benign spindle cells (H&E, 400×). (c) CD34 immunostain positivity of solitary fibrous tumor (IHC, 100×)
11.1.6.1 Pseudomyxoma Peritonei (PMP) in goblet cells of gastrointestinal tract and not by ovarian
Secondary mucinous involvement of the peritoneum is known mucinous tumors. Some scholars have suggested that pseudo-
as pseudomyxoma peritonei (PMP), but the terminology is not myxoma peritonei does not arise from ruptured ovarian
specific as the term is used to describe several clinical scenar- tumors; on the contrary, the associated ovarian borderline
ios where the patient presents with mucinous ascites [61–63]. tumors are in fact secondary or metastatic lesions [69].
In the past most authors considered pseudomyxoma peritonei
to originate from the ovary. This was because more frequently 1. Clinical characteristics: The clinical symptoms of pseu-
than not, both ovaries were also involved, and demonstrated domyxoma peritonei are vague and nonspecific. They
histological features of mucinous borderline tumor. In recent typically occur in patients ranging from 33 to 82 years
years it has being shown that the majority of pseudomyxoma (mean 47 years) of age. Patients may present initially
peritonei originate from the gastrointestinal tract, most com- with abdominal distention, pain, or fullness depending on
monly from the vermiform appendix, while some originate the severity of disease. With disease progression, more
from the colorectum, or rarely from the pancreas and biliary mucin accumulates, increasing abdominal distention,
tract [64, 65]. A few cases of pseudomyxoma peritonei have which can be accompanied by a mechanical or functional
been found to be associated with ovarian mucinous borderline ileus. On rare occasions patients may incidentally be
tumors associated with ovarian mature cystic teratomas [66– diagnosed during surgical procedures or hernia repair.
68]. Genetic studies have revealed that most pseudomyxoma 2. Pathologic findings: A low-grade mucinous neoplasm of
peritonei express the MUC2 protein, which is only expressed the vermiform appendix is the leading source of second-
Fig. 11.25 Appendiceal mucinous neoplasm. Low-power view show- Fig. 11.26 Abundant acellular mucin pool dissecting peritoneum par-
ing muscular wall of the appendix infiltrated by the mucinous tumor tially surrounded by reactive mesothelial cells (H&E, 200×)
(H&E, 100×)
a b
Fig. 11.27 Low-grade mucinous neoplasm resulting in pseudomyxoma peritonei. (a) A few neoplastic cells are floating in the mucin pool (H&E,
400×); (b) occasionally intestinal type mucinous epithelium is recognizable (H&E, 400×)
ary peritoneal mucinous tumors (Fig. 11.25). The primary similar to those of a hyperplastic polyp or low-grade
appendiceal mucinous lesions may range from mucinous mucinous neoplasm. Some authors prefer the term “acel-
adenomas to low-grade appendiceal mucinous neoplasms lular mucin” or mucinous epithelium consistent with
to frankly invasive adenocarcinoma [70]. Other sources pseudomyxoma peritonei. The peritoneal lesion may be
of secondary peritoneal mucinous tumor are usually asso- accompanied by conspicuous fibroblastic reaction and
ciated with high-grade colorectal adenocarcinoma with reactive mesothelial cells. The ovaries may also show
destructive invasion. abundant acellular mucin with or without free-floating
Morphology of the epithelial component of PMP dif- tumor cells dissecting the ovarian parenchyma
fers and such morphologic differences determine the clin- (Fig. 11.27a). Intestinal type epithelium is usually evident
ical course and prognosis. Low-grade tumors usually (Fig. 11.27b). Various designations have been used in the
demonstrate acellular mucin or scant, bland, mucin- literature describing this phenomenon, e.g., well-
containing epithelial cells floating in mucinous fluid differentiated mucinous adenocarcinoma, disseminated
(Fig. 11.26). The epithelial cells, when present, may be peritoneal mucinous adenosis, and secondary low-grade
a b
Fig. 11.28 High-grade mucinous neoplasm of the gastrointestinal tract secondarily involving the peritoneum. (a) Mucin and neoplastic cells
(mucicarmine, 200×). (b) Higher power view showing prominent nucleoli of the tumor cells (mucicarmine, 400×)
peritoneal mucinous neoplasm. The current authors favor 4. Immunohistochemical characteristics: Immunohis
the designation of low-grade peritoneal mucinous tochemical staining characteristics of most peritoneal sec-
neoplasm [70]. ondary mucinous neoplasms are similar to those of the
High-grade mucinous neoplasms usually show more appendix, expressing a CK7−/CK20+ phenotype, as
epithelial cells and moderate to marked nuclear pleomor- opposed to the CK7+/CK20− phenotype seen in primary
phism and prominent nucleoli (Fig. 11.28a, b). Signet- ovarian tumors. This supports the recent evidence that most
ring cells, when present, should alert the pathologists to secondary peritoneal mucinous tumors originate from the
search for gastric carcinoma or invasive lobular carci- appendix. It is important to recognize that occasional appen-
noma of the breast. dicular tumors may be positive for both CK7 and CK20 in
It is noteworthy that peritoneal secondary mucinous varying amounts. The positive staining should be diffuse
tumors often involve bilateral ovaries, and can have strik- and strong if to be supportive in differentiating one site from
ing similarities to primary ovarian mucinous cystadeno- the other; in some cases staining will be equivocal.
mas, intestinal type mucinous borderline tumors, or 5. Pathology report: Pseudomyxoma peritonei is a clinical
primary ovarian mucinous adenocarcinoma [71]. Cross term and therefore should not be used as a diagnosis in a
sections of the tumor may reveal numerous cysts of varying pathology report. The pathology report should consider
sizes containing abundant mucus. The ovarian capsule may (a) the nature of the appendiceal or ovarian tumor (benign,
be involved, and therefore must be differentiated from borderline, or malignant), and whether the primary lesion
mechanical involvement of acellular mucin associated with was ruptured; (b) the nature of the intra-abdominal dis-
a ruptured ovarian primary mucinous tumor. It is important ease, classified as acellular mucinous ascites, cellular
to note that some mucinous tumors metastatic to the ova- mucin, organizing mucin, or septated (lobulated) mucin;
ries may undergo “reverse maturation” causing their epi- and (c) the grade of the epithelium if present in the mucin
thelium to appear similar to that seen in a mucinous (benign, borderline, or malignant). Pathology reports that
cystadenoma; therefore, the determination of primary ver- explicitly characterize these components help clinicians
sus secondary ovarian mucinous lesions should not be plan appropriate management of these cases.
based on the identification of “precursor” epithelium. 6. Treatment and prognosis: The clinical course of a peri-
3. Sampling: Proper and adequate sampling of peritoneal toneal secondary mucinous tumor is determined by the
secondary mucinous neoplasms is paramount. All lesions presence or absence of neoplastic cells within the
should be extensively sampled, including grossly normal mucin, their grade, and the mucin volume [72]. Intra-
vermiform appendix. The vermiform appendix should be abdominal ascites with acellular mucin is associated
entirely submitted for microscopic examination to deter- with better prognosis. The clinical course may be indo-
mine the nature of any epithelial lesion, and to establish lent if the mucinous epithelial cells appear benign or
primary source of the tumor. Immunohistochemistry and mildly atypical. Patients whose mucinous ascites is
molecular characterization may be needed to determine associated with mucinous adenocarcinoma may be
the origin of the tumor. associated with lymph node or visceral metastasis.
These patients have a worse prognosis. The goals of 11.2 S

ection 2: Diseases of the Müllerian
surgical treatment include debulking with an intention System
to resolve or prevent mechanical obstruction and to pre-
serve natural function as much as possible. For patients The concept of secondary Müllerian system was proposed
with an obviously malignant neoplasm, treatment usu- in the late 1960s and widely accepted until the end of
ally consists of tumor debulking accompanied by intra- 1990s. The concept aimed to explain the pathogenesis of
peritoneal chemotherapy [73]. Müllerian lesions within and above the pelvic brim. Based
on common embryogenesis from the coelomic membrane,
11.1.6.2 Gliomatosis Peritonei it was theorized that Müllerian tissue be organized into
Gliomatosis peritonei is a rare disease, often associated with primary and secondary Müllerian systems. The primary
mature or less commonly immature teratomas of the ovaries. Müllerian system is composed of epithelial and stromal
It presents as mature glial tissue on the surface of the perito- cells lining the unfused and fused segments of Müllerian
neum. In some cases the glial tissue may be the result of ducts resulting in the fallopian tubes, uterus, uterine cer-
implantation of neuroglial tissue after the rupture of the ovar- vix, and upper third of the vagina, whereas similar tissue
ian teratoma. However, a recent molecular study showed that formed from metaplasia on the ovarian coverings, visceral
the glial tissue may also originate from the pluripotential serosa, free peritoneum, and omentum makes up the sec-
peritoneal stem cells [74]. ondary Müllerian system [76]. Ovarian-peritoneal
Müllerian diseases such as endometriosis, endosalpingio-
1. Microscopy: The implants are typically composed
sis, ectopic deciduosis, disseminated peritoneal leiomyo-
entirely of glial tissue with no other component of the matosis, and ovarian epithelial neoplasms were thought to
teratoma (Fig. 11.29a–c). Further classification of perito- arise from the secondary Müllerian system. The concept
neal gliomatosis is discussed in Chap. 8. of a secondary Müllerian origin of these d iseases, pro-
2. Treatment and prognosis: Most gliomatosis peritonei are posed by Lauchlan, was based on indirect and circumstan-
either grade 0 or grade 1 (Fig. 11.30). These patients have tial evidence [76, 77].
good prognosis and do not require further treatment. The following observations were made in favor of sec-
Recurrence or malignant transformation may appear in ondary Müllerian system: the majority of primary perito-
patients with grade 2 or grade 3 diseases. These patients neal carcinomas are of serous type, although tumors of
may require additional chemotherapy to control disease other cell types have also been identified. The relative fre-
progression. quency of malignant serous tumors involving omentum is
much higher than that of endometrioid carcinoma (15:1), so
is the ratio of their benign counterparts of endosalpingiosis
11.1.6.3 I mplanted Leiomyoma Following versus endometriosis (10:1). The inference drawn from this
Morcellation observation is that serous and endometrioid neoplasms may
Minimally invasive laparoscopic surgical procedures have arise primarily in the omentum as well as anywhere in the
recently been popularized in the USA because of shorter gynecologic tract [78]. The presence of epithelial implants,
postoperative hospital stays and faster patient recovery. with and without epithelial proliferation in the omentum,
Laparoscopic hysterectomy with morcellation is one such has been reported to be associated with a higher risk of
procedure where bulky uteri with leiomyomata can be cut recurrence in serous borderline tumor of the ovary even
into smaller fragments inside the abdomen with the help of a after bilateral salpingo- oophorectomy [79]. The overall
morcellator and removed from the body through a smaller proliferative activity of Müllerian epithelia may be the
opening created in the anterior abdominal wall. The proce- underlying risk factor for these neoplasms. This offers
dure was deemed to be fairly safe; however, unintended con- additional support that serous neoplastic proliferations in
sequences have been encountered just a few years of the the peritoneum likely represent a field effect rather than a
introduction of the procedure [75]. A number of incidental focal disease with widespread metastasis. Thorough exami-
malignancies were reported in these morcellated specimens nation of the epithelia of all Müllerian-derived reproductive
causing management challenges. Parasitic leiomyoma of the organs in a series of ovarian carcinomas revealed presence
peritoneum is one of the less consequential events that have of endometrial intraepithelial carcinoma (EIC), serous
been encountered (Fig. 11.31a). These leiomyomas are often tubal intraepithelial carcinoma (STIC), and/or endometrial
detected incidentally, even after many years of the initial hyperplasia in more than half of the cases [80]. Coexistence
intra-abdominal morcellation procedure. Patients with tor- of these preinvasive lesions was common and thought to
sion of the peritoneal leiomyoma may present as acute abdo- represent field effect, although implantation of migrating
men, a medical emergency (Fig. 11.31b). tumor cells has also been postulated.
a c
Fig. 11.29 Gliomatosis peritonei. (a) Numerous small gray-white (H&E, 40×). Inset: Higher power view on the right (H&E, 100×, 200×).
tubercles of various sizes and shapes in the omentum (gross photo- (C) positive staining for GFAP (IHC, 40×)
graph). (b) The small tubercles represent typical neurofibrillary tissue
Recently a theory proposed that many lesions of the sec-

ondary Müllerian system probably are not primary tumors
arising from malignant transformation of metaplastic epithe-
lia in the peritoneum but rather are metastases from the fim-
bria of the fallopian tubes (see the chapter on fallopian
tubes). This theory has gained traction such that bilateral sal-
pingectomies are now widely performed whereas the ovaries
are preserved, reversing a decades-old practice.
Klymenko et al., postulated that the epithelial ovarian
tumors metastasize via transcoelomic route. The cells from
the fallopian tube tumor detach from the primary site, either
as a single cell or as a small group of cells, anchor themselves
with the submesothelial matrix, and grow. This is possibly an
example of a highly permissive microenvironment which
allows epithelial-mesenchymal transition and vice versa [81].
Fig. 11.30 Gliomatosis peritonei. Grade 0 gliomatosis with uniform This primary fallopian tube theory, although not totally
glial cells (H&E. 400×) free of challenge, began with an observation in early 2001
Fig. 11.31 (a) Implanted leiomyoma following laparoscopic hysterec- abdomen mimicking ruptured ectopic pregnancy. Gross and micros-
tomy with morcellation (H&E, 20×). (b) Infarcted leiomyoma. Had copy (H&E, 20×). Positive smooth muscle actin (SMA) immunostain
morcellation 9 years ago, Now pregnant, and presented with acute (IHC, 20×)
when Peik et al. reported dysplastic changes in prophylacti- larger than the involvement of the surface of either ovary, and
cally removed fallopian tubes of women predisposed to total submission and examination of both fallopian tubes do
developing ovarian carcinoma [82]. Crum et al. called atten- not reveal any in situ or invasive carcinoma [84].
tion to the distal fallopian tube and proposed that migrating Investigators have recently used advanced molecular
tumor cells from the fallopian tube are an important source of techniques to characterize the relationship between serous
serous carcinoma in the omentum, rather than arising in the tubal intraepithelial carcinoma (STIC) and high-grade serous
peritoneum [83]. As a result of this theory, it has now been carcinoma (HGSC) in detail. They have found similarities
proposed that primary peritoneal serous carcinoma should between STIC and HGSC which may support the fallopian
only be diagnosed when ovarian parenchymal involvement is tube origin theory. Perhaps more interestingly it was also dis-
less than 5 × 5 mm, involvement of extra-ovarian sites are covered that not all morphologically bona fide STICs are of
tubal origin [85]. The fallopian tube mucosa can also be a like lesion (Fig. 11.32b). The clinical and pathological char-
receptacle for metastatic carcinomas arising elsewhere, and acteristics as well as the pathogenesis of endometriosis are
the authors cautioned pathologists to be extremely careful in discussed in detail in Chap. 12.
diagnosing STIC without first considering the possibility of
metastasis. Routinely used immunohistochemical stains can
be used to determine if a STIC-like lesion is tubal or non- 11.2.2 Serous (Tubal Type Epithelium) Lesions
gynecologic in origin. PAX 8, WT1, CK7, ER-negative
lesions mimicking STIC may represent metastatic tumors of Tubal type, or serous, epithelial lesions of the peritoneum
non-gynecologic origin. CDX2 positivity will point towards include endosalpingiosis and serous neoplasms. Many con-
a metastatic intestinal lesion. A word of caution here is that troversies abound regarding the pathogenesis, interaction,
positive p53 immunoreactivity should not be considered and even definition of these lesions among the gynecologic
diagnostic of STIC as metastatic breast and colon cancers pathology community. Primary serous adenocarcinoma of
may be p53 positive [86]. In the context of uterine and non- the peritoneum is defined as a serous adenocarcinoma involv-
uterine HGSC, it may be argued that STIC may represent a ing primarily the peritoneum, with relatively uninvolved or
metastasis rather than the site of origin, particularly when only superficially involved normal ovaries. A set of criteria
widespread disease is present. have recently been proposed as described earlier in this chap-
Although assigning a primary site of tumor has limited ter [84]; however, using the size and distribution of tumor as
prognostic and therapeutic relevance in the case of a serous absolute criteria to determine the origin of the disease was
carcinoma with widespread pelvic and omental/peritoneal
involvement, a recent attempt has been made to achieve that
goal based on a survey of pathologists and clinicians [87]. a
It appears, at least as of now, that the origin of peritoneal
serous carcinoma is still evolving. The validity of the sec-
ondary Müllerian system theory cannot be disregarded com-
pletely. The secondary Müllerian system, in theory, offers
explanation for the pathogenesis of all types of Müllerian
epithelia, e.g., serous, endometrioid, mucinous, and transi-
tional, whereas the proposed fallopian tube origin theory can
only explain the origin of serous-type epithelium in perito-
neum. As late Stuart C. Lauchlan once stated “Far from
being a mere receptacle for metastasis from other sites, the
omentum is an important source of primary peritoneal (sec-
ondary Müllerian system) carcinoma” [79].
As a result of the above discussion, it has been proposed
that serous Müllerian tumors be designated as “pelvic serous
carcinoma,” rather than arbitrarily assigned to a specific pel- b
vic organ such as ovary, fallopian tube, or peritoneum.
11.2.1 Endometriosis
Endometriosis is defined as the presence of endometrial

glands and/or stroma outside of the endometrium and myo-
metrium; it is more commonly encountered in the pelvis than
the peritoneum [79]. Endometriosis is typically seen in
females of reproductive age as well as asymptomatic post-
menopausal women. The most common locations involved
are the ovaries, uterosacral ligament, round ligament, broad
ligament, cul-de-sac, rectovaginal septum, serosal surfaces
of the uterus, fallopian tube, rectosigmoid colon, ureters, and
Fig. 11.32 Endometriosis. (a) Endometrioid epithelium is surrounded
urinary bladder. Histologic diagnosis is relatively easy in the by endometrial stromal cells (H&E, 200×). (b) Marked decidual stro-
presence of both the epithelium and stroma (Fig. 11.32a). mal reaction may lead to a “mass-like” lesion; inset: higher magnifica-
Marked decidual stromal reaction may give rise to a tumor- tion (left H&E, 20×; right H&E, 400×)
disputed by some workers as they have suggested that most rectal pelvic peritoneum. It is typically grossly invisible,
high-grade serous adenocarcinomas may derive from early although some may appear as multiple small (1–2 mm)
serous lesions of the fimbria and become widely dissemi- white or yellow spots. Alternatively, the lesion may appear
nated in the peritoneum. Low-grade serous adenocarcinoma opaque or as semitranslucent cysts or granules.
is felt to arise possibly from implants of papillary carcinoma 2. Microscopic examination: Endosalpingiosis may appear as
of the ovaries (serous borderline tumors of the ovaries, or rounded, oval, or cystically dilated glands with no stroma.
even micropapillary serous borderline tumors). Primary The outline of the focus may be somewhat irregular with
serous adenocarcinoma of the peritoneum may be rare, but is slightly crowded glandular epithelium, occasionally with
certainly not nonexistent. intraluminal papillary protrusions. The glands are lined by
a single layer of tubal type epithelium (Fig. 11.33a), com-
11.2.2.1 Endosalpingiosis posed of all three epithelial cells of the normal fallopian
Endosalpingiosis is the presence of benign tubal type epithe- tube: pale ciliated cells, secretory cells, and slightly darker
lium in the peritoneum, sub-peritoneal tissue, or retroperito- peg cells, typically with no cytologic atypia or mitosis. The
neal lymph nodes; it is more frequently encountered in the glands are surrounded by dense connective tissue but not
peritoneum compared to the pelvis [79]. The pathogenesis of endometrial stroma. Occasional mononuclear inflamma-
endosalpingiosis remains unknown. It was thought to arise tory cells may be present. Psammoma bodies may be pres-
from implanted desquamated tubal epithelium from ent within the lumen or nearby stroma. Epithelial tufting,
chronically inflamed fallopian tubes, similar to the implants or more complex epithelial growth, may be seen and some
arising from serous borderline tumor. An alternate explanation authors have designated these lesions “proliferative endo-
was that endosalpingiosis is a metaplastic process of the sec- salpingiosis” [79, 80].
ondary Müllerian system. Given the recently proposed theory Rarely endosalpingiosis may display cytologic atypia
on the role of early tubal lesions of the fimbria in the pathogen- described as “atypical endosalpingiosis.” The lining epi-
esis of serous tumors, the metaplastic theory of secondary thelium appears stratified with varying degrees of cyto-
Müllerian system has been revisited. To avoid confusion, some logic atypia but lacks the characteristics of a typical
investigators suggested using the term “serous change” instead serous borderline tumor. Atypical endosalpingiosis may
of endosalpingiosis. Endosalpingiosis is reported to be ten coexist with peritoneal serous borderline tumor.
times more frequent than endometriosis in the peritoneum, 3. Differential diagnosis: There is much controversy in dif-
whereas in the pelvis the ratio is reversed [79]. ferentiating atypical endosalpingiosis from peritoneal
serous borderline tumors (see below). The differences
1. Gross examination: The lesion is most commonly seen on between endosalpingiosis and serous borderline tumor
the serosa of the uterus, fallopian tubes, ovaries, and utero- are shown in Table 11.3.
a b
Fig. 11.33 Endosalpingiosis. (a) The glandular epithelial cells show of Müllerian duct remnant in a transgender receiving exogenous andro-
characteristic tubal “serous”-type epithelium with readily visible cilia. gen therapy (H&E, 600×)
Note the absence of endometrial stroma (H&E, 400×). (b) Virilization
Table 11.3 Endosalpingiosis versus serous borderline tumor

Serous borderline tumor (primary
Endosalpingiosis and implants)
Location Surface or under Surface or under the peritoneum
the peritoneum
Structure Single round or Single glands, often associated
oval glands with papillary cell clusters,
isolated cell clusters, and
psammoma bodies
Cytology No pleomorphism Mild-to-moderate
pleomorphism, stratified
epithelium
Interstitial Absent May or may not show
reaction desmoplasia
Another differential diagnosis consideration is mesonephric Fig. 11.34 Serous borderline tumor of the peritoneum. Morphologically
duct remnants. Mesonephric duct remnants typically identical to ovarian serous borderline tumor (H&E, 200×)
occur next to the fallopian tubes or within the broad liga-
ments. Mesonephric remnants are typically lined by a
single layer of cuboidal or low-columnar epithelium with- invasive implants. Noninvasive implants can further be
out cilia and are surrounded by layers of smooth muscle. subclassified as desmoplastic or non-desmoplastic (epi-
Virilization of the mesonephric remnants has recently thelial) implants. It may be difficult to differentiate des-
been described in female-to-male transgender patients moplastic noninvasive implants from invasive implants.
receiving testosterone therapy (Fig. 11.33b) [88]. The following features may be helpful: Noninvasive
implants are characterized by localized nondestructive
11.2.2.2 Peritoneal Serous Borderline Tumor fibroblastic growth. Clinically they appear as fibrous
Peritoneal serous borderline tumors are morphologically plaques the surgeon can easily strip from the underlying
identical to ovarian serous borderline tumors. Currently tissue. The relative ratio of epithelial cells to desmoplas-
many unresolved issues exist pertaining to its definition, eti- tic tissue is low, especially when compared to invasive
ology, and related pathology. It is usually associated with implants. Conversely, invasive implants are character-
infertility or chronic lower abdominal pain, typically in ized by epithelium-rich, disseminated, irregular, destruc-
women under 35 years. The tumor presents in the perito- tive growth equivalent to low-grade serous carcinoma.
neum, outside of the ovaries, with localized or disseminated, The typical lobular architecture of the omental fat is dis-
miliary or granular lesions accompanied by pelvic peritoneal turbed. Clinically it is important to differentiate noninva-
and omental fibrous adhesions. Peritoneal serous borderline sive implants from invasive implants because the
tumors may arise from peritoneal endosalpingiosis or prolif- treatments and prognosis are entirely different. Invasive
erative endosalpingiosis. implants have now been considered as low-grade serous
carcinoma. Pathological characteristics of these two
1. Microscopic examination: Peritoneal serous borderline lesions are summarized in Table 11.4. It is worth men-
tumors may present with papillary structures with cellular tioned that these two lesions may be present concurrently
stratification, small clusters of epithelial hyperplasia, and in the same patient (Figs. 11.35, 11.36, and 11.37).
interspersed loose cell clusters. Nuclear pleomorphism
and mitosis may be present but there is no true invasion Occasionally the epithelial lining of noninvasive implants
(Fig. 11.34). Morphologically it may be similar to nonin- may present with atypical features such as papillary, solid,
vasive, desmoplastic implants of ovarian serous border- cribriform, sievelike, or clustering patterns [90–92].
line tumor. Up to 85% of cases are associated with These growth patterns are generally considered features
endosalpingiosis. The survival rate is reported to be 95%, of malignancy, but most experts agree that if these abnormal
which is similar to that of noninvasive peritoneal implants features are localized and confined, their clinical significance
of ovarian serous borderline tumors [89]. may be similar to that of microinvasion of ovarian serous
2. Implants: Most peritoneal implants associated with
borderline tumor, with no significant adverse effects on
serous tumors arise from ovarian serous borderline prognosis [93, 94] (see Chap. 5 for additional morphological
tumor. They can be subclassified as noninvasive and characteristics and further discussion).
Table 11.4 Noninvasive implants versus invasive implants strated that the presence of noninvasive implants has neg-
Noninvasive implants Invasive implants ative impact on long-term prognosis [96] with recurrence
Histology Well demarcated and Irregularly infiltrate visceral in 44%. Survival in this study ranged among 10% less
distinct from the peritoneum or omental than 5 years, 19% between 5 and 10 years, 10% between
underlying tissue adipose tissue with
destructive growth pattern
10 and 15 years, and 5% for more than 15 years. The pres-
Involve interstitial Involve interstitial spaces of ence of invasive implants (i.e., low-grade serous carci-
spaces of omentum omentum resulting in noma) and grossly visible residual disease are major
with intact omental destruction of normal adverse prognostic indicators. Studies have shown that
lobules, well adipose lobules; reactive the average time to recurrence may be as early as 2 years,
demarcated fibrosis surrounds adipose
cells and after recurrence many patients progress to low-grade
Nonsolid or cribriform Solid sheets or nonserous adenocarcinoma [97]. Only a minor fraction of
structures with small cribriform tumor growth patients respond to chemotherapy.
nests or isolated tumor extending beyond
cells surrounded by desmoplastic fibrosis;
small clefts prominent clefts around
11.2.2.3 Malignant Neoplasms
tumor cells and abundant
isolated tumor cells Low-Grade Peritoneal Serous Carcinoma (LGSC)
Cytology None to moderate Prominent nuclear The morphology of low-grade peritoneal serous carcinoma
nuclear pleomorphism, pleomorphism, abundant (LGSC), including psammocarcinoma, is similar to that of
rare mitoses mitoses, and atypical
mitoses invasive implants of serous borderline tumors, characterized
Ancillary Diploid Diploid or aneuploid by the presence of papillary growth pattern (Fig. 11.38) [98];
tests as a result invasive implants are now being considered as
Surgical Easy to strip off Difficult, may result in low-grade serous carcinoma. The cells in LGSC are gener-
stripping bleeding or perforation ally of low nuclear grade, lack frequent mitosis, have absent
to rare atypical mitosis, and lack lymphovascular space inva-
Sometimes it may be difficult to determine if an implant sion. Solid growth may be observed. The average age is
is associated with invasion or not. Biopsy tissue may be too between 50 and 60 years. Atypical clinical presentations
small and overtly calcified, or may have processing artifacts. include abdominal pain or mass-forming lesions. More than
In these instances, it may be essential to designate this lesion 40% of patients are diagnosed incidentally. The primary dif-
as “implant, invasion indeterminate.” ferences between low-grade peritoneal serous carcinoma and
peritoneal serous borderline tumor are the presence of stro-
3. Differential diagnosis: Compared with ovarian serous
mal invasion and confluent growth that may be seen in the
borderline tumors, there are both similarities and differ- former. On rare occasions progression of a low-grade perito-
ences. Some diagnostic dilemmas exist: (A) How to dif- neal serous carcinoma to a high-grade serous carcinoma may
ferentiate primary peritoneal serous borderline tumor occur [99].
from peritoneal implants associated with ovarian serous Psammocarcinoma is a subtype of low-grade peritoneal
borderline tumor, and more importantly whether there is serous carcinoma characterized by having psammoma bod-
any clinical significance? (B) Is the biological behavior of ies in more than 75% of the papillary growths or cell nests
peritoneal serous borderline tumor different from ovarian (Fig. 11.39) along with the presence of stromal invasion.
serous borderline tumor with peritoneal implants? (C) There may be slight nuclear atypia. Typically, the tumor cell
What is the definition of atypical endosalpingiosis? Does nests are composed of less than 15 cells. The patients are
it exist? And if so, does it give rise to peritoneal serous typically around 40 years old, presenting with abdominal
borderline tumor? (D) When accompanied by desmopla- pain or masses. Careful sampling of the excised specimen is
sia, how to differentiate desmoplastic implants of ovarian required to rule out the presence of concomitant high-grade
serous borderline tumor from primary peritoneal serous serous adenocarcinoma.
carcinoma? (E) How to differentiate invasive implants The prognosis of low-grade peritoneal serous carcinoma
from noninvasive implants especially when the lesions and peritoneal psammocarcinoma is fairly good. No patient
elicit conspicuous fibrous stromal reaction. deaths due to psammocarcinoma are recorded in the litera-
4. Prognosis: The prognosis of peritoneal serous borderline ture [100, 101]. The long-term prognosis remains unclear
tumor is largely determined by FIGO staging, the pres- due to limited case reports available.
ence or absence of invasive implants, and the quantity of
postoperative residual disease. Recent studies have shown High-Grade Peritoneal Serous Carcinoma (HGSC)
that 16% of patients with extra-ovarian disease suffered In the past, the incidence of primary peritoneal serous ade-
recurrence or died of disease [95]. Another study demon- nocarcinoma was one-tenth that of ovarian serous adeno-
a b
c d
Fig. 11.35 Noninvasive implant. (a) Solitary implant is seen on the e pithelia (IHC, 40×). (e) Higher magnification shows prominent fibrous
surface of the peritoneum (H&E, 40×). (b) Typical features of serous tissue surrounding small clusters of tumor cells or single tumor cells
borderline tumor seen in higher power view (H&E, 200×). (c) without tissue invasion (H&E, 200×) (a, c, d, and e: courtesy of
Desmoplastic noninvasive implant (H&E, 40×). (d) Immunostaining W. Dwayne Lawrence, MD)
with pancytokeratin shows preponderance of stroma over actual
a b
Fig. 11.36 Comparing noninvasive implant and invasive implant. (a) 100×). (b) Invasive implants with abundant tumor growths destroying
Noninvasive implant with papillary proliferations between fat lobules fat lobules of the omentum (H&E, 40×) (B: courtesy of W. Dwayne
in the omentum. No invasion into surrounding adipose tissue (H&E, Lawrence, MD)
a b
c d
Fig. 11.37 Invasive implant. (a) Invasive implant in the intestinal wall tumor cells resembling low-grade serous carcinomatous cells sur-
(H&E, 20×). (b and c) Invasive implants diffusely present in the omen- rounded by clefts (H&E, 400×)
tal adipose tissue (H&E, 20×). (d) Higher magnification view shows
Fig. 11.38 Gross (left) and

microscopy of low-grade
peritoneal serous
adenocarcinoma with small
papillary clusters of tumor
cells surrounded by
fibrovascular stroma (H&E,
upper right 40×, lower right
200)
Fig. 11.39 Psammocarcinoma,
a low-grade peritoneal serous
adenocarcinoma with more
psammoma bodies than
neoplastic cells. Gross picture
is on the left, low-power view
of the microscopic picture is on
the upper right, while
magnified view is on the low
right (gross photo: courtesy of
W. Dwayne Lawrence, MD)
carcinoma [102]. The traditional criteria for diagnosis of microscopically absent tumor in the ovary, or tumor limited
peritoneal serous adenocarcinoma included (a) size of to the surface of bilateral ovaries without parenchymal
bilateral ovaries being normal or near normal; (b) the tumor invasion; (d) tumor present on the surface as well as paren-
being present mostly in the peritoneum, with only limited chyma of the ovary, but tumor size less than 5 mm2; (e)
tumor involvement on the surface of bilateral ovaries; (c) ovarian parenchymal involvement, with tumor size less
than 5 mm2; and (f) the histology of the tumor being similar
to that of ovarian serous adenocarcinoma of any grade. The
above criteria were based mainly on the size and distribu-
tion of the tumor, which was rather arbitrarily defined. In
recent years, it has been proposed that most ovarian and
peritoneal serous adenocarcinomas arise from the fimbria
of the fallopian tube. This new school of thought chal-
lenged the traditional concepts, terminology, and diagnos-
tic criteria of pelvic serous adenocarcinoma [103]. As a
result, many previously diagnosed primary peritoneal
serous adenocarcinomas would now be considered to arise
from the fallopian tube. Female patients with BRCA gene
mutations are at a higher risk for developing these tumors
(see chapter on fallopian tube) [104, 105]; however, this
theory has only gained acceptance in cases of serous neo-
plasia. Tumors of other histologic subtypes cannot be Fig. 11.40 High-grade peritoneal serous adenocarcinoma. Tumor
explained by this proposed theory. Recent proposed guide- cells may form solid sheet or papillary structures with highly atypical
lines in the diagnosis of primary peritoneal HGSC are dis- nuclei (H&E, 400×)
cussed earlier in this chapter.
Immunohistochemical staining is of little value in differ- The prognosis and management of high-grade peritoneal
entiating these tumors. Unlike endometrial serous adenocar- serous adenocarcinoma are similar to those of ovarian high-
cinoma which lacks WT-1 expression, peritoneal, ovarian, grade serous adenocarcinoma. The most important prognos-
and fallopian tube serous adenocarcinomas all express WT-1. tic indicators are the stage of the tumor, whether optimal
Peritoneal serous adenocarcinoma should also be differenti- tumor debulking is achieved, and tumor response to chemo-
ated from diffuse malignant mesothelioma, especially the therapeutic agents. The average 5-year survival rate is
papillary variant. Malignant mesothelioma expresses cal- approximately 40%.
retinin, h-caldesmon, and CK 5/6, whereas peritoneal serous
adenocarcinoma expresses Ber-EP4 and B72.3 (see previous
section). 11.2.3 Mucinous Diseases
The clinical presentation of patients with peritoneal
serous adenocarcinoma is similar to that of ovarian serous 11.2.3.1 Endocervicosis
adenocarcinoma. The patients are typically between 50 and Peritoneal endocervicosis is defined by the presence of
60 years old. The clinical symptoms are nonspecific, with benign endocervical type mucinous epithelium in the perito-
many presenting with abdominal distention, gastrointestinal neum. This condition is exceedingly rare and may involve
discomfort, increased abdominal girth, and constipation. the serosa of the uterus, urethrorectal cul-de-sac, vaginal
Physical examination may reveal abdominal or pelvic apex, paracervical soft tissue, and urinary bladder according
masses, with or without ascites. Serum CA 125 may be ele- to isolated case reports [108, 109]. When the urinary bladder
vated. The lifetime risk of ovarian carcinoma in BRCA1 is involved, it typically occurs in the posterior wall and
gene-mutated patients is estimated to be 20–50% [106, 107], dome. Microscopic examination shows benign endocervical
whereas the lifetime risk of ovarian carcinoma in a BRCA2 type glands present between smooth muscle layers of the
gene-mutated patient is 15–30% [106, 107]. lamina propria (Fig. 11.41). A few case reports described the
Peritoneal serous adenocarcinoma typically presents as presence of infiltrative growth pattern, slight epithelial
an omental cake. The peritoneal surfaces are covered by dis- atypia, and a periglandular stromal reaction [109]. These fea-
seminated tumor nodules or solid masses. Most nodules are tures may falsely lead to the impression of well-differentiated
located on peritoneal surfaces with invasion into the subepi- adenocarcinoma. The pathogenesis of endocervicosis
thelial mesenchyme, especially omental adipose tissue. remains controversial. Proposed theories include peritoneal
Theoretically, the ovarian tissue should remain normal, and metaplasia from the secondary Müllerian system or a lesion
only have surface involvement, or minimal involvement as arising from the urachal remnant.
described above (Fig. 11.40). Certain subtypes of peritoneal
serous carcinoma may grow on the surface of the peritoneum 11.2.3.2 Mucinous Neoplasms
without tissue invasion, and therefore may be confused with Primarily peritoneal endocervical type mucinous neoplasm
malignant mesothelioma or peritoneal adenocarcinoma of an is a tumor that occurs in extra-ovarian sites, primarily in the
unknown primary. retroperitoneum, in the absence of a primary ovarian muci-
Fig. 11.41 Endocervicosis. The glandular epithelium shows obvious Fig. 11.42 Peritoneal decidual reaction (mucicarmine, 400×)
endocervical type mucinous differentiation (H&E, 200×)
ean section or tubal ligation. Microscopically the decidual

nous neoplasm. The neoplasm is usually a large cystic tumor cells appear benign with abundant cytoplasm and no mito-
with morphologic similarity to its counterparts in the ovary, sis (Fig. 11.42). Occasionally, decidual cells in the omen-
e.g., mucinous cystadenoma, borderline mucinous tumor, or tum may contain abundant basophilic mucin and slightly
mucinous adenocarcinoma [110–112]. Ovarian type stroma eccentric nuclei. These cells may be confused with meta-
may be seen within this tumor, suggesting that the tumor static signet-ring cell carcinoma, but signet-ring cell car-
may arise from ectopic ovarian tissue, which is extremely cinomas are usually positive for PAS-positive neutral
rare. Most believe that this tumor arises directly from the mucin and cytokeratin. Peritoneal decidual reaction may
peritoneum, but the pathogenesis remains elusive. also be confused with the deciduoid variant of peritoneal
malignant mesothelioma. Malignant mesothelioma with
decidual differentiation typically shows significant
11.2.4 Other Epithelial Diseases nuclear pleomorphism and abundant mitotic figures (see
section: Diffuse Malignant Mesothelioma).
Other rare peritoneal epithelial lesions include transitional
cell metaplasia, squamous metaplasia, and clear cell change. 11.2.5.2 Disseminated Peritoneal
The last two entities are extremely rare. The Walthard rest is Leiomyomatosis
a benign transitional type epithelial proliferation, frequently 1. Clinical characteristics: Disseminated peritoneal leiomy-
encountered in the female pelvic peritoneum, especially on omatosis is a rare condition where the peritoneum is
the serosal surfaces of the fallopian tubes, mesosalpinx, and seeded by numerous benign smooth muscle tumors of
mesovarium. varying sizes and shapes [113, 114]. This condition is
most common in women of reproductive age, with up to
70% being pregnant, postpartum, or on oral contraceptive
11.2.5 Submesothelial Interstitial Diseases pills. Most cases are incidentally discovered during cesar-
ean section or tubal ligation. Occasional cases may pres-
11.2.5.1 Peritoneal Decidual Reaction ent with symptoms of pressure or compression similar to
Peritoneal decidual reaction is defined as decidualization of that of uterine leiomyoma.
submesothelial stromal cells in the peritoneum, usually an 2. Histologic features: The lesions typically form nodules
incidental microscopic finding. It is most commonly seen consisting of smooth muscle with no apparent nuclear
on the serosa of fallopian tube, uterus, uterine ligaments, pleomorphism or mitosis (Fig. 11.43). Decidualization
vermiform appendix, and omentum. Most cases of perito- may be seen in pregnant women. In 10% of cases, these
neal decidual reaction occur during pregnancy. Occasional nodules coexist with endometriosis and endosalpingiosis.
cases occur in patients receiving exogenous progestin 3. Pathogenesis: Disseminated peritoneal leiomyomatosis

therapy. may occur as a result of smooth muscle metaplasia of
Peritoneal decidual reaction may present as multiple submesothelial stromal cells. The changes may be associ-
nodules or macules, and are grossly visible during cesar- ated with pregnancy, use of exogenous hormones, post-
Fig. 11.43 Disseminated peritoneal leiomyomatosis. The lesions are Fig. 11.44 Endosalpingiosis involving lymph node in the peritoneal
composed of nodules of smooth muscle cells (H&E, 40×) cavity (H&E, 40×)
partum state, or surgical castration. The lesional cells nodes in pelvic malignancies. The glands are typically located
often express progesterone receptor [115]. in the capsule of the lymph node or between subcortical lym-
4. Treatment and prognosis: Even if not completely excised, phoid follicles. Histologically endosalpingiosis of the lymph
disseminated peritoneal leiomyomatosis is self-limiting. node is similar to endosalpingiosis in other locations
Rare cases have been reported to recur or undergo malig- (Fig. 11.44). Endosalpingiosis in the lymph node must be dif-
nant transformation, resulting in death [114, 116]. Some ferentiated from metastatic low-grade serous neoplasia from
cases of disseminated peritoneal leiomyomatosis may be the ovary. Borderline and malignant serous neoplasms have
treated with gonadotropin-releasing hormone. been reported to originate in pelvic lymph nodes [117].
11.2.5.3 Implanted Leiomyoma 11.2.6.2 Intranodal Decidua

Implanted leiomyoma in the peritoneum is a recently Intranodal decidual change unrelated to endometriosis is
reported entity that occurs as a result of inadvertent seeding very rare. It is usually an incidental finding during extensive
secondary to laparoscopic hysterectomy or myomectomy. sampling of periaortic and pelvic lymph nodes in radical
These patients invariably have a previous history of a mor- hysterectomy specimen for uterine cervical carcinoma.
cellation procedure, or other procedure, and may present Subepithelial decidual reaction may also be seen in the pel-
many years after the antecedent operation [75]. These tumors vis in these cases (Fig. 11.45).
may grow during pregnancy and may undergo torsion lead-
ing to an acute abdomen or may mimic a ruptured ectopic 11.2.6.3 Leiomyomatosis
pregnancy (Fig. 11.31a, b). These lesions are discussed ear- Benign smooth muscle nodules in pelvic and aortic lymph
lier in this chapter in section 11.1.6.3. nodes have been reported (Fig. 11.46) [120, 121], usually
associated with typical uterine leiomyoma. In rare cases,
patients may present with disseminated peritoneal leiomyo-
11.2.6 Lesions of the Lymph Nodes matosis or pulmonary leiomyomatosis. Possible mechanisms
of the disease may include:
11.2.6.1 Endosalpingiosis
Tubal type glandular inclusions of coelomic origin are not 1. Metaplasia of subcoelomic mesenchymal cells or fibro-
uncommonly seen in pelvic and para-aortic lymph nodes myoblastic metaplasia of intranodal decidua cells.
[117]. Depending on the number of lymph nodes sampled or 2. Lymphatic metastasis of leiomyoma (benign metastasiz-
the method of histological sampling for microscopic exami- ing leiomyoma).
nation, the incidence of nodal endosalpingiosis has been 3. Leiomyoma originating within the lymphatics: These

reported to range from 2 to 41% [118, 119]. Almost all cases patients may also present with multiple sclerosis and pul-
of lymph nodal endosalpingiosis are discovered in pelvic or monary leiomyomatosis.
para-aortic nodes removed during surgery for pelvic malig- 4. Metastasis of low-grade uterine leiomyosarcoma.
nancies. Its presence often presents a significant challenge for Intranodal leiomyomatosis is extremely rare. Clini
the pathologists during intraoperative evaluation of lymph copathological correlation is required in each case.
Fig. 11.45 Intranodal decidual reaction. The presence of a central gland Fig. 11.47 Ectopic adrenal rest (H&E, 200×)
suggests that this focus possibly represents endometriosis (H&E, 100×)
zona fasciculata (Fig. 11.47). In rare instances, ectopic adre-

nocortical cells may become hyperplastic and secrete gluco-
corticoids as a result of stimulation by the presence of a
pituitary tumor.
11.3.1.2 Cyst
Cysts of varying size, ranging from microscopic to up to
20 cm or larger, may be seen in the broad ligament. The epi-
thelial lining of some of the largest cysts is typically nonspe-
cific and cannot be further characterized. Some of these cysts
may derive from the Müllerian duct or mesothelium. A few
cases may derive from the mesonephric duct. The presence
of ciliated cells may help to differentiate Müllerian duct-
derived cyst from cysts of the mesothelium or mesonephric
duct. Complications of these cysts include torsion, infarc-
Fig. 11.46 Intranodal leiomyomatosis. The lymph node is almost
completely replaced by smooth muscle cells with small foci of residual tion, or infection.
lymphoid tissue (H&E, 200×)
11.3.1.3 Endometriosis
11.3 S
ection 3: Diseases of the Broad Endometriosis may involve the broad ligament. It is fre-
Ligament quently associated with endometriosis of the pelvis and other
pelvic organs. Detailed clinical presentations, pathological
11.3.1 Tumorlike Lesions characteristics, and pathogenesis of endometriosis are dis-
cussed in detail in Chap. 12.
11.3.1.1 Embryonal Remnants
The most commonly seen embryonal remnants in the broad
ligament are the mesonephric duct remnants, which are com- 11.3.2 Neoplasms
posed of small tubules lined by cuboidal epithelium without
cilia but with a distinct basal membrane. These tubules are The incidence of neoplasia arising in the broad ligament is
frequently surrounded by circular smooth muscle tissue. low, only 20% of that of ovarian tumors. Only about 2% of
Extensive sampling of the peritoneum may reveal ectopic broad ligament tumors are borderline or malignant, while
adrenocortical tissue near the ovarian vein in over 20% of 25% of ovarian tumors are borderline or malignant [122–
females. This ectopic adrenal cortical tissue is arranged in 124]. The clinical presentation of broad ligament tumors is
trabecular or cord-like structures, similar to those seen in similar to that of ovarian tumors.
11.3.2.1 Müllerian Tumors

Serous cystadenoma is the most common Müllerian-type
tumor of the broad ligament. Compared with nonneoplas-
tic simple cysts, serous cystadenoma has thicker cyst wall
with abundant fibrous tissue or ovarian cortex-like stroma.
The cyst wall is devoid of germ cells or follicles allowing
differentiation from primary ovarian tumors. Serous bor-
derline tumor is the second most common tumor of the
broad ligament. The clinical and pathological characteris-
tics of serous borderline tumor of the broad ligament are
similar to those of primary ovarian serous borderline
tumor. Unlike ovarian serous borderline tumors, almost
all broad-ligament serous borderline tumors have a benign
course.
Adenocarcinoma involving the broad ligament may be
Fig. 11.48 Female adnexal tumor of probably Wolffian origin
endometrioid, clear cell, or serous types. The clinical and (FATWO), gross photograph. The cut surface appears solid and firm
pathological characteristics of these tumors are similar to
those of primary ovarian adenocarcinoma. Endometrioid or
clear-cell adenocarcinoma of the broad ligament usually cysts or calcifications (Fig. 11.48). Hemorrhage and
arises in endometriosis. necrosis are rare.
3. Microscopic examination: Classically FATWO has three
11.3.2.2 P apillary Cystadenoma with Von histological patterns: (a) sievelike structures with tra-
Hippel-Lindau Disease beculae and tubules of varying shapes and diameters,
Papillary cystadenoma associated with von Hippel-Lindau sometimes with cystic dilatation similar to adenomatoid
disease in the broad ligament is a benign lesion. Rare reports tumor (Fig. 11.49a); (b) compact tubular structures
are available in the literature [125]. The tumor may be cystic mimicking a solid appearance; and (c) diffuse type with
or solid with a typical diameter smaller than 5 cm. The cyst solid tumor cell nests with a vague spindled appearance
usually contains papillary structures lined by cuboidal epi- (Fig. 11.49b). All three histological subtypes may occur
thelial cells without cilia. The nuclei of these cuboidal cells in the same tumor. Some tumors may have a promi-
are not atypical. There is a distinct basal membrane, similar nently hyalinized stroma or fibrous bands rendering a
to that of the Wolffian duct. lobular appearance. Upon high-power examination the
tumor cells have minimal eosinophilic cytoplasm with
Female Adnexal Tumor of Probable Wolffian Origin occasional spindle cells. The nuclei are pale, rather uni-
(FATWO) form, and with rare or no mitosis. Rare tumors may dis-
1. Clinical characteristics: Originally described in 1973,
play nuclear atypia and increased mitoses, which may
female adnexal tumor of probable Wolffian origin be associated with malignant behavior of the tumor
(FATWO) typically occurs along the mesonephric duct (Fig. 11.50).
remnants in the broad ligament, paratubal soft tissue, and 4. Immunohistochemical characteristics: The tumor cells

ovarian hilum [126]. Recent ultrastructural studies and typically express calretinin, inhibin, CD10, and vimentin
immunohistochemical expression of cytokeratin and and are nonreactive to EMA, Tag72, CEA, ER, and
inhibin support a mesonephric origin of this tumor. This PR. The immunohistochemical phenotype may help dif-
tumor is very rare, with less than 100 cases reported in the ferentiate this tumor from other Müllerian neoplasms.
literature so far. Patients’ age ranges from 15 to 81 years. 5. Ultrastructural characteristics: The tumor cells have a
Clinical presentations include abdominal pain, and mass thick peritubular basal lamina but lack cilia. The presence
lesions, but this tumor is more frequently an incidental of a Golgi apparatus, secretory granules, and glycogen
finding. favors a Wolffian duct origin of this tumor.
2. Gross examination: The tumor is typically unilateral 6. Differential diagnosis: The main differential diagnostic
with a well-demarcated border with or without a cap- consideration is endometrioid adenocarcinoma of the fal-
sule. It is usually located in the broad ligament or lopian tube, especially when the endometrioid
found hanging from the fallopian tube by a pedicle. adenocarcinoma is associated with spindle cells and

Tumor size may range from 1.3 to 20 cm with a mean microacini [127]. Genuine endometrioid adenocarcinoma
tumor size of 8 cm. The cut surface of the tumor is tan contains true glands and is frequently associated with
to yellow, solid, firm, or rubbery with occasional small squamous metaplasia and intraluminal mucin. Unlike
a b
Fig. 11.49 (a) Female adnexal tumor of probably Wolffian origin nantly sievelike structure with cystic dilatations of variable shapes and
(FATWO). Often shows lobular growth pattern with areas that may sizes (H&E, 100×)
appear as solid sheets (H&E, 100×). (b) This tumor displays predomi-
Fig. 11.50 FATWO showing small lumens surrounded by tumor cells with little nuclear pleomorphism (H&E, left 100× and right 400×)
FATWO, it is also frequently present inside the lumen of 7. Treatment and prognosis: Most FATWO has a benign
the fallopian tube. Other differential diagnoses include clinical course with rare instances of malignant behavior
Sertoli-Leydig cell tumor and other ovarian surface epi- [129]. There is no reliable morphological predictor of
thelial tumors. It is noteworthy that inhibin cannot reli- malignant potential and recurrent tumors are usually mor-
ably differentiate FATWO from Sertoli-Leydig cell tumor phologically similar to the primary tumor. Treatment of
as both tumors are positive [128]. choice is surgical resection. Chemotherapy is reserved for
malignant tumors. Because FATWO possesses a low 8. Clement PB, Young RH, Hanna W, et al. Sclerosing peritonitis
associated with luteinized thecomas of the ovary. A clinicopatho-
potential for malignancy, these patients should be fol- logical analysis of six cases. Am J Surg Pathol. 1994;18:1–13.
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mas (thecomatosis) of the type typically associated with sclerosing
11.3.2.3 Ependymoma peritonitis: a clinical, histopathologic, and immunohistochemical
analysis of 27 cases. Am J Surg Pathol. 2008;32:1273–90.
Ependymoma of the broad ligament is extremely rare [130]. 10. Kafiri G, Thomas DM, Shepherd NA, et al. p53 expres-
The average age of presentation is 38 years (range 13–48). sion is common in malignant mesothelioma. Histopathology.
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Endometriosis and Endometriosis-
Associated Tumors 12
Rosalia C. M. Simmen, Charles Matthew Quick,
Angela S. Kelley, and Wenxin Zheng
Abstract 12.1 General Characteristics

Endometriosis is a chronic gynecologic disorder that affects
~10% of adolescent girls and premenopausal women. The Endometriosis is a benign, but chronic, gynecologic condi-
condition, classically defined as the presence of endometrial tion of adolescent girls and reproductive-age women. The
glands and stroma outside of the uterine cavity, is multifac- disease is defined as the presence of viable endometrial
torial and highly recurrent, and causes considerable mor- glands and stroma in extrauterine sites and its development
bidities that can significantly diminish the quality of life of is widely recognized as an estrogen-dependent, pro-
affected women. The disease is linked to immune dysfunc- inflammatory process [1, 2]. Clinical sequelae of endome-
tions, infertility, and increased risk for ovarian and other triosis include painful menstrual periods, pelvic pain, ovarian
cancers. The histological diagnosis of endometriosis, while cysts, and/or infertility [1]. While the prevalence of endome-
typically uncomplicated, may be compromised by the het- triosis is difficult to quantify, it is estimated that 25–50% of
erogeneity of the endometriotic foci which can manifest a infertile women, and 30–80% of women with pelvic pain,
spectrum of lesions with distinct and atypical features of have a diagnosis of endometriosis [3]. Endometriosis may be
stromal and glandular components. Moreover, signs and a disabling condition for many women (estimated at
symptoms of endometriosis remain nonspecific and there is >200 million worldwide) during the prime years of their
a current lack of predictive noninvasive markers. This chap- lives, and endometriosis-related healthcare expenditures are
ter aims to provide current understanding of the etiology, significant [4, 5] . Treatment of endometriosis may include
pathogenesis, and clinicopathologic features of endometrio- medical management and/or surgery [6, 7]. However, as a
sis and to highlight the remaining challenges clinicians and chronic condition without a known cure, endometriosis
pathologists face in the diagnosis, management of symp- remains a challenge for affected women and their healthcare
toms, and provision of care in women with this condition. providers.
Endometriosis affects women of all races and ethnicities,
Keywords with a strong familial association [8]. Susceptibility to endo-
Endometriosis · Pathological features · Endometriosis- metriosis also depends on a variety of environmental, immu-
associated tumors nologic, and endocrine factors [9]. Risk factors for the
development of endometriosis include early onset of men-
arche, longer menstrual bleeding, and short menstrual cycles,
R. C. M. Simmen (*)
Department of Physiology and Biophysics, University of Arkansas while parity and paradoxically obesity and smoking are con-
for Medical Sciences, Little Rock, AR, USA sidered protective [6]. Women with endometriosis also
e-mail: [email protected] exhibit higher rates of concurrent pain, mood, or autoim-
C. M. Quick mune conditions [10, 11].
Department of Pathology, College of Medicine, University of Women with endometriosis may be asymptomatic, or
Arkansas for Medical Sciences, Little Rock, AR, USA
may report a wide range of symptoms including dysmenor-
A. S. Kelley rhea, dyspareunia, chronic pelvic pain, infertility, abnormal
Department of Obstetrics and Gynecology,
University of Michigan Health Systems, Ann Arbor, MI, USA
bleeding, or ovarian cysts [2]. There are currently no well-
validated screening tests for endometriosis, and definitive
W. Zheng
Departments of Pathology, Obstetrics and Gynecology,
diagnosis can only be made by surgical biopsy and histo-
University of Texas Southwestern Medical Center, pathologic confirmation of ectopic endometrium in extra-
Dallas, TX, USA uterine locations [12]. In clinical practice, many women with
406 R. C. M. Simmen et al.
suspected endometriosis receive empiric medical therapy, are stratified into four stages: stage 1 (minimal), 2 (mild), 3
with hormonal suppression and/or pain control, to avoid the (moderate), and 4 (severe). Stage 1 endometriosis is charac-
inherent risks of diagnostic surgery. To assist with concep- terized by small, isolated, superficial endometriosis implants
tion in infertile women, assisted reproductive technologies on the peritoneum or within the ovaries. On the other hand,
such as in vitro fertilization may be employed [13]. As a stage 4 endometriosis is characterized by numerous endome-
chronic condition, endometriosis-related symptoms may triosis lesions, which may be superficial or deeply infiltrat-
progress, regress, or remain stable until menopause, when ing, in addition to dense peritoneal or pelvic adhesions, and
endometriosis generally becomes quiescent. There is increas- possibly a large ovarian endometriosis cyst. The majority of
ing evidence, however, that endometriosis may persist even women with endometriosis are assigned to stages 1–2; how-
in the postmenopausal state [14]. Women with endometriosis ever, there is little correlation between stage of endometrio-
have a two- to threefold increased risk for ovarian cancers sis and severity of pain symptoms [21]. A recent consensus
and other malignancies such as endometrial and breast statement by the World Endometriosis Society has incorpo-
cancers [15]. rated additional endpoints that are highly relevant to women
The definitive diagnosis of endometriosis can only be with endometriosis [22].
made surgically, with histopathologic visualization of both At present, there are no good serum markers with suffi-
endometrial glands and stroma within a surgical biopsy. cient accuracy currently to assess the severity of endometrio-
Endometriosis lesions may vary in appearance at the time of sis. Serum Cancer Antigen-125 (CA-125) levels have been
laparoscopy; the classic description is that of a blue or black reported to significantly differ in patients with pelvic versus
“powder burn lesion,” but implants may also be hemorrhagic extra-pelvic (i.e., pelvic > extra-pelvic) lesions [23]. Another
or nonpigmented [16, 17]. However, even with experienced study failed to confirm this finding and instead observed that
laparoscopic surgeons, there may be inconsistencies between extra-pelvic endometriosis was associated with higher
suspected endometriosis (by visual appearance) and con- patient serum CA-125 levels and lesions displaying increased
firmed endometriosis by histopathology [16, 18, 19], high- expression of the epithelial-mesenchymal transcription fac-
lighting the importance of histologic evaluation. tor ZEB1 than pelvic endometriosis [24]. The use of mag-
netic resonance imaging (MRI) to distinguish endometriotic
tissue from adhesions and fibrosis has been recently reported
12.2 Clinical Relevance and may be suitable for the diagnosis of endometriosis at
unusual anatomic sites in symptomatic patients [25].
The American Society for Reproductive Medicine (ASRM) Given the nonspecific nature of endometriosis symptoms,
has developed the most commonly accepted classification the diagnosis of the condition is often delayed. Indeed, while
system for endometriosis [20]. This guideline accounts for the mean age at diagnosis is ~25–29 years, most patients
lesion size, appearance, anatomic location, and depth of manifest symptoms of pelvic pain and dysmenorrhea at the
invasion of endometriotic lesions visualized during diagnos- start of menarche. Symptoms of endometriosis do not differ
tic surgery (Table 12.1). Based on these parameters, patients between women surgically diagnosed during adolescence
compared with those diagnosed as adults [26]. A summary of
the differential diagnosis of endometriosis depending on the
Table 12.1 American Society for Reproductive Medicine Classification symptom was provided in Mounsy et al. [27]. Dysmenorrhea
for Endometriosisa
in endometriosis may be primary or secondary. Generalized
Depth of endometrial pelvic pain, while characteristic of endometriosis, may also
Stage Location (size) explants
arise from malignant or benign neoplasms, pelvic adhesions,
I. Minimal Peritoneum (1–3 cm) Superficial
Ovary (<1 cm) Superficial pelvic inflammatory disease, obstructive genital anomalies,
II. Mild Peritoneum (>3 cm) Deep endometriosis or non-gynecologic causes. Women with dyspareunia may
Ovary (<1 cm) Superficial have endometriosis but the differential diagnosis also
Ovary-filmy adhesions Superficial includes pelvic infection and bowel or urinary pathology.
III. Moderate Peritoneum (>3 cm) Deep endometriosis
The diagnosis becomes more challenging if the lesions are
Ovary (1–3 cm) Deep endometriosis
Ovary Dense adhesions located in distal sites. Thus, direct visualization (via laparos-
Ovary-filmy adhesions Superficial copy) and histological confirmation of biopsied lesions must
Fallopian tubes(<1 cm) Dense adhesions be strongly considered for cases of suspected endometriosis
IV. Severe Peritoneum (>3 cm) Deep endometriosis to facilitate timely initiation of appropriate therapy.
Ovary (1–3 cm) Deep endometriosis
Ovary Dense adhesions Clinically useful serum biomarkers for diagnosis and
Fallopian tube (>2 cm) Dense adhesions staging of endometriosis and/or to differentiate endometrio-
Cul de sac Complete obliteration sis subtypes are currently lacking. Cancer Antigen (CA) 125,
Reference [20]
a
CA 19-9, and the cytokine interleukin-6 have been suggested
12 Endometriosis and Endometriosis-Associated Tumors 407
as possible noninvasive markers; however, an extensive best explained by the migration or transplantation of endo-
meta-analysis raised questions on their diagnostic specificity metrial cells into ectopic, extrauterine locations.
and accuracy [28]. One study reported that a four-marker Nevertheless, retrograde menstruation occurs frequently
panel of CA-125, macrophage chemotactic protein-1, leptin, in women with patent fallopian tubes who do not develop
and macrophage migration inhibitory factor could diagnose endometriosis [39, 40]. In addition, endometriosis has been
48% of subjects with 93% accuracy [29], but this procedure noted in previously hysterectomized women, and even in
has yet to be incorporated clinically. Tumor necrosis factor men undergoing treatment for prostate cancer [41]. Such
levels in the peritoneal fluids were found to be higher in findings suggest that menstruation is not definitively required
women with than in those without endometriosis [30]; how- for the development of endometriosis and highlight the mul-
ever, the test may have limited application since it relies tifactorial nature of the condition.
upon an invasive procedure.
Recent studies using mouse models of endometriosis [31] 12.3.1.2 Metaplasia
and women with the condition [32] have tested the feasibility An alternative theory is that of coelomic metaplasia.
of using circulating microRNAs (miRNAs) as biomarkers Coelomic epithelial cells are found within the peritoneal cav-
for endometriosis. While the results appear promising, the ity, such as on the surface of the ovary, in addition to the
accuracy and specificity of these identified miRNAs have yet pleural space. It is proposed that coelomic epithelial cells
to be rigorously vetted in clinical settings. may undergo metaplastic transformation into endometrial
cells, leading to ectopic endometrial lesions which ultimately
develop into endometriosis [2, 42]. Metaplasia may be
induced by exposure to chemical insults (such as menstrual
12.3 Pathogenesis of Endometriosis fluid) or high levels of estrogen [43].
Support for this theory includes observations that endo-
Several theories have been proposed to explain the pathogen- metriosis may be found in distant sites such as the pleural
esis of endometriosis. Below, we discuss four theories which cavity, where coelomic epithelium exists, and that endome-
may account for the development and persistence of endo- triosis can occur in prepubertal girls prior to the onset of
metriosis in affected women. It is important to recognize that menarche [33, 44]. Furthermore, case reports have demon-
no individual theory has been accepted to fully explain this strated surgical evidence of endometriosis in women with
complex, multifactorial disorder [33, 34]. Mayer-Rokitansky-Kuster-Hauser syndrome (defined as con-
genital agenesis of the uterus, cervix, and vagina due to fail-
ure of the Mullerian duct to develop), indicating that a
12.3.1 Histogenesis functional uterus is expendable for the development of endo-
metriosis [44–46].
12.3.1.1 Retrograde Menstruation
The concept of retrograde menstruation is the most cited 12.3.1.3 Stem Cell Theory
explanation for the pathogenesis of endometriosis. This In normal menstrual cycles, the human endometrium is con-
theory involves the retrograde flow of endometrial glands tinually regenerated by both local adult progenitor cells and
and stromal cells, sloughed during menses, through the fal- bone marrow-derived multipotent stem cells [41]. Stem cells
lopian tubes and into the peritoneal cavity [2, 35]. are undifferentiated cells which are characterized by their
Implantation and proliferation of these endometrial cells ability to self-renew and to later develop into a variety of
then occur within ectopic sites, where they are resistant to mature cell types [39]. Support for the role of endometrial
apoptosis [9]. stem cells in the pathogenesis of endometriosis and their
Support for the theory of retrograde menstruation has potential involvement in ectopic endometrial proliferation
been demonstrated in animal models [36, 37]. In addition, and differentiation have largely come from experimental
the prevalence of endometriosis is increased in women with mouse and nonhuman primate models [41].
obstructive outflow tract anomalies, such as cervical steno- In women with endometriosis, refluxed stem cells (via
sis, where the likelihood of retrograde menstruation is higher retrograde menstruation) deposited into the peritoneal
[1, 38]. The risk of endometriosis also increases with shorter cavity can subsequently undergo differentiation into endo-
menstrual cycles, increased menstrual frequency, and heavier metrial glands and stroma [35, 41]. The migration of extra-
menstrual flow, lending support to the role of menstruation in uterine stem cells through lymphatic or vascular channels
the pathogenesis of endometriosis [2]. Though not explained may contribute to the development of distant endometrio-
by retrograde menstruation, endometriosis lesions which sis lesions [39]. Understanding the phenomenon of “stem
develop in perineal scars following an obstetric laceration, or cell trafficking” is a growing field of endometriosis
in abdominal incisions after cesarean delivery, are likewise research [47].
12.3.1.4 Tubal Origin of Ovarian Endometriosis significant gene expression similarities between the fallopian
The fallopian tube has been recently proposed as a cellular tube and ovarian endometriosis, compared to expression pro-
contributor to the development of endometriosis [48]. About files between the endometria and ovarian endometriosis. It
a decade ago, it was noticed that there are very early morpho- was concluded that a substantial portion of ovarian endome-
logic changes in cases of ovarian endometriosis, defined as triosis may originate from the fallopian tube [51].
“initial endometriosis” [49]. Subsequently, a study of the cel- The above findings are relevant in light of growing evi-
lular origin of ovarian low-grade serous carcinoma found dence that ovarian epithelial cancers, and possibly endometri-
that ovarian epithelial inclusions (also called as endosalpin- oid cancers, may originate in the fallopian tubes [52–54].
giosis) are most commonly derived from the fallopian tube Additionally, epidemiologic evidence suggests that bilateral
[50]. Considering that initial endometriosis (Fig. 12.1) mor- salpingectomy (defined as the surgical removal of the bilat-
phologically overlaps with ovarian epithelial inclusions, it eral fallopian tubes) may decrease lifetime risk of ovarian
was proposed that ovarian endometriosis, which develops cancer in high-risk (e.g., women with BRCA1/2 gene muta-
from ovarian “initial endometriosis,” may also arise from the tions) as well as in low-risk populations [55–57]. If future
fallopian tube. In a study to evaluate this hypothesis, micro- investigations confirm the contribution of the fallopian tubes
array analysis was used to compare gene expression between to the pathogenesis of endometriosis, the findings may have
the fallopian tube and the endometrium of patients with ovar- significant therapeutic and preventative implications for
ian endometriosis and corresponding lesions. There were reproductive-age women who have completed childbearing.
a b
c d
Fig. 12.1 Initial endometriosis. Shown here are ovarian epithelial-like is present on the top right (c). The dramatic differences noted in the
inclusions in the ovarian cortex. Stromal changes including microcapil- stroma surrounding the ovarian epithelial inclusions are presented at a
lary vessels are present surrounding the epithelial inclusions (a). higher magnification (d). The non-spindle stroma enriched with micro-
Stromal and vascular changes are evident in a magnified view (b). capillary vessels represents the earliest morphologic change of
Another inclusion-like structure shows fresh bleeding adjacent to the endometriosis
glandular structure (c, left and mid-right), while typical ovarian stroma
12.3.2 Etiology located in intergenic or intronic regions and in different chro-

mosomes, have identified WNT4 (wingless-type MMTV
12.3.2.1 Genetics integration site family member 4), GREB1 (growth regula-
Genomic (and proteomic) studies comparing ectopic lesions tion by estrogen in breast cancer 1), FN1 (fibronectin1), ID4
and eutopic endometria from women with endometriosis (inhibitor of DNA binding 4), VEZT (verzatin), and MAP3K4
with endometria from women without the disease have dem- (mitogen-activated protein kinase kinase kinase 4) as candi-
onstrated altered expression of a large number of molecules, date genes. Nevertheless, a major challenge in the under-
but their individual contribution as a mechanistic cause of standing of disease pathogenesis and causes of disease
lesion incidence and establishment remains largely unde- heterogeneity is the identification of which of these genes
fined [58–61]. Table 12.2 provides a partial list of novel, represent “drivers” as opposed to “passengers.”
recently identified genes that have been strongly implicated
in disease establishment, based on clinical (afflicted women) 12.3.2.2 Sex Steroid Hormones and Receptors
and experimental (mouse models of endometriosis) observa- Dysregulation of steroid hormone signaling is a major feature
tions [62–72]. The list does not include steroid hormone of endometriosis, given the estrogen dependence of the dis-
receptors and pro-inflammatory molecules, which are disease. Estrogen-modulated events including cell proliferation,
cussed in more detail in subsequent sections (below). The angiogenesis, and cyst formation are exacerbated in endome-
broad functional spectrum of the listed genes underscores triosis due in part to alterations in the ratio of estrogen recep-
the multifactorial and heterogeneous nature of the disease. tor (ER) isoforms ER-α and ER-β; increased local estrogen
Different mechanisms such as aberrant (hyper- or hypo-) biosynthesis (due to higher aromatase enzyme activity in
methylation, somatic mutations, or posttranslational modifi- ectopic lesions); and decreased progesterone receptor expres-
cations involving microRNAs may explain the loss or gain of sion leading to unopposed estrogen action [77]. The patho-
functions of these genes, leading to abnormal regulation of logical overexpression of ER-β (100 times higher in
endometrial proliferation and apoptosis that characterize endometriosis than in normal endometrial tissue) relative to
endometriosis [73–75]. ER-α is caused by deficient methylation of the ER-β promoter
Genome-wide association studies (GWAS) have been and has been experimentally demonstrated using a mouse
increasingly utilized to evaluate genetic contributions to model of endometriosis, to result in enhanced inflammation
endometriosis [76]. Genetic variants in loci, predominantly and reduced apoptosis in lesions leading to disease progres-
sion [78, 79]. Progesterone resistance is also a characteristic
feature of endometriosis. The loss of progesterone sensitivity
Table 12.2 Genes potentially involved in endometriosis is due to reductions in progesterone receptor expression and
Gene name Model Expression References transcriptional activity, promoted in part by the increased
HOXA10 Women Decrease, stromal EC [47] inflammatory status of endometriotic lesions [59, 80, 81].
P450 Arom Mice Increase, stromal EC [48] Current drugs for the management of endometriosis are
Women Increase, pain aimed at decreasing systemic and local estrogen synthesis,
SRC1 (variant) Mice Increase, stromal EC [50]
reducing estrogen activity, and increasing progesterone sensi-
Women Increase, stromal EC
tivity [82]. Due to side effects from long-term use of these
COUP-TFII Mice Decrease, stromal EC [51]
Women Decrease, stromal EC
medications, ongoing studies continue to explore new thera-
Cx43 Women Decrease, stromal EU [52] pies to increase efficacy with minimal discomfort [83, 84].
KLF9 Mice Decrease, stromal EC [53]
Women Decrease, stromal EC 12.3.2.3 I mmune Response and Inflammatory
REA Mice Decrease, stromal EC [54] Factors
Women Decrease, stromal EC Recent studies have provided support to the link between
PTEN Mice Decrease, stromal EC [55] endometriosis and many immune diseases. Immune dys-
Women Decrease, stromal EC [56] functions associated with endometriosis include systemic
KRAS Mice Increase, EU [57]
lupus erythematosus, rheumatoid arthritis, allergies, and
Women Increase, EU
asthma [11, 85, 86]. Endometriosis patients (and correspond-
a
HOXA10, HomeoboxA10; P450 Arom, P450 aromatase;SRC1 (vari-
ant), steroid receptor co-activator 1 (70 kDa variant); COUP-TFII,
ing ectopic lesions) demonstrate elevated levels of pro-
chicken ovalbumin upstream promoter-transcription factor II; Cx43, inflammatory cytokines, including interleukins (IL)-1, 6,
connexin 43; KLF9, Krüppel-like factor-9; REA, repressor of estrogen 17A, and 33 as well as macrophage-stimulating factors (e.g.,
receptor activity; PTEN, phosphatase and tensin homolog deleted in granulocyte-monocyte colony-stimulating factor) than
chromosome 10; KRAS, Kirsten-ras sarcoma virus oncogene
women without the disease [87]. While it is not clear whether
b
Expression change is relative to endometrium of women without endo-
metriosis; EU eutopic endometrium of women with endometriosis, EC endometriosis is a cause or a consequence of immune
ectopic lesions dysfunctions, removal of ectopic lesions was shown to

significantly reduce the systemic inflammatory profiles in sis accounts for 5–10% of women with disease. Endometriosis
these women, suggesting lesions as major drivers of sys- may also be established at distant locations such as the pleu-
temic inflammation [88]. The enhanced inflammatory status ral space, diaphragm, or breast [16]. The implantation and
of women with endometriosis is likely caused by the highly proliferation of endometrial cells in ectopic sites result in
estrogenic dependence of the disease, given the demon- inflammation, fibrosis, and distortion of normal anatomy.
strated cross talk between pro-inflammatory molecules (e.g., The ovary and peritoneum are the most frequent locations
IL-6) and estradiol during early disease progression [89] and of pelvic endometriosis. Other pelvic sites include the bowel
the role of estrogens in the recruitment of pro-inflammatory [97] or bladder. Extra-pelvic lesions are less common, likely
molecules within ectopic lesions [90]. Thus, recently identi- deeply infiltrating, and found in such anatomic locations as
fied estrogen receptor antagonists that can concurrently sup- hepatobiliary and urinary systems, upper abdomen (lung,
press estrogenic and inflammatory activities [91] may show thorax), abdominal wall, and adrenal glands.
promise as preventative and treatment strategies for Diagnosis of pelvic and extra-pelvic lesions can be chal-
endometriosis. lenging. Endometriosis of the uterine cervix is generally
As mentioned earlier, the role of progesterone resistance asymptomatic and can be mistaken for cervical neoplasia
in the progression of endometriosis may be linked to the due to the presence of a cervical mass [98, 99]. Intestinal
enhanced inflammatory status of women with the disease. endometriosis may present with abdominal pain or gastroin-
Gene expression analyses have shown that loss of progester- testinal bleeding [100], and the differential diagnoses may
one receptor expression in lesions is associated with their include diverticulitis, appendicitis, Crohn disease, irritable
higher expression of inflammatory cytokines [58, 59]. bowel syndrome, carcinoma, and lymphoma. Patients subse-
Mechanistically, it has been demonstrated that inflammatory quently diagnosed with thoracic endometriosis may initially
molecules such as IL-1 and tumor necrosis factor (TNF)-α present with shoulder pain, catamenial pneumothorax, and/
can significantly reduce progesterone receptor expression or hemoptysis [101]. In patients with bowel endometriosis,
[81]. Conversely, progestin treatment of endometriotic stro- lesions display a characteristic “comet” appearance and have
mal cells can suppress TNF-α-induced inflammation [92]. been associated with obliteration of the cul-de-sac and pelvic
The significant contribution of pro-inflammatory mole- pain [102]. Abdominal wall endometriosis occurs when
cules to endometriosis raises the interesting potential for non- endometrial cells attach to the fascia or dermis at the time of
steroidal anti-inflammatory drugs such as prostaglandin obstetrical or gynecological surgery. Approximately 1% of
synthesis inhibitors (e.g., cyclooxygenase-2 inhibitors) and women who have had a caesarean delivery subsequently pre-
diets rich in anti-inflammatory components (e.g., resveratrol sented with focal pain and/or palpable mass near the surgical
in grapes) in the management of endometriosis. While there scar which was diagnosed as endometriosis [103].
is sufficient support to these possibilities in animal models
[93, 94] and in studies using endometriotic stromal cells [95], 12.4.1.1 Peritoneal Endometriosis
their potential has yet to be achieved in a clinical setting [96]. Peritoneal endometriosis, also termed superficial endome-
triosis, is typically present on the surface of the peritoneum
or the serosa of the peritoneal organs. Lesions of endometri-
12.4 Pathologic Features of Endometriosis osis can be single or in clusters. Grossly, they may present as
raised, cystic, polypoid, or nodular.
Endometriosis, pathologically, is defined by the presence of Peritoneal endometriosis may show different colors under
ectopic functional endometrial tissue, which may be accom- gross or laparoscopic examination, based on the “age” of the
panied by cyclic bleeding induced by hormonal changes and disease. Early lesions are typically colorless and 2–3 mm in
associated with adjacent tissue response and accompanying size (Fig. 12.2).The lesions then may become red (fresh or
adhesion or scar formation. recent bleeding) (Fig. 12.3), blue or black (old or remote
bleeding) (Figs. 12.4 and 12.5), and white (inflammation and
fibrosis) (Fig. 12.2), representing different stages of growth.
12.4.1 Clinicopathologic Types It takes years for an early cystic colorless lesion to develop
into a whitish scar-like lesion. Peritoneal lesions may be
Endometriosis lesions are most commonly located in the pel- multifocal (i.e., other lesions are located within a 2 cm area)
vic surface of peritoneum and ovary (peritoneal endometrio- or multicentric (i.e., lesions are located beyond 2 cm from
sis), in the ovary as cysts lined by endometrioid mucosa the main lesion); as many as 50 lesions may involve the
(ovarian endometriomas), and in pelvic structures between peritoneum.
the rectum and vagina as a solid mass comprised of endome- Presence of endometroid epithelia as well as endometrial
triotic tissue with local adipose and fibromuscular tissue stromal cells varies depending on the disease status.
(deep-infiltrating endometriosis). Rectovaginal endometrio- Typically, both can be found in more than 95% of red lesions,
Fig. 12.2 Peritoneal endometriosis. A laparoscopic view of the perito- Fig. 12.4 Peritoneal endometriosis. Shown here are one black,
neal cavity reveals several transparent cystic structures, ranging from 2 “powder-burn” spot in the center and another purple spot in the lower
to 4 mm in size, which represent foci of endometriosis prior to bleeding. area. Both represent relatively old hemorrhage in endometriotic lesions.
Also shown are several white raised nodules (2–3 mm in size) probably Based on the color, the purple lesion is more likely less established than
representing endometriosis with fibrotic changes the black lesion
Fig. 12.3 Peritoneal endometriosis. This laparoscopic view of the Fig. 12.5 Peritoneal endometriosis. Multiple blue and black lesions
peritoneum shows several red-tan, irregular-shaped, slightly raised representing old hemorrhage within foci of endometriosis are shown
lesions, which represent foci of endometriosis with fresh bleeding
and in only 50–60% of bluish or black lesions. The finding (Figs. 12.6, 12.7, 12.8, and 12.9). Large cysts can
clinicopathologic appearance of peritoneal endometriosis is form around the ovary and may acutely rupture, causing
summarized in Table 12.3. release and adherence of their contents to the abdominal
cavity.
12.4.1.2 Ovarian Endometriosis
Endometriosis in the ovary typically presents as a cystic 12.4.1.3 Deep-Infiltrating Endometriosis
lesion with either a single cyst or multilocular cysts. Ovarian Deep-infiltrating endometriosis (also called adenomyosis
endometriotic cysts are termed endometriomas. The cystic externa) is the most severe clinical form of endometriosis
wall is typically thickened because of fibrotic reaction. and in >95% of cases is associated with severe pain. It typi-
Blood clot or condensed blood containing chocolate-like cally presents as solid, multifocal nodules larger than 0.5 cm
material (aptly named “chocolate cyst”) is a common gross in diameter which can grow up to 5–6 cm in size [104, 105].
Table 12.3 Clinicopathologic appearance of peritoneal endometriosis

Microscopic finding of
Gross color Disease status Appearance endometrial tissue (%)
Colorless Prior to Grey small
bleeding cysts
Focally raised Close to 100
Red Early Granular and
bleeding polypoid
Red or Up to 95
yellowish
Blue or Active Burned
black growth appearance
Irregular 50–60
folding
White Healing stage Focal adhesion
Scar <30–50
Fig. 12.8 Ovarian endometrioma. Upon sectioning, this ovarian endo-

metrioma contains multiple small cystic areas containing old blood.
The cyst wall is thickened. Foci of endometriosis are also present on the
serosal surface (lower left)
Fig. 12.6 Ovarian endometrioma. The ovary shows the presence of a blue
cystic lesion on the surface. A brown viscous material seen oozing onto the
surface of the ovarian mass represents an unopened ovarian endometrioma
Fig. 12.9 Ovarian endometrioma. Microscopically, the cyst wall is

lined by a single layer of epithelium. Located underneath are the typical
stromal and vascular changes of endometriosis. Degraded cellular
debris are present within the lumen
In contrast to peritoneal endometriosis and ovarian endome-

triomas, the lesions are found deep within connective tissue
and can cause massive fibrosis and muscular hyperplasia.
Typically, they are present in uterine ligaments or the walls
of pelvic organs such as the bladder, rectum, and pouch of
Douglas (Figs. 12.10, 12.11, and 12.12). Deep-infiltrating
lesions are classically diagnosed by laparoscopy and patho-
logical evaluation to rule out occult malignancy and man-
aged by either laparoscopy or laparotomy [106, 107].
However, these lesions may recur even after surgical
management.
Fig. 12.7 Ovarian endometrioma. Contents of an endometrioma ooze
onto the surface of this ovary
Fig. 12.12 Deep-infiltrating endometriosis involving Douglas’ pouch.

Another example of deep-infiltrating endometriosis involving the pouch
Fig. 12.10 Endometriosis involving round ligament. Endometriosis, of Douglas. A raised nodule is displayed underneath the posterior wall
seen as black and grey-white lesions, is present on the broad ligament. of the uterus (laparoscopic forceps)
The ligament is thickened, possibly due to fibrosis induced by
endometriosis
Table 12.4 Histologic features of endometriosis
Components
Epithelial associated cells Endometrioid or tubal like cells
Glandular or tubular structures
Surface epithelia
Stromal fibrosis, Endometrioid stromal cells
pseudoxanthoma cells, Capillary vessels
macrophages Spiral arteries
Secondary tissue changes Surface adhesions
Smooth muscle proliferation
Fibrosis and scar formation
Microscopic findings of endometriosis are usually influ-

enced by circulating levels of hormones, and lesions may
show proliferative or secretory appearance (Fig. 12.13).
Recognition of the stromal compartment can help in subtle
cases. These cells typically surround the glands or lie just
underneath the epithelial surface. The endometrial stroma is
enriched with capillary vessels and occasionally contains
Fig. 12.11 Deep-infiltrating endometriosis involving Douglas’ pouch. well-developed spiral arteries. Typically, the stromal cells
Shown is a deeply embedded nodule with a blue raised surface (middle are immunopositive for CD10 (also known as common acute
right), typical of a deep-infiltrating endometriosis. Additional areas of
lymphocytic leukemia antigen, CALLA) [99], which aids in
small peritoneal surface involvement are also seen (lower middle)
diagnosis (Fig. 12.14).
Presence of histiocytes is another microscopic feature of
12.4.2 Microscopic Features of Endometriosis endometriosis. There are two kinds of histiocytes—pseudox-
anthomatous cells and hemosiderin-laden macrophages; the
Microscopically, endometriosis is composed of endometri- former is more common than the latter in endometriosis
oid glandular epithelia surrounded by endometrial-like (Fig. 12.15). Pseudoxanthomatous cells result from the deg-
stroma, which is enriched with capillary vessels. The cellular radation of both epithelial cells and red blood cells within the
composition may vary between lesion types. Foci of endo- foci of endometriosis. Hemosiderin-laden macrophages are
metriosis are commonly associated with bleeding, fibrosis, formed when red blood cells become the dominant products
and smooth muscle proliferation. Typical microscopic find- of endocytosis. From this perspective, the presence of pseu-
ings are summarized in Table 12.4. doxanthomatous cells is more specific for endometriosis,
a b
Fig. 12.13 (a) Endometriosis showing proliferative-type endometrial glands. Proliferative endometrium is present in this focus of endometriosis.
(b) Endometriosis showing secretory-type endometrial glands. Secretory endometrium is seen in this focus of endometriosis
Fig. 12.14 CD10 is positive for the stromal cells of endometriosis. Stromal cells of endometriosis stained with H&E (left panel) and immunos-
tained with anti-CD10 antibody (right panel)
since any bleeding-associated lesion can present with

hemosiderin-laden macrophages.
Different locations of endometriosis may have different
gross and microscopic appearances, as demonstrated in rep-
resentative pictures of endometriosis in the ovary (Fig. 12.9),
tubal serosa (Figs. 12.16 and 12.17), uterine serosa
(Figs. 12.18 and 12.19), uterine ligament (Fig. 12.10), endo-
cervical mucosa (Figs. 12.20 and 12.21), colon (Fig. 12.22),
abdominal wall after C-section (Fig. 12.23), omentum
(Fig. 12.24), and lymph nodes (Fig. 12.25).

Fig. 12.15 Pseudoxanthomatous cells and hemosiderin-laden macro-
phages in endometriosis. A representative section of an ovarian cyst
Many conditions can mimic endometriosis. These include
wall associated with an endometrioma. Pseudoxanthomatous cells are corpus luteum cyst, endosalpingiosis, stromal hyperplasia,
present within the lower right corner, while hemosiderin-laden macro- ectopic decidua, and rete ovarii (Table 12.5; Figs. 12.26,
phages are present in the center layer 12.27, 12.28, 12.29, and 12.30). The key diagnostic clue for
Fig. 12.16 Endometriosis involving the fallopian tube. Grossly, the

fallopian tube is thickened. Multiple foci of endometriosis are present
within the tubal wall
Fig. 12.18 Endometriosis involving the uterine serosa. A hysterec-
tomy specimen showing shaggy uterine serosal surface due to severe
adhesions caused by endometriosis
Fig. 12.17 Endometriosis involving the fallopian tube.

Microscopically, endometriosis lines the surface of the cyst wall. The
muscular layer of the fallopian tube is present underneath
Fig. 12.19 Endometriosis involving the uterine serosa.

Microscopically, the serosa shows endometriotic glands and fibrosis
the diagnosis of endometriosis is to find both epithelial and
stromal components, although this is not always easy. While
CD10 is a sensitive immunohistochemical marker of endo- 12.4.4 Special Types of Endometriosis
metrial stroma in ectopic sites, especially in women with
minimal disease, its use is limited in situations where the 12.4.4.1 Polypoid Endometriosis
amount of stroma is sparse. Polypoid endometriosis is a rare type of endometriosis that
There are many other differential diagnoses pathologists presents as large lesions which may simulate polyps and are
should consider. For instance, deeply infiltrating endometri- generally mistaken for malignant tumors [108]. This type of
osis involving the colon can be confused with either meta- endometriosis usually accompanies typical endometriosis at
static cancer or cancer of the colon. When endometriosis is other sites and/or may manifest later in women with a his-
treated by progestin, the stromal cells become decidualized, tory of endometriosis. Lesions occur predominantly at
which can raise the histologic differential diagnosis of gas- mucosal or serosal surfaces of the colon, uterus, cervix, and
trointestinal stromal tumor. The correct diagnosis is usually vagina or within cyst cavities of the ovary but are also found,
not difficult if the basic concepts of endometriosis as well as albeit less frequently, in the omentum, bladder, and
the possibility of its widespread distribution are kept in mind. retroperitoneum.
Fig. 12.20 Endometriosis involving the endocervical mucosa. A col-

poscopic view of the cervix shows blue or black spots on the cervical
mucosa
Fig. 12.23 Endometriosis involving a dermal scar. Resected skin and der-
mal scar are shown on the top panel. Cross section of the specimen shows
Fig. 12.21 Endometriosis involving the endocervical mucosa.
several foci of endometriosis (black spots) and fibrosis (bottom panel)
Microscopically, the superficial endometriosis is located directly
beneath the squamous mucosa
Fig. 12.24 Endometriosis involving the omentum. Foci of endometri-

Fig. 12.22 Endometriosis involving the colon. Colonic mucosa shown osis (upper left) and fatty tissue (bottom) are shown. Extensive chronic
on the left, with a focus of endometriosis shown on the upper right inflammation is present
Fig. 12.25 Endometriosis involving the lymph node. A few endome-

triotic glands are localized underneath the nodal capsule
Fig. 12.26 Corpus luteum of the ovary. A corpus luteum may also con-
tain old blood; however, the cyst wall is thin and without fibrosis. A
Table 12.5 Differential diagnosis of endometriosis characteristic yellow cyst wall is typically present (lower middle)
Disease Similarities Differences

Corpus luteum Fibrosis and A single-time bleed
hemorrhagic instead of repeated
appearance of the episodes of
cystic wall bleeding
Classic yellowish
color
Presence of theca
interna cells without
fibrosis
Without epithelial
and stromal cells
Endosalpingiosis or Locations are similar Absence of
ovarian epithelial to endometriosis endometrioid
inclusions Presence of stromal cells
glandular structures No evidence of
bleeding and
fibrosis
Stromal hyperplasia May appear as May be lined by
glandular or cystic mesothelial cells Fig. 12.27 Endosalpingiosis involving the fallopian tube. The cystic
structures with Absence of gland represents endosalpingiosis. The epithelial lining can be similar
adjacent adhesions bleeding or to the epithelial cells of the endometriosis; however, there is no endo-
epithelial or stromal metrial stroma. Instead, the cyst is surrounded by smooth muscle, indi-
cells cating a tubal location
Ectopic decidua Sheets of decidual Absence of
cells glandular cells
Absence of 20 cm. It can be single or multiple, and is typically associ-
bleeding and
fibrosis
ated with bleeding and/or formation of a cystic space.
Rete ovarii Glandular structures Located in hilar Microscopic features: Microscopically, the polypoid
region masses are composed of an admixture of endometrial glands
Epithelial cells are and stroma; the glands are typically hyperplastic, with or
cuboidal or low without atypia, while the underlying stroma is dense
columnar
No evidence of (Fig. 12.31) [108]. Epithelial metaplastic changes are com-
bleeding mon. However, typical foci of endometriosis are usually
present in adjacent areas.
Differential diagnosis: The most common differential
Gross features: Macroscopically, polyps are solid with a diagnosis is low-grade adenosarcoma. The lack of stromal
round and smooth shape [109]. Polyp size may be as large as atypia and overgrowth differentiates these lesions from ade-
Fig. 12.28 Mesothelial hyperplasia within the peritoneum. Mesothelial

hyperplasia is common in the peritoneum. This image shows mesothe- Fig. 12.31 Polypoid endometriosis involving the fallopian tube. A
lial proliferation in the center, which may occasionally simulate glands. polypoid lesion measuring approximately 5 mm is present in the tubal
No endometrioid stroma is seen serosa. Many endometrial glands with cystic dilations are noted. The
stroma may be fibrotic in areas. These lesions may mimic malignancy
(courtesy of Dr. Li Dong)
nosarcoma. Other entities that may be considered in this set-

ting include fibroepithelial polyp, polypoid adenomyoma,
and Mullerian papilloma.
Prognosis: Polypoid endometriosis behaves in a similar
manner to otherwise typical endometriosis. Gene expression
analyses showing that vaginal polypoid endometriotic
lesions exhibit highly similar profiles with those of perito-
neal endometriosis [110] provide additional support to their
endometriotic nature.
12.4.4.2 Stromal Endometriosis

Stromal endometriosis is another rare type of endometrio-
Fig. 12.29 Ectopic decidua. Ectopic decidual cells may simulate sis, aptly named for the predominance of stroma and rela-
endometrial stromal cells; however, they contain large amounts of tive lack of endometrial type glands. Histologically, the
eosinophilic cytoplasm and lack associated epithelium. These lesions lesions present as small microscopic nodules or plaques of
are common in pregnant patients
endometrioid-type stroma superficially located just beneath
the mesothelial surface, suggesting their potential origin
from mesothelial or submesothelial cells via a metaplastic
process [111]. Associated histological features include
mesothelial proliferation, inflammation, and giant cell or
granuloma formation. It can be mistaken for both malig-
nant and benign neoplasms. Stromal endometriosis is typi-
cally seen in association with classic endometriosis and the
clinical and pathological features of these lesions are
similar.
12.5 O
ther Histological Features
of Endometriosis
The histologic analyses of endometriotic lesions may be

confounded by alterations in the appearance of both the glan-
Fig. 12.30 Rete ovarii. Rete ovarii are typically present within the ovarian dular and stromal components in biopsies. Hormonal
hilar region. They are composed of many irregular or slit-like spaces without (Fig. 12.32) and/or metaplastic changes (Fig. 12.33) may
endometrioid stroma and are commonly surrounded by smooth muscle
Fig. 12.32 Endometriotic cyst found in a term pregnancy. High levels alization (left), and the epithelial lining is not obvious until stained for
of progesterone during pregnancy commonly cause decidual changes in cytokeratin 7 (CK7) (right)
endometriosis. The ovarian cyst shown here displays extensive decidu-
Fig. 12.33 Endometriosis with metaplasia. Metaplasia including Fig. 12.34 Endometriosis with reactive epithelial changes. Nuclear
squamous, mucinous, eosinophilic, and ciliated metaplasia may occur atypia is apparent in this focus of endometriosis; however, epithelial
in endometriosis. Mucinous metaplasia can be seen in this image proliferation and mitotic areas are not visible. The atypical nuclei rep-
resent reactive and/or degenerative changes secondary to the hostile
environment created within endometriosis
alter the presence and/or appearance of endometriotic glands.
Endometriosis, particularly cystic lesions with absent or The stromal component of lesions may also be obscured
scant glands, may be a result of the hostile surrounding envi- or effaced by conditions such as fibrosis, smooth muscle
ronment. Those lesions with glands displaying hyperplasia metaplasia, and presence of infiltrates of foamy and pig-
or atypical hyperplasia are collectively referred to as atypical mented histiocytes [112]. The inflammatory status affects
endometriosis (see below). the histologic diagnosis of endometriosis since these
Reactive “nuclear atypia” in endometriotic glands pres- changes can cause associated morbidities such as infec-
ents as enlargement of the nucleus, hyperchromasia, and tion within endometriotic cysts, florid mesothelial hyper-
multiple, tiny nucleoli, with variable degrees of nucleocyto- plasia, peritoneal inclusion cysts, and pseudoxanthomatous
megaly (Figs. 12.34 and 12.35). These atypical nuclei are not salpingitis [112]. Complication of the diagnosis also
uncommon and represent degenerative changes in the toxic arises when other conditions, such as peritoneal leiomyo-
environment. They could be confused with the hyperplastic matosis or gliomatosis, are admixed with the endometri-
process seen in true atypical endometriosis. otic foci.
features, ovarian cancers are categorized into five subtypes,

namely high-grade serous, endometrioid, clear cell, muci-
nous, and low-grade serous. High-grade serous carcinoma
comprises the majority of ovarian cancers (70%), followed
by endometrioid (10%) and clear cell (10%) cancer subtypes.
The 5-year survival for high-grade serous carcinoma (62%)
is lower than that for endometrioid (100%), clear cell (75%),
and mucinous (80%) carcinomas [117].
Ovarian clear cell carcinoma (OCCC) is highly associated
with endometriosis, followed by endometrioid ovarian carci-
noma (EOC), serous carcinoma, and mucinous carcinoma
[118]. Patients with OCCC and endometriosis have been
found to be significantly younger, to be more likely
nulliparous, and to have poorer overall survival than those
with OCCC alone [119]. Ovarian endometriosis may consti-
Fig. 12.35 Endometriosis with reactive epithelial changes. Similar tute an independent prognostic factor in OCCC since patients
scenario as illustrated in Fig. 12.34 with OCCC and endometriosis also displayed a higher inci-
dence of early-stage disease compared to those with non-
endometriosis-associated OCCC [120]. The pathogenesis of
12.6 Endometriosis-Associated Tumors OCCC arising from endometriosis remains unclear.
and Its Malignant Transformation Endometriosis-associated OCCC and non-endometriosis-
associated OCCC exhibited similar alterations in gene sets
12.6.1 Endometriosis and Ovarian Carcinoma related to the PI3K/Akt, p53, and ERBB2 pathways, with no
differences in frequency [121].
Endometriosis is considered to be a benign disease with
pathological features resembling cancer [113]. In particular,
endometriotic lesions have the ability to invade surrounding 12.6.2 Malignant Transformation
tissues, metastasize to extra-pelvic locations, evade apopto- of Endometriosis
sis, and manifest enhanced angiogenesis. In a study of deep-
infiltrating endometriotic lesions with no associated tumors, Figure 12.36 summarizes the postulated multistep progres-
a significant fraction (10 of 39 cases; 26%) displayed muta- sion of benign endometriotic lesions to ovarian tumors.
tions in genes (ARID1A, PIK3CA, KRAS, PPP2R1A) known Atypical endometriosis is considered to represent an early
to drive cancer development [75]. Such findings provide intermediate step in the neoplastic progression. First
strong support to the cancer-like features of endometriosis. described by Czernobilsky and Morris [122], atypical endo-
The malignant transformation of endometriosis is rare, metriotic lesions are characterized by the presence of epithe-
only reported in about 1% of all documented cases of endo- lial cells with eosinophilic cytoplasm, large pleomorphic
metriosis [114]. The premise that endometrioid ovarian can- hyperchromatic or pale nuclei, increased nuclear-to- cyto-
cer may originate from endometriosis was first described by plasmic ratios, cellular crowding, tufting, and stratification
Sampson in 1925 [113]. The three original criteria for estab- (Fig. 12.37). Atypical endometriosis is found in 8% of cases
lishing the association remain in use to date: (1) evidence of of typical endometriosis and is commonly associated with
coexistence of endometriosis and tumor in the ovary; (2) OCCC and EOC. In an earlier report of OCCC (50 total) and
exclusion of metastasis originating from other sources; and EOC (31 total) cases, 27 and 13, respectively, were associ-
(3) presence of endometrial stroma and epithelial glands in ated with endometriosis and of these 18 of 27 and 7 of 13
tumors. Inclusion of histological proof demonstrating the exhibited atypical endometriosis [123]. In another study
transition of benign endometriotic lesions to neoplastic involving 15 EOC cases, 6 tumors were determined to have
lesions was later incorporated as a fourth criterion [115]. endometriosis, all of which were characterized as atypical
The ovary is the most common site for the development of [124]. Atypical endometriosis in these cases was found to be
malignancy from endometriosis, accounting for ~80% of mixed with, or contiguous to, the tumors [123, 124]. The
endometriosis-associated tumors. The rest of the chronological association between atypical ovarian endome-
endometriosis- associated malignancies are attributed to triosis and OCCC has been previously reported, with a 3-year
malignant transformation of extra-ovarian endometriosis time lapse [125]. In a case report, a 33-year-old woman who
such as the intestines, bladder, abdominal wall, thorax, and had previously undergone three laparoscopic surgeries over a
cervix [116]. Based on the histopathology and molecular period of 10 years for treatment of endometriosis was
Menstrual Fragments
(1)
OVARY
Inflammation
(2)
Estrogen Signaling
Progesterone Signaling
5
ENDOMETRIOMA
Genetic Mutations
Early menarche (3) (ARID1A, PIK3CA)
Late menopause
Infertility
ATYPICAL ENDOMETRIOSIS
Genetic Mutations
(4)
(ARID1A, PIK3CA, PTEN, b-catenin)
5 Others???
OVARIAN CARCINOMA
(OCC, EOC, LGSC) Proliferation
Anchorage-Independence
Invasiveness
Fig. 12.36 Model for multistep progression of benign endometriotic blown carcinoma (4). Not currently known is whether and how additional
lesions to ovarian tumors. Menstrual fragments (from retrograde men- genetic dysregulations result in specific ovarian cancer types (OCC,
struation) attach to the ovary (1), a process promoted by pro-inflammatory, EOC, LGSC). Early menarche, late menopause, and infertility are con-
pro-estrogenic, and anti-progestogenic events (2). Mutations in key genes sidered risk factors for the development of endometrioma to ovarian can-
(e.g., ARID1A, PIK3CA) are considered to promote the progression of an cers (5). OCC, ovarian clear cell carcinoma; EOC, endometrioid ovarian
endometrioma to atypical endometriosis (3) and subsequently to full- carcinoma; LGSC, low-grade serous carcinoma
atypical endometriosis should be followed closely for

extended periods to eliminate the possibility of developing
ovarian cancer.
An important question remains—how may ovarian carci-
noma develop from endometriotic lesions? Huntsman and
his group [127] initially identified tumor suppressor ARID1A
as a mutated gene in OCCC by comprehensive whole-
genome sequencing of 18 samples; 6 of these samples dis-
played somatic ARID1A mutations. Further analyses of
distinct ovarian cancer subtypes demonstrated that ARID1A
mutations were highly associated with OCCC relative to
EOC (55 of 119 OCCC; 10 of 33 EOC) but were not associ-
ated with high-grade serous carcinomas (0 of 76) [127]. Loss
of ARID1A expression was subsequently shown in benign
endometriosis, atypical endometriosis, and endometriosis-
associated OCCC [128, 129]. In these samples, ARID1A loss
Fig. 12.37 Atypical endometriosis. In contrast to Figs. 12.34 and frequently (but not exclusively) coexisted with PIK3CA
12.35, this lesion shows glandular proliferation in addition to nuclear
atypia, which are characteristic of atypical endometriosis mutations. The coincident mutations of ARID1A and PIK3CA
in endometriotic lesions and primary OCCC have been con-
firmed in other studies [43]. Moreover, knockdown of
d iagnosed with grade 1 EOC after her third surgery. A histo- ARID1A in an immortalized endometriosis cell line caused
logical review of her lesions after the second surgery con- phenotypic changes (e.g., anchorage-independent growth,
firmed the diagnosis of atypical endometriosis [126] . These, increased invasive ability) characteristic of neoplastic trans-
and other related findings, suggest that atypical endometrio- formation [130]. The loss of ARID1A coincident with
sis is likely to be a precancerous lesion and patients with increased levels of phosphorylated gamma histone H2AX
(γH2AX), and enhanced activation of the apoptotic pathway, low-grade serous carcinomas and exhibits higher potential
was also demonstrated in EOC and contiguous endometrio- for malignancy and recurrence [138]. By contrast, the non-
sis at greater frequencies than in benign endometriotic serous subtype presents mostly at FIGO stage 1 and has
lesions [131]. Thus, benign endometriotic lesions carrying higher overall survival. One study reported that 30% of bor-
cancer-associated mutations in ARID1A and PIK3CA likely derline serous tumors exhibit endometriosis [139]. In a large
serve as precursors for ovarian malignancies. cohort of women with subfertility [140], an increased risk for
In a review of databases pathologically screened for sus- borderline tumors was associated with both ovarian and
pected cases of atypical endometriosis, Stamp et al. [132] extra-ovarian endometriosis. However, in studies conducted
reported that loss of ARID1A in atypical endometriosis was as part of the Ovarian Cancer Association Consortium, an
consistently associated with the development of ARID1A- association between borderline tumors and self-reported
negative endometriosis-associated ovarian cancer. In another endometriosis was not observed [141]. Further studies are
comparison of atypical endometriosis and neoplastic lesions needed to clarify these associations.
by targeted next-generation sequencing, ARID1A and Numerous analyses have shown that extra-pelvic endome-
PIK3CA genes were confirmed as frequently mutated; muta- triosis can also develop into malignant tumors. Abdominal
tions in genes associated with Notch and Wnt/β-catenin endometriosis-associated clear cell carcinoma [142, 143] has
signaling pathways [131] were also noted. Nevertheless, it been reported and additionally metastasis in the bladder and
remains unclear if endometriosis-associated EOC and OCCC the lymph nodes was also detected [140]. Malignant transfor-
evolve similarly, since the expression of other genes such as mation of deep-infiltrating endometriosis has also been
hepatocyte nuclear factor 1β, hypoxia-inducible factor 1α, reported in the pancreas [144] as well as in the appendix lead-
and NFκ-B p65 was not identical between EOC and OCCC ing to intestinal neoplasia [145]; colon/rectum leading to
and their respective coexisting endometriotic lesions [133]. endometrial stromal sarcoma [146]; vagina [147]; small intes-
Related to the latter, it was recently proposed that OCCC and tine [114]; cervix [148]; and bladder [149]. Because these con-
EOC may originate from distinct cells within endometriotic ditions are relatively rare, the mechanisms underlying their
tissue [134] . progression to neoplasia have yet to be extensively assessed.
Another potential contributory mechanism to ovarian
tumorigenesis implicates the stromal compartment [135].
When compared with more distant ovarian stroma, 12.7 Conclusions
endometriosis-associated ovarian tumors display increased
expression of steroidogenic genes and enzymes involved in The possibility that endometriosis can progress from a
steroid hormone synthesis. Early changes in endometriotic benign to a neoplastic condition, in addition to its comorbidi-
stroma involving the activation of steroid hormone produc- ties, provides a strong impetus for the early detection and
tion may thus lead to abnormal proliferation of adjacent effective management of the disease. To address this chal-
ovarian epithelia to promote neoplastic growth. lenge, it is imperative in the long term to focus resources on
(1) the identification of new targets to monitor early disease
onset, eliminate disease recurrence, and allow targeted ther-
12.6.3 Seromucinous Carcinoma and Other apy; (2) the development of new hormonal treatments with
Endometriosis-Associated Tumors minimal side effects and contraindications while preserving
fertility and ovarian function; and (3) the fine-tuning of cur-
Seromucinous tumors and borderline tumors are less com- rent technologies and development of new procedures to
mon neoplasms of the ovary. Seromucinous tumors typically improve accuracy of lesion diagnosis. In the short term, con-
display papillary architecture, an admixture of cell types, tinuous vigilance to reduce recurrence should be part of the
including endocervical-like mucinous, eosinophilic, squa- standard of care for diagnosed patients.
mous, clear, and signet-ring cells, and morphological overlap
with low-grade serous, mucinous, and endometrioid carcino-
mas [136] . These tumors are associated with endometriosis
at a relatively high frequency (23 of 92 cases) [117]. Similar
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Complications of Early Pregnancy
and Gestational Trophoblastic Diseases 13
Philip P. C. Ip, Yan Wang, and Annie N. Y. Cheung
Abstract 13.1 Early Placental Development

Placenta plays a crucial role in the development of the
fetus. By connecting the fetus to the maternal circulation, 13.1.1 Placenta Implantation
it allows provision of oxygen and nutrients to the fetus
while removing carbon dioxide and metabolic wastes. After fertilization of the ovum at the fallopian tube, morula
The placenta also provides essential hormones for the and blastocyst are formed through cell division (Fig. 13.1).
pregnancy and enables immunological protection for the One week after fertilization, the blastocyst reaches the
fetus against infection and rejection by the maternal uterus. The proliferating and developing trophoblast cells
immune system. In this chapter, pathology of abortions as then begin to adhere to a particular point and infiltrate
well as gestational trophoblastic diseases is discussed. through the endometrium (Fig. 13.2). The entire blastocyst is
Gestational trophoblastic diseases encompass a family of eventually embedded entirely in the endometrial stroma, i.e.,
aggressive neoplasms, nonneoplastic lesions, and lesions implantation, 2 weeks after fertilization. The inner cell mass
with malignant potential that arise from various types of of the blastocyst will develop into embryo, yolk sac, amnion,
placental trophoblasts and may pose challenging prob- and umbilical cord, while the outer trophectoderm will form
lems in differential diagnoses in daily pathology placenta and chorionic membranes [1].
practice. During implantation, the trophectoderm differentiates
into an outer layer of mitotically inactive syncytiotropho-
Keywords blasts and an inner stratum of mitotically active cytotropho-
Pregnancy · ectopic pregnancy · hydatidiform mole · blasts. The fingerlike trophoblast processes permeate through
placental site nodule/plaque · exaggerated placental site · the endometrium with formation of lacunae spaces within
gestational trophoblastic neoplasia · choriocarcinoma · syncytiotrophoblast aggregates. The lacunae are then filled
placental site trophoblastic tumor · epithelioid tropho- with maternal blood from uterine blood vessels eroded by
blastic tumor the trophoblasts, forming the primitive uteroplacental circu-
lation. At the same time, decidualization of the endometrium
develops and provides immunological protection to the
conceptus.
The primary chorionic villi develop by the end of second
week from extensions of the proliferative cytotrophoblasts
into the covering syncytiotrophoblast. This is followed by
P. P. C. Ip
Department of Pathology, The University of Hong Kong, Queen mesenchymal growth into such primary villi which are trans-
Mary Hospital, Hong Kong, SAR, China formed to secondary chorionic villi that completely cover the
Y. Wang surface of the chorionic sac. The tertiary villi then develop
Department of Pathology, HKU-Shenzhen Hospital, when the capillaries and blood cells grow from the villous
Shenzhen, China mesenchyme. There is then establishment of blood flow
A. N. Y.Cheung (*) between the embryonic heart and the villous capillaries by
Department of Pathology, The University of Hong Kong, Queen the end of the third week. Such connection enables exchange
Mary Hospital, Hong Kong, SAR, China
of oxygen, carbon dioxide, nutrients, and waste products
Department of Pathology, HKU-Shenzhen Hospital, between the maternal blood in the intervillous space and
Shenzhen, China
embryonic circulation in the villous capillaries. At the same
428 P. P. C. Ip et al.
Fig. 13.1 Human embryonic

development from 8-cell stage 8-cells stage Morula
to blastocyst [contributed by
Dr. Niu Ziru, Dr. Ye TM, and
Dr. Philip Chiu, Department
of Obstetrics and
Gynaecology, the University
of Hong Kong]
Hatching blastocyst Blastocyst

Zona pellucida
Trophoectoderm
Inner cell mass
lous space, allowing more efficient exchange between

embryonic and maternal circulations.
13.1.2 Classification of Trophoblasts
Human trophoblasts can be categorized into cytotrophoblast,

syncytiotrophoblast, and intermediate trophoblast according
to the morphology and location of the cells [2–5] (Figs. 13.3,
13.4, and 13.5) (Table 13.1). Cytotrophoblasts are consid-
ered as precursors of intermediate trophoblasts and syncytio-
trophoblasts. These cells are small and polygonal and with
clear cytoplasm, distinct cell boundary, and a single, cen-
trally located vesicular nucleus. Syncytiotrophoblasts are
terminally differentiated mitotically inactive cells. They have
Fig. 13.2 Attachment of blastocyst onto endometrium in mouse. LE amphophilic or eosinophilic cytoplasm and multiple small
Luminal epithelium, GE Glandular epithelium, SC Stromal cells, BL nuclei. Syncytiotrophoblasts are responsible for the produc-
Blastocyst, ICM Inner cell mass [contributed by Dr. Niu Ziru, Dr. Ye tion and secretion of human chorionic gonadotropin (hCG)
TM, and Dr. Philip Chiu, Department of Obstetrics and Gynaecology, and human placental lactogen (hPL). The histological fea-
the University of Hong Kong]
tures of intermediate trophoblasts are transitional between
cytotrophoblasts and syncytiotrophoblasts. According to
time, cytotrophoblastic shell is formed by the proliferative their locations, intermediate trophoblast is further subcate-
cytotrophoblasts that outspread the syncytiotrophoblast. gorized into the villous intermediate trophoblast at the core
Anchoring or stem villi are then formed with attachment to of the villous trophoblast columns; extravillous implantation
the endometrium through such cytotrophoblastic shells. site intermediate trophoblasts around the implantation site at
From the stem villi, the branching terminal villi further endometrium; and extravillous chorionic intermediate tro-
develop to be surrounded by maternal blood in the intervil- phoblasts at the chorion of placenta.
13 Complications of Early Pregnancy and Gestational Trophoblastic Diseases 429
Fig. 13.3 Photomicrographs showing cytotrophoblasts (CT), syncy-

tiotrophoblasts (ST), and villous intermediate trophoblasts (VIT) in the
chorionic villi Fig. 13.5 Photomicrographs showing extravillous chorionic interme-
diate (arrow) at the chorion of placenta
In surgical specimens, particularly uterine curettings, it is

important to demonstrate the existence of pregnancy products
as evidence of intrauterine pregnancy and to exclude signifi-
cantly the possibility of ectopic pregnancy. The application of
cytokeratin immunohistochemistry, particularly cytokeratin
7, as well as sensitive and specific trophoblast markers is
helpful in specimens where distinct chorionic villi or tropho-
blast cells cannot be found. Such trophoblast biomarkers are
also useful in the differential diagnoses of trophoblastic
lesions and non-trophoblastic pathology in the female genital
tract; the latter includes various epithelial and smooth muscle
tumors. This application will be further illustrated in subse-
quent sections on gestational trophoblastic diseases.
Fig. 13.4 Photomicrographs showing extravillous placental site inter-

mediate trophoblasts (arrow) infiltrating the decidua physiologically 13.2 Challenges for Pathologists
Diagnosis and management of diseases related to early

13.1.3 Biomarkers for Trophoblasts pregnancy need the close communication between patholo-
gists and gynecologists. Differential diagnoses of the fol-
Biomarkers for trophoblasts are useful both for clinical diag- lowing issues are particularly important. (1) Spontaneous
nostic purpose in routine pathology and in embryological abortion: Pathologic examination is crucial in the confirma-
research. The former supports existence of pregnancy at spe- tion of intrauterine pregnancy or indicating the possibility
cific location while the latter helps to delineate cells of tro- of ectopic pregnancy. The exact causes of abortion can be
phoblast lineage [6, 7] (Table 13.1). identified by histopathology in only a small proportion of
In addition to traditional pregnancy-related hormone cases, e.g., detection of cytomegalovirus infection
markers, such as hCG and hPL, more trophoblast biomark- (Fig. 13.6). (2) Ectopic pregnancy: The possibility of ecto-
ers have been described recently, including inhibin-alpha, pic pregnancy should always be considered when samples
melanoma cell adhesion molecule (Mel-CAM or MUC18), from women of reproductive age group are examined.
histocompatibility leukocyte antigen G (HLA-G), Timely diagnosis and management of ectopic pregnancy
HSD3B1, c-mos, and p63 genes [4, 5, 8–13]. Differential need the alertness and close collaboration of gynecologists
expression of individual marker in subpopulation of tro- and pathologists. (3) Hydatidiform mole or other tropho-
phoblast exists. blastic tumors:
Table 13.1 Phenotypes of different types of trophoblasts [10]

CT ST IT
Villous Implantation site Chorionic type
Villous Extravillous
Morphology
Shape Round, uniform, Large Polyhedral Polymorphic and large Round and polyhedral
small syncytial
Nucleus Mononuclear Multinuclear Mononuclear Mononuclear, occasionally multinuclear, Mononuclear,
nuclear membrane irregular occasionally multinuclear
Markers
hCG − ++++ − −/+ −
hPL − +++ −/+ ++++ −/+
Inhibin-α − +++ − −/+ ++
p63 +++ − + − +++
Mel-CAM − − −/++++ ++++ −/+
PLAP − −/+ − −/+ +++
c-mos − +++ ++ − −
HLA-G − − +++ +++ +++
HSD3B1 − +++ +/− ++ ++
LESION
Potentially Hydatidiform moles
malignant
Malignant Choriocarcinoma Placental site trophoblastic tumor Epithelioid trophoblastic
tumor
Nonneoplastic Exaggerated placental site Placental site nodules and
plaques
Fig. 13.6 Photomicrographs showing CMV inclusions (arrows) found Fig. 13.7 Photomicrograph of a second-trimester placenta of a fetus
at the chorionic villi of a case of intrauterine death. Immunohistochemistry diagnosed to have trisomy 21 during prenatal screening
confirms CMV antigens (inset)
Recurrent abortion can be defined as the loss of three or more

13.3 Early Pregnancy Complications consecutive pregnancies (reviewed in [15]).
Karyotype abnormalities are the main causes of miscar-
13.3.1 Spontaneous Abortion riage in early pregnancy. The most common karyotype
anomalies include trisomy (Fig. 13.7), X monosomy, and
13.3.1.1 Clinical Features and Risk Factors triploidy. Such abnormalities usually do not recur in future
Spontaneous abortion refers to loss of pregnancy before the pregnancies.
viability of the fetus is reached, usually by 24 weeks of ges- Epidemiologically, maternal age and number of previous
tation [14]. Most of the spontaneous abortions are sporadic. miscarriages are two major risk factors for predicting further
abortion. Environmental risk factors, such as smoking, alco-

hol, and obesity, have also been reported to increase the risk
of recurrent abortions, although clear dosage-dependent evi-
dence is conflicting. Maternal factors comprise conditions
such as cervical incompetence and uterine abnormalities.
The most treatable cause of recurrent abortion is probably
the presence of antiphospholipid antibodies, including lupus
anticoagulant leading to thrombotic diseases.
Genetic factors include chromosomal abnormalities of the
embryo and the parents. It is estimated that chromosomal
abnormalities of the embryo account for half of recurrent
miscarriage. On the other hand, among 2–5% of couples with
recurrent miscarriage, one of the partners may be a carrier of
a balanced structural chromosomal abnormality, usually a
balanced reciprocal or Robertsonian translocation [15].
In recent years, NLRP7 (NOD-like receptor, pyrin domain Fig. 13.8 Photomicrograph of a first-trimester spontaneous abortion
containing 7) gene of autosomal recessive heritage is found with myxoid and fibrotic degeneration of chorionic villi
to be associated with recurrent hydatidiform moles or spon-
taneous abortions [16–18]. Placental abnormalities may be
found in live or aborted fetuses associated with NLRP7
mutations [16]. cular chorionic villi occur after death of the embryo
Investigation on cytogenetic, anatomical, hormonal, (Fig. 13.8). If the villous edema is obvious (hydropic abor-
immunological, and other abnormalities is usually not neces- tion), it is important to differentiate from hydatidiform mole
sary for most cases of spontaneous abortions. On the other and all the villi need to be sent for histological examination.
hand, women with a history of recurrent abortions should be In contrast to hydatidiform mole, the villi from spontane-
managed in special clinics for professional management, ous abortion are usually regular in shape. Large villi or cen-
including provision of the above tests, to provide guidance tral cistern are rare. The villi may show hypovascularity or
for management of subsequent pregnancies. collapsed blood vessels. Fetal red blood cells may be identi-
fiable. The trophoblast population is reduced. However, focal
13.3.1.2 Macroscopic Examination of Abortion polar proliferation of cytotrophoblasts or villous intermedi-
Specimens ate trophoblasts may still be observed in some villi forming
Abortion placental tissue may be pale pink or greyish color trophoblast columns.
with spongy or velvety appearance. If placenta or fetal parts In some cases, the causes of abortion may be identified
can be identified macroscopically, sampling of placental tis- through microscopic examination of the chorionic villi. For
sue and decidua for histological examination is usually ade- instance, morphological manifestations of viral infections
quate. Otherwise, the entire sample should be embedded for (such as cytomegalovirus (Fig. 13.6) or parvovirus) may be
histological examination. In particular, pathologists need to detected. Occasionally, abortion caused by infection, such
carefully check blood clot present for sac-like or transparent as group B streptococcus or Listeria, may exhibit severe
tissue within. acute inflammation of decidua as well as acute villitis. On
If vesicles are found during macroscopic examination or the other hand, endometrial inflammation and necrosis is a
if clinical or ultrasound features are suspicious of hydatidi- common secondary change in spontaneous abortion and
form mole, samples may be taken for flow cytometry or cyto- should not be regarded as evidence of infection-complicated
genetic analysis in the fresh state. Prior discussion among pregnancy.
gynecologists, pathologists, and experts specialized should Fetal chromosome abnormalities such as trisomy may
be established for such practice. On the other hand, diagnosis be associated with mild villous abnormalities and tropho-
and classification of hydatidiform mole can usually be blastic hyperplasia, but genetic analysis is necessary for
achieved by morphological and immunohistochemical eval- diagnosis. Most abortion evacuation specimens contain
uation together with molecular pathology tests on formalin- placental implantation sites (Fig. 13.4). Sometimes, vigor-
fixed paraffin-embedded placental tissues nowadays. ous proliferation of trophoblast-infiltrating decidua and
myometrium is present and may even display atypia.
13.3.1.3 Microscopic Findings Pathologists must be aware that these are nonneoplastic
Pathological features: Edema and myxoid degeneration as physiological processes and misdiagnosis of trophoblastic
well as villous fibrosis and sclerosis of the eventually avas- tumor must be avoided.
13.3.2 Ectopic Pregnancy that in cases when continued growth of residual incompletely
removed trophoblasts infiltrated deeply in the muscle wall of
13.3.2.1 R isk Factors and Clinical the fallopian tube or other sites persistent pain and irregular
Manifestations vaginal bleeding with persistently raised hCG in blood and
Ectopic pregnancy refers to the implantation of conceptus urine may result. This may be described as persistent ectopic
outside uterus or at unusual sites within the uterus. It occurs pregnancy [21]. Ectopic pregnancy may occur, mainly in
most commonly at the fallopian tube, followed by the ova- cases treated by non-radical surgery.
ries, uterine cornu, cervix, vagina, and other organs. Tubal
pregnancy occurs mainly at the ampulla, followed by isth- 13.3.2.3 P
athological Examination of Excised
mus and fimbria [14]. Fallopian Tube
In recent decades, the incidence of ectopic pregnancy has
increased significantly, from 0.4% to 1.6% according to some Macroscopic Examination
studies [19]. The risk factors include history of tubal surgery, Fallopian tube excised for ectopic pregnancy should be
sexually transmitted diseases, spontaneous or therapeutic examined for presence or absence of rupture and embryos.
abortion, pregnancy at advanced maternal age, use of intra- The fallopian tube may display variable degree of local or
uterine contraceptive device, as well as smoking. In addition, diffuse dilatation and serosal congestion. Blood clot and pla-
structural abnormalities of the fallopian tube including con- cental tissue may protrude from rupture. Pathologist should
genital defects, chronic salpingitis, recanalization after tubal check carefully whether there is amniotic sac or fetal tissue
ligation, as well as cilia dysfunction also increase the risk. in the blood clot. If embryo or placental tissue cannot be
Chronic salpingitis includes non- granulomatous (e.g., identified at the ruptured site, the entire fallopian tube should
Chlamydia trachomatis and mycoplasma) and granulomatous be cut open for examination. Adequate number of blocks
(e.g., Mycobacterium tuberculosis) salpingitis. should be taken.
It is estimated that 2–10% of pregnancies following
assisted reproduction implant at the fallopian tube although Microscopic Examination
the reason is unclear. It may be due to exogenous Microscopic examination is important to identify chorionic
gonadotropin-induced secondary changes in hormone levels, villi at possible ectopic sites. If villi are absent, the presence
or due to diseases underlying infertility [20]. The increased of extravillous implantation-site intermediate trophoblasts
application of assisted reproduction may thus increase the can still confirm the diagnosis of ectopic pregnancy. The
incidence of ectopic pregnancy. Tubal inflammation with implantation-site intermediate trophoblast is often found at
scarring and incomplete obstruction of the tube may also the smooth muscle bundles of the fallopian tube infiltrating
explain the increased incidence. Moreover, the increased to the serosa or replacing the blood vessel wall.
sensitivity of imaging and laboratory technologies may have The villous morphology may be normal in tubal pregnan-
diagnosed early ectopic pregnancy that cannot be diagnosed cies. In some cases, villous morphological changes may
in previous era. occur, such as villous fibrosis, edema, and hydropic degener-
Common symptoms of tubal pregnancy include abdomi- ation (Fig. 13.9). While one should bear in mind the rare pos-
nal pain and irregular vaginal bleeding, accompanied by his- sibility of ectopic hydatidiform mole and choriocarcinoma,
tory of amenorrhea. Some patients may develop shock due to avoiding overdiagnosis is equally important [22, 23]. Florid
intra-abdominal hemorrhage. However, one must bear in polar trophoblastic proliferation in association with hydropic
mind that atypical medical history and negative signs cannot villi as well as extensive aggregates of extravillous tropho-
completely rule out ectopic pregnancy. In particular, unrup- blast may be found in tubal ectopic gestation. On the other
tured ectopic pregnancy may be painless with even absence hand, the absence of circumferential trophoblastic prolifera-
of adnexal tenderness during examination. Positive preg- tion and conspicuous stromal karyorrhexis should shed doubt
nancy test supports diagnosis of pregnancy but cannot distin- on the diagnosis of ectopic hydatidiform mole. Examination
guish between abnormal intrauterine pregnancy and ectopic of all sampled tissue as well as adjunct immunohistochemical
pregnancy. and molecular tests can usually allow proper diagnosis.
13.3.2.2 Principles of Diagnosis

Ultrasound examination is helpful in the diagnosis of ectopic
pregnancy and confirms intrauterine pregnancy. The diagno- 13.4 Gestational Trophoblastic Disease
sis of intrauterine pregnancy can exclude ectopic pregnancy
since coexisting intrauterine and ectopic pregnancies are Gestational trophoblastic diseases (GTD) include a spectrum
extremely rare. Various options of management exist, includ- of trophoblastic disorders with distinct morphology and clin-
ing methotrexate and/or surgical treatment that comprise ical behaviors as well as origins from various trophoblast
incision or excision of the fallopian tube. It has been reported population (Table 13.1). They can be developed from tropho-
13.4.1 Classification of Gestational

Trophoblastic Diseases
GTD with major pathology at chorionic villi include com-

plete hydatidiform mole, partial hydatidiform mole, and inva-
sive hydatidiform mole. Recently, the term abnormal villous
morphology (lesion) has been introduced to describe non-
molar lesions with villous abnormalities simulating a partial
hydatidiform mole [24]. Table 13.3 compares the clinical,
pathological, and genetic features of these lesions [4, 5, 24].
In gestational trophoblastic neoplasms, chorionic villi are
absent and these include choriocarcinoma, placental site tro-
phoblastic tumor, and epithelioid trophoblastic tumor [24].
In exaggerated placental site and placental site nodules and
plaques, nonneoplastic proliferation of extravillous tropho-
blasts occurs [24].
Fig. 13.9 Hydropic chorionic villi (V) in fallopian tube with tropho-
blasts impinging at the smooth muscle wall (M)
13.4.2 Epidemiology
Table 13.2 WHO classification of gestational trophoblastic disease
Molar pregnancies Gestational trophoblastic disease has the highest incidence
Complete hydatidiform mole in African, Asian, and Latin American countries than in
Partial hydatidiform mole
Caucasian societies. It is estimated that gestational tropho-
Invasive hydatidiform mole
blastic disease occurs in 2–13/1000 pregnancies in Asia
Abnormal (non-molar) villous
lesions while the incidence in the United States and Europe is 0.5–
Nonneoplastic lesions 1.84/1000 pregnancies [26–36]. It is noteworthy that there
Exaggerated placental site may be variations in the diagnostic definitions of hydatidi-
Placental site nodule and form moles and persistent trophoblastic disease. Moreover,
plaque some uterine curettings or tissue passed per vagina related to
Neoplasms clinical diagnosis of missed abortion has not been sent for
Choriocarcinoma
histopathological examination leading to underdiagnosis of
Placental site trophoblastic
tumor hydatidiform mole. The incidence of choriocarcinoma is
Epithelioid trophoblastic often difficult to appraise due to lack of diagnostic tissue
tumor biopsy to differentiate postmolar choriocarcinoma from
invasive mole. It is reported to occur in around 1–9 in 40,000
pregnancies [37]. The incidences of PSTT and ETT are
blasts of the chorionic villi, implantation site, or chorion [13, lower than choriocarcinoma.
24], with close association with underlying chromosomal The main factors associated with increased risk of gesta-
composition [4, 5, 24, 25]. They may be considered as trans- tional trophoblastic disease include maternal age of <15 or
plants with pure or dominant paternal origin that invades the >40 years and a prior hydatidiform mole, although dietary and
maternal body, sometimes in uncontrolled manner. socioeconomical statuses have also been implicated [28, 30,
Hydatidiform moles or molar pregnancies are the most com- 36, 38–41]. Indeed, it is observed that the incidence of hyda-
mon type of GTD) and the majority regresses after uterine tidiform moles in Asia has apparently been declining [42, 43].
evacuation. However, a small proportion of hydatidiform Reduction in birth rates as well as improvement in diet and
moles may develop persistently elevated serum human cho- economy have been proposed to be the attributing factors.
rionic gonadotropin (hCG) in association with possibility of
developing choriocarcinoma. Treatment therefore needs to
be considered. Such cases are grouped under gestational tro- 13.5 Hydatidiform Mole
phoblastic neoplasia (GTN) cases together with the frankly
malignant members of the GTD) family (Table 13.2) [26]. It 13.5.1 Complete Hydatidiform Mole
is noteworthy that gestational trophoblastic neoplasia can
occur after non-molar pregnancy, including spontaneous 13.5.1.1 Genetic Composition
abortion, ectopic pregnancy, or even term pregnancy with In complete hydatidiform mole, there is villous hydropic
live delivery. change with little or no fetal development. It is usually
Table 13.3 Similarities and differences between types of molar and non-molar diseases with hydropic chorionic villi [modified from [4, 5, 24]
Complete mole Early complete mole Partial mole Hydropic abortus
Clinical features Second-trimester vaginal First-trimester missed Late first or early Late first or early
bleeding, high hCG levels abortion second-trimester missed second-trimester missed
abortion abortion
Gross features Large amount of tissue with Usually normal Few vesicles, gestational Small amount, may have
prominent vesicles sac may present gestational sac
Fetal parts Absent Absent Present but may be Usually absent
abnormal
Villous population Wide range of large and small Mainly small hydropic Two populations of Similar size
hydropic villi villi hydropic and nonhydropic
Villous shape Round, bulbous Prominent club-shaped Irregular Round and smooth
stromal projections
Scalloped villous Rare Rare Prominent Rare
contour
Trophoblastic Common, irregular Absent Common, round Occasional, single cell
inclusions
Villous trophoblastic Marked, circumferential, marked Mild, polarized, Mild, with trophoblast Usually absent. If found,
hyperplasia cytologic atypia mild-to-moderate atypia snouts. Focal mild atypia normally polarized. No
atypia
Central cisterns Common Not prominent Not prominent if in first Absent
trimester
Stroma appearance Mucoid, bluish, no fibrosis Mucoid, bluish, cellular Nonhydropic villi are Variable
with immature stellate fibrotic, with ectatic blood
cells vessels
Stromal karyorrhexis Common Prominent Absent Absent
Nucleated red blood None None Present Present
cells
Extravillous Hyperplastic, marked cytologic Mild hyperplasia, Normal, no atypia Normal, no atypia
trophoblasts atypia, may show exaggerated mildly atypical
placental site
P57 immunostain Negative Negative Positive Positive
Ki-67 of High (>70%) High (>70%) High (>70%) Low (<25%)
cytotrophoblasts
Karyotype Diandric diploidy (46XX, 46XY) Diandric diploidy Diandric triploidy Biparental dipliody
(46XX, 46XY) (69XXY, 69XXX) (46XX, 46XY)
d iploid (46, XX or 46 XY) with a paternal only genome [24, transparent, and of various sizes (Fig. 13.11). Some may
44, 45] (Fig. 13.10). reach 1 cm or more in diameter. The vesicles are often
admixed with blood clot and decidua while normal placental
13.5.1.2 Clinical Features or fetal tissues are not found, except in cases in which there
Patients usually present with second-trimester vaginal bleed- is a concurrent twin pregnancy [52].
ing, and a large-for-dates uterus, accompanied by markedly Histologically, the chorionic villi are irregular in shape
elevated serum hCG levels [46]. There may be hyperemesis and sizes. Some may be strikingly edematous (Fig. 13.12)
gravidarum and other symptoms related to preeclampsia, while some may show club-shaped stromal projections
hyperthyroidism, and hyperreactio luteinalis [47, 48]. Rarely, (Fig. 13.13) [53, 54]. They may appear avascular, and
there is vaginal passage of molar vesicles or manifestations enlarged with cistern formation. Numerous small blood
related to metastases. In those presenting in the first trimes- vessels are usually present but they are more conspicuous
ter, there is usually an abnormal ultrasound scan with absence with CD31 immunohistochemistry [55, 56]. Karyorrhectic
of fetal heartbeat [49]. The typical “snowstorm” pattern may debris is prominent and especially in early moles
not be well developed in such early cases and the clinical (Fig. 13.14) [46, 53, 55].
diagnosis is commonly a missed abortion [50, 51]. In first-trimester complete hydatidiform moles, the cen-
tral cisterns may be small or absent. The villous stroma is
13.5.1.3 Pathological Findings pale to bluish in hematoxylin and eosin-stained sections
The classical appearance of grossly evident vesicles may not (Fig. 13.15), and fibrosis is usually not a conspicuous find-
be readily appreciable especially if presentation is in the first ing. Intravillous trophoblastic inclusions are not common but
trimester. When present, the vesicles are grapelike, semi- may be seen. There is circumferential hyperplasia of the
a Normal Fertilization b Monospermic Complete

Hydatidiform Mole
Ovum, 23X Empty Ovum

46XX 46XX
Sperm, Sperm,
23X 23X
c Dispermic Complete Hydatidiform d Partial Hydatidiform Mole

mole
Empty Ovum Ovum, 23X

69 XXX/ 69 XXX/
46XX/ 46XY 69 XYY
Both Both
Sperm, Sperm,
23X or 23X or
23Y 23Y
Fig. 13.10 Chromosome compositions in normal conceptus and hyda- chromosome and duplicates. In dispermic complete mole (c), two
tidiform moles. Normal fertilization involves fusion of one haploid sperms enter an empty ovum and unite. In contrast, two haploid sets of
chromosome from both the father and mother (a). Diploid chromosome paternal chromosomes fuse with an ovum with intact maternal haplo-
composition is also seen in most complete moles. In monospermic type to produce triploid genome in a partial mole (d) [47]
complete mole (b), one sperm enters an empty ovum with no maternal
Fig. 13.12 Photomicrograph of a complete mole with prominent cis-

tern formation and circumferential trophoblast hyperplasia
cytotrophoblasts, villous intermediate trophoblasts, and syn-

cytiotrophoblasts. Syncytiotrophoblasts may contain cyto-
Fig. 13.11 Obvious vesicles are found in a case of complete hydatidi- plasmic vacuoles and form lacelike projections from the
form mole surface. There is also marked proliferation of extravillous
Fig. 13.13 Photomicrograph of a complete mole with club-shaped

villi with florid trophoblastic proliferation
Fig. 13.16 The nuclei of the cytotrophoblasts (CT) and stromal cells
(S) of this complete mole are negative for p57 immunoreactivity while
the villous intermediate trophoblast (VIT) can be strongly positive
trophoblasts. The hyperplastic trophoblasts usually exhibit

severe nuclear atypia and hyperchromasia, which is often
apparent under low magnification. The degree of nuclear
pleomorphism may be indistinguishable from that is seen in
choriocarcinomas.
13.5.1.4 Biomarkers
The p57 immunohistochemistry is useful in confirming diag-
nosis (Fig. 13.16) [57, 58]. It has been shown to correlate
with genotyping and can serve as a reliable marker for diag-
nosis of complete hydatidiform moles, as well as identifying
mosaic conceptions [59]. The p57 is the protein product of
the cyclin-dependent kinase inhibitor 1C (CDKI1C) gene
Fig. 13.14 Photomicrograph of a complete mole with cistern forma-
(p57, Kip2) on chromosome 11p15.5, which is a paternally
tion and apoptosis of stromal cells
imprinted, maternally expressed gene. Lack of maternal
chromosomes in complete mole renders the loss of expres-
sion in the villous trophoblasts and stromal cells. P57 immu-
noreactivity is usually retained in the villous intermediate
trophoblast and implantation-site extravillous intermediate
trophoblasts among decidua and may serve as an internal
positive control. Almost all complete hydatidiform moles are
p57 negative.
It is also important to be aware of aberrant p57 expres-
sion in some special scenarios. Rare cases of complete
moles may show aberrant expression due to the retention of
maternal copy of chromosome 11 such as in trisomies. In
androgenetic/biparental mosaic/chimeric conceptuses
(which may show either typical complete mole morpholo-
gies or absence of trophoblastic hyperplasia), there is dis-
cordant p57 expression with different expression profile in
the villous cytotrophoblasts and stromal cells in same villi,
Fig. 13.15 Photomicrograph of an early complete mole with club-shaped i.e., positive immunoreactivity in cytotrophoblast but nega-
villi and myxomatous stroma. Cistern formation is inconspicuous tive in villous stromal cells, or vice versa [59, 60]. Divergent
expression may also be seen in twin gestations, in which the fertilization of an empty ovum by one (monospermic) or two
p57 is absent in the villi of the complete hydatidiform mole (dispermic) sperms (Fig. 13.10). In 80–90%, it is a result of
but retained in those from the non-molar conceptus [61]. fertilization of an empty ovum by one sperm (homozygous)
Familial biparental diploid products of gestation or com- and in 10–20% of an ovum by two sperms (heterozygous)
plete moles related to NLRP7 mutations may show variable with absence or subsequent loss of maternal chromosomes.
levels of p57 expression and evidence of fetal development Such absence of maternal alleles facilitates the diagnosis of
and mild trophoblastic proliferation resembling triploid par- complete moles using microsatellite analysis (Fig. 13.17).
tial mole. Such differential diagnosis should be kept in mind Mitochondria DNA of maternal origin, however, exists [64].
particularly in cases with a history of recurrent molar Rarely, they are tetraploid (containing four paternal haploid
pregnancies. chromosomes, with a 92 XXXX karyotype) [44, 65–67].
Stromal apoptotic index has been shown to be higher in
complete hydatidiform mole than in partial mole of normal Biparental Complete Moles
placenta [56]. Overexpression of mRNA and protein of the Rare cases of recurrent complete moles are biparental dip-
transcription factor Nanog has also been shown to increase the loidy (as opposed to androgenetic diploidy) and are thought
risk of persistent gestational trophoblastic disease [62, 63]. to be familial in origin. They have been shown to be related
to maternal mutations in NLRP7 or KHDC3L (C6orf221)
13.5.1.5 Genetic Profile genes [16, 17, 68–70]. The mutations cause multiple epigen-
Complete hydatidiform mole has a diploid androgenic only etic defects which result in the failure to establish maternal
genome (two sets of paternal chromosomes) arising from identity at imprinted loci and with abnormal expression of
Fig. 13.17 Microsatellite 120 122 124 126 128 130 132 134 136 138 140 142 144 146 148 150 152 154 156 158
polymorphisms of the decidua
(upper panel) and villi (lower 560
panel) of a case of complete
hydatidiform mole. The 490
patient is heterozygous for the
marker generating alleles of
420
136–153 bp. The
hydatidiform mole is
homozygous giving rise to 350
allele 145 bp
280
210
140
70
0
PATIENT 136 153
800
600
400
200
0
HM 145
imprinted genes. It is estimated in a recent study that reces- among patients with recessive mutations and ovum donation
sive NLRP7 and KHDC3L mutations were found in 55% and was found to be helpful [71].
5% of patients with recurrent moles, respectively [69]. Indeed, in a study on products of gestations from patients
Genotyping of available molar tissues from these patients with two defective NLRP7 alleles, all the conceptuses were
confirmed the diploid biparental contribution to all molar tis- found to be biparental diploid (Figs. 13.18 and 13.19).
sues from patients with recessive mutations in the known Variable p57 (KIP2) expression was found [70]. Positive p57
genes. Such genetic predisposition can be identified by expression was found in cases with missense NLRP7 muta-
appropriate genetic tests. Suitable genetic counselling and tions and was strongly associated with the presence of
assisted reproduction may be provided in experienced cen- embryonic tissues of inner cell mass origin and mild tropho-
ters. Live births (7–15% of pregnancies) have been reported blastic proliferation, features often considered supporting
Fig. 13.18 Multiplex short tandem repeat genotyping results for a dip- For example, at marker D16S539, the complete mole received a 278 bp
loid biparental complete hydatidiform mole from a patient with bial- allele from the father and a 286 bp allele from the mother [contributed
lelic mutations in NLRP7. Genotypes at three informative markers are by Dr. Rima Slim, McGill University Health Center Research Institute
shown and demonstrate at each of the three markers the presence of one Glen Site]
allele inherited from the mother and another inherited from the father.
both villous trophoblasts and stromal cells facilitates their

diagnoses [58].
In trisomy 11, the histologic appearance may resemble a
typical complete mole. However, the triplicated chromosome
11 (the same chromosome on which the CDKI1C gene is
located) can result in retained expression of p57 [58, 74].
Placental mesenchymal dysplasia may be confused with
hydatidiform moles since there are usually a population of
hydropic villi with central cisterns. Unlike hydatidiform
moles, the hydropic change in placental mesenchymal dys-
plasia usually involves the stem rather than terminal villi.
The villous blood vessels are also thickened with fibromus-
cular hyperplasia. The p57 immunostain shows a discordant
pattern and is expressed in the villous trophoblasts but not in
the stromal cells. The fetus may be normal or shows features
Fig. 13.19 Photomicrograph of a HM from a patient with diploid of Beckwith-Wiedemann syndrome [75, 76].
biparental biallelic NLRP7 mutations [contributed by Dr. Rima Slim,
McGill University Health Center Research Institute Glen site]
13.5.1.7 Prognosis and Outcome
Persistent gestational trophoblastic disease occurs in 15–20%
diagnosis of triploid partial moles. In contrast, cases with of patients with complete hydatidiform moles in which the
protein-truncating NLRP7 mutations were negative for p57 serum hCG failed to normalize after the initial uterine curet-
(KIP2) expression and displayed florid trophoblastic prolif- tage [26, 31, 77]. It is noteworthy that hCG assays for moni-
eration with absence of embryonic tissues and excessive tro- toring of GTN should be able to detect all forms of hCG and
phoblastic proliferation [70]. may be different from those for routine pregnancy test [26].
In fact, negative pregnancy test has occasionally been reported
13.5.1.6 Differential Diagnosis in patients with GTD [78]. Residual molar villi are usually
The differential diagnoses include early complete hydatidi- found in repeated curettages. The risk of persistent disease is
form mole, and conditions in which there is abnormal vil- higher in those with a maternal age of >40 years, previous
lous morphology but have retained maternal genetic molar pregnancy, pre-evacuation hCG levels of >100,000
component. They include hydropic abortions, partial hyda- mIU/ml, a markedly enlarged uterus, and the presence of
tidiform moles, trisomy 11, and placental mesenchymal hyperreactio luteinalis, preeclampsia, hyperthyroidism, or
dysplasia [25]. trophoblastic emboli [61]. Those having a heterozygous gen-
In early hydatidiform mole, central cisterns are not well otype may also have a higher risk [79]. Uterine curettage per-
developed. The hydropic villi usually have club-shaped formed in the first trimester does not appear to help reducing
stromal bulbous projections and the stroma is usually more the frequency of persistent disease, although metastatic dis-
hypercellular with many stellate cells, accompanied by ease and choriocarcinoma are less frequent.
striking stromal karyorrhexis [56]. There is a prominent Complete cure is usually seen either in patients who do
labyrinthine network of villous stromal canaliculi. not have metastasis, or only if the metastases are confined to
Trophoblastic hyperplasia is typically focal when com- the lungs or vagina, or when the serum hCG is <40,000 mIU/
pared with a second-trimester complete mole, and the pro- mL. Even for those who have more extensive metastases and
cess involves both villous surface and chorionic plate. hCG >40,000 mIU/mL, cure may be achieved in >80% of
Cytologic atypia is apparent even at this early stage [53]. cases. The risk of subsequent choriocarcinoma was reported
The loss of p57 immunoreactivity in the villous tropho- to be 2–3% although risk is as high as 13% in Asian popula-
blasts and stromal cells confirms the diagnosis of a com- tions (see under subsequent section on choriocarcinoma)
plete hydatidiform mole. [31, 80]. Rarely, minimally invasive and quiescent GTD has
Hydropic abortus and partial hydatidiform moles may been described (defined as patients with elevated hCG who
have hydropic villi but they both lack the club-shaped stro- show a falling trend on follow-up). False-positive hCG assay
mal projections and stromal karyorrhexis of complete hyda- needs to be excluded and the need of chemotherapy is con-
tidiform mole [53–55, 72, 73]. Although early abortus may troversial [81, 82].
show some degree of circumferential trophoblastic prolifera- Recurrent complete mole is defined by discovering a new
tion, they generally lack the nuclear atypia of a complete gestational trophoblastic disease after a post-chemotherapy
hydatidiform mole. The retained p57 immunoreactivity in remission. Recurrent complete mole has been reported to
occur in 1–1.8% who has had a previous complete mole, and

10–18% who has had two complete moles [83, 84].
13.5.2 Partial Hydatidiform Moles
13.5.2.1 Definition
Partial hydatidiform mole shows diandric triploidy (one
maternal and two paternal sets of chromosomes). They con-
tain a mixture of normal-sized and enlarged hydropic chori-
onic villi with localized and mild degree of trophoblastic
hyperplasia [75, 85, 86].

Patients usually present with vaginal bleeding or missed
abortion in the late first or early second trimester. The serum Fig. 13.21 Photomicrograph of a partial mole. Relatively normal-
hCG is usually low or normal for gestational age [46, 51]. sized sclerosed villi and hydropic villi with cistern are both present
Preeclampsia may occur later than for a complete hydatidi-
form mole [87]. Ultrasound scan of the uterus may show
small or normal for dates uterus, presence of a fetus, and
focally cystic placenta [88].

Gross appearance is dependent on the age of gestation. First-
trimester partial moles may be indistinguishable from nor-
mal pregnancies. In a well-developed case, there is usually a
mixture of markedly hydropic vesicles and normal placental
tissue (Fig. 13.20). The fetus and an intact gestational sac
may be seen [75].
Histologically, there are two populations of hydropic and
normal-sized chorionic villi (Fig. 13.21). The hydropic villi
are at least two to three times larger than the normal ones
Fig. 13.22 Photomicrograph of a partial mole. Trophoblastic prolif-

eration is mild
[75]. They show central cisterns but the frequency is less

than that in complete hydatidiform mole. The villi are often
irregular in shape, with scalloped borders and trophoblastic
inclusions (invaginations of trophoblasts into the villous
stroma). Trophoblastic hyperplasia is focal and mild com-
pared with a complete mole (Fig. 13.22), and characterized
by sprouts or knuckles of cells projecting from the villous
surface. Circumferential hyperplasia is less common. The
majority of hyperplastic cells are syncytiotrophoblasts and
they quite often contain prominent cytoplasmic vacuoles and
appear lacelike when the cells are arranged in sheets. In the
villous stroma, there are fetal vessels containing nucleated
red blood cells. Some of the blood vessels may appear
ectatic. The normal-sized chorionic villi often have a fibrous
Fig. 13.20 Vesicles can be found in part of a placenta in this case of stroma [54, 75]. The morphologic features of a classical par-
partial hydatidiform mole tial mole may not always be present and may vary consider-
rental diploid POG/complete moles with missense NLRP7

mutations.
Early complete hydatidiform mole may show immature
hydropic chorionic villi without well-developed central cis-
terns (see under complete hydatidiform mole). Presence of
fetal vessels and nucleated red blood cells, and retained p57
staining, will support a diagnosis of partial mole or hydropic
abortion [72]. It has also been suggested that the MIB1 pro-
liferative index (ki-67) in molar specimens is increased to
>70%, in contrast to hydropic abortus which usually has an
index of <25% [92]. For definitive diagnosis, DNA genotyp-
ing is the best method in distinguishing between molar and
non-molar gestations [58, 93] (Fig. 13.24).
Even though the majority of abnormal conceptuses
with a triploid karyotype are partial hydatidiform moles
Fig. 13.23 The cytotrophoblasts and stromal cells of this partial mole (with two paternal and one maternal sets of chromo-
are positive for p57 immunoreactivity somes), rare cases may be digynic triploid pregnancies
(two maternal and one paternal sets of chromosomes) in
which there may be abnormal villous morphology resem-
ably from case to case, and the appearance is dependent on bling a partial mole [73, 94]. Trisomies may show promi-
the gestational age. For example, in early partial mole there nent trophoblastic inclusions or trophoblastic knuckles
may only be very few hydropic villi and the trophoblastic but these features may be i nconsistently present.
hyperplasia may be absent. Fetal tissue, chorionic and Cytogenetic studies and DNA genotyping would be useful
amnion membranes, and umbilical cord tissue may be pres- for these cases [58, 66, 93].
ent [72, 73].
13.5.2.7 Prognosis and Outcome
13.5.2.4 Biomarkers Persistent gestational trophoblastic disease occurs in 0.5–5%
Although there is no specific immunohistochemical marker of patients with partial hydatidiform moles [61, 77, 95]. The
for diagnosis of partial hydatidiform mole, p57 is useful in persistent disease may be due to invasive mole and meta-
the distinction from complete hydatidiform mole. In partial static mole [96]. The risk of subsequent choriocarcinoma is
mole, the villous trophoblasts and stromal cells are immuno- <0.5% [80, 97].
reactive for this marker (Fig. 13.23) [72]. The p57 immuno-
expression is also retained in hydropic abortus and therefore
this marker cannot be used to distinguish it from a partial 13.5.3 Invasive Hydatidiform Mole
mole [57, 58, 61, 85].
13.5.3.1 Definition
13.5.2.5 Genetic Profile When there is the myometrial and/or vascular invasion by
Almost all partial hydatidiform moles have a triploid karyo- molar villi, or presence of metastases in extrauterine sites.
type [72, 73, 86] (Fig. 13.10). Most are 69XXY (70%), fol-
lowed by 69XXX (27%), and the least common are 69XYY 13.5.3.2 Clinical Features
(3%) [86, 89]. Rarely, they are tetraploid in which there are Invasive hydatidiform moles occur in 5–10% of complete
three sets of paternal and one set of maternal chromosomes hydatidiform moles, in particular heterozygous/dispermic
[90]. It should be noted that, while almost all partial moles type [98]. Rarely do invasive moles follow a partial hydatidi-
are triploid, not all triploid conceptuses are partial moles (see form mole [96]. Patients with invasive hydatidiform mole
under differential diagnosis below) [91]. usually have persistent vaginal bleeding and persistently
high post-evacuation serum hCG levels, and repeat uterine
13.5.2.6 Differential Diagnosis curettage shows absence of any chorionic villi [99].
The main differential diagnoses include entities in which Distinction from choriocarcinoma is difficult.
abnormal chorionic villi are found. These are hydropic with
or without other abnormal villous morphologies [25]. They 13.5.3.3 Pathological Findings
include complete hydatidiform mole, hydropic abortions, Definitive diagnosis is made by finding of molar villi invad-
gestations with chromosomal abnormalities, placental mes- ing the myometrium and/or myometrial blood vessels
enchymal dysplasia, twin gestations, as well as familial bipa- (Figs. 13.25 and 13.26). Alternatively, the histologic
Suspected Hydatidiform Mole
IHC: p57
Positive (villous stroma, Negative
cytotrophoblast)
Genotyping
Biparental Diandric Androgenetic

Diploidy Triploidy Diploidy
Partial Complete
Non-
Hydatidiform Hydatidiform
Molar
Mole Mole
Fig. 13.24 Flowchart of diagnosis in cases suspected of hydatidiform mole [modified from Banet N et al. Mod Pathol 2014 [59]]
Fig. 13.26 Hydropic chorionic villi (V) with florid trophoblast prolif-
eration impinging at the myometrium (M) of the uterus in this case of
invasive mole
Fig. 13.25 Invasive mole. A uterus with extensive replacement by

molar vesicles
d etection of metastases (with presence of molar chorionic

villi) involving other pelvic sites (broad ligament, vagina,
and vulva) and distant metastases (commonly in the lungs)
would confirm the suspicion.

As most cases of clinical suspect invasive moles are not man-
aged by hysterectomy, pathologic diagnosis is difficult. In
repeat curettage specimens, a diagnosis of invasive mole
cannot be made unless there is sufficient myometrium
included to assess invasion.
In placenta accrete and increta, there is a normal placenta
but it has implanted the myometrium without an intervening
decidual layer. In these cases, the chorionic villi do not show
the features of hydropic change or trophoblastic proliferation
Fig. 13.27 Photomicrograph of a spontaneous abortion. The dilated
as seen in hydatidiform moles. If an invasive complete mole stem villi may be misinterpreted as central cisterns
is suspected, a positive p57 immunostain would be useful.
13.5.3.5 Prognosis and Outcome cases in which the p57 expression profile is equivocal,
Invasive mole is often a clinical diagnosis. Patients usually molecular genotyping can be used to make a definitive diag-
have persistent elevated hCG levels but without residual nosis [57, 58, 66, 73, 93]. Hydropic abortus typically shows
molar tissue identified in the uterus on repeated curettage. biparental diploidy, while complete and partial hydatidiform
These cases are considered persistent gestational trophoblas- moles show androgenetic diploidy and diandric triploidy,
tic disease or gestational trophoblastic neoplasia as it is usu- respectively (see under complete and partial hydatidiform
ally not possible to distinguish invasive/metastatic mole moles for rare exceptions).
from choriocarcinoma. Nonetheless, most patients are cured In a problematic hydropic abortus, the spectrum of villous
if treated with chemotherapy [24]. abnormality may range from small, fibrotic villi to larger,
hydropic villi, which can potentially mimic partial hydatidi-
form mole [72, 73, 75]. The chorionic villi in a hydropic
13.6 S
pecific Issues of Diagnosis abortus usually do not exceed two to three times the size of
and Management in Relation those of the background small villi and do not have typical
to Hydropic Villi central cisterns. It is important not to overinterpret dilated
stem villi as central cisterns (Fig. 13.27). Another clue to
13.6.1 Hydropic Abortus and Abnormal support a hydropic abortus includes attenuated (rather than
(Non-molar) Villous Lesions snouting) surface trophoblasts. Villous trophoblastic hyper-
plasia is commonly observed in non-molar abortuses with
In routine surgical pathology practice, hydropic change of cho- abnormal karyotype, such as trisomies, digynic triploid preg-
rionic villi is a common finding in uterine evacuation samples. nancies, and placental mesenchymal dysplasia [72, 74, 75].
The challenge is to distinguish hydropic abortus from hydatidi- If molecular genotyping is not readily available, it is accept-
form moles. There is significant interobserver and intraob- able to sign out such cases as “abnormal villous morphology,
server variability in morphologic diagnoses even among features indeterminate for partial hydatidiform mole”
experienced pathologists who subspecialize in gynecologic (Fig. 13.28) [24]. These patients may be followed up for a
pathology [61, 73, 100]. Table 13.3 lists the similarities and short duration until the serum hCG is normalized.
differences between entities with problematic hydropic change.
From a practical standpoint, when hydropic change is
identified in the initial sections selected for histology, all 13.7 Choriocarcinoma
remaining tissue of the same specimen should be examined
to exclude hydatidiform moles. All recent curettage speci- 13.7.1 Definition
mens should also be reviewed. Application of p57 immunos-
tain should help to exclude most cases of complete Choriocarcinoma is a malignant gestational trophoblastic
hydatidiform moles, with the exception of androgenetic/ tumor in which there is simultaneous proliferation of inter-
biparental mosaic/chimeric conceptuses and twin gestations mediate, cytotrophoblasts and syncytiotrophoblasts of the
(see under complete hydatidiform moles) [60]. In difficult chorionic villi.
Fig. 13.28 A case that is being considered as having “abnormal villous

morphology” with features indeterminate for partial mole
13.7.2 Clinical Features Fig. 13.29 Metastatic choriocarcinoma to the lung as hemorrhagic
nodules
Choriocarcinomas are seen in women of reproductive age
group, and rarely in teens and postmenopausal women [101].
They are two times more common in non-Caucasians than
Caucasians with highest incidence reported in Asians,
Africans, and Latin Americans [29, 102–109]. The usual pre-
sentation is abnormal vaginal bleeding or extrauterine hem-
orrhage and a highly elevated serum hCG level [101, 110].
The majority of choriocarcinomas (50%) are developed after
a complete hydatidiform mole, an abortion (25%), normal
pregnancy (22.5%), and ectopic pregnancy (2.5%) [50, 80,
97, 109, 111, 112]. The tumors usually develop after a
latency of a few months to more than 14 years (with a mean
of 13 months after a complete hydatidiform mole and a mean
of 1–3 months after a normal pregnancy) [50, 80, 97, 101,
111]. The remainder of cases develop after a partial hydatidi-
form mole. The risk of post-molar choriocarcinoma is 2–3%
and <0.5% for complete and partial moles, respectively.
Fig. 13.30 Frozen section of a lung nodule reveals metastatic
Rarely, the presentation is the incidental identification of a
choriocarcinoma
choriocarcinoma in a term placenta during microscopic
examination [113, 114]. It is important to identify intrapla-
cental choriocarcinoma for further investigation and follow- clear intermediate trophoblasts and cytotrophoblasts are
up due to the significant risk of metastasis in both the mother usually surrounded by multinucleated syncytiotropho-
and baby. blasts in the periphery forming a biphasic and plexiform
pattern (Figs. 13.30 and 13.31) [24, 110]. All the tumor
cells show significant cytologic atypia and nuclear hyper-
13.7.3 Pathological Findings chromasia, appreciable on low magnification. They have
prominent nucleoli and are mitotically active. Some cells,
Grossly, the tumor is typically hemorrhagic and alternates especially the intermediate trophoblasts, may contain
with fleshy and necrotic areas (Fig. 13.29). It may be large striking cytoplasmic clearing. Tumor necrosis and hemor-
and involves both endometrium and myometrium with rhage are often a prominent feature. In tumors treated with
extension into cervix with extensive tissue destruction preoperative chemotherapy, the number of syncytiotropho-
[115]. Ectopic sites include fallopian tubes and/or ovaries blasts may be proportionally less than intermediate tro-
are uncommon [116, 117]. Histologically, the tumor grows phoblasts and cytotrophoblasts but can be highlighted by
in diffuse and infiltrating sheets and invades the myome- hCG immunohistochemistry (Fig. 13.32) [118]. Rare cases
trium or surrounding structures. The sheets of mononu- of choriocarcinoma may contain a minor component of
Mel-CAM (CD146), HLA-G, and MUC-4. Cytotrophoblasts

are typically negative for Mel-CAM [11, 12, 120–123].
13.7.5 Genetic Profile
The majority of choriocarcinomas have a XX sex chromo-

some composition [124]. Complex karyotypes with amplifi-
cations of 7q21-q31 and loss of 8p12-p21 have been reported
[125, 126].
Recent genotyping study showed that gestational chorio-
carcinoma can be androgenetic or biparental [127]. Majority
are androgenetic XX associated with CHM. Biparental cho-
riocarcinoma, particularly those found postpartum, is related
to intraplacental choriocarcinoma which may not be detected
Fig. 13.31 Photomicrograph of a choriocarcinoma with plexiform in routine examination (Fig. 13.33). Occasionally, androge-
pattern and coexisting mononuclear cytotrophoblasts and multinucle- netic choriocarcinoma found with but separate from a coex-
ated syncytiotrophoblasts isting intrauterine placenta may be due to dispermic twin
pregnancy or originate from a pregnancy hydatidiform mole.
13.7.6 Differential Diagnoses
The differential diagnoses include other gestational tropho-

blastic tumors, non-gestational choriocarcinoma, high-grade
carcinoma with trophoblastic differentiation, complete hyda-
tidiform mole, and other nonneoplastic trophoblastic lesions
[25, 128] (Tables 13.4 and 13.5).
Choriocarcinoma is distinguished from other gestational tro-
phoblastic tumors, PSTT and ETT, by a very high serum hCG
(choriocarcinoma which is much higher level than both placen-
tal site trophoblastic tumor and epithelioid trophoblastic tumor),
presence of a distinctive plexiform growth pattern consisting of
three cell types, and a MIB1 proliferative index >90%.
Fig. 13.32 The cytoplasm of syncytiotrophoblasts in choriocarcinoma

are immunoreactive for hCG
placental site trophoblastic tumor or epithelioid tropho-

blastic tumor [119].
13.7.4 Biomarkers
All trophoblasts are stained with cytokeratins. The syncytio-

trophoblasts are diffusely immunoreactive for hCG
(Fig. 13.32), inhibin, and HSD3B1. The MIB1 proliferative
index (ki-67) is >90%. The intermediate and cytotropho- Fig. 13.33 Photomicrograph of an intraplacental choriocarcinoma
blasts are immunoreactive for these markers but to a lesser extending from the villi (V) of a term placenta [contributed by Professor
degree. Intermediate trophoblasts also typically express hPL, Harold Fox, University of Manchester]
Table 13.4 Histopathological characteristics of trophoblastic lesions

EPS PSN CCA ETT PSTT
Discrete mass − − + + +
Chorionic villi + − − − −
Fibrinoid deposit + + − − +
Vascular invasion + − + + +
Extravillous trophoblast + + − + +
Syncytiotrophoblast + − + − −
Mitosis −/rare −/rare + + +
Pan-cytokeratin + + + + +
hCG + Focal + +(ST) Focal + Focal +
hPL + Focal + +(IT) Focal + +
α-Inhibin + + +(ST) Focal + +
Mel-CAM + Focal + +(IT) Focal + +
P63 − + + + −
Ki-67 <5% <5% >90% 10–25% > 10%
EPS exaggerated placental site, PSN placental site nodule, CCA choriocarcinoma, ETT epithelioid trophoblastic tumor, PSTT placental site tropho-
blastic tumor
Table 13.5 Differentiated diagnosis of choriocarcinoma

Other GTN (PSTT Non-gestational CCA High-grade carcinoma with Complete
CCA and ETT) (germ cell tumor) trophoblastic differentiation hydatidiform mole
Serum hCG Markedly Mildly elevated Markedly elevated Mildly elevated Markedly elevated
level elevated
Chorionic Absent Absent Absent Absent Present
villi
Cell CT, ST, IT IT CT, ST, IT Epithelial cell CT, ST, IT
component
hCG stain +++ +(Focal) +++ + +++
CCA choriocarcinoma, GTN gestational trophoblastic neoplasia, PSTT placental site trophoblastic tumor, ETT epithelioid trophoblastic tumor, CT
cytotrophoblasts, ST syncytiotrophoblasts, IT intermediate trophoblasts
Pure non-gestational choriocarcinoma in the corpus is rare, 13.7.7 Prognosis and Outcome

and can be distinguished from gestational tumor by detailed
reproductive history and DNA polymorphism analysis. Choriocarcinomas are aggressive and have a propensity to
Identification of typical adenocarcinoma features else- metastasize to distant organs, commonly brain, lungs, and
where, a mild elevated of serum hCG, and limited hCG kidneys [129]. Disease duration greater than 4 months from
immunostaining facilitates the distinction of a poorly differ- delivery, pretreatment hCG level >100,000 mIU/mL, pres-
entiated carcinoma with trophoblastic differentiation from ence of liver, or brain metastases at diagnosis were among
choriocarcinoma [4]. Such ectopic hCG production has been poor prognostic factors [31, 130, 131]. Nevertheless, with
reported in carcinomas of the lung and breast as well as mel- modern chemotherapy regimens, the prognosis has been
anoma and lymphoma [2, 3]. drastically improved with cure achieved in >90% of patients
Trophoblasts in a complete hydatidiform mole may show [97, 108, 109].
striking nuclear atypia comparable to that seen in
choriocarcinoma. Presence of hydropic villi, which may be
scanty, supports a complete hydatidiform mole [58].
Nonneoplastic trophoblastic lesions may be encountered 13.8 Placental Site Trophoblastic Tumor
in small and limited uterine curettage samples and may result
in diagnostic difficulty especially when a history of a prior 13.8.1 Definition
pregnancy or abortion is unknown to the pathologist. Isolated
degenerating trophoblasts without accompanying chorionic Placental site trophoblastic tumor is a malignant tropho-
villi may be seen. The nuclei usually have a smudged appear- blastic tumor of intermediate trophoblasts. The cell of ori-
ance and there is often fibrin deposition (see subsequent sec- gin is believed to be extravillous implantation-site
tion on placental site nodule and plaque). trophoblasts [132].
The affected women are usually in the reproductive age

group (with a mean age of 30) and commonest presentation
is abnormal vaginal bleeding but some may have amenorrhea
or abdominal distention, simulating a normal pregnancy.
Rarely, the presentation is that of a postmenopausal woman.
An antecedent full-term pregnancy is found in more than
two-thirds of women, with a median latent period of
18 months. The remainder follows a non-molar abortion or
miscarriage [132–136]. Glomerular diseases including lupus
nephritis are occasionally found in patients with PSTT [137,
138].
Fig. 13.35 Confluence mass of PSTT found next to pieces of endome-

13.8.3 Pathological Findings trium in a uterine curetting
The tumor involves both endometrium and myometrium and

presents as infiltrative masses ranging from 1 to 10 cm and
cervical involvement is found in <10% of cases (Fig. 13.34).
More than half of the cases invaded to outer half of myome-
trium and sometimes the serosa. The cut surface is usually
fleshy, and alternates with white and yellow solid areas.
There is often necrosis and hemorrhage but to a lesser extent
compared with choriocarcinoma. Quite often, the diagnosis
is made in a uterine curettage specimen (Fig. 13.35) and
procedure-related perforation may occur in cases with almost
full-thickness myometrial invasion. Microscopically, the
Fig. 13.36 Conspicuous perivascular growth with fibrin deposit in

PSTT
tumor cells are arranged in sheets and dissect the myometrial

smooth muscle bundles. The classical feature is an angiocen-
tric-angioinvasive pattern of blood vessel wall involvement
by groups of tumor cells. The involved vessels show fibri-
noid change accompanied by tumor penetration into the vas-
cular lumina (Fig. 13.36). Coagulative tumor necrosis and
infarct-type necrosis are common. Most tumor cells are
mononucleate and have polygonal shape, but some may
appear spindle. A small number of cells may also be binucle-
ate or multinucleate and it is important to distinguish from an
under-sampled choriocarcinoma. The cells may have eosino-
philic or clear cytoplasm. Nuclear pleomorphism is pro-
nounced and pseudonuclear inclusions and nucleoli are
prominent. The mitotic count is low with a mean of 5 per 10
high-power fields (Fig. 13.37). The background endome-
trium may show decidual change and/or Arias-Stella reaction
Fig. 13.34 Tumor nodules of PSTT found at resected uterus [132, 136, 139].
Fig. 13.37 Solid aggregates of PSTT tumor cells with nuclear pleo- Fig. 13.39 The tumor cells of PSTT are often negative for p63 and
morphism and brisk mitotic figures may be helpful to distinguish from poorly differentiated non-
keratinizing carcinoma in a cervical biopsy
Fig. 13.38 The cytoplasm of PSTT tumor cells is positive for hPL Fig. 13.40 Focal immunoreactivity for hCG can be demonstrated in
PSTT
13.8.4 Biomarkers
13.8.6 Differential Diagnoses
The tumor cells are positive for cytokeratins, hPL
(Fig. 13.38), CD10, inhibin, Mel-CAM (CD146), and HLA- The differential diagnoses include choriocarcinoma, epithe-
G. It is often negative for p63 (Fig. 13.39). The hCG staining lioid leiomyosarcoma, poorly differentiated carcinomas,
is usually limited to the multinucleated cells (Fig. 13.40). melanomas, and exaggerated placental site reaction [25]
The MIB1 proliferative index (ki-67) is usually >10% [10, (Tables 13.4 and 13.6).
120, 139]. Unlike placental site trophoblastic tumor, choriocarci-
noma usually has a combination of features including very
high serum hCG, a hemorrhagic mass, and a plexiform
13.8.5 Genetic Profile growth but lacking the angiocentric and angioinvasive pat-
tern of placental site trophoblastic tumor (see under differen-
There is usually a paternal X chromosome. There are occa- tial diagnosis of choriocarcinoma). Poorly differentiated
sional cases which show genetic imbalances [124, placental site trophoblastic tumor may be indistinguishable
140–143]. from some choriocarcinomas and may rarely coexist.
Table 13.6 Differentiated diagnosis of PSTT

Poorly differentiated
PSTT CCA Epithelioid leiomyosarcoma carcinomas
Serum hCG level Mildly elevated Markedly elevated Normal Normal
Histological feature Angiocentric- Hemorrhagic mass with Arranged in sheets, nests, Arranged in sheets,
angioinvasive pattern plexiform growth cords that may form a nests, cords
plexiform pattern
Tumor cell origin IT CT, ST, villous IT Smooth muscle cell Epithelial cell
Fibrinous deposition + − − −
hCG immunostain + +++ − −
Pan-cytokeratin + + − +
Muscle marker − − + −
PSTT placental site trophoblastic tumor, CCA choriocarcinoma, IT intermediate trophoblasts, CT cytotrophoblasts, ST syncytiotrophoblasts
Fig. 13.41 Spindle-shaped PSTT cells with eosinophilc degeneration Fig. 13.42 Spindle-shaped PSTT cells resembling leiomyosarcoma
resemble keratinizing squamous cell carcinoma of cervix
Distinction from epithelioid leiomyosarcoma, poorly differ- other pelvic sites, and metastases to lymph nodes, lungs,
entiated carcinomas, and melanomas in the uterine corpus or and liver. Half of these patients may die from tumor.
cervix may be difficult particularly during interpretation of fro- Metastases and recurrent tumors respond poorly to che-
zen section or small biopsies (Figs. 13.41 and 13.42). motherapy and often result in fatality. Pathologic features
Identification of more typical histopathological features and associated with poor outcome include extensive necrosis,
immunohistochemical profiling are helpful in the differential cells with clear cytoplasm, deep myometrial invasion, and
diagnoses. PSTT usually shows permeation of blood vessel wall, >5 mitotic figures per 10 high-power fields. In multivari-
splitting apart of well-preserved myometrial cells, and conspicu- ate analysis, FIGO stage III/IV, a latency of ≥2 years
ous fibrinoid deposit. Epithelioid leiomyosarcomas may be con- since last pregnancy, and presence of clear cells are inde-
firmed by absence of the distinctive vascular pattern of placental pendently associated with a poor prognosis [133,
site trophoblastic tumor; immunoreactivity for h-caldesmon, 144–147].
desmin, and actin; and negative for hPL and inhibin. Poorly dif-
ferentiated carcinomas usually show some histologic evidence of
a better differentiated component (squamous or glandular) and
an immunoprofile of hPL/hCG/inhibin nonreactivity. 13.9 Epithelioid Trophoblastic Tumor
13.9.1 Definition
13.8.7 Prognosis and Outcome
Epithelioid trophoblastic tumor is a malignant trophoblastic
The majority of patients present at FIGO stage I [132]. tumor of intermediate trophoblasts. The cell of origin is
Approximately 30% are high stage with involvement of believed to be chorionic-type trophoblasts [148].
The affected women are usually in the similar age group as

placental site trophoblastic tumors (with a mean age of
36 years) and commonest presentation is abnormal vaginal
bleeding and a mildly elevated serum hCG. In addition to the
corpus, 50% of tumor commonly arises in the lower uterine
segment and cervix and often have a long interval from an
antecedent pregnancy (with a mean of 6 years), which may
be a term pregnancy, abortion, or hydatidiform mole
[148–152].
Fig. 13.44 The ETT cells are positive for p63
13.9.3 Pathological Findings

tive index (ki-67) ranges from 10% to 25% [10, 12, 120,
Grossly, the tumor may be nodular infiltrative masses but 155, 156].
often with involvement of mucosa associated with ulceration
[148, 153]. The cut surface may show necrosis and hemor-
rhage. Microscopically, the tumor cells are arranged in 13.9.5 Genetic Profile
expansile nodules, nests, or cords separated by abundant
extracellular eosinophilic hyaline-like material (Fig. 13.43) The majority lack Y chromosome complement [124]. Rare
[148, 151, 154]. Geographic necrosis and perivascular viable comparative genomic hybridization studies showed an undis-
tumor cells are often striking. In some cases, decidualized turbed genome [140, 157]. There are some suggestions of
stromal cells may be found at the periphery. The tumor cells malignant transformation from a preexisting placental site
are mononuclear, well-defined cell membrane, uniform in nodule [158].
size with eosinophilic or clear cytoplasm. There is moderate
nuclear atypia and a low mitotic count (range between 0 and
10 mitotic figures per 10 high-power fields, with a mean of 13.9.6 Differential Diagnosis
2) [139].
These include squamous cell carcinoma, epithelioid leio-
myosarcoma, and other gestational trophoblastic tumors [25]
13.9.4 Biomarkers (Table 13.4). In small biopsies, distinction from placental
site nodule may be difficult.
There is immunoreactivity for H3D3B1, CD10, and cyclin Some of the gross (cervical mucosal involvement) and
E but also cytokeratins, EMA, and p63 (Fig. 13.44). Staining microscopic features (epithelial involvement resembling
for other trophoblastic markers, such as hPL, hCG, inhibin, high-grade squamous intraepithelial lesion, eosinophilic
Mel-CAM, and HLA-G, may be focal. The MIB1 prolifera- hyaline material) and immunoprofile (positive staining for
cytokeratins, EMA, and p63) of epithelioid trophoblastic
tumors mimic those of squamous cell carcinomas. Overt
squamous differentiation, absence of staining with tropho-
blastic markers, and a normal serum hCG level support squa-
mous cell carcinoma [151, 159, 160].
Epithelioid leiomyosarcoma usually contains a compo-
nent of more typical smooth muscle tumor differentiation
and is immunoreactive for smooth muscle markers.
Compared with epithelioid trophoblastic tumor, placental
site trophoblastic tumor has a more infiltrative dissecting
growth, has a typical angiocentric and angioinvasive pattern,
and shows more extensive staining with hPL and Mel-CAM
and negative for p63. Epithelioid trophoblastic tumors may
coexist with other gestational trophoblastic tumors as mixed
Fig. 13.43 A metastatic ETT presented as lung nodule. Cellular nod-
ules and nests are separated by abundant extracellular eosinophilic tumors. Some choriocarcinomas which have been treated
material with chemotherapy may show degenerative features which
are difficult to distinguish from some epithelioid trophoblas-

tic tumors [161].
Placental site nodules are hypocellular and diffusely hya-
linized, and the cells are mitotically inactive, negative for
cyclin E. The MIB1 proliferative index is <5%. Atypical pla-
cental site nodule is a term applied to indeterminate lesions
when the spectrum of features between a nodule and an epi-
thelioid trophoblastic tumor is unclear [155, 158].
13.9.7 Prognosis and Outcome
The only histologic feature associated with a poor outcome

is a high mitotic count >6 per 10 high-power fields. Patients
without metastases have excellent prognosis. In 25% of
patients, there is blood-borne metastasis and half of these
usually died of tumor [151, 162].
Fig. 13.45 Photomicrograph of exaggerated placental site reaction
found with complete mole
13.10 Exaggerated Placental Site
13.10.1 Definition 13.10.4 Differential Diagnosis
Exaggerated placental site is the unusual prominence of Placental site trophoblastic tumor is favored in the presence
implantation-site intermediate trophoblasts found at the of a mass (clinically or radiologically), high serum hCG lev-
implantation site of a placenta (synonym: exaggerated pla- els, destructive myoinvasion, typical angioinvasive pattern,
cental site reaction) [139, 163]. tumor necrosis, and a MIB1 proliferative index >10%. A low
MIB1 index and presence of decidua and villi are in favor of
exaggerated placental site.
13.10.2 Pathological Findings
Exaggerated placental site may be seen in first-trimester 13.10.5 Prognosis and Outcome

induced or spontaneous abortions and has been suggested to
be more common in association with an underlying hydatidi- Exaggerated placental site usually regresses spontaneously.
form mole (Fig. 13.45) [163]. There is usually no gross There is no proven genetic relationship with placental site
lesion. The distinction between what constitutes a normal or trophoblastic tumor. The consistent XX genome of PSTT is
exaggerated placental site is unclear and subjective. In a not seen in cases of exaggerated placenta site [140, 166].
definitive case of exaggerated placental site, there is a strik-
ing increase in the number of intermediate trophoblasts in
the endometrium and myometrium, either in small nests, 13.11 Placental Site Nodules/Plaques
sheets, or individually, and without destructive invasion of
the myometrium such that the myometrial anatomy is 13.11.1 Definition
preserved. These cells are recognized under low-power mag-
nification due to the nuclear atypia, hyperchromasia, and These are circumscribed nodules or plaques composed of
multinucleation [164]. They are usually mitotically inactive chorionic-type intermediate trophoblasts within an abun-
[13, 139]. dantly hyalinized stroma [139, 167–169].
13.10.3 Biomarkers 13.11.2 Pathological Findings
The intermediate trophoblasts are immunoreactive for cyto- Nodules or plaques are usually discovered in hysterectomy
keratins, hPL, inhibin, Mel-CAM (CD146), and MIB1 pro- or uterine curettage specimens when the patient is undergo-
liferative index (ki-67) <1% [122, 123, 165]. ing investigations for other gynecological conditions, such as
abnormal menstrual bleeding. Patients are usually in their pleomorphic nuclei with smudged nuclear chromatin.
reproductive years and had an antecedent pregnancy dating Mitotic figures are typically absent. Some cells may contain
back to 8 years (with a mean of 3 years). Rarely, the presen- cytoplasmic eosinophilic hyaline material. Fibrinoid necro-
tation is of someone being investigated for postmenopausal sis and dystrophic calcification are common. Rarely, necrotic
bleeding. The usual sites of involvement are lower segment or degenerated chorionic villi with ghost outline are also
endometrium, and endocervix [167]. Only 25% of lesions seen [168].
are grossly visible as tan to brown solid nodules.
Microscopically, the lesion is hypocellular and has abundant
eosinophilic hyalinized stroma in which individual and clus- 13.11.3 Biomarkers
ters of cells are seen (Fig. 13.46). The cells have variable
amount of eosinophilic to clear cytoplasm, and irregular and The cells are immunoreactive for cytokeratins, EMA, CD10,
p63, and inhibin (Fig. 13.47). Implantation-site trophoblast
markers such as hPL and Mel-CAM are less often positive.
The MIB1 proliferative index (ki-67) is <8%. Unlike epithe-
lioid trophoblastic tumors, nodules are negative for cyclin E
[11, 13, 123, 155, 170].
Decidual reaction may mimic placental site nodules. The

decidualized stromal cells are usually more uniform in size
and shape and lack nuclear hyperchromasia. They do not
express the immunomarkers of a placenta-site nodule.
Exaggerated placental site is less often hyalinized and less
well circumscribed.
Unlike placental site nodule, the cells in placental site tro-
Fig. 13.46 Hypocellular nodule of PSN with conspicuous eosino- phoblastic tumor are implantation-site intermediate tropho-
philic hyalinized stroma is detected incidentally in a uterine curetting blasts and immunophenotypically different. A placental site
a b
Fig. 13.47 The chorionic intermediate trophoblasts at this PSN are negative for inhibin (a) but positive for p63 (b)
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Overview of Placenta Pathology
14
John Paul B. Govindavari and Anna R. Laury
Abstract 14.1.1 Fertilization, Fertilized Egg

The placenta is a very common, but often underappreci- Development and Migration,
ated, surgical pathology specimen. Gross examination of and Implantation
the placenta should be organized and routine, in order to
efficiently identify abnormalities; only a proper gross Fertilization takes place in the fallopian tube 24–48 h after
examination will allow appropriate diagnosis. Gross find- ovulation, creating a zygote. As the early embryo travels
ings and lesions discussed here include those of the through the fallopian tube, the zygote becomes a morula
umbilical cord (length, knots, coiling, insertion), mem- (mass of 12–16 cells) and is encased in a nonadhesive pro-
branes (discoloration, plaques, insertion), and disc (size, tective coating called the zona pellucida. Once a fluid-filled
infarcts, abnormal shapes). The histologic findings are cavity forms, the morula transitions to the blastocyst stage.
also discussed by site: cord (inflammation, thrombosis, This stage is also accompanied by cellular differentiation,
remnants), membranes (pigment, lesions, chorionicity of with the surface cells becoming the trophoblast, which even-
twins, maternal arteriopathy), and disc (villous maturity, tually gives rise to extraembryonic structures like the pla-
infarcts, hydropic change, villitis, specific infections). centa, as the inner cells become the embryo. As the embryo
Finally, there is a discussion of the unifying diagnoses: finally enters the uterine cavity after its journey through the
maternal vascular malperfusion, fetal vascular malperfu- fallopian tube, it exposes the outer covering of syncytial tro-
sion, and amniotic fluid infection sequence. phoblasts within 72 h [1, 2].
About 6–7 days after conception, implantation occurs.
Keywords This appears to occur in three distinct stages: apposition, sta-
Placenta · Infarct · Maternal arteriopathy · Villitis ble adhesion, and invasion. The first step, apposition, occurs
Maternal vascular malperfusion · Fetal vascular when the blastocyst adheres to the uterine wall, which occurs
malperfusion most often in the posterior fundus of the uterus. This initial
weak adherence is followed by a complex series of incom-
pletely understood changes which allow the next two steps,
stable adhesion and subsequent invasion, to occur [1, 2].
14.1 Introduction By day 10 after conception, the blastocyst is completely
embedded within the stroma of the endometrial lining, with
Placenta, Latin for flat cake, is a commonly encountered sur- uterine epithelium regrowing to cover the implantation site.
gical pathology specimen. Unfortunately, the placenta is fre- Cytotrophoblasts invade the endometrial stroma, glands,
quently overlooked as a specimen of little value. Much vasculature, and myometrium [1, 2]. This step establishes the
information can be gained from a focused examination of the uteroplacental circulation, placing trophoblasts in direct con-
placenta, both grossly and microscopically, when examined tact with maternal blood [3].
by a knowledgeable surgical pathologist.
14.1.2 Membrane and Placental Development
J. P. B. Govindavari · A. R. Laury (*) As the placenta develops, the entire blastocyst surface is ini-
Department of Pathology and Laboratory Medicine, Cedars-Sinai tially covered by villi. To form the membranes, most of the
Medical Center, Los Angeles, CA, USA
newly formed villi regress and the intervillous space obliter-
460 J. P. B. Govindavari and A. R. Laury
ates, a process which spreads over the blastocyst surface. trophoblastic cover and poorly developed fetal capillar-
The chorion, obliterated intervillous space, villous remnants, ies, and make up very little of the term placenta
and trophoblastic shell fuse, forming the smooth chorion. (Table 14.1).
The small cells that line the inner surface of the trophoblast
eventually form the amnionic epithelium. Early in gestation
the amnionic mesoderm and the chorionic mesoderm fuse, 14.1.5 General Rules of Pathologic Evaluation
but the fusion of the amnion and chorion is never complete,
and the two membranes can always easily slide against each When approaching a placenta, it is helpful to use a system-
other [1, 2]. atic approach to inspect the three main components: the disc,
the membranes, and the umbilical cord. The order is less
important than a standard routine, although in practice it may
14.1.3 Twin/Multiple Pregnancy Development be easiest to examine the cord and membranes prior to the
disc as these will be removed before obtaining the placental
This will be covered later in the chapter. weight. Additionally, it is important not to overlook any
extraplacental tissue (such as a fetus papyraceus or large
amounts of blood clot) that may be present [2, 4–7].
14.1.4 Chorionic Villi
Practically all maternofetal and fetomaternal exchange takes 14.1.6 Fixation

place at the chorionic villi, which have a dual blood supply
from the fetal and maternal circulations. All tertiary villi Whether or not to fix a placenta before gross examination has
have the same basic structure: an outer shell composed of been somewhat controversial, but it is generally believed that
syncytiotrophoblasts, which are bathed in maternal blood. an initial fresh examination is preferable. The placenta can
The cytotrophoblasts are positioned between the outer syn- be palpated more easily, and gross assessment may become
cytiotrophoblasts and the basement membrane of the villous difficult following fixation due to the decreased pliability
structure. The villous stroma is composed of connective tis- inherent to formalin fixation. For fresh placentas, dry storage
sue cells (fibroblasts) and fetal vessels. The initial villous in plastic buckets at 4 °C is recommended. After 72 h of dry
development from primary to secondary villi, and finally ter- storage, there may be changes in vascular architecture, and
tiary villi, has occurred by week 4 (when the heart begins to therefore the placenta should be fixed within 48 h if it cannot
beat); tertiary villi contain fetal vessels, which will allow the be examined macroscopically within that time. With fresh
villi to provide oxygen and nutrients to the developing placental tissue, it is possible to perform microbiology stud-
embryo [1, 2]. ies such as bacterial cultures and karyotyping for chromo-
There are five types of tertiary villi: somal analysis, which may be useful in earlier gestations
when the differential diagnosis can include a molar preg-
1. Stem villi: These villi are the thick-walled, fibrous villi nancy, or if some form of placental mosaicism is clinically
that provide the initial branches and structure for the vil- relevant. The weight of the placenta increases following fixa-
lous tree (Fig. 14.1a). tion by up to 10% [2, 6, 8].
2. Immature intermediate villi: Bulbous in shape, with a tro- There are some benefits to examining the placenta after
phoblastic cover and a distinctive loose stroma, these formalin fixation. Fixed placentas are less infectious, subtle
structures are the continuation of the stem villi. areas of infarction are more apparent, and sections/blocks
3. Mature intermediate villi: These villi branch from the are easier to cut. Formalin is the preferred agent for fixing
immature intermediate villi into longer and more slender placentas; other fixatives may cause artifact, both grossly
structures. Their stroma is more dense and cellular, with and microscopically [8].
increasing numbers of capillaries (Fig. 14.1b).
4. Terminal (free) villi: The final representation of the vil-
lous tree, these structures consist of grapelike outgrowths 14.2 G
ross Features and Findings
of the mature intermediate villi. They have scant connec- of the Placenta
tive tissue and a thin trophoblastic layer, which is in direct
contact with sinusoidally dilated capillaries (Fig. 14.1c). 14.2.1 Basic Gross Examination
5. Mesenchymal villi: The precursors of all other villous
categories, these villi are thought to sprout continuously 14.2.1.1 Integrity
throughout pregnancy, though most copiously in the first One of the first things to note when examining the disc is
and second trimesters. Mesenchymal villi have a thick integrity: Are the cotyledons complete and intact? Intactness
14 Overview of Placenta Pathology 461
a b
Fig. 14.1 Tertiary chorionic villi. (a) Three types of villi are readily contain scant connective tissue, with more than 50% of the volume con-
identified in this photomicrograph. The large stem villus (SV) is notable sisting of capillaries. (b) Immature intermediate villus (IV) with reticu-
for its dense fibrotic stroma and large vessels. The mature intermediate lar stroma and fluid-filled channels. (c) Most of the villi in this picture
villus (MV) has a dense cellular stroma, and over 50% of the volume is represent terminal villi (TV). There is scant connective tissue and a thin
taken up by capillaries. Terminal villi (TV) are the smallest villi, and trophoblastic layer, which directly contacts the dilated capillaries
refers to the presence or absence of disrupted cotyledons. that the cotyledons may be disrupted, but still comprise a
In an intact placenta, the entire maternal surface will appear complete placenta when pieced together, though this can be
smooth and shiny due to the (thin) layer of decidua that is very difficult to determine with certainty (Fig. 14.3).
normally present. Areas of disruption appear roughened Missing placental tissue affects accurate weight measure-
and reddish, due to exposed villi (Fig. 14.2a, b). ment and more importantly can indicate retained placental
Completeness refers to receipt of the entire placenta. Note tissue within the uterus.
Table 14.1 Five types of chorionic villi

% at
Villi type Present Maximum term Features
Mesenchymal Throughout 0–8 weeks <1 Primitive stroma, thick trophoblastic cover, few vessels
gestation
Immature intermediate 8 weeks to term 14–20 weeks 5–10 Reticular stroma with fluid-filled stromal channels
villi
Stem villi 12 weeks to term Term 20–25 Dense fibrotic stroma, myofibroblastic perivascular sheath, large
vessels
Mature intermediate villi Third trimester Third 25 Dense cellular stroma, >50% capillaries
trimester
Terminal villi Third trimester Term 40–50 >50% volume is capillaries
a b
Fig. 14.2 Integrity of the placental disc. (a) Maternal surface with exposed villi, near where the umbilical cord emerges. (b) The focus of
mostly intact cotyledons, which are identified by their smooth, slightly disruption closer up. The roughened surface is clearly in contrast with
shiny appearance. There is a focus of roughening, corresponding to the smooth, shiny intact cotyledons
Another reason for a focally roughened maternal surface is

adherent myometrium, which is seen in placenta accreta. Due
to the abnormal implantation, these placentas often require
manual removal which frequently results in disrupted cotyle-
dons and a fragmented placenta/maternal surface for which
completeness cannot be reliably determined (Fig. 14.4).
14.2.1.2 Shape
While usually round to ovoid, placental shape is highly vari-
able, and of not much importance as long as the overall
growth/weight is appropriate. Uterine cavity abnormalities
(i.e., septate uteri, scars, and leiomyomas) can result in
unusual shapes. For example, should a placenta implant in
the lateral uterine sulcus, a bilobate placenta can result, with
a velamentously inserted cord between the lobes (Fig. 14.5).
In the early stages of placental development, the entire sac
is covered by chorionic villi, most of which regress and flat-
Fig. 14.3 Completeness of the placental disc. This maternal surface is ten out to form the smooth fetal membranes. A succenturiate
composed predominantly of intact cotyledons; however, one fragment
is received separately (bottom of image). In this instance, the placenta lobe (Fig. 14.6) results when an area away from the main
is likely disrupted but complete placental disc fails to regress [7, 9].
14.2.1.3 Color
Color of the villous tissue or placental parenchyma is mostly
determined by the hemoglobin content, with immature placen-
tal parenchyma appearing significantly paler than discs at
term. Color is not particularly specific, but may correlate with
a clinical setting or suggest a diagnosis. Hydropic placentas,
which are usually seen with hydropic infants and fetuses, will
have a very pale color with coarse texture on cut section.
Massive fetomaternal hemorrhage results in a remarkably pale
placenta, often with an otherwise unremarkable exam, though
intervillous thrombi are not unusual (Fig. 14.7). Very deep red
placentas suggest increased blood content or congestion, such
as in twin-twin transfusion syndrome [2, 5–7, 10] (Fig. 14.8).
14.2.1.4 Weight
Fig. 14.4 Disruption of the placental disc. This placenta required man-
ual removal for presumed placenta accreta. The maternal surface is The placenta should be weighed with the membranes
markedly disrupted; completeness cannot be assessed trimmed and the cord removed. As stated previously, fixation
Fig. 14.7 Placental pallor in a term placenta. This cross section of the
parenchyma reveals notable placental pallor, as well as a small intervil-
lous thrombus (top middle), but is otherwise normal. This is an example
of massive fetomaternal hemorrhage (image courtesy of Stephanie
Yagi, DO)
Fig. 14.5 Placental shape. This is a bilobed singleton placenta with a mem-
branously inserted umbilical cord located between the two discrete lobes
Fig. 14.6 Succenturiate lobe. There is a separate island of well-developed Fig. 14.8 Twin-twin transfusion syndrome. The contrast between the
placental parenchyma located away from the main disc. Note the large- markedly pale donor twin side and the very dark, congested, recipient
sized vessels traversing the membranes to reach the accessory lobe twin territory is readily apparent
can increase the weight by up to 10%. There are established the infant and more may be removed when retrieving cord
normal weight ranges for placentas, and small placentas blood, etc. [12, 13]. Long cords are associated with an
(<10th percentile) and large placentas (>90th percentile) are increased incidence of cord entanglement, cord prolapse, true
associated with varying pathologies and maternal conditions. knots, excessive coiling, and constriction. Short cords are cor-
Ideally, weight norms should be established for the popula- related with a range of neonatal problems (from fetal distress
tion in which the pathologist practices, though this is not and low APGAR scores to depressed IQ and developmental
always simple. Large-for-gestational-age placentas can be anomalies). However, as cord length is thought to arise from
seen in diabetic pregnancies, maternal anemia, or retropla- fetal movement, it is unclear whether the short cord is a con-
cental hematoma. Fetal factors leading to a large for gesta- sequence or cause of these abnormalities [12, 13].
tion age can include states of fetal stress such as hypoxia or
respiratory distress. Small-for-gestational-age placentas can 14.2.2.3 Cord Insertion
be seen in cases of reduced uteroplacental blood flow, such The umbilical cord may insert into the chorionic plate at any
as gestational hypertension or preeclampsia, as well as a location; the insertion site is described qualitatively as cen-
variety of fetal conditions [2, 6, 7, 10, 11]. tral, eccentric (sometimes called paracentral), marginal, and
velamentous (membranous). Central and eccentric insertions
account for more than 90% of placentas. Velamentous is the
14.2.2 Umbilical Cord least frequent (and most worrisome); the rest are marginal
(Fig. 14.9).
The umbilical cord connects the developing fetus to the pla- Velamentous insertion is considered more susceptible to
centa. The cord contains three vessels: two umbilical arteries vessel rupture, and is associated with intrauterine growth
which carried deoxygenated blood from the fetus to the pla- restriction, stillbirth, and neonatal death. Interestingly, the
centa, and a single, larger, umbilical vein, which carries oxy- incidence of velamentous insertion increases with maternal
genated blood from the placenta to the fetus. The protective smoking, advanced maternal age, and diabetes mellitus, as
gelatinous connective tissue in which the vessels course is well as in multiple gestations, congenital malformations, and
called Wharton’s jelly; it is composed mainly of mucopoly- pregnancies achieved with in vitro fertilization. The vessels
saccharides with scattered fibroblasts and macrophages. At of these cords are more vulnerable to injury because they
term, the umbilical cord is pearly white in color, about 60 cm lack the protective layer of Wharton’s jelly as they course
in length, averages 1.0–1.5 cm in diameter, and is helical in through the membranes to the disc (Fig. 14.10). Marginally
shape, with an average of 1–3 coils for every 10 cm [12, 13]. inserted cords (those less than 1 cm from the disc edge) are
The cord inserts into the fetal surface of the placenta disc similarly associated with adverse outcomes, though not as
[14]. When examining the umbilical cord, it is important to
note color, length, diameter, coiling, insertion, and configu-
ration, and to assess the vasculature both for number of ves-
sels and for thrombi or hematomas.
14.2.2.1 Color
The normal cord is pearly white. If discolored, there will
usually be a similar discoloration of the fetal surface and/or
membranes. Green or brown discoloration is seen with
meconium discharge before delivery. Yellowed cords are
associated with maternal hyperbilirubinemia, or acute funisi-
tis accompanying an ascending infection. Focal plaque-like
discolorations of the cord are often noted in candidal infec-
tions of the amniotic fluid. Red discoloration can be iatro-
genic but may also be due to necrosis, thrombosis, or
hemolysis in the setting of fetal demise [12, 13, 15].
14.2.2.2 Length
The average length of an umbilical cord at term is 60 cm. A
long cord is defined as one measuring over 70 cm, and short
Fig. 14.9 Marginal insertion of the umbilical cord. The cord insertion
cords as 40 cm or less. It is important to note that calling a is directly at the disc edge. There is a vessel running unprotected
cord a “short cord” at the time of gross examination may not through the membranes (left side); however, the cord itself does not
be accurate due to the fact that some length is left attached to insert into the membranes
Fig. 14.10 Velamentous, or membranous, cord insertion. The protec- c

tive layer of Wharton’s jelly ends as the cord inserts into the fetal mem-
branes. The large vessels are easily identified coursing freely through
the membranes to reach the placenta disc
clearly as a velamentous insertion, and the definition of mar-

ginal insertion varies considerably between studies [12–14].
14.2.2.4 Coiling Fig. 14.11 Cord coiling. (a) A normally coiled umbilical cord. (b)
The usual umbilical cord has a counterclockwise/left-turn Hypercoiled umbilical cord (>3 coils per 10 cm) in a preterm gestation.
(c) Hypocoiled umbilical cord (<1 coil per 10 cm). There is essentially
coil. The average umbilical coiling index (UCI) is approxi- no cord twist in this term cord
mately 0.3 coils/cm (or about 1 coil every 5 cm) [16]. Both
hyper- (>90th percentile) and hypocoiled (<10th percentile)
cords are associated with adverse outcomes in the preg- 14.2.2.6 Thrombi
nancy, with hypercoiled cords associated with fetal growth Venous thromboses are more common than arterial thrombo-
restriction and hypocoiled cords associated with meconium sis (with the latter being more often lethal). The cause is usu-
staining, low Apgar scores, and NICU admission [17] ally physical compression of umbilical vessels and/or
(Fig. 14.11). damage to the vessel walls, but there may be an underlying
cause (e.g., maternal diabetes, hypercoagulable state).
14.2.2.5 Single Umbilical Artery Grossly, areas of thrombosis can show swelling and discolor-
As stated previously, there are normally two arteries and ation, and at times are visible on cut section; old thrombi
one vein in the human umbilical cord. Initially, a second may calcify [12, 13].
umbilical vein is present, but it atrophies during the second
month of pregnancy [18–20]. Single umbilical artery
(SUA) is the commonest true congenital anomaly of 14.2.2.7 Hematoma
humans, with a prevalence ranging from 0.2% to 11%, While rare, true hematomas have serious consequences when
depending on the population studied [18–20]. The loss of they occur, and are associated with a 50% fetal mortality
an umbilical artery is secondary to the thrombotic atrophy rate. They occur due to rupture of one or more umbilical ves-
of a normal artery or, less commonly, due to primary agen- sels with varying underlying causes including short cords,
esis of an artery. The vast majority of children with an iso- trauma, inflammation, aneurysms, hemangiomas, and cord
lated SUA grow and develop normally. However, the rate entanglement. Grossly, there will be elongated, fusiform
of chromosomal abnormalities and/or associated congeni- swelling of the cord and marked dark red discoloration. It is
tal malformations is increased in fetuses with important not to confuse this with iatrogenic cord hemor-
SUA. Congenital malformations associated with single rhage associated with cord clamping. Cut sectioning will
umbilical artery include neural tube and cardiac defects, as reveal hemorrhage throughout the cord. The cord surface
well as respiratory, gastrointestinal, musculoskeletal, and may range from unstained (acute rupture) to red discolor-
genitourinary anomalies [19]. ation (in subacute to remote ruptures) [12, 13].
a b
Fig. 14.12 (a) False knot. Dilated umbilical vessels are present in the midportion of the cord. (b) True knot. This knot was easily reducible; note
the absence of congestion or apparent constriction on either side of the knot
14.2.2.8 Knots, True and False 14.2.3.2 Color

False knots are formed by umbilical vessel redundancy, are Green-brown discoloration of the membranes can be due to
very common, and are not pathologic, and gross assessment meconium staining (the cord may be discolored too) or
is sufficient. True knots, also a gross finding, are usually ascending infection. In cases of meconium staining, the
loose and inconsequential to the infant or fetus. If tight, true membranes will also be slimy and edematous. Similarly,
knots can lead to significant vascular compromise. opaque membranes may be a sign of long-standing meco-
Congestion of the cord on one side of the knot can be a sign nium or ascending infection. It is not unusual to see both
of a tight true knot, as can marked thinning of the cord at the meconium pigment and ascending infection in the same pla-
knot (which is visible when untied) [12, 13] (Fig. 14.12). centa. Red-brown discoloration of the membranes covering
the fetal surface is a sign of old hemorrhage and results from
small areas of decidual necrosis [2, 5].
14.2.3 Membranes
14.2.3.3 Amniotic Bands
Normal placental membranes are smooth, glistening, slightly If there is premature partial rupture of the amniotic sac (in
translucent, and pinkish-tan in color. They insert at the outer which only the amnion is stripped away and the chorion
margin of the placental disc, which typically coincides with stays intact) then amniotic bands can form. These will float
the peripheral limit of the vascular plate [2, 5]. in the amniotic fluid and can occasionally constrict parts of
the growing fetus. In severe cases this leads to early amputa-
14.2.3.1 Insertion tions as the fetus grows beyond the vascular constraints of
The usual membrane insertion pattern is called a “marginal” the constriction [21]. Grossly, thin adhesion-like threads and
insertion. Circummarginate insertions are notable for a flat fragments are visible between parts of the fetal plate or
ridge of fibrin at the point the membranes contact the pla- between the fetal plate and umbilical cord, or sometimes
centa surface, demarcating the extent of the vascular plate. It even attached to the amputated fetal tissue [22] (Fig. 14.14).
is generally believed to have no pathologic significance,
although extensive cases may represent reduction of vascular 14.2.3.4 Other
plate that might affect fetal circulation. Similar to circum- Amnion nodosum consists of small, yellow-white, caseous,
marginate, circumvallate placentas show a double-backed easily removed plaques that consist of sloughed keratin, hair,
membrane fold where the membranes contact the placenta and other debris from the fetus. Amnion nodosum is a patho-
surface, and are associated with prematurity and chronic logic finding, usually associated with oligohydramnios [2].
bleeding. The latter is because hemorrhage often occurs in Squamous metaplasia, on the other hand, consists of nod-
this marginal region, presumably causing the membranes to ules/small plaques that are similar in color to the amnion
separate from the disc and then later refold on themselves [2, nodosum, but are tightly adherent and not readily removed
5] (Fig. 14.13). [2]. Squamous metaplasia is considered a normal finding at
Fig. 14.14 Amniotic band. The presence of free strips of amnion, seen
here adjacent to the umbilical cord insertion site, indicates disruption of
the amniotic sac. This example likely occurred at the time of delivery
tions with demise of one or more fetuses, the tissue may not
be completely resorbed. In this situation, a firm mummified
fetus papyraceous can be identified; depending on the gesta-
tional age of demise and time of delivery the tissue can range
c from very firm and sclerotic to semi-firm and necrotic.
Placenta membranacea, also called placenta diffusa, is a rare
developmental abnormality of the human placenta in which
fetal membranes are covered diffusely by chorionic villi of
varying thickness [2] (Fig. 14.15).
14.2.4 Placental Disc
14.2.4.1 Maternal Surface

Examining the maternal surface starts with assessing for
intactness of the cotyledons; incompleteness suggests the
possibility of retained placental tissue (discussed earlier). A
thick white layer involving the maternal surface is indicative
Fig. 14.13 Membrane insertion. (a) Normal (marginal) insertion. Despite of a maternal floor infarction, which is actually fibrin entrap-
the abnormal cord insertion, the free membranes begin right at the margin
of the disc. (b) Circummarginate insertion. There is a dense band of fibrin ping the basal villi, as opposed to a true infarction [2].
concentrically around the periphery, bringing the point where the mem- Retroplacental hemorrhage is found on the maternal sur-
branes lift off closer to the center of the disc. (c) Circumvallate insertion. face, always overlies villous tissue, and is a sign of prema-
There is a dense band of fibrin located at the periphery of the disc, and in ture separation (corresponding to the clinical diagnosis of
addition a flap is present at the bottom portion of the insertion. The flap
consists of membranes folded back on themselves abruption). The gross appearance of retroplacental hemor-
rhage depends on how much blood is trapped, and for how
long it has been present. A recent hemorrhage may show
term, and is noted most frequently near cord insertion. very little change, and may not be grossly apparent at all.
Occasionally, a yolk sac remnant is encountered. These are Acute abruption is a clinical diagnosis that will not necessar-
round, firm/calcified discs (~2 mm) within the membranes; ily have any gross or histologic findings, though it can be
they have no clinical significance. In multigestation concep- associated with amniotic fluid infection (“inflammatory
a b
c d
Fig. 14.15 Plaques on the fetal membranes. (a) Squamous metaplasia. associated with prolonged oligohydramnios. They are removable. (c)
These small plaques are commonly seen in term placentas, especially Yolk sac remnant. Present as a single, firm nodule in the free membranes
near the umbilical cord insertion site. They are not removable. (b) or fetal surface of the disc, this is a normal, if unusual, finding. (d) Fetus
Amnion nodosum. The plaques (upper left, inset) are pathologic and papyraceous. The dark pigment of the retina often stands out (arrow)
abruption”). If bleeding is confined behind the placenta for a prenatal ultrasound. The majority of these are not otherwise
significant amount of time, the overlying hematoma com- clinically significant and represent chorionic or subchorionic
presses the villous tissue and can lead to infarct, with notable hemorrhage; the appearance can be relatively dramatic
thinning of the disc in that area (Fig. 14.16). Chronic mar- (Fig. 14.18).
ginal retroplacental hemorrhage can result in chorioamniotic
hemosiderosis, which reflects hemorrhage into the amniotic 14.2.4.3 Parenchyma
fluid [2]. Cut sectioning of the normal placental disc reveals a dark
red, spongy surface. Serial sectioning of the disc at regular
14.2.4.2 Fetal Surface intervals (approximately 1–2 cm) is important to unveil any
The fetal surface is assessed for subchorionic fibrin and infarcts or thrombi.
thrombotic material, both of which can increase through Obstruction of the uteroplacental (maternal) circulation
pregnancy. Patchy fibrin deposition is usually of little signifi- leads to placental infarcts, defined in part by villous necrosis.
cance. A dull, opaque appearance to the fetal surface can be Minor infarcts are seen in about a quarter of placentas, but
a sign of ascending infection, with more severe cases appear- they are not of much clinical significance unless at least 30%
ing more dramatic due to the numerous neutrophils and of the placenta is involved. Single infarcts, especially at the
tissue necrosis (Fig. 14.17). Thrombosed fetal vessels are not placental margin, are not unusual in term placentas, but
rare, with chalky deposits representing calcified old throm- remember that any infarct in a preterm placenta is considered
boses [2, 5, 10]. In some cases, a cyst may be identified on abnormal [2, 4, 5]. Compared to adjacent tissue, placental
a b
Fig. 14.16 Retroplacental hemorrhage. (a) Maternal surface showing adherent blood clot, consistent with hemorrhage occurring prior to delivery.
(b) Cross section of remote retroplacental hemorrhage; the underlying placental parenchyma is thinned due to the presence of the confined blood
a b
Fig. 14.17 Discolored membranes. (a) Green-tinged membranes are suggestive of meconium staining. (b) Dull, opaque membranes are often
associated with a significant acute fetal inflammatory response, such as to amniotic fluid infection
infarcts are firmer and granular; the appearance progresses pallor that retains the usual consistency of villous parenchyma
from red and hemorrhagic to yellow to tan-white over time. (as contrasted with the denser firmness of an infarct). The base
Palpation can aid in detecting earlier infarcts, as can formalin of the triangle is usually located at the basal plate and can
fixation. Infarcts are more common at the periphery, with sometimes be visualized more easily in a fixed specimen [23].
central infarcts more indicative of true pathology, especially Intervillous thrombi are found within the parenchyma,
if multiple [2, 5] (Fig. 14.19). expanding the intervillous space. Early thrombi are fresh red
Clusters of avascular villi are caused by prolonged or recur- clots, which evolve to laminated thrombi, and eventually
rent occlusions within the fetal vasculature, which can eventu- white lesions. They can be differentiated from infarcts by
ally lead to a whole branch of the villous tree becoming their shiny quality and lack of granularity [2, 5] (Fig. 14.20).
avascular and atrophic. If there is a large enough focus of avas- An entity that can be confused with infarcts and thrombi
cular villi, it may be visible grossly as an area of triangular is the chorangioma, a firm fleshy lesion usually found under
a b
Fig. 14.18 Placental surface cysts. (a) A relatively large subamniotic/subchorionic cyst, or hematoma. As here, this finding is most often seen near
the cord insertion. (b) Multiple small amniotic and subamniotic/chorionic cysts, some with hemorrhage. These are of no clinical consequence
cm 1 2 3 4 5
Fig. 14.20 Intervillous thrombus. There is a large laminated thrombus

in this preterm placenta, surrounded by pale parenchyma
c the chorionic plate with varying degrees of hemorrhage and

infarction [24] (Fig. 14.21). It is possible to see single or
multiple reddish-brown well-circumscribed nodules often
located in marginal or subchorionic region which suggests
the possibility of a chorangioma (this will be discussed in
greater detail in the histologic section of this chapter).
Fig. 14.19 Placental infarcts. (a) Cross section of placenta showing

multiple infarcts of various ages. There is very little normal paren- 14.2.5 Twin/Multiple Gestation Pregnancy
chyma visible in this section; the small strip of parenchyma in the mid- Development
dle just deep to the fetal surface appears relatively uninvolved. (b) Two
well-defined infarcts, one with unusual pseudocystic change. (c) The
pale tan area on the far left is a more remote area of infarction, and just
With the rise in the use of fertility-enhancing therapies and
adjacent is a more recent infarct. Even the recent area of infarction has an older average maternal age, the incidence of multiple
a sharp, well-defined border with uninvolved parenchyma births has increased dramatically over the past three decades.
a their own specific complications such as twin-to-twin trans-

fusion syndrome, discordant growth restriction, and malfor-
mations [25].
A brief statement on the development of twin/multiple
pregnancies: zygosity refers to the type of conception; twins
can be either monozygotic or dizygotic. Dizygotic (fraternal/
nonidentical) twins are more common and result from mul-
tiple ovulation with near-synchronous fertilization of two
ova by two sperm cells. Monozygotic twins result from the
fertilization of one ovum by two sperm cells and the subse-
quent division. The reasons why both monozygosity and
dizygosity occur are not fully elucidated but are believed to
be multifactorial [25].
b Related to zygosity is the type of placentation, or chorion-
icity, of the resulting placenta. Dizygotic zygotes each devel-
ops its own amnion, chorion, and placental circulation. A
fused placental mass (still with separate components) devel-
ops when the two blastocysts implant close to one another.
Monozygotic pregnancies are not as straightforward, with
the type of placentation depending on when the zygote
divides, with early division (with the 3 days of fertilization)
resulting in dichorionic placentas. Late division is defined as
8–12 days after fertilization and results in a monoamnionic-
monochorionic placenta. Division in between those time
periods results in diamnionic-monochorionic placentas.
Division later than 12 days results in conjoined
monoamnionic-monochorionic twins [25].
14.2.6 Gross Examination of the Twin

c
and Multigestation Placenta
All twin and other multigestation placentas should be evalu-

ated, at least macroscopically. The placentas should be
labeled at the time of delivery to identify which cord belongs
to which infant. As fixation may compromise any potential
vascular injection studies (if indicated/possible), fresh exam-
ination of twin placentas is preferred.
14.2.6.1 Chorionicity
One of the first things that should be assessed grossly is the
chorionicity (how many discs are present) and amnionicity
(how many amniotic sacs are present) of the placenta. Zygosity
cannot be determined by placental examination, with the excep-
Fig. 14.21 Chorangioma. (a) This mass lesion is well defined, multi- tion of monochorionic placentas, which occur only with mono-
lobulated, and somewhat fleshy. (b) The lesion is clearly demarcated zygosity (taking care to exclude fused discs). Useful algorithms
from the surrounding parenchyma. (c) On high power, the mass is com- have been described previously regarding the assessment of
posed of small, bland capillary-type vascular structures set within in a twin placentation (histologic depictions of various membrane
hyalinized stroma
configurations are presented later in this chapter):
Perinatal mortality of twins is roughly five times that of (a) Separate or fused discs: Separate discs (connected by only
singletons, largely due to increased prematurity rates in the membranes) are diagnostic of diamniotic-dichorionic pla-
twin population. Monochorionic twins, in particular, have centas. Fused discs are dichorionic and usually diamniotic
(see below). Single discs by definition are always mono-

chorionic, and may be diamniotic or monoamniotic.
(b) Dividing membrane present or absent: In cases with a
single disc or with fused discs, the placenta is examined
for the presence of a dividing membrane. If no dividing
membrane can be identified, it is suggestive of a
monoamniotic-monochorionic placenta. It is important
to remember that the dividing membranes may be
stripped or disrupted, giving the false impression of a
monoamniotic placenta. Fused placenta discs should
always have started with a dividing membrane.
(c) Layers of the dividing membrane: Careful examination
of the layers of the dividing membrane allows the pro-
sector to differentiate between diamniotic-dichorionic
and diamniotic-monochorionic placentas. A relatively
thick, slightly opaque dividing membrane composed of Fig. 14.22 Anastomoses in a twin placenta. Vessels clearly traverse
3–4 layers is indicative of diamniotic-dichorionic, pro- this monochorionic disc, from the area of one cord insertion to the
viding that there are clearly separated chorionic vascular other. Foci where an artery and vein enter the disc together are sites of
beds. Very thin, translucent, two-layered dividing mem- possible arteriovenous anastomoses (circle)
branes, less firmly attached to the chorionic plate, are
seen in diamniotic-monochorionic placentas.
Twin placentas deemed dichorionic can be grossed as one

normally does singleton placentas, with each placenta
addressed separately. If the discs are fused, however, the pla-
cental weight should be combined (do not cut and weigh the
portions separately!). Monochorionic twin placentas, on the
other hand, have an increased rate of major complications,
some of which have been associated with gross placental
findings; these findings should be searched for and docu-
mented, specifically the type of cord insertion, degree of pla-
cental sharing, and presence or absence of artery-artery (AA)
and vein-vein anastomoses (VV) [11, 25, 26].
14.2.6.2 Anastomoses
Regarding inter-twin anastomoses, it is useful to note that
Fig. 14.23 Laser ablation of anastomoses for twin-twin transfusion
chorionic arteries are identified by their tendency to run syndrome. The irregular to oval areas in the center (arrow) are the sites
superficial to their accompanying veins (arteries travel over of in utero laser ablation
veins). AA and VV anastomoses are superficial and do not
penetrate the chorionic plate, and are usually of minimal sig-
nificance. Arteriovenous (AV) anastomoses, however, are dye is injected through these, allowing the examiner to visu-
deeper, occur at the villous capillary level, and cannot be alize the anastomoses [11, 25, 26]. In practice, this is very
seen when examining the chorionic plate. One can instead rarely performed.
describe/sample the sites of an unpaired artery and vein in
close proximity to one another [11, 25, 26] (Fig. 14.22). 14.2.6.3 Laser Treatment
Injection studies are not routinely needed, but may be In cases of severe chronic TTTS, possible prenatal treat-
pursued for academic purposes, at clinician/parent request, ments include serial amnioreduction, and fetoscopic laser
or in cases of laser ablation for twin-twin transfusion syn- coagulation (ablation) of the communicating vessels.
drome (TTTS). To perform an injection study, the umbilical Depending on the timing of the photocoagulation, gross find-
cords are sectioned, with a stump left for cannulation of the ings range from hemorrhagic clotted vessels with interrup-
vessels. Manual “milking” of the superficial vessels removes tion of dye filling (if examined within 1 month of
remaining intravascular blood. Umbilical catheters are photocoagulation) to absence of inter-twin anastomoses with
inserted into the umbilical vein and arteries of each cord and subchorionic fibrin deposition [25] (Fig. 14.23).
14.2.6.4 Fetus Papyraceus 14.3 H

istologic Features and Findings
When a fetus in a multigestation pregnancy dies in utero, it is of the Placenta
either partially or completely reabsorbed. This results, in
some instances, in a flattened, parchment-like state known as 14.3.1 Umbilical Cord
fetus papyraceus. In some instances a sclerotic placental
component also remains. Many umbilical cord findings are only identified grossly
(knots, length, etc.).
14.2.7 Gross Examination of the Placenta 14.3.1.1 Basic Structure

in Fetal Demise Histologically, the vessels are surrounded by the mucoid
extracellular matrix known as Wharton’s jelly, and the cord
In instances of midgestation or term fetal demise, pathologic is surfaced by a single layer of cuboidal amniotic epithelium.
examination is incomplete without inclusion of the placenta; Microscopic examination of the umbilical cord consists pri-
if an etiology of demise is identified, it is most often found marily of looking for inflammation, and assessing the vascu-
there. Gross evaluation for these placentas is not much dif- lature for thrombi and number of arteries.
ferent than routine examination. Most critically, a proper Other normal structures that may be present within a cross
review of clinical records is important in discerning areas of section of the cord include developmental remnants. Not
focus during analysis, but all placental components should uncommonly, allantoic or vitelline duct remnants are identi-
be given fair attention. For example, if the Kleihauer-Betke fied (Fig. 14.24). In some cords, dilated small capillary-sized
test is positive (indicating fetal hemoglobin in the maternal vessels are noted; the significance of this is unknown.
blood), be sure to note if the parenchyma appears more pale
than usual. If the mother has a history of preeclampsia, look 14.3.1.2 Acute Inflammation
carefully for infarcts. If the demise was relatively remote, the Funisitis is acute inflammation of the substance of the umbil-
fetus will be macerated and the placenta firm and small for ical cord, and represents an acute fetal inflammatory
dates. Take care to look for discrete thrombi within the response. Initially, the response tends to involve margination
umbilical cord and fetal surface of the disc. of neutrophils out of the umbilical vein (which is bringing
Fresh tissue may be saved for possible cytogenetics stud- oxygenated blood back from the placenta to the fetus) at the
ies and culture for organisms, if indicated or requested; how- placental disc end of the cord, followed by involvement of
ever these studies are rarely informative. the arteries, and finally the infiltrate extends into Wharton’s
Specific findings that can be associated with fetal demise jelly (at which point it is termed funisitis) [12, 13, 15]
are discussed later in the chapter (see Constellation Disorders (Fig. 14.25). Though most often associated with amniotic
in particular). fluid infection (see also the section on amniotic fluid infec-
a b
Fig. 14.24 Embryologic remnants in the umbilical cord. (a) Allantoic remnant. As seen here, these are most often lined by mucin-rich epithe-
duct remnant. These structures are lined by a cuboidal to flat epithelial cells, but rarely other tissue types are noted. A muscular layer or
lium, resembling transitional type epithelium or urothelium. A muscu- associated small vessels are occasionally seen
lar wall is always lacking. (b) Vitelline (omphalomesenteric) duct
a b
c d
e f
Fig. 14.25 Acute inflammation in the umbilical cord. (a) Funisitis. umbilical vessel. (d) A robust neutrophilic infiltrate extending beyond
Low power of the umbilical cord with acute inflammation marginating the vessel and into Wharton’s jelly (funisitis). (e) Gross appearance of a
out of the vessel and spilling into Wharton’s jelly (arrow). (b) Higher thrombosed umbilical artery (arrow). (f) Thrombosed and calcified
power of an umbilical vessel with neutrophils present between the mus- umbilical artery
cle fibers. (c) Acute inflammation confined to the muscular wall of the
tion below), these findings can also be seen with in utero (c) Chorion, including the sclerotic villi of early gestation
meconium exposure. When associated with meconium, the (chorion laeve) and trophoblasts
inflammation tends to be more pronounced in the umbilical (d) Maternal decidua
cord than the chorionic plate, and meconium-laden macro-
phages should be identifiable histologically. 14.3.2.2 Meconium
Meconium, the bile-stained intestinal content of the fetus, is
14.3.1.3 Thrombi occasionally expressed at delivery or prior to delivery. If
Thrombi will show usual organization with alternating expelled into the amniotic fluid well prior to delivery, it can
fibrin and clot within the lumen, as in any other vessel [12, stain and irritate the fetal membranes, will be preserved
13, 27]. within macrophages, and can therefore be identified histo-
logically. Meconium expressed at the time of delivery will
rinse off easily and won’t be found within macrophages on
14.3.2 Membranes histologic examination. Meconium-laden macrophages are
large, are round to ovoid, have slightly granular yellow-
When examining the membranes histologically (Fig. 14.26), brown material filling their cytoplasm, and are usually iden-
the pathology to be evaluated ranges from pigment in the tified in the subamniotic spongy layer. If meconium has been
membranes to evidence of an inflammatory response and to present in the amniotic cavity for many hours, the amnionic
searching for maternal arteriopathy within the decidua. epithelium may show degenerative changes, including vacu-
olization of the cytoplasm, heaping up of cells, hobnailing,
14.3.2.1 Basic Structure dissociation, loss of cells, and necrosis. Meconium staining
Histology of the extraplacental membranes consists of: affects the amnion before the chorion, as the macrophages
travel through the layers of the membranes (Fig. 14.27).
(a) Cuboidal amniotic epithelium, with its underlying base-
ment membrane 14.3.2.3 Squamous Metaplasia
(b) A hypocellular “spongy” layer with scattered fibroblasts, This is a finding that is present in more than half of term
which is really a potential space placentas. It is not a true pathologic finding, but a sign of
placental maturity. The amniotic epithelium becomes strati-
fied with focal keratinization of the epithelium, resembling
squamous epithelium. It is most often identified near the
umbilical cord insertion (Fig. 14.28a).
7
1
2 3
Fig. 14.26 Fetal membranes. The membranes are composed of several

layers, starting with the amniotic epithelium (1) with its underlying
basement membrane and fibroblast layer (2). The spongy layer (3) is a
potential space that divides the amnion from the chorion. The reticular
layer of the chorion (4) contains fibroblasts, next to which is the base- Fig. 14.27 Pigment-laden macrophages in fetal membranes. The
ment membrane of the chorion and the chorionic trophoblasts (5). The slightly granular brownish pigmented meconium is present in macro-
final layer is decidua (6), which is the only maternal tissue component phages (arrow). The amniotic epithelium exhibits reactive changes,
present, and is where spiral arteries are most easily identified (7) including heaping up, cytoplasmic vacuolization, and dissociation
a b
c
d
Fig. 14.28 Fetal membranes. (a) Squamous metaplasia. Keratinizing sac remnant. A well-defined, circumscribed, and calcified plaque, just
epithelium is present, in contrast to the normal cuboidal amniocytes under the amniotic epithelium. (d) Fetus papyraceous, with ghost out-
(upper right of image). (b) Amnion nodosum. Grossly identified plaques lines of devitalized and calcified fetal tissues
are composed of degenerated squamous cells, hair, and debris. (c) Yolk
14.3.2.4 Amnion Nodosum absent, and there are usually few signs of degeneration [21].
This condition is associated with prolonged oligohydram- Amniotic bands need to be assessed grossly.
nios of any cause, though the mechanism is not understood.
Microscopically, the nodules are composed of sloughed fetal 14.3.2.6 Acute Chorioamnionitis
squamous cells and hair, mixed with hyaline and protein- The pattern of pathologic findings commonly referred to as
aceous debris. There is no associated inflammation. The nod- “chorioamnionitis” is most often indicative of ascending
ules are usually situated superficially on the amniotic surface, amniotic fluid infection. Its definition is the presence of neu-
but sometimes extend through to the spongy layer trophils (PMNs) within the fetal membranes. Eosinophils
(Fig. 14.28b). Other lesions such as yolk sac remnant and may be present, especially in protracted infections, though
fetus papyraceous may be seen in Fig. 14.28c, d chronic inflammatory cells are generally not a significant
respectively. component of the response. PMNs may be present within the
decidua and/or chorion, even in the absence of an infectious
14.3.2.5 Amniotic Bands process. The term “acute chorioamnionitis” should be
Histologic sections show normal-appearing amnionic epithe- reserved for instances of inflammation extending into the
lium and underlying connective tissue. Inflammation is subepithelial hypocellular space to involve all layers of the
a b
Fig. 14.29 Acute chorioamnionitis. (a) Acute inflammation extends infiltrates and necrosis of the amniotic epithelium (arrow). (c)
all the way up from the decidua (bottom of image) through the chorion Chorionitis. The neutrophils are dense within the chorion, but have not
and spongy layer into the amnion and is present just under the epithe- yet crossed into the reticular or amniotic layers; chorioamnionitis
lium. (b) Necrotizing chorioamnionitis with confluent neutrophilic should not be reported here
membranes [15, 23, 28] (Fig. 14.29). See also the section on chorionic villi. These free villi are covered by a thin syn-
amniotic fluid infection sequence. cytiotrophoblastic layer, with a discontinuous cytotro-
phoblastic layer, which is in contact with sinusoidal
capillaries. The dense collection of capillaries and sinu-
14.3.3 Placental Disc soids in terminal villi comprises at least 50% of the stro-
mal volume in these small structures. Syncytial knots,
Findings within the parenchyma of the disc (and its compart- which are aggregates of syncytiotrophoblast nuclei pres-
ments) are often related to lesions initially discovered upon ent along one surface of terminal villi, are also a sign of
gross examination, and to histological findings of the umbili- villous maturity (Fig. 14.30).
cal cord and membranes. (a) Hypermaturity: In instances of underperfusion, or
A brief discussion of villous maturation is merited before placental hypoxia, the tertiary villi respond to
additional findings of the disc are elaborated. Various types decreased blood flow and poor oxygenation by
of villi have been discussed previously; what follows is a exhibiting accelerated maturation. There is an
summary of what to look for in terminal villi when assessing increase in mature tertiary free villi (relative to ges-
maturity. tational age), as well as an increase in syncytial
knots (so-called Tenney-Parker change). It is gener-
1. Maturity mature terminal villi are found in the third tri- ally agreed that knots in >20% villi preterm or >30%
mester of pregnancy, and are the smallest versions of at term are considered increased, though this is a
a very subjective measure. Hypermaturity is most eas-

ily appreciated in a second-trimester placenta with
extensive mature terminal villi and prominent syn-
cytial knots (Fig. 14.30a).
(b) Immaturity placental villous “immaturity,” best

termed delayed villous maturation, can be seen after
36 weeks gestation, and has been associated with
diabetes mellitus, Beckwith-Wiedemann syndrome,
and fetal demise. The features include clusters of
intermediate-type villi (at least ten) with abundant
stroma, and increased numbers of centrally located
capillaries with a large diffusion distance (vessel-to-
villous surface distance) (Fig. 14.30c). There will
also be fewer tertiary villi than expected. Similar to
the evaluation of hypermaturity, this assessment is
b very subjective, but should be considered only when
the amount is significant (involving at least 30% of
villi in one full section) [23].
2. Maternal Decidual Arteriopathy
During a normal gestation, the spiral arteries of the
decidua undergo significant remodeling as trophoblasts
invade and replace the maternal endothelial cells, result-
ing in ectatic, open vessels which are crucial for ade-
quate perfusion of the placenta. Should this fail and the
smooth muscle layer persist, maternal decidual
arteriopathy occurs. This results in decreased blood flow
to the placenta, apparently due to one, or a combination,
of the following: overall lower supplied volume, higher
pressure “jets” of blood that don’t mix sufficiently, or
intermittent vasoconstriction associated with the mater-
c nal vascular response to a variety of stimuli. Examination
of the maternal decidual vessels shows small spiral
arteries with intact smooth muscle walls. Fibrinoid
necrosis of muscular wall (with a brightly eosinophilic,
glassy appearance) with foamy macrophages can also be
seen; in the past, this was termed the “severe” pattern,
though this does not correlate well with severity of clini-
cal disease (Fig. 14.31). Remember that this process is
multifocal and does not affect every spiral artery.
Arteriopathy is most easily identified in the membrane
roll, which has the largest surface area in which to iden-
tify affected vessels [23]. See also the section on mater-
nal vascular malperfusion below.
3. Acute Villitis
Rarely, neutrophils may be identified in fetal capillaries
and the stroma of tertiary villi; if present, a diagnosis of
Fig. 14.30 Villous maturity. (a) Mature terminal villi in a 39-week
acute villitis should be made. Acute villitis is an indicator
placenta with attenuated cytotrophoblastic surface layer; vessels take of fetal sepsis. Occasionally, stains can highlight caus-
up the majority of the villous volume. (b) Hypermaturity in a ative organisms, though this is not altogether reliable.
31-week placenta. The small size of the terminal villi and extensive Additionally, the medical record should be consulted to
syncytial knots are much more than expected at this gestational age.
(c) Delayed villous maturation in a 40-week placenta. The large ter-
determine if the infant is being treated for possible sep-
minal villi with more centrally placed capillaries are typical of an sis. If the status of the infant is unknown, the obstetrician
earlier gestational age or pediatrician should be contacted right away [28].
a b
c d
Fig. 14.31 Maternal decidual arteriopathy. (a) Transformed vessels muscular wall. (c) Fibrinoid necrosis with acute atherosis. The brightly
within the decidua; there is no discernable smooth muscle layer and the eosinophilic vessels stand out from the pale decidual cells in this exam-
lumens are widely patent. (b) Decidual vessels with retention of the ple. (d) Fibrinoid necrosis with atherosis, higher power. At this power,
the lipid-laden macrophages within the fibrinoid material are apparent
4. Villitis of Unknown Etiology if it is identified in multiple slides. High-grade lesions

Villitis of unknown etiology (VUE) is not an uncommon are those involving more than ten villi in at least one
finding, and has been reported in 3–5% of placentas sub- focus. High-grade villitis is further classified as patchy
mitted to pathology. The histologic findings can range when it is seen in one or more slides, and diffuses if at
from cases in which chronic inflammation involves a least 30% of the villi are affected (Fig. 14.32). The
small cluster of 5–10 villi to significant, diffuse, involve- affected foci may be confined to the parabasal areas,
ment. By definition, this diagnosis excludes any chronic paraseptal areas, scattered randomly throughout the
villitis with an identified etiology, such as infection. The parenchyma, or in any combination. Villitis confined to
inflammatory component consists primarily of lympho- the basal and parabasal regions has been associated with
cytes and histiocytes; significant numbers of plasma pregnancies achieved with assisted reproductive tech-
cells should not be present. A viral etiology should be niques, but overall the significance of the variable distri-
considered if plasma cells are easily encountered. It is butions is unknown [23].
recommended that VUE be graded, since the association 5. Infarct
with adverse outcomes is much stronger with more Histologic examination of remote infarcts shows pale,
extensive involvement. Low-grade lesions are those eosinophilic ghost villi, which is due to loss of nuclear
affecting fewer than ten villi per focus, with more than basophilia. The intervillous space is obliterated by fibrin
one focus required. Low-grade villitis is further classi- deposition as well as agglutination of the villi. Villous
fied as focal if it involves only one slide, and multifocal stromal fibrosis and cytotrophoblastic proliferation are
a b
c d
e f
Fig. 14.32 Villitis of unknown etiology (VUE). (a) Focal VUE. A one full-thickness section). (d) High-grade VUE, also a diffuse pattern.
cluster of hypercellular villi are present in the middle of the image. This example is relatively subtle; the top half of the image is composed
Though the finding is focal, this would be classified as high grade as of affected villi while the lower half is relatively spared. (e) Higher
>10 contiguous villi are involved. (b) On high power, the infiltrate is power appearance of the diffusely involved, sclerotic villi. (f) An immu-
identified as lymphocytic. Also note the lack of villous capillaries in the nohistochemical stain for CD3 (nuclear) confirms that the infiltrate is
affected villi. (c) High-grade VUE, diffuse pattern (involves >30% of composed predominantly of lymphocytes
absent (Fig. 14.33). Foci of more recent infarction show increased, or more prominent, syncytial knots, which
more subtle changes, including villous crowding, con- retain their nuclear basophilia. In foci of avascular villi,
gestion, a mild inflammatory response, and stromal the villous stroma is eosinophilic and hyalinized, and
karyorrhexis [4–6, 10]. It is important to distinguish lacks stromal capillaries. Finally, the intervillous space
infarcts from avascular villi. is predominantly open and contains maternal blood; it is
6. Avascular Villi not obliterated as with an infarct [6, 10, 23] (Fig. 14.34).
Clusters of avascular villi tend to be closely apposed to 7. Intervillous Thrombi
normal villi, and thus appear sharply demarcated from If enough time has passed for the thrombus to be prop-
the surrounding parenchyma. This finding is differenti- erly organized, it will have the usual appearance of an
ated from an infarct in several ways. First, the tropho- organized clot, with the alternating red and pink lines of
blastic layer is still viable due to perfusion by maternal Zahn. The red is composed of entrapped red blood cells
blood in the intervillous space. There may also be and the pink is composed of fibrin. Grossly, it can be
a b
Fig. 14.33 (a) Edge of a placental infarct. The infarcted villi (top) are bordered by a rim of ischemic parenchyma, including prominent syncytial
knots. (b) The center of the infarct shows ghostlike villous structures with near-complete loss of nuclear basophilia
a b
*
*
Fig. 14.34 (a) The cluster of avascular villi (*) stands out from the contrasted with unaffected tissue on the right. Note the open intervil-
background of unaffected villi due to its brightly eosinophilic hyalin- lous space occupied by maternal blood, and the lack of significantly
ized stroma. Note the lack of fetal capillaries, and retained nuclear increased intervillous fibrin deposition
basophilia of the trophoblasts. (b) A larger focus of avascular villi (left)
a b
Fig. 14.35 (a) Intervillous thrombus with prominent laminations ischemia, including increased fibrin deposition, prominent syncytial
(lines of Zahn). (b) The edge of a large intervillous thrombus. As shown knots, and a mild chronic inflammatory response. Over time, the villi
here, the parenchyma just next to a thrombus can show evidence of can become completely infarcted
difficult at times to distinguish these from infarcts but (b) Partial hydatidiform mole (PHM): In a well-developed
microscopic examination usually makes it clear which partial hydatidiform mole, two relatively discrete vil-
pathology is present (Fig. 14.35). lous populations can be seen. One population is
8. Meconium composed of large hydropic structures, and the other of
Meconium-laden macrophages can also be seen in the smaller, more normal-appearing villi. The hydropic
chorionic plate of the disc, under the amniotic epithe- villi have occasional central cisterns, exhibit areas of
lium, just as in the membranes. If there is a history of lacy trophoblastic hyperplasia (without atypia), and are
meconium-stained fluids or if the fetal surface has a notable for their unusual peripheral architecture. The
green tinge, it may be prudent to carefully examine the hydropic villi of partial moles often have prominent
specimen microscopically. invaginations of the surface, creating a scalloped
9. Hydropic Change appearance (“fingers and toes,” or “coast of Norway”).
This finding is usually noted in very early gestations, There should also be evidence of fetal tissue, often
such as in therapeutic or missed abortion specimens. noted in the form of nucleated red blood cells.
Swollen or dilated villi, with lightly basophilic hypocel- Immunohistochemical staining for p57 will be positive
lular stroma and few to no residual vessels, are the hall- within the villous stromal cell nuclei (Fig. 14.36c, d).
marks of hydropic change. These changes can be (c) Complete hydatidiform mole (CHM): Well-developed
associated with degeneration due to fetal/embryonic examples of complete hydatidiform moles will have
demise, aneuploidy, partial hydatidiform mole (PHM), diffuse, rounded enlargement of the villi. Central cis-
or complete hydatidiform mole (PHM). A brief over- terns and inclusions are easily identified, and lacy cir-
view of molar pregnancy is present below; more infor- cumferential trophoblastic hyperplasia will be found.
mation on this topic is presented in Chap. 13. Prominent implantation site with notable trophoblas-
(a) Hydropic degeneration due to demise: In hydropic tic atypia is often associated with CHM, but this can
degeneration, a sign of lost pregnancy, there will be be a very subjective feature. No fetal tissues are pres-
enlarged round to oval villi with edematous stroma, a ent. CHM is due to uniparental (paternal) diploidy,
few residual vessels, atrophy of the syncytiotropho- and as such immunohistochemical staining for the
blasts, and evidence of embryonic or fetal tissue. maternally expressed protein p57 will be absent in the
While pseudocystic spaces may be seen, so-called villous stromal nuclei. Staining can be seen in the
inclusions (spaces lined by trophoblasts) within the extravillous trophoblasts, and does not exclude an
villi will be absent, and trophoblastic hyperplasia will interpretation as CHM (Fig. 14.36e–g).
not be present. In instances of demise, there is often Histologic diagnosis of suspected molar pregnancies,
an admixture of variably sclerotic and edematous villi particularly early in gestation, can be frustrating; it is not
[5] (Fig. 14.36a, b). entirely sensitive or specific, and suffers from high inter-
a b
c d
e f
Fig. 14.36 (a) Hydropic and sclerotic changes in a trisomy 16 concep- atypia is lacking and circumferential proliferation is absent. Villous
tus. Central cisterns are present, but inclusions and trophoblast hyper- contours tend to be complex and irregular. (e) Complete hydatidiform
plasia are absent. The edematous and sclerotic changes are present mole (CHM) showing edematous change of most villi, with prominent
along a spectrum; a discrete dual population is not present. (b) Hydropic central cisterns. Circumferential trophoblastic hyperplasia is present
change in a trisomy 16 conceptus; note also the irregular villous con- (*). (f) Trophoblast inclusions (*) are a feature of CHM. (g)
tours without trophoblast hyperplasia. (c) Partial hydatidiform mole Trophoblastic hyperplasia with atypia in a CHM. (h)
(PHM). Large edematous villi with central cisterns (right) are admixed CHM. Immunohistochemistry for p57 shows complete loss of nuclear
with a second population of smaller, more typical-appearing (or fibrous) staining in the villous trophoblasts. Extravillous trophoblasts often
villi (left). Note the irregularly contoured villous in the lower left. (d) show multifocal positive nuclear staining
PHMs exhibit some degree of trophoblastic hyperplasia (*), but notable
g h
Fig. 14. 36 (continued)
and intra-observer variability. Apart from immunohisto- more fibrous appearance of normal stem villi), and
chemical staining for p57 and clinical impression, there prominent fibromuscular vasculature with fibroblastic
are few useful tools to assist in separating molar gesta- overgrowth. Trophoblastic hyperplasia is absent
tions from non-molar pregnancies. In particular, it can be (Fig. 14.37b–d). As the pregnancy progresses, the abnor-
challenging to distinguish a PHM from other types of mal vascular component may become more pronounced,
aneuploid or hydropic gestations. In the clinical setting of and evidence of degenerative changes may appear [30].
a patient actively desiring pregnancy, the distinction can 11. Chorangiosis/Chorangiomatosis/Chorangioma
be immediately relevant. All three of the following conditions can be seen in
Conventional karyotyping and ploidy analysis cannot cases of chronic placental underperfusion, and are
distinguish between diandric triploidy and other triploid thought to be an adaptive response:
gestations, though a diploid result can exclude a partial (a) Chorangiosis: To diagnose chorangiosis, one needs
mole (and karyotype can identify a trisomy, for example). >/= 10 fields of placental parenchyma with >/= 10
More advanced genetic techniques may be of help, though terminal villi, each with 10 or more capillaries per
they are not yet routinely in use at most facilities [5, 29]. cross section. This is seen more frequently in diabetic
10. Placental Mesenchymal Dysplasia and preeclamptic pregnancies, and the placenta is
Placental mesenchymal dysplasia (PMD) is a rare, often large for gestational age. This is likely a normal
benign condition that is characterized by placentomeg- finding at high elevations.
aly. It is associated with Beckwith-Weidman syndrome (b) Chorangiomatosis: This extremely unusual lesion can
(in about a quarter of the cases), fetal growth restriction, be either localized or multifocal, and consists of
and gestational hypertension. Clinically, PMD is easily chorangioma-like lesions that, rather than forming a
mistaken for a molar pregnancy due to the striking cys- single nodule, extend into adjacent stem villi. The
tic villous changes; however, unlike molar gestations, it lesional vessels are surrounded by pericytes and there
can be associated with a viable, and even normal, fetus/ is increased stromal collagenization.
infant. (c) Chorangioma: This is an intraparenchymal nodule
On gross examination there will be an abundance of composed of capillaries, stromal cells, and surround-
tissue, or a large-for-gestational-age placenta ing trophoblasts. A villous structure is expanded by
(Fig. 14.37). Grossly visible cystic structures and pale, the abnormal vascular proliferation, and there may be
friable zones are typically interspersed within an other- associated trophoblastic hyperplasia with pleomor-
wise relatively normal-appearing parenchyma phism and atypia. These lesions are usually located in
(Fig. 14.37a). In third-trimester or term placentas, the the subchorionic or marginal zones of the disc, and
chorionic plate vasculature may be prominent, com- there can be either a single nodule or (less often) mul-
posed of dilated and tortuous vessels. Histologically, the tiple nodules. The majority of chorangiomas are inci-
changes of PMD vary somewhat with gestational age. dental, but if large (>5 cm) they can be associated
Even in early gestation, PMD is most notable for the with complications including polyhydramnios, fetal
large, hydropic stem villi with central cisterns (not inclu- thrombocytopenia, heart failure, and hydrops [24]
sions), myxoid change (in marked contrast with the (Table 14.2).
a b
c d
Fig. 14.37 Placental mesenchymal dysplasia (PMD). (a) Gross with cisterns are one of the hallmark findings in PMD. (c) Myxoid
appearance. This 13-week conceptus was clinically compatible with a change with prominent vasculature and fibroblastic stromal overgrowth.
complete mole; the specimen contained >70 g of tissue. There are many (d) Higher power showing the unusual vascular changes
easily appreciated cystic structures (circled). (b) Edematous stem villi
Table 14.2 Hypervascular lesions

Gross Microscopic Clinical features/prognosis
Chorangiosis – Not visible grossly – Formal definition rule of tens: – May be adaptive
– Placenta may be LGA At least 10 fields with at least 10 terminal – Unclear if it affects fetal outcome
villi which each contains at least 10
capillary profiles
Chorangiomatosis – Not visible grossly – No discrete nodular foci (unlike – Associated with other vascular
– No discrete nodules chorangioma) abnormalities
– Involves stem villi – Associated with AMA,
– Lesional vessels surrounded by pericytes preeclampsia, multiple gestation,
– Increased stromal collagenization preterm delivery, IUGR
– May be associated with platelet
sequestration and DIC
Chorangioma – Discrete nodule(s) – Composed of capillaries, stromal cells, – Never malignant
– Dark and soft (vascular) trophoblasts – Large lesions may be associated
or firm and tan (fibrotic) – Expanded villous structure by vascular with complications
– Usually marginal or proliferation
subchorionic – May show trophoblastic hyperplasia,
pleomorphism, and atypia
LGA large for gestational age, AMA advanced maternal age, IUGR intrauterine growth restriction, DIC disseminated intravascular coagulation
a b
Fig. 14.38 (a) Diamniotic dichorionic twin placenta. Chorion (*) is present between the two layers of amnion. (b) Diamniotic monochorionic
twin placenta. The two layers of amnion are directly apposed
12. Microscopic Examination of the Twin Placenta The pathologic findings of MVM include both gross and
Microscopically, twin placentas are examined in much microscopic changes. Grossly, there is evidence of poor pla-
the same fashion as singletons, with a major exception cental growth (a small [<10th percentile]-for-gestational-age
being confirming chorionicity when analyzing the layers disc), and evidence of maternal vascular disruption/occlu-
of the dividing membranes. Dividing membranes from a sion such as infarcts and retroplacental hemorrhage
diamniotic, dichorionic placenta (Fig. 14.38a) will have (Fig. 14.39a).
a trophoblast layer in the middle; monochorionic divid- The microscopic changes include confirmation of infarc-
ing membranes will have amnion directly apposed to tion, abnormal spiral arteries (maternal decidual arteriopa-
amnion (Fig. 14.38b). thy), and features of placental hypoxia. The histologic
13. Lasers findings of infarction and decidual arteriopathy are described
Laser-treated vessels show necrosis with focal hemor- above (Fig. 14.39b–d). Features of placental hypoxia include
rhage, clusters of avascular villi, and fibrin deposition in accelerated villous maturation (villous hypermaturity; see
the underlying parenchyma [25]. above) and distal villous hypoplasia. Distal villous hypopla-
sia is characterized by a notable reduction in distal/terminal
villi in relation to the intermediate and stem villi. The remain-
14.4 Constellation Syndromes ing villi tend to be elongated, with prominent syncytial knots,
and evidence of accelerated maturation. This finding is best
Constellation syndromes are a group of disorders that encom- appreciated on low power, and should involve at least 30% of
pass findings in multiple parts of the placenta, both gross and one full-thickness section [5, 23].
microscopic, and are due to a single underlying etiology.
14.4.2 Fetal Vascular Malperfusion

14.4.1 Maternal Vascular Malperfusion
Fetal vascular malperfusion (FVM) refers to a group of
The pattern of findings termed maternal vascular malperfu- findings that result from inadequate fetal blood flow to the
sion (MVM) develops as a consequence of impaired, or placenta. The underlying causes of fetal vascular malper-
insufficient, maternal blood flow to the placenta due to fusion are many, and similar findings can be identified in
abnormal spiral artery perfusion. The abnormal blood flow is instances of intrauterine demise and live birth, which com-
due, at least in large part, to problematic or incomplete plicates interpretation in some cases; vascular changes are,
remodeling of the maternal vasculature by trophoblasts. The of course, very common in the setting of demise. The
cause of abnormal remodeling is still unknown, but is most underlying reason for fetal vascular malperfusion includes
strongly associated with preeclampsia/eclampsia and mater- anything that would disrupt normal flow to the placenta,
nal hypertension; however, it is also seen with increased fre- such as fetal vascular thrombosis, hypercoagulability,
quency in multiple gestations, and other types of abnormal umbilical cord constriction, or fetal cardiac dysfunction, to
implantation. name a few.
a b
c d
Fig. 14.39 Maternal vascular malperfusion in a placenta from an upper portion of the image. This could be seen immediately adjacent to
intrauterine fetal demise at 31 weeks. (a) Gross appearance of multiple an infarct, but this change was present diffusely throughout the pla-
central infarcts. (b) Maternal decidual arteriopathy with fibrinoid centa. (d) A smaller “microinfarct” which was not appreciated grossly.
necrosis. (c) Low-power appearance of a large infarct (bottom of The agglutinated focus of villi in the top middle of the image shows
image), contrasted with the hypermature villi (for 31 weeks) in the nuclear smudging and loss of fetal capillaries
The established findings of FVM are predominantly tified in the most distal portions of the villous tree, resulting
microscopic, but relevant gross findings include the presence in randomly scattered small foci of avascular villi
of an umbilical cord thrombus, thrombi within the chorionic (Fig. 14.34).
plate vasculature, or a tight umbilical cord knot. The princi- The other pattern, which is due to segmental/complete
pal finding microscopically is clusters of avascular villi, as occlusion of a large fetoplacental vessel (often by thrombus),
described previously. To be identified as a “cluster” there leads to larger, more discrete foci of degenerating down-
should be at least 3–4 villous structures affected, with large stream villi. These villi initially show degenerative changes
foci including 10 or more villous cross sections; at least 3 (villous stromal karyorrhexis, vascular remodeling) and
separate foci should be identified to qualify as a diagnosable eventually lose all of their vessels, which results in a large
lesion (Fig. 14.40d–e). focus of avascular villi (Fig. 14.40f). When extensive, this
Fetal vascular malperfusion can have variable distribution pattern has been termed fetal thrombotic vasculopathy and
patterns. If associated with obstructive umbilical cord lesions has been associated with increased risk of fetal CNS injury,
such as hypercoiling or stricture, abnormal placental inser- as well as other adverse outcomes.
tion site, or long-standing fetal entanglements, the overall The associated vascular changes, other than a well-
histological features are suggestive of globally increased developed unequivocal thrombus, are more subtle and con-
venous pressure and poor circulation. The changes are iden- troversial. Additional vascular lesions that may be important
a b
c d
e f
Fig. 14.40 Global fetal vascular malperfusion in the setting of a tight rhexis. Thought to be an early sign of fetal vascular malperfusion,
umbilical cord knot. (a) A large, organizing thrombus is present in a karyorrhectic debris with extravasated/fragmented red blood cells are
chorionic plate vessel (*). (b) Downstream from the large thrombus, present in the villous stroma. (e) A cluster of avascular villi (right side
foci of intramural fibrin deposition are present (*). (c) Partially obstruc- of image) are present adjacent to uninvolved villi. (f) A larger zone of
tive vascular changes in a stem villous. (d) Villous stromal karyor- avascular villi; uninvolved villi are present at the upper right
to identify include vascular ectasia (large fetal vessels a

dilated to four times the size of adjacent similar vessels),
intramural fibrin deposition (formerly termed “intimal fibrin
cushion”), and stem vessel obliteration. Intramural fibrin
deposition is characterized by deposition of fibrin within the
vessel wall, often admixed with fragmented red blood cells,
or in long-standing lesions, calcification. Stem vessel oblit-
eration refers to the presence of notable thickening (“fibro-
muscular hyperplasia”) of the stem villous vessels, which
results in luminal obliteration. Remember that in instances
of fetal demise, the changes of decreased fetal blood flow
will begin quickly; diffuse changes involving nearly all of
the parenchyma are more likely a result of demise than evi-
dence of an etiology. Even in a background of diffuse
change, it may be possible to identify earlier, more well-
developed lesions. Organized thrombi are always consid- b
ered premortem events, but loose, myxoid changes to the
fetal vessels that can resemble remodeling are nearly always
diffuse or multifocal and are due to demise [5, 23, 31].
Diffuse vascular changes are nearly always a consequence
of demise, rather than the cause of it.
14.4.3 Amniotic Fluid Infection Sequence
The amniotic fluid infection sequence (AFIS) describes

the acute maternal and fetal inflammatory response to
ascending infection of the amniotic fluid, usually due to
cervicovaginal flora. E. coli and group B streptococci are
some of the most common causes of ascending amniotic
fluid infection. Fig. 14.41 Amniotic fluid infection sequence. (a) The maternal acute
The response can be considered as two parts: the maternal inflammatory response is chorioamnionitis; neutrophils are present
within the amnion of the fetal membranes. (b) The fetal inflammatory
inflammatory response and the fetal inflammatory response.
response is identified in the umbilical cord and chorionic plate vessels;
The maternal response is seen most easily in the membranes, neutrophils are marginating out of the lumen and into the vessel wall
where the inflammation originates from the decidual blood
supply (deciduitis, subchorionitis), and moves into the cho-
rion (chorionitis), and finally into the hypocellular zone just value in staging and grading the histologic response
beneath the amniotic epithelium (chorioamnionitis). The (Table 14.3). In particular, attention should be paid to the
maternal response can also be identified on the fetal surface presence and extent of the fetal response, which is more
of the placenta, where neutrophils migrate from the intervil- likely to indicate clinical disease, and to accurate docu-
lous space, through the chorion, and into the amnion. Fetal mentation of the location of inflammation. Neutrophils
inflammation is noted initially in umbilical vein, and then confined to the subchorionic space or the chorion, for
progresses to involve the umbilical arteries and finally example, should not be diagnosed as chorioamnionitis.
Wharton’s jelly (funisitis). Sections of umbilical cord taken Necrotizing inflammation, meaning karyorrhectic neutro-
closer to the fetal end demonstrate inflammation earlier in phils, often with evidence of tissue damage (such as
the course of infection than sections closer to the placental amniocyte necrosis), represents the final stage of inflam-
disc (Fig. 14.41). mation. The grade refers to the presence (Grade 2) or
Though it is understood that the clinical and histologic absence (Grade 1) of confluent neutrophils and/or micro-
severity does not correlate well, there still may be some abscess formation [23].
Table 14.3 Grade and stage of the inflammatory response to ascending amniotic fluid infection (Amsterdam Placental Workshop Group
Consensus Statement [23])
Stage Grade
Maternal inflammatory response
(Evaluated in the membranes)
1. Acute chorionitis or subchorionitis: Neutrophils within subchorionic fibrin, subchorial 1. Not severe
intervillous space, or at the choriodecidual interface 2. Severe: Confluent neutrophils or
2. Acute chorioamnionitis: Neutrophils extend into fibrous chorion and/or amnion subchorionic microabscesses
3. Necrotizing chorioamnionitis: Karyorrhexhis of neutrophils, amniocyte necrosis, and/or
amnion basement membrane hypereosinophilia
Fetal inflammatory response
(Evaluated in the large fetal vessels of the umbilical cord and placental surface)
1. Chorionic vasculitis or umbilical phlebitis: Neutrophils are present within the vessel wall 1. Not severe
2. Involvement of umbilical vein, and at least one artery: Neutrophils are present in the walls 2. Severe: Confluent or near-confluent
of at least two umbilical vessels neutrophils within a vessel wall,
3. Necrotizing funisitis: Neutrophils extend through a vessel wall into Wharton jelly, associated with vascular smooth muscle
with karyorrhextic/necrotic debris attenuation
a
14.5 Specific Infections
14.5.1 Candida
The presence of Candida is very common; at least 20–50%

of pregnant women are colonized; 50% of infants will be
colonized, and 10% of these infants will develop systemic
disease. The incidence of candidal colonization is higher in
women with a cerclage in place. The vast majority of infec-
tions (80%) are due to Candida albicans. Premature delivery
(prior to 28 weeks) is associated with increased incidence of
disseminated disease, and has a high risk of neonatal mortal-
ity. Evidence of candidal infection, particularly in a premature
placenta less than 28 weeks, is a critical finding and should
be communicated to neonatology immediately [32]. b
Grossly, the umbilical cord may show yellow-white
plaques, which are characteristic of this infection.
Histologically, the plaques are revealed to be subamnionic
microabscesses; associated necrotizing funisitis and acute
chorioamnionitis can also be seen. Organisms (Fig. 14.42a)
are usually very difficult to see without special stains, but are
easily identified with routine fungal stains (Fig. 14.42b).
Yeast forms with pseudohyphae are present within the micro-
abscesses of the umbilical cord, and may or may not be iden-
tified within the inflammation seen on the membranes.
Villous edema may be present, but granulomatous inflamma-
tion and inflammation involving the intervillous space are
not usually associated with candidal infection [32, 33].
14.5.2 Listeria Fig. 14.42 Candida infection. (a) Section of a membrane roll reveals
numerous yeast forms, some with signs of budding. (b) GMS stain of
the same placenta highlights the organisms
Listeria monocytogenes infection occurs in approximately
9/100,000 pregnancies, and about 20% of these infections white nodules can be identified scattered throughout the pla-
result in fetal or perinatal demise. Grossly, the amniotic fluid cental parenchyma. Histologically, the hallmark of listeriosis
appears meconium stained (even in premature deliveries is the presence of prominent acute intervillositis with micro-
unlikely to have passed meconium), and on cut section small abscess formation, which is what forms the white nodules
seen grossly. The villi themselves are relatively spared from growth restriction. Grossly, the placenta affected by syphilis is
inflammation, as this is a hematogenously spread infection thick, friable, and frequently pale. In about half of the cases, the
that is acquired via the maternal blood. Organisms are usu- umbilical cord has a “barber pole” appearance with chalky
ally appreciable with a gram stain [6, 28]. white necrotic debris surrounding the vessels. Histologically,
the “barber pole” appearance is due to severe necrotizing
funisitis, with a prominent (mostly degenerated) acute inflam-
14.5.3 Toxoplasmosis matory cell infiltrate in Wharton’s jelly; spirochetes may be
identified with silver stains if antibiotic therapy had not yet
Infection with toxoplasmosis can have severe consequences, been initiated. The villi may show chronic lymphoplasmacytic
with 5–15% of infections resulting in stillbirth. Among sur- villitis, increased nucleated red blood cells, villous edema, and
viving infants, though most will appear asymptomatic, at increased numbers of Hofbauer cells [6, 15, 38].
least 85% will develop chorioretinitis if they are not treated.
Grossly, there are no specific features of this protozoal infec-
tion in the placenta. Histologically, the intracellular organ- 14.5.7 Zika
isms are found in amniotic epithelial cells, stromal cells
between amnion and chorion, and villous stromal Hofbauer Infection with the Zika virus has recently become a wide-
cells. Pseudocysts and true cysts may occasionally be seen, spread topic of interest as a significant congenital infec-
which harbor many organisms. Rupture of these cysts results tion. While not all mothers who have been exposed to the
in a lymphohistiocytic or granulomatous villitis with multi- virus will give birth to affected infants, the recent surge
nucleated giant cells and necrosis [6, 28]. in incidence and awareness has certainly made it a con-
sideration for obstetricians. Serologic testing of the
mother and infant is the mainstay of diagnosis, but there
are reports of placental pathology associated with con-
14.5.4 Cytomegalovirus genital infections. The histologic changes, when present,
tend to be mild, and are nonspecific. The villi are
Cytomegalovirus (CMV) is the most common congenital viral enlarged, partly due to villous edema, but also due to
infection, occurring in 1–2% of newborns. Congenital CMV increased numbers of Hofbauer cells in the villous
acquired early in gestation can lead to prematurity, hydrops, stroma. Interestingly, no significant acute or chronic vil-
growth restriction, and fetal demise. Grossly, the placenta may litis has been noted. RNA probes for the virus will high-
appear hydropic. Histologic findings are most often present light the villous stromal/Hofbauer cells, indicating the
only in cases with severe clinical findings. The histologic fea- presence of Zika within them [39].
tures include lymphoplasmacytic villitis, hyalinized villi, or
avascular villi with hemosiderin-laden macrophages. Viral
inclusions, when present, can be found in villous stromal References
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Placenta and Pregnancy-Related
Diseases 15
Erica Schollenberg, Anna F. Lee, Jefferson Terry,
and Mary Kinloch
Abstract 15.1 Introduction

The placenta is unique among surgical pathology speci-
mens in that it reflects the (patho)physiologies of two The placenta is unique among surgical pathology specimens
patients: the mother and the fetus. Placental examination in that it offers a chronicle of the intrauterine environment
may offer diagnostic, prognostic, and therapeutic infor- that reflects the (patho)physiologies of two patients: the
mation of clinical relevance to both neonates and their mother and the fetus. Placental examination may offer diag-
mothers. Pathological processes of relevance to future nostic, prognostic, and therapeutic information of immediate
pregnancies may also be identified, facilitating precon- clinical relevance to both neonates and their mothers.
ception counseling as well as suggesting monitoring and Pathological processes of relevance to future pregnancies
potential intervention in subsequent gestations. In the set- may also be identified, facilitating preconception counseling
ting of intrauterine or neonatal demise, the placenta may as well as suggesting monitoring and potential intervention
be the only, and often most useful, source of information in subsequent gestations. In the setting of intrauterine or neo-
regarding a potential cause of death. The following chap- natal demise, the placenta may be the only source of infor-
ter describes the clinical and pathologic features of both mation regarding a potential cause of death. This chapter
common placental pathologies and uncommon lesions describes the clinical and pathologic features of both com-
with important clinical implications with which the mon placental pathologies and uncommon lesions with
pathologist should be familiar. important clinical implications with which the pathologist
should be familiar.
Keywords
Placenta · Pathology · Obstetric
15.1.1 Indications for Examination
The majority of gestations, deliveries, neonates, and placen-

tas are normal, and for practical reasons, pathologic exami-
nation is not required for all placentas. The proportion of
placentas submitted for examination depends on the acuity
and complexity of obstetric care provided at the health cen-
ter. A list of relevant indications for pathologic examination
should be agreed upon by all stakeholders (pathologists,
E. Schollenberg (*)
IWK Health Centre, Halifax, NS, Canada obstetricians, neonatologists) to maximize the clinical value
of placental examination. The indications for examination
Dalhousie University, Halifax, NS, Canada
e-mail: [email protected] endorsed by the College of American Pathologists guidelines
provide a useful basis. These include pre-existing maternal
A. F. Lee · J. Terry
Children’s and Women’s Health Centre of British Columbia, diseases or gestationally significant health conditions, gesta-
Vancouver, BC, Canada tional diseases, abnormalities in the current pregnancy, preg-
University of British Columbia, Vancouver, BC, Canada nancy complications, fetal or neonatal abnormalities, or
placental abnormalities (Table 15.1) [1].
M. Kinloch
Saskatoon City Hospital, Saskatoon, SK, Canada In many laboratories serving routine and high-risk obstet-
ric services approximately 10–20% of placentas are
University of Saskatchewan, Saskatoon, SK, Canada
494 E. Schollenberg et al.
Table 15.1 Indications for placental examination human tissues must be conducted by the laboratory regard-
Maternal history less of whether medical examination is indicated.
Pre-existing diabetes mellitus, vascular disease, or other The placental requisition for examination should include,
gestationally significant medical condition at a minimum, the gestational age and the indication for
Substance abuse
examination. Some hospitals use purpose-designed placental
Previous obstetric history
requisitions with fields to record relevant obstetric details
Prior recurrent pregnancy loss or late fetal/neonatal loss
Prior significant obstetric complication
and indications for examination, which facilitates provision
Maternal conditions arising in pregnancy of relevant clinical history and appropriate requests for
Peripartum fever or suspected infection examination. Placentas are most commonly accessioned as
Gestational diabetes surgical specimens under the maternal record; a special pro-
Preeclampsia or pregnancy-induced hypertension vision in the laboratory information system or reporting sys-
Maternal trauma tem ideally also makes the report available in the neonate’s
Current pregnancy chart.
Preterm labor or delivery (<37 completed weeks gestation)
Post-term delivery (≥42 completed weeks gestation)
Prolonged rupture of membranes (>24 h prior to delivery)
Excessive bleeding prepartum
15.1.2 Gross Examination and Sampling
Suspected placental abruption
Oligohydramnios or polyhydramnios Placentas may be examined in the laboratory in the fresh- or
Placenta accreta/increta/percreta or previa formalin-fixed state. The advantages of formalin fixation
Meconium-tinged amniotic fluid include better characterization of some types of discrete
Termination for anomalies or suspected gestational trophoblastic lesions, decreased infection potential, less mess from unfixed
disease blood, and better fixation of sampled blocks if processing is
Fetal hydrops done on the same day as block sampling. On the other hand,
Fetal demise in utero
even with large volumes of fixative, formalin permeates and
Neonatal
Perinatal or neonatal demise
fixes bloody tissues very slowly, mitigating some of the
Need for resuscitation or ventilation, poor Apgar (<7), low cord abovementioned advantages. Examination in the fresh state
blood pH allows for sampling for specialized molecular genetic tech-
Neonatal anemia niques that are incompatible with formalin, faster turnaround
Low birth weight (<10th percentile) times, and use of considerably less fixative. The chosen
Macrosomia (birth weight >95th percentile) examination protocol depends on the workflow and resources
Seizure of the specific lab.
Sepsis or suspected infection
A placental gross examination should include descriptors
Admission to neonatal intensive care unit
of the umbilical cord, membranes, and disc including fetal
Major congenital anomalies, including confirmed or suspected
aneuploidy surface, maternal surface, and parenchymal cut surface
Multiple gestation with discordant weight, premature delivery, and/ (Table 15.2). Use of standardized grossing templates facili-
or clinically significant question regarding chorionicity tates thorough and reproducible examinations [2]. Explicit
Placental comparison of observed disc weight with gestational age-
Small or large placenta (either absolutely or relative to neonatal adjusted expected weight is recommended [3]. It should be
size)
noted that formalin fixation affects placental measurements,
Abnormal umbilical cord insertion (marginal or velamentous) or
length (short or excessively long) including increasing disc weight by up to nearly 8% [4]. It is
Abnormal umbilical cord vessels (single umbilical artery, suspected often more useful to document macroscopic lesions photo-
thrombosis) graphically than it is to submit numerous sections of similar-
Umbilical cord true knot appearing areas.
Discrete lesions of the disc (mass, hematoma, infarction) According to recently published consensus guidelines,
Abnormal color (abnormal pallor, green-stained membranes) minimum sections recommended for microscopic examina-
Table adapted from [1] tion are roll of extraplacental membrane from the margin to
the rupture site, two cross sections of the umbilical cord from
s ubmitted for pathologic examination. If resources allow, it different areas of the cord, three full-thickness sections of the
is advisable to store unsubmitted placentas from all remain- placental disc, and representative samples of discrete lesions
ing deliveries for a period of time (1 or 2 weeks) to allow for [5]. Increasing the number of grossly normal sections sub-
placental examination if the need becomes evident postna- mitted for histologic examination will increase sensitivity;
tally. Refrigerated storage without formalin fixation pre- however, most grading schemes for common and clinically
serves tissues sufficiently. In some jurisdictions, disposal of relevant pathological entities are based on examination of a
15 Placenta and Pregnancy-Related Diseases 495
Table 15.2 Elements of a placental gross examination and recognized placental reporting protocols do not presently
description exist; however, development of local reporting protocols
Unique patient identifiers may improve clinician understanding and facilitate research.
Placenta received fresh or in formalin
Singleton or multiple gestation (see Sect. 15.12)
Umbilical cord 15.2 Placental Infection
Attached or separate; number of segments
Number of vessels
Placental inflammation and infection may sometimes be
Length and average diameter
used interchangeably, but they imply different disease states
Insertion (central, eccentric, distance to margin, marginal,
velamentous, furcate, etc.) in the placenta. Placental infections can have inflammatory
Coiling (number of total coils or coils per 10 cm) cells, but not all placentas with inflammatory cells have
General descriptors (edematous, discolored, surface lesions, etc.) infections. Most inflammatory patterns in the placenta can be
Discrete lesions (varices, true knots, vessel thrombosis, etc.) distinguished by location of the inflammatory infiltrate and
Membranes cellular composition. This section deals with common and
Insertion into disc (normal, circummarginate, circumvallate) typical patterns of placental infections, and the section fol-
Rupture site distance from margin lowing covers inflammatory patterns not associated with
General descriptors (translucent, opaque, green, brown,
infectious etiologies.
hemorrhagic)
Velamentous vessels
Disc
Weight (after removal of membranes and umbilical cord) 15.2.1 Ascending Intrauterine Infection
Dimensions
Shape (round, oval, bilobed, accessory lobe, etc.) Ascending intrauterine infection is also referred to as amni-
Fetal surface otic fluid infection sequence or syndrome. The histopatho-
General descriptors (color, etc.) logic descriptor chorioamnionitis should not be used
Discrete lesions
interchangeably with these clinicopathologic terms.
Chorionic plate vessels (distribution, thrombosis, etc.)
Identifiable microbes are typically bacterial, and this type of
Maternal surface
Completeness
placental infection has its sentinel declaration in the placental
Presence, size, and quality of hematomas membranes, which are the first point of contact with the outside
Discrete lesions world. The closed cervical os and mucous plug act as natural
Cut surface of parenchyma barriers against outside contamination of the amniotic sac
General descriptors (congested, pale, firm, mottled, etc.)
Discrete lesions (number, size, color, consistency, location, etc.) 15.2.1.1 Clinical Features
The incidence of ascending uterine infection is inversely
associated with gestational age. There is an over 90% asso-
set number of tissue sections, and increasing the sections ciation of acute chorioamnionitis with spontaneous preterm
submitted may lead to overestimation of grade. In general, delivery at 20 weeks; this association steadily decreases with
submission of extra sections of grossly normal placenta increasing gestational age to 5.1% at term [7, 8].
should be restricted to specific indications requiring increased The most common organisms are cervicovaginal bacteria
sensitivity (e.g., searching for maternal metastases). from the lower genital tract. Common organisms include
Important gross findings and abnormalities are discussed Ureaplasma urealyticum, Escherichia coli, Gardnerella vag-
in the sections below. The reader is also referred to other com- inalis, and group B Streptococcus (GBS).
prehensive resources on gross pathology of the placenta [6]. A requisition stating “query acute chorioamnionitis” is a
common indication for placental examination when there is
maternal fever or tachycardia. Other possible clinical find-
15.1.3 Standardized Reporting ings include fetal tachycardia, uterine tenderness, foul-
smelling vaginal discharge, and maternal white cell count
The value of standardized reporting for improving clinical increase. Common clinical scenarios are preterm rupture of
interpretation and research in cancer has been well estab- membranes and prolonged premature rupture of membranes.
lished, and generally accepted cancer reporting protocols are Risk factors and contributors include many etiologies such
now in widespread use. Considerable progress has been as incompetent cervix, previous infection (such as bacterial
made in defining, refining, and standardizing many placental vaginosis), cervical instrumentation such as cerclage, and
pathological processes [5], and placental pathology report- vaginal hemorrhage. The clinical severity and histologic
ing could similarly benefit from this approach. Universally findings do not always correlate.
15.2.1.2 Gross Features Table 15.3 Staging and grading of maternal and fetal inflammatory
Color and opacity are both important descriptors of the pla- responses in ascending intrauterine infection
cental membranes. Normal placental membranes are shiny Maternal inflammatory response
and translucent, almost transparent. The neutrophilic exu- Stage Acute subchorionitis or Grade Not severe as defined
1 chorionitis 1
date from an ascending intrauterine infection causes opacifi-
Stage Acute chorioamnionitis; Grade Severe: confluent
cation of the membranes, making them thick and dull-white 2 polymorphonuclear 2 polymorphonuclear
(Fig. 15.1). The neutrophilic exudate can also cause a green- leukocytes extend into leukocytes or
brown discoloration; however, this is not a specific finding fibrous chorion and/or subchorionic
amnion microabscesses
because meconium staining and biliverdin breakdown can
Stage Necrotizing
also cause similar discoloration. Even in cases of severe 3 chorioamnionitis:
inflammation, the gross findings may be relatively karyorrhexis of
unimpressive. polymorphonuclear
leukocytes, amniocyte
necrosis, and/or amnion
15.2.1.3 Microscopic Features basement membrane
The Amsterdam Placental Workshop Group Consensus hypereosinophilia
Statement from July 2016 provides the latest standard in the Fetal inflammatory response
diagnostic criteria for acute chorioamnionitis [5] (Table 15.3). Stage Chorionic vasculitis or Grade Not severe as defined
There is consensus that location (staging) and composition 1 umbilical phlebitis 1
Stage Involvement of the Grade Severe: near-confluent
of the inflammatory response should be documented. In
2 umbilical vein and one 2 intramural
addition, classification of the severity (grading), and separa- or more umbilical polymorphonuclear
tion of fetal from maternal inflammatory responses, is arteries leukocytes with
useful. attenuation of vascular
smooth muscle
Stage Necrotizing funisitis
Maternal Inflammatory Response 3
See Table 15.3 for the recommended staging and grading
Reproduced with permission from [5]
system.
Stage 1: Acute subchorionitis or chorionitis includes
acute inflammation in the form of neutrophils beneath the (Fig. 15.2). Stage 2: Acute chorioamnionitis refers to a neu-
chorion, with minimal extension into the cellular chorion, trophilic infiltrate within the chorion (above the cellular cho-
without the presence of neutrophils elsewhere. This stage is rion), with or without early involvement of the amnion
considered an early response to an ascending infection. (Fig. 15.3). Stage 3: Necrotizing chorioamnionitis includes
Strictly speaking, this is not a true chorioamnionitis any cases with neutrophil karyorrhexis and/or overt necrotic
damage to the amnion (Fig. 15.4).
Note that even severe/advanced chorioamnionitis can be
surprisingly patchy, with relative or complete sparing of the
chorionic plate or membranes in some fields.
Fetal Inflammatory Response

See Table 15.3 for the recommended staging and grading
system.
Stage 1: Chorionic vasculitis or umbilical phlebitis
describes fetal neutrophils migrating from the fetal circula-
tion, out through the umbilical vein or chorionic vessels
(Fig. 15.5). This inflammation is often seen to be chemotacti-
cally oriented toward the source of infection (the amniotic
fluid). In the wall of the vein, early/sparse infiltrating neutro-
phils are best looked for in between the layers of vascular
smooth muscle. Stage 2: Umbilical arteritis includes cases
with neutrophilic inflammation of any two or more of the
umbilical vessels (Fig. 15.6). Stage 3: Necrotizing funisitis
refers to concentric neutrophilic inflammation within the
Fig. 15.1 In acute chorioamnionitis, the neutrophilic infiltrate can
cause opacification of the membranes, chorionic plate, and Wharton’s ground substance (Wharton’s jelly) around one or more
jelly surrounding the umbilical vessels umbilical vessels (Fig. 15.7).
a b
Fig. 15.2 Acute subchorionitis or chorionitis (maternal inflammatory response stage 1) denotes neutrophilic inflammation within subchorionic
fibrin, beneath the chorion, with (a) no or (b) minimal extension into the cellular chorion (original magnifications 200×)
a b
Fig. 15.3 Acute chorioamnionitis (maternal inflammatory response can be graded as either (a) mild or moderate (grade 1) or (b) severe
stage 2) refers to a neutrophilic infiltrate within the chorion, above the (grade 2) (original magnification 100×)
cellular chorion, with or without early involvement of the amnion, and
a b
Fig. 15.4 Low- (a) and higher-power (b) views of necrotizing chorioamnionitis (maternal inflammatory response stage 3), with neutrophil karyor-
rhexis, amniocyte necrosis, and hypereosinophilia of the amnion basement membrane (original magnifications 40× and 100×)
Like the maternal inflammatory response, the inflamma- least two umbilical cord cross sections. In general, the fetal
tion can be variable and patchy in different parts of the fetal inflammatory response lags stagewise behind the maternal
circulation. This is part of the reason for recommending at inflammatory response. The fetal inflammatory response
a b
Fig. 15.5 (a) Umbilical phlebitis (fetal inflammatory response stage 1) with fetal neutrophils migrating out through a chorionic plate vessel
with fetal neutrophils migrating from the fetal circulation via the umbil- (original magnifications approximately 100×)
ical vein. (b) Chorionic vasculitis (fetal inflammatory response stage 1)
may be lacking or absent in second-trimester fetuses, who

have immature immune systems. Despite being referred to as
vasculitis/phlebitis, it is important to understand that the
fetal inflammatory response is not true vasculitis.

The gross appearance of a placenta with bacterial infection is
non-specific; cloudiness or discoloration of the membranes
can be due to adherent villous or decidual tissue, excess sub-
chorionic fibrin, meconium, or hemorrhage.
Neutrophilic inflammation in the placental membranes,
chorionic plate, and umbilical cord is generally considered
indicative of ascending bacterial infection. Identification of
the specific infectious agent (by histology or culture) is not
Fig. 15.6 Fetal inflammatory response stage 2, with neutrophilic usually practical and is not required to guide empiric treat-
involvement of an umbilical artery (original magnification 40×)
ment of either the mother in labor or the potentially septic
neonate. It has been noted that chorioamnionitis due to GBS
may show unimpressive maternal inflammation, even in
cases with significant fetal infection. Isolated subchorionitis
may be seen in prolonged labor or induction of labor; in
these settings subchorionitis likely represents early ascend-
ing infection secondary to rupture of membranes rather than
a primary process.
Note is made here of an uncommon, but highly signifi-
cant, pattern of umbilical cord inflammation. Peripheral/
eccentric neutrophilic funisitis (which can appear grossly
and/or microscopically on the umbilical cord surface as
punctate microabscesses) correlates with candidal infection
(Fig. 15.8). Although Candida spp. are common normal and
pathogenic flora of the lower genital tract, they can rarely
Fig. 15.7 In necrotizing funisitis (fetal inflammatory response stage
3), neutrophils form concentric rings in the ground substance surround- cause amniotic fluid infection. A high index of suspicion
ing umbilical vessels (original magnification 40×) should be maintained with this pattern of inflammation, and
a b
Fig. 15.8 (a) Neutrophil collection on the surface of an umbilical cord in a case of (b) Candida infection (original magnification 200×)
special stains ordered to identify invasive fungal Clinical Features

organisms. This is a food-borne illness, and in most jurisdictions, its
diagnosis in pregnancy is a public health reportable disease.
15.2.1.5 Prognosis Maternal illness is most commonly mild, with either fever
The outcome of ascending amniotic fluid infection depends alone or a mild flu-like or gastrointestinal illness. Sometimes
on many clinical factors such as duration of infection, provi- the mother is asymptomatic. By comparison, fetal infection
sion of maternal antibiotics intrapartum, severity of fetal sep- is severe and rapidly fatal.
sis, virulence of the etiologic organism, and especially
gestational age of the newborn infant [8]. Chorioamnionitis Gross Features
is a contributing factor in a large minority of preterm deliver- The gross findings are seen in both the placental membranes
ies. In general, potential fetal sepsis is of much more concern and the placental disc. The membranes can be opaque and
at young gestational ages, whereas term infants may mani- thick. There may be outlines of septic infarcts in the pla-
fest very little morbidity. In most cases, empiric antibiotics centa, characterized by geographical zones of pale yellow-
are provided whenever fetal infection is suspected. Histologic white discoloration.
confirmation of chorioamnionitis is most clinically useful
when provided to the neonatal care team within 48 h of deliv- Microscopic Features
ery, since this may guide discontinuation or completion of a Listeria monocytogenes is a gram-positive rod but can often
full antibiotic course regardless of the clinical picture. stain indeterminately on histologic Gram staining. The
organisms are typically easily found, if not specifically iden-
tifiable, on histology, due to heavy colonization. The hall-
15.2.2 Other Placental Infections mark finding in this infection is neutrophilic infiltration
throughout the intervillous space, membranes, and within
15.2.2.1 Acute Intervillositis villi (Fig. 15.9). Septic infarcts and abscesses may be seen
Acute intervillositis refers to neutrophils in the intervillous (Fig. 15.10).
space with associated abscesses. It is most commonly associ-
ated with Listeria monocytogenes. The incidence of L. mono- Differential Diagnosis
cytogenes in pregnancy is 12 per 100,000 [9]. Pregnant Maternal sepsis with other bacteria may produce identical
women are at a much higher risk than the general population, acute intervillositis and villitis; however, bacteria are typi-
where the incidence is 0.7 per 100,000 people. cally sparse and primarily located in the maternal blood
a b
Fig. 15.9 (a) Acute necrotizing villitis and acute intervillositis, caused genes (gram-positive rods) on its surface (gram stain; original magnifi-
by Listeria monocytogenes infection (original magnification 100×). (b) cation 400×)
Umbilical cord cross section showing colonies of Listeria monocyto-
(causative agent of syphilis) and cytomegalovirus (CMV)

(Fig. 15.11). Maternal disease may be asymptomatic, and
symptoms partially depend on whether this is a new primary
infection or a reactivation or later stage of disease. Primary
infection is most likely to be passed across the placenta to the
fetus. Another etiology of villitis is parvovirus B19, which
can also cause potentially severe fetal anemia. Varicella zos-
ter virus can be transmitted transplacentally, whereas herpes
simplex virus is usually acquired during delivery through an
infected lower genital tract.
Microscopic Features
See Table 15.4 for characteristic features of syphilis and
CMV infection of the placenta.
Distinction between infectious villitis of this type and the
much more commonly encountered chronic villitis of unknown
etiology (VUE) is discussed below in the section on VUE.
Fig. 15.10 Intervillous abscess in placental Listeria infection (original
magnification 20×) 15.2.2.3 Placental Parasitic Infections
Parasitic infections of the placenta are individually and col-
space. The clinical history is usually sufficient for lectively uncommon in North American practice. Two are
differentiation. worth mentioning for their specific clinical contexts and
characteristic microscopic appearances.
Prognosis Placental malaria is a significant public health concern in
Pregnancy outcome depends on the gestational age at time of many parts of the world; in North America it is encountered
infection. In the second trimester, fetal loss is common. The mainly in immigrants and recent travelers. Malarial infection
neonate remains vulnerable to Listeria sepsis and meningitis of the placenta occurs mainly within the maternal blood
in the weeks following delivery. (intervillous) space and correlates with maternal parasitemia.
The most common causative species is Plasmodium falci-
15.2.2.2 Chronic Infectious Villitis parum. The microscopic appearance is typically one of
chronic histiocytic intervillositis with hemozoin pigment as
Clinical Features well as organisms within maternal erythrocytes, although the
The incidence is related to the two etiologic infectious agents histologic appearance and parasite burden depend on the
associated with most of these cases: Treponema pallidum timing and chronicity of infection (Fig. 15.12) [10, 11].
a b
Fig. 15.11 Villitis caused by cytomegalovirus (a, original magnification 200×; b, immunohistochemical stain for cytomegalovirus showing
nuclear positivity, original magnification 100×)
Table 15.4 Syphilis versus cytomegalovirus placental infection

Feature Syphilis Cytomegalovirus
Placenta size Large placenta Large and pale or small
and fibrotic
Inflammatory Histiocyte- Plasma cell-predominant
cell predominant
Location of Villi Villi
inflammation
Other Proliferative Diagnostic intranuclear
histologic endovasculitis, inclusions
features necrotizing umbilical
periphlebitis
Ancillary tests Warthin-Starry CMV
histochemical stain immunohistochemical
stain (nuclear)
Fig. 15.13 Toxoplasma in placental membranes, with edema and

chronic inflammation mimicking meconium exposure (original magni-
fication 600×)
Toxoplasmosis of the placenta occurs only rarely despite

the ubiquity of the causative organism (Toxoplasma gondii).
The highest risk for transmission to the fetus occurs at later
gestational ages, but infection can cause fetal loss at any
stage of pregnancy [12]. The organisms appear within mem-
branes or villi in the form of either tachyzoite-filled
pseudocysts or bradyzoite-filled true cysts (Fig. 15.13).

Congenitally infected neonates are at risk for low birth
weight, as well as eye and brain damage.
Fig. 15.12 Placental malaria with minimal inflammation but frequent

organisms within maternal red blood cells (original magnification 15.3 Noninfectious Placental Inflammation
400×)
15.3.1 Chronic Histiocytic Intervillositis

Transmission to the fetus or neonate is relatively uncommon,
but there is a significant risk of pregnancy loss and low birth This lesion is sometimes also referred to as chronic intervil-
weight neonates. lositis (of unknown etiology; CIUE) or massive chronic
intervillositis. This term implies an unidentified noninfec- 15.3.1.4 Prognosis

tious etiology that is thought to be immunologic. There is a high risk of recurrence with repeated pregnancy
loss (>50% in some series) [15]. This should be mentioned in
15.3.1.1 Clinical Features the report, for future pregnancy planning and management,
Chronic histiocytic intervillositis is seen in placentas of first- since not all clinicians are familiar with the implications of
and second-trimester spontaneous abortions or from infants this finding. Preventative treatments using aspirin or steroids
with severe growth restriction. There may be a history of have met with varying degrees of success.
recurrent pregnancy loss. There is an association with mater-
nal autoimmune conditions (see Table 15.5) [13, 14].
15.3.2 Villitis of Unknown Etiology
The diagnostic feature is collections of histiocytes within the Villitis of unknown etiology (VUE) is defined as chronic
intervillous space (Fig. 15.14). These stain positively with noninfectious lymphohistiocytic inflammation of the termi-
CD68 immunoperoxidase (cytoplasmic). There is often nal villi that can result in fibrotic destruction of the villous
increased perivillous fibrin deposition. These findings may stroma and capillaries.
be focal or diffuse. There may be associated chronic villitis,
but in this diagnosis, the intervillous inflammation 15.3.2.1 Clinical Features
predominates. The prevalence of VUE varies widely depending on the diag-
nostic criteria used, selection of placentas for study, and the
15.3.1.3 Differential Diagnosis obstetric population [16]. In one study, a prevalence of 17.5%
A similar intervillous histiocytic infiltrate is typical of placental was reported in small for gestational age neonates, compared
malaria. Other placental infections should also be considered in with 11.5% in normal-sized neonates [17].
the differential diagnosis, although most of these present with
either predominantly chorioamnionitis (usual ascending amni- 15.3.2.2 Microscopic Features
otic fluid infection, toxoplasmosis), neutrophilic intervillositis A grading system first proposed by Redline is based on the
(Listeria), or chronic villitis (viruses, syphilis). number of villi involved per microscopic focus [18] (see
Table 15.6). The inflammation tends to be patchy and can be
Table 15.5 Autoimmune conditions associated with chronic histio- detected at low to medium power as an area of increased vil-
cytic intervillositis lous cellularity (Fig. 15.15). There is often associated periv-
Primary antiphospholipid syndrome illous fibrin deposition and agglutination of villi. On higher
Raynaud’s phenomenon power, the infiltrate is typically composed of predominantly
Pernicious anemia maternal lymphocytes of the T lineage, as well as increased
Systemic lupus erythematosus numbers of fetal and maternal histiocytes. Rare plasma cells
Celiac disease and histiocytic multinucleated giant cells may also be seen;
Sjogren’s syndrome if prominent these should prompt a search for an infectious
a b
Fig. 15.14 Chronic histiocytic intervillositis in (a) early spontaneous abortion and (b) fetal demise at term (original magnifications 100× and 200×)
etiology. Evaluation of vessels is crucial to identify the pres- vascular space. The similarity of MFI and MPFD suggests
ence of associated vascular damage (similar in appearance to they represent parts of a common pathogenetic spectrum.
that seen in fetal vascular malperfusion). The underlying etiology of MFI/MPFD is unclear but is
likely multifactorial and may involve aberrant maternal
15.3.2.3 Differential Diagnosis immune responses and/or coagulation abnormalities [21].
The most important consideration in the differential diagno-
sis of VUE is not to miss a significant placental infection. 15.3.3.1 Clinical Features
See Table 15.7 for distinguishing features. MFI/MPFD typically presents with intrauterine growth
restriction (in up to 100% of cases) and premature delivery
15.3.2.4 Prognosis (up to 60%); intrauterine demise may occur in up to 50% of
High-grade chronic villitis of unknown etiology and villitis affected pregnancies [21]. Oligohydramnios and elevated
with associated vascular damage have been shown to be maternal serum alpha-fetoprotein may be associated prenatal
associated with poor outcome, in particular adverse neuro- findings. MFI/MPFD may be suspected by the combination
logical outcomes [19, 20]. of growth restriction, oligohydramnios, and echogenic pla-
centa seen on prenatal ultrasound. There may be a history of
infertility.
15.3.3 Maternal Floor Infarction and Massive
Perivillous Fibrinoid Deposition
Table 15.7 Chronic villitis of unknown etiology versus villitis of
Maternal floor infarction (MFI) and massive perivillous infectious etiology
fibrinoid deposition (MPFD) are rare entities with overlap-
Feature VUE Infectious villitis
ping phenotypes characterized by excessive deposition of
Prevalence Common Rare
perivillous fibrin and fibrinoid that obscures the maternal Gestational Most common in Any trimester
age third trimester
Table 15.6 Grading chronic villitis of unknown etiology Inflammatory Lymphocytes, Histiocytes (including
cells especially T cells, granuloma formation or
Low grade Fewer than ten contiguous villi involved per focus and histiocytes giant cells) or plasma cells
Focal Only present on one slide may predominate
Multifocal Present on multiple slides Distribution Patchy, often with Diffuse
High At least one focus of inflammation with more than ten basal predominance
grade involved villi Specific None Viral inclusions or
Patchy Multiple foci on one or more slides findings microorganisms
Diffuse Involving more than 30% of sampled distal villi Special stains N/A Viral and histochemical
Table adapted from [5] stains may be informative
a b
Fig. 15.15 In villitis of unknown etiology (VUE), lymphohistiocytic inflammation of the villi is typically patchy (a) and associated with agglu-
tination of distal villi (b) (original magnification 200×)
a b
Fig. 15.16 (a) In massive perivillous fibrinoid deposition, excess fibrinoid appears and makes the placenta firm with a pattern of lacelike tan
fibrinoid. (b) Low-power view showing excessive deposition of fibrinoid around villi (original magnification 10×)
15.3.3.2 Gross Features Table 15.8 Diagnostic criteria for maternal floor infarction/massive
perivillous fibrin deposition
Placentas affected by MFI/MPFD are usually small for ges-
tational age but may be normal or even large by weight Pattern Diagnostic criteria
Classic Basal fibrinoid involving entire maternal floor
depending on the extent of fibrinoid deposition. Unfixed pla-
At least one slide with fibrinoid thickness ≥3 mm
centas are unusually firm and stiff, and the maternal surface Transmural Encasement of ≥50% of villi in at least one slide
appears pale. Sectioning reveals dense, firm, tan-white Non-basal (focal) fibrinoid distribution pattern
parenchyma in a distribution varying from conspicuous ori- Borderline Encasement of ≥25% to <50% of villi in at least
entation along most or all of the maternal surface (the MFI one slide
pattern) to more discrete foci extending from the maternal Non-basal (focal) fibrinoid distribution pattern
surface to the chorionic plate and involving 50% or more of Table adapted from [21]
the placental disc volume (the MPFD pattern) (Fig. 15.16a).
but fibrinoid is not abundant, and intervillous histiocytic
15.3.3.3 Microscopic Features infiltrates are present. The gross and microscopic appearance
Despite differences in distribution, MFI/MPFD both involve of MFI/MPFD can resemble primary infarction; however,
extensive perivillous deposition of fibrin and fibrinoid mate- the villi in MFI/MPFD will be separated by abundant fibrin/
rial that fills the intervillous spaces (Fig. 15.16b). Extravillous fibrinoid. VUE and fetal vascular malperfusion may produce
trophoblast within the fibrinoid material may be prominent. similar regressive changes in affected villi, but complete vil-
Encasement of villi produces regressive changes including lus encasement by fibrinoid will not be present.
loss of villous trophoblast, vessels, and stromal cells.
Inflammatory cells, including lymphocytes and neutrophils, 15.3.3.5 Prognosis
may be seen in the vicinity of degenerating villi. Mass effect Although rare, MFI/MPFD is an important entity to recog-
disrupts local maternal blood flow leading to the features of nize because it is associated with poor outcomes and has a
maternal vascular malperfusion and development of intervil- significant risk of recurrence in future pregnancies. In addi-
lous thrombi in adjacent parenchyma. Semiquantitative diag- tion to those described above, MFI/MPFD is also a risk fac-
nostic criteria for MFI/MPFD based on gross and microscopic tor for neonatal death and neurological impairment [22].
findings have been proposed (Table 15.8).
15.3.3.4 Differential Diagnosis 15.4 Meconium

Focal perivillous fibrin and fibrinoid deposition accrue nor-
mally in all placentas and should not be overinterpreted as Meconium is the sum of ingested amniotic fluid debris, exfo-
MFI/MPFD; application of diagnostic criteria avoids this liated gastrointestinal epithelial tissue, and gastrointestinal
potential pitfall. Chronic histiocytic intervillositis can be excretions that can be expelled by the fetus or neonate
associated with development of extensive perivillous fibrin, per anus.
15.4.1 Clinical Features changes characterized by cytoplasmic vacuolization, atypia,

and eventually necrosis of the amniotic epithelium and
Meconium release into the amniotic fluid can be associated edema of the fibrous chorioamnion. It also elicits an inflam-
with fetal stress; however, it also occurs in up to 15–25% of matory response, attracting phagocytic placental histiocytes
normal term births and is thus not a specific marker of fetal (Fig. 15.18a). The amount of meconium present is generally
stress. The presence of meconium in the amniotic fluid is proportional to the amount of meconium released and time
more likely with increasing gestational age, and it is a com- of exposure, but this cannot be reliably inferred from histo-
mon finding in postdates delivery of both live-born and still- logic examination.
born infants.
15.4.2 Gross Features
The meconium-exposed placenta may have particularly

edematous (“slimy”) membranes. Sloughing of the amniotic
layer from the underlying chorion is common. Meconium
may be apparent on the placental surface. The intensity of
overt meconium staining, which appears brownish-green, is
dependent on the volume of meconium released and the
duration of exposure (i.e., the time interval between fetal
passage of meconium and delivery) (Fig. 15.17).
15.4.3 Microscopic Features
Meconium appears microscopically as pale tan-brown amor-

phous material with a low refractive index within the chorio- Fig. 15.17 Fetal surface of a placenta with meconium staining, from a
amniotic tissues. Meconium is caustic and induces reactive case of fetal demise near term
a b
Fig. 15.18 (a) Meconium appears as tan, poorly refractile pigment tive changes (original magnification 400×). (b) Meconium extending to
within the chorioamniotic tissues and histiocytes. Amniocyte cytoplas- the umbilical vessels may induce smooth muscle vasospasm and necro-
mic vacuolization and edema, seen here, are commonly associated reac- sis (original magnification 100×)
The caustic nature of meconium may also induce vaso- 15.5.1 Umbilical Cord Length and Diameter
spasm and vascular medial necrosis in umbilical and chori-
onic plate vessels, which may have serious consequences for Umbilical cord length increases with gestational age with a
the fetus (Fig. 15.18b). In this situation, meconium and vacu- normal range at 38 weeks gestation of approximately
olated meconium-laden macrophages are seen in and around 35–70 cm [23, 24]. Unusually long umbilical cords pose an
the media of umbilical and chorionic plate vessels. increased risk of fetal cord entanglement, true knot forma-
tion, and cord prolapse, all of which may obstruct umbilical
blood flow with potentially disastrous consequences
15.4.4 Differential Diagnosis (Fig. 15.19). Short umbilical cords, especially when less
than 10 cm, are associated with limb-body wall complex and
Meconium can be differentiated from hemosiderin by the fetal developmental abnormalities. Accurate assessment of
presence of the above-described reactive changes and nega- umbilical cord length is frequently limited by submission of
tive iron special staining. Lipofuscin, which is not commonly incomplete cords for assessment.
encountered in the placenta, resembles meconium by light Umbilical cord diameter also increases with gestational
microscopy and cannot be definitively differentiated by spe- age with a normal range of approximately 0.8–1.2 cm at
cial staining. 38 weeks gestation [25]. Ground substance (Wharton’s jelly)
Meconium may be artifactually displaced in the potential surrounding the umbilical vessels provides a protective cush-
space between the amnion and chorion after delivery. This ion that prevents vascular occlusion (Fig. 15.20a). Narrow
can be differentiated from true meconium staining by its dis- umbilical cords have reduced ground substance and are at
tribution, which may involve but is not restricted to the increased risk of vascular compression and fetal vascular
amniotic-chorionic cleft. malperfusion (FVM) (Fig. 15.20b). Increased umbilical cord
diameter is usually the result of edema (Fig. 15.21). When
umbilical cord edema is marked, it may appear as cystic
15.4.5 Prognosis spaces on prenatal imaging; however, these are almost
always pseudocystic spaces. True umbilical cord cysts,
Most infants born with pre- or perinatal meconium exposure which most commonly arise from the omphalomesenteric
have no clinical sequelae. Although meconium can be asso- duct remnant, are rare.
ciated with poor neonatal outcomes, it is not an independent
predictor, and prognostically relevant placental abnormali-
ties associated with meconium release should be sought.
Prolonged intrauterine exposure to thick meconium can
rarely result in meconium aspiration syndrome, a form of
neonatal respiratory distress caused by massive meconium
aspiration. Meconium aspiration syndrome cannot be reli-
ably predicted by placental examination. Meconium-
associated vascular necrosis is a significant risk factor for
central nervous system damage and neonatal death [20].
15.5 Abnormalities of the Umbilical Cord
Commonly encountered intrinsic abnormalities of the umbil-

ical cord include variance in length, diameter, and extent of
coiling, localization of the cord insertion site, and the num-
ber of umbilical cord vessels present [23]. Extrinsic abnor-
malities that may involve the umbilical cord, such as the fetal
inflammatory response of amniotic fluid infection syndrome,
are considered elsewhere in this chapter. Most umbilical
cords are not entirely submitted for examination, and it is
important to recognize this limitation in assessment of Fig. 15.19 True umbilical cord knot associated with long (84 cm)
umbilical cord abnormalities. umbilical cord
a b
Fig. 15.20 (a) Connective tissue and ground substance surrounds and stents umbilical vessels. (b) Narrow umbilical cords (0.4 cm at 38 weeks,
in this case) lack protective ground substance (original magnifications 100×)
meter (coiling index) is approximately 0.2 [26, 27]. An

abnormal coiling index at term has been variably defined
between 0.1 and 0.3–0.4; however, what truly constitutes
abnormal coiling remains a topic of debate [28].
Both hypo- and hypercoiling are associated with poor
outcomes, including fetal demise, developmental
abnormalities, aneuploidy, and fetal hypoxia/ischemia [29].
Hypercoiling is associated with FVM, especially when
umbilical cord ground substance is depleted allowing com-
pression of adjacent umbilical cord loops (Fig. 15.22) [30].
Hypocoiling is thought to be an indicator of lack of fetal
movement and may be associated with fetal abnormalities
that inhibit movement, such as neuromuscular disorders.
Artifactual hypercoiling occurs after intrauterine demise
and is especially prominent in the setting of moderate and
advanced macerative change. Care must be taken when con-
sidering hypercoiling as a cause of intrauterine demise in this
setting.
15.5.3 Umbilical Vessels

Fig. 15.21 Umbilical cord dilatation typically results from edema
The most commonly encountered abnormality of the umbili-

15.5.2 Umbilical Cord Coiling cal vessels is single umbilical artery. A single umbilical
artery (Fig. 15.23) can be associated with developmental
Like cord length, umbilical cord coiling increases with ges- abnormalities of the renal and cardiovascular systems, aneu-
tational age. At term, the average number of coils per centi- ploidy, and increased risk of FVM and related abnormalities.
the placental disc develops through trophotropism, although

some have suggested localization of the umbilical cord inser-
tion site is a stochastic event [31].
Regardless of the physiology, marginal cord insertions,
which occur at the placental disc margin (Fig. 15.24a), and
velamentous insertions, which terminate in the membranes
(Fig. 15.24b), are risk factors for mechanical umbilical blood
flow occlusion and FVM. A furcate umbilical cord is charac-
terized by loss of the protective ground substance prior to the
cord reaching the chorionic plate (Fig. 15.24c), which
exposes the umbilical vasculature to increased risk of
mechanical flow occlusion and FVM.
Velamentous and furcate cord insertions are also at
increased risk of vascular rupture, which can lead to cata-
strophic fetal hemorrhage. Marginal and velamentous
insertions occur more commonly in the setting of fetal
developmental abnormalities and twin-twin transfusion
syndrome; in the latter, release of angiogenic factors
related to blood flow obstruction may play a pathogenetic
role [32].
Fig. 15.22 Umbilical cord hypercoiling (coiling index 0.89 in this
example) is a risk factor for fetal blood flow restriction
15.5.5 False Versus True Knots
False knots are outpouchings of the umbilical cord usually

containing one or more umbilical vessels; they have no
apparent functional significance, even when complex
(Fig. 15.25). False knots are associated with vascular redun-
dancy which may mimic extra umbilical vessels on cut
sections.
True knots may or may not have functional consequences.
True knots contain at least a “half-hitch” that can be tightened
by applying traction on the ends. Thus, true knots have a
potential of cord accident if the knot is so tight that the
umbilical vessels collapse resulting in flow restriction. True
knots may be completely asymptomatic; therefore, the iden-
tification of one during gross placental examination does not
imply that there was a cord accident. Furthermore, cord acci-
dents are dynamic phenomena that require clinical correla-
tion for diagnosis. However, one observation that a true knot
Fig. 15.23 Single umbilical artery
may have been sufficiently tightened to cause disruption in
vascular flow is the presence of differential congestion on
either side of the knot, with one side showing vascular con-
Persistence of the right umbilical vein is very rare and typi- gestion and the other side showing pallor (Fig. 15.26). True
cally associated with multiple fetal anomalies. Umbilical knots may also cause chronic vascular flow abnormalities
vessel redundancies, which sometimes appear as false knots and features of fetal vascular malperfusion.
within the cord, are more common and should not be mis-
taken for additional umbilical vessels.
15.6 Fetal Vascular Malperfusion
15.5.4 Umbilical Cord Insertion Fetal vascular malperfusion (FVM) is a diagnostic term that
has been recommended to replace fetal thrombotic vascu-
The site of umbilical cord insertion into the placental disc is lopathy and fetal vascular flow restriction to describe abnor-
generally thought to initiate centrally and then “migrate” as malities in fetal perfusion of the placenta [5, 33]. FVM is
a b
Fig. 15.24 (a) Marginal, (b) velamentous, and (c) furcate umbilical cord insertions are risk factors for mechanical obstruction of umbilical blood
flow
defined by pathologic features of thrombosis or ischemia in ties (see previous section) and/or presence of oligohydram-
the fetal vasculature of the placenta. nios [34]. Compromised fetal cardiac output may be primary,
as in structural cardiac defects, or secondary, such as in high-
output failure secondary to fetal anemia.
Most causes of FVM fall within two groups: obstruction of 15.6.2 Gross Features
umbilical cord blood flow and compromised fetal cardiac
output. Of these, umbilical cord flow restriction is more Thrombosis of fetal vessels may be partially or completely
common and is usually related to umbilical cord abnormali- occlusive and in larger vessels may be seen grossly. Clusters
a b
Fig. 15.25 Redundancies, outpouchings, or varices of umbilical vessels are sometimes referred to as false knots. They have no apparent func-
tional significance, whether simple (a) or complex (b)
a b
Fig. 15.26 Placentas from intrauterine fetal demises at (a) 36 weeks and (b) 20 weeks of gestation. Note the true knots in the umbilical cords with
differential congestion of vessels on either side
of avascular distal villi may also be seen on gross examina- wall in the chorionic plate or stem villus. Histologic features
tion as an area of pale parenchyma. Placentas with extensive of early true thrombosis include mural fibrin deposition
FVM may be small for gestational age. (Fig. 15.27a) with loss of appreciable endothelium between
the thrombus and vessel wall (Fig. 15.27b). Over time, nonoc-
clusive thrombosis results in restoration of the vascular lumen
15.6.3 Microscopic Features and fibrin incorporated into the vessel wall (Fig. 15.28a),
while occlusive thrombosis causes luminal obliteration with or
Fetal vascular thrombosis is more likely to be recognized on without recanalization (Fig. 15.28b). Mural fibrin eventually
microscopic examination as fibrin layered against a vessel calcifies, which is a sign of remote thrombosis (Fig. 15.28c).
a b
Fig. 15.27 Fetal vascular thrombosis and post-delivery or post-demise shows loss of intervening endothelium and extension of fibrin into the
intravascular coagulation can both present as mural fibrin collections vascular intima (b, original magnification 200×)
(a, original magnification 20×), but true fetal vascular thrombosis
Downstream stream effects of FVM present initially as setting of fetal demise if temporally incongruous features of
villous stromal hemorrhage and karyorrhexis (Fig. 15.29a), FVM are present (e.g., focal intramural fibrin, calcification),
which represent degenerative changes in villous capillaries. but making such a differentiation should be approached con-
With time the villi become avascular (Fig. 15.29b). servatively. See the section on late fetal demise, below, for an
Hemosiderin resulting from villous stromal hemorrhage may approach to this differential diagnosis.
be present in avascular villi. Foci of villous stromal hemor-
rhage, karyorrhexis, and avascular villi are usually sharply
demarcated from adjacent unaffected villi (Fig. 15.30). 15.6.5 Prognosis
Intervillous thrombi can be seen in the setting of FVM
where they arise from mixing of maternal and fetal blood The clinical significance of FVM is increased risk of still-
related to stromal villous hemorrhage extending into the birth, fetal growth restriction, and development of neurologi-
maternal blood space, but are not specific for FVM. A rare cal abnormalities [34–36]. Grading schemes have been
finding in FVM is erythropoietic islands arising in chorionic developed in an attempt to quantify FVM for prognosis. The
plate and stem villous stromal tissue adjacent to areas of fetal most recent grading scheme is summarized in Table 15.9.
vascular thrombosis. Aside from low and high grades, the findings can be described
as either segmental (occurring in the distribution of a chori-
onic or stem villous vessel) or global (diffuse changes
15.6.4 Differential Diagnosis attributable to obstruction of flow to or from an umbilical
vessel).
Mimics of FVM include amniotic fluid infection
inflammation- related mural thrombi, but these are easily
recognized by the intermixed acute inflammatory infiltrate 15.7 Maternal Vascular Malperfusion
(Fig. 15.31). Avascular distal villi may result from chronic
villitis, which can be indistinguishable from avascular villi In the normally developing placenta, uterine artery remodel-
resulting from FVM. Differentiation of chronic villitis from ing begins in the late first trimester, and placental perfusion
FVM as the cause of avascular distal villi is based on the lack commences around 12 weeks gestation. Arteries lose their
of an apparent vascular distribution and the presence of muscular media and become thin-walled. The uterine spiral
inflamed adjacent villi, if present. arteries therefore become a low-pressure arterial supply to
Intrauterine fetal demise leads to fetal vascular changes the placental disc that is resistant to systemic vasoconstric-
similar to FVM. Pre-demise FVM can be recognized in the tive signals. The term maternal vascular malperfusion refers
a b
Fig. 15.28 (a) The intravascular component of nonocclusive fetal vas- thrombi lead to obliteration of the vascular lumen (original magnifica-
cular thrombosis disappears with time, but fibrin incorporated into the tion 100×). (c) Calcification of intramural fibrin is a marker of remote
vascular wall remains (original magnification 200×). (b) Occlusive fetal vascular thrombosis (c, original magnification 100×)
to both pathologies of the uterine (decidual) vessels and the with pathology of the decidual vessels. Hypertensive
downstream effects on placental development [5]. disorders affect approximately 5–10% of pregnancies

and are relatively more common in young and older
mothers.
15.7.1 Clinical Features The clinical presentation may reflect acute or chronic fail-
ure of adequate provision of oxygen and nutrients to the
Pre-existing hypertension, pregnancy-induced hyperten- fetus, such as intrauterine growth restriction, fetal distress, or
sion, acute hypertension/preeclampsia, and related disor- even fetal demise in utero. Placental abruption is associated
ders are the maternal clinical features typically associated with hypertensive disorders of pregnancy.
a b
Fig. 15.29 (a) Upstream restriction of fetal blood flow results in mal karyorrhexis) (original magnification 200×). (b) Over time these
degeneration of downstream distal villi vasculature. Initially this degenerative debris are cleared leaving avascular villi (original magni-
appears as villous hemorrhage and endothelial apoptosis (villous stro- fication 200×)
Fig. 15.30 A characteristic feature of fetal vascular malperfusion is a

sharp distinction between avascular distal villi and adjacent uninvolved
distal villi (original magnification 100×)
Fig. 15.31 Intense fetal inflammatory infiltrates in the placental chori-

15.7.2 Gross Features onic plate vessels can mimic early true fetal vascular thrombosis; how-
ever, close inspection usually reveals intervening endothelium and a
Decidual artery lumens can be identified, by careful inspec- lack of intramural fibrin (original magnification 200×)
tion, as small dark indentations on the basal surface of the
placenta. When choosing blocks of the placental disc for Decidual vasculopathy cannot directly be observed mac-
embedding, ideally the basal surface will include a layer of roscopically, but its downstream effects may be evident, such
decidua with vessels. as placental hypoplasia and infarcts.
15.7.3 Microscopic Features
It should be kept in mind that the vast majority of the uterine

arterial system remains unknown to the pathologist examin-
ing the placenta, and what few distal branches of the decid-
ual vessels are incidentally included in routinely sampled
blocks may provide only hints of occult significant
pathology.
15.7.3.1 Normal Decidual Vessels

Normal decidual arteries of the membranous decidua can
have very thin muscular walls throughout pregnancy
(Fig. 15.32). Normal arteries of the basal decidua normally
become more ectatic during the second trimester; tropho-
Fig. 15.33 Two decidual vessels with mural hypertrophy, a form of
blast invasion may be seen. By the end of the third trimester, decidual vasculopathy. The muscular walls of the vessels comprise
all arteries underlying the central part of the disc should be more than one-third the total vessel circumference. Contrast with the
completely remodeled, with no identifiable muscular layer. normal vessel on the right (original magnification 200×)
15.7.3.2 Decidual Vasculopathy The presence of residual smooth muscle in basal decidual
Decidual vasculopathy or arteriopathy includes a variety of vessels near term, with or without persistence of invading
abnormalities ranging from incomplete adaptation of vessels trophoblast, indicates incomplete adaptation for pregnancy.
to more severe pathologies. Pathology of the decidual arter- Decidual mural hypertrophy describes hypertrophic muscu-
ies correlates imperfectly with the presence of hypertensive lar layers in either membranous or basal decidual arteries and
disorders of pregnancy and fetal or placental growth is pathologic. A muscular layer with thickness greater than one-
restriction. third of the vessel diameter is a useful criterion (Fig. 15.33).
Acute atherosis refers to subendothelial foamy macrophages
of an arterial wall in any part of the decidua and may be accom-
panied by acute fibrinoid necrosis (Fig. 15.34). Unremodeled
Table 15.9 Grading of fetal vascular malperfusion (FVM)
arteries provide the substrate for the development of this acute
Low-grade One chorionic plate or stem villus thrombus lesion. Luminal thrombosis may be present.
FVM and/or
<45 avascular distal villi Decidual vasculopathy is often accompanied by perivas-
High-grade Two or more chorionic plate or stem villus cular inflammation with lymphocytes, although this finding
FVM thrombi on its own is not diagnostic.
and/or
≥45 avascular distal villi, in at least two foci
15.7.3.3 Histologic Sequelae
Adapted from [5] In addition to the vascular changes described above, the fol-
lowing accompanying histologic changes may be seen:
accelerated villous maturation or distal villous hypoplasia,
villous infarcts, and basal or retroplacental hematomas.
15.7.4 Prognosis
The outcome of pregnancies affected by decidual vasculopa-

thy is variable and depends on severity and timing of pathol-
ogy. The mechanism of poor fetal outcome is acute or chronic
placental malperfusion. Adverse outcomes may include pre-
term delivery and its complications, fetal distress, placental
abruption, perinatal asphyxia with potential long-term neu-
rologic sequelae, growth restriction (classically asymmet-
ric), and perinatal demise [37]. In severe cases of
Fig. 15.32 Normal decidual vessels show appropriate adaptation for
pregnancy, with complete loss of muscular layer or only a single incon- preeclampsia/eclampsia or HELLP syndrome, maternal
spicuous layer of myocytes remaining (original magnification 200×) death can occur [38].
a b
Fig. 15.34 (a) Acute atherosis of decidual vessels, with fibrinoid necrosis of the walls and (b) foamy macrophages (original magnifications 200×)
There is a risk of recurrence in subsequent pregnancies, become paler, firmer, and more homogeneous (Fig. 15.35).
especially if preeclampsia was severe or had preterm onset. This tinctorial and textural difference is more evident in the
fixed than in the fresh state. They usually involve the basal
portion of the disc with variable extension toward the fetal
15.8 Placental Ischemia and Infarction surface.
The size and/or quantity of infarcted parenchyma should be
Villous ischemia results from inadequacy or interruption of estimated in the gross description, either in absolute terms or
maternal blood supply via the uterine spiral arteries. This is as an approximate percentage of placental disc volume. The
often due to the decidual vascular pathology described in the location should also be noted, as small marginal infarcts are
section above on maternal vascular malperfusion, but can not uncommon at term. It is not necessary to exhaustively
also be caused by maternal conditions not necessarily affect- sample infarcted parenchyma if the macroscopic appearance
ing the arteries themselves. Premature separation of the pla- is typical; if multiple lesions appear grossly similar, one repre-
cental disc from the uterine arterial supply (abruption) also sentative block often suffices. Sampling of surrounding appar-
causes ischemia of the supplied portion of the disc. ently unaffected parenchyma is often more informative.
In general, central infarcts are abnormal since this should
be an area of optimized maternal blood supply. Additionally,
15.8.1 Clinical Features large infarcts (>1–2 cm), multiple infarcts, and any infarcts
in the preterm or undersized placenta indicate inadequacy of
The underlying cause may be a primary condition affecting utero-placental perfusion.
maternal vascular health, such as pre-existing hypertension, The placenta may have other gross features of maternal
diabetic vasculopathy, smoking, cocaine use, thrombophilia, vascular malperfusion, most notably hypoplasia and/or gross
or hemoglobinopathy. Maternal hypotension or shock can evidence of abruption.
also cause ischemia of the placenta. The cause may be pri-
marily a gestational one, as in decidual vasculopathy, or ana-
tomically abnormal placental implantation (e.g., in the lower 15.8.3 Microscopic Features
uterine segment or overlying a submucosal leiomyoma).
Because the normal term placenta has significant excess Histologically, early villous infarcts appear as crowding or
capacity, small infarcts near or at term, especially near the collapse of the villous architecture with loss of the interven-
disc margin, rarely cause problems. ing intervillous maternal blood space (Fig. 15.36). Infiltration
by neutrophils may be a prominent, though transient, feature
(Fig. 15.37). As the infarct matures, there is progressive loss
15.8.2 Gross Features of nuclear staining in the villous stromal cells. The syncytio-
trophoblastic nuclei usually first appear smudged and even-
The macroscopic appearance of an infarct, as in other organs, tually also lose their nuclear staining (Fig. 15.38). A remote
depends on the age of the lesion. Acute infarcts may appear infarct is a good example of coagulative or white infarction
darker than surrounding parenchyma, whereas older infarcts (despite the dual blood supply of the placenta), in which
a b
Fig. 15.35 Placental disc cross sections showing multiple infarcts at varying stages, from (a) recent (dark red and hemorrhagic) to (b) remote
(pale and firm)
a b
Fig. 15.36 (a) At low power, early villous infarcts appear as localized increased syncytial knots and nuclear smudginess are apparent (original
areas of villous condensation and congestion with collapse of the inter- magnification 200×)
villous space (original magnification 10×). (b) At higher power,
a b
Fig. 15.37 (a, b) Infarcts may be transiently surrounded by a rim of infiltrating neutrophils which quickly undergo karyorrhexis (original magni-
fications 10× and 200×)
a b
Fig. 15.38 (a) Remote infarcts appear as well-defined areas of agglutinated pale villi (original magnification 20×). (b) At high power, villous
outlines are maintained but nuclei are faded (original magnification 200×)
a b
Fig. 15.39 Intervillous thrombi are common discrete parenchymal lesions that can mimic infarcts. On gross (a) and microscopic (b) examination,
however, they can be seen to not involve villi (except peripherally) and have characteristic lines of Zahn (b, original magnification 20×)
nuclear detail is lost but architectural outlines of villi remain 15.8.4 Differential Diagnosis
(so-called ghost villi).
Aside from frank infarction, the villi in an affected placenta Another relatively common discrete gross parenchymal
may elsewhere show changes of acute and/or chronic ischemia lesion is the intervillous thrombus (IVT). These are local-
on the basis of inadequate perfusion of the placenta. In severe ized areas of intervillous hemorrhage, composed most
cases of chronic underperfusion, distal villous hypoplasia may often of both maternal and fetal blood. They can be distin-
be evident (described in next section). Other changes attrib- guished macroscopically from infarcts in that they are often
uted to ischemia include increased syncytial knots and/or polygonal instead of round, are not typically basally
prominent protrusion of syncytial knots on villous surfaces located, and are composed of laminated layers. On micro-
(Tenney-Parker change). Villous agglutination and perivillous scopic examination they can be seen to be composed of
fibrin deposition are non-specific features of villous injury that alternating layers of red cells and fibrin with platelets (lines
may precede histologic evidence of infarction. of Zahn). Ischemic or infarcted villi may be present at the
Examination of sampled decidual vessels may or may not periphery, but there are no ghost villi within the center of
disclose evidence of decidual vasculopathy. the lesion (Fig. 15.39).
a b
Fig. 15.40 Chorionic villi in the late first trimester are relatively edematous-appearing stroma. Developing fetal vessels contain nucle-
homogeneous in size, shape, and appearance. There are distinct layers ated red blood cells (a, original magnification 100×, b, original magni-
of synctiotrophoblast and cytotrophoblast lining the villi, which have fication 400×)
15.8.5 Prognosis 15.9.1.1 Villi in the First Trimester

The very earliest stages (the first few weeks postconception)
The larger the affected portion of the placental disc, the of placental development will not be covered here, as these
higher the likelihood of adverse fetal or neonatal outcome. specimens rarely produce clinically recognized abortions
Adverse outcomes that can be attributed to acute or acute-on- sent to surgical pathologists. The chorionic villi most often
chronic ischemia include fetal distress, abnormal umbilical encountered in first-trimester products of conception are
blood flow on Doppler ultrasound, perinatal asphyxia, and from mid- to late-first trimester (Fig. 15.40). The villous
fetal demise. There may be concurrent clinical evidence of sizes at this stage are more similar to each other than the
chronic ischemia including fetal growth restriction and gross greater variability seen in later gestation. The villi are lined
placental hypoplasia. by abundant syncytiotrophoblast and a continuous recogniz-
able layer of underlying cytotrophoblast cells. The stroma is
loose and edematous-appearing with few mesenchymal
15.9 Disorders of Villous Maturation cells. Early developing vessels may be inconspicuous or may
and Development contain abundant nucleated fetal red blood cells.
A reasonably accurate clinical estimate of gestational age 15.9.1.2 Villi in the Second Trimester
must be provided to the pathologist evaluating a specimen. In Over the course of the second trimester, the villous stroma
order to objectively assess disorders of villous maturation, becomes less edematous and more collagenized, with pro-
one must be familiar with the range of villous shapes, sizes, gressively more vascularization (Fig. 15.41). As the villous
and vascularity in the normally developing placenta. tree branches, there is more variability in villous size.
15.9.1.3 Villi in the Third Trimester

15.9.1 Normal Villous Development In the third trimester, the population of smallest (most distal)
villi becomes more numerous, and the average size of distal
Several texts explain normal development of the villous tree villi becomes smaller (Fig. 15.42). The nuclei of the syncytio-
in detail, including the typical appearances, functions, and trophoblast tend to pile up in so-called syncytial knots; the
relationships between the five developmental types of villi: cytotrophoblast is inconspicuous. These distal or terminal
mesenchymal villi, immature intermediate villi, stem villi, villi eventually contain numerous capillary cross sections. At
mature intermediate villi, and terminal (or distal) villi [39, term, a typical distal villus contains numerous capillary cross
40]. For the purposes of this text, we will summarize the sections comprising more than half of its total area, as well as
expected morphologies in each trimester. multiple vasculosyncytial membranes, where capillaries abut
a b
Fig. 15.41 Villi in the second trimester undergo further branching, resulting in greater variability of size. Villi become more collagenized and
more vascularized (a, original magnification 100×, b, original magnification 400×)
a b
Fig. 15.42 These term villi are mostly small distal villi with abundant capillaries and vasculosyncytial membranes. Larger villi are stem villi
containing conducting vessels (a, original magnification 100×, b, original magnification 400×)
the thinned syncytiotrophoblast directly (the site of maternal- be assessed immediately adjacent to a discrete pathologic
fetal gas and nutrient exchange). The larger villi are stem villi lesion.
containing conducting venous and arterial branches with no It is important to remember that the changing appearance
vasculosyncytial membranes; these often become lined by a of various villous types exists on a spectrum; even occasional
layer of fibrin rather than syncytiotrophoblast. immature villi may be encountered at term. One should be
familiar with the expected villous populations seen across a
15.9.1.4 Assessment of Villous Maturation range of gestational ages, in order to recognize aberrations of
Villous maturity cannot be assessed in a single field, but development or maturation.
instead is a gestalt based on multiple complete disc cross The most helpful way to assess villous development is by
sections. Appearance of the villi at the margin and immedi- comparison with whole-slide normal age-matched controls.
ately under the chorionic plate may give a false impression Single textbook figures usually do not suffice to show the full
of accelerated maturation. Likewise, maturation should not range of villous morphologies and sizes at any gestational age.
15.9.2 Delayed Villous Maturation (Distal

Villous Immaturity)
The pathophysiologic mechanism of this disorder of placen-

tal development is not clear. The paucity of mature vasculo-
syncytial membranes typical of the term placenta is thought
to impair oxygen and nutrient exchange required by the fetus
approaching term. The diagnosis of delayed villous matura-
tion/distal villous immaturity is usually reserved for
immature-appearing placentas at or near term (>34 weeks)

The most important maternal risk factor for this finding is
diabetes, either pre-existing or gestational [41]. See below
for a discussion of the effects of diabetes on placental devel- Fig. 15.44 Chorangiosis refers to diffuse hypercapillarization of distal
opment. Villous immaturity can also be seen with maternal villi, usually defined as at least ten capillary cross sections per distal
villus, seen in at least ten fields in at least three different sections (origi-
obesity and/or excessive weight gain in pregnancy (possibly
nal magnification 100×)
indicating occult hyperglycemia not diagnosed as gestational
diabetes).
illarized distal villi (≥10 capillary cross sections per terminal
15.9.2.2 Gross Features villus, seen in ≥10 villi in ≥10 fields over 3 sections)
These placentas are often (but not always) large for gesta- (Fig. 15.44).
tional age. Although the neonate is often large, the placenta
may be relatively even more so, with a decreased fetal-
placental weight ratio. The cord may also be thick. 15.9.2.4 Differential Diagnosis
The differences may be subtle and in general diagnostic
15.9.2.3 Microscopic Features reproducibility is poor [42]. The differential diagnosis should
The villi overall appear immature relative to the documented always include incorrect documented gestational age.
gestational age (Fig. 15.43). Specifically, there will be too
many immature intermediate villi and not enough mature 15.9.2.5 Prognosis
distal villi with well-developed capillarization. The distal Delayed villous maturation is typically (but not exclusively)
villi that are present are on average larger than normal. The seen in combination with large-for-dates or frankly macroso-
villous stroma may appear edematous and/or hypercellular. mic fetuses. These large but immature fetuses of diabetic
In some placentas delayed villous maturation is accompa- mothers have increased risk of demise in utero near term and
nied by chorangiosis, which is defined as diffusely hypercap- a small risk of neonatal death [41]. Distal villous immaturity
is probably not an independent risk factor for poor outcomes,
once maternal and fetal factors are taken into account.
15.9.3 Accelerated Villous Maturation
Accelerated villous maturation is a term sometimes applied

to placentas with a subjective appearance of accelerated mat-
uration, but falling short of the criteria for distal villous
hypoplasia (see below) (Fig. 15.45). Features that may be
abnormal for gestational age include predominance of inap-
propriately small distal villi and increased syncytial knots.
15.9.4 Distal Villous Hypoplasia

Fig. 15.43 Delayed villous maturation/distal villous immaturity: this
term placenta shows a deficiency of mature distal villi with vasculosyn- This villous phenotype is the result of chronic malperfusion
cytial membranes (original magnification 100×) (from any cause). It is thought that the fundamental
Fig. 15.46 Distal villous hypoplasia in a grossly hypoplastic near-

term placenta. The villi are small and sparse (original magnification
Fig. 15.45 Accelerated villous maturation: in this 30-week gestation 100×)
placenta, the distal villi appear similar to term distal villi (original mag-
nification 100×) comparison with an age-matched normal control will fre-
quently highlight the differences. In normal placentas, an
d evelopment problem is one of deficient branching of the appearance similar to DVH can often be seen immediately
developing villous tree [43]. below the chorionic plate, due to the relative hypoxia in this
part of the maternal circulation. The diagnosis of distal vil-
15.9.4.1 Clinical Features lous hypoplasia should be reserved for those cases in which
In its well-developed form, distal villous hypoplasia (DVH) the findings are diffuse or, at minimum, involve a large area
is strongly associated with severe preeclampsia with preterm (>30%) of one slide.
onset. Other hypertensive disorders of pregnancy are also Associated findings may include ischemic villous
risk factors. This phenotype has also been associated with changes, infarcts, and other features of maternal vascular
autoimmune disorders, severe malnutrition, and smoking. malperfusion or preeclampsia.
Distal villous hypoplasia is often associated with fetal
growth restriction, particularly early-onset growth restric- 15.9.4.4 Prognosis
tion, which may be severe. There may be abnormal umbilical There is a significant risk of perinatal morbidity and mortal-
arterial Doppler studies and fetal distress with indicated pre- ity, resulting from the combination of low birth weight and
term delivery. prematurity.
Distal villous hypoplasia may be a discordant feature in
twin or multiple gestations. In monochorionic twins compli-
cated by twin-to-twin transfusion, the donor twin’s placental 15.9.5 Villous Development in Chromosomally
villi may appear hypoplastic. In dichorionic twins with dis- Abnormal Placentas
cordant growth, the smaller twin may have a disadvantaged
placental implantation site with poorer perfusion and DVH. Except in the case of molar pregnancies, the gross and micro-
scopic features of chromosomally abnormal (aneuploid) pla-
15.9.4.2 Gross Features centas are non-specific and have poor interobserver
These placentas are most often small for gestational age. diagnostic concordance [44–46]. Hydrops is not uncommon
They may have other stigmata of acute or chronic ischemia in some aneuploidies, but is non-specific; see the section on
or preeclampsia, including infarcts and retroplacental or hydrops, below. Gestational trophoblastic disease is dis-
marginal hematomas. In cases associated with inadequate cussed in another chapter.
perfusion due to non-ideal anatomic site of implantation, the
umbilical cord insertion may be marginal or velamentous. 15.9.5.1 Clinical Features
These placentas may be encountered in a variety of clinical
15.9.4.3 Microscopic Features scenarios, including termination of pregnancy for fetal
The distal villi appear very small and sparse (Fig. 15.46). anomalies with or without prenatally confirmed aneuploidy,
Frequently seen are long skinny distal villi studded with hob- unexpected fetal demise in any trimester, or unexplained
nailed syncytial knots. Stem villi appear relatively more fetal growth restriction. Examination of the fetus by com-
prominent due to the paucity of distal villi. Side-by-side plete postmortem examination and chromosomal studies will
usually be more informative than placental examination in usually characterized grossly by large placental size, large-
isolation. caliber thick-walled and tortuous chorionic plate vessels, and
hydropic villi (Fig. 15.49). Some of the microscopic features
15.9.5.2 Gross Features (edema and cisterns) resemble those of molar pregnancy, but
Placentas may be either very small for gestational age (which rather than trophoblastic hyperplasia, abnormal vascular
is typical for trisomy 18 and digynic triploidy), small-to- development predominates, including thick-walled stem
appropriate for gestational age (trisomy 21), or large for ges- vessels as well as chorangiomatous capillary proliferations
tational age (monosomy X with hydrops, molar pregnancy). (Fig. 15.50). This type of placental maldevelopment is clas-
sically associated with Beckwith-Wiedemann syndrome,
15.9.5.3 Microscopic Features although other genetic, imprinting, and chromosomal etiolo-
Villi may appear completely normal. Not uncommonly, vil- gies have been described [48].
lous development is diffusely but non-specifically altered. In
general, clues to aneuploidy include accelerated or delayed
villous maturation, variable villous morphology in different
areas (“villous dysmaturity”), villous edema, villous stromal
hypercellularity, complex villous outlines, predominance of
intermediate villi, trophoblast (pseudo)inclusions, and stip-
pling of trophoblast basement membranes (Figs. 15.47 and
15.48). None of these features have individually been shown
to predict aneuploidy (and all are occasionally seen in dip-
loid gestations), but in the correct clinical setting, the gestalt
may be useful in suggesting chromosomal testing to explain
a pregnancy loss or anomalous fetus.
15.9.6 Placental Mesenchymal Dysplasia
Placental mesenchymal dysplasia is a specific placental phe- Fig. 15.47 Aneuploid placenta (trisomy 18) at mid-gestation, with
notype sometimes referred to as “pseudo-mole” [47]. It is immature convoluted villi (original magnification 20×)
a b
Fig. 15.48 Non-specific features that can be seen in aneuploid placentas are (a) trophoblast pseudo-inclusions and (b) stippling and edema
(manifested as clefting beneath the trophoblast basement membrane) (original magnifications 100×)
a b
Fig. 15.49 Two cases of placental mesenchymal dysplasia with abnormal vessels and cyst-like masses, at (a) 32 weeks and (b) 35 weeks. Both
neonates had congenital anomalies, but neither had genetically confirmed Beckwith-Wiedemann syndrome
placentas of mothers with either pregestational diabetes or ges-

tational diabetes [49]. Good insulin control can mitigate the
excessive placental weight [50]. Placentas from women with
long-standing diabetes with significant end-organ damage may
however be small for gestational age. Single umbilical artery
has also been associated with diabetic gestations [51].

Placentas from diabetic mothers show increased angiogene-
sis and distal villous immaturity/delayed villous maturation
[49]. Chorangiosis is also common. See description of both
of these patterns above (Sect. 15.9.1).
15.9.7.4 Prognosis
Fetuses of diabetic mothers are at increased risk of macroso-
Fig. 15.50 Placental mesenchymal dysplasia. The cystic lesions seen mia, congenital anomalies, neonatal respiratory distress,
grossly correspond to edematous stem villi (original magnification 20×) neonatal hypoglycemia, early spontaneous abortion, as well
as late (term or post-dates) stillbirth. A long-term implication
for the maternal patient diagnosed with gestational diabetes
15.9.7 Effects of Maternal Diabetes is an estimated 50% risk of developing type 2 diabetes within
on Placental Development 20 years [52].

Diabetes in pregnancy is either pregestational type 1 diabetes 15.10 Abruption
mellitus, pregestational type 2 diabetes mellitus, or gesta-
tional (pregnancy-induced) diabetes mellitus. The effects on Placental abruption refers to premature separation of the pla-
placental and fetal development depend on duration of dis- centa from the decidua, and can be divided into three catego-
ease, degree of chronic diabetic visceral vasculopathy, glyce- ries based on the associated pathological findings and clinical
mic control during pregnancy, and whether there is also context: acute, subacute, and chronic.
hypertension. Maternal diabetes causes structural and func-
tional changes in the placenta; none of these are sensitive nor
specific. 15.10.1 Clinical Features
15.9.7.2 Gross Features Maternal risk factors for abruption include

The most common gross alteration is increased placental eclampsia/preeclampsia, vasoactive drugs (e.g., cocaine), and
weight and central thickness, which are commonly observed in trauma. Acute and subacute abruption classically present as
a b
Fig. 15.51 Acute placental abruption is associated with retroplacental hematoma formation that deforms the maternal surface (a, formalin-fixed,
b, fresh)
acute abdominal or back pain and tetanic rigidity of the

uterus. The bleeding, which is of maternal origin as the decid-
ual arteries bleed into the retroplacental space, may be overt
or concealed. Abruption may also be asymptomatic in the
mother but manifest as unexplained fetal distress or preterm
labor. Ultrasound can be useful for the diagnosis and follow-
up of abruption in the non-emergent setting [53].
Chronic abruption differs from acute/subacute abruption
in that it is not severe enough to prompt spontaneous or iat-
rogenic delivery. Chronic abruption usually has a history of
excessive, persistent, or intermittent vaginal bleeding with-
out the other symptoms and signs of acute abruption.
Deformation of the maternal surface of the placenta by a ret-

roplacental hematoma is virtually pathognomonic of acute or
subacute abruption (Fig. 15.51), but is not a sensitive marker.
Chronic abruption may be recognized grossly as fibrin col-
lections typically seen around the disc margin (Fig. 15.52).
Fig. 15.52 Chronic abruption-associated marginal thrombus demon-
Hemosiderin discoloration of the placental membranes may strating the typical friable maroon-tan appearance
be apparent and when prominent and diffuse should prompt
diagnosis of diffuse chorioamniotic hemosiderosis
(Fig. 15.53), which is thought to be related to chronic peri- Subacute abruption is defined by the presence of histo-
placental separation and related hemorrhage [54]. pathological features of early placental infarction in the clin-
ical setting of acute abruption. Microscopic features of early
placental infarction include terminal villous aggregation,
15.10.3 Microscopic Features loss of syncytiotrophoblast chromatin detail, and increased
syncytiotrophoblast cytoplasmic eosinophilia (Fig. 15.54).
Acute abruption does not produce specific histopathological Chronic abruption is characterized by periplacental
changes, which by definition take time to develop. hemorrhage(s) showing degenerative changes including
Fig. 15.53 Extensive chronic abruption leads to grossly visible heme Fig. 15.54 Early ischemic changes associated with subacute abruption
breakdown products that stain the placental membranes green-brown include loss of nuclear chromatin detail and cytoplasmic eosinophilia in
(diffuse chorioamniotic hemosiderosis). Marginal thrombus is a typical affected syncytiotrophoblast (original magnification 200×)
concurrent finding and is present in this example
a b
Fig. 15.55 Characteristic microscopic findings in chronic abruption include hemosiderin in the (a) membranous tissues and (b) chorionic plate
(Perls’ Prussian blue stain; both original magnifications 100×)
retromembranous degenerating blood, retromembranous bleeding into this potential space (Fig. 15.55b). Small areas
thrombus, and hemosiderin-laden macrophages and hemo- of remote infarction related to areas of chronic abruption
siderin deposits (Fig. 15.55a). Hemosiderin deposits in the may be present, particularly at the disc margin (Fig. 15.56).
chorionic plate are also seen in chronic abruption and may Chronic abruption-oligohydramnios sequence (CAOS)
conform to the juncture of the amnion and chorion, implying describes chronic abruption associated with oligohydram-
15.11 Abnormal Placental Implantation
15.11.1 lacenta Accreta, Increta,

P
and Percreta
Pathologically invasive trophoblast, in which villi and basal

fibrin are found adjacent to or within myometrium, without
intervening decidua (endometrium altered for pregnancy),
has been divided into three anatomically defined types with
associated increasing severity of clinical consequences.
Placenta accreta refers to deficiency of decidua without
obvious thinning or invasion of the myometrium. Placenta
increta is used to describe extension of villi into the myome-
trium, which can also be seen as thinning of the myometrium.
Placenta percreta is the situation in which villous tissue
extends through the myometrium to the serosa of the uterus
or adjacent structures (e.g., bladder), with or without gross
uterine perforation.

Fig. 15.56 Marginal chronic abruption may be associated with adja- These lesions occur most often when the placenta implants
cent placental infarction (original magnification 10×) in a uterus with pre-existing deficiency or alteration of the
endometrium. The most common risk factor by far is previ-
ous Cesarean section. Not unexpectedly, increasing rates of
nios. Microscopic features of chronic abruption are exten- Cesarean section have contributed to a significant increase in
sive, and hemosiderin is prominent. Oligohydramnios is the incidence of placenta accreta and associated conditions,
thought to arise from abruption-related membrane ischemia, most recently estimated to occur in nearly 1 in 500 deliveries
necrosis, and rupture. CAOS is frequently complicated by [57, 58]. The risk increases significantly after two or more
amniotic fluid infection syndrome. previous such surgeries. Other clinical risk factors include
other types of uterine surgery, for example, myomectomy for
leiomyoma or endometrial curettage or ablation.
15.10.4 Differential Diagnosis Placenta accreta can also occur when the placenta
implants anywhere with suboptimal, relatively deficient
Care must be taken not to confuse delivery-related adherent decidua, such as in the lower uterine segment (in which case
blood as acute abruption; non-specific adherent blood can be it is usually associated with placenta previa), the uterine
recognized by the lack of associated placental deformation cornu, or overlying a submucosal leiomyoma.
and easy removal from the disc maternal surface. Microscopic Placenta accreta/increta/percreta has variable presenta-
features of subacute abruption may be found in early infarction depending on gestational age and severity. It can be
tion related to maternal vascular malperfusion and prolonged detected on prenatal ultrasound imaging with fair sensitivity
placental retention after induction of labor; correlation with and high specificity and further characterized as necessary
clinical history is important to discern between these possi- with MRI [59]. It may present unexpectedly in the immedi-
bilities. Hemosiderin of chronic abruption may be confused ate postpartum period as postpartum hemorrhage and/or as
with meconium; positive special staining for iron will iden- delay or failure of placental separation.
tify hemosiderin. When diagnosed prenatally, significant placenta accreta/
increta/percreta requires management by a specialized
obstetrics service to make decisions about timing of delivery,
15.10.5 Prognosis type of delivery, surgical approaches, and to anticipate the
need for hysterectomy. In cases of placenta percreta detected
Acute and subacute abruption can be associated with preterm in mid-gestation, gravid hysterectomy prior to fetal viability
birth, birth asphyxia, stillbirth, and maternal hemorrhage. may be required.
Chronic abruption, when diffuse chorioamniotic hemosider-
osis is present, is an independent risk factor for development 15.11.1.2 Gross Features
of cerebral palsy [55]. CAOS is associated with increased In the most common scenario encountered by the surgical
risk of amniotic fluid infection and poor outcomes, including pathologist, the specimen is a manually delivered placenta
long-term neurological damage [56]. with no obvious macroscopic abnormalities related to abnor-
Fig. 15.57 Placenta increta in the lower uterine segment and cervix in
a hysterectomy specimen
Fig. 15.58 Placenta accreta with chorionic villi implanted immedi-
ately above a layer of extravillous trophoblast and myometrium, with-
mal implantation. Rarely grossly evident adherent myome- out intervening decidua (original magnification 40×)
trium is evident.
In more severe cases, hysterectomy may have been referred to this finding as occult placenta accreta or basal
required either after placental delivery due to persistent hem- plate myometrial fibers (Fig. 15.59); there is a plausible
orrhage, or the hysterectomy specimen may be received with connection and case-control evidence that this finding is
the placenta still attached (Fig. 15.57). In this case, it is help- associated with placenta accreta in subsequent pregnancies
ful to approach the examination and sampling similarly to [61, 62].
that used for invasive endometrial cancers; that is, the In placenta increta, gross myometrial thinning will also
following should be documented: anatomic location of
be evident microscopically, and the absence of decidua can
implantation (fundal, anterior/posterior, lower uterine seg- be confirmed. Note that the myometrium of the lower uterine
ment, cervix), relationship to parametrial and paracervical segment is physiologically very thin in late pregnancy (com-
resection margins, depth of invasion (on cross section), parison with a section of uterine wall not underlying the pla-
thickness of uninvolved myometrium, and involvement of cental disc provides a control). The microscopic picture of
serosal surface. Photographs are helpful. A standardized pro- placenta percreta may be less clear as frank serosal perfora-
tocol has been published [60]. Principles of standard placen- tion will often be accompanied by hemorrhage and/or dis-
tal examination also apply. ruption due to surgical dissection off an adjacent structure
(Fig. 15.60).
In the case of a delivered placenta not accompanied by a
uterus, microscopic examination is probably insensitive for 15.11.1.4 Prognosis
confirming a clinical suspicion of placenta accreta. This is in Abnormal placental implantation is a risk factor for preterm
part due to the fact that the diagnostic features may be hidden delivery, perinatal mortality [58], indicated Cesarean sec-
in retained products. Furthermore, considering the very lim- tion, postpartum hemorrhage, delayed placental delivery,
ited sampling typical for placental pathology (three blocks hysterectomy, and even maternal mortality. The recurrence
from a 400 to 500 g organ), it is not unexpected that diagnos- risk in subsequent pregnancies for women who do not
tic microscopic fields may be missed simply due to extremely undergo hysterectomy is high.
limited sampling of the maternal surface.
When myometrium is present on the basal surface in a
microscopic section, there is most often an intervening layer 15.11.2 Placenta Previa and Vasa Previa
of basal fibrin and extravillous trophoblast underlying villi,
as opposed to villi lying immediately upon myometrial cells Placenta and vasa previa describe placental implantation
(Fig. 15.58). Immunohistochemical stains can be used to dif- over the inner cervical os. In placenta previa, the placental
ferentiate decidua and trophoblast if necessary: decidual disc covers the os, while in vasa previa, the disc regresses
cells are CD10 positive (cytoplasmic/membranous) and leaving placental membrane with velamentous umbilical
keratin negative (cytoplasmic), whereas extravillous tropho- vessels covering the os (Fig. 15.61). Placenta and vasa previa
blast stains oppositely. predispose to abruption; features of chronic abruption are
The significance of incidentally seeing the histologic typically found. Occasionally, large hematomas with evi-
picture of placenta accreta in a patient without clinical evidence of recurrent bleeding may be present. Associated disc
dence of abnormal implantation is debated. Some have infarction and atrophic regression may also be seen. Since
a b
Fig. 15.59 Myometrial cells can be seen adherent to the basal surface and magnification with desmin immunohistochemical stain, c, original
of the placenta, with only rare decidual cells intervening between them magnification 400×)
and the basal trophoblast (a, original magnification 100×, b, same field
Fig. 15.61 A case of delivered placenta previa with vasa previa. The
Fig. 15.60 The right side of the picture demonstrates increta, with section of velamentous vessels with deficient parenchyma overlaid the
thinning of the normal uterine wall thickness, and the left side of the cervical os
picture shows percreta, with chorionic villi invading into extrauterine
space (original magnification 20×)
15.12 Multiple Gestation

the placenta is implanted over the adjacent lower uterine
segment, features of maternal vascular malperfusion and 15.12.1 Clinical Features
placenta accreta/increta/percreta may also be present. Vasa
previa is also at risk of fetal vascular flow restriction and In North America, data from 2014 to 2015 record approxi-
vascular rupture. mately 33 twin births out of every 1000 total births. Triplet
and higher-order multiples are around 300 times less fre- Table 15.10 Specific details to include in gross description of a mul-
quent than twins [63, 64]. tiple gestation placenta
Risk of multiple gestation is increased in some ethnic Whether cords have been matched to specific neonates (e.g., “cord
clamp on twin B”)
groups, with advancing maternal age, with higher parity, and
Chorionicity (monochorionic, dichorionic, trichorionic, etc.)
with a personal or family history of prior twins or multiples.
Amnionicity: within each chorionic sac, how many amniotic sacs
An increasingly important contributor to multifetal preg- are present (monoamniotic, diamniotic)?
nancy rates is the use of assisted reproductive technologies Description of dividing membrane (opaque versus translucent)
[65]. Many pregnancies that begin as multiple gestations Number of discrete placental discs? If multiple, separate, or fused?
have asymptomatic occult spontaneous abortion of one twin Separate discs: weigh each separately
prior to the second trimester (so-called vanished twin). Single or fused disc: weigh together
(To be compared against multiple gestation-specific normal values)
Intercordal distance (distance between cord insertions)
For monochorionic placentas, placental share (percentage of the
15.12.2 Gross Features fetal surface covered by each twin’s chorionic plate vessels)
The gross description of multiple gestation placentas involves

specialized terms. Chorionicity of the placenta refers to the
number of chorionic sacs present. Amnionicity refers to the
number of amniotic sacs contained within a chorionic sac.
A placenta composed of a single chorionic sac is known
as monochorionic. Within the chorionic sac, there may be a
single or multiple amniotic sacs (monoamniotic, diamniotic,
triamniotic, etc.). In this type of placentation, the fetuses
share a single placental bed. These fetuses are by definition
monozygotic, i.e., arising from a single zygote that under-
goes twinning.
Frequently, twin and higher multiple gestations are char-
acterized by each fetus having its own gestational sac with
amnion, chorion, and placental bed. In this situation, fetuses
do not share a placental bed. These fetuses may be monozy-
gotic, arising from a single zygote that undergoes early twin-
ning, or dizygotic, arising from two separate eggs fertilized Fig. 15.62 Separating membranes of a dichorionic, diamniotic twin
by separate sperm. Such gestations are denoted by “dichori- placenta. The middle of the separating membranes is composed of two
onic,” “trichorionic,” etc. apposed layers of chorion (one from twin 1, one from twin 2). The
chorion from each twin’s placenta is surfaced by a layer of amnion,
Commonly encountered twin scenarios include:
which faces their respective amniotic cavities. There are four total tissue
Dichorionic, diamniotic: These consist of two discrete layers depicted in this photomicrograph. From left to right: amnion 1,
placental discs each with its own amnion and chorion. Each chorion 1, chorion 2, amnion 2 (original magnification 100×)
fetus resides in its own amniotic and chorionic sacs, and the
dividing membrane consists of two core layers of chorion
flanked by two layers of amnion. This membrane is grossly 15.12.3 Microscopic Features
opaque. The discs may be separate or fused.
Monochorionic, diamniotic: This placenta consists of a Chorionicity can be confirmed microscopically by evaluat-
single placental disc with one chorion and two amniotic sacs. ing the tissue layers of the dividing membrane. The divid-
Each fetus resides in its own amniotic sac, and the dividing ing or separating membrane refers to the wall of the
membrane consists of two layers of amnion only. The mem- gestational sac separating the fetuses. In dichorionic pla-
brane appears thin and translucent. centation, the dividing membrane is composed of four lay-
Monochorionic, monoamniotic: This placenta consists of ers: amnion 1, chorion 1, chorion 2, and amnion 2
a single placental disc with a single chorion and single (Fig. 15.62). In monochorionic placentation, the separating
amnion. Two fetuses reside together in the same amniotic membrane is composed of two layers: amnion 1 and amnion
sac. There is no dividing membrane. There is a high risk of 2 (Fig. 15.63).
cord entanglement [66]. When assessing the placenta from a multiple birth, one
In addition to routine observations made for any gross should compare the villous development of each placental
placental description, several multiple-gestation-specific disc (if multichorionic) or each infant’s “side” of the disc (if
details should be noted (see Table 15.10). monochorionic). Discrepant villous development may help
Table 15.11 Quintero staging system for twin-to-twin transfusion

Stage I: DVP <2 cm in donor and >8 cm in recipient
Stage II: Cannot visualize donor bladder
Stage III: Critically abnormal Doppler studies (umbilical artery
absent or reversed end-diastolic velocity, reversed ductus venosus
flow, pulsatile umbilical vein flow)
Stage IV: Hydrops in either fetus
Stage V: Death of one or both fetuses
DVP Deepest vertical pocket of amniotic fluid. Adapted from [68]
twin vascular anastomosis is presumed to occur when

placental vessels from each twin enter and exit the same
cotyledon. The opposing vessels are presumed to share a
capillary bed in the distal chorionic villi. Therefore, the con-
dition is not seen in dichorionic twins, in which two discrete
Fig. 15.63 Separating membranes of a monochorionic, diamniotic placental discs are formed with no vascular connections
twin placenta, consisting of two layers of amnion with the deep surfaces between the discs [69]. TTTS has been rarely reported in
apposed. The amniotic epithelium faces the amniotic cavity (original monochorionic, monoamniotic, twins. It should be noted that
magnification 100×) although inter-twin vascular anastomoses are commonly
seen in MCDA twin placentas, only a subset of MCDA twins
to explain discordant birth weights (i.e., differences of >10% develop TTTS. Therefore, vascular anastomoses are a pre-
between birth weights). requisite, but not a guarantee of TTTS development. In fact,
there is some evidence that certain types of inter-twin anas-
tomoses (namely, artery-to-artery) may be protective against
15.12.4 Prognosis the development of TTTS [70, 71].
Since symptomatic TTTS can lead to death or severe mor-
The risk of adverse obstetric and neonatal outcomes for bidity in one or both fetuses, techniques have been developed
twins and especially higher-order multiples is well- to disrupt the anastomoses and separate the fetal circulations.
documented [65]. Obstetric risks include increased risk of Selective laser ablation targets and coagulates vascular anas-
hypertensive disorder, spontaneous abortion or fetal demise, tomoses deemed physiologically abnormal, which are identi-
and preterm labor. Risks to the fetuses and neonates include fied by fetoscopic visualization and intraoperative Doppler
higher rates of congenital anomalies as well as predictable studies [67]. More recently, a technique called Solomonization
complications arising from low birth weights and p rematurity. has been introduced, in which a laser line is drawn across the
There are unique risks associated with monozygotic twins, vascular equator to coagulate it [72, 73], with the aim of
one of which is discussed below. separating/isolating the respective twin circulations. Laser
ablation of vascular anastomoses is performed on eligible
individuals during the second trimester. Complications
15.12.5 Twin-to-Twin Transfusion include bleeding/infection, premature rupture of membranes,
demise of one or both twins following the procedure, and
15.12.5.1 Clinical Features conversion of the procedure to selective reduction of a twin
Twin-to-twin transfusion syndrome (TTTS) is a condition if conditions are unfavorable to perform laser ablation.
primarily affecting monozygotic twins sharing a monochori-
onic, diamniotic (MCDA) placenta. In MCDA placentation, 15.12.5.2 Gross Features
the placental vascular circuit is shared by the twins. The placenta associated with twin-to-twin transfusion syn-
Complications can arise when one twin receives more blood drome is typically a MCDA twin placenta (Fig. 15.64).
flow than the other twin, resulting in a recipient and a donor The separating membranes have no relationship with the
twin. The Quintero system is commonly used to stage the orientation of the vascular equator. Examination of the fetal
severity of the condition by ultrasound (Table 15.11). vessels of the chorionic plate is facilitated by entirely remov-
Hydrops results either from fetal anemia (donor twin) or ing the reflected membranes and fetal surface amnion. The
high-output cardiac failure from volume overload (recipient vascular equator is the imaginary line where the vessels from
twin) [67, 68]. both twins meet. It is in the center of the disc if the placental
Development of TTTS depends on the existence of inter- share is equal. In cases of uneven placental share, the vascu-
twin vascular anastomoses at the vascular equator. An inter- lar equator is skewed toward one end of the disc.
The integrity of intact anastomoses can be tested by twin. This allows for identification of anastomoses involving
injecting air using a syringe into the fetal surface vessel from vessels too thin to inject with air. For detailed information on
one twin (near the equator), then gently massaging the air this technique, the reader is directed to the technical paper
bubble into the parenchyma, and observing the bubble [74]. Air and dye injection maneuvers require a relatively
appearing in an adjacent fetal surface vessel from the other intact placenta. Fragmented placentas cannot be successfully
twin. A highly sensitive technique for identifying vascular injected. A case in which one or more fetuses died in utero
anastomoses during gross pathology examination has been may be challenging to inject.
developed by a group in the Netherlands [72–74]. This tech- Identifying inter-twin vascular anastomoses can provide
nique involves injection of different-colored pathology dyes an explanation for in utero hemodynamic variations/abnor-
into one artery and one vein of the umbilical stumps of each malities in the twins. Another purpose of identifying anasto-
moses is to evaluate the quality and success of laser ablation.
The gross appearance of ablation sites depends on the time
elapsed between ablation and delivery. Initially they may not
be visible, but as the ablated parenchyma ages, the sites
become firm, fibrotic, and yellow, similar to subchorionic
infarction or fibrin deposition (Fig. 15.65a).
Symptomatic TTTS may be associated with congested
parenchyma on the recipient twin’s side and pale paren-
chyma on the donor twin’s side (Fig. 15.65b). The twin pla-
centa associated with TTTS could include demise-related
changes if one or both twins undergo demise (Fig. 15.66).

The separating membranes are monochorionic and diamni-
Fig. 15.64 Monochorionic, diamniotic twin placenta at 25 weeks of otic. Without dye-injection studies, it is not possible to deter-
gestation. The pregnancy was complicated by twin-to-twin transfusion mine from a histologic section which vessels came from
syndrome and intrauterine demise of the twin on the right at 24 weeks. which twin. If there was differential congestion of the two
The twin on the left was live-born at 25 weeks. Laser ablation was not
performed in this case. There are at least seven surface vascular anasto-
sides, similar findings may be seen microscopically. The
moses at the vascular equator identified by visual inspection, including chorionic villi may appear edematous if the fetus was
vein-artery, artery-vein, artery-artery, and vein-vein hydropic. There may be accelerated villous maturation and
a b
Fig. 15.65 (a) Monochorionic, diamniotic twin placenta delivered at cular equator by visual inspection or by air injection technique. Some
36 weeks of gestation. Selective fetoscopic laser ablation was per- firm yellow patches are visible where the laser was applied. These
formed at 23 weeks of gestation. Both twins were live-born. Gross resemble infarcts microscopically. (b) Same placenta, demonstrating
examination shows no residual intact vascular anastomoses at the vas- maternal surface with differential congestion
procedure and diffuse demise-related changes if there is

demise of one or both twins.

Not all discordant growth in twins is attributable to TTTS. In
either mono- or dichorionic gestations, twins may be discor-
dant for intrauterine growth restriction because of subopti-
mal placental implantation of one twin or have different
amniotic fluid volumes due to rupture of only one twin’s
amniotic sac. In dichorionic gestations, twins may have dis-
cordant size or hydrops due to one but not both twins being
affected by a genetic, chromosomal, or anatomical anomaly.
15.12.5.5 Prognosis
Outcome depends on severity (including Quintero stage) of
the hemodynamic imbalance. In general, the earlier in preg-
nancy the condition is detected, the more severe its potential
Fig. 15.66 Monochorionic, diamniotic twin placenta from a preg- consequences. There is high mortality particularly for TTTS
nancy complicated by twin-to-twin transfusion syndrome. Selective presenting in the second trimester, if left untreated, with
fetoscopic laser ablation was attempted at 16 weeks, but pregnancy was
excess mortality for the donor rather than the recipient twin.
complicated by extreme preterm labor and delivery at 22 weeks result-
ing in demise of both twins. Ablation sites at the vascular equator are
visible as subchorionic hemorrhagic patches. No residual vascular
anastomoses could be demonstrated by air injection technique or by 15.13 Fetal Hydrops
visual inspection
Hydrops fetalis is defined as the accumulation of fluid in two

or more body compartments [76, 77]. Development of fetal
hydrops can be associated with development of maternal
edema, in a complication known as mirror syndrome
(Ballantyne syndrome). There are many possible underlying
etiologies, which are briefly discussed below.
The placenta is large for gestational age by weight and three-

dimensional size, owing to fluid retention in chorionic villi.
The cut surface of the placenta is pale, and the texture of the
chorionic villi may be boggy and friable [78]. If the underly-
Fig. 15.67 Laser ablation of twin-to-twin transfusion syndrome; villi ing etiology is a placental tumor, it may be grossly detected
with infarct-like changes with increased perivillous fibrin deposition as a space-filling lesion.
(original magnification: 20×)
fetal normoblastemia due to chronic hypoxia and/or fetal 15.13.3 Microscopic Features
anemia. The histology of ablation sites is non-specific and is
related to tissue damage and repair [75]. The histology In a hydropic placenta, there is diffuse or focal chorionic vil-
depends on the interval between laser ablation and delivery. lous edema. The affected chorionic villi are expanded by fluid
There may initially be a thrombohematoma that becomes a and enlarged. Edematous villi are especially prominent in
remote organized thrombus. Infarcted villi, avascular villi, third-trimester placentas, when villi are normally expected to
and subchorionic fibrin deposition are also seen (Fig. 15.67). differentiate into small terminal villi with reduced stroma and
Coexisting findings may include chorioamnionitis if there is numerous close-packed profiles of capillary vessels.
premature rupture of membranes secondary to the ablation Edematous villi show capillaries that appear small in caliber
Table 15.12 Causes of nonimmune fetal hydrops

Infection
Parvovirus
Cytomegalovirus
Zika virus [82]
Other TORCH infections
Aneuploidy
Monosomy X
Trisomy 21
Congenital or acquired fetal anemia
Parvovirus infection
Thalassemia
Chronic feto-maternal hemorrhage
Fig. 15.68 Chorionic villi from a placenta infected by human parvovi- Fetal lymphatic abnormalities [83]
rus B19. There are increased circulating nucleated red blood cells, some
Noonan syndrome
of which contain viral inclusions. The villi are hydropic, characterized
by increased empty spaces between villus stromal cells and lifting of Trisomy 21
the villus trophoblast from the stroma (clefting) (original magnifica- Monosomy X
tion: 100×) Fetal cardiac dysfunction
Maternal systemic lupus erythematosus with fetal heart block
Fetal right-sided cardiac structural abnormalities (e.g., tricuspid
and spaced apart. Villous stromal cells are dispersed by edema. atresia, Ebstein malformation)
There may be an increase in Hofbauer cells (villus stromal Fetal myocarditis
macrophages). When fetal anemia is present, within villous Fetal rhabdomyoma
capillaries there may be increased circulating fetal nucleated Fetal hepatic dysfunction
red blood cells (normoblasts) or more primitive erythroid pre- Inborn errors of metabolism, e.g., Niemann-Pick [84], MPS VII
[85]
cursors (erythroblasts). There may be separation of the villous
Fetal renal dysfunction
trophoblast from the stroma leading to a cleft-like space. Congenital nephrotic syndrome
Mineralization of the villous trophoblast may occur. Placental tumors
The presence of viral cytopathic effect, possibly accom- Giant chorangioma [86–88]
panied by infectious villitis, can reveal an underlying infec- Choriocarcinoma in situ [89]
tious etiology for the hydrops (Fig. 15.68). Stromal cells Metastatic maternal and fetal tumors [90]
with foamy cytoplasm and vacuolated trophoblast may point MPS VII Mucopolysaccharidosis type VII
to an underlying storage disorder. Review of maternal and
fetal/neonatal history and laboratory investigations is neces-
sary to narrow down the differential diagnosis. When red blood cell alloimmunization is clinically
excluded, the condition is specified as nonimmune hydrops
fetalis (NIHF). NIHF now account for the majority of fetal
15.13.4 Differential Diagnosis hydrops cases. There are multiple categories of underlying
causes, including congenital infections, fetal aneuploidy,
Red cell alloimmunization (development of maternal anti- congenital or acquired fetal anemia, fetal high-output heart
bodies to circulating fetal red blood cell antigens) leads to failure, fetal structural congenital heart disease, fetal liver
fetal hydrops if maternal antibodies cross the placenta and dysfunction, fetal renal dysfunction, and fetal tumors. Other
destroy enough fetal red blood cells to cause clinically sig- etiologies include primary placental tumors and metastases
nificant fetal anemia (hemolytic disease of the newborn). from mother or fetus to the placenta. Table 15.12 summa-
Maternal antibodies can develop against rhesus antigen (D rizes the very broad differential diagnosis [80, 81]. Hydrops
antigen) in Rh-negative mothers and less commonly to minor that develops in one twin in monozygotic pair is discussed in
red cell antigens. Hydrops secondary to maternal sensitiza- the section on twin-to-twin transfusion syndrome.
tion to D antigen is now rare due to routine administration of
anti-D immune globulin during pregnancy in eligible
Rh-negative mothers. Maternal antibodies against major 15.13.5 Prognosis
blood group antigens (ABO incompatibility) rarely occur, as
the IgM antibody is too large to cross the placenta into fetal Outcome depends partially on the underlying etiology of
circulation. Nonetheless, cases of fetal hydrops due to devel- hydrops, as well as its prenatal severity. In general, outcomes
opment of maternal antibodies against fetal A or B antigens are poor for prenatally diagnosed hydrops [91].
have been reported in the literature [79].
15.14 Fetal Demise of pregnancy loss (e.g., viral placentitis, histiocytic

intervillositis).
15.14.1 Early Pregnancy Loss
15.14.1.1 Clinical Features 15.14.2 Placental Changes in Late Fetal Loss

Spontaneous abortion [92] (miscarriage) in the first trimester
is extremely common, affecting an estimated 10–20% of 15.14.2.1 Clinical Features
clinically recognized pregnancies and an even greater pro- Fetal demise becomes less likely as gestation proceeds. For
portion of those not diagnosed prior to the first missed men- this reason, for unexpected fetal loss in the second half of
strual period. The etiologies are myriad; the earlier the pregnancy, one is more likely to be asked clinical questions
miscarriage, the more likely the cause is one of nonviable about etiology, fetal, and placental abnormalities. In the ideal
chromosomal complement. When examining these products scenario, a consented complete postmortem examination with
of conception, a few things should be kept in mind. One may indicated chromosomal testing should be at least considered
be able to answer specific clinical questions such as approxi- in all cases of unexplained fetal demise, as well as for selected
mate gestational age or gross features of aneuploidy. cases of terminations for unexplained fetal anomalies. Many
Laboratories should have policies in place to determine indi- of the placental pathologies discussed in this chapter can
cations for chromosome testing, as well as type of testing result in fetal demise; their specific features are discussed in
and who coordinates it (clinician or laboratory). appropriate sections. This section focuses on expected post-
mortem placental changes after demise in utero.
15.14.1.2 Gross Features
Gross description of first-trimester and fragmented second- 15.14.2.2 Gross Features
trimester products of conception should include at minimum Examination of the placenta should follow the general prin-
the amount of material received (often easiest recorded as an ciples outlined in the introductory section. One may consider
aggregate weight) and a list of grossly identifiable compo- taking extra sections when the suspected cause of death is
nents (villi, gestational sac with or without embryo, fetal placental.
parts, umbilical cord, clot, decidua). Villi should be described Chromosome testing (molecular aneuploidy detection,
specifically if they are abnormal (e.g., hydropic). If no villi chromosomal microarray, or karyotype) generally requires
are identified after careful gross search, this should be explic- sampling of fresh tissue. In most cases fetal tissue proper is
itly noted. Absence of identifiable gestational sac or fetal preferred to placental tissue (which may be contaminated
components is not uncommon, even when one has been doc- with maternal material). When fetal-placental chromosomal
umented on ultrasound. discrepancy is a diagnostic possibility, one may consider tak-
Examination of the embryo or fetus can be as detailed as ing samples from each.
size and practical constraints allow. For embryos, recording Placentas from demised fetuses tend to undergo stereo-
of the crown-rump length suffices. For fetuses, foot length is typic degeneration the longer they are retained in utero, with
the single most useful measurement to correlate with gesta- preserved maternal but not fetal circulation. The placenta
tional age. Obvious fetal anomalies should be noted, although may appear diffusely pale. The umbilical cord is often darkly
artifacts of surgical curettage or extraction are common. discolored with loss of vascular tone. Careful examination of
the cord is indicated. If labor has been induced or augmented,
15.14.1.3 Microscopic Features artifactual hematoma suggestive of abruption may be
One should confirm the presence of villi and/or trophoblast present.
invasion into decidua. If no villi are identified grossly or
microscopically in a spontaneous or iatrogenic abortion 15.14.2.3 Microscopic Features
specimen, this should be reported to the responsible physi- The placenta from a very recently demised fetus may show
cian as a potential missed ectopic pregnancy [93]. Villi no postmortem changes. After just a few hours of in utero
should be assessed to confirm generally appropriate develop- retention, one may begin to see intravascular karyorrhexis.
ment for gestational age, especially to rule out the presence Stem vessels then begin to show involutional changes includ-
of molar pregnancy-associated findings. Many early miscar- ing endothelial disintegration, fibrous luminal organization,
riages will have diffuse mild hydropic change; trophoblast and red cell extravasation; these are similar to those changes
proliferation is limited; depending on the interval to evacua- that can be seen in fetal vascular malperfusion (Fig. 15.69a).
tion, villi may instead appear fibrotic. Necrosis, hemorrhage, No fibrin thrombi or calcification of vessel walls should be
and inflammation of the decidua are common. Because these seen in purely postmortem change. Eventually (after a period
specimens are often fragmented and degenerated, one can of days to weeks), as the fetal vascular tree involutes, the
only rarely make a specific diagnosis suggestive of etiology capillaries of the distal villi likewise involute, and eventually
a b
Fig. 15.69 Changes following intrauterine fetal demise include involution of large fetal vessels, (a) stem vessels, and (b) distal capillaries (origi-
nal magnifications 100×)
Table 15.13 Postmortem vascular changes versus premortem fetal

vascular malperfusion in stillbirth 15.15 Tumors of the Placenta
Postmortem vascular Premortem fetal vascular
Feature involution malperfusion 15.15.1 Chorangioma
Umbilical Non-specific; darkly Gross cord lesion such as
cord discolored after long true knot, tight fetal Chorangiomas are the most common tumor encountered in
period of retention entanglement, organized the placenta. Their etiology is unclear, but they are more com-
thrombus
Anatomic Random, diffuse Segmental, suggesting a
monly encountered in the setting of placental hypoxia sug-
distribution specific vascular distribution gesting a reactive pathogenetic mechanism. Chorangiomas
Temporal All changes at Temporally heterogeneous, are benign but can attain very large sizes where they may
distribution similar stages especially with respect to compromise fetal cardiac output and be associated with del-
apparent timing of demise eterious mass effects.
Large vessel Non-specific Intramural fibrin; calcified
Grossly chorangiomas appear as a red to tan solid mass
changes thrombi
(Fig. 15.70a). Infarction is common and may give the lesion
a more homogenous gray appearance. Microscopically cho-
distal villi are avascular and fibrotic [94] (Fig. 15.69b). The rangiomas are a mass of fetal capillaries with a lobular archi-
villous stroma and trophoblast layer are maintained by the tecture circumscribed by chorionic tissue and
maternal blood supply. syncytiotrophoblast (Fig. 15.70b). The vascular features may
be partially or completely obliterated by infarction.
15.14.2.4 Differential Diagnosis Chorangiocarcinoma, sometimes also called as atypical
The findings of placental examination in the setting of unex- chorangioma, is variant of chorangioma that consists of
plained stillbirth should be combined with those of fetal typical chorangioma surrounded by proliferative tropho-
postmortem examination as well as ancillary and clinical blast. Despite its name, chorangiocarcinoma appears to be
information in order to provide the most useful information benign.
to the clinician and patient. The placental examination pro-
vides evidence of a cause of death in many such cases, but
these findings must be interpreted in the correct clinical con-
text. Any of the diagnostic entities discussed in this chapter 15.15.2 Choriocarcinoma
in placentas of live-born infants may be seen in stillbirth
cases; one should be familiar with expected postmortem Choriocarcinoma may occur as primary tumor of the pla-
changes in order not to miss significant, nor overinterpret centa, although this is exceedingly rare [96]. The histopatho-
artifactual, findings. logical features are the same as in choriocarcinomas elsewhere
The lesion most likely to be confused with or obscured by and include distinct malignant appearing cytotrophoblastic
postmortem fetal vascular involution is fetal vascular malp- and syncytiotrophoblastic components (Fig.15.71). Primary
erfusion, including those cases attributable to umbilical cord placental choriocarcinomas are at high risk of maternal
pathologies and accidents [95] (Table 15.13). metastasis.
a b
Fig. 15.70 Chorangiomas typically appear as (a) round or lobulated red-tan masses, (b) microscopically comprised of lobules of capillaries
within chorionic tissue histologically similar to adjacent villi (original magnification 100×)
15.16 Other Obstetric Disorders
Previously, we have discussed common maternal conditions

with variably specific placental phenotypes, including infec-
tion (Sect. 15.2), preeclampsia and other hypertensive disor-
ders (Sects. 15.7, 15.8, and 15.9.3), and diabetes (Sects.
15.9.1 and 15.9.6). There are some uncommon obstetric
disorders that, while not associated with specific placental
stigmata, bear mentioning because of significant risk of
maternal or fetal complication.
15.16.1 Intrahepatic Cholestasis

of Pregnancy
Fig. 15.71 Primary placental choriocarcinoma with cytotrophoblastic Intrahepatic cholestasis of pregnancy (ICP) typically pres-
and syncytiotrophoblastic components (original magnification 40×) ents in the third trimester with maternal pruritus, liver dys-
function, and increased serum bile acids [97]. The
15.15.3 Placental Metastasis pathogenesis of ICP is unclear but appears to be complex
with pregnancy hormones and genetic susceptibility playing
Metastases of maternal malignancies to the placenta are central roles. ICP is characterized by an increased risk of
exceedingly rare. Melanoma is most common; carcinomas perinatal complications, particularly preterm birth and still-
(e.g., breast) occur less frequently. Placental tumor deposits birth, which is related to the level of maternal serum bile
may metastasize further to the fetus with disastrous conse- acids. The etiology of fetal distress has not been defined but
quences. Fetal metastases to the placenta are also rare and com- likely includes the direct toxic effects of increased bile acids
prised of tumors that may present congenitally such as on the fetal heart [98]. Meconium staining of the fetus and
neuroblastoma and leukemia. These typically appear histologi- placenta is a common finding in ICP. Specific placental fea-
cally as limited to circulating tumor cells in the fetal vascula- tures of ICP have not been identified, although ICP may be
ture. Metastasis from fetus to mother has not been reported. associated with MVM-like changes [99, 100]. Interestingly,
treatment of ICP with ursodeoxycholic acid has been treatment in a multicenter prospective study. Autoimmunity.
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Principles and Practical Guidelines
of Intraoperative Consultation 16
Hannah Goyne, Emily Paull Acheson,
and Charles Matthew Quick
Abstract carcinoma are just some examples. The most important first
Frozen section analysis of the gynecologic tract is a com- step in evaluating any specimen is to ask oneself, what does
plex task due to the number of organs, tumors, and entities the surgeon want to know, followed by how do I process this
involved. Awareness of the importance of a thorough specimen to answer this question?
gross evaluation, careful selection of samples, and the Gross evaluation of gynecologic specimen is often com-
numerous histologic features associated with this plex. In general, all specimens should be properly oriented,
endeavor is a must. This chapter acts to serve as a quick measured, and weighed before sectioning. The serosa
reference to some of the more common epidemiologic, should be carefully inspected to look for tumor deposits,
gross, and histologic features of some of the more com- which should be differentially inked if present. Many spec-
mon entities encountered in intraoperative consultation of imens, such as uteri and ovaries, require complex section-
the female reproductive system. ing to assure enough tissue is exposed and that the extent of
disease can be delineated. Selection of the optimal tissue
Keywords for freezing is predicated on a proper gross exam, identifi-
Intraoperative consultation · Frozen section cation of sometimes subtle features, and the avoidance of
Endometrium · Myometrium · Products of conception pitfalls such as tumor necrosis. Random sections may be
Ovary · Fallopian tube · Peritoneum · Lymph node prescribed in the case of a grossly unapparent lesion.
Additionally, if loss of diagnostic material is a concern
(such as in grossly unremarkable fallopian tubes), frozen
sectioning may be contraindicated. A description of these
16.1 Introduction intricacies for each type of specimen that may be encoun-
tered is detailed below.
The performance of intraoperative consultation centered on Histologic evaluation of frozen section slides requires a
gynecologic pathology is a daunting task. In general, this working knowledge of the vast number of tumors that may
practice can help to inform the surgeon of the appropriate affect a patient. Obviously, this is complicated by the fact
course of action in ongoing cases. This may take the form of that many tumors are capable of displaying subtle histologic
a staging procedure or the cessation of surgery. The different changes that may be overlooked. Furthermore, evaluation of
organs that comprise the gynecologic tract often require dif- “frozens” can be made more difficult by the relatively
fering types of analysis to help complete this goal: diagnosis decreased histologic resolution that is part and parcel of fro-
of a mass in ovarian carcinoma, intraoperative staging of an zen sectioning. When evaluating a case, never hesitate to ask
endometrial carcinoma, and margin evaluation in a vulvar for additional sections or deeper levels if the possibility of
either will help. The purpose of this chapter is to serve as a
primer on how to approach various specimens and scenarios
H. Goyne · E. P. Acheson · C. M. Quick (*) that could occur during intraoperative consultation of the
Department of Pathology, College of Medicine, gynecologic tract. Brief statements on some of the more
University of Arkansas for Medical Sciences,
Little Rock, AR, USA
common entities have been provided, yet more detailed
e-mail: [email protected]; [email protected]; descriptions of the entities herein are presented elsewhere in
[email protected] this book.
542 H. Goyne et al.
16.2 F
rozen Section Analysis of Vaginal used to specify margins. Mass lesions and areas of discolor-
and Vulvar Samples ation should be identified and described, and the distance to
each margin is measured. In general, a perpendicular section
16.2.1 Purpose of Frozen Section Evaluation of the closest margin should be chosen for freezing.
In general, the purpose of surgical consultation in regard to

vaginal, and most vulvar, lesions is to determine whether 16.2.3 Common Entities
there is a neoplastic or dysplastic process at the surgical mar-
gin. If the margins are positive, the surgeon can take addi- 16.2.3.1 Squamous Cell Carcinoma
tional tissue to achieve a tumor-free margin, if possible. The vast majority of vaginal lesions, and most vulvar tumors,
Narrow margins may be a necessity for large lesions or lesions are squamous in nature. In both sites, carcinoma typically
near special sites or structures (e.g., urethra, clitoris, or anus). appears as a raised white lesion, often with ulceration,
Margin evaluation is usually carried out in patients with squa- whereas dysplasias are often plaque-like discolorations
mous cell carcinoma; however, some mesenchymal vulvar (Fig. 16.1a, b). Endophytic and papillary growth can also be
neoplasms may also require an intraoperative consultation for seen. Histologically, the lesion is composed of irregularly
margin status (i.e., aggressive angiomyxoma). Resections in shaped jagged nests of squamous epithelium in the stroma
Paget disease are often plagued by positive margins. In some below the basement membrane or below the epidermal-
cases, surgeons may try to verify margin status via frozen sec- dermal junction. A desmoplastic stromal response is typi-
tion. In these cases, careful scrutiny of the epithelium is key cally present.
in identifying the enlarged, somewhat pale cells that are
indicative of Paget disease. In general, frozen section is not 16.2.3.2 Paget Disease
recommended to evaluate melanoma. Frozen section evalua- Extra-mammary Paget disease often presents as an irregular,
tion of melanocytic lesions is discouraged because the already red, occasionally ulcerated lesion. In many cases the disease
subtle histology will be likely distorted on frozen section, and extends well past the edges of the grossly visible lesion,
wide margins are preferred in melanoma excisions [1]. leading to positive margins in many cases; therefore, margin
evaluation is a common request by surgeons. When evaluat-
ing frozen section slides of this lesion, careful attention to
16.2.2 Gross Specimen Processing the epidermis for the presence of enlarged, pale to gray cells
is helpful. It is important to remember that Toker cell, mela-
Grossly, the specimen is oriented and margins inked. If the noma in situ, and some forms of vulvar intraepithelial neo-
lesion is received oriented, then differential inking may be plasia and basal edema may mimic Paget cells. If one of
a b
Fig. 16.1 (a) Squamous cell carcinoma of the vulva presenting as a tan, circular, plaque-like mass. Note the adjacent areas of high-grade dysplasia
identified by their exophytic, white configuration. (b) Patchy high-grade vulvar dysplasia presenting as an ill-defined, white discoloration
16 Principles and Practical Guidelines of Intraoperative Consultation 543
these mimics is suspected, then a descriptive diagnosis, 16.3 Frozen Section Analysis of the Cervix
warning of atypical cells, is appropriate.
16.3.1 Purpose of Frozen Section Evaluation
16.2.3.3 Vulvar Intraepithelial Neoplasia (VIN)
Two variants of VIN exist, classic and differentiated type. In general, frozen section evaluation of the cervix outside of
The classic type is associated with HPV, particularly type 16, the setting of possible extension of endometrial adenocarci-
whereas differentiated VIN is associated with chronic inflam- noma is rare. On rare occasion, a surgeon may send a biopsy,
matory states as opposed to HPV infection. Histologically, or small conization specimen, to determine if invasive dis-
classic VIN has atypia found throughout the layers of epithe- ease is present and, thus, which type of hysterectomy should
lium. Enlarged nuclei, hyperchromasia, multinucleation in be performed. Another possible scenario involves margin
the lower epithelial layers, and abnormal mitotic figures are evaluation of trachelectomy specimen, although this is not
characteristic of the lesions. Apoptosis may be present. The always performed at certain institutions. In cases with pos-
surface may show atypical parakeratosis with or without sible lymph node involvement, nodal tissue may be sent to
koilocytes. Low-grade dysplasia demonstrates increased rule out metastasis. Frozen sectioning of therapeutic LEEP
thickness of the basal layer, occasional binucleation, and specimen is generally contraindicated, as it may destroy
enlarged nuclei. Koilocytic atypia is often present, but under- diagnostic tissue.
stated when compared to cervical koilocytes. High-grade
dysplasia displays full-thickness loss of maturation. The
cells have a high nuclear to cytoplasmic ratio giving the epi- 16.3.2 Gross Specimen Processing
thelium a basaloid appearance.
Differentiated VIN is often associated with an inflamma- Small cone specimen for diagnosis should be measured
tory dermatosis. They are typically seen in older women with and evaluated for gross evidence of disease. In the case of
clinical presentations of lichen sclerosis and lichen simplex a grossly apparent lesion, one representative section of
chronicus. Histologically, they have severe basal atypia, said lesion should be submitted for sectioning. If no lesion
elongation of the rete ridges, and abrupt keratinization [2]. is grossly apparent, the two random, perpendicular sec-
The diagnosis of differentiated-type VIN may be difficult; tions of the cervix should be submitted. Trachelectomy
the presence of dermal hyalinization (indicative of lichen specimen may, on occasion, be sent for evaluation of the
sclerosis), severe basal atypia, and increased, or atypical, margins. The ectocervical and endocervical aspects of the
mitotic figures in the basal layers can be helpful. A more specimen should be identified, and the outer surface of the
detailed explanation of the features and diagnosis of VIN can cervix and paracervical tissue should be carefully inked.
be found in Chap. 6 (Volume I). Application of a drying agent, such as alcohol, should be
applied to the inked surface, which should be allowed a
short time to sufficiently dry before sectioning. Once the
16.2.4 Diagnosis and Reporting ink is dried, the specimen should be opened by a single
excision, allowing visualization of the endocervical canal.
When reporting the frozen section, mention the presence of Depending on the location and configuration of the lesion,
squamous cell carcinoma and/or dysplasia and if the lesion is a shave (if the lesion is distant from the edge) or perpen-
at the margin. If the margins are negative, report the distance dicular (if the lesion is close to the edge) should be taken.
to that margin whether obtained via gross or microscopic In the case of deeply invasive or ulcerative lesions, a sec-
means. If dysplasia is present, report it and state if it is low or tion demonstrating the lesion and underlying radial margin
high grade. The diagnosis may be challenging when there is should be taken as well.
tangential sectioning, obscuring inflammation, involvement
of adnexal structures by in situ neoplasia, melanocytic prolif-
erations, herpetic infection, squamous eddies in irritated seb-
orrheic keratosis, and pseudoepitheliomatous hyperplasia 16.3.3 Common Entities
associated with a granular cell tumor [1]. When situations
such as this arise, requesting of additional levels as well as a 16.3.3.1 Squamous Cell Carcinoma
brief chart review can be helpful in providing guidance. In Squamous cell carcinoma may be exophytic or ulcerative.
the case of difficult squamous lesions, a diagnosis of inva- Histologically, the lesion is similar to squamous cell
sion should only be rendered when unequivocal evidence of carcinoma seen elsewhere and is composed of irregularly
invasion is present; if lacking, a diagnosis of “suspicious for shaped jagged nests of squamous epithelium in the stroma
invasion” will allow the surgeon to make a therapeutic deci- below the epithelial basement membrane. A desmoplastic
sion based on their observations. stromal response is typically present.
544 H. Goyne et al.
16.3.3.2 Endocervical Adenocarcinoma uterine segment. If the mass approximates the cervix, make
Similar to their squamous counterparts, endocervical adeno- a longitudinal section (parallel to and along the endocervical
carcinomas may present as a polypoid, as an exophytic mass, canal) to evaluate for cervical invasion. Any suspicious areas
or as an ulcerative lesion. In most cases, irregular, infiltrative should be submitted for frozen section. If no polyps or
glands with prominent desmoplasia can be seen extending masses are present, inspect the endometrium lining for any
into the endocervical stroma. On occasion, these tumors may firm, white areas, as this may represent carcinoma. Avoid
lack desmoplasia as well as obvious invasion. In this latter rubbing the endometrial lining. Thinly serially section the
case, it is appropriate to report the margin status alone and endomyometrium (bread loafing). Inspect the myometrium
defer the final diagnosis to examination of permanent for the area of deepest invasion, and submit a full-thickness
sections. section for frozen evaluation. Grossly, invasion of the myo-
metrium presents as a tan to white mass, often with a firm
consistency, replacing the normal myometrial texture
16.3.4 Diagnosis and Reporting (Figs. 16.3 and 16.4). The best time to evaluate the depth of
myometrial invasion is to examine the sections by removing
In cases sent for diagnosis, such as small cones, the reporting the oozing blood by a cutting blade or knife immediately
of the presence of invasive disease is the primary objective. after sectioning the endomyometrium. Adenomyosis may
In cases where there is no unequivocal evidence of invasion, mimic invasion and is characterized grossly by thick myo-
a descriptive diagnosis is appropriate. Trachelectomy speci- metrial trabeculae with pinpoint dark or red hemorrhages.
mens are usually sent for evaluation of the margins, as the
histotype of the tumor is known in most cases.
16.4.3 Common Entities
16.4 F
rozen Section Analysis 16.4.3.1 Endometrial Polyp
of Endometrial Lesions One of the most common causes of abnormal uterine bleed-
ing is an endometrial polyp. Characteristic histologic fea-
16.4.1 Purpose of Frozen Section Evaluation tures include fibrous or collagenous stroma, thick-walled
vessels, and/or benign glands with an irregular architecture,
When evaluating endometrial lesions, it is important to often displaying cystic change.
determine if carcinoma is present and, if so, the type. In addi-
tion, the grade, depth of invasion into the myometrium, pres- 16.4.3.2 Adenomyosis
ence of cervical stromal invasion, and involvement of serosal, Ectopic endometrial glands and stroma in the myometrium
ovarian, or fallopian tube tissue should be detailed if define adenomyosis. These foci may become involved by
possible. endometrial carcinoma and should not be confused with
deep invasion (Fig. 16.5a, b). The presence of endometrial
stroma and normal glands surrounding the malignant glands
16.4.2 Gross Specimen Processing is a helpful clue. Surrounding desmoplasia should be absent.
First, measure and weigh the uterus. Carefully inspect the 16.4.3.3 Endometrioid Intraepithelial
serosal surface and cervix (if present) for any lesions or Neoplasia (EIN)
irregularities. If an area suspicious for serosal implants is This lesion is the precancerous counterpart to endometrioid
present, it should be inked and sampled. Orient the uterus adenocarcinoma. Five criteria are necessary to make this
using the peritoneal reflection, which is lower posteriorly diagnosis and include the following: (1) EIN stands out/dif-
than anteriorly. Alternatively, if adnexa are present, the fal- fers from background endometrial glands, (2) there is gland
lopian tubes typically lie anterior to the ovaries. Inspect the crowding (gland to stroma ratio >50%), (3) size exceeds
surface of the ovaries and diameter of the fallopian tubes. 1 mm, (4) benign diagnostic mimics are ruled out, and (5)
Orient, remove, and serially section the adnexa for evidence carcinoma is excluded. This lesion is discussed in detail in
of any mass or lesion. Ink the anterior and posterior radial Chap. 17 (Volume I).
surgical margins, and bivalve the uterus, along the lateral
edges, with a pair of sharp scissors or by holding the uterus 16.4.3.4 Endometrioid Adenocarcinoma
upside down with a long handle forceps and then cutting Most of these lesions are characterized histologically by
with a sharp knife (Fig. 16.2a, b). Inspect the endometrial well-defined, tubular glands that are lined by malignant,
cavity for polyps and/or masses, and measure them if pres- stratified or pseudostratified, columnar epithelium.
ent. Take note how far away the mass is from the cervix/lower Architecturally the glands are complex and appear fused or
a b
Fig. 16.2 (a) A properly oriented uterus and bilateral adnexa. (b) After aspects with sharp scissors. Note the carcinoma present in the lower
removal of the adnexa and inking of the lower uterine segment and uterine segment in both the anterior and posterior halves
radial cervical margin, the uterus should be opened along the lateral
debris in the gland lumens. Stromal histiocytes are seen in

about 15% of endometrioid adenocarcinomas. A back-
ground of EIN is also present in about 20–45% of endome-
trioid adenocarcinomas. Variants of endometrioid
adenocarcinoma include secretory, villoglandular, small
non-villous papillae, microglandular, sertoliform, ciliated,
and oxyphilic [3].
16.4.3.5 Clear Cell Carcinoma

Clear cell carcinoma of the endometrium accounts for less
than 1% of all endometrial carcinomas. They can have
tubulo-cystic, solid, and papillary growth patterns (Fig. 16.7a,
b). The epithelial lining is cuboidal. The cells are polygonal
Fig. 16.3 Endometrial adenocarcinoma invading the myometrium. with clear or vacuolated cytoplasm and have high-grade
Grossly, the tumor appears to invade greater than 50% in this case
nuclei. An eosinophilic acellular matrix may be present in
between the glands. Stromal hyalinization and hobnail cells
cribriforming; occasionally they demonstrate a labyrinthine may be present as well. The rule of thumb is not call clear
quality (Fig. 16.6a, b). Nuclear pleomorphism should be cell carcinoma on frozen section because of presence of can-
relatively minimal. The tumor may show necrosis or necrotic cer cells with clear cytoplasm.
546 H. Goyne et al.
16.4.3.6 Endometrial Serous Carcinoma pleomorphism. Nucleoli are prominent and mitotic figures
Pure serous carcinomas account for about 1–10% of endo- are frequent.
metrial carcinomas. The tumors can have a solid, papillary,
micropapillary, glandular, or slit-like glandular pattern 16.4.3.7 Carcinosarcoma
(Fig. 16.8a, b). The nuclei are high grade and show marked Uterine carcinosarcomas are also known as malignant mixed
Mullerian tumors (MMMT). They tend to occur in elderly
women, are highly aggressive, and have a poor prognosis.
Grossly they are often polypoid/exophytic (Fig. 16.9).
Histologically, any subtype of endometrial carcinoma com-
bined with a high-grade malignant mesenchymal component
should be present. The neoplasms may contain homologous
(tissues normally found in the uterus) or heterologous (tissues
not normally found in the uterus, e.g., cartilage) elements [4].
16.4.4 Diagnosis and Reporting
When EIN is seen in the setting of no grossly obvious endo-

metrial mass, a diagnosis of “at least EIN on 1 representative
section” is appropriate. If carcinoma is present, the type of
carcinoma (if possible) and depth of invasion into the myo-
metrium should be reported. In addition, report if the cervix,
adnexa, and serosa are negative. The bilateral cornua should
be fully exposed to allow thorough assessment, particularly
when no apparent lesion is found in the endometrial cavity. If
no gross lesion is present in the endometrial cavity, two ran-
dom sections (one anterior and one posterior
endomyometrium) should be taken, as some endometrial
cancers, particularly endometrial serous carcinoma, may
have deep myometrial invasion without an apparent mass in
the cavity [5]. If no grossly suspicious lesions exist outside
Fig. 16.4 A large, exophytic endometrial adenocarcinoma presenting
of the endometrium, frozen sectioning of the cervix, adnexa,
as an endometrial polyp and serosa is not indicated.
a b
Fig. 16.5 (a) Adenomyosis may be recognized grossly as thick myo- adenomyosis. Note the presence of smooth outer contours of the
metrial trabeculae with areas of hemorrhage (photo courtesy of involved areas as well as uninvolved adenomyosis
Katelynn Campbell, M.D.). (b) Endometrial adenocarcinoma involving
a b
Fig. 16.6 (a) Well-differentiated endometrioid adenocarcinoma with fused, cribriforming glands and immature morular metaplasia. (b)
Labyrinthine glands with intraluminal papillary growth and necrotic luminal debris
a b
Fig. 16.7 (a) Clear cell carcinoma of the endometrium growing as tubules and cysts. Note the prominent cellular hobnailing. (b) Clear cell carci-
noma with small, hyalinized papillae
a b
Fig. 16.8 (a) High-grade serous carcinoma. Note the presence of numerous exfoliated tumor cells and “cracks and crevices” within the epithelial
surface. Nuclear pleomorphism and prominent nucleoli are easily seen. (b) High-grade serous carcinoma with solid growth
548 H. Goyne et al.
Fig. 16.10 A subtle focus of MELF. This growth pattern may be iden-

tified at low power by searching for areas of myxoid change and inflam-
matory cells. High-power examination will often reveal the presence of
eosinophilic tumor cells
It is also worth noting that evaluating for depth of invasion in

this pattern can be challenging because the malignant epithe-
lium is more difficult to identify and lymphatic involvement
resembles macrophages. Additionally, it may be hard to dis-
tinguish tumor in lymphatic spaces from true myometrial
invasion. The presence of myxoid areas associated with
inflammation within the myometrium helps to identify
Fig. 16.9 Carcinosarcoma and its classic presentation as a large,
MELF at low power (Fig. 16.10).
fleshy, polypoid tumor
Excision of the pelvic and/or para-aortic lymph nodes may 16.5 F

rozen Section Analysis of Suspected
be indicated if the carcinoma has cervical stromal invasion or Pregnancy
the tumor is more than 50% invasive into the myometrium.
When grading endometrioid adenocarcinoma, the amount of 16.5.1 Purpose of Frozen Section Evaluation
solid component present determines the grade of the tumor. If
the tumor is less than 5% solid, it is designated as FIGO I, The goal of frozen evaluation in the setting of a suspected
5–50% FIGO II, and >50% FIGO III. Areas of squamous dif- pregnancy is to determine if a pregnancy is intrauterine vs.
ferentiation in endometrioid adenocarcinoma should not be tubal by identifying placental villi and/or the implantation
counted as solid growth. If severe nuclear atypia is present in site. Conservative management can be implemented if an
endometrioid carcinoma, the grade increases by 1. Endometrial intrauterine pregnancy is confirmed. The patient should be
serous carcinoma, clear cell carcinoma, and carcinosarcoma monitored closely, and surgical intervention may be neces-
are considered high-grade. A frozen section diagnosis of sary when pregnancy cannot be confirmed.
serous, clear cell or carcinosarcoma will prompt the surgeon to Patients with serologic evidence of pregnancy (elevated
perform a full staging procedure as well as omentectomy and hCG) and vaginal bleeding or pelvic pain may have an ecto-
multiple peritoneal biopsies. To increase diagnostic accuracy, pic pregnancy. Rapid hCG levels and transvaginal ultrasound
pre-hysterectomy endometrial biopsies should be reviewed if detect most ectopic pregnancies, but the most reliable was to
available as awareness of clinical history and communication exclude an ectopic pregnancy by histologic confirmation.
with surgeons is critical. In some ambiguous cases, taking Noninvasive test has a 40% false-positive rate [2, 3].
additional sections may increase diagnostic confidence.
A diagnostic pitfall in the evaluation of endometrioid ade-
nocarcinoma centers on the microcystic, elongated, and frag- 16.5.2 Gross Specimen Processing
mented (MELF) pattern of myoinvasion. In practice, some
groups report the presence of MELF on frozen sectioning as The majority of specimens submitted for intraoperative
it is associated with a higher rate of lymph node metastasis. consultation are endometrial curettings, which have a very
high sensitivity and specificity. Typically, the submitted

tissue consists of either an endometrial biopsy or tissue
from the vaginal vault. Special methods can be used to
identify chorionic villi including rinsing the specimen
with saline until free of blood to inspect for white villous
tissue and floating the specimen in a Petri dish with saline
to examine with naked eye or under dissecting microscope
for spongy tissue. The villi should be white and have com-
plex architecture with acute angle branching. Choose the
tissue most likely to be villi and submit for frozen section.
Continue to submit tissue for frozen evaluation until intra-
uterine pregnancy is confirmed or until all the tissue is sub-
mitted. If the sample is small, submit the entire specimen
for frozen evaluation [1]. It is important to note that villi
may often be found within submitted blood clots; therefore
these should not be discarded or ignored in the search for Fig. 16.12 Trophoblasts and “bubble gum” pink fibrinoid matrix com-
villous tissue. monly seen in an implantation site
16.6 F
rozen Section Analysis
16.5.3 Diagnosis and Reporting of Myometrial Lesions
If viable chorionic villi (Fig. 16.11), with or without implan- 16.6.1 Purpose of Frozen Section Evaluation
tation site (Fig. 16.12), are identified, “intrauterine preg-
nancy” may be reported. Scant scattered villi may represent The purpose of the majority of intraoperative consultation
contamination from a tubal pregnancy, and this should be centered on the myometrium is to rule out malignancy in a
discussed with the consulting clinician. Implantation site presumed leiomyoma. Occasionally, other neoplasms such
alone without villi is highly suggestive of intrauterine preg- as endometrial stromal sarcoma or uterine tumor resembling
nancy; however, implantation site contamination from a ovarian sex cord tumor may be a diagnostic consideration.
tubal pregnancy cannot be completely ruled out in this sce-
nario. The presence of decidualized endometrium may be
seen in the setting of any pregnancy, including ectopic, and 16.6.2 Gross Specimen Processing
therefore is not indicative of an intrauterine pregnancy in
isolation. The specimen usually consists of a hysterectomy or resection
of specific lesions from the uterus. In the case of a leiomy-
oma, the tumor is typically composed of a firm, well-
circumscribed mass (Fig. 16.13a–d), which is measured and
weighed. It is important to document the weight of the speci-
men as it may impact patient charges in some practice set-
tings. Serially section the mass at 1 cm intervals, and inspect
the cut surface for necrosis and/or hemorrhage. Any soft
areas, tissue adjacent to necrosis, and areas of hemorrhage
should be sampled. Leiomyomata may have hydropic change
and degeneration making gross evaluation for malignancy
challenging (Fig. 16.14a–d). If the specimen is not well-
circumscribed, this may suggest malignancy.
16.6.3.1 Leiomyoma
Fig. 16.11 Scattered, immature chorionic villi present within a large Leiomyomata are the most common gynecologic tumor
blood clot and are commonly seen in hysterectomies regardless of the
550 H. Goyne et al.
a b
c d
Fig. 16.13 (a) Multiple leiomyomata distorting the myometrium and uterine specimen with a large, pedunculated serosal leiomyoma and a
endometrial cavity. (b) Numerous submucosal leiomyomata projecting smaller intramural leiomyoma
into the endometrial cavity. (c) A single submucosal leiomyoma. (d) A
surgical indication. Grossly, they are firm, well-circum- Finally, cotyledonoid dissecting leiomyomas may grossly
scribed, tan-white masses that have a whorled, bulging appear invasive and similar to low-grade endometrial stro-
appearance on cut surface (Fig. 16.13a–d). They should mal tumors. Histologically, the tumors are composed of
lack hemorrhage and necrosis; however, degenerative fascicles of bland spindle cells with cigar-shaped nuclei.
changes may be present (Fig. 16.14a–d) and are typically The fascicles intersect at 90° angles. Epithelioid and myx-
centrally located and well demarcated. Long-standing oid variants can be seen as well. Mitotic activity should be
leiomyomata may undergo calcification as well. The rare to absent. The proliferation of these tumors is stimu-
lesions may bulge into the endometrial cavity or form sub- lated by progesterone; therefore, mitotic activity may
serosal nodules. When large and/or numerous, they can increase in the secretory phase of the menstrual cycle.
severely distort the uterus and endometrial cavity. Several Mitotic activity may increase after surgery, during post-
clinical settings and variants of leiomyoma may grossly be menopausal hormone or tamoxifen therapy. If mitotic fig-
concerning for malignancy. In the setting of previous ures are seen, they should not be atypical. Tumor necrosis
embolization, hormonal therapy, and pregnancy, the leio- should be absent; however, infarct-type necrosis is allowed.
myoma may undergo infarction or apoplexy, leading to a Nuclear atypia should not be present. Occasionally long-
hemorrhagic cut surface. Hydropic leiomyomas and highly standing leiomyomata undergo ancient or symplastic
cellular leiomyomas may lack the distinct, fascicular, changes and can have bizarre nuclei, but mitotic activity
bulging cut surface of otherwise more typical leiomyomas. should not be increased.
a b
c d
Fig. 16.14 (a) The bosselated cut surface of a leiomyoma with degen- degeneration of a leiomyoma. (d) Patchy cystic and red degeneration in
erative changes. (b) Degenerative change in a leiomyoma often consists a large leiomyoma
of centrally located cystic change or discoloration. (c) So-called “red”
16.6.3.2 Leiomyosarcoma power fields (HPF). Epithelioid leiomyosarcomas

Leiomyosarcomas account for 25% of all uterine mesenchy- (Fig. 16.17) require >5 mitotic figures/HPF, while myxoid
mal neoplasms. Most tumors present as large masses (usu- leiomyosarcomas (Fig. 16.18) only require ≥2 mitotic fig-
ally > 10 cm) and have infiltrative borders. The cut surface ures/HPF [2].
appears heterogeneous with areas of hemorrhage and necro-
sis (Fig. 16.15a, b). Notably, the tumors will not bulge upon 16.6.3.3 Adenomatoid Tumor
sectioning, as compared to their benign counterpart. They This lesion is composed of benign mesothelial cells, with a
usually have a soft, fleshy consistency and are gray, tan, or gland-like appearance, that are usually present within the
yellow in color. Three histologic criteria (i.e., the Bell crite- outer half of the myometrium. On initial inspection they may
ria) must be met to diagnose malignancy: (1) presence of resemble a lipoleiomyoma, which is in the differential diag-
nuclear pleomorphism, (2) increased mitotic activity, and (3) nosis. Nuclear atypia and mitoses are not present. Grossly,
coagulative tumor necrosis. Histologically, these tumors are they may appear as poorly circumscribed soft tissue masses.
typically composed of spindled cells with diffuse nuclear
pleomorphism (Fig. 16.16). Geographic, coagulative tumor 16.6.3.4 Adenomyosis/Adenomyoma
necrosis and increased mitotic activity are usually conspicu- Adenomyosis is characterized by ectopic placement of
ous. For classic (spindle cell) variants of leiomyosarcoma, benign endometrial glands and stroma in the myometrium.
increased mitotic activity is defined as >10 per 10 high- Grossly, the process appears as thick, trabeculae with
552 H. Goyne et al.
a b
Fig. 16.15 (a) The cut surface of a leiomyosarcoma demonstrating irregular borders and extensive hemorrhage and necrosis. (b) Leiomyosarcoma
with a fleshy cut surface, degenerative change (lower left) and necrosis (far right)
Fig. 16.16 Nuclear pleomorphism in leiomyosarcoma is often pro- Fig. 16.17 An epithelioid leiomyosarcoma composed of round cells
nounced; as in this example, albeit, atypia in isolation is not diagnostic with ample clear cytoplasm. In some cases, these tumors may be diffi-
of malignancy cult to classify as mesenchymal
pinpoint hemorrhages in the myometrium. Occasionally, arterioles scattered throughout the lesion. These tumors are
areas of adenomyosis may for a mass lesion, termed distinguished from endometrial stromal nodules by the pres-
adenomyoma. ence of myometrial infiltration (>3 mm) and/or lymphovas-
cular invasion.
16.6.3.5 Endometrial Stromal Lesions
Endometrial stromal lesions are typically divided into two
types: stromal nodule and stromal sarcoma. Endometrial 16.6.4 Diagnosis and Reporting
stromal sarcomas are rare, accounting for 0.2% of all uterine
malignancies and 15% of uterine sarcomas [6]. Myometrial If malignancy is present, the surgeon may elect to perform a
invasion appears as fingerlike projections, and, grossly, they hysterectomy instead of myomectomy alone. If a benign
have been described as a “bag of worms” within the myome- diagnosis is made, such as a leiomyoma, conservative man-
trium (Fig. 16.19a, b). Histologically, they resemble agement may be implemented. This is particularly important
proliferative endometrial stroma with numerous thin-walled for women who want to maintain their fertility.
Leiomyoma may be diagnosed if there are not features of 16.7 F

rozen Section Analysis of Fallopian
malignancy (i.e., no tumor necrosis, nor nuclear atypia, and Tube Lesions
mitotic figures are not increased). If some features of malig-
nancy are present, but not sufficient for a diagnosis of sar- 16.7.1 Purpose of Frozen Section Evaluation
coma, “atypical smooth muscle neoplasm,” with deference
to more sampling and permanent sections, may be reported. The goal of the intraoperative consultation of the fallopian
Additional sections may be helpful to determine malignancy tube is to determine if a mass in the fallopian tube is benign
in difficult cases, and the threshold for ordering them should or malignant. Another reason for consultation may be to
be low. When sufficient histologic features for malignancy diagnose a tubal pregnancy, which is discussed elsewhere in
are present, a diagnosis of “smooth muscle neoplasm, favor this chapter. If carcinoma is confirmed, additional biopsies
leiomyosarcoma” can be made. If the neoplasm is poorly dif- may be taken for staging. If ectopic pregnancy is confirmed,
ferentiated and a diagnosis of leiomyosarcoma cannot be salpingectomy or salpingotomy is performed.
made in confidence, “poorly differentiated spindle cell neo-
plasm” may be reported. 16.7.1.1 Gross Specimen Processing
First measure the length and diameter of the fallopian tube and
take note if there is a fimbriated end. A plastic clip/ring may be
present around the fallopian tube from previous tubal ligation,
which can be described grossly. Check the serosal surface and
fimbria for adhesions, discoloration, cysts, purulent exudates,
or areas of rupture. Palpate the fallopian tube for any firm
areas and look for areas of increased diameter/nodules, and
serially cross-section through them if present. Take note of the
type of fluid or contents inside the fallopian tube on section-
ing. Submit any suspicious areas for frozen evaluation. If
grossly normal, frozen section is not indicated. Frozen sec-
tioning of tubes from patients undergoing prophylactic salpin-
gectomy is contraindicated as small lesions may be destroyed.
16.7.2.1 Tubal Pregnancy

Fig. 16.18 Myxoid leiomyosarcoma is often composed of spindled
cells set in a gray-blue myxoid matrix. Nuclear atypia and mitotic activ- As mentioned previously, evaluation of the tube may be for
ity are typically inconspicuous purposes of ruling in an ectopic pregnancy. Presence of villi,
a b
Fig. 16.19 (a) Endometrial stromal sarcoma presenting as multiple wormlike tan-yellow protrusions (lower left aspect). (b) Innumerable polyp-
oid projections in an extensive endometrial stromal sarcoma
554 H. Goyne et al.
implantation site, and even embryonic tissue in advanced red, nucleoli. Numerous mitotic figures, pleomorphism, and
cases is diagnostic (Fig. 16.20). apoptotic bodies are easily appreciated. High-grade serous
carcinoma may be diagnosed in the presence of invasion,
16.7.2.2 Serous Carcinoma which may be bilateral in up to 20% of cases.
The most common primary carcinoma of the fallopian tube is
serous carcinoma, which accounts for 90% of all tubal carci- 16.7.2.3 Endometriosis
nomas. Serous tubal intraepithelial carcinoma (STIC) is the in Endometriosis is very common and is found in about 10% of
situ form of high-grade serous carcinoma and may be identi- tubal specimens. Histologically, it is characterized by endo-
fied on frozen section; however, frozen sectioning of grossly metrial glands and stroma in the muscularis, subserosa, or
normal tubes to identify STIC is contraindicated, as previously mesosalpinx (Fig. 16.23). Older lesions may be surrounded
stated. If a mass lesion is present, a portion may be sampled by fibrosis and hemosiderin-laden macrophages.
for frozen sectioning (Fig. 16.21). The epithelium may show
thickening, loss of polarity, and high nuclear-to-cytoplasmic 16.7.2.4 Transitional Cell Lesions
ratios with loss of cilia (Fig. 16.22). The nuclei are hyperchro- Walthard cell rests are benign and consist of transitional
matic and enlarged and have prominent, sometimes cherry metaplasia of mesothelial cells or subcolumnar cells
Fig. 16.20 Cross section of an advanced tubal ectopic pregnancy dem- Fig. 16.22 Serous tubal intraepithelial carcinoma (STIC) and a small
onstrating from left to right: tubal wall, implantation site, chorionic focus of invasive serous carcinoma. Note the increased thickness of the
villi, and embryonic tissue tubal epithelium and clusters of shed cells present within the lumen
Fig. 16.21 Section of serous carcinoma involving the wall of the fal- Fig. 16.23 Endometriosis with pre-decidual change within the wall of
lopian tube forming a grossly appreciable mass lesion the fallopian tube
Fig. 16.24 Walthard cell rests on the serosal surface of the fallopian Fig. 16.25 Adenomatoid tumor of the fallopian tube. These tumors
tube. Grossly these may appear as small paratubal cysts appear to be composed of small glands or vascular spaces at low power
(Fig. 16.24). They are commonly seen adjacent to the fimbria sequela of the disease results in fusion of tubal plicae and is
and serosa. Traditionally, transitional cell carcinoma has termed follicular salpingitis. Mycobacterium tuberculosis
been described as a carcinoma that resembles malignant uro- causes granulomatous salpingitis and can mimic a mass.
thelial epithelium, but is now believed to be variants of high-
grade serous carcinomas by many investigators [7, 8].
16.7.3 Diagnosis and Reporting
16.7.2.5 Salpingitis Isthmica Nodosa
The prevalence of salpingitis isthmica nodosa varies, but is If the fallopian tube is grossly normal, the pathologist should
relatively common. It is a condition that is analogous to ade-render a negative gross description to the submitting surgeon
nomyosis (i.e., tubal epithelium is located in the muscular and recommend fixation and permanent sections. When an
wall of the fallopian tube). The gross appearance is typicallyinvasive high-grade carcinoma is present, this can be reported
a yellow to white nodule near the tubal isthmus. as such, with an additionally comment favoring serous carci-
noma if appropriate. Serous tubal intraepithelial carcinoma
16.7.2.6 Adenomatoid Tumor is difficult to diagnose on frozen section. If atypia is present,
The most common benign tumor of the fallopian tube is the a diagnosis of “severe tubal atypia” with deference to perma-
adenomatoid tumor. Grossly, the tumor is small, well- nent sections is warranted. If products of conception are
circumscribed, and usually located on the serosal surface. identified either grossly or on frozen section, a diagnosis of
The cut surface is typically white. The lesion is composed of tubal ectopic pregnancy should be rendered.
small irregular gland-like spaces lined by a single layer of
benign mesothelial cells (Fig. 16.25). Intervening smooth
muscle or hyalinized stroma may be present. 16.8 Frozen Section Analysis
of Ovarian Masses
16.7.2.7 Infectious Disorders
Pelvic inflammatory disease (PID) is the clinical term for 16.8.1 Purpose of Frozen Section Evaluation
infectious salpingitis. Women with this condition are at a
greatly increased risk of developing an ectopic pregnancy. The primary purpose of an intraoperative consultation for an
Most cases of PID are caused by sexually transmitted disease ovarian/pelvic mass is to determine whether the process is
(e.g., Neisseria gonorrhoeae and Chlamydia trachomatis), benign or malignant and potentially to provide a precise diag-
but two other causes include instrumentation and use of nosis or tumor grade. If benign, the surgeon can proceed con-
intrauterine devices. Grossly, early cases will present as a servatively, which is especially important in women who
purulent exudate (pyosalpinx) in the fallopian tube, followed wish to maintain fertility. If malignant, the pathologist should
by tubo-ovarian adhesions, and finally by hydrosalpinx. try to determine whether it is a primary or metastatic tumor as
Histologically, early infection will result in acute inflamma- this will alter treatment. This can be particularly challenging
tion followed by chronic inflammation and adhesions. Late in mucinous tumors, in which there are many overlapping
556 H. Goyne et al.
histologic features seen in both primary and metastatic dis-

ease. Review of the patient’s history, i.e., colonoscopy reports,
radiology reports (does tumor appear unilateral or bilateral),
family history of colon or ovarian cancers, and possible perti-
nent symptoms (constipation, diarrhea, etc.), may be helpful
in some cases. If metastatic disease is suspected, the surgeon
will “run the bowel” and look for tumor elsewhere in the
abdomen. If the tumor is primary, the surgeon can perform a
total abdominal hysterectomy and bilateral salpingo-oopho-
rectomy, debulk large tumors, and perform a peritoneal wash-
ing and lymph node biopsies.
16.8.2 Gross Specimen Processing
One of the most critical parts of intraoperative consultation

of the ovary relies on the gross appearance of the tumor, and
at times, the pathologist can make a diagnosis based on gross Fig. 16.26 A serous cystadenoma composed of a thin membrane of
impression alone. The first step in grossing an ovarian tumor fibrous tissue
is to measure and weigh specimen, taking care not to rub or
abrade the surface. Check for any roughened areas, adhe- evident in benign, borderline, and low-grade tumors. High-
sions, irregularities, or defects on the surface. If present,grade serous carcinoma lacks discernable histologic tubal dif-
these areas may represent carcinoma involving the ovarian ferentiation despite commonly arising from the fallopian tube.
surface. Differentially ink these areas to identify them both Benign serous tumors are bilateral 10–20% of the time
for the purposes of frozen and routine sectioning. Serially and are typically cystic. A serous cystadenoma should be at
section the ovary. If the mass is cystic, check the lining for
least 1 cm in size, but usually range from 3 to 10 cm, with a
any papillary excrescences, areas of thickening or nodules, smooth serosal and interior surface (Fig. 16.26). They can be
and, when present, sample preferentially from these areas. unilocular or multilocular. The cyst cavity is often filled with
Evaluate the cyst contents after sectioning. If fluid is present,
thin, clear, watery fluid. The cyst lining is smooth and may
check the color and consistency. Thin and clear fluid may be vary in capsule thickness. In the presence of stromal over-
seen in a serous neoplasm, whereas thick and viscous fluid growth producing more than a few papillae with broad
may signal a mucinous neoplasm, although this is not always fibrous stromal cores, the term cyst adenofibroma may be
the case. Brown, or hemorrhagic, fluid may be seen in the used. The epithelium that lines the glands, cysts, and papillae
setting of ovarian torsion, endometrioma, or nongestational of these benign lesions typically demonstrates ciliated,
choriocarcinoma. Note if the cyst contents have hair, carti- cuboidal to columnar epithelium with very little stratifica-
lage, teeth, and/or keratinaceous debris, which are suggestive
tion. The cells have a small amount of eosinophilic cyto-
of a mature cystic teratoma. If the mass is partially cystic and
plasm, oval nuclei with or without small nucleoli, and rare
solid, sample more heavily in the solid areas, avoiding areasmitoses.
of necrosis. If the mass is heterogeneous, take multiple sec- When more than 10% of the tumor demonstrates com-
tions from different appearing areas for frozen evaluation. It
plexity in the form of hierarchical branching of papillae and
is not uncommon to submit multiple sections from ovarian epithelial stratification, a diagnosis of serous borderline
masses for freezing. tumor is appropriate. These tumors are bilateral in around
25% of patients. In general, the gross appearance is similar
to that of a cystadenoma; however, the cyst lining will dem-
16.8.3 Common Entities: Surface onstrate fleshy, papillary excrescences (cauliflower-like pro-
Epithelial Tumors jections) (Fig. 16.27). In other cases, the papillary
excrescences can be quite pronounced and appear as a “car-
16.8.3.1 Serous Neoplasms pet.” Histologically, the tumors exhibit broad, sometimes
Serous neoplasms are the most common subtype of epithelial- edematous, branching papillae with stratified epithelium that
stromal tumors. About 60% are benign, 10% are borderline, can appear to shed and float in the extracellular space
and 30% are malignant. They are composed of cells that, at (Fig. 16.28a, b). The cells are usually cuboidal to columnar
least focally, resemble fallopian tube epithelium, which is with only mild to moderate atypia; mitoses should be infre-
composed of secretory and ciliated cell types. This is most quent. Psammoma bodies and a background of serous cyst-
adenoma may be present. Borderline tumors can be they tend to more solid than borderline tumors, and histo-
distinguished from low-grade serous carcinomas by the logically stromal invasion or markedly complex epithelial
absence of significant micropapillary or cribriform growth growth (extensive micro-papillae or cribriforming) should be
and lack of invasion into the stroma. This may be challeng- present. Clear spaces between individual nests of tumor cells
ing on frozen section due to the nature of complexity of the and the stroma are a helpful diagnostic feature. Psammoma
lesions, limited sampling, and oblique sectioning. The bodies are often numerous. The nuclei are round to oval and
pathologist should look for papillary structures and epithe- may have nucleoli, but should lack significant atypia. The
lium with a small cleft separating them from the surrounding mitotic index is higher than that of borderline serous tumors
stroma as well as a stromal response to aid in the diagnosis but should be less than 10 per 10 high-power fields.
of invasion (Fig. 16.29). Grossly, high-grade serous carcinoma demonstrates areas
Low-grade serous carcinomas often merge morphologi- of solid growth with necrosis. There may be papillary or cys-
cally with (i.e., arise from) serous borderline tumors. Grossly, tic growth as well (Fig. 16.30). High-grade serous carcino-
mas demonstrate a wide array of morphologic patterns.
Papillae (Fig. 16.31), pseudo-endometrioid cribriforming
glands, solid growth, and transitional-type epithelium have
been demonstrated in these tumors. The most reliable histo-
Fig. 16.27 Soft, fleshy, papillary excrescences covering the serosal

surface of an ovary in a case of a serous borderline tumor. Exuberant
cases may completely obscure the normal ovarian architecture and Fig. 16.29 Invasive low-grade serous carcinoma. Note the presence of
mimic carcinoma a clearing around the epithelial nests and stromal desmoplasia
a b
Fig. 16.28 (a) Stratified, tufted epithelium in a borderline tumor. (b) The epithelial proliferation in a borderline tumor will often lead to free float-
ing islands of relatively bland epithelium
558 H. Goyne et al.
Fig. 16.32 Pseudo-glandular (pseudo-endometrioid) high-grade

serous carcinoma. Bizarre nuclear pleomorphism is a helpful diagnostic
Fig. 16.30 High-grade serous carcinoma presenting as a solid and cys- clue. In general, more traditional serous carcinoma may be found else-
tic mass with areas of conspicuous necrosis where in these tumors; therefore extensive sampling is advised
benign, borderline, and malignant. They are characterized by

abundant mucin within the epithelial cells. Approximately
80% of mucinous tumors are benign, 10% are borderline,
and 10% are malignant, although the percentage of malig-
nant tumors appears less common than once thought [9]; this
may be due to differing diagnostic criteria and the realization
that many tumors were metastatic to the ovaries. Seidman
et al. reported that only 3 of 124 (2.4%) cases were primary
mucinous carcinomas of the ovary [9]. They noted that uni-
lateral mucinous carcinomas <10 cm were usually meta-
static, while unilateral mucinous carcinomas ≥10 cm were
typically primary, a trend that held in about 90% of their
cases [9].
In general, mucinous tumors are the largest ovarian neo-
plasms and typically are multilocular, solid, and cystic, with
Fig. 16.31 A frozen section of high-grade serous carcinoma with focal
a smooth surface. The fluid is usually viscous, occasionally
papillary formation (bottom left). The cells are markedly pleomorphic thin, and clear, and the cut surface appears glistening
and composed predominately of nuclear material, imparting a hyper- (Fig. 16.33). If present, malignant components may be iden-
chromatic hue to the tumor tified by solid growth (Fig. 16.34). Mucinous tumors are well
known for having histologic heterogeneity with the potential
logic feature is nuclear atypia, typically seen as enlarged of malignant areas composing a small component of the
nuclei, with prominent, often violaceous, nucleoli, and tumor; for this reason, careful examination of each cyst
numerous mitoses. Pleomorphism is a common feature, and within the mass and heavy sampling (at least two sections/
markedly bizarre cells may be present (Fig. 16.32). The cells cm) are advised.
tend to be discohesive, and “fracture” lines may be seen Histologically, mucinous cystadenomas have a simple
within the epithelium. Necrosis may be extensive, and psam- columnar mucinous epithelium with basally located nuclei
moma bodies are usually not as prominent as seen in more without atypia (Fig. 16.35). Occasional goblet and/or neuro-
benign serous lesions. endocrine cells may be seen. The stroma is typically fibrous
and will resemble ovarian stroma. Cyst rupture can occur
16.8.3.2 Mucinous Neoplasms leading to mucin extravasation with accompanying necrosis,
Mucinous neoplasms of the ovary are the third most common inflammation, and occasional giant cell formation, which
epithelial-stromal tumors, accounting for about 15% of all may mimic invasion (Fig. 16.36). The term mucinous cystad-
ovarian tumors. Like serous tumors they are classified as enofibroma is appropriate when there is a significant portion
Fig. 16.33 Typical appearance of the cut surface of a mucinous bor-

derline tumor. These tumors tend to be multicystic with areas of solid
growth. Extensive solid growth may be suggestive of a carcinoma and
should be preferentially sampled Fig. 16.35 A mucinous cystadenoma composed of cysts lined by sim-
ple, columnar mucinous epithelium
Fig. 16.34 A mucinous carcinoma with a predominately solid cut

Fig. 16.36 Epithelial complexity in a mucinous borderline tumor.
surface
Note the large cyst in the middle of the image which has ruptured, lead-
ing to a surrounding lympho-histiocytic reaction and fragmentation of
the epithelium. This finding may mimic invasion
of stromal overgrowth with an overlying simple columnar
epithelium.
Two types of mucinous epithelium may be seen in border- sized cysts lined by colonic-type mucinous epithelium.
line tumors, endocervical and intestinal type, accounting for Based on the presence of atypia or invasion, they may be
15% and 85%, respectively. Endocervical-type mucinous subdivided into intestinal-type mucinous borderline tumors
borderline tumors architecturally resemble their serous with intraepithelial carcinoma or stromal microinvasion.
counterparts in that they have papillae with stratified epithe-
lium and epithelial tufting (Fig. 16.37). The epithelium 16.8.3.3 Endometrioid Neoplasms
ranges from columnar to cuboidal, and nuclei are slightly The second most common group of epithelial-stromal tumors
atypical in most cases; neutrophils are often seen scattered in of the ovary is the endometrioid neoplasms, comprising
the epithelium, stroma, and mucin (Fig. 16.38). Adjacent between 8% and 21% of cases. Up to 20% are associated with
endometriosis may be present, and some cases appear to endometriosis [2]. Benign and borderline endometrioid tumors
arise in the setting of an endometriotic cyst. Intestinal-type are rare in the ovary. Grossly, the tumors are a m
ixture of solid
mucinous borderline tumors are often composed of variably and cystic components, with solid tumors tending to be more
560 H. Goyne et al.
Fig. 16.39 Endometrioid adenocarcinoma of the ovary presenting as a

Fig. 16.37 Endocervical-type mucinous tumors often display a cystic solid mass. Endometriosis present within the adjacent cystic structure
and papillary architecture, similar to that seen in serous borderline with hemorrhage was present
tumors. The presence of serous borderline tumor architecture and muci-
nous epithelium is a clue to this diagnosis cell carcinoma are relatively similar in the uterus and
endometrium. Within the ovary, the majority of clear cell
carcinomas display a prominent papillary pattern with hya-
linized stroma, lined by a non-stratified, or minimally strati-
fied, epithelium composed of clear cells with atypical nuclei.
These tumors are often heterogeneous and may display cys-
tic, glandular, or solid growth as well. In fact, most tumors
are often composed of a mixture of growth patterns.
Psammoma bodies are sometimes present.
16.8.3.5 Brenner Tumors

Brenner tumors account for about 5% of benign, epithelial
ovarian tumors. Borderline and malignant Brenner tumors
are rare. They are unilateral in about 90% of cases, and are
associated with a second tumor, usually mucinous cystade-
noma, in a quarter of cases [2]. The tumors are usually small,
well-circumscribed, white to yellow masses and can be
Fig. 16.38 Eosinophilic, mucinous epithelium with mild atypia and entirely solid or have a cystic component (Fig. 16.40a, b).
scattered neutrophils in an example of endocervical-type mucinous bor- Microscopically, they are composed of small islands of
derline tumor transitional-type epithelium set in a fibrous stroma. The cells
grow in a syncytium with pale, pink cytoplasm. The nuclei
malignant (Fig. 16.39). The cysts may be filled with clear, are kidney-shaped often with a longitudinal groove. Mitotic
mucinous, or hemorrhagic fluid. Well-differentiated endome- figures are rare to absent.
trioid carcinomas grow in a manner similar to their uterine
counterparts. The epithelium that lines the glands is stratified
and may grow in papillary, microglandular, insular, and solid 16.8.4 Common Entities: Sex Cord Stromal
patterns. Squamous and mucinous metaplasia may be present. Tumors
16.8.3.4 Clear Cell Neoplasms *More in depth discussion of these entities can be found in
Clear cell carcinomas comprise about 5% to 12% of ovarian Chap. 9.
epithelial-stromal tumors [2]. Benign and borderline tumors
are exceptionally rare in this category. Approximately 40% 16.8.4.1 Fibroma/Thecoma
of clear cell carcinomas are confined to the ovary [2]. Fibromas, along with fibrothecomas, are the most common
Carcinomas often display areas of solid growth, but invari- sex cord stromal tumor, constituting 80% of this group [2].
ably demonstrate cystic areas as well. Hemorrhage and Fibromas are usually unilateral; however, they are also the
necrosis are often present. The histologic features of clear most common bilateral sex cord stromal tumor. Grossly, the
a b
Fig. 16.40 (a) Brenner tumors are firm, typically solid masses with a tan-white cut surface. (b) Occasionally, cystic areas or mucinous cystic
tumors may be present
tumors are firm and have a lobulated, smooth surface. The

cut surface is white and solid with a firm or rubbery quality.
A thecomatous component may be identified grossly by
their yellow color. Histologically, the tumors are composed
of bland, uniform, spindle cells arranged in a storiform pat-
tern. The nuclei are elongated with tapered ends. Cytologic
atypia should be absent, and mitotic figures should be not
significantly increased. Atypical mitotic figures should be
absent. Thecomas are usually unilateral. They are firm,
smooth-surfaced, yellow, solid tumors with a lobulated cut
surface (Fig. 16.41). Histologically, they are similar to fibro-
mas, but their cells display a more abundant vacuolated
cytoplasm.
16.8.4.2 Granulosa Cell Tumors

Two types of granulosa cell tumors, adult and juvenile, exist.
The adult type is typically seen in menopausal or postmeno-
pausal women, while juvenile granulosa cell tumors are usu-
ally seen in women younger than 30 years of age. Both types
are almost always unilateral and grossly; they are usually
solid with a cystic component (Fig. 16.42). Microscopically,
adult granulosa cell tumors have a wide range of associated
features (Fig. 16.43a–d). Architecturally they can range from
an epithelioid/organoid pattern to solid and spindled in
appearance. Trabecular, insular, gland-like, microfollicular, Fig. 16.41 Thecoma with a solid, tan-yellow cut surface
macrofollicular, and “watered silk” patterns may be present.
The nuclei have delicate membranes with grooves and folds. cytoplasm, which is sometimes vacuolated. Fluctuating lev-
Call-Exner bodies may be seen. Marked cytologic atypia els of hormones in the patient may impart a luteinized
may be seen, but is typically not diffuse. Juvenile granulosa appearance in this or for that matter any sex cord stromal
cell tumors are characterized by a vaguely nodular prolifera- tumor; therefore, a quick chart review for the patient’s medi-
tion of cells within a myxoid or edematous background. cation history should be taken in all cases.
Cystic spaces containing a proteinaceous material are scat-
tered throughout the tumor. Call-Exner bodies are usually 16.8.4.3 Sertoli-Leydig Cell Tumor
not seen. Compared to the adult type, the nuclei are more Sertoli-Leydig cell tumors are rare tumors that occur most
frequently large and hyperchromatic. The cells have ample commonly during the fourth decade of life. Grossly they are
562 H. Goyne et al.
composed of unilateral, solid, and cystic masses. The cut sur-

face ranges in color from yellow to brown and may display
hemorrhage and/or necrosis (Fig. 16.44a, b). The more com-
mon, well-differentiated tumors display a prominent corded
and tubular architecture. Leydig cells, with ample pink cyto-
plasm, may be seen scattered between the tubules in the
stroma. They may also be found in small aggregates at the
periphery of the mass. Intermediately differentiated tumors
display less of the corded pattern in favor of a more nodular
growth pattern, and poorly differentiated tumors are often
spindled and overtly malignant appearing.
16.8.5 Common Entities: Germ Cell Tumors
16.8.5.1 Epidermoid Cyst

This lesion is typically small and found in older adults. It is
Fig. 16.42 The typical hemorrhagic, solid, and cystic appearance of a composed exclusively of squamous epithelium without skin
granulosa cell tumor appendages.
a b
c d
Fig. 16.43 (a) Micro- and macrocystic growth in an adult-type granu- in an adult-type tumor. (d) High-power examination can often reveal
losa cell tumor. Note the presence of small follicles within the solid coffee bean-shaped nuclei with occasional nuclear grooves. While help-
components. (b) Trabecular, corded, and diffusely solid (right side) ful in some cases, this is not a diagnostic feature of adult-type granulosa
growth in an adult-type granulosa cell tumor. (c) Diffuse or solid growth cell tumors
a b
Fig. 16.44 (a) A Sertoli-Leydig cell tumor with a prominently cystic growth pattern. (b) Solid growth in a Sertoli-Leydig cell tumor
Fig. 16.45 A mature cystic teratoma with solid and cystic growth and hair
16.8.5.2 Mature Cystic Teratoma Fig. 16.46 Immature teratomas may appear as frankly malignant,
solid tumors, as seen in this example, or as a solid component in an
The mature cystic teratoma is the most common germ cell otherwise mature teratoma. Areas of fleshy, solid growth should always
tumor of the ovary. The classic appearance is a unilocular be preferentially sampled when evaluating these lesions
cyst filled with keratinaceous debris, oily brown to tan seba-
ceous material, and hair (Fig. 16.45). A raised protuberance,
known as Rokitansky’s nodule, may be present in the cyst 16.8.5.3 Dysgerminoma
composed of adipose tissue with overlying skin. Dysgerminoma is a rare, malignant germ cell tumor account-
Histologically, a wide variety of tissues may be present. The ing for approximately 1% of all ovarian germ cell tumors [2].
most common tissues include skin, skin appendages, adipose They are most common in the second and third decades of
tissue, respiratory epithelium, cerebral cortex, bone, carti- life. Of note, it is one of the most common neoplasms seen
lage, cerebellum, meninges, and peripheral nerve. Areas of during pregnancy. The tumors grow rapidly and may be
grossly apparent solid growth with necrosis may be seen in bilateral in a small number of cases. Grossly, the tumors are
immature teratoma (Fig. 16.46); because of this, when evalu- solid and firm with a uniform, tan-pink, cerebriform cut sur-
ating a mature teratoma, any and all areas that are fleshy, face (Fig. 16.47). Histologically, the tumor is composed of
solid, or necrotic should be sampled. cords and nests of uniform, polygonal cells, with ample
564 H. Goyne et al.
Fig. 16.48 Dysgerminoma is composed of large polygonal cells with

ample clear to eosinophilic cytoplasm. The nests of cells are often sepa-
rated by fibrous bands and variable numbers of lymphocytes
Fig. 16.47 The cut surface of a dysgerminoma frequently displays a

tan to white, cerebriform (“brain-like”) cut surface. Patches of necrosis
are apparent in this example
c ytoplasm, separated by fibrous bands (Fig. 16.48). Nuclei

are often large when compared to background cells. Within Fig. 16.49 Metastatic disease involving both ovaries. Note the pre-
the fibrous bands, variable numbers of lymphocytes are usu- dominately serosal distribution and involvement of the ovaries and fal-
lopian tubes
ally present.
16.8.5.4 Yolk Sac Tumor 16.8.6 Common Entities: Metastasis

Yolk sac tumor is also known as endodermal sinus tumor. It
is the second most common malignant ovarian germ cell Primary mucinous tumors of the ovary are usually 10 cm or
tumor and is most frequently seen in the second and third larger. Metastatic lesions are more often bilateral and affect
decades of life. Grossly, yolk sac tumor is nearly always uni- both ovaries; however, high-grade serous carcinomas often
lateral and large. Most tumors are >10 cm, oval-shaped, affect both ovaries (likely secondary to early and frequent
encapsulated, and yellow to gray in color. They typically metastasis). Ovarian cortical involvement of multiple nod-
contain cystic and solid areas with extensive necrosis and ules and/or surface implants suggests metastatic disease
hemorrhage. There are numerous histologic patterns includ- (Fig. 16.49). The pattern of surface encasement is especially
ing microcystic, macrocystic, myxomatous, solid, endoder- common in metastatic tubal serous carcinoma. Homogenous
mal sinus, alveolar-glandular, polyvesicular, papillary, expansion of ovarian parenchyma without cyst formation
hepatoid, glandular, and primitive endodermal. Eosinophilic can be seen in lymphomas, signet ring cell tumors, and
hyaline droplets and Schiller-Duval bodies may be present, breast carcinoma. Large tumors with obvious necrosis and
aiding in the diagnosis. hemorrhage are commonly seen in colonic metastasis.
Infiltrative glands and single cells that encompass normal lesions, as to not miss small areas of solid growth. Sections
ovarian structures are suggestive of metastasis as well [2, 9]. should be taken from solid, soft, and/or fleshy areas. In
It is important to remember that the residual ovarian stroma lesions grossly suspicious for borderline tumor or carcinoma,
surrounding the metastasis may become luteinized, mimick- but microscopically benign, additional sections (up to 4–5)
ing a sex cord stromal neoplasm. Awareness of this phenom- should be taken. If a mucinous carcinoma is encountered, the
enon, especially in younger patients, can help to avoid next step should be to rule out metastasis. This is particularly
misinterpretation. true when cancer involves both ovaries, is smaller than 10 cm
(particularly <5 cm), and/or is associated with psuedomyx-
oma peritonei. It may be helpful to remember that primary
16.8.7 Diagnosis and Reporting ovarian mucinous carcinoma is a rare finding. In addition, it
is also important to remember that “benign”-appearing muci-
Age is an important factor to consider when encountering an nous epithelium does not rule out metastasis, as some metas-
ovarian neoplasm. The most common ovarian neoplasms tasis (such as pancreatic carcinoma) may show remarkably
overall, and among women younger than 50 years of age, are bland lining epithelium.
of germ cell origin. Epithelial neoplasms are most common in Benign mesenchymal processes, such as spindle cell
women older than 50 years of age. Overall, stromal neoplasms lesions, may be reported as “benign or low-grade spindle cell
are uncommon [10]. When considering the benign neoplasms, neoplasms.” If marked cellularity, necrosis, pleomorphism,
benign cystic teratoma is the most common overall and in or atypia is present, the pathologist may report “atypical or
women younger than 50. The second most common subset is malignant spindle cell lesion,” depending on the degree of
serous and the third most common mucinous [10]. concern.
The most common tumors of low malignant potential are
serous borderline tumors, mucinous borderline tumors, and
endometrioid borderline tumors, in that order. Of note, endo- 16.9 F
rozen Section Analysis of Peritoneal
metrioid borderline tumors are rare [10]. The most common Lesions
malignant tumors of the ovaries are serous carcinomas and
tend to increase in incidence with age. 16.9.1 Purpose of Frozen Section Evaluation
In cases where a diagnosis of carcinoma can be made, it is
best practice to report a subtype (e.g., serous, mucinous, The frozen section analysis of peritoneal masses is not
endometrioid, etc.) if possible. The grade of the tumor (i.e., uncommon in the setting of a gynecologic tumor. This is
low vs. high) should be reported as well, as it may prompt a attributable to serous carcinoma’s tendency to seed the peri-
more extensive staging procedure. In some cases there will toneal cavity causing widespread disease. In many surgeries
be ambiguity regarding the primary source of the tumor, in this setting, it is technically easy (and commonplace) to
especially in cases of mucinous carcinoma. In these cases, biopsy the omentum or a peritoneal implant in order to estab-
the possibility of metastasis should be conveyed to the sur- lish a diagnosis or extent of spread. That being said, there are
geon, triggering a search for other possible sources of tumor a number of processes that may involve the peritoneal cavity
in the abdomen. In general the number of sections of tumor and mimic serous carcinoma or other malignancies.
examined intraoperatively should be reported to convey the Knowledge of these entities is critical in constructing a
extent of evaluation to the operating room. If carcinoma is robust differential diagnosis.
uncertain, a descriptive diagnosis is preferable, and the
pathologist should defer to permanent sections.
In the case of borderline tumors, adding the phrase “at 16.9.2 Gross Specimen Processing
least borderline tumor” is appropriate given the heteroge-
neous nature of these lesions. Again the pathologist should Grossly, peritoneal specimens sent for intraoperative consul-
report how many sections were examined. About a fourth of tation are noncomplex. They are usually removed entirely or
these lesions will show areas of carcinoma on additional sent as small biopsies. Inking is generally not indicated as
sampling. Subtyping (i.e., serous, mucinous, endometrioid) margin status is inconsequential. Occasionally sectioning of
these lesions is appropriate when possible [2]. larger specimen, such as omentum, should be performed to
Ovarian mucinous lesions are well known for low diag- identify focal lesions. Representative sections, avoiding
nostic accuracy at the time of frozen section evaluation. A necrosis, of larger lesions should be submitted, while freez-
good rule of thumb is to open every cyst for large cystic solid ing the entirety of small samples is routine practice.
566 H. Goyne et al.
16.9.3.1 Metastatic Gynecologic Disease

In patients with a demonstrable ovarian mass, intraoperative
consultation of the omentum or peritoneal surfaces is com-
mon. In general, there are three groups of tumors that should
be considered in this differential diagnosis: serous border-
line tumors, low-grade serous carcinoma, and high-grade
serous carcinoma. The diagnosis of high-grade serous carci-
noma is usually straightforward and based on the identifica-
tion of severe nuclear atypia, prominent nucleoli, and a
brisk mitotic rate.
The evaluation of implants in the setting of serous border-
line tumor is critical, as the identification of invasion will
reclassify a borderline tumor as a low-grade serous carci-
noma. There are two types of implants seen in the setting of Fig. 16.51 Noninvasive implants of serous borderline tumor may
borderline tumor, the noninvasive implants and the desmo- commonly be present within the fibrous connective tissue of the omen-
plastic implant. Noninvasive implants range from sparse to tum; this does not represent invasive disease
abundantly cellular and may line, but not invade, the under-
lying peritoneal surface (Fig. 16.50). In other areas, the pres-
ence of these implants in fat lobules (Fig. 16.51) may be
concerning for invasion; however, a well-circumscribed bor-
der should argue in favor of benignity. Desmoplastic implants
are usually seen by the surgeon as “pasted-on” plaques that
can be peeled off. Histologically, these lesions are often
composed of abundant desmoplasia with relatively infre-
quent epithelial elements, which may be concerning for inva-
sion (Fig. 16.52). Occasionally, single cells may be seen
within the desmoplastic stoma, which should not be over-
called as invasive disease (Fig. 16.53). The proportion of
desmoplasia relative to epithelium is usually skewed in favor
of the desmoplastic component, a key histologic clue to the
diagnosis.
Fig. 16.52 Desmoplastic implants are predominantly composed of

desmoplasia, with scattered glandular elements. These implants are
often peeled off of the peritoneum, and, therefore, no fat is present in
the surgical specimen
“Invasive implants” represent a historical term that was

once used to describe disease seen in the setting of a border-
line tumor; however, this entity was revised by the WHO in
2014 to represent low-grade serous carcinoma. Generally,
these lesions are obviously destructive and composed of
small angulated, to round, epithelial nests set in a desmoplas-
tic stroma (Fig. 16.54). Often, a small area of clearing may
be seen around the invasive epithelium, and in general the
ratio of epithelium to desmoplasia is higher than that seen in
desmoplastic implants.
16.9.3.2 Non-gynecologic Metastatic Disease

Fig. 16.50 A noninvasive implant of serous borderline tumor adherent This may take many forms, the most of which is metastasis
to a peritoneal surface from the gastrointestinal tract. Gastric cancer, especially the
Fig. 16.53 Occasionally single cells and irregularly shaped glands Fig. 16.55 Metastasis from a signet ring cell tumor. A central pool of
may be present in desmoplastic implants; these are not indicative of mucin contains occasional, small histiocytoid cells, while larger aggre-
invasive disease gates of signet ring cells can be seen in the upper left and bottom right
corners of the image
Fig. 16.54 Irregularly shaped nests of glandular epithelium seen in a

low-grade serous carcinoma
Fig. 16.56 Free floating strands of mucinous epithelium should be
searched for in the evaluation of mucin in cases of pseudomyxoma
peritonei
signet ring cell type, may metastasize widely and present as
a diffuse thickening of the peritoneum or omentum. The
tumor cells are often small with conspicuous cytoplasmic of advanced appendicular disease, usually low-grade appen-
mucin, often forming vacuoles which displace the nucleus diceal mucinous neoplasms (LAMN). In general these lesions
(Fig. 16.55). Occasionally, these cells may lack abundant are not sent for frozen sectioning, as the diagnosis and extent
mucin and appear as a histiocytic proliferation. are obvious; however, if consultation is requested, evaluation
Pancreatic adenocarcinoma has a tendency to metastasize of the mucin for epithelial elements, usually seen as strips of
widely by the time of diagnosis. In most cases, there is an low-grade mucinous epithelium, is appropriate (Fig. 16.56).
identifiable (or previously identified) pancreatic mass, which
can be helpful. In general, metastases from pancreatic adeno- 16.9.3.3 Mesothelial Tumors
carcinomas are composed of mucinous glands with accompa- A range of mesothelial lesions may be sampled for intraop-
nying desmoplasia. Perineural invasion is a frequent finding erative consultation, ranging from hyperplastic proliferations
and may be helpful in aiding in the differential diagnosis. to high-grade mesotheliomas. Reactive mesothelial prolifer-
Pseudomyxoma peritonei, once thought to be largely due ations are common, while their low- and high-grade malig-
to ovarian mucinous tumors, is not an infrequent p resentation nant counterparts are relatively rare.
568 H. Goyne et al.
Fig. 16.57 Reactive mesothelial cells seen growing in tufts and small Fig. 16.58 Mesothelioma composed of bland, eosinophilic cells grow-
papillary structures. Note that the lining of the structures is low cuboi- ing in papillae. This tumor is remarkably similar to low-grade serous
dal and that even at low magnification it is apparent that atypia is absent carcinoma, and discrimination between the two may not be possible on
frozen section
Reactive (papillary) mesothelial hyperplasia is a common 16.9.3.4 I nclusions, Cysts, and Other Reactive
histologic finding, which is rarely appreciated as a gross or Ectopic tissues
entity. It is usually composed of relatively bland, polygonal During the course of any abdominal surgery, a myriad of
cells lining the omental or peritoneal surface forming tufts or masses and cysts may be identified and sampled. These
papillae (Fig. 16.57). These lesions may occasionally dem- lesions are usually readily identifiable as benign, and in most
onstrate necrosis; however severe atypia should be absent. cases statement of such with a descriptive diagnosis will suf-
Most cases display mild atypia at most. Spindled growth fice. The following lesions and tissues are the most com-
may occur in some tumors, but, again, should lack nuclear monly encountered:
atypia. In most cases, an inciting event such as previous sur-
gery, inflammation, or endometriosis is the cause of these • Endometriosis—Endometriosis presents as a blue, brown, or
proliferations, although it may not be apparent in the sam- black discoloration or cyst. Histologic examination will
pled material. Low-grade, well-differentiated mesotheliomas reveal varying proportions of endometrial glands, stroma,
are typically small and incidentally identified at the time of and hemorrhage, which may be in the form of pigment-laden
surgery. These tumors share many histologic features with macrophages (Fig. 16.59). Occasionally, endometriosis may
their reactive counterparts, and their discrimination should become mass forming or polypoid, mimicking malignancy.
not be attempted during frozen section analysis. If a well- • Endosalpingiosis—deposits of tubal-type epithelium,
differentiated mesothelioma is suspected, the surgeon should which may be seen throughout the body. Endosalpingiosis
be altered to the possibility, and the tumor should be heavily ranges from small cysts to larger, partially cystic masses,
sectioned for histologic evaluation. which may contain papillary structures. The identification
High-grade mesothelioma is relatively uncommon, yet of otherwise unremarkable fallopian tube epithelium,
should be in the differential diagnosis of most low-grade composed of ciliated and secretory cells, is the major his-
(and some high-grade) serous carcinomas (Fig. 16.58). tologic hallmark (Fig. 16.60).
These tumors are often grossly large, bulky, and widespread, • Peritoneal inclusion cysts—small to large simple cysts
which may mimic high-grade serous carcinoma. In addition, lined by a bland mesothelial lining (Fig. 16.61).
they frequently display nuclear atypia, mitotic activity, peri- • Decidua—Any peritoneal surface may display decidual
toneal invasion, and necrosis. To further complicate evalua- changes similar to those seen in the endometrium
tion between these lesions, high-grade mesothelioma may (Fig. 16.62). These may present as tan/white plaques or
grow in papillary, solid, tubule-papillary, and sarcomatoid nodules, are usually associated with pregnancy, and, thus,
patterns. Suffice to say that in the vast majority of cases, the seen at the time of cesarean section.
differential diagnosis includes low- and high-grade serous • Granulomatous peritonitis—Keratin, infections, sarcoid,
carcinoma, including the primary peritoneal variant, and the gallstones, and foreign material may all lead to granu-
diagnosis should be based on permanent sections and use of loma formation in the peritoneum. Keratin granulomas
immunohistochemistry. are relatively common and are usually seen in the setting
Fig. 16.59 A serosal deposit of endometriosis with decidual change. Fig. 16.61 Low magnification view of a peritoneal inclusion cyst. The
When identified during cesarean section, the endometrium may show lining epithelium is low cuboidal and lacks atypia
this effect
Fig. 16.60 A small, cystic, peritoneal deposit of endosalpingiosis. Fig. 16.62 A carpet-like plaque of peritoneal deciduosis lining the
Note the presence of psammoma bodies, which is a common outside of the fallopian tube
occurrence
of mature cystic teratomas or severe inflammation with Grossly, it appears as red or brown nodules that may be
squamous metaplasia. Gallstone peritonitis may be seen mistaken for lymph nodes. This finding may be associated
following cholecystectomy, and foreign bodies may be with prior abdominal trauma.
identified in patients with extensive surgical histories and • Sclerosing mesenteritis—a reactive thickening of the
in cases of bowel perforation associated with diverticular mesenteric fat, which can mimic a malignant process.
disease or Crohn’s disease. Histologically, this lesion is composed of lobules of
• Peritoneal leiomyomatosis—diffuse involvement of the fat, separated by fibrous bands (Fig. 16.63). Fat necro-
peritoneal surfaces by innumerable, “benign” smooth sis, calcification, and inflammation are usually present
muscle tumors. This disease may primary, which is rare, and are a useful hint to the reactive nature of this
or secondary to prior morcellation of uterine tumors. disease.
• Gliomatosis—is the presence of mature glial tissue with • Fat necrosis/infarcted epiploica—Nodules of necrotic fat
small, round nuclei and fibrillary, eosinophilic cytoplasm may be identified by the surgeon and may mimic a malig-
growing on the peritoneal surfaces. This phenomenon nant process due to the firmness of the masses.
may be seen sporadically or associated with a teratoma. Histologically the presence of variably sized, necrotic fat
• Splenosis—the presence of histologically unremarkable, cells, chronic inflammation, and calcification can help to
splenic-type tissue located anywhere in the peritoneum. make the diagnosis.
570 H. Goyne et al.
suffice. Small nodes may be entirely submitted for

sectioning.
Recently, sentinel lymph node excision has become more
commonplace in some gynecologic oncology practices.
While the current protocol differs at many institutions, the
general consensus is that sentinel nodes should not be sub-
mitted for frozen sectioning as this may destroy diagnostic
tissue. If intraoperative consultation is desired in these cases,
thin sectioning (2–3 mm) of the node with touch imprints is
an alternative method that may be considered. The issue of
processing sentinel nodes is rapidly evolving, and those who
are in centers where it is practiced should apprise themselves
of current trends in the practice.
Fig. 16.63 Sclerosing mesenteritis demonstrating poorly formed fat

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Gynecologic Cytology
17
Uma Krishnamurti, Marina Mosunjac,
Georgios Deftereos, and Krisztina Z. Hanley
Abstract ous parts of the gynecologic tract, corresponding

The American Cancer Society’s estimates about 12,820 surgical specimen, and benign pitfalls and mimickers.
new cases of invasive cervical cancer will be diagnosed The peritoneal surface in women can give rise to vari-
each year in the United States. About 79 million Americans ous benign Mullerian lesions. It is important to be
are infected with HPV. The Bethesda System for report- familiar with the cytomorphologic characteristics of
ing cervical cytology has forged our understanding of these lesions to avoid misinterpreting them as malig-
HPV biology and provides an infrastructure for system- nant. Primary peritoneal lesions of the pelvic perito-
atic and evidence-based cervical cancer screening and neum encountered in gynecologic pathology include
management guidelines. Direct detection of HPV, e.g., by various benign, low malignant potential, and malignant
testing for HPV DNA or HPV-produced mRNA of known tumors of both mesothelial and Mullerian origin.
oncogenic genes, has found its place in new screening Interpretation errors can be significantly reduced if
strategies. HPV 16 and 18 being the most prevalent and immunohistochemical stains are applied to aid in the
most oncogenic HPV types resulted in need for HPV identification of malignant cells. The best and most
genotyping. helpful antibody panel in the diagnostic workup of pel-
HPV DNA detection-based methods are currently vic washings should include stains that can identify a
the most suitable way of approaching this issue and second population of cells, characterize them, and
have led to the development of different platforms. localize or suggest a primary site. Minimally invasive
Testing for HPV status in formalin-fixed, paraffin- surgical procedures (robotic and laparoscopic hysterec-
embedded histological samples, mainly for prognostic tomy) have been associated with various histologic arti-
reasons (but also as an aid in differential diagnosis), is facts due to “displacement” of tissue fragments of
mainly done using either DNA in situ hybridization or endometrial cancer into vascular channels and possibly
p16 immunohistochemistry. through the fallopian tubes into peritoneal surfaces and
Pelvic washings (PW) are now routinely performed for therefore are detected in pelvic washings.
staging of gynecologic malignancies, and results are sig-
nificant component of the final pathologic and clinical
stage of ovarian cancers.
Cytologic evaluation of PW starts with clinical his- Keywords
tory. As pelvic washings are routinely performed in HPV testing · cervical cytology · pelvic washing · ascites ·
patients who present with known gynecologic malig- immunohistochemistry · mesothelial cells
nancy or with imaging findings of a “lesion or mass” in
gynecologic tract, it is essential that the pathologist
interpreting washing cytology is familiar with the clini-
cal findings, histologic tumor types that occur in vari- 17.1 Cervical Cancer Screening
17.1.1 Epidemiology
U. Krishnamurti · M. Mosunjac · K. Z. Hanley (*)
Emory University Hospital, Atlanta, GA, USA
As recently as the 1940s, cervical cancer was a major cause
of death among women of childbearing age in the United
G. Deftereos
States. The American Cancer Society’s estimates for cervical
University of Utah School of Medicine, Salt Lake City, UT, USA
572 U. Krishnamurti et al.
cancer in the United States for 2017 are that about 12,820 Cameron, the director of the American Cancer Society,
new cases of invasive cervical cancer will be diagnosed and sponsored the First National Cytology Conference in
that 4210 women will die of cervical cancer [1]. However, Boston, in 1948, to showcase the unmistakable success of
worldwide, cervical cancer incidence is over 500,000 cases the Papanicolaou method in detecting early cervical disease
annually with 275,000 deaths/year [2]. and funded the training of pathologists by George
About 79 million Americans are infected with HPV. Of Papanicolaou. It was Cameron who christened the test as the
19 million people who newly acquire sexually transmitted “Pap test” [8]. In 1954, Dr. Papanicolaou produced the Atlas
diseases each year, the majority (about 14 million people) of Exfoliative Cytology, which was truly a masterpiece [9].
become newly infected by HPV each year. Of these, 49% of The generalization of exfoliative cytology was also sup-
cases are in young people (15–24 years of age) [3]. Clinical ported by the National Cancer Institute and the US Public
manifestations of HPV infection include genital warts (con- Health Service. With a simple Pap test, cervical cancer inci-
dylomas), intraepithelial neoplasia, and carcinomas of the dence and death rates declined by more than 60% over the
lower anogenital tract, particularly uterine cervical squa- last 40 years [1, 10, 11]. Even with newer advances such as
mous cell carcinoma (SCC) [3]. HPV and other biomarker testing, cervical cytology is still
the most successful cancer prevention program! Even in
women who have been HPV vaccinated, it is a highly spe-
17.1.2 History of Pap Test cific screening regimen. Cervical cytology is the first-line
screening test in many situations, especially where resources
The Pap test was invented by and named after George are limited.
Papanicolaou, who started his research in 1923. He first
announced his method of examining vaginal smears, now
commonly known as the “Pap test,” at the 1928 Battle Creek 17.2 C
ollection Of Cervical Cytology
Conference in Michigan [4]. There is controversy whether Samples [12]
credit for the “Pap test” should be given to Papanicolaou or
to Aurel Babes. A year earlier in 1927, Aurel Babes and It is crucial to properly collect and submit cervical cytology
Constantin Daniel presented their findings from examination samples. One half to two thirds of false negatives are due to
of cellular material obtained from the uterine cervix on slides patient conditions present at the time of sample collection
that were air dried and stained with Giemsa stain to diagnose and operator-related issues [13, 14].
cervical cancer [5]. The method by Babes was radically dif- Samples for Pap test should be collected within approxi-
ferent from that by Papanicolaou. Dr. Papanicolaou should mately 2 weeks (10–18 days) after the first day of a woman’s
receive the credit for the use of exfoliative cytology, the wet last menstrual period. Within 48 h prior to the test, the woman
fixation, the staining technique, the systematic classification should not douche and use tampons, birth control foams, jel-
of cells with intermediate stages between the normal and the lies, vaginal creams, or vaginal medications. Also, she should
cancerous cell, and the envisioning that the method could be refrain from intercourse 48 h prior to the test [15].
applied to large numbers of women in the cancer-bearing The laboratory requisition must be legibly and accurately
period of life to detect cervical cancer in its early stages, i.e., filled out before obtaining the cellular sample.
the “Pap test” as is commonly employed [6]. Information in the laboratory requisition as required by
The Pap test was finally on the map only after a leading CLIA’88 [16] are:
article in the American Journal of Obstetrics and Gynecology
in 1941 by Dr. G. Papanicolaou and Dr. Herbert Traut, a • Name (any name change in the past 5 years should be
gynecologist [7]. A monograph entitled Diagnosis of Uterine noted)
Cancer by the Vaginal Smear that they published contained • Age and/or date of birth
drawings of the various cells seen in patients with no disease, • Menstrual status
inflammatory conditions, and preclinical and clinical carci- • Previous abnormal cervical cytology result
noma. The outstanding illustrations in the monograph were • Previous treatment, biopsy, or surgical procedure
by Hashima Murayama, who was later a staff illustrator with • Risk status for developing cervical cancer, e.g., “high risk”
the National Geographic Society. Both Papanicolaou and his • Source of specimen, e.g., cervical, vaginal
wife dedicated the rest of their lives to teaching the technique • Hormone/contraceptive use
to other physicians and laboratory personnel [8]. • Relevant clinical findings (abnormal bleeding, grossly
The purpose of the Pap test is to detect precancerous visible lesion, etc.)
abnormalities, which can be destroyed when detected (using
loop electrocautery excision procedure, cryotherapy, or sur- Laboratories should have a written procedure specifying
gical excision), thus preventing cancer. Dr. Charles the requirements for proper specimen identification. The
17 Gynecologic Cytology 573
specimen vial or glass slide must be labeled with a unique Table 17.1 Comparison of LBC systems
identifier which is usually the patient’s first and last names. SurePath ThinPrep
A second identifier such as date of birth, medical record Cell separation method from the Centrifugation Filtration
number, social security number, or collection date may be suspension
Cell deposition method on slide Sedimentation Controlled
used based on the laboratory policy.
pressure
A cervical cytology specimen is usually collected with Circular diameter for microscopy 13 mm 20 mm
the patient in the dorsolithotomy position. A sterile or single-
use bivalve speculum of appropriate size is inserted into the
vagina without lubrication. The position of the speculum then the collection device is discarded. The cap is tightened
should allow for complete visualization of the cervical os so that the torque line on the cap passes the torque line on
and ectocervix. The endocervix, transformation zone, and the vial.
ectocervix should all be sampled [17]. The currently avail-
able collection devices include endocervical brushes, 17.2.1.2 Collection for SurePath [22]
wooden and plastic spatulas, and plastic “broom-type” For SurePath cytology, the sample is collected using either a
samplers. broom-like device or combination brush/spatula with detach-
able heads. The detachable head is dropped into the BD
SurePath™ vial and then the cap tightened and transported
17.2.1 Liquid-Based Cytology to the laboratory.
While both SurePath and ThinPrep systems are automated
Liquid-based cytology (LBC) is an alternative to conven- and result in a well-preserved approximate monolayer of
tional Pap smears. The US FDA approved the ThinPrep cells, with a background devoid of blood and mucus, there
(Hologic, Marlborough, MA) in 1996 and SurePath (previ- are some differences between the two liquid-based systems
ously known as Auto-Cyte Prep) in 1999 (BD TriPath, (Table 17.1).
Burlington, NC). Both liquid-based cytology and conven-
tional smears are acceptable for cytologic screening [18, 19]. 17.2.1.3 Advantages of LBC
In the United States, in 2006–2007, liquid-based cytology • Immediate fixation with enhanced nuclear and cytoplas-
was used in approximately 75% of Pap tests, and by 2014 it mic details.
was estimated to be about 93% of Pap tests. • Less screening time than a conventional smear.
Liquid-based methods require the use of collection • Additional samples can be prepared as needed.
devices that have been approved by the FDA for use with the • Cleaner background.
particular specimen preparation instrument, and manufactur- • Reduced unsatisfactory rate.
ers’ directions must be followed [20]. • Suitability for other tests, e.g., HPV testing,
chlamydia/gonorrhea, and trichomonas testing.
17.2.1.1 Collection for ThinPrep [21] • Suitability for automated analysis.
For ThinPrep cytology, the broom or brush/spatula can be
used for collection. For collection using the brooms, the cen- 17.2.1.4 Disadvantages of LBC
tral bristles of the broom are inserted into the endocervical • Abnormal cells are dispersed.
canal deep enough to allow the shorter bristles to fully con- • Epithelial cells especially endocervical cells and imma-
tact the ectocervix. The broom is gently pushed and rotated ture metaplastic cells appear smaller than in conventional
in a clockwise direction five times. With the “broom-like” smears.
device, the ectocervical and endocervical specimens are col- • Scanty LBC preparations can be difficult to screen and
lected simultaneously. interpret.
For collection using the brush/spatula, adequate sampling • More expensive than conventional test.
from the ectocervix is obtained by rotating the plastic spatula • Background material such as blood, mucus, or tumor dia-
360 degrees around the entire exocervix while maintaining thesis when present appears different.
tight contact with exocervical surface. After that an endocer-
vical brush device is inserted into the cervix until only the
bottommost fibers are exposed. This is slowly rotated 1/4 or 17.2.2 Conventional Cervical Cytology
1/2 turn in one direction.
For both collection methods, the collection device (broom Air-drying greatly limits specimen evaluation by obscuring
or spatula and brush) is rinsed as quickly as possible into the cellular details. Therefore, for conventional cervical cytology
PreservCyt solution by rotating it in the vial ten times and specimens, to prevent air-drying, it is important to immedi-
then swirled vigorously to further release the material, and ately fix the sample. This can be achieved by either immersing
the slide in alcohol or by using spray cytology fixatives. While ogy terminology (LAST), and the increasing use of HPV
applying, spray fixatives should be 6–10 in. (15–25 cm) from vaccinations. All these were justifications for the 2014
the glass slide. Specimens fixed in alcohol can be transported Bethesda System. There was no consensus workshop held
to the laboratory in the alcohol container itself or transported for the 2014 Bethesda System update. Following literature
in an air-dried manner after 20–30 min of fixation. review, the proposed content for the atlas was conceived by a
select group of cytopathologists, clinicians, and epidemiolo-
gists. Based on the feedback received from individuals in 59
17.3 C
ervical Cytology Reporting System countries worldwide on the proposed updates, the positions
and Its Progresses and contents were fine-tuned and then included into the 2014
Bethesda System and the most recent atlas. The 3rd edition
In the first few decades of cervical cytology, there was poor of the atlas published in 2015 has a new chapter on a risk
reproducibility and lack of standardization of laboratory assessment-based management [25].
reports of Papanicolaou smears [23]. The Bethesda System In addition to standardizing the reporting of cervical
(TBS) is a standardized system widely used for reporting cytology worldwide, TBS has advanced our understanding
Pap smear results. The goal of the first Bethesda workshop, of HPV biology and provided the framework necessary for
which was convened in December 1988 and chaired by Dr. the development of systematic and evidence-based cervical
Robert Kurman, was to find a better way of reporting cervi- cancer screening and management guidelines [25].
cal cytology. It is named The Bethesda System (TBS) TBS has clear criteria for specimen adequacy, and a
because the first conference where the system was devised “statement of adequacy” is an essential part of the report
was held in Bethesda, Maryland. serving as an important quality assurance element. The ter-
TBS terminology has the following fundamental guiding minology is based on the underlying pathobiology of the
principles: morphologic changes of cervical epithelial abnormalities.
TBS has standard reporting terms and criteria for each inter-
• Terminology used by the laboratory must communicate pretive category. Squamous intraepithelial lesion (SIL) is
appropriate and relevant clinical relevant information to divided into low- and high-grade lesions. The two-tier termi-
the clinician. nology reflects the different biologic states between low-
• Terminology should be consistent across different labora- grade lesion (representing productive HPV infections and
tories but also flexible so that it can be modified to suit the self-limiting state) and high-grade lesion (representing a pre-
needs of various laboratories and diverse geographic cancer state).
settings.
• Terminology should be continuously updated to repro-
duce the most up-to-date understanding of the tumor biol- 17.4 E
valuation and Reporting of Cervical
ogy of cervical neoplasia and incorporate advances in Cytology Specimens
laboratory practice. Additional workshops were convened
in 1991 and 2001. The Pap smear/cervical cytology report should have the
following main headings (Table 17.2):
There have been three editions of the Cervical Cytology
Bethesda System atlas that encompass the definitions and Table 17.2 The 2014 Bethesda System for reporting cervical
cytologic criteria of cervical cytology interpretations along cytology
with explanatory notes and images. It was in 1994 and 2004 Specimen type
that the first two editions of TBS atlas were published [23, Indicate conventional smear (Pap smear) vs. liquid-based
24]. The workshop in 2001 utilized the Internet, providing preparation vs. other
everyone an opportunity for input. This resulted in more than Specimen adequacy
2000 comments and more than 400 participants from over • Satisfactory for evaluation (describe presence or absence of
endocervical/transformation zone component and any other
two dozen countries in the actual meeting [24]. With the quality indicators, e.g., partially obscuring blood, inflammation,
increasing use of liquid-based cytology by many laborato- etc.)
ries, images and criteria specific to liquid-based cytology • Unsatisfactory for evaluation (specify reason)
were included in the 2004 atlas. Specimen rejected/not processed (specify reason)
Specimen processed and examined, but unsatisfactory for
Between 2001 Bethesda System and 2014 Bethesda evaluation of epithelial abnormality because of (specify reason)
System, there had been many changes in the practice of cer- General categorization (optional)
vical cytology and pathology, including the primary HPV • Negative for intraepithelial lesion or malignancy
screening with Pap as triage, the new screening and manage- • Other: See Interpretation/Result (e.g., endometrial cells in a
ment guideline (ASCCP 2012), the changes in histopathol- woman ≥45 years of age)
Table 17.2 (continued) • Automated Review

• Epithelial cell abnormality: See Interpretation/Result (specify • Educational Notes and Suggestions (optional)
“squamous” or “glandular”)
Interpretation/result
Negative for intraepithelial lesion or malignancy
17.4.1 Specimen Type
Nonneoplastic findings (optional to report)
• Nonneoplastic cellular variations
Squamous metaplasia The report should indicate if conventional smear (Pap smear),
Keratotic changes liquid-based preparation, or other specimen type was
Tubal metaplasia examined.
Atrophy
Pregnancy-associated changes
• Reactive cellular changes associated with:
Inflammation (includes typical repair) 17.4.2 Specimen Adequacy (Table 17.2)
• Lymphocytic (follicular) cervicitis
Radiation
This section should report if the specimen is:
Intrauterine contraceptive device (IUD)
• Glandular cells status post hysterectomy
Organisms • Satisfactory for evaluation with a description of quality
• Trichomonas vaginalis indicators.
• Fungal organisms morphologically consistent with Candida spp. • Unsatisfactory for evaluation with specification of
• Shift in flora suggestive of bacterial vaginosis
reason.
• Bacteria morphologically consistent with Actinomyces spp.
• Cellular changes consistent with herpes simplex virus • The third category of “less than optimal” which was
• Cellular changes consistent with cytomegalovirus renamed as “satisfactory but limited by” in 1991 was
Others eliminated in 2001 [25].
• Endometrial cells (in a woman ≥45 years of age)
(Specify if negative for squamous intraepithelial lesion) The minimum number of squamous cells required for
Epithelial cell abnormalities adequacy:
Squamous cell
• Atypical squamous cells • 5000 for liquid-based preparations (LBP)
Of undetermined significance (ASC-US)
Cannot exclude HSIL (ASC-H) • 8000–12,000 for conventional smears
• Low-grade squamous intraepithelial lesion (LSIL)
• High-grade squamous intraepithelial lesion (HSIL) Borderline or low squamous cellularity: 5000–20,000
With features, suspicious for invasion cells
• Squamous cell carcinoma
Glandular cell
For a specimen to be satisfactory for evaluation, there
• Atypical should be adequate squamous cellularity. For conventional
Endocervical cells smears, there should be 8000–12,000 well-preserved and
Endometrial cells well-visualized squamous epithelial cells. Adequate liquid-
Glandular cells (NOS) based preparations should have an estimated minimum of
• Atypical
Endocervical cells, favor neoplastic 5000 well-preserved and well-visualized squamous epithe-
Glandular cells, favor neoplastic lial cells or squamous metaplastic cells (Fig. 17.1). This
• Endocervical adenocarcinoma in situ cell range should be estimated without counting individual
• Adenocarcinoma cells. For estimating cellularity reference, images of differ-
Endocervical
Endometrial ent cell counts in the Bethesda Atlas are a useful guide. In
Extrauterine addition, the 2001 Bethesda System also published images
Not otherwise specified (NOS) to help in estimating squamous cellularity in conventional
Other malignant neoplasms: (specify) smears.
Adjunctive testing Table 17.3 summarizes the guidelines for estimating
Computer-assisted interpretation of cervical cytology
cellularity in liquid-based preparations. A minimum of
Educational notes and comments (optional)
ten microscopic fields, usually at 40×, should be assessed
along a diameter that includes the center of the preparation,
• Specimen Type and the average number of cells per field is then estimated.
• Specimen Adequacy With a 13 mm diameter of SurePath preparation, the average
• General Categorization (optional) number of estimated squamous cells is 7.4 cells/HPF (field
• Interpretation/Result number 20 eyepiece/40× objective) and 9.0 cells/HPF (field
• Ancillary Testing number 22 eyepiece/40× objective).
If a minimum of ten well-preserved endocervical or squa-

mous metaplastic cells are present singly or in clusters, it is
considered to be an adequate representation of the transfor-
mation zone.
With the exception of women who have had a total hyster-
ectomy, the Specimen Adequacy section of the cytology
report should state whether the EC/TZ component is present.
Whether an endocervical component is required for a
sample to be considered adequate is controversial. According
to the 2014 TBS update, while absence of an EC/TZ compo-
nent does not warrant an early repeat screening, recording its
presence is still recommended as a quality indicator. In addi-
tion, it is also useful information to have in women with prior
abnormal history of pre-neoplastic or malignant glandular
abnormalities [26].
Fig. 17.1 Pap smear satisfactory for evaluation with adequate squa- Unsatisfactory for evaluation
mous cellularity (SurePath, Papanicolaou stain, 100×)
Specimen rejected/not processed
Table 17.3 Guidelines for estimating cellularity of liquid-based Specify reason which may include slide broken beyond
preparations repair or lack of patient identifiers.
FN20 FN20 FN20 FN22 Sample processed and examined, but unsatisfactory for
eyepiece eyepiece eyepiece eyepiece evaluation of epithelial abnormality (the report should
10× 40× 10× 40× specify reason)
objective objective objective objective • Low squamous cellularity (Fig. 17.2a, b).
Prep Number of Number of Number of Number of
• More than 75% of squamous cells are obscured by
(diameter in cells/field for cells/field cells/field cells/field
mm) 5 K total for 5 K total for 5 K total for 5 K total blood, mucus, lubricant, or inflammation, if no abnor-
SurePath 118.3 7.4 143.2 9.0 mal cells are detected.
[13]
ThinPrep 50.0 3.1 60.5 3.8 When 50–75% of the cells are obscured, the specimen
[20]
should be reported as being partially obscured following the
FN field number satisfactory term. The percentage of cells obscured, not the
slide area obscured, should be evaluated, although minimal
With a 20 mm diameter of ThinPrep, the average number cellularity criteria should also be applied.
of estimated squamous cells is 3.1 cells/HPF (field number Any specimen with abnormal cells is satisfactory for
20 eyepiece/40× objective) and 3.8 cells/HPF (field number evaluation, such as atypical squamous cells of undetermined
20 eyepiece/40× objective). significances (ASC-US), atypical glandular cells (AGC), or
The minimum cellularity criteria are developed for cervi- other abnormal cells.
cal cytology in premenopausal women. The 5000 cell thresh- At any age, an unsatisfactory specimen does not become
old should not be rigidly applied to postmenopausal women satisfactory on account of the presence of benign endome-
with atrophic changes, to vaginal specimens after hysterec- trial cells.
tomy, or to post-therapy specimens [25]. Women who are The use of lubricants is not recommended since it can
postmenopausal, who have had radiation/chemotherapy, or adversely impact the cellularity of ThinPreps [27, 28].
who have had hysterectomy may have fewer than 5000 cells SurePath specimens do not appear to be impacted adversely
in their LBC specimens, but such specimens may still be by the presence of interfering substances [29, 30].
considered adequate. Professional judgment and hierarchical The College of American Pathologists (CAP) survey data
review are suggested when specimen adequacy is evaluated. shows that the 50th percentile rates for unsatisfactory speci-
Although strict criteria may not be applicable to every case, mens in US laboratories are 0.3% for SurePath, 1.1% for
in most situations, samples with fewer than 2000 cells should ThinPrep, and 1.0% for conventional preparations [31].
be considered as unsatisfactory. Unsatisfactory rates significantly higher than these should
It is not essential to have an endocervical/transforma- prompt the laboratory to carefully evaluate for possible
tion zone (EC/TZ) component for a specimen to be con- causes that may relate to sampling methodology, preparation
sidered adequate. technique, patient population, or interpretation thresholds.
a b
Fig. 17.2 Pap smear unsatisfactory for evaluation. (a) Unsatisfactory due to scant cellularity (SurePath, Papanicolaou stain, 100×). (b)
Unsatisfactory for evaluation due to scant cellularity with predominantly acute inflammation SurePath, Papanicolaou stain, 200×)
17.4.3 General Categorization (Optional) squamous cells-cannot exclude a high-grade squamous

intraepithelial lesion (ASC-H), high-grade squamous
Under this, key headings from the Interpretation/Result cat- intraepithelial (HSIL), and squamous cell carcinoma.
egory can be repeated, and these are: The glandular epithelial cell abnormalities include atypi-
cal cells (endocervical cells, endometrial cells, or glandular
• Negative for intraepithelial lesion or malignancy cells NOS), atypical cells favor neoplastic (endocervical
• Other: See Interpretation/Result (e.g., endometrial cells cells, endometrial cell, or glandular cells NOS), endocervi-
in a woman ≥45 years of age) cal adenocarcinoma in situ, and adenocarcinoma (endocer-
• Epithelial cell abnormality: See Interpretation/Result vical, endometrial, extrauterine, and not otherwise specified,
(specify “squamous” or “glandular” as appropriate) NOS).
17.4.4 Interpretation/Result 17.4.5 Ancillary/Adjunctive Testing
Table 17.2 presents the recommended Bethesda System This section should provide a brief description of the test
terminology for reporting the findings. method(s) and report the result in a manner that can be easily
The main interpretation categories for adequate speci- understood by the clinician.
mens are:
• Negative for intraepithelial lesion or malignancy (NILM) 17.4.6 Automated Review [32]
• Epithelial cell abnormality, which can be further specified
as squamous cell or glandular cell If a case is examined by an automated device, such as by
• Other (endometrial cells in a woman ≥45 years of age computer assistance, the device used should be specified.
with specification if the specimen is “negative for squa- Irrespective of the result, the report should state if the spec-
mous intraepithelial lesion”) imen was processed successfully or if there was review of
• Other malignant neoplasms (specify) only the device identified fields of view or a full manual
screening. If only device identified fields of view were
The negative for intraepithelial lesion or malignancy cat- reviewed, the interpretation as well as adequacy informa-
egory reports nonneoplastic findings and organisms that may tion obtained from the computer assessment must be
be present. reported. Even if manual screening/review is not per-
The squamous epithelial cell abnormalities include atypi- formed, a laboratorian with appropriate training and autho-
cal squamous cells undetermined significance (ASC-US), rization must review and verify the results generated by the
low-grade squamous intraepithelial (LSIL), atypical instrument.
17.4.7 Educational Notes and Comments The nucleus is eccentrically placed with a finely granular
Appended to Cytology Reports chromatin. Normal endocervical cells have inconspicuous
(Optional) nucleoli, but reactive endocervical cells can have prominent
nucleoli (Fig. 17.5a, b).
The suggestions should be concise and in keeping with clini-
cal follow-up guidelines published by professional organiza- 17.5.2.2 Endometrial Cells
tions. References to relevant publications may be included. These can be seen in younger women, and benign endome-
The 2012 consensus guidelines of the American Society trial cells are not reportable in women less than 45 years of
for Colposcopy and Cervical Pathology (ASCCP) are fol- age. They are usually identified in the first 12 days of the
lowed for managing patients with abnormal cervical cancer menstrual cycle. They appear as small dark hyperchromatic
screening tests and cancer precursors [26]. cells arranged in balls (Fig. 17.6a). Sometimes, endome-
trial cells show a dual cell population of larger glandular
cells in the periphery and small, dark, stromal cells in the
17.5 Normal Cellular Elements center (Fig. 17.6b). Endometrial cells may be seen out of
The normal cellular elements are squamous cells, endocervi-

cal cells, endometrial cells, and lower uterine segment cells.
17.5.1 Squamous Cells (Table 17.4)
Superficial, intermediate, or parabasal cells constitute squa-

mous cells in cervical cytology specimens can be (Figs. 17.3
and 17.4).
17.5.2 Glandular Cells
17.5.2.1 Endocervical Cells

These cells can be present as a cohesive flat sheet of cells
with a honeycomb appearance, as strips with a picket fence
appearance, or as isolated cells. The cells have an abundant Fig. 17.3 Superficial and intermediate squamous cells. (SurePath,
vacuolated cytoplasm because they are mucin producing. Papanicolaou stain, 100×)
Table 17.4 Squamous cells in Pap smear

Superficial cell Intermediate cell Parabasal cell
Cell size 35–50 μm 45–50 μm 15–30 μm
(diameter)
Cell cytoplasm • Abundant • Thick with rounded outlines or • Round to oval dense
• Thin • Thin with polygonal outlines • Less abundant than superficial and
• Delicate transparent • Green or golden yellow due to intermediate cells
• Usually eosinophilic glycogen • Blue-green to gray-blue
• Keratohyalin granules±
Nuclear • 10–15 μm2 • 35 μm2 • 50 μm2
characteristics • Pyknotic • Finely granular evenly distributed • Finely granular evenly distributed
chromatin with occasional chromatin with occasional
chromocenters chromocenters
• Longitudinal groove • Indistinct nucleolus
Comments • Estrogen related • Navicular cells are boat shaped and • Predominant in postmenopausal and
• More frequent in the first half have abundant glycogen postpartum states
(proliferative phase) of the • More frequent in the second half
menstrual cycle (secretory/luteal phase) of the
menstrual cycle
• It functions as size reference for
nuclei of other cells in cervical
cytology
a b
Fig. 17.4 Parabasal cells. (a) Parabasal cell in a normal Pap smear (SurePath, Papanicolaou stain, 100×). (b) Predominance of parabasal cells in
atrophy (SurePath, Papanicolaou stain, 600×)
a b
Fig. 17.5 Endocervical cells. (a) Normal endocervical cells in a honeycomb pattern; (SurePath, Papanicolaou stain, 100×). (b) Singly dispersed
endocervical cells with a basally placed nucleus and intracytoplasmic mucin (SurePath, Papanicolaou stain, 100×)
a b
Fig. 17.6 Endometrial cells. (a) Endometrial cells as small dark hyperchromatic cells arranged in balls. (b) Endometrial cells as a dual cell popu-
lation of larger glandular cells in the periphery and small, dark, stromal cells in the center (exodus) (SurePath, Papanicolaou stain, 600×)
phase, in women with endometritis, intrauterine devices, or and fragments of squamous cytoplasm. Excessive cytolysis
endometrial polyps [33]. Endometrial cells are in the dif- may render a Pap smear difficult to evaluate.
ferentials of hyperchromatic crowded groups that also
include lower uterine segment cells, HSIL, squamous cell 17.5.3.3 Trophoblastic Cells and Decidual Cells
carcinoma, AIS, small-cell carcinoma, and endometrial Trophoblastic cells are seen very rarely, in about 0.1% of Pap
carcinoma. smears from pregnant women. Syncytiotrophoblastic cells are
large with abundant cytoplasm, multiple nuclei with slightly
irregular nuclear contours, and a granular chromatin pattern.
17.5.2.3 Lower Uterine Segment Syncytiotrophoblasts may sometimes show a tail that represents
Sometimes lower uterine segment (LUS) or endometrium where the cells separate from the placenta (Fig. 17.9). The pres-
may be sampled, particularly if there is a shortened endocer- ence of these cells does not reliably indicate an imminent abor-
vical canal as in cases of women post-conization. Lower tion [34]. Decidual cells are isolated cells with degenerative
uterine segment is seen as large fragments of glands and changes. Decidual cells have abundant granular cytoplasm, a
stroma. Compared to endocervical cells, LUS cells are more large vesicular nucleus, and a prominent nucleolus.
hyperchromatic, show a higher nuclear to cytoplasmic ratio,
and more likely show mitoses.
17.5.3 Other Cells
17.5.3.1 Inflammatory Cells

Neutrophils are seen in all Pap smears and do not always
indicate infection. They are increased after infection or
injury (Fig. 17.2b). Lymphocytes and plasma cells are rare
but may be seen in follicular cervicitis. Histiocytes are non-
specific and may be seen in normal Pap smears (Fig. 17.7a).
They may also be seen in association with pregnancy, IUD,
endometrial proliferations, and radiation.
17.5.3.2 Lactobacilli
These are gram-positive rod-shaped bacilli (Fig. 17.8). They
Fig. 17.8 Lactobacilli. Note the numerous rod-shaped bacilli causing
produce lactic acid and reduce the pH and are believed to cytolysis with fragments of squamous cytoplasm. Also present are
possibly offer protection from infection by pathogens such numerous neutrophils (SurePath, Papanicolaou stain, 600×)
as Candida. Lactobacilli can cause cytolysis, resulting in a
smear with numerous bacilli, bare intermediate cell nuclei,
Fig. 17.9 Syncytiotrophoblastic cell seen as a large cell with abundant

cytoplasm, multiple nuclei, and a tail where the cell has separated from
Fig. 17.7 Histiocytes (SurePath, Papanicolaou stain, 600×) the placenta (SurePath, Papanicolaou stain, 400×)
17.6 Benign Cytological Changes • Glandular cells status post hysterectomy

• Infectious organism
The category of benign cytological changes applies to all speci- • Other
mens in which no intraepithelial lesion or malignancy is identi- –– Endometrial cells (in a woman >45 years of age)
fied. It encompasses a wide spectrum of nonneoplastic/benign
changes that include reactive and reparative changes in response 17.6.1.1 Nonneoplastic Cellular Variants
to systemic or local injury and to a particular infectious organism. Nonneoplastic cellular variants are a subgroup of findings
in cervical Pap smear that occur as a protective response
to local or systemic injury and include squamous metapla-
17.6.1 Nonneoplastic Findings sia (SM), keratotic changes, and tubal metaplasia
(Table 17.5).
Even though it is optional to report specific nonneoplastic
findings that are not associated with an organism [25], 17.6.1.2 Hormonal Alterations
marked reactive and reparative changes should be subjected The mucosa of the female genital tract is sensitive to hor-
to additional hierarchical review as these changes may cause monal changes. Maturation of squamous epithelium is driven
concern and could be overinterpreted as premalignant or by high levels of estrogen.
even malignant lesions. Benign cytological changes that are Atrophy occurs as a normal aging process as a result of
optional to report may be subcategorized to: reduced estrogen level. Similar changes can be seen in
other low estrogen states such as premenarche, postpar-
• Nonneoplastic cellular variants tum, status post bilateral oophorectomy, or Turner syn-
–– Squamous metaplasia drome [35].
–– Keratotic change Pregnancy-associated changes reflect increased proges-
–– Tubal metaplasia terone effect resulting in lack of maturation and predomi-
• Hormonal alterations nance of intermediate cells [34] (Table 17.6).
–– Atrophy
–– Pregnancy-associated changes 17.6.1.3 Reactive Cellular Changes
• Reactive changes associated with Trauma, radiation [36], and nonspecific infection can cause
–– Inflammation a wide array of morphological changes in squamous and
–– Lymphocytic follicular cervicitis endocervical cells. Reactive and reparative changes in
–– Radiation response to inflammation and injury are among the most
–– Intrauterine contraceptive device (IUD) common benign changes encountered in cervical Pap
Table 17.5 Three subtypes of protective response of cells to local or systemic injury
Squamous metaplasia Keratotic change Tubal metaplasia
Definition Metaplastic process in which glandular Protective mechanism usually in Metaplastic process in which normal
endocervical epithelium is replaced by association with HPV endocervical epithelium is replaced by
squamous type of cells Includes previously used terms epithelium that resembles cells of the
Immature metaplasia is a transitional • Keratosis normal fallopian tube (Fig. 17.12)
developmental stage in which cells keep • Parakeratosis
characteristics of both endocervical and • Dyskeratosis
squamous epithelium (Fig. 17.10a, b) • Hyperkeratosis
Mature metaplastic cells are
morphologically indistinguishable from
squamous cells
Criteria Immature metaplasia Miniature superficial squamous Ciliated columnar cells in groups or singly
Sheets and single cells cells with orangeophilic High N/C ratio nuclei might be enlarged
Higher N/C ratio cytoplasm and small round dark pleomorphic and hyperchromatic
Oval nuclei with smooth borders nucleus (Fig. 17.11) Cytoplasm may be vacuolated
Finely granular chromatin Hyperkeratosis
No nucleoli Anucleated mature squamous
Dense cyanophilic cytoplasm with sharp cells
borders “Ghost cells without nuclei”
“Spider cells” (Fig. 17.10b, c)
Differential LSIL ASC-US AGUS
diagnosis HSIL Adenocarcinoma
ASC-US
a b
Fig. 17.10 (SurePath, Papanicolaou stain). (a) Mature metaplastic with extended cytoplasmic processes called “spider cells” resulted from
cells with dense cytoplasm and well-defined cell borders (400×). (b) mechanical force used to extract cells. N/C ratio increased, nuclear
Cluster of immature metaplastic cells with both features of columnar membranes smooth, chromatin powdery with no nucleoli (600×)
endocervical cells and squamous cells (400×). (c) Metaplastic cells
Fig. 17.11 (SurePath, Papanicolaou stain). Cluster of anucleated squa- Fig. 17.12 Tubal metaplasia (SurePath, Papanicolaou stain). Tubal
mous cells (hyperkeratosis) admixed with some cells that still contain metaplasia. Endocervical cells with prominent terminal bar and cilia. N/C
small pyknotic and hyperchromatic nuclei (parakeratosis) (400×) ratio slightly increased, nuclei round to oval with fine chromatin (600×)
Table 17.6 Definition, morphological features, and differential diagnosis of atrophy and pregnancy-related changes in the cervical smear
Atrophy Pregnancy-associated change
Definition Thinned squamous epithelium is a result of decreased Alterations in squamous epithelium due to
hormonal stimulation in postmenopausal women pregnancy-induced hormonal changes. Relative low
level of estrogen and high level of progesterone lead
to incomplete maturation of the squamous cells
resulting in an intermediate cell—dominant pattern
Criteria Flat monolayered sheets with parabasal-like cells with no Intermediate-like cells with boat-shaped pattern
nuclear overlap (Fig. 17.13a) (navicular cells) are frequently seen (Fig. 17.14a)
Slight increase in N/C ratio (Fig. 17.13b) Basophilic to clear cytoplasm rich in glycogen
Chromatin evenly dispersed Vesicular nuclei with delicate chromatin pattern
Nuclear membranes regular
Sight anisonucleosis (Fig. 17.13b, d)
“Blue blobs” refer to globular collections of basophilic
amorphous material and crushed overlapping parabasal
cells (Fig. 17.13c)
Degenerated small parakeratotic-like cells and histiocytes
may be present
Background Inflammatory exudate
Clear
Differential diagnosis HSIL HPV changes (Fig. 17.14b)
ASC-US
LSIL
a b
c d
Fig. 17.13 Atrophy (SurePath, Papanicolaou stain). (a) Low power of absence of nucleoli, and smooth nuclear borders and no overlap (400×).
atrophic smear showing smaller single and parabasal cells with cyano- (c) Tighter cluster of atrophic cells, periphery of the cluster, shows typi-
philic cytoplasm and slightly enlarged nuclei (100×). (b) High power cal features as seen in picture b (400×). (d) Slight anisonucleosis often
showing parabasal cells with increased N/C ratio, fine chromatin, seen in atrophic smear and should not be interpreted as ASC-US (400×)
a b
Fig. 17.14 Pregnancy changes (SurePath, Papanicolaou stain). (a) change in which there is perinuclear clearing with condensation and
Smear composed mostly of intermediate cells showing peripheral fold- folding-like features of the cytoplasm at the periphery. However,
ing of cytoplasm giving cells boat-like features that are known as navic- nuclear features are typical of LSIL (600×)
ular cells (400×). (b) Contrast those to HPV changes with koilocytic
Table 17.7 The most common subtypes of benign reactive cellular changes
Inflammation and repair (Fig. 17.15a–e) Radiation IUD
Cytoplasmic Cytoplasmic vacuolization Cytoplasmic Vacuolization
changes Polychromasia vacuolization Glandular cells present singly or in small
Perinuclear halos Polychromasia clusters
Increased N/C ratio Large bizarre cells Small dark cells with scant cytoplasm
“Spiderlike” metaplastic reactive cells Normal N/C ratio Increased N/C ratio
Cohesive sheets in the “school of fish” pattern Fig. 17.15f
Cytoplasmic boundaries well defined
Nuclear changes Binucleation Multinucleation Wrinkled, degenerated chromatin
Prominent single or multiple nucleoli Prominent nucleoli Prominent nucleoli
Enlargement
Non-overlapping
Smooth chromatin with mild hyperchromasia
Smooth nuclear borders
Background Inflammation may be seen Calcifications
Actinomyces
Differential Nonkeratinizing SCC Herpes cytopathic Adenocarcinoma
diagnosis Endocervical adenocarcinoma effect HSIL
LSIL
Recurrent carcinoma
smears [37]. When e xuberant, such changes pose a diag- 17.6.1.4 G landular Cell Status Post
nostic challenge and can mimic premalignant and malig- Hysterectomy
nant conditions (Table 17.7). Benign-appearing glandular cells can be seen in approximately
Lymphocytic (follicular) cervicitis is a subtype of chronic 2% of vaginal Pap smears in women after hysterectomy. The
cervicitis characterized by the presence of mature lymphoid findings are more common in women with the history of radia-
follicles. In addition to the above inflammatory reactive tion therapy compared to women with hysterectomy alone. It is
changes, numerous t lymphoid cells with tangible body mac- postulated that those glandular cells r epresent therapy-induced
rophages are seen in those Pap smears [38]. metaplasia of squamous epithelium [39].
a b
c d
e f
Fig. 17.15 Reactive changes/repair (SurePath, Papanicolaou stain). (600×). (d) Compare with atypical repair showing a cluster with some
(a) Cluster of intermediate cells mixed with neutrophils showing anisonucleosis, nucleoli, and coarser chromatin (400×). (e) Tight
enlarged nuclei with nucleoli. However, nuclear boarders are smooth, inflammatory perinuclear white halos present in this reactive cluster of
and cells show no significant overlap or anisonucleosis (400×). (b) intermediate cells. Multinucleated endocervical cell. Cluster of colum-
Reactive metaplastic cells showing increased N/C ratio and “school of nar cells, one with two nuclei, enlarged nuclei with coarser chromatin,
fish” appearance (600×). (c) Changes consistent with repair. Cells with smooth nuclear borders, and non-overlapping cells (600×). (f) Reactive
enlarged nuclei but very prominent nucleoli and smooth nuclear board- glandular cells associated with IUD. Cells show nuclear enlargement,
ers. Neutrophils are admixed with cells and cells are non-overlapping nucleoli and cytoplasmic vacuolization (400×)
17.6.1.5 Organism-Related Nonneoplastic mended that benign-appearing endometrial cells be

Changes reported in women ≥40 years of age. This increased
Organism-related nonneoplastic changes include specific reporting of benign-appearing endometrial cells resulted
morphological cellular changes associated with microorgan- in a decreased predictive value for endometrial cancer.
isms as well as identification of organisms. Cervical cytol- Since 2001, there had been little evidence to support endo-
ogy has a relatively high specificity for some organisms. metrial cancer detection in women under 45 years of age.
While fungal and parasitic organisms can be seen and identi- The 2014 Bethesda System recommends the report of
fied themselves, specific viral cytopathic changes are indica- benign-appearing endometrial cells in women ≥45 years
tive of particular viral infection. The most commonly seen of age to increase the positive predictive value and to
organisms and the accompanied cytomorphologic changes reduce unnecessary endometrial biopsies. In fact, the 2012
are described in Table 17.8. ASCCP management guidelines recommend that endome-
trial biopsy evaluation should be done only in postmeno-
17.6.1.6 Others pausal women [40].
The presence of endometrial cells in postmenopausal Cytologically benign endometrial cells should be reported
women is considered abnormal and often raises the con- in women aged 45 or older. In a smear that is otherwise nega-
cern of endometrial neoplasm. Since 1988 reporting of tive for intraepithelial lesions, the report should include both
benign-appearing exfoliated endometrial cells in post- endometrial cells present in a woman ≥45 years of age and
menopausal women was recommended by The Bethesda negative for intraepithelial lesion. In a smear that shows epi-
System. However, this recommendation was not always thelial cell abnormalities, the report should include the par-
easy to follow due to unclear, inaccurate, or unknown ticular epithelial abnormality (such as ASC-US, LSIL, HSIL,
menopausal status to the laboratory and the large varia- or others) and endometrial cells present in a woman
tions in age. Therefore, the 2001 Bethesda System recom- ≥45 years of age.
Table 17.8 Nonneoplastic findings in related organisms

Bacterial
Trichomonas vaginosis Actinomyces
(Fig. 17.16b) Candida (Fig. 17.16a) (Fig. 17.16c) (Fig. 17.16d) Herpes (Fig. 17.16e) CMV
Organism Pear shapes Small uniform Small Tangled clumps
itself pale 15–30 μm budding yeast coccobacilli of filamentous
Vesicular 3–7 μm adhered to the organisms
eccentrically Pseudohyphae squamous cells “Cotton balls”
located nucleus without true Radial
Eosinophilic septations but with distribution of
granules complete filaments
Flagella rarely constriction
seen
Cellular Perinuclear Spearing of “Clue cells” Ground-glass Cellular and
changes halos squamous cells appearance of nuclear
along the multinucleated nuclei enlargement
pseudohyphae with peripheral Large
“Shish kebab” effect margination of eosinophilic
chromatin intranuclear
Dense eosinophilic inclusions with
intranuclear inclusions prominent halo
with clear halo Small cytoplasmic
“Cowdry” inclusions basophilic
inclusions
Affects
endocervical and
stromal cells
Background Three- Neutrophils Large number of Neutrophils
dimensional neutrophils and adhered to
clusters of absence of microcolonies of
neutrophils lactobacilli organisms
“Poly-balls” “Clubs”
Neutrophils
a b
c d
Fig. 17.16 Specific organisms (SurePath, Papanicolaou stain). (a) Bacterial vaginosis: coccobacilli adhered to the surface of superficial
Candida: clustered superficial and intermediate cells that appear to be cell in relatively clean background. Features are suggestive of bacterial
speared by pseudo-hyphal elements of Candida giving it appearance of vaginosis and shift in vaginal flora (400×). (d) Actinomyces: cluster of
kebab (600×). (b) Trichomonas: pear-shaped organism presents bacteria with thin filaments at periphery (600×). (e) Herpes; multinucle-
between superficial cells showing small nucleus and eosinophilic gran- ated cell with intranuclear eosinophilic inclusions consistent with
ules. Some organisms are adhered to the cytoplasm of the cells and are “Cowdry B-type” inclusions (400×)
recognized by presence of cytoplasmic red granules (600×). (c)
17.7 A
typical Squamous Cells tive of HSIL. Within ASC, greater than 90% of cases should
and Squamous Intraepithelial Lesions be ASC-US and less than 10% should be ASC-H. Compared
to ASC-US, ASC-H has a higher predictive value for the
17.7.1 Atypical Squamous Cells diagnosis of HSIL (47, 48). Positivity for HR-HPV in ASC-H
is as high as that in HSIL cytology [45].
When we talk about atypical cells in cytology in general, we It should be emphasized that cytology interpretation is
usually refer to a set of morphological changes that do not fit based on the entire specimen instead of single cells.
into clearly defined categories. It is important to define the
“atypical” category as precisely as we can to avoid the over- 17.7.1.1 A typical Squamous Cell
use of the term to avoid potential overtreatment or treatment of Undetermined Significance
delay. (ASC-US)
Historically the term “atypia in squamous epithelium” Squamous cell changes that are suspicious for but quantita-
encompassed a wide spectrum of changes including “inflam- tively or qualitatively do not fulfill the criteria for LSIL are
matory atypia, “reactive atypia,” “suspicious findings,” or classified as ASC-US. The ASC-US interpretation is influ-
findings of uncertain nature. In the 1988 and 1991 Bethesda enced by the quantity of the atypical squamous cells, the
Systems, the term atypical cells of undetermined signifi- degree of abnormalities, specimen preservation artifacts, and
cance (ASC-US) was used to define cellular changes that are clinical settings [46]. Cellular changes close to LSIL and
more marked than can be attributable to reactive changes, but atypical parakeratosis represent the most common situations
quantitatively or qualitatively fall short of a definitive diag- when an ASC-US interpretation is made (Table 17.9).
nosis of squamous intraepithelial lesion (SIL) [23, 41]. In the In reality, ASC-US lesion does not exist. The interpreta-
2001 Bethesda System, ASC was created to describe squa- tion of ASC-US is the result of the light microscopy capabil-
mous cell changes that suggest SIL but is qualitatively or ity and the pathologist’s interpretation ability. The ASC-US
quantitatively insufficient for a definitive interpretation of category represents the need for interpretation comfort zone
such [42]. for pathologists. When pathologists are afraid of missing
Although ASC is defined as cytologic changes suggestive SIL, the interpretation of ASC-US will increase. The fre-
of SIL, the ASC category usually can be associated with a quency of ASC-US interpretation can be reduced when the
wide spectrum of changes, including artifact, atrophy, pathologists’ experience increases.
inflammation, LSIL, HSIL, and even cancers. HSIL is identi- Morphological nuclear features of ASC-US include varia-
fied in cervical biopsies in about 10–20% of patients with an tion in nuclear size with nuclear enlargement no more than
ASC-US interpretation. While ASC diagnoses should not be three times the intermediate cell nucleus, mild hyperchroma-
overused, there is no ideal rate of ASC. However, it has been sia, and limited nuclear membrane irregularities. Most com-
suggested by expert panels that the rate should be kept to less mon cytoplasmic changes are dense orangeophilic cytoplasm
than 5% of all Pap cases. In a high-risk population, the ASC/ and koilocyte-like changes. Not all of those changes have to
SIL ratio should not exceed 3:1 [43, 44]. be present in a single Pap smear. One or more of those mor-
Due to its equivocal nature, some authors suggest remove phological features is sufficient for diagnosis of ASC-US
the ASC category. However, elimination of ASC category (Table 17.9).
would decrease the sensitivity of Pap test. Approximately
40–50% patients with an interpretation of ASC are infected
with the high-risk HPV. As the most frequent Pap test inter- Table 17.9 Definition and cytomorphologic criteria for ASC-US
pretation category, ASC is also the most common interpreta- ASC-US (Fig. 17.17a–e)
tion prior to a biopsy diagnosis of HSIL. There are several Definition Changes suggestive of but do not
fulfill the criteria of LSIL
reasons to keep the ASC category: (1) we need an interpreta-
Criteria 2.5–3× nuclear enlargement Fig. 17.17a
tion category to covey the equivocal cellular changes, (2) compared to intermediate cells
there is no clear-cut of cellular changes between interpreta- Variation in nuclear size Fig. 17.17a, b
tion categories, (3) ASC is not a new concept and has been Mild hyperchromasia without Fig. 17.17b
widely used, and (4) gynecologists are familiar with the granularity
interpretation of ASC-US. Limited irregularities of nuclear Fig. 17.17c
membranes
ASC is further separated into atypical squamous cells of
Vacuoles resembling koilocytes
undetermined significance (ASC-US) and atypical squamous but not well defined
cells-cannot exclude high-grade squamous intraepithelial Dense orangeophilic cytoplasm, Fig. 17.17e
lesion (ASC-H) [25]. This separation is necessary as most parakeratotic cells
ASC cases show changes more suggestive of LSIL, and a Presence of some but not all Fig. 17.17d
small proportion of ASC cases display features more sugges- HPV-related changes
a b
c d
Fig. 17.17 ASC-US (SurePath, Papanicolaou stain). (a) Single atypi- (d) Three atypical cells. Top one with enlarged, hyperchromatic, and
cal metaplastic cell with nucleus 2–3× of adjacent intermediate cell irregular nucleus. Middle one with binucleation and bottom one with
showing mild hyperchromasia, nuclear irregularity, and perinuclear increased N/C ratio but lacking other features such as hyperchromasia
clearing suggestive of HPV changes (600×). (b) Single atypical inter- and nuclear irregularities. Taken together features are suggestive but not
mediate cell with enlarged wrinkled and hyperchromatic nucleus quantitatively or qualitatively sufficient for the diagnosis of LSIL
(600×). (c) A group of superficial and intermediate cells showing mild (600×). (e) Atypical parakeratotic cells showing slight enlargement and
nuclear enlargement and nuclear membrane irregularities with coarser hyperchromasia as well as some anisonucleosis. Such findings are best
chromatin. Features are suggestive but not diagnostic of LSIL (400×). categorized as ASC-US as they do not fulfill all criteria for LSIL (400×)
17.7.1.2 C ytological Alterations that Should 17.7.1.4 C

ommon Patterns Classified as ASC-US
Be Left Out of the Category of ASC-US or ASC-H
The ASC-US interpretation should be reserved for cellular
abnormalities that are between clear-cut reactive/reparative Atypical Repair
process and definitive squamous intraepithelial lesion. The Reactive/reparative cellular changes secondary to injury man-
ASC-US interpretation should be avoided if the cellular ifest as flat sheets of cohesive epithelial cells showing nuclear
changes can be explained by a reactive process (some of streaming and nuclear enlargement with prominent nucleoli
these changes are listed below). (Fig. 17.15c). These cellular changes should belong to the
category of negative for intraepithelial lesion or malignancy.
• Mild nuclear enlargement in superficial and intermediate Sometimes, reactive/reparative changes can be extensive and
cells without the HPV-like changes, hyperchromasia, and exaggerated with unusual features such as cell discohesion,
nuclear membrane irregularities nuclear crowding, marked nuclear pleomorphism, and chro-
• Anucleated squames and parakeratotic cells with pyk- matin coarseness. In such cases, benign nature of those groups
notic small nuclei (Fig. 17.11) is in question, and distinction from SIL or carcinoma may be
• Focal nuclear enlargements in atrophic smears without difficult [47, 48] (Fig. 17.15d). However, such changes do not
significant hyperchromasia and nuclear membrane irregu- particularly resemble LSIL. With prominent nucleoli and
larities (Fig. 17.13c) mitoses, the changes may more likely mimic invasive squa-
• Immature metaplasia without anisonucleosis (Fig. 17.10c) mous carcinoma or adenocarcinoma. However, they are dif-
• Reactive changes with mild karyomegaly (Fig. 17.15b) ferent from invasive carcinoma due to the lack of necrotic
debris, the absence of numerous individual malignant cells,
and the lack of coarsely textured chromatin. Such cases show-
17.7.1.3 A typical Squamous Cells Cannot Rule ing features between typical reactive/reparative changes and
Out High Grade (ASC-H) carcinoma should be best subcategorized as “atypical repair”
ASC-H refers to cellular changes that are suggestive but are under a subgroup of ASC.
not diagnostic of HSIL. ASC-H cells are usually sparse, Although morphologically similar, atypical and typical
small, and sometimes difficult to detect. The most common repair differ considerably in cell arrangements, presence or
two morphological patterns of ASC-H are small cells with absence of pleomorphism, nuclear changes, and mitotic
high N/C ratio/atypical immature metaplasia and small activity (Table 17.11).
crowded cells (Table 17.10).
Atypia with Atrophy
Atypia associated with atrophy has long been recognized as
Table 17.10 Morphological patterns and differential diagnosis of a diagnostic dilemma [49]. This is because parabasal cells in
ASC-H atrophy have higher nuclear to cytoplasmic ratio than inter-
Morphological mediate cells and may show slight hyperchromasia. Mild
patterns of ASC-H Cytologic features Differential diagnosis nuclear enlargement without significant hyperchromasia and
Small cells with Single or small groups Isolated nuclear pleomorphism has been considered “postmeno-
high N/C ratio or of fewer than ten cells endocervical cells
pausal atypia” (Fig. 17.13c). The presence of rare enlarged
“atypical Size of the cells is Degenerated
immature similar to that of endometrial cells and pleomorphic nuclei is typical for atrophic smear and
metaplasia” metaplastic cells Macrophages should not be overcalled as ASC. Such cases usually test
(Fig. 17.18a–c) Nuclei are 1.5–2.5 times IUD changes negative for HR-HPV. Indeed, squamous atypia in post-
larger than those of Postpartum decidua
menopausal women is less often associated with a biopsy-
metaplastic cells
Some cells show nuclear proven SIL than in a premenopausal woman [50]. ASC or
irregularities and ASC-H associated with atrophy should be reserved for cases
hyperchromasia with where SIL or HSIL is seriously considered. ASC is consid-
coarse chromatin
ered when nuclear hyperchromasia, irregular nuclear con-
Morphological Aggregate of cohesive Reactive or
patterns of overlapping cells neoplastic tour, coarse and irregular chromatin distribution, and marked
“small crowded Irregular nuclear borders endocervical cells nuclear pleomorphism are seen in atrophic smears [51].
cells” May resemble a Atrophy with crush
(Fig. 17.18d) glandular pattern artifact Atypical Parakeratosis
(Fig. 17.13d)
Marked radiation Atypical parakeratosis must be distinguished from benign
atypia parakeratosis (a form of a benign reactive change). While
Artifactual layering benign parakeratotic cells are arranged in small clusters with
of the cells small round degenerative-appearing nuclei and orangeo-
a b
c d
Fig. 17.18 ASC-H (SurePath, Papanicolaou stain). (a) Isolated single with increased N/C ratio and scant cytoplasm. Features of HSIL are
cell that appears significantly smaller than surrounding cells, with high present; however quantitatively only those two cells were identified as
N/C ratio and small rim of dense cytoplasm, nuclear coarse chromatin, atypical, and therefore diagnosis of ASC-H is best suited (400×). (d)
and nuclear membrane irregular. Findings are suggestive for HSIL Crowded sheet pattern of ASC-H showing cohesive overlapping cells
however quantitatively insufficient for definitive diagnosis (400×). (b) with high N/C ratio, slightly hyperchromatic, and some with irregular
Single cluster of cells with high N/C ratio, wispy scant cytoplasm, and boarders. Such clusters can be seen in atrophy or reactive changes.
anisonucleosis with one prominent large nucleus with coarser chroma- Follow-up biopsy on this 47-year-old women showed HSIL (600×)
tin but relatively smooth nuclear boarders (600×). (c) Two small cells
philic cytoplasm, atypical parakeratotic cells are arranged in rent understanding of HPV infection biology. While LSIL
three-dimensional clusters with larger hyperchromatic and represents HPV production stage and is usually due to a tran-
irregular nuclei with increased N/C ratio [52]. However, the sient infection, HSIL represents a precancerous lesion. The
atypia and the N/C ratio fall short of LSIL due to lack of major goal of cervical cancer screening is to detect and treat
definitive features of HPV-associated changes. In such cases, HSIL. This two-tiered system has been widely adopted. In
it is appropriate to interpret the changes as ASC-US if the 2012, the Lower Anogenital Squamous Terminology (LAST)
changes are suggestive of LSIL and ASC-H and if the Standardization Consensus Conference also recommended a
changes suggest HSIL [53] (Fig. 17.17e). two-tiered histopathologic nomenclature with a single set of
diagnostic term for all HPV-associated preinvasive squa-
mous lesions of the lower anogenital tract regardless of
17.7.2 Intraepithelial Lesion anatomic site and regardless of gender. This histopathology
nomenclature mirrors the Bethesda cytology reporting for
The Bethesda System uses the two-tiered system for report- SIL [54]. This two-tiered histopathologic nomenclature in
ing cervical cytology: LSIL and HISL. This reflects our cur- the anogenital tract may be further qualified with appropriate
Table 17.11 Morphological differences of typical and atypical repair Table 17.12 Morphological features of LSIL
Morphological features of typical and atypical repair Morphological features of LSIL
Atypical repair Usually in superficial Large size Fig. 17.19a, b
(Fig. 17.15d) Typical repair (Fig. 17.15c) or intermediate Mature with well-defined
Cell Sheets with crowding Cohesive flat sheets with squamous cells cytoplasm
arrangement and overlapping no overlapping and (Fig. 17.20a–e) Nuclei > than 3× that of Fig. 17.19a, b
crowding normal intermediate cells
Discohesion with No single cells Slightly increased N/C
single cells ratio
Steaming Loss of nuclear Nuclear streaming Hyperchromatic or Fig. 17.19a, b
streaming and “School of fish” normochromatic nuclei
polarity arrangement Keratotic cells with Fig. 17.19c
Pleomorphism Marked Mild to moderate enlarged nuclei
pleomorphism of pleomorphism of nuclei Anisonucleosis
nuclei No nucleoli
Nuclei Large nucleoli Large nucleoli HPV-related changes Sharply delineated large Fig. 17.19d
Coarse chromatin Pale evenly distributed irregular perinuclear
chromatin clearing (koilocytic
Mitosis Mitoses Mitosis change) associated with
the enlarged and/or
binucleated nucleus
–IN terminology. –IN refers to the generic intraepithelial
neoplasia terminology, without specifying the location. For a
specific location, the appropriate term should be used. For a From time to time, pathologists may encounter cases
–IN3 lesion, for example, CIN3 is used for cervical lesion, showing features of LSIL and also a few cells suggestive of
AIN3 for anal lesion, VIN3 for vulvar lesion, PeIN3 for HSIL. Since 2001, there have been literatures suggesting the
penile lesion, VaIN3 for vaginal lesion, and PAIN3 for peri- use of an intermediate category (LSIL-cannot exclude HSIL,
anal lesion. LSIL-H) to handle cases with such changes. The risk of
HSIL found in these cases was between typical LSIL and
17.7.2.1 L ow-Grade Squamous Intraepithelial typical HSIL. Subsequently, the issue was submitted to
Lesion (LSIL) online open discussions, and a decision was made to limit
LSIL includes koilocytes and CIN1. LSIL is most commonly terminology to LSIL and HSIL. There are several reasons for
seen in intermediate or superficial cells. The classical fea- such decisions: (1) LSIL-H is an intermediate category, (2)
tures of LSIL were described by Reagan and Hamonic in the management guideline applies to LSIL and HSIL, (3)
1956 and are included in Table 17.12 [55]. disease biology does not support the intermediate category,
Although perinuclear halo is frequently seen in LSIL, the (4) LSIL-H has poor reproducibility, (5) LSIL-H may be
diagnosis of LSIL does not require the presence of a perinu- overused, and (6) the use of LSIL-H can cause confusion to
clear halo. Also, an interpretation of LSIL cannot be made in clinicians. The 2014 Bethesda System recommends the
cells showing only perinuclear halo without the typical interpretation of both LSIL and ASC-H when a smear shows
nuclear features of LSIL. Nuclear changes are the basis of definitive LSIL and a few cells suggestive of HSIL. There are
LSIL. also other options: (1) report LSIL and comment the possi-
bility of HSIL, and (2) report ungradable SIL and specify
17.7.2.2 H igh-Grade Squamous Intraepithelial reason for such in the comment. These should represent a
Lesion (HSIL) small proportion of cases as most cases should be separated
HSIL is a precancerous lesion and includes CIN2 and CIN3. into either LSIL or HSIL. In general, the management of
In high-grade lesions, the overall size of the cells is reduced LSIL and ASC-H is the same. In younger women, however,
compared to LSIL, but nuclear to cytoplasmic ratio is greatly the addition of ASC-H in the pathology report will result in
increased due to minimal cell differentiation. Two major pat- colposcopy.
terns of HSIL can be seen: individual small cells with high
N/C ratio (Fig. 17.20a, b) and syncytial clusters of dysplastic Differential Diagnosis and Problematic
cells (Fig. 17.20c). Syncytial hyperchromatic groups are Patterns of HSIL
more prominent and are easier to spot, while single dysplas- There are mimickers of HSIL. Different patterns in HSIL
tic cells can be overlooked during routine screening due to may generate a different set of differential diagnosis. For
their small size. In both patterns, nuclei are hyperchromatic example, HSIL in small hyperchromatic crowded groups
with coarse chromatin and irregular nuclear membranes. should be differentiated from immature squamous metapla-
Mitoses can be observed in syncytial clusters (Table 17.13). sia, atrophy, endometrial cells, and tubal metaplasia. While
a b
c d
Fig. 17.19 LSIL (SurePath, Papanicolaou stain). (a) Binucleated and can be seen in HPV-associated lesions. Keratinizing cells showing
enlarged irregular nuclei, more than three times of intermediate cell nuclear abnormalities and increased N/C ratio should be categorized
nuclei and coarse chromatin. Less prominent koilocytic change with according to degree of abnormality. Increase in nuclear size and nuclear
some cytoplasmic clearing and condensation of cytoplasm at periphery irregularities in addition to presence of a classic koilocyte supports the
(600×). (b) Disproportionally large cells with multiple nuclei. Nuclear diagnosis of LSIL. Compare with Fig. 17.17e (400×). (d) HPV cyto-
chromatin does not always have to be coarse and in this case is “washed pathic effect consisting of clear perinuclear halo,“koilocyte” with
out” and pale; however multinucleation, irregular shapes of nuclei, and nuclear enlargement, coarse chromatin, and nuclear membrane irregu-
large size of this cell are consistent with HPV changes (600×). (c) larities (600×)
Parakeratotic cells with slightly increased size of hyperchromatic nuclei
increased nuclear to cytoplasmic ratio can be seen in any of coarseness of chromatin, absence of nucleoli, and quality
the HSIL mimickers, marked nuclear membrane irregulari- and amount of cytoplasm should be helpful clues
ties, coarse chromatin with significant anisonucleosis, over- (Table 17.15).
lap and nuclear crowding, and atypical mitotic figures are the
major hallmarks of HSIL (Table 17.14). HSIL with Endocervical Gland Involvement
Single HSIL cells should be differentiated from mimick- Colonization of endocervical glands by HSIL poses a diag-
ers with a similar pattern. These may include immature squa- nostic problem in cervical smears. Such architectural
mous metaplasia, isolated atrophic cells, inflammatory cells, arrangement of HSIL within endocervical glands can mimic
decidualized stromal cells, and isolated endocervical cells. atypical and malignant glandular lesion such as AIS and
The morphological features of those atypical single cells adenocarcinoma. Clues to recognizing the squamous nature
mimickers with high nuclear to cytoplasmic ratio are some- of the lesion include spindling of the cells in the central
times even more difficult to discern from features of HSIL areas of cellular clusters and flattening of the nuclei at the
than when atypical cells are in syncytial group; however, periphery.
a b
Fig. 17.20 HSIL (SurePath, Papanicolaou stain). (a) Low power view in Figure b. showing cells with large, hyperchromatic and irregular
of cluster of seven cells that appears smaller than the rest of the smear nuclei with coarse chromatin consistent with HSIL (400×). (c) Crowded,
but with extremely high N/C ratio (100×). (b) High power of the cluster hyperchromatic pattern of HSIL arranged in syncytial group (400×)
Table 17.13 High-grade squamous intraepithelial lesion (HSIL) syncytial aggregates of malignant cells with large nuclei,
Morphological features of HSIL coarse chromatin with chromatin clearing, and prominent
Immature Usually smaller parabasal-sized Fig. nucleoli. Tumor cells are usually surrounded by a back-
squamous or cells 17.20a ground of blood and necrotic debris often referred to “dirty
parabasal cells Single discrete cells or Fig.
background” or tumor diathesis (Fig. 17.23a–c). Cervical
syncytium-like groups 17.20b
Nuclear changes Enlarged nuclei Fig.
smears with keratinizing squamous cell carcinomas contain
High N/C ratio 17.20a, b less prominent “dirty background” and usually show single
Marked nuclear contour with malignant cells of different shapes and sizes including
irregularities of nuclear “tadpole-shape” (Fig. 17.23d). Tumor cells in keratinizing
membranes
Marked hyperchromasia
squamous cell carcinoma often show orangeophilic cyto-
Marked chromatin coarseness plasm and large irregular markedly hyperchromatic nuclei
Mitoses Present usually with inconspicuous nucleoli (Table 17.16).
17.8 Squamous Cell Carcinoma 17.9 A

typical Glandular Cells
and Intraepithelial Glandular Lesion
Squamous cell carcinoma of the cervix can be morphologi-
cally divided into keratinizing and nonkeratinizing types. The cervical smear was generally used for detection of squa-
Nonkeratinizing carcinoma is more common and usually mous lesions. Glandular lesions are now attracting more
produces very cellular smear consisting of loose sheets and attentions due to better collection devices that are able to
Table 17.14 Differential diagnosis of small hyperchromatic crowded groups

Benign endometrial
Immature squamous cells: exodus and
HSIL metaplasia (Fig. 17.22a) Atrophy (Fig. 17.21b) exfoliated Tubal metaplasia
N/C ratio Variable to very High N/C Lower N/C ratio N/C ratio varies Increased N/C Increased
ratio compared to HSIL Can be increased ratio
Nuclear Marked nuclear Smooth nuclear Nuclear membrane Smooth Smooth
membrane membranes irregularities membranes irregularities can be
(Fig. 17.22b) present
Chromatin Coarse chromatin Bland chromatin Chromatin with Bland to mildly Bland
May be normochromatic or degenerated coarse
pale appearance
Nucleoli No nucleoli May have nucleoli Usually no nucleoli May have small Present
nucleoli
Cellular Single cells or syncytial Flat arrangement of Single cells or flat Exodus or Crowded groups
arrangement arrangement (Fig. 17.20b, polygonal cells sheets of cells crowded groups with parallel nuclear
c) arrangement
Nuclear Nuclear crowding is Nuclei are evenly No nuclear Nuclear crowding Mild nuclear
crowding usually seen when in distributed without crowding can be seen overlapping can be
groups (Fig. 17.20c) overlapping or seen
crowding
Mitoses Present Usually no mitosis Not seen Present Usually no mitosis
Anisonucleosis Present Not seen Mild nuclear Not seen Mild nuclear
variation may be variation may be
seen seen
a b
Fig. 17.21 HSIL vs. atrophy (SurePath, Papanicolaou stain). (a) shows slightly overlapping cluster of smaller cells with hyperchromatic
Cluster shows overlapping cells with increased N/C ratio and anisonu- nuclei with smooth boarders, slight anisonucleosis. N/C ratio is not as
cleosis, coarse chromatin, irregular nuclear boarders, and mitotic high; changes are consistent with atrophy (400×)
figures consistent with syncytial pattern of HSIL (600×). (b) Cluster
obtain endocervical cells, increased awareness, and increased reactive cellular changes of endocervical cells share some
incidence of adenocarcinoma. morphological features of AGC and can be difficult to dif-
Atypical glandular cells (AGC) refer to cellular changes ferentiate. Glandular extension of HSIL also can mimic AGC
that fall between definitive benign reactive process and and accounts for about 30% of women referred to colpos-
unequivocal AIS or adenocarcinoma [56–58]. Glandular cel- copy for AGUS diagnosis [44].
lular abnormalities are considerably less common than squa- Cytological features of AGC are related to underlying his-
mous type, and the AGC diagnosis should represent less than tological abnormality and the origin of atypical glandular
1% of all cervicovaginal smears. Even though AGC should cells. The most common underlying lesion associated with
be reserved for changes in which the diagnosis of AIS or the interpretation of AGS is squamous intraepithelial lesions
adenocarcinoma was seriously considered, it is still a chal- (including low- and high-grade lesions), followed by benign
lenging diagnosis for many cytopathologists [59]. Marked lesions (such as polyps and microglandular hyperplasia) and
a b
Fig. 17.22 HSIL vs. squamous metaplasia (SurePath, Papanicolaou ers (600×). (b) Compared to similar cluster of cells, however, nuclei are
stain). (a) Cluster of cells with slightly increased N/C ratio, dense cyto- larger, nuclear boarded irregular, and coarser chromatin (600×)
plasm and fine, smudged chromatin, and smooth regular nuclear board-
Table 17.15 Differential diagnosis of HSIL and single cells

Differential diagnosis of HSIL and single cells
HSIL Immature squamous Isolated atrophic cells Inflammatory cells Decidualized Isolated endocervical
metaplasia vs. HSIL vs. HSIL (Fig. 17.22b) vs. HSIL stromal cells vs. cells vs. HSIL
(Fig. 17.22b) HSIL
Small cells Small cells Small cells Small cells Large cells Small cells
High N/C ratio High N/C ratio High N/C ratio High N/C ratio Usually low N/C Low N/C ratio
ratio
No nucleoli May have Nucleoli No nucleoli May have nucleoli Nucleoli Nucleoli
Coarse Fine chromatin Degenerated May show coarse Smudged chromatin Normochromatic
chromatin chromatin, smudgy granular chromatin
Irregular nuclear Smooth nuclear borders Regular nuclear Usually smooth Usually smooth Smooth nuclear
borders, grooves borders nuclear membranes nuclear membranes membranes
Scant cytoplasm Moderate amount of blue Scant cytoplasm Usually abundant Granular cytoplasm Vacuolated cytoplasm
cytoplasm cytoplasm
then adenocarcinoma in situ (AIS) and invasive adenocarci- Category of AGC-favor neoplastic includes the diagno-
noma [60]. sis in which some but not all the features of AIS is present.
AGC can be further subclassified as “not otherwise speci- Nuclear feathering is one of the crucial features of AIS, and
fied” or “favor neoplastic” depending on the severity of mor- when not present AIS cannot be confidently diagnosed in
phological changes present. AGC can also be classified as cervical smears.
AGC-NOS, AGC-endocervical, and AGC-endometrial based
on the particular changes present. In cases interpreted as
AGC-favor neoplastic, the cytological abnormalities are 17.10 Adenocarcinoma
more pronounced quantitatively and qualitatively and par-
tially overlap with features of adenocarcinoma in situ Invasive adenocarcinoma should be subclassified as endo-
(Fig. 17.24a–cb, Table 17.17). AIS typically shows groups of cervical or endometrial origin whenever it is possible.
cells in rosette formations with crowding and feathering of However, such distinction may not be possible because of
nuclei. Nuclei are elongated with coarser chromatin but the overlapping morphological features. Adenocarcinoma
without conspicuous nucleoli (Fig. 17.24dc). There is cells from both endocervical and endometrial origin contain
increased N/C ratio. If some but not all these characteristics enlarged nuclei with prominent nucleoli and coarsely
are present, the changes can be interpreted as AGC-favor clumped chromatin (Fig. 17.25a–d). Morphological features
neoplastic (Table 17.17). Pap test detects only 38–50% of of invasive adenocarcinoma, nonkeratinizing SCC, and
AIS, and only 1.1–4.7% of women diagnosed with AGC HSIL colonizing the glands can overlap and are delineated
have biopsy-confirmed AIS [61, 62]. in Table 17.18.
a b
c d
Fig. 17.23 Invasive squamous carcinoma (SurePath, Papanicolaou nonkeratinizing squamous cell carcinoma (600×). (c) Keratinized squa-
stain). (a) Cluster of cells with features of HSIL and adjacent tumor mous cell carcinoma showing a large keratinized cluster of cells
diathesis. Findings are suggestive of nonkeratinized squamous cell car- admixed with necrotic debris (600×). (d) High power shows atypical
cinoma (400×). (b) Syncytial cluster of cells with highly pleomorphic keratinized and nonkeratinized cells including “tadpole” cells with
cells, coarse chromatin, irregular nuclear boarders, and marked overlap. hyperchromatic irregular nuclei and elongated cytoplasmic “tail”
Marked anisonucleosis with other features of HSIL raises a concern for (600×)
Table 17.16 Morphological features of keratinized SCC, nonkeratinized SCC, and HSIL
Keratinized SCC Nonkeratinized SCC HSIL
Cell Cells are predominantly isolated, Single or in aggregates with poorly defined Single or in syncytial aggregates
arrangement less often in aggregates cytoplasmic boarders
Cell size Marked variation Mostly smaller cells compared to keratinizing Small cells
squamous cell carcinoma
Cell shape Caudate and spindle-shaped cells Round to elongated cells Usually round cells
are seen
Cytoplasm Dense orangeophilic Wispy scant cytoplasm with indistinct boarders Delicate bluish cytoplasm
Nuclei Irregular, multinucleated Markedly irregular nuclear borders Markedly irregular nuclear
borders
Coarse irregular chromatin with Coarse irregular chromatin with chromatin clearing Coarse irregular chromatin
chromatin clearing
Nucleoli Less common than in Often present and may be prominent Inconspicuous
nonkeratinized ca
Tumor Less common than in Often present Not present
diathesis nonkeratinized carcinoma
a b
Fig. 17.24 AGUS (SurePath, Papanicolaou stain). (a) Atypical endo- of endocervical cells showing enlarged nuclei and prominent nucleoli
cervical cells show nuclear enlargement, some prominent nucleoli and (600×). (c) Endocervical AIS - Pseudostratified cluster with enlarged
a sheetlike arrangement (400×). (b) Crowding and overlapping pattern elongated and hyperchromatic nuclei suggestive of “feathering” (600×)
Table 17.17 Morphological features of reactive glandular cells, AGC, and AIS
Morphological features of benign reactive glandular changes, AGC, and AIS
Benign reactive AGC “not otherwise specified” AIS (Fig. 17.19d)
Glandular changes (Fig. 17.19a–cb)
Cellular Sheets and strips Small to large tissue fragment Small to large tissue fragment
arrangement Honeycomb if in sheets No honeycomb arrangement Syncytial arrangement
Crowding Usually no nuclear crowding or nuclear Variable nuclear crowding and Obvious nuclear crowding and
overlap overlapping overlapping
Vertical orientation of cells at
periphery
Feathering No No Yes
Nuclei Rounded to oval Rounded to oval Coarse granular Oval to elongated nuclei,
Mild variable hyperchromasia chromatin “cigar-shaped”
Nucleoli may be present Nucleoli may be present Marked hyperchromasia
No nucleoli
N/C ratio Slightly increased N/C ratio Variable increase in cell size and N/C Markedly increased N/C ratio
ratio
Cytoplasm Adequate volume of cytoplasm Cytoplasm scant to moderate Cytoplasm scant
Mitoses Absent Mitoses may be present Frequent mitoses
a b
c d
Fig. 17.25 Adenocarcinoma (SurePath, Papanicolaou stain). (a) Tight cells with prominent nucleoli are seen at the periphery of the cluster,
tridimensional cluster of glandular cells with enlarged nuclei, promi- endometrial adenocarcinoma (600×). (d) Irregular cluster of cells with
nent nucleoli, and coarse chromatin. Patient with endometrial serous high N/C ratio, with coarse chromatin, and some with prominent nucle-
carcinoma (600×). (b) Cluster of glandular cells with wispy cytoplasm oli. Cells at the periphery retained columnar shape, endocervical adeno-
and large nuclei with prominent nucleoli, endocervical adenocarcinoma carcinoma (600×)
(400×). (c) Three-dimensional cluster with a grape-like structure. Large
small-cell carcinoma of the cervix is similar to its counterpart

17.11 Other Malignant Tumors in the lung. Pap smear may show clusters of small cells with
high N/C ratio, hyperchromatic nuclei with salt and pepper
Malignant neoplasms, other than primary adenocarcinoma or chromatin, scanty cytoplasm, nuclear molding, frequent mitotic
squamous cell carcinomas, are less commonly detected in the figures, apoptotic bodies, nuclear smearing artifact, and tumor
cervicovaginal smears. These malignancies include primary diathesis [63, 64]. Small-cell carcinoma can be confused with
cervical, vaginal, and endometrial tumors as well as metastatic follicular cervicitis on cytology; however, follicular cervicitis is
tumors. Several most common types are presented below. characterized by the presence of lymphocytic cells with lym-
phoglandular bodies and without the characteristic features of
small-cell carcinoma.
17.11.1 Small-Cell Carcinoma
Small-cell carcinomas of the cervix are rare, and they are 17.11.2 Malignant Melanoma
aggressive malignancies that occur in a wide age range and are
usually asymptomatic in the early stage. Small-cell carcinoma Up to 5% of malignant melanomas in women occur in the
is commonly associated with HPV type 18. Morphologically, gynecologic tract. Although the most common site is vulva,
Table 17.18 Differential diagnosis for endocervical and endometrial adenocarcinoma

Endometrial
Endocervical adenocarcinoma adenocarcinoma Nonkeratinized SqCC HSIL colonizing glands
Cellularity Abundant Sparse Abundant Not too many
Cell type Columnar, larger Cuboidal, smaller Pleomorphic, larger Squamous, smaller
Cell Single Single Single Syncytial clusters
arrangement Two- and three-dimensional Small tight three- Syncytial aggregates with Flattening of the cells at
clusters, rosettes, feathering dimensional clusters, poorly defined cell boarders the edge
Syncytial aggregates balls Loss of central polarity
Loss of polarity
Nuclei Enlarged, elongate, pleomorphic, Smaller, round Markedly enlarged Markedly enlarged
larger
Coarse irregular dark chromatin Coarse irregular pale Coarse, clumped chromatin Coarse, clumped chromatin
chromatin
Irregular membranes Irregular membranes Irregular membranes Irregular membranes
Nucleoli Macronucleoli present Small to prominent May be prominent Inconspicuous
Cytoplasm Finely vacuolated or granular, Very scant, basophilic, Moderate and often Scant
more eosinophilic, rare vacuolated amphophilic
neutrophils Neutrophils common
Mitoses Present Present Present Present
Tumor Present, coarse Present, watery Present, coarse Absent
diathesis
Associations SIL Risk factors, histiocytes SIL
melanomas can arise in the vagina and cervix. Melanomas be present but usually as a minor component [67]
are characterized by isolated or loosely cohesive cells that (Fig. 17.26c).
can be epithelioid or spindled with large nucleoli and cyto-
plasmic pigment [65] (Fig. 17.26a). 17.11.4.1 Metastatic Tumors
The most common metastatic tumors detected in Pap smears
are ovarian and fallopian tube serous adenocarcinomas. They
17.11.3 Non-Hodgkin Lymphomas have the usual cytological features of high-grade adenocarci-
noma including single cells or three-dimensional clusters of
Most cases of non-Hodgkin lymphomas in the cervix and large cells with irregular nuclear borders and prominent nucle-
vagina are seen in advanced stage of disease. Rarely, lym- oli. Psammoma bodies can be detected and are seen as lami-
phoma may arise as a primary tumor in the cervix or the nated dark blue calcifications on Papanicolaou stain. Tumors
vagina. Cytological samples may be negative if mucosa is not from the rectum, colon, bladder, and urethra can spread
involved. If mucosa is involved, the smears are usually cellular directly to the cervix or vagina [68]. Metastatic tumor can also
and are similar in morphology to lymphomas originating in be from as the breast, kidney, lung, and pancreas. When poorly
the lymph nodes. The major morphologic characteristics of a differentiated, such tumors exhibit large hyperchromatic
non-Hodgkin lymphoma include discohesive malignant cells malignant cells without any distinguishing features. It is
with high N/C ratio, prominent nucleoli, and mitotic activity important to recognize those as malignant, but specifying the
[66] (Fig. 17.26b). Lymphoglandular bodies may be seen. primary site may not be possible without clinical history,
Differential diagnosis includes follicular cervicitis, small- biopsy, and additional immunohistochemical stains.
cell carcinoma, and invasive nonkeratinized squamous cell
carcinoma.
17.12 Newly Developed Techniques
17.11.4 M
alignant Mixed Mesodermal 17.12.1 Automated Screening
Tumors
17.12.1.1 ThinPrep Imaging System (TIS) [69]
Malignant mixed mesodermal tumors usually occur in the The ThinPrep Imaging System (TIS) uses location-guided
uterine corpus. When detected by Pap smear, it mostly repre- screening to assist the cytotechnologist in reviewing
sents a tumor that has originated in the uterine body and has ThinPrep Pap slides.
extended to the cervix. Much of the tumor that sheds into the
cervix originates from the high-grade epithelial part of the Major components of the TIS are:
tumor and will have features of high-grade adenocarcinoma • Image processor for computer image analysis
or undifferentiated carcinoma. Malignant spindle cells may • Review Scope providing automated microscope location
a b
Fig. 17.26 Metastatic malignancies (SurePath, Papanicolaou stain). macrophages and lack of spectrum of maturation forms of lymphocytes
(a) Single large cells with prominent nucleoli and spiderlike cytoplas- indicate hematopoietic malignancy, large cell lymphoma, and primary
mic projections filled with brown pigment. Patient was diagnosed with uterine (600×). (c) Large multinucleated spindled cell with prominent
vaginal/cervical malignant melanoma (600×). (b) Numerous lymphoid nucleoli, primary rhabdomyosarcoma of the uterus (400×)
cells with scant cytoplasm in loose groups. Absence of tangible body
The image processor has three principal components: –– It holds 10 cassettes and each cassette can hold 25
• Image processor controller with internal server slides.
–– Comprised of computer and software to capture and –– It scans slides and selects 22 fields of view (FOV),
analyze the slide images as well as store the results of most likely to contain abnormal cells. FOV is based on
the analysis. optical density measurements and other features. The x
–– The server is the central data manager that stores, and y coordinates of the 22 FOV are stored in a data-
retrieves, and transmits information based on the slide ID. base that is retrieved later.
• Imaging processor • Computer user interface equipment
–– Is a tabletop unit with hardware used to image the cassettes –– Consists of the monitor, keyboard, and mouse that are
of previously stained and coverslipped ThinPrep slides. like those in a personal computer.
The Review Scope has three components: review.” Of slides requiring further manual review, it selects
• Microscope with automated stage. at least 15% for a second manual review. Slides classified as
• Twenty-two fields of view (FOV) are presented to the unsatisfactory for analysis must also undergo manual review.
reviewer by automatic slide movement. However, the BD FocalPoint Slide Profiler is not approved
• Manual review of the slide may also be performed. for screening women at high risk for cervical cancer. On
• An automated marking system allows the reviewer to evaluation in a clinical trial, the BD FocalPoint Slide Profiler
mark sites either physically or electronically for further detected significantly more abnormal slides (ASC-US or
review. greater) than regular practice (86% vs. 79%) [77]. BD
• The display unit is used to communicate with the reviewer. FocalPoint Slide Profiler archives about 16–17% of Paps as
• The pod is used to control the microscope. not requiring further review resulting in a modest gain in
• It is used by the cytotechnologist to navigate to the 22 productivity [77, 78].
FOV. It was in 2008 that the FDA approved the BD FocalPoint
• To navigate from one FOV to the next is done using the GS Imaging System which consists of the BD FocalPoint
shortest distance. Slide Profiler and a BD FocalPoint GS Review Station,
• Cytotechnologist can change objectives and advance or which uses location-guided screening to assist the cytotech-
return to FOV. nologist. The SurePath slide is first evaluated by the BD
FocalPoint Slide Profiler, which then uses algorithms to
If no abnormal cells are detected in any of the 22 FOV, the select ten fields of view (FOV) most likely to harbor abnor-
case can be reported as negative. If any abnormal cells are mal cells. These ten FOV are presented to the cytotechnolo-
found, the entire slide must be reviewed. gist at the Review Station. If no abnormality is detected in
Implementation of TIS has been found to increase pro- the FOV, the slide can be reported as negative with no further
ductivity [70, 71], since the 22 FOV represent about 25% of review. If any abnormality is found in the FOV, the slide
the screening area [72]. In addition, studies have shown that must undergo full manual review.
TIS detected more abnormal cases (including ASC-US or Evaluation of the BD FocalPoint GS Imaging System
more severe lesions) than manual review (82% vs. 76%) showed that detection of HSIL+ increased by 19.6% and of
[70]. Other studies have reported that TIS resulted in a higher LSIL+ by 9.6% in the computer-assisted arm, but there were
detection rate of LSIL and HSIL [73, 74]. significant decreases in specificity. The two study arms of
regular practice vs. computer-assisted screening were not
17.12.1.2 B
D (Becton Dickinson) FocalPoint GS statistically significant for sensitivity and specificity of
Imaging System [75] ASC-US+ [79]. The BD FocalPoint GS Imaging System also
Components of the BD FocalPoint GS Imaging System are: increases productivity [80].
• BD (Becton Dickinson) FocalPoint Slide Profiler

• BD FocalPoint GS Review Station 17.12.2 he Motivation Behind DNA-Based
T
Detection of HPV
The BD (Becton Dickinson) FocalPoint Slide Profiler,
previously known as the AutoPap System Primary Screener, Since high-risk HPV type (HR-HPV) is the only HPV type
was approved by the FDA in 1998 as a primary screening that causes HSIL and invasive carcinoma, all management
device for conventional smears and in 2002 was approved for guidelines recommend detecting HR-HPV types. However,
screening SurePath slides. most HR-HPV infection disappears spontaneously without
The BD (Becton Dickinson) FocalPoint Slide Profiler causing cancer. Most LSIL cases are also associated with
uses programmed algorithms from planimetry and optical HR-HPV, and LSIL does not indicate low-risk HPV.
micrometry to assess various morphologic cell parameters Nevertheless, testing for HR-HPV is very important compo-
like nuclear size, nuclear-cytoplasmic ratio, and nuclear con- nent of cervical cancer screening. Currently, there are at least
tour for diagnosing squamous and glandular lesions [76]. In 16 HR-HPV types including types 16, 18, 31, 33, 35, 39, 45,
this system, 288 slides can be loaded simultaneously for 51, 52, 56, 58, 59, 66, 68, 73, and 82. Among these, 16 and
screening (36 trays with 8 slides/tray). It screens slides per 18 together cause approximately 70% of all cervical cancers.
preset algorithms at 4× magnification for a visual map of the HPV 16 is more often associated with squamous lesions, and
entire slide. Subsequently, 1000 fields are captured at 20× HPV 18 is frequently seen in glandular lesions. Compared to
magnification. The system then assigns a score ranging from Pap test, testing for HPV is associated with higher sensitiv-
0.0 to 1.0 according to the probability of detecting abnormality, but lower specificity. Combined Pap and HPV testing
ity. Up to 25% of slides are deemed as needing “no further increases sensitivity but decreases specificity. Combined
testing has a very high negative predictive value (NPV). If HPV detections platforms for histological specimens have
HR-HPV is negative, risk of HSIL in 3 years is very low. been made [85, 86].
Almost all HSIL cases are seen in women with persistent Other biomarkers for HPV have been proposed, which are
HR-HPV infection. discussed in the relative section, but which are not currently
In the search for suitable platforms for clinical HPV used in the clinical setting.
detection, primarily in screening algorithms for cervical car-
cinoma, but also for prognostic and differential diagnostic
purposes in other squamous carcinomas, it has become evi- 17.12.3 ain Platforms for Molecular HPV
M
dent that DNA-based methods are currently the most suitable Testing
way of approaching this issue and has led to the development
of different platforms. In contrast to other viral infections, 17.12.3.1 Platforms for HPV DNA Detection
the use of other virological methods, such as culture in vitro Cobas® 4800 HPV Genotyping. The cobas® HPV test
culture and immunological methods, such as serology-based (Roche Molecular Diagnostics, Branchburg, NJ) is a qualita-
assays, is not suitable for HPV detection. This limitation is tive test, on a real-time PCR platform, that is approved by the
mainly associated with HPV infection natural history, but FDA to detect HPV in liquid cytology specimens. This test
also with characteristics of the HPV replicative circle: HPV specifically identifies 14 HR-HPV subtypes, including 16
infection and proliferation are tightly linked to the presence and 18. Results are reported as negative or positive for HPV
of well-differentiated squamous cell, with infection of lower 16, HPV 18, and for pooled “other” HR-HPV subtypes,
strata of the squamous epithelium and with capsid produc- which include types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66,
tion occurring in terminally differentiated squamous cells and 68.
[81]. This renders in vitro culturing of HPV difficult and not Hybrid Capture II. The Hybrid Capture II (HCII), avail-
suitable for clinical testing. While there are HPV infections able from Qiagen (Hilden, Germany; previously available
recognized in many mammalian species, there is a species- through Digene, Gaithersburg, MD), was the first FDA-
specific differentiation for all the different HPV types, mak- approved assay for HPV detection and employs a sandwich
ing the introduction of animal models problematic. Further, enzyme-linked immunosorbent assay (ELISA) platform.
the introduction of “viruslike particles” (VPLs) has not only The DNA of HPV, if present in the sample, hybridizes to a
aided in the production of HPV vaccinations but has also led series of HPV-specific RNA probes. The produced hybrid
to the development of serologic assays. Nonetheless, the pro- DNA-RNA molecules are then captured by proprietary anti-
duction of HPV antibodies happens in a subset of patients body. This is detected with the use of a second, peroxidase-
that have prolonged HPV infections and only in interval of conjugated antibody and a chemiluminescence substrate.
12–15 months after initial HPV infection [82]. Therefore, The emitted light is captured and measured by a luminome-
this kind of detection is incompatible with the purposes of a ter. This test can detect either low-risk HPV types (LR-HPV;
screening test and is moreover not suited for detecting HPV 6, 11, 42, 43, 44) or HR-HPV (16, 18, 31, 33, 35, 39, 45, 51,
infections that are acute. 52, 56, 58, 59, 68).
The importance of HPV genotyping is also reflected in Roche Linear Array (LA). This is a reverse line blot
the American Society for Colposcopy and Cervical Pathology assay for HPV genotyping, which is available commercially.
(ASCCP) for cervical cancer screening guidelines, as spe- Roche Linear Array is based on the aforementioned
cific HR-HPV type (HPV 16/18 vs. other) determine man- PGMY09/11 PCR system and detects 37 HPV types (6, 11,
agement of women who are HR-HPV positive [83]. 16, 18, 26, 31, 33, 35, 39, 40, 42, 45, 51, 52, 53, 54, 55, 56,
Testing for HPV status in formalin-fixed, paraffin- 58, 59, 61, 62, 64, 66, 67, 68, 69, 70, 71, 72, 73, 81, 82, 83,
embedded (FFPE) histological samples, mainly for prognos- 83, IS39, CP6108) (Roche Diagnostics, Pleasanton, CA).
tic reasons (but also as an aid in differential diagnosis), More in detail, the products of HPV PCR are created using
especially in head and neck squamous cell carcinomas, is biotin-labeled primers, which are hybridized to a type-
currently mainly done using either DNA in situ hybridization specific HPV probe-containing strip, and are then detected
(ISH) or p16 immunohistochemistry (IHC). Both these tests with the aid of streptavidin-conjugated horseradish peroxi-
have limitations, such as the fact that they are highly depen- dase, along with a chromogenic substrate.
dent on the experience of the pathologist, but are also labor Amplification (PCR)-Based Methods. One of the
intensive. In addition, HPV ISH has a relatively low sensitiv- advantages of PCR-based methods is the high analytical sen-
ity, and p16 IHC is not 100% specific for demonstrating sitivity; however, a limitation they face is that assays that are
HPV tumorigenesis as it is a surrogate marker of HPV infec- type-specific can only detect a specific HPV type or may be
tion and does not directly identify the presence of HPV [84, also other, closely related types, which make these less than
85]. More recently, efforts to validate the use of existing optimal for clinical testing. Despite the use of PCR-based
platforms mainly in Europe, there are no available PCR- quently hybridized to a set of types of specific beads [93] and
based HPV detection assays in the US market. Two well- attached to HPV type-specific probes. The beads that have
described examples can employ nondegenerate consensus HPV DNA hybridized to them are then labeled with
primers, used under low stringent amplification conditions, phycoerythrin-conjugated streptavidin which is detected by
such as the GP5/GP6 and GP5+/GP6+ primer set [87, 88], the Luminex 100 instrument. This assay has been validated
which detects a total of 27 HPV types, and the MY09/MY11 for clinical use for detection and genotyping of 37 HPV
primer set [88]. The MY09/MY11 degenerate primers target types (6, 11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 45, 51, 52, 53,
specific, highly conserved sequences of HPV 6, 11, 16, 18, 54, 55, 56, 58, 59, 61, 62, 64, 66, 67, 68, 69, 70, 71, 72, 73,
and 33, located at a 450-bp region of the L1 ORF of the HPV 81, 82, 83, 83, IS39, CP6108).
[89] and uses nested primers for HPV types 16, 18, and 31. Cervista. The Cervista HR-HPV test detects DNA
Subsequently, mixed primers were developed to address genomic sequences of L1, E6, and E7 HPV genes, but offers
sensitivity-reproducibility issues associated with the use of no genotyping. The Cervista HPV 16/18 assay offers identi-
degenerate primers, such as the PGMY09/11 and SPF primer fication and differentiation of the two most common
sets and systems. HR-HPV types. Clinical comparison between the Cervista
PGMY09/11 primers were created in order to improve on platform and Aptima, and mRNA-based HPV detection
MY09/MY11, and, by comparison to the original MY09/ assay offered by the same company (described below),
MY11/HMB01 primer set, the PGMY09/11 are found to be reported a low specificity for Cervista [94].
associated with higher sensitivity and specificity, but also in
the reproducibility of detecting HPV types that were previ- 17.12.3.2 Platforms for HPV mRNA Detection
ously not efficiently primed (a more significant issue in The main platform, Aptima HPV, is commercially available
lower viral loads). for HPV detection and genotyping in the United States through
SPF1/SPF2 (Microgen Bioproducts, Camberley, UK) is a Hologic (Marlborough, MA). The Aptima detects mRNA
short consensus fragment system for HPV PCR, consisting from E6 and E7 HPV genes and is designed to detect 14
of six primers (four forward and two reverse) which amplify HR-HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59,
a short (65-bp) fragment of HPV DNA, while the updated 66, and 68). The FDA approved the complementary Aptima
version of this platform (SPF10) consists of the addition of genotype assay detection, and genotyping of HPV 16 and
four additional primers (ten total), thus increasing analytical HPV 18/45 (it does not distinguish among the two types) is
sensitivity [90]. The advantage of this PCR test is that, as the offered for women with positive Aptima HPV detection test.
amplicon size is small, it is more suitable for testing on FFPE Given the central role that the E6 and E7 genes and their
blocks or specimens of lower quality/degraded DNA. product in HPV pathogenesis, as well as their documented
Roche Diagnostics (Pleasanton, CA) produced a HPV overexpression, which correlates with integration of the
PCR detection system, utilizing a 96-well microplate, genomes of HPV in cervical carcinoma, testing for HR-HPV
launched in Europe for clinical use of the Amplicor HPV E6/E7 mRNA in cervical samples could have higher speci-
test, able to detect a total of 13 HR-HPV types [91]. The kit ficity, compared with DNA testing, for the high-grade cervi-
uses 12 different biotin-labeled primers, targeted to amplify cal lesion detection. There are studies available that have
a 165-bp region in the L1 gene of the genome of these HPV suggested that HPV mRNA testing ameliorates specificity
viruses, subsequently captured by a fixed probe set. However, for CIN2-or-higher lesions (CIN2+), in comparison to DNA
this system is no longer commercially available. assays [95–97], but also higher positive predictive value
The INNO-LiPA HPV Genotyping II Extra. This is a [98]. However, these results have been contradicted by dif-
genotyping assay (Fujirebio, Tokyo, Japan) which is based ferent publications, showing no significant differences
on the SPF PCR system and employs type-specific probes between DNA and RNA testing methods and specifically in
for 32 HPV genotypes (6, 11, 16, 18, 26, 31, 33, 35, 39, 40, their performance for the detecting of CIN2+ [99, 100].
42, 43, 44, 45, 51, 52, 53, 54, 56, 58, 59, 61, 62, 66, 67, 68, There is a long series of HPV-related testing platforms
70, 73, 81, 82, 83, 89). In a comparison study between this available in literature [101] that are beyond the scope of this
platform and the Roche LA, the authors found that, while chapter and are thus not included in this list.
results were comparable (for shared genotypes), the sensitiv-
ity for HPV 16 was higher with the LA and was higher for
HPV 31, 53, and 66 with the INNO-LiPA [92]. This platform 17.12.4 Biomarkers and Molecular
is not commercially available in the United States. Application
The Liquid Bead Microarray (LBMA) Assay. The
LBMA assay utilizes the Luminex-based platform (Luminex Our knowledge of the biology of HPV and its role in cervical
Corporation, Austin, TX). In this process DNA of HPV is cancer is changing how we screen for this disease. Direct detec-
amplified using biotin-labeled consensus primers, subse- tion of HPV, e.g., by testing for HPV DNA or HPV-produced
mRNA of known oncogenic genes (E6, E7), has become part Methylation is a known epigenetic factor important in
of the screening strategies for cervical cancer. Further, as HPV cancer, and there are several studies that have looked into
types 16 and 18 account for the majority of cervical cancers but methylation of both HPV and human genomes, in associa-
also the types with the highest virulence, there is the need for tion with cervical cancer. It has been suggested that HPV 16
HPV genotyping in cervical cancer guidelines. shows differential methylation patterns, especially with
It has become clear that the majority of women with pre- regard to L1, L2, and E2 genes in association with cervical
cancerous lesions will regress, and only a minority will prog- cancer [107–109]. A series of studies have suggested that
ress to developing invasive cervical carcinoma. Therefore, measurement of individual CpG DNA methylation sites on
there is the need to find biomarkers that can separate women HR-HPV genomes can be utilized for epidemiological pur-
with similar clinical characteristics into those who will prog- poses, but also to follow up women with documented
ress and others who will regress. HR-HPV infections. The same studies have shown a correla-
tion between methylation levels and persistence of infection
for HPV 16, with yearly increments of 0.5–0.7% in cases of
17.12.5 Cytological and Histological persistent infection [107, 110]. There is a potential utility for
Correlation of Disease tracking HR-HPV infections in order to predict risk of sub-
sequent to high-grade dysplasia and/or cancer.
The Bethesda classification of squamous intraepithelial lesions Further, a long list of human genes investigated as possi-
can be correlated with the histologic diseases. In this aspect, ble methylation biomarkers of cervical cancer [111–123],
cytologic LSIL correlates histologic LSIL (including koilo- with numbers exceeding 100 genes proposed as biomarkers
cytic changes and CIN1). Cytologic HSIL corresponds to his- of this kind; however, no single gene has been proven suffi-
tologic HSIL (including CIN2 and CIN3). In contrast to the ciently sensitive and specific for identifying lesions in the
progression from tubular adenoma to high-grade dysplasias to CIN3+ category. The more feasible approach seems to be
invasive tumor in colon cancer, HPV infection and cervical that of gene panels, and two genes with evidence of good
carcinogenesis, does not show a linear progression from low- sensitivity/specificity performance are MAL and CADM1
grade to high-grade dysplasia. Instead, LSIL is associated with [112, 113, 118, 124, 125].
HPV infections that are transient, while HSIL represents a pre- Other epigenetic markers are microRNAs, with a multi-
cancerous lesion. However, an LSIL diagnosis in patients por- tude of available studies attempting a microRNA expression
tends a higher risk for a subsequent HSIL diagnosis, probably assessment in cervical carcinomas and in serum of women
in association with the likelihood of repeated HPV infections with and without cervical cancer, which have reported lists
in the same patients. of microRNAs upregulated and downregulated [126–134]
and may play a role in cervical carcinoma (Table 17.19).
17.12.5.1 HR-HPV Detection and Genotyping
Another important observation is that the specific HPV type Table 17.19 List of microRNAs reported to be upregulated or down-
detected in LSIL is indicative of the risk of a subsequent regulated in cervical cancer
HSIL or carcinoma diagnosis. Multiple studies, both cross- microRNAs miR-9, miR-10a, miR-15b, References:
sectional [102–104] and prospective [105, 106], have shown upregulated in miR-20a, miR-20b, miR-21, [30–32,
cervical cancer miR-27a, miR-34a, miR-127, 34–38]
the different virulence and carcinogenicity associated with
miR-133a, miR-133b, miR-141,
different types of HR-HPV. In fact, the current ACCP guide- miR-145, miR-155, miR-196a,
lines recommend that women be managed differently if HPV miR-199a*, miR-199a,
types 16 and 18 are found upon genotyping [83]. miR-199b, miR-199-s,
miR-200a, miR-203, miR-214,
miR-221, miR-224, miR-500,
17.12.5.2 Other Proposed Biomarkers miR-505, miR-711, miR-888,
Other possible biomarkers have been proposed, which miR-892b, miR-1246, miR-
mainly relate to genetic, epigenetic proteomic/metabolic 1290, miR-2392, miR-3147,
miR-3162 miR-4484
changes that are seen in association with HPV infections and
microRNAs Let-7a, Let-7b, Let-7c, References:
cervical cancer. Many of these, including those listed, are not downregulated miR-26a, miR-27b, miR-30d, [30, 31, 37]
clinically used, but could shed further light into the biology in cervical miR-34a, miR-100, miR-103b,
of HPV and on the interactions between HR-HPV viruses cancer miR-125a, miR-125b, miR-126,
and different mechanisms of host response, which may result miR-141, miR-143, miR-145,
miR-149, miR-200b, miR-200c,
in cervical cancer genesis and progression or in spontaneous miR-203, miR-204, miR-375,
regression. As the presence of HPV infection does not equate miR-451, miR-3185, miR-3196,
with carcinogenesis, there are several proposed markers of miR-3960, miR-4324, miR-
cervical cancer, as well as markers of clinical outcome. 4467, miR-4488, miR-4525
Other proposed biomarkers include serum protein mark- (Roche Molecular Diagnostics, Branchburg, NJ) as a pri-
ers of disease [135, 136], histone acetylation status [137], mary screening method for cervical cancer 25 years old or
metabolomics, and transcriptomics [138], and their clinical older women [154].
validity remains to be ascertained. There are definite advantages of HPV DNA testing, as
evinced by several studies, such as higher sensitivity for pre-
cancerous lesions, higher precision (reproducibility), but it
17.12.6 The Relationship Between Cytology has actually lower specificity, when compared to cytomor-
and HPV Testing phological primary screening [155–158]. What is now con-
sidered a landmark population-based study on the viability
Since its inception and implementation, cervical cancer of HPV DNA testing for cervical cancer screening, exam-
screening by Pap test has resulted in a continuous decline in ined more than 4000 Planned Parenthood patients, showed
cervical cancer incidence and cervical cancer-related mortal- that 30% of women under the age of 30 had positive results
ity in the United States in recent decades [139]. Pap test has for HR-HPV and would thus require colposcopy follow-up,
known limitations for its low sensitivity (30–60% for a sin- thus rendering primary HPV testing non-feasible for this age
gle Pap smear) [140–143] and poor intra- and interobserver group [159]. These results have contributed to the current
concordance [144, 145]. Despite its shortcomings, Pap test guidelines and FDA approval for HPV testing as a method
has proven so effective that by the mid-1990s, the epidemio- for primary screening in women over age 30 or older.
logically most significant factor of risk for cervical carci- In Europe, where primary cervical carcinoma screening by
noma in the United States was actually not being screened HPV testing was first implemented, randomized trials com-
for it with the use of Pap smears [146, 147]. paring HPV versus cytological primary screening in female
Understanding the importance of HR-HPVs in cervical population age 30 or older concluded that testing for HPV is
cancer pathogenesis, along with the subsequent development a better screening method for cervical carcinoma, in compari-
of platforms for molecular detection of these HPVs, has per- son to cytology [160–162]. Moreover, after concluding that
mitted the introduction of molecular testing in the cervical negative results in HPV testing are associated with low risk
cancer screening guidelines [83, 148] and has contributed in for either CIN3/carcinoma in situ/invasive cervical carcinoma
improving this screening process. In fact, subsequent meta- in the following 5 years, studies have suggested prolonging
analysis studies showed how triage of patients with ASC-US the follow-up screening interval to 5 years [163, 164].
diagnoses, utilizing HPV-specific testing, improves accuracy Despite all the advantages that HPV testing clearly offers
(meaning more sensitive with comparably specific or compa- for cervical cancer screening, primary HPV screening has
rably sensitive and more specific) compared to repeat cytol- some limitations, mainly connected to the disease course of
ogy [149–153]; as such, HPV testing has become the HPV infections and cervical carcinomas. Indeed, HPV test-
preferred follow-up method, although follow-up cytology is ing offers a snapshot of HPV infection status at any given
still acceptable [83]. Further studies have permitted to iden- moment, and thus a single test cannot offer information on
tify the benefit for specific subgroups within the female pop- the transient or persistent nature of an HPV infection, which
ulation, and we thus now know that, because of the very high becomes a bigger issue in the younger female population, in
prevalence of and transient nature of the vast majority of which HPV infections are much more prevalent.
HPV infections in young women, testing for HPV is not indi- In fact, most cervical HPV infections are not persistent;
cated for women 20 years old or younger [83]. Moreover, however, it is this minority of persistent HPV infections
conservative follow-up is indicated for this group, based on (usually defined persistent at 6 months, if due to the same
current guidelines [83, 148]. Based on the same guidelines, HPV type and with no intervening negative HPV tests) that
concurrent Pap test and HPV testing (referred to as co- are shown to be associated with the development of CIN3 or
testing) are preferred or acceptable strategy women aged worse [15, 165–172]. The findings in normal controls in the
30–64. Finally, the importance of HPV genotyping is also PATRICIA HPV vaccine clinical trial showed that the longer
reflected in the ASCCP for cervical cancer screening as it is HPV infections were associated with increased risks of sub-
an acceptable follow-up for women 30 years old or more, sequent CIN lesions, with a 6-month length of infection car-
with negative Pap smears but positive HPV co-testing. Given rying the highest risk for CIN detected on follow-up,
our knowledge on the increased virulence and oncogenicity followed by infections that are persistent, but last less than
of HPV 16 and 18, women may be sent for colposcopy if 6 months. Expectedly, transient HPV infections were associ-
they have HPV 16 or 18 detected, while they may undergo ated with lower risks for developing CIN. More specifically,
co-testing again after 1 year if positive for other HR-HPV women with 6 months or longer infection due to HPV 16 or
types [83]. HPV 33 had a 25 times higher risk for CIN3/CIS/cancer, in
Following implementation in several European countries, comparison to other, non-oncogenic, persistent HPV infec-
in 2014, the FDA has approved the Roche cobas test for HPV tions. The added risk for CIN3/CIS/cancer was also seen
with infection by HPV types 18, 31, and 45, when persistent Table 17.20 Initial management guidelines of Pap and HPV testings
[173]. With this in mind, it is not yet fully understood Pap test Combined tests (Pap and
whether it is the persistence of HPV DNA positivity that Management alone HPV)
truly is important in development of precancerous lesions, or Immediate colposcopy SqCC
it represents a marker for the presence of subclinical HSIL HSIL, HPV+
HSIL AGC, HPV+
(CIN2/CIN3).
HSIL, HPV−
A large Finnish (n = 54,218) general population study
ASC-H, HPV+
among females ages between 25 and 65 compared cytomor- ASC-H
phological and HR-HPV molecular (DNA targeting, fol- AGC ASC-H, HPV−
lowed by cytology for positive DNA results) screening AGC, HPV−
methods. For both study cohorts, the cytology diagnosis of LSIL, HPV+
LSIL and worse warranted colposcopy and biopsy. The ASC-US, HPV+
study findings suggested that, although HPV testing alone LSIL
had high sensitivity, the specificity of the HPV test alone is Repeat testing in ASC-US NILM, HPV+
6–12 months LSIL, HPV−
significantly inferior, compared to Pap smear. In fact, intro-
Repeat testing in 3 years ASC-US, HPV−
ducing cytology follow-up for positive molecular results
NILM
increased specificity to nearly identical values of those of
Repeat in 5 years NILM, HPV−
Pap smear alone, for the entire age population tested (99.2%
vs. 99.1% for CIN2+, P = 0.13). In conclusion, these find-
ings suggested that cytology triage following a positive recommendation is against HPV testing, in order to avoid
HPV testing result may reduce the referral rate to colpos- harm by overtreatment. In females aged 30–65, combined
copy to levels comparable to those of cytology screening. testing (Pap and HPV tests) is recommended in 5-year inter-
More specifically, for females 35 years old or more, molecu- vals. An alternative method is Pap test every 3 years in this
lar HPV testing with subsequent Pap smear on positive age group. It should be emphasized that HPV testing is lim-
results actually improved specificity, when compared to ited to HR-HPV and the HPV test mentioned in the guide-
cytology-based screening. Contrarily (and expectedly), lines refers to only HR-HPV.
women younger than 35 had referrals more frequently when Management algorithm is very complex and includes
screened by HPV testing vs. screened by Pap smears detailed follow-up guidelines for women with abnormal test
(RR = 1.27, 95% CI = 1.01–1.60), and this could mean more results. The principle is to apply equal management for equal
unnecessary follow- up with more lesions identified and risks. Readers can refer to the original publication if inter-
treated that would not progress to cancer [174, 175]. ested (ref 26). The major management guideline is summa-
Additional studies evinced that CIN3+ lesions (CIN3, CIS, rized in Table 17.20.
invasive carcinoma, adenocarcinoma in situ) showed that It should be noted that guidelines cannot replace clinical
the combination of HPV testing with Pap smear follow-up judgment. Currently, there is no test or treatment that is
was a more sensitive screening strategy compared to cytol- 100% effective. Women who undergo regular Pap and HPV
ogy alone in detecting these CIN3+ lesions [176] and testing can still develop cervical cancers.
showed that this is a viable approach and could be the way
screening is done in the future.
17.13 C
ytology of Ascites and Pelvic
Washings
17.12.7 P
ap Test and HPV Testing
Management Guidelines 17.13.1 Formation of Ascites
The recently published consensus guidelines by the American The pelvic and peritoneal cavities are lined by serous mem-
Society of Colposcopy and Cervical Pathology (ASCCP), branes, which consist of connective tissue rich in capillaries
the American Society of Cancer (ASC), as well as the and lymphatics, covered by a layer of mesothelial cells. The
College of American Pathologists (CAP) emphasize the bal- pelvic and peritoneal cavities normally contain a small
ance between benefits and harms associated with Pap test, amount of clear fluid ranging from 7 to 16 mL [177]. This
HPV testing, and related treatment (ref 26). Based on this fluid is continuously produced by ultrafiltration of plasma
guideline, all women should start cervical precancer and through semipermeable endothelial cells. The fluid is
cancer screen at the age of 21. In women aged 21–29, Pap absorbed through lymphatics and capillaries. The balance
test is recommended to be repeated in 3-year intervals. As between formation and reabsorption determines the amount
transient HPV infection is common in this population, the of serous fluid, influenced by hydrostatic pressure in capil-
laries, plasma oncotic pressure, and permeability of capillar- [186]. As low-stage non-myoinvasive papillary serous carci-
ies. Accumulation of fluid between the parietal and visceral noma of the endometrium can present with extrauterine dis-
serous lining of body cavities is termed effusion, which is ease at the time of initial diagnosis [187–189] and
always considered pathologic. The effusion in the peritoneal high-grade, high-stage endometrioid carcinomas are often
cavity is known as ascites. Effusions can be transudate or associated with positive PW suggestive of extrauterine dis-
exudate. Transudates are usually benign and caused by ease, patients with these diseases are treated with adjuvant
increased hydrostatic pressure, e.g., congestive heart failure chemotherapy [190].
and cirrhosis. Exudates can be malignant and are usually due In recent years, laparoscopic hysterectomy, laparoscopy-
to serous membrane damage as in carcinomatosis or infec- assisted vaginal hysterectomy, and robotic hysterectomies
tion. The peritoneal cavity can hold up to 20 L of fluid. have gained popularity in gynecologic oncology. The
Draining (paracentesis) and microscopic examination of the intrauterine balloon used during these minimally invasive
fluid can provide valuable clinical information on the cause surgical procedures creates positive pressure inside the
of ascites. For this reason, microscopic examination of pel- uterine cavity, and as a result, tissue fragments from the
vic and peritoneal fluids is important to rule out an underly- uterine cavity may be “displaced” into vascular spaces,
ing malignancy. into the fallopian tubes, and onto peritoneal surfaces. It is
important to recognize these artifacts, since misinterpreta-
tion may lead to overtreatment with unnecessary adjuvant
17.13.2 Clinical Significance of Pelvic therapy (Fig. 17.27a, b).
Washings It is controversial whether minimally invasive surgical
procedures are associated with a higher incidence in posi-
Pelvic lavage or washing (PW) cytology was first described tive PW. Some studies concluded that endometrial carci-
in a study by Keettel and Elkins in 1956 as a potential way noma cells exfoliate from the tumor surface because of
to detect early spread of ovarian carcinoma cells [178]. positive intrauterine pressure and gain access to the perito-
Since then many studies evaluated the clinical value of PW neal cavity via the fallopian tubes [191]. These studies have
and found correlation with prognosis in patients with gyne- shown that PWs from minimally invasive hysterectomies
cologic malignancies [179–181]. PW is now routinely per- were more likely to have malignant cells, as compared to
formed for staging of gynecologic malignancies, and the those p erformed without the uterine manipulator. A study
results are significant component of the final pathologic and by Hu et al. [192] on patients treated for low-stage and low-
clinical stage of ovarian cancers. The role and clinical sig- grade endometrial carcinomas showed that PWs were more
nificance of PW in endometrial tumors has been evaluated likely to have malignant tumor cells if minimally invasive
by several studies [182–185]. Due to the lack of correlation surgical methods were used (20.6% versus 0%). Another
between positive PW and clinical outcome, PW results are study by Krizova et al. [193] concluded similar findings,
no longer part of the staging process of uterine malignancies specifically 5/40 (12.5%) in minimally invasive versus
a b
Fig. 17.27 (a) Cluster of cytologically low-grade endometrioid adeno- metrioid adenocarcinoma in pelvic washings. Robotic hysterectomy for
carcinoma in pelvic washings. Robotic hysterectomy for non- non-myoinvasive FIGO grade1 endometrioid adenocarcinoma
myoinvasive FIGO grade1 endometrioid adenocarcinoma (ThinPrep, (ThinPrep, Papanicolaou stain, 400×)
Papanicolaou stain, 200×). (b) Cluster of cytologically low-grade endo-
4/161 (2.5%) in hysterectomies without a uterine manipu-

lator. Contamination of the pelvic peritoneum via fallopian
tubes is also supported by frequent finding of carcinoma
cells in manipulated hysterectomies as compared with
those done by abdominal hysterectomy. There is appealing
evidence that positive PWs in these scenarios have no
impact on clinical outcome. Although routinely performed,
results of PWs in pathologic staging of primary endome-
trial carcinomas are no longer incorporated into the final
FIGO stage, but they are still reported.
17.13.3 Characteristics of Pelvic Washings
Due to the collection method and nature of the specimen,

the cellular components of PW are predominantly traumati- Fig. 17.29 Skeletal muscle fragments are common findings in pelvic
cally exfoliated mesothelial cells (Fig. 17.28). Additionally, washing (cell block, H&E stain, 100×)
inflammatory cells, blood elements, fibrin, skeletal muscle
(Fig. 17.29), psammoma bodies (Fig. 17.30), and adipose
tissue can often be identified in cell blocks [194, 195]. PW
can also show collagen balls that are dense homogenous
round structures, surrounded by a single layer of flat meso-
thelial cells. They are thought to represent exfoliated small
papillary stromal projections from the ovarian surface [196].
While the cytomorphologic features of both benign and
malignant cellular elements are similar in ascites and PW,
there are some important differences one should be aware of.
In PW mesothelial cells are exfoliated in large, often folded
sheets (Fig. 17.31), whereas in ascites mesothelial cells form
three-dimensional groups or spontaneously shed as single
cells (Fig. 17.32). Mesothelial cells in ascites may show
degenerative changes making distinction from malignant
cells difficult (Fig. 17.33).
Fig. 17.30 Psammoma bodies are homogenous red or purple struc-

tures, sometimes surrounded by epithelial cells (ThinPrep, Papanicolaou
stain, 200×)
There are no defined adequacy criteria for PW in terms

of cellularity, but generally a representative or satisfac-
tory PW should be cellular, rich in monolayer sheet frag-
ments of mesothelial cells [197].The distinction between
negative and unsatisfactory specimen is a common
Fig. 17.28 “String” of benign mesothelial cells on pelvic washing dilemma when the specimen is essentially acellular or
(ThinPrep, Papanicolaou stain, 200×) consists of blood elements only. Some suggests that an
Fig. 17.31 Traumatically exfoliated folded sheets of benign mesothe- Fig. 17.33 Ascitic fluid with numerous well-preserved and degener-
lial cells are characteristic findings in pelvic washings (ThinPrep, ated benign mesothelial cells, inflammatory cell, and histiocytes (Cell
Papanicolaou stain, 100×) block, H&E stain, 100×)
17.13.4 Specimen Collection and Slide

Preparation
Upon entering the peritoneal cavity, peritoneal surfaces (para-

colic gutter, pelvis, cul-de-sac, abdominal peritoneum, and dia-
phragm surfaces) are irrigated with sterile normal saline, which
then is collected and submitted for microscopic examination
[195, 200]. Cytomorphologic evaluation of PW heavily relies
on preservation of cellular components in the specimen, which
requires proper collection and sample preparation. Ascitic fluid
collected via paracentesis and PW collected intraoperatively
are obtained under sterile conditions and should be placed in a
clean dry large container. The container should be sterile if
microbiology studies are anticipated. Ideally the specimen
should be transported to the laboratory immediately for pro-
cessing; otherwise it can be stored in a refrigerator at 4C for
several days [201]. Anticoagulants, such as heparin, disodium
Fig. 17.32 Ascitic fluid often shows clusters and single benign meso-
EDTA, or acid citrate dextrose, can be added; these do not
thelial cells that spontaneously shed from the peritoneal surface
(ThinPrep, Papanicolaou stain, 200×) affect cellular morphology details. The use of fixates, espe-
cially neutral-buffered formalin, is not recommended due to
poor staining quality with Diff-Quik (DQ) and Papanicolaou
adequate PW sample should contain at least a few well- stains. Alcohol-based fixatives, such as 50% ethanol, or fixa-
preserved groups of benign mesothelial cells or unequivo- tives used for liquid-based slide preparations such as CytoLyt
cal malignant cells [198]. (Hologic LTD, Thermo Fisher Scientific) and CytoRich
False-negative rates of PW may be due to specimen collec- (Becton, Dickinson and Company, NJ) can be added if pro-
tion, scant cellularity, or interpretation errors. Interpretation longed specimen storage or transportation is anticipated, but at
errors can be significantly reduced if immunohistochemical that point the specimen is only suitable for Papanicolaou
stains (IHC) are applied to aid in the identification of malig- staining.
nant cells [199]. If PW samples are bloody, a lysing reagent should be added
False-positive results are often caused by misinterpreta- to remove obscuring blood. Hanks balanced salt solution mixed
tion of benign Mullerian epithelium (endosalpingiosis, endo- with methanol (2:1 ratio) is a highly effective lysing agent and
metriosis) or reactive mesothelial cells as malignant. can be added following centrifugation to the pallet [194].
Specimen processing and slide preparation (number of

slides, staining method) are laboratory dependent. Direct smears
(DQ and Papanicolaou stained) can be made both from uncon-
centrated (semiquantitative evaluation of cellularity) and con-
centrated specimens. Liquid-based preparation methods
(SurePath, ThinPrep) however are widely used and have numer-
ous advantages over direct smears, including concentrated and
even distribution of cellular elements, well preservation of cel-
lular details, and less frequent false-negative results [202, 203].
Paraffin-embedded cell blocks are routinely prepared
from PW, allowing not only IHC workup in suspected malig-
nancy but also testing for prognostic markers (mismatch
repair protein, Her2/neu overexpression) and molecular
studies [204]. Various cell block preparation methods have
been described, with variable cellular yield, including clot-
ting methods such as HistoGel (Thermo Scientific Richard- Fig. 17.34 Folded sheet of benign mesothelial cells showing classic
Allan Scientific Waltham Mass), gelatin, agar, thrombin, as honeycomb appearance of cytologically uniform bland mesothelial
well as newer techniques like collodion bag. In a study by cells (ThinPrep, Papanicolaou stain, 200×)
Balassanian et al., collodion bag technique proved to be
superior cell block preparation method, as it provides good ated, which include two-zone (dense center) staining of cyto-
cellular preservation of cytomorphology and provides a con- plasm and fuzzy cell borders (aka “lacy skirt”) due to
centrated sample, thus yielding a high-quality cell block microvilli [206] (Fig. 17.36). So-called windows, referred to
specimen [205]. the clear space or gap between adjacent mesothelial cells, are
Cytospin smears can be made from concentrated unfixed also a common finding in mesothelial cells and are caused by
PW specimen, stained with Diff-Quik (DQ) or Papanicolaou surface microvilli [197].
method. However, if ancillary studies are needed, the cellu- Reactive mesothelial cells can show significant morpho-
larity of additional cytospin or cell block preparations from logic overlap with carcinoma cells. Increased nuclear to
the residual material is often variable, as the most concen- cytoplasmic ratio, nuclear hyperchromasia, chromatin
trated sample is used for the initial slides. clumping, prominent macronucleoli, irregular nuclear mem-
branes, and mitotic figures are some of the wide variety of
cytomorphologic features seen in reactive mesothelial cells
17.14 Morphologic Evaluation which can make interpretations of PW challenging
(Fig. 17.37a–c) [197, 200, 206, 207]. Table 17.21 summa-
17.14.1 Morphologic Variation of Normal rizes the cytomorphologic features of benign and reactive
Mesothelial Cells mesothelial cells.
Degenerative changes in mesothelial cells can also pose a
Normal mesothelial cells in PW are commonly arranged in diagnostic challenge. Intracytoplasmic vacuoles can mimic
flat sheets as they are mechanically stripped of the peritoneal mucin vacuoles and misinterpreted as adenocarcinoma.
surfaces. These large sheets are often folded and distorted Large cytoplasmic vacuoles, displacing the nucleus, may
(Fig. 17.34); however, their characteristic low-power appear- resemble signet ring cells (Fig. 17.38).
ance makes identification of mesothelial origin easy. Orderly As often emphasized, the most practical approach to dis-
honeycomb arrangement of oval to round mesothelial cells, tinguish benign/reactive mesothelial cells from malignancy
with central or slightly eccentric nuclei, is reassuring cyto- is based on lack of a foreign (second) population of cells.
logic findings of benign mesothelial cells. On high power,
benign mesothelial cells exhibit fine, evenly distributed
washed out chromatin, inconspicuous nucleolus, and deli- 17.14.2 Morphological Features
cate bluish-green abundant cytoplasm on Papanicolaou stain of Mesothelial Hyperplasia
(Fig. 17.35a). Within the same sheet of mesothelial cells,
variation in nuclear size and shape, occasional binucleation, Mesothelial hyperplasia is rarely diagnosed on PW. When
and longitudinal nuclear grooves are not uncommon findings suspected, it is mainly because of the cellularity and the
(Figs. 17.35b). On DQ-stained specimen, the characteristic architectural arrangement of mesothelial cells. Reactive
cytoplasmic details of mesothelial cells are readily appreci- inflammatory conditions, benign mesothelial cysts, and neo-
a b
Fig. 17.35 (a) High power view of benign mesothelial cells. Eccentric 400×). (b) Benign mesothelial cells occasionally show some degree of
nucleus, smooth nuclear membrane, washed out chromatin, and small nuclear size and shape variation within a sheet or group of mesothelial
nucleolus are characteristic findings (ThinPrep, Papanicolaou stain, cells (ThinPrep, Papanicolaou stain, 200×)
of malignant mesothelioma [209, 210]. Papillary fragments

are often seen, which at first is alarming, especially in a cel-
lular sample. However, lack of cytologic atypia and unifor-
mity of cells should favor a benign process.
17.14.3 Common Benign Findings of Pelvic

Fluids
The peritoneal surface in women can give rise to various

benign Mullerian lesions. It is important to be familiar with
the cytomorphologic characteristics of these lesions to avoid
misinterpretation. Since on initial microscopic examination
these cells might appear “foreign,” the best approach is to
Fig. 17.36 Benign mesothelial cells on Diff-Quik stained ascitic fluid carefully examine them under high power and compare them
(Cytospin, Diff-Quik, 600×) to the background mesothelial cells. Endosalpingiosis,
referred to as “ectopic” fallopian tube epithelium, can involve
ovarian surface, pelvic peritoneum, uterine serosa, omentum,
plastic mesothelial lesions, such as well-differentiated papil- and even lymph nodes. On PW, epithelial cells from endosal-
lary mesothelioma (WDPM), can exfoliate mesothelial cells pingiosis tend to be sparse and present as small aggregates or
that in PW appear atypical and exhibit nuclear pleomor- three-dimensional groups of tightly packed, uniform hyper-
phism, multinucleation, and mitotic figures. chromatic cells [201, 211]. Cilia or terminal bars might be
Multilocular peritoneal inclusion cysts are benign lesion identified. Rarely psammomatous calcifications may be seen
that develops in a setting of prior pelvic surgery, pelvic in the center of the epithelial cell clusters. The epithelial cells
inflammatory disease, or endometriosis. Cysts can be large are cytologically bland, with fine chromatin and small nucle-
and often multiloculated without papillary proliferation olus [197, 200]. Endosalpingiosis needs to be distinguished
[195, 208]. PWs in these rare tumors tend to be hypercellular from epithelial cells shed from SBT and LGSC, as overinter-
and show mesothelial cells in clusters, sheet, and single cells. pretation them as neoplastic or malignant will upstage the
Cytologically the mesothelial cells may show atypia and patient.
mimic malignant mesothelioma. All three cellular components of endometriosis are rarely
WDPM, a rare tumor of uncertain malignant potential, seen in PW. Most often, rare glandular epithelial cells with or
may pose a diagnostic challenge, as the architectural arrange- without stromal cells are seen. As in endosalpingiosis, cells
ment of exfoliated mesothelial cells strongly resembles those derived from endometriosis tend to be sparse and present in
a b
Fig. 17.37 (a) Reactive mesothelial cells often exhibit nuclear size ing nuclear enlargement and prominent nucleoli (ThinPrep,
and shape variation, binucleation, and hyperchromasia (ThinPrep, Papanicolaou stain, 200×). (c) Mitotic figures are not uncommon find-
Papanicolaou stain, 200×). (b) Sheet of reactive mesothelial cells show- ings in reactive mesothelial cells (cell block, H&E, 100×)
tight three-dimensional hyperchromatic clusters, especially specimen are essential to distinguish these benign Mullerian
when stromal cells are also present (Fig. 17.39a, b) [200, cells from metastatic carcinoma. IHC have limited or essen-
211]. Their resemblance to endometrial cells on cervical tially no utility in distinguishing endometriosis or endosal-
smears can help in identifying them. Nevertheless, mild pingiosis from low-grade serous or endometrioid neoplasia,
cytologic atypia, degenerative changes, and even mitotic fig- as their staining profile is identical.
ures can be misleading findings for malignancy. Characteristic Psammoma bodies are rarely seen in PW and usually best
histologic features of endometriosis are often appreciated on appreciated on cell block sections (Fig. 17.40). If seen on
cell block preparations. Correlation with clinical history, smear preparations, they can be confused with collagen
intraoperative findings, and corresponding surgical resection balls. The red or purple staining characteristic on
Table 17.21 Cytologic features of benign and malignant mesothelial Papanicolaou stain and cracking artifact can help in their rec-
cells [197, 200, 206]
ognition (Fig. 17.30). The presence of psammoma bodies
Benign mesothelial cells Malignant mesothelial cells without associated epithelial cells does not indicate malig-
Uniform cells Morphologic variation nancy, as they can be seen in several benign/low-grade con-
Monolayer sheets Cell balls and papillary
ditions, such as endosalpingiosis, mesothelial hyperplasia,
fragments
Low N/C ratio High N/C ratio
ovarian serous cystadenomas, and serous borderline tumors
Round to oval uniform nuclei Nuclear pleomorphism [200]. They are also common findings in serous carcinomas
Evenly distributed fine chromatin Hyperchromasia and may even be the predominant findings, as seen in psam-
Inconspicuous to prominent Prominent macronucleolus mocarcinoma [212].
nucleolus Epithelial cells from benign serous ovarian tumors (cyst-
Absent or rare mitotic figures Mitotic figures common adenofibroma, cystadenoma) may be seen in PW if the tumor
Absent psammoma bodies Psammoma bodies common ruptures or involves the ovarian surface. As both tumors
N/C nuclear to cytoplasm characteristically show minimal epithelial proliferation and
small non-branching papillae, they have identical appear-
ance in PW, including simple papillae of cohesive orderly
and uniform columnar cells with cilia and minimal cytologic
atypia (Fig. 17.41). Psammoma bodies may be present.
Correlation with corresponding surgical specimen is essen-
tial to avoid interpretation of these cells as malignant.
Cytologic features of various serous tumors and their benign

mimicker are summarized in Table 17.22. Both serous bor-
derline tumor (SBT) and low-grade serous carcinoma
(LGSC) tend to yield cellular PW samples, especially if the
tumor extends beyond the ovary. The histologic diagnosis of
LGSC is based on the presence of stromal invasion or inva-
sive implants. There is significant cytomorphologic overlap
Fig. 17.38 Degenerative changes, such as intracytoplasmic vacuoles between SBT and LGSC; therefore reliable distinction on
in mesothelial cells, need to be distinguished from true mucin vacuoles cytology alone is often not possible. Findings of micropapil-
(ThinPrep, Papanicolaou stain, 100×) lary groups, background single cells, mild nuclear pleomor-
a b
Fig. 17.39 (a) Cluster of benign endometrial glands on pelvic washing from a patient with ovarian surface endometriosis (ThinPrep, Papanicolaou
stain, 100×). (b) Corresponding cell block shows endometrial gland fragments and stroma, characteristic of endometriosis (cell bock, H&E, 200×)
Fig. 17.40 Psammoma bodies are often seen on pelvic washings from Fig. 17.42 A “second population” of high-grade carcinoma cells often
patients with ovarian surface of peritoneal involvement by serous bor- “stand out” on low power from the background mesothelial cells. Large
derline tumors or serous carcinoma (cell block, H&E, 200×) three-dimensional groups of tumor cells are easy to appreciate
(ThinPrep, Papanicolaou stain, 20×)
cells in PW, they often “stand out” on low power, especially

if the tumor cells are larger than histiocytes or benign meso-
thelial cells (Fig. 17.42). Cytoplasmic features, such as
keratinization or mucin vacuoles, are also helpful in identi-
fying non-mesothelial foreign cells. In general, high-grade
metastatic carcinomas from gynecologic origin often pres-
ent as large clusters of cells, with high nuclear to cytoplas-
mic ratio, irregular nuclear membranes, abnormal chromatin
distribution, pleomorphic bizarre nuclei, and prominent
nucleoli (Fig. 17.43a–c). The amount of tumor cells in PW
varies from rare clusters to pure population of tumor cells.
Tumor extent on peritoneal and serosal surfaces, rupture of
a cystic tumor, status of neoadjuvant chemotherapy, and
tumor histology (carcinoma versus sarcoma) contribute to
cellularity of PW.
Gynecologic tumors that exfoliate medium-sized cells,
similar in size to benign/reactive mesothelial, are the most
challenging to diagnose in PW cytology, as the foreign cell
Fig. 17.41 Bland serous epithelial cells from a ruptured serous cystad- population is difficult to appreciate on low power. Tumor
enoma (ThinPrep, Papanicolaou stain, 100×) cells from serous borderline tumors (SBT) closely resemble
reactive mesothelial cells even on high power magnification.
phisms, and prominent nucleoli may be suggestive of LGSC Other non-epithelial tumors exfoliate single cells and can
over SBT [195, 197]. The best approach is to diagnose the be challenging to diagnose on PW. Cells from lymphomas,
PW sample as “positive for serous neoplasm” and suggest sarcomas, and sex cord-stromal tumors can be easily over-
correlation with histologic findings. looked in the sea of benign mesothelial cells, histiocytes, and
blood components.
Microscopic findings of mucin, necrotic debris, and abun-
17.14.5 Morphological Features of Metastatic dant psammoma bodies in the background can be useful
Malignant Cells diagnostic clues in PW and should prompt high power scru-
tiny for the presence of non-mesothelial second cell
Like in effusion cytology, the diagnosis of metastatic malig- population.
nancy in PW relies on identification of a “second or foreign It is essential to compare the cytomorphologic features of
population” of cells. When there is abundance of malignant suspicious cells in PW (smears and cell block) to the corre-
Table 17.22 Cytologic features of low-grade serous tumors, high-grade serous tumors, and their mimickers [195, 197, 201, 211, 213]
Cytologic
features Endosalpingiosis Serous cystadenoma Serous borderline tumor High-grade serous carcinoma
Cellularity Low Low to moderate Moderate, variable Hypercellular
Cell Tightly cohesive small Cohesive, orderly Crowded and rare single Crowded and numerous single
arrangement groups
Papillae Simple, small, Simple, Branching, large, 3D Irregular, large, branching 3D
non-branching non-branching
Pleomorphism None to minimal None to minimal Uncommon, degenerative atypia Marked and obvious
Nuclear Low N/C ratio, fine Low N/C ratio, fine Variable N/C ratio, moderate Variation in size, shape, high
features chromatin, inconspicuous chromatin, 1–2 small atypia, coarse chromatin, rare N/C ratio, coarse chromatin,
nucleoli nucleoli small prominent nucleoli prominent nucleoli
Cytoplasm Scant basophilic Moderate basophilic Minimal cytoplasmic vacuoles Prominent cytoplasmic vacuoles
Mitosis Absent Absent Rare Common
Psammoma Common Sometimes Common Common
bodies
N/C nuclear to cytoplasm, 3D three-dimensional
a b
Fig. 17.43 (a) High-grade serous carcinoma of the ovary. Marked of markedly atypical carcinoma cells. Mitotic figure is noted (ThinPrep,
cytologic atypia, nuclear hyperchromasia, nucleomegaly, and promi- Papanicolaou stain, 200×). (c) High-grade serous carcinoma of the
nent nucleoli are readily seen (ThinPrep, Papanicolaou stain, 200×). (b) ovary. Marked cytologic atypia, nuclear hyperchromasia, nucleomeg-
High-grade serous carcinoma of the ovary. Three-dimensional cluster aly, and prominent nucleoli are readily seen (cell block, H&E, 200×)
sponding surgical specimen [213]. This is particularly impor-

tant when the differential diagnosis is between benign
mimickers (such as endometriosis and endosalpingiosis) and
low-grade epithelial neoplasms (such as low-grade endome-
trioid carcinoma, serous carcinoma, and SBT).
IHC on PW cell block preparation can be very helpful in
the differential diagnosis if the tumor is from a non-Mullerian
origin, such as the gastrointestinal tract, lung, and breast.
However, both epithelial markers and Mullerian markers are
positive in benign Mullerian lesions (such as endosalpingio-
sis and endometriosis).
Cytologic evaluation of PW starts with clinical history. As
PW are routinely performed in patients who present with
known gynecologic malignancy or with imaging findings of a
“lesion or mass” in gynecologic tract, it is essential that the
pathologist is familiar with the clinical findings, histologic
Fig. 17.44 Clear cell carcinoma of the ovary. Marked cytologic atypia,
tumor types that can occur in various parts of the gynecologic
clear to eosinophilic finely vacuolated cytoplasm. (ThinPrep,
tract, the findings in the corresponding surgical specimen, and Papanicolaou stain, 400×)
diagnostic pitfalls. It is estimated that 48–60% of women with
primary ovarian malignancy have positive PW at the time of
initial surgery [213, 214]. Although subclassification of gyne- static colon carcinomas are usually diffusely positive for
cologic malignancies on PW is rarely necessary, malignant CK20 and CDX2 but negative for CK7. Metastasis from gas-
cells seen in ascites may need further classification, especially trointestinal, pancreaticobiliary, or endocervical primary
if neoadjuvant treatment is considered. Table 17.23 is a sum- sites should always be considered in the diagnostic workup
mary of cytologic features of common metastatic gynecologic [220, 221] of mucinous ovarian neoplasms.
malignancies and their IHC staining profiles. Diagnosis of sex cord-stromal tumors can be challenging
on PW as the characteristic histologic features (such as Call-
17.14.5.1 General Considerations Exner bodies) are usually not seen. Granulosa cell tumor on
High-grade serous carcinoma (HGSC) of the ovary is the PW presents as tight clusters of small hyperchromatic cells,
most common malignant surface epithelial tumors that pres- with high nuclear to cytoplasmic ratio, occasional nuclear
ent with positive PW during staging laparotomy. Primary grooves, and angulated nuclei (Fig. 17.45). Sertoli-Leydig
peritoneal HGSC cannot be distinguished from primary cell tumors, depending on grade, may present as uniform
ovarian counterpart cytologically [215]. tightly packed, cytologically bland tumor cells or high-grade,
The characteristic histologic features of ovarian or endo- sarcomatoid, pleomorphic malignant cells.
metrial clear cell carcinoma are often not present on The cytologic features of germ cell tumors in PW depend
PW. High-grade cytologic atypia and intracytoplasmic hya- on the histologic type, and germ cell tumors can be easily
line globules may be identified (Fig. 17.44), while papillary mistaken for a high-grade carcinoma (Fig. 17.46) [222].
tissue fragments with “hobnail” arrangement of tumor cells Clinical history, patient’s age, and correlation with corre-
are best identified on tissue fragments on cell block samples. sponding surgical specimen are of paramount diagnostic
Over 80% of primary mucinous ovarian tumors are benign importance. Rupture and spillage of dermoid cyst contents
mucinous cystadenomas, followed by mucinous borderline may result in keratin debris and granulomatous reaction.
tumors. Mucinous carcinomas are rare and represent less Peritoneal involvement by mature glial tissue (gliomatosis
than 4% of all ovarian carcinomas [216, 217]. As most peritonei) can present on PW as fibrillary material and high-
mucinous carcinomas of the ovary are low stage, PW is most lighted by GFAP stain. The clinical significance of PW in
often negative. If tumor ruptures and spills into the pelvic malignant germ cell tumors is not well documented [223].
cavity, PW may be positive. In this situation, PW may show While PW is still routinely performed during surgical
abundant extracellular mucin and only rare strips of epithe- staging of uterine primary tumors, results are no longer com-
lial cells [218, 219]. Intestinal-type mucinous ovarian tumors ponents of FIGO staging. The cytologic characteristics of
show similar IHC profile to colorectal carcinoma, and there- primary uterine carcinomas are identical to their ovarian
fore ancillary studies have limited utility in differentiating counterparts. As peritoneal surface involvement by endome-
primary from metastatic mucinous tumors. In general, how- trioid carcinoma of the uterus occurs in advanced-stage dis-
ever, primary ovarian tumors are usually diffusely positive ease or in tumors with deep myoinvasion [224, 225], it is
for CK7 and focally positive for CK20 and CDX2, and meta- important to exclude benign mimickers before PW is consid-
Table 17.23 Cytomorphologic characteristics and immunohistochemical features of the common metastatic gynecologic malignancies in pelvic
fluid cytology [199, 217, 222, 236–251]
Tumor type Architecture Nucleus Cytoplasm IHC Pitfalls and pearls
Ovarian surface epithelial tumors
High-grade Branching Irregular, pleomorphic, Vacuolated, “soap P53+ (80%) or 0 (null), WT-1+ in
serous carcinoma papillary, single hyperchromatic, bubble” p16+, WT-1+ mesothelial cells,
cells prominent nucleolus some ER+/−,
PR−/+, p53 wild
type in 20%
Mucinous Strips of tall Pleomorphism, Mucin displacing CK7+>>CK20+, Rule out
carcinoma mucinous cells, hyperchromasia, nucleus, signet ring CDX2+/−, mCEA+ PAX8, metastasis
3D clusters prominent nucleolus cells DPC4+
Endometrioid Cohesive Elongated, enlarged, Scant, fine vacuoles or ER+, PR+, PTEN−, High grade may
carcinoma clusters, acini less pleomorphic than granules, squamous or WT-1−, vimentin+, nuclear be p53+
HGSC, inconspicuous mucinous β catenin+
nucleoli differentiation
Clear cell Hyalinized Round nuclei, less Clear to eosinophilic, Napsin A+, HNF-1β+
carcinoma papillae, acini, pleomorphism than fine vacuoles, distinct
often single cells HGSC, prominent cell borders, hyaline
nucleolus globules
Germ cell tumors
Dysgerminoma Cellular, large Irregular, coarse Scant, delicate OCT-4, PLAP+, CD117+ D2-40+, AE1/
tumor cells, clumped chromatin, one vacuolated cytoplasm AE3+
single and or multiple nucleoli perinuclear dot
clusters like
Yolks sac tumor Papillary and Vesicular nuclei, 1–2 Scant vacuolated AFP+, SALL-4+,
cohesive groups prominent nucleoli cytoplasm, intracellular glypican-3+, PLAP+, AE1/
hyaline globules AE3+
Embryonal Tight clusters and Large pleomorphic, Scant delicate OCT-4+, CD30+, AE1/
carcinoma acini coarse chromatin, cytoplasm, indistinct AE3+, CD117−
prominent nucleoli cell borders
Immature Clusters of small Small round uniform, Delicate fibrillary AE1/AE3+, neuroendocrine
teratoma cohesive cells, neuroendocrine cytoplasm markers+, GFAP+
rare rosettes chromatin pattern
Sex cord tumors
Granulosa cell Small and large Eccentric Scant delicate Inhibin A+, calretinin+, Luteinized
tumor clusters hyperchromatic, EMA−, CD99+ stromal cells
(especially if granular chromatin, membranous, SF-1+ stain similarly,
ruptured) grooves, more mesothelial cells
pleomorphism in calretinin+
juvenile type
Sertoli-Leydig Tight clusters, Grade dependent: Clear abundant to scant Inhibin A+, calretinin+, Luteinized
cell tumor balls or papillae hyperchromatic with EMA−, CD99+ stromal cells
inconspicuous nucleoli (membranous), Melan A+, stain similar,
or sarcomatoid and SF-1+ mesothelial cells
pleomorphic calretinin+
Biphasic tumors
Carcinosarcoma Epithelial cells in Pleomorphic, Vacuolated, dependent AE1/AE3+, PAX8+ in
(MMMT) clusters, papillae, hyperchromatic, on epithelial epithelial component, AE1/
spindled cell prominent nucleolus, component. May have AE3+ in mesenchymal
component may rarely malignant heterologous features component, MyoD1,
be present spindled cells (rhabdoid, chondroid) myogenin for rhabdoid diff
3D three-dimensional, HGSC high-grade serous carcinoma, + positive, − negative, +/− can be positive, −/+ rarely positive, diff differentiation
ered positive in a low-stage, low-grade endometrioid carci- 17.14.6 Cytologic Diagnosis of Primary
noma. Iatrogenic contamination of the peritoneal cavity, Peritoneal Tumors
associated with robotic and laparoscopic hysterectomies,
and transit of tumor cells via fallopian tubes are other possi- Primary peritoneal lesions of the pelvic peritoneum encoun-
bilities to consider. tered in gynecologic pathology include various benign,
Carcinosarcomas often exfoliate the carcinomatous com- low malignant potential and malignant tumors of both
ponent, and sarcomatoid cell clusters with elongated bizarre mesothelial and Mullerian origin. Most primary Mullerian
nuclei are rarely seen [226]. tumors of the peritoneum are serous neoplasms, and occa-
sionally tumors may arise from peritoneal endometrio-

sis. Histologically primary peritoneal serous tumors range
from SBT and low-grade serous carcinomas (LGSC), to
HGSC. These resemble their ovarian counterparts cytologi-
cally and immunohistochemically.
Primary mesothelial lesions in the pelvis include a range
of reactive changes, low-grade neoplasms, and malignant
mesothelioma. As mentioned above, mesothelial papillary
hyperplasia is a reactive process, often encountered as a
response to chronic irritation, inflammation, or an underly-
ing neoplastic process. The various mesothelial neoplasms
will be described below.
Multilocular peritoneal inclusion cyst (MPIC) is an
uncommon disease of the pelvic peritoneum in women of the
reproductive age. There is often a prior history of pelvic sur-
gery, endometriosis, or inflammation. Therefore, some
authors consider such lesions nonneoplastic reactions.
However, some other authors feel that these are low-grade
Fig. 17.45 Granulosa cell tumor in pelvic washing. Tight cluster of neoplasms due to their potential of recurrence. Histologically
hyperchromatic cells, minimal cytoplasm, and occasional nuclear these tumors often consist of large multilocular cysts, lined
grooves (ThinPrep, Papanicolaou stain, 400×)
by a simple cuboidal or flat mesothelial lining. Mild nuclear
atypia, squamous metaplasia, and “hobnail”-type changes
are often seen. PWs in these tumors are hypercellular and
mostly composed of sheets or clusters of mesothelial cells,
intermixed with squamous cells [195, 208]. When the
specimen shows cytologic atypia and high cellularity, dis-
tinction from malignant mesothelioma can be challenging.
Well-differentiated papillary mesothelioma (WDPM), a
tumor of uncertain malignant potential, is an uncommon dis-
ease of the peritoneum. The majority of WDPM occurs in
women, but they can also arise from tunica vaginalis in men
[227]. WDPM are often found incidentally during abdomi-
nopelvic surgery as multiple white firm nodules on the pelvic
Fig. 17.46 Germ cell tumor (dysgerminoma) shows high-grade cyto- peritoneum and omentum. Microscopically, they are com-
logic atypia and can be very difficult to distinguish from high-grade posed of numerous papillary fronds lined by a single layer of
carcinoma on cytology alone (ThinPrep, Papanicolaou stain, 400×) cytologically bland mesothelial cells, without stromal inva-
sion (Fig. 17.47) [209, 210]. When these tumors are encoun-
tered on PW, they retain their papillary architecture, but they
can also form structures similar to “collagen balls” with a
central hyalinized core, surrounded by benign-appearing
single layer of mesothelial cells. Cytologically, the mesothe-
lial cells from WDPM are monotonous with abundant cyto-
plasm and distinct cell borders. Mitotic activity and nuclear
atypia are uncommon in WDPM. WDPM can be easily mis-
interpreted as SBT on PW cytology. IHC stains are very
helpful in differentiating these two tumors.
Adenomatoid tumor is another incidental pelvic lesion
with similar gross presentation as WDPM. The characteristic
histologic findings of adenomatoid tumor include multiple
cystic spaces, lined by flat benign-appearing mesothelial
cells with pale cytoplasm, fine chromatin, and small nucle-
oli. The cystic spaces are separated by variable amount of
Fig. 17.47 Well-differentiated papillary mesothelioma of the pelvis stroma. The diagnosis of adenomatoid tumor on PW is rarely
and omentum on pelvic washing (cell block, H&E, 200×) made for two reasons: (1) tumor usually does not exfoliate a
a b
Fig. 17.48 (a) Primary peritoneal malignant mesothelioma. Low (ThinPrep, Papanicolaou stain, 200×). (c) Primary peritoneal malignant
power shows large clusters and papillary fragments of mesothelial cells mesothelioma. Low power shows large clusters and papillary fragments
(ThinPrep, Papanicolaou stain, 100×). (b) Primary peritoneal malignant of mesothelial cells (cell block, H&E, 100×)
mesothelioma. Large papillary fragment of atypical mesothelial cells
significant number of tumor cells, and (2) the characteristic ings. Histologically, MM shows a cystic papillary or a diffuse
histologic features of adenomatoid tumor are not appreciated growth pattern. The diagnosis of MM on PW is challenging
on PW. The cytologic features of adenomatoid tumor have because invasion into adjacent normal structures is required
only been described in fine-needle aspiration specimens that for a definitive diagnosis and invasion cannot be evaluated in
show sheets and clusters of round to oval tumor cells with cytology [230]. In cellular specimens, MM usually presents
eccentric vesicular nuclei, fine chromatin, and vacuolated as large clusters, balls, or papillary fragments of atypical
cytoplasm [228, 229]. mesothelial cells (Fig. 17.48a–c). Cytologic atypia of meso-
Primary malignant mesothelioma (MM) of the perito- thelial cells is variable in MM. Compared to benign meso-
neum is rare. It is more often seen in males, with only around thelial cells, however, MM cells are larger, with higher
8% of cases encountered in women. History of asbestos nuclear to cytoplasmic ratio and prominent nucleoli. The
exposure is a known risk factor. Ascites and diffuse perito- mesothelial origin can be recognized based on the presence
neal involvement by tumor are the usual intraoperative find- of dense central and lacy peripheral cytoplasm, distinct cell
borders, and intercellular windows [195, 231]. Binucleation, original tumor. On PW, residual carcinoma cells are often
multinucleation, and mitotic figures (including atypical arranged as single cells, but small papillary clusters may
forms) are readily identified in MM. The absence of a “for- be seen. The presence of psammoma bodies is variable,
eign” cell population and identification of spectrum of cyto- and they trigger additional workup (such as to perform
logic atypia ranging from benign/reactive to atypical to additional levels and IHC stains on cell block).
malignant are helpful features to distinguish MM from carci- Cytologically, carcinoma cells after chemotherapy show
nomas. The cytologic features of reactive mesothelial cells, bizarre degenerative changes, multinucleation, abundant
malignant mesothelioma, and adenocarcinoma are summa- vacuolated eosinophilic cytoplasm with an overall low
rized in Table 17.24. Rare variants of MM are challenging to nuclear to cytoplasmic ratio, smudgy clumped chromatin,
diagnose on a biopsy sample and even more challenging on and prominent nucleoli [234]. Foamy histiocytes, necrotic
fluid cytology. These include the sarcomatoid, lymphohistio- debris, cholesterol crystal, foreign body giant cells, and
cytoid, rhabdoid, and deciduoid variants. Their diagnosis acute inflammatory cells are also common findings. As
heavily relies on IHC and the awareness of these rare sub- residual malignant cells may be sparse and poorly pre-
types of MM [232]. served and appear bizarre and more atypical than the orig-
inal tumor, an undifferentiated malignancy or a second
primary tumor may even enter the differential diagnosis.
17.15 Cytologic Changes After Treatment Therefore, IHC stains may be of a great value to identify
residual microscopic disease in PW and to confirm their
Neoadjuvant chemotherapy followed by interval debulk- origin. A study by Wang et al. showed the IHC staining
ing surgery is widely used for advanced-stage high-grade profile of treated ovarian carcinoma cells is identical to
ovarian and primary peritoneal carcinomas. Clinical those prior to treatment [235]. It is important to note that
assessment of treatment response and need for additional tumor typing and grading are not possible on PW obtained
chemotherapy are based on histologic evaluation for during interval debulking surgery and should be deferred
residual disease on surgical specimen. Histologic features to the surgical specimen.
often seen in high-grade ovarian carcinomas following
neoadjuvant chemotherapy include degenerative changes
in tumor cells (such as with smudgy chromatin, bizarre 17.16 Ancillary Studies
atypia, and cytoplasmic vacuoles), numerous psammoma
bodies without associated viable tumor cells, fibrosis, Metastatic high-grade carcinoma is usually easy to diagnose
foamy histiocytes, necrosis, and acute inflammation on PW, as tumor cells “stand out” as a second (foreign) pop-
[233]. It is important to be familiar with these cytologic ulation of three-dimensional cellular aggregates with readily
changes, as residual tumor cells often do not resemble the recognizable cytologic features of malignancy. On the other
Table 17.24 Cytomorphologic characteristics of reactive mesothelial cells, mesothelioma, and adenocarcinoma on pelvic fluid specimen [194,
195, 197, 200, 201, 231]
Cytologic features Reactive mesothelial cells Mesothelioma Adenocarcinoma
Cellularity Moderately cellular Hypercellular Hypercellular
Cell arrangement Monolayer or small groups Large 3D cell groups with knobby Single cells, 3D cell groups with smooth
with knobby outline outline, papillae outline (community borders), true glands
Pleomorphism Minimal or absent Present, giant cells, multinucleated Variation in cell size and shape, bizarre
cells atypical cells
Intercellular Present Present Absent
windows
Cell borders Microvilli, cytoplasmic blebs Prominent microvilli, cytoplasmic Sharp cell borders
blebs
Cytoplasm Two-tone, degenerative Two-tone, fine vacuoles (lipid, Vacuolated (mucin)
vacuoles glycogen)
Nuclear features Reactive, uniform nuclei, Hyperchromatic, central, Eccentric, irregular, abnormal chromatin
prominent nucleoli may be pleomorphism, macronucleoli
seen
Distinct second Absent Spectrum of changes without obvious Distinct second population
population second population
Nuclear features of Absent Nuclear enlargement, prominent Nuclear enlargement, prominent nucleoli,
malignancy nucleoli, atypical mitosis may be seen atypical mitosis present
3D three-dimensional
Table 17.25 Commonly used immunohistochemical markers and their staining pattern in pelvic fluid specimens [201, 232, 246, 252, 253]
Carcinoma Mesothelial
IHC marker cells cells Potential pitfalls
MOC-31 M
BerEP-4 M
B72.3 M or C
CD15 C or M Only 30–60% of ovarian carcinomas+
(Leu-M1)
CK7 C C Most primary ovarian carcinomas+
CK20 C Only rare ovarian carcinomas (mucinous) are CK20+
AE1/AE3 C C Not useful
EMA C MI
mCEA C Only + in mucinous carcinomas
CK5/6 C Some carcinomas are positive
Calretinin C and N Sex cord tumors+
WT-1 N N Stains surface epithelial cells from adnexa, small-cell carcinoma of hypercalcemic type,
some sex cord tumors
D2-40 M Lymphatic endothelial cells+
Thrombomodulin M Stain urothelial cells, some carcinomas+
ER, PR N 5% of mesothelial cells are ER+, <5% of mesothelial cells are PR+
PAX8 N N* Renal and thyroid tumors+, mesothelial cells from pelvic surface epithelium+
M membranous, C cytoplasmic, N nuclear, MI microvillous
N* PAX8 expression, especially with polyclonal antibody, has been reported in benign peritoneal mesothelial cells and mesothelioma [253]
hand, cells of benign processes (such as endometriosis and

endosalpingiosis), cystadenoma, and borderline epithelial
tumors are often bland and resemble mesothelial cells. In
equivocal cases, ancillary IHC studies on cell block sections
can aid in the differential diagnosis. IHC can be performed
on the formalin-fixed paraffin-embedded cell block prepara-
tions. It is most helpful to perform a panel of immunostains
including both mesothelial and epithelial markers. The most
commonly used adenocarcinoma markers include BerEP4,
B72.3, Moc-31, and CD15 (Leu M-1). The commonly used
mesothelial markers are calretinin, WT-1, D2-40, CK5/6,
and thrombomodulin. Table 17.25 provides on overview and
staining characteristics of the commonly used mesothelial
and epithelial markers in the diagnostic workup of pelvic
fluid in gynecologic pathology.
17.16.1 Epithelial Markers
MOC-31, BerEP4, and B72.3 appear to be the most sensitive

and specific markers for adenocarcinoma, especially if used
as part of a panel (Fig. 17.49). Other broad-spectrum epithe-
lial markers, such as AE1/AE3 and CK7, are expressed in
Fig. 17.49 Epithelial marker BerEP4 highlights metastatic carcinoma
both carcinomas and mesothelial cells and thus are not help- cells on pelvic washing in a membranous staining pattern (BerEp4, cell
ful to their distinction. However, these epithelial markers can block, 400×)
be used to distinguish mesothelioma or carcinoma from
melanoma.
Additional panel(s) of organ specific immunostains is CK7, CK20, and GATA3 (Fig. 17.50). The most frequently
generally used to determine the primary site of carcinoma used markers in gynecologic pathology include HCG,
cells in PW. These markers include PAX8, TTF-1, CDX2, inhibin, PLAP, OCT-3/OCT-4, CD117, CD30, and AFP.
Fig. 17.52 D2-40 stains mesothelial cells in membranous pattern and

can be used as part of an immunohistochemical pattern for identifica-
tion of mesothelial cells (D2-40, cell block, 400×)
from neoplastic. Although calretinin (Fig. 17.51) and

Fig. 17.50 Nuclear stain PAX8, a sensitive and specific Mullerian WT-1 are the most widely used mesothelial IHC markers
marker, is often used in gynecologic pathology for the workup of pelvic in effusions, their use in PW needs caution as WT-1 is also
washing (PAX8, cell block, 400×)
positive in serous tumors of the ovary and calretinin is also
positive in sex cord-stromal tumors. D2-40 (Fig. 17.52) is
another sensitive marker for mesothelial cells, but it is also
positive in vascular neoplasms and certain types of germ
cell tumors.
17.16.3 Antibody Panels
The most helpful antibody panel in the diagnostic workup of

tumors in the PW should include stains that can distinguish
mesothelial cells from carcinoma cells. When malignancy is
established, an organ specific panel is needed to characterize
the tumor cells for suggestion of the primary site. The first-
line antibody panel should include two mesothelial markers
and two epithelial markers. CD68 may also be useful to rec-
ognize histiocytes if pelvic fluid contains numerous single to
loosely aggregated mildly atypical cells that are negative for
epithelial and mesothelial markers. When there is a prior his-
tory of tumor, a narrower panel including markers specific to
the known tumor can be selected.
When a surgical specimen is available, comparison of
the cells in the pelvic fluid to the tumor in the surgical spec-
Fig. 17.51 Mesothelial marker calretinin can be used to identify imen may be the most cost-effective diagnostic workup
mesothelial cells. The characteristic staining pattern is nuclear and method.
cytoplasmic (calretinin, cell block, 400×)
17.16.2 Mesothelial Markers References

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Index
A Anaplastic carcinoma, 210

Abnormal uterine bleeding, 3, 8, 14, 16, 23, 27, 35, 95, 275, 277, 282, Anaplastic lymphoma kinase (ALK), 21, 27, 28, 39, 40
299, 300, 310, 324, 327, 330, 352, 544 Androgen, 84, 86–88, 94, 95, 97, 274, 286, 287, 299, 300, 310, 319,
Abscess, 65, 100, 116 324
Accelerated villous maturation/advanced villous maturation, 486, 514, insensitivity syndrome, 94
520, 521, 531 Angiosarcoma, 43, 240
Actinomyces, 65, 100, 575 Anti-Müllerian hormone (AMH), 85, 92, 94, 95
Actinomycosis, 100, 101 Antiphospholipid antibody, 431
Activity, 310 Apoplectic leiomyoma, 19
Acute chorioamnionitis, 476, 477, 490, 495–497 Apoptosis, 86, 89, 303, 407, 409, 436, 543
Acute chorionitis, 496, 497 Arias-Stella reaction, 447
Acute peritonitis, 368, 372 Assisted reproduction, 85, 432, 438
Acute salpingitis, 66, 67 Atretic follicles, 83, 85, 106, 107
Acute subchorionitis, 496, 497 Atypical carcinoid, 359
Adenocarcinoma Atypical endometriosis, 419–422
clear cell, 190, 350, 398 Atypical glandular cells (AGC), 595
endometrial, 184, 347, 350, 373, 543, 545, 546, 600 Atypical glandular cells NOS, 575, 577
endometrioid, 34, 131, 161, 166, 176, 178, 181, 185, 304, 330, Atypical hyperplasia (AH), 34, 97, 419
332–335, 338, 341, 344, 347–350, 354–356, 544, 548, 560 Atypical immature squamous metaplasia, 590, 593
fallopian tubal, 128 Atypical leiomyoma, 24, 25, 29, 30
mucinous, 333, 336, 338, 340, 383 Atypical placental site nodules, 451, 453
ovarian, 192, 193, 195, 334, 337–339, 344, 398 Atypical polypoid adenomyoma (APA), 34–35, 373
serous, 387, 390–394, 600 Atypical proliferating tumor, 126, 133
variants, 545 Atypical proliferative Brenner tumor, 133
Adenocarcinoma in situ (AIS), 596 Atypical proliferative clear cell tumour, 295
Adenofibroma, 31, 33, 128, 132, 142, 164, 174–176, 183, 185, 189, Atypical proliferative serous tumors, 126, 127, 145, 147
190, 192, 195, 196, 205, 299, 310 Atypical seromucinous proliferative tumor, 126
Adenoid cystic carcinoma, 361 Atypical squamous cells, 575, 588
Adenoma malignum, 313 Atypical squamous cells of undetermined significance (ASC-US),
Adenomatoid tumor, 35, 41, 58, 61, 62, 223, 224, 372–376, 398, 551, 575–577, 586, 588, 591, 602, 606
555, 619 Autoimmune oophoritis, 92, 93, 100
Adenomyoma, 34, 35, 43, 223, 551 Autoimplants, 372
Adenomyomatous polyp, 34, 35
Adenomyosis, 4, 5, 43, 544, 546, 551, 555
Adenosarcoma, 12, 13, 16, 30–34, 41, 58, 61, 185, 186, 279, 417 B
with sarcomatous overgrowth, 33 Bacterial vaginosis (BV), 495, 575
Adenosis, 382 Basal cell, nevoid syndrome, 279
Adenosquamous carcinoma, 344 Basal cell carcinoma (BCC), 240, 248
Adrenal cortical rests, 397 Basement membranes, 79, 314, 318, 460, 475, 542
Adult granlosa cell tumor (AGCT), 90, 114, 243, 274–276, 282, 285, Bastocyst, 427
300–310, 317, 319, 561 BCOR, 1, 9–13, 28
Agenesis of the ovary, 407 Bizarre giant cell, 558, 584
Aggressive angiomyxoma, 542 Bizarre leiomyoma, 19, 25, 29, 30, 282, 550
Allelic genes, 127 Blastocyst, 427, 428, 459, 460, 471
Alveolar rhabdomyosarcomas, 41 Blastomyces dermatitidis, 102
Alveolar soft part sarcoma (ASPS), 37, 38 Blepharophimosis, ptosis and epicanthus inversus syndrome, 303
American Joint Committee on Cancer (AJCC), 56 Borderline Brenner tumor, 133, 215, 217–219
Amnion, 427, 441, 460, 466, 467, 471, 475, 486, 489, 491, 496, 497, Borderline endometrioid tumors, 559
506, 525, 529, 530 Borderline mucinous tumors, 58, 205, 206, 208, 212, 213, 395
nodosum, 466, 476 Breast cancer, 72, 162, 335, 354, 355, 357, 406
Amniotic band syndrome, 466, 467, 476 Breast cancer gene (BRCA), 134, 136, 141
W. Zheng et al. (eds.), Gynecologic and Obstetric Pathology, Volume 2, https://doi.org/10.1007/978-981-13-3019-3
632 Index
Brenner tumors, 132, 133, 203–227, 298, 299, 343, 344, 561 Colorectal cancers, 324, 329
Broad ligament, 21, 54, 79, 80, 226, 310, 367–384, 386–390, Colposcopy, 70, 592, 595, 606, 607
393–400, 413, 443 Columnar epithelial cells, 226
Compaction/morula, 124
Complete hydatidiform mole (CHM), 433, 435, 437, 439–441, 443,
C 444, 446, 482, 483
Calcification, 17, 60, 71, 86, 87, 109, 152, 158, 175, 215, 216, 219, Complex papillary, 165
249, 253, 266–268, 277, 278, 280, 282, 286, 287, Confidence interval, 553
293, 310, 312, 313, 373, 398, 489, 511, 512, 534, Confined placental mosaicism, 460
550, 569, 584 Confluent growth, 390
Calcifying fibrous pseudotumor, 372 Congenital adrenal hyperplasia, 95
Call-Exner body, 344 Corpus albicans cysts, 104
Calretinin, 7, 14, 41, 62, 79, 87, 98, 103, 281, 289, 293, 298, 312, 316, Corpus luteum cysts, 108, 109, 414
344, 368, 394, 623 Corticosteroids, 274
Cambium layer, 41, 42 Cotyledonoid dissecting leiomyoma, 19, 21, 550
Candida albicans, 490 Crystals of Reinke, 292, 293, 295, 296, 299, 300, 302
Carcinoids with mixed patterns, 246 Cystadenofibroma, 103, 142–144, 205, 614
Carcinoid tumor, 244, 310, 339, 341–344 Cystadenoma, 67, 103, 125, 126, 141, 142, 144, 145, 204–208, 214,
Carcinoma in situ (CIS), 606, 607 614, 622
Carcinomatosis, 167, 369, 608 Cysteine, 303
Carcinosarcoma, 12, 13, 25, 31, 33, 34, 41, 43, 58–61, 123, 187–189, Cystic corpora lutea, 92, 108
237, 279, 318, 546, 548, 618 Cystic granulosa cell tumor, 89
Cell adhesion molecule (CAM), 430 Cystic nephroma, 317
Cell block, 611, 613, 615, 617, 621, 622 Cytokeratin (CK), 14, 16, 41, 79, 81, 99, 115, 211, 216, 221, 223, 262,
Cell-renal cell carcinoma, 358 279, 291, 297, 298, 351, 368, 377, 380, 395, 398, 445, 446,
Cellular fibroma, 275, 277–279, 303 448–452
Cellular leiomyoma, 19, 29 Cytomegalovirus (CMV), 102, 430, 431, 491, 500, 501, 533, 575
Cervical adenocarcinoma, 344 Cytospin, 611, 612
Cervical cancer, 344, 347, 571, 572, 578, 591, 602–606 Cytotrophoblasts (CT), 253, 262, 427–429, 431, 435, 436, 441,
Cervical intraepithelial neoplasia (CIN), 606 443–445, 460, 518
Cervix, 14, 34, 41, 61, 67, 122, 213, 214, 312, 325, 329, 333, 335,
373, 384, 407, 410, 416, 420, 422, 432, 439, 527, 543, 544,
546, 572, 573, 594, 599, 600 D
Chondrosarcoma, 60, 61, 240 Decidua, 429, 431, 434, 437, 451, 461, 475–477, 513, 514, 526, 527,
Chorangiocarcinoma, 535 534, 568
Chorangioma, 469–471, 484, 535, 536 Decidual changes, 419, 447, 568, 569
Chorangiosis, 484, 520, 523 Decidual vasculopathy, 513–515, 517
Choriocarcinoma, 88, 253, 261, 262, 352, 430, 432, 433, 436, 439, De-differentiated carcinoma, 10
441, 443–448, 450, 535 Delayed villous maturation, 478, 520, 522, 523
Chorion, 428, 429, 433, 460, 466, 471, 475–477, 486, 489, 491, 496, Depth of invasion, 406, 527, 544, 546, 548
497, 505, 506, 525, 529 Dermoid cysts, 234, 248, 308, 369, 617
Chorionic gonadotropin, 293 Desmin, 3, 5–7, 10, 13, 14, 16, 20, 21, 24–28, 34, 36–40, 42, 80, 115,
Chorionic intermediate trophoblasts, 428, 452 187, 279, 281, 284, 287, 289, 292, 293, 351, 356, 378, 380,
Chromogranin A, 216, 222, 293, 338, 343 449
Chromosome abnormalities, 431 Desmoplastic non-invasive implants, 149–151, 389, 391
Chronic deciduitis, 489 Desmoplastic small round-cell tumor (DSRCT), 225, 356, 378, 379
Chronic intervillositis, 501–502 Diandric diploidy, 434
Chronic salpingitis, 64, 69, 71, 432 Diandric triploidy, 440, 443, 484
Chronic villitis, 479, 491, 502, 503, 511 DICER1 syndrome, 317
Ciliated metaplasia (tubal metaplasia), 419 Diffuse decidual leukocytoclastic necrosis, 466
Circumvallate placentas, 466 Diffuse leiomyomatosis, 21
Cistern, 434, 436, 440, 485, 522 Diffuse malignant mesothelioma (DMM), 371, 375, 377–379
Classic vulvar intraepithelial neoplasia, 543 Diffusion-weighted imaging, 134
Clear cell adenocarcinoma (CCA), 398 Dissecting gonadoblastoma, 266
Clear cell carcinoma, 23, 58, 61, 129, 131, 135, 146, 161, 191, 195, Dissecting leiomyoma, 21
253, 258, 259, 295, 355, 358, 420, 545, 560, 617, 618 Disseminated peritoneal leiomyomatosis (DPL), 22, 384, 395–396
Clear cell cystadenoma, 189 Distal villous fetal thrombotic vasculopathy, 508
Clear cell renal cell carcinoma, 358 Distal villous hypoplasia (DVH), 486, 514, 517, 520, 521
Clear cell tumors, 164 Distal villous immaturity, 520, 523
Clitoromegaly, 313 Divergent differentiation, 5, 266
Clue cells, 586 Driver gene, 131, 409
Coagulative necrosis, 17, 18, 249 Driving factor, 95
Coagulopathy, 537 Dualistic model of ovarian carcinogenesis, 121–123, 126
Coelomic epithelium, 407 Dysfunctional uterine bleeding, 104
Collagen balls, 609 Dysgerminoma, 221, 231, 249, 251, 253, 254, 258, 260–262, 264,
Colloid carcinoma, 331 266–268, 311, 360, 563, 564, 618
Colonize, 70, 354 Dyskeratosis, 581
Index 633
Dysmenorrhea, 104, 406 Enlarged villi, 434, 439, 440, 482, 532
Dyspareunia, 405 Eosinophilic clear cell carcinoma, 35
Dysplasia, 542, 543 Eosinophilic metaplasia, 64
Eosinophilic secretion, 226, 244, 342
Ependymoma, 247, 400
E Epidermoid cyst, 562
Early pregnancy, 84, 87, 427–434, 436–441, 443–453, 534 Epithelial membrane antigen (EMA), 9, 10, 13, 14, 24, 81, 115, 211,
E-cadherin, 122 216, 217, 221, 222, 225, 251, 258, 262, 275, 279, 280, 284,
Eclampsia, 486, 514, 523 287, 289, 292–294, 297, 298, 303, 304, 306, 310, 312, 313,
Ectopic 316, 317, 319, 356, 368, 371, 376, 378, 398, 450,
decidua, 69, 86, 89–90, 414, 417, 418 452, 622
decidual reaction, 377 Epithelial-mesenchymal transition (EMT), 122, 385
pregnancy, 53, 61, 65–69, 90, 99, 107, 373, 429, 432, 433, 444, Epithelial metaplasia, 32
548, 553, 555 Epithelial non-invasive implants, 149, 389, 391, 566
Edema of umbilical cord, 506, 508 Epithelioid angiomatosis, 27
Embryo, 67–69, 86, 90, 91, 427, 431, 432, 459, 460, 534 Epithelioid leiomyoma, 19, 20
Epithelial membrane antigen (EMA), 9, 10, 13, 14, 24, 81, 192, 197, Epithelioid leiomyosarcoma, 26, 27, 448–450, 551, 552
211, 216, 218, 225, 251, 253, 260, 275, 284, 287, 292, 293, Epithelioid trophoblastic tumor (ETT), 27, 433, 445, 446, 449, 450,
310, 313, 317, 350, 356, 376, 378, 398, 452, 622 452, 453
Embryonal carcinoma, 236, 253, 258–262, 264, 318, 618 Epoophoron, 81
Embryonal rhabdomyosarcoma (ERMS), 41, 42 Estradiol, 80, 92, 104, 410
Endocervical adenocarcinoma, 324, 344, 345, 544, 584 Estrogen, 5, 10, 19, 31, 59, 79, 84, 86, 97, 130, 148, 157, 159, 174,
Endocervical adenocarcinoma, usual type, 214, 346, 350 195, 214, 225, 274, 282, 286, 298, 300, 310, 319, 324, 407,
Endocervical curettage, 352 409, 410, 421, 581
Endocervicosis, 122, 369, 394, 395 Estrogen receptor (ER), 59, 156, 159, 160, 196, 214, 284, 333, 338,
Endodermal sinus, 192, 196, 253, 255, 564 340, 376
Endometrial adenocarcinoma, 282, 347, 373, 543, 545, 546 Estrogen receptor alpha (ERα), 131
Endometrial carcinoma, 34, 62, 72, 129, 131, 182, 183, 300, 347–350, European Medicines Agency, 135
541, 544–546, 608, 609 Ewing's sarcoma, 225, 226, 247, 248, 379
Endometrial clear cell carcinoma, 617 Exaggerated placental site (EPS), 430, 433, 434, 446, 448, 451, 452
Endometrial curettage, 13, 526 Exogenous hormones, 94, 395
Endometrial endometrioid carcinoma, 182 Expansile growth, 207, 208
Endometrial glands in background, 544 Extramammary Paget disease (EMPD), 542
Endometrial hyperplasia, 183, 218, 275, 282 Extravillous trophoblast, 432–436, 446, 482, 483, 504, 527
Endometrial intraepithelial carcinoma (EIC), 384
Endometrial serous carcinoma (ESC), 59, 60, 62, 348, 546, 548
Endometrial stromal nodule (ESN), 1–8, 16, 552 F
Endometrial stromal sarcoma (ESS), 2, 3, 7, 8, 12, 13, 22, 25, 40, 43, Fasciitis, 38
187, 222, 351, 352, 422, 552, 554 Female adnexal tumor of probable Wolffian origin, 224, 226, 275, 310,
Endometrial stromal tumor(s), 2–3 398–400
with sex cord-like elements, 6, 7, 14, 281 Fetal growth restriction, 465, 484, 511, 512, 518, 521
with smooth muscle differentiation, 5–7, 25 Fetal inflammatory response, 469, 473, 489, 490, 496–498, 506
Endometrioid adenocarcinoma, 34, 131, 157, 161, 166, 304, 335, 338, Fetal thrombotic vasculopathy, 487, 508
344, 349, 350, 354–356, 398, 544, 548, 560 Fetiform teratoma, 234, 238–239
Endometrioid adenofibroma, 175 Fetus papyraceous, 467, 468, 476
Endometrioid carcinoma, 131, 183, 185 Fibroblast, 17, 123–125, 253, 273, 277, 280, 282, 283, 372, 380, 460,
with ciliated cell differentiation, 131 464, 475
with corded and hyalinized component, 317 Fibrosis, 24, 54, 65, 66, 72, 87, 94, 95, 112, 278, 286, 310, 336, 369,
with mucinous differentiation, 166 370, 376, 378, 384, 390, 410, 412, 413, 416, 417, 419, 431,
with sertoli-like or sex cord-like elements, 310 432, 434, 479, 491, 554, 621
with squamous differentiation, 131, 179, 347, 369 Fibroma, 111, 112, 114, 128, 215, 274, 275, 277–279, 281, 284, 289,
Endometrioid cystadenoma, 174–175 300, 301, 303, 327, 339, 351, 352, 360
Endometrioid intraepithelial neoplasia (EIN), 34, 544 Fibromatosis, 38, 110–113, 279
Endometrioid stromal sarcoma, 187, 279 Fibrosarcoma, 187, 211, 240, 274, 275, 279–282, 286
Endometrioid tumor, 59, 174–176, 182, 183, 185, 333, 335 Fibrothecoma, 111, 274, 277, 279, 280, 282, 284, 285, 307,
Endometrioma, 104, 173, 174, 177, 411, 414, 421, 556 319, 560
Endometriosis, 4, 70, 96, 103, 115, 129, 130, 133, 183, 185, 203, 259, Follicular cervicitis, 575, 580, 581, 584, 600
325, 387, 397, 405, 406, 408, 413, 415, 416, 419, 422, 559, Follicular phase, 85, 104
612, 619 Foreign body, 66, 116, 208, 347, 369, 373, 569
Endometriosis-associated tumors, 420, 422 Food and Drug Administration (FDA), 573, 602, 603, 606
Endometriotic cyst, 104, 105, 109, 115, 419, 559 Fumarate hydratase, 29, 30
Endometritis, 580
Endomitosis, 124
Endoreplication, 124, 125 G
Endosalpingiosis, 58, 64, 70, 96, 102–104, 142, 151–153, 167, 369, Gartner’s ducts, 226
384, 387–389, 395, 396, 408, 414, 417, 568–570, 610, Gastric cancer, 324, 329, 566
612–614, 617, 622 Gastric type, adenocarcinoma, 346
634 Index
Gastrointestinal stromal tumor (GIST), 279, 280, 380, 415 Human androgen receptor gene assay, 132
Germ cell tumor, 196, 197 Human chorionic gonadotrophin, 84, 87–89, 105, 428, 433, 548
Germline mutation, 29, 55, 57, 72, 129, 131, 135, 141, 221, 303, 317, Human immunodeficiency virus, 65
352, 354 Human papillomavirus, 214, 346, 347, 350, 543, 572, 574, 582, 603, 607
Gestational diabetes mellitus, 494, 520, 523 Human placental lactogen (hPL), 428
Gestational hypertension, 464, 484 Hyaline degeneration (hyalinization), 250
Gestational trophoblastic diseases (GTD), 429, 432, 433 Hydatid cyst, 58, 70
Ghost villi, 479, 517 Hydatidiform mole, 231, 429–433, 436–439, 441, 443, 445
Gland-poor endometriosis, 43 Hydatids of Morgagni, 70
Glandular cell abnormality, 577 Hydropic abortion, 431, 439, 441
Glandular epithelium, 240, 331, 350, 388, 395, 567 Hydropic degeneration, 18, 432, 482
Glassy cell carcinoma, 344 Hydropic leiomyoma, 18, 19, 28, 550
Gliomatosis peritonei, 234, 235, 238, 384, 385 Hydrops fetalis, 532
Goblet cell carcinoids, 244–246, 291, 335, 337, 338 Hypercalcemic type, small-cell carcinoma, 220, 221, 226
Gonadal ridge, 274 Hyperchromatic crowded groups, 580, 592, 595
Gonadoblastoma, 250, 253, 254, 264–268 Hyperkeratosis, 582
Gonadoblastoma with malignant germ cell tumor, 250 Hyperplasia with atypia, 483
Gonadotropin-releasing hormone (GnRH), 19, 22, 396 Hyperreactio luteinalis, 88–89, 95, 434
Gonorrhea, 68, 99, 573 Hyperthecosis, 84, 95–97, 279, 286, 293, 300
Gorlin’s syndrome, 274, 277, 279 Hypertrophy of myometrium, 43
Granular cell tumor, 543
Granulomatous peritonitis, 369, 568
Granulosa cell, 6, 14, 16, 82, 85, 86, 90, 92, 104–106, 274–277, 282, I
285, 299–308, 310, 312 Immature intermediate villi, 460, 462, 518, 520
Granulosa cell tumors (GCT), 14, 85, 88, 105, 221, 243, 258, 277, Immature teratoma, 114, 234–238, 262, 379, 384, 563, 618
279, 282, 284, 286, 299, 303, 306–309, 317, 319, 344, 351, Immune hydrops fetalis, 533
356, 561, 562, 617, 618 Immunne checkpoint, 135
Growing teratoma syndrome, 238 Immunocytochemistry (immunohistochemistry), 3, 10–12, 14, 16, 19,
Growth factors, 86 21, 25, 26, 30, 32–37, 39, 40, 43, 55, 62, 79, 80, 87, 103,
Gynandroblastoma, 275, 303, 317 133, 195, 213, 214, 220–222, 250, 257, 260, 277, 299, 430,
Gynecologic Cytology, 571–623 434, 484
Implantation, 68, 86, 90, 91, 410, 427, 431, 432, 521, 549
Implantation of fertilized egg, 68, 459
H Implantation site, 68, 91, 239, 428, 432, 433, 436, 446, 451, 452, 482,
Hair-an syndrome, 233, 275 548, 549, 554
Hamartoma, 379, 380 Implantation site intermediate trophoblast, 432
Haploid, 435, 437 Implants, 128, 149–151, 153, 167, 168, 234, 235, 240, 339, 389, 390,
Heave menstrual bleeding (menorrhagia), 38, 300 392, 406, 526, 544, 564, 566, 567
Hemangioma, 61, 224, 465 Imprinted genes, 438
Hemangiosarcoma (angiosarcoma), 27, 43, 240 Inclusion cysts, 57, 64, 102, 103, 122, 142, 144, 619
Hemangiopericytoma, 42, 286, 287, 289 Incomplete abortion, 433, 440
Hepatoid carcinoma, 223 Infantile uterus, 231, 232
Hereditary leiomyomatosis and renal cell carcinoma syndrome, 29 Infarcted appendix epiploica, 373
Herpes, 491, 500, 586, 587 Infarct type necrosis, 447, 550
Herpes simplex virus (HSV), 491, 500 Infiltrative pattern of invasion, 212
Heterogeneous tumors, 12, 126, 173, 243 Inflammatory myofibroblastic tumor, 1, 21, 26, 28, 38–40, 372, 379,
High grade adenocarcinoma of the appendix, 600 380
High-grade endometrioid stromal sarcoma, 59 Inhibin, 7, 14, 16, 80, 85, 87, 92, 98, 225, 307, 398, 399, 429, 445,
High-grade neuroendocrine carcinoma, 341, 344 448, 449, 451, 452, 622
High-grade peritoneal serous carcinoma, 58, 127 Initial endometriosis, 130, 408
High-grade serous carcinoma (HGSC), 54–60, 62, 65, 123, 125–130, Insular carcinoid, 244, 303, 344
133–136, 141, 154–161, 303, 305, 324, 354, 380, 390, 554, Insulin-like growth factor II mRNA-binding protein 3 (IMP-3),
555, 564 24, 26
High-grade squamous intraepithelial lesion (HSIL), 450, 575, 577, Intercellular bridges, 368
588, 591–593, 595, 596 Intermediate trophoblast, 69, 260, 428, 429, 436, 444–446, 449, 451, 453
High-risk HPV, 588 Intermediate villi, 518, 522
Hilar cell nodular hyperplasia, 94 Intervillous spaces, 427, 428, 459, 469, 479, 481, 489, 490, 499, 500,
Hilar cell tumor/hilus cell tumor, 99, 292 502, 504, 516
Hilus cell, 71, 80, 97–99, 144 Intestinal hamartoma, 317
Hilus cell hyperplasia, 71, 97–99 Intestinal type mucinous carcinoma, 132, 559, 617
Hobnail cell, 166, 177, 197, 350, 545 Intra-abdominal desmoplastic small round cell tumor, 378–379
Homeobox, 122 Intraepithelial carcinoma, 132, 148, 165, 208, 209, 352, 559
Homologous adenosarcoma, 31 Intraepithelial neoplasia, 542, 572
Homosexual precocity, 263 Intrahepatic cholestasis of pregnancy (ICP), 536
Homunculus, 234, 238 Intranodal decidua, 396
Hormone replacement therapy, 92 Intraplacental choriocarcinoma, 444, 445
Index 635
Intrauterine device, 100, 101, 555, 580 Lymphoma, 17, 43, 62, 221, 359, 360, 410, 564, 600
Intravenous leiomyomatosis (IVL), 7, 16, 21–22 Lymphovascular invasion, 4, 10, 36, 37, 241, 307, 328, 339, 347, 355,
Invasive implants, 147, 149–151, 153, 389, 390, 392, 614 359, 552
Invasive mole, 433, 442, 443 Lymphovascular space invasion, 305, 334, 339, 343, 347, 390
Lynch syndrome, 181, 193, 195
Lynch syndrome related endometrial cancer, 185
J
Juvenile granulosa cell tumor, 307, 379, 561
M
Macrofollicular, 300, 301, 307, 561
K Maffucci’s syndrome, 274, 281
Keratinizing squamous cell carcinoma, 449, 594, 597 Malignant Brenner tumor, 123, 131–133, 215, 218, 219, 358, 359, 560
Koilocytes, 543, 592 Malignant melanoma, 239, 249, 304, 357, 369, 599
Krukenberg tumors, 246, 291, 317, 325, 327–330, 336, 337, 339, Malignant mesothelioma (MM), 162, 372, 374–378, 394, 612, 619,
340, 355 620
Malignant mixed mesodermal tumors, 600
Malignant mixed Müllerian tumor (MMMT), 59, 123, 133–134, 237
L Massive ovarian edema, 110, 111, 279, 286
Large cell neuroendocrine carcinoma, 222 Massive perivillous fibrin deposition, 504
Large solitary luteinized follicle cyst, 89, 105 Maternal inflammatory response, 489, 496, 497
Large vessel fetal thrombotic vasculopathy, 487 Mature cystic teratomas, 132, 133, 210, 232–234, 239, 381, 569
Leiomyoma, 7 Mature intermediate villi, 460, 462
with bizarre nuclei, 19, 25, 29, 30, 279 Mature solid teratomas, 234
Leiomyomatosis, 7, 21, 384, 395–397, 419, 569 Mature teratomas, 232
Leiomyosarcoma (LMS), 7, 10, 12, 13, 16, 18, 21–29, 37, 40, 61, 281, Mayer-Rokitansky-Kuster-Syndrome, 407
350, 351, 380, 396, 551–553 Medulloepithelioma, 247, 317
Leiomyosarcoma with osteoclast-like giant cells, 5 Meigs’ syndrome, 274, 279
Leukemia, 43, 359, 360, 536 Melanocytic lesions, 542
Leydig cell, 14, 71, 80, 97, 266, 273, 274, 297, 315, 562 Melanocytic tumor, 249
Leydig cell proliferations, 71 Melanoma cell adhesion molecule, 429
Leydig cell tumor, 274, 275, 277, 292, 293, 295, 296, 299, 303, 310, Melanosis, 54, 369
314–318 Menarche, 135, 154, 254, 274, 405–407, 421
Lichen sclerosus (sclerosis), 543 Menopause, 41, 57, 80, 84, 85, 96, 154, 274, 406, 421
Lichen simplex chronicus, 543 Menstrual cycle, 19, 54, 104, 108, 550, 578
Lineage infidelity, 122, 131 Menstruation, 407, 421
Lipid-rich Sertoli cell tumor, 310 Merkel cell carcinoma, 361
Lipofuscin, 54, 71, 98, 506 Mesenchymal neoplasms, 551
Lipoleiomyoma, 19, 21, 551 Mesenchyme, 122, 234, 394, 427
Lipoma, 21 Mesonephric ducts, 226, 389, 397, 398
Liposarcoma, 21, 61, 380 Mesonephric remnants, 226, 389
Liquid-based cytology, 573, 574 Mesothelial hyperplasia, 64, 113, 370–372, 376, 419, 568, 614
Listeria, 431, 490, 500, 502 Mesothelioma, 41, 62, 90, 113, 157, 162, 168, 223–225, 279, 324,
Lobular endocervical glandular hyperplasia, 62 372, 376, 379, 395, 567, 568, 621, 622
Lobulated ovary, 292 Mesovarium, 98
Loop electrosurgical excision procedure of cervix (LEEP), 543 Metaplastic papillary tumor, 58, 64
Loss of heterozygosity (LOH), 25, 55, 133, 153, 181, 190, 210, 221, Metastasizing leiomyoma, 22, 396
279 Metastatic carcinoma, 62, 88, 152, 213, 613
Lower uterine segment (LUS), 31, 34, 344, 450, 515, 526–528, 544, Metastatic renal cell carcinoma, 295
545, 580 Microcystic, elongated, and fragmented (MELF), 548
Low-grade endometrial stromal sarcoma (LGESS), 1, 2, 20, 279, 281, Microcystic stromal tumor (MST), 275, 283, 289, 296–298
350, 352 Microfollicular, 90, 300, 301, 307, 561
Low-grade endometrial stromal sarcoma with limited infiltration, 3 Microglandular hyperplasia, 595
Low-grade mucinous neoplasm of the appendix, 381 Microinvasion, 132, 148, 149, 152, 165, 190, 208, 209
Low-grade peritoneal serous carcinoma (LGSC), 390 Microinvasive carcinoma, 209
Low-grade serous carcinoma, 58, 59, 123, 126, 127, 130, 133, 141, Microphthalmia-associated transcription factor (MiTF), 36
157–164, 389, 422, 557 MicroRNA/miRNA, 407, 409, 605
Low grade squamous intraepithelial lesion (LSIL), 592, 602, 605 Mitogen-activated protein kinase (MAPK), 153, 160, 409
Low-risk HPV, 602, 603 Mitotic activity, 8, 15, 19, 21, 28, 29, 31, 33, 40, 56, 59, 64, 65, 87, 90,
Luminal epithelium (LE), 428 111, 156, 158, 160, 162, 209, 221, 222, 224, 225, 227, 236,
Luteal phase, 17 330, 331, 333, 351, 376, 550, 551, 553, 568, 590, 600, 619
Luteinization, 105, 232, 301 Mitotically active cellular fibroma, 278
Luteinized follicular cyst, 89, 105, 106, 109 Mitotically active leiomyoma, 19
Luteinized thecoma, 87, 275, 279, 282–286, 293 Mitotic index, 24, 25, 29, 197, 283, 293, 295, 307, 557
Luteinized thecoma associated with sclerosing peritonitis, 282–287 Mixed epithelial-mesenchymal tumors, 58
Luteinizing hormone (LH), 84 Mixed germ cell-sex cord-stromal tumors, 264
Luteoma of pregnancy, 87, 89, 308 Mixed germ cell tumors, 249, 264, 265, 268, 317
636 Index
Monodermal teratomas, 298 Nuclear grooves, 15, 90, 241, 299, 301–304, 307, 356, 562, 617
Morula, 427, 459 Nuclear molding, 599
Morular metaplasia, 34, 547
Mucinous adenocarcinoma, 316, 339, 382, 383, 395
Mucinous adenofibromas, 205 O
Mucinous borderline tumor, 148, 164, 207, 209–212, 338, 340, 345, Omental mesenteric myxoid hamartoma, 380
347, 381, 559, 560 Opportunistic salpingectomy, 135
with intraepithelial carcinoma, 209 Ovarian atrophy, 96
with microinvasion, 209, 211 Ovarian cortex, 80–82, 90, 92, 97, 102, 103, 126, 128, 273, 283, 313,
Mucinous carcinoid, 244, 292, 329 324, 398, 408
Mucinous carcinoma, 63 Ovarian cortical fibromatosis, 112–113
gastric type, 345 Ovarian epithelial carcinomas, 129–134, 220, 356
signet-ring cell type, 225 Ovarian epithelial inclusion, 122, 346, 408, 417
Mucinous cell carcinoid, 245, 291 Ovarian hilus, 71, 80, 296
Mucinous cyst, 561 Ovarian inclusion cysts, 142
Mucinous cystadenocarcinoma, 338 Ovarian infection, 99, 102
Mucinous cystadenoma, 103, 132, 143, 204–206, 338–340, 383, 395, Ovarian pregnancy, 91, 239, 262
559, 560 Ovarian remnant syndrome, 114–115
Mucinous metaplasia, 58, 62 Ovarian stromal hyperplasia, 286
Mucinous tumor, 132, 206, 208, 310, 334, 343, 382, 383 Ovarian stromal hyperthecosis, 286, 293
Müllerian adenosarcoma, 31, 33, 34 Ovarian surface epithelium, 57, 79, 80, 102, 113, 121, 141, 142, 352,
Müllerian duct, 397 353
Multispectral fluorescence imaging, 134 Ovarian torsion and infarction, 111, 112
Mural nodules, 63, 204, 210, 211 Ovulatory cycle, 82, 83
Mutation, 61, 126, 128, 190, 195, 196
Myofibroblastoma, 380
Myometrial invasion, 1, 9–11, 27, 34, 345, 447, 449, 544, 546, 548, 552 P
Myxoid Paget’s disease, 542
degeneration, 17, 431 Pap smears, 167, 352, 573–575, 580–584, 588, 599, 600, 606, 607
hamartoma, 379 Papillary cystadenoma (with von hipple-lindau disease), 398
leiomyoma, 19–21, 28, 40 Papillary proliferation of the endometrium, 143, 207, 392, 612
leiomyosarcoma, 12, 18, 21, 27–28, 40, 551 Papillary tubal hyperplasia, 58, 64
material, 20, 255 Papilloma, 58, 64, 143, 418
Parabasal cells, 578, 590
Parakeratosis, 543, 588, 590
N Parasitic leiomyoma, 384
Necrotic pseudoxanthomatous nodules, 369 Parietal, 256, 258, 259, 367, 375, 608
Necrotizing chorioamnionitis, 477, 496, 497 Partial hydatidiform mole (PHM), 433, 439–441, 443, 444, 482, 483
Necrotizing funisitis, 490, 491, 496, 498 Pelvic inflammatory disease (PID), 64, 66–68, 83, 91, 99, 100, 114,
Negative for intraepithelial lesion, 574, 577, 586, 590 406, 555
Neisseria gonorrhoeae, 65, 555 Pelvic washings, 153, 607–609
Neuroblastoma, 222, 226, 359, 379, 536 Perimenopause, 97, 98
Neuroblastoma, 222, 226, 247, 349, 361, 379, 536 Peripheral neuroectodermal tumor, 222
Neuroectodermal-type tumors, 247 Peritoneal fibrosis, 286, 369
Neuroendocrine carcinoma, 222 Peritoneal inclusion cysts, 224, 371, 372, 375, 419, 568, 569, 612
non-small-cell type, 222 Peritoneal serous borderline tumors, 167–168, 388–390
Neuroendocrine differentiation, 335, 337 Perivascular epithelioid cell tumor (PEComa), 1, 35–38
Neuroendocrine neoplasms, 243, 342 Peutz-Jeghers syndrome (PJS), 62, 274, 310, 312, 334
Neurofibromatosis type 1 (NF1), 129 Phoshatase and tensin homolog (PTEN), 166, 409
Neuron-specific enolase (NSE), 225, 293 Picket fence, 578
Nevoid basal cell carcinoma syndrome, 281 Pituitary adenoma, 249
Nodular goiter, 317 accreta, 462, 463, 494, 526–528
Non-gestational choriocarcinoma, 261, 262, 445, 446, 556 increta, 527
Non granulomatous histiocytic lesions, 369 membranacea, 467
Non-hilar cell, 296 percreta, 526, 527
Non immune hydrops fetalis (NIHF), 533 Placental alkaline phosphatase, 197
Non-invasive implants, 389 Placental infections, 499–503
Non-invasive low-grade serous carcinoma, 127 Placental inflammation, 495, 496, 498–501
Non-keratinizing carcinoma, 448, 594 Placental mesenchymal dysplasia (PMD), 439, 441, 443, 484, 485,
Non-keratinizing squamous cell carcinoma, 448 522, 523
Non-luteinized follicle cyst, 104, 105 Placental site nodules and plaques, 430, 433
Non-small cell neuroendocrine carcinoma (NSCNEC), 222 Placental site trophoblastic tumors, 69, 350, 430, 433, 445, 446,
Nuclear atypia, 21, 24–27, 29, 37, 42, 64, 156, 158, 175, 189, 190, 448–453
194, 207, 215, 236, 245, 256, 278–282, 286–288, 291, 293, Placentomegaly, 484
295, 307, 310, 312, 316, 317, 319, 336, 350, 371, 377, 390, Pleuropulmonary blastoma, 317
419, 436, 446, 450, 548, 551, 553, 558, 566, 568 P53 nonsense mutation(null-pattern), 156
Index 637
Polycystic ovarian syndrome (PCOS), 94–95, 110 Secretory cell outgrowth, 55, 127, 128
Polyembryoma, 258, 261–263 Sectioning and Extensively Examining the Fimbria (SEE-FIM), 53,
Polypoid adenomyoma, 418 72, 134
Polypoid endometriosis, 70, 415, 418 Selective estrogen receptor modulators, 19
Polyvesicular, 192, 196, 256, 564 Seminoma, 249, 250
Postmenopausal bleeding, 3, 12, 14, 23, 35, 300, 452 Sentinel lymph node, 570
Precancer, 607 Seromucinous, 422
Pre-eclampsia, 88, 440, 464, 473, 485, 514, 523 Seromucinous adenofibromas, 164
Premature ovarian failure (POF), 91–92, 94 Seromucinous borderline tumors, 164–167, 214
Preovulatory follicle, 82, 83, 104 Seromucinous carcinoma, 123, 129–131, 133, 135, 157, 164, 166
Preterm birth, 526, 536 Seromucinous cystadenoma, 164
Primary carcinoid tumor, 342 Seromucinous tumors, 131, 164, 203, 205, 207, 333, 422
Primary carcinoma, 329, 354, 554 Serous, 58
Primary follicles, 81, 82, 92, 93, 104 Serous adenocarcinoma, 376, 378, 387, 388, 393, 394, 400
Primary tumor, 34, 43, 132, 238, 246, 262, 323–325, 327, 330, 335, Serous adenofibroma, 58, 61, 143
338, 340, 342–344, 347, 349–354, 357, 379, 385, 399, 535, Serous borderline tumor (SBT), 58, 72, 126, 141–142, 144–153, 159,
600, 617, 621 163, 164, 167, 209, 370, 371, 375, 384, 388–391, 398, 556,
Primitive neuroectodermal tumor (pnet), 226, 235, 237, 247, 379 557, 560, 565, 566, 570, 614, 615
Primordial follicle, 81, 82, 94, 104 Serous borderline tumor−micropapillary variant, 126, 127
Primordial germ cells, 231, 232 Serous carcinoma, 53, 55, 57–60, 64, 102, 122, 123, 125–129, 134,
Progesterone, 19, 54, 70, 79, 80, 84, 86, 108, 116, 159, 180, 195, 274, 135, 146, 153, 154, 156, 158, 164, 166, 168, 180, 181, 189,
324, 409, 410, 419, 550, 581 196, 203, 215, 218–220, 225, 260, 305, 318, 352, 358, 359,
Progesterone receptor (PR), 5, 10, 26, 34, 80, 116, 148, 157, 159, 214, 386, 387, 389, 390, 392, 394, 420, 421, 546, 547, 554–558,
225, 284, 396, 409, 410 564–568, 608, 614, 617–619
Progestin, 59, 68, 70, 89, 410, 415 Serous cystadenoma, 67, 103, 104, 126, 127, 142–144, 158, 164, 398,
Progestin therapy, 13, 352, 395 556–557
Proliferative phase, 4, 12, 281, 578 Serous endometrial intraepithelial carcinoma, 56
Prophylactic bilateral salpingectomy, 127 Serous ovarian cancer, 219
Psammoma body, 293 Serous psammocarcinoma, 220, 390
Pseudocarcinomatous hyperplasia, 64, 65 Serous serous carcinoma, 129
Pseudoepitheliomatous hyperplasia, 543 Serous tubal epithelial carcinoma (STIC), 133
Pseudomyxoma peritoneii, 567 Serous tubal intraepithelial carcinoma (STIC), 53–58, 62, 72, 123,
Pseudopapillary, nodular, 307 127–130, 134, 141, 154, 168, 349, 352, 354, 384, 386, 387,
p53 signatures, 54, 55, 127–130, 141 554, 555
Pushing border, 40 Serous tubal intraepithelial lesion, 58
Serous tumor, 126, 144–146, 316, 371, 375
Sertoli cell, 6, 14, 227, 299, 310
R Sertoli cell tumor (SCT), 90, 275, 311
Red degeneration, 551 Sertoli-Leydig cell tumor (SLCT), 16, 243, 247, 274, 310, 314–316,
Resistant ovary syndrome, 94 343, 344, 349–351, 399, 561, 563, 618
Rete ovarii, 81, 132, 144, 223, 414, 417, 418 Sertoli-Leydig cell tumor with heterologous Elements, 316
Rete testis, 81, 223 Severe preeclampsia, 521
Retinal anlage tumors, 249 Sex-cord element, 299–300
Retrodifferentiation, 254 Sex cord-stromal tumor (SCSTs), 16, 180, 227, 247, 265, 266, 268,
Retroplacental hemorrhage, 467–469, 486 273–275, 277, 279, 282, 292, 300, 303, 310, 312, 313, 317,
Rhabdomyoma, 533 319, 325, 351
Rhabdomyosarcomas (RMS), 26, 32, 33, 41, 42, 61, 222, 226, 237, Sex cord-stromal tumor with annular tubules (SCTAT), 267, 268, 274,
314, 317, 379 275, 312, 313
Sex steroid hormone, 409
Signet-ring-like cells, 193
S Signet ring stromal tumors (SRSTs), 279, 289–292, 317
Salpingitis isthmica nodosa, 58, 62, 65, 68, 69, 555 Simple cysts, 70, 102, 103, 105, 398, 568
Sarcomas, 1, 8–13, 19, 26, 31, 33, 61, 239, 280, 318, 380, 552, 615 Simple papillae, 614
Sarcomatoid, 133, 279, 281, 282, 300, 301, 303, 304, 307, 315, 316, Single exon gene, 303
319, 568, 618, 621 Single umbilical artery (SUA), 465, 494, 507, 508, 523
Sarcomatous overgrowth, 32–34 Single-exon gene, 303
Schiller-duval body, 192, 258–260, 263, 308, 564 Small cell carcinoma of the hypercalcemic type (SCCH), 222, 251,
Schistosomiasis, 65, 102 253, 304, 309, 329, 357, 360
Sclerosing stromal tumor (SST), 274, 275, 279, 284, 286–289, 291, Small cell carcinoma, pulmonary type, 222, 361
298, 303, 329 Small placentas, 464
Sebaceous tumors, 248 Smooth muscle tumor, 1, 5–7, 16, 19–26, 28, 35, 37, 39, 40, 279, 395,
Seborrheic keratosis, 543 429, 450, 453, 569
Secondary follicles, 81, 82, 104 Smooth muscle tumors of uncertain malignant potential, 16, 24, 26, 28
Secondary Müllerian system, 121, 122, 384 Solid, (pseudo)endometrioid, transitional cell carcinoma-like (set),
Secondary tumors, 127, 323–361 128
Secretory cell expansion (SCE), 55, 127 Solitary fibrous tumor, 35, 42, 380, 381
638 Index
Somatic cell, 132 Trabecular carcinoid, 243, 244, 246, 247

Somatic missense mutation, 224, 303 Transformation zone, 573, 574, 576
Somatic mutations, 124, 129, 135, 157, 159, 218, 221, 298, 303, 308, Transition, 17, 24, 126, 130, 218, 240, 328, 329, 385, 420
310, 317, 409 Transitional cell carcinoma/transitional carcinoma, 155, 215, 219, 308,
Spectrum, 35, 53, 54, 57, 83, 85, 96, 110, 113, 127, 153, 237, 274, 344, 347, 358, 555
275, 361, 409, 432, 443, 451, 483, 503, 519, 581, 588, 621, Transitional cell metaplasia/transitional metaplasia, 81, 133,
622 215, 217, 395, 554
Spindle cell endometrioid carcinoma, 279, 300, 307 Tree, these structures consist of grape-like outgrowths of
Splenosis (implantation of splenic tissue), 372, 373, 569 the mature, 460
Spontaneous abortions, 239, 429–431, 433, 443, 451, 502, 523, 529, Trichomonas vaginalis, 575
530, 534 Triploid, 435, 437, 439, 441, 443, 484, 522
Spontaneous preterm birth, 495 Trophoblastic hyperplasia, 431, 434, 439–441, 443, 482–485, 522
Squamous cell carcinoma, 219, 220, 237, 239, 344–347, 356, 359, Trophoblastic implants, 373
450, 453, 542, 543, 572, 575, 577, 580, 594, 599, 600, 603 Trophoblastic inclusions, 434, 440, 441
Squamous epithelial cells, 575, 577 Truncating mutations, 25, 317
Squamous intraepithelial lesion (SIL), 574, 588, 590, 595, 605 Tryptophan, 303
Squamous metaplasia (SM), 240, 372, 395, 398, 466, 468, 475, 476, Tubal carcinomas, 554
569, 575, 581, 619 Tubal dysplasia, 54, 128
Stem cells, 122, 123, 125, 222, 232, 238, 384, 407 Tubal hyperplasia, 58
Stem villi, 428, 443, 460, 462, 484–486, 519, 521, 523 Tubal metaplasia, 31, 575, 581
Steroid cell tumor, 87, 274–276, 292–296, 298, 303, 309, 311, 318, Tubal prolapse, 70
357, 358 Tubal serous tubal intraepithelial carcinoma, 127
Steroid hormone, 80, 83, 84, 122, 123, 409, 422 Tuberculosis, 65, 66, 100, 101, 234, 369, 432, 555
Steroidogenic factor 1 (SF-1), 15, 275, 276 Tuberous sclerosis complex, 35, 37
Storiform pattern, 38, 217, 277, 561 Tubo-ovarian serous carcinoma, 325
Stromal endometriosis, 418 Tubular Krukenberg tumor, 317
Stromal hyperplasia, 84, 96–98, 279, 286, 300, 414, 417 Tumor cell necrosis, 24, 25, 29, 37, 38, 40
Stromal hyperthecosis, 95, 97, 98, 286, 293 Tumor heterogeneity, 155, 349
Stromal luteinization, 94, 244, 324, 325, 327, 328, 330 Tumors associated with rete ovarii, 223
Stromal luteoma, 97, 275, 292 Tumors of low malignant potential, 62, 206, 565
Stromal tumor, 276 Tumors, secondary, 254
Stromal tumor with minor sex-cord element, 280, 299, 300 Tumor staging, 134
Struma ovarii, 216, 240, 241, 243, 247, 298, 304, 315, 343, 357, 360 Turner syndrome, 92, 266, 581
Strumal carcinoid, 243, 244, 247 Twin-twin transfusion syndrome, 463, 472, 508
Surface papilloma, 143, 144
Symplastic leiomyoma, 29, 282
Synaptophysin, 222, 225, 237, 246, 247, 338, 343, 356 U
Syncytial knots, 477, 478, 481, 482, 486, 516–518, 520, 521 Umbilical cord, 427, 441, 460, 462, 464, 465, 467, 468, 472–475,
Syncytiotrophoblasts (ST), 250, 251, 253, 260–263, 427–429, 435, 486, 487, 489–491, 494, 495, 497–500, 506–510,
440, 443–446, 449, 460, 477, 482, 515, 518, 519, 524, 525, 521, 534, 535
535, 536, 580 Umbilical cord blood, 509
Syphilis, 491, 500–502 Umbilical cord flow, 509
Umbilical cord knots, 487, 488, 506
Umbilical phlebitis, 496, 498
T Unclassified adenocarcinoma, 220
Tamoxifen, 31, 104, 174, 550 Undifferentiated carcinoma, 9, 13, 123, 131, 133–134, 187, 220, 240,
Teratoid carcinosarcoma, 237 241, 279, 353, 357, 360, 361, 600
Teratoma, 58, 114, 132, 133, 210, 214, 216, 220, 231, 232, 234, 235, Undifferentiated small cell carcinoma, 182
237–241, 243–247, 254, 264, 303, 310, 325, 333, 336, 338, Undifferentiated uterine sarcoma (UUS), 1, 8, 10, 12–14, 25
343, 352, 357, 360, 361, 369, 384, 556, 563, 565, 569 Urothelial carcinoma, 154, 164, 216–219, 355, 358
Teratomatous, 297, 298 Uterine sex cord-like tumor, 5, 16
Teratoma with malignant transformation, 239 Uterine tumor resembling ovarian sex-cord tumor (UTROSCT),
Terminal villi (TV), 428, 439, 461, 462, 477, 478, 484–486, 502, 532 14–16
Testosterone, 80, 84, 87, 95, 124, 292, 295, 389 Uteroplacental vascular system, 468
The Cancer Genome Atlas (TCGA), 124, 157
The lower anogenital squamous terminology standardization project
for hpv-associated lesions (last), 591 V
The secondary Müllerian system, 367, 384, 385, 387, 388, 394 Vaginal bleeding, 40, 41, 68, 105, 226, 232, 261, 274, 292, 432, 434,
Theca cells, 82, 84, 92, 94, 95, 104–108, 114, 273, 274, 282 440, 441, 444, 447, 450, 524
Thecoma, 217, 274, 275, 277, 279, 282–287, 289, 293, 297–300, 302, Varicella, 500
303, 318, 351, 560–561 Varicella-zoster virus, 519, 520
Thecomatosis, 283 Varices, 495, 510
Thrombophilia, 515 Velamentous insertions, 464, 508
Tophoblastic inclusions, 434 Villitis of unknown etiology (VUE), 479, 480, 500, 502, 503
Torsion of the tube, 70 Villous edema, 490, 491, 522
Index 639
Villous fibrosis, 431, 432, 491 X

Villous intermediate trophoblast (VIT), 429, 431, 435, 436 Xanthogranulomatous, 66, 67, 99
Villous stromal-vascular karyorrhexis, 487, 513
Villous trophoblast columns, 428
Vulvar intraepithelial neoplasia (VIN), 543 Y
Yolk sac, 192, 197, 223, 224, 231, 232, 236, 251, 253, 257, 263, 308,
341, 350, 427, 467, 468, 476
W Yolk sac tumors, 192, 196, 197, 224, 236, 237, 253–255, 257–261,
Walthard nest, 132, 133, 215, 217, 395, 554, 555 264, 266, 298, 341, 349, 564, 618
Well-differentiated papillary mesothelioma (WDPM), 374, 375, 612, Ywhae, 9, 10, 12
619
Wolffian duct, 226, 398
World Health Organization (WHO), 1, 8, 19, 58, 144, 275, 286, 292, Z
433, 566 Zoster, 500

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Wenxin Zheng

Gynecologic and Obstetric

Gynecologic and Obstetric

ISBN 978-981-13-3018-6 ISBN 978-981-13-3019-3 (eBook)

© Science Press & Springer Nature Singapore Pte Ltd. 2019

Dallas, TX Wenxin Zheng

To my everything, Shelly, and my wonderful children Dexter, Bernice, and Alice.

1 Uterine Mesenchymal Lesions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

16 Principles and Practical Guidelines of Intraoperative Consultation. . . . . . . . . . 541

Oluwole Fadare Dr. Oluwole Fadare is a Professor of

Donghui Guo Dr. Guo graduated from the Fourth Military

Charles Matthew Quick Dr. Charles “Matt”hew Quick is an

Danhua Shen Dr. Danhua Shen, Associate Professor of

Wenxin Zheng Dr. Zheng is a tenured Professor in the

ovarian serous carcinoma, molecular mechanism of progestin

Emily Paull Acheson Department of Pathology, College of Medicine, University of Arkansas

Mary Kinloch Saskatoon City Hospital, Saskatoon, SK, Canada

Abstract ­ esenchymal tumors that may be encountered in the uterus.

© Science Press & Springer Nature Singapore Pte Ltd. 2019 1

Fig. 1.2 Endometrial stromal nodule. This is an example of an endo-

mass, or occur deep within the myometrium with no appar-

endometrial stromal neoplasms. Similarly, HCL like other

1.2.1.6 Differential Diagnosis 1.2.2 E

Fig. 1.10 Endometrial stromal tumors with smooth muscle differentia-

of LGESS/ESN, but may not be present or be difficult to

1.2.2.12 Management and Outcomes

(“dedifferentiated carcinoma”) rather than HGESS. In cases 1.2.4 U

1.2.4.5 Differential Diagnosis 1.2.5.3 Gross Findings

1.2.5 Undifferentiated Uterine Sarcoma

1.2.5.2 Clinical Features

while type 2 represents what we currently consider to be

1.2.7.2 Clinical Features

1.2.7.3 Gross Findings

varying degrees, particularly in the luteal phase of reproduc-

1.3.1.5 Secondary and Iatrogenic Changes

but large hemorrhagic areas are not characteristic. Similarly,

1.3.1.4 Microscopic Findings

1.3.2.3 Highly Cellular Leiomyoma

1.3.2.4 Epithelioid Leiomyoma

1.3.2.7 Leiomyoma with Other Cellular 1.3.2.10 Intravenous Leiomyomatosis

1.3.2.11 Benign Metastasizing Leiomyoma

1.3.2.12 Disseminated Peritoneal

a­ppearance of typical uterine leiomyoma. Similarly, the

1.3.3.1 Definition (Conventional

1.3.3.2 Clinical Features

Fig. 1.30 Conventional leiomyosarcoma, microscopic appearance.

that do not meet these diagnostic thresholds may be catego-

1.3.3.6 Genetic Profile including STUMP and atypical leiomyoma (“leiomyoma

diagnosis of epithelioid LMS is broad and includes other

t­ypically show normal p53 and p16 staining. Perhaps even

1.4.2 Mullerian Adenosarcoma

1.4.2.2 Clinical Features

Fig. 1.40 Adenosarcoma, low-power histologic appearance. Low-­

Fig. 1.42 Adenosarcoma, microscopic appearance. (a) Periglandular

>25% of the tumor. Sex cord-like differentiation may also

Dallas, TX Wenxin Zheng

1 Uterine Mesenchymal Lesions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

16 Principles and Practical Guidelines of Intraoperative Consultation. . . . . . . . . . 541

Abstract esenchymal tumors that may be encountered in the uterus.

1.2.1.6 Differential Diagnosis 1.2.2 E

1.2.2.12 Management and Outcomes

1.2.4.5 Differential Diagnosis 1.2.5.3 Gross Findings

1.2.5 Undifferentiated Uterine Sarcoma

1.2.5.2 Clinical Features

1.2.7.2 Clinical Features

1.2.7.3 Gross Findings

1.3.1.5 Secondary and Iatrogenic Changes

1.3.1.4 Microscopic Findings

1.3.2.3 Highly Cellular Leiomyoma

1.3.2.4 Epithelioid Leiomyoma

1.3.2.7 Leiomyoma with Other Cellular 1.3.2.10 Intravenous Leiomyomatosis

1.3.2.11 Benign Metastasizing Leiomyoma

1.3.2.12 Disseminated Peritoneal

appearance of typical uterine leiomyoma. Similarly, the

1.3.3.1 Definition (Conventional

1.3.3.2 Clinical Features

1.3.3.6 Genetic Profile including STUMP and atypical leiomyoma (“leiomyoma

typically show normal p53 and p16 staining. Perhaps even

1.4.2 Mullerian Adenosarcoma

Fig. 1.40 Adenosarcoma, low-power histologic appearance. Low-

1.4.5 Atypical Polypoid Adenomyoma

1.5.6 Angiosarcoma Features that are helpful in distinguishing between an

2.2 Fallopian Tube Anatomy

2.3 elationship with Pelvic Serous

Papillomas 2.4.2.3 Malignant Tumors

2.6.2 Tubo-ovarian Abscess

2.6.2.2 Granulomatous Salpingitis

2.6.2.3 Evolution and Outcomes Pyosalpinx

2.6.3.4 Secondary Disorders Associated

2.6.5 Pregnancy-Related Changes

2.6.7.1 Torsion of the Tube 2.6.7.3 Paratubal Cyst

2.7.2 Uterus with Attached Bilateral Tubes 2.7.4 T

Abstract 3.1 natomy, Histology, and Function

a trophies and corpora albicantia and large vessels remain in

3.2 Pregnancy-Associated Findings

3.2.1 Corpus Luteum of Pregnancy

3.2.1.1 Clinical Features

3.2.2.1 Clinical Features

3.2.2.3 Differential Diagnosis

3.2.3 Hyperreactio Luteinalis

3.2.3.1 Clinical Features

3.2.3.3 Differential Diagnosis

3.2.4.1 Clinical Features

3.2.6.3 Differential Diagnosis

3.2.7 Ovarian Ectopic Pregnancy

3.2.7.1 Clinical Features

3.3.3.1 Clinical Features

3.3.5 Ovarian Endometriosis

3.4 varian Findings in Perimenopausal

3.4.1 Ovarian Atrophy