Thyroid Surgery

Thyroid Surgery
Thyroid Surgery
Principles and Practice
Edited by
Madan Laxman Kapre
First edition published 2020
by CRC Press
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Library of Congress Cataloging-in-Publication Data
Names: Kapre, Madan, editor.

Title: Thyroid surgery : principles and practice / edited by Madan Kapre.
Other titles: Thyroid surgery (Kapre)
Description: First edition. | Boca Raton : CRC Press, 2020. | Includes bibliographical references and index. |
Summary: “This book will bridge a gap between the huge platform of literature available on the subject of thyroid
surgery and the pratical working reality. The pearls in techniques and surgical procedures will be exhaustively
detailed with authors’ individual experience enriched with quality photographs”-- Provided by publisher.
Identifiers: LCCN 2020006268 (print) | LCCN 2020006269 (ebook) | ISBN 9781138483781 (hbk) | ISBN 9780429086076 (ebk)
Subjects: MESH: Thyroid Diseases--surgery | Thyroid Gland--surgery | Thyroid Neoplasms--surgery | Thyroidectomy
Classification: LCC RD599.5.T46 (print) | LCC RD599.5.T46 (ebook) | NLM WK 280 | DDC 617.5/39--dc23
LC record available at https://lccn.loc.gov/2020006268
LC ebook record available at https://lccn.loc.gov/2020006269
ISBN: 9781138483781 (hbk)

ISBN: 9780429086076 (ebk)
Typeset in Minion
by Nova Techset Private Limited, Bengaluru & Chennai, India
CONTENTS
Preface vii
Acknowledgments ix
Editor xi
Contributors xiii
Introduction xvii
CHAPTER 1 HISTORY AND EVOLUTION OF THYROID SURGERY 1

Cheerag Patel and Subhaschandra Shetty
CHAPTER 2 SURGICAL ANATOMY OF THE THYROID 7

Ashutosh Mangalgiri and Deven Mahore
CHAPTER 3 CLINICAL ASSESSMENT OF THE THYROID NODULE 15

Madan Laxman Kapre, Shripal Jani, and Priya Dubey
CHAPTER 4 IMAGING OF THE THYROID 21

Alka Ashmita Singhal
CHAPTER 5 PATHOLOGY OF THE THYROID 45

R. Ravi
CHAPTER 6 MEDICAL MANAGEMENT OF THYROID DISORDERS 51

Himanshu Patil and Shailesh Pitale
CHAPTER 7 ANESTHESIA FOR THYROID SURGERY 57

Vidula Kapre, Shubhada Deshmukh, Pratibha Deshmukh, Meghna Sarode, and Rajashree Chaudhary
CHAPTER 8 SAFE THYROIDECTOMY 67

Madan Laxman Kapre, Sankar Viswanath, Rajendra Deshmukh, and Neeti Kapre Gupta
CHAPTER 9 SURGERY FOR MULTINODULAR GOITER 75

Madan Laxman Kapre, Sanoop Elambassery, Neeti Kapre Gupta, M. Abdul Amjad Khan, and Gauri Kapre Vaidya
CHAPTER 10 MANAGEMENT OF RETROSTERNAL GOITER 79

Belayat Hossain Siddiquee
CHAPTER 11 REMOTE ACCESS ENDOSCOPIC AND ROBOTIC THYROIDECTOMY 83

Kyung Tae
CHAPTER 12 ROBOTIC THYROIDECTOMY 91

Neil S. Tolley and Christian Camenzuli
CHAPTER 13 INTRA-OPERATIVE NEURAL MONITORING 97

Rahul Modi
v
CHAPTER 14 SURGICAL MANAGEMENT OF DIFFERENTIATED THYROID CANCERS 105
Anil D’cruz and Richa Vaish
CHAPTER 15 MANAGEMENT OF NODAL METASTASIS IN THYROID CANCER 113

Neeti Kapre Gupta, Ashok Shaha, Madan Laxman Kapre, Nirmala Thakkar, and Harsh Karan Gupta
CHAPTER 16 COMPLICATIONS OF THYROID SURGERY 119

Gregory W. Randolph, Dipti Kamani, Cristian Slough, and Selen Soylu
CHAPTER 17 LOCALLY ADVANCED THYROID CANCER 127

Amit Agarwal and Roma Pradhan
CHAPTER 18 SURGICAL MANAGEMENT OF MEDULLARY THYROID CANCERS 135

Anuja Deshmukh and Anand Thomas
CHAPTER 19 SURGICAL MANAGEMENT OF ANAPLASTIC THYROID CANCERS 147

Deepa Nair and K.S. Rathan Shetty
CHAPTER 20 POST-TREATMENT SURVEILLANCE OF THYROID CANCER 151

Abhishek Vaidya
CHAPTER 21 APPLICATIONS OF RADIOISOTOPES IN THE DIAGNOSIS AND

TREATMENT OF THYROID DISORDERS 161
Chandrasekhar Bal, Meghana Prabhu, Dhritiman Chakraborty, K. Sreenivasa Reddy, and Saurabh Arora
CHAPTER 22 SYSTEMIC THERAPY (TARGETED THERAPY AND IMMUNOTHERAPY)

FOR THYROID CANCERS 173
Abhishek Vaidya and Amol Dongre
CHAPTER 23 SURGICAL MANAGEMENT OF PARATHYROID DISORDERS 179

Neeti Kapre Gupta, Gregory W. Randolph, and Dipti Kamani
CHAPTER 24 PEDIATRIC THYROID SURGERY 187

Rajendra Saoji
Index 191
vi Contents
PREFACE
The seeds of this book were sown by the students getting off the bus It was then that, quite unexpectedly, Miss Shivangi from Taylor &
returning from their annual Thyroid Surgical Camp of Chikhaldara, Francis approached us and very kindly offered to take the thread of
Melghat. Armed with the art and craft of thyroid surgery, they this new book forward.
wanted more insight into the science of it. I soon realized the magnitude of the task. Some unforeseen health
Our first book Atlas of Thyroid Surgery answered the question of issues almost stalled the process, and I am grateful to my publishers
“how?” but there were more questions, like “when?,” “why?,” and for graciously bearing with the delay.
“how much?” that remained unanswered. With this book we have endeavored to bring forth a blend of
Thyroid surgery has undergone several paradigm shifts, from being surgical rationale, multidisciplinary decision-making, basic surgical
a life-threatening exercise to a minimally invasive procedure. More principles, and techniques for both the novice and the expert alike.
than any other surgery, it highlights the need to respect tissues, We have tried to include authors from across the globe to present a
nerves, and vessels. Skill, precision, and the fine line between holistic viewpoint on thyroid management.
aggression and conservatism in surgery is nowhere as important as
Thyroid surgery can be performed with some grams of steel but
it is in the management of thyroid disease. To do justice to all this
needs nerves of steel.
was well beyond the scope of an atlas or a workshop.
vii
ACKNOWLEDGMENTS
What worth is your knowledge if it does not dispel the darkness how difficult it must have been for them to draw that extra ounce of
of ignorance? What worth is your skill if it does not make others energy and precious time to painstakingly write their chapters. I am
skillful? What worth is a teacher’s greatness if their students do not grateful to all of them.
become greater than themselves? And I wish to express my gratitude to my colleagues in my own
I have been fortunate to find worthy colleagues, “Men and Women institute, fellows who worked with us, and the secretarial backup
of Wisdom,” and worthy publishers, CRC Press, Taylor & Francis I received. Running the risk of missing a few names inadvertently
Group, who came together to disseminate the wisdom, skill, and and asking for their pardon, I am grateful to my fellows who have
great clinical prowess in the field of thyroid surgery. been burdened by tasks beyond their working hours. Dr. Neeti
First, I wish to thank Miss Shivangi Pramanik and Miss Himani has been great in gathering bits and pieces provided by Amjad,
Dwivedi who had the faith and patience to bear with us, the authors Sankar, Sanoop, Shripal, and Priya. She has been my real support
and the editor. It was their disciplined approach that laid the in compiling this book.
foundation for this book, given to us by the publisher CRC Press, Finally, I am in great debt to my family, my wife Vidula, my
Taylor & Francis Group. daughters Neeti and Gauri, and my sons-in-law Abhishek and
All my colleague authors who penned the chapters are the worthy Harsh for their unconditional support and sufferings in the making
men and women of wisdom. I am appreciative and conscious of of this book.
ix
EDITOR
Dr. Madan Laxman Kapre is the and Neck Oncology. He has been President of the Laryngology
Director at Neeti Clinics in Nagpur, and Voice Association of India and of the Maharashtra State ENT
India. He is the Founder and associations. For his work in tribal hills endemic for goiter, he has
Governing Council Member of the received lifetime achievement awards by two prestigious national
Asia Pacific Thyroid Society, Seoul, organizations: Foundation of Head and Neck Oncology and Indian
South Korea; Advisory Committee Academy of Otolaryngologist and Head and Neck Surgeons. His
of the Asia Pacific Society of Thyroid research work includes mandibular mucoperiosteal flap for closure
Surgery; and the Chairman of the of oral defects after surgery of oral cancers and intraoperative
Indian Subcontinent Symposium to cytology for clearance of surgical margins. He is very active
3rd WCTC, Boston, USA. He is the academically and has authored/edited many books including
Founder and President of the Indian Atlas of Thyroid Surgery (Jaypee Brothers Medical Publishers,
Society of Thyroid Surgeons, past 2013), Atlas on Surgery of Trismus of OSMF (Springer Singapore,
President of the Foundation of Head & Neck Oncology in India, 2018), and Essentials of Head and Neck Surgery (Byword Books,
and the Founding President of the Vidarbha Society for Head December 2011).
xi
CONTRIBUTORS
Amit Agarwal Amol Dongre

Department of Endocrine Surgery Consultant Medical Oncologist
Sanjay Gandhi Post Graduate Institute Alexis Multispeciality Hospital
of Medical Sciences (SGPGIMS) Nagpur, India
Lucknow, India
Priya Dubey
Saurabh Arora Association of Otorhinolaryngologists and
Department of Nuclear Medicine Head and Neck Surgery (AOI-HNS)
All India Institute of Medical Sciences (AIIMS) Neeti Clinics
New Delhi, India Nagpur, India
Chandrasekhar Bal Sanoop Elambassery

Department of Nuclear Medicine ENT and Head and Neck Surgeon
All India Institute of Medical Sciences (AIIMS) Malabar Hospital
New Delhi, India Kozhikode, India
Christian Camenzuli Harsh Karan Gupta

Hammersmith Hospital Consultant ENT Surgeon
Imperial College NHS Trust Neeti Clinics
London, United Kingdom and
Consultant ENT Surgeon
Dhritiman Chakraborty American Institute of Oncology
Department of Nuclear Medicine Nagpur, India
All India Institute of Medical Sciences (AIIMS)
New Delhi, India Neeti Kapre Gupta
Consultant Head and Neck Surgeon
Rajashree Chaudhary Neeti Clinics
Consultant Anesthesiologist and
Neeti Clinics Consultant Head and Neck Surgeon
Nagpur, India American Institute of Oncology
Nagpur, India
Anil D’cruz
Consultant Head and Neck Surgeon Shripal Jani
Apollo Hospitals Foundation of Head and Neck Oncology (FHNO)
and Neeti Clinics
TATA Memorial Hospital Nagpur, India
Mumbai, India
Dipti Kamani
Anuja Deshmukh Division of Thyroid and Parathyroid Endocrine Surgery
Department of Head and Neck Surgery Department of Otolaryngology – Head and Neck Surgery
TATA Memorial Centre Massachusetts Eye and Ear Infirmary
Mumbai, India Harvard Medical School
Boston, Massachusetts
Pratibha Deshmukh
Department of Anesthesia Madan Laxman Kapre
Indira Gandhi Medical College Neeti Clinics
Nagpur, India and
Consultant Head and Neck Surgeon
Rajendra Deshmukh American Institute of Oncology
Visiting Consultant ENT Surgeon and
Neeti Clinics R.S.T. Regional Cancer Institute
Nagpur, India Nagpur, India
Shubhada Deshmukh Vidula Kapre

Department of Anesthesia Consultant Anesthesiologist
Lata Mangeshkar Medical College Neeti Clinics
Nagpur, India Nagpur, India
xiii
M. Abdul Amjad Khan R. Ravi
Department of ENT and Head and Neck Surgery Institute of Surgical Pathology
Citizens Specialty Hospital Nagpur, India
Hyderabad, India
K. Sreenivasa Reddy
Deven Mahore Department of Nuclear Medicine
Government Medical College All India Institute of Medical Sciences (AIIMS)
Gondia, India New Delhi, India
Ashutosh Mangalgiri Rajendra Saoji

Department of Anatomy Department of Pediatric Surgery
Chirayu Medical College Government Medical College
Bhopal, India Nagpur, India
Rahul Modi Meghna Sarode

ENT – Head and Neck Surgery Consultant Anesthesiologist
Dr. L H Hiranandani Hospital Neeti Clinics
Mumbai, India Nagpur, India
Deepa Nair Ashok Shaha

Head and Neck Oncosurgeon Senior Consultant Head and Neck Surgery
Tata Memorial Hospital Jatin P. Shah Chair in Head and Neck Surgery
Mumbai, India Memorial Sloan Kettering Cancer Center
New York, New York
Cheerag Patel
Department of Otorhinolaryngology, K.S. Rathan Shetty
Head and Neck Surgery Department of Head and Neck Oncology
Auckland District Health Board Kidwai Memorial Institute of Oncology
Auckland, New Zealand Bangalore, India
Himanshu Patil Subhaschandra Shetty

Consultant Endocrinologist ORL Head and Neck Surgery
Dew Hospital Middlemore Hospital
Nagpur, India Auckland, New Zealand
Shailesh Pitale Belayat Hossain Siddiquee

Consultant Endocrinologist Department of Otolaryngology
Trinity Institute and Dew Hospital Bangabandhu Sheikh Mujib Medical
Nagpur, India University (BSMMU)
Dhaka, Bangladesh
Meghana Prabhu
Department of Nuclear Medicine Alka Ashmita Singhal
All India Institute of Medical Sciences (AIIMS) Senior Consultant Radiology
New Delhi, India Medanta – The Medicity
New Delhi, India
Roma Pradhan
Department of Endocrine Surgery Cristian Slough
DR Ram Manohar Lohia Institute of Medical Sciences Otolaryngology – Head and Neck Surgery
Lucknow, India Willamette Valley Medical Center
McMinnville, Oregon
Gregory W. Randolph
The Claire and John Bertucci Endowed Chair Selen Soylu
in Thyroid Surgery Oncology Department of General Surgery
Harvard Medical School Istanbul University
and Cerrahpasa Medical Faculty
Division of Thyroid and Parathyroid Endocrine Surgery Istanbul, Turkey
Department of Otolaryngology – Head and Neck Surgery
Massachusetts Eye and Ear Infirmary Kyung Tae
Harvard Medical School Department of Otolaryngology – Head and
and Neck Surgery
Department of Surgery, Endocrine Surgery Service College of Medicine
Massachusetts General Hospital Hanyang University
Boston, Massachusetts Seoul, Korea
xiv Contributors
Nirmala Thakkar Gauri Kapre Vaidya
Consultant ENT Surgeon Consultant ENT Surgeon
Neeti Clinics Neeti Clinics
Nagpur, India and
Consultant ENT Surgeon
Anand Thomas American Oncology Institute
Department of Surgical Oncology Nagpur, India
Malabar Cancer Centre
Kerala, India Richa Vaish
Consultant
Neil S. Tolley Head and Neck Oncosurgeon
Senior ENT Consultant TATA Memorial Hospital
ENT – Thyroid Surgeon Mumbai, India
Hammersmith Hospital
Imperial College NHS Trust
London, United Kingdom Sankar Viswanath
Consultant ENT and Head and Neck Surgeon
Abhishek Vaidya Avitis Institute of Medical Sciences
Consultant Palakkad, India
National Cancer Institute (NCI)
and
Visiting Consultant ENT and Head and Neck Surgeon
Neeti Clinics
Nagpur, India
Contributors xv
INTRODUCTION
Madan Laxman Kapre
How common are thyroid nodules? The more you look for them, the For asymptomatic nodules detected either during a routine clinical
more you find them. Their incidence is also directly proportional examination by a general practitioner or by an observer, the patient
to the tools applied for their detection; clinical and radiological requires sympathetic reassurance to prevent cancer psychosis, as
being the front-runners. Whether there is an absolute increase in these nodules are harmless and need not be subjected to further
the occurrence of thyroid nodules is debatable. Certainly, it is our investigations.
observation that in central India, which is the author’s work domain, The nodules detected by imaging and/or already being investigated
the incidence in the urban population is almost on par with the rural by primary physician will merit its evaluation on the information
population, which is quite a revelation given that it is thought to be presented by the imaging studies. Although more information on
endemic in the hilly areas of the Melghat district of central India. this topic shall be available to readers in relevant topics on imaging
The prevalence of thyroid nodules detected by thyroid ultrasound of the thyroid, it is rather relevant to make some basic observations.
at health check-ups was 34.2% [1]. Thyroid nodules were more A small, <2 cm size solid nodule may be more ominous than a large
prevalent in women and older age groups. cystic nodule.
As most of the nodules are asymptomatic, and the incidence of
thyroid carcinoma in them is quite low, about 1.2% [2], the clinician
must be very judicious to select the patient for further evaluation.
THYROID FUNCTIONAL ASSESSMENT
With increasing awareness and access to information on electronic
media, not creating cancer phobia in patients is becoming a
challenge. Preventing psychological stress to the patient and family
Assessment of the functional status of the thyroid gland is vital
while detecting early thyroid cancer that can be treated with less
for anesthetic assessment should the patient require surgical
morbid surgery is becoming a tall task for surgeons.
treatment. However, it will also help in assessing possible pathology.
It is very encouraging that even in developing countries, Hyperthyroid status is very rarely associated with malignancy,
endocrinological, surgical, and medical services are growing at and such a situation will require a referral to an endocrinologist.
a rapid pace and are of high quality. As a result, there are several Hypothyroidism indicates loss of functional thyroid parenchyma
clinicians of varied backgrounds who are involved in initial diagnosis and suggests a disease accordingly.
and subsequent surgical management. It is a matter of teamwork
and evolving strategy to evaluate and manage thyroid nodules.
Thyroid nodules are often diagnosed by endocrinologists while
they are clinically small. Adding to this is the rising occurrence of CHANGING FRONTLINE INVESTIGATION
“incidentaloma.” Accurately diagnosing and evaluating a patient is
a great clinical responsibility.
The incidence of thyroid nodules in the past was considered in It is now fairly well accepted that ultrasonological assessment has
a subset of patients in urban, rural, and hilly areas. It was also overtaken fine needle aspiration cytology (FNAC) as the primary
believed to be due to an iodine-deficient diet. However, the thyroid investigation method. Size, echogenicity, margins, loss of halo, and
nodules pathogenesis has shifted away from the theory of iodine circularity will naturally give reasonable stratification of nodule.
deficiency. Long study periods in large populations are needed, and Similarly, the presence of occult lymph nodes in the neck away from
this increases the likelihood of bias from changes in unmeasured the thyroid naturally indicates a papillary thyroid carcinoma. More
risk factors other than iodine intake. There is also the additional details are available in relevant chapters.
uncertainty of the lag-time between changes in iodine exposure
and changes in incidence of thyroid cancer; the lag-time between
increasing iodine intake and the resolution of diffuse goiter and FINE NEEDLE ASPIRATION CYTOLOGY
nodules in adult populations is several decades. Accurate dietary
assessment of iodine intake is notoriously difficult [3]. (SCOPE AND LIMITATION)
FNAC was once a rare test; however, it has moved into second
WHICH THYROID NODULE NEEDS EVALUATION? position after ultrasound in the current state of practice. It is a
simple, painless office procedure, but it can be the beginning of
stress and anxiety to the patient and family. Hence, we should be
Symptomatic nodes are far easier to investigate, as the patient has clear in our planning as to which of the thyroid nodules should be
shown willingness for further work-up. Asymptomatic nodules are subjected to this test. It should be considered in situations where
the ones that require judicious examination in order to safeguard there is considerable evidence of clinical and radiological evaluation
against a patient’s anxiety and stress originating from investigating that a nodule under investigation has a considerable risk of being
“tumorous” conditions. malignant.
xvii
We have tried to analyze and study the application of these
procedures with their limitations of various risk evaluating tools
NEWER ADVENTS OF RISK ASSESSMENT
in appropriate chapters. Beginning with history and clinical
examination, one can start moving down the algorithm. Then
by applying appropriate biochemical tests one can assess the
Molecular/genetic mapping and the advent of elastography have
functionality of the thyroid. Ultrasonography, FNAC, and more
added to our current risk assessment schemes. Genetic mutation
imaging such as contrast CT/MRI will map the disease more
guides our decision-making towards extents of surgery and in
accurately.
particular the clearance of nodal disease in the central compartment
of neck level VI. Throughout the chapters of this book, we have envisaged a readership
of learners and the learned. I, along with my colleague authors, hope
Elastography is another very helpful application of ultrasonography
this book will prove valuable for both.
to characterize the compactness/hardness of thyroid nodules. It
helps to differentiate thyroiditis of inflammatory origin from solid
tumors which are likely to be malignant. Ultrasound elastography is
a dynamic technique that estimates stiffness of tissues by measuring
REFERENCES
the degree of distortion under external pressure.
1. Moon JH et al. Prevalence of thyroid nodules and their

SUMMARY
associated clinical parameters: A large-scale, multicenter-
based health checkup study. Korean J Intern Med.
2018;33:753–62.
The real reward of working through the maze of various tests and
evaluating the results is the confidence of performing fewer surgical 2. Fernando JR, Raj SEK, Kumar AM, Anandan H. Clinical study
procedures, e.g., hemithyroidectomy, or less aggressive neck of incidence of malignancy in solitary nodule of thyroid. Int J
dissection particularly in the central compartment of neck level Sci Stud. 2017;5(4):232–6.
VI. This is the real progress over the decades where our patients are 3. Zimmerman MB, Galetti V. Iodine intake as a risk factor for
benefiting from fewer surgeries and have a better understanding of thyroid cancer: A comprehensive review of animal and human
their condition. studies. Thyroid Res. 2015;8:8.
xviii Introduction
Chapter 1
HISTORY AND EVOLUTION OF THYROID SURGERY
Cheerag Patel and Subhaschandra Shetty
CONTENTS
Introduction 1
The History of Goiter 1
The History of the Thyroid and Parathyroid Hormones 2
The History of Surgery and of Surgical Instruments 3
The History of Thyroid Surgery 4
Future Directions 5
References 5
in 1811) and goiter [1]. Since then, countless medical practitioners have
prescribed iodine as an integral treatment for goiter—including French
INTRODUCTION
physician Jean Guillaume Auguste Lugol, after whom our commonly
used Lugol’s Solution (aqueous iodine) is named [2]—which features in
the World Health Organization’s List of Essential Medicines [3].
It was Sir Winston Churchill who professed that:
Equally as important as our understanding of goiter and the
“Those who fail to learn from history are doomed to repeat it.” importance of iodine has been the evolution of our knowledge of
the thyroid gland’s anatomical structure and function.
This expression serves as an important reminder that as progress Belgian physician and anatomist Andreas Vesalius was the first to
is made, it is of paramount importance that we acknowledge and provide the anatomical description of the thyroid gland in 1543
appreciate the history that has brought us to the present. In modern as “two glands…one on each side of the root of the larynx” [4].
day, thyroid surgery is commonly practiced throughout the world Interestingly, he proposed that the function of the thyroid gland was
for a variety of pathological conditions. However, the history of to lubricate the tracheal lumen [2].
thyroid surgery has been wrought with mortality, trepidation, Adding to our anatomical understanding of the thyroid gland
and discouragement. In this first chapter, we explore this history was the discovery of the isthmus in around the 1540s by Italian
in further detail so that we may duly appreciate the serendipitous anatomist Bartholomew Eustachius—considered a founder of the
discoveries, tenacious perseverance, and unfortunate mortalities modern discipline of human anatomy [1]. Humanity’s appreciation
that helped to pave the path to the operations that thyroid surgeons, and acknowledgment of thyroid enlargement is certainly evident in
all across the world, perform today. various pieces of artwork throughout our long history.
Perhaps one of the earliest artistic depictions of thyroid enlargement
is the Adena Pipe (Figure 1.1), a pipe discovered in Ohio, USA in
THE HISTORY OF GOITER
1901, approximated by radiocarbon dating to be 2,000 years old [5].
Renaissance-era art from the 1400s–1700s in Europe demonstrates
The enlargement of the thyroid gland is a pathological phenomenon goiter in various pieces of artwork. One of the more iconic paintings
that has attracted physician and surgeon fascination throughout that depicts thyroid enlargement is that of a boy “possessed by Satan”
humanity’s history. in the corner of The Transfiguration by Raffaello Sanzio (Figure 1.2) [6].
As shown in Table 1.1, in around 2600 bc, the ancient Chinese Though our understanding of the thyroid gland’s anatomy was
were some of the first to describe thyroid enlargement and its evolving significantly in the 16th century, it is evident that our
treatment with seaweed [1]. Since this early reference, humanity’s understanding of its function(s) was still very much in its infancy.
understanding of the thyroid gland in both its normal function and It seems that Vesalius’s theory for the function of the thyroid gland
in disease has evolved constantly, with historic milestones marking persisted until the mid-18th century; from this point on in history,
groundbreaking discoveries and landmark achievements. our understanding of its function underwent further evolution.
A review of the timeline of the treatment of goiter demonstrates German anatomist C. H. T. Schreger (1768–1833) demonstrated
a unifying theme that eventually culminated in a revolutionary an appreciation of the significant vascularity of the thyroid gland
discovery and subsequent treatment propositions. Seaweed, sponge, and attributed this to his proposed theory for the function of the
and eventually minced or ground thyroid extract feature heavily thyroid gland—to act as a vascular shunt protecting against a sudden
and repeatedly in the way we historically treated goiter [2]. In today’s increase in blood flow to the brain [2].
context, this makes resounding sense given the high concentrations of German anatomist Herbert von Luschka (1820–1874) considered
iodine that exist in all of these. However, it was not until 1820, in the the thyroid gland to simply be a physical cushion against
last 200 years, that Swiss physician Jean-Francois Coindet understood muscular pressure and trauma for the vital airway, phonatory, and
and acknowledged the casual link between iodine deficiency (after neurovascular structures in the neck [2]. It was not until the late
Bernard Courtois’ groundbreaking discovery of elemental iodine 18th century that our understanding of the thyroid gland’s function
History and Evolution of Thyroid Surgery 1

The History of the Thyroid and Parathyroid Hormones
Table 1.1 A brief timeline of the history of goiter and our (a)
understanding of it
Time Description
2600 bc Goiter is known in China—treated with burnt

sponge, seaweed, and animal thyroid.
1400 bc–400 ad Ayurvedic (traditional Indian) medicine in India
provides detailed descriptions of galaganda (b)
(goiter)
460 bc–375 bc “…when glands of the neck become diseased
themselves, they become tubercular and
produce struma…” –De Glandulis, Hippocrates
23 bc–79 ad “…Only men and swine are subject to swellings
of the throat, which are mostly caused by the
noxious quality of the water they drink…”
–Gaius Plinius Secundus of Pliny
130–210 ad Galen of Pergamon describes “mutism” and
Figure 1.1 The Adena Pipe, Ohio Historical Society Archeology
“semi-mutism” as complications of (thyroid)
Collection, Columbus, Ohio, USA (a) Anterolateral view; (b) Closer view
surgery by way of scraping with a fingernail,
“tubercular” nodes. of neck region.
340 ad Ko-Hung, famous Chinese alchemist,
recommends seaweed for treatment of goiter began to align with our current modern-day understanding.
for people living in mountainous regions. Swiss anatomist and physiologist Albrecht von Haller (1708–1788)
550 ad Aëtius of Amida describes exophthalmic goiter proposed that the thyroid (along with thymus and spleen) was a
and recognizes the importance of preservation ductless gland whose secretions directly entered the bloodstream [2].
of the vocal nerves (recurrent laryngeal nerve)
for phonation.
∼950–960 ad Abu al-Qasim al-Zahrawi (Albucasis)—considered
to be the greatest surgeon of the middle THE HISTORY OF THE THYROID AND
ages—first describes the thyroidectomy
procedure and needle biopsies for goiter. PARATHYROID HORMONES
1170 ad Roger of Palermo describes treatment of goiter
with ashes of sponges and seaweed.
∼1250 ad The Bamberg Surgery (surgical textbook) As described earlier in this chapter, our understanding of the
provides a detailed description of surgical endocrine functions of the thyroid gland only seems to have begun
thyroidectomy. emerging in the late 18th century. Punctuating the timeline of
1475 ad Chinese physician Wang Hei describes treatment humanity’s understanding of the thyroid gland and its disorders
of goiter with minced/powdered animal are the landmark endocrine discoveries of thyroid function: in 1914
thyroid. by American chemist and Nobel Prize recipient Edward Calvin
1500 ad Leonardo da Vinci first illustrates the thyroid Kendall [7] and in 1952 by British biochemist Rosalind Pitt-Rivers
gland. and Canadian endocrinologist Jack Gross [8].
∼1540 ad Bartholomew Eustachius first describes the Edward C. Kendall was responsible (and famous) for the discovery
isthmus of the thyroid gland. of many hormones and biochemical compounds, which ultimately
1543 ad Andreas Vesalius first provides anatomic earned him the Nobel Prize in Physiology or Medicine (1950). One
description and illustration of the thyroid gland. of his accomplishments was the isolation in 1914 of a crystalline,
∼1650 ad Thomas Wharton provides the modern name, iodine-containing compound extracted from the thyroid gland
thyroid, after the shape of an ancient Greek that was responsible for the physiological effects of the thyroid
shield. function—a compound which he named Thyroxine (T4) [7].
1811 ad Bernard Courtois discovers iodine.
In 1950, Jack Gross joined Rosalind Pitt-Rivers at the National Institute
1820 ad Jean Francois Coindet describes iodine deficiency
for Medical Research (NIMR) in London to begin investigating
as the cause for goiter and begins treatment
with iodine.
an unknown iodine-labeled spot on paper chromatograms of
human plasma extract [9]. In 1952 they published a scientific paper
1829 ad J. G. A. Lugol recommends aqueous iodine for
the treatment of goiter.
identifying a chemical compound that resembled Thyroxine but had
a shorter half-life—3,5,3′-Triiodothyronine (T3) [8].
1831 ad Francisco Freire-Allemao (Brazil) proposes iodine
prophylaxis to prevent goiter on a government Another important milestone in our understanding of thyroid
administered, public health basis. endocrinology and a vital contribution to the field of thyroid-related
1835 ad Robert Graves describes a syndrome of palpitations, clinical medicine was the synthesis of Thyroxine in 1927—thirteen
goiter, and exophthalmos in three women. years after its discovery and isolation—by Welsh chemist Charles
1862 ad Armand Trousseau introduces the term Graves’ Harington [10].
disease. American physician John Thomas Potts is another important
1883 ad Emil Theodor Kocher describes myxedema as a contributor to the field of endocrinology, his research interest
complication of total thyroidectomy. focused on the endocrine control of calcium (and bone) metabolism
1909 ad Emil Theodor Kocher—considered the father of [11]—though not a direct endocrine product of the thyroid gland,
modern thyroid surgery—receives the Nobel this is a crucial endocrine and physiological system to understand
Prize for his work on thyroid surgery. and appreciate as an important potential complication of thyroid
2 History and Evolution of Thyroid Surgery

The History of Surgery and of Surgical Instruments
(a)
(b)
Figure 1.2 The Transfiguration by Raffaello Sanzio (Vatican Museum, Rome) (a) Complete painting; (b) View of boy possessed by Satan.
surgery. In 1972, J. T. Potts’s laboratory at the National Institutes reserved for the more daring surgeons of the time, with pain being
of Health (NIH) defined the amino acid sequence of the bovine the single most important restricting factor. Evidence of this is
parathyroid hormone (PTH), followed shortly by the sequence for the somewhat alarming fact that in pursuit of reducing operative
the human hormone [11]. This important milestone has allowed pain, meticulousness and precision were often overwhelmingly
modern-day thyroid surgeons to specifically define the hormone substituted for “slashing speed” [14]. An above-knee amputation in
deficiency that can result from thyroid surgery, where occasionally London was once recorded as being completed in a mere 25 seconds
and certainly unintentionally—though sometimes intentionally— from skin incision to wound closure (1846–1847) [14]. November 18,
the neighboring parathyroid glands are removed or devascularized. 1846 marked the date that American surgeon Henry Jacob Bigelow
published his landmark paper titled “Insensibility during surgical
operations produced by inhalation” [15]. Though initially met with
THE HISTORY OF SURGERY AND a degree of skepticism, with some surgeons describing this newly
OF SURGICAL INSTRUMENTS discovered inhalational anesthesia as needless luxuries, it eventually
became abundantly clear that the advent of this procedure afforded
surgeons the time to be more precise in their surgical technique [14].
Surgery, a method of treatment for physical illness by means of It also afforded them the opportunity to surgically venture into parts
bodily penetration and traumatic manipulation, has existed for of the human anatomy that were previously restricted by unbearable
many millennia. It has certainly evolved and been subject to its own pain and the echoing screams of the awake patient.
share of adventurous discovery, refinement, and controversy over Though again initially met with resistance and skepticism by the
the course of human history. surgical community, the works of Viennese obstetrician Ignaz
Two procedures that are considered perhaps the oldest forms of surgery Semmelweiss and British surgeon Joseph Lister were landmark
in humanity’s history are male penile circumcision [12] and human milestones in the evolution of surgery [14]. In 1847, Ignaz
skull trephining [13]. Though much debate still exists about the exact Semmelweiss reported a significant reduction in puerperal sepsis
timing of circumcisions first being performed, there exist references simply by the adoption of rigorous handwashing by all medical staff
to ancient Egyptian circumcisions around 450 bc as representations involved in the delivery of each baby.
of socio-economic status amongst the upper class [12]. Joseph Lister is appropriately credited for his emphasis on the
Trephining was the surgical procedure by which circular holes, often importance of aseptic technique and the use of his antimicrobial
measuring approximately 4 cm in diameter, were made in the skull carbolic acid (phenol) system for surgical asepsis (Figure 1.3) [14].
of the patient [13]. Again, the exact indication of this is unclear. It Equally as important to the evolution of surgery was the growing
is hypothesized, however, that the procedure was perhaps a form of breadth and sophistication of surgical instruments.
decompressive craniotomy for unremitting headaches. Evidence of Considered to be the oldest surgical instrument to have been used by
this procedure dates back to at least the Neolithic period. humans, evidence of the surgical knife in the form of a flint dagger
More recently, in the last two centuries, surgery has seen its most dates, according to archeological analysis, as far back as 10000–8000
pronounced evolution, allowing it to cement its place in curative bc [16]. Since these prehistoric variants of the modern day scalpel, the
(and non-curative) treatment of physical illness. Without a doubt, knife has undergone multiple reincarnations with the use of copper
the two most important advents that have permitted the explosion in 3500 bc, and bronze and then iron in 1400 bc. The disposable
of the surgical specialty have been anesthesia and asepsis. Prior to scalpel that is so well known to today’s surgeons was first introduced
the discovery of anesthesia in 1846, surgery was a limited practice by American surgeon John Murphy after he adapted the disposable

The History of Thyroid Surgery
Figure 1.3 Joseph Lister demonstrates phenol system for surgical asepsis.
safety razor produced by King Camp Gillette in 1901 (founder of the Figure 1.4 Emil Theodor Kocher.
Gillette Safety Razor Company) [17]. John Murphy’s disposable scalpel,
however, was not technically satisfactory. In 1914, American engineer
Morgan Parker adapted John Murphy’s disposable three-piece scalpel The surgical management of thyroid disease, however, has been
to a significantly more technically intuitive two-piece scalpel—the viewed with trepidation, as a rather daring undertaking, and has
same that is used in operating theatres across the world today [17]. only really evolved to what it is today in just over the last century.
The timeline for the evolution of surgical instruments is interspersed One of the earliest records of a successful thyroid surgery is from ∼950–
with certain milestone inventions. 960 ad when Moorish physician/surgeon Albucasis removed a large
goiter under opium sedation using simple ligatures and cautery irons
Hungarian surgeon Aladar Petz is credited as being the inventor of
to achieve adequate hemostasis [22]. Attempts and records in history of
modern-day surgical staplers after modifying a much more clunky
further thyroid surgery since then were somewhat sparse, particularly
mechanical suturing device invented by Hungarian surgeon Humer
relative to the frequency with which they are performed today.
Hultl in 1909 [18]. He used his instrument for the very first time
in 1920 on a young patient who underwent partial gastrectomy for Famed American surgeon William Steward Halsted analyzed
gastric ulcer disease. completed thyroid surgeries before the mid-19th century and
reported 40% mortality [22]. Other important surgeons of the time
History reports that the thermal energy from heated stones was
such as Scottish surgeon Robert Liston and American surgeon
used as a means of cautery for hemostasis in prehistoric times and
Samuel David Gross emphasized the dangers of operating on
that surgeons had used electricity and cautery before the early 20th
the thyroid and discouraged it. Samuel D. Gross is quoted in his
century [19]. However, the single most important figure in this
1,000-page surgical textbook A System of Surgery as saying: “Can
particular sub-field of surgical technology is American inventor
the thyroid in the state of enlargement be removed? Emphatically,
William T. Bovie who invented the first practical electrosurgical
experience answers no. Should the surgeon be so foolhardy to
device, which was popularized by American surgeon Harvey
undertake it…every stroke of the knife will be followed by a torrent
Cushing (the father of modern day neurosurgery) [19]. Bovie’s
of blood and lucky it would be for him if his victim lived long
invention has gone on to be the basis for modern-day electrocautery
enough for him to finish his horrid butchery…” [22]. It was not until
devices so commonly used for cutting tissue and coagulating blood
esteemed Swiss surgeon Emil Theodor Kocher (Figure 1.4)—the first
during surgery (including thyroid surgery).
ever surgeon to receive the Nobel Prize in Physiology or Medicine
American surgeon William Wayne Babcock is credited for many (1909)—demonstrated his meticulous technique before and during
innovations in modern day surgery. One of the most recognized of thyroid surgery and reported his successes, that thyroid operations
these by modern-day thyroid surgeons is probably the invention of an became more common [22]. He was a pupil of Austrian surgeon
atraumatic tissue holding forceps specifically designed to hold tubular Theodor Bilroth, who himself first reported on 36 thyroidectomies
organs—appropriately named after him: the Babcock forceps [20]. with an over 40% mortality rate (16 died). Subsequently, as more
More recent advances in surgical technology that have added to advanced methods of antisepsis and hemostasis were emerging,
the success of surgery include intraoperative neurophysiological Theodor Bilroth reported on a further 48 thyroidectomies between
monitoring; particularly its refinement at the turn of the new 1877 to 1881, this time with a dramatic decrease in mortality to
millennium that has added to the success of thyroid surgery (among 8.3% [22].
other surgeries) by helping reduce the intraoperative complication of Theodor Kocher—considered the father of modern-day thyroid
recurrent laryngeal nerve injury [21]. surgery—practiced with stringent aseptic technique both before
and during surgery on the thyroid [22]. He also preached an astute
focus on anatomy and carried out precise enucleation of the thyroid
THE HISTORY OF THYROID SURGERY with an emphasis on hemostasis. He sought to achieve hemostasis
by carefully dissecting and controlling vessels as they traversed from
the thyroid gland’s surrounding capsule to its substance. Towards
As described earlier in this chapter, thyroid disease—particularly the end of his surgical career, Kocher reported on more than 500
that characterized by goitrous enlargement—has been acknowledged, thyroidectomy cases at the Swiss Surgical Congress in 1917 with a
documented, and treated for at least the last four millennia. mortality rate of 0.5% [22].
4 History and Evolution of Thyroid Surgery

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FUTURE DIRECTIONS
7. Kendall EC. Landmark article, June 19, 1915. The isolation in
crystalline form of the compound containing iodine, which
The likes of Henry Jacob Bigelow (anesthesia), Joseph Lister occurs in the thyroid. Its chemical nature and physiologic
(antisepsis), Theodor Kocher (father of modern-day thyroid surgery activity. By E.C. Kendall. JAMA. 1983;250(15):2045–6.
techniques), and others described in this chapter have been vital in 8. Gross J, Pitt-Rivers R. 3:5:3′-triiodothyronine. 1. Isolation from
laying down the bedrock for what has become today’s significantly thyroid gland and synthesis. Biochem J. 1953;53(4):645–50.
safer thyroid surgery. Additional important technological 9. Tata JR. Rosalind Pitt-Rivers and the discovery of T3. Trends
advancements over the last few decades, particularly for thyroid Biochem Sci. 1990;15(7):282–4.
surgery, have been those in improving hemostasis—achieving what
10. Harington CR, Barger G. Chemistry of Thyroxine: Consti-
has arguably been the biggest historical hurdle in thyroid surgery.
tution and synthesis of Thyroxine. Biochem J. 1927;21(1):
New technologies such as mechanical clip appliers (i.e., Ligaclip ®, 169–83.
Surgiclip®), electrothermal bipolar-activated devices (i.e., Ligasure ®),
11. Marcus R. Present at the beginning: A personal reminiscence on
and ultrasonic vibration systems (i.e., Harmonic Focus ®) have all
the history of teriparatide. Osteoporos Int. 2011;22(8):2241–8.
contributed to this growing pool of vessel-ligating instruments in
the pursuit of improved surgical hemostasis [23]. 12. Raveenthiran V. The evolutionary saga of circumcision from a
religious perspective. J Pediatr Surg. 2018;53(7):1440–3.
Considering the prevailing focus of current emerging technologies
in thyroid surgery, it seems that a particular future direction 13. Prehistoric Surgery January 1/8, 2019. JAMA. 2019;321(1):110.
(among others) will be the pursuit and refinement of minimalizing 14. Gawande A. Two hundred years of surgery. N Engl J Med.
surgical access. 2012;366(18):1716–23.
Robotic thyroidectomy surgeries appear to be the most significant 15. Bigelow HJ. Insensibility during surgical operations produced
advancement with respect to minimalizing access, particularly with by inhalation. Bost Med Surg J. 1846;35(16):309–17.
their variety of approaches, including gasless transaxillary approach, 16. Brill JB. The history of the scalpel: From flint to zirconium
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approach [24].
17. Ochsner J. Surgical knife. Tex Heart Inst J. 2009;36(5):441–3.
Though it may be difficult to predict with certainty what the next
century of thyroid surgeries will look like, one is inclined to say that 18. Olah A. Aladar Petz, the inventor of the modern surgical
the future of thyroid surgery looks to be as bright as its history has staplers. Surgery. 2008;143(1):146–7.
been colorful. 19. O’Connor JL, Bloom DA. William T. Bovie and electrosurgery.
Surgery. 1996;119(4):390–6.
20. Laios K. Professor William Wayne Babcock (1872–1963) and
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Basic principles and recent update. J Korean Med Sci.
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24. Pan JH et al. Robotic thyroidectomy versus conventional open
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Med Hypotheses. 2018;118:6–8.

Chapter 2
SURGICAL ANATOMY OF THE THYROID
Ashutosh Mangalgiri and Deven Mahore
CONTENTS
Introduction 7
Embryology of the Thyroid Gland 7
Capsule of the Thyroid Gland 9
Blood Supply of the Thyroid Gland 10
Parathyroids 12
The Nerves 12
Ligament of Berry 13
Pyramidal Lobe 13
References 13
from below, and the presence of a pyramidal lobe unilaterally or

bilaterally. One of the rare forms is the presence of the isthmus above
INTRODUCTION
the cricoid cartilage [1].
SURGICAL ANATOMY
The thyroid gland probably boasts of one of the most intricately PLATYSMA MUSCLE
arranged anatomical configurations and innumerable variations. The platysma is classified under panniculus carnosus, a muscle
Therefore, sound knowledge of anatomy is paramount for present in the superficial fascia. The platysma is supplied by the
performance of successful and safe surgery. The following text will cervical branch, one of the terminal branches of the facial nerve.
discuss the surgical anatomy of the thyroid in a manner akin to The platysma of both sides runs upwards medially from the level of
performing the steps of thyroidectomy. This would aid the readers the second rib to the lower border of the mandible. Raise the flap in a
in cadaveric dissection as well as live surgery. In a nutshell, the sub-platysmal plane. The sub-platysmal plane is an avascular plane.
elevation of flaps should be sub-platysmal, you should retract or We have to keep in mind that the platysma is absent in the midline,
cut the strap muscles, identify the middle thyroid vein if present, so we should identify it laterally (Figure 2.1).
address the superior pole, identify the recurrent laryngeal nerve,
address the inferior pole, and finally the ligament of Berry. ANTERIOR JUGULAR VEINS
However, the skill of preserving the nerves and the parathyroids, Anterior jugular veins are paired veins running parallel upwards
especially respecting their vasculature, is what sets apart an from the jugular venous arch. The midline avascular plane is
accomplished surgeon.
“When you learn to treat the nerves and the parathyroids with
respect and care during the performance of thyroid surgery,
then you will be a man, my friend….”
EMBRYOLOGY OF THE THYROID GLAND
An endodermal diverticulum descends in the form of primordium

of the thyroid gland. The thyroid diverticulum descends as the
thyroglossal duct from the foramen cecum of the tongue. The
thyroglossal duct follows a particular pathway during its descent.
First, it passes through the tongue, then descends anterior to the
hyoid, winding round the inferior border of the hyoid, until it
reaches behind the hyoid. Finally, it descends in the neck. In the
neck, the thyroglossal duct forms a bi-lobed structure, which finally
attains a definitive shape of the thyroid gland. The fifth pharyngeal
arch contributes as ultimobranchial body. C-cells of the thyroid
gland are believed to be originating from neural crest cells. In the
neck, the two lobes are connected by the isthmus. Many anomalous
presentations have been described in the literature, like the absence
of one of the lobes, the absence of the isthmus, two lobes connected Figure 2.1 Intra-operative picture of the platysma muscle.
Surgical Anatomy of the Thyroid 7

Embryology of the Thyroid Gland
identified between these anterior jugular veins. Usually the anterior

jugular veins are paired but you may get single or multiple veins also.
The anterior jugular veins are now exposed.
STRAP MUSCLES
Now let us see the relation of the strap muscles. They are in two
planes: superficial and deep. In the superficial plane we can identify
the sternohyoid and the superior belly of the omohyoid.
So, the relation of the strap muscles from within outward is
sternothyroid, sternohyoid, superior belly of omohyoid, and part
of sternomastoid. If we want to know the lateral, anterior, and
inferior relation, laterally is the sternothyroid, anteriorly are the
sternohyoid and the superior belly of the omohyoid, and inferiorly
is the sternomastoid.
Strap Muscles: These infrahyoid muscles are arranged in two planes:
superficial and deep. The sternohyoid and the superior belly of the
omohyoid are arranged in the superficial plane and the sternothyroid
in the deep plane (Figures 2.2 through 2.4).
In large goiters, strap muscles are so thinned out that they appear
as thin fascia. Strap muscles are to be preserved during surgery as
far as possible.
If the need to cut the strap muscle arises, we should keep in mind
that the nerve supply of the strap muscles should be preserved. The
division of muscle should be above the nerve supply done by the
ansa cervicalis.
ANSA CERVICALIS
The straps are innervated by a looped structure known as ansa
cervicalis, embedded in the anterior wall of the carotid sheath. Ansa
cervicalis has (1) anterior root, (2) posterior root, (3) loop of ansa
(Figures 2.5 and 2.6).
Figure 2.3 Cadaveric dissection showing strap muscles and their nerve
supply.
Figure 2.2 Cadaveric dissection showing strap muscles and their nerve Figure 2.4 Cadaveric dissection showing strap muscles and their nerve
supply. supply.
8 Surgical Anatomy of the Thyroid

Capsule of the Thyroid Gland
CAPSULE OF THE THYROID GLAND
The thyroid is suspended by an investing layer of deep fascia,

which forms the false capsule of thyroid and moves because of its
attachment to the cricoid thyroid gland. A true capsule is formed by
condensation of fascia surrounding the gland. The vascular plexus
underlies the true capsule (Figure 2.7).
RELATIONS
Relations of the lobe of the thyroid gland:
• Each lobe has a medial, lateral, and posterior surface.
• The lateral surface is related outside inwards to the
sternocleidomastoid, which covers the lower part of the thyroid
lobe. The sternohyoid medially and the superior belly of the
omohyoid laterally cover the gland in the superficial plane, and
in the deeper plane the sternothyroid muscle covers the gland.
• The medial or the deeper surface of the gland is in relation with
two tubes, i.e., the esophagus and the trachea; two nerves, i.e.,
the recurrent laryngeal nerve and the external branch of the
superior laryngeal nerve; and two muscles, i.e., the inferior
constrictor and the cricothyroid muscle.
• Posteriorly it is related to the carotid sheath and its contents
(Figure 2.8).
RELATIONS OF THE ISTHMUS

The isthmus has two surfaces anterior and posterior and two borders
superior and inferior. The isthmus may be absent at times. It may present
above the cricoid cartilage in case the thyroid is an inverted U shape [1].
The anterior surface is related to the sternohyoid and sternothyroid
muscles. The posterior surface is related to the 2nd to 4th rings of
the trachea.
Figure 2.5 Anatomy of the ansa cervicalis. The upper border is related to the anastomosis between the anterior
branches of the superior thyroid arteries and the pyramidal lobe
when present. The inferior lobe is related to multiple inferior thyroid
veins emerging at the inferior surface and the thyroid ima artery
when present.
Figure 2.6 Anatomy of the ansa cervicalis. Figure 2.7 Capsule of the thyroid.

Blood Supply of the Thyroid Gland
Figure 2.8 Relations of the thyroid gland.
SUPERIOR THYROID ARTERY

The superior thyroid artery lies at the upper pole along with the
BLOOD SUPPLY OF THE THYROID GLAND
superior laryngeal nerve. The superior thyroid artery divides at
the upper pole of the thyroid into anterior and posterior branches.
The anterior division runs over the anterior border and then at
The blood supply of the thyroid gland comes from the superior
the upper border of the isthmus to the anastomosis with its fellow
thyroid artery, the branch of the external carotid artery. This artery
from the other side. It is important to remember this branch as it
contributes in a major way to supply the thyroid gland. Another vessel
may serve as a major bleeder. The posterior division descends over
supplying the thyroid gland is the inferior thyroid artery. The inferior
the posterior border and forms the anastomotic channel with the
thyroid artery provides a major contribution to the parathyroid gland.
ascending branch from the inferior thyroid artery.
The thyroid gland receives blood mainly through the superior and
inferior thyroid arteries (Figure 2.9). INFERIOR THYROID ARTERY
The inferior thyroid artery branches off from the thyrocervical
trunk, ascends behind the carotid sheath, and then descends at the
lower pole. At the lower pole, the inferior thyroid artery divides into
multiple branches to supply the thyroid gland. It also provides a
separate branch to the inferior parathyroid gland.
The ascending branch from the inferior thyroid artery supplies the
superior parathyroid gland through the anastomotic channel. Thus,
the inferior thyroid artery supplies both the parathyroid glands and
should be regarded as the parathyroid artery.
THYROID IMA ARTERY

An additional branch from the innominate or right common
carotid or from the arch of the aorta may arise to supply the thyroid
gland. If present, it ascends in front of the trachea and terminates
into the isthmus; this may be the reason for severe bleeding during
tracheostomy.
PYRAMIDAL ARTERY
The pyramidal artery was described recently by Mangalgiri et al.
[2] in a study on cadavers and during live surgeries. The pyramidal
artery was present in those cases in which the pyramidal lobe was
well developed. The pyramidal artery branches off from the superior
thyroid artery just before its division. The pyramidal artery runs
medially and then upwards along with the pyramidal lobe. If the
Figure 2.9 Blood supply of the thyroid gland. pyramidal lobe runs along the right side of the artery, it will arise

Blood Supply of the Thyroid Gland
Figure 2.10 Pyramidal lobe artery. Figure 2.12 The short and stumpy middle thyroid vein.
from the right superior thyroid artery (STA), and if the pyramidal IMPORTANT STEP TO AVOID DISASTER
lobe runs along the left side, it will arise from the left STA. If the The middle thyroid vein is of utmost importance. It is to be identified
pyramidal lobe arises from the isthmus, then the artery may arise and secured. It is not really in the middle but a little towards the
from the left or right STA (Figure 2.10). inferior pole. It is a stout and short vein but may look thinner if
it is stretched by traction and countertraction of the thyroid lobe
THYROID VEINS (Figure 2.12).
Usually, the thyroid gland is drained by the superior thyroid vein,
the middle thyroid vein, and the inferior thyroid vein. The superior
thyroid vein and the middle thyroid vein drain into the internal NERVE SUPPLY OF THE THYROID GLAND
jugular vein. The inferior thyroid vein drains into the brachiocephalic The nerve supply of the thyroid gland comes from the parasympathetic
vein. Often, a fourth vein is seen between the middle thyroid artery and the sympathetic nerves; from the vagus nerve and the superior,
and the inferior thyroid vein. If it drains into the internal jugular middle, and inferior ganglia of the sympathetic trunk respectively
vein, then it is called the fourth vein of Kocher (Figure 2.11). (Figure 2.13).
Figure 2.11 Venous drainage of the thyroid gland. Figure 2.13 Nerve supply of the thyroid.

The Nerves
The lymphatic drainage of the gland is categorized in two groups:

(1) the upper one into the prelaryngeal and jugulo digastric lymph
node (JDLN) (III) and (2) the lower one into the pretracheal and
level 4, 5, 6.
PARATHYROIDS
DEVELOPMENT
The parathyroid (PT) glands have variable positions. The position of
the superior PT gland is almost constant. The paired superior glands
arise from the IV branchial pouch. They are situated at the junction
of the upper and middle thirds of the posterior border of the thyroid,
one on each side and embedded in the capsule of the gland.
The paired inferior parathyroid glands arise from the III branchial
pouch. They may have ectopic locations such as the intrathyroid,
anterior mediastinum, posterior mediastinum, or central
compartment of the neck. The inferior parathyroids are known for
their variable location and number.
The inferior parathyroid glands are commonly found in relation to
the inferior thyroid artery, and the ligation of this vessel should be
done after preserving the blood supply of the parathyroid.
LYMPHATIC DRAINAGE
Figure 2.14 Relation of the superior thyroid artery to the external
The lymphatic of the parathyroid follows the blood vessels and drains
branch of superior laryngeal nerve.
into pre- and paratracheal lymph node (LN), the deep cervical LN,
and the mediastinal LN.
The nerve supply of the parathyroid comes from non-myelinated
Reeves’s space is the avascular space between the superior pole of
nerves derived from the superior or middle sympathetic ganglion
the thyroid and the cricothyroid muscle. This is also one of the
or directly from the plexus on the fascia on the posterior surface of
landmarks by which to identify the EBSLN.
the lateral lobe of the thyroid gland.
RECURRENT LARYNGEAL NERVE
This is a branch from the vagus nerve. It winds around the subclavian
THE NERVES artery on the right side and the arch of the aorta on the left side. After
winding around, it runs upward and medially in the neck. In the
neck, the RLN runs in a tracheoesophageal groove.
Two nerves which lie in close proximity to the thyroid gland are There are many landmarks to identify the RLN:
the external branch of the superior laryngeal nerve (EBSLN) and
1. Beahr’s triangle
the recurrent laryngeal nerve (RLN). Both are to be identified and
preserved. Still, many surgeons ignore the EBSLN or rather do not 2. Lore’s triangle
try to identify it. Identifying this nerve should be of high importance 3. Nodule of Zuckerkandl
as it is the tenor of the vocal cord, and damage to it will definitely 4. Cricothyroid joint
effect singers and professional voice users. The most feared nerve for 5. Berry’s ligament
beginners is the RLN. We now discuss the surgical anatomy of these
two nerves. BEAHR’S TRIANGLE
Beahr’s triangle is bounded laterally by the common carotid artery,
EXTERNAL BRANCH OF THE superiorly by the inferior thyroid artery, and medially by the
SUPERIOR LARYNGEAL NERVE recurrent laryngeal nerve (Figure 2.15).
Joll’s triangle and Reeves’s space are the accepted landmarks for
identifying the EBSLN. Before describing the landmarks, let us LORE’S TRIANGLE
understand the Cernia et al. classification of EBSLN. According to Lore’s triangle is bounded medially by the trachea/esophagus,
Cernia et al. [3], there are three variations of the EBSLN position: laterally by the carotid artery, and superiorly by the surface of the
Type 1 crosses the superior thyroid artery more than 1 cm away inferior pole of the thyroid.
from the superior pole of the thyroid.
NODULE OF ZUCKERKANDL
Type 2a crosses the superior thyroid artery less than 1 cm from the
Emil Zuckerkandl (1849–1910), an Austrian anatomist in 1902,
superior pole of the thyroid.
described a protuberance arising from the posterior border of the
Type 2b crosses the superior thyroid artery under cover of the
thyroid lobes. This protuberance was termed as processus posterior
superior pole of the thyroid.
glandulae thyroidea. It is a thickening or a nodule in the posterior
Joll’s triangle is bounded laterally by the part of the superior pole aspect of the gland. Whenever the nodule of Zuckerkandl is present
of the thyroid and the the superior vascular pedicle, superiorly and identified, it is one of the important and reliable landmarks in
by the attachment of the strap muscle, and medially by the midline identifying the RLN. The nodule of Zuckerkandl directly points
(Figure 2.14). toward the RLN (Figure 2.16).

References
RLN with Berry’s ligament is not known. The RLN can be superficial to
Berry’s ligament, deep to it, or sometimes split around Berry’s ligament.
After identifying the RLN, it is very important that it should not be
traced throughout the course of surgery, as this may jeopardize the
blood supply and leave the patient with RLN palsy.
NON-RECURRENT LARYNGEAL NERVE (NRLN)

Whenever the RLN is not identified via the landmarks mentioned
previously, the possibility of non-recurrent laryngeal nerve should
be considered. The possibility of non-recurrent laryngeal nerve is
more on the right side because it is associated with an anomaly
of the right subclavian artery. The embryologically right NRLN is
secondary to a vascular disorder called arteria lusoria, in which the
fourth arch on the right involutes instead of persisting on the right
as the subclavian artery. Three types of variations are described for
the NRLN:
Type 1: The NRLN arises directly from the vagus and travels with
the superior thyroid pedicle vessels.
Type 2A: The NRLN travels transversely, parallel, and superficially
in relation to the trunk of the inferior thyroid artery.
Type 2B: The nerve travels transversely parallel, but deep to or
between the branches of the inferior thyroid artery.
Figure 2.15 Anatomy of Beahr’s triangle.
LIGAMENT OF BERRY
The ligament of Berry or suspensory ligament, which is nothing but

condensation of deep cervical fascia, is attached to the trachea. This
attachment is responsible for the movement of the thyroid gland
during deglutition.
PYRAMIDAL LOBE
This structure is often ignored, and therefore it is the most common

cause of residual tissue after total thyroidectomy. It is more
commonly seen on the right side and sometimes it is bilateral. The
pyramidal lobe has a dedicated artery—pyramidal artery—and runs
postero-lateral to the levator glandulae thyroidae.
REFERENCES
Figure 2.16 Relationship of the RLN to the nodule of Zuckerkandl.
1. Mangalgiri AS, Mahore D, Kapre M. Study of a unique

CRICOTHYROID JOINT ‘inverted u’ shaped thyroid gland and its clinical importance.
The relation of the cricothyroid joint and the RLN is constant and very Indian J Otolaryngol Head Neck Surg. 2014 Jun;66(2):224–5.
much reliable. Many surgeons prefer this as the first landmark to
2. Mangalgiri A, Mahore D, Kapre M. Pyramidal artery: An
identify the RLN. This landmark is considered to be reliable because
artery to pyramidal lobe-A new nomenclature. Indian J
the nerve enters inside the larynx from this joint.
Otolaryngol Head Neck Surg. 2018 Jun;70(2):313–8.
BERRY’S LIGAMENT 3. Cernea CR, Ferraz AR, Nishio S, Dutra A Jr, Hojaij FC, dos
Berry’s ligament is not exactly a landmark for identifying the RLN, Santos LR. Surgical anatomy of the external branch of the
but it is the region where damage can be done if the relation of the superior laryngeal nerve. Head Neck. 1992 Sep-Oct;14(5):380–3.

Chapter 3
CLINICAL ASSESSMENT OF THE THYROID NODULE
Madan Laxman Kapre, Shripal Jani, and Priya Dubey
CONTENTS
History Taking 15
Physical Examination 17
HISTORY TAKING
History taking is a scientific art. The science and art in deciphering

the information that the patient volunteers about their illness are
asking the right questions, in the right sequence, and with empathy,
to begin forming a clinical picture. The patient often narrates his/her
own diagnosis if you have the patience to listen to their complaints.
We shall endeavor to provide our question algorithm to achieve this
in this chapter. Coupled with appropriate clinical examination, we
often come to a reasonably accurate diagnosis that enables us to
apply appropriate investigations.
Firstly, as mundane as it may be, age, sex, family history, and
geographical location of our patient is very relevant as it will help
us understand risk stratification, which shall be dealt with in
appropriate sections of well differentiated thyroid carcinomas. Then
we can focus our attention on extracting symptoms which will be
relevant to the function of the thyroid gland.
Loss of appetite, weight gain, lethargy, loss of hair, and
roughness of skin point to hypofunction of the gland; increased
appetite yet weight loss, restlessness, and sweaty palms point to
hyperfunction. Proptosis, ecchymosis, and recurrent corneal
ulceration clearly point to a thyro-toxic state (Figures 3.1 and Figure 3.1 Thyrotoxic state.
3.2). While a hypofunctioning gland with a nodule indicates
possible malignancy, a hyperfunctioning gland with a nodule is
usually benign.
Additionally, in female patients, the thyroid hormone produces
symptoms due to activity on estrogen-dependent physiology. The
thyroid gland is generally enlarged at puberty, pregnancy, and
menopause. Menstrual cycle irregularities are to be enquired into
to exclude hypo- or hyperthyroidism.
Children also need special attention as aberrant thyroid glands and
anomalies of the thyroglossal duct ranging from lingual thyroid to
thyroglossal cysts occur in this age group (Figure 3.3). Previously
drained midline tuberculous abscesses in an Indian context leading
to sinus formation is often confused with the congenital variety
(Figures 3.4 and 3.5).
In long standing nodules, recent onset of pain, rapid increase
in size, voice changes, and dysphagia indicate malignant
transformation in the pre-existing thyroid nodule. By their
location in the tracheoesophageal groove, posteriorly located
nodules may cause dysphagia. However, acute bleeding in
benign goiterous nodules can cause pain. Intense pain and severe
odynophagia spell acute thyroiditis like autoimmune thyroiditis
or chronic or acute suppurative infection of the thyroid gland
(Figures 3.6 and 3.7). Figure 3.2 Thyrotoxic state.
Clinical Assessment of the Thyroid Nodule 15

History Taking
Figure 3.3 Thyroglossal cyst. Figure 3.5 Midline tuberculous abscess.
Figure 3.6 Suppurative infection of the thyroid gland.
Figure 3.4 Midline tuberculous abscess.
Voice changes are attributed to two mechanisms. It could be

because of the structural changes within the vocal folds as in the
edematous cords of hypothyroidism. Or, more ominously, it could
be due to altered vocal cord dynamics, i.e., vocal cord palsy or
fixation due to infiltration of the RLN and/or the cricothyroid
joint by malignant disease. Slow and insidious involvement of
the RLN due to malignant infiltration gives adequate time for
compensation by the opposite vocal cord, and there may not be
voice alteration.
Malignant infiltration of the upper trachea may cause hemoptysis
in case of obvious thyroid disease. Retro-sternal extension and Figure 3.7 Suppurative infection of the thyroid gland.
16 Clinical Assessment of the Thyroid Nodule

Physical Examination
mediastinal crowding by goiter causes difficulty in breathing,

particularly when lying down in a supine position. It could also be
due to bilateral abductor palsy in a rare situation of advanced thyroid
cancer. Prominent neck veins and centripetal blood flow indicates
superior mediastinal obstruction.
PHYSICAL EXAMINATION
The physical examination also requires a disciplined approach.

General examination is directed towards signs of thyroid dysfunction
in distant organs where the thyroid hormone acts. Subclinical
hypofunction would be considered in an obese patient with a gruffy
fatigued voice and edematous looking facies. An anxious look,
prominent eyes, exposed cornea, sweaty handshake, and tremors
observed in the patient would indicate a thyrotoxic state. The rapid,
often collapsing pulse of hyperthyroidism is unmistakable. Figure 3.8 Dysfunctional gland or physiological enlargement.
A local examination should begin with the inspection of the neck.
Enlarged neck veins and their direction of flow should forewarn The authors wish to make an important observation on
the clinician about superior mediastinal obstruction by benign demonstration of tenderness of the thyroid gland. Sitting across the
retrosternal goiter or metastatic lymph nodes of papillary carcinoma patient, putting the flat of the fingers on the thyroid gland firmly,
of the thyroid. The external jugular veins on either side indicate and asking the patient to swallow, wincing of the face will give
lateral most extent of the benign large thyroid which the authors away tenderness and the diagnosis. The outcome of such a clinical
have encountered in many of their rural tribal practices. maneuver in the authors’ opinion will with relative certainty be a
diagnosis that Globus hystericus is truly thyroiditis.
As patients range from incidentally imaged small nodules to
massive neck masses shouting their presence as a patient enters the The presence of nodes in the lateral compartment is an obvious
room, we should have some uniform way of describing the goiter indicator for malignancies of the thyroid. Neck nodes in higher levels,
size. We follow a grading system that is quite easy to communicate i.e., grades II and III, indicate papillary carcinomas whereas nodes in
among treating colleagues, from surgeon to anesthetist to level V point toward the possibility of medullary carcinomas.
operating room support staff, so that an appropriate preparatory The assessment of retrosternal extension is performed by a few
schedule can be made. Grade I goiter is seen only when the patient bedside clinical maneuvers (Figures 3.9 and 3.10). The more common
hyperextends the neck. Grade II goiter is one that is seen as the one is having the patient in a supine position with a hyperextended
patient sits in a neutral neck position. Grade III goiter is seen as neck. Upon swallowing, the clinician tries to insinuate their fingers
obvious nodular projection on the anterior neck, yet their lower across the lower border of the thyroid swelling. The ability to do so
borders can be seen on swallowing movements. Grade IV goiters gives the clinician confidence of cervical delivery of the retrosternal
are as in grade III, but where their lower border is not seen on goiter. Pemberton’s sign is demonstrated in the following manner.
swallowing movements. The patient stands and slowly takes his/her arms up to full stretch.
Simple as it may sound, palpation of the thyroid should be This will narrow the superior mediastinum.
performed using the following special method and not only by a
cursory “neck feel” of an experienced senior surgeon. We stand
behind the patient with the neck relaxed and flexed to examine
the thyroid nodules. A soft and uniformly enlarged thyroid
can be due to physiological enlargements, as mentioned earlier,
or a dysfunctional gland (Figure 3.8). Late stage Hashimoto’s
thyroiditis will have hard and smallish gland. On the other
hand, in early stages of the disease, the gland is tender and
markedly nodular. Uniform, yet firm, non-tender glands are
usually present in lymphomas. Nodularity of the gland, either
unilaterally or bilaterally, can best be assessed with patience and
with effort to locate the laryngeal framework and trachea first.
In the perspective of the trachea, the nodule can be conveniently
lateralized, even when some of these large nodules may appear
bilateral in the beginning. One large dominant nodule may hide
smaller nodules located posteriorly. We then focus our attention
towards the mobility of the gland on swallowing. If the thyroid
moves on deglutition, however large it may be, it is within the
confines of its fascia and not breaking out to get fixed to adjoining
structures. This is important as benign lesions, however big they
are, will not breach fascia, while malignant nodules might breach
and invade into adjoining soft tissue like muscle, RLN, trachea, Figure 3.9 Bedside clinical maneuvers for assessment of retrosternal
or the esophagus. extension.

Figure 3.10 Bedside clinical maneuvers for assessment of retrosternal Figure 3.11 Telelaryngoscope to assess the mobility of the vocal cords.
extension.
Clinical questionnaire for functionality:

A mass lesion already compromising the venous return will
• Weight gain
exaggerate the effect leading to facial puffiness and fullness of
• Weight loss
neck veins and difficulty in breathing. Respiratory symptoms
• Hair loss
must be enquired into. Hoarseness of voice with difficulty in
• Appetite
breathing would indicate unilateral RLN palsy with or without
• Sleep
laryngotracheal invasion. However, a normal voice and difficulty
• Sweating
in breathing is a rather more sinister symptom as it would indicate
• Palpitation
bilateral involvement of the RLN with or without laryngotracheal
• Eye symptoms
invasion.
• Menstrual irregularity
Patients who will provide a history of changed sleeping patterns,
either taking additional pillows or preferring to sleep in lateral
• Tremors
positions, probably have retrosternal extension causing compression. Suggested proforma for clinical documentation:
Morbid obesity and thick, bull necks pose considerable difficulties 1. Size of the nodule
in the assessment of necks. A thorough patient history paired 2. Location of the nodule
with suitable clinical examination often comes to the rescue
of the surgeon. In resource restricted situations, a very focused
investigation and avoiding unnecessary tests help economizing on
time and cost.
Last, but not least, is the assessment of the functionality of the
recurrent laryngeal nerves. All thyroid surgeons must train
themselves either using old-fashioned bullseye lamps and indirect
laryngoscopy mirrors or modern-day telelaryngoscopes to assess
the mobility of the vocal cords both before and after surgery. A
normal voice is no insurance for normally mobile cords as slow
and insidious RLN involvement can so often get compensated.
(Figure 3.11) The authors will insist on full endoscopic evaluation
of the upper airways and the pharyngoesophageal segment where a
laryngotracheal or upper esophageal invasion is suspected.
Recommended clinical questionnaire for thyroid swellings:
• Duration of the nodule

• Bilateral or unilateral
• Recent change in size
• Recent onset of pain
• Recent change in voice
• Onset of dysphagia
• Breathing difficulty
• Presence of lateral neck mass
• Cough or hemoptysis
• Positive Pemberton’s sign Figure 3.12 Diagrammatic representation of right sided solitary thyroid
• Inability to sleep supine nodule located at the superior pole with an ipsilateral level III lymph node.
18 Clinical Assessment of the Thyroid Nodule

3. Number of nodules 9. Condition of the overlying skin

4. Unilateral or bilateral 10. Cervical lymphadenopathy
5. Position and centrality of laryngotracheal framework 11. Documentation of vocal fold mobility
6. Consistency: Soft/Firm/Hard Diagrammatic representations may help to standardize the depiction
7. Mobility and communication of relevant clinical examination findings of a
8. Ability to palpate the lower border of the thyroid gland thyroid nodule (Figure 3.12).

Chapter 4
IMAGING OF THE THYROID
Alka Ashmita Singhal
CONTENTS
Introduction 21
Thyroid Ultrasound 21
Thyroid Nodules 26
Follicular Neoplasm 29
Papillary Thyroid Carcinoma 29
Papillary Thyroid Microcarcinoma 30
Medullary Thyroid Carcinoma 30
Anaplastic Carcinoma 31
Metastasis to the Thyroid 40
Conclusion 42
References 42
the transducer. Gray-scale imaging is combined with Doppler [4–6]

ultrasound. Color, power, and spectral Doppler give the vascularity
INTRODUCTION
information. We aim to use the highest possible transducer frequency
to achieve the required depth of imaging. The basic determinant of
resolution and image quality is the transducer frequency. Appropriate
Thyroid ultrasound and radionuclide imaging are the most common
focus must be adjusted to have a narrower beam width at the area
diagnostic modalities used in the management of thyroid disorders.
of interest and hence improved resolution. Gain settings, including
Nuclear scintigraphy is used for the evaluation of metabolic activity
Doppler settings, should be optimum, not under- or overwritten.
of the nodules and the physiologic thyroid function. Ultrasound
Ultrasound artifacts could be inherent due to the modality itself
is the mainstay of thyroid imaging and helps in evaluation
or due to an improper technique. Inherent ultrasound artifacts are
of both diffuse thyroid disorders and focal thyroid nodules.
related to the ultrasound beam characteristics, the propagation of
Advanced Doppler evaluation along with sono-elastography
sound in the various tissues, and the assumptions made in image
and contrast-enhanced ultrasound are useful adjuncts. TIRADS
processing. Some of the artifacts [7] in ultrasound imaging are
scoring, ultrasound guided fine needle aspiration, and Bethesda
used as a valuable tool in image interpretation. Notable artifacts for
cytopathology are combined to give a risk stratification for thyroid
thyroid ultrasound are posterior enhancement or cystic enhancement
nodules. Computed tomography (CT), magnetic resonance imaging
(Figure 4.1) distal to a fluid-filled cystic structure, posterior acoustic
(MRI), and positron emission tomography (PET) are advised in
shadowing (Figure 4.2) distal to calcifications, reverberations,
select cases.
and comet tail. Both cystic enhancement and posterior acoustic
THYROID ULTRASOUND
HISTORY AND EVOLUTION

The thyroid gland, owing to its superficial location in the neck, was
one of the first organs to be studied by ultrasound, as early as 1960
[1,2]. Since then ultrasound has gone through a dynamic change
with evolving technology and has added elements of Doppler,
elastography, and contrast-enhanced ultrasound.
ULTRASOUND PRINCIPLE AND PHYSICS

Modern ultrasound equipment consists of a sensitive transducer
containing a piezoelectric crystal [3], keyboard, software, hardware,
and display. A piezoelectric crystal emits sound waves in response
to electric stimulation and receives the reflected echo, which is
processed to produce a corresponding display image. Sound waves
need a material medium to transfer. Ultrasound gel is used as a basic
coupling medium to enable transfer of the sound waves into the body
by overcoming the air barrier. The degree of attenuation of the sound Figure 4.1 Posterior enhancement (yellow arrow) posterior to a colloid
waves into the body depends on the intrinsic tissue properties through cyst, suggesting uniform character and minimal attenuation of sound
which sound travels into the medium and the echoes reflected back to through it.
Imaging of the Thyroid 21

Thyroid Ultrasound
Figure 4.4 Comet tail artifact. A type of reverberation artifact seen

due to crystallization of the colloid which gives a tiny sharp interface and
leads to a triangular tapering echo (yellow arrows).
Figure 4.2 Posterior acoustic shadowing (blue arrow) noted distal to
calcification (yellow arrow). As most of the sound is reflected back from
dense calcifications, very little penetrates through, the area posterior to
them is not insonated, and appears dark (shadows).
shadowing are attenuation errors related to the sound beam and

tissue properties. When a strongly reflective (example: calculus) or
a highly reflective (example: bone) structure comes in the path of an
ultrasound beam, the amplitude of the beam distal to the structure
is diminished, hence the echoes returning from the area behind the
structure are also diminished and appear as dark areas or “shadows.”
Conversely, when a weakly attenuating structure (example: a clear
cyst) is in the path of an ultrasound beam, the sound is attenuated
to a lesser extent as compared to adjacent tissues at the same level,
hence more amplitude sound waves reach the area and are returned
leading to an increased transmission seen as a bright band beyond the
low attenuating structure. This artifact helps in understanding the
composition of the tissue, and when present, posterior enhancement
suggests a cystic structure. Figure 4.5 Tiny punctate echogenic foci (yellow open arrows) or
microcalcifications which are seen in papillary thyroid carcinoma are due
to the psammoma bodies. These do not show the comet tail artifact or
any posterior shadowing.
Reverberation artifacts (Figure 4.3) occur when ultrasound echoes

are repeatedly reflected between two highly reflective surfaces
resulting in an image display having multiple equally spaced signals
in the far field, as in the case of tracheal surface in the neck. The
comet tail artifact (Figure 4.4) is a small triangular reverberation
artifact noted characteristically posterior to the colloid particles,
and it fades distally. Here the sequential echoes are very close to each
other and not perceived separately, and as they diminish in intensity
in the far field they give a tapering “triangular” appearance. The tiny
punctate echogenic foci seen in the papillary carcinoma thyroid do
not show this artifact (Figure 4.5).
THYROID ULTRASOUND ANATOMY

The normal thyroid gland [8] is an H-shaped gland draped over the
trachea with the right and left lobes connected by a narrow isthmus
and on ultrasound shows a smooth homogenous hyperechoic
echotexture with a thin echogenic peripheral thyroid capsule
(Figure 4.6a–e). On color Doppler, few vessels can be identified,
Figure 4.3 Reverberation artifacts (white arrows) from the anterior mainly the superior and the inferior thyroid arteries at the poles.
wall of trachea (yellow arrow). These occur due to sound waves reflecting The sternocleidomastoid and the strap muscles sternothyroid and
many times from a sharp acoustic interface into the deeper tissues with sternohyoid are seen antero-laterally and appear as hypoechoic
diminishing intensity. structures. The carotid sheath (containing the common carotid
22 Imaging of the Thyroid

Thyroid Ultrasound
(a) (b)
(c)
(d)
(e)
Figure 4.6 (a–e) Normal thyroid (isthmus and lobes) transverse and longitudinal and scan with color Doppler showing the smooth homogenous
hyperechoic echotexture and a few vessels on color Doppler.
artery [CCA], the internal jugular vein [IJV], and the vagus nerve) superior and inferior thyroid artery may be well seen at the poles.
and scalenus anterior muscles are seen postero-laterally. The Venous drainage is mainly to the IJV. The thyroid has an extensive
esophagus is seen posteriorly. A normal adult gland measures subcapsular and intrathyroidal lymphatic network. Metastasis
40–50 mm in craniocaudal length, 12–18 mm in transverse width, from the thyroid primary are common in level 6 and level 2–4. The
and 10–12 mm in anterio-posterior depth. The gland is supplied by recurrent laryngeal nerve [9] lies in the posterior relation to the mid-
the superior thyroid artery, a branch of the external carotid artery, part of the thyroid gland along with the inferior thyroid artery. The
and the inferior thyroid artery, a branch of the subclavian artery. The ectopic superior parathyroids [10] are usually located behind the

Thyroid Ultrasound
(a) (b)
Figure 4.7 (a) Image of thyroid nodule taken with 7–11 MHz transducer showing a heterogeneous hypoechoic nodule. (b) Image of the same
thyroid nodule taken with 12–14 MHz transducer showing additional image clarity with well delineated punctate echogenic foci and anterior capsular
breach (arrow). Biopsy proved papillary carcinoma thyroid.
mid-thyroid at the point of the crossing of the inferior thyroid artery cases for complete assessment of the lymph nodes and other neck
and the recurrent laryngeal nerve. The ectopic inferior parathyroids structures. Scanning is done in both longitudinal and transverse
are located around the lower pole of the thyroid glands. The nodule directions. Color and power Doppler are used to assess vascularity.
of Zuckerkandl may appear as a prominent pseudomass behind the Color flow gives a graphic display of both speed and direction,
mid-part of thyroid [11]. while power Doppler is the sum of the total flow, hence increased
sensitivity to low flow, though more prone to flash artifacts.
EMBRYOLOGY AND ECTOPIC THYROID GLANDS Sono-elastography can be applied for stiffness information of the
The thyroid gland is a mesodermal derivative originating from the nodules.
floor of the mouth at the level of the foramen cecum [12,13]. The
thyroglossal duct invaginates and descends anterior to the trachea, ULTRASOUND IN DIFFUSE THYROID DISORDERS
bifurcating to form the two thyroid lobes. Ectopic thyroid tissue AUTOIMMUNE THYROIDITIS
and abnormalities of the thyroglossal duct are found along this The common forms of thyroiditis are chronic lymphocytic and
path. The pyramidal lobe is formed from the last part of the Graves’ disease. Chronic lymphocytic thyroiditis could be atrophic
thyroglossal duct. thyroiditis or goitrous Hashimoto’s thyroiditis. Postpartum
thyroiditis and silent thyroiditis are usually self-limiting.
ULTRASOUND TECHNIQUE AND PATIENT POSITION
The thyroid gland is located very superficially in the anterior upper
neck and easily amenable to ultrasound; however, it is dependent
on proper technique [14] and experience of the examiner.
Adequate exposure of the neck area and proper patient positioning
is important. The patient is placed in a supine position with a
pillow behind the shoulders to slightly extend the neck; however,
caution must be observed in elderly patients. Alternative positions
such as a tilted sitting position may also be adopted. A variety of
transducers may be needed to be used for one scan to achieve a
comprehensive and a detailed image. A linear 7–11 MHz transducer
may be adequate for most examinations; however, the use of a
higher frequency 12–14 MHz and even 14–16 MHz small footprint
transducer provides further details of very superficial nodules
(Figure 4.7a and b).
An additional advantage of small footprint transducers is that they
are better to maneuver around the trachea and clavicles to look for
lymph nodes and other pathology. For large multinodular goiters
and masses, a curved C4-6 transducer with deeper penetration is
required. Use of panoramic view (Figure 4.8) is preferred over the
split screen merge technique to measure large thyroids and to give Figure 4.8 A panoramic view of the thyroid can be used to give a
pictorial representation of and relation of any abnormality with pictorial representation of the whole gland in one image and help
the neck structures. A systematic approach to scan the entire neck communicate the anatomical relation of the structures in the neck and
area from under the jaw line up to the clavicles must be done in all of any associated pathology.

Thyroid Ultrasound
(a) (b)
(c)
Figure 4.9 (a) A 35-year-old female with thyrotoxicosis. Patient photograph showing exophthalmos and diffuse swelling in the anterior neck
suggesting thyroid enlargement. (b and c) Gray-scale ultrasound showing diffuse enlargement of both the lobe of the thyroid with decreased
echogenicity or hypoechoic echotexture, involving the whole of the thyroid. The hypoechogenicity is similar to the overlying strap muscles.
ULTRASOUND FINDINGS IN THYROIDITIS the degree of hypoechogenicity and vascularity corresponds to the
A diffuse or multifocal decrease in echogenicity (Figure 4.9a–c) level of circulating antithyroid antibodies. Small reactive cervical
demonstrated on ultrasound is the hallmark of many types of lymph nodes may be seen.
thyroiditis [15,16]. This decrease in echogenicity may be due to
an increase in the intrathyroidal blood flow, increased cellularity HASHIMOTO’S THYROIDITIS
of the thyroid follicles with decreased colloid production, or Hashimoto’s thyroiditis [17,18], also known as lymphocytic
lymphocytic infiltration. The decrease in echogenicity occurs thyroiditis or chronic autoimmune thyroiditis, is a subtype of
even before the bio-clinical abnormality and correlates with the autoimmune thyroiditis. Patients are usually hypothyroid, although
circulating level of thyroid antibodies [17,18]. On color and power there may be a brief hyperthyroid early phase. Ultrasound features
Doppler studies, increased blood flow is noted throughout the (Figure 4.11a–d) depend on the severity and phase of the disease.
gland (Figure 4.10a–c). Return of the normal thyroid echogenicity Generally, the gland is diffusely enlarged with a heterogeneous
and blood flow is noted on resolution of the disease. However, echotexture. The presence of hypoechoic micronodules (1–6 mm)
heterogeneity may persist if the chronic thyroiditis ensues and with surrounding echogenic septation is also considered to have
fibrosis may set in within the gland, resulting in a coarsened a relatively high positive predictive value. Color Doppler usually
echotexture. shows normal or decreased flow, but occasionally hypervascular
Graves’ disease is an autoimmune thyroid disease and is the most flow may be seen. Associated prominent reactive cervical nodes may
common cause of thyrotoxicosis. On ultrasound, the thyroid gland be present, especially in level VI. Large nodules may be present in
is mildly enlarged with a hypoechoic and slightly heterogeneous nodular Hashimoto’s thyroiditis. In long standing cases, a typical
echotexture. Ultrasound is required to evaluate size, echotexture, nodular “swiss-cheese” appearance (Figure 4.12a–d) is seen. There
vascularity, and nodules. A characteristic hypervascular “thyroid is a higher reported risk for papillary thyroid carcinoma, hence
inferno” pattern is noted on color Doppler in Graves thyrotoxicosis. nodules need to be carefully evaluated and suspicious nodules
Ultrasound is also used in evaluating the response to treatment as should be biopsied [19,20].

Thyroid Nodules
(a) (b)
(c)
Figure 4.10 (a–c) A 35-year-old female with thyrotoxicosis. Color Doppler ultrasound showing profound increase in vascularity of the whole of
the thyroid, giving the appearance of “thyroid inferno.” (a) Right lobe. (b) Left lobe. (c) Panoramic view.
In Riedel thyroiditis, inflammation extends beyond the confines of higher the cumulative score, the higher the TIRADS level and the
the gland into adjacent tissues and typically presents as a hard goiter likelihood of malignancy.
with compression symptoms on the trachea. Each nodule is evaluated for its size:
Composition: [cystic/almost completely cystic (0), spongiform (0),
mixed cystic and solid (1), solid/almost completely solid (2),
THYROID NODULES cannot determine (2)].
Echogenicity: [anechoic (0), hyperechoic (1), isoechoic (1),
hypoechoic (2), very hypoechoic (3), cannot determine (1)].
A thyroid nodule is defined as a region of parenchyma Shape: [not taller than wide (0), taller than wide (3)].
sonographically distinct from the remainder of the thyroid. Margins: [smooth (0), ill-defined (0), lobulated/irregular (2), extra-
Incidence of thyroid nodules is on the rise with the advent of high thyroidal extension (3), cannot determine (0)].
resolution transducers and incidental nodules detected on CT, MRI, Echogenic foci: [none (0), large comet tail artifacts (0),
or PET-CT done for other indications. Thyroid nodules [21,22] macrocalcifications (1), peripheral calcifications (2), punctate
could be solitary or multiple as in multinodular goiter. Most thyroid echogenic foci (3)].
nodules are benign. To screen out and select suspicious nodules
for FNAC (fine needle aspiration cytology) is still a challenge
Thorough cervical lymph node assessment is done. Color Doppler
and various methods of ultrasound TIRADS (Thyroid Imaging,
to assess vascularity and elastography to assess the stiffness of the
Reporting, and Data System) scoring are currently being used.
nodules is done. Correlation with cytopathology and Bethesda
TIRADS [23] scoring is done by choosing the correct lexicon, and
scoring is done.
risk stratification is done to select the nodules for FNA or follow
up depending on the appropriate size criteria. With multiple TIRADS risk category: [TR1 (0 points), TR2 (2 points), TR3
nodules, each nodule should be scrutinized for suspicious features (3 points), TR4 (4–6 points), TR5 (≥7 points)].
and selected for FNA on the basis of sonographic features. Scoring The recommendations for FNA/follow up as per size and TIRADS
is determined from five categories of ultrasound findings. The [24] category are as follows.

Thyroid Nodules
TALLER-
SIZE THAN- TOTAL TI-RADS
No IMAGES (mm) COMPOSITION ECHOGENICITY WIDE MARGINS ECHOGENIC FOCI POINTS LEVEL
X X
X X
X X
X X
X X
C Cystic 0 A Anechoic 0 No 0 S Smooth 0 N None 0 0 Pts TR1 Benign

Sp Spongiform 0 ↑ Hyperechoic 1 Yes 3 ID Ill-defined 0 CT Comet-Tail 0 2 Pts TR2 Not
Suspicious
M Mixed cystic 1 = Isoechoic 1 L Lobulated 2 M Macrocaks 1 3 Pts TR3 Mildly
and nodule Suspicious
TWO largest nodules
S Solid 2 ↓ Hypoechoic 2 I Irregular 2 PC Periph calc 2 4–6 Pts TR4 Mod
and any with
Suspicious
IMPORTANT FEATURES
↓↓ Very hypoechoic 3 E Extra- 3 P Punctate 3 7+ TR5 Highly
thyroidal ext Suspicious
*If cystic or spongiform, do
not add further points for
other categories
(a) (b)
(c) (d)
Figure 4.11 (a–d) Longitudinal and transverse sonogram showing diffuse parenchymal hypoechogenicity with ill-defined focal hypoechoic areas
(yellow arrows) and echogenic lines due to fibrosis (white arrows). On color Doppler only minimal vascularity is seen. Patient is clinically hypothyroid.

Thyroid Nodules
(a) (b)
(c) (d)
Figure 4.12 (a–d) Transverse and longitudinal sonogram in patient with long standing hypothyroidism due to Hashimoto’s disease showing the
marked hypoechogenicity with echogenic fibrous septa, giving the gland a characteristic “swiss-cheese” appearance.
TR1 and TR2: no FNA required a bright focus with a posterior triangular shadowing known
TR3: ≥1.5 cm, follow-up, ≥2.5 cm FNA as a comet tail artifact. The comet tail artifact is likely due
• follow-up: 1, 3, and 5 years to the presence of microcrystals and is a classical feature of
TR4: ≥1.0 cm, follow-up, ≥1.5 cm FNA colloid nodules. Colloid nodules are also known as adenomatous
• follow-up: 1, 2, 3, and 5 years nodules or colloid nodular goiter. Although they may grow to be
TR5: ≥0.5 cm, follow-up, ≥1.0 cm FNA large multinodular thyroids (Figure 4.17a and b), they will usually
• annual follow-up for up to 5 years not spread beyond the thyroid gland. A thorough scrutiny of each
nodule is done for any suspicious features [25].
Biopsy is recommended for suspicious lesions (TR3 – TR5) with the
above size criteria.
The cancer risk as per ACR TIRADS is 0.3% for TR1, 1.5% for TR2, MALIGNANT THYROID NODULES
4.8% for TR3, 9.1% for TR4, and 35% for TR5. The main objective of the management of thyroid nodules is to
identify the suspicious nodules for malignancy and do the FNA
BENIGN THYROID NODULES [26]. The suspicious ultrasound features include: solid composition;
Purely cystic nodules (Figure 4.13a and b) are well defined marked hypoechogenicity; irregular or microlobulated margins;
anechoic cysts within the capsule of the thyroid. They show taller than wide nodule; presence of microcalcification, punctate
smooth walls and characteristic posterior acoustic enhancement. echogenic foci, or broken rim calcifications; abnormal heterogeneous
They are scored as TIRADS 1. Spongiform nodules (Figure 4.14) vascularity on color Doppler [27]; presence of local invasion; and
composed of >50% aggregates of microcystic component are metastasis. When multiple nodules (≥4) are present, only the four
specific for benign thyroid nodules. Colloid nodules (Figure 4.15) highest scoring nodules, not necessarily the largest, should be
are the most common benign thyroid nodules. They can be as scored, reported, and followed up. Interval enlargement [28–30] on
small as 3–4 mm or be as large as to be completely replacing the follow-up is felt to be significant if there is an increase of 20% and
thyroid gland. They are usually well defined cystic or mixed 2 mm in two dimensions, or a 50% increase in volume. Further CT,
solid cystic (Figure 4.16a and b), iso- to hypoechoic nodules. MRI, or PET-CT may be required for complete evaluation. Papillary
A characteristic feature of colloid nodules is tiny echogenic or thyroid cancer and follicular carcinoma comprise the majority of

Papillary Thyroid Carcinoma
(a) (b)
Figure 4.13 (a and b) Transverse and longitudinal gray-scale sonogram showing a well-defined clear anechoic cyst, located within the confines of
the thyroid capsule. TIRADS 1. (tr: trachea, ms: strap muscles, thy: thyroid, C: cyst).
Figure 4.15 Gray-scale ultrasound right lobe thyroid sonogram

showing a small well-defined clear hypoechoic cyst typical of a colloid
Figure 4.14 Longitudinal gray scale sonogram showing a typical
nodule (a comet tail artifact may be seen in them).
spongiform thyroid nodule consisting of aggregates of microcystic
components of at least 50% of nodule volume. These nodules are
benign and do not need any further investigations. on histologic examination and thus cannot be made by ultrasound
or by FNA cytology [31–33].
cases. Other common subtypes are Hurthle cell neoplasm, anaplastic HURTHLE CELL NEOPLASM
carcinoma, and medullary carcinoma. Lymphoma and metastasis Hurthle cell neoplasm [34] on ultrasound (Figure 4.19a–d) imaging
are rarely seen. is predominantly solid with mixed internal echogenicity with both
hyperechoic and hypoechoic components. They have ill-defined
margins with partial halo.
FOLLICULAR NEOPLASM
PAPILLARY THYROID CARCINOMA

Follicular adenomas are encapsulated true neoplasms of the
thyroid gland. On ultrasound they are seen as solid well-defined
isoechoic to hyperechoic nodules. Features of loss of halo and Papillary thyroid carcinoma accounts for 60%–70% of thyroid
more hypoechoic echotexture are suggestive of carcinoma. The cancer [35–38]. It can be seen as a multicentric form and
differentiation of follicular adenoma from a follicular carcinoma may be micro-nodular (<1 cm size nodule). It spreads along
(Figure 4.18) is based on the presence of capsular or vascular invasion lymphatics to regional lymph nodes, and distant metastasis is

Medullary Thyroid Carcinoma
(a) (b)
Figure 4.16 (a and b) Transverse sonogram. (a) Gray scale and (b) color Doppler showing a mixed solid cystic, iso- to hypoechoic nodule, located
within the confines of the thyroid capsule. On color Doppler minimal peripheral vascularity is seen. TIRADS 2.
commonly to lung and bone. Characteristic ultrasound features or near total thyroidectomy is often advised. The evaluation of the
(Figures 4.20 through 4.22) are a solid or a mixed solid cystic cervical lymph nodes, both lateral and central compartments, needs
hypoechoic or very hypoechoic mass lesion with punctate (Figure to be very thorough and detailed. Availability and use of a small
4.23) echogenic foci within. The margins may be lobulated or footprint transducer is helpful in evaluating the central compartment
irregular or ill-defined. Extrathyroidal extension and metastatic as it can be maneuvered around to the trachea along the lower pole
lymph nodes show features similar to primary lesions such of thyroid with ease due to its smaller size. The lymph nodes must be
as hypoechoic texture and punctate foci and cystic changes. measured in three dimensions and evaluated with color Doppler and
On color Doppler, central heterogeneous vascularity is seen sono-elastography.
(Figures 4.24 through 4.26).
MEDULLARY THYROID CARCINOMA

PAPILLARY THYROID MICROCARCINOMA
Medullary thyroid carcinoma (MTC) [42–45] comprises 3%–5%

Papillary thyroid microcarcinoma (PTMC) [39–41] by definition of thyroid cancers and can be sporadic or familial (autosomal
includes papillary thyroid carcinoma with the nodule measuring less dominant pattern of transmission), associated with multiple
than 10 mm in greatest dimension (Figure 4.27a and b). Most of these endocrine neoplasia (MEN) 2a and MEN 2b. RET proto-oncogene
are often incidental diagnoses on imaging (ultrasound or CT) done for mutation is found in almost all of the hereditary cases. It arises from
other abnormalities. They often present with cervical masses which parafollicular cells, or C cells. Serum calcitonin levels are elevated
may be metastatic lymph nodes (Figure 4.28a–e). FNA is needed which is used both in diagnosis and follow-up. Ultrasound features
to establish the diagnosis. As these are frequently multifocal, total overlap with papillary carcinoma and comprise a solid ill-defined
(a) (b)
Figure 4.17 (a and b) A 45-year-old female with multinodular goiter. Longitudinal sonogram of the thyroid showing a well-defined almost solid
hypoechoic nodule with minimal vascularity on color Doppler. TIRADS 3. Biopsy showed benign follicular adenoma.

Anaplastic Carcinoma
heterogeneous hypoechoic nodule. The calcifications seen here

are often coarser. On color Doppler they show heterogeneous
vascularity, and often cervical (paratracheal and lateral cervical)
metastasis are seen at presentation (Figures 4.29 and 4.30). Distant
metastasis occurs to liver, lungs, bone, and to brain and skin. The
risk of distant metastasis increases with the size of the thyroid
tumor, extension of the tumor beyond the thyroid capsule, and
presence and extent of lymph node metastasis. PET-CT is needed
for further evaluation.
ANAPLASTIC CARCINOMA
Anaplastic carcinoma [46–48] is one of the most aggressive

malignancies and usually presents as a rapidly enlarging mass with
local compressive symptoms, often with distant metastasis via the
bloodstream to brain, liver, lungs, and bone. On ultrasound there is
often a large very hypoechoic mass (Figure 4.31) involving the whole
Figure 4.18 Ultrasound right thyroid of a 43-year-old female showing of the gland and possibly extending beyond with local invasion and
a well-defined solid 3.1 × 3.0 cm solid, iso- to hyperechoic nodule with metastasis.
peripheral calcifications (arrow). TIRADS 5 (S/solid/2, ≈/Isoechoic/1, Anaplastic carcinoma is rare (<1% of all thyroid masses) but
S/smooth/0, PC/peripheral Calc/2, 5 pts/TR4/moderately suspicious). extremely aggressive. Patients are usually elderly with a history of
Biopsy showed follicular carcinoma thyroid. goiter and present with a rapidly growing neck mass. The tumor
(a) (b)
(b)
(c) (d)
Figure 4.19 (a and b) Transverse and longitudinal scan of right lobe thyroid showing a well-defined mixed solid cystic 31 × 17 × 25 mm hypoechoic
nodule with ill-defined margins. TIRADS 4 (mixed cystic and solid/1, ↓/hypoechoic/2, No/0, ID/ill-defined/0, PC/peripheral Calc/2 = 5 pts/TR4/mod
suspicious). (c and d) FNAC showed Bethesda III AUS with Hurthle cell predominance.

(a) (b)
Figure 4.20 (a and b) Transverse and longitudinal scan of right lobe thyroid with color Doppler showing a well-defined solid hypoechoic nodule
with lobulated margins. TIRADS 4 (S/solid/2, ↓/hypoechoic/2, L/lobulated/2, N/none/0 = 6 pts/TR4/mod suspicious). On FNA, few smears showed
small crowded groups with enlarged hyperchromatic, slightly irregular nuclei (? Papillary tips) with scant colloid and focal cytological and architectural
atypia, suspicious of follicular neoplasm with possibility of follicular adenoma/FVPTC/NIFTP.
(a) (b)
(c) (d)
Figure 4.21 (a and b) Transverse and longitudinal scan of right lobe thyroid showing a 28 × 11 mm exophytic heterogeneous hypoechoic nodule
with likely ETE (extrathyroidal extension, curved arrow) along the anterior capsular surface. On color Doppler heterogeneous vascularity is seen within
the nodule. TIRADS 5 (S/solid/2, ↓/hypoechoic/2, No/0, ETE/3, N/None/0 = 7pts/TR5/suspicious). (c and d) FNAC showed papillary Ca. Pap stained
smear shows crowded sheets and papillary clusters of thyroid follicular cells with intranuclear cytoplasmic inclusion.

(a) (b)
(c)
Figure 4.22 (a–c) Two small (12 × 11 mm & 7 × 6 mm) very hypoechoic heterogeneous nodules (curved arrows) in left lobe thyroid with punctate
foci and peripheral broken rim calcifications. TIRADS 5 (S/solid/2, ↓↓/very hypoechoic/3, No/0, ID/Ill-defined/0, P/Punctate/3, 8 pts/TR5/suspicious).
FNAC showed papillary carcinoma (multicentric PTC).
invades locally and distant metastases most commonly involve the

lungs, bones, brain, and liver. Mean survival is 6 months, with a
5-year survival rate of 7%. CT is needed for full assessment.
PRIMARY THYROID LYMPHOMA

Primary thyroid lymphoma [49,50] is rare (<2% of thyroid
cancers). The peak incidence is during the seventh decade, and the
male/female ratio is 1:3. Clinically patients present with a rapidly
enlarging painless mass, often with compressive symptoms.
History of preceding long-standing auto-immune thyroiditis or
Hashimoto’s disease may be given. Most patients have elevated
anti-thyroglobulin antibodies. Ultrasound features comprise
solid hypoechoic, often pseudocystic masses on a background of
thyroiditis.
ULTRASOUND ELASTOGRAPHY
Ultrasound elastography [51–53] measures tissue elasticity or
Figure 4.23 Transverse sonogram of the right lobe thyroid showing a stiffness, which is in turn used as an adjunct to characterize the
heterogeneous hypoechoic nodule (curved arrow) with numerous punctate lesions. The technique involves application of a small mechanical
echogenic foci. TIRADS 5 (S/solid/2, ↓/hypoechoic/2, No/0, ID/ill-defined/0, force during scanning, and the degree of distortion is used to
P/punctate/3, 7+/TR5/Highly suspicious). FNAC Bethesda VI: PTC. estimate the stiffness of the tissue of interest (Figures 4.32 and 4.33)

(a) (b)

(c)
Figure 4.24 (a and b) Transverse sonogram showing a suspicious isthmus nodule (curved arrows) very close to trachea. Image calyceal dilation 10 mm. showing ipsilateral level two lymph nodes with similar
punctate echogenic foci within. Ln + TIRADS 5 (S/solid/2, ↓↓/very hypoechoic/3, No/0, E/extrathyroidal ext/3, N/none/0, LN+, 9+/TR5/Highly suspicious). Biopsy: papillary CA.
(a) (b)
(c)
Figure 4.25 (a–c) Ultrasound of thyroid showing a heterogeneous hypoechoic solid nodule (curved arrows) with ill-defined/irregular margins and multiple tiny punctate echogenic foci. TIRADS 5. Biopsy
papillary carcinoma. Image calyceal dilation 10 mm. Showing associated ipsilateral metastatic left level 3 lymph node.

(a) (b)
(c) (d)
(e)
(f )
Figure 4.26 (a–f) Ultrasound thyroid (gray scale and color Doppler) showing a large heterogeneous hypoechoic mass in the right lobe thyroid with
multiple tiny punctate echogenic foci. TIRADS 5. Biopsy papillary carcinoma. Associated multiple metastatic left level 3 and level 4 lymph nodes.

(a) (b)
Figure 4.27 (a and b) Micronodular papillary thyroid carcinoma in a 35-year-old female. Biopsy proven. Longitudinal sonogram showing a
heterogeneous hypoechoic nodule with few tiny punctate echogenic foci. On elastography the lesion appears hard in stiffness.
(a)
(b)
(c) (d) (e)
Figure 4.28 (a–e) Micronodular multicentric papillary thyroid carcinoma in a 41-year-old female with (c and d) large cervical metastatic lymph
nodes (level 3) at presentation. Biopsy proven. Longitudinal sonogram showing two sub-centimeter heterogeneous ill-defined hypoechoic nodules
(curved arrows) with heterogeneous vascularity. Note the tiny punctate echogenic foci in the cervical metastatic nodes.
and is color-coded as per the manufacturer. Soft tissues deform Microcalcification and cystic changes [55,56] in regional lymph
more than hard tissues. There are various studies on this nodes are highly suspicious (Figure 4.35a and b). Loss of normal
technique’s role in predicting malignancy; however, currently it fatty hilum, irregular, or rounded appearance with irregular
is being used as an adjunct in both thyroid nodule and lymph internal hypervascularity (Figure 4.36a and b) are suspicious
node assessment. features. A thorough evaluation of both the central [57,58] and
lateral compartment must be done in all cases. Availability of a
small footprint transducer is helpful in evaluating the spaces
LYMPHADENOPATHY around the trachea and bones. Biopsy is suggested for suspicious
The presence of local lymphadenopathy with any suspicious features lymph nodes. Post-thyroidectomy assessment of the thyroid
for malignancy must be noted [54]. A typical reactive lymph node bed and the nodal compartments must be very thorough and
may be ovoid to rounded hypoechoic and show hilar vascularity on meticulous. Further cross sectional imaging may be advised for
color Doppler (Figure 4.34). detailed mapping.

(a) (b)
(c) (d)
(e)
Figure 4.29 (a–e) Ultrasound neck done in a 33-year-old female for routine health check-up showing diffuse heterogeneous right lobe thyroid
echotexture as compared to contralateral side. Associated large heterogeneous hypoechoic masses in neck with increased vascularity on color Doppler.
Biopsy findings were Bethesda VI, medullary carcinoma, with associated metastatic right level 3 and 4 lymph nodes with calcification at diagnosis.
(a) (b)
Figure 4.30 (a and b) CEMRI in the same patient as in Figure 4.29. T1 weighted image axial and coronal scan showing multiple well defined
lobulated homogenous masses in the neck along the jugulo-diagastric chain (extending from level II to V regions) with mild to intense enhancement
on contrast images. Biopsy confirmed metastatic medullary carcinoma thyroid.

(a) (b)
Figure 4.31 (a and b) A 73-year-male. Gray-scale ultrasound showing a large, solid lobulated very hypoechoic mass involving isthmus and left lobe
thyroid. Color Doppler showing mild vascularity in this case. Extrathyroidal extension (ETE) is suggested. Biopsy: Anaplastic carcinoma.
(a) (b)
(c)
Figure 4.32 (a–c) Longitudinal scan with color Doppler showing a heterogeneous hypoechoic nodule with lobulated margins and internal vascularity
on color Doppler. Corresponding real-time qualitative elastogram showing the lesion in the yellow to red zone, suggesting a moderately stiff nodule,
suggesting malignancy on elastography. FNA showed Bethesda V, papillary thyroid carcinoma.

Metastasis to the Thyroid
(a) (b)
(c)
Figure 4.33 (a–c) Longitudinal and transverse sonogram of right lobe showing a suspicious hypoechoic taller than wide right thyroid nodule/ n +
TIRADS 5 (S/solid/2, ↓↓/very hypoechoic/3, Yes/3, L/lobulated/2, N/none/0, LN+, 10+/TR5/Highly suspicious). Biopsy: Papillary CA.
METASTASIS TO THE THYROID
Metastasis to the thyroid is rare and is a part of disseminated

metastasis from breast, colon, kidney, lung, and melanoma.
These cases are often detected as incidentalomas on PET-CT
(Figure 4.37) and are sent for ultrasound. Ultrasound features are
usually of a non-specific solid heterogeneous hypoechoic mass
with disorganized vascularity. Associated other regional and
distant metastases are seen. FNA is usually indicated for definitive
Figure 4.34 Longitudinal ultrasound of left upper neck (Level II) showing
assessment.
a typical ovoid reactive lymph node with hilar vascularity on color Doppler.

Metastasis to the Thyroid
(a) (b)
Figure 4.35 (a and b) Longitudinal sonogram of left neck showing a heterogeneous hypoechoic ill-defined thyroid nodule at lower pole with
multiple punctate echogenic foci (straight arrows) and associated cystic metastatic cervical lymph node (curved arrow) in the central compartment
(level VI). FNA confirmed papillary thyroid carcinoma.
CONTRAST-ENHANCED ULTRASOUND IMAGING elastography have been gradually applied to the diagnosis of cervical
Contrast-enhanced ultrasound (CEUS) is a very promising lymph node metastasis. However, it is not clear whether contrast-
diagnostic technique that could improve the diagnostic accuracy of enhanced ultrasound and elastography combined with conventional
identifying benign thyroid lesions to spare a large number of patients ultrasound improve the accuracy of lymph node metastasis diagnosis.
an unnecessary invasive procedure. Contrast-enhanced ultrasound
enhancement patterns are different in benign and malignant lesions COMPUTED TOMOGRAPHY (CT), MAGNETIC RESONANCE
[59,60]. Ring enhancement was predictive of benign lesions, whereas IMAGING (MRI), AND PET-CT
heterogeneous enhancement was helpful for detecting malignant Further cross sectional imaging like CT [61,62] and MRI [63–66]
lesions. Currently, contrast-enhanced ultrasound and ultrasound must be advised in patients with clinical symptoms of hoarseness
(a)
(b)
Figure 4.36 (a and b) Longitudinal sonogram of left upper neck in a post-operative PTC patient showing a hypoechoic level 3 lymph node with
heterogeneous vascularity. FNA confirmed papillary thyroid carcinoma. Sono-elastography of the lymph node showing intermediate stiffness.

References
ultrasound suspicion for significant ETE (extrathyroidal extension),

bulky, posteriorly located, or inferiorly located lymph nodes
incompletely imaged by ultrasound; and cases of rapid progression
or enlargement. In locally invasive thyroid malignancy (such as
anaplastic carcinoma), the imaging modalities help to evaluate
the extrathyroidal spread of a tumor to the larynx, trachea, and
adjacent major vessels and provide evidence of regional or distant
metastases. On contrast-enhanced CT (CECT), heterogeneous
masses with or without calcifications or enhancement are seen in
thyroid cancer (Figure 4.38a–c). A systematic approach to evaluate
neck lymph nodes and mapping must be done as nodal metastasis
and its extent affects the management planning and prognosis
Figure 4.37 FDG-PET-CECT. Axial scan showing subtle hypodensity significantly [67–69].
18F-FDG PET-CT [70] is suggested to evaluate for distant metastasis.
with increased FDG uptake (SUVmax-9.9) in the left lobe of the thyroid.
(These thyroid incidental nodules account for a significant number of Diffusion-weighted MRI (DWI) and perfusion imaging with
detected thyroid nodules). dynamic contrast-enhanced MRI (DCE-MRI) are other techniques
to evaluate for metastatic lesions.
of voice with or without vocal cord paresis or paralysis, progressive
dysphagia or odynophagia, mass fixation to surrounding structures POST-THYROIDECTOMY/HEMI-THYROIDECTOMY
on palpation, respiratory symptoms, hemoptysis, stridor, or The postoperative thyroid bed should appear as a narrow area of
positional dyspnea. Other indications would be large size of tumor increased echogenicity between the common carotid artery laterally
or mediastinal extension, incompletely imaged on ultrasound; and the trachea medially. Any abnormality in the area should be
carefully evaluated to differentiate between sequelae of surgery,
residual thyroid, or recurrence.
(a)
CONCLUSION
Ultrasound evaluation of the thyroid is the fundamental basis

of diagnosis and management of thyroid pathologies. A lot of
care, detail, and experience is required to do a meticulous neck
ultrasound using proper technique for both gray scale and
Doppler. A thorough reference to the patient clinical information
and correlation must be made. Examination includes and extends
beyond the thyroid to complete neck evaluation in all cases.
(b) Choose the correct lexicon and give a TIRADS score for the thyroid
nodules. Use elastography as an adjunct. Advise of further imaging
if suggested. Give a well-documented report. Get a Bethesda score
correlation and follow up.
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50. Thieblemont C et al. Primary thyroid lymphoma is a for evaluating metastatic cervical lymph nodes in patients
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Chapter 5
PATHOLOGY OF THE THYROID
R. Ravi
CONTENTS
Non-Neoplastic Lesions of the Thyroid 46

Neoplastic Lesions 47
Reference 50
Suggested Reading 50
Fine needle aspiration cytology (FNAC) has been commonly Common lesions encountered in day to day practice are as follows:
practiced all over the world for more than five decades. A solitary goiter, cysts, thyroiditis, follicular neoplasia (including HN),
thyroid nodule is frequently encountered in clinical practice and papillary carcinoma, medullary carcinoma, poorly differentiated
is four times more common in females than in males. Malignancy follicular carcinoma (including insular carcinoma), squamous
in the thyroid is also more common in females. The majority of the carcinoma in thyroid, Non Hodgkin Lymphoma (NHL), and
clinically palpable solitary thyroid nodules are dominant nodules in parathyroid cysts.
a multinodular goiter. As cancer is more common in solitary nodules,
all solitary thyroid nodules (STNs) are viewed with suspicion. USG
(ultrasonography) and thyroid scinti-scanning are non-invasive Table 5.1 The Bethesda System for reporting of Thyroid
Cytopathology (recommended diagnostic categories and risk
screening techniques used. Malignancy incidence of solitary cold
of malignancy according to SZ Ali and ES Cibas modified)
nodules varies from 10.4%–44.7%. In the context of thyrotoxic Graves’
disease, 50% of clinically apparent cold nodules have been shown to Diagnostic categories of FNA thyroid Risk of malignancy
be malignant with very aggressive behavior. I. Non-diagnostic or unsatisfactory
FNA cytology has the advantage of being more rapid, less traumatic, II. Benign 0%–3%
and cost effective (economical). Sampling is also more representative Consistent with benign follicular nodule
(due to ease of several needle passes). Complications are practically (goiter, colloid nodule, etc.)
non-existent, and diagnostic accuracy is as good or better than core Consistent with lymphocytic thyroiditis
biopsy. Diagnostic pitfalls nevertheless exist. Consistent with granulomatous thyroiditis
(sub-acute)
This chapter briefly discusses the utility of fine needle aspiration
III. Atypia of undetermined significance or 5%–15%
cytology in thyroid lesions and also summarizes the management
follicular
protocol in thyroid lesions in relation with cytology findings. To Lesion of undetermined significance
minimize the disparity in diagnosis by clinicians, radiologists, and (AUS/FLUS)
cytopathologists/pathologists, the Bethesda system for reporting IV. Follicular neoplasm or suspicious for a 15%–30%
of thyroid cytopathology (BSRTC) is presently the most popular follicular neoplasm (specifying for Hurthle
and worldwide accepted reporting system. There are six diagnostic cell type of neoplasm recommended)
categories of FNAC of the thyroid with special emphasis on risk of Figure 5.1a and b
malignancy (ROM). V. Suspicious for malignancy (suspicious for 60%–75%
Coming to consensus on the definition of adequate cytology in the papillary carcinoma, medullary carcinoma,
thyroid has been a difficult task. Cytologically benign appearing metastasis, lymphoma)
lesions can be deemed adequate if each of a minimum of two VI. Malignant (papillary carcinoma, poorly 97%–99%
smears contain six clusters of benign cells; others go to the extent of differentiated carcinoma, medullary
recommending at least six smears, with each smear containing no carcinoma, anaplastic carcinoma, squamous
carcinoma, metastatic, and lymphoma)
less than 10 to 15 clusters of benign follicular cells. There are cases on
record where just a few clusters of cells have been sufficient to arrive
at a diagnosis. The best judge of specimen adequacy is a cytologically
diagnostic sample in which it has been possible to give a clinically Table 5.2 Bethesda System—Relationship to clinical algorithms [1]
relevant cytological diagnosis. This is possible in the hands of an
experienced cytopathologist. Category Malignancy R (%) Management
Adequate cytology can be further subdivided into four groups: ND 1 to 4 Repeat FNA w/US
benign, undetermined, suspicious (IV and V), and malignant (VI). Benign <1 Follow-up
Benign categories include normal thyroid, goiter, and inflammatory AUS 5 to 10 Repeat FNA
lesions like lymphocytic thyroiditis and deQuervans’ thyroiditis. The SUS FN 5 to 30 Lobectomy
malignant smears are papillary, medullary, poorly differentiated, SUS FN HN 15 to 45 Lobectomy
undifferentiated carcinoma lymphoma, and metastasis. The
SUS MALIG 60 to 75 Lobectomy or total
suspicious categories include follicular neoplasm and oncocytic
Malignancy 97 to 99 Total thyroidectomy
lesions (Tables 5.1 and 5.2).
Pathology of the Thyroid 45

Non-Neoplastic Lesions of the Thyroid
(a) (b)
Figure 5.1 (a,b) Papanicolaou stain. Hurthle cell neoplasm.
Uncommon lesions are: acinar or microfollicular patterns. Fire flair cells may be seen in toxic
sarcomas, SEETLE (spindle cell tumor with thymic like differen- goiter. Presence of Hurthle cells in smears of nodular goiter makes
tiation), CASTLE (carcinoma with thymic like differentiation), a distinction from Hurthle cell neoplasm difficult. If Hurthle cells
mucoepidermoid carcinoma, teratoma, etc. It is beyond the scope of are few and the background is colloid with monomorphic follicular
this chapter to include all the lesions. The commonly encountered cellist, it is likely to be Hurthle cell change in a goiter. Otherwise,
lesions are dealt with within this chapter. Hurthle cell changes compatible with Hurthle cell neoplasm/
nodular goiter may be given as differential diagnosis. If fire flair cells
appear in more than 50% of follicular cells, toxic goiter or Graves’
disease are a possibility.
NON-NEOPLASTIC LESIONS OF THE THYROID
THYROIDITIS
Clinical presentation is of paramount importance. In thyroiditis,
COLLOID GOITER the background is bloody with many lymphoid cells, epitheloid cells,
Aspirate yields thick or thin brownish fluid. There is abundant granuloma, and multinucleated giant cells with scattered follicular
colloid with or without blood. Follicular cells are seen in epithelial cell groups. Occasional follicular cells may show nuclear
monolayered groups, cells appear uniform, and do not show any grooves and inclusions. However, nuclear overlap is seldom seen. In
nuclear abnormal features. The pitfall is the entire aspirate may not all such instances, clinical and radiological impression plays a very
show any follicular cells; only cyst macrophages may be seen. In important role. Anti-microsomal antibodies are also very useful.
cases where the radiology is colloid goiter, a cytological diagnosis of Sub-acute thyroiditis is clinical, and cytology may show many
colloid goiter with cystic degeneration may be given. Nodular goiter multinucleate giant cells with neutrophils and lymphocytes in a
might show both monolayered sheets of follicular cells and cells in dirty background (Figure 5.2).
(a) (b)
(c)
Figure 5.2 Lymphocytic thyroiditis. (a) Thyroid follicles with sheets of lymphocytes; (b) thyroid follicles, lymphocytes, and occasional giant cell;
(c) thyroid follicles with sheets of Lymphoid cells.
46 Pathology of the Thyroid

Neoplastic Lesions
(a) (b)
Figure 5.3 (a,b) H and E stain. Follicular neoplasia.
(a) (b)
Figure 5.4 (a,b) Nuclear inclusions in a case of NIFTP.
NEOPLASTIC LESIONS
FOLLICULAR NEOPLASIA
Differentiating follicular adenoma from carcinoma is not
cytologically possible because of strict criteria of diagnosis of
follicular carcinoma by capsular and vascular invasion. FNA helps
to identify lesions that can be picked up for surgical excision. There
is bloody background, moderate to high cellularity, uniform cells
in acinar (follicular), and honey comb pattern. The main problem is
distinction of hyperplasia from neoplastic proliferation. Nuclear size
is often helpful though not diagnostic in distinguishing follicular
hyperplasia from neoplasia (Figure 5.3).
Neoplastic follicles usually would show nuclear enlargement more
than 1.5 times the size of cells in non-neoplastic lesions. With
the use of the Bethesda reporting system, all such lesions can be
reported as Bethesda IV I e Follicular Neoplasia, and the final call Figure 5.5 EFVPTC or NIFTP histology.
regarding the surgical management is made by clinical and USG
findings criteria. In 2016, a new entity was introduced: Non-invasive PAPILLARY CARCINOMA
follicular thyroid neoplasm with papillary nuclear features (NIFTP) Females are more commonly affected by papillary carcinoma
(Figure 5.4). The article appeared in JAMA 2016 as “Nomenclature than males, 4:1, and 60% to 80% of thyroid cancers are papillary
Revision for Encapsulated Follicular Variant of Papillary Thyroid carcinoma (Figure 5.6). FNAC usually shows papillary arrangement
Carcinoma.” Thyroid tumors currently diagnosed as Non-Invasive (picket-fencing) (Figure 5.7), intranuclear grooves and inclusions,
EFVPTC (Encapsulated Follicular Variant of Papillary Thyroid optically clear nucleus, thick chewing gum like colloid, and few
Carcinoma) have a very low risk of adverse outcome and should multinucleate giant cells (Figure 5.8). Psammoma bodies may be
be termed NIFTP (Figure 5.5). This reclassification will affect a present. FNAC of 11%–35% cases of papillary carcinoma may show
large population of patients worldwide and result in a significant Psammoma bodies. It is important to note that Psammoma bodies
reduction in psychological and clinical consequences associated are also seen in nodular goiter; however, other cytological criteria
with the diagnosis of cancer. are helpful in making a diagnosis.

Neoplastic Lesions
(a) (b)
(c)
Figure 5.6 (a,b) Bone metastases in papillary carcinoma thyroid; (c) clinical picture of papillary carcinoma thyroid with metastases in skull.
Figure 5.8 Papillary carcinoma cytopathology.

Figure 5.7 Picket-fencing in papillary thyroid lesion.
MEDULLARY CARCINOMA pink colloid, which in fact is amyloid (Figure 5.9). In the background,
This represents 10% of all thyroid cancers. Cytological criteria are round squamous metaplasia may be seen. Serum calcitonin is high and is of
cells and plasmacytoid cells, spindle cells, polygonal cells, cells with great utility in making a diagnosis in absence of immunocytochemistry
reddish granular cytoplasm, salt and pepper chromatin, and amorphous for calcitonin, chromogranin, and synaptophysin.

Neoplastic Lesions
(a) (b)
Figure 5.9 (a,b) Medullary carcinoma thyroid.
INSULAR CARCINOMA AND POORLY DIFFERENTIATED Other rarer lesions are difficult to pick up on cytology alone and are also
CARCINOMAS fortunately of rarer occurrence. For details of these rarer conditions,
Smears are cellular with scant or no colloid. Cells are arranged appropriate relevant text may be referred to (Figures 5.13 and 5.14).
in monolayered, trabecular, follicular, and dissociated pattern. It is also beyond the scope of this chapter to cover every lesion; however,
Necrosis is often present in the background. Tumor cells are small there is emphasis on role of the surgical pathologist in handling the
with pale scant cytoplasm and high N C ratio. Nuclear overlap is thyroid specimen, proper grossing, and surgical pathology reporting.
frequent and intracytoplasmic vacuoles may be seen. Foci of Hurthle
It is essential to know all the clinical details before grossing. Age,
cells change and clear cell change may be seen (Figure 5.10).
indication of surgery, pre-operative radiology findings, cytology
Other lesions like anaplastic carcinomas (Figure 5.11) and report, any history of prior surgical procedure, family history of thyroid
lymphomas (Figure 5.12) are not a diagnostic difficulty in disease if any (MEN syndrome, etc.), and type of specimen received
clinical and cytological practice. Possibility of metastasis and in pathology laboratory are mostly lobectomy (hemithyroidectomy),
systemic diseases are to be excluded clinically and sometimes by near total thyroidectomy, total thyroidectomy, and completion
immunohistochemistry. thyroidectomy.
Figure 5.10 Poorly differentiated carcinoma thyroid. Figure 5.11 Anaplastic carcinoma thyroid.
(a) (b)
Figure 5.12 (a) Non-Hodgkin’s lymphoma (NHL) in thyroid; (b) Cell block of NHL-thyroid.

Suggested Reading
Location of tumor, unifocal or multifocal.

Vascular or lymphatic invasion identified/not identified.
Extrathyroid extension.
Mention the inked surgical margins.
Adjacent thyroid status.
Parathyroid glands.
And the final impression may be done by using WHO TNM
classification.
T – Primary Tumor.
TX – Primary Tumor cannot be assessed.
T1 – Tumor 2 cm or less limited to thyroid.
T2 – Tumor more than 2 cm but not more than 4 cm limited
to thyroid.
T3 – Tumor more than 4 cm, limited to thyroid or minimal
extrathyroid extension.
T4a – Tumor of any size extending beyond thyroid capsule
invading subcutaneous soft tissue, larynx, trachea,
Figure 5.13 Muco-epidermoid carcinoma of thyroid. Muco-epidermoid recurrent laryngeal nerve.
carcinoma of thyroid and salivary glands develop from ultimobranchial T4b – Tumor invaded paravertebral fascia or encases carotid
pouch in embryo. Hence all lesions of salivary gland occur in thyroid as well. artery.
All anaplastic thyroid carcinomas are considered T4
(4a intrathyroid and 4b with extrathyroid extension).
Regional lymph nodes (N).
NX – Lymph nodes cannot be assessed.
N0 – No nodal metastasis.
N1 – Regional nodal metastasis.
N1a – Metastasis to Level VI (pretracheal, paratracheal, and
prelaryngeal, Delphian lymph node)
N1b – Metastasis to unilateral, bilateral, or contralateral
cervical or superior mediastinal lymph nodes.
Distant metastasis (M).
Mx – Cannot be assessed.
M0 – No distant metastasis.
M1 – Distant metastasis.
Of course pathologists and surgeons hand-shake, not only in the

diagnostic exercise, or, have a final say in histopathology, but, their
mutual exchanges intra-operatively can benefit enormously to make
Figure 5.14 Teratoma of thyroid. a personalized treatment strategy.
STEPS IN GROSSING
Describe the type of specimen, weigh the specimen, measure the REFERENCE
dimensions of each lobe, and look for any other masses attached to
the gland. Orient the specimen; in case of completion thyroidectomy,
identify the residual portion of the thyroid lobe or thyroid bed, 1. Edmund S, Cibas MD, Syed Z, Ali MD. The Bethesda System
describe the external surface, capsule intact or breached, and try for Reporting Thyroid Cytopathology. Am J Clin Pathol.
to look for parathyroid glands. Ink the thyroid completely from 2009;132:658–65.
external surface and either slice the lobes transversely from upper
to lower lobe (bread loafing) or bisect longitudinally. Observe the
cut section, consistency, cystic, hard mass lesion, number of nodules, SUGGESTED READING
color of nodule, and any calcification. Look for circumscription of
nodule (encapsulated or invasive). Note distance from tumor to inked
surface, note presence of any extrathyroid extension. Take following
Dey P. Diagnostic Cytology. Jaypee Brothers.
sections: (a) Tumor with capsule; (b) Tumor with adjacent thyroid,
isthmus, adjacent normal thyroid of other lobe, and parathyroid Greene FL, Komorowski AL, Kazi R, Dwivedi R (eds). Clinical
gland if any. After the final grossing, the histopathology report may Approach to Well Differentiated Thyroid Cancers. Byword
be reported in the following format. Books Private Limited.
Grossing of Surgical Oncology specimens Tata Memorial Hospital
department of Pathology.
SPECIMEN TYPE Jayaram G. Atlas and Test Book of Thyroid Cytology. Arya Publications.
Type of carcinoma (papillary, follicular medullary, poorly Orell SR, Sterrett GF. Fine Needle Aspiration Cytology. Churchill
differentiated carcinoma). Livingstone Elsevier.
In case of papillary carcinoma, mention differentiation.
World Health Organization. Classification of Tumours. Tumours of
Endocrine organs.

Chapter 6
MEDICAL MANAGEMENT OF THYROID DISORDERS
Himanshu Patil and Shailesh Pitale
CONTENTS
Graves’ Disease 51
Thyroiditis 52
Hypothyroidism 53
Suggested Reading 54
amounts, reflecting the ability of the gland’s concentrated iodine.

In addition to radioactive iodine uptake, a scan of the thyroid can
GRAVES’ DISEASE provide additional information about the size of the thyroid gland.
TSH receptor antibody measurement can be performed. The advantages
of the TSI assay is that it measures TSH receptor-stimulating antibodies
Graves’ disease is an autoimmune disorder characterized by the
which are relevant to hyperthyroidism. Their presence will differentiate
presence of clinical hyperthyroidism and autoimmune antibodies
Graves’ disease from other causes of hyperthyroidism.
against thyrotropin or thyroid-stimulating hormone (TSH)
receptors. The presentation of the disease varies with age. Circulating Treatment of any medical condition is directed at its cause;
TSH receptor antibodies are present in at least 90% of patients. An unfortunately, the immune dysregulation in Graves’ disease remains
interesting aspect is its association with ophthalmopathy. obscure. Therefore, treatment is directed at the thyroid gland rather
than the underlying autoimmunity.
Graves’ disease is seen commonly in women between ages 20–50
years. The incidence is 1–10 per 100,000, however, it varies with Antithyroid drugs remain the first choice of initial therapy in children,
iodine content in geographical areas. Cigarette smoking and adolescents, and adults. They do not directly affect iodine uptake or
stressful life events have also been linked to Graves’ disease. hormone release by the thyroid. Within the thyroid both Propylthiouracil
(PTU) and Methimazole inhibit thyroid hormone synthesis by interfering
The thyroid glands of patients with Graves’ disease are infiltrated
with intrathyroidal iodine utilization and iodotyrosine coupling, both of
with antigen specific T cells. There are abnormalities in T cell
which are catalyzed by thyroid peroxidase (TPO). Extrathyroidally, PTU
function that allow TSH receptor antibodies to develop, which not
inhibits conversion of T4 to T3 in peripheral tissues. Serum halflife of
only stimulate TSH receptor action in thyrocytes but may also cross
PTU and Methimazole is 1 and 4–6 hrs, respectively.
react with orbital antigens.
Anti-thyroid drug therapy can be used in two ways: primary therapy
The main feature of hyperthyroidism is related to the action of
can be given for 1–2 years in hopes that the patient will achieve
thyroid hormone excess and increased adrenergic activity.
remission, or it can be used for a few months prior to ablative therapy.
Typical manifestations include weakness, fatigue, anxiety,
Methimazole is the first choice, once-a-day drug, which improves
tremulousness, heat intolerance, and weight loss. Recent studies
compliance and the toxicity is more predictable. PTU could be
have shown that elderly patients may develop congestive cardiac
considered in patients with mild drug reaction to Methimazole, or
failure and reversible cardiomyopathy.
in the first trimester of pregnancy.
Weight loss despite voracious eating, hyperdefecation, deranged
For patients who are hyperthyroid on low drug doses but
liver functions, vitiligo, and graying of hair may indicate presence
hypothyroid on larger doses, some physicians prefer a “block and
of anti-melanocyte antibodies. Elevated thyroid hormones are
replace technique” regimen.
associated with decreased bone mineral density (more marked
in postmenopausal women), and generalized proximal muscle Prospective studies on long treatment with antithyroid drugs have
weakness and hand tremors are common. not shown to be more effective, therefore 12–18 months duration of
therapy is reasonable.
Central nervous system (CNS) manifestations include irritability,
restlessness, nervousness, and impatience. Depression, suicide, and Anti-thyroid drug side effects can be split into minor and major.
criminal behavior is unusual. Rarely they present with neurological Minor side effects include rash, arthralgia, hair loss, abnormal taste,
findings like chorea. and smell sialadenitis. Major side effects include severe polyarthritis,
agranulocytosis, aplastic anemia, vasculitis, severe hepatitis, cholestasis,
Thyroid hormone measurements include total T4, total T3, and TSH.
hypoprothrombinemia, and insulin-autoimmune syndrome.
Recent advances now allow direct measurement of free T4 which
is a superior technique. Total T4 measurements are affected by Major side effects are rare. Agranulocytosis is typically seen in the
hormone blinding proteins, drugs (oral contraceptive pills [OCPs], first three months of therapy, but there are notable exceptions.
androgens, and opiates) and medical conditions like hepatitis, Liver toxicity is a rare but serious side effect. Hepatic involvement
cirrhosis, and nephrotic syndrome. Free T4 levels are unchanged in with PTU typically presents as clinical hepatitis with malaise,
these circumstances. Approximately 5% of patients will have normal anorexia, jaundice, and tender hepatomegaly.
serum free T4 levels and elevated serum T3 levels. Routine assessment of blood cell count is not currently recommended;
Patients with hyperthyroidism will usually present with concentrated some clinicians monitor complete blood count and liver functions
higher amounts of radioactive iodine, rather than with normal prior to antithyroid drug titrations.
Medical Management of Thyroid Disorders 51

Thyroiditis
BETA ADRENERGIC BLOCKERS • Riedel’s thyroiditis

Blockade of adrenergic pathways provide patients with considerable • Drug induced thyroiditis
relief from adrenergic symptoms such as tremors, palpitations, • Radiation thyroiditis
anxiety, and heat intolerance.
Although Propranolol was the initial choice of drugs used in the dose CHRONIC LYMPHOCYTIC THYROIDITIS
of 80–160 mg/day in undivided doses, similar effects are produced This is one of the most common of all autoimmune disorders. In this
by 50–200 mg of Atenolol or Metoprolol or 40–80 mg of Nadolol. condition there is enhanced presentation of thyroid antigens and
Propranolol or Esmolol can be used intravenously for patients who reduction in immune tolerance with an increase in Th-1 lymphocyte
are acutely ill. activity and destruction of thyroid follicles. This destruction results
from several effects of cytokine induced apoptosis and ICAM-1
POTASSIUM IODIDE THERAPY mediated CD8 + cell mediated cytotoxicity. Almost all patients have
Potassium iodide (KI) can be used to treat mild hyperthyroidism. antithyroid antibodies in their serum, most commonly anti-thyroid
Two Japanese studies found that it can be useful in patients who are peroxidase (anti-TPO) antibodies, but also anti-thyroglobulin
allergic to antithyroid drugs. (anti-TG) antibodies. Patients often have thyroid enlargement with
normal thyrotropin (TSH). Progression is very slow and occurs
RADIOIODINE THERAPY over years.
I-131 therapy for Graves’ disease has been used for more than It is estimated that genetic susceptibility contributes 70%–80%
70 years. The goal of therapy is to render the patient permanently towards the disorder. Environmental factors contribute to 20%–30%
hypothyroid. This process takes about three months. of chronic thyroiditis.
There are two approaches to decide the therapeutic dose of radioactive Low levels of selenium have been associated with Hashimoto’s
iodine for patients with Graves’ disease. The first method is to thyroiditis, however, there is no consistent data showing the benefit
calculate the size of the thyroid gland and deliver 80–200 µC of I-131 of selenium supplementation. Presence of thyroid antibodies usually
per gram of thyroid tissue. The second method is simple and consists does not in itself warrant treatment. A higher antibody titer may
of administering the typical fixed dose of 10–15 µC of I-131. This predict the rapidity of progression to hypothyroidism.
practice does not account for the size and activity of the thyroid gland.
Thyroxine replacement is initiated and TSH is maintained in the low
Typically, radioactive iodine therapy is administered to induce one-third of normal to maintain euthyroidism.
hypothyroidism. 10%–20% of patients will require a second
dose and 1% may need a third dose to induce permanent
INFECTIOUS/POST-INFECTIOUS THYROIDITIS
hypothyroidism.
Infectious thyroiditis is an inflammatory process caused by the
I-131 is believed to exacerbate existing ophthalmopathy. It is invasion of the thyroid gland by mycobacteria, fungi, protozoa,
important to take a relevant history and perform a thorough clinical or flat worms. Infectious thyroiditis is rare due to the presence of
examination. If ophthalmopathy is moderately severe or progressive, abundant vascularity, iodine, and hydrogen peroxide and in its
it is important to include the ophthalmologist and obtain a CT scan encapsulation.
or MRI to evaluate the presence or extent of the disease.
Streptococcus; staphylococcus; escherichia; salmonella; bacteroides;
Franklin et al. suggested that I-131 was associated with a higher pasturella; treponema; mycobacterium; and several fungi including
incidence of thyroid cancer. They retrospectively studied 7,417 coccidioides, aspergillus, candida, and nocardia spp have been
patients treated in Birmingham, England with radioactive iodine associated with thyroiditis.
for Graves’ disease. On analyzing 72,073 patients at their year of
Often the infection is caused by direct extension of an internal
follow-up, 634 cancer diagnoses were found. The relative risk of
fistulous tract between the pyriform sinus and the thyroid.
cancer mortality was also decreased, as well as the incidence of
This extension tends to develop more commonly in the left
cancers of the pancreas, bronchus, trachea, bladder, and lymphatic-
thyroid lobe compared to the right. Infectious thyroiditis with
hematipoetic system. However, there was significant increase in the
thyrotoxicosis has been reported to occur after repeated FNA of
risk of mortality of cancers of the small bowel and thyroid, although
the thyroid gland.
the absolute risk of the cancers was small.
Patients present with pain, swelling, hot, and tender thyroid. They
Total or near total thyroidectomy is also an option for selected
may also have signs of cervical lymphadenopathy and signs of
patients with Graves’ disease. This therapy is generally reserved
systemic infection. Laboratory data may reveal an elevated white
for patients not controlled on antithyroid, who are allergic
blood cell (WBC) count and increased ESR. Patients may have
to antithyroid drugs and do not want radioactive therapy, or
symptoms of thyrotoxicosis.
who have a particular reason for surgery like large goiter with
co-existing hyperparathyroidism and solitary nodules with In one study’s data, 12 out of 56 cases were hyperthyroid; however,
suspicious aspirate. most of them were euthyroid biochemically and the radioactive
iodine uptake will usually be normal. CT of the neck and thyroid
ultrasound may reveal an abscess or pus collection.
Treatment depends on identification of causative agent, and systemic
THYROIDITIS antibiotics tailored to the specific infectious agent. An abscess, if
present, will require surgical exploration and drainage.
Thyroiditis is an inflammation of the thyroid gland, of which there DE QUERVAIN’S (SUB-ACUTE) THYROIDITIS
are various causes as discussed in the following sections. De Quervain’s (sub-acute) thyroiditis is a painful swelling of the
• Chronic lymphocytic thyroiditis thyroid gland thought to be triggered by a viral infection, such as
• Silent thyroiditis mumps or the flu. Sub-acute thyroiditis is closely associated with
• Postpartum thyroiditis HLA-B35 in 70% of patients, suggesting genetic susceptibility to
• Sub-acute thyroiditis antecedent viral infections.
52 Medical Management of Thyroid Disorders

Hypothyroidism
It is most commonly seen in women aged 20 to 50. It usually causes Amiodarone is a widely used class III antiarrhythmic used for
fever and pain in the neck, jaw, or ear. The thyroid gland can also release therapy of ventricular and supra-ventricular arrhythmias. Incidence
too much thyroid hormone into the blood (thyrotoxicosis), leading of AIT (Amiodarone induced thyrotoxicosis) varies between 0.003%
to symptoms of an overactive thyroid gland (hyperthyroidism) such to 11.5%. In one study of 1,448 patients, 30 developed AIT.
as anxiety, insomnia, and heart palpitations. These symptoms settle AIT type 1 is caused by increased synthesis in autonomously
after a few days. Symptoms of an underactive thyroid gland often functioning thyroid tissue due to exposure of high amounts of
follow, lasting weeks or months, before the gland recovers completely. iodine. AIT type 2 results from cytotoxic destruction of thyrocytes.
Non-steroidal anti-inflammatory drugs (NSAIDS) or salicylate are Amiodarone should be discontinued, however, this may not be
used initially to treat sub-acute thyroiditis. Corticosteroids can always be possible for patients with life threatening arrhythmia.
be used in severe cases of pain and non-responders. Prednisone is Patients with AIT type 1 should be treated with Methimazole. For
administered in a typical dose of 40 mg/day with a tapering dose patients with AIT type 2, Prednisone can be used for 1–2 months
of 10 mg/week and withdrawal over four weeks. Beta blockers may before tapering.
control the thyrotoxic symptoms but are rarely needed in presence
of NSAIDS and corticosteroids. RADIATION-INDUCED THYROIDITIS
The thyroid gland can sometimes be damaged by radiotherapy
POSTPARTUM THYROIDITIS (PPT) treatment or radioactive iodine treatment given for an overactive
Postpartum thyroiditis only affects a small number of women who thyroid gland. This can either lead to symptoms of an overactive or
have recently given birth. underactive thyroid gland. Low thyroid hormone levels are usually
permanent, and require lifelong thyroid hormone replacement
It is characterized by the presence of transient painless thyrotoxicosis treatment.
with low radioactive iodine uptake and a hypothyroid phase which
is followed by thyroid recovery. However, not every woman with
postpartum thyroiditis will go through both these phases.
HYPOTHYROIDISM
Women who are prone to develop PPT are likely to have pre-existing
asymptomatic thyroiditis. During pregnancy, the maternal immune
system may be suppressed with subsequent rebound thyroid Hypothyroidism is a clinical syndrome described in 1894 by Gull
antibodies after delivery. Studies have shown that higher levels of under the name of myxedema in view of swollen skin and excess
thyroid antibodies are associated with higher thyroid dysfunction. deposition of mucin (myx-). Murray reported the treatment of
Postpartum thyroiditis is associated with HLA types HLA-DR3, myxedema by hypodermic injection of sheep thyroid extract; eating
HLA-DR4, and HLA-DR5. ground thyroid extract proved equally beneficial.
One study mentioned significant increase in thyroid volume in 8 Prevalence:
to 20 weeks of gestation patients who later developed postpartum
thyroiditis. Another study mentioned that the thyroid size Hypothyroidism: 18/1,000 F, 1/1,000 M
before, during, and after pregnancy was not a useful indicator Unsuspected: 3/1,000 F, 0/1,000 M
for development of postpartum thyroiditis. Hence, even though Known: 15/1,000 F, 1/1,000 M
postpartum thyroiditis may be associated with a goiter, the presence Subclinical: 75/1,000 F, 28/1,000 M
of goiter is not a predictive indicator of postpartum thyroiditis. Incidence:
Treatment of thyrotoxic postpartum thyroiditis is often not needed Hypothyroidism: 4.1/1,000 F/year, 0.6/1,000 M/year
since symptoms are usually mild. Beta blocking agents can be used
in symptomatic patients. CENTRAL HYPOTHYROIDISM
Negro et al. studied 85 euthyroid antibody positive patients in the Reduced Thyroxine in central hypothyroidism is due to a lack of
first trimester and supplemented some with Selenium, 200 g starting thyroid stimulation by TSH due to lesions of the pituitary gland.
at 12 weeks of gestation, and some with a placebo. Postpartum Word central hypothyroidism is preferred as lesions may involve
thyroiditis developed significantly less in women who received both sites. A TSH response to exogenous TRH would suggest a
Selenium than in those who received the placebo. However, this pituitary cause; a delayed response would indicate a hypothalamic
study needs further confirmation and determination of adverse cause.
events before Selenium therapy is recommended.
CENTRAL (HYPOTHALAMIC/PITUITARY)
• Loss of functional thyroid tissue
•
DRUG-INDUCED THYROIDITIS
Some examples of drugs are Interferons (used to treat cancer), Tumors
Amiodarone (for heart-rhythm problems), and Lithium (taken for • Trauma
bipolar disorder). • Vascular
• Infectious
In patients treated with Interferon-alpha, 5% to 15% develop
• Infiltrative
clinical thyroid disease. Therapy with Interleukin-2 is associated
• Chronic lymphocytic hypophysitis congenital
with painless thyroiditis in approximately 2% of patients. The
• Functional defect in TSH release
most common side effect of Lithium is development of goiter and
• Mutation in gene coding for TRH receptor
hypothyroidism, but it can also induce hyperthyroidism due to
thyroiditis.
• Drugs: Dopamine, Glucocorticoids, Levothyroxine withdrawal
Tyrosine kinase inhibitors are used in a broad spectrum PRIMARY HYPOTHYROIDISM

of malignancies and have been associated with hypo- and • Loss of functional thyroid tissue
hyperfunctioning of the thyroid gland. Thyroid dysfunction is • Chronic autoimmune thyroiditis
common in patients on Sunitinib, which targets tyrosine kinase and • Reversible autoimmune hypothyroidism
vascular endothelial growth factors. • Surgery and irradiation

Suggested Reading
• Infiltrative and infectious diseases Urogenital

• Sub-acute thyroiditis Renal plasma flow and glomerular filtration rates are reduced. Serum
• Thyroid dysgenesis creatinine is increased to 10%–20%. Hyponatremia may occur.
• Functional defects in thyroid hormone synthesis
• Congenital defects in thyroid hormone synthesis Reproductive
• Iodine deficiency and iodine excess Juvenile hypothyroidism leads to sexual maturation. In adult
• Drugs: antithyroid agents, Lithium, goiterogenic hypothyroid males, semen analysis is normal, but ED is common
but recovers fully. Some women may present with amenorrhea-
chemicals—natural and synthetic
galactorrhea syndrome, which results from hyperprolactinemia due to
CLINICAL FEATURES thyroid hormone deficiency. Overt hypothyroidism may be associated
Energy and Metabolism with increased spontaneous abortion, premature delivery, and/or low
Slowing of a wide variety of metabolic processes results in decreased birth weight and fatal distress in labor.
energy expenditure, oxygen consumption, and use of substrate.
Gastrointestinal
Reduced thermogenesis is related to characteristic cold intolerance,
Constipation, malabsorption, achlorhydria, B12 deficiency,
body weight increases by 10% due to increased body fat, and
abnormal liver functions (usually reversible), and hypotonia of
retention of water and salt.
gallbladder can present in some patients.
Increase in cholesterol occurs as a result of increased LDL.
Hematopoetic System
Skin Anemia, microcytic and hypochromic, disappears with thyroxine
Skin changes are prevalent among hypothyroid individuals and treatment. Leukocytes, thrombocytes, and granulocyte lympho-
include dry, pale, thick, rough with scales and the skin feels cold. cytes are normal. Leukopenia may be associated with B12 deficiency.
Pallor is related to reduced skin blood flow and anemia. Hair
becomes brittle and coarse. Endocrine
Low insulin, like growth factor serum concentration, may lead to
Nervous System growth retardation. Hypothyroidism in the presence of a pituitary
Thyroid hormones are essential for normal brain development. mass does not always indicate central hypothyroidism. Rarely, this
Congenital hypothyroidism if left untreated leads to mental alteration may cause a distinct pituitary macro adenoma in severely
retardation and neurologic abnormalities. Hypothyroid patients are hypothyroid patients with high TSH levels, but that shrinks after
slow in movements, less alert, and less able to concentrate. Speech thyroid hormone replacement.
can be slow, and hearing impaired patients may sleep longer and
report daytime drowsiness. Severe anxiety and agitation occur in Adrenal
a condition called myxedematous madness. Depression that may Metabolic clearance and production of cortisol are decreased in
develop is likely related to reduced synthesis and rarely turnover hypothyroidism. Serum cortisol and 24 hour urinary cortisol
of 5 HT. remain within normal limits.
Hashimoto’s encephalopathy is an otherwise unexplained clinical
DIAGNOSIS
manifestation of central nervous system dysfunction and linked to
One rationale of clinical examination is to increase the likelihood
the presence of thyroid antibodies.
of hypothyroidism which will increase the diagnostic accuracy.
Elevated free T4 and low ash indicates primary hypothyroidism.
Muscles
Myalgia, stiffness, weakness, fatigue, and cramps are prevalent in TREATMENT
the hypothyroid patient. Half relaxation time of Achilles tendon All current guidelines recommend Levothyroxine for
reflex is prolonged in many hypothyroid patients, but substantial hypothyroidism, to be taken 30–60 mins prior to breakfast. The
overlap may be present in euthyroid patients. halflife of Thyroxine is approximately seven days, hence, skipping
dose or single dose omission is of little consequence.
Joints
Arthralgia and joint stiffness are common complaints. Synovial The full replacement dose of Levothyroxine is 1.6 mcg/kg/day, to
effusions are rare. aim for TSH in the low to normal range.
There is new interest in the combination of Levothyroxine and
Bones Liothyronine. Eleven meta-analysis of randomized clinical trials
Hypothyroidism is associated with reduced bone turnover, found no difference in the effectiveness of LT4 and LT3 combination
increased mineralization, and increased fracture susceptibility. therapy versus T4 mono therapy in terms of pain, fatigue, anxiety,
Urinary excretion of hydroxyproline serum, alkali phosphatase, depression, and quality of life.
and osteocalcin levels can be decreased. Serum calcium is usually
normal.
SUGGESTED READING
Cardiovascular System
Cardiovascular dynamics in hypothyroidism include an increased
peripheral vascular resistance and reduced cardiac output; aortic
stiffness may be increased. Cardiovascular symptoms include GRAVES’ DISEASE
dyspnea and decreased exercise tolerance.
Bahn RS. Graves Ophtalmopathy. N Engl J Med. 2010;362:726–38.
Respiratory Barbesino G, Tomer Y. Clinical review; Clinical utility of TSH
Shortness of breath weakens respiratory muscles and impairs receptor antibodies. J Clin Endocrinol Metab. 2013;98:
pulmonary function. 2247–55.
54 Medical Management of Thyroid Disorders

Suggested Reading
Bartalena L, Fatourechi V. Extrathyroidal manifestations of Lee HJ, Li CW. Immunogenetics of autoimmune thyroid disease.
Graves’ disease: A 2014 update. J Endocrine Invest. 2014;37: Comprehensive Review. 2015;64:82–90.
691–700. Nokolai TF. Lymphocytic thyroiditis with spontaneously resolving
Lin TY, Shekar AO, Li N, Yeh MW. Incidence of abnormal liver hyperthyroidism and subacute thyroiditis, long term follow up.
biochemical test in hyperthyroidism. Clin Endocrinol(Oxf). Arch Intern Med. 1981 Oct;141(11):1455–8.
2017;86:755–9. Nordyke RA, Gibert Fl, Jr, Lew C. Painful subacute thyroiditis in
Morshed SA, Davies TF. Graves’ disease mechanisms; role of Hawaii. West J Med. 1991;155:61–3.
stimulating, blocking, and cleavage region TSH receptor Woollen LB, Mc Conahey WM, Beahrs OH. Granulomatous
antibodies. Harm Metals Res. 2015;47:727–34. thyroiditis (de Quervain’s thyroiditis). J Clin Endocrinol
Siu CW, Yeung CY, Lau CP, Kung AW, Tse HF. Incidence of clinical Metab. 1957;17:1202–21.
characteristics and outcome of congestive heart failure as
initial presentation in patients with primary hyperthyroidism. HYPOTHYROIDISM
Heart. 2007;93:483–7. Carle A, Pedersen B, Knudsen N. Gender differences in symptoms
Smith TJ, Hegediis LG. Graves’ disease. N Engl J Med. of hypothyroidism; a population -based Dan Thyr study.
2016;375:1552–65. Clin Endocrinol (Oxf.). 2015;83:717–25.
Wiersinga WM. Advances in treatment of active, moderate to Chaker L, Bianco AC, Jonklass J. Hypothyroidism. Lancet.
severe Graves’ opthalmopathy. Lancet Diabetes Endocrinol. 2017;390:1550–62.
2017;5:134–42. Guglielmi R, Frasoldati A. Association of clinical endocrinologists’
statement - Replacement therapy for primary hypothyroidism -
THYROIDITIS brief guide for clinical practice. Endocr Pract. 2016;22:1319–26.
Amino N et al. High prevalence of transient postpartum thyroiditis Peeters RP. Subclinical hypothyroidism. N Eng J Med.
and hypothyroidism. N Eng J Med. 1982;306:849–52. 2017;376:2556–65.
Anjan RA, Weetman AP. The pathogenesis of Hashimoto’s Surks MI, Hollowell JG. Age-specific distribution of serum
thyroiditis. Horm. Metal Res. 2015;47:702–10. thyrotrophin and antithyroid antibodies in US population;
Fatourechi V, Aniszewski JP, Fatourechi GZ. Clinical features implications of prevalence of subclinical hypotyroidism. J Clin
and outcome of subacute thyroiditis in an incidence cohort; Endocrinol Metab. 2007;92:4575–82.
Olmsted county. Minnesota, study. J Clin Endocrinol Metab. Wichmann J, Winther KH, Bonnema SJ, Hegedus L. Selenium
2003;88:2100–5. supplementation significantly reduces thyroid autoantibody
Hennessy JV. Clinical review; Riddle’s thyroiditis; clinical review. levels in patients with chronic autoimmune thyroiditis: A
J Clin Endocrinol Metab. 2011;96:3031–41. systematic review and metaanalysis. Thyroid. 2016;26:1681–92.
Hutfless S. Significance of pre diagnostic thyroid antibodies in Wiersinga WM, Duntas L, Fadeyev V, Nygaard B. Guidelines: The use
women with autoimmune thyroid disease. J Clin Endocrinol of LT4 + LT3 in treatment of hypothyroidism. Eur Thyroid J.
Metab. 2011;96(9):E1466–71. 2012;1:55–71.

Chapter 7
ANESTHESIA FOR THYROID SURGERY
Vidula Kapre, Shubhada Deshmukh, Pratibha Deshmukh, Meghna Sarode,

and Rajashree Chaudhary
CONTENTS
Introduction 57
Main Content 57
Pre-Operative Preparation 60
Induction of Anesthesia 61
Post-Operative Complications 62
Regional Anesthesia 63
Cervical Epidural Anesthesia 63
Authors’ Experience/Pearls of Wisdom 66
Conclusion 66
References 66
1. Metabolic: The specific purpose here is to assess whether the

patient is euthyroid, hypothyroid, or hyperthyroid.
INTRODUCTION
As such, the importance of any co-morbidity in the pre-
operative period lies in:
While thyroid surgery is the most common endocrine surgery • Its incidence, as in how often we are likely to encounter
performed across the world [1], it can be very challenging for the it in our patients posted for surgery, and
surgeons as well as the anesthesiologists. Anesthesia management • Its impact on patient outcome and accordingly
for thyroid surgery is particularly demanding because it can pose anesthesia management during the peri-operative
problems to the anesthesiologist during the pre-operative, intra- period.
operative, and post-operative periods. The incidence of sub-clinical and overt hypothyroidism is 4.6%–
Pre-operatively, the issues are metabolic if the patient is not 9.5%, while that of sub-clinical and overt hyperthyroidism is
euthyroid and airway management in case of large goiters. 1.3%–2.2% [2], so it is quite likely that patients whom we have to
Intra-operatively, the main concerns are the cardiovascular anesthetize for thyroid surgery may be hypo- or hyperthyroid, and
changes due to hypo- or hyperthyroidism. They are further we have to be alert to assess this in the pre-operative period, because
compounded by the use of anesthetic drugs and endotracheal thyroid dysfunction has a variable clinical presentation depending
intubation. In addition, the requirement of the anesthesiologist on the age of the patient, the degree of dysfunction, concomitant
during the intra-operative period is to provide stable disease, and duration of disease [2]. During the pre-operative
hemodynamics to reduce the risk of hemorrhage due to the assessment, chances of picking up an altered thyroid state will
large vessels in the vicinity. depend on thorough knowledge of presentation of altered thyroid
Post-operatively, anesthesiologists are likely to face critical events function and high degree of suspicion.
due to airway compromise either because of a large hematoma Since thyroid hormones stimulate virtually all metabolic processes
or bilateral recurrent laryngeal nerve damage. in the body—synthetic as well as catabolic—altered thyroid function
can present itself through varied clinical manifestations outlined in
For the scope of this chapter, we shall restrict ourselves to anesthesia
Table 7.1 [2].
management as it pertains to thyroid surgery only. We will refrain
from detailing the general anesthesia management issues which one As such, in hypothyroidism, there is overall slowing of metabolic
would have to deal with for any surgery. activity and hyperthyroidism is a hypermetabolic state.
As mentioned previously, anesthesia management for thyroid We can see from Table 7.1 that out of all clinical manifestations,
surgery begins with intense involvement of the anesthesiologist from the most significant ones are the cardiovascular changes. They are
the pre-operative period, extending to the intra-operative and post- likely to worsen, even become life threatening in the peri-operative
operative periods. period. Hence during pre-op assessment it is worthwhile to focus
on any evidence of cardiovascular changes associated with hypo- or
hyperthyroidism.
In hypothyroidism there is bradycardia, decreased cardiac output,
MAIN CONTENT and reduced blood volume, which may get further aggravated by
cardiac depressant effects of anesthetic drugs and blood loss during
surgery. Abnormal baroreceptor function poses problems because if
PRE-OPERATIVE ASSESSMENT there is a fall in cardiac output, the normal tachycardic response is
Pre-operative assessment for thyroid surgery focuses on two main blunted so the blood pressure cannot be restored and there may be
aspects: catastrophic hypotension.
Anesthesia for Thyroid Surgery 57

Main Content
Table 7.1 Clinical manifestations of hypothyroidism and hyperthyroidism
Hypothyroidism System affected Hyperthyroidism
Weight gain General Weight Loss

Fatigue Heat intolerance
Cold intolerance and hypothermia Anxiety/nervousness
Hyponatremia Insomnia
Elevation of creatine phosphokinase Muscle weakness
Dry and coarse skin, pretibial myxedema (non-pitting edema) Skin Excess perspiration
Dry and coarse hair Palmer erythema
Hair loss
Goiter Head and Neck Ophthalmopathy (Graves’ disease only:
Hoarse voice proptosis and chemosis)
Enlarged tongue
Periorbital edema
Constipation Gastrointestinal Frequent stools/diarrhea
Myalgia Musculoskeletal Tremor
Muscle cramps
Carpel tunnel syndrome
Depression Nervous System Anxiety/nervousness
Decreased concentration Hyperkinesis
Dementia
Irregular menstrual periods/amenorrhea Reproductive Irregular menstrual periods/amenorrhea
Menorrhagia Light menstrual flow
Galactorrhea with elevated prolactin levels Infertility
Infertility Gynecomastia (males)
Increase risk of miscarriage
Bradycardia Cardiovascular Tachycardia
Decreased cardiac output Increased myocardial contractility
Reduced blood volume Arrythmias
Abnormal baroreceptor function Cardiomegaly
Hypercholesterolemia Increased cardiac output
Pericardial effusion Palpitations
Congestive heart failure Dyspnea on exertion
Increased peripheral vascular resistance Bounding pulses
Atrial fibrillation
Exactly opposite is the case of hyperthyroidism where there is is important to identify them during pre-operative assessment, and
tachycardia, increased myocardial contractility, and tendency toward our anesthesia management should be as if we were dealing with
arrythmias which may be precipitated due to sympathetic response to overt hypo- or hyperthyroidism.
intubation, extubation, and arythmogenic volatile anesthetic agents. Detailed cardiac evaluation is done if there are any signs of ischemic
With this background comes the importance of detailed clinical heart disease or arrythmias.
history and clinical examination which may give pointers to the It is not necessary to highlight for surgeons the importance of pre-
metabolic state of the patient. operative assessment of vocal cord function.
Routine biochemistry is done for all patients. Calcium estimation is 2. Airway assessment is the second most important aspect in
not mandatory but will provide baseline levels. Thyroid-stimulating pre-operative assessment for thyroid surgery. In case of
hormone (TSH) estimation is mandatory in every patient unilateral goiters, there may be tracheal deviation (Figures 7.1
undergoing thyroid surgery. The American Thyroid Association’s and 7.2).
(ATA) guidelines recommend level A for TSH estimation even if the
Retrosternal goiters can cause compression of the trachea in that
patient may not exhibit any clinical signs and symptoms of hypo- or
region. Long-standing large goiters can cause tracheal narrowing
hyperthyroidism.
and tracheomalacia (Figure 7.3).
We are all aware of sub-clinical hypo- or hyperthyroidism wherein
Large goiters pose a difficult airway situation, right from induction
the thyroid hormone levels are normal but TSH levels may be raised
of anesthesia, to bag mask ventilation, to intubation (Figure 7.4).
or lowered respectively (Table 7.2).
Upon induction of anesthesia, the sheer size of the gland may cause
Although evidence suggests that this group of sub-clinical hypo- or
tracheal compression. Bag mask ventilation may be difficult due to
hyperthyroidism does not warrant any treatment pre-operatively, it
pressure of the gland on the airway. Most importantly, the presence
of large goiter in the anterior part of the neck precludes two crucial
Table 7.2 Levels of Thyroid hormones in subclinical thyroid disorders
maneuvers of airway management (Figure 7.5):
Sub-clinical
hypothyroidism
Sub-clinical
hyperthyroidism • External manipulation in the neck by assistant to bring the
larynx into view during laryngoscopy and intubation
Raised TSH Levels Lowered • Surgical anterior neck access to the airway
Normal T3 Levels Normal
To avoid the situation of an airway emergency, it is very important to
Normal T4 Levels Normal
do thorough airway assessment in the pre-operative period.
58 Anesthesia for Thyroid Surgery

Main Content
Figure 7.2 Left-sided deviation of the trachea.
HISTORY
• Duration of thyroid enlargement is important because
long-standing goiters have a greater likelihood of causing
tracheomalacia.
• History of dyspnea, especially with the patient in supine
Figure 7.1 A case of large right-sided goiter. position or lateral position with a unilateral goiter, gives an
indication of compression of the trachea.
(a)
(b)
Figure 7.3 (a and b) Tracheal compression by retrosternal goiter.

Pre-Operative Preparation
Figure 7.6 Malampatti grading of patient.
• Adequacy of oropharynx for laryngoscopy and intubation

Figure 7.4 Large goiters present an airway risk. which can be graded by universally familiar Malampatti
grading. The patient should be made to sit upright, open the
mouth as wide as possible, and stick out the tongue without
phonation (Figure 7.6).
• Grade I: Faucial pillars, uvula, soft and hard palate
visible.
• Grade II: Uvula, soft and hard palate visible.
• Grade III: Base of uvula, soft and hard palate visible.
• Grade IV: Only hard palate visible.
Grade III and IV are indicators for difficult intubation. If these
parameters suggest a difficult airway, we have to remember that the
presence of an enlarged thyroid will compound the difficulty.
Airway assessment vis-à-vis the enlarged thyroid should focus on:
• Size of the gland
• Retrosternal extension
• Whether trachea is palpable
• Tracheal deviation
In a multivariate analysis by Bouaggad, factors for difficult intubation
in thyroid surgery were assessed. The conclusion was that the presence
of large goiter alone is not associated with higher incidence of difficult
intubation. However, a cancerous thyroid may pose difficulty during
intubation because of tracheal invasion and laryngeal fibrosis [3].
RADIOLOGICAL ASSESSMENT
A plain lateral neck x-ray gives an idea of effective mandibular
Figure 7.5 External manipulation of neck during laryngoscopy. length and posterior depth of the mandible. An increase in posterior
depth of the mandible more than 2.5 cm poses problems during
• Reduced effort tolerance or dyspnea in a seemingly innocuous laryngoscopy and intubation [4]. Computed tomography (CT) of
thyroid enlargement should ring a bell for possibility of the neck will show tracheal deviation or compression caused by the
retrosternal extension causing tracheal compression. enlarged thyroid gland (Figure 7.7).
• Hoarseness of voice indicates involvement of recurrent
The observations of airway assessment will determine the
laryngeal nerve on one side, and we have to be alert about any
preparation and approach towards airway management.
possibility of inadvertent damage to recurrent laryngeal nerve
on the other side during surgery. This will cause bilateral vocal
cord palsy and stridor in the immediate post-operative period.
PRE-OPERATIVE PREPARATION
EXAMINATION
• Initial airway examination should include bedside indices to
The main goal of pre-operative preparation is to render the patient
assess.
• Cervical and atlanto occipital joint function which can be euthyroid if they are not already so.
judged by the range of flexion and extension of the neck. Management of hypo- or hyperthyroidism is best done by an
• Temporomandibular joint function which can be assessed by endocrinologist. Hypothyroidism is treated with an oral supplement
mouth opening and sliding of the mandible. of the synthetic form of LT4 [2]. Thyroid hormone levels will reach
• Mandibular space determines ease of laryngoscopy and can be normal range in a few weeks, but TSH level normalization takes up
evaluated on the basis of thyromental distance, which is the to three weeks. Treatment for primary hyperthyroidism is achieved
distance between the thyroid notch and symphasis menti when by antithyroid medication like Methimazole and Propylthiouranil.
the neck is extended. It should be at least 6 cm. B blockers are used to ameliorate cardiovascular and neuromuscular

Induction of Anesthesia
These are some of the aids which will help during intubation or aid
in oxygenating the patient in a difficult airway situation.
INDUCTION OF ANESTHESIA
AWAKE INTUBATION
Patients for awake intubation can be administered a mild anxiolytic,
like Alpraxolam 0.25 mg, the night prior to surgery. On the day of
surgery, Glycopyrolate 0.2 mg is administered as antisialogogue.
Airway anesthesia is achieved by nebulization with 4% lignocaine.
Bilateral superior laryngeal nerve blocks and transtracheal injection
of local anesthetic solution is desirable but may not be possible due
to the goiter. In the operating theater, with all monitors attached,
the patient is pre-oxygenated and sedated with IV Fentanyl 50 mg
and midazolam 1 mg. Intubation can be achieved with the help of
a fiberoptic bronchoscope (Figure 7.9). If it is not available and the
anesthesiologist is skilled, blind nasal intubation is an alternative.
GENERAL ANESTHESIA
For the scope of this chapter it will suffice to mention drugs of choice
that are used in the context of thyroid surgery and the reasoning behind
Figure 7.7 Tracheal deviation and compression. it. For pre-medication, Glycopyrolate is used as it does not produce
tachycardia. Midazolam is a good sedative with anterograde amnesia.
Fentanyl is a potent analgesic which prevents surges of heart rate and
symptoms of thyrotoxicosis. Any of the thyroid-related medications blood pressure. Propofol is useful as an induction agent because it
should be administered on the day of surgery. blunts the sympathetic response to laryngoscopy and intubation.
Most importantly it causes some relaxation of the pharyngeal muscles
PREPARATION OF AIRWAY MANAGEMENT so that while the patient is breathing spontaneously, we can perform
Pre-operative airway assessment will give an idea of the degree laryngoscopy and assess whether we will be able to intubate the patient.
of difficulty. In patients found to have difficult airways further This will avoid a disastrous situation where after administering a
compounded by the goiter or patients with large or retrosternal goiters muscle relaxant, we are not able to intubate or ventilate the patient.
causing tracheal compression, it is safest to prepare for awake intubation.
Preparing a patient for awake intubation requires thorough counseling A muscle relaxant is injected to facilitate intubation only if the
in order to gain the confidence and cooperation of the patient. anesthesiologist has confidence of intubating the patient and
certainty of ventilating the patient with bag and mask. The muscle
Before embarking upon intubation for thyroid surgery, all difficult relaxant of choice in case of difficult intubation is Succinylcholine
airway aids should be readily available, in working condition, and because it is short acting.
well laid out (Figure 7.8):
• Laryngoscope with long blade, McCoy blade
Flexometallic reinforced endotracheal tubes are preferred because
• Video laryngoscope
they will not kink during any surgical manipulation or changing of
• Intubating LMA
head or neck position.
• Stilette, bougies MAINTENANCE OF ANESTHESIA

• Rigid laryngoscope The goals during maintenance of the anesthesia are to provide stable
• Intubating fiberoptic bronchoscope hemodynamics and avoiding surges of heart rate or blood pressure.
Maintaining the deep plane of anesthesia, and avoiding hypoxia and
hypercarbia will reduce the chances of arrhythmias.
In hyperthyroid patients there are chances of arrythmias, which
are further compounded by sympathetic responses to laryngoscopy
and intubation and use of volatile anesthetic agents. To avoid this,
Figure 7.8 Difficult airway aids. Figure 7.9 Fiberoptic bronchoscope.

Post-Operative Complications
the plane of anesthesia should be deep, with good analgesia, and • Large hematoma causing direct compression of airway
use of volatile anesthetic agents with less arrhythmogenicity like • Laryngeal edema due to venous obstruction caused by
Sevoflourane and Desflurane. Dexmedetomidine is a useful drug hematoma [9]
which can be used intra-operatively. It has the benefit of maintaining • Bilateral recurrent laryngeal nerve damage [10,11]
heart rate, blood pressure, and provides analgesia. It also reduces • Tracheomalacia
post-operative nausea and vomiting [5–7].
To guard against complications of a large hematoma, the patient
In hypothyroid patients, the low cardiac output and reduced blood should be closely monitored during the post-operative period.
volume with the additional cardiac depressant effect of anesthetic In case of acute stridor, drastic measures of removing sutures at
agents may cause precipitous hypotension. To avoid this we bedside to release hematoma can be life-saving. For definitive airway
should use a judicious dosage of anesthetic agents, adequate fluid management, the patient may need to be intubated.
replacement, and use of cardiovascular stable muscle relaxant like
If the surgeon is aware or in doubt of bilateral recurrent nerve
Vecuronium.
damage or tracheomalacia, the anesthesiologist should extubate the
Use of balanced anesthesia with the agents mentioned in this section, patient over a tube exchanger (Figure 7.10).
and anti-Trendelenburg tilt will provide a good operating field and
The patient should be monitored closely, and if there are any signs
reduce surgical blood loss.
of airway obstruction the patient can be intubated over the tube
MONITORING exchanger. If there is unanticipated acute stridor due to bilateral
Routine monitoring should include monitoring of the heart rate, recurrent laryngeal nerve damage or tracheal collapse due to
non-invasive blood pressure (NIBP), O2 saturation, end-tidal CO2 tracheomalacia, tracheostomy may be the only answer. Definitive
(EtCO2) concentration, electrocardiogram (ECG), and temperature. procedures can be carried out later in a planned manner.
These parameters should be watched vigilantly during the entire
SPECIAL SITUATIONS
peri-operative period.
1. Intra-operative nerve monitoring: In case surgeons want to use
Any derangement in these parameters can give early indications of intra-operative nerve monitoring, the anesthesiologist will have
hemodynamic instability, respirating inadequacy, onset of arrythmias, to use special endotracheal tubes with integrated electrodes.
and hypo- or hyperthermia in case of hypo- or hyperthyroidism. Tube placement should be such that the electrodes are at the
RECOVERY FROM ANESTHESIA level of the vocal cords.
Once the surgeon has ensured hemostasis and surgery is complete, During surgery the surgeon can confirm presence of the
the esthetic agents are switched off, the effect of the neuromuscular recurrent laryngeal nerve by stimulating any structure
blocking agent is reversed, and the patient is ventilated with 100% resembling it. If there is significant deflection on the monitoring
oxygen. screen, it indicates that it is the recurrent laryngeal nerve and
the surgeon should take care to protect it.
The following guidelines should be followed during extubation:
• There is complete reversal of neuromuscular paralysis and the
Anesthesia management should be such that at the time of
stimulation of the recurrent laryngeal nerve the patient is not
patient’s respiratory efforts are adequate according to oxygen
under the influence of muscle relaxants. For this the anesthesia
saturation (SpO2) and EtCO2.
• The patient should be extubated in a slightly deep plane of
may be maintained with the patient under spontaneous
ventilation. If the size of the thyroid gland is very large, the
anesthesia to avoid surges in heart rate and blood pressure
patient is obese, or there are other co-morbidities, it is advisable
which can cause hemorrhage in the post-operative period. The
to maintain the patient under a short acting muscle relaxant
deep plane of anesthesia also protects against the possibility
like Cisatracurium and allow the action to wear off nearer to
of arrythmias due to sympathetic stimulation during
the time of stimulation of the RLN.
laryngoscopy and extubation.
• It is desirable that the anesthesiologist be able to note and 2. Although it is the rule that all patients are rendered euthyroid
before thyroid surgery, for the sake of completeness it is
document normal functioning of both vocal cords at the time
of extubation. worthwhile to outline the management in case of myxedema
• If there is any suspicion of tracheomalacia or bilateral RLN coma and thyroid storm.
damage, extubation should be over an airway exchanger so Myxedema coma: Signs of myxedema coma are severe
that the patient can be oxygenated and if there are any signs bradycardia, hypotension, hypothermia, and hyponatremia
of respiratory distress can be intubated immediately over the eventually leading to coma.
airway exchanger.
Management involves:
Post-operative pain can be controlled with the help of systemic
• Tracheal intubation and controlled ventilation.
NSAIDs or use of local anesthetic injected in the area of superficial
cervical plexus and suture line [8].
• Levothyroxine 200–300 ugm IV over 5–10 min
followed by 100 ugm IV in 24 hrs.
Post-operative nausea and vomiting can be controlled with the help
of Ondansetron, Palanosetron, or Metocloparamide. As mentioned,
• Hydrocortisone 100 mg IV followed by 25 mg IV
6 hrly.
Dexmedetomidine used intra-operatively contributes toward • Fluid and electrolyte therapy as indicated.
antiemetic effect. • Measures to raise patient’s body temperature.
3. Thyrotoxic storm: Thyroid storm will manifest as severe
tachycardia, hyperthermia, atrial fibrillation, and cardiac failure.
POST-OPERATIVE COMPLICATIONS
Management includes administration of:
• Cold IV fluids.
For the anesthesiologist, the dreaded post-operative complication • Sodium Iodide either through nasogastric tube or IV
after thyroid surgery is airway obstruction due to: 6 hrly.

Cervical Epidural Anesthesia
Figure 7.10 Extubation over tube exchanger.
• Propylthiouracil 200–400 mg through nasogastric goiters that are too small in size. The risks involved with deep
tube. cervical plexus block does not make it an attractive proposition.
• Hydrocortisone 100 mg IV 6 hrly.
• Propranolol 10–40 mg 6 hrly through nasogastric tube
or Esmolol infusion.
• Cooling body temperature.
CERVICAL EPIDURAL ANESTHESIA
• Meperidine 25–50 mg IV 6 hrly to prevent shivering.
• Digoxin for heart failure, especially in case of atrial
The past couple of decades have shown a resurgence in the use of
fibrillation with rapid ventricular rate.
cervical epidural anesthesia for thyroid surgery.
There are some studies in literature, albeit not a very large sample
size, with the unanimous conclusion that the “cervical epidural
REGIONAL ANESTHESIA route can be safely used for surgery on thyroid gland and should
be considered in patients where difficult endotracheal intubation is
anticipated and in whom altered thyroid functional status makes
Thyroid surgery can be performed under regional anesthesia if them vulnerable to cardiovascular complications under general
• General anesthesia is contraindicated anesthesia” [12].
• Significant risk is anticipated with respect to difficult intubation Due to the relative uniqueness of this technique and the authors’ vast
or likelihood of arrhythmias
• Or in special situations
experience with it, it is in order to give a detailed account of cervical
epidural anesthesia for thyroid surgery.
Although thyroid surgeries have been reported under superficial and It is a regional anesthesia technique wherein local anesthetic solution
deep cervical plexus blocks, they can be considered for unilateral is injected into the cervical epidural space. Usually C7-T1 or C6-C7.

This achieves a block of the cervical and brachial plexus which is

adequate for thyroid surgery [13].
INDICATIONS
• Difficult endotracheal intubation in case of large goiters
• Altered thyroid functional status
• Surgery on ASA III, IV patients
• Special situations where general anesthesia may be
contraindicated or undesirable
COUNSELING
Patients found suitable for cervical epidural anesthesia are thoroughly
counseled. Pre-operative counseling specially for cervical epidural
anesthesia is essential to gain the patient’s confidence and cooperation.
Although the anesthesia technique blocks pain fibers from the
surgical site, the neck extended position of the patient and tracheal
manipulation during surgery can be discomforting. The patient
should be made aware of this, while at the same time be reassured
that they will be administered sedation to take care of the discomfort.
During counseling, emphasis is on the following points:
• The patient is informed of the block that will be administered.
• They are told about the neck extension position in which they
will be lying during surgery.
• They are also told they may have some cough when surgeons
Figure 7.11
handle the trachea. Epidural anesthesia tray.
• They are assured that they will be sedated and, if need arises,
can be put under general anesthesia.
PRE-MEDICATION
Patients are given anxiolytic in the form of T. Alprazolam 0.25 mg
and T. Ranitidine the night prior and on the day of surgery.
METHOD
Patients are pre-loaded with intravenous (IV) crystalloid solution. IV
Glycopyrrolate is administered. A monitor is attached. The patient is in
a sitting position with the height adjusted so that the patient’s neck is at
waist level of the anesthesiologist. The patient is made to hold a pillow
with both arms. This gives them stability, and while both arms hold the
pillow across the chest, the back becomes relaxed (Figures 7.11–7.17).
With all aseptic precautions, the anesthesiologist prepares the
epidural trolley. The solution used is 9 mL of 0.25% preservative
free Bupivacaine + 1 mL fentanyl. This solution is used to prime
the epidural catheter. The patient’s back of the neck is cleaned and
draped. The space chosen is C7-T1, C7 spinous process (vertebra
prominence) being easy to palpate. 2% Lignocaine with Adrenaline
is injected in the skin and subcutaneous tissue. An 18/16 G epidural
needle is introduced at the C7-T1 space, with the direction being
Figure 7.12 Surface landmarks for epidural block.
perpendicular to the spine with bevel facing cranially. The needle is
advanced until it is gripped in the ligamentum flavum. The epidural
space is located by loss of resistance to the injection of air technique.
Once the epidural space is entered, the stilette is removed and the
epidural catheter is introduced through the needle. The catheter
should go in very smoothly without any force required. About
15 cm of catheter is introduced to be sure that it is freely going
into the epidural space. Keeping the catheter steady, the epidural
needle is withdrawn. Markings on the needle give an idea of the
depth of the epidural space from the skin. It is usually 3–4 cm.
An additional 4 cm catheter is left in the space and the rest of the
catheter is withdrawn. Sterile clear dressing is given at the entry
point of the catheter making a loop of the catheter to avoid kinking
and accidental pull on the catheter. The catheter is taped along the
shoulder and down the forearm on the same side as the IV cannula.
After checking for aspiration of blood or cerebrospinal fluid (CSF),
2 mL of test dose is administered. After observation for 15 min, the Figure 7.13 Insertion of the epidural needle.

Figure 7.14 Identifying the epidural space.

Figure 7.17 Injection port of the catheter.
Figure 7.15 Introduction of the epidural catheter.
Figure 7.18 Patient ready for surgery.
Figure 7.16 Adjusting the length of the catheter in epidural space.
rest of the local anesthetic solution is injected. After another 15 min

the patient is given a neck extension position with a shoulder pillow.
Oxygen is administered by nasal prongs. The patient is sedated with
IM 2 mg Butorphanol and 2 mg Midazolam. After checking the
adequacy of the anesthesia, the surgery begins.
Figure 7.19 Surgery in progress.
INTRA-OPERATIVE MANAGEMENT
The patient’s heart rate, NIBP, Sp02, and ECG are monitored. IV fluids
are administered as per the surgical demand and BP of the patient. pain relief. At our practice we remove the catheter after this first dose
Every hour 4 mL of top-up of the same are given (Figures 7.18–7.21). of post-operative analgesia as the patients are managed in the wards
of rural hospitals where strict asepsis may not be followed. Also, the
POST-OPERATIVE PAIN MANAGEMENT nursing staff at the rural hospitals are not trained to manage epidural
At the end of the surgical procedure, 4 mL of 0.125% preservative catheters. As it is a regional anesthesia technique, the patient does
free Bupivacaine is injected through the catheter for post-operative not require much monitoring post-operatively in the ward.

References
• Skill in airway management, especially in case of large goiters.

• Understanding and cooperation between surgical and
anesthesia teams.
The anesthesiologist should be able to adapt their technique to facilitate
surgeons’ requirements, e.g., intra-operative nerve monitoring.
It helps if anesthesiologists are familiar with and experienced in
awake fiberoptic intubation in case of anticipated difficult intubation.
The authors’ experience suggests that it also helps to be conversant
in an alternative anesthesia technique such as cervical epidural
block. When administered with due precaution and skill, it is
absolutely safe. Although not a technique of choice in routine
cases, it is a useful tool for the anesthesiologists managing complex
thyroid surgeries.
REFERENCES
Figure 7.20 Surgery completed under epidural anesthesia.
1. Bajwa SJ, Sehgal V. Anesthesia and thyroid surgery: The

never ending challenges. Indian J Endocrinol Metab. 2013
Mar;17(2):228.
2. Gregory W. Randolf. Textbook on Surgery of Thyroid and
Parathyroid Glands. Chapter 3, pp. 25–33.
3. Bacuzzi A, Cuffari S, Anesthesia for thyroid surgery:
Perioperative management. Int J Surg. 2008;6(Suppl. 1):S82–S85.
4. Khan R. Airway Management. Chapter 4. Paras medical
publisher, pp. 18–21.
5. Bajwa SJ et al. Dexmedetomidine and clonidine in epidural
anaesthesia: A comparative evaluation. Indian J Anaesth. 2011
Mar;55(2):116.
6. Bajwa SJ, Arora V, Kaur J, Singh A, Parmar SS. Comparative
evaluation of dexmedetomidine and fentanyl for epidural
analgesia in lower limb orthopedic surgeries. Saudi J Anaesth.
Figure 7.21 Patient can drink water at the end of surgery. 2011 Oct;5(4):365.
7. Bajwa SJ, Gupta S, Kaur J, Singh A, Parmar SS. Reduction in the
incidence of shivering with perioperative dexmedetomidine: A
randomized prospective study. J Anaesthesiol, Clin Pharmacol.
AUTHORS’ EXPERIENCE/PEARLS OF WISDOM 2012 Jan;28(1):86.
8. Dieudonne N, Gomola A, Bonnichon P, Ozier YM. Prevention
of postoperative pain after thyroid surgery: A double-blind
General anesthesia is the standard and chosen technique for thyroid randomized study of bilateral superficial cervical plexus
surgery. blocks. Anesth Analg. 2001 Jun 1;92(6):1538–42.
Cornerstones for success in anesthesia management are: 9. Rovó L, Jóri J, Brzózka M, Czigner J. Airway complication
• Optimization of the patient’s metabolic status pre-operatively. after thyroid surgery: Minimally invasive management
• Airway assessment and preparation management of the of bilateral recurrent nerve injury. Laryngoscope. 2000
Jan;110(1):140–4.
difficult airway.
• Cardiovascular stability during the intra-operative period so 10. Ozbas S, kocak S, Aydintug S, Cakmak A, Demirkiran MA,
as to minimize blood loss and provide a good operating field Wishart GC. Comparison of the complications of subtotal,
for the surgeon. near total and total thyroidectomy in the surgical management
• Preparedness for management of airway obstruction in the of multinodular goitre. Endocr J. 2005;52(2):199–205.
post-operative period in eventuality of bilateral recurrent
11. Timmermann W, Dralle H, Hamelmann W, Thomusch O,
laryngeal nerve palsy, large hematoma, or tracheomalacia.
Sekulla C, Meyer T, Timm S, Thiede A. Does intraoperative
nerve monitoring reduce the rate of recurrent nerve palsies
during thyroid surgery? Zentralbl Chir. 2002 May;127(5):
CONCLUSION 395–9.
12. Khanna R, Singh DK. Cervical epidural anaesthesia for
thyroid surgery. Kathmandu Univ Med J. 2009;7(3):242–5.
Anesthesia management for thyroid surgery requires: 13. Dhummansure D, Kamtikar S, Haq MM, Patil SG. Efficacy
• Knowledge of metabolic issues in patients with thyroid disorder and safety of cervical epidural anaesthesia for thyroid surgery.
and their effect on the cardiovascular system of the patient. Int J Sci Stud. 2015 Oct 1;3(7):245–50.

Chapter 8
SAFE THYROIDECTOMY
Madan Laxman Kapre, Sankar Viswanath, Rajendra Deshmukh, and Neeti Kapre Gupta
CONTENTS
Who Is at Risk? 67
The Size 67
Anesthesia 68
Appliances and Technology 68
Learning Curve 69
Identifying the Injuries 73
References 73
Nowhere was it as rewarding as visiting the archives of thyroid and most often results from a combination of advanced age, giant
surgery in the making of a safe thyroid surgeon. From being labeled goiters, and upper airway complications [13].
as butchery (Samuel Gross) and being banned in Europe as an While as many as a third of the patients succumbed to this surgery
extremely unsafe surgical procedure, it has come a long way to be in past, it would be a matter of grave concern should such eventuality
a safe and most gratifying surgery. In 1846, Robert Liston called occur now. Not understanding the importance of Spencer Wells’
thyroid surgery “a proceeding by no means to be thought of” after hemostatic forceps and the discovery of antibiotics and thyroid
performing five thyroidectomies [1]. Two years later, Samuel Gross hormones, the surgical training scenario backed up with newer
wrote: “Can the thyroid in the state of enlargement be removed? technological advances have made thyroid surgery one of the safest
Emphatically, experience answers no. Should the surgeon be so yet skilled surgical maneuvers. An attempt is made to share our
foolhardy to undertake it…every stroke of the knife will be followed learning curves and make this chapter a good read for the learner
by a torrent of blood and lucky it would be for him if his victim lived and learned alike. In the preceding pages we have categorized the
long enough for him to finish his horrid butchery. No honest and importance of being safer surgeons as paying adequate attention to
sensible surgeon would ever engage in it.” [2]. the old dictum “forewarned is forearmed.” Skilled surgeons treat
Surgery progressed further with newer methods of infection their patients by repair/removal/cutting/alteration/replacement of
prophylaxis, such as the use of carbolic acid in antisepsis by the diseased part/organ. So before starting to make an incision on a
Joseph Lister of Glasgow in 1867 [3]. The introduction of steam patient, the surgeon requires not only confidence, a sound knowledge
sterilization of instruments by Ernst von Bergmann in 1886 [4] of the organization of macro- or microforms and structures and
and intra-operative antisepsis with a cap and gown by Gustav their shapes, sizes, and locations, and the correct diagnosis of the
Neubar in 1883 [5] reduced the incidence of infection significantly disease, but also the anatomical relationship to the disease [14].
in the post-operative period. In 1874, Spencer Wells and Jules Pear
reached a landmark in surgery by introducing the first effective
hemostatic forceps.
WHO IS AT RISK?
Theodor Billroth performed 36 thyroidectomies experiencing
16 deaths, in Zurich and Vienna [6]. With the use of newer methods
of antisepsis and hemostasis between 1877 and 1881, Billroth
Let us first identify the patients who are more likely to have either
performed 48 thyroidectomies and was able to decrease the mortality
intra-operative or post-operative problems. This will help us not
to 8.3% [7]. Theodor Kocher, a pupil of Billroth, during his first 10 years
only to take appropriate preventive measures but also prepare and
in Berne, had performed 101 thyroidectomies, experiencing a mortality
counsel our patients adequately.
of 2.4%. By 1895, the mortality rate improved to about 1% [8].
There are two aspects of this: One is the issue of functionality or
Thyroidectomy is now considered as a surgical triumph and most
physiology and the other is anatomy. The altered physiology, i.e.,
skilled craftsmanship among all surgical procedures.
hyperthyroidism or hypothyroidism, is best resolved with the help of
The incidence of permanent complications after thyroidectomy is our endocrinology colleagues and should be operated only on well-
low [9–12]. Two classical complications specific to thyroidectomy prepared euthyroid patients [15]. Actual details of this are beyond
arise due to the close anatomic proximity of the thyroid gland with the realm of this chapter.
the recurrent laryngeal nerves (RLN) and with the parathyroid
glands: temporary dysphonia occurs in 5%–11% of cases and may be
permanent in 1%–3.5% of cases, and temporary hypoparathyroidism
occurs in 20%–30% of cases and may be permanent in 1%–4% of THE SIZE
cases [9]. These data are drawn from the largest published series and
reflect the rate of complications seen at centers of expertise [9–12].
Post-operative compressive hematoma with acute dyspnea is a rare It is ironic that large benign thyroid masses are relatively easy to
but severe complication that may result in death or severe long-term operate as they alter past the structures rather than invade them
sequelae. Death after thyroidectomy is very uncommon (0.065%) [16] (Figure 8.1). The real issue lies in the delivery of these large
Safe Thyroidectomy 67
Appliances and Technology
Figure 8.2 Large multinodular goiters in short neck individuals.
Figure 8.1 RLN often gets pulled out vulnerably.
goitrous masses. The next structural issue is the invasion and fixity
of the thyroid masses to neighboring anatomical structures. Loss of
mobility of the thyroid and dysfunction of the structure involved,
i.e., cord palsy or dysphagia, will appropriately suggest spreading.
Any history of aspiration or reflex cough on drinking liquids may
suggest invasion of the external branch of the superior laryngeal
nerve (EBSLN), and one needs to warn the patient of the possibility
of worsening of this symptom. Pre-operative ultrasonography (USG)
or computed tomography (CT) of the chest may indicate an aberrant
subclavian artery and thus a non-recurrent RLN [17]. Prominent neck
veins with retrograde venous flow is an indication of venous obstruction
in the superior mediastinum [18]. Retrosternal goiter if benign has its
blood supply from the neck but retrosternal malignant thyroid may
have additional vessels from the adjoining superior mediastinum.
Hemoptysis or respiratory difficulty in a malignant thyroid would
forewarn the surgeon about tracheal invasion [19], and one needs to
get prepared for such eventuality.
A short neck, an obese patient, or a cervical spine abnormality will need
larger incisions and adequate surgical exposure (Figures 8.2 and 8.3). Figure 8.3 Large multinodular goiters in short neck individuals.
The pathology of goiter malignant thyroid lesion would force the
surgeon to anticipate and plan the surgical procedure. Papillary surgical team. Hypotensive anesthesia [21] is an advantage, while
cancers would mean addressing the neck nodes while follicular accurate placement of the endotracheal tube will avoid a lot of
lesions may have an embolus in the jugular vein [20]. As there anxiety about loss of signal later. While operating a hyperthyroid
is no proven fall back plan for medullary cancers arising from adenoma or Graves’ disease, it is best to divide the muscle and avoid
parafollicular cells, the best surgical procedure can be summed up unnecessary handling of the gland. Needless to say the various out
as “wherever the disease takes you” and hence aggressive excision flow channels for blood should be ligated at the earliest (Figure 8.4).
has to be planned.
APPLIANCES AND TECHNOLOGY

ANESTHESIA
As there are separate chapters on the aspect of safety, the authors

Although there is a separate chapter on this aspect of safe thyroid prefer to use more easily available and practiced technological
surgery, the authors cannot emphasize enough the importance of support. The first on the list, of course, is accurate mapping of the
establishing a sound rapport between the anesthesia team and the disease with available imaging techniques. This gives very important
68 Safe Thyroidectomy
Learning Curve
Figure 8.5 Position for thyroid surgery.
Figure 8.4 A unique technique of cervical epidural anesthesia.
information regarding the presence of lymph nodes, embolism of

the jugular vein with malignant thrombus, or the presence of non-
recurrent RLN.
Hypotensive anesthesia and judicious use of electrosurgical devices
will minimize blood loss.
Magnification by way of optical loupe [22] or microscope offers a
clear advantage. However, there is considerable learning involved
in getting used to these devices. Endoscopes and their application
in thyroid surgery are adequately dealt with elsewhere in this book.
LEARNING CURVE
Figure 8.6 Incision planning.

Before one endeavors thyroid surgery in the operating room,
modern day surgical apprentices are fortunate to have access
to several other learning opportunities. Video demonstration,
cadaveric dissection, and hands-on surgical workshops are a few
to mention which can prepare an apprentice for thyroid surgery.
We cannot emphasize enough the sound anatomical knowledge of
the area of concern. The authors believe that a surgeon is primarily
an applied anatomist [14].
STEPS OF SAFE THYROID SURGERY

1. Position: The patient is placed supine with pillow or roll under
the shoulder to give maximum possible head extension. This
allows the thyroid to be brought up in the neck and to be made
fairly superficial (Figure 8.5).
2. Incision: Ideally, it is marked up in the sitting position in a
suitable skin crease before anesthesia. It is generally placed
two-fingers breadth above the suprasternal notch or midway
between the cricoid prominence and suprasternal notch. The
width of the incision is tailored according to the size of the
thyroid, rarely beyond the sternocleidomastoid muscle and
equal on either side (Figure 8.6).
3. Midline dissection: The sizable number of the goiter is
unilateral, and hence the surgical procedure of choice may
be hemithyroidectomy. It is crucial to identify and divide the
deep fascia from the suprasternal notch to the thyroid notch
superiorly (Figures 8.7 and 8.8). Figure 8.7 Midline dissection LGT (Levator glandulae thyroidea).
Learning Curve
Figure 8.10 Management of strap muscles.
Figure 8.8 Midline dissection LGT (Levator glandulae thyroidea).
Figure 8.11 Management of strap muscles.
6. Management of upper pole: The key here is again adequate

exposure and ligating the superior thyroid vessels by
skeletonizing each. This avoids injury to the external branch of
the superior laryngeal nerve whatever may be the course of the
nerve. It exposes and helps release the upper pole displaying the
whole breadth of the cricopharyngeal muscles and the EBSLN
(Figure 8.12).
7. Dissecting the superior parathyroid: The next step is to identify
Figure 8.9 Platysma is deficient in midline. and separate the thyroid gland in the sub-capsular plane. The
upper parathyroids are encountered, and care is taken not to
dissect the fascia lateral to the parathyroids. Hereafter a branch
4. Elevation of flap: The skin flaps are raised on either side of posterior division of the superior thyroid artery is seen to
subplatysmally in a relatively avascular loose areolar tissue supply the parathyroid before entering the post aspect of the
plane. Upwards the flap elevation reaches the hyoid bone and upper pole (Figure 8.13).
downwards it exposes the suprasternal notch (Figure 8.9). 8. Dissecting the lower pole: Some authors advise releasing the
5. Management of strap muscles: There is no pride lost if one has to lower pole before moving to the upper pole for a very good
divide the strap muscles to get a safe, unhanded delivery of the reason. At this point, the surgeon is fresh, and the best chance
thyroid in the wound. The lateral extent is the carotid sheath, to encounter any variation of the inferior parathyroid gland
ligating the middle thyroid vein away, if present. If one should is usually now. The inferior parathyroid could be anywhere
decide to divide the strap muscles, it is done above the insertion from within the thyroid gland to anywhere in the superior
of ansa cervicalis into the straps muscles. In such case both mediastinum. Great care is taken to preserve both anterior as
muscles are raised upwards and downwards in unison up to well as venous drainage of the parathyroids at the lower pole
their bony/cartilage attachments (Figures 8.10 and 8.11). (Figures 8.14 and 8.15).
Learning Curve
Figure 8.12 Management of the upper pole.
Figure 8.15 Dissecting the lower pole.
Figure 8.13 Dissecting the superior parathyroid.

Figure 8.16 Right non-recurrent RLN.
9. Managing the RLN (Recurrent Laryngeal Nerve): Having secured

both sets of parathyroid, surgical focus now shifts to the RLN.
Author recommends demonstration rather than dissection
between the two major branches of the inferior thyroid artery.
There are several anatomical landmarks for identification of the
RLN. However, the authors rely on and recommend identifying
the RLN under the nodule of Zuckerkandl. This is safe, secure,
and avoids unnecessary exposures of the RLN (Figures 8.16
through 8.20).
10. Berry’s ligament: Once the RLN is traced up to its insertion
in the larynx at the cricothyroid joint, the width of Berry’s
ligament, the posterior condensation of thyroid fascia is divided
completing the procedure on the given side (Figures 8.21
and 8.22).
11. Dividing the isthmus: This is the final release of the ipsilateral
thyroid lobe. The authors recommend removal of the isthmus
and release of the contralateral lobe from trachea in all cases.
This avoids an unsightly midline hump should the isthmus
Figure 8.14 Dissecting the lower pole. hypertrophy as a result of the loss of lobe.
Learning Curve
Figure 8.17 Left non-recurrent RLN. Figure 8.20 Relation of RLN to the inferior thyroid artery.
Figure 8.21 Berry’s ligament.

Figure 8.18 RLN with its divisions.
Figure 8.19 (1) Nodule of Zuckerkandl. (2) Cricothyroid joint. (3) RLN. Figure 8.22 Berry’s ligament.
References
for postoperative complications in benign goiter surgery:

Prospective multicenter study in Germany. World J Surg. 2000
IDENTIFYING THE INJURIES
Nov 1;24(11):1335–41.
10. Bellantone R, Lombardi CP, Bossola M, Boscherini M, De
We all make mistakes. They may be caused by a surgeon’s judgment, Crea C, Alesina P, Traini E, Princi P, Raffaelli M. Total
by misadventurous surgical maneuvers, or by a forced error through thyroidectomy for management of benign thyroid disease:
situations beyond the surgeon’s control. But mistakes shall remain Review of 526 cases. World J Surg. 2002 Dec 1;26(12):1468–71.
mistakes if we do not learn from them. Bad scars, hematomas, 11. Efremidou EI, Papageorgiou MS, Liratzopoulos N,
and infections are due to violation of basic surgical principles and Manolas KJ. The efficacy and safety of total thyroidectomy in
elaborating on these is beyond the scope of this chapter. We shall the management of benign thyroid disease: A review of 932
restrict ourselves to the RLN/parathyroid. cases. Can J Surg. 2009 Feb;52(1):39.
12. Duclos A et al. Influence of experience on performance of
RLN INJURIES
individual surgeons in thyroid surgery: prospective cross
The RLN may have to be excised for disease clearance. This can be
sectional multicentre study. BMJ. 2012 Jan 11;344:d8041.
either totally anticipated, i.e., a paralyzed vocal cord is pre-operatively
noted, or unanticipated. The authors suggest to work on the opposite 13. Gómez-Ramírez J, Sitges-Serra A, Moreno-Llorente P,
side first so that the surgeon is at their best. In an unanticipated situa- Zambudio AR, Ortega-Serrano J. Rodríguez MT, del Moral JV.
tion, the nerve injury may be obvious transection or neuropraxia [23]. Mortality after thyroid surgery, insignificant or still an issue?
Primary approximation and microscopic nerve repair is the procedure Langenbeck’s Arch Surg. 2015 May 1;400(4):517–22.
of choice if possible. Otherwise, cable nerve grafting is strongly advised. 14. Singh R, Tubbs RS. Should a highly skilled surgeon be an
advanced anatomist first? A view point. Basic Sciences of Med.
PARATHYROID INJURIES 2015;4(4):53–7.
These are the real test of thyroid surgeons. Herein lies the real 15. Palace MR. Perioperative management of thyroid dysfunction.
importance of intra-operative recognition of the injury. Health Serv Insights. 2017 Feb 17;10:1178632916689677.
The injury can be vascular or accidental extirpation. There could be a 16. Mok VM, Oltmann SC, Chen H, Sippel RS. Schneider DF.
simple element on the capsule, which can be quickly and adequately Identifying predictors of a difficult thyroidectomy. J Surg Res.
resolved by inching the fibrous capsule of the gland. If the parathyroids 2014 Jul 1;190(1):157–63.
[24] are accidentally removed then re-implantation is strongly advised.
17. Morais M, Capela-Costa J, Matos-Lima L, Costa-Maia J.
The technique and rationale is covered elsewhere in the book.
Nonrecurrent laryngeal nerve and associated anatomical
variations: The art of prediction. Eur Thyroid J. 2015;4(4):234–8.
18. De Filippis EA, Sabet A, Sun MR, Garber JR. Pemberton’s sign:
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4. Garrison FH. An Introduction to the History of Medicine. 4th 22. D’ORAZI V, Panunzi A, Di Lorenzo E, Ortensi AL, Cialini M,
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TC, Ottaviani F, Buemi A, Di Stefano P, Mourad M. Meta-
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Chapter 9
SURGERY FOR MULTINODULAR GOITER
Madan Laxman Kapre, Sanoop Elambassery, Neeti Kapre Gupta, M. Abdul Amjad Khan,
and Gauri Kapre Vaidya
CONTENTS
Evolution of MNG 75
Genesis of the Thyroid Nodule and MNG 75
Follow-Up Strategy for MNG Surgery 76
References 77
The philosophy of treatment and surgical strategies for multinodular

goiter (MNG) needs to be based on the risk factors, namely discomfort
due to size and cosmesis. One also needs to take into consideration
the possibility of cancer phobia due to readily available reading
material via health magazines and other information channels.
Before we start strategizing our optimal surgical care, let us first
discuss these aspects.
As the number of nodules increases, the risk ofthem being malignant
decreases. There is no real statistical information available, but it is
quoted at around 5% to 15% [1,2,14].
Discomfort due to size depends upon the location of the nodules. The
posteriorly located nodule may produce dysphagia-like symptoms
whereas the nodules may cause breathing discomfort when lying
supine in a retrosternal location. As the nodules are benign, they
push the structures around and never really invade them. In this case,
symptoms such as hoarseness of voice due to involvement of the RLN
are very rare. The authors have had the privilege of working in tribal
areas in the hills of Melghat, India, where massively large Chikhaldara
Figure 9.2 Tattooing is an ancient Voodoo way of treatment.
goiters were found to cause no symptoms (Figures 9.1 and 9.2).
Cosmetic issues are more prevalent in urban populations, and
treatment should be assessed on the risk-benefit ratio and discussed
with the patient before embarking on surgery. EVOLUTION OF MNG
It is rather relevant to understand the pathogenesis of MNG so

that its malignant potential is truly understood [15]. As the process
is not “neoplastic” and it is often bilateral, it is very important to
assess sudden rapid growth or pain or any symptoms pertaining
to either invasion or pressure. This information should be taken
into consideration when evaluating investigative treatments and
subsequent decision-making.
GENESIS OF THE THYROID NODULE AND MNG
INDICATION FOR SURGICAL TREATMENT

While there are some obvious surgical indications, such as
large MNG, there are certain subtle areas, which require special
mention, such as in male patients, rapid growth in size and recent
appearance of pressure symptoms of malignant transformation
in previously benign MNG [3,4,12,13]. The recommendation is
ultrasonographically guided fine needle aspiration cytology of the
suspicious nodule. Similar issues arise in patients with MNG with
hyperthyroidism. It is difficult to predict which of the bilateral/
Figure 9.1 Chikhaldara multinodular goiter. unilateral MNGs are responsible for toxic symptoms. There could
Surgery for Multinodular Goiter 75

Follow-Up Strategy for MNG Surgery
Figure 9.3 Often such massive goiters are unilateral. Figure 9.5 Total thyroidectomy is the surgical procedure of choice.
be an argument in favor of radionuclide imaging or Doppler along hemostasis. Hence, in a massive Chikhaldara goiter, it is best to do
with ultrasonography (USG) for localized increased activity [5,6]. total thyroidectomy. Bilateral MNG with retrosternal extension
However, the authors suggest proceeding with the surgical treatment is another case where one must perform total thyroidectomy for
based on other parameters. All efforts should be made to stabilize reasons of safety.
the toxic symptoms and optimally achieve euthyroid status.
ISSUES RELATED TO FUNCTION
OPTIMIZING SURGICAL TREATMENT It is argued that if one manages to keep some thyroid tissue, it will save
There is really no great debate around treatment of unilateral the patient’s dependence on exogenous thyroid support. However, it
multinodular goiter (Figure 9.3). The surgery of choice is excision of is very doubtful that the remainder of the tissue is adequate, and the
the ipsilateral lobe with the isthmus. The removal of the isthmus is patient may still require Thyroxine supplementation. The authors
very critical as any future hypertrophy of the isthmus will create a experienced the case of a patient requiring Thyroxin support after
midline hump. Obviously, if the initial indication was cosmesis, this having been subjected to hemithyroidectomy. About a third of
is rather an embarrassing situation too. The following list presents patients requires long term Thyroxine support and about 20% of
options for surgical treatments: them need it permanently [7–9].
• Unilateral lobectomy with isthmusectomy ISSUES RELATED TO THE PARATHYROID

• Total thyroidectomy It may be advisable to consider lesser surgery for the safety of the
• Sub-total thyroidectomy parathyroids. However, experience teaches us that it is the superior
• Near total thyroidectomy set of parathyroids that are saved in all cases, and the real concern
There are several opinions, and the following factors should be is about the inferior set of parathyroids. There is no real statistical
considered in decision-making. evidence or trials to support this argument.
STRUCTURAL ISSUES LOW RESOURCES, HIGH VOLUME DISEASE

It is very difficult to find a reasonably nodule-free area during The social and economic situation in Chikaldhara is really different.
the surgical dissection (Figures 9.4 and 9.5). It is sometimes more Oral Thyroxine is not as much of an economic burden as is the cost of
hazardous to try to find a suitable dissecting plane and achieve calcium supplements. We have been in this situation for a number of
years, and it is our considerate opinion that treatment depends greatly
on available surgical skills and the need for very careful monitoring.
FOLLOW-UP STRATEGY FOR MNG SURGERY
It is worth while to discuss the specimen with the pathologist and

examine all nodules after sectioning. To subject all nodules for
histological examination, though ideal, is not practical. Hence, only
the suspicious nodules may be subjected to histology. Should any
of them prove to be malignant, they should be subjected to further
treatment on their own merit.
In case of unilateral lobectomy and isthmusectomy, it is observed
that they are likely to become hypothyroid and hence should be
monitored [7–9]. There is no available statistical information on the
incidence of MNG in the contralateral lobe. We feel that the patient
Figure 9.4 Always examine the specimen for inadvertent removal of should not be allowed to become hypothyroid, as a resultant high
the parathyroid. thyroid-stimulating hormone (TSH) may stimulate nodularity.
76 Surgery for Multinodular Goiter

References
Revision surgery after earlier hemithyroidectomy for contralateral 6. Sarr A et al. Toxic nodular goitre. Daker Med. 2007;52(2):135–40.
lobe is not a difficult proposition if the planes were not violated 7. Chotigavanich C, Sureepong P, Ongard S. Hypothyroidism
in the previous surgery. However, when the residual thyroid after hemithyroidectomy: The incidence and risk factors.
tissue becomes nodular and deserves surgical excision, it is a very J Med Assoc Thai. 2016 Jan;99(1): 77–83.
hazardous proposition. Such surgeries must be done at tertiary high
8. Said M, Chia V, haigh PT. Hypothyroidism after
volume centers with intra-operative nerve monitoring [10]. It may
hemithyroidectomy. World J Surg. 2013 Dec;37(12):2839–44.
also require similar localization of the parathyroid gland both pre-
operatively and intra-operatively with advanced imaging studies [11]. 9. Vaiman M et al. Hypothyroidism following partial thyroidectomy.
Otolaryngol Head Neck Surg. 2008 Jan;138(1):98–100.
10. Gremillion G et al. Intraoperative recurrent laryngeal nerve
REFERENCES monitoring in thyroid surgery: Is it worth the cost? Ochsner J.
2012 winter;12(4):363–6.
11. Ethan F et al. Preoperative imaging for parathyroid localization
1. Gadolfi PP et al. The incidence of thyroid carcinoma in in patients with concurrent disease: A systemic review. Head
multinodular goitre: Retrospective analysis. Acta Biomed. Neck. 2018;40:1577–87.
2004 Aug;75(2):114–7. 12. Kennedy JS. The pathology of dyshormonogenetic
2. Bombil I et al. Incidental cancer in multinodular goitre post goiter.The Journal of Patholgy.1969 Nov;99(3).
thyroidectomy. S Afr J Surg. 2014 Feb;52(1):5–9. 13. Ghosserin RA, Rosai J, Hoffes C. Dyshormonogenetic goiter:
3. Jie Luo BS et al. Are these predictors of malignancy in patients A clinicopathology study of 56 cases. Endocr Pathol. 1997
with multinodular goitre? J Surg Res. 2012 May;174(2):207–10. winter;8(4):283–92.
4. Dogan L et al. Total thyroidectomy for the surgical treatment 14. Brix TH, Hegedus L. Genetic and environmental factors in the
of multinodular goitre. Surg Today. 2011 Mar;41(3):323–7. aetiology of simple goiter. Ann Med. 2000 Apr;32(3):153–6.
5. Luster M, Verbury FA, Scheidbauer K. Diagnostic imaging 15. Derwahl M, Studer H. Nodular goiter and goiter nodule;
work up in multinodular goitre. Minerva Endocrinol. 2010 Where Iodine deficiency falls short of explaining the fact.
Sep;35(3):153–9. Exp Clin Endocrinol Diabetes. 2001;109(5):250–60.
Surgery for Multinodular Goiter 77

Chapter 10
MANAGEMENT OF RETROSTERNAL GOITER
Belayat Hossain Siddiquee
CONTENTS
Introduction 79
Clinical Manifestations 79
Investigation for RSG 79
Classification 80
Treatment 81
Conclusion 82
References 82
e.g., symptoms of airway obstruction (shortness of breath, dyspnea,

minimal voice change), symptoms of compression of the great veins
INTRODUCTION in the neck (flushing of the face, engorged veins in the neck and chest)
(Figure 10.1), and symptoms of food way compression (dysphagia) [6].
Rarely, a malignant retrosternal goiter can give rise to lymph node
Retrosternal goiter (RSG) was first described by Albrecht von Haller swelling in the neck (central or lateral due to metastasis). Obstructive
in 1749 [1] as the extension of thyroid tissue below the upper opening sleep apnea due to retrosternal goiter is also reported [7].
of the chest. When should thyroid swelling be labeled as retrosternal
goiter? At least four definitions are available in the literature:
a. Candela et al. in 2007 defined the entity as any goiter that INVESTIGATION FOR RSG
descends below the plane of the thoracic inlet or grows into the
anterior mediastinum for more than 2 cm [2].
b. Shingh et al. in 1994 suggested that a retrosternal goiter existed
i. Plain radiology
when more than 50% of the goiter was below the plane of the
Chest x-ray P/A and lateral view reveals:
thoracic inlet [3].
a. Superior mediastinal opacity
c. A surgical definition was used by White et al. in 2008 defining b. Tracheal deviation (Figure 10.2)
a retrosternal goiter as any goiter which required dissection in
ii. CT scan is indicated when the goiter is sufficiently low down
the mediastinum [4].
in the chest to plan for a surgical approach, assess the total
d. Goldenburg et al. as early as 1957 defined a retrosternal goiter goiter volume, and in case of malignancy to see extrathyroid
as one reaching the level of the 4th thoracic vertebra [5]. extension, adhesion, and invasion to the adjacent structures
All these definitions have their limitations. In the first and second and lymphadenopathy (both cervical and mediastinal) [8]
definition there is nothing indicated about the total volume of the (Figures 10.3 and 10.4).
goiter and whether the retrosternal portion remains in the thorax in
all postures and situations. Many goiters in erect posture sink into
the thorax to some extent but in the supine position, particularly on
the operating table (OT), come up to be confined only in the neck.
Every thyroid surgeon will agree that most retrosternal goiters do
not require dissection in the mediastinum, as it is possible to drag
them up from the neck through cervical incision.
We propose this definition: Retrosternal goiter is one where the goiter
remains in the mediastinum in any posture, entirely or partly. The
volume of the retrosternal portion is a matter of consideration, not
the percentage of total goiter volume. A big goiter of less than 20%
thoracic extension can give rise to symptoms of inlet obstruction.
CLINICAL MANIFESTATIONS
The retrosternal goiter is often asymptomatic, and a diagnosis is

incidental during radiological investigation of a cervical goiter as
part of a pre-operative check-up. But in the majority of cases they
may present categorically with symptoms of retrosternal goiter, Figure 10.1 Venous engorgement and flushing of skin in neck and chest.
Management of Retrosternal Goiter 79

Classification
Figure 10.4 CT scan showing retrosternal goiter just above the arch
of the aorta.
v. Ultrasonographic evaluation of the retrosternal portion of the

thyroid is not as good as in cervical goiter, as it is hampered by
the bony structures of the thoracic cage [11].
In addition, thyroid hormone assays with TSH and other
investigations for general fitness for major surgical procedures are
Figure 10.2 Tracheal shifting by retrosternal goiter.
required.
CLASSIFICATION
There are many classifications available in the literature, mainly

based on anatomical location. This is a classification of retrosternal
goiter from the surgical point of view.
1. Where a significant portion of the cervical goiter persistently
remains in the mediastinum but there is no adhesion with the
mediastinal structures (Category 1).
2. A goiter that is entirety in the mediastinum. These may be the
goiters that wholly sink into the mediastinum from the neck
or primary mediastinal thyroid, which is likely to derive blood
supply from mediastinal vessels (Category 2).
3. Any RSG with suspicion of malignancy (clinical and/or
radiological) (Category 3).
The advantage of this classification is that it is possible to make a pre-
operative plan regarding surgical approach and anticipate probable
surgical complications correlating with the clinical features.
CATEGORY 1
The goiter has a portion in the neck. The retrosternal portion derives
blood supply from the neck vessels. It is usually possible to drag the
Figure 10.3 X-ray chest showing retrosternal goiter. retrosternal portion via a cervical collar incision without significant
bleeding or any other complication like recurrent laryngeal nerve
palsy or parathyroid insufficiency.
The high iodine content of the thyroid gives it higher attenuation
in comparison to surrounding soft tissues and is more useful in CATEGORY 2
identifying thyroid extension into the mediastinum. The goiter sinks into the mediastinum. If the lower limit is not
iii. CT-guided FNAC for perfect sampling, to ensure safety and approachable digitally or if the primary mediastinum thyroid,
avoid hemorrhage. which is developmentally located in the thorax, derives its
iv. MRI is superior in more precise evaluation of the retrosternal blood supply from the mediastinal vessels, it should be removed
goiter, especially its relation to extension and invasion of the by a sternotomy approach for complete removal to minimize
adjacent structure [9,10]. complications.
80 Management of Retrosternal Goiter

Treatment
CATEGORY 3 Table 10.2 Sex ratio among the two groups, i.e., cervical goiter and RSG
The goiter has produced pre-operative features of malignancy like Sex No. of patients Percentage Ratio
vocal cord palsy and lymphadenopathy, and the CT scan features
extracapsular spread and invasion of adjacent structures like Cervical goiter (n = 1,065)
trachea, esophagus, etc. These may or may not be attached to vital Female 781 73.33% 2.75:1
structures like pleura, lung, or vessels. There is a chance of massive Male 284 26.67%
perioperative bleeding and major complications from damage Retrosternal goiters (n = 26)
to these vital structures. There is also the possibility of clearance
Female 18 69.23% 2.25:1
failure, which often remains undetected. Adequate exposure is to be
Male 8 30.77%
ensured, and sternotomy may be required.
TREATMENT
There is a general argument that surgical removal should be

performed even in the absence of clinical symptoms or signs. The
widely accepted reasons for that are:
i. Diagnosis of malignancy could be missed as FNAC from the
mediastinal portion of the thyroid is difficult and potentially
dangerous because of the location of the big thoracic vessels [12].
ii. RSG gives rise to life-threatening emergencies because of
sudden or rapid enlargement secondary to hemorrhage and/or
malignant change.
iii. Thyroxin suppression or radio iodine ablation are rarely
successful in RSG to reduce size [13].
Retrosternal goiter has some special features related to cervical
goiter which indicates the surgery is obligatory in all the diagnosed
cases. Clinical assessment of retrosternal goiter is not as efficient
as in cervical goiter due to the inaccessibility of the intrathoracic
portion, and ultrasonography images are not as good as in cervical
goiter due to artifact generated by bones of the thoracic cage [14]. The
retrosternal portion is difficult to approach for needle biopsy. These
issues illustrate the complications to get a clear understanding about
the clinico-pathological nature of retrosternal goiter. The history of
retrosternal goiter shows a progressive community presenting in
the fifth and sixth decade of life. Advancing age is associated with
increasing comorbidity, implying that operation at an earlier stage
of goiter may be associated with a reduced rate of complications [15]. Figure 10.5 Age distribution curve of cervical and retrosternal goiter.
The presenting symptoms, i.e., those of compression of airways,
major neck vessels, or foodways in the thoracic inlet region, can only
be alleviated by surgical removal of the goiter. But the age incidence showed quite the reverse. Retrosternal goiter
Although generally thought to be uncommon, acute problems may usually shows progressive growth commonly presenting during the
occur in 5%–11% of retrosternal goiter [16,17]. Hemorrhage in the fifth or sixth decade of life. In our series, among the cervical goiter,
nodule, secondary to prolonged mechanical pressure precipitate 77.84% were below the age of 50, whereas in retrosternal goiter,
development of a laryngeal edema and congestion. 69.23% were above 50 years of age. In cervical goiter, the age range
was 9 to 78 years with a mean age of 40 (SD 14.33) and in retrosternal
A 5-year study from July 2012 to June 2017 at the Department of
goiter the age range was 27 to 70 years with a mean age of 53 (SD
Otolaryngology-Head & Neck Surgery, Bangabandhu Sheikh Mujib
12.29). The age distribution curve of cervical and retrosternal goiter
Medical University, Dhaka, Bangladesh, revealed that out of 1,091
are shown in Figure 10.5.
patients who underwent thyroid surgery, only 26 (2.38%) were found
to have retrosternal goiter and 1,065 (97.61%) were found to have SURGICAL MANAGEMENT
cervical goiter. As per the criteria, the pre-operative categorization Only around 2% of retrosternal goiters require surgical access other
is shown in Table 10.1. The sex ratio between cervical goiter and than standard collar incision [4,18].
retrosternal goiter was very similar (Table 10.2).
The surgical approach required in our series is shown in Table 10.3
Table 10.1 Pre-operative categorization of retrosternal goiters and Figure 10.6.
(n = 26)
COMPLICATIONS OF SURGERY
Category 1 Significant portion in the mediastinum 21 (80.77%) The main complications of thyroid surgery were compared in
Category 2 Entirely in the mediastinum 2 (7.69%) retrosternal goiter in contrast to cervical goiter (Tables 10.4 and 10.5).
1 primary in the mediastinum, 1 sinks Post-operative hemorrhage occurred in 2 cases of retrosternal goiter
from the neck
out of 26 (7.69%), whereas it occurred in only 5 out of 1,065 cases of
Category 3 Malignant, PTC (per-operative) 3 (11.54%) cervical goiter (0.43%).
Management of Retrosternal Goiter 81

References
Table 10.3 Surgical approaches required in selective cases of Categories 2 and 3 only. Surgery for
retrosternal goiter is associated with a higher risk of complications.
Category 1 (n = 21) Cervical (all cases)
Category 2 (n = 2) Cervical + sternotomy -1
Sternotomy -1
REFERENCES
Category 3 (n = 3) Cervical -2
Cervical + sternotomy -1
Note: Sternotomy required in 3 cases out of total 26 RSG
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Total thyroidectomy: 444 Temporary: 34 9.41%
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16. Mackle T, Meaney J, Timon C. Tracheoesophageal
compression associated with substernal goitre. Correlation of
symptoms with cross-sectional imaging findings. J Laryngol
Otol. 2007;121:358–61.
CONCLUSION
17. Ben Nun A, Soudack M, Best LA. Retrosternal thyroid goiter:
15 years’ experience. Isr Med Assoc J. 2006;8:106–9.
The mean age of patients with retrosternal goiter is higher than cervical 18. Mack E. Management of patients with substernal goiters.
goiter and mostly presents in middle age and above. Sternotomy is Surg Clin North Am. 1995;75:377–94.
82 Management of Retrosternal Goiter

Chapter 11
REMOTE ACCESS ENDOSCOPIC AND ROBOTIC THYROIDECTOMY
Kyung Tae
CONTENTS
Introduction 83
The History of Robotic/Endoscopic Thyroidectomy 83
Robotic/Endoscopic Thyroidectomy Classification 83
Author’s Experience 86
Conclusions 87
References 89
(ABBA) uses two breast ports and an axillary port. The bilateral
axillo-breast approach (BABA) requires two incisions in the areola
INTRODUCTION and two incisions in each axillary area [13]. The unilateral or bilateral
axillo-breast approaches with CO2 insufflation use one breast port
and two axillary ports on one or both sides, respectively.
Remote access endoscopic and robotic thyroidectomies via cervical,
axillary, anterior chest, breast, postauricular facelift, and transoral The facelift (retroauricular) approach employs postauricular
approaches have been developed over the past 20 years to avoid and occipital hairline incisions [15]. Also, it allows for a smaller
or hide visible neck scarring; such scarring is a major concern in dissection area and a shorter distance from the incision site to the
thyroid surgery, especially in young women [1]. thyroid gland than the transaxillary approach.
The transoral approach may include sublingual, vestibular, or
combined approaches [1,15–17]. Moreover, the transoral approach is
considered as a form of true natural orifice transluminal endoscopic
THE HISTORY OF ROBOTIC/ENDOSCOPIC surgery (NOTES) and is less invasive in terms of working space than
THYROIDECTOMY other types of remote access thyroidectomy.
In 1997, the first endoscopic thyroidectomy was performed using

ROBOTIC/ENDOSCOPIC THYROIDECTOMY
a cervical approach with carbon dioxide (CO2) insufflation [2].
Miccoli et al. developed the minimally invasive video-assisted CLASSIFICATION
thyroidectomy (MIVAT) technique without CO2 insufflation,
to avoid CO2-related complications, in 1999 [3]. Since then,
various remote-access thyroidectomy methods via axillary, breast, Remote access robotic and endoscopic thyroidectomy can be
anterior chest, postauricular, and transoral routes have been classified according to the use of CO2 gas insufflation and the site
developed. of the incision (Table 11.1) [1]. Carbon dioxide insufflation methods
Video-assisted neck surgery (VANS) without CO2 insufflation include the cervical, axillary, breast, anterior chest, and transoral
involves a 3 to 4 cm main oblique incision in the anterior chest wall approaches, as well as various axillo-breast approaches such as the
below the clavicle, and a 5 mm incision in the lateral neck that is ABBA, BABA, and unilateral or bilateral axillo-breast approaches.
used to insert a 5 mm endoscope. The axillary approach with CO2 Gasless methods include the MIVAT, anterior chest, axillary,
insufflation that uses three axillary incisions was developed in 2000 postauricular facelift, and transoral approaches. There are also
[4]. The gasless transaxillary approach was first developed using a various modifications and combinations of these approaches.
6 cm axillary incision and one small anterior chest port, but it has
OPERATIVE PROCEDURES
progressed to involve the use of a single axillary incision without an
Of the various remote access thyroidectomy procedures, the
anterior chest port [5]. The gasless transaxillary approach has also
gasless transaxillary approach, BABA, gasless postauricular facelift
been modified to create gasless unilateral axillary (GUA) and gasless
approach, and transoral vestibular approach are commonly used
unilateral axillo-breast (GUAB) approaches [6–10]. The GUAB
today. The operative procedures of these four approaches are as
approach involves the use of a small breast areola port in addition
follows.
to the main axillary incision. The breast port provides a wide angle
between the robotic or endoscopic instruments, making it easier to THE GASLESS UNILATERAL AXILLARY (GUA) APPROACH
manipulate them and avoid collisions. However, the robotic GUAB A 5- to 6-cm skin incision is made in the axillary fossa (Figure 11.1a)
approach has evolved into the GUA approach that does not use a [1,6–10], and a skin flap is elevated under direct vision in the plane
breast port but offers better cosmesis [11]. of the subplatysmal layer over the pectoralis major muscle from
The breast approach using CO2 insufflation uses two breast ports the axilla to the anterior neck area. The dissection encompasses
and one parasternal port [12]. The axillo-bilateral breast approach the space between the two heads of the sternocleidomastoid (SCM)
Remote Access Endoscopic and Robotic Thyroidectomy 83

Robotic/Endoscopic Thyroidectomy Classification
Table 11.1 Classification of robotic and endoscopic thyroidectomies placed in a plastic bag through the 12 mm breast port. The midline
Carbon dioxide (CO2) insufflation methods of the strap muscles is re-approximated, a suction drain is placed,
Cervical approach and the skin is closed.
Anterior chest approach
Axillary approach THE GASLESS POSTAURICULAR FACELIFT APPROACH
Breast approach with parasternal port A skin incision is made in the postauricular sulcus, curved
Axillo-breast approach posteriorly at the upper third of the auricle, and continued along
Axillo-bilateral breast approach (ABBA) the occipital hairline (Figure 11.3a) [1,14,18]. The skin flap is
Bilateral axillo-breast approach (BABA) elevated in the plane of the subplatysma over the SCM muscle
Unilateral/bilateral axillo-breast approach under direct vision, posteriorly to the posterior border of the
Transoral approach
SCM muscle, superiorly to the lower border of the mandible, and
Gasless methods inferiorly to the sternal notch. The great auricular nerve and the
Minimally invasive video-assisted thyroidectomy (MIVAT) external jugular vein are identified and preserved. The sternohyoid
Anterior chest approach
and sternothyroid muscles are dissected and retracted upwards to
Video-assisted neck surgery (VANS)
Axillary approach
expose the thyroid gland, after which an external retractor is placed
Axillary approach with anterior chest port to maintain the working space (Figure 11.3b). A 30° face-down
Single incision axillary approach endoscope and three robotic instruments including Maryland
Gasless unilateral axillo-breast (GUAB) or axillary (GUA) approach dissectors, Prograsp forceps, and Harmonic curved shears are
Facelift (retroauricular) approach inserted through the postauricular incision (Figure 11.3c). The
Transoral approach parathyroid glands are identified and preserved, and the RLN is
Source: Reproduced from Tae et al. Clin Exp Otorhinolaryngol identified in the tracheoesophageal groove and preserved (Figure
2019;12:1–11. 11.3d). Berry’s ligament and the thyroid isthmus are dissected, and
the lobectomy with isthmusectomy is completed (Figure 11.3e).
Afterwards, a suction drain is placed and the wound is closed layer
by layer.
muscle and progresses below the sternothyroid and sternohyoid
muscles to expose the thyroid gland. An external retractor is used THE TRANSORAL VESTIBULAR APPROACH
to maintain an adequate working space without CO2 insufflation A 1.5- to 2-cm horizontal incision is made at the end of the lower
(Figure 11.1b). A second 0.5-cm (endoscopic procedure) or 0.8- lip frenulum, and two lateral incisions are made close to the oral
cm (robotic procedure) skin incision is made just inferior to the commissure to avoid a mental nerve injury (Figure 11.4a) [1].
axillary incision to insert a trocar. The purpose of this second Epinephrine diluted in normal saline is injected into the submental
axillary incision is to minimize the length of the main axillary area for hydrodissection. Blunt dissection of the submental area
incision. Three robotic arms including a 30° face-down robotic is performed using a dilator. A 30° rigid endoscope is placed in
endoscope, Prograsp forceps, and a Maryland dissector are then the center, and 5– or 8 mm trocars are inserted on either side
inserted through the main axillary incision port. The Harmonic of the endoscope for two endoscopic dissectors or monopolar
curved shears (dominant hand side) are placed at the second electrocautery. The CO2 insufflation pressure is set at 5 to 6 mmHg.
axillary incision port in a right-side approach (Figure 11.1c). In A working space is usually created in the plane of the subplatysmal
an endoscopic procedure, a 30° face-down endoscope and other layer by endoscopy without a surgical robot. The skin flap is
endoscopic instruments are placed at the main axillary incision, widened to the level of the sternal notch inferiorly and the SCM
and the energy-based devices or endoscopic instruments are muscle laterally (Figure 11.4b). After creating the working space,
inserted through the second axillary incision port and the main a 30° robotic endoscope and robotic instruments such as bipolar
axillary incision. Maryland forceps or monopolar scissors are placed on either
The superior thyroid vessels are cut individually close to the side of the endoscope. If necessary, a third robotic instrument,
thyroid gland, using the Harmonic curved shears, to preserve the such as Cardinal forceps, is inserted through the right axillary
external branch of the superior laryngeal nerve (Figure 11.1d). The port (Figure 11.4c). The midline fascia between the strap muscles
superior parathyroid gland is identified and carefully preserved is divided and the sternohyoid and sternothyroid muscles are
with an intact blood supply. The thyroid gland is then retracted dissected to expose the thyroid gland (Figure 11.4d). Next, the
medially, and the paratracheal lymph nodes and perithyroidal isthmus is dissected and divided, and a thyroidectomy is performed
soft tissue are dissected while preserving the entire recurrent while preserving the RLN and parathyroid glands (Figure 11.4e).
laryngeal nerve (RLN) (Figure 11.1e). The isthmus is divided, and Special care must be taken to preserve the RLN when dissecting
the ipsilateral total lobectomy with a central neck dissection is the Berry’s ligament area. The lobectomy with isthmusectomy is
completed (Figure 11.1f). Finally, a suction drain is inserted and completed (Figure 11.4f), and the specimen is removed using a
the wound closed. plastic bag via the central oral incision or the axillary port. The
divided strap muscles are re-approximated and the surgical wound
THE BILATERAL AXILLO-BREAST APPROACH (BABA) in the oral vestibule is closed with absorbable sutures; usually no
After making incisions on both upper circumareolar areas, the drain is required.
working space is elevated to the level of the thyroid cartilage
superiorly and to the medial border of the SCM muscle laterally. An ADVANTAGES AND LIMITATIONS OF REMOTE ACCESS
endoscope is placed through the right breast port, and the left breast THYROIDECTOMY
port is used for the endoscopic or robotic instruments. Two axillary Remote access endoscopic and robotic thyroidectomy has many
cannulas are inserted, and the working space is maintained using advantages. It provides excellent cosmesis and a magnified surgical
CO2 insufflation at a pressure of 5 to 6 mmHg (Figure 11.2) [1]. The view [1,19]. Notably, robotic procedures using the da Vinci Surgical
midline fascia between the strap muscles and the isthmus is divided. System (Intuitive Surgical, Sunnyvale, California) can provide
The thyroid gland is dissected while preserving the parathyroid a 3-dimensional 10–12-fold magnified view, making it easy to
glands and RLNs. Then, the resected specimen is removed and identify the parathyroid glands and RLN. It also provides the ability
84 Remote Access Endoscopic and Robotic Thyroidectomy

Robotic/Endoscopic Thyroidectomy Classification
(a) (b)
(c) (d)
(e) (f )
Figure 11.1 The gasless unilateral axillary (GUA) approach. (a) A 5 to 6 cm main skin incision is made in the axillary fossa, and a second 0.5 or
0.8 cm skin incision is made just inferior to the main axillary incision to insert a trocar. (b) After creating a working space, an external retractor is
placed to maintain an adequate working space without carbon dioxide (CO2) insufflation. (c) Three robotic arms including a 30° face-down robotic
endoscope, Prograsp forceps, and a Maryland dissector are then inserted through the main axillary incision port, and the Harmonic curved shears
are placed at the second axillary incision port in a right-side approach. (d) The superior thyroid vessels are cut individually close to the thyroid gland,
using Harmonic curved shears, to preserve the external branch of the superior laryngeal nerve. (e) The thyroid gland is then retracted medially, and
the paratracheal lymph nodes and perithyroidal soft tissue are dissected while preserving the whole course of the recurrent laryngeal nerve. (f) The
surgical view after the thyroid lobectomy is shown.
to use three robotic instruments simultaneously and enables fine complained of asymmetric and band-like contractures of the neck,
motion scaling, hand-tremor filtering, innovative instrumentation anterior chest, and axillary areas that might be caused by fibrotic
with extended freedom of motion, and surgical education [1]. The contractures of soft tissue and muscles [20,21].
use of a third robotic instrument is very important for obtaining Bilateral and total thyroidectomies are rather difficult via unilateral
counter-traction that can facilitate dissection and improve surgical facelift and transaxillary approaches, although lobectomy can
dexterity. be done easily using these approaches [1]. However, lobectomy is
However, remote access thyroidectomy also has several currently recommended for small, low-risk thyroid cancers; hence,
disadvantages. It is not a minimally invasive surgery in terms of skin this could provide a rationale for surgeons to consider facelift and
flap elevation for creating a working space, nor is it a maximally transaxillary approaches [22].
invasive surgery, but it requires a wide dissection area to reach the The high cost of robotic thyroid surgery is another major drawback.
thyroid gland. Nonetheless, the thyroidectomy procedure itself is Also, it is a technically difficult procedure with a steep learning
as refined as the conventional method [1]. Also, some patients have curve that presents an issue in terms of patient safety. Moreover,

Author’s Experience
Generally, CO2 insufflation methods have the advantage of

exposing and maintaining the working space following a small
skin incision made in a remote access site beyond the neck [1].
Therefore, post-operative cosmesis may be better, potentially, than
when using gasless methods that require long skin incisions at a
remote site. However, CO2 insufflation can result in CO2-related
complications such as subcutaneous emphysema, hypercapnia,
respiratory acidosis, cerebral edema, and CO2 embolisms although
there is a low risk of an adverse event if pressure levels of 4 to
6 mmHg are used [28]. Gasless methods have the advantage of
maintaining a clear surgical view without gas fumes and the
absence of complications related to CO2 insufflation. They also
enable surgeons to use instruments employed in a conventional
thyroidectomy to dissect skin flaps and control bleeding [1]. Also,
surgical view clarity is greater with gasless methods, such as the
gasless transaxillary and facelift approaches, than in the BABA and
transoral approaches [1].
Surgical invasiveness related to skin flap elevation is greatest in
the BABA and transaxillary approach, and least in the transoral
Figure 11.2 The bilateral axillo-breast approach (BABA) with carbon approach. However, the working space is widest in the transaxillary
dioxide (CO2) insufflation. Four skin incisions are made: two in the areola approach, making it easy to place and manipulate three robotic
and one in each of the two axillary areas. (Reproduced from Tae et al. or endoscopic instruments. Meanwhile, the BABA and transoral
Clin Exp Otorhinolaryngol 2019;12:1–11.) approach make it easier to perform total thyroidectomy than the
transaxillary and facelift approaches. Especially, the working space
of the facelift approach is narrow, and it is very difficult to approach
the contralateral thyroid lobe via the unilateral incision [18]. The
the operative time of a robotic thyroidectomy is significantly latter permits one to perform a selective lateral neck dissection; a
longer than that of a conventional thyroidectomy due to the central neck dissection can be performed in all four approaches.
longer flap dissection time and the time needed for robot docking However, this is relatively difficult in the BABA due to an inadequate
[23–26]. angle of approach. Post-operative cosmesis is very good in all the
procedures.
Although there are many reports of the feasibility and safety of
SALIENT POINTS
• Of remote access robotic and endoscopic thyroidectomy
remote access thyroidectomy, complication rates are potentially
higher, especially during the learning curve and when performed
techniques, transaxillary, BABA, postauricular facelift, and by low-volume surgeons, because of the challenging surgical
transoral approaches are commonly used today.
• The various approaches have their own advantages and
techniques. In meta-analyses, rates of complications such as RLN
paralysis and hypoparathyroidism were not significantly different
disadvantages. Therefore, we need to understand the advantages in robotic and conventional thyroidectomies [23–26]. However,
and limitations of each.
• Remote access thyroidectomy is feasible and comparable to
in subgroup analyses, transient RLN paralysis was higher in the
robotic procedure than in the conventional procedure [24]. Also,
conventional thyroidectomy in highly selective patients.
• Strict patient selection criteria are important for the patient’s
there can be serious complications such as injury to the esophagus
and trachea, compromised airways due to hematomas, and, in rare
safety and the success of the surgery.
• The most important advantage of remote access thyroidectomy
instances, serious CO2 embolisms [28].
Unusual complications can also occur. For instance, a transient
is its excellent cosmesis.
• Disadvantages of remote access thyroidectomy include the
brachial plexus injury has been reported in the robotic transaxillary
approach. Also, the marginal branch of the facial nerve can be
invasiveness needed to create the working space, longer
injured in the postauricular facelift approach, possibly as a result
operative time, higher cost, and technical difficulty.
of a robotic instrument compressing the nerve at the narrow
postauricular port [18]. Mental nerve injuries can also occur in the
transoral approach.
AUTHOR’S EXPERIENCE Therefore, strict patient selection criteria are needed for successful
surgical outcomes. The safety of patients must be the first priority,
especially during the steep learning curve. Also, an appropriate
Of the four common remote access thyroidectomy techniques (the training program for surgeons is required [29]. Furthermore, the
gasless transaxillary approach, BABA, the gasless postauricular possibility of converting to an open procedure should always be
facelift approach, and the transoral vestibular approach), the author discussed with patients before surgery.
has used the gasless transaxillary, postauricular, and transoral Cosmetic excellence is the main reason patients and surgeons choose
approaches for thyroidectomies since 2005 [6–11,18,19,27]. robotic and endoscopic thyroidectomy approaches. Cosmetic outcomes
Each of the four most common remote access thyroidectomy are indeed superior in robotic and endoscopic thyroidectomies than
procedures has its own advantages and disadvantages as shown in in conventional surgeries [7,26]. Long-term cosmetic satisfaction
Table 11.2 [1]. Therefore, it is difficult to conclude which approach after scar maturation is also significantly greater in the transaxillary
is best. approach than in a conventional thyroidectomy [19].

Conclusions
(a) (b)
(c)
(d)
(e)
Figure 11.3 The postauricular facelift approach. (a) A skin incision is made in the postauricular sulcus, curved posteriorly at the upper third of
the auricle, and continued along the occipital hairline. (b) The skin flap is elevated in the sub-platysmal plane over the sternocleidomastoid (SCM)
muscle under direct vision to expose the thyroid glands. (c) A 30° endoscope and three robotic instruments including Maryland dissectors, Prograsp
forceps, and Harmonic curved shears are inserted through the postauricular incision. (d) The recurrent laryngeal nerve (RLN) is identified in the
tracheoesophageal groove and preserved. (e) Thyroid lobectomy with isthmusectomy is complete.
The oncologic outcome is an important issue in the treatment of

thyroid cancer and should not be neglected or overlooked in favor
CONCLUSIONS
of cosmesis or functional outcomes. However, the literature on
oncologic outcomes, such as locoregional recurrences and disease
survival after robotic or endoscopic thyroidectomy, is very limited.
A robotic and endoscopic thyroidectomy using a remote access
In some studies, oncologic outcomes, including disease-specific
approach is feasible and offers a comparable outcome to a conventional
survival and recurrence rates, were not significantly different in
transcervical thyroidectomy in highly selective patients; it also
robotic transaxillary or conventional thyroidectomies, although
yields excellent cosmesis. However, it has disadvantages in terms of
the follow-up periods were rather short [30,31]. Further studies with
surgical invasiveness for the working space, longer operative times,
long-term follow-ups and large patient samples are needed to assess
higher costs, and technical difficulties. Strict patient selection criteria
the ultimate long-term oncologic outcomes of remote access robotic
are very important. We also need to understand the advantages and
and endoscopic thyroidectomy.
limitations of various types of remote access thyroidectomies.

Conclusions
(a) (b)
(c) (d)
(e) (f )
Figure 11.4 The transoral vestibular approach with carbon dioxide (CO2) insufflation. (a) A 1.5 to 2 cm horizontal incision is made at the end of the
lower lip frenulum, and two lateral incisions are made close to the oral commissure to avoid mental nerve injury. (b) A working space is created in the
plane of the sub-platysmal layer by endoscopy without a surgical robot to the level of the sternal notch inferiorly and the SCM muscle laterally. (c) After
creating a working space, a 30° robotic endoscope and two robotic instruments, such as bipolar Maryland forceps and monopolar scissors, are placed on
either side of the endoscope, and Cardinal forceps are inserted through the right axillary port. (d) The midline fascia between the strap muscles is divided
and the sternohyoid and sternothyroid muscles are dissected to expose the thyroid gland. (e) The dissection of the superior pole is performed while
preserving the superior parathyroid gland. (f) Thyroid lobectomy with isthmusectomy is complete while preserving the recurrent laryngeal nerve (RLN).
Table 11.2 Comparison of remote access thyroidectomies
Gasless axillary BABA Gasless facelift Transoral
Invasiveness needed for working space ++++ ++++ +++ ++

Manipulability of instruments in working space ++++ +++ +++ +++
Operative time +++ ++++ +++ +++
Clarity of surgical view ++++ +++ ++++ +++
Applicability of total thyroidectomy ++ +++ + +++
Applicability of central neck dissection +++ ++ +++ +++
Applicability of lateral neck dissection ++++ ++ ++++ +/-
Cosmetic satisfaction +++ ++++ +++ ++++
Complication rate + + + +
Source: Reproduced from Tae et al. Clin Exp Otorhinolaryngol 2019;12:1–11.
Abbreviation: BABA; Bilateral axillo-breast approach.

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Chapter 12
ROBOTIC THYROIDECTOMY
Neil S. Tolley and Christian Camenzuli
CONTENTS
Introduction 91
Indications and Contraindications 91
Concluding Remarks 95
Authors’ Experience and Pearls of Wisdom 95
References 95
associated with longer operative time. However, this is only a relative

contraindication. Increasingly, patients with high body mass index
INTRODUCTION (BMI) are being accepted owing to improved instrumentation and
surgical expertise. Another anatomical consideration is having good
neck mobility, which is important for positioning. Patients with a
Minimally invasive access thyroid surgery has been around for more history of previous surgery or radiotherapy to the neck should not
than a decade. Initially this took the form of endoscopic procedures be offered this surgery.
that were reported as early as 1997 [1]. These procedures offered a
magnified view for safer dissection and also moved the incision Tumors that are small (≤4 cm) and do not extend beyond the thyroid
away from the neck developing the concept of remote-access thyroid capsule are ideal for a robotic approach. With increasing experience
surgery in an attempt to improve cosmetic results. Endoscopic this has, however, become a relative contraindication since robotic
thyroidectomy was, however, a challenging operation offering thyroidectomy can be extended to include neck dissection for
significant limitations in terms of hand-to-eye coordination because nodal metastases [3]. Anaplastic thyroid cancer and cancers that
of the 2D nature of the image, unstable image due to assistant-held are invading surrounding structures are not appropriate for this
endoscopes, unsuitable instrumentation (often using laparoscopic procedure. The presence of thyroiditis around the tumor increases
instruments), limited range of motion, and line of site access. All of the difficulty of dissection and therefore is considered a relative
these made fine dissection difficult. Most endoscopic techniques also contraindication.
require the need for carbon dioxide insufflation to keep the working Thyroid surgery in Graves’ disease is challenging and robotic
space opened. This has been associated with a number of adverse thyroidectomy was not initially considered a suitable treatment.
outcomes including air embolism, hypercapnia, and respiratory This view has largely changed over the years with most surgeons
acidosis. accepting this indication for the robotic approach. Caution needs
The robotic approach to thyroid surgery was pioneered by Chung to be applied when embarking on robotic surgery in patients
and colleagues in 2007 using the da Vinci• Surgical System robot with advanced Graves’ disease, especially in the hands of the
platform (Intuitive Surgical, Sunnyvale, California) [2]. The inexperienced [4]. Substernal extension of the goiter is considered
introduction of the robotic system has provided solutions to the an absolute contraindication.
limitations inherent with endoscopic techniques. The robot offers
a stable magnified 3D image and offers the surgeon seven degrees TECHNIQUE
of freedom by virtue of using endowristed instrumentation. Most Throughout the years several different approaches have been used
of the present robotic techniques also eliminate the need for carbon to perform robotic thyroidectomy. This section will review the
dioxide insufflation. These advantages make robotic thyroidectomy principle operative steps of the commonly used techniques and
a favorable option for patients concerned about their scar or those discuss the advantages and limitations of each.
patients that have an inherent biological predisposition to keloid and
TRANS-AXILLARY APPROACH
hypertrophic scarring.
This was the first approach used for robotic thyroidectomy. After
general anesthesia is achieved, the patient is placed in a supine
position with the neck extended. The contralateral arm is tucked
INDICATIONS AND CONTRAINDICATIONS on the side of the patient. The ipsilateral upper limb is elevated with
the shoulder internally rotated. The elbow is then flexed with the
back of the hand resting on the central forehead (the salute position),
Robotic thyroidectomy can be performed using several established making sure there is appropriate support and padding. Improper
and developing techniques that will be discussed in the next section. positioning of the arm can lead to nerve injury, and therefore some
Common to all techniques are a set of selection criteria that should groups routinely use peripheral nerve monitors in an attempt to
be followed to ensure best possible outcomes. avoid this complication. It is strongly recommended that the arm is
Patients who are either very concerned about having a visible scar not placed in forced extension due to brachial plexus tension.
in the neck or else who have a history of adverse healing (e.g., The incision line is then marked. A line is drawn from the thyroid
keloids) could be considered. The ideal candidate for a robotic cartilage to the anterior axillary line and from the sternal notch to
procedure is not obese since this presents increased difficulty and is the anterior axillary line. An incision of around 5 cm will take place
Robotic Thyroidectomy 91
Indications and Contraindications
between these markings on the lateral border of pectoralis major. It

is important that the patient is marked prior to surgery so that an
optimal site for the incision is chosen; otherwise the incision can
extend onto the upper arm.
After the incision, dissection is carried out subcutaneously and a flap
superficial to the pectoralis major fascia is developed. This dissection
continues until the anterior aspect of the sternocleidomastoid
muscle is encountered as far as the sternal notch. At this point
the avascular plane between the sternal and clavicular heads of
the sternocleidomastoid is identified and dissected leading to the
separation of the two heads and exposure of the thyroid lobe.
Dissection should proceed at least to the external jugular vein and
often posterior to this. This permits less tension on the superior flap
which might otherwise interfere with the optimal function of the
robotic instruments. This occurs as a consequence of lateral pressure
on the trocars that is transmitted to the cogs of the robotic arm
which control the unique motion to the endowristed instruments.
The omohyoid, which is a landmark for the superior pole of the
thyroid lobe, is retracted cranially but usually divided. The strap
muscles are dissected off the thyroid lobe. It is important to divide
the inferior and superior attachments of the sternothyroid muscle.
If a hemithyroidectomy is being performed, the strap muscles are
raised to the contralateral third of the thyroid lobe. A self-retaining Figure 12.1 Positions of robotic arms, camera, and retractor in
retracting device with integrated suction (Modena or Chung) is transaxillary approach. (Reproduced with permission from Tae K et al. Clin
then introduced. The authors’ preference is for the Modena, which Exp Otorhinolaryngol. 2019 Feb;12(1):1–11.)
is far better engineered. This device should be assembled from
the contralateral side and placed below the sternal head of the
sternocleidomastoid and strap muscles to keep the operating space After identifying the RLN and parathyroid glands, the superior pole
exposed. The robot is then docked. The camera arm and instrument vessels are identified and divided. The same approach and care is
arms should be positioned to allow maximum mobility without taken to identify and preserve the external laryngeal nerve as in any
clashing of the other robotic arms. The camera arm should be placed standard lateral approach thyroidectomy.
first at an angle of 220°. The camera endoscope should be inserted to The superior thyroid pole is approached by using the 8 mm bipolar
its maximum travel before insertion into the space. The 8- or 12-mm forceps to retract the pole caudally and medially. The Maryland
30°-down endoscope should be placed low laterally and high medially and Harmonic devices are used to dissect, seal, and divide the
at the site of the thyroid. The two operator arms are then inserted low superior thyroid vessels. The nerve stimulator probe is used to
and laterally for similar reasons and technique. Finally, the fourth make sure there is a safe distance between the external branch of
retractor arm is placed superiorly along the camera endoscope the superior laryngeal nerve and the vessels before sealing. The
(Figure 12.1). Space does not permit a large degree of movement superior parathyroid should be identified and dissected and the
when using this arm. As dissection proceeds it can often be removed upper pole separated from the cricothyroid muscle. The bipolar
altogether to facilitate a greater operating space. In terms of robotic forceps is now adjusted to provide more medial retraction of the
instrumentation, the 5 mm Maryland dissector is loaded on the thyroid lobe. The RLN is followed superiorly to the laryngeal entry
non-dominant hand and an energy-sealing device (e.g., Harmonic• point. Nerve stimulation is regularly employed during dissection,
Ethicon Endo-surgery, Cincinnati, Ohio) on the dominant hand. and attention needs to be paid with regard to heat generation by
The 8 mm bipolar forceps have been found to be gentler and the Harmonic instruments and traction of the RLN if it should pass
more versatile than the Prograsp forceps. The author prefers to through Berry’s ligament. The inferior parathyroid is identified and
conduct dissection with the 5 mm DeBakey and 5 mm Maryland dissected off the thyroid. The inferior thyroid vessels are dissected,
instruments before using the 5 mm Harmonic instrument (Figure sealed, and transected as intracapsular dissection of the thyroid
12.1). This allows precise delineation of the recurrent laryngeal nerve lobe proceeds. Dissection progresses medial to the nerve using the
(RLN) and parathyroid glands. Intra-operative neural monitoring is Maryland dissector and sealing device to dissect the thyroid off
used as a standard of care. The Harmonic instrument employs old the trachea. The isthmus is then divided using the sealing device,
C14 harmonic technology that can safely seal vessels up to 3 mm. and the thyroid is retrieved. If the operation performed is a total
It has the disadvantage of not being endowristed—a significant thyroidectomy (TT), the strap muscles have to be fully dissected off,
handicap. A Ligasure® 8 mm instrument, which is endowristed, is the thyroid lobe. Where indicated, it is the authors’ preference to
available but it can only seal and not cut. It is bulky and inferior to approach thyroidectomy from the right side due to the more oblique
the Harmonic instrument in the authors’ opinion. The operating and vertical course of the RLNs on the right and left side respectively.
table assistant has the role of supplying the console surgeon with The superior pole vessels are divided in addition to the inferior and
cotton pledgets during dissection, changing these as appropriate, middle thyroid veins. The assistant retracts the trachea medially to
and providing compression of structures such as the internal jugular facilitate this. Dissection of the contralateral lobe off the trachea
vein. The assistant is also tasked with providing arm-resets if clashes then proceeds to mobilize this lobe. Dissection continues between
occur and ensuring that the instruments or arms are not harming the trachea and thyroid until the contralateral tracheoesophageal
patient structures out of the console operative field of the surgeon. groove is reached. The RLN is then identified and confirmed with
Furthermore, the assistant is utilized to troubleshoot problems the nerve stimulator and dissection continues until the thyroid is
that may occur with the robotic instruments and employ the nerve free and retrieved. After meticulous hemostasis, all instrumentation
stimulator probe where required. is removed. A drain is not necessary and the authors’ preference is
92 Robotic Thyroidectomy
not to use one. Some surgeons routinely drain after this procedure
as the amount of subcutaneous dissection amounts to three times
that compared to a traditional cervical approach. Skin is closed with
subcuticular absorbable sutures and dermabond [5].
Specific complications associated with this approach include chest wall
paresthesia due the extensive dissection to develop the flap, pressure
from the retractor, and brachial plexus neuropathy. This approach is
relatively contraindicated for patients with a history of chest wall or
axillary surgery and patients who suffer from conditions that limit
their shoulder mobility such as arthritis or rotator cuff injury [6].
AXILLO-BREAST APPROACH
The site and size of the axillary wound used in the transaxillary
approach have received criticism because despite being an
improvement from a cervical incision, an axillary wound cannot
always be covered with clothing and therefore still leads to a visible
scar. The axillo-bilateral breast approach (ABBA) was the original
procedure developed to try to decrease the size of axillary wound.
This has now been largely superseded by a further modification
Figure 12.2 Positions of robotic arms and camera in BABA.
known as bilateral axillo-breast approach (BABA). These approaches
(Reproduced with permission from Tae K et al. Clin Exp Otorhinolaryngol.
minimize the axillary scar, and the peri-areolar scars typically heal
2019 Feb;12(1):1–11.)
nicely and are easily covered by clothing.
In the BABA approach, after general anesthesia, the patient is placed superficially to the RLN and cranially releasing Berry’s ligament.
in the supine position with a pillow under the shoulders. The arms The superior pole is then dissected using one of the following three
are kept by the patient’s side. Guidelines are then drawn marking approaches: lateral, antero-medial, or postero-medial. Care should be
the thyroid cartilage notch, cricoid cartilage, suprasternal notch, given to leave the cricothyroid fascia intact and therefore protect the
midline, the anterior border of the sternocleidomastoid muscle external laryngeal nerve. The superior parathyroid gland should also
bilaterally, superior border of the clavicle, and 2 cm below the border. be dissected and preserved. When the specimen is free, it is put in
The incisions of around 8 mm in length are also marked in both an endobag and extracted through the left axillary port which might
axillae and peri-areolar lines. Trajectory lines are then marked from need to be extended. In a total thyroidectomy, dissection continues in
the incision sites to the cricoid cartilage. These guides are important a similar fashion on the other side.
to direct the operating space, which should be limited to the thyroid
At completion, the operative field is washed with warm saline and
cartilage cranially, sternocleidomastoid muscles laterally, and 2 cm
hemostasis is achieved. The midline raphe is closed with an absorbable
below the clavicles caudally. The operating space is then injected
continuous suture. If drains are required they are inserted through
with diluted adrenaline (1:200,000) below the platysma, which helps
the axillary ports. The skin is closed with absorbable subcuticular
to hydrodissect the area and facilitate raising of the flap. A 12 mm
sutures [7].
circumareolar incision is carried out on the right nipple. A mixture
of diathermy and blunt dissection (using a vascular tunneler) is used RETROAURICULAR APPROACH
to develop a subcutaneous narrow tunnel to the working zone. An This was described in 2011 by Terris and colleagues using the
8 mm circumareolar incision is made in the left nipple and similar standard incision used for facelift and parotid surgery [8].
dissection is carried out. Ports are inserted and a low pressure (5 to After general anesthesia, the patient is positioned supine with
6 mmHg) carbon dioxide insufflation is temporarily instituted. The the head slightly tilted to the opposite side. The incision site is
remaining space is dissected using an energy sealing device under marked in the retroauricular space extending from the posterior
endoscopic view (camera inserted through the 12 mm port). An auricular sulcus down to the mastoid along the hairline. After
8 mm incision is carried out in each axilla at this point. The robot is the incision, a subcutaneous dissection is performed exposing the
then docked inserting the camera through the right areola and an sternocleidomastoid. During this part of the dissection care is taken to
energy sealing device arm through the left areola. Prograsp forceps avoid damage to the greater auricular nerve and the marginal branch
and Maryland dissector are inserted through the axillary ports and of the facial nerve. Dissection continues subplatysmally, exposing
the remainder of the operating space is developed (Figure 12.2). the strap muscles down to the sternal notch. The dissection should
The linea alba cervicalis is divided at this point which separates continue by opening the strap muscles and clearing the connective
the strap muscles. The isthmus is divided centrally along its whole tissue to expose the thyroid gland. A self-retaining retractor is fixed
length using the energy sealing device exposing the trachea. The lobe in a position that retracts the strap muscles. The robot is docked
being dissected is at this point retracted medially with the Prograsp with the Maryland dissector and energy sealing device controlled
forceps whilst the straps are retracted laterally with the Maryland by the non-dominant and dominant hand respectively (Figure 12.3).
dissector. Lateral dissection is carried out to expose the thyroid lobe The superior thyroid pole is retracted antero-inferiorly using the
in its entirety. Prograsp forceps arm and the superior thyroid vessels are identified,
The dissection then continues infero-laterally. The identification of the sealed, and transected. The superior parathyroid should then be
inferior thyroid artery is an important landmark to the identification identified and dissected off the thyroid gland in order to preserve
of the RLN. The use of blunt dissection helps to avoid damage to the it. The lobe is now retracted medially and the RLN identified
nerve while developing the plane. Intra-operative neuromonitoring is through careful dissection. The nerve needs to be dissected up to the
also possible with this robotic approach. The inferior parathyroid gland laryngeal insertion point. A safe space needs to be created between
is identified and dissected away from the thyroid lobe. The inferior the nerve and the thyroid gland. The inferior parathyroid should be
vessels are dissected, sealed, and divided. The dissection continues identified and dissected away from the thyroid gland. The inferior
Figure 12.3 Positions of robotic arms and camera in retroauricular

approach. (Reproduced with permission from Tae K et al. Clin Exp
Otorhinolaryngol. 2019 Feb;12(1):1–11.)
thyroid vessels are identified, sealed, and transected. The thyroid

lobe is then dissected off the trachea and the isthmus divided. Once
free, the thyroid is delivered through the retroauricular incision. If
required, a drain can be inserted. The subcutaneous tissue is closed Figure 12.4 Positions of robotic arms and camera in TOETVA.
with interrupted absorbable sutures and the skin is closed with (Reproduced with permission from Tae K et al. Clin Exp Otorhinolaryngol.
subcutaneous absorbable suture. 2019 Feb;12(1):1–11.)
The main disadvantage of this approach is that only a unilateral
lobectomy can be performed. The approach itself is more comfortable inferior thyroid vessels are identified, sealed, and transected. If the
for ENT surgeons who are trained in parotid surgery and are familiar operation is a total thyroidectomy, identical dissection takes place
with the relevant anatomy. Compared to the transaxillary and BABA on the contralateral side. When the thyroid is free, it is extracted in
approaches, subcutaneous dissection is significantly less in this an endobag through the central port. The strap muscles are closed
approach. This may reduce operation time and infection risk [9]. with a continuous absorbable suture. The buccal mucosa is closed
with an interrupted absorbable suture [11].
TRANSORAL APPROACH
Transoral robotic thyroidectomy is the latest reported technique. The This technique is being hailed by some as the ultimate solution for
transoral endoscopic thyroidectomy through a vestibular approach minimally invasive thyroid surgery. It promises a scarless technique
(TOETVA) was pioneered by Anuwong in 2016 [10]. The anesthetized and limits the dissecting space due to the close proximity to the
patient is placed in the supine position with slight neck extension. thyroid gland [12]. The use of robotic equipment has overcome
Three incisions are carried out in the gingival-buccal sulcus of the the main obstacle of a restricted working space. The procedure has
lower lip: a 2 cm incision in the midline around 1 cm above the been associated with chin hypoesthesia due to mental nerve damage
frenulum and two 6 mm incision lateral and anterior to the inferior and flap perforation. It also utilizes gas insufflation to maintain the
canines. Blunt dissection is used through the central incision until operating space open with well-documented complications.
the periosteum of the chin is reached. Diluted adrenaline (1:500,000)
is injected subplatysmally for hydro-dissection. Blunt development
of the subplatysmal plane is carried out down to the sternal notch. SALIENT POINTS
Similar dissection is carried out through the lateral incisions.
The robot is docked at this point with the camera in the midline, • Strict inclusion and exclusion criteria are important to
ensure favorable patient outcomes.
the Maryland dissector on the left, and energy sealing device on the
• There are different approaches to robotic thyroidectomy
right. Carbon dioxide insufflation at a low pressure (5 to 6 mmHg) having advantages and disadvantages.
is used to maintain the operative space (Figure 12.4). • Robotic thyroidectomy is safe for low risk and favorable
The linea alba cervicalis is opened and the strap muscles are prognosis cancer.
dissected off the thyroid lobe. The isthmus is divided centrally. • It offers superior cosmetic results when compared to the
The superior pole is dissected carefully with identification, sealing, conventional cervical approach.
and transection of the superior thyroid vessels. The superior
parathyroid gland is identified and dissected off the thyroid lobe.
The lobe is subsequently retracted inferiorly and the RLN identified. OUTCOMES
Nerve stimulator devices can be used to confirm nerve integrity. Any surgical procedure on the thyroid gland must be compared
The nerve is dissected up to its insertion into the larynx. Berry’s with the gold standard of conventional open thyroidectomy for
ligament is then divided with the dissection continuing caudally. safety, completeness of resection in oncological cases, and patient
The inferior parathyroid should be identified and dissected off. The satisfaction.
94 Robotic Thyroidectomy
References
The evidence accumulated so far has shown that robotic

thyroidectomy is safe with similar complication rates to
REFERENCES
conventional surgery. Robotic procedures take longer than open
procedures and have a significant increased cost compared to
conventional surgery [13]. Excellent outcomes have also been
replicated in patients undergoing robotic thyroidectomy for 1. Hüscher CS, Chiodini S, Napolitano C, Recher A. Endoscopic
Graves’ disease [14]. right thyroid lobectomy. Surg Endosc. 1997;11(8):877.
The value of robotic thyroidectomy has also been evaluated in low- 2. Kang S et al. Robot-assisted endoscopic surgery for thyroid
risk excellent prognosis thyroid cancer. Studies reveal that robotic cancer: Experience with the first 100 patients. Surg Endosc.
thyroidectomy is as safe as conventional thyroid surgery for 2009;23(11):2399–2406.
thyroid cancer with similar rates of R0 resections and recurrence 3. Paek SH, Kang KH, Park SJ. Expanding indications of robotic
rates [15]. thyroidectomy. Surg Endosc. 2018;32(8):3480–3485.
The advantage of robotic thyroidectomy is purely cosmetic, which is 4. Aidan P, Pickburn H, Monpeyssen H, Boccara G. Indications
closely related to patient satisfaction. While all the other outcomes for the gasless transaxillary robotic approach to thyroid
are comparable between the two techniques, the scale is heavily surgery: Experience of forty-seven procedures at the American
tipped toward robotic techniques when it comes to cosmetic Hospital of Paris. Eur Thyroid J. 2013;2(2):102–109.
outcome [13,16]. 5. Alzahrani HA, Mohsin K, Ali DB, Murad F, Kandil E. Gasless
trans-axillary robotic thyroidectomy: The technique and
evidence. Gland Surg. 2017;6(3):236–242.
CONCLUDING REMARKS 6. Patel D, Kebebew E. Pros and cons of robotic transaxillary
thyroidectomy. Thyroid. 2012;22(10):984–985.
7. Koo DH, Bae DS, Choi JY. Bilateral axillo-breast approach
Robotic surgery, despite its current controversial status, has
robotic thyroidectomy: Introduction and update. Surgical
nonetheless existed in standard surgical practice for more than
Robotics. 2017: doi:10.5772/intechopen.68951.
10 years, being used in thousands of patients worldwide. Robotic
techniques will continue to evolve and the Lindy effect supports 8. Terris DJ, Singer MC, Seybt MW. Robotic facelift
the premise that it is now firmly established within the surgical thyroidectomy: II. Clinical feasibility and safety. Laryngoscope.
armamentarium. Advances in technology and competition will 2011;121(8):1636–1641.
make it safer, easier, and cheaper to use, which will lead to a 9. Alabbas H, Bu Ali D, Kandil E. Robotic retroauricular thyroid
larger number of surgeons and institutions adopting robotic surgery. Gland Surg. 2016;5(6):603–606.
techniques—the Rogers adoption phenomenon. It is very likely 10. Anuwong A. Transoral endoscopic thyroidectomy vestibular
that the indications and procedures amenable for a robotic approach: A series of the first 60 human cases. World J Surg.
approach will expand in the future. Single port robotic platforms 2016;40:491–497.
launched in 2019 offer exciting potential for the robotic thyroid
11. Richmon JD, Kim HY. Transoral robotic thyroidectomy (TORT):
surgeon.
Procedures and outcomes. Gland Surg. 2017;6(3):285–289.
12. Sun H, Dionigi G. Applicability of transoral robotic thyroidectomy:
Is it the final solution? J Surg Oncol. 2019;119(4):541–542.
AUTHORS’ EXPERIENCE AND PEARLS OF WISDOM
13. Sun GH, Peress L, Pynnonen MA. Systematic review and
meta-analysis of robotic vs conventional thyroidectomy
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surgeon or institution. It should only be undertaken by surgeons 2014;150(4):520–532.
with a high-volume practice to provide a suitable case load to 14. Kwon H et al. Comparison of bilateral axillo-breast approach
maintain skills, expertise, and justify the time and cost involved. robotic thyroidectomy with open thyroidectomy for Graves’
Its adoption should only be considered after a surgeon has attained disease. World J Surg. 2016;40(3):498–504.
expert status in conventional thyroid surgery. 15. Pan J et al. Robotic thyroidectomy versus conventional open
Mandatory training, proctorship, audit, appraisal, and credentialing thyroidectomy for thyroid cancer: A systematic review and
are required to ensure that this technology is introduced into their meta-analysis. Surg Endosc. 2017;31(10):3985–4001.
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Neil Tolley pioneered robotic thyroid and parathyroid surgery in the thyroidectomy approaches: Meta-analysis and systematic
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Chapter 13
INTRA-OPERATIVE NEURAL MONITORING
Rahul Modi
CONTENTS
How Common Is RLN Paralysis? 97

Importance of a Laryngeal Exam—Pre-Operative and Post-Operative Assessment 97
Intra-Operative Neural Monitoring—Utility and Applications 98
Standards for Intra-Operative Nerve Monitoring 98
New Horizons in IONM 100
References 103
The importance of preserving the integrity of the laryngeal nerves figures in the range of 1%–2% for permanent paralysis in expert
in thyroid and parathyroid surgery cannot be overemphasized. Both hands; however, this number was found to increase substantially
the superior and the recurrent laryngeal nerves (RLN) play a very when routine post-operative laryngoscopy was done to assess vocal
important role in ensuring a robust voice and the dynamic nature of cord function [6]. More broad based studies have found the incidence
the glottis. The famous Greek physician and anatomist Galen (2nd of nerve paralysis to vary from 2.3% to as high as 26% [7]. A review of
century AD), identified and named the recurrent laryngeal nerves. more than 25,000 patients found the average rate of RLN paralysis to
However, since human dissections were considered a taboo during the be around 9.8%. Unilateral vocal paralysis can cause significant voice
middle ages, it was only in the 16th century that Vesalius provided change severe enough to demand a change in vocation, especially for
detailed anatomic drawings of both the superior and recurrent professional voice users, along with possible aspiration and dysphagia,
laryngeal nerves in his famous textbook De humani corporis fabrica [1]. whereas bilateral vocal cord paralysis can become a life-altering
As understanding of the surgical anatomy improved over the years, complication requiring tracheostomy tube dependence, gastrostomy
the treatment outcomes became better. In the late 19th century, to avoid aspiration, and grave impact on overall quality of life.
Kocher pioneered safe thyroid surgery in Europe whereas the
same was practiced in the United States by Halsted based upon his
observation with Kocher. Identification of the RLN during surgery
slowly became the gold standard in preserving the structural IMPORTANCE OF A LARYNGEAL EXAM—
integrity of the nerve over several decades, however, there were PRE-OPERATIVE AND POST-OPERATIVE ASSESSMENT
some initial reservations. It was Lahey in the 1930s who pioneered
routine identification and dissection of the nerve during thyroid
surgery to ensure structural integrity [2]. With focus on improving Ipsilateral vocal cord paralysis is an important predictor of
surgical outcomes by reducing nerve palsy rates, intra-operative invasiveness in thyroid malignancy. Up to 70% of cases of invasive
nerve monitoring (IONM) has been developed over the years as a thyroid cancer may have unilateral vocal cord paralysis [8]. Voice
useful adjunct to visual identification. change is present in only a third of the patients with vocal cord
The need for additional monitoring during surgery rests upon the paralysis, hence making a pre-operative laryngeal exam imperative
insight that a visually preserved nerve may not be functional as for accurate diagnosis of vocal cord paralysis. The knowledge of vocal
physical injuries such as stretch or compression and thermal injuries cord function in the pre-operative setting also helps the surgeon
due to electro-cautery may remain unnoticed during surgery. IONM in surgical planning, patient counseling, and prevents significant
has emerged as a reliable tool in predicting a functioning nerve at the medicolegal problems due to wrongful accusation. IONM is also
end of a lobectomy. Studies have repeatedly shown a high negative more accurate and reliable with the knowledge of pre-operative
predictive value (NPV) >95% in prognosticating nerve functioning vocal cord function. A laryngeal examination is important in the
at the end of surgery [3–5]. post-operative setting as well, as patients with vocal cord paralysis
may not have voice change and voice change may arise with vocal
Thyroid surgery is unique in that one routinely performs bilateral
cord paralysis [8]. Various international guidelines including those
neural dissection, hence putting both the nerves at risk. Thus, a
recommended by the German Association of Endocrine Surgeons [9],
bilateral vocal cord paralysis is a realistic possibility with adverse
the British Association of Endocrine and Thyroid Surgeons (BAETS)
impact on quality of life.
[10], and the International Neural Monitoring Study Group (INMSG)
This chapter aims to provide an overview of the technical recommend routine use of pre-operative and post-operative
considerations both in terms of application and utility of IONM of laryngeal examinations for all thyroidectomies [11]. The National
the RLN and SLN during thyroid and parathyroid surgery. Comprehensive Cancer Network (NCCN) [12] and the American
Thyroid Association (ATA) [13] recommend the same for all thyroid
malignancies. The American Academy of Otolaryngology—Head and
HOW COMMON IS RLN PARALYSIS? Neck Surgery (AAO-HNS) recommends routine voice assessment
both in the pre-operative and post-operative setting [14]. Use of
pre-operative laryngeal examination is recommended in patients
RLN paralysis rates during thyroid and parathyroid surgery have with suspicion of invasive thyroid disease, history of previous neck
possibly been underreported in the past. Earlier studies have quoted surgery, or any evidence of voice change. Post-operative laryngeal
Intra-Operative Neural Monitoring 97
Standards for Intra-Operative Nerve Monitoring
examination is a must in patients with any change in voice after nerve [18]. This information is important as resection of such
thyroid surgery. Intra-operative nerve monitoring plays a valuable a nerve may possibly worsen the aspiration or dysphagia by
role in predicting post-operative vocal cord function. disabling the residual functional nerve fibers. IONM can thus
provide a unique insight into the functional status of the nerve
compared to visual inspection alone.
3. Surgical Management in the Event of Intra-operative RLN
INTRA-OPERATIVE NEURAL MONITORING—UTILITY
Injuries: One of the most important advantages of using the
AND APPLICATIONS IONM system is the ability to accurately predict the post-
operative function of the nerve during surgery. This is of
immense importance to the surgeon, especially during bilateral
A recent systematic review published in the Cochrane database [15] thyroid surgery or total thyroidectomy. Visual identification
failed to show any advantage of using IONM over visual examination alone of the RLN, the hitherto gold standard, is fraught with
in preventing temporary or permanent paralysis of the recurrent inaccuracies and may adversely impact surgical decision-
laryngeal nerve. Although there was a trend toward better outcomes making. Unrecognized RLN palsy is not uncommon, and only
in the IONM section, it was not found to be statistically significant. about 10% of the neural injuries were identified accurately intra-
This could probably be because of paucity of well-designed and operatively [6,7,19]. This is due to the fact that neural injuries
executed trials with a large number of participants and diligent secondary to blunt trauma or thermal injury may have been
follow up to come to an effective conclusion. Given the overall low missed. Thus, visual confirmation alone as an indicator for
rates of permanent RLN paralysis this might be a difficult task. What structural integrity of the nerve is not accurate in predicting a
is, however, interesting to note is that despite the lack of published functional outcome. In contrast, multiple studies have suggested
evidence in favor of use of IONM, there is a general trend toward a high negative predictive value close to 95% for IONM, especially
increased usage/acceptance. A recently published survey [16] of more when used in accordance with established standards [3–5,20–
than 1,000 thyroid surgeons noted that surgeons <45 years of age and 23]. A surgeon thus can proceed for surgery on the contralateral
those with <15 years of experience tend to use it more frequently than side with great confidence that the ipsilateral nerve is not only
others. Also, the use of IONM was found to be more common in North structurally intact but also functionally preserved. In the event
America (70.4%) than elsewhere (27.4%), and the majority (>80%) of of an injury, IONM can also help the surgeon in tracing the site
users routinely performed it in all their thyroid surgeries. Also, smaller of the injury, thus simultaneously acting as a learning tool and
case studies have shown better outcomes in revision cases, retrosternal allowing to take any remedial action. IONM systems, however,
goiters, and surgeries for invasive thyroid cancer [17]. have a lower positive predictive value [11,23,24]. This arises
IONM has been found to be useful mainly in these scenarios: partly from the way a loss of signal (LOS) event is recorded and
subsequent troubleshooting is done to differentiate equipment
1. Neural mapping, especially in complex thyroid surgeries
malfunction from a true neural injury. Studies have suggested
2. Discerning different pathologic states of RLN that a standardized definition of LOS with a universally
3. Surgical management in the event of intra-operative RLN accepted troubleshooting algorithm along with knowledge of
injuries (prognostication) normative range of neural parameters will significantly help
The utility of IONM is best realized when the electric stimulation of in providing more accurate neural prognostication [25]. The
the nerve complements visual identification. IONM can be performed INMSG has done pioneering work in defining a true LOS and
in various ways. Invasive and non-invasive modalities exist. The suggested a detailed algorithm to standardize troubleshooting
most commonly used modalities include use of surface electrodes during surgery. This has been described in greater detail in a
either prefixed to a special endotracheal tube or electrodes that can later section on interpretation of loss of signal during IONM.
be applied over regular ET tubes. Conventional IONM involves
intermittent neural stimulation, whereas newer methods are utilizing
continuous neural stimulation. The monitoring systems may relay
an audio signal alone or in combination with an electromyographic STANDARDS FOR INTRA-OPERATIVE
(EMG) waveform. These waveforms provide useful information such NERVE MONITORING
as the amplitude and latency of the signal which are further helpful in
prognostication of neural function and predicting outcomes.
1. Neural Mapping Using IONM: For surgeries where one can INTRODUCTION
expect an abnormal course of the RLN secondary to history of Considerable heterogeneity exists in the usage of IONM across
previous neck or thyroid surgery, invasive disease, or inherent various centers. This may arise due to multiple reasons ranging
anomalous course of the nerve, such as a non-recurrent laryngeal from usage of different monitoring methods, use of different
nerve, the use of IONM can provide critical information. stimulators, or use of different recording techniques. These technical
Linear, paratracheal stimulation of the nerve using a 2 mA differences make uniform applicability of IONM a challenge. It is
current along the expected course of the nerve can be utilized to therefore important to define certain monitoring standards for
chart the course of the nerve prior to actual visualization. This ensuring optimum wide-scale usability of IONM. Standards also
is especially useful while operating in revision surgeries where help in reducing common setup-related errors by following certain
the thick scar tissue may obviate accurate visual identification, predefined algorithms. The INMSG has developed guidelines with
and electrical stimulation can guide the surgeon to perform the the goal of achieving the aforementioned objectives.
surgery safely. Routine use of IONM is recommended to enable
the surgeon as well as the operating room team to be familiar TECHNIQUE—IONM
with the system and interpret the recorded signal critically. A basic setup of the neural monitoring equipment is shown in
2. Utility of IONM in Different Pathologic States of IONM: In the Figure 13.1a and b.
presence of a vocal cord paralysis in the pre-operative setting, The most preferred neural monitoring equipment is an endotracheal
residual EMG signal may still be recorded from an invaded tube-based system that includes a graphic monitor documentation of
98 Intra-Operative Neural Monitoring

Standards for Intra-Operative Nerve Monitoring
(a)
(b)
Figure 13.1 (a and b) Basic monitoring equipment set-up (Adapted from Jeannon JP et al. Int J Clin Pract. 2009 Apr;63(4):624–9.) (Abbreviations:
ET = endotracheal tube; REC = recording electrodes; GND = ground electrodes).
the EMG waveform. It consists of a recording side and a stimulation Similar to any other task in the OR, IONM is teamwork, with the
side. Both needle-based electrodes or surface electrodes may be major participants being the surgeons, anesthesiologist, and the
used for recording EMG data from the thyroarytenoid or vocalis monitoring technician. IONM requires a clear understanding of
muscle. Prefabricated endotracheal tubes with paired stainless the entire process by all its participants. A key member of the team
steel electrodes exposed at the level of the glottis are available for is the anesthesiologist, who should understand that there are some
this procedure. Alternatively, adhesive pads with thin electrodes special considerations for administering anesthesia during IONM.
which can be placed over a standard tube can be used. Additional It has been shown that use of muscle relaxants during anesthesia
(attachment) electrodes to record posterior cricoarytenoid (PCA) may attenuate EMG response and may make it difficult to perform
muscle twitch are available, however, they add very little to the quantitative analysis during IONM. The central guiding principle
sensitivity of the system [26]. Monopolar or bipolar stimulating for the anesthesiologist during IONM for thyroid and parathyroid
electrodes may be used for stimulation, monopolar electrodes being surgery is the avoidance of prolonged muscle relaxation and
preferable for mapping whereas bipolar electrodes are used for focal preservation of spontaneous muscular activity. Hence, use of muscle
stimulation. relaxants or paralytic agents to maintain anesthesia should be
avoided. A combination of inhalational anesthesia with intravenous
THE SETUP agents such as Propofol provides sufficient depth to avoid any
Adherence to a standard setup algorithm reduces the monitoring inadvertent movement at the level of the cords.
related problems faced intra-operatively. While the IONM equipment
is being setup, it is important to keep the electrocautery unit more Use of short acting muscle relaxants is acceptable at the time of
than 10 feet away from the neural monitoring unit to avoid electrical induction. The endotracheal tube should be inserted without the
interference. This setup is compatible with both Harmonic• and use of any lubricant jelly or any other coating. Excessive salivation
Ligasure• technologies. After the equipment is setup, care is taken may also obscure the EMG signals, therefore it is recommended to
to ensure that the recording side and the stimulation side circuitry is use suction and possibly a drying agent.
complete. The setup also requires implanting ground electrodes over As discussed previously, special endotracheal tubes are available
the shoulder or the sternum area. Poor grounding can lead to a noisy which have the recording electrodes embedded over the surface.
baseline, making it difficult to interpret the EMG data. Alternatively, adhesive pads can be used over standard electrodes.

New Horizons in IONM
It is critical that these electrodes should abut closely to the vocal As soon as a LOS is encountered, assessment of the laryngeal
cords, hence selection of the largest possible size tube for intubation twitch response to ipsilateral and contralateral vagal stimulation
is important to ensure low impedance. Tube selection gains should be performed to evaluate the integrity of the IONM setup.
additional importance during SLN monitoring. Darr et al. [27] Presence of laryngeal twitch establishes that the stimulating side
found that use of a special tube can also improve the monitoring of the equipment is functioning adequately. A common recording
responses. equipment issue faced is a displaced or a malpositioned ET, hence
It is prudent to check proper placement of the tube once it is secured, this should also be checked by the anesthesiologist and readjusted
as this is the first and foremost step in ensuring an optimum if required. Other issues related to adequacy of current and use of
monitoring setup. As the tube can move in or out appreciably after paralytic agents should also be considered. A detailed algorithm
positioning the patient, it is imperative that proper tube placement depicting steps for identification of a true LOS from a false positive
checks are performed once the patient is in the final position. LOS is shown in Figure 13.2. Aggressive adherence to the algorithm
Endotracheal tube movement up to 6 cm has been documented and outlined previously improves positive predictive value in the setting
can lead to poor electrode contact with the vocal cords [28]. of a loss of signal. To be called a true LOS, the event must satisfy
three conditions:
The one commonly followed method by our group that has proved to be
consistently reliable is presence of respiratory variations. Respiratory 1. Presence of a satisfactory EMG (amplitude >100 uV) prior to
variations are small waveforms with amplitudes between 30 and the event
70 uV which cause coarsening of the baseline EMG that is seen during 2. No or low response (i.e., 100 uV or lower) with stimulation at
a small window of time when the effect of the muscle relaxant given 1–2 mA in a dry field
at the time of induction wears off and the patient is in a lighter plane 3. Absence of laryngeal twitch and/or a glottic twitch on ipsilateral
of anesthesia just before the patient starts to move spontaneously or vagal stimulation
“buck.” In absence of respiratory variation, a repeat direct laryngoscopy
preferably by the surgeon to confirm tube placement is essential. A A true LOS should prompt the surgeon to identify the site of the
recently published study by our unit found that identification of injury. This provides an opportunity to treat the nerve injury
respiratory variation was possible in 91% of their patients, whereas the if possible and also acts a learning exercise. This may impact the
remaining 9% required a repeat laryngoscopy [29]. It was also found surgical plan and the surgeon may consider postponing surgery on
that presence of respiratory variations independently predicted a good the contralateral side. IONM guided staging of thyroid surgery is
intra-operative evoked vagus and RLN response obviating a need for a discussed in greater detail in a later section.
repeat laryngoscopy in all patients. At final positioning, the impedance
of the electrodes should be <5 ohms and that the imbalance between PASSIVE EMG ACTIVITY DURING IONM
the two sides should be less than 1 ohm. Higher impedance imbalance Any passive EMG activity occurring frequently may signify mechanical
may suggest inappropriate tube placement requiring repositioning nerve injury or a thermal stress secondary to cautery usage. This should
whereas if the overall impedance is high then the ground electrodes prompt an urgent evaluation by the surgeon. One needs to ascertain
require a check or replacement. that the cautery muting device is attached to both the monopolar and
bipolar cautery cables to avoid interference artifacts.
INTRA-OPERATIVE SETUP
MONITORING SAFETY
Once the setup is complete, it is important to set the monitor event
Multiple studies have established safety of repetitive stimulation
threshold at 100 uV and the stimulator probe to a pulsatile output
of the facial nerve in otological and neuro-otological surgery,
of 4 per second. At the initiation of surgery, the absence of paralytic
and various workers have reported that application of IONM for
agents can be checked by stimulation of the strap muscles. This
RLN during thyroid and parathyroid surgery as safe [11]. Based
results in a gross muscle twitch which also confirms a functional
on literature review as well as their cumulative experience, the
stimulation side.
International Neural Monitoring Study Group has specified that
Pre-dissection suprathreshold vagal nerve stimulation is key in repetitive stimulation of the RLN or vagus is not associated with
establishing the functionality of the system. It is only after this is neural injury. IONM has been safely employed in children and
verified that one can truly accept any tissue as not being the RLN. adults assuming proper patient isolation and grounding [11].
A suprathreshold current of 2 mA is useful for neural mapping; once
the nerve has been identified, the current can be reduced to 1 mA
for further testing and end of surgery prognostication. Caragacianu
et al. [30] found no statistically significant difference exists between
NEW HORIZONS IN IONM
the amplitude when stimulated by suprathreshold levels at 1 or 2 mA.
Normative values were thus defined at 1 mA. Amplitude of >250 uV
was found to be highly predictive of a functioning RLN. Other
NEURAL MONITORING AND STAGED THYROIDECTOMY
factors such as latency and shape of the waveform were not found
IN THYROID CANCER SURGERY—AN EMERGING
to have a significant predictive value [30]. Repetitive stimulation of
CONCEPT
the RLN at levels of 1 and 2 mA has been reported to be extremely
Presence of bilateral nodal metastases are frequently seen in
safe and no detrimental effects have been reported [30]. It should
thyroid cancers. Surgeries in these patients typically involve a total
be noted that any negative response is not termed as true negative
thyroidectomy, central neck dissection, along with bilateral lateral
unless a true positive has been established.
neck dissection. Apart from being extensive, these surgeries carry a
high risk of complications. In the lateral neck these include cranial
LOSS OF SIGNAL (LOS) DURING IONM: PROBLEM- nerve injuries, chyle leak, post-operative bleeding, and possible
SOLVING AND TRUE LOS internal jugular vein sacrifice, whereas in the central compartment/
Loss of signal during IONM could be encountered due to various neck these include bilateral RLN palsy and hypoparathyroidism. It is
reasons during a surgery. The surgeon should first rule out thus challenging to ensure both safety and efficacy while performing
equipment/setup-related LOS before labeling it as a true LOS. surgery in patients with bulky nodal disease.

Figure 13.2 Intra-operative LOS evaluation standard.
Staging of surgery may offset some of these complications, especially of bilateral VCP drops to zero from 17% in bilateral surgery where
those which are temporary in nature. An RLN with neuropraxia LOS is incorporated in the surgical strategy.
may recover between the two stages of surgery reducing the risk of
bilateral vocal cord palsy (VCP). Similarly, parathyroid glands may It is the policy in our practice to offer staging of surgery upfront to
recover functionally in the intervening period. Merchavy et al. [31] patients with extensive bilateral nodal disease. Apart from reducing
have reported significantly lower incidence of transient hypocalcemia the incidence of complications as described previously, we have
in patients undergoing completion thyroidectomy when compared to found that it also prevents/reduces surgical fatigue thus ensuring
patients undergoing total thyroidectomy. Benefits of staging bilateral better outcomes. Similar practices have also been reported by other
radical neck dissection have been documented earlier. It was Frazzell, tertiary care referral centers. Dralle et al. [34] found that 94% of
in 1961 [32], who proposed a planned staging of surgeries where surgeons in Germany would stage a total thyroidectomy if they
ligation of bilateral internal jugular veins was anticipated. Staging of encountered an LOS during the surgery. This is especially true for
thyroidectomy was suggested first by Luigi Porta in 1811. centers with a higher case load. However, a detailed pre-operative
consent process is imperative when staging of surgery is being
Routine use of IONM makes it possible for surgeons to make an contemplated as a possibility [35].
informed decision with regards to staging of surgery. Evidence
suggesting utility of LOS as a decision-making tool during surgery is Management of recurrent laryngeal nerve depends upon the pre-
slowly accumulating. Goretski et al. [33] have reported that incidence operative vocal cord function (Figure 13.3).
Figure 13.3 Management algorithm for the recurrent laryngeal nerve with preoperative vocal cord paralysis [50].

SUPERIOR LARYNGEAL NERVE MONITORING Table 13.1 Mild and severe combined amplitude
Recently published guidelines on SLN monitoring by the
Mild Combined Event (mCE): Amplitude decrease of >50%–70%
International Neural Monitoring Study Group [36] have highlighted with a concordant latency increase of 5%–10%
the fact that neural monitoring of the SLN is associated with higher
Severe Combined Event (sCE): Amplitude decrease of >70% with a
rates of nerve identification than through visual identification. The concordant latency increase of >10%
laryngeal head of the sternothyroid serves as a useful landmark for
identification of the external branch of the superior laryngeal nerve
(EBSLN). A twitch in the cricothyroid muscle seen upon stimulation
is currently the most accurate measure of nerve localization. A
specially designed electrode array incorporated on an endotracheal
tube can also record EMG activity from glottis in 100% of the
patients [27]. For a detailed discussion on the technique and utility
of SLN monitoring, the reader is requested to refer to the guidelines
published by the INMSG [36].
CONTINUOUS VAGAL MONITORING AND NEURAL

INJURY PREVENTION
One of the biggest drawbacks of the existing IONM formats is that
it only allows the surgeon to intermittently stimulate and evaluate
the functional integrity of the RLN. Although immensely useful in
resolving a surgeon’s dilemma, the nerve remains at risk for injuries
in between stimulations [22,37]. This could possibly explain the
suggestion that in its present format, IONM may have limited ability
to prevent neural injury [9,22,38–43]. An ideal IONM format would
be the one that provides real time EMG data which can alert the
surgeon before irreversible neural damage sets in. Early studies Figure 13.4 APS electrode on vagus nerve.
have shown that continuous IONM or CIONM can provide that
information. It is important, however, that the accepted format
differentiates true events from electrical artifacts. Combining
reduction in amplitude with increase in latency, our group has
defined mild and severe combined events (Table 13.1), which when
identified, can prevent irreversible neural damage. Modification
of a surgical maneuver when such an event occurs can prevent
development of a complete LOS and subsequent VCP. It is evident
that given the nature of IONM overall, these systems are more useful
for preventing impeding neural damage secondary to a stretch or
compression [44] than an inadvertent transection of the nerve by
the surgeon.
INTRA-OPERATIVE IDENTIFICATION OF NON-RECURRENT

LARYNGEAL NERVE
The non-recurrent laryngeal nerve (NRLN) is an anatomical
variant of the RLN with no functional impact, the only
consequence being increased susceptibility to intra-operative
injury by a surgeon unaware of its presence. The presence of right
NRLN is reported as 0.5%–1% of all RLNs and left NRLN being
reported as only 0.04% [45,46]. Our series on NRLN monitoring
recommends an electrophysiologic algorithm where presence
of positive EMG response to proximal stimulation of the vagus
nerve at the superior border of thyroid cartilage and absence of
EMG response to distal stimulation of the vagus nerve below the
inferior border of fourth tracheal ring reliably identifies an NRLN
[47] (Figure 13.4). Currently, no dependable technique of pre-
operative acknowledgement or exclusion of NRLN is available.
The aforementioned electrophysiologic algorithm reliably alerts a
surgeon regarding the presence of NRLN prior to the dissection
in the related cervical region. This vagal stimulation technique
for NRLN identification is supported by Brauckhoff et al. [48].
Anatomically, three types of NRLN are described in the literature
(Figure 13.5). Essentially, the right NRLN behaves similarly to the
right RLN, in terms of amplitude, threshold, and latency. Some
workers have suggested that a latency of less than 3.5 ms strongly
suggests a NRLN [49]. However, further studies are warranted
before it is considered a definitive indication of NRLN. Figure 13.5 Non-recurrent laryngeal nerve with its variants.

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Chapter 14
SURGICAL MANAGEMENT OF DIFFERENTIATED

THYROID CANCERS
Anil D’cruz and Richa Vaish
CONTENTS
Introduction 105
Active Surveillance as an Alternative to Surgery 105
Completion Thyroidectomy 106
Debate of Hemi- versus Total Thyroidectomy 107
Surgical Tips and Tricks 108
References 109
mortality. In another study by Oda et al., of 2,153 low-risk PTMC,

1,179 patients chose observation and 974 immediate surgery [8]. The
INTRODUCTION
authors concluded that the oncological outcomes in the groups were
similar but unfavorable events (vocal cord palsy, hypoparathyroidism,
hematoma, and surgical scar) were more prevalent in the immediate
There is a reported thyroid cancer epidemic worldwide attributed
surgery group. There was no PTMC-related death in either group.
to liberal and widespread use of imaging [1]. The age standardized
Haser et al. reviewed the existing literature and suggested active
incidence of thyroid cancer in females has risen from 1.5/100 000 to
surveillance as a safe and viable option with the potential to be a
7.5/100 000 between 1953 and 2002 [2]. This change in trend is seen
long-term management strategy for low-risk PTMC [9]. However,
in many countries across the globe including the USA, France, and
there is a need to select the patients carefully and strictly adhere to
Italy, but is most marked in Korea as a result of an active screening
the follow-up protocol. Brito et al. proposed a clinical framework to
program in that country [3,4]. The majority of these cancers are small
facilitate risk stratification in these patients classifying PTMC patients
when detected—less than 2 cm in diameter—and treatment has
as ideal, appropriate, or inappropriate for active surveillance based on
not translated into an overall reduction in mortality from thyroid
three domains, namely tumor/neck ultrasound features (e.g., size of
cancer [5]. The most plausible explanation for this phenomenon
the primary tumor and location within the thyroid gland); patient
is overdiagnosis of these indolent cancers, many of which would
features (e.g., age, comorbidities, willingness to accept observation);
otherwise not have manifested clinically during the life span of the
and medical team features (e.g., availability and experience of the
individual. This is corroborated by the fact that thyroid cancer is
multidisciplinary team) [10]. The patients should be counseled in
identified incidentally at autopsy in 8%–65% of individuals who died
detail about the pros and cons of the procedure and the awareness,
of other causes [6].
impact on the psychology, and quality of life should be factored into
the decision algorithm.
ACTIVE SURVEILLANCE AS AN ALTERNATIVE SURGERY FOR DTC

TO SURGERY Thyroid cancers are a disease with surgery being the mainstay
of treatment. The need, as well as the extent of surgery, must be
balanced taking into account the indolent nature of the majority
Active surveillance has been advocated for small cancers <1 cm, of these cancers against the potential morbidity of treatment.
referred to as micropapillary thyroid cancers. The biological The thyroid is in close proximity to the recurrent laryngeal nerve
rationale for this approach is that these cancers are detected due to (RLN) and the parathyroids, placing them at risk during surgery.
the widespread use of imaging, and many of them would probably The reported incidence for temporary and permanent RLN palsy
have remained dormant through the life span of the individual. is 2.1%–8.3% and 0.3%–1.7%, while temporary and permanent
There is a school of thought that suggests observation of these select hypocalcemia ranges between 3.3%–34% and 1.1%–10%, respectively
cases of papillary microcarcinoma and active intervention only [11]. The morbidity varies with the extent of surgery performed for
in the event of disease progression. This strategy is proposed for the primary, experience of the surgeon, and volume of work at the
papillary microcarcinoma that are deemed low risk with localized treating center. The morbidity of surgery, therefore, is unacceptable
disease, non-aggressive histology, and no evidence of metastasis or given that 99% of patients are alive at 20 years in the vast majority
local invasion. The data supporting this philosophy is predominantly of cases [12]. The extent of the surgery needs to be carefully weighed
from Japan. In a study, Ito et al. observed 1,235 patients with low-risk against this potential morbidity.
papillary thyroid microcarcinoma (PTMC) followed up periodically The main goal at surgery is complete clearance of the disease to reduce
with neck ultrasonography [7]. The patients were monitored for the risk of recurrence. The minimum surgery for thyroid cancer is
tumor enlargement, development of neck node metastasis, and an ipsilateral complete extracapsular lobectomy. Nodulectomy or
progression to clinical disease. At 10 years, the incidence rates of these partial thyroidectomy is to be deprecated. The logical reason is that
parameters were 8.0%, 3.8%, and 6.8% respectively. In all 191 patients should completion thyroidectomy be warranted for any reason,
who underwent surgery for various reasons, there was no reported reoperation in a violated thyroid bed carries an increased risk of
Surgical Management of Differentiated Thyroid Cancers 105

Completion Thyroidectomy
nerve and parathyroid damage. The isthmus is usually a part of a entails hemithyroidectomy on one side plus subtotal resection on
lobectomy procedure making the hemithyroidectomy the procedure the other side and subtotal thyroidectomy bilaterally, was popular
of choice when indicated (see the following section). For a similar at one time but is now obsolete and not recommended for reasons
reason, subtotal thyroidectomy, leaving behind significant residual cited previously [16]. In a quarter to half of patients presenting
thyroid tissue in both tracheoesophageal grooves, is condemned as with a solitary nodule, fine needle aspiration cytology (FNAC) is
it is associated with higher chance of recurrence as well as increased inconclusive and reported indeterminate (Bethesda III, IV & V)
risk of complications at repeat surgery. Total thyroidectomy is with a rate of malignancy on final histology ranging from 5%–6.5%
therefore to be performed when indicated with an attempt to [17–19]. While molecular markers have been extensively researched
remove all apparent thyroid disease. However, given the fact that to help resolve this conundrum by either ruling in or ruling out
these cancers have an excellent prognosis, surgical enthusiasm must cancer, these tests are not yet the standard of care due to prohibitive
be tempered against potential morbidity and a bit of thyroid tissue costs, as well as the lack of a single comprehensive test with sufficient
(typically described as less than 1 gm) if left back in the region of positive and negative predictive values to be cost effective [20].
Berry’s ligament to safeguard the point of entry of the recurrent Surgery is often considered in these patients on the perceived risk
laryngeal nerve or the blood supply to the parathyroids is prudent. of malignancy based on high risk clinical factors (age, gender,
Such a procedure is called near total thyroidectomy. It must, however, family history, prior radiotherapy), size of the nodule, and high-risk
be kept in mind that lack of surgical expertise must not be used as sonographic features (macrocalcification, hypoechogenicity, etc.).
a cover when performing a near total thyroidectomy. Meticulous Lobectomy is the optimal initial and definitive therapeutic surgical
clearance of all thyroid tissue and disease is important as it decreases procedure for the majority of these cancer patients and termed a
loco regional recurrence as well as facilitates the radioiodine diagnostic lobectomy [21,22]. Such patients should be counseled
treatment for microscopic residual disease and metastasis. that the final histology may reveal malignancy and if they fall into
high risk, completion thyroidectomy may be warranted as a second
EXTENT OF SURGERY procedure.
The surgery of primary thyroid gland disease is either total or
hemithyroidectomy, as mentioned previously. Hemithyroidectomy
is advocated for low risk cancers occurring in young patients, usually
females, with the classical variant of well differentiated thyroid COMPLETION THYROIDECTOMY
cancers, with tumors less than 4 cm in diameter, predominantly
unifocal and intraparenchymal, and without evidence of regional or
distant metastasis (Table 14.1) [35]. Proponents of hemithyroidectomy Resurgery in form of completion thyroidectomy is warranted in
cite similar survival to total thyroidectomy in this group of patients cases that required total thyroidectomy upfront but were offered
across many large series with tens of thousands of patients [13]. a lesser procedure. Such surgery should be contemplated either
There is logically a low incidence of associated morbidity as only immediately after initial surgery (within the first few days) or after
one-side nerve and parathyroid glands are at risk. Any recurrence 2–3 months, once the inflammation/fibrosis and adhesions settle to
can be treated as and when it occurs in the relatively untouched field make surgery simpler and decrease potential morbidity [23]. Intra-
on the opposite side with no determinant to outcomes [14]. However, operative nerve monitoring (IONM) should be considered in thyroid
serum thyroglobulin cannot be used as an accurate marker for resurgeries to protect the RLN. In a study of 854 cases of resurgery
detecting recurrence with an intact thyroid lobe in situ. Conversely, in benign and malignant conditions, the transient nerve palsy was
total thyroidectomy, which entails removal of both the lobes of the significantly less with IONM compared to nerve visualization alone.
thyroid along with the isthmus, is advocated in cases with large There was also a trend of lesser permanent palsy with the use of
tumors, aggressive histology, multifocal disease, and in the presence IONM which, however, was not statistically significant [24]. Various
of regional or distant metastasis (Table 14.1). While theoretically meta-analysis and systemic reviews have been performed to assess
it is associated with higher morbidity as both sides’ nerves and the effect of IONM; however, results are conflicting [25]. A review
parathyroids are at risk, the procedure is safe in the hands of an addressing the methodological quality assessment of these meta-
experienced surgeon. Total thyroidectomy is recommended in all analyses concludes that the quality is critically low [26]. A well-
cases where adjuvant radioiodine therapy is considered. In addition, powered large randomized controlled trial is needed to produce
since there is no residual thyroid tissue after this procedure, serum more robust evidence. However, given the potential benefit it is
thyroglobulin becomes a reliable marker for follow-up and to detect prudent and medico-legally safer to use IONM in this setting.
disease recurrence [15]. The Hartley Dunhill procedure, which Surgery for PTC Aggressive Variants: Tall cell variant, columnar
variant, solid/trabecular variant, hobnail variant, and diffuse
sclerosing are aggressive histological variants of PTC. These tumors
Table 14.1 Low risk versus high risk thyroid cancers are associated with biologically more aggressive cancers manifested by
High risk (total higher stage, larger T-size, vascular invasion, distant metastasis, and
Factors Low risk (lobectomy) thyroidectomy) extrathyroidal extension [27]. These cancers should be treated with
total thyroidectomy upfront followed by radioiodine ablation [28].
Age [34] <55 years >55 years
Radiation Exposure/Fallout: These cancers occur as a result of
Size <1 cm >4 cm
radiation exposure during childhood or adolescence. The risk of
Extent of disease Intrathyroid Gross extrathyroid developing cancer varies with the dose of radiation and the age at the
Histology Differentiated papillary Aggressive variants time of exposure. Younger age and mean dose more than 0.05–0.1 Gy
Minimally invasive of papillary are associated with an increased risk [29]. The usual latent period
follicular carcinoma Widely invasive
from exposure to manifestation of thyroid cancers is 5–10 years. PTC
follicular carcinoma
is the most commonly associated thyroid cancer. Radiation induced
Focality Unifocal Multifocal
cancers are typically multifocal with extrathyroidal extension. Many
Nodal metastasis Absent Present of these cancers also present with advanced disease and distant
(regional/distant)
metastasis [30]. Hence, total thyroidectomy is recommended as the
Source: Adapted from Thyroid Cancer: ASCO tumor board. initial surgical procedure in this situation.
106 Surgical Management of Differentiated Thyroid Cancers

Debate of Hemi- versus Total Thyroidectomy
Familial Well-Differentiated Thyroid Cancers: Approximately study results also showed that use of radioiodine remnant ablation
5% of well-differentiated thyroid cancers are familial. These are did not improve the excellent outcomes (achieved before 1970)
commonly associated with syndromes like Familial Adenomatous further in this group of patients. Mazzaferri et al. in a study of 1,355
Polyposis, Gardner’s syndrome, Carney’s complex, Werner’s patients looked at the long-term impact of the surgical and medical
syndrome, Cowden’s disease, etc. These cancers are more aggressive therapy in papillary and follicular thyroid cancers [39]. The authors
than sporadic cancers and are more often associated with concluded that for tumors >1.5 cm with no distant metastasis,
extrathyroidal extension, multifocality, regional metastasis, and a near total thyroidectomy followed by radioactive iodine ablation
higher incidence of recurrence [31–33]. Such cases should be offered reduces tumor recurrence and mortality. Recently published meta-
total thyroidectomy for the reasons cited. The cribriform morular analysis addressed this issue for tumors ≤1 cm, which included six
histological variant should alert the clinician to the possibility of studies (1980–2014) with 2,939 patients, of which 72.6% underwent
familial adenomatous polyposis, and the patient should be screened total thyroidectomy and 27.5% lobectomy [40]. The recurrence
for colonic polyps. rates were significantly higher in lobectomy compared to total the
thyroidectomy group. However, the mortality rates in the two groups
were similar. Another meta-analysis of 13 studies with 7,048 patients
DEBATE OF HEMI- VERSUS TOTAL THYROIDECTOMY concluded that the gender male, extra thyroid extension, lymph node
metastasis, tumor size more than 2 cm, distance metastasis, and
subtotal thyroidectomy were the risk factors influencing recurrence
Despite most guidelines suggesting that a hemithyroidectomy is [41]. In another recently published study from Korea, the authors
an adequate surgical procedure for nodules less than 4 cms in the analyzed 16,057 patients with 5,266 having a tumor size between
absence of other adverse features, there has been considerable debate 1 and 4 cm [42]. The mean tumor size was 1.84 ± 0.74 cm. Of all,
for more than two decades on the adequacy of this procedure for 4,292 (81.5%) total thyroidectomy and 974 (18.5%) lobectomies
nodules between 1–4 cm in size. were performed. Recurrence rates following total thyroidectomy
were 5.7% compared to 9.4% following lobectomy (Table 14.2). The
The widely followed ATA guidelines (2015) are not very definitive
lobectomy has lower disease-free survival (DFS) and higher disease-
on this issue and state:
specific survival (DSS) compared to total thyroidectomy. The extent
of surgery was an independent risk factor for DFS but not for DSS.
“For patients with thyroid cancer >1 cm and <4 cm without
extrathyroidal extension, and without clinical evidence In contrast, there are studies to support the role of lobectomy in
of any lymph node metastases (cN0), the initial surgical cancers up to 4 cms in diameter. Adam et al. performed updated
procedure can be either a bilateral procedure (near total or analysis of NCDB thyroidectomies with tumor size of 1–4 cm.
total thyroidectomy) or a unilateral procedure (lobectomy). The study included 61,775 patients of which 54,926 underwent
Thyroid lobectomy alone may be sufficient initial treatment total thyroidectomy and 6,849 lobectomies. After making
for low-risk papillary and follicular carcinomas; however, the adjustments for patient demographic and clinical factors, including
treatment team may choose total thyroidectomy to enable comorbidities, extrathyroidal extension, multifocality, nodal and
RAI therapy or to enhance follow up based upon disease distant metastases, and radioiodine treatment, the overall survival
features and/or patient preferences” [36]. (OS) was similar in the two groups for tumor size of 1–4 cm and
also after stratifying according to the tumor sizes 1–2 and 2.1–4 cm
This ambiguity stems from conflicting results across large published (Table 14.3).
series in the literature. The evidence in favor of total thyroidectomy Haigh et al. identified 5,432 thyroidectomies in Surveillance,
in nodules >1 cm comes from various studies. From the National Epidemiology, and End Results (SEER) database. According to
Cancer Database (NCDB), Bilimoria et al. reported 52,173 patients AMES classification (age, metastasis, extrathyroidal spread, size),
who underwent thyroid surgery between 1985–1998, of which 43,227 4,402 (81%) were categorized as low-risk and 1,030 (19%) as high-
(82.9%) had total thyroidectomy and 8,946 (17.1%) had lobectomy risk, 92.5% of tumors were smaller than 5 cm, and 85.4% were
[37]. Of these, 23.9% were tumors <1 cm, 29.8% were 1–2 cm, and intrathyroidal. Total thyroidectomy was performed in 83.2% of the
46.3% were tumors >2 cm. The study results showed that the extent low-risk cancers and 92.1% of the high-risk tumors. The 10-year
of surgery impacted the recurrence and survival significantly in survival rate in the low-risk group was 89% after total thyroidectomy
patients with tumors >1 cm after making adjustments for tumor, compared to 91% after partial thyroidectomy (P = 0.07). Whereas
treatment, and hospital characteristics. Similar results were obtained in high-risk patients, the 10-year survival rate was 72% after total
for tumors sized between 1–2 cm after omitting the potential thyroidectomy compared to 78% after partial thyroidectomy
confounding effect of larger tumors. The limitation of the study,
however, was that the details of disease characteristics and patient
factors that could have influenced the results were not defined by Table 14.2 Studies comparing hemi- versus total thyroidectomy:
the authors. Hay et al. published six decades of temporal trends Recurrence rates
in initial therapy and long-term outcomes in the management of Study End point HT TT Results
thyroid cancers including 2,444 patients [38]. For the patients with
MACIS (distant Metastasis, patient Age, Completeness of resection, Hay et al. 20-year local 14% 2% Significant
(1940–1991) recurrence
local Invasion, and tumor Size) score <6 (low risk), between 1940
and 1949, lobectomy as the initial procedure that was performed in 20-year regional 19% 6% Significant
nodal metastasis
70%, and during 1950–1959 in 22% of cases. Total thyroidectomy
accounted for 91% of the initial procedure between 1960 and 1999. Bilimoria et al. 10-year recurrence 9.8% 7.7% Significant
(1985–1998) rate
Radioactive ablation was performed in 3% of cases after total
thyroidectomy between 1950 and 1969, which increased to 18%, Nixon et al. 10-year local 0% 0% NS
(1986–2005) recurrence
57%, and 46% in successive decades. The 40-year rates for cause
specific mortality and tumor recurrence was significantly higher 10-year regional 0% 0.8% NS
recurrence
between 1940 and 1949 compared to between 1950 and 1999. The

Surgical Tips and Tricks
Table 14.3 Studies comparing hemi- versus total thyroidectomy: Survival outcomes
Sample size total/

Study Patient population lobectomy Endpoints Result Recommendations
Hay et al. Low-risk (AMES) 1,663 Cause specific Not significant (NS) Seven-fold difference
(1940–1991) papillary thyroid Total thyroidectomy mortality (CSM), for CSM and distant in local recurrence,
cancer (PTC), Mayo (TT): 1,468 (88.2%) recurrence rate metastasis, optimal surgery is
clinic Hashimoto’s significant for nodal total thyroidectomy
thyroiditis (HT): 195 and local recurrence
(11.73%)
Mendelsohn et al. PTCs 22,724 Disease specific NS Benefit of total
(1998–2001) T1–4N0-1, SEER TT: 16,760 (73.7%) survival, overall thyroidectomy is not
database HT: 5,964 (26.2%) survival (OS) uniform across all
populations
Bilimoria et al. PTC 52,173 Ten-year recurrence Improved for total Total thyroidectomy
(1985–1998) T1–4N0-1 TT: 43,227 (82.85%) and survival thyroidectomy, for PTC ≥ 1 cm
NCBS HT: 8,946 (17.15%) significantly
Nixon et al. WDTC 889 Ten-year OS, NS Lobectomy is safe
(1986-2005) T1/2N0 TT: 528 (59.39%) disease specific option for
MSKCC HT: 361 (40.61%) survival, recurrence intrathyroidal
free survival malignancy
Adam et al. PTC, 61,775 OS (adjusted) NS Tumor size alone
(1998–2006) T1/2N0-1 TT: 54,926 (88.91%) questionable
NCDB HT: 6,849 (11.09%) indication for total
thyroidectomy
(P = 0.66). The authors concluded that the extent of thyroidectomy patient and family must be taken into confidence and the pros and
had no significant impact on survival in these patients. In another cons of the procedures discussed.
SEER database study, Barney et al. included 23,605 patients between
1983 and 2002. Results showed that 10-year OS and cause-specific
survival (CSS) were similar in total thyroidectomy when compared SURGICAL TIPS AND TRICKS
to hemithyroidectomy both on univariate and multivariate analysis.
Mendelson et al. studied 22,724 patients from the SEER database, of
which 5,964 underwent lobectomy. There was no survival difference Samuel Gross once stated of thyroid surgery: “Can the thyroid in the
between patients who underwent total thyroidectomy versus state of enlargement be removed? Emphatically, experience answers
lobectomy. In a study from MSKCC, 899 patients with pT1T2N0 ‘NO’. Should the surgeon be so foolhardy to undertake it, every stroke
were analyzed, and 59% of patients underwent total thyroidectomy of the knife will be followed by a torrent of blood and lucky it would
and 41% lobectomy. The results of the study showed that extent of be if his victim lived long enough for him to finish his horrid butchery.
surgery did not impact OS, local recurrence, or regional recurrence. No honest and sensible surgeon would ever engage in it.” It was Kocher
Song et al. performed propensity score matched paired analysis on who standardized the procedure of thyroidectomy and was awarded
recurrence in a cohort of 2,345 patients to compare the outcomes the Nobel Prize in 1909 for his work on thyroid surgeries. Thyroid
of lobectomy versus total thyroidectomy. Of all patients, 83.7% surgery has come a long way since then, and today thyroidectomy is a
underwent total thyroidectomy and 16.3% lobectomy. There was safe procedure. A detailed description of thyroidectomy is out of scope
no significant difference in DFS between the two groups. Extent of this chapter. While there is no substitute to a thorough knowledge of
of surgery was not an independent factor affecting persistent or thyroid anatomy and meticulous surgery, a few tips and tricks that the
recurrent disease. authors find useful in reducing the morbidity of thyroidectomy from
Interpretation of these Results: These studies are large but mainly literature and personal experience are mentioned in the following
retrospective and therefore have limitations and a selection bias. It section. There is a recent interest in minimally invasive and remote
is pertinent to note that even in studies advocating lobectomy for access surgery which are covered elsewhere in this book.
nodule size up to 4 cm, the majority of patients underwent a total 1. Incision: For open access surgery, the incision must be adequate
thyroidectomy in upwards of 60% of patients. Details regarding in length balancing proper exposure against cosmesis. Small
patient characteristics, tumor characteristics, and completeness of incisions result in inadequate exposure and excessive traction
surgery are missing in many studies. These studies are heterogenous leading to necrosis of the skin edges and poor cosmesis on
in terms of aims and end points. The end points in these studies healing. An incision is best placed in a natural skin crease
are very varied and include overall survival, cause specific survival, extending from anterior border of one sternocleidomastoid to
disease free survival, locoregional recurrence, need for radioiodine the other two fingers’ breadth above the suprasternal notch.
ablation, and morbidity. A randomized trial would be ideal to Placing it too low will drag the incision into the chest and result
provide convincing results but is implausible due to the very large in a hypertrophic scar. For similar reasons the incision should
sample size required, given an excellent outcome, few events, and the be placed slightly higher in patients with large pendulous
need for prolonged follow-up. breasts. It is prudent to mark the incision in the sitting position
In clinical practice and in the real-world scenario there is no prior to induction for easier identification of the best suited skin
debate that lesions <1 cm that are intrathyroidal are treated with crease rather than when the neck is in extension.
a hemithyroidectomy while a total thyroidectomy is recommended 2. The incision should be symmetrically equal on both sides of the
for lesions greater than 4 cms. While survival is similar in lesions midline even if the procedure is performed on one side as it is
between 1 and 4 cm and recommended in the ATA guidelines, the esthetically more acceptable.

References
3. The external branch of the superior laryngeal nerve (EBSLN)

is classically described to be located in Joll’s triangle (midline,
superior pole of the thyroid and the superior pedicle laterally
and the insertion of the straps superiorly). However, it is
easier to consider the relationship of the nerve to the superior
pedicle of the thyroid. In the majority of patients, the nerve
is a centimeter away from the junction of the superior pole
with the thyroid and ligating the superior pedicle close to the
gland will safeguard the nerve. Similarly, induvial ligation of
the branches on the superior pole helps identify and preserve
a low-lying nerve. Overzealous attempts at demonstrating the
nerve should be avoided as it can result in troublesome bleeding
from small vessels, which places the nerve at risk.
4. Parathyroids: The parathyroids are variable in location but in
the vast majority of patients the superior parathyroid is located
close to the nodule of Zuckerkandl in the middle third of the
lobe of the thyroid gland in relation to its posterior border. The
inferior parathyroid which can be more variable in position is
typically located within a centimeter from the inferior pole. The
superior parathyroid is always dorsal to the recurrent laryngeal
nerve and the inferior ventral to it. This plane of the recurrent
laryngeal nerve to the parathyroids is often referred to as the
plane of Payne and Pyrtec. If the parathyroids are not found in
their usual location they should be searched dorsal or ventral
to the nerve depending on which gland is being searched. The
glands are symmetrically placed on both sides in 70%–80% of Figure 14.1 Capsular dissection of thyroid lobe with ligation of tertiary
cases and this helps making contralateral identification easier. branches of inferior thyroid artery: Ligaclip ® to mark the parathyroid.
Despite locating the gland, hypoparathyroidism results due to
disruption to its blood supply. This is safeguarded by performing
Embryonal rests are in relationship to the inferior pole usually
capsular dissection which is literally hugging the thyroid gland
in continuity but can occasionally be isolated and at a distance
and ligating the tertiary branches of the inferior thyroid artery
away. The surgeon should ensure meticulous clearance of
beyond the parathyroid and close to the thyroid capsule. This
disease in these areas.
also minimizes the risk to the recurrent laryngeal nerve.
10. Recurrent laryngeal nerve: The RLN is classically located where
5. Parathyroids are identified, dissected off the thyroid gland, and
it forms one of the boundaries of Beahr’s triangle, the other
reflected laterally to preserve the blood supply to these glands
two being the carotid and the inferior thyroid artery. The
which traverses lateral to medially. A Ligaclip® is used to tag
recurrent laryngeal nerve may have branches, and awareness
the parathyroids, which helps to achieve hemostasis, avoid the
and identification are imperative to prevent damage. Branching
use of diathermy close to the parathyroid, as well as serve as
may be present in up to 60% of patients and are usually motor
an identification marker should a central compartmental nodal
when cephalad the inferior thyroid artery. In cases of resurgery
clearance be necessary (Figure 14.1).
where it is difficult to identify the nerve amidst the fibrosis, it is
6. Parathyroids are differentiated from fat tissue lymph nodes by prudent to identify the nerve below the scar of the last surgery
their tan color, soft consistency, and a characteristic elliptical in a relatively virgin area. Such cases can be located in Lore’s
or kidney shape with the presence of a vascular hilum. triangle which is lower down in the neck, formed by the trachea
7. If the parathyroid is devascularized inadvertently during the or the esophagus in the midline, carotid artery laterally, and the
surgery, it should be autotransplanted, which is usually into the surface of the lower pole of the thyroid superiorly.
ipsilateral sternocleidomastoid muscle. A dusky parathyroid 11. Aids at thyroidectomy: Various aids such as magnification,
with an intact blood supply is due to venous engorgement hemostasis instruments (Harmonic scalpel), IONM, and
or a subcapsular hematoma. A fine 24/25 G needle is used to Fluoptics for parathyroid localization have been described
puncture the capsule that often results in a return of normal and propagated by various authors with some cited benefits.
color prior to autotransplantation. However, there is no conclusive proof to advocate their routine
8. Meticulous clearance along the isthmus and pyramidal lobe if use. In cases of resurgery, one may consider using intra-operative
present is dissected in its entirety along with the gland. It can nerve monitoring. There is no substitute to meticulous surgical
harbor disease, especially in multicentric PTC as borne out by technique and thorough understanding of the anatomy.
our study where PL contained disease deposits in 10.53% of the
cases [43].
9. Ensuring completeness of thyroidectomy: Areas prone to
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Chapter 15
MANAGEMENT OF NODAL METASTASIS IN THYROID CANCER
Neeti Kapre Gupta, Ashok Shaha, Madan Laxman Kapre, Nirmala Thakkar,
and Harsh Karan Gupta
CONTENTS
Quantification of the Problem 113

Diagnosis 113
Conclusions 116
References 116
iodinated contrast in thyroid cancer imaging. This is largely

due to better understanding of the wash out time of the contrast
QUANTIFICATION OF THE PROBLEM
media. Therefore, there is no harm in using contrast-enhanced CT
scans to provide more anatomical information on nodal metastasis.
Generally, the presence of bulky nodal disease is also associated
Depending upon tumor factors, patient factors, and the imaging
with locally extensive disease and occasionally the presence
modality employed, reported prevalence of neck nodes in differentiated
of distant metastasis. Therefore, contrast CT scans provide a
thyroid cancers is approximately 50%–80% [1–4]. At the first instance,
good one-time imaging opportunity to screen neck nodes, lung
DTC lymphatic spreads to the level VI or central compartment. Later,
nodules, and mediastinal nodes, along with precise information
they may metastasize to superior mediastinal (level VII) lymph nodes
on local extension of the disease. It also gives us an assessment of
and lateral compartment (level I–V). However, levels II–IV are most
the disease extension into the strap muscles or the laryngotracheal
commonly involved. The skip metastasis to level II lymph nodes in
framework. MRI should be reserved for cases where extensive
the absence of level VI nodes, which is in fact the first echelon for
vascular or esophageal involvement is suspected.
differentiated thyroid cancers, is uncommon. Generally, superior pole
nodules follow such a pattern [5]. There is currently no recommendation for PET scan as an upfront
imaging modality to assess nodal disease in thyroid cancers
Nodal disease does increase the risk of recurrence, especially when
(Recommendation 33, ATA Guidelines, 2015) [14].
lymph node metastases are macroscopic, although it does not impact
significantly on survival. It is less clear how the microscopic lymph Thus, the CT scan offers the following advantages:
node metastases impact recurrence and survival [6–10] (Table 15.1). • Improved nodal diagnosis, particularly nodes in the central
compartment
• Detection of extrathyroidal extension, including aerodigestive
tract involvement
DIAGNOSIS
• Imaging of mediastinal nodes and metastatic lung nodules
• Iodinated contrast is no longer contraindicated
It is mandatory that all patients undergo operative neck FNB is an important diagnostic test to be performed pre-operatively
ultrasonography for cervical lymph nodes undergoing thyroidectomy to document metastatic nodal involvement. Additionally, FNB-Tg
for malignancy or suspicion for malignancy. Ultrasound-guided FNB wash out in the evaluation of suspicious cervical lymph nodes is
of sonographically suspicious lymph nodes 8–10 mm in the smallest appropriate in selected patients; however, its interpretation may
diameter should be performed to confirm malignancy. A positive be difficult in patients with a normally functioning thyroid gland
result would obviously change management (Recommendation 33, [16]. Frozen sections provide a very reliable diagnostic tool intra-
ATA Guidelines 2015) [14]. There is enough literature to support operatively. The authors have their own experience with crush imprint
the superiority of CT scan in diagnosis of metastatic nodes [15]. cytology as a surrogate to frozen section examination. This method
Contrast-enhanced CT scan has incremental value over ultrasound of intra-operative pathology has an accuracy of approximately 97%.
in diagnosing level VI nodes, especially with the presence of the
thyroid gland. It also helps in delineating lateral compartment SURGICAL MANAGEMENT OF METASTASES NECK NODES
nodes and their relationship to jugular veins and carotid arteries IN DIFFERENTIATED THYROID CANCERS
better. There is a myth regarding contraindication for use of Management is broadly classified into central compartment neck
dissection and lateral compartment neck dissection.
Table 15.1 Prognosticators for increased risk of nodal metastases Central compartment neck dissection (CCND) in presence of
documented metastatic nodes in a pre-operative setting is referred
Prognosticators of nodal metastasis [11]
to as therapeutic CCND. Nodal dissection done in the absence of
1. Under the age of 15 years [12]
2. Male sex clinical, radiologically proven disease is referred to as prophylactic
3. Extra thyroidal extension CCND.
4. Aggressive pathological variants such as tall cell, columnar cell, Therapeutic CCND is no longer an issue of debate (Recommendation
diffuse sclerosing, or insular 36, ATA Guidelines 2015) and is performed in the following
5. BRAF/TERT mutation positivity [13] scenarios:
Management of Nodal Metastasis in Thyroid Cancer 113

Diagnosis
1. Clinically and radiologically manifested or pathologically artery and to trace and identify the terminal branch or end artery
proven central compartment nodal disease. to the inferior parathyroid gland. This can be marked or clipped
2. Documented lateral compartment nodal diseases. with a Ligaclip ® to ease identification of the parathyroids with their
supplying vessels during further dissection. Some surgeons prefer
Prophylactic central compartment neck dissection, however, attracts the clearance of para-tracheal nodes only medial to the RLN, i.e.,
great controversy. Even in the presence of several meta-analyses, between the RLN and trachea. The presumption is that this results
there is still no consensus statement [17–20]. in lowering the rate of hypoparathyroidism as the majority of
Arguments in support of prophylactic central compartment neck parathyroid blood supply comes laterally. Also, there is an adequate
dissection are: oncological clearance as most of the metastatic nodes are medial
1. No imaging or pathology exam is absolute for detection of to the RLN. The authors, however, believe in thorough ipsilateral
central compartment nodes prior to surgery [21]. CCND. The operating surgeon stands at the head end of the table,
and an assistant applies gentle traction over the cricothyroid joint
2. Intra-operative surgeon assessment is not reliable [22].
anteriorly. This maneuver allows the surgeon to work better along
3. Occult central compartment metastasis are present in up to the RLN clearing all nodes on either side of it (Figures 15.1 and 15.2).
80% of cases. One must also constantly bear in mind variations in the course of the
4. Accurate staging helps in better planning of adjuvant nerve on either side. Being more angulated to the tracheoesophageal
treatment [23]. groove, the right RLN may be at more risk of injury. It is better to
5. Revision surgery in central compartment has significantly keep the nerve in its prevertebral fascia coverings and avoid handling
higher incidence of recurrent laryngeal nerve palsy and to prevent neuropraxic and vascular damage. Magnification by the
hypocalcemia [24,25]. way of optical loops is preferred by some surgeons for allowing
adequate clearance of disease and preservation of the RLN and the
Arguments opposing prophylactic central compartment neck
parathyroids with their vasculature. Use of intra-operative nerve
dissection are:
monitoring during central compartment neck dissection is also
1. Significantly higher incidence of hypoparathyroidism, recommended for reducing chances of RLN injuries, particularly
especially in low volume centers [26]. in revision surgery.
2. No significant detriment to survival outcomes [17,18].
The American Thyroid Association Consensus Statement on central
compartment neck dissection clearly defines anatomical boundaries,
indications, and terminologies for surgical procedures [27]. The
central compartment extends between the carotid arteries laterally
on either side, superiorly from hyoid bone and inferiorly up to the
innominate artery. This includes the pre-laryngeal (delphian), pre-
tracheal, and paratracheal lymph nodes. Level VII lymph nodes are
the superior mediastinal lymph nodes.
All surgeons will minimally differ in philosophies on central
compartment neck dissection (CCND) surgery. The following
surgical procedures are commonly practiced:
• Exploration of central compartment: Minimal dissection

is done to identify presence of metastatic nodes in central
compartment.
In absence of clinically identifiable node, procedure is terminated.
If nodes are identified, a formal CCND is performed.
• Sampling of central compartment: Clinically suspicious nodes Figure 15.1 Completed level 2 to 4 with thyroidectomy.
are subjected to intra-operative pathology assessment (frozen
section or crush imprint cytology)
If reported positive, formal CCND clearance is performed.
• Central compartment nodal clearance: This is often referred to
as therapeutic CCND. This entails clearance of all lymphatic
tissue and fibro fatty tissue from carotid arteries on either
side bilaterally and from hyoid to innominate artery above
downwards.
Quite a few surgeons perform ipsilateral CCND only in an attempt
to preserve contralateral parathyroids and their vasculature.
This entails clearance of pre-laryngeal, pre-tracheal, and para-
tracheal (between carotid and trachea) on the ipsilateral side;
bilateral CCND would encompass clearance of all pre-laryngeal,
pre-tracheal, and bilateral para-tracheal nodes.
SURGICAL TIPS
Dissection in central compartment often commences after the total
thyroidectomy is performed. The key step is actually taken during
the initial ligating of the terminal branch of the inferior thyroid Figure 15.2 Complete central neck dissection from head end.
114 Management of Nodal Metastasis in Thyroid Cancer

Diagnosis
Figure 15.3 Nerve status pre-operative.
In case of nodal disease severely engulfing or involving the RLN, the clearing level V in case level II nodes are involved (Figure 15.4).
following algorithm may prove useful (Figure 15.3). There is always a debate about clearance of level IIb in view of scant
The reasoning for primary nerve repair is the return of function in metastases at this nodal station and increased risk of traction injuries
approximately 50% of patients [28]. This enables maintenance of the to the spinal accessory nerve during this dissection [30]. The level IIb
bulk of the vocal cord muscles and aids voice rehabilitation. clearance should be mandatory in case of positive nodes at level IIa.
In the event of accidental parathyroidectomy along with CCND, auto-
transplantation of the concerned gland must be transplanted in the
strap or the SCM muscles. It is important to mark the transplantation
site and to have a small bit of tissue for histopathological confirmation.
If at the end of the procedure the parathyroid gland appears dusky,
one should suspect hematoma in the parathyroid capsule. A small
nick with a scalpel or needle may help to relieve this hematoma and
the gland may partially or completely regain its color. In this case
nothing is required to be done. For a devascularized gland, however,
auto-transplantation may still yield a more successful outcome.
LATERAL COMPARTMENT
Following are the indications for Neck Dissection:
1. Extensive nodal disease in central compartment
2. Documented nodes in lateral compartment
There is no indication for performing prophylactic lateral compartment
neck dissection (Recommendation 37, ATA Guidelines 2015) [14].
Several philosophies are in practice for managing the lateral neck
in DTC, such as elective nodal sampling, ultrasound directed
compartmental resections, and super selective nodal dissection [29].
Historically, Berry picking or selective sampling and removal of
nodes is condemned. A selective neck dissection clearing all lymph
nodes and fibrofatty tissue from levels II–IV is generally practiced
preserving the sternocleidomastoid muscle, internal jugular vein,
and the spinal accessory nerve. Sacrificing any of these structures
should be considered only in the presence of gross disease with
obvious involvement of the structures. Lymph nodes at the levels Figure 15.4 Left level II–V selective neck dissection, sparing the internal
of I and V should ideally be cleared only in the presence of obvious jugular vein (IJV), sternocleidomastoid (SCM), and spinal accessory nerve
involvement by disease. Some authors recommend the dictum of (SAN).

References
Table 15.2 Risk of nodal recurrence in differentiated thyroid cancers No structural disease should be left behind. As there are very
Risk of recurrence–avg
reasonable survival outcomes in differentiated thyroid cancers it
(range) is the surgeons’ responsibility to procure disease free status with
minimum morbidity in the form of hypoparathyroidism or
Clinically N0, pN0 4% (0%–9%) RLN injury.
Clinically N0, microscopic pN1 6% (4%–11.5%)
No. of nodes ≤5 4% (3%–8%)
No. of nodes >5 19% (7%–21%)
Nodes with extranodal extension 24% (15%–32%) REFERENCES
A very interesting study by Dr. Randolph et al. [31] estimates the

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11. Stack BC Jr. (Chair) et al.; American Thyroid Association
who are poor surgical candidates. Up to 80% resolution of structural
Surgical Affairs Committee. American Thyroid Association
nodal disease and lowering of Tg to acceptable range (<3 ng/mL) has
Consensus Review and Statement Regarding the Anatomy,
been observed. However, multiple sessions are often required and this
Terminology, and Rationale for Lateral Neck Dissection in
technique is not very effective for larger nodes (>2 cm) [32].
Differentiated Thyroid Cancer.
12. Choi YJ, Yun JS, Kook SH, Jung EC, Park YL. Clinical and
imaging assessment of cervical lymph node metastasis in
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papillary thyroid carcinomas. World J Surg. 2010;34:1494–9.
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Chapter 16
COMPLICATIONS OF THYROID SURGERY
Gregory W. Randolph, Dipti Kamani, Cristian Slough, and Selen Soylu
CONTENTS
Introduction 119
Seroma 119
Infection 119
Hematoma 119
Hypertrophic or Keloid Scar 120
Aerodigestive Injury 120
Airway Concerns 120
Salient Points 123
References 123
majority are resorbed spontaneously in 6–8 weeks. Larger and

more uncomfortable seromas can be managed with sterile serial
INTRODUCTION percutaneous aspirations often requiring more than one aspiration.
The aspirated fluid can be sent for culture if there are concerns for
infection. Placement of a drain at the time of surgery, particularly for
“Measure twice, cut once” is a famous carpentry proverb aptly large goiters, may help reduce the rate of seroma formation, although
extrapolated to the surgical world and is of particular relevance there is no clear evidence of their efficacy for this [2,3]. Seromas
when discussing surgical complications. Up until the 19th should not be confused with hematomas, which present with rapidly
century, thyroidectomy was associated with high mortality rate evolving neck swelling and subsequent airway compromise—a true
and was recommended to be performed only to save lives. With surgical emergency.
pioneering work from Kocher, the modern day thyroidectomy is
a safe and elegant procedure. Presently, complications in thyroid
surgery are infrequent but have the potential for high morbidity
and possibly mortality. The avoidance of surgical complications INFECTION
and adequate management of complications is best achieved
through pre-operative and intra-operative diligence. Pre-
operative communication with patients and their families is also With an incidence of 0.5%–3%, surgical site infections after
very important. An informed patient or caregiver can pick up thyroidectomy are rare [4,5]. Usually, for thyroid surgery, peri-
early signs of an evolving complication and can at times be the operative antibiotics are not needed unless the field is contaminated
difference between a minor setback and a major complication. by entry into the aerodigestive tract or a break in sterility during the
Finally, meticulous surgical technique and sound anatomical and procedure [6]. Obesity, extent of the surgery, diabetes, steroid use,
physiological knowledge are critical. smoking, and alcohol intake are predisposing factors for surgical site
infection [5,7,8]. Peri-operative antibiotics can be considered in these
patients, but no clear evidence exists for its efficacy in preventing
infection following thyroid surgery [9]. While oral antibiotics and
SEROMA
local wound care are sufficient for superficial wound infections, deep
wound infection often requires admission, intravenous antibiotics,
incision and drainage of the wound, culture of the wound, and
The incidence of seroma following thyroid surgery varies from
identification of the potential source for the infection. Deep neck
1.3% to 7% [1]. Seroma is more likely to occur following surgery
space infections following thyroidectomy are often associated
for large goiters, total thyroidectomies, those with extensive sub-
with an undiagnosed aerodigestive tract injury and should be
platysmal dissections, and patients with a thick sub-dermal layer.
appropriately addressed, since underestimating such infections is
The symptoms include neck swelling and increased pain, and
perilous as these infections can often progress quickly, descend to
seroma can lead to infection, flap necrosis, and potential wound
the mediastinum, and can result in mortality [10].
healing issues with resulting cosmetic complications. The etiology
of seroma is not well understood, but risk factors include old age,
higher body mass index, and hypocalcemia that may lead to seroma
formation [1]. There is some evidence to suggest that new vessel HEMATOMA
sealing devices when compared to conventional techniques resulted
in fewer post-operative seromas, likely related to less extensive
surgical site dissection and decreased manipulation [1]. Smaller Given the well-vascularized nature of the thyroid gland, meticulous
seromas may be managed conservatively with reassurance as the hemostasis is paramount during its surgery. Post-thyroidectomy
Complications of Thyroid Surgery 119

Airway Concerns
hemorrhage is a rare, but potentially life-threatening complication a water-soluble contrast material, is performed; if there is no leak,
with an incidence of 0.1%–2.1% [11]. It needs emergent intervention. the patient can begin a soft diet. If a leak is detected, then further
With the new vessel sealing devices, it has been found that if post- investigation and treatment options must be sought to avoid fistula
operative hemorrhage does occur, it generally happens in the initial or stricture formation.
post-operative hours [12]. Small tracheal injuries can be primarily repaired. Large defects
Risk factors for post-operative hemorrhage include male gender, may require segmental tracheal resection and subsequent repair, or
malignancy, retrosternal extension, large goiters, Graves’ disease, alternatively a tracheostomy tube can be placed in the defect and
extent of the surgery, and anti-coagulant use [11,13–15]. This is removed at a later date.
particularly important given the new trend of outpatient surgery
for thyroidectomy, so caution should be exercised on discharge of
patients with multiple risk factors for post-operative bleeding. AIRWAY CONCERNS
Post-operative bleeding may occur due to a residual thyroid tissue, an
unsealed vessel, an improperly tied knot, or a patient with a coagulation
defect. Signs for a hematoma are evolving swelling in the neck, increasing DIFFICULT INTUBATION
pain, and developing respiratory distress. Drain usage in thyroidectomy While planning the intubation, assessment of risk factors for
has not been shown to reduce the rate of hematomas, has not been shown difficult intubation is essential. Large goiters, invasive thyroid
to be an effective “warning sign” following thyroidectomy, and indeed cancer, anaplastic thyroid cancer, increased neck circumference,
may actually contribute to hematoma occurrence [3]. Additionally, older age, reduced mouth opening, history of difficult intubation,
drains are associated with surgical site infection, longer hospital stay, and substernal goiter can be predictors of difficult intubation [21,22].
and more post-operative pain [3]. Therefore, routine drain usage in In patients with large goiters, tracheal deviation may occur.
thyroidectomy is not recommended [16]. Furthermore, in aggressive thyroid cancers vocal cord paralysis
Early diagnosis of hematoma development is essential. Larger, can be encountered at the pre-operative stage. Both of these
deeper hematomas, with bleeding deep to the strap muscles, conditions need safe airway management with proper intubation or
may cause venous and lymphatic congestion with subsequent tracheostomy [23]. Checking the larynx, vocal cords, and airway with
laryngopharyngeal edema, airway compromise, tracheal a pre-operative laryngoscopic examination and imaging studies,
compression, and airway obstruction. Immediate evacuation and such as chest x-ray or computed tomography, might anticipate a
decompression of the hematoma is key and paramount to alleviating difficult intubation process. If necessary, anesthesiology should
the impending airway compromise. Consequent intubation for be consulted pre-operatively so that as a team the surgeon and the
airway control should be undertaken with subsequent return to anesthesiologist can decide the best management for the patient. If
the operating room for formal hematoma evacuation, washout, managed properly, patients with a difficult intubation risk can be
and identification of the bleeding source. The main preventive extubated safely. For a secure airway, awake fiberoptic intubation or
approach for post-operative hematoma is meticulous surgery and direct laryngoscopy-aided intubation and intubation after induction
good hemostasis. with inhalational agents are recommended [24].
INJURY TO THE EXTERNAL BRANCH OF THE SUPERIOR

LARYNGEAL NERVE
HYPERTROPHIC OR KELOID SCAR The external branch of the superior laryngeal nerve (EBSLN)
innervates the cricothyroid muscle, which lengthens and tenses
the vocal cords, providing timbre to the voice. Therefore, injury to
Detailed history of previous surgeries, post-operative scar formation, this nerve can result in a lower pitched, husky voice that is easily
and examination for hypertrophic scar or keloid suspicion are fatigued with a substantial reduction in phonatory frequency range,
important. An adequate, symmetrical incision in a natural skin modest increase in phonatory instability (jitter), increased laryngeal
crease can avoid hypertrophic scarring [17]. Post-operative resistance with no objective evidence of glottic insufficiency, and
application of over-the-counter scar care products and avoidance mild deterioration in voice quality most evident during high pitched
of sun are helpful. Despite the precautions taken, patients prone to voice productions, which is particularly pronounced in women and
healing defects will develop hypertrophic scarring or keloids. Scar the singing voice [25,26]. Injury to this nerve can be particularly
revision, intralesional steroid injection, or laser therapy might be devastating to professional voice users. This is most famously
helpful for treatment [18]. illustrated by Amelita Galli-Curci, the great operatic soprano, who
underwent thyroid surgery in 1935 and found that her vocal range
had been greatly impacted, and indeed the surgery ultimately ended
AERODIGESTIVE INJURY her singing career.
The rate of injury to EBSLN following thyroid surgery has also been
variable, depending upon the method of identification, ranging from
Cervical esophagus perforation is a very rare complication 0%–6% when assessed via laryngoscopy and as high as 58% when
after thyroidectomy. It usually occurs due to adherent thyroid assessed by laryngeal electroneuromyography [27].
malignancy affecting adjacent structures such as the trachea or the
Injury to the EBSLN commonly occurs during ligation of the
esophagus. For this reason, pre-operative work-up, imaging, and
superior pole vessels during release of the superior thyroid pole.
endoscopy should be performed rigorously and combined with a
Several surgical techniques have been proposed to avoid injury to
good surgical strategy. When an esophageal injury occurs, the edges
the EBSLN during thyroid surgery and can essentially be divided
of the perforation are debrided and closed in two layers (mucosa
into three main techniques:
and the muscular layer) with absorbable sutures with or without
a strap muscle buttress to the repair. The surgical site is copiously 1. Individual identification and ligation of the superior pole
irrigated, a drain is placed, and IV antibiotics and total parenteral vessels as close as possible to the thyroid capsule without
nutrition are initiated for 7–10 days [19,20]. An esophagram with specific identification of the EBSLN [28].
120 Complications of Thyroid Surgery

Airway Concerns
2. Others advocate for the importance of intra-operative visual is the preferred method to minimize injury [40]. The thyroid surgeon
identification of the EBSLN during thyroid surgery [29]. The must also be familiar with the occurrence of a non-recurrent
drawback of this technique is that up to 20% of EBSLN run laryngeal nerve (NRLN) and other anatomical and pathological
a subfascial course, and hence cannot be visualized intra- variations [41].
operatively [30,31]. The most consistent location of the RLN and NRLN is its most
3. Employing electrical neural stimulation with visualization distal portion where it is covered by the tubercle of Zuckerkandl or
of contraction of the cricothyroid muscle with or without a portion of the ligament of Berry (or both) before it turns below
intra-operative nerve monitoring (IONM) with endotracheal the inferior cricothyroid articulation, and the inferior cornu of the
electrodes [27]. Many researchers have further corroborated thyroid cartilage is an easily palpable landmark to approximate the
that IOMN improves identification and visualization and RLN entry point into the larynx [42]. The nodule of Zuckerkandl and
may improve subjective symptoms following thyroid surgery Berry’s ligament are also where the plane of surgical dissection is most
but have not shown definitive reduction in nerve injury rates adherent and most closely approximates the RLN and therefore places
[32–35]. However, given the widespread use of IONM during the nerve at risk of severance, traction, clamping, or partial resection.
thyroid surgery, there is a growing consensus that its use for Another important adjunct to the visual identification of the
EBSLN monitoring is recommended and aids in identification RLN is IONM. IONM aids in identifying the nerve, mapping the
of this nerve [35]. nerve, assessing nerve function, and identifying the injured nerve
Presently, there is no surgical repair technique available to repair segment. Additionally, IONM allows staging of total thyroidectomy
intra-operatively identified EBSLN injuries; the main stay of after loss of signal in the first lobe avoiding contralateral lobe
management is speech therapy, vocal training, and counseling. resection and subsequently avoiding the risk of bilateral vocal cord
paralysis [43,44].
RECURRENT LARYNGEAL NERVE INJURY Notably, continuous IONM, a more recent advanced form of IONM,
The recurrent laryngeal nerve (RLN) via its motor and sensory fibers has the potential advantage of real-time nerve monitoring. It can
supplies all of the intrinsic muscles of the larynx other than the detect adverse electromyography (EMG) changes that signify an
cricothyroid while receiving sensory and secretomotor fibers from impending RLN injury, thereby allowing a surgeon to prompt a
the glottis, sub-glottis, and trachea. A systematic review of 25,000 corrective action, e.g., aborting or reversing associated maneuvers,
patients reveals an average incidence of temporary RLNP is 9.8% and thus likely avoiding permanent injury [45–47].
permanent RLNP is 2.3% [36] (Figure 16.1).
If transection of the nerve injury is identified at the time of surgery,
Pre-operative assessment should help identify any risk factors for RLN attempts should be made to repair the defect. The techniques of RLN
injury including thyroid carcinoma, need for lymph node dissection, repair include primary end-to-end anastomosis, ansa cervicalis
retrosternal extension, reoperation, and potentially abnormal to RLN anastomosis, and a primary interposition graft [38]. End-
anatomy [37,38]. At the time of pre-operative assessment, it is also to-end nerve approximation is preferred and can be achieved with
prudent to perform flexible fiberoptic laryngoscopy to determine and three or four perineural stitches of 6.0 or 7.0 suture placed using
document baseline vocal cord function. The thyroid surgeon should microsurgical instruments. However, when there is a gap of >5 mm,
be aware of the risk factors for poor regrowth of the RLN following or the anastomosis is under significant tension, a graft can be taken
injury including age, diabetes, smoking, and systemic disease [39]. from the ansa cervicalis, transverse cervical nerve, or supraclavicular
Since the pioneering work of Lahey and Hoover who advocated for nerve [48]. These techniques also apply when sacrifice of the nerve
identification of the RLN at the time of surgery and demonstrated is necessary for oncologic reasons and there is pre-operative vocal
extremely low rates of RLN injury, intra-operative RLN visualization cord paralysis, as patients will experience a normal or improved voice
post-operatively, secondary to the return of thyroarytenoid muscle
tone and bulk, regardless of the length of time of vocal cord palsy [48].
IONM may also be helpful in these scenarios allowing the surgeon
to identify the distal stump of the RLN. Non-surgical management
for RLN injury includes voice therapy, vocal cord injection
augmentation, medialization laryngoplasty (type 1 thyroplasty),
arytenoid adduction, and cricothyroid subluxation [38].
Bilateral vocal cord palsy is a life threatening complication associated
with thyroidectomy. Previous reports place its incidence at 0.6%, but
the advent of IONM and staging procedures have likely decreased
this incidence. A recent review by Sarkis et al. of 7,406 patients found
the incidence to be much lower at 0.09% [49]. Their work and work
by the International Neural Monitoring Study Group corroborate
the importance of IONM to avoid this most dreaded complication
[44,49]. The typical symptoms include inspiratory stridor, but
phonation may be normal due to medial position of the vocal
cords. Acutely, the majority of patients will require intubation and
subsequent tracheostomy to stabilize the airway prior to definitive
treatment [49].
HYPOPARATHYROIDISM
Prevention of hypoparathyroidism following thyroid surgery starts
with pre-operative assessment of serum vitamin D, serum calcium,
and parathyroid hormone (PTH) levels in patients at higher risk of
Figure 16.1 The laryngoscopic view of a vocal cord paralysis with hypoparathyroidism. A recent meta-analysis of pre-operative risk
atrophy of the paralyzed vocal cord on the right. factors for hypoparathyroidism included female sex, Graves’ disease

Airway Concerns
and length of its duration, pre-operative beta-blockade, larger 500–1000 mg three times a day with upward titration if symptoms
thyroid glands, retrosternal goiter, the need for a bilateral central persist. Vitamin D plays a crucial role in calcium absorption and
neck dissection, reoperative thyroid surgery, and higher thyroid bone metabolism and should therefore be administrated, in the
cancer stage [50–53]. Biochemical abnormalities identified should most active form, 1,25-dihydroxy D3 (calcitriol), 0.25 µg PO
be corrected pre-operatively as this can decrease the impact and once daily, when the thyroid surgeon has identified a patient with
severity of hypocalcemia post-operatively particularly in vitamin D hypocalcemia. In patients warranting IV calcium therapy, calcium
deficiency [54]. gluconate is preferred to calcium chloride, as there is less risk of tissue
The incidence range of post-surgical hypocalcemia is generally wide necrosis if extravasation occurs [54]. Ionized calcium, phosphorous,
with reports from 8.3%–38% for temporary cases lasting no greater PTH, and Vitamin D should be checked at regular intervals if the
than 6 months and 0.9%–1.7% for patients experiencing a more patient is not improving or getting worse. The goal is to maintain
permanent complication across multiple series [52,55,56]. It has also a low normal serum calcium with normal phosphorous levels and
been found by multiple studies to be the most common complication low urinary excretion of calcium. For patients with permanent
following thyroid surgery, namely for 63% of the complications [55]. hypoparathyroidism, maintaining calcium and phosphorous levels
Rosato et al. in their series of 14,934 patients also found the incidence is more difficult and requires routine monitoring, adjustments to
of permanent hypocalcemia after surgical interventions for thyroid supplementation as needed, and long-term management by an
cancer was significantly higher (3.3%) [55]. endocrinologist with expertise in this area.
Meticulous capsular dissection along the thyroid gland with A promising new treatment option is recombinant PTH (rhPTH),
subsequent preservation of the parathyroid glands and inadvertent an injectable synthetic human PTH, which has been shown to
disruption of their blood supply is recommended to avert normalize and maintain serum calcium levels, allow discontinuation
hypoparathyroidism. The issue of routine identification of the of vitamin D, and a decrease in calcium supplementation, as well
parathyroid glands versus less gland identification has been as fewer clinical symptoms of hypocalcemia during treatment [63].
controversial with some advocating for identification of at least Unfortunately, the main concern relating to its more widespread use
two glands [57], while others advocate for less parathyroid gland versus conventional treatments in patients with hypoparathyroidism
identification citing a proportional rate of resulting hypocalcemia is its cost [64].
[58]. Puzziello et al. found a proportional association between
HYPOTHYROIDISM
gland identification and temporary hypocalcemia but an inversely
Hypothyroidism is an expected sequel following total thyroidectomy.
proportional relationship with permanent hypocalcemia [56].
Notably, it also occurs in 7%–35% of patients following thyroid
These findings support capsular dissection without extensive lobectomy and is more likely to occur in patients with pre-
dissection and search for the parathyroid glands, but careful existing high thyroid stimulating hormone (TSH), lower free T4,
preservation of glands encountered during thyroid surgery by Hashimoto’s disease, and small size of the remaining thyroid lobe
mobilization away from the plane of dissection while keeping the [65]. The starting dose for Levothyroxine is 1.6–1.8 mcg/kg/day
blood supply of the gland intact. A clearly ischemic and probable and is titrated based on thyroid function testing at 6–8 weeks after
non-viable parathyroid gland identified during surgery should be surgery [65,66]. Additional suppression of TSH beyond normal levels
confirmed pathologically through frozen section and then should is also appropriate for management of higher risk well-differentiated
be autotransplanted into the sternocleidomastoid. However, the thyroid cancer [66].
surgeon should be aware that this practice may result initially in
a temporary hypocalcemia but has no association with permanent THYROID STORM
hypocalcemia [50,57]. Patients undergoing thyroid surgery for hyperthyroidism are at
Traditionally hypocalcemia was post-operatively identified via serial risk of thyroid storm, a life threatening complication affecting
serum calcium levels checked at regular intervals to determine the multiple systems including the cardiopulmonary, thermoregulatory,
need for calcium supplementation. However, serum intact PTH metabolism, neurologic, and gastrointestinal systems [67]. Thyroid
(iPTH) levels have generally superseded this in locations where storm is associated with hyperthyroidism secondary to Graves’
this is available. The timing of iPTH checks post-operatively to disease and less often with toxic nodule or multinodular goiter
predict consequent hypocalcemia accurately is controversial. Most [67]. This complication is believed to precipitate due to the stress of
studies have found that most accuracy at 4 hours post op with a surgery, anesthesia, or thyroid manipulation during surgery [68].
level greater than 10 pg/mL for iPTH and a drop no greater than Recognition and appropriate management of thyrotoxicosis is vital
50% of the iPTH compared to pre-op levels is a reasonable indicator to prevent associated high morbidity and mortality.
for adequate surgery [59–61]. Normal post-operative iPTH levels Pre-operatively, the surgeon should discuss the risk of thyroid storm
accurately predict normocalcemia after total thyroidectomy, and and emphasize the importance of compliance with medication up to
patients with PTH in the normal range can be safely discharged on the day of surgery. Additionally, the American Thyroid Association
an outpatient basis or on the first post-operative day. Regardless of guidelines recommend that the patient should be euthyroid pre-
serum calcium levels or iPTH levels, use of oral calcium supplements, operatively and if this is not possible, beta blockers should be used
either as needed or routinely, will avoid mild symptoms that may to decrease the risk of a potentially lethal thyrotoxic crisis [69].
develop without treatment, and some advocate this for all their The surgeon and anesthesiologist should have experience in this
thyroidectomy patients [62]. situation [69].
If hypocalcemia is identified on serial calcium checks or predicted In the operating room, a shift in vital signs alerts anesthesia to the
on iPTH levels, calcium replacement is recommended. In the possibility of thyroid storm. Systemic decompensation, tachycardia,
acute setting with serum calcium levels less than 7 mg/dL, IV dysrhythmia (usually atrial fibrillation), high fever, and respiratory
calcium gluconate is administered to alleviate symptoms which changes are the most common symptoms [67,69]. A multimodality
can include paresthesia, muscle cramps and spasms, twitching, treatment approach to these patients should be used, including
tetany, seizures, and cardiopulmonary dysfunction. If serum b-adrenergic blockade, antithyroid drug (ATD) therapy, inorganic
calcium is at least 8 mg/dL, then it is treated with oral calcium iodide, corticosteroid therapy, cooling with acetaminophen
carbonate and vitamin D. The starting dose of calcium is usually and cooling blankets, and volume resuscitation initiated to

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Chapter 17
LOCALLY ADVANCED THYROID CANCER
Amit Agarwal and Roma Pradhan
CONTENTS
Introduction 127
Invasion of the Strap Muscles 127
Invasion of the Aerodigestive Tract (Larynx, Trachea, Hypopharynx, and/or Esophagus) 127
Surgical Management 129
Pharyngeal/Esophageal Involvement 132
Vascular Invasion 132
Conclusion 132
References 133
INTRODUCTION INVASION OF THE STRAP MUSCLES
Locally advanced thyroid cancer (LATC) occurs when there is either The strap muscles (sternohyoid, sternothyroid, and omohyoid) are the
extrathyroidal extension from the primary tumor in the thyroid most common structures involved in locally advanced thyroid cancer
or extracapsular extension from involved lymph nodes into the due to their proximity to the thyroid gland. The point that concerns the
surrounding structures. The incidence of invasive disease depends treating doctor is whether the invasion of strap muscles is an important
on the pathology of the thyroid cancer. prognostic factor or not. This was recently answered by a study from
The structures that are in close association with the thyroid gland have Amit M et al. [1]. Gross strap muscle invasion may not be an important
more chance of invasion, like the strap muscles, recurrent laryngeal survival prognostic factor for staging purposes. Although both gross
nerve, trachea, great vessels, vagus nerve, esophagus, and larynx. strap muscle invasion and perithyroidal soft tissue extension may be
predictive for locoregional recurrence, the distinction between them
The surgical treatment of thyroid lesions that invade adjacent
may not be as important for post-operative risk stratification.
structures is controversial but removing as much abnormal tissue
as possible and maintaining the functional integrity of the neck The management of the invasion of the strap muscle includes
structures are basic principles. resection of the involved muscle to obtain negative margins.
The type of thyroid cancer is an important criteria that decides our
management strategy.
For aggressive thyroid cancer like anaplastic and medullary when INVASION OF THE AERODIGESTIVE TRACT (LARYNX,
present with airway compromise, palliative management is the
TRACHEA, HYPOPHARYNX, AND/OR ESOPHAGUS)
treatment of choice because of poor prognosis. This is in contrast
with the differentiated thyroid cancer where resection surgery with
curative intent is the treatment option because of good survival in
Invasion of the aerodigestive tract (ADT) including the larynx,
these patients.
trachea, hypopharynx, and esophagus can be found in 1%–8% of all
According to the new American Joint Committee on Cancer (AJCC) patients with thyroid cancer [2–4].
Staging Manual, 8th Edition, a few changes are important as they
Due to anatomical proximity, respiratory tract invasion can be
relate to locally advanced thyroid cancer.
found in 50% and an esophagus invasion in 25% of locally advanced
Minor extrathyroidal extension detected only on histological thyroid cancers [2].
examination was removed from the definition of T3 disease and
The invasion of the aerodigestive tract in thyroid cancer occurs
therefore has no impact on either T category or overall stages.
from the outer layer (superficial) of these organs to the deeper layer
Older patients with tumors >4 cm confined to the thyroid (T3a) are and then in lumen, which is different from the primary tumor of
classified as stage II regardless of the lymph node status. these organs. In about 3/4th of the patients, at the time of diagnosis,
T3b is a new category for tumors of any size demonstrating gross invasion does not affect the complete wall (non-transmural invasion),
extrathyroidal extension into the strap muscles (sternohyoid, but in 1/4th of patients, transmural invasion with intraluminal
sternothyroid, thyrohyoid, or omohyoid muscles). tumor manifestation is usually found.
Older patients demonstrating gross extrathyroidal extension are When the cartilage is penetrated, the tumor very often grows
classified as stage II if only the strap muscles are grossly invaded horizontally first and then vertically between the mucosa and the
(T3b), stage III if there is gross invasion of the sub-cutaneous tissue, deeper layers before intraluminal manifestation occurs [2]. As
larynx, trachea, esophagus, or recurrent laryngeal nerve (T4a), and a consequence, in intraluminal ADT invasion, the area of tumor
stage IVA if there is gross invasion of the prevertebral fascia or tumor invasion is very often much larger than expected from intraluminal
encasing major vessels (T4b). assessment.
Locally Advanced Thyroid Cancer 127

Invasion of the Aerodigestive Tract (Larynx, Trachea, Hypopharynx, and/or Esophagus)
RESPIRATORY TRACT
Respiratory tract invasion can range from outer cartilaginous
invasion to frank intraluminal ingrowth. It can involve the upper
airway at multiple levels. Even in the presence of distant metastases,
resection is recommended often because of the mortality rate that
is associated with local disease and the need for primary tumor
resection for the effectiveness of other adjuvant therapy.
LARYNX
PRESENTATION
1. Patient may present with voice change, dysphagia, dyspnea, or
hemoptysis.
2. Vocal cord dysfunction on routine pre-operative examination.
3. FNA proven patient on cross sectional imaging demonstrating
invasion.
4. Patient may present with recurrent disease.
All patients with suspicion of invasion must undergo tracheoscopy
or esophagoscopy to know the extent of the disease and to allow for
a better surgical road map.
IMAGING
Imaging is the most important investigation for thyroid cancer.
High frequency ultrasound is the standard method to investigate for
thyroid nodules and to detect lymph nodes in lateral compartment. Figure 17.1 Laryngeal invasion by direct extension of thyroid carcinoma
However, its use in detecting extra thyroidal extension (ETE) and through the cricoid/thyroid cartilage.
invasion of larynx, trachea, and esophagus is limited. Contrast
enhanced computed tomography (CECT) has better sensitivity
(DTC), and surgery is accepted as the treatment of choice. However,
in detecting ETE and for detecting level VI and VII central
it is mandatory to have a good pre-operative evaluation before any
compartment lymph nodes.
major surgical intervention in these cases.
In some instances MRI may also be used to detect ETE.
Tracheal invasion may complicate with hemoptysis (Figure 17.4) or
Laryngeal Invasion dyspnea, and patients often die of hemorrhage or airway obstruction
Laryngeal involvement can occur in various ways, directly or [6]. Tracheal infiltration is associated with impaired tumor-free
indirectly affecting the function or structure of the larynx: survival and increased disease-specific mortality [7,8].
1. It can affect the function of the larynx indirectly by involvement EVALUATION
of the RLN either by primary tumor or by metastatic lymph Initial evaluation with a thorough history and examination is
node. important.
2. Laryngeal invasion can occur by direct extension of thyroid
carcinoma through the cricoid/thyroid cartilage (Figure 17.1) or
by posterior extension around the thyroid cartilage (Figure 17.2)
into the piriform sinus or the cricotracheal invasion.
3. Metastasis to cartilage, which is rare.
Operative treatment of locally invasive thyroid cancer involving the
larynx ranges from shave excision to extended laryngeal resections:
• Shave Excision.
• Partial laryngeal resection.
• Vertical hemilaryngectomy (lateral invasion of hemilarynx)
(Figure 17.3): The defect can be covered with nearby soft tissue,
regional myocutaneous flaps, or free flaps. If only the unilateral
thyroid ala is removed without the underlying soft tissue, then
no additional procedure is required.
• Total laryngopharyngectomy or total laryngectomy:
In LATC, when complete resection is performed, local recurrence
is less common [5]. With a less radical procedure, even after adding
post-operative I-131 therapy or radiotherapy, relapse is frequent.
Persistent growth of an intraluminal mass, followed by vocal fold
paralysis, airway obstruction, and death by asphyxiation or bleeding
occurs.
INVASION OF THE TRACHEA

Tracheal invasion is more common than laryngeal invasion and is Figure 17.2 Laryngeal invasion by posterior extension around the
observed in about 6% of patients with differentiated thyroid cancer thyroid cartilage into the piriform sinus or the cricotracheal invasion.
128 Locally Advanced Thyroid Cancer

Surgical Management
Stage 1: Invades through the thyroid capsule and abuts but does not
invade the external perichondrium of trachea.
Stage 2: Invades in the cartilage or destroys it.
Stage 3: Extends into the lamina propria of the mucosa but does
not breech the mucosa.
Stage 4: Full thickness invasion of the trachea with intraluminal
growth.
SURGICAL MANAGEMENT
Management of differentiated thyroid cancer invading the trachea

depends on:
• Depth of invasion into the wall
• Horizontal and vertical extent
Incomplete wall resections (without opening of the lumen) of the
trachea (shaving) gives excellent results in terms of tumor-free
resection margins and outcome [11]. Deeper invasions, however,
require complete wall resections. Nishida et al. [12] and McCaffery
[13] advocated for shave excision for stage I. The advocates of shave
excision favor it because it avoids morbidity associated with tracheal
resection and also its complications like tracheal stenosis. Nishida
et al. [12] compared patients who underwent shave excision and
those without any tracheal involvement and they found no difference
in local recurrence or overall survival between the two groups. Five
year survival was also similar in patients who underwent radical
resection compared to shave excision of macroscopic disease and
radioactive iodine for microscopic residual disease [14]. However, it
is unclear if shave resection with post-operative radioiodine ablation
and/or external radiation therapy is clearly associated with a higher
Figure 17.3 Vertical hemilaryngectomy (lateral invasion of hemilarynx). recurrence rate and worse prognosis as compared to aggressive
resection with airway reconstruction. This is due to the fact that
studies comparing these surgical approaches have had small study
A thorough physical examination will allow the clinician to suspect cohorts, the extent of disease was different among patients with
airway invasion. Usually, a palpable neck mass or nodule that has DTC, different surgical techniques were used, and retrospective,
recently enlarged will be present. The mass is often hard and displace non-randomized or unmatched cohorts were compared.
or fixed to the surrounding tissue (Figure 17.5). In contrast to these previously discussed studies, the study by Gaissert
Ultrasound scanning is typically not useful for the evaluation of et al. [15] proved that disease-free survival was significantly higher
intraluminal invasion. CT scanning is able to detect the presence after early resection, with 10- and 20-year disease-free survival rates
and delineate the extent of cartilaginous and intraluminal invasion. of 67% and 50%, respectively, whereas after delayed resection (i.e.,
It can also identify structures that are not involved by the carcinoma. patients who underwent shave resection initially) disease-free survival
CT scanning is a reliable tool to evaluate the thyroid gland and at 10 years was only 7%, and none of the patients were alive without
the tumor, identify tissue planes and vascular structures, provide disease after 20 years. Different studies by different authors studied
images of the trachea at different levels, and determine the extent on shave and full thickness resection are shown in Tables 17.1–17.3.
of any stenosis. The important point to note and discuss in patients in which we plan
All intra-laryngotracheal luminal invasions should be confirmed by to do shave resection is the histology of the thyroid cancer. Aggressive
bronchoscopy and neck computed tomography imaging. Endoscopic variants of PTC or tumors with undifferentiated components, such as
diagnosis of luminal invasion is made by confirming localized Hurthle cell carcinomas, may not be radioactive iodine avid, hence
redness that indicates neovascularity and telangiectasias [9]. formal resection instead of shave resection needs to be done [16].
Management to attain best outcome for patients: When the thyroid cancer invades into the cartilage or destroys it (Shin
1. Preoperative evaluation of the disease extent rather than stage 2), then the shave procedure is not sufficient and the patient
surgical surprise. requires formal tracheal resection as mentioned by Nishida et al. [13].
2. Removal of all gross tumor. Shave resection of all gross tumor involving the trachea and larynx
3. Preservation of vital structures while maintaining a balance is possible when DTC is not infiltrating the tracheal perichondrium.
between satisfactory quality of life (QOL) and oncological resection. Several studies have demonstrated that this approach has a lower
morbidity and similar survival rates when compared to full-
4. Every effort should be made to preserve the recurrent laryngeal
thickness resection. In patients who have laryngotracheal wall
nerves.
invasion, shave resection may be associated with a higher recurrence
As tracheal invasion is more common than laryngeal invasion, rate than extended resection. Some small retrospective studies
and a lot of discussion is available in the literature regarding its comparing shave resection to extended resection (en bloc) in patients
management, Shin has classified a staging system of tracheal with tracheal wall invasion have documented improved survival
invasion (Figure 17.6) [10]: rates in patients who had an extended resection.

Surgical Management
(a)
(b)
Figure 17.4 (a and b) CECT of a patient who presented with breathlessness and hemoptysis, showing intra-luminal invasion by thyroid carcinoma.
The complete wall resection on the trachea has been classified by

Dralle et al. [2] according to the extent of involvement.
In patients with limited involvement of the trachea (anterolateral
wall, Dralle type 2) with maximal extent 2 cm vertically and less
than 1/4th of circumference, window resection of the trachea is
possible with either primary closure or muscle patch (strap muscle
or SCM muscle). An anteriorly placed tumor can be managed with
window resection and the defect converted to tracheostomy which
can be downsized and decannulated post-operatively.
In tumors involving >2 cm vertically or >1/4th of circumference
(Dralle type 4), circular wall resection (sleeve) is required with
primary anastomosis. A primary anastomosis can be performed
with maximum resection of 5–6 cm of trachea or 7–8 tracheal rings
(Figures 17.7 through 17.9).
To ensure a tension free repair in such circumstances, various
procedures can be performed:
• Supralaryngeal release to gain extra 2 cm
Figure 17.5 X-ray of chest and neck: soft tissue shadow displacing or • Division of suprahyoid muscle
narrowing the trachea. • Hilar mobilization of trachea through sternotomy

Surgical Management
Figure 17.6 Shin classification. (Adapted from Shin DH etal. Hum Pathol. 1993 Aug;24(8):866–70.)
Table 17.1 Comparative studies of shave and full thickness resection
Locally
invasive Procedure:
DTC/Total ca Shave/
Authors thyroid pts full-thickness RAI/RT FUP period Survival Authors conclusion Comments
Cody HS 12 Shave = 9 3/2 8.7 years 10 yr: 64% Shave as good as full Small cohort
(1981) [19] Full-thickness = 3 resection
Czaja JM 109 Shave = 75 Yes/yes 40 yrs Shave = 48% Equal survival with both. Good number
et al. (1997) Full-thickness = 34 Full-thickness = 58% No gross tumor should of patients
[20] be left behind in shave and very
procedures long
Kasperbauer 49 Shave = 33 Yes/yes 10.3 yrs 5-year survival Equal results with both
(2004) [21] Full-thickness = 16 Shave = 79% procedures
Full-thickness = 75%
Musholt [22] 33 Shave = 17 Yes/yes Shave = 19 mo Procedures resulting in
Full-thickness = 17 Full = 25 mo primary end-to-end
anastomosis of the
upper airways were
associated with lower
peri-operative
morbidity and
improved recurrence-
free survival when
compared with
“window” resections
with muscle flap
reconstruction. In cases
of superficial tracheal
tumor infiltration,
laminar ablations were
sufficient for local
tumor control.

CONCLUSION
Table 17.2 Studies of full-thickness resection
Locally
invasive Procedure:
DTC/Total ca Shave/full - FUP
Authors thyroid pts thickness RAI/RT period Survival Authors conclusion Comments
Nakao et al. 40 -/- 10 yr: 67.7% Combined resection is a good treatment choice
(2004) [23] for survival and good QOL when performed for
local control in patients with differentiated
thyroid cancer
Sywak 2003 7 Yes/yes 19 mo Recurrence = 2 Tracheal resection for locally invasive thyroid
[24] cancer is associated with a return to full dietary
intake within 4 weeks of surgery in most cases.
Function and QOL after this type of surgery are
acceptable
Yang (2000) 8 Yes/− 91 mo Alive = 7 Tracheal resection for locally invasive thyroid All patients
[25] Disease cancer is associated with a return to full dietary had
free = 5 intake within 4 weeks of surgery in most cases. mucosal
Function and QOL after this type of surgery are involvement
acceptable
Table 17.3 Studies with shave excision only
Locally
invasive Procedure:
DTC/Total ca Shave/full - FUP
Authors thyroid pts thickness RAI/RT period Survival Authors conclusion Comments
Park (1993) [17] 16 Shave in all Yes/yes 70.7 mo Recurrence = 12 We feel that a more extensive resection
Mortality = 7 procedure than cartilage shaving should
be considered, even in patients with
superficial tracheal invasion, to increase
the disease-free survival rate.
Points to be kept in mind while mobilizing the trachea: reconstructed with myocutaneous flaps. Larger defects may require a
Tracheal blood supply enters laterally from the inferior thyroid jejunal free flap. For inoperable patients, the esophagus can be stented
artery to join two longitudinal vascular anastomoses. One should for palliation [16,18].
never mobilize the trachea circumferentially in order to avoid Extensive pharyngeal tumors may require radical surgery like total
damage to these vessels. laryngopharyngectomy.
PHARYNGEAL/ESOPHAGEAL INVOLVEMENT VASCULAR INVASION
The pharynx and esophagus can be invaded by the primary tumor Major artery and venous involvement are rare. Venous invasion
or by metastatic lymph nodes. is more common than arterial. CECT scan can be used to detect
Pharyngeal invasion usually occurs after laryngeal invasion, and vascular involvement. Angiography is used to evaluate the full
esophageal invasion usually occurs after tracheal invasion. Invasion extent of vascular invasion.
tends to penetrate the muscular layer with relative sparing of the
mucosa and submucosa. Typically, a well-differentiated thyroid
carcinoma will invade only the outer muscular layer.
CONCLUSION
Dysphagia is the common complaint and may be because of
compression from the mass or direct involvement of the esophagus.
A thorough pre-operative evaluation is necessary if esophageal Reasonable survival and quality of life can be given even to patients
involvement is suspected. Besides cross-sectional imaging, with locally advanced thyroid cancer. Hence, every attempt should
endoscopic ultrasound may be useful in these cases. During be made to achieve R0 resection but without causing extreme
surgery, a Ryles tube or feeding tube placement can be helpful in morbidity. Full-thickness resection in cases of airway invasion is
identification of the esophageal lumen. desirable to control symptoms like hemoptysis or breathlessness,
For esophageal involvement of only the muscular layer, no repair or as well as to improve survival. Therefore, such patients should
simple suture repair is all that is required if an intact submucosal be referred to expert endocrine surgeons for a radical operation.
layer can be maintained. Full-thickness invasion may require partial Various factors like histology, vascular invasion, distant metastases,
resection and immediate repair. However, it should be kept in mind available expertise, age of the patient, and operative fitness has to be
that the repair should be tension free, watertight, and multilayer. taken into account before making the decision of radical excision in
Moderately sized intraluminal defects after resection can be patients of locally advanced thyroid cancer.

References
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Chapter 18
SURGICAL MANAGEMENT OF MEDULLARY THYROID CANCERS
Anuja Deshmukh and Anand Thomas
CONTENTS
Introduction 135
Work-Up 135
TNM Classification AJCC, 8th Edition, for MTC 138
Recurrence/Metastasis/Residual MTC 142
Adjuvant External Beam Radiotherapy (EBRT) 142
Prophylactic Cancer Surgery 142
Salient Points 143
Acknowledgments 144
References 144
D. Somatic mutations involving RET have been identified in

40%–50% of sporadic MTCs. Mutation with M918 T have a
INTRODUCTION more advanced stage, higher rates of recurrences and persistent
disease, and poor long-term survival [2].
E. Because of its origin from the parafollicular C-cells that do
Medullary thyroid cancer (MTC) is a rare malignant neuroendocrine
not express the sodium/iodide symporter, medullary tumors
tumor comprising 5%–10% of all thyroid cancers. It arises from the
do not concentrate radioiodine. Therefore, there is no role of
parafollicular or C-cells of the thyroid gland, which secretes calcitonin.
radioiodine therapy or TSH suppression. It is more aggressive
Hazard et al. recognized the presence of amyloid as a unique feature than differentiated thyroid cancer. There is a very high rate of
of medullary thyroid cancer [1]. recurrence and mortality. Surgery is the mainstay of treatment.
A. It presents in the sporadic form (75%) or the hereditary form F. The parafollicular cells are situated predominantly at the
(25%). The hereditary form is autosomal dominant and part of junction of the upper and middle one-third of the thyroid
the MEN 2A and MEN 2B syndrome. gland. Hence a total thyroidectomy is mandatory in medullary
B. Sporadic MTC is more aggressive than hereditary and thyroid cancer.
commonly presents with metastatic cervical lymph nodes G. The various histological types described are classic (48.9%),
(70%). They are mainly solitary (68%) and less likely bilateral amyloid-rich (38.3%), insular, trabecular, and epithelial
or multifocal (32%). variants. Some may histologically divide into a small cell
C. The RET (REarranged during Transfection), proto-oncogene variant, a giant cell variant, a papillary variant, oncocytic,
on chromosome 10q11.2, is the germline mutation in the squamoid, and clear cell variant type [3] (Figures 18.2 and 18.3).
hereditary form. All patients with medullary thyroid cancer Immunohistochemistry (IHC) analysis shows the presence of
should be screened for germline RET mutation (Figure 18.1). markers for calcitonin, chromogranin, carcinoembryonic
i. It can identify the index case of a germline mutation antigen CEA, and the absence of thyroglobulin (Figure 18.4).
in <10% of cases of sporadic MTC without any family H. Serum calcitonin and serum (CEA) are useful biomarkers
history. This may benefit the whole family to detect for assessment of disease burden and prognostication
MTC in the carrier stage. during the preoperative and postoperative period. Serum
ii. De novo RET mutation is seen in 75% of MEN 2B patients. carcinoembryonic antigen (CEA) has long half-life and lower
iii. It detects the familial cases before an abnormal specificity than calcitonin [2].
biochemical test.
I. Use of serum calcitonin test for screening for MTC is controversial.
iv. Abnormal serum calcitonin test does not mean harbor-
Measurement of basal serum calcitonin levels is adequate.
ing the MTC gene, as various conditions like chronic
Provocative calcitonin stimulation tests are not required [2].
renal failure, pancreatitis, small cell lung carcinoma,
and pernicious carcinoma can result in the same.
v. It is done once in a lifetime to detect asymptomatic
carriers instead of doing serial biochemical tests. WORK-UP
vi. It helps in prognostication depending on age-related
progression pattern and in deciding about the optimal
timing for prophylactic surgery. Pre-operative evaluation is crucial in medullary thyroid cancer
vii. It helps to work up the patient for associated management.
endocrinopathy, such as hyperparathyroidism and A. Clinical evaluation: Sporadic MTC presents in the fourth to
pheochromocytoma. Also, it predicts the approach to sixth decades of life, whereas hereditary MTC presents early in
surgical management and the risk of recurrence [2]. life depending on the germline mutation.
Surgical Management of Medullary Thyroid Cancers 135
Work-Up
Mutated codons Exons Phenotype

NH2
533 8 FMTC
603 10 FMTC
609 FMTC/MEN 2A
611 FMTC/MEN 2A
Cysteine-rich
618 FMTC/MEN 2A
Extracellular
domain
domain
620 FMTC/MEN 2A
Cadherin-like
630 11 FMTC
domains
632/633/634 MEN 2A
634 MEN 2A
640 MEN 2A
641 MEN 2A
648 MEN 2A Cysteine-rich
region
Cell membrane
Transmembrane
768 13 FMTC region
781 FMTC
790/791 FMTC
804 14 FMTC
Tyrosine kinase
844 FMTC Intracellular

domain
tyrosine kinase
883 15 FMTC/MEN 2B
891 FMTC
904 FMTC/MEN 2B
912 16 MEN 2B
918 MEN 2B
922 MEN 2B
COOH
Figure 18.1 Schematic representation of RET proto-oncogene.
Figure 18.2 Histological features of classical MTC: 1A low power (×40) and 1B high power (×400). The tumor cells are present in nests and clusters
and have a plasmacytoid morphology with eccentrically placed nuclei and abundant amount of cytoplasm with intranuclear inclusions. Also shows
collection of eosinophilic amorphous material (top left-hand corner) consistent with Amyloid.
History of thyroid, parathyroid, or adrenal disorder in the family; The typical clinical presentation is a thyroid swelling with neck node
history of sudden death in the family following any general anesthesia metastases (75%–90%) (Figure 18.6). Generally, the pattern of lymph
procedure (undetected secretary pheochromocytoma); presence node spread is from central compartment nodes to the ipsilateral
of marfanoid body habitus; thickened everted eyelids mucosal neck node and then to the contralateral neck node and then to the
neuromas (Figure 18.5); intestinal ganglioneuromatosis (phenotypic superior mediastinal nodes.
appearance of MEN 2B); presence of pruritic lesion involving Some patients present with diarrhea secondary to substances secreted
interscapular area (Lichen planus amyloidosis); history of headache, by the MTC tumors, viz calcitonin, calcitonin gene-related peptide,
palpitation, anxiety, tremor and diaphoresis (pheochromocytoma); and other substances. They may present with ectopic Cushing
and Hirschsprung’s disease may suggest hereditary MTC. syndrome with facial flushing due to corticotropin (ACTH) secretions.
136 Surgical Management of Medullary Thyroid Cancers

Work-Up
Figure 18.3 Histological features of oncocytic variant of MTC: 1C (×100) and 1D (×200). Tumor cells in follicular arrangement with centrally placed
nuclei, intranuclear inclusions, and abundant granular cytoplasm, resembling Hurthle cell variant of PTC.
Figure 18.4 Immunohistochemical features of MTC. A panel showing that MTC cells are diffusely positive for synaptophysin, chromogranin,
and calcitonin (hallmark of MTC).
Figure 18.5 Phenotypic characteristics of MEN 2B syndrome.

TNM Classification AJCC, 8th Edition, for MTC
along with distant metastasis and low chances of

biochemical cure. Unlike calcitonin, CEA is a marker
for early differentiation and is retained even in
aggressive tumors [4].
d. Serum calcium and serum parathyroid hormone levels
are done to rule out hyperparathyroidism.
e. RET proto-oncogene analysis: This is done for all to
evaluate the germline mutation (Figure 18.7).
f. Plasma free metanephrines and normetanephrine should
be done for every medullary thyroid cancer before surgery.
g. Imaging
– Ultrasonography (USG) of the neck has to be done for
evaluation of the thyroid and cervical lymph nodes.
– Distant metastatic workup is done whenever there
are cervical lymph node metastasis or serum
calcitonin level above 500 pg/mL. Computed
tomography (CT scan) of the neck and chest is
done to evaluate the extent of neck disease, lung
Figure 18.6 Medullary thyroid swelling with left thyroid nodule with metastasis, and mediastinal nodes. Three-phase
C634G positivity. multi-detector contrast-enhanced (CE) CT scan
or CE MRI is done for liver metastasis. Axial
Locally invasive MTC (10%–15%) may present with dysphagia, magnetic resonance imaging (MRI scan) with
stridor, hoarseness, or dyspnea. Hematogenous spread (5%–10%) contrast and bone scintigraphy is done to rule
may be to the liver, bones, lung, brain, and soft tissues. out bony metastasis. FDG-PETCT scan is done
to evaluate distant metastatic disease. With high
Any previous surgery of the thyroid or neck should be noted along
serum calcitonin levels, the sensitivity of the PET
with the histopathological report. The vocal cord mobility is assessed
scan increases [7].
pre-operatively irrespective of the voice status.
h. In case of locally advanced MTC, fiberoptic bronchoscopy
A thyroid function test is done to assess the functional status of the and flexible esophagoscopy are done to assess the
gland. involvement of aerodigestive tract with transesophageal
B. Investigations ultrasound to assess esophageal involvement.
a. Fine needle aspiration cytology (FNAC): It is performed
under ultrasonography guidance from the suspicious
thyroid nodule for tissue diagnosis. False-negative TNM CLASSIFICATION AJCC, 8TH EDITION, FOR MTC
report for MTC is <20%. An inconclusive report
should have the FNAC washout fluid for calcitonin
measurement and IHC staining. It lacks certain prognostic factors (Table 18.1) like age, biochemical
b. Serum calcitonin: It is done pre-operatively and post- parameters (serum calcitonin and CEA levels), number of
operatively for MTC confirmation, to decide the extent lymph node metastasis, involved compartment by lymph nodes,
of surgery and prognostication. Low serum calcitonin completeness of resection, and genetic mutation analysis [3].
has a limited lymph node burden and higher calcitonin
levels suggest a considerable disease burden. UNRESECTABILITY CRITERIA
Total thyroidectomy with central compartment neck • Extensive disease involvement of internal carotid artery
dissection with ipsilateral neck dissection is done • Prevertebral fascia involvement
for serum calcitonin level between 40–200 pg/mL. • Involvement of mediastinal structures
Contralateral neck dissection is added for more than • Extensive distant metastasis with extensive locally advanced
200 pg/mL and superior mediastinal clearance is added MTC
to this for more than 500 pg/mL of serum calcitonin
PALLIATIVE SURGERY
level. Less than 1000 pg/mL serum calcitonin patient
Locally advanced MTC is treated with less aggressive surgery with
may achieve 50% biochemical cure rates while more
minimal morbidity for palliation. The decision is based on structures
than 10,000 pg/mL serum calcitonin may not achieve
involved, extent of disease, life expectancy, medical comorbidity,
biochemical cure. Calcitonin is a late marker for terminal
and quality of life. Palliative surgery may be offered to cutaneous,
differentiation and is lost in aggressive tumors [4].
hepatic, lung, brain, and bony metastasis. A multidisciplinary team
A poorly differentiated MTC, a defect in the cellular plays an important role in decision-making.
level and mutation involving calcitonin gene-related
peptide (CGRP) gene may present with normal serum SURGICAL TREATMENT
calcitonin and carcinogenic embryonic antigen CEA In the past, a total thyroidectomy without neck dissection was
levels despite having advanced disease [5,6]. done for MTC. However, current recommendations are a total
c. Serum carcinogenic embryonic antigen (CEA): Low thyroidectomy with a systematic lymph node clearance (central,
level of serum CEA indicates a low incidence of nodal lateral, and mediastinum). This compartment oriented dissection
metastasis to the central, ipsilateral, or contralateral avoids removal of only involved nodes (Berry picking). Sensitivity
compartment. As the serum CEA level reaches of intra-operative palpation to detect lymph node metastasis is very
>100 ng/mL, the patient has a high chance of lymph low (64%) [8]. This avoids the repeated recurrences in the same
node metastasis to central and bilateral compartment compartment, increased morbidity, and poor survival.

(a) Heterozygous variant
G A C G A G C T G T G C C G C A C
59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75
(b) Wild type
A C G A G C T G T G C C G C
60 61 62 63 64 65 66 67 68 69 70 71 72 73
Figure 18.7 Germline mutation C634G (ATA-H, high risk) in RET proto-oncogene.
Miyauchi et al. have advocated unilateral thyroidectomy with oriented surgery may decrease the risk of local recurrences and
ipsilateral central compartment clearance with neck dissection in further morbidity such as infiltration of local structures.
nonhereditary, unifocal, small MTC with low serum calcitonin in Following are the special considerations from the MTC point
patients without germline RET mutation [9]. of view:
However, this is rarely done as they usually present as advanced
disease with abnormal serum calcitonin levels. The surgical
• The neck extension is given so as to aid dissection of the superior
mediastinum. Even though generally MTC warrants extensive
technique for total thyroidectomy is the same as for the differentiated bilateral neck dissection, Kocher’s incision is still preferred
thyroid cancer. However, the clearance is more aggressive than DTC without any vertical extension.
as there is no RAI back up. Size of the primary tumor does not decide
the extent of surgery for thyroid or for neck nodes. Bilateral thyroid
• Cutting strap muscles leads to adherence of neck skin to the
tracheal cartilage directly giving “cobra deformity” which is
tumors have high chances of bilateral lateral compartment nodal cosmetically not acceptable. Therefore, mere large thyroid
metastasis. In the presence of upper pole thyroid tumor, the patient gland and MTC histology do not warrant a strap muscles
may present with lateral compartment nodal metastasis with skip sacrifice. Only in case of extrathyroidal extension, the strap
central compartment. muscles are partially sacrificed.
SURGICAL STEPS
• The parathyroid and recurrent laryngeal nerve makes the
thyroidectomy an interesting and skillful surgery. Parathyroid
Surgical steps are the same for MTC or DTC for performing total
glands receive the blood supply from the inferior thyroid
thyroidectomy. However, the disease clearance is more aggressive
artery. Occasionally the superior parathyroid gland may
than DTC. Intra-operative nerve monitoring and magnification may
be supplied by the superior thyroid artery. The dissection
be used as adjunct for surgery.
over the thyroid and fascia on the lateral aspect and then
Based on location and size of the primary MTC, USG findings, proceeding superiorly helps to preserve this branch instead
cross-sectional studies, serum calcitonin and serum CEA levels, and of taking superior pole vessels directly. Due to extensive
intra-operative frozen section, the extent of the initial neck node central compartment dissection, it is essential to safe guard
compartment dissection is determined. the blood supply of the bilateral superior parathyroid gland.
Patients with lymph node metastasis and higher serum calcitonin The technique of identification of the parathyroid gland is the
levels are systematically not curable. However, a compartment same as in DTC. Indocyanine green (ICG) dye injection along

Table 18.1 AJCC 8th edition staging for medullary thyroid cancer
T category T criteria
Definition of primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor 2 cm or less in greatest dimension, limited to the thyroid
T1a Tumor 1 cm or less, limited to the thyroid
T1b Tumor more than 1 cm, but less than or equal to 2 cm, in greatest dimension, limited
to the thyroid
T2 Tumor more than 2 cm, but less than or equal to 4 cm in greatest dimension, limited
to the thyroid
T3 Tumor more than 4 cm in greatest dimension or with extrathyroidal extension
T3a Tumor more than 4 cm in greatest dimension limited to the thyroid
T3b Tumor of any size with gross extrathyroidal extension invading only to strap muscles
(sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles)
T4 Advanced disease
T4a Moderately advanced disease: Tumor of any size with gross extrathyroidal extension
into the nearby tissues of the neck, including subcutaneous soft tissues, larynx,
trachea, esophagus, or recurrent laryngeal nerve.
T4b Very advanced disease: Tumor of any size with extension toward the spine or into
nearby large blood vessels, gross extrathyroidal extension invading the prevertebral
fascia or encasing the carotid artery or mediastinal vessels.
N category N criteria
Definition of regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No evidence of locoregional lymph node metastasis
N0a One or more cytologically or histologically confirmed benign lymph nodes
N0b No radiological or clinical evidence of locoregional lymph node metastasis
N1 Regional lymph node metastasis
N1a Metastasis to level VI or VII (pretracheal, paratracheal, and prelaryngeal/Delphian or
upper mediastinal) lymph nodes. This can be unilateral or bilateral disease.
N1b Metastasis to unilateral, bilateral, or contralateral lateral neck lymph nodes levels I, II,
III, IV, or V) or retropharyngeal lymph nodes
M category M criteria
Definition of distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
AJCC stage Stage grouping
Prognostic stage groups
I T1 N0 M0
II T2/T3 N0 M0
III T1/T2/T3 N1a M0
IV A T4a Any N M0
IV A T1/T2/T3 N1b M0
IV B T4b Any N M0
IV C Any T Any N M1
with near infrared camera may be used for parathyroid glands the nerve and assess the functional aspect of the RLN and
identification [10]. EBSLN.
• A thorough knowledge of the anatomical variation in this • Central compartment neck node dissection is done with
area is essential for performing total thyroidectomy. Thermal serum calcitonin level >40 pg/mL. It constitutes prelaryngeal,
damage to the cricothyroid muscle should be avoided which pretracheal, and bilateral paratracheal lymph nodes. The
leads to cricothyroiditis, fibrosis, and change in voice pitch. central compartment is cleared from hyoid to suprasternal
Exposure of the RLN in its entire course should be avoided notch and between internal carotid arteries either side
if possible. In case of infiltration of RLN by disease or nodes, laterally. The prelaryngeal and pretracheal dissection is done
a plane of dissection is attempted. If not possible, then the to clear the lymph nodes. Upper mediastinal clearance is
nerve is sacrificed after securing the functional contralateral done if serum calcitonin is >500 pg/mL. It is cleared from
RLN. Intra-operative nerve monitoring may help to trace the suprasternal level to innominate artery on the right side

Table 18.2 Clinico-radiological and biochemical combined criteria for extent of nodal clearance
Extent of surgery for central, lateral,

Clinical/imaging criteria Serum calcitonin criteria and superior mediastinal compartment
No central compartment nodes Serum calcitonin <20 pg/mL Central: Ipsilateral

No central compartment nodes Serum calcitonin 20–50 pg/mL Central: Ipsilateral
or Lateral: Ipsilateral SND (II–V)
Ipsilateral central compartment nodal metastasis
or
Ipsilateral lateral cervical nodal metastasis
Central compartment nodal metastasis Serum calcitonin 50–200 pg/mL Central: Bilateral
or Lateral: Ipsilateral SND (II–V)
Ipsilateral lateral cervical nodal metastasis
Contralateral nodal metastasis Serum calcitonin >200 pg/mL Central: Bilateral
Lateral: Bilateral SND (II–V)
Superior mediastinal nodal metastasis Serum calcitonin level >500 pg/mL Upper mediastinal clearance
Central: Bilateral
Lateral: Bilateral SND (II–V)
and corresponding axial plane on the left side. Meticulous spinal accessory nerve) are saved if not involved. If infiltrated
dissection and securing the vessels with ligation or clip is due to disease, then these structures are sacrificed. Bilateral
important. internal jugular veins should not be sacrificed as this leads
• Bilateral paratracheal dissection is important as it is crucial to severe facial edema and cerebral edema. If it is indicated
for functionality of the RLN and parathyroid viability. The bilaterally, then the jugular vein has been resected as a
tissue between hyoid and cricoid cartilage rarely harbors two-stage procedure. Also, sacrificing the vagus nerve,
lymph nodes. The dissection is started from the carotid artery if necessary, should be attempted only after securing the
laterally and inferiorly. The inferior thyroid artery is preserved contralateral vagus nerve and the RLN. The chyle duct should
and the inferior parathyroid gland along with its blood supply be preserved and any damage to small chyle duct collaterals
is flipped laterally. The fibrofatty tissue along with all lymph should be secured and confirmed by the valsalva maneuver.
nodes are dissected out. The course of the right RLN is more Figure 18.8 shows the intra-operative thyroid bed after
oblique and ventral. The left side RLN is vertical and close to excision, and Figure 18.9 shows the specimen of the same
the tracheoesophageal groove. patient.
• Any devascularized parathyroid is removed and stored • Hemostasis is achieved and strap muscles are approximated
in ice cold isotonic sodium chloride solution and frozen in midline. No drains are kept in the central compartment.
confirmation is achieved. All the parathyroid glands, except Avoid taking out the drain in the midline or below the
in high incidence of hyperparathyroidism MEN 2A cases, are clavicle. The suction drain is placed on either side in the line
autotransplanted in sternocleidomastoid muscle and tagged
by nonabsorbable suture for future identification. In MEN
2A cases with high incidence of hyperparathyroidism, the
devascularized parathyroids are autotransplanted in non-
dominant forearm brachioradialis muscle (heterotopic
muscle bed) after mincing into 1 mm × 3 mm fragments.
A portion of the graft can be removed if graft dependent
hyperparathyroidism develops [2].
• There is no role of prophylactic parathyroidectomy as
hyperparathyroidism is age dependent and requires a second
hit with low penetrance depending on the germline mutation.
The normal well vascularized parathyroid glands are left
in situ.
• The term “compartmental oriented cervical lymphadenectomy”
was coined by Dralle et al. They divided the neck compartment
into cervicocentral right C1a and left C1b compartments,
cervicolateral right C2 and left C3, and mediastinal right C4a
and left C4b compartments [11].
• The lateral neck dissection is usually done from level II to
level V for clearance of all micrometastasis in the neck. Some
surgeons advocate performing less than level II to level V neck
dissection [12]. Table 18.2 shows the extent of neck dissection
based on clinic radio-biochemical criterion [13,14].
• In view of bulky lymph nodal burden and aggressive
thyroid pathology, dissection is done with meticulous Figure 18.8 Intra-operative thyroid bed after total thyroidectomy
hemostasis. The important three non-lymphatic structures with bilateral central compartment clearance and bilateral selective neck
(sternocleidomastoid muscle, internal jugular vein, and dissection (II–V).

Prophylactic Cancer Surgery
oriented lymph node dissection is done instead of Berry picking.

Only in extensively operated fields is selective resection of the
disease done.
Indications for revision surgery are:
1. Incomplete surgery in RET germline mutation positive patient
2. Post-operatively elevated calcitonin >150 pg/mL or with
calcitonin double the baseline post-operative value with
resectable disease
3. Residual MTC on imaging
4. Pre-operative serum calcitonin high, however, histopathology
suggestive of incomplete and inadequate clearance
5. Initial surgery showing C-cell hyperplasia with incomplete
surgery
6. Multicentric tumor with positive tumor margin, less than five
lymph nodes dissection, and extrathyroid extension at the
Figure 18.9 Surgical specimen following total thyroidectomy, bilateral
initial surgery with incomplete surgery [2]
central compartment clearance, and bilateral selective neck dissection
7. Compartmental microdissection to bring down the serum
(II–V) with C634G positivity.
calcitonin level—initial concept described by Norton et al.
of the incision. The wound is closed in layers and subcuticular (1980) [17], Tisell et al. (1986) [18], Dralle et al. (1994), etc. [11]
sutures are taken.
• All patients undergo post-operative laryngeal examination to
assess the vocal cord mobility and are started on Thyroxine
supplement. Hypocalcemic patients are treated with oral and ADJUVANT EXTERNAL BEAM RADIOTHERAPY (EBRT)
intravenous calcium supplements or oral calcium supplements
along with calcitriol depending on the severity of clinical
symptoms and biochemically corrected calcium levels. Dose: 60–66 Gy/6 weeks/4–6 MV photons for adjuvant treatment
• Coexisting pheochromocytoma with MTC: The and 70 Gy for gross residual disease.
pheochromocytoma should always be addressed first and MTC Adjuvant EBRT should be considered in patients at high risk for
surgery later. local recurrence (microscopic or macroscopic residual MTC,
• Coexisting hyperparathyroidism with MTC: Single staged surgery extrathyroidal extension, or extensive lymph node metastases) and
is done. The involved gland is excised and, if required, subtotal or those at risk of airway obstruction [2].
total parathyroidectomy is done for three or four gland disease.
• Isolated pheochromacytoma following initial thyroidectomy:
Work-up is done for the pheochromocytoma and laproscopic
subtotal adrenalectomy or retroperitoneoscopic subtotal PROPHYLACTIC CANCER SURGERY
adrenalectomy with cortical area sparing surgery is done.
Pheochromocytoma should be excluded in patients with
MEN 2 who wish to become pregnant, and if detected during This is the pre-emptive operative removal of an organ prior to
pregnancy, it should be resected prior to the third trimester malignant transformation or while the cancer is “in situ” from an
if possible. asymptomatic individual.
To perform any prophylactic cancer surgery, certain criteria need
to be fulfilled. You et al. have given the following ideal criteria for
prophylactic surgery in cancer. The criteria are fulfilled by MEN 2A
RECURRENCE/METASTASIS/RESIDUAL MTC
and MEN 2B [19].
1. Gene mutation complete or near complete penetrance: MTC
During the post-operative period, serum calcitonin is done at penetrance is 100%
3 months. If it is normal, then it is done every 6 months for 1 year 2. Highly reliable test: RET proto oncogene is highly reliable test
and then yearly [2]. to detect germline mutation
In patients with serum calcitonin >150 pg/mL or where serum 3. Organ at risk is expendable or replacement therapy is available:
calcitonin is doubled, a whole-body evaluation is warranted. Thyroxin supplement is available following prophylactic total
Patients with calcitonin doubling time less than 6 months have thyroidectomy
poor 5-year and 10-year survival rates. Patients with calcitonin 4. Minimal surgical morbidity and mortality: Thyroid surgery is
doubling time of more than 24 months have the best 5-year with minimal morbidity
and 10-year survival rates. Calcitonin doubling time is a better 5. Reliable test for cure: Serum calcitonin is used during follow-up
predictor of survival than the CEA doubling time [15]. In patients with its doubling time
with post-operative elevated calcitonin levels, one forth of patients
may have false negative imaging in spite of having fine military Factors affecting the timing of prophylactic thyroid surgery for
pattern liver metastasis, which may be visible only on laparoscopic mutation positive MTC are [20]:
examination [16]. 1. DNA analysis and genotype and phenotype correlation
If resectable disease is detected, revision surgery is done to achieve 2. Age of onset of MTC: Germline mutation carrier 918 present
biochemical cure. Even during revision surgery, compartment with early (<1 yr) onset MTC than rest

Salient Points
3. Aggressiveness of MTC: Germline mutation 918 is more OUTCOME

aggressive, followed by 634, and then the rest Risk of having stage III/IV MTC at the time of diagnosis increased 12%
4. Lymph node propensity and distant metastatic spread: per year of age at thyroidectomy [21]. Rate of recurrence is 0% versus
Germline mutation 918 present with early lymph node and 34–42% when compared prophylactic versus therapeutic respectively
distant metastasis [22,23]. There is a strong correlation between age at surgery and the
5. Not reliable to use calcitonin levels during early life as the levels rate of disease recurrence following surgery.
are high <3 years
6. In older patients, depending on clinical data and serum SURVIVAL
calcitonin levels. This should be used cautiously as loss to Ten-year survival rate ranges from 21%–100%. Ten-year survival rate for
follow up for periodic visits is common and may present with stages I, II, III, and IV MTC are 100%, 93%, 71%, and 21% respectively
clinically evident disease. [24].
7. Issues with early age thyroid surgery Survival depends on the pre-operative serum calcitonin levels and
• Higher rates of complication their normalization after surgery. It also depends on the age, tumor
• Small, translucent parathyroid glands and difficult to size, stage, lymph node status, distant metastasis, and adequacy of
surgery. However, stage adjustment may show a similar progression
distinguish parathyroids from surrounding tissues
• Warrants experienced surgeons between sporadic and hereditary MTC.
• Magnification
• Low compliance for follow up and evaluation
• Detrimental effect of insufficient thyroid hormone SALIENT POINTS
replacement due to poor compliance leading to
impaired brain development and retarded growth
• Surgery for <2 years age is more challenging [2] • Medullary thyroid cancer is an aggressive disease that falls
between DTC and anaplastic cancer.
SURGERY EXTENT • RET proto oncogene testing, serum calcitonin,
Prophylactic total thyroidectomy is done to clear all C-cell serum CEA, imaging, and ruling out secretary
precursors. Central compartment clearance is done when serum pheochromocytoma comprise the essential pre-operative
calcitonin is >40 pg/mL (serum calcitonin is very high <3 work-up before surgery.
years, therefore not useful). In 918 germline mutation (MEN 2B)
patients, with age >1 year, if parathyroid glands are identified,
• An undiagnosed pheochromocytoma in a patient undergoing
any procedure under general anesthesia may result in
then central compartment clearance is done. There is no role substantial morbidity and even death.
for any prophylactic parathyroidectomy [2]. Table 18.3 shows
the guidelines for screening and timing of prophylactic thyroid
• Medullary thyroid cancer is rare cancer arising from
parafollicular C-cells. Therefore, they do not concentrate RAI,
surgery in MEN syndrome. and there is no role of TSH suppression.
Table 18.3 Guidelines for screening and prophylactic surgery in MEN syndrome
Associated Timing of
endocrinopathy/ Screening for prophylactic surgery Screening for
Hereditary Types abnormality with MTC Incidence MTC for MTC PHEO/HPTH
Autosomal MEN 2A (A) Classic MEN 2A with 50% High risk; ATA-H Before 5 yrs or 11 yrs PHEO
Dominant 1) 634 (634) 20%–30% ATA-H (634): earlier based on for ATA- H
(High risk; Pheochromocytoma 3 yrs elevated serum and ATA- HST
ATA-H) (PHEO) calcitonin levels
Hyperparathyroidism
(HPTH)
MTC: (B) MEN 2A with Cutaneous Rare 36%
Bilateral, lichen planus CLA (634) MEN2A;634
multicentre
C cells are 2) Rest (excluding (C) MEN 2A with Rare 7% MEN2A Moderate risk; ATA- MOD May be 11 yrs HPTH
precursor 918,883,634) Hirschsprung disease HD PHEO 20%–30% ATA- MOD delayed beyond 5 yrs for ATA- H
for MTC (Moderate risk; (609/611/618/620) HPTH 10% (Rest): 5 yrs depending on serum
ATA-MOD) calcitonin levels
(D) Familial MTC None
MEN 2B Pheochromocytoma 50% Highest risk; ATA- HST 16 yrs
3) 918 Multiple mucosal neuroma >95% ATA- HST As soon as possible PHEO/HPTH for
(Highest risk; Marfanoid body habitus 80% (918): Soon and within 1st year ATA-MOD
ATA -HST) Mucosal Neuroma after the birth of life perhaps even
Intestinal in 1st month
ganglioneuromatosis
4) 883 ATA-H (883): ATA- H: Before 5 yrs or
(High risk; ATA- H) 3 yrs earlier based on
elevated serum
calcitonin levels

References
• Distant metastatic work-up is done for serum calcitonin level

more than 500 pg/mL.
• Do not perform hemithyroidectomy or subtotal thyroidectomy
ACKNOWLEDGMENTS
in MTC.
• Surgery is the mainstay of treatment in MTC.
• Subcapsular plane of dissection, thorough knowledge of
The authors would like to acknowledge Dr. Neha Mittal, Assistant
Professor in Pathology Department for microphotographs; Mr. Nilesh
anatomy and its variation, and meticulous dissection are
N Ganthade, Officer in charge of Medical Graphics, Tata Memorial
essential steps for the MTC surgery.
• Systematic compartment wise neck dissection is done under
Centre, Mumbai for graphics; Dr Rajiv Sarin, Professor in Radiation
Oncology Department for germline mutation photograph; and
the pre-operative serum calcitonin level guidance rather than
Dr. Gouri Pantvaidya for surgical photographs.
Berry picking.
• Use pressure to control bleeding instead of the use of
electrocautery near the entry point of the RLN.
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Chapter 19
SURGICAL MANAGEMENT OF ANAPLASTIC THYROID CANCERS
Deepa Nair and K.S. Rathan Shetty
CONTENTS
Introduction 147
Clinical Presentation 147
Treatment 148
Role of Neoadjuvant Treatment 149
References 149
frequently associated with an enlarged neck node [14]. The tumor

may be tender on palpation with features such as redness of external
INTRODUCTION
skin, local rise in temperature, and skin necrosis which may be due
to rapid tumor growth. The tumor is usually hard on palpation and
may be fixed to surrounding structures like the trachea, larynx,
Anaplastic thyroid cancers (ATC) are extremely aggressive
esophagus, great vessels, and also may have retrosternal/mediastinal
undifferentiated tumors arising from the thyroid follicular
extension. Involvement of extrathyroidal structures may lead to vocal
epithelium. They are characterized by rapid progression of the disease,
cord palsy, stridor, dysphagia, and neck venous engorgement [15].
poor outcomes, and with a disease-specific mortality close to 100%
Another pathognomonic feature of ATC is rapid disease progression
[1–3]. The diagnosis of ATC is agonizing news to the patient, and early
due to which the clinical symptoms and signs may evolve during
diagnosis of the disease remains paramount to initiate treatment.
the course of clinical assessment; hence, early diagnosis is the key to
The age-adjusted annual incidence of anaplastic cancer ranges from
achieve meaningful treatment outcomes [2,6,16].
one to two per million persons [4,5] and accounts for 0.9%–9.8% of
all thyroid cancers in the world [6]. ATC, like all thyroid cancers, DIAGNOSIS
have a female predominance and affect older individuals, most ATC can be confirmed by cytological examination like FNAC
commonly in the 6th–7th decade of life, and fewer than 10% occur or core biopsy from the neck mass [17,18]. In a case series of 113
in individuals younger than 50 years [7]. It has been hypothesized fine-needle aspirates in patients with anaplastic thyroid cancer,
that ATC develops from pre-existing differentiated thyroid tumors 107 (94.7%) were diagnostic of malignancy, and 96 of 107 were
due to dedifferentiation, which is supported by the finding that diagnosed with anaplastic thyroid cancer. The remaining 11 were
approximately 20% have a history of differentiated thyroid cancer diagnosed with differentiated thyroid cancer and malignant
and 20%–30% have coexisting differentiated thyroid cancer [8,9]. tumor not otherwise specified [17]. Ultrasonography guided fine-
needle aspiration of solid, non-necrotic tumor is advisable to assist
cytological diagnosis [19]. Core biopsy or infrequently open biopsy
CLINICAL PRESENTATION may be required if FNAC shows necrotic or inflamed tissue without
a specific diagnosis. If core biopsy or open biopsy is to be done,
then the site of biopsy should be along the line of the likely surgical
The most common clinical symptom is a rapidly enlarging neck incision in case of resectable disease. Cytology or biopsy specimen
mass with other concomitant symptoms like pain, dyspnea, should be subjected to immunohistochemistry to aid in diagnosis. A
dysphagia, hoarseness, and cough. These symptoms arise due to highly dedifferentiated ATC may lose TTF1, Tg positivity which is of
involvement of aerodigestive structures like the trachea, larynx, help in differentiating from poorly differentiated thyroid carcinoma
esophagus, recurrent laryngeal nerves, and great vessels [2,8,10]. in which it is retained. Various cytomorphological patterns of ATC
Another hallmark of ATC is the frequency of distant metastasis are spindle cell, pleomorphic giant cell, and squamoid and may
at presentation, which can be seen in up to 50% of cases, leading have a mixture of two or more patterns of varying proportions [6].
to symptoms like chest pain, bone pain, dyspnea, cough, weight On cytopathology, there may be a coexisting differentiated thyroid
loss, and fatigue. Hyperthyroidism may also be a feature due to a cancer, usually papillary carcinoma of the thyroid or infrequently
rapidly enlarging mass leading to destruction of normal thyroid follicular carcinoma of the thyroid. ATC has been reported in up to
tissue causing release of thyroid hormones into the bloodstream or 10% of Hurthle cell carcinomas [20].
thyroiditis [2,8,10].
Lungs are the most common site of distant metastases, where they EVALUATION
can occur in up to 90% of the cases, followed by bony metastases in Clinical evaluation should include laryngoscopy and upper GI
5%–15% of cases; other not so frequent sites are brain, abdomen, and endoscopy to assess the involvement of the aerodigestive tract.
pancreas [6,10–12]. Death is usually due to obstruction or invasion of Appropriate imaging to assess extent and staging should involve
the aerodigestive tract along with distant metastasis [13]. ultrasonography of the neck along with a PET scan as recommended
by ATA [21]. A PET scan would show intense uptake of 18 FDG in
CLINICAL FINDINGS the primary as well as metastatic nodes as ATC are found to be
On clinical examination, the most common clinical finding is a hard highly GLUT1 positive [22]. Patients with anaplastic thyroid cancer
thyroid mass involving one or both lobes of the thyroid and may be may have coexisting differentiated thyroid cancer. The appearance
Surgical Management of Anaplastic Thyroid Cancers 147

Treatment
of distant metastases may not necessarily be from ATC and should Total thyroidectomy with central and lateral neck lymph node
not preclude curative intent. PET scan may help in differentiating dissection is the preferred treatment in ATC. In intrathyroidal
between these two as ATC are hypermetabolic and have more avid tumors without coexisting well-differentiated thyroid cancer,
uptake on PET scanning when compared to differentiated thyroid thyroid lobectomy with wide margins of adjacent soft tissue on
cancer [22–24]. the side of the tumor has been tried as it has been shown that total
If PET scan is not available, then CECT/MRI of the neck, brain, thyroidectomy with complete tumor resection does not prolong
chest, abdomen, pelvis, and a bone scan can be done to assess the survival compared to ipsilateral thyroid lobectomy and is associated
extent of the thyroid tumor and to identify tumor invasion of the with a higher complication rate [16,21]. However, total thyroidectomy
great vessels, upper aerodigestive tract, and distant metastatic sites is generally preferred in ATC to ensure complete tumor resection.
[25]. Brain MRI is recommended as part of an initial work-up in the Total thyroidectomy with therapeutic central and lateral neck node
presence of neurological symptoms. Laboratory investigations are dissection is recommended for stage IVb disease [6,21,34].
done as part of the general work-up [26]. In patients with surgically Neoadjuvant pre-operative radiotherapy (XRT) can be considered
resectable primary tumor, FNAC or biopsy of distant metastatic sites to downstage locally unresectable disease so as to subsequently
may be required to differentiate between well differentiated cancer enable complete gross resection; however, the surgical dissection
and ATC when considering surgery. Thyroglobulin level will be may become challenging in a radiated field along with increased
markedly elevated in distant metastasis due to well differentiated risk of complications. The intent of surgery should be gross total
thyroid cancers unlike in anaplastic carcinoma of the thyroid [27]. resection as debulking surgery may not necessarily prolong survival
Laboratory investigations should include thyroid hormonal profile, and the extent of resection should be weighed against the morbidity
complete blood count, serum biochemistry including BUN, of the procedure, especially in an aggressive disease such as ATC
electrolytes, calcium, and phosphorous, which may be deranged in characterized by dismal survival. Limited resection of the trachea
distant metastases. Serum thyroglobulin may have a role to assess or larynx can be performed if the morbidity is minimal; however,
the possibility of metastatic well-differentiated thyroid cancer laryngectomy, esophagectomy, or sternotomy is generally avoided as
which is markedly elevated if metastatic lesions are from the well- it is associated with higher complications and morbidity rates with
differentiated component of the tumor rather than ATC; however, poor quality of life. De Crevoisier et al. in a prospective study report
it cannot be relied upon as it may also be raised in inflammatory that in a multivariate analysis, gross tumor resection (i.e., R0 or R1)
thyroid disease and goiter. is associated with longer survival [35].
Surgery should be attempted only when R0 or R1 resection is
STAGING possible and is almost always followed by adjuvant radiotherapy
Only about 10% of patients have ATC confined to the thyroid with or without chemotherapy [35–38].
gland. About 40% of ATC have extrathyroidal extension and/or
When ATC is detected incidentally as a microscopic focus within
neck metastases, and up to 50% may have distant metastases at
a differentiated thyroid cancer after thyroidectomy, there is no
presentation [28,29].
adequate evidence to guide a surgical strategy; however, a completion
As per AJCC, 8th Edition, all anaplastic cancers are now classified thyroidectomy is preferred by most followed by radioiodine ablation
according to the same T definitions as differentiated thyroid cancer. [29]. ATA guidelines recommend close observation with frequent
All anaplastic cancers are considered stage IV cancers, intrathyroidal anatomic imaging [21].
disease is stage IVa, gross extrathyroidal extension or cervical lymph
When ATC is detected after a hemithyroidectomy, completion
node metastases are stage IVb, and distant metastases are stage IVc [21].
thyroidectomy is preferred by most surgeons, and this surgical strategy
is also determined by the stage of the coexisting differentiated thyroid
tumor component if present. Thyroid lobectomy with wide margins
TREATMENT for intrathyroidal tumors has been shown to have similar survival
compared to total thyroidectomy in such a scenario and it should
always be followed by adjuvant radiation to the neck. Completion
Management of ATC involves multidisciplinary teams made thyroidectomy is preferred if the stage of coexisting differentiated
up of surgeons, radiation oncologists, medical oncologists, and thyroid tumor component dictates total thyroidectomy and is followed
ancillary specialists. The best definitive treatment involves surgical by radioiodine ablation along with adjuvant radiotherapy. Several
extirpation followed by post-operative external beam radiotherapy large retrospective studies studies have shown that surgery combined
(EBRT) and chemotherapy [30–32]. EBRT and chemotherapy is with radiotherapy provides the longest survival. A meta-analysis of
generally preferred in unresectable disease [6,11,21,33]. 17 retrospective studies by Kwon et al. has shown that radiotherapy
Accurate assessment of performance status, staging, and improves survival in ATC patients. However, it is not certain as to
resectability is important when contemplating surgery. Treatment which cumulative doses, and whether radiotherapy versus combined
decisions and its initiation should be undertaken as early as possible radiochemotherapy before or after surgery is beneficial [39]. In
as the tumor may become unresectable within months if not weeks. aggressive surgeries involving limited tracheal resection, laryngectomy
Surgical treatment may not be feasible in a majority of cases due to is warranted only if R0 resection can be achieved without grossly
the advanced nature of the disease at presentation; however, if the compromising the quality of life [13,40,41]. Surgery is avoided for
disease is confined to the neck and is resectable, then surgery should tumors involving the upper mediastinum, esophagus, and great vessels
be considered if gross tumor resection is possible with minimal as it is associated with higher morbidity rates and poorer survival.
morbidity. Combined modality treatment, i.e., surgery followed Palliative surgery of the resectable primary tumor may be considered
by adjuvant radiotherapy with chemotherapy, has shown the best in stage IVc disease in order to avoid subsequent aerodigestive tract
survival among patients with resectable tumors [30–32]. obstruction and it may enhance quality of life. Complications
Pre-operative staging determines surgical intervention. For patients of surgery are usually higher compared to differentiated thyroid
with stage IVa or stage IVb disease, in whom gross total resection cancers and include hemorrhage, dysphagia, salivary fistulae,
is feasible, surgery should be expedited as complete resection is hypoparathyroidism, chylous fistulae, vocal cord paralysis, and
associated with prolonged disease-free and overall survival [29–32]. surgical site infection [38]. A case series by Brignardello et al.
148 Surgical Management of Anaplastic Thyroid Cancers

References
reported complications like recurrent laryngeal nerve injury in 2 SURVEILLANCE

of 55 patients (3.6%), hypoparathyrodism in 11 of 55 patients (20%), Patients who have undergone a complete resection should undergo
2 of 55 patients required a tracheostoma (3.6%), and hemorrhage was aggressive surveillance with cross-sectional imaging every 1–3
found in 1 of 55 patients (1.8%) [38]. months for the first year, and every 4–6 months thereafter. FDG
In a study by Sugitani et al. [8] 233 patients with stage IVb were evaluated PET is a useful tool to monitor recurrence or to assess the success
retrospectively. Outcomes of patients who underwent super-radical of treatment. Thyroglobulin measurements and radioactive iodine
resection (n = 23) were compared to patients who underwent curative scanning are not useful in ATC [21].
surgery (n = 49), palliative surgery (n = 72), or no surgery (n = 80). To conclude, surgical extirpation of the tumor followed by adjuvant
The one-year cause-specific survival rate for patients who underwent radiotherapy with or without chemotherapy is the optimal treatment
super-radical surgery was similar to patients who underwent restricted modality in operable anaplastic thyroid cancer. Integration of
curative surgery, and significantly better than patients who underwent targeted therapy in the multimodality management of anaplastic
palliative surgery or no surgery (level IV) [42]. thyroid cancer needs to be further investigated to design an optimal
Securing a patent airway may be challenging in patients with large treatment strategy to deal with aggressive tumors.
tumors. Routine tracheostomy is generally avoided as it worsens
the quality of life and has not been shown to prolong survival.
Tracheostomy is considered during acute airway compromise and for
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150 Surgical Management of Anaplastic Thyroid Cancers

Chapter 20
POST-TREATMENT SURVEILLANCE OF THYROID CANCER
Abhishek Vaidya
CONTENTS
Introduction 151
Surveillance Tools for DTC 151
Initial Risk Stratification 153
Dynamic Risk Stratification 155
Surveillance Strategies 157
Summary 158
Acknowledgments 158
References 158
The level of serum Tg is an aggregate of three variables: the mass

of thyroid tissue (benign or neoplastic) in the body, the degree of
INTRODUCTION
thyroid-stimulating hormone (TSH) stimulation, and the thyrocyte’s
innate ability to produce Tg [8].
There has been a recent increase in the incidence of thyroid cancer Since Tg is dependent on TSH levels, Tg measurements should
worldwide [1–3]. However, a significant proportion of this has been always be interpreted relative to TSH levels in the patient. Higher
due to overdiagnosis of subclinical disease, and the disease-specific TSH levels increase serum Tg levels and thus increase its sensitivity
mortality remains unchanged [3]. Differentiated thyroid cancers as a tumor marker for DTC. Serum Tg levels measured in presence
(DTCs) carry a low global mortality rate of about 0.5/100,000 [4], of normal TSH level are called “unstimulated Tg levels” or
with most disease specific mortality occurring in a few patients “suppressed Tg levels,” while Tg measured in presence of elevated
with advanced disease [2]. Overall, most thyroid cancers have a TSH is called “stimulated Tg level.” In a patient who has received
good prognosis with a low risk of mortality. But there remains a initial therapy, the TSH level can be increased by two methods:
significant risk of residual disease and recurrence, only a minority (1) The withdrawal of exogenous Levothyroxine (T4), such that
of which is clinically significant [5]. The combination of increased endogenous TSH levels increase. This is known as thyroid hormone
diagnosis and treatment on one hand and low mortality on the other withdrawal TSH stimulation and may require about 2–4 weeks of
hand results in a large group of treated thyroid cancer patients who T4 withdrawal. (2) The administration of exogenous recombinant
need post-treatment surveillance [5]. Surveillance strategies for TSH (rTSH). This is known as rTSH stimulation of Tg and takes 2–3
DTCs have a significant economic impact, with a study in the United days only. After two doses of rTSH (0.9 mg intramuscularly daily),
States showing that the cost to detect a recurrence in low-risk patient Tg values have been shown to be as accurate as those obtained
is 6–7 times more than the cost for intermediate-risk and high-risk after endogenous TSH elevation after T4 withdrawal [9]. Tg levels
patients [6]. The aim of the surveillance strategy, therefore, should typically increase 10 times after TSH stimulation in DTCs, whereas
be to accurately identify recurrences in high-risk patients and spare this rise may be less than three times in poorly differentiated
additional investigations in those patients at low risk of recurrence. thyroid cancers [8]. RAI ablation also increases Tg sensitivity as
High specificity tools allow identification of those unlikely to have a a tumor marker by removing normal residual remnant thyroid
recurrence; such that safer, cheaper, and less aggressive surveillance tissue after surgery. Thus, the Tg threshold used to define response
strategies could be directed towards this group, whereas those with to treatment depends on residual remnant thyroid tissue, whether
a high risk for recurrence are monitored more aggressively since the patient has undergone total thyroidectomy + RAI ablation
early recurrence diagnosis allows optimal treatment [7]. This chapter or total thyroidectomy alone or lobectomy alone (Tables 20.3
focuses on the surveillance and follow-up strategies in DTC, in the and 20.4).
context of existing guidelines, including the 2015 guidelines of the A single Tg level measurement (stimulated or unstimulated) may
American Thyroid Association. We look at the surveillance tools not give an accurate and complete picture in the context of ongoing
available, the initial and dynamic risk stratification system, and management. Hence it is recommended that serial Tg measurements
follow-up schedules and strategies. should be used to determine disease progress, the response to
treatment, and the need for any additional imaging or therapy.
Several assays are available for Tg measurement, and there is a lack of
SURVEILLANCE TOOLS FOR DTC standardization across assays. Hence Tg should always be measured
by the same method, preferably from the same laboratory. Classic Tg
assays have a sensitivity of about 1 ng/mL, while newer ultra-sensitive
SERUM THYROGLOBULIN assays have a sensitivity of about 0.1–0.2 ng/mL. The sensitivity
Thyroglobulin (Tg) is a circulating protein exclusively synthesized of classic assays can be improved by TSH stimulation. Negative
by thyroid tissue. Its serum levels are a highly sensitive and specific predictive value of TSH-stimulated Tg level approaches 100% [10].
marker for the presence of thyroid tissue in the body. Tg can be The likelihood of disease recurrence is extremely low in the presence
produced both by normal thyroid and neoplastic thyroid cells. of TSH-stimulated Tg levels <1 ng/mL (with the possible exception
Post-Treatment Surveillance of Thyroid Cancer 151

Surveillance Tools for DTC
BOX 20.1 ROLES OF SERIAL TG MEASUREMENT BOX 20.2 EUROPEAN THYROID ASSOCIATION NECK
DURING DTC FOLLOW-UP [14] LYMPH NODE CLASSIFICATION [17]
• In low-risk patients, very low/undetectable Tg may Normal Node
obviate the need for imaging and stringent surveillance • Normal size, ovoid shape, hilum preserved, no hilar
• Tg levels can validate or question the significance of vascularity. No suspicious signs (e.g., microcalcifications,
suspicious imaging findings cystic appearance)
• Rising Tg trend identifies patients who need further
imaging or therapy Indeterminate Node
• In suspected neck nodal recurrence, if FNAC is not • Absence of a hilum
convincing, needle washout of Tg may be helpful in • At least one of the following characteristics:
diagnosing disease • Round shape (PPV 63%)
• In patients with proven loco-regional or metastatic disease, • Increased short axis, ≥8 mm in size in level II and
changes in serial Tg levels help monitor therapy response ≥5 mm in size in levels III and IV
and guide regarding the need for additional therapy • Increased central vascularity
• Whether Tg level is proportionate or disproportionate to
imaging evidence of disease load may indicate the extent
Suspicious Node
of tumor differentiation, and its likelihood of responding
• At least one of these features:
to RAI
• Microcalcifications (PPV 88%–100%)
• Rapid Tg-doubling time (<1 year) is associated with
• Partially cystic appearance (PPV 77%–100%)
worse prognosis
• Peripheral or diffuse vascularity (PPV 77%–80%)
• Parenchymal hyperechoic-looking thyroid tissue
(PPV 66%–96%)
of initial high-risk disease). Risk of residual disease increases as post-
operative thyroglobulin approaches 5–10 ng/mL [7]. Ultrasensitive
Abbreviation: PPV, Positive Predictive Value.
Tg assays may obviate the need for TSH stimulation [11]. The cut-off
using basal ultrasensitive Tg is reported as 0.2–0.3 ng/mL [12]. As
stated, serial measurements of Tg are more informative than a single
A USG guided fine needle aspiration cytology (FNAC) should be
measurement, and the doubling time of Tg over serial measurements
has prognostic significance. A Tg-doubling time of less than 12 done for central compartment nodes more than 8 mm in short-
months has been shown to be associated with increased risk of axis, lateral compartment nodes more than 10 mm in short-axis,
recurrence and decreased cause-specific survival [13]. and those showing persistent suspicious findings [7]. Thyroglobulin
assays in the FNAC needle washout fluid is highly accurate and has
Box 20.1 illustrates the roles that serial Tg measurements may play an adjunctive value for detection of recurrence [20].
during surveillance.
ANTI-THYROGLOBULIN ANTIBODIES (ANTI-TG AB) WHOLE BODY RAI SCANS (WBS)

Anti-thyroglobulin antibodies may interfere with serum Tg RAI scan is based on the thyroid tissue’s preferential concentration
measurements. These are found in about 20% of patients, represent of radioactive iodine (I-131), which allows detection of normal or
an important limitation to the interpretation of individual Tg neoplastic remnant thyroid tissue for potential ablation; it also
values, and may produce both false negative or less commonly false identifies, localizes, and monitors RAI avid DTC metastases [14]
positive results. Hence, anti-Tg Ab should always be measured in (Figures 20.1 and 20.2).
conjunction with Tg measurements. In patients with anti-Tg Ab, Prior to the current usage of Tg and USG for surveillance, RAI scans
serial measurements of these antibodies (preferably using the were the mainstay of thyroid cancer surveillance. RAI scan is usually
same assay) may be a surrogate marker of disease recurrence [15]. done in a TSH-stimulated state, which requires T4 withdrawal of
Declining or steady titers of anti-Tg Ab are associated with disease 3–4 weeks. This causes hypothyroidism, which may be clinically
remission/NED [10]. very symptomatic in many patients; furthermore, it has the risk
of accelerated progression of metastases since these are also TSH
ULTRASONOGRAPHY OF THE NECK (USG NECK) sensitive and may be a cause of concern, especially at critical sites
Most of PTC recurrences occur in the neck. As such, USG neck like the spinal cord or weight bearing bones. Further, the specificity
provides a highly sensitive tool for detection of DTC persistence or of RAI scans in picking recurrent disease is not perfect [14]. Hence,
recurrence. The sensitivity of a good USG neck in identifying neck the response to treatment and completeness is now defined by a
recurrences is as high as 94% compared to about 50% of RAI scan [16]. normal neck USG and very low or undetectable Tg levels [10].
ATA guidelines recommend using a 10-MHz frequency USG neck In patients who have achieved an excellent response to treatment, a
for detection of neck nodes [7]. The European guidelines recommend normal post-treatment RAI scan (no RAI uptake outside the thyroid
examination of the thyroid bed and levels II-VI in both necks using a bed) obviates the need for further diagnostic whole-body RAI
12-MHz neck USG [17]. These guidelines also specify characteristics scans [21]. In current practice, WBS are done for those patients in
to help identify suspicions from benign and indeterminate findings whom the disease stage and risk estimate may warrant further RAI
(Box 20.2). This is important as up to 18% of benign nodes may therapy/ablation. A diagnostic post-surgery RAI WBS may be useful
exhibit suspicious features on USG. if the extent of the thyroid remnant or residual disease cannot be
About 2/3 of neck nodes labeled indeterminate spontaneously accurately ascertained from surgical report or neck ultrasonography,
resolve over time [18], thus waiting and watching may be done for and when the result may influence further treatment decisions
small indeterminate nodes [10]. It is common to find small (<5 mm) [7]. It is important to note the different terminology used with
thyroid bed nodules, but less than 10% of these may progress over regard to RAI scans and treatment. While RAI ablation refers
a 5-year follow-up [19]. Further false positive results of thyroid to the use of RAI to ablate functional normal residual thyroid
bed nodules may be seen in about a quarter due to scar tissue or tissue post-surgery, RAI therapy refers to use of RAI to treat
granuloma which may mimic recurrent disease [10]. structural disease persistence/recurrence, and adjuvant RAI therapy
152 Post-Treatment Surveillance of Thyroid Cancer

Initial Risk Stratification
For neck and chest, a contrast CT is preferred, while for lung

metastases CT without contrast may be used [23]. MRI scan may
provide complementary information for the neck, and especially for
respiratory and gastrointestinal tract disease [23].
According to ATA guidelines, CT scan may be considered in
patients with elevated Tg (especially >10 ng/mL or rising trend),
and negative USG neck [7]. Thus, though CT neck is not a part of the
routine surveillance plan for DTC, it is important when suspected
recurrence is not picked up on USG neck.
POSITRON EMISSION TOMOGRAPHY (FDG-PET) SCANS

FDG-PET is based on the principle of coincidence detection, i.e.,
release of two high energy photons after a positron and electron
collide. The basis of disease localization is the high uptake by
malignant tissues of glucose labeled with a radioisotope (18-FDG)
which is seen on scanning; whereas the CT component provides
spatial resolution.
In DTC surveillance, PET-CT has a role when there is a suspicion of
metastases based on high/rising Tg or clinical findings, but imaging
modalities (RAI scan, USG, or CT) have been unable to localize the
disease [14]. PET-CT may pick up suspected recurrent/metastatic
disease in DTC, which has not been localized by USG, CT scan, or
RAI in about 45%–100% patients, and this may alter management in
Figure 20.1 Post-treatment whole body RAI scan showing intense about 50% [24]. PET-CT showed a sensitivity of 83% and specificity
uptake in thyroid bed. (Figure courtesy of Dr. Shefali Gokhale.) of 84% for detection of non-RAI avid recurrent DTC in a large
meta-analysis [24]. The sensitivity of PET-CT improves with rising
Tg levels, with a maximum sensitivity and specificity at Tg range of
12–32 ng/mL [14].
According to ATA guidelines, FDG-PET scan may be considered
in patients with elevated Tg (especially >10 ng/mL or rising trend)
and negative RAI scan [7]. They also recommend considering FDG-
PET for: (a) part of initial staging in poorly differentiated thyroid
cancers and invasive Hurthle cell carcinomas, (b) a prognostic tool
in patients with metastatic disease to identify lesions and patients
at highest risk of mortality, and (c) evaluation of post-treatment
response after systemic or local therapy of metastatic or locally
invasive disease [7].
INITIAL RISK STRATIFICATION
THYROID CANCER MORTALITY RISK

Several risk stratification systems have been developed to predict
mortality in thyroid cancer. These recognize the importance of
age, distant metastases, extra-thyroidal extension (ETE), tumor
size, and histological grade/differentiation. More commonly the
American Joint Committee on Cancer (AJCC) Tumor-Node-
Metastasis (TNM) staging is used for assessing initial thyroid
cancer mortality risk. The 8th edition of AJCC (2017) brought
Figure 20.2 Post-treatment whole body RAI scan showing local disease some changes to the previous edition for thyroid cancer staging,
with multiple metastases. (Figure courtesy of Dr. Shefali Gokhale.) including the age of increased mortality risk was increased from
45 to 55 years; tumors with microscopic extrathyroid extension
to perithyroidal soft tissues were no longer staged T3; and tumors
refers to RAI for treating possible microscopic foci of disease not with central and lateral compartment metastases were re-staged
seen on imaging [22]. to stage II [25]. These changes are expected to cause down-staging
in about a third of DTC patients. A salient point of TNM staging
COMPUTED TOMOGRAPHY (CT) SCANS for DTCs is that age is an independent prognostic factor. Patients
Cross-sectional imaging using CT scan of the neck and thorax can below the age of 55 years are staged I (without distant metastases)
complement USG in localizing and mapping disease particularly or II (with distant metastases) only. Young patients (<55 years)
in the central compartment before initial surgery. However, as a are not categorized in stages III and IV, reflecting the excellent
surveillance tool post-treatment, CT scan does not find routine prognosis of this group. The detailed TNM classification can
recommendation. But CT scans can provide valuable information be found elsewhere in this book; however, the stages are briefly
in a selected subset with lower neck, mediastinal, or distant disease. described in Box 20.3.

Initial Risk Stratification
low (<2% at 5 years), there is greater risk of disease residual and

BOX 20.3 SALIENT FEATURES OF AJCC STAGING recurrence. Further, the TNM staging does not adequately predict
OF DTCS (8TH EDITION) [25] the recurrence risk in thyroid cancers [7,26]. The American Thyroid
Association (ATA) has devised a risk stratification system to
Age <55 Years:
Stage I: Any tumor factors, any nodal factors, but without predict the risk of disease persistence and recurrence. The 2009
distant metastases ATA recommendations gave an initial three-tiered stratification
Stage II: Any tumor factors, any nodal factors, with distant system that classifies the recurrence risk into low, intermediate,
metastases and high risk categories [27]. Low risk patients are those who have
intrathyroidal DTC, without ETE, vascular invasion, or metastases,
Age ≥55 years: and carry a risk of structural recurrence of <5%. Intermediate risk
Stage I: Tumor up to 4 cm in size, without ETE, and without patients are defined as those who have microscopic ETE, neck node
nodal or distant metastases metastases, radioiodine (RAI) avid disease in the neck outside the
Stage II: Tumor >4 cm in size, or those with ETE, or those thyroid bed, vascular invasion, or aggressive histology type, and
with nodal metastases, but without distant metastases carry a risk of structural recurrence of >5%–20%. High risk patients
Stage III: Tumor with gross ETE invading subcutaneous
have gross ETE, incomplete surgical resection, distant metastases,
tissue, larynx, trachea, esophagus, or recurrent laryngeal
or elevated post-operative thyroglobulin (Tg) values suggestive of
nerve, with or without nodal metastases, but without
distant metastases distant disease and carry a risk of structural disease persistence/
Stage IVA: Tumor with gross ETE invading prevertebral fascia, recurrence of more than 20% [7].
or encasing the carotid artery or mediastinal vessels This system has been validated by analyzing datasets from four
Stage IVB: Any tumor factors, any nodal factors, with distant studies, and the estimates of patients achieving “No evidence of
metastases disease” (NED) after initial therapy are as follows: (1) low risk:
78%–91% NED, (2) intermediate risk: 52%–64% NED, (3) high
risk: 14%–32% NED [26,28–30]. Similarly, the risk of structural
It is noteworthy that TNM staging efficiently predicts mortality; incomplete response was 2%–3% in low-risk patients, 20%–34%
however, within each TNM stage, patients have different risk of in intermediate-risk patients, and 56%–72% for high-risk patients
recurrence, as outlined in the following section. [26,28–30]. The 2009 stratification system has been validated and is
a useful tool in initial risk stratification, but better understanding of
THYROID CANCER RECURRENCE RISK recurrence risk associated with the extent of lymph node metastases,
The goal of any surveillance strategy is to detect any recurrence, specific follicular thyroid cancer (FTC) histologies, and mutational
so that appropriate treatment can be instituted and the risk of status led the ATA to modify the initial risk stratification in its
disease related mortality decreased. As outlined previously, in 2015 guidelines (Table 20.1) [7]. In this classification, the low-risk
thyroid cancer, the risks of recurrence and mortality do not always category also includes low-volume lymph nodal metastases (clinical
go hand in hand [5]. Though the global DTC related mortality is N0 or ≤5 pathologic N1 micrometastases, all less than 0.2 cm in
Table 20.1 American thyroid association (ATA) initial risk stratification system for disease recurrence [7]
Structural recurrence
Risk category Definition risk estimate
Low Risk Papillary Thyroid Cancersa: (with all the below) <5%
• Intrathyroidal, no ETE
• No neck or distant metastases
• No tumor invasion
• Clinical N0 or ≤5 pathologic N1 micrometastases, (<0.2 cm in greatest dimension)
• No vascular invasion
• No aggressive histology
• Complete macroscopic tumor excision
• If RAI given: no avid foci outside thyroid bed
Papillary Microcarcinoma: Intrathyroidal, unifocal/multifocal, no ETE, B-RAF mutated (if known) <5%
Follicular Thyroid Cancers: –
• Intrathyroidal, well differentiated FTC
• Capsular invasion only or minimal (<4 foci) vascular invasion
Intermediate • Microscopic tumor invasion into perithyroidal soft tissue 5%–20%
Risk • Papillary thyroid cancer with vascular invasion
• Clinically N1 or >5 Pathological N1 lymph node metastases (all <3 cm in size)
• Aggressive histology
• Multifocal papillary thyroid carcinoma with B-RAFV600E mutation (if known)
• If RAI post-treatment scan is done: avid foci in neck outside thyroid bed
High Risk • Macroscopic invasion of tumor into perithyroidal soft tissues (gross ETE) >20%
• Incomplete tumor resection
• Distant metastases
• Post-operative Tg level suggestive of distant metastases
• Pathologic N1 with any metastatic lymph node ≥3 cm in largest dimension
• Follicular thyroid cancer with extensive vascular invasion (>4 foci of vascular invasion)
a For low risk category, all of these criteria should be present; ETE: Extrathyroidal extension; RAI: Radioactive Iodine; Aggressive histology includes tall
cell, columnar cell, hobnail variant, diffuse sclerosing.

Dynamic Risk Stratification
greatest dimension), intrathyroidal encapsulated follicular variant MOLECULAR MARKERS

of papillary thyroid carcinoma (FVPTC), intrathyroidal FTC Profiling of molecular markers of thyroid cancer is an attractive
with minor capsular or vascular invasion (<4 foci of vascular prospect since it may help in identifying tumor types that need
invasion), and intrathyroidal papillary microcarcinomas (<1 cm more intensive treatment and surveillance. A large body of work
in size) which are B-RAF wild-type or B-RAF mutated. The has focused on molecular markers for predicting thyroid cancer
intermediate-risk category has been modified to include those outcomes. Incorporation of these markers in existing stratification
patients with certain lymph nodal metastases (that are clinical N1 systems is an attractive concept for tailoring patient management
or >5 pathological N1, all <3 cm in greatest dimension), multifocal and surveillance [32].
papillary microcarcinoma, extrathyroidal extension, or B-RAF
mutated. The high-risk category now also includes large volume B-RAF MUTATIONS
lymph nodal metastases (≥3 cm), and FTC with extensive vascular The most common mutation studied for prognostic implication in
invasion (>4 foci). Thus, the size of the metastatic lymph nodes thyroid cancer is B-RAF. B-RAFV600E is the most common driver
(≤2 mm, >2 mm or ≥3 cm), their number (<5 or >5), nodes with mutation, being present in 40%–60% of all PTCs, especially in
extra-capsular extension, and their location (central or lateral classical and tall cell variants [33]. In several series, this mutation
compartment) should also be taken into consideration when was associated with adverse pathological factors like multifocality,
estimating recurrence risks [10]. Several other stratification systems ETE, lymph nodal metastases, distant metastases, and increased
have also been proposed, including one by a European Consensus risk of recurrence and mortality [32]. However, the impact of B-RAF
Conference [31]. The ATA and European risk stratification systems positivity in some studies was not independent of other tumor
are shown in Tables 20.1 and 20.2. features, thus making the interpretation difficult. Furthermore, the
clinical application of B-RAFV600E as a prognostic marker is marred
It is important to understand that though risk stratification systems
by its low specificity [32]. Thus, B-RAF is unlikely to be used in
give a category-wise classification, the actual risk of recurrence/
isolation, but only in conjunction with other prognostic variables in
persistence is a continuum, with different and often overlapping risk
a multivariable context [34]. Though B-RAF features in the ATA risk
estimate for each specific clinico-pathological or imaging feature.
stratification model (see Table 20.1) for its incremental prognostic
Indeed, the risk of recurrence may vary from less than 1% in very
value, the ATA does not routinely recommend B-RAF evaluation
low risk DTCs to more than 50% in some high-risk cases. Therefore,
for initial post-operative risk stratification [7].
individualized management recommendations should be based not
only on the risk category, but also on individual clinico-pathological RAS MUTATIONS
or imaging risk determinants. These are found in about 40% of FTCs. Some studies have reported
Application of the risk stratification system requires a comprehensive correlation between RAS mutations and metastases and poor
histopathological reporting. The reporting should necessarily survival in FTC and FVPTC [35]. However, RAS mutations are also
include the histological type (e.g., PTC versus DTC), subtype or seen in some follicular adenomas and encapsulated FVPTCs which
variant (e.g., tall cell, columnar cell), tumor size, any presence of are indolent, thus limiting their role owing to specificity issues [32].
ETE, details of capsular and vascular invasion (i.e., absent, <4
foci, ≥4 foci), lymph node involvement, lymph node size, and any TERT PROMOTER MUTATIONS
presence of extranodal extension. Recent studies have focused on TERT promoter mutations as a
prognosticator for unfavorable outcomes in thyroid cancers. Though
If a post-operative RAI scan is done, it will show areas of uptake
these mutations are found in 7%–22% of PTCs and 14%–17% of
within or outside the thyroid bed in the neck or at distant locations.
FTCs, these are commoner in dedifferentiated thyroid cancers, and
The ATA recommends that post-operative RAI scans may be useful
portend a worse prognosis [7,36]. Furthermore, TERT mutations are
when the extent of thyroid remnant/residual is not clear from
common in PTCs with B-RAF mutation, and are associated with
surgical report or neck sonography, and if the results may alter the
high risk of structural disease recurrence [37].
decision to administer RAI or the dose of RAI used for treatment [7].
At present, B-RAF and TERT promoter mutations are included
in risk stratification for recurrence; however, guidelines do not
Table 20.2 European consensus conference risk stratification system [31] recommend their routine evaluation for initial risk stratification
[7,32].
Implication
for RAI
Risk group Definition ablation
Very low • Unifocal microcarcinoma (≤1 cm) No

DYNAMIC RISK STRATIFICATION
Risk • No ETE indication
• Favorable histology for RAI
• Complete surgical excision ablation
The initial risk of recurrence needs to be modified in real-time during
Low Risk • Age <18 years Probable
• T1 >1 cm or T2N0M0 indication follow-up, in accordance with the patient’s response to treatment and
• Less than total thyroidectomy for RAI current findings. While initial stratification yields vital information
• No lymph nodal dissection ablation about a patient’s recurrence and mortality risk, it generates a static, time-
• Unfavorable histology: point specific estimate based on data available initially. To exemplify,
1. Papillary: tall cell, columnar, if a young patient with a low risk thyroid cancer develops neck nodes
diffuse sclerosing with high Tg levels after initial treatment, it would still be classified as
2. Follicular: widely invasive, poorly low risk according to initial stratification. Therefore, there is a critical
differentiated need of a risk stratification system that includes an individual patient’s
High Risk • Incomplete surgical excision Definite response to therapy and current clinical, laboratory, and imaging
• Gross ETE (T3/T4) indication details. Such a real-time, dynamic risk assessment mechanism will
• Lymph nodal involvement for RAI help tailor ongoing management and follow-up. This concept forms
• Distant metastases ablation
the basis of the 2015 ATA Guidelines’ Dynamic Risk Stratification

Dynamic Risk Stratification
system [7]; which is based on the work of Tuttle et al. [26]. It has been and 16%–18% of high-risk patients [7,26,30]. About half of
found that long-term outcomes can be more reliably predicted and these patients eventually achieve NED, about 20% develop
surveillance strategies adapted using a system that adjusts to new data structural recurrent disease, and about 30% continue to have
over time. thyroglobulinemia without structural disease at 5–10 years
ATA’s Dynamic Risk Stratification System incorporates information [7,26,30].
obtained mainly from surveillance tools like serum thyroglobulin C. Structurally Incomplete Response: This implies that there is
(Tg), serum anti-thyroglobulin antibodies (anti-Tg Ab), and neck structural (imaging) or functional (RAI scan/FDG-PET)
ultrasonography (USG), and may also include ancillary imaging evidence of disease at loco-regional or distant sites. This
modalities like RAI scan, cross sectional CT scan, and FDG-PET definition is irrespective of Tg or anti-Tg Ab levels. This kind
scan. This information is used to classify the response to therapy of response is seen in 2%–6% of ATA low-risk, 19%–28%
into four categories (Table 20.3) [7]: intermediate-risk, and 67%–75% of high-risk patients [7,26,30].
A. Excellent Response: This implies that there is no clinical, Within this category, the risk of mortality is about 11% for loco-
biochemical, or structural (imaging) evidence of disease regional disease, while it is as high as 57% for distant metastatic
after initial treatment. If the initial treatment had been total disease [7,30,38].
thyroidectomy and RAI ablation, “excellent response” is D. Indeterminate Response: This implies that the clinical,
defined as stimulated Tg <1 ng/mL, with absence of structural biochemical, structural, and functional findings are neither
and functional evidence of disease, and absence of anti-Tg Ab classifiable as excellent response nor persistent disease.
[7,26,28]. Excellent response after initial therapy is seen in The category definition includes sub-centimeter thyroid
86%–91% of ATA low-risk cases, 57%–63% intermediate-risk bed nodules or neck nodes (non-specific structural), faint
cases, and 14%–16% of high-risk cases [7,26,28]. Several studies RAI uptake in the thyroid bed (non-specific functional), or
have shown that in patients classified as excellent response, unstimulated Tg <1 ng/mL or TSH-stimulated Tg 1–10 ng/mL
the 5- to 10-year risk of recurrence is as low as 1%–4%. The (non-specific biochemical), in the absence of anti-Tg Ab [7].
impact of this dynamic classification is most evident in those This kind of response is present in 12%–29% of ATA low-risk,
initial intermediate or high-risk patients who achieve excellent 8%–23% intermediate-risk, and 0%–4% of high-risk cases. In
response, whose risk of recurrence drops from initial 30%– about 80%–90% of these, the non-specific findings may resolve
40% (ATA risk stratification) to 1%–2% (response to therapy or may remain stable over time. In the remainder 10%–20%,
re-classification). the disease will evolve to either structural or biochemical
B. Biochemical Incomplete Response: This implies that there recurrence [7].
is persistently abnormal unstimulated/stimulated Tg levels
or increasing anti-Tg Ab levels in the absence of structural The definitions, management pathways, and TSH suppression goals
evidence of disease. The definition specifies unstimulated Tg for patients falling into different response to therapy groups is
>1 ng/mL or TSH-stimulated Tg >10 ng/mL. Biochemical elucidated in Figure 20.3.
incomplete response after initial therapy is seen in 11%–19% It is important to understand that the previously discussed dynamic
of ATA low-risk patients, 21%–22% intermediate-risk patients, risk stratification applies to patients who have received total
Table 20.3 Response to therapy reclassification: Based on ATA 2015 guidelines [7]
Response category Definition Outcomes Management principles
Excellent Response 1. Imaging: Negative • Recurrence: 1%–4% 1. Decrease intensity and

and • DSM: <1% frequency of follow-up
2. Non-stimulated Tg <0.2 or 2. Decrease degree of TSH
stimulated Tg <1 suppression
Biochemical Incomplete 1. Imaging: Negative • 30% spontaneously become NED 1. If Tg stable or declining:
Response and • 20% achieve NED after additional therapy continue observation with
2. Suppressed Tg ≥1 or • 20% have structural disease ongoing TSH suppression
stimulated Tg ≥10 or • DSM: <1% 2. If Tg/anti-Tg Ab rising:
rising anti-Tg Ab additional investigations and
additional therapy as required
Structural Incomplete 1. Structural or functional • 50%–85% have persistent disease Based on factors like size,
Response evidence of disease despite additional therapy location, rate of growth, RAI
2. Any Tg level • DSM 11% in those with loco-regional avidity, 18-FDG avidity, either:
Any anti-Tg Ab disease 1. Additional therapy
• DSM 50% in those with distant or
metastases 2. Ongoing Observation
Indeterminate 1. Imaging: Non-specific findings • 15%–20% show structural disease at 1. Continued observation with
Response 2. RAI scan: faint uptake in follow-up appropriate serial imaging
thyroid bed • The remainder resolve or show stable and Tg level monitoring
3. Suppressed Tg <1 or non-specific changes 2. If non-specific changes evolve
stimulated Tg <10 or anti-Tg • DSM: <1% to suspicious: additional
Ab stable or declining in imaging and biopsy
absence of structural/
functional disease
Note: Tg levels are in ng/mL.

Abbreviations: DSM, Disease Specific Mortality; NED, No Evidence of Disease.

Surveillance Strategies
Figure 20.3 Dynamic Risk Stratification System: Definitions, management pathways, and TSH suppression goals.
thyroidectomy with RAI ablation as their initial treatment. However, Table 20.4 Response to therapy reclassification definitions in patients
for low-risk, intrathyroidal PTCs up to 4 cm in size, lobectomy not receiving total thyroidectomy and RAI ablation [39]
is proposed. Similarly, the guidelines do not recommend RAI Definition
ablation for low risk PTCs. Hence, dynamic risk stratification was
modified to make it applicable to those cases where either lobectomy Response Total thyroidectomy
or total thyroidectomy without RAI ablation was performed [39]. category without RAI Lobectomy
The category definitions for these subsets of patients are shown in Excellent • Negative imaging • Stable, unstimulated
Table 20.4. Response • Unstimulated Tg Tg <30
<0.2 or stimulated • Undetectable anti-Tg
Tg <2 Ab
• Undetectable anti-Tg • Negative imaging
Ab
SURVEILLANCE STRATEGIES
Biochemical • Unstimulated Tg >5 • Unstimulated Tg >30
Incomplete or stimulated Tg • Increasing Tg over
Response >10 time
There is a lack of high-quality evidence-based guidelines for
• Increasing anti-Tg • Increasing anti-Tg Ab
surveillance in DTCs [40]. As a result, there are marked differences
Ab value value
in surveillance protocols, with the strategy being influenced by • Negative imaging • Negative imaging
patient profile, individual preferences, and local resources available.
Structural • Structural or • Structural or
The surveillance frequency and tools used currently have a high
Incomplete functional evidence functional evidence
sensitivity, leading to early detection of recurrent/persistent disease.
Response of disease of disease
However, it is unclear whether this leads to better quality of life • Any Tg or anti-Tg Ab • Any Tg or anti-Tg Ab
or survival [10,40]. A judicious use of these surveillance tools is value value
therefore required to ensure optimum follow-up on one hand and
Indeterminate • Imaging: Non- • Imaging: Non-specific
unnecessary investigations on the other.
Response specific findings findings
A brief initial timetable for surveillance tools in different risk • RAI scan: faint • Anti-Tg Ab stable or
groups is provided in Table 20.5. During initial follow-up, uptake declining
unstimulated Tg measurements (using a sensitive assay) should be • Unstimulated Tg
done at 6–12 months, with this frequency being more for high- 0.2–5 or stimulated
risk patients [7]. After surgery, an initial USG of the neck to assess Tg 2–10
• Anti-Tg Ab stable or
the central and lateral compartments should be done at 6–12
declining
months, and then repeated periodically, according to patient’s Tg
levels and risk status [7]. Whole Body RAI Scan has a role mainly Note: Tg levels are in ng/mL.
in intermediate- and high-risk groups. In these, RAI scans may
be done after thyroxine withdrawal or rTSH stimulation, at a LOW-RISK/INTERMEDIATE-RISK PATIENTS
frequency of 12 months. Excellent Response to Therapy after Total Thyroidectomy and RAI
The surveillance strategy varies according to the risk Ablation: If a low-/intermediate-risk patient has an excellent
stratification and response to therapy, and is given for different response to therapy as assessed by Tg and USG (see Table 20.3),
groups, as follows. the subsequent recurrence rate is very low. In these patients,

References
Table 20.5 Timetable for initial use of surveillance tools in DTC (after Total Thyroidectomy, No RAI Ablation: These patients may be
initial thyroidectomy +/- RAI scan) followed-up with unstimulated sensitive Tg levels and anti-Tg Ab
Timeframe (after initial treatment) levels every 6–12 months. USG neck may be done every 6–12 months
Initial risk in those not achieving an excellent response.
category 6 months 12 months 18 months 24 months
HIGH-RISK PATIENTS
Low Risk Tg Tg Tg Tg
Excellent Response to Therapy: In these patients, if initial post-
USG neck USG neck
treatment evaluation shows excellent response to therapy,
Intermediate Tg Tg Tg Tg
surveillance is done every 6–12 months; sensitive Tg and anti-Tg
Risk USG neck USG neck USG neck
RAI scan RAI scan
Ab levels, along with USG neck, are also done every 6–12 months.
High Risk Tg Tg Tg Tg Biochemical Incomplete Response to Therapy: If Tg/anti-Tg Ab levels
USG neck USG neck USG neck USG neck are rising, further tests in form of RAI scan, CT scan, or PET scan
RAI scan RAI scan RAI scan are done.
Additional CT/ Additional The aimed TSH level in high-risk patients is <0.1 mU/L.
PET if indicated CT/PET if
indicated
SUMMARY
surveillance can be limited to unstimulated-Tg and anti-Tg Ab
every 12–18 months. USG neck may be done at 18–24 months. A
USG-guided FNAC should be done only for lesions with suspicious The increasing incidence of thyroid cancers, along with the indolent
features and size >8–10 mm (in central and lateral compartments). nature of most of these, has caused the need for surveillance of a
If the USG is normal, further USG may be done at 3–5 years [10]. large set of such patients. With evolving understanding of the
The goal for TSH suppression should be a level of 0.5–2 mU/L. (See biology of thyroid cancer and better surveillance tools, current
Figure 20.3 and Box 20.4.) policy has shifted away from prolonged surveillance for all, to the
current recommendation of less-intensive shorter surveillance for
Biochemical Incomplete Response to Therapy: As stated previously,
low-risk patients. Intensive surveillance strategy is reserved for
this may be seen in about 10% of low-risk and 20% of intermediate-
those at a high risk of recurrence. It is advisable that the initial
risk cases. In these patients, a trend of serial Tg levels is most
risk estimates be tempered depending on the response to therapy,
important. In these, subsequent TSH-stimulated or sensitive Tg
such that a dynamic risk status guides ongoing surveillance and
measurements along with anti-Tg Ab may be done at 6–12 months.
management. Serum Tg, anti-Tg Ab, and USG neck play frontline
A Tg-doubling time of less than 1 year portends a worse prognosis.
roles as surveillance tools. Most patients of DTC have an initial low
USG neck should also be done every 12–24 months. The level of TSH
risk and an excellent response to therapy. These may be followed up
aimed at is 0.1–0.5 mU/L. In those with an initial intermediate risk,
with annual Tg, anti-Tg Ab, and TSH levels for 5 years, with neck
aggressive histology, or rising trend of Tg/anti-Tg Ab, additional
USG reserved for patients with abnormal findings. Selected subset
imaging may be done in the form of RAI scan, CT scan, or PET scan.
of patients having a higher recurrence and mortality risk benefit
from further imaging and therapy. In the future, incorporation
of molecular proofing may further refine risk groups, and allow
delivery of precision surveillance and medicine.
BOX 20.4 SURVEILLANCE STRATEGIES ACCORDING

TO RISK AND RESPONSE TO TREATMENT
ACKNOWLEDGMENTS
A. Initial Low/Intermediate Risk
1. Excellent Response:
a. TSH level 0.5–2 mU/L
b. Unstimulated Tg and anti-Tg Ab: Every 12–18 The author would like to acknowledge Dr. Shefali Gokhale, Senior
monthly Consultant in Nuclear Medicine at Inlaks & Budhrani Hospital,
c. USG neck: 18–24 months; thereafter at 3–5 years Pune, India for Figures 20.2 and 20.3.
2. Biochemical Incomplete/Indeterminate Response:
a. TSH level 0.1–0.5 mU/L
b. Stimulated Tg or sensitive Tg with anti-Tg Ab:
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2718–26.

Chapter 21
APPLICATIONS OF RADIOISOTOPES IN THE DIAGNOSIS

AND TREATMENT OF THYROID DISORDERS
Chandrasekhar Bal, Meghana Prabhu, Dhritiman Chakraborty,

K. Sreenivasa Reddy, and Saurabh Arora
CONTENTS
Introduction 161
Molecular Basis of Imaging with RAI 161
Non-Radioactive Iodine Imaging 165
Salient Points 169
References 169
group of the thyroglobulin protein to form monoiodotyrosine and

diiodotyrosine. These moieties undergo a coupling reaction to form
INTRODUCTION the hormones triiodothyronine (T3) and thyroxine (T4), which are
then stored in colloid form and released into the systemic circulation.
RAI is incorporated into thyroid tissue, stored, and released from
Historical background: The suggestion by Enrico Fermi about the the thyroid in the same way as non-radioactive iodine, and this is
potential use of radioactive isotopes of iodine-127, the naturally a useful tool to study thyroid gland physiology [5]. The excretion
occurring iodine isotope, in medicine began consequently to his of RAI is mainly by glomerular filtration; however, in hypothyroid
group’s production of new radioisotopes by neutron bombardment patients, a lowered mean glomerular filtration rate (GFR) is observed
of natural elements in 1934 [1]. The first radioactive isotope of iodine, [7] (Table 21.1).
iodine-128, was produced by Robert Evans at the Massachusetts
Institute of Technology [2]. Herz et al. suggested that RAI could be THYROID UPTAKE STUDY
used for studying the physiology of the thyroid gland and for therapy The percentage of radioactive iodine uptake by the thyroid gland is
[3]. Iodine-123 was discovered by I. Pearlman at the Crocker Medical a simple and routine procedure.
Cyclotron at Berkeley in 1949 [4]. In the mid-1940s, the U.S. Atomic
Energy Commission provided a plentiful supply of I-131, and the INDICATIONS
first human subject received RAI at MIT in 1946 [2]. 1. Guidance in determining the activity of 131I to be administered.
The uptake measurement should be performed as close in time
as possible to the treatment.
MOLECULAR BASIS OF IMAGING WITH RAI 2. Differentiation of sub-acute thyroiditis from Graves’ disease is
an essential requirement before administering radioiodine and
other forms of thyrotoxicosis.
RAI follows the same physiological and biochemical pathways as 3. Confirmation of the diagnosis of hyperthyroidism due to
non-radioactive iodine in the diet, where iodine is rapidly absorbed Graves’ disease.
in the upper gastrointestinal tract. The recommended intake for
an adult is 150 µg per day and 200 µg per day during pregnancy. PROCEDURE
Within the blood, iodine is preferentially carried by the red blood Patients should preferably be fasting for approximately four hours
cells (RBCs) (60%), compared to 40% in plasma [5]. From the (hr) before radioiodine ingestion to ensure good absorption. I-131
bloodstream, iodine freely diffuses into the interstitial space. Besides (10–20 uCi) is administered to the patient, and the same activity
the thyroid, other organs involved in the clearance of iodide from in the same volume is kept as standard. Both the neck counts and
the blood are the kidneys, salivary glands, gastric mucosa, sweat standard counts are measured at a given distance (around 25 cm)
glands, and mammary glands. There is also placental transport of from the thyroid probe under identical geometry. The ratio of the
RAI (human thyroid begins to concentrate RAI after the first 12 neck counts to the standard counts (after background subtraction)
weeks of gestation) [6]. The thyroid follicular cells trap iodine and multiplied by 100 provides the percentage of thyroid uptake. Room
incorporate it into thyroid hormones. The iodide trap/sodium iodide background for standard and thigh counts after voiding the urinary
symporter (NIS) is located on the basolateral membrane of follicular bladder provides the background counts for the standard and
cells through which two atoms of sodium are transported along neck, respectively. The background subtracted neck counts can be
with one of iodide. The ability of thyroid tissue and thyroid cancers measured at 2 hr and 24 hr post-administration of tracer dose of
to concentrate RAI depends upon the expression and functional 131I. Percentage uptake at 24 hr is important for dosimetry. Uptake
integrity of NIS. Some differentiated thyroid cancer (DTC) and is calculated as follows:
most anaplastic thyroid cancer (ATC) lose NIS and thus do not Neck counts–thigh counts (background corrected)/administered
show uptake of RAI on diagnostic imaging and are hence insensitive activity ×100 (%).
to RAI therapy. Once trapped, the iodine becomes activated by Normal thyroid uptake values are at 2 hr: 1%–7% and at 24 hr:
oxidation and then organified through binding with the tyrosine 7%–18% [8].
Applications of Radioisotopes in the Diagnosis and Treatment of Thyroid Disorders 161

Molecular Basis of Imaging with RAI
Table 21.1 Properties of radionuclides used for thyroid scintigraphy imaged at 20 to 30 minutes. Esophageal activity may be seen
Sl Physical Mode of Principle Energy
with either radiotracer. It can usually be confirmed by having
no Radionuclide half-life decay photons (keV) the patient swallow water to clear the esophagus.
2. Thyroiditis: It is the most common cause of thyrotoxicosis
1 99m-Technetium 6 hours Isomeric Gamma 140
associated with a decreased %RAIU. Various causes include
transition
granulomatous thyroiditis (de Quervain), silent thyroiditis,
2 Thallium-201 73.1 Electron Mercury 67–83
and postpartum thyroiditis (occurs within a few weeks
hours capture x-rays; 135,
Gamma 167
of delivery, with positive antithyroid antibodies). During
the initial stage of sub-acute thyroiditis, thyrotoxicosis
3 131I-Iodine 8.02 Beta minus Gamma 364,
days 637,
predominates, caused by the release of thyroid hormone as a
285 result of inflammation and increased membrane permeability
4 123I-Iodine 13.2 Electron Gamma 159
and hence suppresses TSH. As the inflammation resolves
hours capture and thyroid hormone levels decrease, the scintigram may
5 124I-Iodine 4.2 days Beta plus Gamma 603,
show inhomogeneity of uptake or regional or focal areas of
(23%), 723, hypofunction (Figure 21.1a and b).
Electron 1691 3. Toxic multinodular goiter (TMNG; aka Plummer disease): The
capture %RAIU is often only moderately elevated or may be in the high
(74%) normal range. The thyroid scan shows high uptake within
6 18F-FDG 110 Beta plus Gamma 633 hyperfunctioning nodules but suppression of the extranodular
minutes (97%), non-autonomous tissue. A nontoxic multinodular goiter may
electron have hot or warm nodules, but the extranodular tissue is not
capture (3%) suppressed (Figure 21.1c and d).
THYROID SCAN (a) (b)

INDICATIONS
1. To relate the general structure of the thyroid gland (e.g., nodular
or diffuse enlargement) to its function. The scan may be useful
in distinguishing Graves’ disease from toxic nodular goiter, a
distinction of significance in determining the amount of I-131
to be given as therapy for hyperthyroidism.
2. To correlate thyroid palpation with scintigraphic findings to
determine the degree of function in a clinically-defined area or
nodule (i.e., palpable).
3. To locate ectopic thyroid tissue (i.e., lingual) or determine (c) (d)
whether a suspected “thyroglossal duct cyst” is the only
functioning thyroid tissue present.
4. To assist in the evaluation of congenital hypothyroidism.
5. To evaluate a neck or substernal mass. Radionuclide scintigraphy
may be helpful to confirm that the mass is functioning thyroid
tissue.
6. To differentiate thyroiditis from Graves’ disease and other
forms of hyperthyroidism.
PROTOCOL (e) (f )
• Radionuclides used: 99mTc-pertechnetate or I-123. I-131 is not

used in routine imaging of the intact gland because of high
radiation exposure.
• Dose: For an I-123 scan, the patient ingests 300–400 µCi
orally. The scan is usually acquired 4 hr later. For a 99mTc-
pertechnetate scan, 3–5 mCi is administered intravenously.
• Timing of imaging: Iodine I-123, 4–6 hr after dose
administration; 99mTc-pertechnetate, 20 minutes after
radiopharmaceutical injection. Early imaging is required
because Tc-99mis not organified and thus not retained within
the thyroid [9]. Figure 21.1 Various cases of thyroid scan: (a and b) Anterior view,
and marker view; shows no tracer uptake in the thyroid bed, in a case
NORMAL AND ABNORMAL THYROID SCINTIGRAPHY [10] of thyroiditis. (c and d) Anterior view and marker view; shows enlarged
1. Normal scan: The normal scintigraphic appearance of the bilateral lobes with heterogeneous tracer uptake and presence of cold
thyroid varies among patients. The gland has a butterfly shape, nodules in the isthmus and left lower pole—dominant nodule, features
with usually thin lateral lobes extending along each side of the of toxic MNG. (e) Shows increased and homogenous tracer uptake in
thyroid cartilage. The thin pyramidal lobe usually is not seen. bilaterally enlarged thyroid lobes, in a case of Graves’ disease. (f) Shows a
The normal gland shows homogeneous uptake throughout. single hot nodule in the left lobe with suppression of surrounding thyroid
Salivary glands are routinely seen with 99mTc-pertechnetate, parenchyma, features of AFTN.
162 Applications of Radioisotopes in the Diagnosis and Treatment of Thyroid Disorders

4. Graves’ disease (GD): Approximately 75% of patients with 7. Thyroid nodules:

thyrotoxicosis have GD as the cause. It is an autoimmune a. Cold nodule: Approximately 85% to 90% of thyroid
disease caused by a thyrotropin receptor stimulating antibody, nodules are cold (hypofunctional) on thyroid scans.
which stimulates thyroid follicular cells, resulting in the The incidence of cancer in a cold thyroid nodule is 15%
production of excess thyroid hormone. A thyroid scan shows to 20%. The dominant nodule is those that are distinctly
a high thyroid-to-background ratio. An elevated %RAIU larger than the other nodules in a multinodular
confirms the diagnosis (Figure 21.1e). Thyroid scan shows goiter or those that are enlarging and require further
increased and homogenous tracer uptake in bilaterally enlarged evaluation. Differentials for cold nodule apart from
thyroid lobes in the case of GD. malignancy include benign conditions such as colloid
5. Single autonomously functioning thyroid nodule (AFTN)/toxic nodule, simple cyst, hemorrhagic cyst, adenoma, and
adenoma (TA): Toxic nodules occur in approximately 5% of abscess.
patients with a palpable nodule. Once an autonomous nodule b. Hot nodule: Radioiodine uptake in a nodule denotes
grows to a size of 2.5–3.0 cm, it may produce the clinical function. A functioning nodule is very unlikely to be
manifestations of thyrotoxicosis. %RAIU may be elevated malignant. Less than 1% of hot nodules are reported to
or more often remain in the normal range. The thyroid scan harbor malignancy. RAI is the usual therapy for toxic
shows uptake in the nodule but suppression of the remainder nodules because the radiation is delivered selectively to
of the gland and low background (Figure 21.1f). Thyroid scan the hyperfunctioning tissue while sparing suppressed
shows a single hot nodule in the left lobe with suppression of extranodular tissues. The suppressed thyroid tissue
surrounding thyroid parenchyma, features of AFTN. results in a low incidence of post-therapy hypothyroidism.
6. Ectopic thyroid: Embryologically, the thyroglossal duct extends After successful treatment, the suppressed tissue regains
from the foramen cecum at the base of the tongue to the function. On occasion, surgery may be performed for
thyroid. Lingual or upper cervical thyroid tissue can present patients with local symptoms or cosmetic concerns.
in the neonate or child as a midline mass, often accompanied c. Indeterminate nodule: When a palpable or
by hypothyroidism. Ectopic thyroid tissue may occur in sonographically detected nodule >1 cm cannot be
the mediastinum or even in the pelvis (struma ovarii). The differentiated by thyroid scan as definitely “hot or
typical appearance of a lingual thyroid is a focal or nodular cold” compared to surrounding normal thyroid,
accumulation at the base of the tongue and absence of tracer it is referred to as an indeterminate nodule. The
uptake in the expected cervical location. Lateral thyroid rests indeterminate nodule may occur with a posterior
may be hypofunctional, functional, hyperfunctional, or be nodule that has normal thyroid uptake superimposed
the focus of thyroid cancer. Ectopic thyroid tissue should be anterior to it, making it appear to have normal uptake.
considered metastatic until proved otherwise (Figure 21.2a–d). For management purposes, an indeterminate nodule
Anterior and lateral views show the single focus of increased has the same significance as a cold nodule.
tracer uptake in the superior aspect of the neck with no evidence d. Discordant nodule: Some hot or warm nodules on thyroid
of tracer uptake in thyroid bed—suggestive of ectopic thyroid scans appear cold on radioiodine scans. This type of
tissue, likely lingual thyroid. observation occurs in only 5% of patients, because some
Figure 21.2 (a–d) Anterior and lateral views show a single focus of increased tracer uptake in the superior aspect of the neck with no evidence of
tracer uptake in the thyroid bed—suggestive of ectopic thyroid tissue, likely lingual thyroid.

thyroid cancers maintain trapping but not organification. Table 21.2 Drugs and foods that decrease or increase the percentage
Of discordant nodules, 20% are malignant. of radioactive iodine uptake
For any thyroid nodule >1 cm in any diameter, a Increased uptake Duration of effect
serum TSH level should be initially obtained. If the Iodine deficiency
serum TSH is subnormal, a radionuclide thyroid Lithium, antithyroid drugs
scan should be obtained to document whether the Decreased uptake
nodule is hyperfunctioning (“hot,” i.e., tracer uptake Thyroid hormones (T4) 2–4 weeks
is higher than the surrounding normal thyroid),
Mineral supplements, vitamins, cough 2–4 weeks
isofunctioning (“warm,” i.e., tracer uptake is equal to medications
the surrounding thyroid), or nonfunctioning (“cold,”
Iodinated skin ointments 2–4 weeks
i.e., has uptake less than the surrounding thyroid
Iodinated drugs (Amiodarone) Months
tissue). Hyperfunctioning nodules rarely harbor
malignancy, and no cytologic evaluation is necessary. Radiographic contrast media (water-soluble 2–4 weeks
intravascular media)
A higher serum TSH level, even within the upper part
of the reference range, is associated with increased Goitrogenic foods: cabbage, turnips
risk of malignancy in a thyroid nodule, as well as more Prior radiotherapy to neck
advanced stage thyroid cancer [11]. Antithyroid drugs
Propylthiouracil (PTU) 3–5 days
131I-WHOLE BODY SCAN (WBS) Methimazole 5–7 days
Whole body RAI imaging is used in the following situations: (1) total
or near-total thyroidectomy prior to ablation of thyroid remnants
and treatment of residual disease, (2) in post-therapy imaging, (3) at PATIENT PREPARATION
6 months follow-up after ablation therapy, (4) as part of surveillance, The patients are prepared by either of these two methods: (1) withdrawal
and (5) in patients with known or suspected metastatic disease. The from thyroid hormone therapy (requires approximately 4–6 weeks of
flowchart in Figure 21.3 depicts the management of thyroid cancer withdrawal from Levothyroxine (T4) replacement therapy, or lack of
patients post-surgery. supplementation altogether after total or subtotal thyroidectomy) or
(2) use of recombinant human TSH (rhTSH). Patients should undergo
two weeks of low-iodine diet to minimize the amount of iodine in the
Surgery-day 1 blood that would compete with the RAI for uptake into thyroid tissue
or thyroid cancer, thus increasing the diagnostic and therapeutic
efficacy of RAI. Various drugs interfere with RAI uptake and should
be avoided, as mentioned previously (refer Table 21.2).
rhTSH (THYROGEN)
Side effects of hypothyroidism (fatigue, depressed mood, cold
Withdrawal of thyroid hormones: 4 weeks
intolerance, dry skin, increase in weight, constipation, hoarseness,
or numbness/tingling, and decreased sweating) can be debilitating for
rhTSH protocol many patients, particularly those with other comorbidities. These
adverse effects can be avoided with Thyrogen, a recombinant form
of TSH (rhTSH), since Thyroxine therapy may be continued. The
protocol differs according to centers. However, the most commonly
followed protocol is shown in Figure 21.4. Blood clearance of RAI is
faster in the euthyroid state favoring a higher target-to-background
Blood test: Day 28 ratio with the use of rhTSH, since GFR is not affected. According
Measure TSH > 30 mIU/I to the recent ATA guidelines, rhTSH mediated therapy may be
indicated in selected patients with underlying comorbidities making
Measure Tg and ATA baseline
iatrogenic hypothyroidism potentially risky, in patients with a
Pregnancy test negative
pituitary disease whose serum TSH cannot be raised, or in patients
in whom a delay in therapy might be deleterious [11].
PROTOCOL
Diagnostic WBS is performed after 24–48 hr of 1–3 mCi of RAI.
Test dose of 131I (2–3 mCi): Day 28
The post-therapy scan is performed preferably after 48–72 hr; few
Whole-body scan and/or spots: authors recommend scan acquisition 5–7 days after administration
Day 29 or 30 of therapy. The scan should extend from the head to the knees or
mid-thighs, plus high-count spot views of the neck and chest, using
a high-energy collimator. If metastases are suspected, imaging can
be done with SPECT/CT, which allows 3D anatomic localization for
documentation, future follow-up, and to guide potential surgical or
external beam radiation therapy. The uptake in the neck and any
Select dose for treatment and
other area is calculated from the counts in a region of interest (ROI)
administer: Day 30 or 31
drawn over the neck, minus background activity obtained from an
ROI over the thigh, divided by the total administered activity. Use of
low-activity 131I (1–3 mCi) potentially reduces the negative impact
Figure 21.3 Post-surgery management of thyroid cancer patients. of 131I WBS on RAI therapeutic efficacy for successful remnant

Non-Radioactive Iodine Imaging
1 2 3 4 5
Day 1: Day 2: Day 3: Day 5:

0.9 mg rhTSH 0.9 mg rhTSH WBS ± therapy Tg measurement
+ 131I-WBS
dose (2mCi)
Figure 21.4 The rhTSH protocol.
ablation (“stunning”). Damle et al. concluded that the interval was 83%, and the specificity was 84% in non–131I-avid DTC.
between diagnostic WBS and post-therapy WBS plays a critically Factors influencing 18FDGPET/CT sensitivity included tumor
important role in causing stunning [12]. dedifferentiation, larger tumor burden, and TSH stimulation.
Physiological uptake is seen in the nasal area, oropharynx, salivary 18FDG PET/CT may prove more sensitive in picking up lesions
glands, stomach, intestines, and urinary bladder. Uptake is located in retropharyngeal or retro-clavicular regions [13].
commonly seen in lactating breasts and must not be confused with b. 68Ga-DOTANOC PET/CT: 68Ga-DOTANOC PET/CT has an
lung uptake. Quantification of uptake after thyroidectomy is an important role in the follow-up of MTC patients, particularly
indicator of the adequacy of surgery, and follow-up scan uptakes those with high Calcitonin values. It also helps select potential
allow the evaluation of therapeutic effectiveness or recurrence. candidates for PRRT therapy [14]. Also, a recent study has
According to the recent ATA guidelines, post-operative diagnostic shown the correlation between 68Ga positive lesions and
RAI WBS may be useful when the extent of the thyroid remnant or Calcitonin levels and between 18F-FDG positivity and CEA
residual disease cannot be accurately ascertained from the surgical levels [15]. Kundu et al. conducted a prospective study evaluating
report or neck ultrasonography, and when the results may alter the 68Ga-DOTANOC PET/CT in comparison with 18F-FDG PET/
decision to treat or the activity of RAI that is to be administered. CT in DTC patients with raised thyroglobulin and negative
Identification and localization of uptake foci may be improved 131I-WBS. 68Ga-DOTANOC PET/CT demonstrated disease
by concomitant single photon emission computed tomography- in 40/62 (65%) patients and 18F-FDG PET/CT in 45/62 (72%)
computed tomography (SPECT/CT). Also, a post-therapy WBS (with patients, with no significant difference on McNemar analysis
or without SPECT/CT) is recommended after RAI remnant ablation (p = 0.226). 68Ga-DOTANOC PET/CT changed management
or treatment, for disease staging and document RAI avidity of any in 21/62 (34%) patients and 18F-FDG PET/CT in 17/62 (27%)
structural disease. Approximately 10% of patients show abnormal patients. The authors concluded that Ga-DOTANOC PET-CT is
uptake on the post-therapy scan not seen on the pre-therapy scan, inferior to 18F-FDG PET/CT on lesion-based but not on patient-
which may alter subsequent therapy [11]. based analysis for detection of recurrent/residual disease in DTC
Star artifact: The high therapeutic dose can result in intense uptake patients with negative WBS scan and elevated serum Tg levels,
in the thyroid bed, which typically has six points of the star caused and that it can also help in selection of potential candidates for
by septal penetration of the hexagonal collimator holes. peptide receptor radionuclide therapy [16]. Another prospective
study by Naswa et al. evaluated 68Ga-DOTANOC PET/CT in
patients with recurrent medullary thyroid carcinoma and
compared with 18F-FDG PET/CT. Their results showed a
NON-RADIOACTIVE IODINE IMAGING
superior sensitivity for 68Ga-DOTANOC PET/CT compared to
18F-FDG PET/CT (75.61 vs. 63.4%). However, the difference was
statistically not significant (p = 0.179) [17].
Non-specific tumor SPECT agents such as 201-Thallium,
123/131I-MIBG, 99mTc-sestamibi, 99mTc-DMSA (V), 111Indium- c. Radiolabeled anti-CEA monoclonal antibodies: Because of the
Octreotide, and PET tracers such as 18F-FDG and 68Gallium- high prevalence of CEA antigen expression on the surface
DOTANOC are useful when poorly differentiated, tall-cell variants, membranes of MTC, imaging with radio-labeled anti-CEA
or cancers composed of Hurthle cells are present, which are often monoclonal antibodies has been investigated [18].
less RAI avid. d. 18F-DOPA and 124I-PET/CT have also shown to be useful in the
a. 18F-Fluorodeoxyglucose (FDG) PET imaging: The recent ATA detection of recurrence in thyroid cancer [19].
guidelines strongly recommend 18FDG PET/CT scan to be e. (I-131 or I-123)-Metaiodobenzylguanidine (MIBG) and
considered in high-risk DTC patients with elevated serum Tg C-11 Hydroxyephedrine: MIBG is similar in structure to
(generally >10 ng/mL) with negative RAI imaging. 18FDG- norepinephrine, one of the circulating catecholamines and a
PET/CT scanning may also be considered as a part of initial sympathetic nerve neurotransmitter. Hydroxyephedrine is
staging in poorly differentiated thyroid cancers and invasive an analog of ephedrine, a sympathomimetic drug. MIBG and
Hurthle cell carcinomas, especially those with other evidence of hydroxyephedrine are taken up in APUD-like neuroendocrine
disease on imaging or because of elevated serum Tg levels. This cells and their tumors in neurosecretory granules and have
is a prognostic tool in patients with metastatic disease to identify proved useful in the diagnosis of MTC. Studies have shown that
lesions and patients at highest risk for rapid disease progression the MIBG scan has a limited sensitivity of 40%–50%. However,
and disease-specific mortality, and evaluation of post-treatment MIBG scan helps in selecting those patients that may respond
response following systemic or local therapy of metastatic or to therapy with high-dose 131I-MIBG [20–22].
locally invasive disease [11]. In a meta-analysis of 25 studies f. 111Indium-Octreotide imaging: The overall sensitivity of
that included 789 patients, the sensitivity of 18FDG PET/CT 111In-octreotide is 82% sensitivity in patients who had no

abnormal uptake on I-131 scintigraphy. It can be used as a dose = [3700 kBq/g × estimated thyroid weight(g)] ÷ 24 hr
predictor for the utility of therapeutic octreotide (Sandostatin), RAIU (%). Success of first dose of radioiodine was defined as
high-dose In-111 octreotide for therapy in patients refractory clinically/biochemically euthyroid/hypothyroid status at the
to I-131, or other analogs, such as Y90-labeled somatostatin end of 3 months without the need for further therapy. The
analogs in octreotide positive patients [23]. authors reported that there was no statistically significant
g. 99mTc-DMSA (V) in MTC: Uptake mechanism depends on difference between the success rates of the two methods at 3
the flow and phosphate groups on tumor as well as the pH of months (the success rate of the first dose was 60% in the fixed
the medium. 99mTc-DMSA(V) yields a high sensitivity tumor group and in calculated dose group it was 65% and hence,
detection rates ranging from 50%–80% in MTC [24]. the fixed dose approach may be used for treatment of Graves’
disease as it is simple and convenient for the patient) [29].
h. 68Ga-PSMA-HBED-CC PET/CT: In DTC, MTC, RAI refractory
thyroid cancer, and ATC, 68Ga-PSMA-HBED-CC PET/CT is • Follow-up within the first 1–2 months after RAI therapy for GD
being tried and seems a potential theragnostic agent [25–27]. should include an assessment of T3, T4, and TSH. Biochemical
monitoring should be continued at 4–6 week intervals for
6 months, or until the patient becomes hypothyroid and is
THERAPY stable on thyroid hormone replacement.
RAI therapy is most commonly indicated in GD, TMNG, TA, and
thyroid cancer.
• When hyperthyroidism due to GD persists after 6 months
following RAI therapy, retreatment with RAI is suggested. In
selected patients with minimal response 3 months after therapy,
GRAVES’ DISEASE (GD) additional RAI may be considered [11].
• Patients choosing RAI therapy as treatment for GD would
likely place relatively higher value on definitive control of
hyperthyroidism, the avoidance of surgery, and the potential TMNG OR TA
side effects of ATDs, as well as a relatively lower value on the • Overt hyperthyroidism due to TMNG or TA can also be
need for lifelong thyroid hormone replacement, rapid resolution treated with RAI therapy. Advanced patient age, significant
of hyperthyroidism, and potential worsening or development of comorbidity, prior surgery or scarring in the anterior neck,
Graves’ ophthalmopathy (GO). small goiter size, RAIU sufficient to allow therapy, and lack
• Absolute contraindications for RAI therapy include pregnancy, of access to a high-volume thyroid surgeon (the latter factor is
more critical for TMNG than for TA) could be an indication
lactation, coexisting thyroid cancer, suspicion of thyroid
cancer, and individuals unable to comply with radiation safety for RAI therapy.
guidelines and used with informed caution in women planning • Absolute contraindications to the use of radioactive iodine
a pregnancy within 4–6 months. include pregnancy, lactation, coexisting thyroid cancer, and
• Sufficient activity of RAI should be administered in a individuals unable to comply with radiation safety guidelines
and should be used with caution in women planning a
single application, typically a mean dose of 10–15 mCi
(370–555 MBq), to render the patient with GD hypothyroid. pregnancy within 4–6 months.
A pregnancy test should be obtained within 48 hr before • Non-functioning nodules on radionuclide scintigraphy
treatment in any woman with childbearing potential who or nodules with suspicious ultrasound characteristics
is to be treated with RAI and verify a negative result before should be managed accordingly. TMNG and TA with high
administering RAI [11]. Damle et al. evaluated the predictive nodular RAI uptake and widely suppressed RAI uptake in
role of 24 hr RAIU with respect to the outcome of radioiodine the peri-nodular thyroid tissue are especially suitable for RAI
therapy in patients with diffuse toxic goiter (DTG). A total therapy.
of 633 consecutive patients with DTG were given fixed-dose • The goal of therapy is the rapid and durable elimination
(185 MBq/5 mCi) of radioiodine between January 1987 and of the hyperthyroid state. The sufficient activity of RAI
December 2006. Of these, 175 patients had an RAIU ≤50% should be administered in a single application to alleviate
and 458 patients had an RAIU >50%. First-dose success hyperthyroidism in patients with TMNG.
rate in the former group was 81.7% and in the second group • The activity of RAI used to treat TMNG, calculated based on
68.6% (p = 0.001). The overall first-dose success was 72%. goiter size to deliver 150–200 µCi (5.55–7.4 MBq) per gram of
Multivariate analysis confirmed significant role of 24 hr RAIU tissue corrected for 24-hr RAIU, is usually higher than that
data to predict a successful outcome. The authors concluded needed to treat GD. Besides, the RAIU values for TMNG may
that 24 hr RAIU value of ≤50% appears to be associated with be lower, necessitating an increase in the applied activity of
a significantly better outcome compared to that of a 24 hr RAI. Follow-up is similar to GD patients.
RAIU value of >50% in patients with DTG given as treatment • For patients with TMNG who receive RAI therapy, the response
a fixed dose of 185 MBq/5 mCi radioiodine [28]. is 50%–60% by 3 months, and 80% by 6 months, with an average
• According to the recent ATA guidelines for the management of failure rate of 15%. There is a 75% response rate by 3 months and
89% rate by 1 year following RAI therapy for TA [11].
hyperthyroidism, the goal of RAI therapy in GD is to control
hyperthyroidism by rendering the patient hypothyroid; this
treatment is beneficial provided sufficient radiation dose is THYROID CANCER
deposited in the thyroid. RAI therapy with I-131 has been a mainstay of thyroid cancer
• RAI can be accomplished equally well by either administering management since its first application was described by Seidlin
a fixed activity or by calculating the activity based on the et al. in 1946 [1]. Initial therapy of thyroid cancer consists of surgical
size of the thyroid and its ability to trap RAI [11]. Jaiswal removal of the thyroid gland and the primary tumor, along with
et al. conducted a prospective study to compare the results the identification and removal of the involved lymph nodes. RAI
of these two approaches in a randomized patient population therapy reduces the rate of cancer recurrence, extends the disease-
with 20 patients in each group. Fixed dose group patients were free interval, and helps to control the inoperable disease. Most
administered 185 MBq of 131I. Calculated dose group patients patients with metastatic disease can be managed successfully for
were given 131I as per the following formula: Calculated many years with RAI therapy.

Women of childbearing age receiving RAI therapy should Typically for remnant ablation, doses of 30 mci are administered as an
have a negative screening evaluation for pregnancy before RAI outpatient procedure. Any patient receiving more than 30 mci needs to
administration and avoid pregnancy for 6–12 months after receiving be admitted to the therapy ward, according to AERB (Atomic Energy
RAI. RAI should not be given to nursing women. Lactating women Regulation Board). Generally, higher activities are used for ablation
should have stopped breastfeeding or pumping for at least 3 months. of thyroid remnants when there is aggressive tumor histology such as
Sperm banking should be considered in men who may receive tall-cell, insular, or columnar-cell PTC variant. RAI remnant ablation
cumulative RAI activities ≥400 mCi. Gonadal radiation exposure is not routinely recommended after thyroidectomy for ATA low-risk
is reduced with proper hydration, frequent micturition to empty the DTC patients. Bal et al. conducted a randomized clinical trial to find
bladder, and avoidance of constipation. Some specialists recommend out the smallest possible effective dose for remnant ablation in cases
that men wait 3 months (or one full sperm cycle) to avoid the of DTC, between July 1995 and January 2002. A total of 565 patients
potential for transient chromosomal abnormalities [11]. were randomized into eight groups according to 131I administered
There is a wide range of therapeutic options available for the activity, starting at 15 mCi and increasing activity in increments of
treatment of thyroid cancer—from simple observation to aggressive 5 mCi until 50 mCi. The successful ablation rate in their study was
treatment with emerging biotechnologies—so patients should statistically different in patients receiving less than 25 mCi compared
routinely undergo risk stratification analysis to determine optimal with those receiving at least 25 mCi [p = 0.006]. However, there was
management. There are three approaches to 131I therapy: empiric no significant intergroup difference in outcome among patients
fixed amounts, therapy determined by the upper limit of blood receiving 25–50 mCi. The authors concluded that patients receiving
and body dosimetry, and quantitative tumor or lesional dosimetry. at least 25 mCi had three times better chance of getting remnant
Dosimetric methods are often reserved for patients with distant ablation than patients receiving lesser activity of 131I, and any activity
metastases or unusual situations such as renal insufficiency, children, between 25 and 50 mCi appears to be adequate for remnant ablation
the elderly, and those with extensive pulmonary metastases. [31,32]. RAI remnant ablation is not routinely recommended after
The efficacy of RAI therapy is related to the mean radiation dose lobectomy or total thyroidectomy for patients with unifocal papillary
delivered to neoplastic foci and also to the radiosensitivity of tumor microcarcinoma, in the absence of other adverse features, according
tissue. The radiosensitivity is higher in patients who are younger, to the recent ATA guidelines [11]. Radioactive iodine lobar ablation
with small metastases from well-differentiated papillary or follicular (RAILA), which avoids complications associated with resurgery, is
carcinoma, and with the uptake of RAI but no or low 18FDG an alternative that has been recently explored in a few international
uptake. The maximum tolerated radiation absorbed dose (MTRD) centers. Santra et al. reported comparable long-term outcome in terms
is commonly defined as 200 rads (cGy) to the blood. The goal is to of recurrence rate and disease-free survival (RAILA in comparison
use the minimum activity necessary to achieve successful thyroid with remnant ablation after CT) [33]. RAI remnant ablation is not
remnant ablation, particularly for low-risk patients [11]. routinely recommended after thyroidectomy for patients with
multifocal papillary microcarcinoma in the absence of other adverse
REMNANT ABLATION features. RAI adjuvant therapy is routinely recommended after total
Radioiodine remnant ablation is considered a safe and effective thyroidectomy for ATA high-risk DTC patients; however, it should be
method for eliminating residual thyroid tissue, as well as microscopic considered after total thyroidectomy in ATA intermediate-risk level
disease if at all present in the thyroid bed following thyroidectomy. DTC patients [11]. Ballal et al. conducted a two-arm retrospective
The rationale is that in the absence of thyroid tissue, serum Tg cohort study with no radioiodine in Gr-I, and adjuvant RAI therapy
measurement can be used as an excellent tumor marker. Another was administered in Gr-II patients, and concluded that intermediate-
consideration is that the presence of significant remnant thyroid risk surgically ablated patients do not need adjuvant RAI therapy
tissue makes detection and treatment of nodal or distant metastases and patients who failed to achieve ablation with first dose of 131I
difficult. Rarely, microscopic disease in the thyroid bed if not ablated, may be dynamically risk stratified as high-risk category and managed
in the future, could be a source of anaplastic transformation [30]. aggressively [34] (Figure 21.5).
(a) (b)
Figure 21.5 131I-WBS shows post 30 mCi 131-I therapy scan of a papillary thyroid cancer patient who underwent total thyroidectomy with the
remnant in the neck (a, red arrow); with the uptake of 3.2%, the 6 months follow-up scan shows a negative WBS with successful remnant ablation
(b, red arrow).

TREATMENT OF PULMONARY METASTASES empirically (100–200 mCi) or determined by dosimetry. Patients

In the management of the patient with pulmonary metastases, undergoing RAI therapy for bone metastases should also be
critical criteria for therapeutic decisions include: (1) size of considered for directed therapy of bone metastases that are visible on
metastatic lesions (macronodular typically detected by chest anatomical imaging. Bone metastases may include surgery, external
radiography, micronodular typically detected by CT, lesions beneath beam radiation therapy, and other local treatment modalities [11]
the resolution of CT); (2) avidity for RAI and, if applicable, response (Figure 21.6).
to prior RAI therapy; and (3) stability (or lack thereof) of metastatic Rare sites of metastases include liver, brain, kidney, adrenal glands,
lesions. Pulmonary metastases should be treated with RAI therapy breast, inguinal, and axillary lymph nodes [37–43]. Secondary
and be repeated every 6–12 months as long as the disease continues malignancies are also reported in literature associated with thyroid
to concentrate RAI and respond clinically because the highest cancer [44].
rates of complete remission are reported in these subgroups. The
selection of RAI activity to administer for pulmonary metastases
TREATMENT OF RAI REFRACTORY DISEASE
can be empiric (100–200 mCi, or 100–150 mCi for patients ≥70
Radioiodine-refractory structurally evident DTC is classified in
years old) or estimated by dosimetry to limit whole-body retention
patients with appropriate TSH stimulation and iodine preparation in
to 80 mCi at 48 hours and 200 cGy to the bone marrow. Pulmonary
four primary ways: (1) the malignant/metastatic tissue does not ever
pneumonitis and fibrosis are rare complications of high-dose RAI
concentrate RAI (no uptake outside the thyroid bed at the first
treatment. Patients with pulmonary micrometastases (<2 mm,
therapeutic WBS), (2) the tumor tissue loses the ability to concentrate
generally not seen on anatomic imaging) that are RAI avid have
RAI after previous evidence of RAI-avid disease (in the absence of
the highest rates of complete remission after treatment with RAI.
stable iodine contamination), (3) RAI is concentrated in some lesions
Significant reduction in serum Tg and the size or rate of growth
but not in others; and, (4) metastatic disease progresses despite
of metastases or structurally apparent disease is considered a
significant concentration of RAI.
response to RAI therapy. Pulmonary function testing, including
the diffusing capacity of the lungs for carbon monoxide, can be When a patient with DTC is classified as refractory to RAI, there is
markers of pulmonary toxicity. Patients with solitary pulmonary no indication for further RAI treatment. Kinase inhibitor therapy
DTC metastases may be considered for surgical resection, although (sorafenib, lenvatinib, vandetanib) should be considered in RAI-
the potential benefit weighed against the risk of surgery is unclear refractory DTC patients with metastatic, rapidly progressive,
[11]. Chopra et al. suggested that patients with macro-nodular symptomatic, and/or imminently threatening disease not otherwise
lung metastases and/or concomitant skeletal metastases have amenable to local control using other approaches. Patients who
reduced odds of achieving remission. The authors also suggested are candidates for kinase inhibitor therapy should be thoroughly
that a significant number of patients recurred even after complete counseled on the potential risks and benefits of this therapy as well
remission with RAI treatment, hence they recommended strict as alternative therapeutic approaches, including best supportive
surveillance especially in patients with age >45 years and/or with care [11] (Figure 21.7).
follicular histology of DTC [35,36].
SIDE EFFECTS AND COMPLICATIONS OF RAI THERAPY
RAI TREATMENT OF BONE METASTASES Although generally safe, RAI therapy has some potential
RAI therapy of iodine-avid bone metastases has been associated side effects, classified as early and late complications [45].
with improved survival and should be employed, although RAI The early complications include gastrointestinal symptoms,
is rarely curative. The RAI activity administered can be given radiation thyroiditis, sialadenitis/xerostomia, bone marrow
(a) (b)
Figure 21.6 131I-WBS anterior and posterior views show increased tracer uptake in the remnant, cervical lymph nodes, and bilateral lungs (a, red
arrows). 131I-WBS anterior and posterior views show increased tracer uptake in the remnant, cervical lymph nodes, bilateral lungs, and few skeletal
sites (skull, thoracic and lumbar vertebrae) (b, red arrows).

References
(a) (b) (c) (d)
(e)
(f ) (g) (h)
Figure 21.7 131I-WBS (anterior and posterior, a and b) shows mild tracer uptake in remnant in the thyroid bed (red arrow). However, the patient
had a Tg level of 3,040 ng/mL. Hence patient was diagnosed with radioactive refractory disease, and 18FDG PET/CT was advised. Images (c–f)
showed multiple soft tissue nodules with increased tracer uptake in bilateral lung fields. Images g and h (red arrows) show local recurrence in the
left thyroid bed.
suppression, gonadal damage, dry eye, and nasolacrimal duct • TSH elevation is achieved by withdrawing Levothyroxine or
obstruction. injection of rhTSH.
The late complications include secondary cancers, pulmonary fibrosis, • Residual thyroid tissues can be ablated with 131I.
permanent bone marrow suppression, and genetic effects. Proper • 131I is not beneficial in a patient with a T1–T2 tumor that has
hydration optimizes renal excretion of I-131, thus minimizing radiation been thoroughly excised.
exposure. Patients are also advised to use lemon-flavored lozenges to • Follow-up of patients is done with 131I-WBS and Tg
promote salivary flow, thus reducing exposure to the glands [46]. measurement.
• When the radioiodine scan is negative and Tg positive, it is
termed Thyroglobulin Elevated Negative Iodine Scan (TENIS);
NON-RAI RADIOTRACER THERAPY
management includes use of empirical high dose therapy (100–
111In-octreotide therapy, 90Y-DOTATATE therapy, 131I-MIBG
200 mCi). Alternatively, the site of cancer can be identified by
therapy, 177Lu-PRRT, and 177Lu-PSMA have also been tried in non-
18FDG PET/CT and treated by surgery or external radiation
RAI thyroid cancer [47–50].
therapy.
• RAI is generally safe, but has a few early and late complications.
SALIENT POINTS
REFERENCES
• RAIU study with 131-I and thyroid scan with 99mTc-pertechnetate

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• RAI therapy is most commonly indicated in GD, TMNG, TA,
2. Chapman E. History of the discovery and early use of
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Chapter 22
SYSTEMIC THERAPY (TARGETED THERAPY AND

IMMUNOTHERAPY) FOR THYROID CANCERS
Abhishek Vaidya and Amol Dongre
CONTENTS
Introduction 173
Molecular Pathogenesis: Genetic Changes and Altered Signaling Pathways 173
Targeted Therapy in Thyroid Cancer 174
Conclusion 176
References 176
(NGS), which has led to the identification of specific abnormalities

of founder significance in most analyzed tumors [10].
INTRODUCTION
The carcinogenesis in thyroid cancers is closely associated with
the activation of various tyrosine cascades and inactivation of
The incidence of thyroid cancer is increasing worldwide [1,2]. tumor suppressor genes, including BRAF phosphatidylinositol-4,5-
On the basis of their degree of differentiation, thyroid cancers bisphosphate 3-kinase (PI3 K) catalytic subunit α (PIK3CA), tumor
derived from follicular cells are classified as differentiated thyroid protein 53 (tp53) mutations, and telomerase reverse transcriptase
cancers (DTC), poorly differentiated thyroid cancers (PDTC), and (TERT) mutation [11]. These pathways may exert their effects
anaplastic thyroid cancers (ATC) [3]. DTCs account for 93% of individually or in association with each other through an extensive
all thyroid cancers [4]. Medullary thyroid carcinomas (MTC) are cross talk.
derived from parafollicular C cells, and account for about 3%–5%
BRAF MUTATIONS AND MITOGEN-ACTIVATED PROTEIN
of thyroid cancers [5]. Most DTCs (including papillary thyroid
KINASE (MAPK) PATHWAY
cancers and follicular thyroid cancers) are well behaved and have
BRAF is the most studied and the most common gene mutation
an excellent survival prognosis [6]. The usual treatment for these
having an important role in thyroid carcinogenesis. It is a serine-
cancers is surgery (lobectomy or total thyroidectomy), with or
threonine kinase, belonging to the family of RAF proteins, and
without radioiodine (RAI) therapy. However, a small subset (<10%)
is an intracellular mediator of the MAPK pathway. The most
of DTCs, many MTCs and PDTCs, and most ATCs are not cured by
common BRAF mutation is BRAF V600E (amino acid substitution),
standard treatment [7]. When grouped together, these “aggressive/
which constitutively activates the serine-threonine kinase, thus
advanced thyroid cancers” have a 5-year survival rate in less than
upregulating the MAPK pathway [9]. This involves the sequential
50%, in stark contrast to the >90% 20-year survival rates for DTCs
activation of MEK and ERK. The activated MAPK pathway plays a
[7]. ATCs account for <2% of all thyroid cancers, but are the most
role in cell growth, proliferation, differentiation, and carcinogenesis.
aggressive, accounting for about 50% of all thyroid cancer mortality
As stated, BRAF strongly activates this pathway. The resulting
[8]. It is in this subset of aggressive and advanced thyroid cancers
intracellular events then upregulate tumor-promoting genes and
that systemic therapy, primarily in the form of targeted therapy and
downregulate tumor-suppressing genes. Thus, BRAF mutation and
immunotherapy, has a role to play.
activation of the MAPK pathway have an important role in thyroid
There has been a greater understanding of molecular pathogenesis cancers, especially papillary cancers [9]. BRAFV600E mutation is seen
underlying thyroid cancers in recent years. Better elucidation of in about 45% of PTCs [12].
thyroid cancer molecular genesis has opened vistas for possible use
of targeted therapy in thyroid cancers. RAS MUTATIONS AND PHOSPHATIDYL INOSITOL 3
This chapter briefly looks at molecular pathogenesis of thyroid KINASE-AKT (PI3K-AKT)/MTOR PATHWAY
cancers and then focuses on targeted therapy and immunotherapy RAS mutations are the second most common in thyroid cancers.
for these cancers. In its normal state, RAS is bound to GTP, and converts GTP to
inactive GDP by its intrinsic GTPase activity. A mutated RAS
loses its GTPase activity, thus constitutively activating GTP. RAS
activates the PI3 K pathway preferentially [12]. PI3 K pathway plays
MOLECULAR PATHOGENESIS: GENETIC CHANGES a key role in cell growth, proliferation, and survival [11]. As stated,
AND ALTERED SIGNALING PATHWAYS the PI3 K pathway is upregulated via RAS, and also by binding of
its p85 subunit to activated tyrosine residues on activated growth
factor receptors, thus showing a cross talk with the receptor tyrosine
A large body of research in recent years has led to the identification kinase (RTK) pathway. mTOR is a regulatory protein of the PI3 K/
of specific genetic changes and putative molecular pathways involved AKT/mTOR pathway and its activation results in the transcription
in thyroid cancers [9]. More recently, the results from the Thyroid and translation of critical growth genes [13]. The PI3KAKT pathway
Cancer Genome Atlas (TCGA) gave a comprehensive analysis of has a predominant role in follicular neoplasms including follicular
papillary thyroid cancers (PTC) using next generation sequencing thyroid carcinoma (FTC) [9,12].
Systemic Therapy (Targeted Therapy and Immunotherapy) for Thyroid Cancers 173
Targeted Therapy in Thyroid Cancer
Figure 22.1 A schematic representation of molecular pathways and genetic changes underlying thyroid cancers.
RET-PTC REARRANGEMENT ALK mutations and rearrangements are mainly found in PDTCs and
RET is a proto-oncogene that encodes a cell membrane receptor ATCs, and they lead to disease progression and aggression [19,20].
tyrosine kinase (RTK). RET is highly expressed in parafollicular The molecular pathways and genetic changes of thyroid cancer are
C cells. It is not usually expressed in follicular cells, but may be illustrated in Figure 22.1.
activated here by chromosomal rearrangement: the RET/PTC
translocation. This translocation constitutively activates tyrosine
kinase activity of RET. RET-PTC activates both the MAPK and
TARGETED THERAPY IN THYROID CANCER
PI3-AKT pathways [9,12]. The most common subtypes of this
translocation are RET/PTC1 and RET/PTC3 [9,12,14]. RET/PTC
induced carcinogenesis is mediated in part by an epidermal growth
MULTI-KINASE INHIBITORS (MKI)/TYROSINE KINASE
factor receptor (EGFR), and thus may be an attractive therapeutic
INHIBITORS (TKI)
target for tyrosine kinase inhibitors (TKI) [15].
The MAPK pathway is one of the most studied pathways in thyroid
PAX8-PPARγ REARRANGEMENT cancer. Data from TCGA has shown that PTC is MAPK driven, with
Another genetic translocation involved in thyroid carcinogenesis the two potent activators being BRAFV600E and mutated RAS.
is PAX8-PPARγ. This translocation leads to the fusion between Several tyrosine kinase inhibitors and multi-kinase inhibitors have
the PAX8 gene and the peroxisome proliferator–activated receptor been tried in advanced, RAI-refractory DTCs and MTCs, with
(PPARγ) gene. PAX8–PPARγ has an inactivating effect on the wild- promising results. For ATC, the results are varied, with a few drugs
type tumor suppressor PPARγ and transactivates certain PAX8- being promising. As of now, the FDA has approved four drugs
responsive genes [16]. This translocation occurs in about 40%–60% targeting the MAPK pathway for treatment of advanced thyroid
of FTC [12]. cancers [7,21]. These are: lenvatinib and sorafenib (for advanced,
RAI-refractory, recurrent DTCs); and vandetanib and cabozantinib
TELOMERASE REVERSE TRANSCRIPTASE (TERT) (for MTCs).
PROMOTER GENE MUTATIONS
TER promoter gene mutation is an important recent discovery in SORAFENIB
thyroid carcinogenesis. Activation of TERT promoter gene results in This MKI targets VEGFR 1–3, PDGFR, RET, RAF, and c-kit [22].
cells acquiring telomerase activity, thus avoiding cell death. TERT In its initial single arm phase II trial for advanced RAI-refractory
is found to be overexpressed in DTCs [7]. About 11% of FTC and thyroid cancers, sorafenib yielded a median progression free
16%–40% of PTC (frequently in association to B-RAF mutations) survival (PFS) of 18 months [23]. This was followed by a phase III,
were found to bear TERT mutations [17]. Coexistence of TERT with multicenter, randomized, placebo-controlled trial (DECISION
BRAF mutation was found to have the worst prognosis for DTC trial). This trial enrolled 417 patients of advanced RAI-refractory
patients [18]. thyroid cancers, and showed a significantly better PFS in the
treatment group (sorafenib 400 mg orally BD) as compared to
ANAPLASTIC LYMPHOMA KINASE (ALK) placebo controls (10.8 months vs 5.8 months; HR 0.59; p < 0.0001)
The ALK gene may undergo either activating mutations or gene [24]. However, there was no benefit in overall survival; further
rearrangements, leading to its activation. Activating ALK, either in toxicity was seen in more than 60% of patients. Nevertheless,
the form of ALK mutants and ALK fusion proteins, promote the sorafenib received FDA approval for the treatment of advanced
activation of MAPK, PI3 K, and JAK/STAT downstream pathways. RAI-refractory thyroid cancers. Sorafenib has also been tried in
174 Systemic Therapy (Targeted Therapy and Immunotherapy) for Thyroid Cancers
Targeted Therapy in Thyroid Cancer
ATC and MTC. In ATC, in a study of 20 patients, partial response Table 22.1 A brief synopsis of MKIs (other than the four FDA
(PR) was achieved in two patients, while five had stable disease (SD) approved) for thyroid cancers [7]
[25]. In a study of 16 advanced MCTs, sorafenib induced PR in one Partial
and SD in 14 [26]. Study response PFS
MKI drug Target phase Patients (%) (months)
LENVATINIB Sunitinib PDGFR, FLT3, II 35 31 12.8
This MKI targets and also inhibits several targets, namely VEGFR c-kit, VEGFR,
1–3, FGFR 1–4, PDGFR, RET, and c-kit [27]. It showed promising RET
activity in an initial phase II single arm trial of 58 treatment naïve Axitinib VEGFR, PDGFR II 60 30 18.1
or re-treated advanced RAI-refractory thyroid cancers [28]. This Motesanib VEGFR, II 93 14 9.3
was followed by a phase III, randomized, placebo-controlled trial PDGFR, c-kit
(SELECT trial). This trial randomized 261 patients to either receive Pazopanib VEGFR, II 37 49 11.7
lenvatinib (24 mg per day in 28-day cycles) or a placebo. There PDGFR, c-kit
was significantly better PFS in the treatment arm (18.3 months vs. Dovitinib FGFR, VEGFR II 40 20.5 5.4
3.6 months; HR 0.21; p < 0.0001). The response rate was promising
Imatinib PDGFR, II 15 0 NA
at 64%, with four patients achieving complete response. The BCR-ABL,
discontinuation rate due to toxicity was 14% [29]. Subsequently, c-kit,RET
lenvatinib was approved by the FDA for treatment of advanced Selumetinib MEK, RAS, II 39 3 8
RAI-refractory thyroid cancers. Owing to its better efficacy and BRAFV600E
safety profile, lenvatinib is currently regarded as the first line MKI
in treatment of such thyroid cancers [30].
SINGLE/SELECTIVE INHIBITORS
VANDETANIB
MKIs form the most accepted and studied targeted therapy for
This MKI has been primarily researched in advanced MTCs. It targets
advanced thyroid cancers. However, certain single target inhibitors
RET, VEGFR, EGFR, and c-kit. Its efficacy was first demonstrated
or selective inhibitors may also be efficacious in certain cases. Several
in a phase II trial of 30 advanced or metastatic hereditary MTCs. In
trials have investigated the role of single target inhibitors; however,
this study, PR was achieved in 22 patients at a dose of vandetanib
without a predictive biomarker, their applicability and results are
300 mg per day [31]. This was followed by a phase III, randomized,
limited [11].
placebo-controlled trial (ZETA trial). This trial included 331 patients
with advanced MTC and showed a significantly better PFS with BRAF INHIBITOR
vandetanib as compared to the placebo group (30.5 months vs Vemurafenib is a selective BRAF inhibitor, which has shown
19.3 months; HR 0.46; p = 0.001) [32]. The side effect profile included encouraging efficacy in a phase II trial including 51 cases of advanced
diarrhea, rash, nausea, and a rare but critical adverse effect in form RAI-refractory PTC displaying BRAF V600E . The study population
of QT prolongation, potentially leading to torsades de pointes [32]. consisted of two as per prior treatment with an anti-VEGFR.
Subsequently, vandetanib became the first FDA-approved drug for Amongst TKI-untreated patients, 10 out of 26 (38.5%) achieved a PR,
treatment of unresectable, locally advanced or metastatic MTC. whereas nine patients (35%) achieved a SD for six months or longer,
Although not approved for RAI-refractory DTC, vandetanib has with a median PFS of 18.2 months. In the TKI-treated group, six of
been tested in a phase II randomized trial in this group of patients. the 22 evaluable patients (27%) experienced a PR, while the other six
Here it was found to have a good efficacy with an improvement in had SD for at least six months, with a median PFS of 8.9 months. A
PFS in those receiving the drug over the placebo group (median PFS further study is ongoing.
11.1 months vs 5.9 months; HR 0.63; p = 0.008) [33]. Vandetanib
is currently being studied in a phase III, randomized trial of 238 BRAF AND MEK INHIBITORS
patients with advanced RAI-refractory thyroid cancers (VERIFY It may be an effective strategy to combine a BRAF inhibitor
trial, NCT01876784). The results of this trial are being awaited at (dabrafenib) with a MEK inhibitor (trametinib) in advanced thyroid
the time of writing this chapter. cancers. A phase II trial recruiting 16 pre-treated ATC patients
reported 69% ORR, including a CR. This, along with about 90% rate
CABOZANTINIB of ongoing responses at 12 months, represents unprecedented results
This is a multi-inhibitor of MET, VEGF-2, and RET. The efficacy for this aggressive disease. Clinical trials employing dabrafenib in
of cabozantinib was initially shown in a phase I study of 37 heavily combination with trametinib or lapatinib are ongoing.
pre-treated MTC patients [34]. This led to a phase III, randomized,
placebo-controlled trial of advanced MTCs (EXAM trial), in which SELUMETINIB
subjects were randomized to receive either cabozantinib (140 mg This drug targets MAP kinases MEK-1 and 2. It was found to reverse
daily) or a placebo. This trial showed a significantly better PFS in the the RAI refractory state in 8 of 20 patients with metastatic thyroid
treatment arm (11.2 months vs 4 months, HR 0.28, p <0.001) [35]. cancer, as assessed by 124I-PET. Selumetinib-treated patients
However, there was no benefit of overall survival between groups. subsequently received RAI achieving PR (n = 5) or SD (n = 3) after
In 2012, cabozantinib was approved by the FDA for treatment of the radio-metabolic treatment. Further, NRAS mutation seems to be
advanced MTCs [36]. a predictive biomarker of selumetinib efficacy. Research is underway
evaluating this molecule.
Cabozantinib has also been tested as a salvage therapy in RAI-
resistant DTCs progressing on VEGFR inhibitors. In a phase II trial ALK INHIBITORS
of 25 such patients, cabozantinib led to 40% overall response rate Owing to their role in carcinogenesis, ALK inhibitors find a role
(ORR), and a 92% disease control rate [37]. in several solid cancers. ALK inhibitors currently include first
Several other multi-kinase inhibitors have been evaluated in generation (crizotinib) or second-generation (ceritinib, alectinib,
different studies for thyroid cancer. A brief synopsis of these is given and brigatinib) inhibitors. There are also immunotherapeutic drugs
in Table 22.1. directed against activated ALK.
References
Ceritinib: This is a second-generation ALK inhibitor that overcomes Studies involving combination targeted therapy with immunotherapy
secondary resistance due to acquired ALK mutations or amplification are underway. One study combining lenvatinib and pembrolizumab
or activation of alternative ALK-independent survival pathways is being carried out by the International Thyroid Oncology Group
(such as EGF, IGF, RAS/SRC, and AKT/mTOR signaling pathways). (NCT02973997). Combination immunotherapy with nivolumab
However, in a study, ceritinib had limited efficacy in ATC patients (anti-PD-1) plus ipilimumab (inhibitor of cytotoxic T lymphocyte
with the ALKL1198F mutation in full-length ALK or the EML4-ALK A4, CTLA4) for all types of thyroid cancer is currently under
fusion protein. An additional trial is currently evaluating this drug investigation (NCT03246958).
in patients harboring ALK mutations or fusions (NCT02289144). Another phase II study is enrolling ATC and PDTC patients to
Crizotinib: This is a second generation TKI targeting ALK, MET, and various targeted therapies in combination with atezolizumab, an
ROS1. It has been extensively researched in ALK-fusion-positive. anti-PD-L1 drug (NCT03181100). The type of targeted therapy is
There is an anecdotal report of one ALK-translocated ATC patient selected on the basis of the driver mutation present in the tumor.
treated with crizotinib achieving a PR. Recently, in a phase Ib study Further trials are also investigating the combination of EBRT given
(PROFILE 1013; NCT01121588), which enrolled 44 ALK-positive to a metastatic site (SBRT) in combination with immunotherapy in
metastatic patients, one patient with advanced MTC achieved a PR. thyroid cancers (NCT02239900, NCT03122496).
However, its utility is restricted by very limited data.
PI3 K/AKT/mTOR PATHWAY INHIBITORS

Thyroid carcinogenesis has a prominent role of activation of the CONCLUSION
PI3 K/AKT/mTOR pathway. Research has shown that targeting this
pathway may be an attractive proposal for patients with advanced
RAIR DTCs and MTCs. Several trials have researched mTOR A small subset of DTCs, larger proportion of MTCs, and most
inhibitors in thyroid cancer. of ATCs will be amenable to cure by standard therapy of surgery
Buparlisib: This is a class I PI3 K inhibitor. It failed to show a with RAI therapy. Systemic therapy has a role to play in such
significant PFS benefit in 43 advanced, RAI-resistant DTCs. Though scenarios. The elucidation of genetic and epigenetic changes
there was a reduction in tumor growth, there was no objective involved in thyroid carcinogenesis has allowed newer drugs
response, and 48.8% of patients had progressed at six months. The against specific targets to be explored in such advanced thyroid
decrease in tumor growth may be due to an incomplete inhibition cancers. Amongst the various targeted therapies studied, only four
of the PI3 K oncogenic pathway. drugs have undergone phase III trials with significant results to
qualify them for FDA approval. Lenvatinib is the first line therapy
Everolimus: This mTOR inhibitor was tested in a phase II trial of
for RAI-refractory advanced thyroid cancers; sorafenib being
38 patients with advanced RAI-resistant DTC. There was a median
the other approved drug in this scenario. For MTCs, vandetanib
PFS of 47 weeks. Two further phase II studies analyzed everolimus
and cabozantinib are approved for metastatic and recurrent
safety and efficacy on seven subjects with MTC, 28 patients with
advanced cancers. The advent of immunotherapy has thrown
metastatic or locally advanced DTC, and seven individuals with
open attractive prospects in systemic therapy of advanced thyroid
ATC. Five patients (71.4%) showed SD, and 4 (57.1%) had an SD
cancers, especially when combined with multi-kinase inhibitors.
lasting >24 weeks. A further phase II trial evaluated everolimus
Results of several such combination trials are awaited in the near
efficacy in patients with RAI-resistant thyroid cancer and correlated
future.
tumor mutational profiling with response. Median PFS were 12.9,
13.1, and 2.2 for DTC, MTC, and ATC cohorts, respectively, and
patients with mutations in the PI3 K pathway appeared to benefit
most from drug treatment.
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10. Cancer Genome Atlas Research N. Integrated genomic 25. Savvides P et al. Phase II trial of sorafenib in patients with
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11. Li Z, Zhang Y, Wang R, Zou K, Zou L. Genetic alterations in 26. Lam ET et al. Phase II clinical trial of sorafenib in metastatic
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Chapter 23
SURGICAL MANAGEMENT OF PARATHYROID DISORDERS
Neeti Kapre Gupta, Gregory W. Randolph, and Dipti Kamani
CONTENTS
Introduction 179
Clinical Profile 179
Diagnosis 179
Minimally Invasive Parathyroidectomy 181
Pathology 183
Conclusions 184
References 184
the clinical presentation of groans, moans, and stones! However,

with increased awareness and better diagnostic tools such as the
INTRODUCTION
advent of an automated serum chemistry analyzer, the detection
of asymptomatic primary hyperparathyroidism has become fairly
common. Therefore, on one hand where there were no doubts
In the early 1900s, physicians considered enlargement of the
regarding indications for surgery in the earlier scenario, indications
parathyroid glands to be caused by deficiency or hypoparathyroidism,
for incidentally detected asymptomatic hyperparathyroid patients
and it was treated with parathyroid extract transplantation. It was
have to be stringent. The revised guidelines, therefore, serve as a very
only when the first parathyroidectomy, performed by Dr. Felix
important reference for making surgical decisions [3].
Mandl in Vienna in 1925, yielded prompt initial successful
outcomes that the real treatment for hyperparathyroidism was Parathyroidectomy should be recommended for the following
determined. Subsequently, the famous yet unfortunate story of asymptomatic hyperparathyroidism patients: (1) those <50 years
marine Captain Charles Martell at Massachusetts General Hospital of age, (2) those who cannot participate in appropriate follow-up,
in Boston provided probably the first real lesson in parathyroid (3) those with a serum calcium level >1.0 mg/dL above the normal
surgery. Captain Martell, so troubled by his bone and renal range, (4) those with creatinine clearance <60 mL/min, or (5) those
conditions subsequent to parathyroid disease, would spend hours with T-score lower than 2.5 SD at any site or any previous fracture
researching gland anatomy and surgical principles at the Harvard fragility [3].
library. He persuaded Dr. Cope and Dr. Churchill [1] to perform
a mediastinal exploration to identify and successfully resect an
ectopic adenoma. This team of doctors went on to perform a series CLINICAL PROFILE
of successful parathyroid surgeries and established the technique at
the endocrinology department in the hospital.
Hyperparathyroidism (HPT) can be divided into primary, Women are affected more than men in a ratio of approximately
secondary, or tertiary. Primary HPT (PHPT) is a result of increased 3:1 and generally in the fifth and sixth decades of life. Syndromic
production of parathyroid hormone (PTH) due to hyperplasia hyperparathyroidism patients generally manifest symptoms in the
or neoplastic pathology of one or multiple parathyroid glands. second or third decade of life. Constitutional complaints, such as
Secondary hyperparathyroidism (SHPT) refers to a compensatory weakness, easy fatigability, depression, and intellectual weariness
increase in PTH secretion in response to low serum calcium levels are frequently reported. Diseases epidemiologically (although not
and is most commonly seen in chronic renal diseases, less commonly etiologically) linked with primary hyperparathyroidism, such as
with long-term lithium therapy, and rarely with gastrointestinal hypertension and peptic ulcer disease, are also seen commonly.
absorption disorders and pseudohypoparathyroidism. Tertiary HPT Kidney stones and fractures, although uncommon, continue to be
(THPT) occurs after longstanding SHPT in which there is severe seen in some neglected population sets. Both general examination
parathyroid hyperplasia, with autonomous PTH secretion that is no and local neck examination may not yield any significant findings
longer effectively responsive to the serum calcium levels. THPT is and the diagnosis is primarily biochemical.
seen in post renal transplant patients who have developed resistance
to PTH receptors.
PHPT could be a result of single adenoma (85%–90%), multiglandular DIAGNOSIS
disease, double adenoma, and rarely parathyroid carcinoma (1%) [2].
Primary HPT is known to occur in syndromic and non-syndromic
situations. MEN1, MEN2A, and hyperparathyroidism with jaw Diagnosis is purely biochemical. Elevated serum PTH and calcium
tumor syndrome are the more significant ones. Table 23.1 illustrates are hallmarks of HPT. Concomitant presence of renal dysfunction,
syndromes commonly associated with hyperparathyroidism. vitamin D deficiency, and phosphate metabolism need to be evaluated
Primary hyperparathyroidism characterized by hypercalcemia and to differentiate the type and cause of HPT. A close differential
increased parathyroid hormone levels was classically described as diagnosis of HPT is familial hypocalcuric hypercalcemia (FHH) [4].
Surgical Management of Parathyroid Disorders 179

Diagnosis
Table 23.1 Syndromic associations with hyperparathyroidism
Genetic
Syndrome Incidence of HPT Co-existent features mutation Surgical management
Multiple Endocrine High (90%–100%) Pancreatic tumors, gastrinomas, stomach ulcers MEN 1 (11q13) Multigland excision
Neoplasia 1 (MEN 1) (Zollinger-Ellison syndrome)
Multiple Endocrine Low (15%–30%) MTC and pheochromocytoma RET (10q21) Excision of hypertrophic
Neoplasia 2A (MEN 2A) glands only
Hyperparathyroidism with High (80%) Fibro-osseous tumors of maxilla or mandible, HRPT2 Multigland excision
Jaw Tumor Syndrome Increased risk of increased risk of renal tumors
(HPTJT) parathyroid (nephroblastomas, hamartomas, or Wilms’
carcinoma tumors), and uterine tumors
Familial Hypocalciuric High Asymptomatic mild hypercalcemia with relative CASR (3q 21–24) Treatment only if
Hypocalcemia (FHH) hypocalciuria, hypermagnesemia in half of the symptomatic
patients, low calcium/creatinine ratio with total
calcium/24-hour urine collection <100 mg
Familial Isolated Low (12%–14%) Very rare MEN 1, CASR, Multigland excision
Hyperparathyroidism HRPT2
(FIHPT)
This can be determined by measuring the urinary calcium excretion parathyroid adenomas, especially for ectopic or small parathyroid
and urinary calcium-creatinine ratio. lesions [9]. For discordant studies or re-explorations, rarely invasive
Several physicians consider that pre-operative localization studies test such as selective venous sampling for PTH may be required [10].
are not necessary for first time explorations. However, in the wake of An ultrasound or CT guided FNAC can also be performed along
minimal access parathyroid surgeries, they have a definite role. These with PTH measurements from the washout to further clinch the
studies become further relevant with re-exploration parathyroid diagnosis [11]. During surgery, intra-operative ultrasound proves to
surgeries. Non-invasive as well as invasive, and structural as be a surgeon’s friend to aid in localization.
well as functional imaging studies are available. As a first line,
ultrasonography (USG) and sestamibi scans are useful diagnostic MANAGEMENT
tools [5] (Figure 23.1). When performed by experienced radiologists, Surgery remains the mainstay of treatment. Medical management
accuracy rates are very high for detection as well as localization of can be employed for patients who are not suitable candidates for
the concerned parathyroid gland harboring the adenoma. Studies surgery. Oral bisphosphonates, calcimimetic agents, and selective
show that a combination of USG and multiplexed ion beam estrogen receptor modulators (especially for post-menopausal
imaging (MIBI) scan has an accuracy of approximately 92% for women) have been tried with reasonable success.
single adenomas [6]. However, sestamibi scan lacks sensitivity for It is aptly said that appropriate surgery performed at the first time
multi-gland disease. Imaging studies are concordant in up to 65% stands the best chance for cure. A thorough knowledge of anatomy
of patients with primary HPT. When results from these tests are is paramount to assure good surgical outcomes.
discordant, SPECT-CT, 4D-CT, and MRI may be employed [7,8]. The
fourth dimension implying timing of contrast perfusion provides SURGICAL ANATOMY
the added advantage of both anatomical and physiological details A large autopsy study identified four parathyroid glands in 84%
about the parathyroid gland in question. The parathyroid adenomas of human cadavers, five or more glands in 13%, and only three
have rapid uptake and early washout of intravenous contrast parathyroid glands in 3% [12]. Normal parathyroid glands are
compared to the thyroid. F-fluorocholine (FCH) PET/CT imaging approximately 5–6 mm in greatest dimension, weigh 15–35 mg,
has been proven superior for accurate pre-operative localization of and can be inconspicuous with their orange-tan color embedded
Figure 23.1 Left-sided inferior parathyroid adenoma visualized on functional imaging.
180 Surgical Management of Parathyroid Disorders

Minimally Invasive Parathyroidectomy
Figure 23.3 Superior and inferior parathyroid glands separated by the

Figure 23.2 Parathyroids with their supplying vasculature and
plane of the recurrent laryngeal nerve.
central compartment nodes seen separately (1- Thyroid, 2- Parathyroid,
3- Central compartment lymph node, 4- Fat).
The surest method of differentiating superior and inferior
parathyroid glands is following the plane of recurrent laryngeal
or flattened within a surrounding yellow fatty tissue envelope. nerve (Figure 23.3). Glands that are dorsal to it are superior and
Parathyroid glands are often confused with central compartment those which are ventral to it are inferior. Intra-thyroidal parathyroid
lymph nodes, fat globules, or rarely thyroid nodules (Figure 23.2). glands are seen in approximately 1% of cases and contrary to
Several characteristics will help to differentiate between the four embryological theories, inferior glands are more often intra-
structures (Table 23.2). thyroidal according to autopsy studies.
The superior parathyroid glands arise from the fourth pharyngeal The following types of surgical procedures exist for the management
pouch and descend along with the thyroid gland. They are generally of hyperparathyroidism:
seen in a 1 cm area around the intersection of the recurrent laryngeal
nerve and inferior thyroid artery roughly near the entry point at the 1. Minimally invasive parathyroidectomy
crico-thyroid joint. The inferior parathyroid glands arise from the 2. Bilateral neck exploration
third pharyngeal pouch and descend down along with the thymus.
There is abundant literature including some meticulously
They are generally seen within 1 cm area from the lower pole of the
conducted meta-analysis to determine superiority between
thyroid gland. Although these are the standard locations for these
the approaches [13]. Jinih et al. conclude that compared with
glands, they are notorious for ectopic presence. Therefore, one must
bilateral exploration, focused exploration has similar recurrence,
be aware of the various anatomically variant locations as follows:
persistence, and reoperation rates but significantly lower overall
1. Dorsum of the superior pole of the thyroid gland complication rates and shorter operative time [14]. The failures
2. Retro-esophageal of focused exploration are often blamed on presence of double
3. Parapharyngeal adenomas or misdiagnosed multiple gland disease. However,
4. Within the carotid sheath chances of these remaining undetected before the end of surgery
are significantly decreased by routine implementation of intra-
5. Thyrothymic tract
operative serum PTH estimations. The decision rests on results
6. Mediastinal of localization studies, history of previous interventions, disease
7. Aorto-pulmonary window status, and often on surgeon/institution preference [15,16]. With
stringent selection criteria, surgeons have reported some success
with minimal parathyroid surgery for negative localization
Table 23.2 Differentiating characteristics for identification
studies as well [17]. Cost effective studies show a superiority of
of parathyroid glands
open minimally invasive over video-assisted parathyroidectomy
Lymph [18]. Also, it is pertinent to note that scar satisfaction rates were
Characteristic Parathyroid Fat node Thyroid no different between the open and minimally invasive or remote
Color Orange tan Yellow Pinkish Reddish access approaches [19]. Therefore, it is necessary to strike a balance
white brown between maximizing cosmesis and ensuring quality and cost-
Hilar vessel Present, can be Absent May or may Absent effectiveness of care.
traced up to not be
inferior present
thyroid artery
MINIMALLY INVASIVE PARATHYROIDECTOMY
Roving signa Positive Negative Negative Negative
Consistency Soft to firm Soft mushy Firm to hard Nodular
Shape Bean shaped Globular Oval to Nodular This implies limited neck exploration to selectively target and excise
round the parathyroid gland in question. Localization studies are a pre-
a Roving sign: The parathyroid gland housed in its capsule glides over the requisite for this procedure and results are most promising for single
thyroid in a roving motion. adenomas. This can further be of the following types:

Minimally Invasive Parathyroidectomy
a. Open minimally invasive parathyroidectomy: A small incision For other scenarios, the sternocleidomastoid muscle is a suitable
(3–3.5 cm) is placed either in the midline midway between the alternative. The auto-graft should be marked with titanium clips
cricoid cartilage and suprasternal notch, preferably in a natural or non-absorbable sutures for ease of identification in case of
skin crease. This allows bilateral exploration if required. re-operative parathyroid or thyroid surgery.
b. Endoscopic assisted minimally invasive parathyroidectomy: For secondary and tertiary hyperparathyroidism, the management
A mini skin incision (1–1.5 cm) is placed horizontally in the is primarily medical. However, patients whose HPT is not controlled
midline or along the anterior border of the sternocleidomastoid or who are symptomatic in spite of maximum medical management
muscle. Earlier requirements of CO2 insufflation are no are surgical candidates. K/DOQI guidelines from the U.S. Kidney
longer deemed essential. The endoscopic assistance provides Foundation have proposed that parathyroidectomy should be
magnification and therefore aids in better identification of the recommended in patients with severe SHPT (persistent serum
vasculature and the recurrent laryngeal nerve. levels of intact PTH >800 pg/mL), associated with hypercalcemia
c. Radio-guided parathyroidectomy: 20 mCi of 99mTc-sestamibi is or hyperphosphatemia, which is refractory to medical therapy. Both
administered half an hour prior to surgery. Intra-operatively, a subtotal parathyroidectomy and total parathyroidectomy with auto-
gamma camera evaluates the functioning parathyroid glands. graft are recommended options (Table 23.4).
In vivo counts are documented. After excision or ex-vivo There is considerable debate between subtotal versus total
counts more than 20 as compared to the remnant, background parathyroidectomy as surgery of choice for patients with MEN 1
activity is considered as successful excision of the concerned disorders, secondary, and tertiary hyperparathyroidism [20,21]. The
parathyroid gland. effects on post-operative serum calcium and PTH measurements,
the chances of recurrence/persistence, and re-operations are similar
BILATERAL NECK EXPLORATION for both the approaches. It is recommended that anything less than
Before the advent of advanced localization studies and intra- a subtotal parathyroidectomy is unacceptable on account of high
operative PTH measurements, bilateral neck exploration was the percentage of failures and recurrences for MEN 1 and secondary
norm. The dictum was: “Do not remove anything until you have seen hyperparathyroidism [22]. In an interesting study by Pitt et al. in
everything.” This is still preferred by many surgeons. All four glands 2009, the scope for less than subtotal resection of parathyroid glands
are examined and the morphologically abnormal glands or those for tertiary hyperparathyroidism was explored [23].
identified on localization studies are resected. Bilateral explorations The morphologically smallest gland without nodularity should be
are essential for the treatment of multiglandular hyperplasia, chosen as the remnant. Inferior parathyroid glands are easier to
syndromic primary HPT, and secondary and tertiary HPT. preserve due to their more ventral location. However, they should
Summarized below are indications for bilateral neck exploration: be marked with metallic clips to ease identification later. Also the
• Multiple endocrine neoplasia syndromes remaining glandular tissue must be confirmed as normal preferably
• Secondary and tertiary hyperparathyroidism by frozen section in order to prevent re-explorations. Even 1–2 mm
• Intra-operative PTH does not fall by >50% even 20 minutes tissue is sufficient for an experienced pathologist to report on frozen
section examination.
after resection of suspected single gland
• Failure to locate suspected gland prompted by localization
OPERATIVE ADJUNCTS
studies or detection of more than one suspicious gland on intra-
operative examination Intra-operative PTH (IOPTH) monitoring with turn-back times
• Localization studies fail to identify abnormal gland as low as 10–15 minutes has truly revolutionized the technique
• Indication for simultaneous thyroid surgery (co-existent goiter of minimally invasive parathyroidectomy [24,25]. It works on
the premise that the half-life of PTH is 3–5 minutes. Therefore,
or thyroid cancer)
• Surgeons often prefer to perform bilateral exploration for a substantial fall of >50% in PTH values 10–20 minutes post
resection is routinely practiced criterion for performance of
discordant pre-operative imaging studies (Table 23.3)
EXTENT OF SURGERY
For primary hyperparathyroidism caused by single adenoma, Table 23.4 Surgical indications for secondary hyperparathyroidism
resection of the involved gland is considered adequate surgery. Intra- Surgical Indications for Secondary Hyperparathyroidism
operative PTH monitoring criteria (mentioned in detail below) guide Modified by Japanese Society for Dialysis Therapy (JSDT)
the surgeon toward successful removal of the gland in question. For Guideline
multiglandular hyperplasia and syndromic HPT, the choice remains
Essential Components
between three to three and a half gland resection, that is subtotal
parathyroidectomy versus total parathyroidectomy with auto-graft. 1. Persistent high serum level of intact PTH level >500 pg/mL
Since subsequent neck surgery for medullary carcinoma thyroid is 2. Hyperphosphatemia (serum P >6 mg/dL) or hypercalcemia (serum
Ca >10 mg/dL), which is refractory to medical therapy
suspected in MEN 2 syndromes, the remnant parathyroid should
3. To detect estimated volume of the largest gland >300–500 mm3
preferably be transplanted in the forearm muscle brachioradialis. or long axis >1 cm
Clinical Findings
If patients have one of the following factors mentioned,
Table 23.3 Advantages and drawbacks of both these approaches
parathyroidectomy should be absolutely recommended:
Minimally invasive Bilateral neck 1. Severe osteitis fibrosa, high bone turnover
thyroidectomy exploration 2. Progressive ectopic calcification
3. Subjective symptoms (bone and joint pain, arthralgia, muscle
Overall morbidity Less More
weakness, irritability, pruritus, depression)
Hypocalcemia Less pronounced More pronounced 4. Calciphylaxis
Risk of recurrence/ More Less 5. Progressive reduction in bone mineral content
persistence 6. Anemia resistant to erythropoietin stimulating agent (ESA)
Risk of overall failure More Less 7. Dilated cardiomyopathy/cardiac failure

Pathology
adequate parathyroidectomy [26]. Some surgeons prefer taking a or severe bone demineralization pre-operatively (hungry bone
pre-incision sample, pre-excision samples (ligation of feeder vessel syndrome).
to the parathyroid adenoma), and 10 minutes post-excision samples.
Evidence also indicates that IOPTH to ≤40 pg/mL are associated REVISION SURGERY
with the lowest persistence rates after parathyroidectomy for Failure of PTH values to normalize 6 months after primary
primary hyperparathyroidism, and patients with values between surgery and persistence or appearance of symptoms suggestive of
41–65 pg/mL will require a careful follow-up [27,28]. hyperparathyroidism should prompt work-up for re-exploration
surgery. The following precautions can help to ensure optimal results
One can also perform PTH estimation on the aspirate from the
for revision surgeries:
excised parathyroid tissue. Values above 2,500 pg/mL are considered
confirmatory. IOPTH improves the success rate of minimally 1. Re-confirm diagnosis.
invasive procedures significantly. In a large prospective study at 2. Review all previous imaging, biochemical, and histology
the University of Wisconsin, the cure rate for initial unilateral reports.
exploration guided by IOPTH is 98.5% versus a predicted rate of 3. Review prior operative notes.
87% when decision-making is based on ipsilateral parathyroid gland 4. Perform localization studies.
appearance alone [29].
5. Utilization of intra-operative adjuncts such as IOPTH, Intra-
Low pre-incision values and co-existing renal disease can sometimes operative nerve monitoring, and loop magnification.
make IOPTH interpretations less reliable. However, similar criteria
6. Some surgeons prefer the back-door technique, where the
of >50% decline in pre-operative values were still a reliable indicator
parathyroid glands are approached laterally from underneath
of success [30].
the strap muscles. This helps to avoid scar tissue in the central
There has also been some critique toward the cost effectiveness compartment from previous surgical intervention.
of IOPTH monitoring since it is not routinely available in all 7. Usual anatomical variations such as thymic, retro-esophageal,
institutions [31]. The CaPTHUS [32] (pre-operative calcium, etc., should be verified before resorting to severe measures such
parathyroid hormone, ultrasound, sestamibi, concordance imaging) as thyroid lobectomy.
scoring model was introduced first in 2006 to predict presence of
single parathyroid adenoma and consequently predict long-term
PARATHYROID CARCINOMA
success after focused neck explorations for hyperparathyroidism.
Parathyroid carcinoma contributes to approximately 1% of all cases
Although it was a very reliable formula to estimate chances of cure
of HPT [33]. Previous head and neck radiation, chronic stimulation
after focused or unilateral parathyroid explorations, it was not
from renal failure, or familial syndromes are likely etiological
acceptable to substitute or replace IOPTH estimations completely
factors. This may be a phenotypic variant of HPT-JT syndrome.
[33] (Table 23.5).
Hallmarks of this disease are significantly elevated serum calcium
(3.75–3.97 mmol/L) and PTH (5–10 times the normal range) and
PARATHYROID AUTOFLUORESCENCE (PTAF) AND INTRA-
suspicious ultrasound or CT features [38]. Clinically, a hard mass
OPERATIVE PARATHYROID GLAND DETECTION
can be palpated in the neck. There may be signs of local invasion
Parathyroid glands can be differentiated from surrounding tissue
such as recurrent laryngeal nerve palsies. There may be presence of
by virtue of their ability to emit autofluorescence when stimulated
features of end organ involvement such as renal disease or skeletal
by near-infrared light. The utilization of PTAF for thyroid and
manifestations.
parathyroid surgeries is a very recent advancement and is still
in early stages. Some initial studies have found its utility in Staging can be broadly classified as:
the identification of parathyroid glands in surgery for primary 1. Disease localized to the parathyroid gland
hyperparathyroidism [34,35]. DiMarco et al. found that routine 2. Local infiltration into surrounding structures
use of PTAF in parathyroid surgery is presently not justified [36]. 3. Distant metastases
With further enhancements in this technology, PTAF’s role in
parathyroid surgery may expand. Adequate surgery should include ipsilateral thyroid lobectomy, central
compartment nodal clearance, and removal of all fibrofatty tissue from
POST-OPERATIVE MONITORING level VI [37]. There is no recommendation of lateral compartment
Several centers are promoting outpatient/same-day discharge neck dissection in the absence of proven or suspected disease.
surgeries for parathyroid pathologies. However, the authors propose Recommendations for adjuvant radiation include R+ resection, the
a period of a minimum 24–48 hours stay in hospital. Serum PTH post-operative lack of normalization of parathyroid hormone, as well
and calcium estimations should ideally be conducted approximately as multifocal recurrence or soft tissue deposits in recurrent patients.
24 and 48 hours post-surgery. Severe hypocalcemia may precipitate
in certain patients, especially those with very high PTH levels
Table 23.5 CaPTHUS scoring model PATHOLOGY
Predictive factor Points
Pre-operative total serum Ca level ≥3 mmol/L or ≥12 mg/dL 1 Morphologically there are meager differentiating features between
Intact PTH level ≥2 times upper limit of normal PTH levels 1 adenoma and hyperplasia. On microscopic examination, the
percentage of fat cells is an important criterion. Hypercellularity
Sestamibi scan results positive for 1 enlarged parathyroid 1
gland
that exceeds 50:50 ratio of oxyphil cells over fat cells implies the
diagnosis of adenoma. A differentiation of parathyroid carcinoma
Neck ultrasound results positive for 1 enlarged thyroid gland 1
over benign tumor may be challenging on an intra-operative
Concordant sestamibi and neck ultrasound study results 1
frozen section. However, the triad of high mitotic rate (>5 per 50
(identifying 1 enlarged gland on the same side of the neck)
high power fields), macro nucleoli, and necrosis are predictors of
Total 0–5
recurrent or metastatic disease. Immunohistochemical staining

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Chapter 24
PEDIATRIC THYROID SURGERY
Rajendra Saoji
CONTENTS
Introductions 187
Benign Conditions Warranting Surgical Management 187
Thyroid Malignant Lesions 188
Who Should Be Operating on Children? 189
Thyroid Pain and Abscess 189
Ectopic Thyroid Gland 189
References 189
autoantibodies to the thyroid-stimulating hormone (TSH) receptor. The

incidence of Graves’ disease in the pediatric population is approximately
INTRODUCTIONS 1 per 100,000 per year. This represents 0.1 per 100,000 in the child
and 3 per 100,000 in the adolescent population [2]. Children with
Graves’ disease should be managed with antithyroid drugs (ATD), viz.
Thyroid pathologies for children treat a varied mix of benign Methimazole and Propylthiouracil (PTU). To counter cardiovascular
and malignant conditions. Functionality of the gland may vary sequelae of the disease process, beta blockers are commonly added to
physiologically and pathologically. Surgical problems are often a the medical management of thyrotoxicosis. Such medications need to
manifestation of the embryological remnant variations, and therefore be given over long periods of time and then discontinued or reduced
thorough anatomical knowledge is a must for due planning, e.g., gradually. Very careful monitoring is needed for side effects such as
thyroid cyst or resultant abscess due to infection prone remnants agranulocytosis, joint pain, fever, skin rash, and the like, resulting
of otherwise uncommon third and fourth branchial arches or from Methimazole. The dose should be adjusted until the patient
thyroglossal duct cyst containing entire thyroid tissue and likewise. is rendered biochemically euthyroid and the symptoms of Graves’
Since these are majorly indolent conditions, it is essential to minimize disease are relieved. The other frequently employed drug PTU has the
or avoid iatrogenic morbidity. Pediatric thyroid cancers are a distinct very serious side effect of liver failure and has been banned for use in
entity with a different biological behavior than the adult counterpart. the pediatric population in many countries. The role of surgery, as a
They are much more aggressive with higher chances of nodal and definitive therapy, comes in when patients either cannot be managed
distant metastases. Many of these require adjuvant treatment in view with Methimazole due to severely troublesome side effects or fail to
of higher stages. However, prognosis is excellent with more than 95% undergo lasting remission. The non-surgical alternative of radioactive
10-year survival outcomes in a major series [1]. iodine is again not suitable for the pediatric population because of risk
Types of thyroid swellings which need surgical attention: of radiation exposure. A potential association between parathyroid
hyperplasia and hyperparathyroidism after radio-iodine therapy has
Goiters Graves’ disease also been reported.
Toxic nodule Therefore, surgery is an acceptable form of therapy for pediatric
Congenital
Graves’ disease. Thyroid surgery should be chosen when definitive
Cysts Simple cyst therapy for Graves’ disease is indicated and the child is too young
Cyst of remnant of third or fourth pharyngeal pouch
for I-131 or the required dose of I-131 is too high.
Abscess Infections of uncommon branchial pouches in close
proximity of thyroid lobe. The operation of choice is total or near-total thyroidectomy,
Neoplastic Adenoma
performed with the intent of rendering the patient hypothyroid.
Differentiated thyroid cancer (DTC) Subtotal thyroidectomy should be avoided due to an unacceptably
Medullary thyroid cancer (MTC) and associated familial high incidence of recurrence. In order to avoid the possibility of
syndromes hemodynamic instability or thyroid storm in the operating room,
Others Ectopic thyroid tissue children with Graves’ disease undergoing thyroidectomy should be
euthyroid prior to surgery, and Methimazole with/out beta-blockers
given as necessary. Methimazole is typically given for one to two
months in preparation for thyroidectomy. Potassium iodide should
BENIGN CONDITIONS WARRANTING be given in the immediate pre-operative period.
SURGICAL MANAGEMENT Potassium iodide (50 mg iodide/drop) can be given as 3–7 drops
three times daily for 10 days prior to surgery. Beta-blockers also
may be needed in patients with persistent tachycardia or allergy to
AUTOIMMUNE THYROIDITIS OR GRAVES’ DISEASE Methimazole.
Graves’ disease is an autoimmune condition which causes Graves’ patients who undergo thyroidectomy are more likely to
hyperthyroidism or thyrotoxicosis secondary to the production of suffer from hypocalcemic complications compared to patients who
Pediatric Thyroid Surgery 187

Thyroid Malignant Lesions
undergo thyroidectomy for other indications [3]. There are several and/or capsular invasion, except in the case of bilateral nodularity,
hypotheses for this finding, including hungry bone syndrome, where a total thyroidectomy is warranted initially.
increased secretion of calcitonin as a result of thyroid manipulation, Incidence of DTC is 0.49 per 100,000 per year, but is rising steeply,
and increased vascularity and inflammation of the gland which may largely because of the rapid expansion of papillary thyroid cancer
cause bleeding that can obscure the operative field or result in direct that has been observed around the world. Compared to adults,
adhesions to the parathyroid glands. At some centers, calcitriol pediatric patients with DTC present with more extensive disease;
(25–50 µg twice per day) is started three days pre-operatively as lymph node involvement at the time of diagnosis is seen in 40%–80%
prophylaxis for post-operative hypocalcemia. of children compared to 20%–50% of adults. Distant metastases at
According to the largest published series of 78 thyroidectomies in presentation is seen in 20%–30% of cases. Nevertheless, prognosis
children from the Mayo clinic over 17 years, the most common risks is favorable, with an associated 5-year survival rate of 95%–99%,
of thyroidectomy include recurrent laryngeal or superior laryngeal and a 20-year survival rate of 90% documented in literature.
nerve injury and permanent hypoparathyroidism (0%–6%) [4]. Owing to the relative rarity of DTC in children, there have been
Other less common risks include bleeding, which can occur up to no prospective randomized clinical trials to determine optimal
72 hours after the time of surgery, and wound infection. management. When thorough lymphadenectomy was performed
in conjunction with total thyroidectomy, patients with clinically
TOXIC NODULE or radiographically positive lymph nodes achieved survival rates
Toxic adenomas are autonomously functioning benign tumors that were similar to those of patients who presented with node-
that cause symptomatic hyperthyroidism. The true incidence of negative diseases. In this particular case, the authors defined
toxic adenomas in children is too low for accurate epidemiologic lymph node management as “complete” if it included a modified
estimates. In the case of children with solitary or unilobar toxic radical neck dissection [5]. Moreover, PTC is frequently multifocal
adenomas, thyroid lobectomy is the recommended procedure (or and bilateral within the thyroid gland; therefore, near-total or
rarely, isthmusectomy, if the toxic nodule is in the isthmus). Subtotal total thyroidectomy is usually indicated. This operative approach
lobectomy and nodulectomy are inadequate resections and increase further facilitates the administration of radioactive iodine post-
the risk of recurrence. As in the case of Graves’ disease, these patients operatively and long term surveillance with thyroglobulin (Tgb)
should be rendered biochemically and clinically euthyroid prior levels. Data also show that risk of recurrence and even survival
to surgery. The risk of lobectomy includes bleeding and recurrent are enhanced statistically with near-total or total thyroidectomy
laryngeal nerve injury. compared to lobectomy in adults. Consequently, there is
growing consensus that children with DTC should undergo total
CONGENITAL GOITER or near total thyroidectomy with central compartment lymph
Another benign thyroid disease that can require surgical node dissection for clinically or radiographically positive lymph
intervention is congenital goiter. Congenital goiters can be solitary node disease.
or multinodular. The true incidence of these pathologies is low MTC arises from the calcitonin-producing parafollicular C cells
enough to preclude epidemiologic estimates. Large goiters can be of the thyroid gland. It has an incidence in children of 0.03 per
symptomatic. If a patient develops symptoms of compression related 100,000 population per year. MTC can occur sporadically or as part
to mass effect, such as discomfort or pain (“globus sensation”), of a spectrum of familial MTC syndromes. In adults, sporadic MTC
dysphagia, dysphonia, or difficulty in breathing particularly when accounts for 65%–75% of MTC, but in the pediatric population,
lying flat, surgery should be considered. Uninodular goiters are sporadic carcinomas are exceedingly rare; the vast majority of MTC
amenable to lobectomy, while multinodular goiters require near- diagnosed in childhood is hereditary. Hereditary MTC can occur
total or total thyroidectomy. independently as familial MTC (FMTC). It can also occur as part
of a triad in the multiple endocrine neoplasia (MEN) syndromes
with pheochromocytoma and primary hyperparathyroidism in
MEN 2A, or with pheochromocytoma, marfanoid habitus, and
THYROID MALIGNANT LESIONS mucosal neuromas with MEN 2B. As such, it is nearly always the
first component of the MEN 2 phenotypes. Both syndromes are
related to selected mutations of the RET proto oncogene. The MTC
Thyroid nodules occur rarely in children but require investigation related to MEN 2B is the most virulent, followed by that of MEN 2A
because the incidence of malignancy is higher in the pediatric and FMTC, respectively. Patients (e.g., parents and parents-to-be)
population than in adults. Evaluation of a thyroid nodule should begin with MTC should be informed about the possibility of inheritable
with a history and physical examination, along with a biochemical cancer syndromes and offered genetic testing and counseling as
evaluation. This is typically followed by an ultrasound. In patients appropriate.
who are hyperthyroid, ultrasound should be followed by a nuclear
medicine (“uptake”) scan in order to determine if the pathology After genetic counseling and RET testing of all first degree relatives,
is a “warm” or “hot” nodule (that is, a toxic adenoma). Suspicious risk categories and recommendations for prophylactic thyroidectomy
nodules should undergo interrogation with an ultrasound-guided have been made by the American Thyroid Association [7] (Table 24.1).
fine-needle aspiration biopsy (FNAB). If the evaluation of a thyroid Post-operatively, patients require diligent surveillance for disease
nodule reveals an FNAB with cytology that is consistent with recurrence. Biochemical evidence of disease recurrence includes
follicular or Hurthle cell neoplasia, surgical excision is warranted new calcitonin elevation or rapid calcitonin or carcinoembryonic
for definitive histologic diagnosis; cytology cannot identify vascular antigen (CEA) doubling time. Palpable disease in the surgical bed
or capsular invasion and discriminate adenomas from carcinomas. or draining nodes is also indicative of recurrent disease. In cases
There are no specific professional society guidelines addressing the of suspected recurrence, imaging with ultrasound is indicated,
approach to follicular or Hurthle cell neoplasms in children. In with the diagnosis confirmed by FNA. If extra-cervical disease is
these cases, the general recommendation is thyroid lobectomy with suspected, computed tomography (and magnetic resonance imaging
completion thyroidectomy if the pathology demonstrates vascular for the liver, in particular) can facilitate confirmation.
188 Pediatric Thyroid Surgery

References
Table 24.1 Risk categories and recommendations for prophylactic require ipsilateral hemithyroidectomy to complete excision of the
thyroidectomy tract and sometimes partial resection of thyroid cartilage to provide
Codon Risk Timing for prophylactic adequate exposure of pyriform fossa sinus.
mutation Syndrome category thyroidectomy
918 MEN 2B Highest As early as possible within the

first year or first month of life ECTOPIC THYROID GLAND
883 MEN 2B High Within first 5 years of life
634 MEN 2A High Within first 5 years of life
In thyroid dysgenesis, nearly 66% of remnants thyroid gland are found
in an ectopic location, anywhere from base of the tongue (lingual
thyroid) to the normal position in the neck (hypoplasia). It may present
as an asymptomatic or symptomatic (breathing or feeding difficulty)
WHO SHOULD BE OPERATING ON CHILDREN?
mass at the base of the tongue or in the midline of the neck at supra-
or infrahyoid position. Sometimes it can get infected if located in
the thyroglossal duct cyst. Clinical importance lies in the fact that
In a literature review examining more than 20 case series reports
ectopically located thyroid tissue could be the only functioning thyroid
on a total of 1,800 pediatric patients, rates of permanent recurrent
tissue available in the body. Should it need to be removed, then a post-
laryngeal nerve injury and permanent hypoparathyroidism were
operative hypothyroid state is expected. Therefore, these patients will
lowest in operations by high-volume thyroid surgeons [6]. The
need lifelong thyroid hormone supplements or transplantation of
reported range of complication rates was considerable:
ectopically located thyroid tissue to other suitable locations and long
• Nerve injury rates ranged from 0% to 40% term surveillance for hypothyroidism.
• Hypoparathyroidism rates varied from 0% to 32%
The authors go on to note, “all surgery should be performed by
high-volume, experienced endocrine, pediatric, and head and neck
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Pediatric Thyroid Surgery 189

INDEX
A B surgery for, 105–106

surgical tips and tricks, 108–109
ABBA, see Axillo-bilateral breast approach BABA, see Bilateral axillo-breast approach Drug-induced thyroiditis, management of, 52
Active surveillance, as alternative to surgery, Babcock, William Wayne, 4 DTC, see Differentiated thyroid cancers
105–106 Babcock forceps, 4
Adena Pipe, 1, 2 Beahr’s triangle, 12, 13
Aerodigestive injury, thyroid surgery and, 120 Berry’s ligament, 13, 71, 72 E
Aerodigestive tract, invasion of, 127–129 Bethesda system for reporting of thyroid Ectopic thyroid, 163
intra-laryngotracheal luminal invasions, cytopathology (BSRTC), 45 EFVPTC, see Encapsulated Follicular Variant of
129 Bigelow, Henry Jacob, 3, 5 Papillary Thyroid Carcinoma
larynx invasion, 128 Bilateral axillo-breast approach (BABA), 83, Embryology, of thyroid gland, 7–8
respiratory tract invasion, 128 84, 86 Encapsulated Follicular Variant of Papillary
tracheal invasion, 128–129 Bilroth, Theodor, 4 Thyroid Carcinoma (EFVPTC), 47
Agranulocytosis, 51 Blood supply, of thyroid gland, 10–12 Eustachius, Bartholomew, 1
Airway concerns, in thyroid surgery, 120–123 inferior thyroid artery, 10 Everolimus, 176
difficult intubation, 120 pyramidal artery, 10–11 External branch of the superior laryngeal nerve
hypoparathyroidism, 121–122 superior thyroid artery, 10 (EBSLN), 12, 109
hypothyroidism, 122 thyroid ima artery, 10
injury to EBSLN, 120–121 thyroid veins, 11–12
thyroid storm, 122–123 Bovie, William T., 4 F
AIT, see Amiodarone induced thyrotoxicosis BRAF inhibitor, 175
ALK, see Anaplastic lymphoma kinase B-RAF mutations, 155, 173 Fine needle aspiration cytology (FNAC), 45
ALK inhibitors, 175–176 BSRTC, see Bethesda system for reporting of FNAC, see Fine needle aspiration cytology
Amiodarone, 53 thyroid cytopathology Follicular neoplasia, pathology of, 47
Amiodarone induced thyrotoxicosis Buparlisib, 176
(AIT), 53 G
Anaplastic lymphoma kinase (ALK), 174
Anaplastic thyroid cancers (ATC) C Gillette, King Camp, 4
clinical presentation, 147–148 Globus hystericus, 17
Cabozantinib, 175 Goiter
clinical evaluation, 147–148
Capsule, of thyroid gland, 9 earliest artistic depictions, 1, 2
clinical findings, 147
CCND, see Central compartment neck history of, 1–2
diagnosis, 147
dissection Graves’ disease, 24, 25, 163
staging, 148
Central compartment neck dissection (CCND), beta adrenergic blockers for, 52
imaging of, 31–40
113–115 management of, 51–52
lymphadenopathy, 37, 40, 41
Ceritinib, 176 potassium iodide therapy, 52
primary thyroid lymphoma, 33
Cervical epidural anesthesia, for thyroid radioiodine therapy, 52
ultrasound elastography, 33, 37, 39, 40
surgery, 63–66 RAI therapy for, 166
neoadjuvant chemotherapy, role of, 149
indications, 64 Gross, Jack, 2
neoadjuvant pre-operative radiotherapy,
intra-operative management, 65 Gross, Samuel David, 4
148
method for, 64–65
overview, 147
post-operative management, 65–66
pathology, 49 H
pre-medication, 64
post-operative external beam radiotherapy,
Colloid goiter, 46
148 Halsted, William Steward, 4
Colloid nodules, 28
treatment of, 148–149 Harington, Charles, 2
Cricothyroid joint, 13
Anesthesia, for thyroid surgery, 3 Hashimoto’s thyroiditis, 25–26
Crizotinib, 176
awake intubation, 61 Hematoma, thyroid surgery and, 119–120
Cushing, Harvey, 4
cervical epidura, see Cervical epidural Hemi-thyroidectomy, 42
anesthesia, for thyroid surgery Hultl, Humer, 4
general, 61 D Hurthle cell neoplasm, 46
induction of, 61–62 ultrasound of, 29, 31
maintenance of, 61–62 Decompressive craniotomy, 3 Hyperparathyroidism (HPT), 179
recovery from, 62 De humani corporis fabrica, 97 minimally invasive parathyroidectomy,
regional, 63 De Quervain’s (sub-acute) thyroiditis, 181–183
Ansa cervicalis, surgical anatomy of, 8, 9 management of, 52–53 bilateral neck exploration, 182
Anterior jugular veins, surgical anatomy Differentiated thyroid cancers (DTC) extent of surgery, 182
of, 7–8 completion thyroidectomy, 106–107 intraoperative parathyroid gland
Anti-thyroglobulin antibodies (Anti-TG AB), extent of surgery, 106 detection, 183
152 hemi-thyroidectomy vs total thyroidectomy, operative adjuncts, 182–183
Asepsis, 3 107–108 parathyroid autofluorescence, 183
ATC, see Anaplastic thyroid cancers low risk thyroid cancer vs. high risk thyroid parathyroid carcinoma, 183
Autoimmune thyroiditis, 24–25 cancer, 106 syndromic associations with, 180
Autonomously functioning thyroid nodule metastases neck nodes in, surgery of, Hypertrophic or keloid scar, thyroid surgery
(AFTN), 163 113–116 and, 120
Axillo-bilateral breast approach (ABBA), 83 nodal recurrence in, risk of, 116 Hypoparathyroidism, 121–122
191
Index
Hypothyroidism, 122 M Nodal metastasis in thyroid cancer

management of, 53–54 diagnosis, 113
central hypothyroidism, 53 Malampatti grading, 60 lateral compartment, 115–116
primary hypothyroidism, 53–54 MAPK pathway, see Mitogen-activated protein metastases neck nodes, in DTC, 113–114
kinase pathway quantification of problem, 113
Maryland dissector, 93 surgical tips, 114–115
I Medullary thyroid cancer (MTC) therapeutic CCND, 113–115
Infections, thyroid surgery and, 119 external beam radiotherapy, adjuvant, 142 Nodule of Zuckerkandl, 12, 13
Inferior thyroid artery, 10 features of, 135 Non-Hodgkin’s lymphoma (NHL), 49
Insular carcinoma, pathology of, 49–50 imaging of, 30–31, 38 Non-invasive follicular thyroid neoplasm with
Intra-operative neural monitoring (IONM), 97, immunohistochemical features of, 137 papillary nuclear features (NIFTP)
106 metastasis, 142 histology, 47
continuous vagal monitoring, 102 oncocytic variant of, histological features nuclear inclusions in, 47
intra-operative setup, 100 of, 137 Non-neoplastic lesions, 46
laryngeal examination, importance of, pathology of, 48, 49 Non-radioactive iodine imaging, 165–169
97–98 pre-operative evaluation, 135–138 Non-RAI radiotracer therapy, 169
loss of signal during, 100, 101 prophylactic cancer surgery, 142–143 Non-recurrent laryngeal nerve (NRLN), 13, 102
neural injury prevention, 102 recurrence, 142 NOTES, see Natural orifice transluminal
neural mapping using, 98 residual, 142 endoscopic surgery
non-recurrent laryngeal nerve, intra- TNM classification AJCC (8th edition) for, NRLN, see Non-recurrent laryngeal nerve
operative identification of, 102 138–142
passive EMG activity during, 100 palliative surgery, 138
surgical steps, 139–142 P
routine use of, 101
safety, 100 surgical treatment, 138–139 Papanicolaou stain, 46
setup, 99–100 unresectability criteria, 138 Papillary thyroid carcinoma, imaging of, 29–30,
and staged thyroidectomy in thyroid cancer MEK inhibitor, 175 32–36
surgery, 100–101 Metastasis to thyroid, imaging of, 40–42 Papillary thyroid microcarcinoma (PTMC), 105
standards for, 98–100 computed tomography, 41–42 imaging of, 30, 37
superior laryngeal nerve monitoring, 102 contrast-enhanced ultrasound, 41 Parathyroid disorders, surgical management of
technique, 98–99 hemi-thyroidectomy, 42 clinical profile, 179
utility and applications, 98 magnetic resonance imaging, 41–42 diagnosis, 179–181
IONM, see Intra-operative neural monitoring positron emission tomography-computed management, 180
Ipsilateral vocal cord paralysis, 97 tomography, 41–42 surgical anatomy, 180–181
Isthmus post-thyroidectomy, 42 minimally invasive parathyroidectomy,
discovery of, 1 Midline tuberculous abscess, 16 181–183
relations of, 9 Minimally invasive parathyroidectomy, 181–183 bilateral neck exploration, 182
131I-whole body scan, 164–165 Minimally invasive video-assisted thyroidectomy extent of surgery, 182
(MIVAT) technique, 83 intraoperative parathyroid gland
Mitogen-activated protein kinase (MAPK) detection, 183
K pathway, 173 operative adjuncts, 182–183
MIVAT technique, see Minimally invasive parathyroid autofluorescence, 183
Kendall, Edward C., 2 video-assisted thyroidectomy parathyroid carcinoma, 183
Kocher, Emil Theodor, 4, 5 technique overview, 179
Molecular pathogenesis, 173–174 pathology, 183–184
mTOR pathway, 173 Parathyroid (PT) glands, 12
L Muco-epidermoid carcinoma, 50 Parathyroid hormone (PTH), history of, 2–3
Laryngeal nerve palsy, recurrent, 82 Multi-kinase inhibitors (MKI), 174–175 Parathyroid insufficiency, 82
LATC, see Locally advanced thyroid cancer Multinodular goiter, surgery of, 75–77 Parker, Morgan, 4
Lenvatinib, 175 evolution of, 75 PAX8-PPARγ rearrangement, 174
Levator glandulae thyroidae, 13 follow-up strategy, 76–77 Pediatric thyroid surgery, 187–189
Linea alba cervicalis, 94 genesis of thyroid nodule, 75–76 autoimmune thyroiditis, 187–188
Lister, Joseph, 3, 5 indications for surgery, 75–76 benign conditions warranting surgical
List of Essential Medicines, 1 optimizing surgical treatment, 76 management, 187–188
Liston, Robert, 4 overview, 75 congenital goiter, 188
Locally advanced thyroid cancer (LATC), structural issues, 76 ectopic thyroid gland, 189
127–133 Murphy, John, 3–4 Graves’ disease, 187–188
aerodigestive tract, invasion of, 127–129 Myxedema coma, 62 malignant lesions, 188
intra-laryngotracheal luminal invasions, overview, 187
129 N right surgeons for, 189
larynx invasion, 128 thyroid pain and abscess, 189
respiratory tract invasion, 128 Natural orifice transluminal endoscopic surgery toxic adenomas, 188
tracheal invasion, 128–129 (NOTES), 83 Petz, Aladar, 4
overview, 127 Neoplastic lesions, pathology of, 47–50 Phosphatidyl inositol 3 kinase-AKT
pharyngeal and esophageal involvement, follicular neoplasia, 47 (PI3K-AKT), 173
132 insular carcinoma, 49–50 Pitt-Rivers, Rosalind, 2
strap muscles, invasion of, 127 medullary carcinoma, 48, 49 Platysma muscle, surgical anatomy of, 7
surgical management, 129–132 papillary carcinoma, 47, 48 Poorly differentiated carcinoma, pathology of,
vascular invasion, 132 poorly differentiated carcinoma, 49–50 49–50
Lore’s triangle, 12 Nerves, of thyroid gland, 12–13 Postpartum thyroiditis, management of, 52
LOS, see Loss of signal Nerve supply, of thyroid, 11–12 Potts, John Thomas, 2
Loss of signal (LOS), 98 Next generation sequencing (NGS), 173 Primary hypothyroidism, 53–54
during IONM, 100, 101 NIFTP, see Non-invasive follicular thyroid Processus posterior glandulae thyroidea, 12
Lugol, Jean Guillaume Auguste, 1 neoplasm with papillary nuclear Prograsp forceps, 93
Lugol’s Solution (aqueous iodine), 1 features Prophylactic cancer surgery, 142–143
192
Index
Propylthiouracil (PTU), 51 Selumetinib, 175 surgical anatomy, see Surgical anatomy, of

PTMC, see Papillary thyroid microcarcinoma Seroma, thyroid surgery and, 119 thyroid gland
PTU, see Propylthiouracil Sirolimus, 176 venous drainage of, 11
Pyramidal artery, 10–11 Skull trephining, 3 Thyroid ima artery, 10
Solitary thyroid nodule (STN), 45 Thyroid Imaging, Reporting, and Data System
R Sorafenib, 174–175 (TIRADS), 26
Strap muscles, surgical anatomy of, 8 Thyroiditis, 162
Radiation-induced thyroiditis, management of, 53 Superior thyroid artery, 10 autoimmune, imaging of, 24–25
Radioiodine (RAI) Suppurative infection, 16 Hashimoto’s, imaging of, 25–26
imaging with, molecular basis of, 161–165 Surgery, history of, 3–4 management of, 52–53
131I-whole body scan, 164–165 Surgical anatomy, of thyroid gland, 7–9 De Quervain’s (sub-acute) thyroiditis,
normal and abnormal thyroid scintigraphy, ansa cervicalis, 8, 9 52–53
162–164 anterior jugular veins, 7–8 drug-induced thyroiditis, 52
thyroid scan, 162 platysma muscle, 7 infectious or post-infectious thyroiditis, 52
thyroid uptake study, 161 strap muscles, 8 postpartum thyroiditis, 52
RAI refractory disease, treatment of, 168 Surgical instruments, history of, 3–4 radiation-induced thyroiditis, 53
RAI therapy Surveillance, post-treatment, of thyroid cancer pathology of, 46, 47
of bone metastases, 168 dynamic risk stratification, 155–157 Thyroid nodule, clinical assessment of, 15–18
for Graves’ disease, 166 initial risk stratification, 153–155 clinical questionnaire for functionality, 18
pulmonary metastases, treatment of, 168–169 molecular markers, profiling of, 155 patient clinical history, gathering, 15–17
remnant ablation, 167 thyroid cancer mortality risk, 153–154 physical examination, 17–18
side effects and complications of, 168–169 thyroid cancer recurrence risk, 154–155 thyroid swellings, clinical questionnaire
of thyroid cancer, 166–167 overview, 151 for, 18
TMNG or TA, 166 strategies for, 157–158 Thyroid nodules, 163–164
RAS mutations, 155, 173 according to risk and response to Thyroid nodules, imaging of, 26–29, 30
Recurrent laryngeal nerve (RLN), 12–13, 16 treatment, 158 benign, 28
management of, 71 high-risk patients, 158 colloid nodules, 28
with preoperative vocal cord paralysis, 101 low-risk or intermediate-risk patients, evaluation for size, 26
robotic thyroidectomy, 92, 93 157–158 malignant, 28–29
RET-PTC rearrangement, 174 surveillance tools for DTC, 151–153 TIRADS risk category, 26–28
Retrosternal goiter (RSG) anti-thyroglobulin antibodies, 152 Thyroid-stimulating hormone (TSH), 151
chest X-ray, 80 computed tomography scans, 153 Thyroid storm, 122–123
classification, 80–81 positron emission tomography scans, 153 Thyroid surgery
clinical manifestations, 79 serum thyroglobulin, 151–152 airway examination, 60
CT scan, 80 ultrasonography of neck, 152 airway management, preparation of, 61
investigation for, 79–80 whole body RAI scans, 152–153 anesthesia for
overview, 79 System of Surgery, A, 4 cervical epidural, 63–66
sternotomy approach for, 82 induction of, 61–62
treatment, 81–82 T regional, 63
rhTSH (thyrogen), 164 complications of, 119–123; see also specific
RLN, see Recurrent laryngeal nerve TA, see Toxic adenoma complications
RLN paralysis, 97 Targeted therapy, in thyroid cancer, 174–176 history of, 4
Robotic or endoscopic thyroidectomy, remote AKT pathway inhibitor, 176 medical history of patient, 59–60
access ALK inhibitors, 175–176 post-operative complication, 62–63
advantages and limitations of, 84–86 immunotherapy, 176 pre-operative assessment, 57–59
axillo-bilateral breast approach, 83 mTOR pathway inhibitor, 176 pre-operative preparation, 60–61
bilateral axillo-breast approach, 83, 84, 86 multi-kinase inhibitors, 174–175 radiological assessment, 60
classification, 83–86 PI3 K pathway inhibitor, 176 Thyroid swellings, clinical questionnaire for, 18
operative procedures, 83–84 tyrosine kinase inhibitors, 174–175 Thyroid veins, 11–12
comparison of, 88 Teratoma, 50 Thyrotoxicosis, 25
experience of, 86–87 TERT promoter gene mutation, 174 Thyrotoxic state, 15
gasless postauricular facelift approach, 84 TERT promoter mutations, 155 Thyrotoxic storm, 62–63
gasless unilateral axillary approach, 83–84, Thyroglobulin (Tg), 151–152 Thyroxine (T4), 2
85 Thyroglossal cyst, 16 TIRADS, see Thyroid Imaging, Reporting, and
history of, 83 Thyroidectomy, 67–73 Data System
postauricular facelift approach, 87 anesthesia for, 68, 69 TMNG, see Toxic multinodular goiter
transoral vestibular approach, 84 appliances and technology for, 68–69 TOETVA, see Transoral endoscopic thyroidectomy
with carbon dioxide insufflation, 88 incision planning, 69 through a vestibular approach
Robotic thyroidectomy, 91–95 injuries in, identifying, 73 Toxic adenoma (TA), 163
indications and contraindications for, overview, 67 Toxic multinodular goiter (TMNG), 162
91–95 parathyroid injuries, 73 Transfiguration, The, 1, 3
outcomes, 94–95 patients at risk, identification of, 67 Transoral endoscopic thyroidectomy through a
overview, 91 position for, 69 vestibular approach (TOETVA), 94
techniques, 91–94 RLN injuries, 73 3,5,3′-Triiodothyronine (T3), 2
axillo-breast approach, 93 safety steps for, 69–72 Tyrosine kinase inhibitors (TKI), 174–175
retroauricular approach, 93–94 size of thyroid masses, 67–68 Tyrosine kinase inhibitors, for drug-induced
trans-axillary approach, 91–93 Thyroid gland thyroiditis, 53
transoral approach, 94 anatomical understanding of, historical
RSG, see Retrosternal goiter perspective, 1–2 U
capsule of, 9
S embryology of, 7–8 Ultrasound, of thyroid gland, 21–26
enlargement of, see Goiter in diffuse thyroid disorders, 24–26
Sanzio, Raffaello, 1 hormones, history of, 2–3 autoimmune thyroiditis, 24–25
Schreger, C. H. T., 1 relations of, 10 Hashimoto’s thyroiditis, 25–26
193
Index
Ultrasound, of thyroid gland (Continued) V Vocal cord palsy (VCP), 101

embryology and ectopic thyroid glands, 24 von Haller, Albrecht, 2
of follicular neoplasm, 29, 31 Vandetanib, 175 von Luschka, Herbert, 1
history and evolution, 21 VANS, see Video-assisted neck surgery
Hurthle cell neoplasm, 29, 31 VCP, see Vocal cord palsy
W
principle and physics of, 21–22 Vertical hemilaryngectomy, 129
technique and patient position, 24 Vesalius, Andreas, 1 Whole body RAI imaging, 164–165
thyroid anatomy, 22–24 Video-assisted neck surgery (VANS), 83 Whole body RAI scans (WBS), 152–153
194

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© 2020 Taylor & Francis Group, LLC

CRC Press is an imprint of Taylor & Francis Group, LLC

Library of Congress Cataloging-in-Publication Data

Names: Kapre, Madan, editor.

ISBN: 9781138483781 (hbk)

CHAPTER 1 HISTORY AND EVOLUTION OF THYROID SURGERY 1

CHAPTER 2 SURGICAL ANATOMY OF THE THYROID 7

CHAPTER 3 CLINICAL ASSESSMENT OF THE THYROID NODULE 15

CHAPTER 4 IMAGING OF THE THYROID 21

CHAPTER 5 PATHOLOGY OF THE THYROID 45

CHAPTER 6 MEDICAL MANAGEMENT OF THYROID DISORDERS 51

CHAPTER 7 ANESTHESIA FOR THYROID SURGERY 57

CHAPTER 8 SAFE THYROIDECTOMY 67

CHAPTER 9 SURGERY FOR MULTINODULAR GOITER 75

CHAPTER 10 MANAGEMENT OF RETROSTERNAL GOITER 79

CHAPTER 11 REMOTE ACCESS ENDOSCOPIC AND ROBOTIC THYROIDECTOMY 83

CHAPTER 12 ROBOTIC THYROIDECTOMY 91

CHAPTER 13 INTRA-OPERATIVE NEURAL MONITORING 97

CHAPTER 15 MANAGEMENT OF NODAL METASTASIS IN THYROID CANCER 113

CHAPTER 16 COMPLICATIONS OF THYROID SURGERY 119

CHAPTER 17 LOCALLY ADVANCED THYROID CANCER 127

CHAPTER 18 SURGICAL MANAGEMENT OF MEDULLARY THYROID CANCERS 135

CHAPTER 19 SURGICAL MANAGEMENT OF ANAPLASTIC THYROID CANCERS 147

CHAPTER 20 POST-TREATMENT SURVEILLANCE OF THYROID CANCER 151

CHAPTER 21 APPLICATIONS OF RADIOISOTOPES IN THE DIAGNOSIS AND

CHAPTER 22 SYSTEMIC THERAPY (TARGETED THERAPY AND IMMUNOTHERAPY)

CHAPTER 23 SURGICAL MANAGEMENT OF PARATHYROID DISORDERS 179

CHAPTER 24 PEDIATRIC THYROID SURGERY 187

Amit Agarwal Amol Dongre

Chandrasekhar Bal Sanoop Elambassery

Christian Camenzuli Harsh Karan Gupta

Shubhada Deshmukh Vidula Kapre

Ashutosh Mangalgiri Rajendra Saoji

Rahul Modi Meghna Sarode

Deepa Nair Ashok Shaha

Himanshu Patil Subhaschandra Shetty

Shailesh Pitale Belayat Hossain Siddiquee

Madan Laxman Kapre

1. Moon JH et al. Prevalence of thyroid nodules and their

HISTORY AND EVOLUTION OF THYROID SURGERY

Cheerag Patel and Subhaschandra Shetty

History and Evolution of Thyroid Surgery 1

2600 bc Goiter is known in China—treated with burnt

2 History and Evolution of Thyroid Surgery

History and Evolution of Thyroid Surgery 3

4 History and Evolution of Thyroid Surgery

6. Sterpetti AV, Fiori E, De Cesare A. Goiter in the art of

History and Evolution of Thyroid Surgery 5

SURGICAL ANATOMY OF THE THYROID

Ashutosh Mangalgiri and Deven Mahore

from below, and the presence of a pyramidal lobe unilaterally or

EMBRYOLOGY OF THE THYROID GLAND

An endodermal diverticulum descends in the form of primordium

Surgical Anatomy of the Thyroid 7

identified between these anterior jugular veins. Usually the anterior

8 Surgical Anatomy of the Thyroid

CAPSULE OF THE THYROID GLAND

The thyroid is suspended by an investing layer of deep fascia,

CHAPTER 21 APPLICATIONS OF RADIOISOTOPES IN THE DIAGNOSIS AND

CHAPTER 22 SYSTEMIC THERAPY (TARGETED THERAPY AND IMMUNOTHERAPY)