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Surgery of the Thyroid and Parathyroid Glands

Daniel Oertli Robert Udelsman (Eds.)

Surgery of the Thyroid

and Parathyroid Glands
With 235 Figures and 52 Tables


Daniel Oertli
Division of General Surgery,
University Hospital Basel,
Vice-Dean of the Medical Faculty,
University of Basel
4031 Basel

Robert Udelsman
Lampman Professor of Surgery and Oncology,
Chairman, Department of Surgery,
Surgeon-in-Chief Yale-New Haven Hospital
Yale University School of Medicine
PO Box 208062
New Haven, CT 06520-8062

Library of Congress Control Number: 2005938803

ISBN-10 3-540-29165-2 Springer Berlin Heidelberg NewYork

ISBN-13 978-3-540-29165-7 Springer Berlin Heidelberg NewYork

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Editor: Gabriele M. Schrder, Heidelberg, Germany

Desk Editor: Stephanie Benko, Heidelberg, Germany
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The Editors are deeply indebted to all authors and We also express our gratitude to the valuable coor-
coauthors who have contributed to Surgery of the dinative work of our editorial assistants in Basel and
Thyroid and Parathyroid Glands. The Editors believe New Haven: special thanks are addressed to Susan
that this textbook is among the most comprehensive Demou, Madeleine Moser, and Dotty Franco.
international references on surgical diseases of the Finally, our profound gratitude goes to all who
thyroid and parathyroid glands. The diligent efforts of were involved in the development of this text, in-
the contributors, who have provided insightful state- cluding our immediate families, who expressed in-
of-the art presentations, are gratefully acknowledged. terest and encouragement in the completion of this
The Editors also wish to pay tribute to the diligent textbook. We greatly appreciate their support, which
work of the Springer-Verlag staff members, who en- stimulated us to pursue the ambitious goal of prepar-
abled the realization of this first edition. Particularly ing what we consider to be a concise, comprehensive
appreciated were the efforts of Gabriele M. Schroeder, textbook.
Executive Editor, and Stephanie Benko, Desk Editor,
who provided strong encouragement and ongoing Daniel Oertli and Robert Udelsman
support during the creation of this textbook. Further-
more, the Editors are most appreciative of the princi-
pal artist, Mr. Jrg Khn, who provided us with excel-
lent drawings.


Thyroid and parathyroid disorders are frequently en- The current edition has been designed primarily to
countered by the endocrine surgeon in daily practice. meet the requirements of young surgeons who wish
The Editors therefore have designed this comprehen- to acquire profound knowledge of basic, clinical, and
sive textbook focusing on surgically relevant thyroid laboratory concepts as well as surgical techniques
and parathyroid diseases. The Editors intend this regarding the thyroid and parathyroid glands, thus
book to become an important reference presenting complementing the surgeons training. These prin-
the latest information regarding the management of ciples are presented together with advancements in
both common and rare thyroid and parathyroid dis- technologic, molecular, cellular, and biologic sciences,
orders. Internationally renowned physicians and sur- thus meeting the criteria of the 21st century defini-
geons have provided detailed outlines and discussions tion of each subspecialty involving care of patients
on operative techniques and treatments accompanied with thyroid and parathyroid disease. The prepara-
by rationales for particular approaches advocated by tion of the text material has been a labor of love and
the authors. The topics cover all surgically relevant represents an honest attempt to provide information
thyroid and parathyroid pathologies, the preoperative that we believe is not only of clinical importance to
surgical evaluation, decision making, and operative surgeons, but also to endocrinologists, radiologists,
strategies including high quality step-by-step illustra- and pathologists dealing with patients with thyroid
tions of the current surgical techniques. Furthermore, and parathyroid disorders.
experts are presenting the molecular basis for thyroid It is hoped that the reader will find the material in
neoplasia and the current understanding of the ge- our textbook as helpful and exciting as we do.
netics of inherited thyroid and parathyroid diseases.
Moreover, evolving modern operative techniques like Daniel Oertli and Robert Udelsman
the minimally invasive videoscopic approach to the
thyroid and parathyroid glands are discussed in this

Table of Contents

1 History of Thyroid and Parathyroid 12 Anaplastic Thyroid Carcinoma . . . . . . . . . . 161

Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Christian Passler, Reza Asari, Christian Scheuba,
Hans-Dietrich Rher and Klaus-Martin Schulte and Bruno Niederle

2 Embryology and Surgical Anatomy 13 Thyroid Lymphoma and Other Metastatic

of the Thyroid and Parathyroid Glands . . . . 13 Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
William B. Stewart and Lawrence J. Rizzolo Rebecca S. Sippel and Herbert Chen

3 Evaluation of Hyperthyroidism 14 Multinodular and Retrosternal Goiter ... 179

and Hyperthyroid Goiter . . . . . . . . . . . . . . . . 21 Rachel Rosenthal and Daniel Oertli
Mirjam Christ-Crain, Nils G. Morgenthaler,
and Beat Mller 15 Surgery for Hyperthyroidism ........... 191
Peter E. Goretzki and Bernhard J. Lammers
4 Diagnostic Imaging of the Thyroid
and Radioiodine Therapy . . . . . . . . . . . . . . . . 31 16 Thyroiditis ............................ 207
4.1 Walter Wiesner, Hermann Engel, and Wolfgang Michel Adamina and Daniel Oertli
4.2 Egbert U. Nitzsche and Jan Mueller-Brand 17 Complications in Thyroid and Parathyroid
Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
5 Evaluation of Thyroid Nodules . . . . . . . . . . . 45 Andrea Frilling and Frank Weber
Michel Procopiou and Christoph A. Meier
18 Outcomes Analysis in Thyroid Surgery:
6 Fine-needle Aspiration Cytology A Review of Patient and Provider
of the Thyroid . . . . . . . . . . . . . . . . . . . . . . . . . . 61 Predictors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
Anne E. Busseniers and Susan A. Silver Kate V. Viola and Julie Ann Sosa

7 Technique of Thyroidectomy . . . . . . . . . . . . . 81 19 Physiology and Pathophysiology

Daniel Oertli of the Parathyroid Glands and Preoperative
Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
8 Surgery for the Solitary Thyroid Nodule .. 91 Elizabeth H. Holt and Silvio E. Inzucchi
Prabhat K. Bhama and Gerard M. Doherty
20 Parathyroid Imaging ................... 245
9 Modified Radical Neck Dissection . . . . . . . 101 David Cheng, Ludwig A. Jacob, and Leslie Scoutt
Robert Udelsman
21 Conventional Surgical Management
10 Thyroid Pathology ..................... 109 of Primary Hyperparathyroidism . . . . . . . . 261
Zubair W. Baloch and Virginia A. LiVolsi Heather Yeo, Paola Uranga, and Sanziana Roman

11 Surgery for Medullary Thyroid Cancer . . . 147 22 Minimally Invasive Parathyroidectomy .. 269
Oliver Gimm Tobias Carling and Robert Udelsman
X Table of Contents

23 Endoscopic Parathyroidectomy ......... 277 26 Parathyroid Carcinoma . . . . . . . . . . . . . . . . . 311

Paolo Miccoli and Gabriele Materazzi Janice L. Pasieka and Moosa Khalil

24 Multiglandular Parathyroid Disease 27 Reoperative Parathyroid Surgery . . . . . . . . 327

and MEN Syndromes . . . . . . . . . . . . . . . . . . 285 Cord Sturgeon, Nadine Caron, and Quan-Yang Duh
Peter Langer, Detlef K. Bartsch,
and Matthias Rothmund 28 Outcomes Analysis in Parathyroid
Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
25 Pathophysiology and Leon D. Boudourakis and Julie Ann Sosa
Treatment of Secondary
and Tertiary Hyperparathyroidism . . . . . . 293 Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
Ulrich Gller and Michael Mayr

List of Contributors

Michel Adamina Anne E. Busseniers

Division of General Surgery, Metropolitan FNA Service,
University Hospital Basel, Washington, DC; Bethesda, MD,
Spitalstrasse 21, USA
4031 Basel, and
Switzerland Department of Pathology,
Vrije Universiteit Brussels,
Reza Asari Brussels,
Division of Endocrine Surgery, Belgium
Department of Surgery,
Vienna University Hospital, Tobias Carling
Vienna, Department of Surgery,
Austria Yale University School of Medicine,
New Haven, CT,
Zubair W. Baloch USA
Department of Pathology and Laboratory Medicine,
University of Pennsylvania Medical Center, Nadine Caron
Philadelphia, PA, Department of Surgery,
USA University of California San Francisco and
UCSF Comprehensive Cancer Center at Mt Zion
Detlef K. Bartsch Medical Center,
Department of Surgery, San Francisco, CA,
Philipps-University, Marburg, USA
Herbert Chen
Prabhat K. Bhama Department of Surgery,
Division of Endocrine Surgery, University of Wisconsin,
University of Michigan Medical School, H4/750 Clinical Science Center, 600 Highland
Ann Arbor, MI, Avenue,
USA Madison, WI,
Leon D. Boudourakis
Yale University School of Medicine, David W. Cheng
New Haven, CT, Department of Diagnostic Radiology,
USA Yale University School of Medicine,
New Haven, CT,
XII List of Contributors

Mirjam Christ-Crain Ulrich Gller

Department of Endocrinology, Department of Surgery,
John Vane Science Centre, Divisions of General Surgery and Surgical Research,
Barts and the London Medical School, University of Basel,
Charterhouse Square, Basel,
London, Switzerland
Elizabeth H. Holt
Gerard M. Doherty Section of Endocrinology,
Division of Endocrine Surgery, Yale University School of Medicine,
University of Michigan Medical School, New Haven, CT,
Ann Arbor, MI; 2920B Taubman Health Care Center, USA
Box 0331, 1500 E. Medical Center Drive,
Ann Arbor, MI, Silvio E. Inzucchi
USA Section of Endocrinology,
Yale University School of Medicine,
Quan-Yang Duh New Haven, CT,
Department of Surgery, USA
University of California San Francisco and
Veterans Affairs Medical Center, Ludwig A. Jacob
San Francisco, CA, Section of Interventional Radiology,
USA Department of Radiology,
University Hospital Basel,
Hermann Engel Basel,
Institute of Radiology and Nuclear Medicine, Switzerland
Hospital Waid,
Zrich, Moosa Khalil
Switzerland University of Calgary,
Pathologist, Calgary Laboratory Services,
Andrea Frilling Calgary, Alberta,
Department of General Surgery, Canada
Visceral surgery and Transplantation,
University Hospital Essen, Bernhard J. Lammers
Essen, Department of Surgery,
Germany Lukaskrankenhaus of the Heinrich-Heine University
Oliver Gimm Neuss,
Department of General, Germany
Visceral and Vascular Surgery, University of Halle,
Ernst-Grube-Strasse 40, Peter Langer
06097 Halle, Department of Surgery,
Germany Philipps-University Hospital, Baldingerstrasse,
D-35043 Marburg,
Peter E. Goretzki Germany
Department of Surgery,
Lukaskrankenhaus of the Heinrich-Heine University Virginia A. LiVolsi
Dsseldorf, Department of Pathology and Laboratory Medicine,
Neuss, University of Pennsylvania Medical Center,
Germany Philadelphia, PA,
List of Contributors XIII

Gabriele Materazzi Bruno Niederle

Department of Surgery, Division of Endocrine Surgery,
Azienda Ospedale Universit di Pisa, Department of Surgery,
Pisa, Medical University of Vienna,
Italy Whringergrtel 1820,
A-1090 Vienna,
Michael Mayr Austria
Division of Transplantation Immunology and
Nephrology, Department of Internal Medicine, Egbert U. Nitzsche
University of Basel, Basel, University of Basel,
Switzerland School of Medicine,
Christoph A. Meier Division of Nuclear Medicine and PET Center,
Endocrine Unit, Division of Endocrinology, Aarau General (Cantonal) Hospital, Aarau,
Diabetes and Nutrition, Switzerland
Department of Internal Medicine, University
Hospital Geneva, Daniel Oertli
CH-1211 Geneva 14, Division of General Surgery,
Switzerland University Hospital Basel,
Vice-Dean of the Medical Faculty,
Paolo Miccoli University of Basel,
Department of Surgery, Basel,
Azienda Ospedale Universit di Pisa, Switzerland
Italy Janice L. Pasieka
Division of General Surgery,
Nils G. Morgenthaler Department of Surgery,
Institut fr Experimentelle Endokrinologie, Faculty of Medicine, University of Calgary,
Charit Campus Mitte, Calgary, Alberta,
Universittsmedizin Berlin, Canada
Germany Christian Passler
Division of Endocrine Surgery,
Jan Mueller-Brand Department of Surgery,
University of Basel, Vienny University Hospital,
School of Medicine, Basel; Vienna,
Division of Nuclear Medicine and PET Center, Austria
University Hospital Basel,
Basel, Michel Procopiou
Switzerland Division of Endocrinology, Diabetes and Nutrition,
Department of Internal Medicine,
Beat Mller University Hospital Geneva,
Dept. of Endocrinology, CH-1211 Geneva 14,
Diabetology and Clinical Nutrition, Switzerland
University Hospital,
Petersgraben 4, Lawrence J. Rizzolo
Basel, Section of Anatomy,
Switzerland Department of Surgery,
Yale University School of Medicine,
PO Box 208062,
New Haven, CT 06520-8062,
XIV List of Contributors

Hans-Dietrich Rher Rebecca S. Sippel

Klinik fr Allgemein und Unfallchirurgie, Department of Surgery,
Universittsklinikum Duesseldorf, University of Wisconsin,
Moorenstrasse 5, H4/710 Clinical Science Center,
40225 Dsseldorf, 600 Highland Avenue,
Germany Madison, WI,
Sanziana Alina Roman
Section of Endocrine Surgery, Julie Ann Sosa
Department of Surgery, Sections of Oncologic,
Yale University School of Medicine, Endocrine, and General Surgery,
PO Box 208062, Yale University School of Medicine,
New Haven, CT 06520, 330 Cedar Street,
USA New Haven, CT 06520-8062,
Rachel Rosenthal
Division of General Surgery, Wolfgang Steinbrich
Department of Surgery, Institute of Diagnostic Radiology,
University Hospital Basel, University Hospital Basel,
Spitalstrasse 21, Petersgraben 4, 4031 Basel,
CH-4031 Basel, Basel,
Switzerland Switzerland

Matthias Rothmund William B. Stewart

Department of Surgery, Department of Surgery,
Philipps-University, Yale University School of Medicine,
Marburg, PO Box 208062,
Germany New Haven, CT 06520-8062,
Christian Scheuba
Division of Endocrine Surgery, Cord Sturgeon
Department of Surgery, Department of Surgery,
Vienny University Hospital, Northwestern University Feinberg School of
Vienna, Medicine,
Austria Division of Gastrointestinal and Endocrine Surgery,
Chicago, IL,
Klaus-Martin Schulte USA
Department of Endocrine and General Surgery,
Kings College Hospital, Robert Udelsman
Denmark Hill, Department of Surgery,
London SE5 9RS, Yale University School of Medicine,
UK PO Box 208062,
New Haven, CT 06520-8062,
Leslie M. Scoutt USA
Department of Diagnostic Radiology,
Yale University School of Medicine, Ana Paola Uranga
New Haven, Connecticut Department of Surgery,
USA Yale University School of Medicine,
330 Cedar Street FMB 102,
Susan A. Silver New Haven, CT 06520, USA
Metropolitan FNA Service,
Bethesda, Washington, DC,
List of Contributors XV

Kate V. Viola Walter Wiesner

Sections of Oncologic, Medical Radiology Center,
Endocrine, and General Surgery, Klinik Stephanshorn,
Yale University School of Medicine, Brauerstrasse 95,
330 Cedar Street, 9016 St. Gallen,
New Haven, CT 06520-8062, Switzerland
Heather Yeo
Frank Weber Department of Surgery,
Department of General Surgery, Yale University School of Medicine,
Visceral Surgery and Transplantation, 330 Cedar Street FMB 102,
University Hospital Essen, New Haven, CT 06520-8062,
Essen, USA

1 History of Thyroid and Parathyroid Surgery

Hans-Dietrich Rher and Klaus-Martin Schulte

Contents sents a major pathway for the import and export of

ideas, a trafficking place, where anatomy, physiology,
1.1 Introduction . . . 1 biological and analytical chemistry, imaging, and sur-
1.2 Recognition of Goitrous Disease . . . 1
gical technique have ideally met and influenced each
1.3 Anatomy of the Thyroid Gland . . . 1
1.4 Early Attempts at Surgery . . . 2
1.5 Thyroid Physiology . . . 2
1.6 Morbidity of Thyroid Surgery During
the Nineteenth Century . . . 3
1.2 Recognition
1.7 Relevance of Postoperative Loss of Goitrous Disease
of Thyroid Function . . . 3
1.8 Surgery for Hyperthyroidism . . . 4 In the first and second centuries, Celsus and Galen
1.9 Thyroid Cancer Surgery . . . 5 described cervical masses such as cysts, tuberculous
1.10 Thyroid Surgery in Modern Times . . . 5 lymph nodes (scrofula), and goiters. In the eleventh
1.11 Discovery of the Parathyroid Glands . . . 6 century, the Arabic scientist Abulkasim, working in
1.12 Parathyroid Preservation . . . 7 Cordoba, Spain, differentiated natural, endemic goiter
1.13 Tetany and Hypoparathyroidism . . . 7 from non-natural goiter [17]. Between the eleventh
1.14 Hyperparathyroidism and the mid-thirteenth century, the renowned medi-
and Parathyroidectomy . . . 8 cal school of Salerno near Naples, Italy, gave advice
1.15 Different Forms of Hyperparathyroidism . . . 10 for conservative treatment of goiter disease using sea
References . . . 10 products such as burned sponge. On the other hand,
the school recommended cauterization or seton im-
plants in order to induce necrotizing inflammation
and tissue destruction for selected cases [9]. In these
1.1 Introduction times, nothing was really known about the organic
source of goiter formation.
Endocrine surgery is the concept and practice of sur-
gically applied human physiology. This concept has
deep historical roots and has been nourished by many 1.3 Anatomy of the Thyroid Gland
thoughts, ideas, and discoveries. Several individuals
influenced this interesting field primarily provid- In 1543, the anatomist Andrea Vesalius (15141564;
ing answers to human physiology and secondarily to Fig. 1.1) originally described glandulae laryngis
questions on surgical technique. Indeed, the proper in his inauguration of modern anatomy De Humani
function of the thyroid as an endocrine gland was Corporis Fabrica published in Basel, Switzerland. The
discovered by a surgeon. Moreover, surgeons pio- first distinct image of the thyroid gland with the typi-
neered the recognition of parathyroid disease. Unlike cal horseshoe shape dates back to the work of Julius
in any other field, operative principles in endocrine Casserius (15451616) [23]. Casserius was a servant
surgery have been developed after recognition of the of Hieronymus Fabricius of Aquapendente, Professor
homeostatic regulations of different endocrine organ and Chairman of Anatomy and Surgery at the Uni-
systems. Hence interest in molecular biology resulted versity of Padua between 1609 and 1616. The first uti-
in a profound understanding of the endocrine con- lization of the term glandula thyreoidea was made
trol of cellular homeostasis. This resulted in the first by Thomas Wharton, London, UK (1656) and by Al-
entirely gene-directed surgical procedure in man, the brecht von Haller, Gttingen, Germany. They attrib-
prophylactic thyroidectomy in multiple endocrine uted endocrine secretory properties to this ductless
syndrome 2A. Historically, endocrine surgery repre- gland.
2 Hans-Dietrich Rher and Klaus-Martin Schulte

Fig. 1.1 Andreas Vesalius (15141564) was a Belgian anato-

mist and physician whose dissections of the human body and
descriptions of his findings helped to correct misconceptions
prevailing since ancient times. As Professor of Anatomy in Fig. 1.2 Lorenz Heister (16831758) served as an army sur-
Padua (Italy) Vesalius wrote the revolutionary texts De Humani geon in several German campaigns before becoming Professor
Corporis Fabrica, seven illustrated volumes on the structure of of Anatomy and Surgery at Altdorf. Distressed at the inferior
the human body state of surgery he published his Chirurgie (Nuremberg, 1718)

1.4 Early Attempts at Surgery Thyroid surgery remained a life-threatening proce-

dure during these times even in the hands of the most
Over several following centuries, written sources skilled surgeons. The mainly fatal outcome after goiter
documented that attempts were undertaken for surgi- surgery motivated the leading German surgeon Jo-
cal removal of goiters. The indication for surgery was hann Dieffenbach from Berlin to make the statement
primarily given by extensive cervical masses or severe in 1848 that goiter surgery is one of the most thank-
tracheal obstruction resulting in dyspnea. However, less, most perilous undertakings. Also the French
the operative results were disastrous with extremely Academy of Medicine criticized any thyroid opera-
high mortality because of fatal bleeding or infection. tion in 1850, and Bernhard Rudolph Conrad Langen-
In 1742, Lorenz Heister (16831758; Fig. 1.2), who beck (18101887) vehemently warned to avoid it.
had founded scientific surgery in Germany, first de-
scribed the surgical removal of a thyroid gland. While
describing thyroid colloid substance in 1754, he was 1.5 Thyroid Physiology
among the first who acknowledged the practical value
of the understanding of endocrine substances. Heis- Surgeons provided the first substantial evidence of
ter already knew that goiters can turn malignant, endocrine secretion by the thyroid gland. Thomas
as he thought, after they had been treated with acid Wilkinson King (18091847) from London wrote in
substances. He also recognized the erosion of neck his observations on the thyroid gland:
vessels by malignant goiters and gave attention to The most important novel fact concerning the thy-
thyroid cancer. In 1792, the French surgeon Pierre Jo- roid gland is doubtless this, that its absorbent vessels
seph Desault (17441795) demonstrated that a partial carry its peculiar secretion to the great veins of the
thyroid resection may be feasible and thereby opened body and the most simple and satisfactory method of
the proper way into thyroid surgery at a time when demonstrating this fact is to expel the contents of the
hormone replacement was not even theoretically healthy gland by repeated and gentle compressions, into
known [10]. the lymphatics of the surface and then to coagulate the
Following this, Johann August Wilhelm Hedenus fluid on the surface Whilst the nourishment of a part
(17601836) operated on six patients who had suf- is indispensable to its existence, the influence which it
fered from airway obstruction by giant goiters [24]. exerts upon the circulating fluids may be more or less
1 History of Thyroid and Parathyroid Surgery 3

needful for the healthful subsistence of the entire ani-

mal [27].
In the same volume, Sir Astley Cooper (1768
1841) had included a report on his experimental
thyroidectomies in dogs. In 1827 he observed how
slowly the dogs recovered after a period of stupor and
tiredness. In 1859 the German physiologist Moritz
Schiff (18231896) published his experiences of total
thyroidectomy and showed that all thyroidectomized
dogs and guinea pigs eventually died postoperatively.
Some simultaneously appearing treatises on the coin-
cidence of goiter and cretinism should have rendered
obvious the nature of an endocrine organ, but these
observations remained without general practical con-
sequences. Because this seemed so ridiculous to his
contemporaries, Sir Felix Semon (18491921) was
unable to publish his hypothesis in 1883 that myx-
edema and cretinism were caused by the loss of thy-
roid function. Fig. 1.3 Theodor Billroth (18291894) obtained his medical
degree from the University in Berlin in 1852 and became as-
sistant to Bernhard von Langenbeck in 1854. He was appointed
1.6 Morbidity of Thyroid Surgery Professor of Clinical Surgery in Zurich in 1860 and Professor
During the Nineteenth Century of Surgery at the University of Vienna in 1867. Courtesy of
Prof. U. Boschung, Institute of Medicine History, University of
Intra- and postoperative bleeding was the major prob- Berne, Switzerland
lem in thyroid surgery of those days and surgeons had
just learned how to tackle it. William Blizzard (1743
1835) tried to cure thyroid overfunction by ligation principles of antisepsis [30]. Third, in 1874, Thomas
of the upper pole arteries. Luigi Porta (18001875) Spencer Welles developed hemostatic forceps for
contributed in two major respects. First he performed surgery. These new developments enabled surgeons
a targeted adenoma excision in 1849. Second, his at- to substantially refine their operating technique.
tempt to cure thyroid hyperfunction by unilateral This pioneering era in thyroid surgery was domi-
arterial ligation failed and therefore Porta concluded nated by Theodor Billroth, who worked in Zurich,
that bilateral ligations would be necessary. Edmund Switzerland, between 1860 and 1867 and later on in
Rose (18361914) followed up this idea. After suc- Vienna, Austria, and by his disciple Anton Wlfler
ceeding Theodor Billroth as the Surgical Chairman in (18501917). Their efforts targeted at complete re-
Zurich, Switzerland, Rose published his treaty on Der moval of the thyroid gland in order to facilitate in-
Kropftod und die Radikalkur der Krpfe (death by goi- traoperative hemostasis after describing techniques
ter and radical cure of goiters). He stated that goitrous using ligation of the arteries [57].
recurrence could only be prevented by a complete re- In 1879, Claude Bernard stated that We do not
moval of the gland. For this he described meticulous know anything about the use of these organs (i.e.
ligation of every single vessel feeding the gland whilst thyroid, thymus), we dont even have an idea about
respecting the recurrent laryngeal nerves, the vagal their utility and importance... Of note, this statement
nerves, as well as the hypoglossal nerves. coincides with the first thyroidectomy for a goiter as-
The main problems during the nineteenth century sociated with exophthalmus performed by Ludwig
were bleeding and infection. Being among the leading Rehn (18491930).
surgical experts in Europe, Theodor Billroth (1829
1894; Fig. 1.3) reported an intraoperative mortality
of 36% for thyroid surgery. During the second half of 1.7 Relevance of Postoperative
the nineteenth century, three key factors largely con- Loss of Thyroid Function
tributed to the development and progress of thyroid
surgery. First, William Morton from Boston, USA, in- The discovery of the importance of human thyroid
vented inhalation anesthesia in 1846. Second, in 1867, function dates back to 1882 and should be attributed
Lord Joseph Lister from Glasgow, UK, introduced the to the surgeon Jacques-Louis Reverdin (18421929;
4 Hans-Dietrich Rher and Klaus-Martin Schulte

Fig. 1.4 Jacques-Louis Reverdin (18421929), Professor of

Surgery, Geneva, Switzerland. Courtesy of Prof. U. Boschung,
Institute of Medicine History, University of Berne, Switzerland Fig. 1.5 Theodor Kocher (18411917), Professor of Surgery. In
1872, he became Chairman at the University Hospital in Berne
and remained in this post in spite of several invitations to for-
Fig. 1.4), and to his cousin Auguste Reverdin (1848 eign universities. Courtesy of Prof. U. Boschung, Institute of
1908). They called this postoperative state myxo- Medicine History, University of Berne, Switzerland
edeme opratoire. A letter of J.-L. Reverdin to The-
odor Kocher in 1882 described a case of cretinism
following thyroidectomy. In 1883, Reverdin pub- understanding of the consequence of complete loss of
lished on the thyroprivic consequences of 22 thy- thyroid function can be attributed to the Reverdins
roidectomies. Thereafter, he vehemently advocated and to Kocher, the recognition of postoperative tet-
to avoid thyroidectomy and omitted this operation any was made by Billroth and his pupils Wlfler and
[47]. Theodor Kocher (18411917; Fig. 1.5), however, von Eiselsberg. They recognized the association be-
resolutely pursued the issue that had been raised by tween parathyroprivic symptoms and the loss of the
the Reverdins. This culminated in his historic manu- parathyroid glands.
script Ueber Kropfexstirpation und ihre Folgen (on the
removal of goiter and its consequences) [28]. For his
work, Kocher was later awarded the Nobel prize for 1.8 Surgery for Hyperthyroidism
physiology or medicine in 1909.
Starting from the personal case of the eleven-year- Thyroid operations were initially performed to solve
old Maria Bichsel in 1874, Kocher developed the mechanical airway obstruction. Attention to hyper-
concept of kachexia thyreopriva that summarizes thyroidism was paid much later in time. Caleb Hillier
the various consequences for the entire body due to Parry first described an exophthalmic goiter [43].
the lack of thyroid hormone function. After 1883, In the English and the German literature, the clini-
Kocher strongly promoted the use of the unilateral cal complex of autoimmune hyperthyroidism was de-
operation to avoid the thyroprivic state. This concept scribed by Robert James Graves (Fig. 1.6) and by Carl
found worldwide acceptance and was transferred to Adolf von Basedow (Fig. 1.7), respectively [1,15]. In
the United States by Charles Mayo, the pioneer of en- 1884, Ludwig Rehn (18491930) from Frankfurt,
docrine surgery in the new world [3638]. Germany, opened the way for surgical cure of Graves
In parallel one of Billroths disciples Johann v. Mi- disease [46]. Mikulicz expanded the indication for
kulicz-Radecki (18501905) recognized the problems surgery by exophthalmic goitre. Initially, many of
of too extensive thyroid surgery. He replaced the these patients were treated with a unilateral approach,
complete thyroidectomy by a bilateral partial resec- resulting in recurrences.
tion in order to reduce the potential local harm to the During the first two decades of the twentieth cen-
parathyroids (whose function was only partially un- tury, the unilateral operation for thyroid toxicosis was
derstood) and to the laryngeal nerves. The remnant still the mainstay in the United States. In many in-
would take over the thyroid function. Whereas the stances a multistage procedure was performed. After
1 History of Thyroid and Parathyroid Surgery 5

Fig. 1.6 Robert James Graves (17961853)

initial occlusion of the thyroid arteries, a lobectomy Fig. 1.7 Carl Adolf von Basedow (17991854)
was done in a second operation. A third interven-
tion was often indicated if the disease persisted or re-
curred. F. Hartley (New York, USA, 1905) and Thomas high-dose iodine according to Plummer has been re-
Dunhill (Melbourne, Australia, 1907) changed this placed by thyrostatic drug therapy that allows for a
paradigm [11,22]. They showed that hyperthyroidism fine hormonal tuning and for timing of surgery. Mod-
can be cured by unilateral lobectomy and contralat- ern surgical treatment of hyperthyroidism consists of
eral subtotal resection. Dunhill also surmounted the a differentiated approach with either near-total or to-
contraindications for surgery in the presence of car- tal thyroidectomy for immunogenic hyperthyroidism
diac symptoms. He demonstrated that surgery may and with lobectomy for toxic adenomas.
be successful even in patients with tachyarrhythmia
and cardiac failure. The reports on his successes were
first doubted and ignored, and Dunhill decided to 1.9 Thyroid Cancer Surgery
travel from Australia to the United Kingdom and the
United States. In the United States, his technique and Histopathology has emerged as the preeminent tool
his indications were well accepted, although without for the classification of thyroid cancers. This led to
being quoted by the leading surgeons. This may be the the recognition of the biologically different behavior
reason why both Dunhill and Hartley were ignored of different cancer subtypes and to the introduction
until their preferred operation was elevated to the of differentiated surgical strategies. Another major
standard surgical technique for hyperthyroidism. An- step is the, still incomplete, acceptance of prognostic
other milestone was made by Charles Mayo, Henry scoring systems including tumor, node, metastases
Plummer, and Walter Boothby from the Mayo Clinic (TNM), European Organization for Research and
in the 1920s. They showed that the risks and severity Treatment of Cancer (EORTC), Age, Grade, Extent,
of perioperative thyroid storm were greatly reduced Size (AGES), Age, Metastases, Extent, Size (AMES),
by preoperative peroral administration of large doses and the Metastases, Age, Completeness of resection,
of iodine using the Wolff-Chaikoff effect [44,45,55]. Invasion, Size (MACIS). All these classifications al-
Perioperative mortality in 600 patients was reduced low the comparison of treatment results in cohorts
from 5% to less than 1%. The introduction of radioio- from different continents treated with a broad range
dine ablation therapy in 1942 and of thyrostatic drugs of regimens.
in 1943 dramatically changed the treatment patterns
in hyperthyroidism and almost replaced surgery for
a while. 1.10 Thyroid Surgery
During the 1950s the repertoire of diagnostic tools in Modern Times
expanded. By detection of stimulating antibodies, the
immunogenic nature of hyperthyroidism can now be Since 1980 molecular medicine has provided major in-
proven and classified. The preoperative therapy using sights into the impact of genetic mutations eventually
6 Hans-Dietrich Rher and Klaus-Martin Schulte

leading to thyroid tumors. This has not only yielded

a further possibility of tumor classification accord-
ing to their specific genetic changes, but it has also
opened the path to the recognition of specific cancer
predispositions in individual family members. Since
mutations of the RET protooncogene can be detected
in peripheral blood lymphocytes, prophylactic thy-
roidectomy can be cancer preventive. Presymptom-
atic thyroidectomy in individuals with the mutated
RET protooncogene represents the first indication in
the history of surgery which is fully and solely based
on the genetic proof of a malignant trait, i.e., medul-
lary thyroid cancer. Genetic research has also proven
the unifying causative changes in familiar syndromes,
such as multiple endocrine neoplasia type I and II
[53,54] and diseases caused by changes in the succi- Fig. 1.8 Sir Richard Owen (18041892) was a pioneering Brit-
nate dehydrogenase complex. The lively interchange ish comparative anatomist who coined the term dinosauria
between basic molecular research and clinical prac-
tice has revolutionized endocrine surgical practice.
The recent years represent an industrious period
of relentless technical research and improvement in
endocrine surgery. This has reduced the operative
risks with regard to all forms of complications. Bleed-
ing is now rare, and most thyroid surgery can safely
be performed without the need of drainage. Infection
has virtually disappeared. Due to vigorous protection
of the anatomical structures and consequent identi-
fication of the recurrent laryngeal nerve, permanent
nerve palsies occur in less than 1% of cases. Hypo-
parathyroidism has been reduced to frequencies be-
low 1% due to meticulous preparation techniques and
the generous use of parathyroid autotransplantation.
Mortality is almost nil.
The most recent enrichments of the surgical reper-
toire are the targeted, minimally invasive, and endo- Fig. 1.9 Ivar Sandstrm. Reprinted with permission from Or-
scopic approaches. The evolutionary progress of tech- gan CH (2000) J Am Coll Surg 191:284
niques and indications is underway. A more secure
estimation of the safety of these techniques needs fur-
ther consolidation of data and experiences. (Fig. 1.8). He discovered them when he was dissect-
ing a rhinoceros that had died in the London Zoo.
The respective paper was eventually published in the
1.11 Discovery Zoological Proceedings of London [41]. He was not
of the Parathyroid Glands given credit for his observation because he never per-
formed histological confirmation. This state of affairs
Small things often go unnoticed. It is no surprise that lasted until 1887 when the medical student Ivar Sand-
this holds true for the parathyroid glands that even strm (Fig. 1.9) described tiny glandular elements in
today may sometimes be difficult to retrieve. Al- 50 dissected human bodies. He gave a comprehensive
though Thomas Wharton gave a detailed report on description of their appearance, position, size, and
the glandulae thyroideae in 1656, he did not men- blood supply. His publication contains various issues
tion the parathyroid glands. of far-reaching importance, such as the finding that
The first description of the parathyroid glands the blood supply derives from the inferior thyroid ar-
was by the London anatomist and curator of the tery and may be multiple. His work On a New Gland
Natural History Museum, Sir Richard Owen, in 1850 in Man and Several Animals was rejected by German
1 History of Thyroid and Parathyroid Surgery 7

editors and eventually published in Swedish in the

Uppsala Medical Journal [48]. This may have contrib-
uted to the lack of recognition of this brilliant young
man who later committed suicide.

1.12 Parathyroid Preservation

Sandstrms detailed dissection of the parathyroids

and their blood supply were consolidated by the me-
ticulous work of Herbert M. Evans, Johns Hopkins,
Baltimore, who identified the variations of blood
vessels and thereby heralded the protection of glan-
dular function by maintenance of their blood supply.
His mentor, William Halsted (Fig. 1.10) immediately Fig. 1.10 William Stewart Halsted (18521922) was a true sur-
derived the correct instinctive conclusion, that the gical innovator. Halsted revolutionized surgery by insisting on
thyroid artery should be ligated proximal to the thy- skill and technique rather than brute strength. Using an experi-
roid gland while sparing the parathyroid end arter- mental approach, he developed new operations for intestinal
ies [20]. and stomach surgery, gallstone removal, hernia repair, and dis-
Kocher and Billroth were the two exponents of orders of the thyroid gland. He first practiced in New York and
thyroid surgery at the end of the nineteenth century. in 1886 became the first Professor of Surgery at Johns Hopkins
Each had founded a surgical schoolKocher in Bern
and Billroth in Viennaand the respective postop-
erative outcomes reflected the particular techniques gical complications and preceded the discovery of the
utilized in each school. Kocher experienced the symp- parathyroid function.
toms associated with radical removal of the thyroid,
leading to postoperative hypothyroidism cachexia
strumipriva. Billroths patients experienced tetany. 1.13 Tetany
Halsted gives another example of his surgical instinct and Hypoparathyroidism
when he associated these differences to the characters
of operating surgeons: In 1891 the French physiologist Eugene Gley clarified
Kocher, neat and precise, operating in a relatively the relation between parathyroid gland function and
bloodless manner, scrupulously removed the entire thy- tetany [14]. He described tetany in rats and rabbits as
roid gland, doing little damage outside the capsule. Bill- a consequence of the removal of the thyroid and para-
roth, operating more rapidly, and as I recall his manner, thyroid glands. Moreover, he could show that removal
with less regard for tissues and less concern for hemor- of the parathyroids alone would have the same effect.
rhage, might easily have removed the parathyroids or The concept of parathyroid transplantation was born.
at least interfered with their blood supply, and have left The first parathyroid autotransplantation was per-
remnants of the thyroid [19]. formed in 1892 by Anton von Eiselsberg (Fig. 1.11),
This description still is of enormous value since it Vienna, Austria. He transplanted thyroid and para-
teaches us about some of the virtues needed for suc- thyroid tissue into the preperitoneal space of cats and
cessful endocrine surgery. showed that tetany was absent and new vessels had
Billroths pupils discovered the symptom complex formed at the transplants. In contrast, tetany occurred
of postoperative hypocalcaemia. Anton Wlfler gave after these transplant were removed [12].
a full and detailed account of tetany in the first patient Also William J. MacCallum at Johns Hopkins, Bal-
who had undergone a total thyroidectomy by Theodor timore, described the use of parathyroid extracts to
Billroth [56]. The patient recovered after having expe- cure tetany in experimental animals [31,32]. He trans-
rienced the full range of symptoms over a period of ferred upcoming knowledge about the role of calcium
three weeks. Nathan Weiss collected more data from in nerve conduction and muscle action and formed
patients with postoperative tetany [51]. These experi- a hypothesis that the parathyroid glands may play a
ences stimulated Mikulicz to develop his technique of role in calcium metabolism. This ingenious conclu-
protection of the posterior thyroid capsule. Surgical sion was later proven in experiments by Carl Voegtlin
knowledge about the parathyroids emerged from sur- and it was shown that tetany caused by parathyroid-
8 Hans-Dietrich Rher and Klaus-Martin Schulte

Fig. 1.12 Felix Mandl (18921957) was Professor of Surgery

Fig. 1.11 Baron Anton von Eiselsberg was Professor and Chair- and Chairman of the Department of Surgery at the Franz-Jo-
man at the Allgemeines Krankenhaus in Vienna, Austria seph-Spital, Vienna, Austria. Reprinted with permission from
Organ CH (2000) J Am Coll Surg 191:284

ectomy could be corrected with parathyroid extract

or by injections of calcium [33]. This was a major of the twentieth century, the problems of hyperpara-
advance, although MacCallum remained uncertain thyroidism still remained unrecognized. Both physi-
about the value of his own discoveries for another ologists and surgeons investigated parathyroid action
decade. In 1907, William Halsted at Johns Hopkins and regulation of calcium metabolism. In 1906 Ja-
used parathyroid extract and calcium chloride to treat cob Erdheim reported that the enlarged parathyroid
postoperative tetany [18]. He reported on the cure of glands were associated with bone diseases like osteitis
hypoparathyrosis by parathyroid transplantation. fibrosa cystica and osteomalacia. His false conclusion
However, the problems with parathyroid extracts were was that the glands were enlarged as a consequence
the difficulty of their production, the lack of stability, of bone disease [13]. Although no evidence was pro-
and the variability of biological activity. Adolf Hansen duced to support this assumption, it was generally ac-
developed a method for hormone extraction from bo- cepted. With this background of medical error, we can
vine parathyroid glands. In animal experiments, these understand how Felix Mandl (18921957; Fig. 1.12)
extracts were able to cure tetany and raise the serum treated his patient Albert Gahne. The patient suffered
calcium of parathyroprivic dogs. They also induced from bone pain and from a fracture of the femur. Ra-
osteoporosis after administration over a prolonged diographs demonstrated numerous bone cysts and
period [21]. These findings were substantiated with the patients blood and urinary calcium levels were
detailed experiments conducted by James P. Collip elevated. Mandl first administered parathyroid ex-
[6,7]. An immunoassay for parathyroid hormone de- tract which failed. He concluded that the dose was
tection in peripheral blood was developed by Yalow too low and obtained fresh parathyroid tissue from a
and Berson [4,58]. In 1977 the DNA sequence of the trauma victim; this was grafted into the patient with-
gene for parathyroid hormone was identified [3] and out success. Mandl received sharp criticism from his
the respective cDNA was cloned in 1981 [25]. Today, colleagues at the annual meeting of the Vienna Sur-
human recombinant parathyroid hormone is avail- gical Society just because he had failed to prove that
able for treatment of hypoparathyroidism. he really had transplanted parathyroid tissue and not
something else. Somehow his mind turned around
and in 1925 he explored the neck of his patient and
1.14 Hyperparathyroidism removed a parathyroid tumor. This was now followed
and Parathyroidectomy by a clinical success and it inverted the paradigm
[34,35]. However, the patient later died from a recur-
After parathormone (PTH) deficiency was recog- rence. Mandl might have operated on the first case of
nized and could be treated during the first decade parathyroid cancer.
1 History of Thyroid and Parathyroid Surgery 9

Fig. 1.14 Oliver Cope. Reprinted with permission from Organ

CH (2000) J Am Coll Surg 191:284

Fig. 1.13a,b Charles Martell, Captain of US merchant marine.

Reprinted with permission from Bauer E, Federman DD (1962)
Metabolism 11:22

In the United States E.J. Lewis at Cook County

Hospital, Chicago, performed the first excision of a
parathyroid tumor, again likely to be a carcinoma, in
1926 [16]. Unfortunately, the patient suffered from
The case of Captain Charles Martell (Fig. 1.13)
illustrates the problems of ectopic parathyroid ad-
enoma [2]. The patient was a master mariner of the
U.S. merchant marine with transport duties in the
North Atlantic. In 1918, he was 22 years of age, about
1.85 m tall, and obviously in fine physical condition Fig. 1.15 Edward Churchill. Reprinted with permission from
(Fig. 1.13a). A year later, Captain Martells disease Organ CH (2000) J Am Coll Surg 191:284
became manifest with severe osteopathy and nephro-
lithiasis. In 1926 when Martell entered the Massachu-
setts General Hospital (MGH) for surgery, the patient tumor was to be sought in the chest, and he urged
had shrunk by about 18 cm (Fig. 1.13b). By this time a mediastinotomy. The seventh operation was per-
he had experienced eight fractures and suffered from formed by Churchill, with Copes assistance, and a
marked kyphosis and bone deformities. The two first mediastinal encapsulated brown tumor of 3 cm in
cervical explorations done by Dr. E.P. Richardson diameter was found. The two surgeons excised only
were unsuccessful. A third operation was performed 90% of the adenoma, attaching the remnant with its
in 1932 by Dr. Russell Patterson in New York City, vascular pedicle to the region of the sternal notch.
with no tumor being discovered, and Martell re- Despite this, tetany developed three days after sur-
turned to the MGH. Dr. Oliver Cope (Fig. 1.14) and gery. Six weeks postoperatively a kidney stone became
Dr. Edward D. Churchill (Fig. 1.15) performed three impacted in the ureter and Captain Martell died from
subsequent cervical reinterventions without finding larnygospasm shortly after a surgical intervention to
an adenoma. relieve his ureteral obstruction. After 1932, Cope and
The captain, who was often found in his room Churchill performed a number of successful parathy-
reading anatomy texts, was now convinced that the roidectomies.
10 Hans-Dietrich Rher and Klaus-Martin Schulte

came popular [26]. The general recommendation was

that of total or subtotal parathyroidectomy with or
without autotransplantation and cryopreservation of
tissue [52].
For both situations, the difficult adenoma in pri-
mary hyperparathyroidism and for retrieval of super-
numerary glands in secondary hyperparathyroidism,
attempts were made to improve preoperative local-
ization by selective catheter angiography and venous
sampling and computed tomography. Both did not
offer satisfactory results. Rather they led to the quota-
tion: The most convincing localisation is to locate an
experienced endocrine surgeon.
Fig. 1.16 Fuller Albright. Reprinted with permission from Or- Further technical innovations significantly influ-
gan CH (2000) J Am Coll Surg 191:284 enced parathyroid surgery. In 1989, A.J. Coakely no-
ticed that technetium sestamibi is rapidly taken up by
the parathyroids [5]. This has provided surgery with
Isaac Y. Olch performed the first successful opera- a potent tool for preoperative imaging, useful both in
tion of a parathyroid gland in the United States. In primary and redo situations. A focused surgical access
1928, he removed a 3 3 cm adenoma from the left is possible thanks to preoperative scintigraphy and
inferior thyroid pole from a patient at Barnes Hospi- cervical ultrasonography. Quick methods for assess-
tal of the Washington University School of Medicine ment of PTH emerged. In 1988, Nussbaum provided
in St. Louis, Missouri. The definitive breakthrough of evidence that PTH measures can be produced during
parathyroid surgery occurred in the late 1920s and the operation and thereby identify success [39]. This
early 1930s and can be ascribed to the group around has rendered intraoperative frozen section much less
Fuller Albright (Fig. 1.16) who studied in detail the important. Various combinations of imaging tech-
pathophysiology of parathyroid bone disease and niques and intraoperative hormone assessments are
recognized hyperparathyroidism as a distinct clinical actually under consideration with regard to success
syndrome. rates and cost efficiency.
Uniglandular disease may well be approached by
minimally invasive techniques, such as focused mini-
1.15 Different Forms incisions or endoscopy.
of Hyperparathyroidism Today, the diagnosis of hyperparathyroidism can
readily be made. The association between elevated
One of the major issues was the discovery that para- PTH and bone disease is well understood, whereas
thyroid surgery may well be unsuccessful despite re- the effects of elevated PTH on the central nervous
moval of one adenoma. Double adenomas and mul- system needs further investigation. Parathyroid sur-
tiglandular hyperplasia became recognized disease gery for primary hyperparathyroidism has nowadays
entities of primary hyperparathyroidism. This led a success rate close to 99%, operative complications
Paloyan and many others to the recommendation of are below 1%, and mortality is virtually nil.
subtotal parathyroidectomy in all cases. The dominant
adenoma and at least two further glands would have
to be resected to prevent recurrence [42]. With the References
more widespread availability of calcium and PTH as-
says the disease was considered to be due to hormone 1. Basedow CA von (1840) Exopthalmos durch Hypertro-
excess rather than adenoma formation. Early unsuc- phie des Zellgewebes in der Augenhhle. Wochenschr
cessful operations in cases of multiple diseased glands Gesamte Heilkunde 6:197
shifted the entire field of parathyroid surgery toward 2. Bauer W, Federman DD (1962) Hyperparathyroidism
a principal bilateral exploration of all glands. In 1982, epitomized: the case of Captain Charles E. Martell. Me-
this paradigm was challenged when Tibblin advo- tabolism 11:2129
cated unilateral surgery for single adenomas [49]. 3. Baxter JD, Seeburg PH, Shine J, Martial JA, Goodmann
In the late 1960s and 1970s surgery for secondary HM (1977) DNA sequence of a human coding for a poly-
peptide hormone. Clin Res 25:514A
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1 History of Thyroid and Parathyroid Surgery 11

4. Berson SA, Yalow RS, Aurbach GD, Potts JT Jr (1963) Im- 26. Katz AI, Hampers CL, Wilson RE, Bernstein DS, Wachman
munoassay of bovine and human parathyroid hormone. A, Merrill JP (1968) The place of subtotal parathyroidec-
Proc Natl Acad Sci USA 49:613617 tomy in the management of patients with chronic renal
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2 Embryology and Surgical Anatomy

of the Thyroid and Parathyroid Glands
William B. Stewart and Lawrence J. Rizzolo

Contents In this case, a lingual thyroid is located at the junc-

tion of the oral and pharyngeal parts of the tongue
2.1 Embryology of the Thyroid . . . 13 (Fig. 2.1b). Ectopic thyroid tissue may occur at any
2.2 Embryology of the Parathyroid Glands . . . 13
point along the pathway of the descent of the thy-
2.3 Anatomy of the Thyroid Gland . . . 14
roid. In rare conditions, the thyroid may descend
2.3.1 General Topography and Relations . . . 14
into the thorax. There may also be remnants of the
2.3.2 Blood Supply . . . 15
thyroglossal duct that hypertrophy and become cys-
2.4 Anatomy of the Parathyroid Glands . . . 17
tic (Fig. 2.1c). Ectopic thyroid tissue may also be en-
2.5 Nearby Relations of the Thyroid and
Parathyroid at Risk During Surgery . . . 18
countered laterally in the neck [9]. Evaluation of the
2.5.1 External Laryngeal Nerve . . . 18 patient should consider whether the ectopic tissue
2.5.2 Recurrent Laryngeal Nerve . . . 18 is the sole active thyroid tissue. In very rare circum-
References . . . 19 stances thyroid tissue may be encountered inferior to
the diaphragm in association with the gastrointestinal
tract. This thyroid tissue, a struma ovarii, is derived
from an ovarian germ cell tumor [5].
2.1 Embryology of the Thyroid

The primordial thyroid gland is first identifiable dur- 2.2 Embryology

ing the fourth week of gestation, beginning as an of the Parathyroid Glands
endodermal invagination of the tongue at the site of
the foramen cecum (Fig. 2.1a). The foramen cecum The parathyroid glands develop from the third and
lies where the midline intersects the sulcus termina- fourth pharyngeal (branchial) pouches (Fig. 2.1a).
lis, which divides the tongue into anterior two thirds These pharyngeal pouches develop in association
(oral part) and posterior one third (pharyngeal part). with the aortic arches that encircle the developing
The thyroid diverticulum begins its descent through foregut. The pharyngeal arches have a mesodermal
the tongue carrying with it the thyroglossal duct. The core, covered on their superficial surface by ectoderm
path of descent carries the developing gland anterior and on their deep surface by endoderm. The pha-
to the hyoid bone and the larynx. During the descent ryngeal pouches lie between successive pharyngeal
in the fifth week, the superior part of the duct degen- arches and are endodermal evaginations of the fore-
erates. By this time, the gland has achieved its rudi- gut. The inferior parathyroid glands (parathyroid III)
mentary shape with two lobes connected by an isth- come from the third pharyngeal pouch and the supe-
mus. It continues to descend until it reaches the level rior parathyroid glands (parathyroid IV) come from
of the cricoid cartilage at about the seventh week. By the fourth pharyngeal pouch. During the fifth week
the twelfth week of development, thyroid hormone is of development, the developing glands detach from
secreted. The distal part of the thyroglossal duct de- the pouches and descend to join the thyroid gland
generates but may remain as a pyramidal lobe [8]. during the seventh week. It should be noted that the
There is also a contribution to the thyroid from inferior parathyroid glands actually arise from a more
the fifth pharyngeal pouch (ultimobranchial body). superior pharyngeal location (pouch III) than the su-
These cells are believed to be neural crest in origin. perior thyroids (pouch IV). This relationship may be
They migrate into the thyroid and differentiate into explained by the relationship of the developing infe-
the calcitonin-producing C cells (Fig. 2.1a) [4]. rior parathyroid gland with the thymus. The thymus
A number of developmental errors can affect thy- arises from the caudal portion of the third pharyn-
roid development. The thyroid may fail to descend. geal pouch. As the thymus descends into the thorax,
14 William B. Stewart and Lawrence J. Rizzolo

Fig. 2.1 Embryology of the thyroid and parathyroid. a Schematic view from behind with the vertebral column, esophagus, and
trachea removed. The foramen cecum and emerging thyroglossal duct are indicated in the tongue. Dashed arrow shows migration
of thyroid along the anterior wall of the neck. Laterally, the pharyngeal pouches are numbered. These are evaginations of the foregut
into the mesoderm that contains the aortic arches. Each pouch lies inferior to the aortic arch of the same number. The parathyroid
glands originate in the pharyngeal pouches and migrate into position as indicated by the dashed arrows. Note the co-migration of
the inferior parathyroids with the thymus gland. b CAT scan with intravenous contrast demonstrates the concentration of iodine
into an undescended (lingual) thyroid gland. The anterior two thirds of the tongue lies anteriorly to the gland. c CAT scan at the
level of the hyoid bone exhibits a thyroglossal duct cyst. b and c courtesy of Dr. James Abrahams, Department of Diagnostic Imag-
ing, Yale University School of Medicine

Table 2.1 Location of 54 ectopic parathyroid glands identified tion posterior to the thyroid. Sometimes, however, the
by Shen and co-workers [13] inferior parathyroid glands are carried into the thorax
Location Number along with the thymus. The ectopic parathyroid gland
High cervical 1
may be found in a number of locations (Table 2.1).
The most common locations were intrathymic or par-
Aorticopulmonary window 2
aesophageal in the neck [13].
Posterior mediastinum 3
Carotid sheath 5
Intrathyroid 6 2.3 Anatomy of the Thyroid Gland
Anterior mediastinum (non-thymic) 9
2.3.1 General Topography and Relations
Intrathymic 13
Paraesophageal (neck) 15 The right and left lobes of the thyroid are connected
at the midline by the isthmus of the gland. A pyrami-
dal lobe may extend superiorly from the isthmus or
it is accompanied by the inferior parathyroid glands. from the medial portions of the left or right lobes. The
Normally the attachment to the thymus is lost and the thyroid extends from the level of the fifth cervical ver-
inferior parathyroid glands take up their normal posi- tebra to the first thoracic vertebra. The gland weighs
2 Embryology and Surgical Anatomy of the Thyroid and Parathyroid Glands 15

Fig. 2.2 Thyroid gland and its relations at the level of the thyroid cartilage. An unembalmed cadaver was frozen and sectioned (Vis-
ible Human Project, National Institutes of Health). The orientation is the same as for a CAT scan with patients left on the right side
of the image. Color enhancement demonstrates major arteries (red), veins (blue), and nerves (yellow). Note the close relationship of
the superior pole of the thyroid gland with the carotid sheath and sympathetic chain

about 30 g, being somewhat heavier in females than of the thyroid lies anterior to the second and third
in males [12]. The thyroid is surrounded by a sleeve tracheal rings. The description of relationships to im-
of pretracheal fascia sometimes called the perithyroid portant neural structures will be deferred to that sec-
sheath. Posteriorly, a thickening of this fascia attaches tion.
the gland to the cricoid cartilage. This fascia is the lat-
eral ligament of the thyroid (ligament of Berry).
The anterior surface of the thyroid is related to 2.3.2 Blood Supply
the deep surface of the sternothyroid, sternohyoid,
and omohyoid muscles (Figs. 2.2, 2.3). Where these As with other endocrine organs, the thyroid gland has
muscles are absent in the midline, the isthmus of the a rich blood supply with abundant anastomoses. The
gland is subcutaneous. Laterally the gland is related arterial supply is bilateral from both the external ca-
to the carotid sheath, which contains the common rotid system, through the superior thyroid artery, and
carotid artery, the internal jugular vein, and the va- the subclavian system, through the inferior thyroid
gus nerve. Posteriorly, the superior parts of the lobes branch of the thyrocervical trunk (Fig. 2.4). There
of the thyroid are related to the longus colli and lon- may be a single thyroid ima artery that arises from the
gus capitis muscles. Medially, the superior part of the brachiocephalic artery.
thyroid is related to the larynx and laryngopharynx, The superior thyroid artery is normally the first
which includes the cricothyroid and inferior pharyn- branch of the external carotid artery, though fre-
geal constrictor muscles and the thyroid and cricoid quently it may arise more inferiorly from the common
cartilages. Medially, the inferior part of the thyroid is carotid artery. This vessel descends to the superior
related to the trachea and the esophagus. The isthmus pole of the thyroid along with the external laryngeal
16 William B. Stewart and Lawrence J. Rizzolo

Fig. 2.3 Thyroid gland and its relations at the level of the third tracheal ring. Note the posteromedial relationships of the thyroid
gland with the recurrent laryngeal nerve and middle thyroid veins. The thoracic duct (green) is atypically dilated close to where it
joins the left internal jugular and subclavian veins. The inferior thyroid artery follows a looping course. In this image it is seen su-
perior to its origin from the thyrocervical trunk of the subclavian artery. It will loop superiorly and medially before descending to
join the thyroid gland near the recurrent laryngeal nerve. An inferior right parathyroid gland (orange) is evident near the recurrent
laryngeal nerve and middle thyroid veins. Major nerves (yellow), arteries (red), and veins (blue) are indicated

nerve. As it reaches the thyroid, the artery divides gland to anastomose with the posterior branch of the
into anterior and posterior branches (Fig. 2.5). The superior thyroid artery. The inferior branch supplies
anterior branch parallels the medial border of the the inferior part of the gland as well as the inferior
lobe and anastomoses in the midline with the anterior parathyroid glands. The inferior thyroid artery may
branch of the other side. The posterior branch anasto- be absent on either side. There is evidence that there
moses with branches of the inferior thyroid artery. are anthropologic differences in the incidence of thy-
The inferior thyroid artery takes a looping course. roid ima arteries, as well as in the symmetric origin of
It ascends along the anterior scalene muscle (Fig. 2.3). the superior thyroid arteries [17].
It turns medially to pass posteriorly to the carotid There are three main venous pathways from the
sheath and usually posteriorly to the sympathetic thyroid: the superior, middle, and inferior thyroid
trunk as well. It descends along the longus colli to veins (Fig. 2.6). The superior thyroid vein accompa-
reach the inferior pole of the thyroid. There it passes nies the superior thyroid artery and drains into the
to the thyroid either anteriorly or posteriorly to the internal jugular vein. The middle thyroid vein is un-
recurrent laryngeal artery. At the thyroid, the artery accompanied and drains directly into the internal
branches into superior and inferior branches. The jugular vein. Because of its posterior course, it is at
superior branch ascends on the posterior part of the risk when forward traction is applied to the gland, as
2 Embryology and Surgical Anatomy of the Thyroid and Parathyroid Glands 17

Fig. 2.4 Arterial supply of thyroid and parathyroid glands is

divided into a superior and a inferior system. Superior and in-
ferior thyroid arteries are indicated.

Fig. 2.6 Venous drainage of the thyroid and parathyroid glands.

Superior, middle and inferior thyroid veins are indicated.

in a thyroidectomy (Fig. 2.3). There are often a num-

ber of inferior thyroid veins that drain into the inter-
nal jugular or the brachiocephalic veins.
The lymphatic drainage of the lateral part of the
thyroid follows the arterial supply. These lymphatic
vessels either ascend with the superior thyroid artery
or descend with the inferior thyroid artery to reach
the jugular chain of nodes. Between these two arter-
ies, lymphatic vessels may pass directly to the jugular
nodes. The medial aspect of the gland drains superi-
orly to the digastric nodes and inferiorly to the pre-
tracheal and brachiocephalic nodes [15].

2.4 Anatomy
of the Parathyroid Glands
There are normally two pairs of parathyroid glands,
located along the posterior aspect of the thyroid gland
Fig. 2.5 Arterial supply of the thyroid derived from the four (Fig. 2.7). The superior parathyroid glands normally
main vessels of the gland. Note the anterior and posterior divi- lie at the level of the middle third of the thyroid, while
sions of the superior artery. The inferior thyroid artery comes the inferior parathyroid glands lie at the level of the
from a posterolateral position to enter the thyroid gland close inferior third. Generally, the superior parathyroid
to the recurrent laryngeal nerve glands are supplied by the inferior thyroid artery, the
18 William B. Stewart and Lawrence J. Rizzolo

to its target. The external laryngeal nerve is frequently

entrapped in the vascular pedicle that transmits the
superior thyroid vessels. Consequently the nerve may
be injured during the ligation of these vessels [2,3].

2.5.2 Recurrent Laryngeal Nerve

The recurrent laryngeal nerve, a branch of the vagus,

supplies the remainder of the laryngeal musculature
as well as sensation on and inferior to the vocal folds
(Figs. 2.2, 2.3). On the right side, the nerve loops pos-
teriorly to the subclavian artery to ascend obliquely
until it reaches the tracheoesophageal groove near the
inferior extent of the thyroid (Fig. 2.7). On the left
side the nerve loops posteriorly to the arch of the aorta
and ascends to the larynx in the tracheoesophageal
groove. The nerve may divide into a number of
branches that also supply the trachea and esophagus
[10]. The nerve has a very close relationship with the
inferior thyroid artery, where it might lie either an-
teriorly or posteriorly to the vessel (Fig. 2.7). Because
the left inferior thyroid artery may be absent in 6%
of individuals, the identification of the recurrent la-
ryngeal nerve may be more complicated [14]. The
nerve may also be closely related to or within the
ligament of Berry. Care must be taken in both re-
Fig. 2.7 Schematic dorsal view shows the course of the inferior traction and division of the ligament to ensure that
laryngeal nerve in relation to the inferior thyroid artery, the the nerve is preserved. There are some cases where
thyroid gland, and the parathyroid glands the nerve may run through the substance of the gland
In a small number of individuals (approximately
superior thyroid artery, or both. Anastomotic con- 1%) the right subclavian artery arises distally from
nections within the thyroid allow both vessels to con- the arch of the aorta [1]. As a consequence the right
tribute, especially to the superior parathyroid glands. recurrent laryngeal nerve is not pulled into the tho-
A number of methods have been advocated for local- rax by its relationship with the subclavian artery. This
izing the glands. These include ultrasonography [6], non-recurrent right laryngeal nerve passes directly to
intraoperative methylene blue [7], and technetium the larynx posterior to the common carotid artery.
sestamibi scans [18]. It runs parallel to the inferior thyroid artery and can
ascend for a short distance in the tracheoesophageal
groove [15]. It is, therefore, at risk for injury during
2.5 Nearby Relations surgery.
of the Thyroid and Parathyroid The vagus nerve and sympathetic trunk are within
at Risk During Surgery or closely related to the carotid sheath (Figs. 2.2, 2.3,
2.8). The vagus nerve may receive some of its blood
2.5.1 External Laryngeal Nerve supply from the inferior thyroid artery [15]. Conse-
quently, the artery should not be ligated too close to
The external laryngeal is a division of the superior la- its origin. Lymph node dissection along the carotid
ryngeal nerve, a branch of the vagus. This nerve sup- artery and near the vertebral artery or any manipu-
plies the cricothyroid muscle. Since this muscle is in- lation near the superior pole of the thyroid gland
volved in movements of the vocal apparatus, damage should also be performed with care to ensure that the
to the nerve will impair phonation. The nerve may cervical sympathetic chain ganglia are not damaged
run near the superior pole of the thyroid on the way or removed (Figs. 2.2, 2.3).
2 Embryology and Surgical Anatomy of the Thyroid and Parathyroid Glands 19

Fig. 2.8 Schematic anterior view depicts the courses of the superior and inferior laryngeal nerves in relation to the trachea and the
larynx. Note also the course of the vagus nerve within the sheet of the common carotid artery and the internal jugular vein

Removal of large thyroid tumors may require divi- References

sion of the infrahyoid muscles. Care must be taken to
identify the branches of the ansa cervicalis that supply 1. Abboud B, Aouad R (2004) Non-recurrent inferior laryn-
these muscles. The course of the ansa as it descends geal nerve in thyroid surgery: report of three cases and
from the hypoglossal nerve is highly variable. Nor- review of the literature. J Laryngol Otol 118:139142
mally, a superior division of the muscles will ensure 2. Bellantone R, Boscherini M, et al (2001) Is the identifica-
the preservation of the nerve supply. tion of the external branch of the superior laryngeal nerve
mandatory in thyroid operation? Results of a prospective
randomized study. Surgery 130:10551059
3. Droulias C, Tzinas S, et al (1976) The superior laryngeal
nerve. Am Surg 42:635638
20 William B. Stewart and Lawrence J. Rizzolo

4. Dyson MD (1995) Endocrine system. In: Williams PL 11. Page C, Foulon P, et al (2003) The inferior laryngeal nerve:
(ed) Grays anatomy. Churchill Livingstone, New York, surgical and anatomic considerations. Report of 251 thy-
pp 18811906 roidectomies. Surg Radiol Anat 25:188191
5. Ghanem N, Bley T, et al (2003) Ectopic thyroid gland in 12. Shaheen OH (2003) Thyroid surgery. Parthenon Publish-
the porta hepatis and lingua. Thyroid 13:503507 ing, New York
6. Haber RS, Kim CK, et al (2002) Ultrasonography for 13. Shen W, Duren M, et al (1996) Reoperation for persistent
preoperative localization of enlarged parathyroid glands or recurrent primary hyperparathyroidism. Arch Surg
in primary hyperparathyroidism: comparison with 131:861867; discussion 867869
(99m)technetium sestamibi scintigraphy. Clin Endocrinol 14. Sherman JH, Colborn GL (2003) Absence of the left in-
(Oxf) 57:241249 ferior thyroid artery: clinical implications. Clin Anat
7. Kuriloff DB, Sanborn KV (2004) Rapid intraoperative lo- 16:534537
calization of parathyroid glands utilizing methylene blue 15. Skandalakis JE, Carlson GW, et al (2004) Neck. In: Skan-
infusion. Otolaryngol Head Neck Surg 131:616622 dalakis JE (ed) Surgical anatomy, vol 1. Paschalidis Medi-
8. Larsen WJ (2001) Human embryology. Churchill Living- cal, Athens, pp 3116
stone, New York 16. Sturniolo G, DAlia C, et al (1999) The recurrent laryngeal
9. Livolsi VA (1990) Surgical pathology of the thyroid. Saun- nerve related to thyroid surgery. Am J Surg 177:485488
ders, Philadelphia 17. Toni R, Della Casa C, et al (2003) Anthropological varia-
10. Mirilas P, Skandalakis JE (2002) Benign anatomical mis- tions in the anatomy of the human thyroid arteries. Thy-
takes: the correct anatomical term for the recurrent laryn- roid 13:183192
geal nerve. Am Surg 68:9597 18. Udelsman R, Donovan PI (2004) Open minimally inva-
sive parathyroid surgery. World J Surg 28:12241226

3 Evaluation of Hyperthyroidism and Hyperthyroid Goiter

Mirjam Christ-Crain, Nils G. Morgenthaler, and Beat Mller

Contents synthesis requires the availability of iodine and is in-

creased by thyroid-stimulating hormone (thyrotro-
3.1 Introduction . . . 21 pin; TSH) from the anterior pituitary gland through
3.2 Thyroid Physiology . . . 21
a specific thyroidal TSH receptor. Thyroid hormones
3.3 Thyroid Function Tests . . . 22
are almost entirely bound to plasma proteins and only
3.4 Hyperthyroidism . . . 23
a small percentage circulates in the free, bioavailable
3.4.1 Graves Disease . . . 23
form. Etiology of Graves Disease . . . 23
The synthesis of T4 and T3 by the thyroid gland in- Pathogenesis of Graves Disease . . . 23 Clinical Manifestations of Graves Disease . . . 24
volves four major steps: (1) active transport of iodine Laboratory Assessment into the thyroid cell; (2) oxidation of iodine and io-
of Graves Disease . . . 25 dination of tyrosyl residues in thyroglobulin (Tg); (3) Treatment of Graves Disease . . . 25 coupling of iodotyrosine molecules within thyroglob- Treatment of Graves Ophthalmopathy . . . 27 ulin to form T3 and T4; (4) proteolysis of thyroglobu-
3.4.2 Toxic Adenoma and Toxic Multinodular lin, with release of free hormones into the circulation
Goiter . . . 27 (Fig. 3.1). Toxic Adenoma . . . 27 After iodine is transported into the thyroid cell, it Toxic Multinodular Goiter . . . 27 is oxidized and incorporated into tyrosyl residues in
3.4.3 Complication of Hyperthyroidism: Thyrotoxic Tg. Tg is stored in the colloid space at the center of
Crisis (Thyroid Storm) . . . 28 the thyroid follicles. The coupling of iodotyrosyl resi- Treatment of Complications dues in Tg is catalyzed by the enzyme thyroperoxi-
of Hyperthyroidism . . . 28 dase. Thereby, two molecules of diiodotyrosine (DIT)
References . . . 28 couple to form T4, and one molecule of monoiodoty-
rosine (MIT) and a DIT couple to form T3. Antithy-
roid drugs are potent inhibitors of thyroperoxidase
and will block thyroid hormone synthesis. With the
3.1 Introduction process of proteolysis through lysosomal enzymes hy-
drolysis of thyroglobulin occurs, releasing T4, T3, DIT,
The primary intention of this chapter is to focus on and MIT. T4 and T3 are released into the circulation,
the diagnosis and treatment of the two most prevalent while DIT and MIT are deiodinated and the iodine
hyperthyroid states, i.e., Graves disease and solitary is conserved within the thyroid. Iodide organifica-
and multinodular goiter. In addition, we aim to pro- tion and Tg proteolysis are inhibited by excess iodide,
vide some concise information on thyroid physiology called the Wolff-Chaikoff effect. As this is a transient
and thyroid function tests. effect, both normal and autonomous thyroid cells can
escape from the inhibiting iodide effect within days
to weeks with recurrence of euthyroidism or hyper-
3.2 Thyroid Physiology thyroidism, respectively. Conversely, if the gland is
unable to escape iodide-induced hypothyroidism
The thyroidal parenchyma consists of two major cell will ensue, especially in the presence of autoimmune
types, the thyrocytes releasing thyroid hormones and Hashimoto thyroiditis.
the C cells secreting mature calcitonin [1]. The two In the circulation, thyroid hormones are trans-
main thyroid hormones l-thyroxin (T4) and to a much ported bound to carrier proteins. Only 0.04% of T4
lesser extent l-triiodothyronin (T3) are produced by and 0.4% of T3 are free, which represents the fraction
the follicular epithelial cells of the thyroid gland. The that is indeed responsible for hormonal activity. There
22 Mirjam Christ-Crain, Nils G. Morgenthaler, and Beat Mller

Fig. 3.1 Synthesis of thyroid hormones in the thyroid follicles

are three major thyroid binding hormones: thyroxin- where hypothalamic thyrotropin-releasing hormone
binding globulin (TBG), transthyretin, and albumin. (TRH) stimulates the synthesis and release of anterior
The daily secretion of the normal thyroid gland pituitary TSH, which in turn stimulates growth and
is about 100 nmol of T4 and about 5 nmol of T3. The hormone secretion by the thyroid gland.
biologic activity of thyroid hormones is greatly de-
pendent on the location of the iodine atoms. Deio-
dination of the outer ring of T4 produces T3, which 3.3 Thyroid Function Tests
is three to eight times more potent than T4. On the
other hand, deiodination of the inner ring of T4 pro- Secretion of thyroid hormones T4 and T3 is regulated
duces reverse T3, which is metabolically inert. The by pituitary thyrotropin (TSH). TSH secretion, in
deinodinase processes depend on specific deiodinat- turn, is controlled through negative feedback by thy-
ing enzymes that differ in their local concentration roid hormones. There is a negative log-linear relation-
and activity dependent on localization within the tis- ship between serum-free T4 and TSH concentrations
sue and the organism. The most important, type 1 5- [2]. This means that very small changes in serum-
deiodinase, is largely found in liver and kidney and in free T4 concentrations induce very large reciprocal
lesser quantities in the thyroid gland, skeletal muscle, changes in serum TSH concentrations. As a result,
and other tissues. The major function of type 1 5-de- thyroid function is best assessed by measuring serum
iodinase is to provide T3 to the plasma and hence the TSH.
peripheral target tissues of thyroid hormone action. First- and second-generation TSH radioimmuno-
This activity of this enzyme is increased in hyper- assay had detection limits of about 1 and 0.1 mU/l,
thyroidism and decreased in hypothyroidism. About respectively. Since this detection limit is just below
80% of T4 is metabolized by deiodination, 35% to T3, the normal range for TSH, about 0.34.0 mU/l, these
and 45% to reverse T3. The remainder is inactivated assays can be used as screening tests to distinguish
in the liver and secreted into the bile. The metabolic hyperthyroidism from euthyroidism and hypothy-
clearance rate of T4 is about 10% per day and the roidism. However, since the range of subnormal TSH
half-life of T4 is about 7 days. The body pool of T3 is measurement is very limited in values near or at the
much smaller and the turnover rate more rapid, with detection limit, TRH testing was necessary to distin-
a plasma half-life of only 0.2 days. The rapid clear- guish the degree of hyperthyroidism. With third-gen-
ance of T3 is due to lower binding affinity for thyroid eration TSH chemoluminescent assays the detection
binding proteins. limit is about 0.01 mU/l. They can therefore provide
The growth and function of the thyroid gland and detectable TSH measurements even in mild, subclini-
the peripheral effects of thyroid hormones are mainly cal hyperthyroidism and make stimulation tests ob-
controlled by the hypothalamic-pituitary-thyroid axis, solete [3].
3 Evaluation of Hyperthyroidism and Hyperthyroid Goiter 23

Serum total T4 and T3 are usually measured by patients with Graves disease have circulating thyroid
radioimmunoassay, chemoluminometric assay, or a antibodies. Females are affected five times more com-
similar immunometric technique. Virtually all of se- monly than males and smoking is another risk factor
rum T4 and T3 are bound to TBG or albumin. Serum for the development and severity of Graves disease
total T4 and T3 measure both bound and unbound and especially ophthalmopathy [4].
(free) T4. Since drugs and illness can alter concentra-
tions of binding proteins, the free and total hormone
levels may not be concordant. It is therefore necessary Pathogenesis of Graves Disease
to measure free hormone concentrations. Free T4 con-
centrations are in the nanomolar range, in contrast to T lymphocytes become sensitized to antigens within
free T3 levels which are present only in picomolar lev- the thyroid gland and stimulate B lymphocytes to
els in the circulation. Therefore, the assays for free T4 synthesize antibodies to these antigens. One group
are considered more reliable. of autoantibodies is directed against the TSH recep-
tor site on the thyroid cell membrane. These autoan-
tibodies stimulate the TSH receptor independently of
3.4 Hyperthyroidism TSH, which leads to an increase in growth and activ-
ity of the thyroid cell. Rarely, a subgroup of these au-
Hyperthyroidism is the clinical syndrome that results toantibodies, although picked up by the assay, block
when tissues are exposed to high levels of circulating the TSH receptor without intrinsic stimulation and
thyroid hormones. In most instances, hyperthyroid- thus are inhibitory to the thyroid function resulting
ism is due to hyperactivity of the thyroid gland. Occa- in hypothyroidism. Conversely, in some patients with
sionally, hyperthyroidism may be due to other causes hyperthyroid autoimmune thyroiditis, TSH receptor
such as excessive ingestion of thyroid hormones or antibodies are not found but thyroperoxidase autoan-
excessive secretion of thyroid hormones from ectopic tibodies are present, also referred to as hashitoxico-
sites. Of the various forms of hyperthyroidism, the sis. This might suggest an overlap in the pathogenesis
most common forms are Graves disease, toxic ad- of hyperthyroid (i.e., Graves disease) and hypothy-
enoma, and toxic multinodular goiter. roid (i.e., Hashimotos disease) autoimmunity. Alter-
natively, transient hashitoxicosis could also be due to
an initial and transient release of thyroid hormone
3.4.1 Graves Disease as a result of the inflammatory destruction of thy-
roid follicles. In this context, a common pathogenesis
Graves disease is the most common form of hyper- might exist in patients suffering from silent thyroid-
thyroidism. It may occur at any age, with a peak inci- itis, a lymphocytic thyroiditis that can occur during
dence in the 20- to 40-year age group. As with most the postpartal period.
autoimmune diseases, it is more commonly found in The presence of TSH receptor antibodies is posi-
females than in males. The syndrome consists of one tively correlated with activity and with relapse rate of
or more of the following features, which can occur the disease. There is an underlying genetic predisposi-
together or independently: hyperthyroidism, oph- tion, but it is unclear what triggers the acute episode.
thalmopathy, and dermopathy (pretibial myxedema). Some factors are suggested to incite the immune re-
Graves disease is an autoimmune disorder in which sponse of Graves disease, namely iodide excess, lith-
TSH receptor antibodies bind to and stimulate the ium therapy, viral or bacterial infections, and with-
thyroid gland, causing an excessive secretion of T4 or drawal of glucocorticoids. It has been suggested that
T3 or both, resulting in the clinical manifestation of stressful life events may trigger an episode of Graves
hyperthyroidism. disease [5]. Conversely, during pregnancy the clini-
cal manifestations of the autoimmune syndrome can
be attenuated, with a common recurrence during the Etiology of Graves Disease postpartal period. The pathogenesis of Graves oph-
thalmopathy may involve cytotoxic lymphocytes and
Graves disease is an autoimmune disorder of un- antibodies sensitized to a common antigen such as
known cause with a prevalence of 0.2%. There is a the TSH receptor found in orbital fibroblasts, orbital
strong family predisposition in that about 15% of muscle, and thyroid tissue.
patients with Graves disease have a close relative
with the same disorder and about 50% of relatives of
24 Mirjam Christ-Crain, Nils G. Morgenthaler, and Beat Mller Clinical Manifestations Table 3.1 Clinical activity score (CAS) for a standardized clin-
of Graves Disease ical assessment of Graves Ophthalmopathy
CAS item Score
The clinical manifestations of Graves disease can in- Pain Painful, oppressive feeling on or be- 1
volve almost any organ system and can be divided into hind the globe during the last 4 weeks
symptoms common to any form of hyperthyroidism
Pain on attempted up, side, or down- 1
and those specific to Graves disease [6]. Usually there
gaze during the last 4 weeks
is a palpable, diffusely enlarged, smooth goiter that
initially is soft but becomes progressively firmer. Be- Redness Redness of the eyelids 1
cause of the increased vascularity of the gland, there Diffuse redness of the conjunctiva, 1
may be a systolic bruit heard with the stethoscope. covering at least one quadrant
Patients commonly report nervousness, malaise, irri- Swelling Swelling of the eyelids 1
tability, inability to concentrate, easy fatigability, and Chemosis 1
intolerance to heat. There is often marked weight loss
Swollen caruncle 1
without loss of appetite. Other clinical symptoms are
excessive sweating, hand tremor, and mild or moder- Impaired Increase of proptosis of 2 mm during 1
ate muscle weakness. In patients over 60 years of age, function a period of 13 months
cardiovascular and myopathic manifestations may Decrease of eye movements in any 1
predominate with the most common presenting com- direction 5 during a period of
plaints of palpitations, dyspnea on exertion, tremor, 13 months
nervousness, and weight loss. A clinical score may be Decrease of visual acuity of 1 line(s) 1
used to quantify the clinical symptomatology and for (using a pinhole) during a period of
follow-up examination [7]. In addition, vitiligo, pru- 13 months
ritus, osteoporosis, and gynecomastia can also occur. Maximal CAS score 10
Graves ophthalmopathy (GO) occurs together
with hyperthyroidism in 4660% of patients, in 30%
of patients hyperthyroidism may occur several years
before any eye symptoms are present, and only in descending frequency) lid retraction, edema, exoph-
about 10% of cases may the eye symptoms precede thalmus, motility disorders, and visual impairments
the thyroidal symptoms [8]. GO is most likely to oc- (Fig. 3.2). About 50% of all patients with Graves dis-
cur between 40 and 50 years. Clinical signs are (in ease develop visible eye symptoms, however, more

Fig. 3.2 Endocrine ophthalmopathy (EOP)

3 Evaluation of Hyperthyroidism and Hyperthyroid Goiter 25

Table 3.2 NOSPECS classification of Graves Ophthalmopathy

NOSPECS score 0 1 2 3
Lid retraction No Yes
Soft tissue inflammationa 0 14 58 >8
Proptosis <17 mm 1718 mm 1922 mm >22 mm
Site difference <1 mm 12 mm 34 mm >4 mm
Extraocular muscle in- No Upgaze >20 Upgaze <20
volvement Abduction >35 Abduction <35
Corneal defects No Yes
Optic nerve compression No Yes

Upper lid edema 02, lower lid edema 02, conjunctival injection 1, conjunctival chemosis 1

than two thirds of symptom-free Graves disease pa- necessary [12,13]. If they are negative, a radioactive
tients show eye muscle enlargement in the magnetic iodine uptake should be determined to differentiate
resonance tomography (MRT) [9]. Most Graves dis- Graves disease from other causes of hyperthyroidism.
ease patients develop mild to moderate GO, but only A diffusely elevated uptake of radioiodine is diagnos-
35% of patients develop very severe GO with opticus tic for Graves disease, whereas a localized increased
compression. uptake is suggestive for toxic nodular disease. A low
Standardized clinical assessment of the severity uptake is seen in patients with subacute thyroiditis or
and activity of GO is mandatory for successful treat- a flare-up of Hashimotos thyroiditis. Low uptakes will
ment. The most recent and widely accepted protocol also be found in patients who are iodine loaded or,
for a standardized assessment of the clinical activity rarely, in association with a struma ovarii.
score (CAS) was proposed by Mourits and colleagues
[10]. The severity of the disease can be assessed by a
modified NOSPECS classification, which includes all Treatment of Graves Disease
disease manifestations (Tables 3.1, 3.2) [11].
Thyroid dermopathy consists of thickening of the Although autoimmune mechanisms are responsible
skin, particularly over the lower tibia, due to accumu- for the syndrome of Graves disease, management
lation of glycosaminoglycans. It is relatively rare, oc- has been largely directed toward controlling the hy-
curring in about 23% of patients with Graves disease perthyroidism. The initial therapeutic approach con-
and is usually associated with ophthalmopathy with a sists of both rapid amelioration of symptoms with a
very high serum titer of TSH receptor antibodies. beta-blocker and measures aimed at decreasing thy-
Symptoms specific for Graves disease are diffuse roid hormone synthesis. For this purpose, three treat-
goiter, ophthalmopathy, and dermopathy; all other ment options are available: antithyroid drug therapy,
symptoms are common to any form of hyperthyroid- radioactive iodine, and surgery [14]. There is regional
ism. variation in their use. Initial radioiodine treatment
is favored in North America and antithyroid drugs
nearly everywhere else. The treatment options and Laboratory Assessment advantages and disadvantages should be discussed
of Graves Disease with each patient. Whatever treatment is used, initial
monitoring should consist of periodic clinical assess-
The laboratory findings in Graves disease are essen- ment and measurement of free T4. Serum TSH con-
tially the combination of a suppressed TSH and el- centration may remain low for several weeks after the
evated free T4 and T3 levels. If eye signs are present, patient becomes euthyroid.
the diagnosis of Graves disease is obvious. If eye signs
are absent, TSH receptor autoantibodies confirm the
diagnosis. Modern assays employing human recom- Antithyroid Drug Therapy
binant TSH receptor have a greater than 95% sensitiv-
ity, and if they are positive, the diagnosis of Graves Antithyroid drug therapy is most useful primarily in
disease is confirmed and no other diagnostic tests are young patients with a first episode of Graves disease.
26 Mirjam Christ-Crain, Nils G. Morgenthaler, and Beat Mller

In Europe and in Asian countries it is the preferred Radioactive Iodine

initial therapy for most patients. Either propylthio-
uracil (PTU) or methimazole (MMI) is considered In the USA, treatment of Graves disease with iodine-
a first-line agent in the treatment of Graves disease. 131 (131I) is the preferred therapy for most patients
PTU and MMI inhibit iodination of Tg, iodotyrosine over the age of 21 years. It has this popularity because
coupling, and Tg synthesis. In addition, PTU, but of its efficacy and few side effects, the most frequent
not MMI, inhibits conversion of T4 to T3 [15]. PTU of which is treatable thyroid failure. Follow-up studies
should be administered 23 times daily because of a have not implicated 131I treatment in a higher risk of
shorter half-life, whereas <20 mg MMI can be given carcinoma in general, leukemia, or lymphoma [18].
once daily. The customary starting dose of PTU may Therapy with 131I does increase the gonadal radiation
be 300450 mg/day in divided doses and of MMI exposure, but a higher risk of fetal malformation in
3045 mg daily. PTU is preferred during pregnancy, subsequent pregnancies has not been demonstrated,
since it may cross the placenta to a lesser degree than however this is based only from anecdotal experi-
MMI. The aim of antithyroid drug treatment is to ence. Thus, 131I should be administered with caution
restore a euthyroid state within 12 months. When to any female patient of childbearing age. Radioactive
the patient becomes euthyroid, maintenance therapy iodine is given in a dose of 515 mCi on the basis of
may be achieved with a lower single morning dose, assessment of the size of the thyroid [19]. This results
commonly 2550 mg PTU or 2.55 mg MMI. Al- in ablation of the thyroid within 618 weeks [20]. The
lergic reactions to antithyroid drugs involve either a main side effect of radioiodine treatment is develop-
rash (about 5% of patients) or agranulocytosis (about ment of hypothyroidism. Conversely, approximately
0.5% of patients). The rash can be managed by simply 10% of patients fail the first radioiodine treatment
administering antihistaminics, and unless it is severe and require a second dose. These are usually patients
it is not an indication for discontinuing the medica- with severe hyperthyroidism or very large goiters.
tion. Agranulocytosis requires immediate cessation of Pretreatment with antithyroid drugs before radioio-
all antithyroid drugs, institution of appropriate anti- dine treatment reduces its effectiveness, primarily due
biotic therapy, and shifting to an alternative therapy, to a radioiodine-uptake independent effect [21]. This
usually radioactive iodine. Agranulocytosis is usually is particularly a problem with PTU which can have a
heralded by sore throat and fever. Thus, all patients re- radioprotective effect [22]. However, in patients with
ceiving antithyroid drugs should be instructed that if severe hyperthyroidism, especially in the presence of
sore throat or fever develops they should see a physi- cardiac comorbidity, antithyroid drug pretreatment
cian for a white blood cell and differential count. Cho- should be performed for 48 weeks before radioio-
lestatic jaundice, angioneurotic edema, hepatocellular dine administration, since the drugs reduce thyroid
toxicity, and acute arthralgia are serious, but rare, side hormone secretion rapidly and thereby reduce the
effects that also require cessation of therapy. A com- risk of development of thyrotoxic crisis soon after
plete blood count and liver function tests should be radioiodine treatment. An interruption of thyrostatic
obtained initially and perhaps every 3 months during therapy for 3 days prior to radiotherapy will restore
treatment, although the side effects of agranulocytosis radioiodine uptake with stable thyroid hormone lev-
cannot be accurately predicted. els [23].
The duration of antithyroid drug therapy is quite Radioiodine treatment can induce worsening of
variable, but should be at least 6 months [16]. At GO, particularly in smokers. The worsening of oph-
our center, the most common treatment duration thalmopathy is often transient and can be prevented
is 18 months. After discontinuation of antithyroid by glucocorticoid treatment (40 mg prednisone daily
drugs, the incidence of relapse is quite high and is with tapering over a period of 3 months) [24].
5060% even in selected patients [6]. Predictors of
persisting remission are a reduction of the size of the
thyroid to normal after treatment, TSH receptor anti- Surgery
bodies that are no longer detectable, and a low dose of
antithyroid drugs to control the disease. Conversely, Subtotal thyroidectomy is the preferred treatment op-
large goiter size, persisting high levels of TSH recep- tion in selected patients with Graves hyperthyroid-
tor autoantibodies, and severe hyperthyroidism ini- ism, especially those with a large goiter, and those with
tially (i.e., markedly elevated T3 levels) are negative a coexistent thyroid nodule whose oncologic nature is
prognostic factors [17]. unclear. To minimize perioperative risk, the patient
should be treated with an antithyroid drug until clini-
3 Evaluation of Hyperthyroidism and Hyperthyroid Goiter 27

cal euthyroidism is achieved. There is disagreement Toxic Adenoma

about how much thyroid should be removed. Total
thyroidectomy is usually not necessary, unless maybe Patients who have a solitary autonomous nodule as
in patients with severe progressive ophthalmopathy the cause of their hyperthyroidism generally have a
to remove antigen stimulation. However, if too much palpable thyroid nodule. The prototypic patient is an
tissue is left, the risk for relapse increases. Thus, most older individual, usually over 40, who has noted re-
surgeons perform subtotal thyroidectomy and leave cent growth of a long-standing thyroid nodule. These
23 g of thyroid tissue on either side of the neck. lesions slowly increase in size and gradually suppress
Thereafter, a significant fraction of patients require the other lobe of the gland. Nodules more than 3 cm
TSH-guided thyroid supplementation following thy- in diameter evolve to cause more frequently clinical
roidectomy for Graves disease. Hypoparathyroidism hyperthyroidism than do smaller nodules. The di-
and recurrent laryngeal nerve injury occur as compli- agnosis is made by a thyroid scan, where a localized
cations of surgery in about 1% of cases, depending on increased uptake of radioiodine is seen with a de-
the experience of the surgeon. creased or completely absent uptake in the remaining
thyroid gland. Clinical symptoms of a toxic adenoma
are the classic symptoms of hyperthyroidism, indis- Treatment of Graves Ophthalmopathy tinguishable from the symptoms in Graves disease,
except that ophthalmopathy and dermopathy do not
Mild-to-moderate ophthalmopathy often improves occur. The differential diagnosis from other causes
spontaneously. The only treatment modality shown of hyperthyroidism usually poses no difficulty, with
to improve mild disease is smoking cessation. Other, the distinction resting on the anatomy of the thyroid
symptomatic options for therapy are sleeping with by physical and scan examination and the presence
head raised, use of artificial tears, and diuretic treat- or absence of typical signs of Graves disease or TSH
ment. An important therapeutic aim is to obtain eu- receptor antibody. Toxic adenomas are almost al-
thyroidism of the thyroid. Severe ophthalmopathy, ways follicular adenomas and virtually never malig-
in particular impaired vision, improves in about two nant. They are easily managed by administration of
thirds of patients who are treated with high-dose glu- antithyroid drugs such as PTU or MMI, followed by
cocorticoid treatment, orbital radiation, or both [25]. treatment with radioactive iodine or unilateral lobec-
Due to the fluctuating nature of the disease, it is de- tomy. 131I doses of 2030 mCi are usually required to
bated which fraction of this beneficial effect can be destroy the benign neoplasm. Radioactive iodine is
attributed to a side effect-prone steroid therapy. Or- preferable for smaller toxic nodules but larger ones
bital decompression is effective in patients with optic are best managed surgically.
neuropathy and exophthalmus, either as initial ther-
apy or after the failure of glucocorticoid treatment
[26]. However, it has to be emphasized that there are Toxic Multinodular Goiter
no adequately powered, randomized, placebo-con-
trolled studies available for the treatment of GO. In Toxic multinodular goiters that cause hyperthyroid-
particular, the place of other medical treatments, for ism are usually very large. They occur mostly in older
example, immunosuppressive drugs and octreotide, patients, similar to toxic adenomas. Clinically, the
remains unclear. patients present with typical symptoms of hyper-
thyroidism, and ophthalmopathy is extremely rare.
Toxic multinodular goiters occur equally in men and
3.4.2 Toxic Adenoma women. On physical examination, the thyroid gland
and Toxic Multinodular Goiter is multinodular and enlarged. The nodules usually are
benign follicular adenomas.
Toxic adenoma and toxic multinodular goiter are Radioiodine scans reveal multiple functioning
common causes of hyperthyroidism, second in preva- nodules in the gland or occasionally an irregular,
lence only to Graves disease. They can appear at any patchy distribution of radioactive iodine.
age, although they most frequently occur in patients Hyperthyroidism in patients with multinodular
older than 40 years. Toxic nodular or multinodular goiters can often be precipitated by the administration
goiters are not believed to have an autoimmune etiol- of iodide (iodide-induced hyperthyroidism). Thereby,
ogy since TSH receptor antibodies are absent. some thyroid adenomas do not develop or escape the
Wolff-Chaikoff effect and cannot adapt to an iodide
28 Mirjam Christ-Crain, Nils G. Morgenthaler, and Beat Mller

load. Thus, they are driven to excess hormone pro- symptoms induced by increased adrenergic tone, an-
duction by a high level of circulating iodide. tithyroid drugs to block new hormone synthesis, an
The long-term management of toxic multinodular iodinated radiocontrast dye to inhibit the peripheral
goiter using antithyroid drugs is cumbersome as, in conversion of T4 to T3, an iodine solution to block the
contrast to thyroid autoimmunity, autonomy will per- release of thyroid hormone, and glucocorticoids to
sist. Control of the hyperthyroid state with antithy- reduce T4-to-T3 conversion.
roid drugs followed by subtotal thyroidectomy is the
therapy of choice, but often these patients are elderly
and have other illnesses that make them poor candi- References
dates for surgery. In these cases, the toxic nodules can
be destroyed with 131I, but the multinodular goiter 1. Wartofsky L (2001) The thyroid gland. In: Becker KL (ed)
will remain, and other nodules may become toxic, re- Principles and practice of endocrinology and metabolism.
quiring repeated doses of 131I. Lippincott Williams & Wilkins, Philadelphia, pp 308471
2. Spencer CA, et al (1990) Applications of a new chemi-
luminometric thyrotropin assay to subnormal measure-
3.4.3 Complication of Hyperthyroidism: ment. J Clin Endocrinol Metab 70:453460
Thyrotoxic Crisis (Thyroid Storm) 3. Christ-Crain M, et al (2002) Basal TSH levels compared
with TRH-stimulated TSH levels to diagnose different de-
grees of TSH suppression: diagnostic and therapeutic im-
Thyrotoxic crisis is the acute exacerbation of all of the
pact of assay performance. Eur J Clin Invest 32:931937
symptoms of hyperthyroidism, often presenting as
4. Utiger RD (1995) Cigarette smoking and the thyroid. N
a syndrome that may be of life-threatening severity.
Engl J Med 333:10011002
Hyperpyrexia, agitation, delirium, psychosis, stupor,
5. Winsa B, et al (1991) Stressful life events and Graves dis-
or coma are common. Although thyrotoxic crisis may ease. Lancet 338:14751479
occur in patients with longstanding untreated hyper- 6. Weetman AP (2000) Graves disease. N Engl J Med
thyroidism without a known precipitating event, it is 343:12361248
more often precipitated by thyroidal or non-thyroidal 7. Zulewski H, et al (1999) Evaluation of procollagen III pep-
surgery, by the peripartum or postpartum period, by tide as a marker of tissue hyperthyroidism in long-term
131I therapy, by administration of iodine-containing treated women with TSH suppressive doses of thyroxine.
materials, or by infections. Exp Clin Endocrinol Diabetes 107:190194
8. Bartley GB, et al (1996) Chronology of Graves oph-
thalmopathy in an incidence cohort. Am J Ophthalmol Treatment of Complications 121:426434
of Hyperthyroidism 9. Kendall-Taylor P, et al (1998) Clinical presentation of thy-
roid associated orbitopathy. Thyroid 8:427428
The therapeutic options for the treatment of thyro- 10. Mourits MP, et al (1997) Clinical activity score as a guide
toxic crisis are the same as those for uncomplicated in the management of patients with Graves ophthalmopa-
hyperthyroidism, except that the drugs are given in thy. Clin Endocrinol (Oxf) 47:914
higher doses and more frequently. In addition, full 11. Gerding MN, et al (2000) Assessment of disease activity in
support of the patient in an intensive care unit is es- Graves ophthalmopathy by orbital ultrasonography and
sential, since the mortality rate from thyroid storm is clinical parameters. Clin Endocrinol (Oxf) 52:641646
substantial. In addition to specific therapy directed 12. Morgenthaler NG (1999) New assay systems for thyrotro-
pin receptor antibodies. Curr Opin Endocrinol Diabetes
against the thyroid gland, supportive therapy may be
critical to the final outcome. Many patients require a
13. Schott M, et al (2005) TSH-receptor autoantibodies in
substantial amount of fluid, while others may require
Graves disease: recent developments in the diagno-
diuresis because of congestive heart failure. Infections
sis and therapy monitoring. Trends Endocrinol Metab
need to be identified and treated, and hyperpyrexia 16:243248
should be aggressively corrected. Acetaminophen is 14. Singer PA, et al (1995) Treatment guidelines for patients
preferable to aspirin, which can increase serum-free with hyperthyroidism and hypothyroidism. Standards of
T4 and T3 concentrations by interfering with protein Care Committee, American Thyroid Association. JAMA
binding. 273:808812
The therapeutic regimen typically consists of 15. Cooper DS (1984) Antithyroid drugs. N Engl J Med
multiple medications, each of which has a different 311:13531362
mechanism of action: beta-blockers to control the
3 Evaluation of Hyperthyroidism and Hyperthyroid Goiter 29

16. Maugendre D, et al (1999) Antithyroid drugs and Graves 22. Imseis RE, et al (1998) Pretreatment with propylthiouracil
disease: prospective randomized assessment of long-term but not methimazole reduces the therapeutic efficacy of
treatment. Clin Endocrinol (Oxf) 50:127132 iodine-131 in hyperthyroidism. J Clin Endocrinol Metab
17. Schott M, et al (2004) Levels of autoantibodies against hu- 83:685687
man TSH receptor predict relapse of hyperthyroidism in 23. Walter MA, et al (2005) Paired comparison of radioiodine
Graves disease. Horm Metab Res 36:9296 uptakes and thyroid hormone levels on/off simultaneous
18. Saenger EL, et al (1968) Incidence of leukemia following carbimazole medication. A prospective paired compari-
treatment of hyperthyroidism. Preliminary report of the son. Nuklearmedizin 44:3336
Cooperative Thyrotoxicosis Therapy Follow-Up Study. 24. Bartalena L, et al (1998) Relation between therapy for hy-
JAMA 205:855862 perthyroidism and the course of Graves ophthalmopathy.
19. Farrar JJ, et al (1991) Iodine-131 treatment of hyper- N Engl J Med 338:7378
thyroidism: current issues. Clin Endocrinol (Oxf) 25. Bartalena L, et al (1997) Treating severe Graves ophthal-
35:207212 mopathy. Baillieres Clin Endocrinol Metab 11:521536
20. Franklyn JA (1994) The management of hyperthyroidism. 26. Garrity JA, et al (1993) Results of transantral orbital de-
N Engl J Med 330:17311738 compression in 428 patients with severe Graves ophthal-
21. Walter MA, et al (2004) Radioiodine therapy in hyperthy- mopathy. Am J Ophthalmol 116:533547
roidism: inverse correlation of pretherapeutic iodine up-
take level and post-therapeutic outcome. Eur J Clin Invest

4 Diagnostic Imaging of the Thyroid

and Radioiodine Therapy
4.1 Walter Wiesner, Hermann Engel, and Wolfgang Steinbrich
4.2 Egbert U. Nitzsche and Jan Mueller-Brand

Contents 4.1 Sonography of the Thyroid

4.1 Sonography of the Thyroid . . . 31 4.1.1 Basics and Technique
4.1.1 Basics and Technique . . . 31
4.1.2 Examination and Findings . . . 31
According to its superficial anatomic location, the
4.1.3 Diffuse Abnormalities of the Thyroid . . . 32
thyroid gland may easily be assessed by sonography. Diffuse Goiter . . . 32
Linear transducers with a width of 7.59 cm and fre- Nodular Goiter . . . 32
quencies of around 10 MHz are used. Sonography of Graves Disease . . . 32 Acute Thyroiditis . . . 33
the thyroid gland should also always be combined Subacute Thyroiditis de Quervain . . . 33 with a sonography of the surrounding soft tissues Hashimotos Thyroiditis . . . 33 and of the cervical vessels. It allows the exact meas- Chronic Fibrosing Thyroiditis urement of the thyroid volume and assessment of the
(Morbus Riedel) . . . 34 parenchymal texture of the thyroid gland with identi- Involvement of the Thyroid fication of diffuse or focal abnormalities of the gland
in Autoimmune Disorders . . . 34 itself and of potential abnormalities within the sur-
4.1.4 Focal Lesions . . . 34 rounding structures [14]. Cysts . . . 34 Compared to other imaging modalities sonogra- Calcifications . . . 34 phy of the thyroid gland offers the best spatial reso- Hyperplastic Nodules . . . 34 lution. Lateral resolution is 0.51 mm and this is Adenoma . . . 35 also valid for tiny calcifications. For solid or cystic Carcinoma . . . 35 lesions the detection levels are 34 mm and 2 mm, Metastases and Lymphomas . . . 35 respectively. By using the combination with color Cervical Lymph Nodes . . . 35 Doppler sonography additional information may be
4.1.5 Analysis and Interpretation achieved regarding the local perfusion in focal or dif-
of Sonographic Findings . . . 35 fuse abnormalities. Furthermore, exact fine-needle
4.1.6 Sonographic Follow-up of Patients aspirations or biopsies may be performed under so-
with Thyroid Carcinoma . . . 36
nographic guidance. As an imaging modality sonog-
4.2 Nuclear Medicine Imaging of the Thyroid
raphy is particularly attractive due to its low cost and
and Radioiodine Therapy . . . 37
lack of toxicity.
4.2.1 Radioisotopic Imaging
of the Thyroid Gland . . . 37 Introduction . . . 37 Radioactive Nuclides Commonly
4.1.2 Examination and Findings
Used for a Thyroid Scan . . . 37 Quantitative Scintigraphy . . . 37 For sonography of the thyroid the patient should be
4.2.2 Radioiodine Therapy for Treatment positioned supine. A pillow may be placed beyond
of Hyperthyroidism and Benign Non-toxic the neck of the patient in order to achieve good dor-
Multinodular Goiter . . . 39 sal flexion of the cervical spine. During a systematic
4.2.3 Radioiodine Treatment of Differentiated analysis of the thyroid the gland should be first im-
Thyroid Cancer . . . 40 aged entirely in axial planes including the isthmus, Indications for and Details and then each lobe should be imaged in its axial and
of Radioiodine Therapy . . . 40 longitudinal plane separately. Every sonographic ex- Follow-up after Radioiodine Treatment . . . 41 amination of the thyroid must include measurement
References . . . 43 of the thyroid volume.
32 Walter Wiesner, Hermann Engel, Wolfgang Steinbrich, Egbert U. Nitzsche and Jan Mueller-Brand

Fig. 4.1 Normal thyroid gland. Symmetric lobes with homoge-

neous parenchyma Fig. 4.2 Diffuse goiter. Symmetrically enlarged thyroid gland
with mildly inhomogeneous and hypoechoic echotexture of its
Regarding the description of sonographic find-
ings the international terminology should be used:
isoechoic, hypoechoic, hyperechoic, anechoic, diffuse their anteroposterior diameter enlarges only relative
or focal, homogeneous or heterogeneous, smooth or to the total increase in size. The longer a struma dif-
irregular, with dorsal echoenhancement or dorsal fusa persists, the more it happens that small regres-
echoblock. Findings within the thyroid gland should sive changes will be observed within the gland. These
be separated from findings outside the gland, and in- range from a mild irregularity of the parenchyma to
terpretation of findings should always be made at the anechoic, hypoechoic, or hyperechoic areas that rep-
end of the report and also be separated strictly from resent small cystic degenerations, fibrosis, or calcifi-
their initial description. cation, respectively (Fig. 4.2) [14].
The volume of the thyroid gland may be achieved Attention: In any diffuse goiter one can find pre-
by using the formula: anteroposterior (AP) diameter existent or new focal lesions that range from degen-
craniocaudal (CC) diameter lateral diameter erative and regressive changes to benign or malignant
0.53 for each lobe (= volume in milliliters). neoplasias. However, independently from the pres-
The normal thyroid has a smooth contour and ence of a struma diffusa the sonographic criteria for
shows a fine granular homogeneous, slightly hyper- such focal lesions are always the same and correspond
echoic sonographic pattern (Fig. 4.1). Its total volume to those discussed in the following section.
may range up to 18 ml in women and up to 25 ml in
men. The isthmus should not exceed 1 cm in its an-
teroposterior diameter and both lobes should per- Nodular Goiter
form a symmetric elevation during swallowing.
Regarding abnormalities of the thyroid gland that A thyroid with multiple nodules is termed struma no-
may be detected by sonography one has to differen- dosa or multinodosa. Usually the nodules represent
tiate between focal and diffuse findings, although colloidal, regressive and cystic, hemorrhagic or hy-
these may of course also be found in combination. perplastic nodules, which may appear hyperechoic or
Diffuse and focal abnormalities of the thyroid gland hypoechoic on sonography. The function of a nodule
and their sonographic appearances will be discussed can not be estimated by sonography; for this scintig-
separately. raphy is needed. Furthermore, application of iodine
should be avoided in nodular goiters because of the
risk of inducing hyperthyrosis.
4.1.3 Diffuse Abnormalities of the Thyroid Diffuse Goiter Graves Disease

A diffuse enlargement of the thyroid gland with a Graves disease (morbus Basedow) represents an au-
normal echogenicity of its parenchyma is termed toimmune disease that leads to a diffuse enlargement
struma diffusa. In such cases both lobes of the thyroid of the thyroid gland in combination with a hyperthy-
gland are usually symmetrically enlarged especially rosis and an endocrine ophthalmopathy. The thyroid
in their craniocaudal and lateral diameters, while gland is usually enlarged especially in its anteropos-
4 Diagnostic Imaging of the Thyroid and Radioiodine Therapy 33

cally and shows an inhomogeneous and hypoechoic

pattern. Occasionally the hypoechoic regions may
appear as quite well defined hypoechoic nodules that
may be palpable and quite painful, although typically
there is also pronounced tenderness of the entire or-
gan in such cases [6]. Together with the typical clini-
cal presentation of an ill patient presenting with fever
and increased infectious parameters despite normal
or even decreased WBC count, the clinical diagnosis
is usually easy to make. Therefore, scintigraphy or a
biopsy are not needed in these cases.

Fig. 4.3 Graves disease (morbus Basedow). Slightly asym-

metrically enlarged gland with inhomogeneous parenchyma, Hashimotos Thyroiditis
hypoechoic areas, and ball-shaped lobes
Hashimotos thyroiditis represents an autoimmune
thyroiditis with diffuse infiltration of the thyroid
terior diameter (depth) which results in ball-shaped gland by numerous lymphocytes and plasma cells.
lobes (Fig. 4.3). The gland is typically hypoechogenic This disease usually affects middle-aged women and,
and this is caused by the microfollicular texture, the apart from a certain genetic predisposition and a pre-
low content of colloid, as well as by the relative hyper- disposing age and gender, mainly dysregulations in
perfusion of the gland [5]. the cellular immune system and viral infections are
However, in cases where Graves disease involves discussed as etiologic factors.
an endemic goiter this hypoechoic pattern may be ab- In the initial stage the thyroid gland is usually of
sent since it will be overlaid by the preexistent fibrotic normal size or just slightly and asymmetrically en-
and regressive changes within the gland. Regression larged and shows a mild inhomogeneous hypoecho-
of the anteroposterior diameter of the thyroid gland genicity. However, the hypoechoic pattern of the
in Graves disease and an increasing echogenicity of thyroid parenchyma usually appears only after mani-
the parenchyma may be signs of remission, although fested hypothyrosis. Tenderness is absent and rarely
hypoechogenicity of the gland may persist for months hyperthyrosis may be present for a short time in the
even after euthyrosis is reached in certain cases. very initial phase of inflammation [7]. A variant of
this acute or hypertrophic form of Hashimotos thy-
roiditis is the so-called atrophic Hashimotos thy- Acute Thyroiditis roiditis that represents the chronic and late stage of
the disease. Here, the gland is typically atrophic with
Acute infectious thyroiditis is rare. It usually repre- areas or bands of hyperechoic, fibrotic parenchyma
sents pyogenic infection in combination with focal within (Fig. 4.4). Hashimotos thyroiditis is associated
or diffuse infections of the surrounding soft tissues
and rarely an isolated viral infection. In such cases the
parenchyma of the gland will appear homogeneously
or inhomogeneously hypoechoic and enlarged. Espe-
cially in pyogenic cases local inflammatory changes
such as edema, hyperthermia, and hyperemia will be
present as well as tenderness of the gland and the sur-
rounding tissues, depending on the degree of inflam-
mation. Subacute Thyroiditis de Quervain

Subacute thyroiditis de Quervain is a granulomatous

inflammation of the thyroid gland, which is usually Fig. 4.4 Hashimotos thyroiditis, chronic stage. Small gland
preceded by a simple infection of the upper airways. with inhomogeneous hyperechoic echotexture of the paren-
The thyroid gland is typically enlarged asymmetri- chyma
34 Walter Wiesner, Hermann Engel, Wolfgang Steinbrich, Egbert U. Nitzsche and Jan Mueller-Brand

with an increased risk of papillary carcinoma and of

primary lymphoma of the thyroid (see following sec-
tion on thyroiditis) and there is also an increased fre-
quency of polyendocrinopathies. Chronic Fibrosing Thyroiditis

(Morbus Riedel)

Chronic fibrosing thyroiditis (morbus Riedel) repre-

sents an autoimmune thyroiditis as well, but here it
is the fibrosing component with subsequent hypothy-
rosis that is dominating. The thyroid gland may be Fig. 4.5 Complicated (hemorrhagic) cysts. Well-defined cyst
diffusely enlarged or already atrophic and it may be with multiple echoes
impossible to distinguish the organ sonographically
from the surrounding fibroses [8]. The entire organ
and the surrounding tissues may be very hard during a viscous content and with high protein levels or in
palpation and the thyroid gland will typically show a hemorrhagic cysts (Fig. 4.5) [14]. Most cysts in the
significantly reduced mobility and elevation during thyroid gland represent cystic changes within primary
swallowing. According to the increased amount of solid lesions such as cystic degenerations in nodular
fibrotic tissue the gland will appear hyperechoic and hyperplasias, adenomas, or rarely even carcinomas.
in contrast to chronic Hashimotos thyroiditis the so- These so-called complicated cysts are usually irregu-
nographic distinction between the gland and the sur- larly shaped with tiny echoes, septations, lobulations,
rounding tissues may be extremely difficult. and diffuse or focally thickened walls and rarely even
solid wall adherent papillary formations that protrude
into the cyst lumen. Involvement of the Thyroid
in Autoimmune Disorders Calcifications
Hashimotos thyroiditis may occur in combination
with atrophic sialadenitis (Sjgrens syndrome), rheu- Calcifications are often found in a nodular goiter.
matoid arthritis, lupus erythematodes, primary bili- Solid calcifications appear as bright reflexes with
ary cirrhosis, and other autoimmune endocrinopa- dorsal echoblock. However, rarely calcifications may
thies or even (cutaneous) autoimmune disorders [9]. also be limited to the walls of complicated cysts or be
Riedels syndrome may also occur together with other found as tiny stipulated calcifications within hyper-
fibrosing autoimmune disorders, such as idiopathic plastic or regressive nodules [14]. These must be dif-
retroperitoneal fibrosis (Ormonds disease), pelvic ferentiated from so-called psammomatous microcal-
fibrosis, mediastinal fibrosis, primary sclerosing chol- cifications that may be found in papillary carcinomas
angitis, or orbital pseudotumor [10]. In such cases the of thyroid.
terms multifocal autoimmune syndrome or multifo-
cal idiopathic fibrosclerosis (MIF) are used, respec-
tively. However, the sonographic appearances in such Hyperplastic Nodules
cases are identical to those described above.
Hyperplastic nodules that occur especially in en-
demic nodular goiters represent nodular hyperpla-
4.1.4 Focal Lesions sias but not true autonomous neoplasias and must
therefore be strictly differentiated from true adeno- Cysts mas [14]. Sonographically hyperplastic nodules
show an isoechoic to hyperechoic pattern in almost
Dysontogenetic cysts of the thyroid gland are rare and 90% of cases (Fig. 4.6). They often present with some
appear as round, well-defined anechoic lesions with small cysts and calcifications resulting from necro-
dorsal echoenhancement. However, dorsal echoen- ses and hemorrhage. However, if such secondary
hancement may be absent in small cysts or cysts with changes involve larger areas of a hyperplastic nod-
4 Diagnostic Imaging of the Thyroid and Radioiodine Therapy 35

Fig. 4.6 Huge hyperplastic nodule. Solid, isoechoic, and ho- Fig. 4.7 Follicular carcinoma: two solid, hyperechoic nodules.
mogeneous nodule Differentiation from hyperplastic nodules or adenomas is im-
possible by sonography alone

ule it may become more and more hypoechoic on Metastases and Lymphomas
Rarely metastases from melanomas, lung carcino-
mas, breast carcinomas, renal carcinomas, and even Adenoma adenocarcinomas of the gastrointestinal tract may be
found in the thyroid gland [13]. Furthermore, lym-
Adenoma represents a true epithelial neoplasia and phomaswith increased incidence in Hashimotos
it may have different microscopic subtypes, includ- thyroiditisand leukemias may involve the thyroid
ing, for example, oncocytic adenoma (oncocytoma). gland. Most of these lesions are hypoechoic but apart
These lesions are usually hypoechoic and they often from a potential bilaterality and multifocality they
also show pronounced hypervascularization on Dop- can not be differentiated from other neoplasias on the
pler sonography [11]. basis of their sonographic presentation. The diagnosis
Attention: The term autonomous adenoma as in such cases is usually based on the medical history
used in scintigraphy does not always represent a true of the patient and on the results of fine-needle aspira-
adenoma but it may also rarely represent an autono- tions and biopsies.
mous hyperplastic nodule and, therefore, the term
focal autonomia should be used instead for the scinti-
graphic description of such lesions (see below). Cervical Lymph Nodes

Evaluation of cervical lymph nodes should be included Carcinoma during sonographic assessment of the thyroid gland.
Low-level echogenicity of well-circumscribed masses
Carcinomas of the thyroid gland are hypoechoic in is the classic sonographic appearance of enlarged
almost 80% of cases and in 20% of cases they appear lymph nodes (Fig. 4.8). However, in some cases the
as inhomogeneous lesions with solid hypoechoic and appearance is echo-free. Inflammatory processes
cystic changes [14]. However, 1% of all carcinomas may also exhibit a cystic nature. Differentiation of
may show a homogeneously hyperechoic echotexture inflammatory from neoplastic processes is not always
(Fig. 4.7). Papillary carcinomas may appear with a possible by sonographic criteria alone. To confirm a
distinct image due to microcalcifications and psam- neoplastic process, biopsy is therefore recommended.
moma bodies and may be distinguished sonographi-
cally from other types of tumors. Papillary carcino-
mas have an increased incidence in patients with 4.1.5 Analysis and Interpretation
Hashimotos thyroiditis and medullary carcinomas of Sonographic Findings
may occur in patients with multiple endocrine neo-
plasias (MEN2) or in association with the familial The points mentioned above make it clear that,
medullary thyroid carcinoma syndrome [12]. apart from cysts, an isolated interpretation of the
sonographic aspect of a focal lesion in the thyroid
36 Walter Wiesner, Hermann Engel, Wolfgang Steinbrich, Egbert U. Nitzsche and Jan Mueller-Brand

negative results from fine-needle aspirations or biop-

sies may occur in up to 10% of cases, surgery is often
recommended for growing nodules.
Complicated cysts with solid, hypoechoic areas
(wall thickening, papillary, or polypoid formations)
should also be punctured or biopsied for diagnostic
reasons. Simple cysts should be tapped only for thera-
peutic reasons to reduce their size.

4.1.6 Sonographic Follow-up of Patients

with Thyroid Carcinoma

Ultrasonography is an accessible and non-invasive

examination that is of great value in the determina-
tion of postsurgical remnants before ablative therapy
and has proved to be highly sensitive in the monitor-
ing of local recurrence and metastatic lymph nodes
[14]. High-resolution ultrasonography also enables
early detection of recurrent cancer in the thyroid
bed or within the cervical lymphatic basin especially
in patients with elevated serum thyroglobulin [15].
Fig. 4.8 Ultrasonographic appearance of an enlarged hy- Moreover, sonography is useful in patients who have
poechogenic cervical lymph node. The histology of the surgi- undergone partial thyroidectomy in whom follow-up
cally removed specimen revealed a metastasis from a papillary with serum thyroglobulin measurements and radio-
thyroid carcinoma iodine studies are not optimal.
When suspicious lymph nodes are detected, their
possible metastatic nature may be ascertained by fine-
gland will usually not allow its definite characteriza- needle aspiration cytology and by measurement of
tion. Here, the clinical constellation, laboratory find- thyroglobulin in the aspirate.
ings, as well as scintigraphy must be included into the High-resolution ultrasonography was positive in
diagnostic workup in order to make the right decision almost one third of 100 thyroid cancer patients stud-
for fine-needle aspirations, if needed. ied by Simeone and coworkers and only seven were
In cases where a sonographically detected nodule false-positive studies [16]. In 25 patients the diagno-
shows focal autonomia on scintigraphy, the diagnosis sis of recurrent cancer was confirmed with surgery or
is established and, disregarding if it is a hypoechoic radioactive iodine scanning (sensitivity 96%, specific-
nodule (probably autonomous adenoma) or a hyper- ity 83%). In contrast, palpation was negative in 17 out
echoic nodule (probably autonomous hyperplastic of the 25 patients (sensitivity 32%, specificity 100%).
nodule), fine-needle aspiration biopsy is not generally In another study evaluating 89 subjects who under-
recommended since the risk of a malignant autono- went surgery for thyroid carcinoma, ultrasonography
mia (carcinoma) is only 1% in such cases. detected neoplastic disease with a sensitivity of 65%,
Isoechoic or hyperechoic nodules in an endemic specificity of 86%, and overall accuracy of 82%. The
nodular goiter do not need to be biopsied, since the overall accuracy for scintigraphy was 88% and for
risk of malignancy is only about 1% in such cases thyroglobulin was 91% [15].
even when the lesions appear as a cold nodules on
scintigraphy. Nevertheless, sonographic follow-up ex-
aminations must be performed and fine-needle aspi-
ration or biopsy are essential when the nodule grows
over time.
In contrast, a scintigraphically cold nodule that
appears hypoechoic on sonography must always be
biopsied according to the statistically significantly in-
creased risk of malignancy in such cases. Since false-
4 Diagnostic Imaging of the Thyroid and Radioiodine Therapy 37

4.2 Nuclear Medicine Imaging such as pure gamma radiation, low energy of 140 keV,
of the Thyroid and short physical half-life of 6 hours. Since 99mTc is
and Radioiodine Therapy a generator-produced radionuclide, it is quickly avail-
able for routine use. Following intravenous injection,
4.2.1 Radioisotopic Imaging it takes about 1520 minutes for maximum uptake,
of the Thyroid Gland which is a factor of 10 lower compared to iodine. In
this early phase the percent uptake of 99mTc pertech- Introduction netate reflects the iodination rate. Between 15 and
30 minutes a plateau is reached for 99mTc pertech-
Thyroid scintigraphy renders, at one point in time, netate kinetics while, in contrast, uptake of iodine
information about the global and regional functional raises continuously. This difference in kinetics occurs
status of the thyroid. It is observer independent and because 99mTc pertechnetate is not incorporated into
reproducible with low inherent radiation exposure. In organic iodine compounds of the thyroid. It should
contrast, ultrasound (see above) is a sensitive means be noted that the uptake of 99mTc pertechnetate is not
of detecting structural changes of the thyroid gland. specific for thyroid cells.
Scintigraphic imaging of the thyroid includes deter- 123I has a physical half-life of 13 hours, pure
mination whether either solitary or multiple nodules gamma radiation, and low energy of 159 keV. It is
are functional (normal, hot, cold), whether cervical taken up into thyroid cells and incorporated into or-
masses contain thyroid tissue, and it can demonstrate ganic iodine compounds. Because of the latter, imag-
whether metastases from thyroid cancer concentrate ing at later time points is enabled with the benefit of
iodine for the purpose of radioiodine therapy. In the improved thyroid to background ratio. This defines its
majority of cases conclusive interpretation of ultra- special use for the detection of dystopically situated
sonic and scintigraphic imaging findings is possible lingual thyroid tissue, substernal mediastinal thyroid
in combination with clinical, laboratory, and cyto- tissue, or rarely a struma ovarii.
logical findings. Today the use of 131I is limited to follow-up diag-
The technique of thyroid scintigraphy is based on nostics in the case of thyroid cancer and in the course
the principle that functional active thyroid cells in- of radioiodine therapy. This is because of its unfavor-
corporate iodine. Iodine uptake proceeds in two phases. able physical properties for scintigraphic imaging
First, iodine is actively taken up through the sodium/ (i.e., physical half-life of 8.1 days, beta and gamma
iodine symporter, a protein of the basal cell membrane radiation, and high energy of 364 keV).
(iodination). Second, iodine is quickly incorporated
into organic iodine compounds (iodization). While
the first of the two phases represents an unspecific Quantitative Scintigraphy
process in which other ions such as pertechnetate may
compete with iodine, the incorporation to organic This is the present method of choice for scintigraphic
compounds is a very specific process. evaluation of the thyroid gland. The image is recorded
Quantitative thyroid scintigraphy enables assess- using a specially designed thyroid collimator with a
ment of the rate of thyroidal iodine uptake. Iodine computer-linked gamma camera. Use of such a sys-
uptake is self-controlled, in part by the iodine con- tem enables high-quality images of the thyroid to be
tent of the thyroid cells and in part by stimulators taken paralleled by calculation of global and regional
such as thyroid-stimulating hormone (TSH). In case thyroidal radiopharmaceutical uptake in percent of
of autonomy, thyroid uptake may be increased despite the administered amount of radioactivity. In this re-
these regulating mechanisms. gard, 99mTc uptake is to be considered equivalent to
thyroidal iodine clearance (Fig. 4.9), while 123I uptake
represents true iodine uptake. Radioactive Nuclides Commonly Used 99mTc uptake is dependent on endogenous TSH
for a Thyroid Scan stimulation and, via autoregulation of the thyroid,
on intrathyroidal iodine content. 99mTc uptake in a
For thyroid scintigraphy the following radionuclides healthy thyroid gland amounts to between 0.5% and
are in use: 99mTc, 123I, and 131I. 2% of total body radioactivity. In geographic regions
99mTc is mainly used as a radionuclide in the form of with iodine deficiency 99mTc uptake is between 2%
99mTc pertechnetate for thyroid scintigraphy. In con- and 8% in a euthyroid goiter.
trast to 131I, 99mTc has beneficial physical properties
38 Walter Wiesner, Hermann Engel, Wolfgang Steinbrich, Egbert U. Nitzsche and Jan Mueller-Brand

Fig. 4.9 99mTc scintigraphy: normal thyroid scintigraphy, there Fig. 4.11 99mTc scintigraphy: high uptake throughout both
is homogeneous uptake throughout the gland lobes in Graves disease

Fig. 4.10 99mTc scintigraphy: virtually no uptake in a thyroid Fig. 4.12 99mTc scintigraphy: high unifocal uptake in a case of
gland with autoimmune thyroiditis unifocal autonomy (singular toxic nodule, toxic adenoma)

Low 99mTc uptake is observed after iodine exposi-

tion, such as application of iodine-containing contrast
agents for radiodiagnostic imaging, iodine-contain-
ing drugs and beauty aids, disinfectants, following ad-
ministration of perchlorate, during thyroid hormone
therapy, as well as disease-related in cases of autoim-
mune thyroiditis, subacute thyroiditis de Quervain
(Fig. 4.10), and secondary hypothyroidism. In con-
trast, high 99mTc uptake is observed for several causes
of hyperthyroidism (Figs. 4.114.13), most frequently
Graves disease, iodine deficiency, during antithyroid
drug and lithium therapy, and in cases of inherited Fig. 4.13 99mTc scintigraphy: high multifocal uptake in multi-
enzymatic defects. focal autonomy (toxic multinodular goiter)
In addition to basal thyroid scintigraphy (in cases
of normal TSH concentration) the suppression scin-
tigram of the thyroid (rare but important) enables omy. In cases of functional relevant autonomy 99mTc
depiction of the global and regional regulation of thy- uptake ranges from >1% up to 2%, because of slight if
roidal iodine uptake in cases of disseminated or focal any depression of 99mTc uptake via TSH suppression.
(uninodular, e.g., unifocal or multinodular, e.g., mul- The extent of autonomy results from the amount of
tifocal) thyroidal autonomy. Following thyrosuppres- autonomic thyroid tissue and its functional activity.
sive therapy based on thyroid hormone administra- Today it is well known that under suppression a 99mTc
tion, 99mTc uptake declines to less than 0.5% in healthy uptake of >2.5% indicates increased risk of manifesta-
thyroid glands or small diffuse goiters without auton- tion of hyperthyroidism in cases of increased iodine
4 Diagnostic Imaging of the Thyroid and Radioiodine Therapy 39

Fig. 4.14 A normal FDG PET scan. Coronal sections from ventral to dorsal at different depth levels of the body and a sagittal sec-
tion at the slice level of the vertebral column. There is high uptake in the brain. The urinary bladder is illustrated because of renal
elimination of FDG. There is moderate uptake in the skeletal muscles, liver, spleen, kidneys, and red bone marrow

intake. Therefore, the result of the suppression scinti- differentiated and fast-growing tumor is likely to take
gram is an important parameter for a definitive thera- up an increased amount of FDG (means G3 is much
peutic decision to eliminate autonomy as a cause of better suited than G2, G1 is not suitable for FDG PET
hyperthyroidism. imaging), and a high mitotic rate permits better FDG
For positron emission tomography (PET) imag- PET imaging results. However, FDG is not a specific
ing of the thyroid, 124I (physical half-life 4.15 days) cancer imaging PET agent, and false-positive results
and 94mTc (physical half-life 52 minutes) may be used may be observed because of inflammation. Todays
in cases of benign disease. For evaluation of can- state of the art examination is integrated PET/com-
cer disease of the thyroid, fluorine-18 (18F; half-life puted tomography (CT), a single, two-in-one ap-
109.8 minutes)-labeled 2-deoxy-2-d-glucose (FDG) proach to cancer imaging that permits both func-
(Fig. 4.14) is used. It is indicated especially for the tional (PET) and morphologic (CT) examination at a
detection of recurrent and metastatic disease of dif- single appointment rather than two separate PET and
ferentiated (papillary or follicular) thyroid cancer. For CT examinations and subsequent imperfect image fu-
medullary thyroid cancer, 18F-labeled 3,4-dihydroxy- sion.
phenylalanine (F-DOPA) is increasingly used in addi-
tion to established imaging techniques. Because of its
broad availability, FDG PET is widely used for cancer 4.2.2 Radioiodine Therapy for Treatment
imaging in almost all known PET sites throughout of Hyperthyroidism and Benign
the world, while the other agents are available at se- Non-toxic Multinodular Goiter
lected PET sites.
Positron emission tomography enables an im- Radioiodine therapy is safe and effective and is the
proved cancer lesion to background ratio resulting most popular treatment option for hyperthyroidism
in higher sensitivity in cancer detection compared in the United States. Elsewhere its use becomes in-
with other nuclear medicine imaging techniques. The creasingly popular. While the treatment of non-toxic
use of FDG PET for detection of cancer is based on nodular goiter was limited to thyroxine (T4)-sup-
the observation of enhanced glycolysis in malignant pressive hormone therapy or thyroidectomy in the
transformed (cancer) cells. It is used as a glucose ana- past, radioiodine therapy is now being considered
log following the principle of competitive substrate as an alternative treatment option. Radioiodine is
kinetics until formation of 18F-labeled FDG-6-phos- administered orally as sodium 131I in a capsule. It is
phate via the hexokinase reaction in cancer cells. The rapidly incorporated into the thyroid. Its beta emis-
latter means in practice, normal blood glucose levels sion causes extensive local thyroid tissue damage. The
are mandatory in order to have optimized conditions aim of the radioiodine therapy is elimination of the
for cancer detection. It should be noted that a less- cause of hyperthyroidism, accepting hypothyroidism
40 Walter Wiesner, Hermann Engel, Wolfgang Steinbrich, Egbert U. Nitzsche and Jan Mueller-Brand

and lifetime thyroxine hormone replacement therapy, into two varieties, carcinomas of the follicular epithe-
and/or decrease of goiter size. Apart from causing hy- lium and carcinoma of the parafollicular or C cells.
pothyroidism, radioiodine therapy is quite safe and The most common thyroid cancer type is papil-
effective. Regarding the side effects of radioiodine lary carcinoma. Papillary cancer usually grows slowly
therapy, in about 1% of treated patients radiation thy- and metastasizes typically into regional lymph nodes,
roiditis may be observed, which is usually adequately where it may remain indolent for many years. How-
treated with non-steroidal antiinflammatory drugs ever, acceleration of disease may occur at any time
for analgesia. Radioiodine therapy is a valid, safe, and in the individual course of the disease. Overall, fol-
effective treatment option, especially for elderly pa- licular carcinoma or follicular elements in papillary
tients in whom surgery is contraindicated. A multi- cancer account for those cases of thyroid carcinoma
cystic goiter with individual cystic lesions exceeding in which significant quantities of radioiodine are con-
2 cm in diameter is not well suited for radioiodine- centrated in situ or in metastases. Less common are
mediated decrease of goiter size. Pregnancy is an ab- the follicular tumors with three different variants that
solute contraindication for radioiodine therapy. differ in their clinical course and abilities to take up
radioiodine. Follicular carcinomas mimic histologi-
cally normal thyroid tissue and predominantly me-
4.2.3 Radioiodine Treatment tastasize into lung and/or bone. Medullary thyroid
of Differentiated Thyroid Cancer cancer does not take up radioiodine and is discussed
separately (see Chapter 11). Anaplastic carcinoma is
For differentiated thyroid cancer, the aims of the ra- histologically undifferentiated, highly malignant, fast
dioiodine therapy are first, postsurgical thyroid rem- growing, and usually afflicts the elderly. It is rapidly
nant ablation, and with that elimination and cure of fatal because of extensive local invasion and it is re-
possible small thyroid cancer remnant(s), and second, fractory to radiation.
therapy of radioiodine-concentrating metastases.
Three rationales exist for ablation of residual thy-
roid tissue with 131I: (1) destruction of any micro- Indications for and Details
scopic foci of disease remaining after surgery, (2) of Radioiodine Therapy
increased specificity of 131I scanning for detection of
recurrent or metastatic disease based on elimination Two indications are generally accepted for 131I ad-
of uptake by residual normal thyroid tissue, and (3) ministration in patients with differentiated thyroid
improved value of measurements of serum thyro- cancer: ablation of presumably normal thyroid tissue
globulin as a tumor marker. that may remain after thyroidectomy, and treatment
Cancer of the thyroid is a rare tumor. Most patients and cure of known residual or metastatic disease.
suffering from thyroid cancer present with a thyroid Radioiodine therapy in form of 131I is the most effec-
nodule (Fig. 4.15), while a few patients present with tive non-surgical treatment for differentiated thyroid
cervical lymphadenopathy or lung, bone, liver, or carcinoma. 131I causes cytotoxicity by the emission of
brain metastases. Thyroid carcinomas are classified short path length (12 mm) beta radiation. 131I up-
take is dependent upon adequate stimulation by TSH,
and is reduced in the presence of stable iodide. There-
fore, whenever radioiodine imaging or treatment are
planned, the patient should avoid all iodine-contain-
ing medications and dietary intake of iodine (foods
allowed are fresh meat, poultry, potatoes, rice, wheat
or rye bread, fresh or frozen vegetables, and fresh or
frozen fruit).
For destruction of any microscopic foci of disease
remaining after surgery, ablation of postoperative
remnant thyroid tissue is recommended for almost
all patients with differentiated thyroid carcinoma
(exception: papillary cancer of 1.0 cm in diameter or
Fig. 4.15 An 123I scan shows a cold nodule in the right lobe of less) and those with extrathyroidal tumor disease (i.e.,
the thyroid. Fine-needle aspiration revealed papillary thyroid direct invasion through the capsule of the gland or lo-
cancer cal and/or regional lymph node metastases). Thyroid
4 Diagnostic Imaging of the Thyroid and Radioiodine Therapy 41

remnant ablation destroys any remaining thyroid of bone loss, atrial fibrillation, and cardiac dysfunc-
tissue in the neck, which may be present even after tion [2224]. Therefore, it seems reasonable to vary
total thyroidectomy. Ablation after primary surgery the dose of thyroxine according to the extent of dis-
is associated with a reduction of about 50% in local ease and the likelihood of recurrence based on clini-
and regional recurrence. In addition, long-term dis- copathologic staging for differentiated thyroid cancer.
ease-specific mortality appears to be reduced in pa- For low-risk and high-risk thyroid cancer patients, we
tients with primary tumors 1.01.5 cm in diameter or recommend target basal TSH levels of 0.10.3 mU/l
greater, multicentric tumors, or soft tissue invasion at and 0.010.05 mU/l, respectively. If either risk factor
diagnosis [1719]. of cardiac or skeletal disease are present, a lower level
The uptake of radioiodine by thyroid tissue is de- of TSH suppression is mandatory. In addition, in pa-
termined by imaging of the gamma radiation that is tients who remain disease free for more than 10 years
emitted by radioiodine. Thyroid remnant imaging after primary therapy the dose may be lowered.
and ablation are performed 46 weeks after surgery External beam radiotherapy may be useful for pa-
in the hypothyroid patient. The serum TSH concen- tients with metastatic disease refractory to radioio-
tration should be at least 25 mU/l before imaging dine or with tumors not concentrating iodine. Results
is performed. As an alternative to thyroid hormone of a recent multicenter study indicate a diminished ac-
withdrawal, injection of recombinant human TSH ceptance of adjuvant external beam radiotherapy for
(rhTSH) on l-thyroxine therapy is available as a use- differentiated thyroid carcinoma [25]. The discussion
ful method to stimulate radioiodine uptake and thy- about the benefit of adjuvant radiation after surgical
roglobulin secretion by neoplastic thyroid follicular resection is controversial. It may be useful in selected
cells. The use of rhTSH has the great advantage of individual cases as a result of interdisciplinary con-
avoiding the unpleasant side effects of hypothyroid- sent of involved specialty representatives. External ra-
ism experienced by most patients undergoing the diotherapy after incomplete surgical resection may be
conventional follow-up strategy. helpful to control local residual tumor and it is used
Treatment of known residual or recurrent and/or for palliation in patients with skeletal metastases, spi-
metastatic disease is performed following the same nal cord compression from vertebral metastases, or
patient preparations as described for ablation. Re- intracranial metastases [26]. Recurrent tumor in the
garding the extent of disease, 5,5507,400 MBq are neck may be diagnosed based upon clinical examina-
administered, dependent on the location of metasta- tion and/or rising serum thyroglobulin concentra-
ses and presence of soft tissue or skeletal metastatic tions and/or diagnostic imaging. The most sensitive
disease. Higher doses may be given to patients pre- technique for detection of local or regional cervical
senting with recurrent disease after previous therapy. tumor recurrence is ultrasound. In addition, iodine
Post-therapy scanning is performed about 7 days after scintigraphy (Fig. 4.16), 99mTc-labeled methoxy-iso-
131I administration for documentation of therapeu- butyl-isonitril (MIBI) scintigraphy (Fig. 4.17), or
tic radioiodine concentration in the target (remnant PET (Fig. 4.18) as a whole body tool for search of
and/or metastatic) thyroid tissue and for screening of metastatic spread may be used. Recent study results
further metastatic lesions. indicate that uptake of FDG in a large volume of tis-
All patients following surgery and radioiodine sue correlated with poor survival. More lesions were
thyroid remnant ablation should receive thyroid hor- detected if thyroxine therapy was discontinued and if
mone supplementation to prevent hypothyroidism the patient was hypothyroid before PET scanning or
and to minimize potential TSH stimulation of tumor recombinant TSH was administered [27,28].
growth. For the latter, the hypothesis is that reduc-
tion of serum TSH concentrations to below normal
lower concentration decreases morbidity and mortal- Follow-up after Radioiodine Treatment
ity in patients with differentiated thyroid carcinoma.
Although not proven, at least one study suggested Although most recurrences of differentiated thyroid
improved relapse-free survival when serum TSH con- cancer occur within the first 5 years after initial treat-
centrations were undetectable during follow-up [20]. ment, recurrences may occur many years or even de-
Results from a multicenter prospective tumor registry cades later and long-term follow-up is warranted. For
suggest that increasing TSH suppression is associated follow-up, the frequency of examinations for the in-
with improved progression-free survival in high-risk dividual patient depends on risk stratification, based
papillary carcinoma patients [21]. However, aggressive on primary complete staging. A low-risk carcinoma
thyroxine therapy has some risks such as acceleration means women aged 1545 years, unifocal, highly
42 Walter Wiesner, Hermann Engel, Wolfgang Steinbrich, Egbert U. Nitzsche and Jan Mueller-Brand

differentiated papillary or follicular cancer, less than target basal TSH level 0.010.05 mU/l. Several fol-
or equal to T2 N0 M0 tumor stage, and target basal low-up schemes are recommended, but none of them
TSH level 0.10.3 mU/l [T1 (<1 cm) usually hemithy- is generally accepted.
roidectomy only, no radioiodine therapy, thyroid At our institution we are practicing the following
hormone (T4) suppression]. High-risk thyroid cancer management:
includes any tumor stage higher than T2 N0 M0 and Completion of primary therapy and confirmation
of successful thyroid remnant ablation (131I scan,
thyroglobulin, cervical ultrasound). Effectiveness
of T3 hormone medication is based on clinical
and laboratory examination, and thyroid hormone
therapy is later switched to T4 hormone.
Follow-up examinations include physical exami-
nation, thyroglobulin, chest X-ray, cervical ultra-
sound, and a 99mTc MIBI scan. In high-risk patients,
this is done annually until 5 years, at 2-year inter-
vals until 10 years, and thereafter at 3-years inter-
Fig. 4.16 An 131I scan demonstrating metastatic spread of vals. Low-risk patients are followed up annually
differentiated thyroid cancer and its ability to concentrate ra- until 2 years, at 2-year intervals until 6 years, and
dioiodine for the purpose of radioiodine therapy. Depicted are subsequently and finally after a 4-year interval.
anterior (left) and posterior (right) views of the body trunk of a
patient with bony metastatic disease from follicular carcinoma. A single negative 131I scintigraphic study after com-
Note, there is normal depiction of the stomach plete ablation has a lower predictive value for relapse-

Fig. 4.17 A 99mTc MIBI scan showing spread of papillary thyroid cancer into a contralateral right cervical lymph node

Fig. 4.18 An FDG PET scan of the body trunk for detection of metastatic spread of papillary thyroid cancer in a case of repeatedly
measured rising serum thyroglobulin level but negative 131I scan, indicating on coronal sections from ventral to dorsal at different
depth levels of the body lymph node and bilateral lung metastatic disease
4 Diagnostic Imaging of the Thyroid and Radioiodine Therapy 43

free survival than do two consecutive annual nega- 10. Tutuncu NB, Erbas T, Bayraktar M, Gedik O (2000) Mul-
tive studies. Annual 131I imaging is recommended by tifocal idiopathic fibrosclerosis manifesting with Riedels
Grigsby et al. for surveillance until two consecutive thyroiditis. Endocr Pract 6:447449
annual negative studies are obtained, after which re- 11. Wiesner W, Engel H, von Schulthess GK, Krestin GP, Bicik
peat imaging at 35 years appears to be satisfactory I (1999) FDG PET-negative liver metastases of a malig-
[29]. nant melanoma and FDG PET-positive Hrthle cell tu-
Side effects of radioiodine therapy are overall mor of the thyroid. Eur Radiol 9:975978
rarely observed. In the short term, radiation thy- 12. Gertner ME, Kebebew E (2004) Multiple endocrine neo-
roiditis, painless neck edema, sialadenitis (promo- plasia type 2.Curr Treat Options Oncol 5:315325
13. Michelow PM, Leiman G (1995) Metastases to the thyroid
tion of salivary flow reduces such risk), nausea, tu-
gland: diagnosis by aspiration cytology. Diagn Cytopathol
mor hemorrhage, or edema may occur, in particular
when high doses are administered. Regarding chronic
14. do Rosario PW, Fagundes TA, Maia FF, Franco AC,
complications, secondary malignancies and infertility
Figueiredo MB, Purisch S (2004) Sonography in the diag-
have been reported, primarily for high-dose radioio- nosis of cervical recurrence in patients with differentiated
dine treatment. Maxon and Smith [30] have reviewed thyroid carcinoma. J Ultrasound Med 23:915920
the literature on leukemia occurring after 131I therapy 15. Rodriguez JM, Reus M, Moreno A, Martinez M, Soria
and found 14 cases from a group of over 2,700 pa- T, Carrasco L, Parrilla P (1997) High-resolution ultra-
tients who received large activities of 131I, which is ten sound associated with aspiration biopsy in the follow-up
times higher than the normal prevalence of leukemia. of patients with differentiated thyroid cancer. Otolaryngol
To minimize the likelihood of leukemia, Beierwaltes Head Neck Surg 117:694697
advocates a 1-year interval between therapies while 16. Simeone JF, Daniels GH, Hall DA, McCarthy K, Kopans
the total cumulative administered activity should not DB, Butch RJ, Mueller PR, Stark DD, Ferrucci JT Jr, Wang
exceed 29.6 GBq [31]. Overall, the relatively low in- CA (1987) Sonography in the follow-up of 100 patients
cidence of radiation-induced malignancies supports with thyroid carcinoma. AJR Am J Roentgenol 148:4549
the benefit/risk ratio in favor of radioiodine therapy. 17. Mazzaferri EL, Jhiang SM (1994) Long-term impact of
initial surgical and medical therapy on papillary and fol-
licular thyroid cancer. Am J Med 97:418428
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ral history, treatment and course of papillary thyroid car-
1. Gritzmann N, Koischwitz D, Rettenbacher T (2000) So- cinoma. J Clin Endocrinol Metab 71:414424
nography of the thyroid and parathyroid glands. Radiol 19. Wong JB, Kaplan MM, Meyer KB, et al (1990) Ablative
Clin North Am 38:11311145 radioiodine therapy for apparently localized thyroid carci-
2. Hegedus L (2001) Thyroid ultrasound. Endocrinol Metab noma: a decision analytic perspective. Endocrinol Metab
Clin North Am 30:339360 Clin North Am 19:741760
3. Solbiati L, Osti V, Cova L, Tonolini M (2001) Ultrasound 20. Samaan NA, Schultz PN, Hickey RC, et al (1992) The re-
of thyroid, parathyroid glands and neck lymph nodes. Eur sults of various modalities of treatment of well differen-
Radiol 11:24112424 tiated thyroid carcinoma: a retrospective review of 1599
4. Baskin MD, Face HJ (1997) Thyroid ultrasonography: a patients. J Clin Endocrinol Metab 75:714720
review. Endocr Pract 3:153157 21. Cooper DS, Specker B, Ho M, et al (1998) Thyrotropin
5. Baldini M, Castagnone D, Rivolta D, et al (1997) Thy- suppression and disease progression in patients with dif-
roid vascularisation by color Doppler ultrasonography in ferentiated thyroid cancer: results from the National Thy-
Graves disease. Changes related to different phases and to roid Cancer Treatment Cooperative Registry. Thyroid
long-term outcome of the disease. Thyroid 7:823828 8:737744
6. Birchall IW, Chow CC, Metreweli C (1990) Ultrasound 22. Ross DS (1994) Hyperthyroidism, thyroid hormone ther-
appearances of de Quervains thyroiditis. Clin Radiol apy and bone. Thyroid 4:319326
41:5759 23. Sawin CT, Geller A, Wolf PA, et al (1994) Low serum thy-
7. Sostre S, Reyes MM (1991) Sonographic diagnosis and rotropin concentrations as a risk factor for atrial fibrilla-
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14:115121 24. Biondi B, Fazio S, Carella C, et al (1994) Control of ad-
8. Papi G, LiVolsi VA (2004) Current concepts on Riedel thy- renergic overactivity by beta blockade improves the
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sociation of the acral type of pustular psoriasis, Sjogrens 78:10281033
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44 Walter Wiesner, Hermann Engel, Wolfgang Steinbrich, Egbert U. Nitzsche and Jan Mueller-Brand

25. Biermann M, Pixberg MK, Schuck A, Heinecke A, Kopcke 28. Chin BB, Patel P, Cohade C, et al (2004) Recombinant hu-
W, Schmid KW, Dralle H, Willich N, Schober O (2003) man thyrotropin stimulation of fluoro-d-glucose positron
Multicenter study differentiated thyroid carcinoma emission tomography uptake in well differentiated thyroid
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noma with radioactive iodine. Semin Nucl Med 8:7994

5 Evaluation of Thyroid Nodules

Michel Procopiou and Christoph A. Meier

Contents and death from thyroid cancer is even less com-

mon with an estimated annual death rate of 0.25 per
5.1 Introduction . . . 45 100,000 in the US population. Moreover, the ever-in-
5.2 Frequency of Thyroid Nodularity . . . 45
creasing discovery of thyroid nodules by high-reso-
5.3 Etiology of Thyroid Nodules and
lution radiological imaging procedures performed
Risk for Malignancy . . . 46
for other indications raises the problem of how inci-
5.4 Pathogenesis of Thyroid Nodularity . . . 47
dentally discovered lesions should be investigated in
5.4.1 Clinical Conditions Predisposing
a cost-effective and safe manner to identify the rare
to the Formation of Nodules and Goiters . . . 47 Iodine Deficiency . . . 47
patient with a clinically significant malignancy. External Radiation . . . 47 In the present chapter the clinical criteria prompt-
5.5 Clinical Presentation of Thyroid Nodules . . . 47 ing the evaluation of thyroid nodules are reviewed,
5.6 Relevance of Clinical Risk Factors for as is the currently recommended diagnostic ap-
Malignancy in Nodular Thyroid Disease . . . 47 proach that principally relies on fine-needle aspira-
5.7 Which Nodules Should be Evaluated tion (FNA) biopsies. The clinical implications of the
for Malignancy? . . . 48 different cytological diagnoses are discussed, with
5.8 Diagnostic Approach to a Thyroid special emphasis on the management of indetermi-
Nodule . . . 49 nate, microfollicular lesions. Finally, the evidence for
5.8.1 Fine-needle Aspiration . . . 50 and against suppressive thyroid hormone therapy for Unsatisfactory Sample . . . 50 benign thyroid nodules and multinodular goiters is Benign Lesion . . . 51 presented, with particular consideration of high-risk Malignant Lesion . . . 51 patients with prior external radiation therapy to the Microfollicular Lesion . . . 51 neck region.
5.8.2 Cystic Lesions . . . 52
5.8.3 Additional Tests . . . 53 Thyroid Scan . . . 53 5.2 Frequency Ultrasonography . . . 53
of Thyroid Nodularity Calcitonin Level . . . 54 Thyroglobulin Levels . . . 55
Thyroid nodules, either solitary or within a mul-
5.9 Treatment and Follow-up of Benign
tinodular gland, are very frequent occurrences. In
Thyroid Nodules . . . 55
autopsy series, 3060% of thyroids are found to har-
5.9.1 Natural History of Nodules and
Role of Repeat FNA . . . 55
bor nodules, with nearly 40% of these nodules being
5.9.2 Role of Levothyroxine (L-T4)
larger than 2 cm (see [15] and references therein).
Suppressive Therapy . . . 56 With modern ultrasonographic techniques detecting
References . . . 57 thyroid nodules of a few millimeters, the frequency
of nodularity was estimated at 1667% in unselected
subjects [98]. From such population studies it be-
comes apparent that thyroid nodules are extremely
frequent in the normal population, and their preva-
5.1 Introduction lence increases with advancing age. Starting at the age
of 20, the prevalence of nodules detected by palpation
Thyroid nodules are very frequent findings and their increases by 1% for each decade of age or by 10% per
prevalence steadily increases with age. However, clin- decade if detected by ultrasound [59]. About half of
ically significant thyroid cancer is a rare malignancy such patients present with a solitary nodule, while the
46 Michel Procopiou and Christoph A. Meier

other half harbors multiple nodules. When palpation lowed by follicular cancers and the much rarer ana-
is used as the mode of detection, nodules are found plastic carcinomas. The non-epithelial cancers such
in 520% of the normal population, most of which as thyroid medullary carcinoma and thyroid lympho-
exceed the size of 1 cm, which is usually the thresh- mas are even less frequent tumors, the latter being as-
old for detection by physical examination. As for the sociated with Hashimotos thyroiditis.
nodules detected by ultrasonography, nearly 50% of The low prevalence of thyroid cancer within pal-
patients with a clinically solitary nodule have in fact a pable nodules contradicts the prevalence of cancers
multinodular gland on echographic examination [13]. in autopsy and surgical series with careful histologi-
The prevalence of thyroid nodules and multinodular cal analysis, describing foci of mostly papillary can-
goiters strongly depends on the iodine intake, and it is cers in up to 17% and 13% of the glands, respectively
lower in iodine-replete areas, such as the USA. How- [15,47,61,74,82,83,97]. If one estimates that 20% of the
ever, even in iodine-sufficient regions the occurrence population have a multinodular thyroid and that 5%
of clinically detectable nodular thyroids or sporadic of these patients harbored a thyroid cancer, the esti-
goiters is observed in up to 47% of the population mated prevalence in the general population would be
[75,101]. around 10 per 1,000 [45,94]. However, the prevalence
of clinically relevant thyroid malignancies is only
0.0250.050 cases per 1,000 persons, strongly sug-
5.3 Etiology of Thyroid Nodules gesting that less than 1 of 200400 histological micro-
and Risk for Malignancy carcinomas leads to clinically relevant disease. Hence,
the histological definition of a thyroid cancer is not
The histological nature of thyroid nodules reveals in always predictive of clinically relevant malignant bio-
the vast majority either a cystic or solid adenoma or a logical behavior of the lesion within the life span of
colloid nodule, both of which represent various stages the patient. This is particularly true for non-palpable
of nodule formation and degeneration within a nodu- thyroid lesions below 1 cm, which are incidentally
lar thyroid gland (Table 5.1). Indeed, 30% of nodules detected by radiological or ultrasonographic proce-
represent a mixture of solid and cystic components, dures for other indications and which harbor cancers
with pure thin-walled cysts being very rare. Graves as frequently as larger nodules [72]. Clinicians should
disease and chronic lymphocytic Hashimotos thy- always keep in mind these fundamental epidemiolog-
roiditis can give rise to nodules, as may subacute de ical figures while trying to exclude cancer in a given
Quervains thyroiditis or an infection. Less than 10% nodule. It has been estimated that among the US pop-
of palpable thyroid nodules are malignant and with ulation, 1018 million persons have palpable nodules,
the increasing use of FNA biopsy for ever smaller le- a number rising to 75125 million persons when ul-
sions, this figure is closer to 5%. The risk of a concom- trasound detection is used [58]. However, only 12,000
itant thyroid cancer within a longstanding multinod- thyroid cancers are diagnosed in the USA, with 1,000
ular gland has been well investigated and is similar to persons dying as a consequence of thyroid cancer per
that in a solitary thyroid nodule, i.e., less than 510% year. As stated by Mazzaferri, looking for aggressive
[8,19,20,33,34,72,99]. Over 80% of the malignancies thyroid cancer in thyroid nodules resembles finding
present in palpable nodules are papillary cancers, fol- a needle in the haystack [58].

Table 5.1 Etiology of thyroid nodules

Benign lesions (9095%) Malignant lesions (510%)
Adenomas (follicular, microfollicular, Hrthle cell neoplasms) Primary thyroid cancers:
Colloid nodule Epithelial cancers: papillary, follicular, anaplastic
Chronic lymphocytic thyroiditis (Hashimoto) Other cancers: medullary thyroid cancer, primary thyroid
lymphoma, other rare cancer types
Rare causes: Metastatic cancer to the thyroid gland:
True epithelial cyst Renal, breast, lung, colon, melanoma, and other cancer types
Infections (bacterial, tuberculosis)
Acute thyroiditis (de Quervains thyroiditis)
Infiltrative (sarcoidosis, amyloidosis, lipomatosis)
5 Evaluation of Thyroid Nodules 47

5.4 Pathogenesis Patients, and particularly women, are most sensitive

of Thyroid Nodularity to external radiation before adolescence, where an
increase in thyroid nodules and cancers is observed
5.4.1 Clinical Conditions Predisposing already at doses of 10 cGy, and which persists for at
to the Formation of Nodules least four decades after the initial exposure [89,90].
and Goiters Nearly 40% of such patients develop nodules with a
maximal incidence 2030 years after irradiation, and Iodine Deficiency over one third of these lesions were found to be ma-
lignant after thyroidectomy [27,87,88].
Iodine deficiency is the most frequent factor contrib-
uting to the development of multinodular goiters, af-
fecting over 1.5 billion persons worldwide, i.e., nearly 5.5 Clinical Presentation
30% of the worlds population in 1990 [23]. In 1990, of Thyroid Nodules
over 650 million people were estimated to be affected
by goiter due to iodine deficiency, which is particu- The size and nodularity of the thyroid gland increases
larly severe and prevalent in central Africa and some over time and the presence of a nodular gland is of-
areas of China. However, efforts by the WHO and ten first detected either by the patients themselves or
private organizations were successful in reducing the by the physician during a routine physical examina-
number of persons with inadequate iodine intake by tion or a radiological examination of the neck. Most
ascertaining a minimal supply of 150 g iodine per patients with nodular goiters are asymptomatic and
day [31]. the medical concerns essentially revolve around three
The pathogenesis of nodular goiter formation has questions: (1) the presence of thyroid dysfunction,
been intensively studied and debated over the past de- (2) the presence of a malignancy, and (3) the likeli-
cades. Classically it was thought that the presence of hood of a progressive increase in size of the nodule
a persistent, although often only marginal, elevation ultimately leading to symptoms. Some patients can
of thyroid-stimulating hormone (thyrotropin, TSH) present with a rapidly enlarging, and sometimes pain-
levels, for example in situations of iodine deficiency, ful, thyroid mass, which may reflect degeneration and
was the prime stimulus leading to thyrocyte prolifera- hemorrhage into a previously undetected adenoma-
tion and the formation of a diffusely enlarged gland tous nodule or cancer, or alternatively may indicate
already during childhood and adolescence [25,30]. the presence of an aggressive malignancy, particularly
Subsequently, nodules appear as the patient ages, anaplastic carcinoma or lymphoma.
finally leading to a multinodular goiter. While the
important role of iodine deficiency and the growth-
promoting contribution of TSH are uncontested, a 5.6 Relevance of Clinical Risk
modified concept has emerged over the past decade, Factors for Malignancy
whereby the thyroid has an inherent propensity to in Nodular Thyroid Disease
form nodules with age, and that this phenomenon is
amplified by the presence of additional factors, such Belfiore et al. examined different risk factors for ma-
as iodine deficiency and elevated TSH levels, further lignancy in a series of 5,637 patients from Sicily (Italy)
promoting thyrocyte proliferation and nodule forma- with cold thyroid nodules [8]. The global rate of non-
tion [24]. medullary thyroid cancer was 4.6% (259 cancers). The
risk of malignancy was greater in males (8.2% ver-
sus 4.2%) but as nodules were much more frequent External Radiation in women (female:male ratio = 8.3), more cancers
were still found among women (female:male ratio =
External radiation to the neck during childhood is the 4). Extreme ages also increased the risk of cancer for
best established environmental risk factor for the de- patients younger than 20 years (6.5% risk) and older
velopment of thyroid cancer [86]. In addition, the in- than 60 (more than 6.6% risk). This finding was par-
creased thyroid cancer incidence in children exposed ticularly striking for those older than 70 years (16.4%
to the fall-out from the Chernobyl accident has shown risk) in relation to an increased rate of anaplastic
that radioiodine is equally carcinogenic, although this cancers. Sex and age interacted giving higher risks
does not appear to be the case for the doses used in the for older men (50% risk). The authors found no risk
diagnosis and treatment of thyroid disorders [69,77]. difference between single nodules and multinodular
48 Michel Procopiou and Christoph A. Meier

glands. These epidemiological risk factors are cer- 5.7 Which Nodules Should be
tainly not sensitive or specific enough to change clini- Evaluated for Malignancy?
cal management when used in a given patient, with
the exception of the combination of old age and male Most experts would agree that palpable solitary nod-
sex. Hamming and colleagues assigned patients on ules above 1 cm should be investigated in euthyroid
clinical grounds into three risk categories (high, mod- patients [34,98]. This limit is justified by the very low
erate, and low risk for malignancy) [41]. The analysis recurrence rate and the virtually absent mortality
was performed in 169 patients with histological con- for differentiated thyroid cancers below 10 mm [60].
firmation of cytological FNA diagnosis with a total of Since the presence of an autonomous nodule, Graves
39 thyroid cancers (23%). Thirty-one patients were in disease, or Hashimotos thyroiditis may result in erro-
the high-risk clinical group with a 71% rate of cancer. neous cytological diagnoses, it is important to rule out
The remaining patients were in the moderate (38%) hyper- or hypothyroidism by measuring a serum TSH
and low (44%) suspicion categories with a similar risk level before proceeding further with the evaluation
of cancer (14% and 11%, respectively). Clinical find- of a nodule. The prevalence of multinodular glands
ings (fixation to adjacent structures, vocal cord pa- in elderly persons from marginally iodine-sufficient
ralysis, and enlarged lymph nodes) were the relevant regions (such as certain parts of Europe) is still con-
criteria to the high-risk category but even when these siderable, and the risk for a malignancy in these pa-
ominous findings were present a final benign diagno- tients without additional risk factors is no higher than
sis was made in 2030% of cases. In conclusion, pa- that observed for a solitary nodule [8,19,20,33,72,99].
tients investigated for nodular thyroid disease rarely Hence, a reasonable approach consists in the evalua-
present with malignant signs but, when they do, they tion of the dominant nodule in a multinodular gland
must be taken into account in evaluating the need for of a euthyroid patient, with the term dominant refer-
surgery or repeated FNA. Single epidemiological risk ring here to either the largest nodule or the one that
factors have low utility in individual patients. A list of has recently increased significantly in size. In elderly
risk factors for malignancy is given in Table 5.2. patients with multinodular goiters without a radia-
tion history before adolescence and without recent
changes in the size of the existing nodules or the ap-
pearance of new lesions, we usually only evaluate nod-
Table 5.2 Clinical risk factors for malignancy in patients with ules above 1.5 cm, while following the evolution clini-
nodular thyroid disease. Adapted from references [8,41] cally. It would be erroneous to assume that the best
History Patient Physical quality of care is delivered by evaluating all thyroid
characteristics examination nodules, including FNA, irrespective of their size and
Thyroid cancer in Age <20 years Firm nodule
their clinical context (multinodular gland, age of the
family history a or patient, radiation history), since the probability for the
MEN type 2 a presence of a cytologically suspicious (i.e., microfol-
licular) lesion is 20% and since most of these patients
Rapid nodule Age >60 years Fixation to
will eventually undergo a thyroidectomy to exclude
growth adjacent neck
the presence of a follicular cancer that is present in
structures a
1020% of all microfollicular lesions. Hence, once the
History of neck Male sex Vocal cord paraly-
decision is made to aspirate a nodule, the patient has
irradiation before sis a
an a priori probability of 1020% for a thyroidectomy,
adolescence a
which is unnecessary in 8090% of the cases! From
Enlarged regional these considerations and the clinical irrelevance of
lymph nodes a most occult papillary microcarcinomas, it can be con-
Nodule diameter cluded that nodules below 1 cm (or <1.5 cm within
>4 cm a a multinodular goiter) should not require further
evaluation in most patients and that these lesions can
When present these factors are probably the best clinical pre- be followed clinically unless the patient presents with
dictors of malignancy specific risk factors for malignancy (such as local or
distant metastases of unknown origin, family history
of thyroid cancer, or irradiation before adolescence).
This strategy applies to thyroid incidentalomas, nod-
ules that are discovered on an imaging study ordered
5 Evaluation of Thyroid Nodules 49

for a non-thyroid disease (usually an ultrasound) or tween clinical follow-up, biopsy, and surgery. Clini-
as part of the evaluation of a clinically solitary appar- cians must not forget in their cancer quest that death
ent thyroid nodule [15]. A new way of finding thyroid from cancer is a rare event and that microscopic can-
incidentalomas has been recently reported in patients cers seldom lead to significant disease [105].
undergoing positron emission tomography (PET) us-
ing the radiotracer fluorodeoxyglucose (FDG). Nor-
mally the thyroid gland is not visualized on whole- 5.8 Diagnostic Approach
body FDG-PET scan but incidental diffuse or focal to a Thyroid Nodule
increased uptakes have been reported in large series
in 0.6% and 1.6% of cases, respectively. Diffuse uptake Classically, thyroid scanning with radioiodine was
is indicative of a benign process (thyroiditis) but focal used to distinguish between benign, hot nodules,
uptake is associated with a significantly increased thy- with further evaluation being reserved for cold le-
roid cancer risk (3050% in those selected for FNA) sions. However, this approach is fraught with various
[91]. This latter uptake pattern may therefore warrant problems: (1) 8085% of the nodules are cold, hence
further investigation depending on the general and requiring further work-up anyway, and, moreover,
oncological condition of the patient. most patients with autonomous hot nodules can also
While the above discussion is appropriate for pa- be identified on the basis of a low TSH serum level;
tients with nodules below 4 cm, it is recommended (2) thyroid scintigraphy may be falsely reassuring for
to operate on non-functioning lesions above this size cold nodules under 2 cm, where the overprojection of
without necessarily performing a prior biopsy. This normal thyroid tissue may mimic the presence of a
approach is justified by the high potential of such functioning nodule; and (3) the use of 99mTc pertech-
nodules to become locally symptomatic and the dif- netate is practical and economical, but it may result
ficulty in confidently excluding a malignancy, present in 38% of cases in the false-positive capture of the
in more than 40% of lesions of this size, by aspiration tracer (see For these reasons and with the
cytology [102]. FNA in such nodules could give a perfection of the technique and interpretation of thy-
higher rate of false-negative cytology potentially due roid cytology, the preferred approach now consists
to sampling issues. of the biopsy of the nodule by FNA (Fig. 5.1). A thy-
Finally, patient preferences must be taken into ac- roid scan is indicated in the small fraction of patients
count, for example when choices must be made be- with a low or low-normal TSH as FNA can safely be

Fig. 5.1 Diagnostic algorithm for the evaluation of thyroid nodules

50 Michel Procopiou and Christoph A. Meier

avoided if the nodule is clearly scintigraphically hot (Table 5.3). Such an approach based on FNA has been
(see Besides the clinical reasons discussed shown to reduce the number of unnecessary thyroid-
above, this algorithm is also more cost-effective, since ectomies while increasing the cancer yield in patients
a minority of the patients (less than 10%) will un- finally submitted to surgery [14,35]. Figure 5.2 gives
dergo both an FNA and a thyroid scan, as compared an overview of cytological diagnosis after FNA and
to 90% when the reverse order is followed. Experience corresponding probabilities of malignant and benign
of the physician performing the FNA and expertise histological diagnoses, which are further detailed be-
of the cytopathologist are crucial in order to obtain low.
proper sampling of the nodule and a correct cytologi-
cal diagnosis. Unsatisfactory Sample

5.8.1 Fine-needle Aspiration First, the sample may be unsatisfactory in its cel-
lularity in 520% of the cases, although no univer-
After exclusion of hypo- or hyperthyroidism by meas- sally accepted criteria exist defining the adequacy of
uring a TSH level, the FNA biopsy is the first and a specimen. Criteria for adequate material vary from
most important diagnostic procedure in the evalua- a minimum of five groups of cells to as many as ten
tion of a thyroid nodule. Aspiration cytology of the groups on each of two slides [14]. The often quoted
thyroid has an overall diagnostic accuracy of over definition of Hamburger requires at least six clusters
95%, with a sensitivity of typically over 95% and a of benign cells on each of two slides prepared from
specificity above 95% even in multinodular glands separate aspirates, for a diagnosis of benign [40]. The
[19,33,35,50,52,53]. Since the technique and inter- rate of inadequate samples is largely dependent on the
pretation of FNA biopsies are described in detail in experience of the physician performing the aspiration
Chapter 6, only a brief summary of the clinically rel- and on the criteria used to judge adequacy, but even
evant conclusions is discussed here. The cytopathol- in the most experienced hands the rate of non-diag-
ogy laboratory should classify the sample into one nostic biopsies is around 5%. Other factors that in-
of four categories, each of which is heterogeneous in crease the rate of unsatisfactory samples are dilution
etiology, but similar in the subsequent management of aspirated thyrocytes (either by blood in vascular-

Table 5.3 Classification of thyroid FNA biopsy results

Clinical relevance Cytology Management
Benign Macrofollicular Clinical follow-up
Malignant Papillary cancer (or other cancers types, such as ana- Surgery (specific management for the anaplastic
plastic carcinoma, medullary carcinoma, lymphoma) carcinoma and thyroid primary lymphoma)
Suspect Microfollicular (= follicular neoplasm) Surgery
Inadequate Insufficient material Repeat FNA

Fig. 5.2 Correlation between FNA cytology and histological diagnosis. Data from references [33,35]
5 Evaluation of Thyroid Nodules 51

ized nodules or by fluid in cystic lesions) or lesions Microfollicular Lesion

technically difficult to biopsy [14]. While a possible
explanation is the presence of a degenerated fibrotic The result of a microfollicular lesion (also called fol-
or colloid nodule, it is important to emphasize that licular neoplasms, or simply suspicious) is reported
samples with insufficient material do not provide re- in 1020% of aspirated thyroid nodules, leaving the
assurance and the procedure needs to be repeated. clinician with the differential diagnosis between a
Indeed, in one surgical series around 10% of oper- follicular adenoma and a follicular cancer, the latter
ated nodules with previous non-diagnostic biopsies being present in less than 1020% of microfollicular
turned out to be cancers [62]. Performing more than lesions [34,37,85]. This cancer rate can even be lower
one aspiration during the first FNA decreases the rate than 10% depending on the cytological criteria used
of unsatisfactory samples [7]. Repeat FNA is worth- to define microfollicular lesions. Since the cytological
while because it will provide adequate sampling in features of aspirates from autonomous benign nodules
5070% of patients [8,33]. may mimic those present in follicular cancers (micro-
follicular lesions), it is important to perform the cy-
tological evaluation of a thyroid nodule only after the Benign Lesion euthyroid state of the patient has been ascertained.
Hence, in hyperthyroid patients with a low TSH a
Around 70% of all aspirates will be interpreted as be- radioiodine scan should be performed and an FNA
ing of a benign macrofollicular nature, reflecting the should only be done if the nodule is scintigraphically
presence of an adenomatous or colloid nodule. Once cold (see It is generally recommended that
the presence of a malignant lesion in a dominant nod- patients with microfollicular lesions should undergo
ule has been ruled out by FNA, such patients should a partial thyroidectomy with intraoperative histology,
be followed clinically. Since the false-negative rate for which will allow the extension of the procedure to a
a malignancy is usually less than 5%, a rebiopsy is not near-total thyroidectomy if vascular or capsular inva-
warranted unless the nodule changes significantly in sion is found, i.e., the diagnosis of a follicular cancer is
size (see 5.9.1). made. However, given the relatively low a priori likeli-
hood for the presence of a malignancy in such lesions
(typically 1020%), this approach should be individu- Malignant Lesion alized, for example in elderly patients with increased
surgical risk or a shortened life expectancy. In such
A reading of the biopsy sample as malignant occurs patients the history of the growth of the nodule, its
in about 5% of the aspirated nodules. A papillary size and the presence of cervical lymph nodes allow a
thyroid cancer is present in the vast majority of these more refined, although subjective, assessment of the
patients and thanks to its specific cytological features risk of malignancy, which should be balanced against
this diagnosis can be made with over 9095% sen- the operative risk. It should also be kept in mind that
sitivity and specificity. Hence, surgery is warranted the careful clinical follow-up of such surgically high-
in such patients without further tests or imaging. In risk patients (for example by ultrasonographical meas-
rare cases, the cytology may suggest the presence of urements of the nodule size after 3, 6, and 12 months
anaplastic cancer, medullary carcinoma, a metastasis, and then every 612 months) should allow the detec-
or a lymphoma. While the false-positive rate for the tion of most, but certainly not all, clinically relevant
diagnosis of papillary cancer of FNA biopsies is typi- malignant lesions, allowing then a reevaluation of the
cally below 5%, the cytological features of aspirates indication for surgery.
from autonomous benign nodules may mimic those The management of patients with microfollicular
present in follicular cancers (microfollicular lesions, lesions currently entailing an unnecessary thyroidec-
see below), emphasizing that the biopsy of nodules tomy in 8090% of the patients might potentially be
in hyperthyroid patients should be avoided. Finally, improved by the advent of novel immunological and
the lymphocytic infiltrates found in Hashimotos thy- molecular markers.
roiditis may erroneously indicate the presence of a While cytology alone is, by definition, incapable of
thyroid lymphoma and hence the latter diagnosis re- distinguishing microfollicular adenomas from follic-
quires careful evaluation by the pathologist using flow ular cancers, with the latter being defined by capsular
cytometry. or vascular invasion, specific surface molecules and
genetic rearrangements have recently been detected
52 Michel Procopiou and Christoph A. Meier

in follicular cancers. For example, the presence of the with a minimal solid aspect in the cyst wall. The find-
adhesion molecules galectin-3 and CD44v6 by im- ing of a cystic component in a thyroid lesions does
munocytochemistry was reported to distinguish ad- not give any information on the potential for malig-
enomas and cancers with up to 95% specificity and nancy of the nodule. The risk is neither increased nor
87% sensitivity [5,32,68]. The use of immunostain- reduced. Consequently, cystic nodules should be as a
ing for galectin-3 and CD44v6 was tested in a large rule managed in the same way as purely solid nodules
multicenter study retrospectively on 1,009 thyroid but a specific approach emphasizing some particu-
tissues and cell blocks and prospectively on 226 fresh larities is given in Fig. 5.3.
cytological samples [6]. In the prospective part of de los Santos and colleagues reported on a retro-
this study, galectin-3 immunostaining had excellent spective series of 221 thyroidectomies performed for
sensitivity (100%) and specificity (98%) allowing dis- nodular diseases [22]. Thirty-two percent (n = 71)
crimination between benign and malignant lesions were cystic lesions and 68% (n = 150) were purely
on preoperative FNA material. CD44v6 had a much solid. Malignancy rates were statistically not different
lower diagnostic accuracy with 35% of benign lesions between these two groups (14% versus 23%). There
showing CD44v6 expression (false-positive results). was no difference in the fluid color from benign and
Although most of the publications report detection malignant lesions, and bloody fluid was seen in about
of galectin-3 in nearly all cases of follicular or papil- 80% of cystic lesions. Among the cystic thyroid nod-
lary carcinomas, some other studies have not repro- ules, only 3 were true cysts and all of the cancers were
duced these enthusiastic results. In one study, five of papillary carcinomas. The fluid should be aspirated
five follicular carcinomas were negative in galectin-3 and evaluated cytologically. Any palpable residue af-
immunochemistry [28]. Another group found that ter evacuation of the liquid component requires an
galectin-3 did not reliably distinguish benign from FNA biopsy of this solid part. Recurring cystic lesions
malignant follicular lesions [63]. Five of 19 follicular should be reaspirated with cytological evaluation.
carcinomas had negative immunostaining for galec- Surgery should be considered after multiple recur-
tin-3 while 23 of 32 benign follicular adenomas where rences because of an increased risk of malignancy
positive [63]. The results where much better for pap- despite benign FNA or if repeated FNA do not reach
illary carcinoma, but this thyroid cancer is usually sufficient material for proper cytological evaluation
readily identified with standard cytology. [1]. One concern with this approach is the number
The rearrangement and fusion of the PAX8 and of inadequate samples, which is higher for cystic
PPAR genes has the potential to become a specific, than purely solid nodules, particularly for large cysts
but apparently not very sensitive, genetic marker for (>3 cm). Recent studies have emphasized the role of
malignancy in thyroidal cytological specimens [48]. ultrasound-guided FNA. In one study, fluid analysis
Other molecular candidates (such as oncofetal fibro- after initial simple aspiration was non-diagnostic in 40
nectin, telomerase, high mobility group 1 protein, of 42 nodules, but the use of ultrasound-guided FNA
and BRAF mutation) require further investigations yielded an adequate sample in 117 of 124 (94.4%) of
[11,18]. cystic nodules (defined as more than 50% of the nod-
In summary, while galectin-3 is a potentially ule filled with fluid) [12]. In this prospective series,
promising marker for the differential diagnosis of mi-
crofollicular lesions, it currently awaits confirmatory
studies for its routine use. Table 5.4 Differential diagnosis of thyroid cystic lesions
Benign Malignant
Adenoma (functioning or Papillary cancer
5.8.2 Cystic Lesions non-functioning)
Rare: true cyst, hydatid cyst Rare: other types of thyroid
Upon aspiration or ultrasound examination, a thyroid
cancer or metastases
nodule may turn out to be a cystic nodule, rather than
a solid one. Pure cysts lined by epithelial cells are very Non-thyroidal (rare)
rare and the vast majority of thyroid cystic lesions Thyroglossal duct cyst
contain a solid part. They result from degeneration (rarely carcinoma)
of a solid lesion, most frequently from a benign ad- Parathyroid cyst
enoma or a papillary cancer (Table 5.4). Roughly 30%
Cystic hygroma
of thyroid nodules present a cystic component rang-
ing from a small area to a predominant cystic part Brachial cleft cyst
5 Evaluation of Thyroid Nodules 53

Fig. 5.3 Specific management algorithm for cystic thyroid nodules

the rate of malignancy was at least 4% (not all patients In patients with nodules <2 cm the overprojection
with inadequate or suspicious findings on FNA were of normally functioning thyroid tissue may hide the
operated on) and cystic nodules represented 25% of presence of a cold nodule. Alternatively, an autono-
all nodules referred for FNA at this institution. How- mous nodule not yet resulting in a suppressed TSH
ever, this high FNA success rate was not confirmed in level may display no enhancement of tracer uptake
a retrospective series from Boston. Even with the use compared to the surrounding follicles (indeterminate
of systematic ultrasound guidance, initial FNA was scan). Only the finding of a clearly hot (hyperfunc-
non-diagnostic in more than 50% of cystic nodules tional) nodule is reassuring and such a nodule does
(nodules with >50% of cystic component) [2]. not need to be biopsied.

5.8.3 Additional Tests Ultrasonography Thyroid Scan The role and use of ultrasonography in the initial
evaluation of nodular thyroids is controversial and its
With the advent of FNA biopsies, the importance of routine use is not universally recommended [64,93].
thyroid scans in the evaluation of nodular thyroids was Certain ultrasonographic features have been associ-
greatly reduced. However, it has a role in patients with ated with malignancy (hypoechogenicity, microcal-
a low or low-normal TSH level, indicating developing cifications, irregular margins, and intranodular vas-
thyroid autonomy and hence the possible presence of cularization) while other findings are suggestive of
a toxic adenoma which is associated with microfol- benignity (coarse calcifications, thin and well-defined
licular cytology. Therefore, such patients should un- halo, regular margin, and low or absent intranodular
dergo a thyroid scan to exclude the presence of a truly flow) [42,72]. However, the echographic criteria and
autonomous thyroid nodule, appearing hot on a 123I their accuracy for determining the benign or malig-
scan, as these nodules are almost never malignant nant nature of a nodule are insufficient even in the
[14]. Since the use of 99mTc pertechnetate results in the opinion of authors who use it systematically [42]. In
false-positive capture of the tracer in 38% of thyroid one study no single echographic sign was predictive
cancers, 123I is the preferred isotope for this examina- for malignancy in patients with non-palpable nod-
tion. 123I is devoid of this problem because it requires ules, although the combination of hypoechogenicity
an intact organification step after trapping [14]. with another ultrasound malignancy sign could be
54 Michel Procopiou and Christoph A. Meier

effective in selecting high-risk nodules for FNA [72]. of a first inadequate sample. However, we are uncon-
The utility and reproducibility of these echographic vinced that the systematic use of thyroid ultrasound
signs should be confirmed in other centers before significantly improves patient care beyond clinical
widespread use. The ultrasound examination adds to management by an expert physician in nodular dis-
the cost of the evaluation of a thyroid nodule with- ease [57]. Thyroid ultrasound might in fact not only
out providing clinically relevant decisional support in add to costs, but also increase patient anxiety with the
most patients with a palpable nodule [76,93,95]. Ad- disclosure of incidental and insignificant findings, a
ditional drawbacks of ultrasound examination are the phenomenon known as labeling.
added costs and most significantly its high operator
Recent studies evaluating the use of ultrasound Calcitonin Level
have reached unexpected conclusions. Papini et al.
evaluated prospectively 494 patients with non-pal- Medullary carcinoma of the thyroid (MTC) is a rare
pable nodules referred for ultrasound examination tumor derived from the neuroendocrine thyroid
and ultrasound-guided FNA [72]. The authors found C cells [66]. Twenty percent of cases occur as heredi-
31 cancers among the 402 patients with adequate tary tumors (MEN type 2A, rarely type 2B or familial
samples (8%) and the incidence was similar in nod- MTC) while the majority of cases are sporadic [92].
ules measuring 810 mm compared with nodules of Fifty percent of sporadic cases present with metastatic
1115 mm. Eleven of these cancers showed extracap- cervical adenopathy at diagnosis and 10-year disease-
sular invasion (36%). While these results might be specific survival is about 50% for patients older than
interpreted as justifying a more aggressive approach 40 years [92]. More than 50% of cases are diagnosed
toward nodules below 10 mm, one has to keep in only after a surgical procedure has been performed to
mind the very low incidence of clinically significant rule out thyroid carcinoma [66]. Except for families
cancers. If the results of this study were extrapolated with inherited tumor syndromes, medullary thyroid
to the whole US population where as many as 50% of cancers are present in less than 0.5% of thyroid nod-
patients have thyroid nodules on ultrasound exami- ules, corresponding to about 5% of all thyroid cancers.
nation, more than 2 million American citizens should In order to detect these sporadic cases earlier and to
be living with an invasive thyroid cancer, while we perform the appropriate surgical intervention, some
know that the true US annual incidence of thyroid groups have advocated screening patients with thy-
cancer and death from thyroid cancer are much lower roid nodular disease with serum calcitonin. Calcito-
(around 12,000 and 1,000 per year, respectively). Pos- nin is secreted by the thyroid C cells and is a sensitive
sible explanations for these findings are: (1) a referral marker of MTC. In one series from France of 1,167
bias in the population examined and (2) that the de- solitary nodules, 16 medullary cancers (1.4%) were
tected cancers, although showing capsular invasion, present, 3 of which were detected by FNA [67]. Nearly
might not have an aggressive clinical behavior [100]. 60% of these medullary cancers were <1 cm in size.
In a study evaluating the usefulness of ultrasonogra- Although only 25% of these medullary cancers were
phy in the management of nodular thyroid disease, detected by cytology, calcitonin levels were elevated in
the authors found that it altered clinical management nearly 90%. This has led to the claim that serum cal-
for 63% of patients (109 of 173), but they compared citonin should be routinely measured in patients with
their echographic findings to the referring physicians thyroid nodules. However, 20 of the 1,151 patients
examination, 61% of them being primary care phy- without a medullary cancer also had elevated serum
sicians [2]. Besides, some of the changes in manage- calcitonin concentrations, resulting in a false-positive
ment would probably not have been judged necessary rate of 59% for this test. A recent prospective series
in other centers. from Italy of 10,864 patients found 44 cases of MTC
In contrast, ultrasonography may be an important with only 3 false-positive tests [26]. This is the lowest
tool in determining the origin of an unclear neck rate of false-positive tests (6.4%) so far published in a
mass, as well as in assisting in the diagnosis of a mul- prospective study. In the series from Vierhapper, the
tinodular gland and the definition of the dominant rate of false-positive tests for basal calcitonin was 81%
nodule(s), which require cytological evaluation [65]. and still 57% after pentagastrin stimulation [104].
Similarly, the ultrasound-guided FNA biopsy of inci- The reasons for these differences are unclear. They
dentally discovered, but non-palpable thyroid nod- might be due to different cut-offs or selection of the
ules above 1 cm is helpful in obtaining a representa- populations screened. Interestingly, Vierhapper et al.
tive specimen and may more generally be considered note that the number of MTC diagnosed by screen-
when a repeated FNA has to be performed because ing during their study was higher than the predicted
5 Evaluation of Thyroid Nodules 55

incidence by their institutions past experience [104]. 45% either decreased or disappeared while only 20%
Systematic screening could therefore diagnose indo- enlarged. FNA was repeated in 116 cases (87%) and
lent forms of MTC earlier (with an apparent ben- showed suspicious findings in 4 patients, but only 1
efit), while really aggressive MTC would still present follicular cancer was confirmed after surgery (plus
at an advanced stage. Given the high probability for two incidental papillary carcinomas discovered in
a false-positive result that would lead to a thyroidec- nodules different from the ones biopsied). Similarly,
tomy despite a reassuring cytological result, as well as 22% of patients in the control groups of trials of levo-
the unknown clinical relevance of sporadic medullary thyroxine-suppressive therapy, had significant reduc-
microcarcinomas, most experts would currently not tion in nodule size without therapy [36]. Alexander
recommend the routine measurement of basal serum and colleagues evaluated 268 patients in a follow-up
calcitonin levels [92]. However, any cytological sus- study with a mean interval of 20 months after the di-
picion for an MTC should prompt an immunocyto- agnosis of benign thyroid nodule based on FNA [3].
logical staining for calcitonin on FNA, which has an Thyroid ultrasound showed an increase in volume
excellent sensitivity and specificity. (volume change 15%) in 39% but only in 4% using
In the event of a patient referred to the surgeon a different criterion (>50% change in maximal diam-
with an elevated calcitonin serum level, the value eter). However, no patient or physician is likely to no-
should be confirmed with a validated assay and refer- tice a 15% or 30% change in the volume of a nodule
ence range. In case of a borderline abnormal result, and these small increases are of no clinical relevance.
a stimulation test with pentagastrin should be used In this series, 61 patients underwent repeated FNA
and the patient evaluated for an alternative cause of a (74 FNA) with only one suspicious result confirmed at
false-positive result, such as renal failure. FNA should surgery as a papillary carcinoma. Grant et al. from the
then be performed with appropriate immunohisto- Mayo Clinic reported follow-up on 680 patients who
chemical staining for calcitonin. However, it should underwent FNA in 1980, the first year this technique
be kept in mind that the calcitonin serum dosage may was used in their institution. Among the 94% of the
result from an occult medullary carcinoma differ- patients for whom information was available 6 years
ent from the nodular lesion that prompted the initial later, only 0.7% of initially benign nodules were dem-
evaluation. onstrated to be malignant [39]. Similarly, Lucas et al.
studied the value of routine repeated FNA in 116 fe-
males with benign nodular disease [55]. All patients Thyroglobulin Levels had a second FNA after a 1-year interval without any
change to a suspicious or malignant finding.
It is important to note that the measurement of thy- In conclusion, data from follow-up series show
roglobulin levels is not helpful for the exclusion of a that 2040% of nodules will show an increase in size
thyroid cancer, since there is substantial overlap be- during follow-up. After a first FNA with benign cytol-
tween thyroglobulin levels in patients with any thy- ogy, even nodules that grow have a very low risk of
roid disorder (particularly multinodular disease) and malignancy (<2%) because of the very high sensitivity
thyroid cancer [21,56,96]. However, in a patient pre- of FNA. In spite of the low predictive value for malig-
senting with metastatic disease of unknown origin nancy of nodule growth after a cytological diagnosis
and a nodular thyroid, the measurement of a thyro- of benignity, a new evaluation should be considered.
globulin level can be a helpful tool in the exclusion Hence, when the clinical suspicion for a malignancy
of a differentiated thyroid cancer as the underlying is high (see Table 5.2 and subsection 5.8.3), such as in
malignancy. patients with otherwise unexplained suspicious cervi-
cal lymph nodes, a history of prior radiation therapy
to the neck during childhood or adolescence, or the
5.9 Treatment and Follow-up presence of a rapidly enlarging nodule or gland, re-
of Benign Thyroid Nodules peat FNA or surgery should be considered even if the
first cytology is reassuring [52]. We do not recom-
5.9.1 Natural History of Nodules and Role mend systematic repeat FNA because of its low yield
of Repeat FNA (<2%) and its potential risk of increasing the rate of
unnecessary thyroidectomies.
In a series of 532 patients found to have benign thy- The follow-up of patients with a history of external
roid nodules after FNA, 134 (25%) could be reevalu- neck irradiation in childhood is conceptually similar,
ated 911 years later [49]. On clinical examination, but it requires the annual palpation and/or ultrasound
around 35% of nodules did not change in size and
56 Michel Procopiou and Christoph A. Meier

examination of the thyroid gland for at least four de- atrial fibrillation [84], and cardiovascular death [73].
cades, even if no nodules are initially present. Moreover, any effect of the treatment disappears when
the treatment is stopped [36,46].
Data are even scarcer for non-toxic multinodular
5.9.2 Role of Levothyroxine (L-T4) goiter, with only three controlled studies being avail-
Suppressive Therapy able [9,54,107]. In the most recent trial, Wesche et
al. compared the efficacy of 131I versus suppressive
Several studies examined the effect of suppressive T4 L-T4 treatment in sporadic non-toxic nodular goiter
therapy on the evolution of solitary nodules, some (57 patients completed follow-up) [107]. Forty-three
demonstrating a lack of efficacy and others showing a percent of the patients in the L-T4 group responded
reduction in the volume of a small fraction of nodules. to therapy with a modest 22% mean decrease in goi-
Some studies were non-randomized or uncontrolled ter size. A significant loss of bone mass density was
trials and varied in methodological issues such as in- observed in this group. Treatment with 131I was more
clusion criteria (truly solitary nodules or multinodu- effective with a 46% goiter reduction in responders
lar goiters, cystic lesions), doses and length of therapy, (97% of the group). However, large doses of 131I are re-
documentation of TSH suppression during therapy, quired (around 50 mCi) leading to long hospital stays
and assessment of the response to therapy. A recent in most countries, depending on their regulatory re-
meta-analysis found 14 randomized controlled tri- quirements. In conclusion, surgery is the therapeutic
als addressing the issue of T4 suppression for solitary option of choice for patients with goiters if they need
thyroid nodules [79]. Nine studies met the selection any treatment. The vast majority of patients with as-
criteria representing a total of 596 patients (mostly ymptomatic goiters can be followed without specific
women, mean age 3648 years old) [4,17,38,51,70,7 treatment [44].
1,78,106,108]. The mean nodule volume or diameter For all these reasons (see Table 5.5), like other ex-
reduction were not statistically significant between perts, we do not advocate L-T4 suppression therapy
the L-T4-treatment group and the control group as for benign nodular thyroid disease [36,44] except for
measured by ultrasound. In five pooled studies, 39 of very particular situations.
180 patients (22%) in the L-T4 group and 18 of 178 Finally, the question of therapy with suppressive,
patients (10%) in the control group had a nodule vol- rather than replacement doses of L-T4 needs to be
ume reduction defined as greater or equal to 50%, but considered, which is particularly relevant since the
the difference did not reach statistical significance. In long-term recurrence rate of nodular goiters is above
six studies reporting the proportion of patients with
nodule growth, increase of nodule volume was ob-
served in 59 of 237 patients in the L-T4 group (25%) Table 5.5 Reasons why L-T4 suppressive therapy is not a use-
and 89 of 234 patients in the control group (38%). ful treatment in benign nodular thyroid disease
This inhibition of nodule growth by TSH suppression Natural history of thyroid nodules shows clinically
in 34% (CI 1449%) of the subjects was statistically detectable growth in a minority of patients (<20%). Most
significant. Another meta-analysis of six trials (five of nodules either shrink spontaneously or do not grow
six included in the Richter et al. paper [79]) also con- significantly in size
cluded [16] that L-T4 suppressive therapy is not effec- Results from prospective studies are contradictory.
tive in decreasing the volume of solitary nodules. Meta-analyses conclude to no or at best to a very modest
According to these meta-analyses, L-T4 suppres- effect of L-T4 suppressive therapy on the size or volume of
sive therapy may be somewhat effective in inhibiting nodule or growth of new nodules
the growth of new or existing nodules and has at best No study addressed the issue of the clinical relevance of
a very modest effect in reducing the size of solitary the treatment on outcomes that matter to the patients
thyroid nodules. However, no study has evaluated (symptoms, reduction in the number of unnecessary
the clinical relevance of this treatment on outcomes thyroidectomies versus osteoporosis and cardiovascular
that matter for the patients (patient satisfaction, im- side effects)
pact on health-related quality of life, reduction in
Studies included mostly middle-aged women (mean age
the number of unnecessary thyroidectomies, costs). 3648 years old) and follow-up was short (usually less
Follow-up in these studies were in general very short than 18 months)
(1218 months) and side effects poorly documented.
Any effect of suppressive therapy regresses when treat-
Indeed, a low TSH has been documented to be asso-
ment is stopped
ciated with an increased risk for osteoporosis [103],
5 Evaluation of Thyroid Nodules 57

40% over 30 years after partial thyroidectomy [80]. 10. Bistrup C, Nielsen JD, Gregersen G, Franch P (1994) Pre-
In randomized trials the suppressive treatment with ventive effect of levothyroxine in patients operated for
thyroxine was generally ineffective, except for a pos- non-toxic goitre: a randomized trial of one hundred pa-
sible benefit in iodine-deficient areas [10,43,80,81]. tients with nine years follow-up. Clin Endocrinol (Oxf)
However, one notable exception may be patients with 40:323327
a nodular thyroid and with a history of external ir- 11. Bojunga J, Zeuzem S (2004) Molecular detection of thyroid
radiation to the neck, where suppressive therapy with cancer: an update. Clin Endocrinol (Oxf) 61:523530
T4 reduced the postoperative recurrence rate 2.5- 12. Braga M, Cavalcanti TC, Collaco LM, Graf H (2001) Ef-
fold after correction for the extent of surgery and sex ficacy of ultrasound-guided fine-needle aspiration biopsy
in the diagnosis of complex thyroid nodules. J Clin Endo-
[29]. When such high-risk patients require surgery
crinol Metab 86:40894091
for benign nodules, a total, rather than partial, thy-
13. Brander A, Viikinkoski P, Nickels J, Kivisaari L (1991)
roidectomy is often the wiser procedure. Apart from
Thyroid gland: US screening in a random adult popula-
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6 Fine-needle Aspiration Cytology of the Thyroid

Anne E. Busseniers and Susan A. Silver

Contents Malignant Lymphoma . . . 74

6.1 Introduction . . . 61 Metastases to the Thyroid . . . 74
6.2 FNA of the Thyroid . . . 62 6.6 FNA of the Thyroid in Children and
6.2.1 Accuracy . . . 62 Adolescents . . . 74
6.2.2 Indications . . . 63 6.7 FNA of the Thyroid in Pregnancy . . . 75
6.2.3 Contraindications . . . 63 6.8 Cytologic Diagnostic Challenges in
6.3 The FNA Procedure for Palpable Lesions . . . 63 FNA of the Thyroid . . . 75
6.3.1 Equipment . . . 63 6.8.1 Cystic Lesion of Thyroid with Scant
6.3.2 Preparation and Examination or Absent Follicular Cells . . . 75
of the Patient . . . 63 6.8.2 Cellular Follicular Lesion . . . 76
6.3.3 FNA with Aspiration Device 6.8.3 Prominent Hrthle Cell Proliferation . . . 76
(Aspiration Technique) . . . 64 6.8.4 Cytologically Atypical Cells . . . 76 Amount of Suction . . . 64 6.8.5 Hrthle Cell Neoplasm Versus Directions of the Needle . . . 64 Papillary Carcinoma . . . 76 Number of Passes . . . 65 6.8.6 Atypical Lymphoid Proliferation . . . 77 Sampling of a Multinodular Gland . . . 65 References . . . 77
6.3.4 Non-aspiration Technique . . . 65
6.3.5 Complications . . . 65
6.3.6 Preparation of the Aspirated Sample . . . 65
6.3.7 Types of Aspirated Material 6.1 Introduction
and Clues to Their Origin . . . 66
6.3.8 The Final Report . . . 66 Thyroid nodules are common in the general popula-
6.4 Cytologic Diagnostic Categories . . . 66 tion and their incidence increases with age. An esti-
6.5 Cytologic Diagnoses . . . 66 mated 40% of the United States population harbors
6.5.1 Approach . . . 66 thyroid nodules, approximately half of which are soli-
6.5.2 Terminology Used tary on physical examination [17,34]. An increasing
in Microscopic Descriptions . . . 67
number of these are found incidentally on imaging
6.5.3 The Unsatisfactory Aspirate . . . 67
studies of the neck (e.g., magnetic resonance imag-
6.5.4 Benign Lesions . . . 69
ing, full-body scan, carotid Doppler) performed for Subacute Granulomatous Thyroiditis
unrelated reasons. Only about 12,000 new thyroid
(de Quervains Thyroiditis) . . . 69
cancers are diagnosed each year in the United States Hashimotos Thyroiditis . . . 69 Riedels Thyroiditis . . . 69
with approximately 1,000 deaths from the disease. Adenomatoid Nodule . . . 70 Many more people, though, have clinically silent thy- Cellular Adenomatoid Nodule . . . 70 roid cancers. The latter represent clinically insignifi-
6.5.5 Indeterminate Neoplasms . . . 70 cant papillary carcinomas found in up to 35% of thy- Follicular Neoplasm . . . 70 roid glands evaluated at autopsy or at surgery [62,91], Hrthle Cell Neoplasm . . . 71 manifest as small subcentimeter-sized nodules [99].
6.5.6 Malignant Neoplasms . . . 72 It would therefore be clinically and fiscally irrespon- Papillary Carcinoma . . . 72 sible to remove all thyroid nodules surgically. Fine- Medullary Carcinoma . . . 73 needle aspiration (FNA) has become the ultimate test, Insular Carcinoma . . . 74 in conjunction with clinical judgment, to triage those Giant and Spindle Cell individuals who will most benefit from surgery.
(Anaplastic) Carcinoma . . . 74 The summary of our experience and practice with
FNA of the thyroid is presented in this chapter. This
62 Anne E. Busseniers and Susan A. Silver

practice includes obtaining a detailed, targeted history the detection of thyroid cancers during neck explora-
from the patient, reviewing relevant imaging studies tion, with a concomitant 50% reduction in the num-
if applicable, doing a targeted physical examination, ber of thyroid surgical procedures performed [51,59].
performing the aspiration procedure, reviewing the Recent publications have focused more on limitations
adequacy of the sample prior to the patient leaving of the FNA technique, namely, inadequate and incon-
the office, rendering a diagnosis, and communicat- clusive samples. For a number of reasons, an accuracy
ing it to the referring physician. The latter is generally rate of 100% has not been achieved and is likely not
accomplished within 24 hours of the procedure. The achievable; as such, histologic evaluation of the surgi-
preliminary pathology results and their implications cally resected lesion remains the gold standard.
are often discussed with the patient at the end of the Reported sensitivity and specificity rates of FNA
consultation, particularly when the diagnosis is be- for the diagnosis of thyroid neoplasia differ widely
nign. We serve as consultants both to our patients and [30]. The latter is primarily due to how these rates
to our clinicians and, therefore, the final cytopathol- are calculated. For example, in some studies, carci-
ogy report often includes a recommendation based nomas and benign neoplasms are evaluated as one
on the sum total of information gleaned from the category [74], indeterminate/suspicious cases are
patients office visit [20]. We concur with Lawrence variably considered [5,11], and not all reports include
and Kaplan [80] that the person obtaining the history, only histologically confirmed cases [22]. Studies us-
performing the physical examination, reviewing per- ing histologically verified cases show mean sensitivity
tinent records, and performing and interpreting the and specificity rates of 77.7% and 85.4%, respectively
FNA is in a unique position to make such a recom- [1,5,68,76,103,112]. Table 6.1 summarizes the sensi-
mendation. tivity, specificity, positive predictive value, negative
predictive value, and accuracy rates published in the
recent literature. Clearly, the wide ranges depicted
6.2 FNA of the Thyroid here are contributed to by wide variability in experi-
ence and training of the aspirator and/or diagnosti-
6.2.1 Accuracy cian. When one keeps sight of the fact that the pur-
pose of thyroid FNA is to triage patients for surgery,
Arriving at an accurate FNA diagnosis involves a sys- the relatively low specificity rates cited in the litera-
tematic chain of events, not all of which are in the con- ture are not as problematic as the reported sensitivity
trol of the aspirator/cytopathologist. A demarcated, rates. The latter, as alluded to elsewhere in this chap-
accessible target must be identified. The composition ter, is largely a function of interpretative and sampling
of the nodule must be amenable to penetration by a errors.
thin needle; for example, densely fibrotic and calci- Although the yield of obtaining a malignant diag-
fied lesions generally do not yield cells. The size of the nosis on repeat FNA in the follow-up of a presum-
nodule must be within a certain range to allow rep- ably benign thyroid nodule may be low, rebiopsy re-
resentative sampling; specifically, very small nodules portedly reduces the rate of false-negative diagnoses
may be missed by aspiration and very large nodules from a mean of 5.2% to less than 1.3% [29,42]. The
may harbor an unsampled malignancy. Proper tech- routine performance of repeat FNA in the follow-up
nique must be used to obtain an adequate sample. of patients with benign nodular thyroid disease with
Proper preparation of the sample is necessary to min- or without any clinical changes is, however, of limited
imize artifacts. Accurate interpretation requires an value [44]. Clinical factors rather than repeat FNA
experienced cytopathologist. The final diagnosis must
be communicated clearly, using consistent terminol-
ogy, to ensure proper treatment. A deficiency in any Table 6.1 Statistical parameters of FNA of the thyroid [1, 5, 22,
link in the chain may result in an inaccurate diagno- 68, 73, 76, 103, 112, 116, 121]
sis, with sampling and interpretative errors account- Range
ing for the majority of such cases [41,122]. Sensitivity 38100%
The early literature on FNA of the thyroid focused
Specificity 6798.2%
primarily on what the procedure could achieve,
namely, providing a sensitive and cost-effective tool Positive predictive value 3499%
for the detection of malignancy [59]. With refined di- Negative predictive value 66.3100%
agnostic and technical acumen, the current success of Accuracy 7294.4%
thyroid FNA has accomplished a twofold increase in
6 Fine-needle Aspiration Cytology of the Thyroid 63

may hold precedence in surgical management of pa- located in the posterior aspect of a lobe, one should
tients with benign nodular thyroid disease [83,94]. be able to detect and aspirate nodules as small as
As the study of thyroid disease at the molecular 45 mm, without the added expense of ultrasound
level evolves, its application to FNA samples will un- guidance.
doubtedly continue to refine the triaging of patients
for surgery. Currently, these methods are not appli-
cable to everyday practice. 6.3.1 Equipment

The following equipment is recommended: 10-cc sy-

6.2.2 Indications ringe holder; 10-cc syringes; 23- and 25-gauge nee-
dles, short and long; alcohol pads; gauze; glass slides
There are numerous diagnostic procedures available with frosted end; grease pencil; Xylocaine gel and/or
to aid in rendering a diagnosis of a thyroid lesion. If ice pack; hair dryer; liquid medium (e.g., Cytolyte) for
these procedures are not used rationally, it will un- needle rinses; rapid stain (e.g., Diff-Quik stain, rapid
doubtedly lead to an unjustifiable increase in cost H&E); microscope (Fig. 6.1).
with little practical gain [103]. The utilization of FNA
varies considerably among experienced surgeons and
on different continents. Chen et al. [32] recently com- 6.3.2 Preparation and Examination
pared the utilization of FNA in a center in the United of the Patient
Kingdom to one in the United States. FNA was more
commonly employed in the US (84%) than in the UK A properly informed patient is less anxious and will
(52%). In a retrospective analysis of all thyroid carci- more readily tolerate multiple passes without the use
nomas using the Netherlands Pathology Database, it of a local anesthetic (see further on). For this reason,
was determined that only 66% of patients were ana- we allow ample time to explain each step of the pro-
lyzed using FNA prior to surgery [55]. cedure in detail and answer any questions the patient
Rational indications for performing FNA of the may have.
thyroid in the United States include the initial diag- Skillful palpation is a critical step in ensuring that
nostic test of a solitary cold nodule, a dominant new the material is aspirated from the appropriate area.
or enlarging cold nodule in a gland showing multi- It takes practice and patience and, in our opinion, is
nodularity, thyroiditis, clinically inoperable carci- of paramount importance in obtaining an adequate
noma, and metastatic disease to the thyroid. In ad- and representative sample. We initially examine the
dition, it may provide psychologic reassurance of patient in an upright seated position, with shoulders
benign disease and relieve neck pain caused by sud- down and neck muscles relaxed. Often, the nodule
den enlargement of a cyst. will be visible when the patient swallows, especially
if he or she is not overweight. The lump appears
as an asymmetric shadow that moves up and down
6.2.3 Contraindications when the patient is talking and/or swallowing. Nod-
ules as small as 5 mm may be visible when located
There are no specific contraindications to the proce- in the isthmus or anterior aspect of either lobe. The
dure. The needles are sufficiently thin (23 gauge or
smaller) that the procedure can be performed safely
on patients who are anticoagulated. In patients with
mitral valve prolapse, prophylactic antibiotic therapy
is not indicated.

6.3 The FNA Procedure

for Palpable Lesions
The reader is referred to a detailed description of the Fig. 6.1 Basic equipment used for FNA. Alcohol pads, gauze,
procedure as it pertains to palpable thyroid nodules syringe holder, 10-cc syringe, 25-gauge (5/8 and 1 inch in
in a chapter by Busseniers [19]. With practice and in- length) needle, 23-gauge (1 and 1 inch in length) needle, and
creasing competency, and provided the target is not glass slides
64 Anne E. Busseniers and Susan A. Silver

patient is then asked to lie back and a pillow is placed muscle. The placement of the needle is easily guided
under his or her shoulders to hyperextend the neck. using the thumb of the other hand (Fig. 6.2a). We do
The chin, however, does not have to be lifted exces- not recommend lifting the lump between index finger
sively since this may stretch the skin at the base of the and thumb and inserting the needle laterally through
neck to such an extent that the nodule is more dif- the sternocleidomastoid muscle. Once inserted, the
ficult to feel. We keep the table at a mild upward in- needle is moved rapidly back and forth in the same
cline to diminish vertigo. When the nodule is located plane as its insertion, while applying minimal or no
in the lateral or posterior aspect of the lobe, we have suction. This may be done in only one direction or
found it useful to have an assistant push down on the in a tight circular fashion, with the beveled edge of
contralateral lobe. This will often result in the nodule the needle used as a small cutting device to dislodge
assuming a more superficial location, facilitating the cells and tissue fragments. Material will quickly ap-
insertion of the needle. pear in the needle hub. If the contents are noted to
We do not advocate injection of a local anesthetic. be bloody, suction should be released immediately
It not only results in an additional needle stick, but, in and the needle withdrawn. Pressure is then applied at
our experience, the actual injection of the anesthetic the puncture site. The entire procedure lasts approxi-
is painful, produces a secondary lump overlying the mately 1015 seconds.
one to be sampled, and makes insertion of the needle
at the proper depth more difficult. Furthermore, if the
anesthetic becomes admixed with the aspirated sam- Amount of Suction
ple, it may distort the cells due to osmosis, rendering
cytologic interpretation difficult. For a particularly The thyroid gland is vascular and so are the major-
anxious patient, a topical gel or a small ice pack may ity of lesions occurring in it (notable exceptions are
be applied over the site to be aspirated. inflammatory conditions and cysts composed of col-
loid). Therefore, one must be attentive to applying
suction gradually, and only when indicated, in order
6.3.3 FNA with Aspiration Device to prevent a sudden rupture of capillaries resulting
(Aspiration Technique) in a sample diluted by blood. If one encounters resis-
tance to the insertion of the needle and little material
After definitively defining the nodule by palpation, appears in the needle hub after a few seconds, one is
the aspirators middle and ring fingers of one hand are most likely dealing with a thyroiditis, a papillary can-
placed at the superior and inferior edge of the lump, cer, or some other type of sclerotic lesion. In this in-
and the patient is asked to swallow. The latter is use- stance, gradual suction may be applied, which usually
ful in confirming the location of the nodule and also does not require more than 35 cc of pressure.
reduces the likelihood of the patient swallowing dur-
ing the procedure, which could result in a tear in the
thyroid capsule. Directions of the Needle
The aspiration site is cleaned with alcohol and dried
prior to insertion of the needle. The needle is then in- It is best to maintain the needle in one direction while
serted into the center of the lump, perpendicular to obtaining a sample. It is, however, our practice to use
the skin and just medial to the sternocleidomastoid small circular movements as explained above. With

Fig. 6.2 Technique. a Aspiration tech-

nique. Second and third fingers of one
hand immobilize the lump while the
thumb guides the needle into the lesion,
perpendicular to the skin. b Non-
aspiration technique. The plunger is
removed from the syringe, the lesion is
immobilized with the third and fourth
fingers of one hand, while the other
hand holds the syringe as one would
grip a pencil
6 Fine-needle Aspiration Cytology of the Thyroid 65

increasing experience, nodules may be sampled mul- greater proximity to the nodule. It allows for increased
tidirectionally, with redirection of the needle under- precision when aspirating very small nodules (under
taken when the needle tip is just beneath the surface 5 mm), and it is also less threatening to patients.
of the lesion. If one knows that the lesion is at least partially cys-
tic, we recommend using the aspiration technique to
take the first sample. Fluid from large cysts can easily Number of Passes be removed. The non-aspiration technique may then
be performed on any remaining solid component of
We usually perform one aspirate per palpable cen- the nodule.
timeter of the lesion, ensuring that each pass is per-
formed in a different area. For a 3-cm nodule, for
example, we obtain samples from the upper, middle, 6.3.5 Complications
and lower aspects of the lesion. Larger nodules may
require more samples to reduce the possibility of a The following complications are possible: local in-
false-negative result due to sampling error. fection, hematoma, localized pain, and vasovagal
episodes. In our experience and that of others, these
complications are exceedingly rare [10]. We encour- Sampling of a Multinodular Gland age our patients to resume their normal activities fol-
lowing the procedure, and recommend the use of an
Careful evaluation of the multinodular thyroid is in- ice pack or a non-steroidal anti-inflammatory drug to
dicated, as the presence of one pathologic process by alleviate any local discomfort.
no means excludes the possibility of a second con-
current pathologic entity. In one series of 1,330 cases
involving the FNA of two or more palpable nodules, 6.3.6 Preparation of the Aspirated Sample
two different pathologic diagnoses were rendered in
1% of cases [124]. Sample preparation varies considerably among labo-
Multinodular thyroid disease carries a risk of ma- ratories, and is largely dependent on the experience
lignancy in the range of 513.7%, comparable to that and preferences of the pathologists who interpret the
which exists for solitary thyroid nodules [49,117]. FNA material. An otherwise adequate sample may
Many of these malignancies represent occult carci- be wasted if the material is not smeared or handled
nomas, usually papillary carcinoma, which by con- properly. The importance of having properly pre-
vention are smaller than 1015 mm. Of note, occult pared smears consisting of a thin, even layer of mate-
carcinomas account for up to 60% of all cases of pap- rial cannot be overemphasized.
illary carcinoma [24]. In our laboratory we prepare, on average, three to
six smears per pass, and rinse the remainder of the
material in Cytolyte for preparation of thin-layer
6.3.4 Non-aspiration Technique (ThinPrep; Cytyc, Marlborough, MA) slides. If tis-
sue fragments are visible floating in the fluid, a cell
When using the non-aspiration technique, a syringe block is prepared. To prepare the smears, small drops
holder is not required. The plunger is removed from of material are placed in the middle of one edge of the
the syringe to which the needle is attached. The lump long axis of a slide. The edge of another slide is used to
is immobilized with one hand, in the same fashion as spread the material evenly across the slide (Fig. 6.3a).
described earlier. The hand used to perform the pro- If the material is highly viscous or bloody, an addi-
cedure holds the syringe at its base close to the needle tional slide may be placed on top of the drop of mate-
hub, much like holding a pen or pencil (Fig. 6.2b). The rial to facilitate the gentle spreading of the material
remainder of the procedure is similar to the aspira- across the slide (Fig. 6.3b).
tion technique. Once material is visible in the needle Depending largely on the preferences of the cytopa-
hub, the needle is withdrawn and pressure is applied thologist, the cytologic smears may then be air-dried
at the puncture site. The plunger is then placed back and subsequently stained using Diff-Quik, or alterna-
into the syringe and used to expel small drops of ma- tively, alcohol-fixed and stained with Papanicolaou or
terial onto the slides. hematoxylin and eosin stains. Some laboratories pre-
The greatest advantage of the non-aspiration tech- pare both air-dried and alcohol-fixed smears. Fixa-
nique is that it allows the aspirator better control with tion must be immediate if the slides are to be alcohol-
66 Anne E. Busseniers and Susan A. Silver

Fig. 6.3 Slide preparation. a A small drop of aspirated material is placed at the edge of the slide, while the edge of another slide or
coverglass is used to drag the material along to spread it evenly. b If the material is highly viscous or bloody, an additional slide may
be placed on top of the drop of material to facilitate gentle spreading of the material across the slide

fixed. This is necessary to prevent air-drying artifact number of passes performed, type of sample ob-
which may result in an inconclusive diagnosis. tained (hemorrhagic, amount of cyst fluid if any),
number of smears prepared, needle rinse prepara-
tion, and types of any ancillary tests performed
6.3.7 Types of Aspirated Material Findings of on-site evaluation for specimen ad-
and Clues to Their Origin equacy
Microscopic description
Colloid: Colloid appears viscous, pale yellow, and Final diagnosis
shiny when smeared on slides. Care must be taken so Recommendations
that the material does not wash off the slide during
slide preparation.
Cyst fluid: The fluid varies from straw-colored to 6.4 Cytologic Diagnostic Categories
pale or dark green/brown to a cloudy dark-brown.
Dry tap: This occurs when no material appears in Four diagnostic categories are traditionally used to
the needle hub after a few seconds of aspiration. It classify FNA specimens: benign, malignant, suspi-
generally indicates placement of the needle into soft cious/indeterminate, and unsatisfactory (Table 6.2).
tissue/skeletal muscle of the neck, and is associated Percentages of each of these categories may vary
with acute discomfort. A dry tap may also indicate widely for a given laboratory depending upon a num-
fibrosis within the nodule. ber of factors including the patient population, the ex-
Blood: Blood appears immediately upon inser- perience and skill of the aspirator, and the experience
tion of the needle due to sampling a highly vascular and skill of the pathologist interpreting the sample.
lesion or puncturing a vessel. The aspiration should
be stopped immediately and pressure applied to the
puncture site. The procedure may be repeated with a 6.5 Cytologic Diagnoses
smaller gauge needle and with the patient in an up-
right seated position. 6.5.1 Approach

The best approach is to evaluate each aspirate smear

6.3.8 The Final Report in a consistent fashion for four basic components: (1)

A complete final report typically includes:

Patient demographics Table 6.2 Distribution of cytologic diagnostic categories [20,
Clinical history: signs and symptoms associated 40, 110, 116]
with thyroid disease and their duration, ultrasound Literature range Busseniers
and uptake scan findings, family history of thyroid Benign 2275% 82.5%
disease, history of exposure to irradiation
Malignant 1032% 3.5%
Physical examination: location and size of
nodule(s), status of cervical lymph nodes Suspicious/indeterminate 1542% 13%
Procedure: size of needles used, aspiration mode Unsatisfactory 543.1% 1%
(aspiration versus non-aspiration technique),
6 Fine-needle Aspiration Cytology of the Thyroid 67

smear background, (2) cellularity, (3) architectural Microfollicles: Follicular epithelial cells arranged in
patterns, and (4) cellular detail. a small circular cluster with lumina which may or may
Our approach is to first scan the background of not contain colloid. When seen three-dimensionally,
the smears at low power for the presence of blood, the circular arrangement is still prominent but, un-
colloid, thin cystic fluid, granular material, inflam- like spherules, the nuclei show marked overlap and
matory cells, and a tumor cell diathesis. Once the the borders are irregular (Fig. 6.7).
background is assessed, the cellularity and composi- Oxyphilic cells: Follicular epithelial cells with abun-
tion of the cells present are evaluated. These cells may dant, finely granular cytoplasm. The cytoplasm of
include follicular epithelial cells including those with these cells contain numerous mitochondria which
Hrthle cell change, squamous metaplastic cells, lym- account for the granularity seen by light microscopy
phocytes, and histiocytes. Note is made of any atypi- (Fig. 6.8).
cal cells, and cells present that are not typically seen Psammoma bodies: Round calcified structures with
in primary lesions of the thyroid. The dimension of well-demarcated concentric lamellations (Fig. 6.9).
each cellular component is evaluated relative to the Sheets: Monolayers of follicular epithelial cells with
standard red blood cell; with respect to the follicular delicate cytoplasm, ill-defined cytoplasmic borders,
cell population, the degree of nuclear monotony is and evenly spaced nuclei arranged in a so-called hon-
also noted. Malignant cytologic features are assessed eycomb fashion (Fig. 6.10).
as well. As part of the smear evaluation, architectural Spherules: Three-dimensional representation of
patterns assumed by the cells are noted. Finally, any non-neoplastic thyroid follicles. They appear as round
specific cellular features such as the presence of in- to ovoid cellular structures, with smooth contours
tracytoplasmic nuclear pseudoinclusions and nuclear and evenly spaced, round and regular nuclei. Colloid
grooves are noted. may be seen within them (Fig. 6.11).
Tubules: Follicular cells arranged in parallel arrays
(Fig. 6.12).
6.5.2 Terminology Used
in Microscopic Descriptions
6.5.3 The Unsatisfactory Aspirate
Acinar structures or rosettes: Follicular epithelial cells
arranged in a circular two-dimensional fashion with- Unsatisfactory aspirates include samples containing:
out definite central lumen formation. They probably Blood only
represent tubules (see further on) in cross-section Hemodiluted samples with a paucity of thyroid
(Fig. 6.4). epithelial cells
Fire flares: Rounded empty spaces bordered by cy- Thyroid follicular epithelial cells entrapped in a
toplasm at the periphery of a sheet of follicular epi- blood clot
thelial cells (Fig. 6.5). Minimal thyroid material, such as scant colloid
Intranuclear pseudoinclusion: Invagination of the and rare follicular cells
cytoplasm into the nucleus which creates the illusion Cyst contents with a scanty follicular epithelial cell
of an empty hole in the nucleus (Fig. 6.6). component

Fig. 6.4 Acinar structures or rosettes. Fig. 6.5 Fire flares. Rounded empty spa- Fig. 6.6 Intranuclear pseudoinclusion.
Follicular epithelial cells are arranged ces bordered by cytoplasm at the periph- The inclusion occupies at least one third
in a small circular fashion without defi- ery of a sheet of follicular epithelial cells of the nuclear surface, has a dense rim of
nite central lumen formation (Diff-Quik (Diff-Quik stain) chromatin, and the same hue as the cyto-
stain) plasm (Diff-Quik stain)
68 Anne E. Busseniers and Susan A. Silver

Fig. 6.7 Microfollicles. Follicular epithe- Fig. 6.8 Sheet of oxyphilic cells (left of Fig. 6.9 Psammoma body shown at high
lial cell nuclei are relatively monotonous center) as seen in adenomatoid nodule, magnification to illustrate the concentric
in size, and arranged in small spherical admixed with follicular epithelial cells calcific lamellations (Diff-Quik stain)
structures with nuclear overlap, scalloped showing small, regular nuclei. Note the
edges, and little cytoplasm (Diff-Quik prominent granularity of the oxyphilic
stain) cell cytoplasm (Diff-Quik stain)

Fig. 6.10 Sheets of follicular epithelial Fig. 6.11 Spherules of varying sizes as Fig. 6.12 Tubules as seen in a follicular
cells. Note the delicate cytoplasm with seen in adenomatoid nodule and cellu- neoplasm. The follicular epithelial cells
paravacuolar granules, ill-defined cyto- lar adenomatoid nodule. The follicular are arranged in longitudinal, parallel ar-
plasmic borders, and evenly spaced nuclei epithelial cells have delicate cytoplasm, rays. Note the thick, inspissated colloid
within these sheets. The nuclear size is and evenly spaced nuclei. The edge of the located centrally, and nuclear enlarge-
predictable and approximates the size of a spherules is smooth; some internal colloid ment with nuclear rim irregularity (Diff-
red blood cell (Diff-Quik stain) is also noted (Diff-Quik stain) Quik stain)

Only material of non-thyroid origin (e.g., skeletal [105]. In one study, 44% of nodules resected follow-
muscle) ing an FNA classified as unsatisfactory proved to be
neoplastic, 50% of which were malignant [18]. Subse-
There exist no specific criteria for classifying a thyroid quent studies have reported malignancies in 3751%
aspirate as satisfactory. Some authors have suggested following an initially non-diagnostic FNA [13,33].
using a minimal number of follicular epithelial cells It is generally accepted that on-site evaluation of
present on the smears [8]. It is our position, however, the specimen for adequacy, prior to discharging the
that if so few cells are present, the sample is likely to patient, decreases the unsatisfactory rate. However,
be unsatisfactory. On the other hand, a diagnosis of it should be noted that obtaining an adequate sample
papillary carcinoma, for example, can be rendered on for cytologic interpretation is size-dependent. Carpi
just a few groups of cells, if all cytologic criteria are et al. [26] reported an improved FNA adequacy rate
met. from 64% to 87% with increase in mean nodule size
Unsatisfactory samples should not be construed from 0.7 to 1.1 cm. Suggestions for minimizing the
as benign. Likewise, microscopic descriptions in an number of unsatisfactory samples include selecting
FNA report should be interpreted with caution; a re- individuals to aspirate and interpret samples who are
port stating no malignant cells present is worthless qualified and maintain expertise [116].
if the microscopy describes a paucicellular sample. If
there is a clinical or radiologic indication to aspirate a
nodule and the FNA is unsatisfactory, repeat FNA will
yield adequate material in at least 50% of these cases
6 Fine-needle Aspiration Cytology of the Thyroid 69

6.5.4 Benign Lesions consistency. However, up to 25% of aspirated cases of

chronic thyroiditis present as a clinically solitary nod- Subacute Granulomatous Thyroiditis ule [48]. Although the gland is usually not tender on
(de Quervains Thyroiditis) palpation, painful Hashimotos thyroiditis has been
reported [78].
Although the diagnosis is typically made clinically, The classic smear of Hashimotos thyroiditis
some patients present with unilateral enlargement of (Fig. 6.14a,b) has an admixture of follicular cells,
the gland or a solitary palpable nodule that is usually oxyphilic cells, and lymphoid cells including small,
hard in consistency and not necessarily painful to pal- mature lymphocytes, follicular center cells, and
pation. plasma cells [101]. Lymphocytes being fragile, may be
The smears may be highly cellular with bare crushed, appearing as a tangle of threads. Germinal
follicular epithelial nuclei and small groups and centers may be seen as well as histiocytes and mul-
sheets of follicular epithelial cells exhibiting small, tinucleated giant cells. The latter usually contain less
regular nuclei, some with degenerative change and than 1012 nuclei. The follicular cells and oxyphilic
others with reactive features. There are abundant (Hrthle) cells are arranged in sheets, groups, and
histiocytes, aggregates of epithelioid histiocytes acinar structures. Microfollicles may also be seen. The
(granulomas), and multinucleated giant cells, some amount of colloid in the smears is moderate to scant.
with engulfed colloid [56,67]. These multinucleated The diagnosis of chronic lymphocytic (Hashimotos)
cells may be quite large and composed of 1030 thyroiditis rests upon finding a combination of fol-
oval-shaped nuclei. Inflammatory cells including licular epithelial cells with oxyphilic cell change, and
mature lymphocytes and occasional neutrophils lymphoid cells including plasma cells.
may also be present. Colloid is usually abundant and
fragmented, and, along with the inflammatory cells,
creates a background of granularity and cell debris Riedels Thyroiditis
(Fig. 6.13a,b) [50].
The thyroid gland is hard and often small on palpa-
tion. Hashimotos Thyroiditis The smears are generally paucicellular and notable
for fragments of fibrous tissue with bland spindle-
On palpation, the thyroid gland is generally mod- shaped cells and myofibroblasts [63]. Follicular epi-
erately enlarged with a nodular surface and a meaty thelial cells are scanty. Hrthle cells and lymphoid

Fig. 6.13 Subacute granulomatous

thyroiditis. a Group of loosely cohesive
spindle-shaped cells in a background of
inflammatory debris. b Multinucleated
giant cells on the left. The background
shows dense colloid (Diff-Quik stain)

Fig. 6.14 Chronic lymphocytic

(Hashimotos) thyroiditis. a Pleomorphic
population of lymphoid cells includes
small, mature lymphocytes, a plasma cell,
and follicular center cells. A lymphoid
tangle is present at 12 oclock. b Oxyphilic
epithelial cells admixed with lymphoid
cells (Diff-Quik stain)
70 Anne E. Busseniers and Susan A. Silver

follicular center cells are not conspicuous. The FNA is overlap or may show lack of cohesiveness. Tissue
often deemed unsatisfactory [3]. fragments may be evident. Microfollicles usually are
absent. Cytoplasm is abundant, often delicate, frayed,
and pale blue to gray. The follicular epithelial cell nu- Adenomatoid Nodule clei may show variability in size, up to two to three
times the size of red blood cells. Cytoplasmic fire
The nodule is non-tender and soft to rubbery on pal- flares are a common finding [21].
The smears show abundant colloid, either dense
or watery. Colloid is best appreciated on air-dried 6.5.5 Indeterminate Neoplasms
direct smears, with the classic cracking artifact or
in a mosaic/flowery pattern (Fig. 6.15). Colloid may Follicular Neoplasm
be difficult to appreciate on slides prepared from liq-
uid-based medium, where it appears as fragments An inherent limitation of thyroid FNA is its inabil-
of paper-thin, transparent, pale gray-blue material. ity to distinguish follicular adenoma from follicular
When aspirated by an experienced individual, the carcinoma. The reason for this limitation is that the
smears may be highly cellular. Follicular epithelial diagnostic distinction between follicular adenoma
cells are arranged in sheets, small groups resembling and carcinoma is based on the presence or absence of
clusters of grapes, and in spherules of variable sizes, thyroid capsular and/or vascular invasion by the neo-
individually or in tissue fragments (Figs. 6.10, 6.11). plastic cells. This determination requires evaluation
Bare follicular cell nuclei may be present in the back- of the resected neoplastic tissue. The more important
ground (Fig. 6.15). The follicular cell nuclei are small, distinction to make as a cytopathologist is between a
approximating the size of red blood cells, and have non-neoplastic adenomatoid nodule and a follicular
thin, transparent cytoplasm. An admixture of spin- neoplasm.
dle-shaped cells, histiocytes, and follicular cells with A lesion with an FNA diagnosis of follicular neo-
oxyphilic (Hrthle) cell change are commonly seen in plasm has a high probability (8095%) of represent-
the background [21]. ing a follicular neoplasm at surgery, but overall,
only 2024% of these represent follicular carcinoma
[4,15,27,46,48,52,53,58,64,74,75,81,88,114]. A higher Cellular Adenomatoid Nodule incidence of malignancy is found in men, in nodules
larger than 3 cm, and in patients over age 40; these
On palpation, the lesion may seem harder or more features may be useful in planning and triaging pa-
rubbery than the ordinary adenomatoid nodule be- tients for surgery [12]. Similarly, nodules that are hard
cause of a predominance of follicular epithelial cells to palpation or that are solitary and hypoechoic may
relative to the amount of colloid. help define a subset of patients with an FNA diagno-
The smears are often described as cellular, consist- sis of follicular neoplasm who are at increased risk of
ing of follicular epithelial cells arranged in spherules, malignancy [102]. Some studies, however, have not
sheets, groups, rosettes, and tubules. The cells may shown age and gender to correlate with malignancy
in follicular neoplasms [6].
Smears prepared from FNAs of follicular adenoma
and follicular carcinoma are strikingly similar, as a
result of overlapping histologic appearances between
these two entities. Indeed, the follicular cells compris-
ing follicular adenoma and carcinoma are indistin-
guishable cytologically.
Smears prepared from the FNA of a follicular
neoplasm generally fall into three categories: (1) ex-
tremely cellular with scant colloid; (2) hemorrhagic;
and (3) cystic, due to degenerative change. In our
Fig. 6.15 Colloid with a mosaic pattern (cracking due to dry- experience, abundant colloid may rarely be present
ing artifact) seen in adenomatoid nodule with abundant colloid and is usually associated with a predominantly mac-
(colloid cyst). Note the small, bare follicular cell nuclei in the rofollicular or mixed micro- and macrofollicular ad-
background (Diff-Quik stain) enoma. The striking amount of colloid seen in such
6 Fine-needle Aspiration Cytology of the Thyroid 71 Hrthle Cell Neoplasm

As with follicular neoplasms, a distinction between

Hrthle cell adenoma and Hrthle cell carcinoma
cannot be reliably made by FNA as it requires evalu-
ation for the presence or absence of capsular and/or
vascular invasion on the resected neoplasm (in the
absence of metastatic disease).
Approximately 1015% of thyroid neoplasms diag-
Fig. 6.16 Follicular neoplasm with a monotonous popula- nosed as Hrthle cell neoplasm by FNA are malignant
tion of follicular epithelial cells showing enlarged, overlapping [53,92]. It has been suggested by Chen et al. [31] that
nuclei, rosettes, and a microfollicle with inspissated colloid at Hrthle cell carcinomas are more likely to be larger
3 oclock (Diff-Quik stain) than Hrthle cell adenomas; the authors reported a
65% incidence of carcinoma among Hrthle cell neo-
plasms 4 cm.
neoplasms emphasizes the necessity of both adequate Hrthle cell neoplasms are typically soft on palpa-
and representative sampling. tion. Aspirates generally yield high cellularity with lit-
The classic appearance of a follicular neoplasm on tle colloid [118]. Since Hrthle cell neoplasms repre-
FNA smears has minimal colloid in the background. If sent a variant of follicular neoplasm, the architectural
present at all, it is seen in small, dense, round or oval- arrangement of the neoplastic cells is similar in aspi-
shaped fragments (so-called casts), representing col- rates of both. Hrthle (oxyphilic) cells are arranged
loid expelled from microfollicles by the smearing tech- in microfollicles with or without inspissated colloid.
nique. The smears are usually cellular and composed Three-dimensional tissue fragments are common
of a monotonous population of follicular epithelial with a sense of cellular disorganization [104]. The
cells with mild to moderate nuclear enlargement [21]. Hrthle cells have a relatively monotonous appear-
An exception is the rare atypical adenoma in which ance with minimal pleomorphism and fairly abun-
enlarged, hyperchromatic nuclei may be seen, similar dant cytoplasm with characteristic granularity [66].
to that described in other endocrine neoplasms. The The nuclei may be binucleated, are often eccentrically
cytoplasm of the follicular cells is nearly transparent, located, and typically have macronucleoli.
sometimes inconspicuous, and typically not abundant While Hrthle cells may be a prominent feature in
due to a relatively increased nuclear to cytoplasmic FNAs of non-neoplastic Hrthle cell lesions, includ-
ratio. As such, the nuclei are the prominent feature ing adenomatoid nodules and Hashimotos thyroid-
in these smears and are arranged as acini (Fig. 6.4), itis, features reported to be specific for Hrthle cell
tubules (Fig. 6.12), and microfollicles (Fig. 6.7) seen neoplasms include a predominance (>90%) of dis-
singly or within tissue fragments. Microfollicles may cohesive Hrthle cells with abundant granular cyto-
or may not contain central dense colloid (Fig. 6.16). plasm, macronucleoli, intracytoplasmic lumina, and
A prominent capillary network may also be seen in abundant capillaries (Fig. 6.17) [113,120]. Of note,
the background or within these tissue fragments and, the degree of cellularity or presence of microfollicles
when seen in contiguity with microfollicles, should are not useful in the distinction between non-neo-
not be misinterpreted as a papillary architecture. plastic and neoplastic Hrthle cell lesions [113]. Aspi-

Fig. 6.17 Hrthle cell neoplasm. a Discohesive sheets of oxyphilic cells, some with intracytoplasmic vacuoles. b Binucleated oxy-
philic cells with prominent nucleoli. c Prominent capillary network within tissue fragments composed of oxyphilic cells (Diff-Quik
72 Anne E. Busseniers and Susan A. Silver

rates of Hrthle cell neoplasms usually do not contain ders (Fig. 6.20b) [70]. The cytoplasm often contains
ordinary follicular cells or lymphoid cells. However, if septate vacuoles, which have been likened to soap
a Hrthle cell neoplasm undergoes cystic degenera- bubbles (Fig. 6.20b) [95]. Increased nuclear to cyto-
tive change, foamy and pigmented histiocytes may be plasmic ratio, with nuclei enlarged up to four times
present along with scant cellularity. the size of red blood cells, is characteristic (Fig. 6.19).
However, it is the morphology of the nuclei that is
the single most important diagnostic feature. The
6.5.6 Malignant Neoplasms nuclei exhibit fine, powdery chromatin with a soli-
tary, inconspicuous, eccentrically located nucleolus Papillary Carcinoma [106]. The chromatin may be seen dispersed to the
periphery of the nucleus (Fig. 6.20). Intranuclear cy-
On palpation, the nodule is usually well defined and toplasmic pseudoinclusions are generally readily ap-
has a rubbery consistency. One may encounter some preciated (Fig. 6.6). Note that intranuclear inclusions
resistance upon insertion of the needle. In such cases, encompass at least one third of the nuclear surface
increased suction may be required in order to obtain and do not extend beyond the nuclear rim. It is im-
material in the needle hub. If the tumor is calcified, a portant to apply these criteria in recognizing these
gritty sensation may be appreciated when moving the inclusions since a number of artifacts may mimic
needle; it is even possible to hear the scraping of the them, namely, red blood cells superimposed on fol-
needle within the lesion. The neoplasm may be soft to licular epithelial nuclei, and degenerative vacuoles
palpation if a significant cystic component is present. (most often seen in cystic lesions). With careful scru-
Microscopically, the smears consist primarily of tiny, intranuclear pseudoinclusions are found in up
neoplastic cells. Aspirates of papillary carcinoma to 90% of adequately sampled papillary carcinomas
usually contain sparse colloid, and the colloid that is [70,82]. In most cases of papillary carcinoma, longi-
present is of a different nature than that seen in other tudinal grooves are visible in the nuclei, imparting a
thyroid lesions. The colloid in papillary carcinoma is coffee bean or cerebriform appearance [87]. The latter
typically described as dense, pasty, or bubblegum-like
(Fig. 6.18). The architectural arrangement of the neo-
plastic cells varies from the classic papillary finger-like
projections, which may or may not contain a fibrovas-
cular core (Fig. 6.19), to sheets of cells with nuclei in
close proximity but not overlapping (Fig. 6.20a), to
single cells [70,95].
The cells of papillary carcinoma are generally
uniformly enlarged with minimal pleomorphism.
Marked cellular pleomorphism is rare and suggests
anaplastic transformation. The cells have either finely
granular cytoplasm resembling oxyphilic cells or Fig. 6.18 Papillary carcinoma showing characteristic dense
dense cytoplasm with well-defined cytoplasmic bor- colloid described as bubble gum-like (Diff-Quik stain)

Fig. 6.19 Papillary carcinoma. At low Fig. 6.20 Papillary carcinoma. a Note monotonously enlarged nuclei, increased nu-
magnification, a central fibrovascular core clear to cytoplasmic ratio without nuclear overlap, dispersed chromatin with eccentric
of a papilla is conspicuous, with papillary nucleolus, and nuclear grooves (hematoxylin and eosin stain). b The cells show nuclear
carcinoma cells arranged at its periphery enlargement, focal cytoplasmic vacuolization resembling soap bubbles, and dense cy-
(Diff-Quik stain) toplasm with well-defined cytoplasmic borders. An intranuclear inclusion is present at
12 oclock (Diff-Quik stain)
6 Fine-needle Aspiration Cytology of the Thyroid 73

represent cytoplasmic invaginations through the full Medullary Carcinoma

length of the nucleus (Fig. 6.18). Although nuclear
grooves may be seen in a variety of benign thyroid On palpation, the lesion usually presents as a hard,
lesions, when present in the majority of the nuclei this solitary, well-circumscribed mass with a predilection
feature is highly suggestive of papillary carcinoma for the upper poles of the thyroid.
[111]. It should be noted that both nuclear grooves The aspirates yield cellular samples composed of
and chromatin dispersed to the periphery are best ap- neoplastic neuroendocrine cells and amyloid, seen
preciated in fixed rather than air-dried smears. in varied proportions. The neoplastic cells are loosely
Psammoma bodies, which represent concentric la- cohesive and are often seen as individual cells in
mellated calcified bodies formed from the necrosed smears (Fig. 6.21). The cells may form microfollicles
tips of papillae, are highly characteristic of any papil- and papillary projections and may therefore mimic
lary neoplasm (Fig. 6.9); they are identified in 2040% other thyroid neoplasms [123]. A classic presentation
of papillary carcinomas [82,95]. Other features that is a combination of plasmacytoid and spindle cells
may be seen in smears of papillary carcinoma include with occasional bizarre tumor cells mimicking ana-
multinucleated giant cells, a lymphoid background, plastic giant cells [69]. The nuclei are often positioned
and cystic degenerative change. eccentrically in the cytoplasm and have an evenly dis-
tributed chromatin pattern, as seen in other neuro-
endocrine neoplasms. Often, the nucleus is seen pro-
Variants of Papillary Carcinoma truding beyond the cytoplasmic border. Intranuclear
cytoplasmic pseudoinclusions are not uncommon.
Follicular Variant of Papillary Carcinoma Mitotic activity is usually minimal. The cytoplasm is
typically dense with well-defined borders, and may
Smears from the follicular variant of papillary carci- contain a fine dusting of red (neuroendocrine) gran-
noma are cellular. The neoplastic cells are arranged ules, best appreciated on smears stained with Diff-
in acinar structures and also as monolayered and/or Quik. When a cytologic diagnosis of medullary carci-
branching sheets [47]. The cytologic diagnosis of this noma is suggestive but not definitive, it may be helpful
variant rests on the identification of the same charac- to stain an alcohol-fixed smear or cell block slide with
teristic nuclear features of usual papillary carcinoma, calcitonin immunostain. A recommendation in the
namely, monomorphism, powdery chromatin, intra- pathology report to obtain serum calcitonin and car-
nuclear cytoplasmic pseudoinclusions, and longitudi- cinoembryonic antigen (CEA) levels is also suggested
nal grooves. Psammoma bodies, multinucleated giant to aid in confirming the diagnosis.
cells, and lymphocytes may be present [86]. The amount of amyloid present is variable, and in-
The follicular variant of papillary carcinoma results versely correlates with the cellularity. It is reportedly
in a suspicious, equivocal diagnosis on FNA more present in 6580% of aspirates [16,89,115]. Grossly,
frequently than does the usual papillary carcinoma amyloid may be recognizable to the aspirator as a
[65]. The sensitivity of FNA for this variant (25%) is white, chalky substance. In smears, it has been com-
significantly lower than that for usual papillary car- pared to waxy candle drippings. As amyloid may
cinoma (74%) [84]. Fulciniti et al. [47], however, has closely resemble colloid, special histochemical stains
reported the accuracy of FNA diagnosis of this vari- (e.g., Congo red) are often required to confirm its pres-
ant to approach 90%. ence. Coarse calcifications may also be seen, although
psammoma bodies are seen in less than 10% of cases.

Other Variants of Papillary Carcinoma

Other variants of papillary carcinoma include scle-

rosing, tall cell, columnar, Hrthle cell, Warthin-like,
and the macrofollicular encapsulated variant. With
the exception of the latter two entities, these variants
are associated with a more aggressive behavior than
usual papillary carcinoma [9,28,35,38,82,106]. Owing
to the rarity of these lesions, their cytologic descrip-
tion falls outside the scope of this chapter. Fig. 6.21 Medullary carcinoma. The poorly cohesive malig-
nant cells show plasmacytoid features with eccentric nuclei
(Diff-Quik stain)
74 Anne E. Busseniers and Susan A. Silver

A number of variants of medullary carcinoma

have been described including spindle cell, papillary,
mixed follicular/medullary carcinoma, small cell, and
giant cell variants [36,69,93]. Insular Carcinoma

Insular carcinoma is considered intermediate in be-

havior between the well-differentiated and less ag- Fig. 6.22 Anaplastic carcinoma. Bizarre malignant giant cells
gressive malignancies (papillary carcinoma and fol- have scant cytoplasm, nuclear pleomorphism, and nuclear rim
licular carcinoma), and the more aggressive anaplastic irregularities (Diff-Quik stain)
carcinoma [23].
On palpation, the nodule is rubbery and averages
larger than 2 cm. enlarging thyroid gland and a preexisting history of
The smears are highly cellular, populated by a diffuse goiter. There is a strong association with
monomorphic follicular cells present singly and also Hashimotos thyroiditis [60,90].
arranged in acini, tubules, and follicles. Loose aggre- The cytologic appearance is similar to that of
gates and groups with no distinguishing architecture lymphomas at other sites. The most common type
are also observed. The cells have relatively bland, deli- of lymphoma to arise in the thyroid gland is non-
cate, and ill-defined cytoplasm, oval to round nuclei, Hodgkins lymphoma, B cell type [109]. The smears
inconspicuous nucleoli, and a high nuclear to cyto- are relatively cellular with individual large lymphoid
plasmic ratio [97,100]. cells in the background. The lymphoid cells have
scant cytoplasm that is blue-gray on Diff-Quik stain.
Some subtypes, such as the immunoblastic type, Giant and Spindle Cell show macronucleoli. Crushed chromatin (lymphoid
(Anaplastic) Carcinoma tangles) is commonly seen as are groups of atypi-
cal lymphoid cells with individual cell necrosis. The
This diagnosis is often suspected clinically. Patients smears contain very little to no colloid, and may show
typically present with a rapidly enlarging mass, pos- evidence of Hashimotos thyroiditis in the background
sibly resulting from malignant transformation of a [37]. When a diagnosis of lymphoma is suspected in
preexisting thyroid neoplasm [25]. To palpation the our laboratory, material is set aside for flow cytomet-
mass is hard, and often quite large with an irregular ric analysis.
nodular surface.
The smears of anaplastic carcinoma are usually
very cellular, regardless of the experience of the as- Metastases to the Thyroid
pirator. The neoplastic cells are large with extreme
pleomorphism and readily apparent malignant fea- Metastases to the thyroid are very uncommon. In
tures including irregular chromatin, macronucleoli, one study, the incidence at autopsy and at thyroidec-
and mitoses. The cells may have a spindled and gi- tomy for metastatic malignancy was 0.5% and 1.2%,
ant cell morphology (Fig. 6.22) [57]. The background respectively [79]. Metastases are most likely to oc-
frequently shows necrotic cellular debris (malignant cur in the clinical setting of a patient with a known
diathesis) with inflammatory cells [54]. primary [119]. Clinically, renal cell carcinoma is the
The differential diagnosis includes a high-grade most common type of metastatic disease to the thy-
sarcoma such as malignant fibrous histiocytoma roid; at autopsy, colorectal, lung, breast, and renal cell
[108], a variant of medullary carcinoma, and meta- carcinoma along with melanoma and malignant lym-
static carcinoma. phoma prevail [43,96]. Malignant Lymphoma 6.6 FNA of the Thyroid

in Children and Adolescents
Secondary involvement of the thyroid, although rare,
is more common than primary lymphoma involving Thyroid nodules in children and adolescents are
the thyroid. Patients typically present with a rapidly uncommon. FNA has been found to be as reliable
6 Fine-needle Aspiration Cytology of the Thyroid 75

in children as in adults for the definitive diagnosis and follicular and Hrthle cell neoplasms. Parathyroid
of thyroid nodules [2]. Khurana et al. [72] reported cysts, thyroglossal duct cysts, and branchial cleft cysts
a 24.6% prevalence of malignancy in their series of may also be aspirated in the vicinity of the thyroid.
thyroid FNAs in 57 children and adolescents with An estimated 9% of cysts are malignant when surgi-
surgical follow-up. Papillary carcinoma (n = 11) and cally excised [39,61]. A pre-FNA ultrasound, if avail-
follicular carcinoma (n = 3) accounted for the malig- able, may be useful to the aspirator in conveying the
nancies in this series. presence and extent of a cystic component. The FNA
procedure may be therapeutic if the cyst fluid can be
evacuated in its entirety. This, however, occurs infre-
6.7 FNA of the Thyroid quently. More commonly, a solid component remains
in Pregnancy after the fluid is aspirated, in which case sampling of
this solid component is crucial for diagnosis.
The loss of iodine during pregnancy induces thyroid Grossly, the color of the cyst fluid varies from pale
growth and hyperplasia which is usually diffuse [107]. yellow, to green, to dark brown. The color is not a reli-
A preexisting nodule may increase in size and pres- able indicator of malignancy. However, if the fluid is
ent as an enlarging suspicious lump in a pregnant watery, clear, and colorless, a parathyroid cyst should
woman. The cytologic findings on FNA show similar be considered and the fluid submitted for parathyroid
features as those described for cellular adenomatoid hormone essay. In our practice of nearly 5,000 thyroid
nodules. The smears usually show increased cellular- aspirates, we have encountered only two parathyroid
ity in the background of thin, watery colloid. The fol- cysts.
licular epithelial cells are arranged in groups, sheets, Microscopically, cyst contents may contain choles-
and spherules. Some hyperplastic papillary fragments terol crystals, foamy and pigmented histiocytes (the
may also be seen. The cells in these tissue fragments, latter in the setting of hemorrhage), multinucleated
however, lack the cytologic cellular criteria for papil- giant cells, and follicular cells with shrunken, de-
lary carcinoma. generative nuclei. Squamous metaplastic cell change,
considered a reparative process, is not uncommon in
cystic lesions (Fig. 6.23). These cells may appear quite
6.8 Cytologic Diagnostic atypical and lead to a false-positive diagnosis. Degen-
Challenges in FNA erative follicular epithelial cells may display cytoplas-
of the Thyroid mic and nuclear vacuolization, also seen as a degen-
erative phenomenon in cystic papillary carcinoma.
Cytologic diagnostic challenges pertaining to thyroid Careful attention to the nuclear cytologic features will
FNA arise from several situations including: (1) simi- enable one to make the distinction between benign
lar morphologic appearances between certain types follicular cells and cells of papillary carcinoma. The
of cells; (2) inexperience of the diagnostician; and (3) cyst contents of a neoplasm may also be paucicellu-
absence or paucity of diagnostic cells due to the in- lar. If epithelial cells are present, they may show de-
herent nature of the lesion. generative changes obscuring nuclear detail, which
It is our philosophy that it is the role of the cyto- may lead to a false-negative result [7]. It is therefore
pathologist to keep the number of indeterminate/sus- imperative that a diagnosis not be rendered unless
picious cases to a minimum by consistently applying well-preserved epithelial cells are present in sufficient
strict diagnostic criteria on diagnostic samples only. numbers.
It is incumbent upon the surgeon to understand the
diagnostic limitations of the FNA procedure, which
are summarized below.

6.8.1 Cystic Lesion of Thyroid with Scant

or Absent Follicular Cells

Cystic change occurs in a number of circumstances

with the most common being: (1) degeneration of a
long-standing goiter; (2) hemorrhage into a preexist- Fig. 6.23 Squamous metaplastic cell change in a benign cystic
ing nodule; (3) colloid accumulation; and (4) degener- adenomatoid nodule. The cells are elongated with dense cyto-
ation of neoplasms, most notably papillary carcinoma plasm and discrete cytoplasmic borders (Diff-Quik stain)
76 Anne E. Busseniers and Susan A. Silver

6.8.2 Cellular Follicular Lesion tory background, the cytopathologist must exercise
extreme care not to overdiagnose such cases based on
Thyroid lesions with a follicular architecture cover a these findings.
broad range of diagnoses including hyperplastic epi- Hashimotos thyroiditis may occur concomitantly
thelial changes, follicular neoplasms, and follicular with various thyroid neoplasms including follicular
variant of papillary carcinoma. Up to 30% of lesions adenoma, papillary carcinoma, and malignant lym-
diagnosed with a follicular pattern by FNA are carci- phoma [56,77,85]. As such, careful and representative
noma on final histologic review [14]. In our experi- sampling of the lesion is necessary to reduce the pos-
ence, 75% of lesions diagnosed in this gray-zone cat- sibility of a false-negative diagnosis.
egory of cellular follicular lesion harbor a neoplasm
with near equal distribution between adenomas and
carcinomas (unpublished data). Among the latter, 6.8.4 Cytologically Atypical Cells
both follicular carcinoma and follicular variant of
papillary carcinoma are represented. Atypia is difficult to define. It usually refers to the
presence of some but not all of the cytologic criteria
for malignancy, namely, nuclear enlargement, cellu-
6.8.3 Prominent Hrthle Cell Proliferation lar pleomorphism, and hyperchromatism. Follicular
epithelial cell atypia may be seen following radioac-
Hrthle cell change of non-neoplastic origin is rela- tive iodine therapy as well as after radiation for cervi-
tively common in goiters and Hashimotos thyroid- cal neoplasms of other than thyroid origin. Follicular
itis [45]. As the differential diagnosis of a prominent cell atypia may also be seen in the atypical adenoma,
Hrthle population includes a Hrthle cell neoplasm, Hashimotos thyroiditis, subacute granulomatous thy-
obtaining a representative sample is crucial. Multiple roiditis (particularly in the acute stages), and in be-
passes from a neoplasm will yield similar cytologic nign thyroid cysts. As previously discussed, inflam-
findings of a monotonous cell population. In goiters mation may induce follicular epithelial cell atypia
and thyroiditis, multiple passes will likely show the resulting in a false-positive diagnosis [98].
varied cytologic components of these lesions. Focal epithelial atypia in the background of cystic
Hashimotos thyroiditis may be a source of both degeneration or inflammation should be interpreted
false-positive and false-negative results. In some with caution. It should be noted that primary thyroid
cases, the oxyphilic (Hrthle) cell change is severe neoplasms typically yield a relatively monotonous
and the inflammatory component minor or not sam- cell population with minimal cellular pleomorphism.
pled [3]. This may lead to an erroneous diagnosis of An exception are the bizarre and pleomorphic cells
follicular neoplasm of Hrthle cell type, emphasizing seen in high-grade malignant neoplasms, although
once again the importance of obtaining a representa- such cases generally do not pose a diagnostic chal-
tive sample. Additionally, inflammation may induce lenge [71].
cellular epithelial changes including nuclear enlarge-
ment, nucleoli, and mild to moderate cellular pleo-
morphism (Fig. 6.24). In the setting of an inflamma- 6.8.5 Hrthle Cell Neoplasm Versus
Papillary Carcinoma

Diffuse Hrthle (oxyphilic) cell change with for-

mation of a Hrthle cell nodule may be a feature of
Hashimotos thyroiditis. Papillary carcinoma, the
most common type of thyroid malignancy, is seen
in immune-compromised glands, the most common
cause of hypothyroidism. Oxyphilic cell change re-
sults in enlargement of follicular epithelial cells and
cytoplasmic features that may resemble those seen in
Fig. 6.24 Hashimotos thyroiditis with cellular atypia. A small papillary carcinoma; the nuclear features, however,
sheet of oxyphilic cells is surrounded by lymphoid cells and are different. Follicular lesions also occur in the back-
plasma cells. Note the markedly atypical cells with nuclear ground of Hashimotos thyroiditis. When the inflam-
enlargement, abundant cytoplasm, and bland chromatin at matory component is the dominant feature, it may
3 oclock (Diff-Quik stain) obscure neoplasia [77].
6 Fine-needle Aspiration Cytology of the Thyroid 77

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fine-needle aspiration biopsy (FNAB) in the management
The differential diagnosis includes Hashimotos thy- of thyroid nodules. Diagn Cytopathol 29:203206
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16. Bose S, Kapila K, Verma K (1992) Medullary carcinoma
promised gland shows increased monotony of the
of the thyroid: a cytological, immunocytochemical, and
lymphoid component. When the FNA procedure is
ultrastructural study. Diagn Cytopathol 8:2832
done with on-site evaluation for specimen adequacy,
17. Brander A, Viikinkoski P, Nickels J, et al (1991) Thyroid
a diagnosis of lymphoma can be suspected and addi-
gland: US screening in a random adult population. Radi-
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7 Technique of Thyroidectomy

Daniel Oertli

Contents the anatomic situation is complicated by prior sur-

gery [5]. However, neuromonitoring does not reliably
7.1 Introduction . . . 81 predict postoperative outcome [6,7]. A recent study
7.2 Extent of Surgery and Definitions . . . 82
based on 288 patients undergoing thyroid surgery
7.3 Preoperative Measures . . . 82
with intraoperative identification and intraoperative
7.4 Positioning and Draping . . . 82
neuromonitoring showed that the incidence of recur-
7.5 Surgical Steps . . . 82
rent nerve lesions in benign, malignant, and recur-
7.5.1 Skin Incision and Creation of Skin Flaps . . . 82
rent thyroid disease was not lowered by the use of in-
7.5.2 Strap Muscles . . . 83
7.5.3 Upper Pole . . . 83
traoperative neuromonitoring [8]. Although an intact
7.5.4 Isthmus and Pyramidal Lobe . . . 84 nerve function can be verified by this method, we do
7.5.5 Hilum of the Gland . . . 84 not recommend the routine use of RLN neuromoni-
7.5.6 Handling of the Parathyroid Glands . . . 85 toring.
7.5.7 Lower Thyroid Pole . . . 86 The endocrine surgeons success depends com-
7.5.8 Removal of the Lobe . . . 86 pletely on his or her devotion to a stepwise meticu-
7.5.9 Wound Closure . . . 86 lous and fine dissection technique. Several dissection
7.6 Reoperative Thyroid Surgery . . . 86 devices have recently been propagated for thyroid sur-
7.7 Minimally Invasive Thyroidectomy . . . 87 gery. The harmonic scalpel using ultrasonic frictional
References . . . 87 heating to seal vessels is widely used in laparoscopic
and open abdominal surgery. It is documented to be
safe and fast for cutting and coagulating tissue. Its use
for dissection during thyroidectomy has been evalu-
7.1 Introduction ated in several studies and has been compared to the
conventional clamp-and-tie technique. Two random-
Thyroidectomy is the most frequent intervention in ized studies [9,10] and two case-controlled studies
endocrine surgery. When performed in specialized [11,12] have shown that the harmonic scalpel signifi-
centers, the operation is safe with low morbidity and cantly shortens the operative time compared to the
a virtually 0% mortality [1]. Complications of thyroid conventional technique. This reduction of up to 20%
surgery are directly correlated to the extent of resec- in operative time has proved to be cost-effective [13].
tion and inversely proportional to the experience of Thyroidectomy using the electrothermal seal-
the operating surgeon [14]. Thus, the cornerstones ing technique has also been introduced and tested
of safe and effective thyroid surgery are an adequate [14,15]. However, this technique did not significantly
training, the understanding of the anatomy and pa- reduce operative time, blood loss, or the complica-
thology, as well as a meticulous dissection technique. tion rate compared to conventional knot-tying but it
The dissection must be based on a sound knowledge increased operative costs in one study [15]. All men-
of three-dimensional topographic anatomy, typical tioned studies compared new ultrasonic or diathermy
landmarks, and possible anatomic variations. The me- dissection devices with the conventional clamp-and-
ticulous dissection technique is achieved by a proper tie technique. However, no comparison with the uti-
exposure of all fine anatomic structures in a blood- lization of hemoclips to secure smaller vessels was
less dry surgical field. The use of magnifying glasses done. Personally, I make liberal use of hemoclips for
(magnification 2.53.5 ), bipolar coagulation, and thyroid and parathyroid surgery and I am convinced
fine titan clips or ligatures is highly recommended. that this speeds up the operation similarly to the use
Neuromonitoring has proved useful for identifying of the quite costly new devices.
the recurrent laryngeal nerve (RLN), in particular if
82 Daniel Oertli

7.2 Extent of Surgery between the medial borders of the sternocleidomas-

and Definitions toid muscles. The appropriate position of the neck
incision is approximately two finger breadths above
Until 2000 there was no uniformly applied definition the sternal notch or in the middle between the sternal
in the literature regarding the extent of thyroidec- notch and the thyroid cartilage. If the incision is too
tomy that should be performed for benign and malig- low, the tendency to keloid formation and resulting
nant pathologies. To fill this gap, Kebebew and Clark unsatisfactory cosmesis is increased.
formulated such a classification (Table 7.1) [16].
Lumpectomy or nodulectomy refer to removal of a
thyroid nodule alone with minimal surrounding thy- 7.4 Positioning and Draping
roid tissue. Partial thyroidectomy involves removal of
a nodule with a larger margin of normal thyroid tis- The patient is positioned with the neck extended.
sue. The definition of subtotal thyroidectomy belongs Rolled towels are placed under the shoulders which
to the bilateral removal of more than 50% of each lobe allow sufficient neck extension. A sponge doughnut is
including the isthmus. Lobectomy or hemithyroidec- placed under the occiput for adequate head support.
tomy refers to the complete removal of one lobe with In order to prevent venous congestion in the neck, the
the isthmus. Near total thyroidectomy is defined as head of the table is elevated to a 30 position during
the total extracapsular removal of one lobe including surgery. Disinfection is performed using an alcoholic
the isthmus with less than 10% of the contralateral agent without iodine which might interfere with post-
lobe left behind. During total thyroidectomy both operative radionuclear scanning and ablative therapy.
lobes and the isthmus are completely removed leaving The surgical field is draped from below the sternal
behind only viable parathyroid glands. notch up to the chin and on the posterior margin of
the sternocleidomastoid muscles.

7.3 Preoperative Measures

7.5 Surgical Steps
All patients should be rendered euthyroid before sur-
gery. Preoperative preparation of patients with thyro- Every surgeon should adopt a stepwise, standardized
toxicosis is particularly critical to avoid operative or strategy for thyroidectomy. One possible way (the
postoperative thyroid storm. The planned procedure authors recommendation) for a successful thyroidec-
should be discussed with the patient and informed tomy is presented below. Modifications may be neces-
consent must be obtained. Routine preoperative la- sary in the case of perithyroidal inflammation, large
ryngoscopy is not necessary if the patient does not re- goiters, or unexpected intraoperative findings.
port voice changes [17]. However, if patients have pre-
viously undergone any type of neck surgery or if the
voice appears to be altered, laryngoscopy is indicated. 7.5.1 Skin Incision and Creation
The tentative skin incision is marked preoperatively of Skin Flaps
using a permanent marker pen on the awake patient
with reclined neck. This is done in a symmetric fash- A curvilinear collar-type incision is placed trans-
ion along the Langers skin lines or in a skin crease in versally along the Langers line of the skin, i.e., the

Table 7.1 Definition of extent of resection

Thyroidectomy procedure Removal of: Indications
Partial (nodulectomy, lumpectomy) Nodule + margin of normal tissue Benign lesion
Subtotal More than one half of the thyroid gland Benign lesion
and isthmus
Lobectomy (= hemithyroidectomy) One entire lobe and isthmus Standard initial treatment for all indeter-
minate nodules
Near-total Lobectomy on one side, isthmectomy and Papillary carcinoma in a low-risk patient,
subtotal resection of contralateral lobe not requiring radioiodine ablation
Total Both lobes and isthmus Any other type of thyroid carcinoma
7 Technique of Thyroidectomy 83

standard Kochers incision. The use of a natural skin when the operating surgeon is positioned on the right
crease if present seems attractive. In order to optimize side of the patient. By predominantly blunt dissection,
cosmesis, the skin incision should be as long as nec- the anterior aspect of the respective thyroid gland is
essary but as short as possible. Personally, the author exposed. Caution should be applied while retracting
believes that a 4- to 5-cm incision allows safe thyroid- the strap muscles to avoid disrupting the medial thy-
ectomy in most cases and results in excellent cosme- roid veins. These veins are isolated and either ligated
sis. However, patients with larger tumors or goiters or clipped and divided. Proper exposure to the lateral
or those with short necks will require a larger inci- aspects of the thyroid gland is achieved using right-
sion for optimal exposure. The incision is carried out angled (de Quervain) retractors. Division of the strap
through the skin and the subcutaneous layer through muscles may be necessary in the case of a very large
the platysma muscle to the lateral extent of the skin goiter, when a central neck dissection is indicated, or
incision. The two skin flaps are created by dissect- in reoperative cases. The two muscles (sternohyoid
ing them away from the strap muscles upward to the and sternothyroid) are separated using diathermia.
thyroid cartilage and downward to the sternal border. Their borders are secured with 2-0 threads that serve
Elevation of the two flaps is almost bloodless if the as stay sutures.
layer beneath the platysma is followed and dissected.
The cranial flap is transfixed using stay sutures that
are secured on two hooks placed on a horizontal rod 7.5.3 Upper Pole
which is placed above the patients head (Fig. 7.1). The
caudal flap is pulled downward using a Roux retractor Using Kochers forceps, lateral retraction of the upper
enabling optimal exposure to the strap muscles. pole of the thyroid lobe is applied in order to open up
the avascular space [18] between the lobe and the cri-
cothyroid muscle, thus exposing the external branch
7.5.2 Strap Muscles of the superior laryngeal nerve [19,20]. This nerve
can sometimes be identified as it descends with the
The approach to the thyroid capsule is done by split- vessels and anterior to the cricoid muscle but is often
ting the strap muscles in the midline. Small crossing not visible (Fig. 7.2). A recent study showed that the
vessels are treated with bipolar coagulation. For a bi- identification and dissection of the superior laryngeal
lateral approach, the left thyroid lobe is first dissected. nerve do not lower the risk of damage compared with
This is usually the more cumbersome preparation the simple transection of the superior vein and ar-

Fig. 7.1 Intraoperative situation after

creation of the superior skin-platysma flap
which is secured with threads. The inferior
flap is retracted using a Roux retractor
84 Daniel Oertli

Fig. 7.2 Lateral and caudal retraction of the upper pole of the
thyroid in order to open up the avascular space between the
lobe and the cricothyroid muscle, thus exposing the external
branch of the superior laryngeal nerve

tery close to the thyroid [21]. The superior vessels are using a vessel loop in order to facilitate further expo-
usually ligated with transfixing sutures. Large goiters sure of the RLN. The nerve may easily be found at its
with prominent superior poles often require more constant landmark, the so-called Zuckerkandl tuber-
than one transection step. culum [24,25], where it crosses beneath the thyroid
gland and enters below Berrys ligament of the thy-
roid cartilage (Fig. 7.3). The RLN can always be iden-
7.5.4 Isthmus and Pyramidal Lobe tified laterodorsally to the ligament of Berry; it never
penetrates the ligament [26]. The left RLN leaves the
By blunt dissection, the isthmus is freed from the un- vagus nerve as the vagus crosses over the arch of the
derlying trachea and divided between transfixing liga- aorta. It hooks around the aorta and ascends again,
tures. If subtotal or total thyroidectomy is performed, similarly to the right RLN, laterally to the trachea to
the division of the isthmus is often not necessary. The its terminal branches within the laryngeal muscles.
pyramidal lobe, which originates more often from the This explains why the left RLN runs closer to the tra-
left thyroid lobe, is traced upward and removed as cheoesophageal groove than the right RLN [27]. The
completely as possible. RLN may pass posteriorly or superficially to the in-
ferior thyroid artery or its branches intertwine with
many variations. Although several methods of local-
7.5.5 Hilum of the Gland izing the RLN have been described, surgeons should
be aware of the variations and must have a thorough
Only the complete division of the superior vessels knowledge of the normal anatomy to achieve a high
enables the surgeon to medially rotate and anteriorly standard of care. This will ensure the integrity and
mobilize the gland which results in optimal exposure safety of the RLN during thyroid surgery. The iden-
of the hilar structures. Capsular dissection, as de- tification of the RLN may be assisted by palpation; it
scribed by Thompson et al. [22], refers to the develop- may be felt like a cord that can be rolled against the
ment of a plane between the thyroid capsule and the trachea [28]. The nerve appears as a white cord com-
tertiary branches of the inferior thyroid artery. The monly accompanied by a small artery. To clearly iden-
branches are ligated or clipped individually directly on tify the RLN, dissection of its crossing point with the
the surface of the thyroid gland. This method, which inferior thyroid artery is critical. Gentle dissection,
is widely practiced today, minimizes surgical damage best performed with a fine curved jaw hemostat, is
to both the parathyroid glands and the RLN [23]. Me- necessary at this point. Although there are many dif-
ticulous dissection steps will then enable identifica- ferent anatomic relationships between the nerve and
tion of the RLN where it crosses the inferior thyroid the artery, the crossing point is one constant anatomic
artery, as well as the two parathyroid glands. It is wise landmark where the RLN can usually be identified.
to preserve as much of the inferior thyroid artery and One exception to this rule is the non-recurrent infe-
its branches as possible, since it supplies the blood to rior laryngeal nerve (Fig. 7.4). This anomaly is found
the two parathyroid glands. Truncal ligation of the in- virtually only on the right side and is associated with
ferior thyroid artery should be omitted. However, it an anomalous right subclavian artery with a reported
is sometimes helpful to hold the trunk of the artery frequency of 0.20.8% [2931].
7 Technique of Thyroidectomy 85

Fig. 7.3 Topographic relationship between the inferior

thyroid artery and the tubercle of Zuckerkandl to the re-
current laryngeal nerve and the superior parathyroid gland

Fig. 7.4 Intraoperative finding of a non-recurrent inferior

laryngeal nerve

7.5.6 Handling of the Parathyroid Glands and not to dissect the gland further than just beyond
the edge of the thyroid to preserve its blood supply.
Regardless of whether a unilateral lobectomy or total The inferior parathyroid gland is usually found at the
thyroidectomy is performed, all identified parathy- inferior pole of the thyroid or within the tongue of
roid tissue should be preserved on its native blood the thymus. Once identified, it is taken off the infe-
supply. If a gland is devascularized during dissection, rior pole in a similar fashion to the superior gland.
it should be transplanted. Although there have been Disruption of the thyroid-thymic ligament should be
sporadic reports of parathyroid autotransplantation, avoided as it provides most of the blood supply to the
it has only been in the last 30 years that the technique inferior parathyroid gland.
has become used and only recently has it become ac- All normal but devascularized parathyroid tissue
cepted as part of routine clinical practice during total should be transplanted into the sternocleidomas-
thyroidectomy [32]. The best way to preserve the para- toid muscle or other convenient muscle at the time
thyroid glands in situ is the extracapsular dissection of thyroidectomy. Sometimes, the gland is partly de-
of the thyroid gland. With the utilization of the extra- vascularized and should then be trimmed back to the
capsular dissection, the parathyroid glands are swept area of good arterial flow and viability. The remaining
off the thyroid capsule and are left in situ with their portion is removed, minced, and autotransplanted.
vascular pedicles. The superior parathyroid gland is Histologic confirmation of parathyroid tissue is cru-
usually found after mobilization of the superior pole cial in the setting of thyroid cancer. Nodal metasta-
of the thyroid. The lateral aspect of the thyroid gland ses from thyroid cancer can mimic parathyroid tissue
superior to the inferior thyroid artery usually reveals and should not be transplanted. There are principally
a fat pad where the parathyroid can be found. This fat two ways to do a parathyroid autotransplantation.
pad including the parathyroid gland should be mobi- First, the gland tissue is removed and minced into
lized off the lateral aspect of the thyroid starting at its tiny cubes that are smaller than 1 mm3. By separating
superior medial edge and sweeping the pad inferiorly the muscle fibers of the sternocleidomastoid muscle, a
and laterally. It is important not to disrupt the fat pad pocket containing about a 1-ml space is created using
86 Daniel Oertli

blunt dissection. The minced tissue is then trans- thyroid gland. This small artery should be isolated
planted into the pocket which is closed and marked and clipped before cutting (Fig. 7.5). The use of any
by hemostatic clips or a non-absorbable thread. It cautery or other thermal dissection device should be
is essential to leave a completely dry pocket behind avoided at this step due to the potential for thermal
since hematoma formation within the pocket would injury of the RLN that is in close proximity to the in-
be prone to phagocytosis including the parathyroid ferior thyroid artery. Inadvertent bleeding from this
tissue. The second possibility to achieve the parathy- artery and uncontrolled attempts of hemostasis at this
roid transplantation is the creation of a parathyroid point of dissection may harm the RLN. Sudden bleed-
suspension using saline which is then aspirated with ing is best handled, with the aid of suction, by iden-
a 2-ml syringe and injected into the sternocleidomas- tifying the vessel stump, and clamping or clipping,
toid muscle with an 18-gauge needle. being constantly aware of the presence of the RLN. If
oozing occurs at this point, the placement of a hemo-
styptic gelatine sponge is advised.
7.5.7 Lower Thyroid Pole

The transection of the vessels running to the lower 7.5.9 Wound Closure
pole is usually done after proper exposition of the
RLN. Veins from the anterior superior mediastinum A postoperative drain can never replace accurate he-
are exposed and divided very close to the thyroid mostasis and is of little or no use if severe postopera-
gland. In up to 12% of cases an accessory ima artery tive bleeding occurs. Two randomized trials did not
may spread into the lower pole. This vessel may origi- show any advantage of drainage after thyroidectomy
nate either from the brachiocephalic trunk, the right [33,34]. The strap muscles are sutured continuously
carotid artery, directly from the aortic arch, the inter- with a 3-0 absorbable thread, the platysma with a 4-0
nal thoracic artery, or from a mediastinal artery. This thread, and the skin is closed by an intradermal run-
vessel may cause intraoperative bleeding especially ning suture using 5-0 absorbable thread. A smooth
when a large retrosternal goiter is bluntly mobilized. collar may be used for the first 24 hours postopera-
tively and the patient should be advised to keep a head
up position of about 30 in order to minimize venous
7.5.8 Removal of the Lobe congestion and swelling of the soft tissues around the
During the final steps of the thyroidectomy, the lobe
is dissected away from the trachea under constant
exposure and preservation of the RLN. The dense 7.6 Reoperative Thyroid Surgery
attachments at the level of the posterior suspensory
ligament (Berry) usually require sharp dissection. At- Avoidance of RLN injury is best achieved by iden-
tention must then be paid to the relatively constant tification of the nerve early during reoperation. The
superior branch of the inferior thyroid artery (crimi- best approach is the identification of the RLN in a
nal branch) that often crosses underneath the RLN previously undissected area and to follow the nerve
and spreads medially from beneath the nerve into the into the dissected scarred region (from the known

Fig. 7.5 Last steps of dissection for thyroid lobec-

tomy: a small superior branch of the inferior thyroid
artery usually crosses underneath the RLN and
spreads medially from beneath the nerve into the
thyroid parenchyma
7 Technique of Thyroidectomy 87

toward the unknown). Although the use of intra- Third, the anterior superior approach exposes the
operative neuromonitoring for confirmation of the region between the superior pole of the thyroid, if
RLN has some theoretical applications for a difficult present, and the larynx. The RLN can be identified as
dissection, visual identification of the RLN is still es- it enters the larynx with dissection in this avascular
sential. Principally three distinct approaches exist for space between the superior thyroid pole and the lar-
reoperative thyroid and parathyroid surgery. ynx. This can even be realized without taking down
First, the lateral or back door approach enters the superior pole vessels. The RLN can be traced infe-
the thyroid bed between the anterior border of ster- riorly and identified in the hilum of the thyroid which
nocleidomastoid and the strap muscles (Fig. 7.6). Lat- is often extensively scarred.
eral mobilizing of the sternocleidomastoid muscle ex-
poses the sternohyoid and underlying sternothyroid
muscles, whose fibers spread out inferiorly and later- 7.7 Minimally Invasive
ally over the carotid artery and jugular vein. Gentle Thyroidectomy
retraction of the carotid artery exposes the paratra-
cheal soft tissue. This area, which is located inferolat- Whereas minimally invasive parathyroidectomy has
erally to the inferior pole of the thyroid, is, if present, become popular among endocrine surgeons, experi-
usually unchanged from previous interventions. Here, ence with minimally invasive thyroidectomy remains
the RLN can usually be identified without difficulty. limited. The feasibility and safety of fully endoscopic
Second, the low anterior approach enters the thy- thyroidectomy or video-endoscopically assisted thy-
roid bed similarly to the primary operation. The strap roidectomy have been proved in a few studies that
muscles are separated in the midline down to the ster- reported a minor risk of complications and a low con-
nal notch and are reflected laterally. The dissection is version rate of 311% [3538]. The key to the success
then carried out in the paratracheal regions inferior of these approaches is a rigorous selection of the pa-
to the area of previous dissection where the right or tients. Inclusion criteria are solitary nodules smaller
left RLN is identified. than or equal to 3 cm, thyroid volume less than 20 ml,
absence of thyroiditis, absence of previous neck irra-
diation, and absence of previous neck surgery. Thus,
minimally invasive thyroidectomies are valid alterna-
tives to conventional surgery for patients with small
solitary nodules [39]. However, only 10.6% of patients
requiring thyroid surgery eventually qualify for this
approach [40].

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thyroid bed between the anterior border of the sternocleido-
mastoid muscle and the lateral border of the strap muscles
88 Daniel Oertli

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7 Technique of Thyroidectomy 89

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8 Surgery for the Solitary Thyroid Nodule

Prabhat K. Bhama and Gerard M. Doherty

Contents 8.2 Lobectomy

for Suspicious Lesions
8.1 Introduction . . . 91
8.2 Lobectomy for Suspicious Lesions . . . 91
Evaluation of a palpable solitary nodule in the thyroid
8.3 Treatment for Differentiated
gland should begin with a comprehensive history and
Thyroid Cancers . . . 93
physical examination. It is typically impossible to dis-
8.3.1 Principles . . . 93
tinguish a benign nodule from a malignant nodule by
8.3.2 Treatment: Papillary Thyroid Cancer . . . 93
palpation, however, there are some clinical findings Total Thyroidectomy . . . 93 Unilateral Lobectomy
that are indicative of malignant disease. A history of
and Isthmusectomy . . . 95 a hard and relatively fast growing nodule is associated Recommendations for Extent of Surgery . . . 96 with a higher risk for malignancy when compared Lymph Node Dissection . . . 96 with a soft and slowly growing nodule. Furthermore,
8.3.3 Treatment: Follicular Thyroid Cancer . . . 98 the presence of a solitary nodule is more indicative of
8.3.4 Treatment: Oncocytic (Hrthle malignancy, whereas a multinodular thyroid is more
Cell) Thyroid Cancer . . . 98 consistent with benign disease. Thyroid function
8.4 Risk Stratification for Cancer Treatment . . . 98 studies may also be useful, since a suppressed thy-
8.5 Summary . . . 98 roid-stimulating hormone (TSH) level is suggestive of
References . . . 99 benign pathology, as it is uncommon for malignant
lesions to cause thyrotoxicosis or thyroiditis [2].
Further evaluation of the solitary nodule is best
done by ultrasound and fine-needle aspiration (FNA).
8.1 Introduction The ultrasound examination of the thyroid gland al-
lows accurate evaluation of the thyroid nodule itself
The solitary thyroid nodule must be carefully evalu- as well as the surrounding thyroid tissue (Fig. 8.1).
ated because of the risk of malignancy, however, se- Characterization of the nodule includes the size,
lective management is paramount due to the high shape, solid versus cystic nature, the presence of calci-
frequency of benign lesions. While 47% of the adult fications in the nodule, and the nature of the borders
population in the USA have a palpable thyroid nod- (smooth, irregular, etc.). The use of ultrasound-guided
ule [1], the vast majority of these patients have benign FNA can improve the diagnostic accuracy (Fig. 8.2),
disease, and do not require surgical resection. but interpretation of the aspirate for definitive diag-
This chapter focuses on the use of lobectomy for nosis may still not be possible. In cases of follicular
nodules suspicious but not diagnostic for carci- neoplasia, FNA is limited in its ability to distinguish
noma, as well as algorithms for treatment of diag- malignant from benign disease, since the diagnosis of
nosed thyroid carcinoma. The extent of surgery for follicular carcinoma is histological. Specifically, iden-
malignant thyroid disease is also discussed, along tification of capsular or vascular invasion is necessary
with strategies for risk stratification for treatment of for diagnosis of malignant disease. This scenario is
differentiated thyroid cancer. Follicular cell-derived similar when dealing with Hrthle cell neoplasms.
thyroid cancers, including papillary thyroid cancer, Although cytological findings of FNA are sufficient
follicular thyroid cancer, and Hrthle cell cancer are for diagnosis in approximately 85% of specimens,
highlighted. 15% of aspirates fail to yield satisfactory results [3,4].
In such cases, pathology reports may be suspicious
for malignant disease, and approximately 20% of such
suspicious lesions will actually be malignant Hrthle
92 Prabhat K. Bhama and Gerard M. Doherty

Fig. 8.1 Longitudinal view of the

left thyroid lobe, with a complex
cystic and solid lesion in the mid to
lower portion of the lobe. There is a
second smaller cystic lesion in the
upper pole of the gland. The cystic
nature of these lesions is empha-
sized by the posterior acoustic
enhancement visible as the whiter
areas posterior (lower on the figure)
to the thyroid lobe

Fig. 8.2 Ultrasound-guided

fine-needle aspiration (FNA) of a
palpable left thyroid lobe lesion.
The ultrasound technique is used to
direct the needle (arrows) to the le-
sion that is to be sampled. Although
ultrasound is not strictly necessary
for the sampling of palpable lesions,
it is helpful for directing the needle
to a specific area within the target
lesion. For non-palpable lesions,
ultrasound in necessary for FNA
8 Surgery for the Solitary Thyroid Nodule 93

or follicular neoplasms. While some have suggested require a large multicenter trial with long follow-
the employment of 123I scintigraphy in cases of suspi- up time. It is unlikely that such trials will ever be
cious nodules, this test is not sufficient for uncovering performed.
malignant disease. The presence of hot nodules on Three primary surgical strategies exist for the
123I scintigraphy is suggestive of benign disease, since treatment of differentiated thyroid cancer: total thy-
malignant neoplasms typically manifest as cold roidectomy, near-total thyroidectomy, and lobectomy
nodules. However, patients with hot nodules on 123I with isthmusectomy. Total thyroidectomy involves
scan have occasionally been found to have thyroid removal of the entire thyroid gland and its capsule,
cancer upon further investigation [5]. whereas near-total thyroidectomy preserves the pos-
Thus, there are currently no investigative proce- terior capsule of the thyroid contralateral to the neo-
dures available to definitively distinguish benign from plasm. These two procedures are generally considered
malignant disease in patients with suspicious lesions together as completely ablative approaches to thyroid
of indeterminate cytology. A recent study indicated carcinoma. Unilateral lobectomy and isthmusectomy
that experienced pathologists may be accurate when is removal of the lobe ipsilateral to the lesion, and re-
predicting benign disease using FNA, however, the moval of the thyroid isthmus. This approach allows
authors determined that the predictive value of the preservation of normal thyroid tissue, thereby obvi-
test was not enough to preclude surgical resection ating the need for lifelong thyroid hormone supple-
[6]. As such, suspicious lesions are considered to be mentation. In addition, unilateral lobectomy with
positive for cancer, and should be treated with sur- isthmusectomy essentially eliminates the risk for hy-
gical resection to avoid the adverse consequences as- poparathyroidism and bilateral vocal cord paralysis.
sociated with untreated thyroid cancer. The principal Subtotal thyroidectomy is a procedure in which pres-
surgical approach to solitary, undetermined nodule is ervation of several grams of thyroid tissue is involved.
ipsilateral lobectomy. The reason for primary removal Due to higher complication rates encountered when
of the entire ipsilateral thyroid lobe is to avoid seri- subsequent surgery is indicated, subtotal thyroidec-
ous complications, since if further surgery is needed a tomy is not a recommended treatment option for pa-
reoperation is difficult and may be harmful in scarred tients with differentiated thyroid cancer [7].
tissue. Regardless of the surgical approach chosen, the
function of the vocal cords should be assessed prior
to surgery by noting any history of voice changes.
8.3 Treatment for Differentiated Examination of the larynx by indirect laryngoscopy
Thyroid Cancers as a visual survey for vocal cord mobility is indicated
whenever there is a history or examination finding of
8.3.1 Principles vocal changes. In the case of unilateral vocal cord pa-
ralysis, extreme caution should be taken to preserve
Differentiated carcinoma of the thyroid includes the contralateral recurrent laryngeal nerve to avoid
both papillary and follicular variants. The primary acute airway compromise. The surgical team should
treatment for these cancers is resection. Although also be prepared to create an alternative airway (i.e.,
surgical intervention is clearly indicated, contro- tracheostomy) if the need arises during surgery or
versy remains regarding the extent of thyroid tissue postoperatively.
that should be removed during the initial operation.
Whereas total thyroidectomy may help ensure
removal of all neoplastic tissue, it leaves the patient 8.3.2 Treatment: Papillary Thyroid Cancer
with no thyroid tissue, necessitating lifelong thyroid
hormone supplementation and exposing the patient Total Thyroidectomy
to the risk of bilateral dissection of the adjacent
normal neck structures. Alternatively, more conser- Total thyroidectomy is a safe and effective primary
vative procedures may leave inconspicuous residual treatment for patients with PTC. In patients with
cancer within the patient. Unfortunately, there are no high-risk lesions or extrathyroidal tumor extension,
prospective randomized clinical trials evaluating the it is generally accepted that total thyroidectomy is
extent of thyroidectomy, adjuvant radioactive iodide the appropriate treatment. However, in patients with
therapy, and TSH suppressive therapy. Because of low-risk lesions, the extent of surgical resection is
the relatively good prognosis and low incidence of controversial. Two key justifications exist for the use
papillary thyroid cancer (PTC), such a study would of near-total or total thyroidectomy in patients with
94 Prabhat K. Bhama and Gerard M. Doherty

PTC. First, removal of the entire thyroid gland may total or completion thyroidectomy, surgical treatment
include the excision of cancer that was occult on the is best implemented by the experienced surgeon.
preoperative assessment, and second, the postop- Papillary thyroid cancer often exists with intra-
erative follow-up surveillance for recurrent disease glandular multifocal disease that may not be identi-
is more sensitive if the entire thyroid is removed. Af- fied upon initial evaluation. In a study of 105 patients,
ter a total or near-total thyroidectomy, postoperative Katoh et al. found that intraglandular cancer foci
radioactive iodine can be used to identify and ablate (other than the tumor regarded as the primary focus)
any residual thyroid cancer, and serum thyroglobulin were present in over 78% of patients. Moreover, these
is a more accurate marker of recurrent or persistent multicentric lesions were found in the contralateral
PTC following total thyroidectomy when compared lobe in 61%. The authors concluded that intraglandu-
with more conservative resections of thyroid tissue. lar metastasis is an important characteristic of PTC
Advocates of more conservative procedures con- [13]. This has also been demonstrated in a high pro-
tend that there is a higher risk of complications fol- portion of microcarcinomas of the thyroid, which
lowing total thyroidectomy. Nonetheless, complica- harbor bilateral foci of disease [14].
tion rates less than 2% after total thyroidectomy have A more recent study indicated that approximately
been reported by numerous surgeons with experience 44% of 182 patients studied harbored histologically
in total thyroidectomy (Table 8.1). Factors determin- confirmed PTC at completion thyroidectomy. This
ing the risk for complication from total thyroidectomy bilaterality was independent of risk classification.
include: the extent of thyroid disease, the experience Bilateral tumors at completion thyroidectomy were
of the surgeon, and the anatomic variation of the para- present in patients of both high- and low-risk classi-
thyroid glands, recurrent laryngeal nerves, and exter- fications. This study suggests total thyroidectomy in
nal laryngeal nerves [810]. Major complications of order to eradicate all neoplastic tissue in patients with
total thyroidectomy include vocal cord paralysis sec- PTC. In addition, the authors recommended comple-
ondary to recurrent laryngeal nerve injury, and hypo- tion thyroidectomy for patients with a history of PTC
calcemia due to injury or resection of the parathyroid that were initially treated with more conservative sur-
glands. Regardless, many surgeons achieve compara- gical therapy [15].
ble complication rates for total thyroidectomy, near- Hay et al., from the Mayo clinic, studied local re-
total thyroidectomy, and more conservative proce- currence, nodal and distant metastases in patients
dures [11,12]. Amongst the <2% of patients who had with low-risk PTC based on the AMES prognostic
complications after total thyroidectomy, tumors were classification system. They found that patients who
more likely to be more invasive and involve the recur- underwent lobectomy for PTC had a higher recur-
rent laryngeal nerve, thereby necessitating resection rence rate (14%) and nodal metastases (19%) than
of the nerve. While these data indicate that compli- those patients treated with procedures involving both
cations following total thyroidectomy are rare, they lobes. However, they found no significant difference
are reported from surgeons with extensive operative in survival rate and distant metastases [16]. Other
experience doing total thyroidectomy. In the hands of studies have demonstrated that between 5% and 10%
less experienced surgeons, complication rates may be of recurrences of thyroid cancer occur in the contra-
higher. Therefore, for patients with PTC necessitating lateral lobe [17], indicating that total thyroidectomy

Table 8.1 Complications reported after total thyroidectomy

Authors, year Number Transient Permanent Transient Permanent
of patients nerve paresis; nerve paresis; hypoparathyroidism; hypoparathyroidism;
number (%) number (%) number (%) number (%)
Thompson, 1978 165 NR 0 NR <2%
Clark, 1988 [45] 160 4 (2.5%) 3 (2%) NR 1 (0.6%)
Ley, 1992 [12] 124 1 (0.8%) 1 (0.8%) 13 (10%) 2 (1.6%)
Tartaglia, 2003 1,636 31 (1.9%) 15 (0.9%) NR 14 (0.9%)
Rosato, 2004 [26] 9,599 195 (2%) 94 (1%) 797 (8.3%) 163 (1.7%)
8 Surgery for the Solitary Thyroid Nodule 95

during the initial operation may have been benefi- thyroidectomy compared to lobectomy and isthmu-
cial in these patients. Moreover, complications due sectomy.
to central neck recurrence are the cause of death in Because of the proximity of the recurrent laryn-
50% of patients who die from recurrent thyroid car- geal nerve with respect to the fascia surrounding the
cinoma [18]. In addition, a review of 1,599 patients thyroid (the visceral portion of the pretracheal layer
with differentiated thyroid carcinoma concluded that of deep cervical fascia), it seems plausible to assume
patients with well-differentiated thyroid cancers who that bilateral procedures place the recurrent laryn-
die from their disease most likely die secondary to lo- geal nerve at greater risk for injury than unilateral
cal recurrence [19]. Such complications may best be procedures. On the one hand, unilateral injury to the
avoided by implementation of total thyroidectomy recurrent laryngeal nerve leaves the ipsilateral vocal
and lymphadenectomy as the primary surgical treat- cord paralyzed in the paramedian position, result-
ment for differentiated thyroid cancers. ing in hoarseness of the voice. In addition, the voice
Finally, there is approximately a 1% risk of progres- may often appear breathy, secondary to incomplete
sion from a differentiated thyroid cancer to anaplastic adduction of the vocal cords. This complication can
thyroid cancer. Whereas the prognosis of PTC is very be treated with medialization of the paralyzed cord
good, anaplastic thyroid cancer results in near uni- via type I thyroplasty. However, morbidity is substan-
form lethality. Therefore, elimination of all PTC via tially increased, along with healthcare costs. On the
total thyroidectomy may prevent progression to ana- other hand, bilateral recurrent laryngeal nerve injury
plastic thyroid cancer from residual tissue left behind can result in acute airway obstruction. This may pres-
during thyroid lobectomy and isthmusectomy. ent as postoperative stridor and dyspnea, and may re-
Total thyroidectomy and central neck lymph node quire endotracheal reintubation with establishment of
dissection is indicated for virtually all patients with an alternative airway via tracheostomy. The incidence
PTC when postoperative radioactive iodine is consid- of recurrent laryngeal nerve injury during total thy-
ered (see below for discussion of lymph node man- roidectomy is approximately 11.5% and likely much
agement). In patients with excellent prognosis (tumor less in the hands of the experienced surgeon.
size less than 1 cm, confined to the thyroid without Total thyroidectomy also places the patient at risk
evidence of any metastatic disease, in an otherwise for lifelong hypocalcemia if all parathyroid tissue
healthy female less than 45 years of age), more con- is unintentionally resected with the thyroid gland,
servative approaches may be used. However, lower re- while unilateral procedures do not. In fact, the most
currence and mortality rates are associated even with common underreported morbidity that does occur
patients who have low-risk PTC and undergo total following thyroidectomy is likely transient hypocal-
thyroidectomy [16,20]. Moreover, patients undergo- cemia [21] that can be monitored effectively without
ing total thyroidectomy can also benefit from more difficulty by frequent postoperative examinations
accurate assessment of disease recurrence or residual of the patient. However, a recent study of over 450
disease using serum thyroglobulin levels. In addition, patients who underwent total thyroidectomy demon-
postoperative radioactive iodine scanning and abla- strated that permanent hypocalcemia occurred in
tion are more effective in patients after total thyroid- only 0.7% of all patients. The authors noted that high
ectomy. In cases where injury to the recurrent laryn- serum phosphorus level on postoperative day 7 was
geal nerve or parathyroid glands cannot be avoided, the only independent factor predicting permanent
near-total thyroidectomy can be employed to leave hypoparathyroidism, and thus, permanent hypocal-
behind a small amount of thyroid tissue, followed by cemia [22].
ablation of residual tissue with radioactive iodine. One retrospective study of 109 patients with non-
medullary thyroid cancer with 5- to 30-year follow-
up demonstrated that significantly more complica- Unilateral Lobectomy tions occur with total thyroidectomy when compared
and Isthmusectomy with partial thyroidectomy. Furthermore, no differ-
ences in cancer mortality or recurrence rates amongst
The use of unilateral lobectomy and isthmusectomy patients treated with total thyroidectomy versus par-
for the treatment of differentiated thyroid cancers is tial thyroidectomy were found. The authors therefore
supported by two arguments. First, unilateral proce- recommended the use of partial thyroidectomy for
dures can avoid the risk of some potential complica- non-medullary thyroid cancers [23]. A more recent
tions of bilateral procedures. Second, some studies study demonstrated that there is no survival benefit
have failed to demonstrate a survival benefit of total with total thyroidectomy when compared with partial
96 Prabhat K. Bhama and Gerard M. Doherty

thyroidectomy in patients with PTC in both low- and dissection in the proximity of the parathyroid glands,
high-risk prognostic groups [24]. putting the glands at risk for injury secondary to sur-
A recent study of incidental multifocal papillary gical manipulation. Therefore, careful stratification of
thyroid microcarcinomas (less than or equal to 1 cm) patients into groups requiring lymph node dissection
found that subtotal thyroidectomy followed by adju- and those not requiring lymph node dissection is im-
vant radioiodine therapy is a therapeutic option for portant for minimizing morbidity.
patients with incidental multifocal microcarcinomas. Approximately 80% of patients with PTC also have
However, the authors did note that future studies microscopic regional lymph node metastases [16].
should be pursued for further evaluation of this tech- The optimal diagnostic and therapeutic approaches
nique [25]. for this have not been entirely clear. Microscopic oc-
Despite the significant, life-changing complica- cult metastases may often be ablated by adjuvant ra-
tions reported in the literature secondary to total thy- dioactive iodine therapy, but they may also be a site
roidectomy, major complications occur in less than of persistent disease that would have easily been re-
2% of all thyroid procedures, and complications are moved at the initial operation. While patients with
significantly more likely in secondary procedures that PTC and matted lymph nodes or tumor extending
may be necessary if there is a recurrence. through the lymph node capsule have a worse prog-
nosis, the prognostic significance of lymph node me-
tastases is controversial. [20,27,28]. Recommendations for Extent Gross nodal disease occurs in 2030% of adult cases
of Surgery of PTC, and is certainly justification for lymph node
dissection (Fig. 8.3) [29]. Moreover, lymph node me-
In our opinion, it is important that patients with PTC tastases are also associated with a higher recurrence
be treated by a surgeon with extensive experience in rate when patients are matched for age and gender.
performing total thyroidectomy. Despite the reported Therefore, nodal metastases confirmed by preopera-
complications following total thyroidectomy, compli- tive ultrasound or intraoperative exploration should
cation rates are minimal in the hands of experienced be treated with node dissection [7]. Specifically, re-
surgeons [26] Furthermore, the high incidence of bi- moval of ipsilateral central neck nodes and perithy-
lateral foci in patients with PTC indicates that these roid lymph nodes (Delphian node and lymph nodes
patients are best treated initially with total thyroid- medial to the carotid sheath) or lateral compartment
ectomy, rather than undergoing a follow-up comple- nodes (levels 25) is important for nodes that have
tion thyroidectomy for recurrent or residual disease identifiable involvement with disease. Compartment-
that was not appreciated at the primary evaluation. based resections of lateral neck nodes are preferable
Moreover, total thyroidectomy allows for more accu- to berry-picking if they are clinically involved. For
rate follow-up using thyroglobulin as a marker of re- lateral compartment disease, the best approach is to
sidual or recurrent disease. Postoperative radioactive perform functional modified radical neck dissection,
iodine scanning and ablation is also more effective during which all fibrofatty tissue with lymph nodes
in patients after total thyroidectomy compared with is removed. This procedure spares motor and sensory
more conservative procedures. Finally, studies show nerves, the sternocleidomastoid muscle, and the in-
that a lower recurrence rate and mortality are associ- ternal jugular vein as well, unless they are involve by
ated with total or near-total thyroidectomy in patients tumor.
with even low-risk PTC. Removal of central neck lymph nodes is associated
Thus, in virtually all patients, excluding those with with an improvement in the regional recurrence rate,
the very best prognosis (tumor size less than 1 cm, and an improved survival rate in retrospective studies
confinement to the thyroid without metastases, in an [3032]. This also has the advantage of demonstrat-
otherwise healthy woman under 45 years of age), to- ing which patients have involved nodes, to make the
tal thyroidectomy is the treatment of choice for papil- selection of radioiodine therapy clear, even for those
lary thyroid carcinoma. who may have otherwise apparently good prognostic
tumors (small size and lack of extrathyroidal exten-
sion). The current American Thyroid Association Lymph Node Dissection Guidelines for the management of differentiated
thyroid cancer now call that a staging/prophylactic
As with any surgical procedure, lymph node dissec- level 6 lymph node dissection for all patients under-
tion carries some risk of iatrogenic injury. Specifically, going thyroidectomy for thyroid carcinoma should be
nodal metastases in patients with PTC often requires considered [33].
8 Surgery for the Solitary Thyroid Nodule 97

Fig. 8.3 Left cervical lymph node

metastases detected on preopera-
tive ultrasound examination of the
neck (arrows). The node has the
characteristics of replacement by
metastatic disease, and was in-
volved by FNA cytology. The node
is globular and irregular in shape,
compared to the typical smooth,
fusiform node contour

Fig. 8.4 Metastatic cancer causing

lymphadenopathy in the left neck
of a teenaged woman with thyroid
carcinoma. Detected upon fol-
low-up examination, this enlarged,
irregular node (arrows) led to a
compartmental node dissection for

Prophylactic lateral neck node dissection is not tients by physical examination and ultrasound can
recommended because in patients it is not associated identify patients with lateral neck nodal disease that
with improved overall survival, and involves violation can then be appropriately treated by therapeutic com-
of additional planes by a substantially more extensive partmental node dissection (Fig. 8.4).
operation. However, follow-up of thyroid cancer pa-
98 Prabhat K. Bhama and Gerard M. Doherty

8.3.3 Treatment: Follicular Thyroid Cancer to developing thyroid cancer. Chances of developing
differentiated thyroid cancers are increased by ex-
Despite differences in histological features, treatment posure to radiation. Such exposures occurred more
for follicular thyroid carcinoma (FTC) is similar to often in the 1940s and 1950s than they do now. For
that of PTC. Surgical resection remains the primary instance, external radiation therapy was used to treat
method of therapy for FTC of the thyroid. Moreover, conditions such as tinea capitis, hypertrophic thymus,
the use of total thyroidectomy versus hemithyroid- tonsillitis, acne, and otitis externa. Multiple studies
ectomy is controversial. When dealing with disease have confirmed the increased risk of thyroid cancers
confined to the thyroid (T12 N0 M0), total thyroidec- and benign thyroid nodules in children exposed to
tomy or hemithyroidectomy with extirpation of cen- low doses of radiation therapy [3538]. It is impor-
tral lymph nodes are both adequate. tant to note that exposure to external radiation beam
For larger tumors (T3T4), more extensive therapy therapy increases the risk of developing PTC, but it is
is warranted. Total thyroidectomy along with postop- not associated with the occurrence of FTC.
erative radioactive iodine therapy is indicated in such It has also been found that patients with familial
cases. Proponents of unilateral procedures maintain adenomatous polyposis (FAP) have a predisposition
that bilateral procedures carry an increased risk of toward developing benign and malignant thyroid
morbidity, secondary to recurrent laryngeal nerve neoplasms, specifically, differentiated tumors [39,40].
and parathyroid gland injury. Once again, morbidity FTCs in particular have been associated with FAP,
is minimal in the hands of the experienced surgeon. Gardners syndrome, and Cowdens syndrome, but are
Since follicular tumors spread primarily via hema- most often sporadic.
togenous routes, cervical lymph node metastases are Furthermore, studies have shown that diets both
not as common in FTC when compared with PTC high and low in iodine can also increase the risk of
(35% versus 67%, respectively). However, therapeutic developing thyroid cancer. When iodine uptake is
modified neck dissection is appropriate for patients sufficient, it is likely that a diagnosed differentiated
with clinically apparent disease. Postoperative radio- thyroid carcinoma will be of the papillary type. FTCs
active iodine scans and radioiodine ablation are also are more common in areas that suffer from iodine
essential to help detect any residual disease and elimi- deficiency and endemic goiter. Regions of the world
nate it. suffering from iodine deficiency can exacerbate goi-
ters by consumption of large quantities of cruciferous
vegetables, which block iodine uptake [41].
8.3.4 Treatment: Oncocytic (Hrthle Cell) Whereas certain environmental and innate fac-
Thyroid Cancer tors can influence ones chance of developing thyroid
cancer, the characteristics of a specific tumor or in-
A variant of FTC, oncocytic carcinoma, is also known dividual can dictate the prognosis of the patient. The
as oxyphilic or Hrthle cell carcinoma. While treat- age at initial diagnosis, patient age, gender, and family
ment strategies are similar to those of FTC, it is im- history are all important factors in determining ones
portant to distinguish the two entities. Radioactive prognosis. Specifically, increased recurrence rates are
iodine uptake in oncocytic carcinoma of the thyroid observed amongst patients under age 20 and over age
is much less than that of FTC, therefore, postopera- 60. Moreover, mortality rates increase steadily after
tive diagnosis and ablation of residual disease with age 40 [42]. Nuclear atypia, tumor necrosis, vascu-
radioactive iodine is more difficult in patients with lar invasion, and other characteristics of histological
oncocytic thyroid cancer. Because of similarities in grade are also influential prognostic factors in pa-
the natural history and prognosis with FTC, treat- tients with thyroid cancer [43].
ment of oncocytic cell carcinoma is similar to that of
FTC [34].
8.5 Summary

8.4 Risk Stratification Thyroid nodules are quite common, and the basis of
for Cancer Treatment their evaluation is the FNA cytology. However, some
tumors cannot be completely characterized by FNA,
Certain environmental and genetic factors play an and so require at minimum a diagnostic ipsilateral
important role in predisposing particular individuals thyroid lobectomy for definitive histology. In such
8 Surgery for the Solitary Thyroid Nodule 99

cases, complete lobectomy is the minimum proce- 13. Katoh R, et al (1992) Multiple thyroid involvement (in-
dure, to avoid the potential need for further operation traglandular metastasis) in papillary thyroid carcinoma. A
on that side of the trachea. clinicopathologic study of 105 consecutive patients. Can-
Differentiated thyroid carcinoma is best treated cer 70:15851590
by total thyroidectomy, which is safe in experienced 14. Pellegriti G, et al (2004) Clinical behavior and outcome
hands. The best prognosis cancers can be managed of papillary thyroid cancers smaller than 1.5 cm in diam-
by lobectomy alone with careful surveillance of the eter: study of 299 cases [see comment]. J Clin Endocrinol
remaining lobe. Lateral neck dissection is reserved Metab 89:37133720
for clinically evident cancer involvement of that com- 15. Pacini F, et al (2001) Contralateral papillary thyroid can-
cer is frequent at completion thyroidectomy with no dif-
partment, though central neck (level 6) node dissec-
ference in low- and high-risk patients [see comment].
tion should be a part of every initial thyroid cancer
Thyroid 11:877881
16. Hay ID, et al (1998) Unilateral total lobectomy: is it suf-
ficient surgical treatment for patients with AMES low-risk
papillary thyroid carcinoma? Surgery 124:958964; dis-
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17. Tollefson HR, Shah JP, Huvos AJ (1972) Papillary carci-
1. Singer PA, et al (1996) Treatment guidelines for patients noma of the thyroid. Recurrence in the thyroid gland after
with thyroid nodules and well-differentiated thyroid initial treatment. Am J Surg 124:468472
cancer. American Thyroid Association. Arch Int Med 18. Silverberg SG, Hutter RV, Foote FW Jr (1970) Fatal carci-
156:21652172 noma of the thyroid: histology, metastases, and causes of
2. Kumar H, et al (1999) Gender, clinical findings, and se- death. Cancer 25:792802
rum thyrotropin measurements in the prediction of thy- 19. Samaan NA, et al (1992) The results of various modali-
roid neoplasia in 1005 patients presenting with thyroid ties of treatment of well differentiated thyroid carcinomas:
enlargement and investigated by fine-needle aspiration a retrospective review of 1599 patients. J Clin Endocrinol
cytology. Thyroid 9:11051109 Metab 75:714720
3. Gharib H, Goellner JR, Johnson DA (1993) Fine-needle 20. DeGroot LJ, et al (1990) Natural history, treatment, and
aspiration cytology of the thyroid. A 12-year experience course of papillary thyroid carcinoma. J Clin Endocrinol
with 11,000 biopsies. Clin Lab Med 13:699709 Metab 71:414424
4. Cersosimo E, et al (1993) Suspicious thyroid cytologic 21. Flynn MB, et al (1994) Local complications after surgical
findings: outcome in patients without immediate surgical resection for thyroid carcinoma. Am J Surg 168:404407
treatment. Mayo Clin Proc 68:343348 22. Pisanu A, et al (2005) Hypocalcemia following total thy-
5. Nagai GR, et al (1987) Scintigraphic hot nodules and thy- roidectomy: early factors predicting long-term outcome.
roid carcinoma. Clin Nucl Med 12:123127 Giornale di Chirurgia 26:131134
6. Smith J, et al (2005) Can cytology accurately predict be- 23. Schroder DM, Chambous A, France CJ (1986) Operative
nign follicular nodules? Am J Surg 189:5925; discussion strategy for thyroid cancer, is total thyroidectomy worth
595 the price? Cancer 58:2320
7. Soh EY, Clark OH (1996) Surgical considerations and ap- 24. Haigh PI, Urbach DR, Rotstein LE (2005) Extent of thy-
proach to thyroid cancer. Endocrinol Metab Clin North roidectomy is not a major determinant of survival in low-
Am 25:115139 or high-risk papillary thyroid cancer. Ann Surg Oncol
8. Udelsman R, Shaha AR (2005) Is total thyroidectomy the 12:8189
best possible surgical management for well-differentiated 25. Dietlein M, et al (2005) Incidental multifocal papillary
thyroid cancer? Lancet Oncol 6:529531 microcarcinomas of the thyroid: is subtotal thyroidectomy
9. Udelsman R (2004) Experience counts [comment]. Ann combined with radioiodine ablation enough? Nucl Med
Surg 240:2627 Commun 26:38
10. Sosa JA, et al (1998) The importance of surgeon experi- 26. Rosato L, et al (2004) Complications of thyroid surgery:
ence for clinical and economic outcomes from thyroidec- analysis of a multicentric study on 14,934 patients oper-
tomy. Ann Surg 228:320330 ated on in Italy over 5 years. World J Surg 28:271276
11. Reeve T, Thompson NW (2000) Complications of thyroid 27. Akslen LA (1993) Prognostic importance of histo-
surgery: how to avoid them, how to manage them, and logic grading in papillary thyroid carcinoma. Cancer
observations on their possible effect on the whole patient. 72:26802685
World J Surg 24:971975 28. Akslen LA, et al (1991) Survival and causes of death in
12. Ley PB, et al (1993) Safety and efficacy of total thyroidec- thyroid cancer: a population-based study of 2479 cases
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100 Prabhat K. Bhama and Gerard M. Doherty

29. Mirallie E, et al (1999) Localization of cervical node 39. Cetta F, et al (2001) Thyroid carcinoma usually occurs in
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23:970973; discussion 973974 sence of biallelic inactivation of the adenomatous polypo-
30. Gemsenjager E, et al (2003) Lymph node surgery in papil- sis coli gene. J Clin Endocrinol Metab 86:427432
lary thyroid carcinoma. J Am Coll Surg 197:182190 40. Cetta F, et al (2000) Germline mutations of the APC gene
31. Tisell LE (1998) Role of lymphadenectomy in the treat- in patients with familial adenomatous polyposis-associ-
ment of differentiated thyroid carcinomas. Br J Surg ated thyroid carcinoma: results from a European coopera-
85:10251026 tive study. J Clin Endocrinol Metab 85:286292
32. Tisell LE, et al (1996) Improved survival of patients with 41. Bacher-Stier C, et al (1997) Incidence and clinical charac-
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with thyroid nodules and well-differentiated thyroid can- initial surgical and medical therapy on papillary and fol-
cer. American Thyroid Association. Thyroid 16:10942 licular thyroid cancer [see comment] [erratum appears in
34. Cooper DS, Schneyer CR (1990) Follicular and Hrthle Am J Med 1995 98:215]. Am J Med 97:418428
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North Am 19:577591 of histologic grading compared with subclassification
35. Ron E, et al (1995) Thyroid cancer after exposure to ex- of papillary thyroid carcinoma [see comment]. Cancer
ternal radiation: a pooled analysis of seven studies. Radiat 88:19021908
Res 141:259277 44. Thompson NW, Nishiyama RH, Harness JK (1978) Thy-
36. Ron E, Modan B (1980) Benign and malignant thyroid roid carcinoma: current controversies. Curr Probl Surg
neoplasms after childhood irradiation for tinea capitis. 15:167
J Natl Cancer Inst 65:711 45. Clark OH, et al (1988) Thyroid cancer: the case for total
37. Shore RE (1992) Issues and epidemiological evidence thyroidectomy. Eur J Cancer Clin Oncol 24:305313
regarding radiation-induced thyroid cancer. Radiat Res 46. Tartaglia F, et al (2003) Complications in total thyroid-
131:98111 ectomy: our experience and a number of considerations.
38. Shore RE, et al (1993) Thyroid cancer among persons Chir Ital 55:499510
given X-ray treatment in infancy for an enlarged thymus
gland. Am J Epidemiol 137:10681080

9 Modified Radical Neck Dissection

Robert Udelsman

Contents radical neck dissection is well-tolerated and results

in excellent cosmetic, functional, and oncologic out-
9.1 Introduction . . . 101 comes [6,7].
9.2 Operative Technique . . . 102
The technique of radical neck dissection was de-
References . . . 107
scribed by George Crile in 1906 [8]. This extirpative
procedure was often used in the setting of metastatic
head and neck cancers, often of squamous cell origin,
with metastases to the cervical lymph nodes. The op-
9.1 Introduction eration encompassed removal of the cervical nodes
and sacrifice of the internal jugular vein, spinal acces-
Neck dissections play an essential role in the manage- sory and greater auricular nerves, as well as the sterno-
ment of head and neck cancer. Their role in the man- cleidomastoid, digastric, and stylohyoid muscles. This
agement of thyroid cancer is somewhat controversial radical neck dissection was modified to encompass an
and limited by the absence of prospective clinical tri- oncologically equivalent cervical lymphadenectomy
als. The dilemma is further complicated by the indo- while preserving functional structures including the
lent history of most well-differentiated thyroid can- sternocleidomastoid muscle, internal jugular vein,
cers and the common occurrence of both clinically spinal accessory and greater auricular nerves, as well
significant and occult cervical lymph node metastases as the digastric and stylohyoid muscles. Accordingly,
particularly in young patients with papillary carci- a modified radical neck dissection is also referred to
noma of the thyroid. A strong indication for modified as a functional or Bocca neck dissection [9].
radical neck dissection in the setting of well-differen- Patients with thyroid cancer are usually treated
tiated thyroid cancer is the finding of cervical lymph- with a total or near-total thyroidectomy followed by
adenopathy by either palpation or an imaging study. radioactive iodine therapy and life-long thyroid hor-
Confirmation of metastatic disease can be obtained mone suppression. A subset of patients either present
by a preoperative fine-needle aspiration (FNA) which with metastatic nodal disease or develop metachro-
can be performed under ultrasound guidance. nous nodal disease later in their course. The most
Cervical lymphadenopathy is not uncommon in frequent sites of metastases are the central cervical
the setting of well-differentiated thyroid cancer. A re- nodes (level VI) bounded by the hyoid bone superi-
cent series reported the frequent occurrence of metas- orly, the innominate vein inferiorly, and bilaterally by
tases in both the central (64.1%) and lateral (44.5%) the carotid sheath [10]. Small lymph nodes are fre-
neck [1]. In the past many surgeons advocated local quently encountered in this central region during ini-
berry picking resections designed to remove grossly tial thyroidectomy and should be resected when they
enlarged nodes [2,3]. These berry picking proce- are suspicious for metastatic disease as evidenced by
dures are associated with a higher local recurrence enlargement, firmness, or irregularity by palpation.
rate necessitating remedial surgery that is associated A modified radical neck dissection refers to resec-
with a higher complication rate [4]. The complica- tion of the lymph nodes in levels II through V and
tion rate associated with functional neck dissections often including the central nodes in level VI. This
is no higher than that associated with berry picking chapter describes the operation in detail. It can be
procedures [4]. It is noteworthy that limited modified performed as an isolated procedure or in combination
neck dissections in which the superior extent of sur- with a total thyroidectomy. It can also be performed
gery is limited to the spinal accessory nerve are also bilaterally. It is often performed for well-differentiated
associated with residual and recurrent disease due to thyroid cancers, most commonly papillary carcinoma
skip metastases [5]. A carefully performed modified of the thyroid. Occasionally patients with follicular
102 Robert Udelsman

or Hrthle cell carcinoma also require modified neck is extended bilaterally and an apron flap is raised su-
dissections. Patients with medullary carcinoma of the periorly. Because the spinal accessory nerve is super-
thyroid present a unique set of challenges and, due ficial it is important for the surgeon to note the sur-
to the absence of effective adjuvant therapy, surgery face landmarks depicting the course of the accessory
plays an even more dominant role in their manage- nerve. If one were to connect a line between the angle
ment. Furthermore, medullary cancer of the thyroid of the mandible and the mastoid process and transect
has an early predilection for both central and lateral this line at a right angle in its mid-portion, the infe-
nodal dissemination. The detailed management plan rior course of that line would be a close approxima-
for medullary carcinoma of the thyroid is beyond the tion of the course of the spinal accessory nerve. It is
scope of this chapter. The description of the operative well worth drawing this on the patients skin at the
procedure for a modified radical neck dissection per- time of surgery. The marginal mandibular nerve is
formed in isolation is described, as the technique of protected superiorly but is rarely seen in this expo-
thyroidectomy is illustrated in Chapter 7. sure. Once the incision is made skin hooks are uti-
lized to develop the anterior flap which is raised with
an electrocautery.
9.2 Operative Technique In Fig. 9.2 the anterior and posterior flaps are com-
pleted and the underlying anatomy is demonstrated.
The patient is placed on the operating table with the The anterior flap is created in the subplatysmal layer
head extended and the neck and anterior chest are and developed as the skin is pulled toward the medial
prepared for surgery (Fig. 9.1). An inflatable thyroid neck. Once the anterior flap has been developed, the
pillow is placed behind the patients back. A linear posterior flap is developed. The sternocleidomastoid
incision is made that extends from the mid-neck as muscle, external jugular vein, and greater auricular
a continuation of a Kocher incision extending supe- nerve are shown. The greater auricular nerve anatomy
riorly to approximately 1 inch below the left earlobe. is extremely important serving as a landmark as the
If a bilateral neck dissection is required this incision nerve emerges from the lateral aspect of the sterno-

Fig. 9.1 An inflatable pillow is placed behind the pa-

tients back and the head is extended and supported by
a head ring. The course of the spinal accessory nerve
is marked on the patients skin. The most commonly
employed incision for thyroid cancer is a continuation
of a Kocher incision along the posterior border of the
sternocleidomastoid muscle superiorly to approxi-
mately 1 inch below the ipsilateral ear lobe
9 Modified Radical Neck Dissection 103

cleidomastoid muscle at Erbs point. The nerve then nocleidomastoid muscle (note there are two heads, a
traverses upward over the muscle going toward the sternal head and a clavicular head) and the muscle is
earlobe. Preservation of this nerve is readily accom- pulled medially. If the patient is particularly muscu-
plished thereby preserving sensation to the earlobe. lar, it is useful to place separate drains around each
As the posterior flap is developed, great care and at- head facilitating enhanced exposure. The omohyoid
tention must be focused on protecting the spinal muscle is identified and deep to it the carotid sheath
accessory nerve which is superior to the greater au- is located. A thin Penrose drain is placed around the
ricular nerve. The trapezius muscle is identified pos- omohyoid and in the majority of cases this muscle
terolaterally and the accessory nerve will course from is preserved. The three structures of the sheath, the
behind the sternocleidomastoid muscle eventually in- common carotid artery, vagus nerve, and internal
nervating the trapezius muscle. A nerve stimulator is jugular vein, are carefully protected. Frequently vessel
quite useful in locating the accessory nerve. Once the loops are placed around these structures to assist with
flaps have been completed, a self-retaining retractor mobilization. One must be very careful not to injure
is used to hold the skin and platysma in place. Fre- the sympathetic trunk that lies deep to the common
quently the skin is sewn to the retractor for added carotid artery as injury to this structure will result in
exposure. At this point, the external jugular vein is Horners syndrome. Occasionally, it is necessary to
identified superiorly and ligated to form the apex of sacrifice the internal jugular vein due to tumor inva-
the tissues that will be unwrapped from the sterno- sion; however, this is unusual in the setting of well-
cleidomastoid muscle. differentiated thyroid cancer. Maintaining the integ-
The fascial sheath covering the sternocleidomas- rity of the anterior jugular veins is important as they
toid muscle is shown being unwrapped in Fig. 9.3. become an effective collateral drainage system when
The flap, once developed, is mobilized from superior the internal jugular vein is sacrificed.
to inferior (Fig. 9.4). Once this has been performed At this point the cervical fat pad extending below
(Fig. 9.4) a Penrose drain is placed around the ster- the clavicle is mobilized from inferior to superior. The

Fig. 9.2 The subplatysmal flaps have been developed

anteriorly and posteriorly. The greater auricular and
spinal accessory nerves have been identified and
preserved. The sternocleidomastoid muscle and the
external jugular vein are visualized
104 Robert Udelsman

Fig. 9.3 The external jugular vein is ligated superi-

orly and the fascial sheath covering the sternocleido-
mastoid muscle is unwrapped. Lymph nodes along
the great vessels of the neck are commonly encoun-
tered at this point

Fig. 9.4 A Penrose drain is placed around the sternocleido-

mastoid and the muscle is pulled anteriorly. The omohyoid
muscle is preserved and the carotid sheath is identified

carotid sheath structures and particularly the thoracic lymphatic leak which often leads to a lymphocele and
duct are protected. An unrecognized injury to the infection. It is prudent to tie the lymphatic tissues in-
thoracic duct can cause a troublesome postoperative feriorly to minimize lymphatic leaks.
9 Modified Radical Neck Dissection 105

Fig. 9.5 The cervical fat pad containing lymphatics

and nodes is mobilized from below the clavicle and
pulled superiorly. The thoracic duct, phrenic nerve,
and brachial plexus are protected. As the specimen
is mobilized it is passed under the omohyoid muscle
and traction is applied to the specimen superiorly

The next step is to identify the phrenic nerve A useful trick to help locate the hypoglossal nerve is
which lies lateral to the vagus nerve (Fig. 9.5). This to follow the branch of the ansa cervicalis nerve as it
is an important landmark to identify as it innervates courses superiorly along the anterior surface of the
the diaphragm. It also represents the deep margin of carotid artery until it joins the hypoglossal nerve at
the specimen lying superficial to the anterior scalene a right angle. Stimulation of the hypoglossal nerve
muscle. All superficial fat and lymph node-bearing will result in a movement of the tongue. In addition,
tissues are resected anterior to the phrenic nerve as the proximal accessory nerve must be identified at
this block of tissue is swept from inferior to superior. the medial aspect of the sternocleidomastoid muscle
The specimen is then passed beneath the omohyoid as soft tissues along the accessory nerve are included
muscle as the dissection continues as shown and the with the specimen. The nerve can be felt like a violin
specimen is pulled superiorly. The omohyoid muscle string if one distracts the sternocleidomastoid muscle
and phrenic nerve are shown, the brachial plexus is posteriorly. It is extremely important to protect this
identified laterally, and superiorly the accessory nerve nerve. All tissues inferior to the digastric muscle and
is seen. Branches of the transverse cervical nerves hypoglossal nerve are resected in continuity with the
are usually sacrificed. However, it is not difficult to specimen as the final tissues are removed from the
preserve one or more of these branches and thereby great vessels and vagus nerve.
maintain sensation to the skin of the ipsilateral shoul- At the completion of the operation, shown in
der. The soft tissues underneath the accessory nerve Fig. 9.7, a Penrose drain has been placed around the
are mobilized and included with the specimen. sternocleidomastoid muscle and the omohyoid mus-
Figure 9.6 shows the specimen has now been mo- cle; the common carotid artery, vagus nerve, internal
bilized off the sternocleidomastoid muscle and has jugular vein, phrenic nerve, brachial plexus, accessory
been passed from the lateral aspect of the muscle un- nerve, and greater auricular nerve are all preserved.
derneath the muscle belly anteriorly. At this point, a Closure is obtained by reapproximating the platysma
thyroid retractor is placed underneath the mandible muscle with interrupted sutures and a subcuticular
and the mandible is pulled superiorly. The parotid and closure of the skin. A drain is always placed due to the
submandibular glands are preserved and the digastric extensive lymphadenectomy.
muscle is identified. Inferior to the digastric muscle The operation is well-tolerated and the vast major-
is the hypoglossal nerve which must be identified. ity of patients are extubated in the operating room.
106 Robert Udelsman

Fig. 9.6 The specimen is passed from its lateral

position underneath the sternocleidomastoid
muscle and is pulled from an inferior-medial
direction. A thyroid retractor is used to pull the
mandible superiorly and the digastric muscle is
identified. The hypoglossal and proximal spinal
accessory nerves are identified and preserved.
The cervical fat tissues with their contained
lymphatics are resected in continuity as the
specimen is pulled off the great vessels

Fig. 9.7 The specimen has been removed. The sterno-

cleidomastoid and omohyoid muscles are intact. The
common carotid artery, internal jugular vein, as well as
the vagus, phrenic, spinal accessory, greater auricular, and
hypoglossal nerves are all preserved. The brachial plexus
is intact
9 Modified Radical Neck Dissection 107

References 6. Gemsenjger E, et al (2003) Lymph node surgery in papil-

lary carcinoma. J Am Coll Surg 197:182190
1. Wada N, et al (2003) Lymph node metastases from 259 pap- 7. Kupferman ME, et al (2004) Safety of modified radical
illary thyroid microcarcinomas. Ann Surg 237:399407 neck dissection for differentiated thyroid carcinoma. La-
2. Raina S, et al (1983) Current attitudes in the management ryngoscope 114:403406
of thyroid cancer. Am Surg 49:110112 8. Crile G (1906) Excision of cancer of the head and neck.
3. Nicolosi A, et al (1993) The role of node-picking lymph- JAMA 47:17861789
adenectomy in the treatment of differentiated carcinoma 9. Bocca E, et al (1980) Functional neck dissection: a de-
of the thyroid. Minerva Chir 48:459463 scription of operative technique. Arch Otolaryngol
4. Munacchio MJ, et al (2003) Greater local recurrence oc- 106:524527
curs with berry picking than neck dissection in thyroid 10. Greene FL, et al (eds) (2002) AJCC cancer staging manual,
cancer. Am Surg 69:191197 6th edn. Springer, New York, pp 7787
5. Pingpank JF, et al (2002) Tumor above the spinal accessory
nerve in papillary thyroid cancer that involves lateral neck
nodes. Arch Otolaryngol Head Neck Surg 128:12751278

10 Thyroid Pathology

Zubair W. Baloch and Virginia A. LiVolsi

Contents 10.1 Normal Thyroid

10.1 Normal Thyroid . . . 109 The normal thyroid is a bilobed gland, connected by
10.2 Developmental Variations . . . 110
an isthmus. It is encased by a thin capsule that does
10.3 Goiter . . . 110
not strip easily and contains sizable venous channels.
10.3.1 Graves Disease . . . 111
The weight of normal thyroid in the United States
10.3.2 Dyshormonogenetic Goiter . . . 112
ranges from 10 to 20 g. The follicle is the functional
10.3.3 Iatrogenic and Related Hyperplasias . . . 112
unit of the thyroid and averages about 20 m in di-
10.4 The Thyroiditides . . . 113
10.4.1 Acute Thyroiditis . . . 113
ameter [1,2,3,4]. A thyroid lobule consists of 2040
10.4.2 Granulomatous Thyroiditis . . . 113 follicles bound together by a thin sheath of connec-
10.4.3 Palpation Thyroiditis . . . 113 tive tissue and supplied by a lobular artery [3,5]. The
10.4.4 Autoimmune Thyroiditis . . . 113 thyroid follicles are formed by a single layer of low
10.4.5 Chronic Lymphocytic cuboidal epithelium. The nucleus of the follicular
Thyroiditis Classification . . . 114 cell is round to ovoid in shape; it is usually centrally
10.4.6 Fibrosing Variant placed with an inconspicuous nucleolus. The follicle
of Hashimotos Thyroiditis . . . 114 is enveloped by a basal lamina and is surrounded by
10.4.7 Painless/Silent Thyroiditis . . . 114 numerous capillaries and lymphatics [5,6]. The fol-
10.4.8 Focal Non-specific Thyroiditis . . . 114 licular lumen contains colloid, partly composed of
10.4.9 Riedels Thyroiditis . . . 115 thyroglobulin, which is evenly applied to the luminal
10.4.10 Combined Riedels Disease cell borders. Calcium oxalate crystals are common in
and Hashimotos Thyroiditis . . . 115 the colloid of adults.
10.5 Amiodarone Injury with Thyrotoxicosis . . . 115 Electron microscopy demonstrates that the nor-
10.6 Miscellaneous Disorders . . . 115 mal flat to low cuboidal follicular cells interdigitate
10.6.1 Radiation Effects . . . 115 and overlap one another, and that they are intimately
10.6.2 Amyloidosis . . . 115 related to the capillaries that surround the follicle; mi-
10.6.3 Black Thyroid . . . 116 crovilli on the apical surface are numerous near the
10.7 Neoplasms . . . 116
cellular margins [6,7].
10.7.1 Benign Neoplasms . . . 116
C cells are intrafollicular and are seen next to the Adenomas and Adenomatous Nodules . . . 116
follicular cells and within the basal lamina that sur-
10.7.2 Malignant Neoplasms . . . 117
rounds each follicle of the normal gland. C cells are Papillary Carcinoma . . . 117
most numerous in the central portions of the middle Follicular Carcinoma . . . 123 Anaplastic Thyroid Tumors . . . 126
and upper thirds of the thyroid lobes [3]. They are Thyroid Sarcoma . . . 127 believed to originate from the C cells that arise from Squamous Cell Carcinoma, Mucoepidermoid the neural crest and migrate with the ultimobranchial
Carcinoma, and Intrathyroidal body into the thyroid. C cells are typically more nu-
Thymoma-like Neoplasms . . . 127 merous in thyroids of infants as compared to adult Medullary Carcinoma . . . 128 glands [8,9]. They are polygonal to spindle shaped,
10.7.3 Lymphoma . . . 130 have light or low density, cytoplasm, and contain
10.7.4 Thyroid Tumors in Unusual Locations . . . 130 numerous membrane-bound cytoplasmic granules
10.7.5 Metastatic Neoplasms . . . 130 containing calcitonin. A small number of C cells (or
10.8 Frozen Section Diagnosis cells similar to them) contain somatostatin and can
and the Thyroid . . . 130 increase in number in some patients [1013].
References . . . 131 C cell aggregates can be sizeable (hyperplastic)
in some adults without any known endocrinologic
110 Zubair W. Baloch and Virginia A. LiVolsi

abnormality [14]. C cell hyperplasia is defined as gland proper and, rarely, can serve as the origin of an
consisting of more than 40 C cells/cm2 and the pres- intrathyroidal cyst [25]. Parathyroid glands, thymic
ence of at least three low-power microscopic fields tissue, small collections of cartilage, and glands lined
containing more than 50 C cells [15]. The small by ciliated cells may be seen in normal thyroids, pre-
solid cell nests of ovoid to spindled epidermoid cells sumably related to defective development of the bran-
in thyroid are also considered to be of ultimobran- chial pouches [3133].
chial origin [15]. Typically, the nests have about the Because of the intimate relationship that exists in
same distribution in the thyroid lobes as the C cells the embryo between the immature thyroid tissue and
[16,17]. The term mixed follicles [18] applies to fol- the adjacent developing skeletal muscle, strips of stri-
licles which are lined by follicular cells and epider- ated muscle are occasionally included within the thy-
moid cells (and sometimes C cells) and contain both roid [3436].
colloid and mucoid material. The ultimobranchial Thyroid tissue can be found in close proxim-
structures probably also give rise to a small propor- ity or within the perithyroidal skeletal muscle. Such
tion of normal thyroid follicles [18]. collections of thyroid tissue are particularly promi-
Oxyphil cells (oncocytes, Askanazy cells, Hrthle nent when the gland is hyperplastic or is affected by
cells) are altered/metaplastic follicular cells; they are chronic lymphocytic thyroiditis; these should not be
enlarged, have granular eosinophilic cytoplasm, and confused with carcinoma [34,37].
have large, hyperchromatic, or bizarre nuclei [19]. Groups of thyroid follicles in lateral cervical lymph
The cytoplasm is filled with enlarged mitochondria. nodes always represent metastatic carcinoma (papil-
They are common in longstanding Graves disease, lary carcinoma) [34,37,38]. A few experienced pa-
autoimmune thyroiditis, thyroids affected by radia- thologists state normal thyroid follicles rarely occur
tion, follicular-derived neoplasms, and some adeno- in cervical lymph nodes [39]. Hence normal thyroid
matous nodules [1921]. tissue lying only within the capsule of a midline node
Small aggregates of lymphoid cells in the thyroid may represent an embryologic remnant and not met-
stroma can be seen in normal thyroid gland [22]. astatic cancer [39,40].
Also present in the interstitial tissue are antigen-pre-
senting dendritic cells; these are sparse in the normal
gland but are increased in autoimmune thyroid dis- 10.3 Goiter
ease [23,24].
Goiter is a diffuse or nodular enlargement of the
gland usually resulting from a benign process or a
10.2 Developmental Variations process of unknown origin [4143]. When there is
a deficiency of circulating thyroid hormone because
The thyroglossal tract extends in the midline from of inborn errors of metabolism, iodine deficiency, or
the foramen cecum at the base of the tongue to the goitrogenic agents, and if the hypothalamic-pituitary
isthmus of the normal gland [25]. The tract consists axis is intact, production of thyroid-stimulating hor-
of connective tissue, the thyroglossal duct, lymphoid mone (TSH; thyrotropin) is increased; consequently,
tissue, and thyroid follicles; it is attached to and may cellular activity and increased glandular activity and
extend through the center of the hyoid bone and is glandular mass result in an attempt to achieve the eu-
intimately related to the surrounding skeletal muscle. thyroid state [4345].
Thyroid tissue may persist at the base of the tongue Worldwide, the most common cause for a deficient
and in some patients may be the only thyroid pres- output of thyroid hormone is an inadequate amount
ent [25,26]. The thyroglossal duct is typically lined of iodine in the diet, leading to iodine-deficiency goi-
by ciliated pseudostratified epithelium. If the duct is ter (endemic goiter) [46,47]. Other causes of hyper-
traumatized or infected, the epithelium may undergo plasia include inborn errors of thyroid metabolism
alteration to transitional or squamous type, or maybe (dyshormonogenetic goiter) [48,49], dietary goitro-
totally be replaced by fibrous tissue. Foreign body re- gens, and goitrogenic drugs and chemicals [5053].
action and chronic inflammation may be conspicu- The pathologic changes of simple non-toxic goi-
ous. If fluid accumulates in part of the thyroglossal ter include one or more of the following: (1) hyper-
duct, a thyroglossal cyst may develop [3,27,28]. plasia, (2) colloid accumulation, and (3) nodularity
Any type of diffuse thyroid disease can involve [41,54,55]. Hyperplasia represents the response of the
lingual thyroid and the thyroid tissue along the thy- thyroid follicular cells to TSH, other growth factors, or
roglossal tract [2830]. In rare instances portions to circulating stimulatory antibodies [34,55,56]. The
of thyroglossal duct are included within the thyroid hyperplasia may compensate for thyroid hormonal
10 Thyroid Pathology 111

deficiency, but in some cases, even severe hyperplasia

does not lead to sufficient hormonal output to avoid
development of hypothyroidism.
If the deficiency of thyroid hormone occurs at
birth or early in life, cretinism or juvenile myxedema
may result, even though the gland is enlarged and hy-
perplastic; this is especially likely when an inborn er-
ror of thyroidal metabolism is present [57,58]. A hy-
perplastic gland is diffusely enlarged, and not nodular
Thyroid follicles are collapsed and contain only
scanty colloid. The follicular cells are enlarged and
columnar in shape with nuclear enlargement, hyper-
chromasia, and even pleomorphism. When the hy- Fig. 10.1 Thyroid follicles lined by low cuboidal epithelium
perplastic stage is extreme and prolonged, there may and expanded by thin colloid consistent with colloid goiter
be confusion with carcinoma because of the degree of
cellularity and the presence of enlarged cells. Because
of follicular collapse and epithelial hyperplasia and TSH and/or iodide deficiency. Growth of goiters
hypertrophy, papillary formation can occur [59]. This therefore may be related to focally excess stimulation
pattern occurs most often in untreated dyshormono- by TSH, stimulation by growth factors, focally abnor-
genetic goiter [48]. The recognition of the benign na- mal iodide concentration, growth-promoting thyroid
ture of this process is possible because of its diffuse antibodies, and poorly understood intrathyroidal fac-
nature [59], unlike carcinoma, in which the tumors tors [47].
grow as localized groups of abnormal cells with a Nodular goiter is essentially a process involving
background of non-neoplastic parenchyma. the entire gland, but the nodularity may be asym-
Thyroid follicles may not remain in a state of con- metric, and individual nodules within the same gland
tinuous hyperplasia but instead undergo a process may vary greatly in size. If one nodule is much larger
called involution, with the hyperplastic follicles reac- or more prominent than the others (dominant nod-
cumulating colloid. The epithelium becomes low cu- ule), distinguishing it from a true neoplasm (such as
boidal or flattened and resembles that of the normal adenoma) may not be possible [37,63]. Several stud-
gland. The gland is diffusely enlarged, soft, and has a ies have shown that about 70% of dominant nodules
glistening cut surface because of the excess of stored in nodular goiter are indeed clonal proliferations
colloid. In addition to large follicles filled with col- [64,65]. The formation of cysts, hemorrhage, fibrosis,
loid, there are foci in the gland where hyperplasia is and calcification further complicates the assessment
still evident (Fig. 10.1). This phase of non-toxic goiter of the gland [34,37].
is often termed colloid goiter [60,61]. The heterogeneity of the generations of replicating
Patients with long-standing thyroid disorders as- follicular cells, in response to outside stimuli, func-
sociated with deficiency of circulating thyroid hor- tional capacity, and rate of growth, forms groups of
mone typically develop nodular goiters that result cells that are hyperfunctional or autonomous, or
from overdistention of some involuted follicles, and both. These form hot nodules that may cause hy-
persistence of the zones of epithelial hyperplasia. The perthyroidism (Plummers disease) [66].
new follicles form nodules and may be heterogeneous
in their appearance, in their capacity for growth and
function, and in their responsiveness to TSH. The 10.3.1 Graves Disease
vascular network is altered through the elongation
and distortion of vessels leading to hemorrhage, ne- This disorder is also termed diffuse toxic goiter; it is
crosis, inflammation, and fibrosis. These localized characterized by diffuse enlargement of the thyroid
degenerative and reparative changes produce some up to several times normal size. The capsule is smooth
nodules that are poorly circumscribed, and others and the gland is hyperemic. The cut surfaces are fleshy
that are well demarcated and resemble true adenomas and lack normal translucence because of loss of col-
(adenomatous goiter) [62,63]. Because the nodules loid. If the patient is untreated, the microscopic ap-
distort vascular supply to some areas of the gland, pearance shows cellular hypertrophy and hyperplasia
some zones will contain larger than normal amounts [34,67]. The follicular cells are tall columnar and are
of TSH and/or iodide and others will have relative arranged into papillary formations that extend into
112 Zubair W. Baloch and Virginia A. LiVolsi

In some patients the lymphocytic infiltration is

very prominent and resembles the gland affected by
chronic lymphocytic thyroiditis [34].

10.3.2 Dyshormonogenetic Goiter

When an inborn error of thyroid metabolism ex-

ists, and a sufficient amount of circulating thyroid
hormone is not available, the normal physiologic re-
sponse of the pituitary to increase TSH causes a larger,
more active thyroid that may or may not be able to
produce enough hormones to reach a euthyroid state.
Fig. 10.2 Graves disease, papillary hyperplasia. Cells lining The prolonged and marked TSH stimulation leads
the papillae show eosinophilic cytoplasm and round nuclei to an enlarged and nodular thyroid; microscopically
with even chromatin pattern (inset) there is enlargement of follicular cells, virtual absence
of colloid, and increased stroma [49,76].
Large follicular cells with bizarre, hyperchromatic
the lumina of the follicles (Fig. 10.2). Blood vessels nuclei may be numerous. The enlarged gland, the bi-
are congested. At the ultrastructural level, microvilli zarre cells, and the cellular nodules have at times been
are increased in number and elongated, the Golgi ap- mistaken for carcinoma [48] (Fig. 10.3). Cancer can
paratus and endoplasmic reticulum are enlarged, and occur in a dyshormonogenetic goiter, but it is very
mitochondria are numerous [56,67]. Lymphoid in- rare [48,77].
filtrates are seen between the follicles, ranging from
minimal to extensive. T cells predominate among the
epithelial cells (cytotoxic suppressor cells) and in the 10.3.3 Iatrogenic and Related Hyperplasias
interstitial tissue (helper inducer cells) where there are
no lymphoid follicles [68]. B cells are numerous in the Chronic ingestion of excess iodide, for whatever rea-
lymphoid follicles. Class II major histocompatibility son, occasionally leads to diffuse hyperplasia. Small
complex antigens are expressed on the epithelial cells, nodules with papillary formations may be numerous.
and these epithelial cells induce the proliferation of Infiltration of lymphocytes may occur [78].
T cells, helping to perpetuate the process [6871]. About 3% of patients given lithium salts for a pro-
Lymphoid hyperplasia may occur elsewhere in the longed period develop goiter or hypothyroidism, or
body: thymus, lymph nodes, and spleen [72,73]. both. Patients so treated have been reported to have
Because nearly all patients now receive antithyroid diffuse hyperplasia with considerable cellular and
medication before surgery, the glands can display nuclear pleomorphism [79].
varying degrees of involution. In some cases they ap-
pear almost normal except for numerous large fol-
licles filled with colloid. A few papillae may remain.
The hyperemia is notably decreased, especially if there
has been preoperative administration of iodide [63].
If the patient has only been treated for symptoms, i.e.,
with beta-blockers, the histology of the gland resem-
bles that of the untreated state [74,75].
If hyperplasia continues for many months or sev-
eral years, oxyphilic/oncocytic metaplasia of the cells
begins to occur, the amount of stroma increases in
an irregular fashion, and nodularity develops, just as
in euthyroid goiter. If the process subsides spontane-
ously or because of the maintenance on antithyroid
medication, the involution may be remarkably com-
plete or irregular (with some foci of hyperplasia evi- Fig. 10.3 Dyshormonogenetic goiter. Variably sized aggregates
dent) [74,75]. of follicular cells and enlarged pleomorphic nuclei (inset)
10 Thyroid Pathology 113

Bromide ingestion may lead to hypothyroidism 10.4.3 Palpation Thyroiditis

because of loss of iodide from the gland. This leads
to hyperplastic C cells, foci of papillary proliferation, Palpation thyroiditis (multifocal granulomatous fol-
and loss of colloid [80]. liculitis) is found in 8595% of surgically resected
thyroids, and probably represents the thyroids re-
sponse to minor trauma. The histologic features of
10.4 The Thyroiditides this lesion include multiple isolated follicles or small
groups of follicles that show partial or circumferential
Although occasionally presenting as nodules or asym- loss of epithelium and replacement of the lost epithe-
metric enlargement of the gland, thyroiditis com- lium by inflammatory cells, predominantly macro-
monly involves the thyroid diffusely. phages [92,93].

10.4.1 Acute Thyroiditis 10.4.4 Autoimmune Thyroiditis

Acute thyroiditis is rare and is almost always due to Common synonyms for autoimmune thyroiditis in-
infection, although acute thyroiditis may be encoun- clude Hashimotos thyroiditis, lymphocytic thyroid-
tered in the thyroid shortly following radiation expo- itis, and struma lymphomatosa [94]. The disorder,
sure [81,82]. The disease is most commonly encoun- most common in women, encompasses a spectrum
tered in malnourished children, elderly debilitated of clinical and pathologic changes, ranging from an
adults, immunocompromised individuals, or in oth- absence of symptoms of thyroid dysfunction to hypo-
erwise healthy patients following trauma to the neck thyroidism and rarely, hyperthyroidism, from a large
[81,83]. Most patients present with painful enlarge- goiter to an atrophic gland, and from scattered clus-
ment of the gland. Microscopically acute inflamma- ters of infiltrating lymphocytes to extensive chronic
tion with microabscess formation is present. Micro- inflammation and scarring with almost complete loss
organisms may be seen. A variety of organisms cause of follicular epithelium [94,95].
thyroiditis including bacteria, fungi, and viruses [84]. Various circulating antithyroid antibodies and
other immune phenomena occur, including in situ
immune complex deposition and basement mem-
10.4.2 Granulomatous Thyroiditis brane changes in the gland and expression of major
histocompatibility complex antigens on the thyroid
Granulomatous subacute thyroiditis, also referred to cells [96,97]. The thyroiditis may be found in the
as non-suppurative thyroiditis or de Quervains dis- same families in which idiopathic hypothyroidism
ease, is a rare entity that usually presents in women and Graves disease are common. It may follow typi-
and has been associated with HLA Bw35 [85]. The cal Graves disease [98].
changes seen in the gland are most likely due to the The hyperthyroid variant of autoimmune thyroid-
response of the thyroid to systemic viral infection itis is closely related to Graves disease and may be
[8688]; some authors suggest that it represents ac- almost identical in its gross and microscopic appear-
tual viral infection of the gland. Most patients with ance to the latter condition, suggesting that this vari-
subacute thyroiditis recover without any permanent ant may indeed be Graves disease [99].
damage to the thyroid. However, some studies have The presence of lymphoid cells in the substance of
reported end stage hypothyroidism in 59% of pa- the thyroid parenchyma probably reflects an abnor-
tients [89]. Microscopically, early in the disease, there mal immunologic state. However, the interrelation-
is loss of the follicular epithelium and colloid deple- ships among classic chronic thyroiditis, its variants,
tion. The inflammatory response, composed initially and non-specific thyroiditis are problematic [34].
of polymorphonuclear leukocytes and even microab- The morphologic and immunopathologic overlap
scesses, progresses until lymphocytes, plasma cells, between non-specific lymphocytic thyroiditis and
and histiocytes become the major inflammatory cells. Hashimotos disease suggest that they represent a
A rim of histiocytes and giant cells replaces the fol- spectrum of autoimmune injury [34,94,100].
licular epithelium. A central fibrotic reaction occurs In Hashimotos thyroiditis the gland is firm and
[90]. Recovery is associated with regeneration of symmetrically enlarged weighing from 25 to 250 g
follicles from the viable edges of the involved areas [94]. The thyroid has a tan yellow appearance attrib-
[91]. uted to the abundant lymphoid tissue. The thyroid
114 Zubair W. Baloch and Virginia A. LiVolsi

indicate autoimmune disease. They basically divided

their patients into four groups:
1. Chronic thyroiditis, oxyphilic. This group contains
patients with classic Hashimotos disease histol-
2. Chronic thyroiditis, mixed. This group shows less
of an infiltrate than group 1 with minimal fibrosis.
Patients demonstrate either eu-, hyper-, or hypo-
3. Chronic thyroiditis, hyperplastic. This group shows
glandular hyperplasia associated with only a small
lymphocytic reaction. Most patients are hyperthy-
Fig. 10.4 Chronic lymphocytic thyroiditis (Hashimotos thy- 4. Chronic thyroiditis, focal. This group shows only a
roiditis). Oncocytic follicular cells (inset showing high power) focal lymphocytic reaction and most patients are
arranged in nodular pattern with a concomitant lymphocytic euthyroid.

10.4.6 Fibrosing Variant

follicles are small and atrophic. Colloid appears dense of Hashimotos Thyroiditis
or may be absent. Follicular cells are metaplastic
and include oncocytic (Hrthle cell), clear cell, and The fibrous or fibrosing variant of Hashimotos thy-
squamous types. In the stroma and in atrophic folli- roiditis comprises approximately 1013% of all cases
cles, a lymphoplasmacytic infiltration with well-devel- of Hashimotos disease. Pathologically, the thyroid ar-
oped germinal centers is found (Fig. 10.4). Variable chitecture is destroyed with severe follicular atrophy,
degrees of interlobular fibrosis are seen [34,94]. The dense keloid-like fibrosis, and prominent squamous
lymphocytic infiltrate is composed of both T and or epidermoid metaplasia of the follicular epithelium
B cells in an almost 1:1 ratio; this differs from the [109,110]. Surgery in this setting can be extremely
peripheral blood, which shows T cell predominance difficult.
[101103]. T lymphocytes within the thyroid are
predominantly suppressor type [104,105], whereas
the peripheral blood of these patients contains mostly 10.4.7 Painless/Silent Thyroiditis
helper T cells. The B cells are usually of the IgG kappa
subclass [103]. Painless thyroiditis is an autoimmune disease that
Patients with Hashimotos thyroiditis are at in- causes painless enlargement of the thyroid gland
creased risk of neoplasia with the most common along with brief hyperthyroidism followed by hypo-
malignancy being malignant lymphoma, B cell type thyroidism. It can occur in the postpartum period
[106,107]. In addition, patients with Hashimotos and is termed postpartum thyroiditis [111113]. Most
disease may be prone to the development of plasma- cases show follicular disruption and lymphocytic in-
cytomas within the gland [107]. A peculiar variant filtration, but stromal fibrous and oxyphilic changes
of mucoepidermoid carcinoma known as sclerosing are rare [111].
mucoepidermoid carcinoma with eosinophilia has
been recognized in patients with Hashimotos disease
[108]. 10.4.8 Focal Non-specific Thyroiditis

Lymphocytic infiltration of the thyroid is found more

10.4.5 Chronic Lymphocytic frequently at autopsy and in surgical specimens since
Thyroiditis Classification the addition of iodide to the water supplies of the
United States about 60 years ago [114,115]. It has
Mizukami et al. established a new classification of been suggested that iodide (iodine) may combine
chronic lymphocytic thyroiditis [94]. This classifi- with a protein, act as an antigen, and evoke an im-
cation is useful because it allows one to see that the mune response localized to the thyroid gland [116].
mere presence of lymphocytes in the thyroid does not Postmortem studies indicate an incidence of focal
10 Thyroid Pathology 115

lymphocytic thyroiditis of about 1520% in women somal antibodies seen in Hashimotos thyroiditis
and rarely in men [114]. These cases show focal ag- [127].
gregates of lymphocytes, occasional germinal center
formation, but oncocytes are rarely present. Follicular
atrophy is also rare [100]. 10.5 Amiodarone Injury
with Thyrotoxicosis
10.4.9 Riedels Thyroiditis Administration of amiodarone may cause thyrotoxi-
cosis, primarily due to the large quantity of iodine in
Riedels thyroiditis (Riedels disease, invasive fibrous the drug [78,128]. Tissue changes are usually focal.
thyroiditis, Riedels struma) has been incorrectly in- Groups of follicles contain degenerated follicular cells
cluded among the thyroiditides [117]. This is really (with granular or vacuolated cytoplasm); some fol-
not a disorder of the thyroid but one that involves the licles have lost follicular cells, and there is partial or
thyroid as well as other structures in the neck or even complete loss of colloid. Zones of fibrosis are evident.
systemic structures; sclerosing mediastinitis, retro- The intervening thyroid tissue is normal [129].
peritoneal fibrosis, pseudotumor of the orbit, and
sclerosis of the biliary tract (sclerosing cholangitis)
[118121]. Riedels disease is an extremely rare entity 10.6 Miscellaneous Disorders
with an incidence of 0.05% of surgical thyroid diseases
and showing a female predominance [122]. Most pa- 10.6.1 Radiation Effects
tients are euthyroid, although hypothyroidism and
hyperthyroidism have been reported [117,122]. Ionizing radiation delivered in small doses to the
Descriptions of the thyroid range from stony hard thyroid glands of infants, children, and adolescents
to woody fixed (ligneous thyroiditis). Histologi- causes a marked increase in the later incidence of
cally, the involved portions of the gland are destroyed benign and malignant neoplasms [130]. Larger
and replaced by keloid-like fibrous tissue associated doses produce more numerous nodules; many of
with lymphocytes and plasma cells [122,123]. The fi- these nodules are particularly cellular, and some are
brous tissue extends into muscle, nerves, and fat, and atypical in their structure and cytologic features,
entraps blood vessels. In about 25% of cases, the para- suggesting premalignant characteristics [131]. The
thyroid glands are also encased [123,124]. There is an cancers that develop after small doses of radiation
associated vasculitis (predominantly a phlebitis) with are mostly papillary carcinomas, are often multicen-
frequent thrombosis [125]. tric or bilateral, and are frequently small [130]. In
Quantitative studies of the immunoglobulin-con- addition to the nodules and neoplasms that occur,
taining cells in fibrous Hashimotos thyroiditis show other changes are believed to be more common as
that cells containing kappa light chains outnumber well, including focal epithelial hyperplasia (possibly
lambda-containing cells (64% versus 36%) whereas incipient nodules), chronic lymphocytic thyroiditis,
in Riedels disease lambda-containing cells comprise oxyphilic metaplasia of follicular cells, and slight
>70% of the immunocyte population. In Hashimo- fibrosis [132,133].
tos thyroiditis, IgA cells make up about 15% of the Large doses of ionizing radiation (e.g., therapeu-
lymphocytes, whereas IgA-containing plasma cells tic radiation for head and neck cancer, or radioiodine
comprise about 45% of the immunocyte population therapy) can initially cause vascular injury and fol-
in Riedels disease. The immunologic evaluation sup- licular cell necrosis. Hemorrhages, edema, and small
ports the separation of the distinctive Riedels lesion numbers of the usual inflammatory cells appear. The
from other thyroiditides [126]. damaged is healed by scarring and the follicular epi-
thelium can show a mixture of atrophic, hyperplastic,
and metaplastic changes [134,135].
10.4.10 Combined Riedels Disease
and Hashimotos Thyroiditis
10.6.2 Amyloidosis
In rare instances the thyroid gland can show features
of both Riedels disease and Hashimotos thyroiditis. The thyroid may be involved by primary or secondary
The histologic picture resembles Riedels disease, amyloidosis. The amyloid deposition may be sufficiently
whereas the serology shows thyroglobulin and micro- uneven to produce a mass. Such an accumulation must
116 Zubair W. Baloch and Virginia A. LiVolsi

be differentiated from that occurring in some cases of

medullary carcinoma [136,137].

10.6.3 Black Thyroid

Prolonged therapy with tetracycline antibiotics, es-

pecially minocycline, may cause the accumulation of
sufficient pigment in the follicular cells to produce a
dark brown to black gland. Much of the pigment is
lipofuscin, but part may be a metabolite of the drug.
Rarely, there may be interference with thyroid func-
tion [138,139].
Fig. 10.5 Follicular adenoma. Thinly encapsulated follicular
patterned lesion and lack of capsular or vascular invasion
10.7 Neoplasms

Thyroid neoplasms demonstrate a variety of morpho- and trabecular [35]. However, since these patterns
logic patterns that complicate their pathologic inter- have no clinical importance, it is not necessary to sub-
pretation [140]. All neoplasms that arise from thyroid divide thyroid adenomas. Relatively common changes
epithelial cells may have some functional capacities. found in adenomas include hemorrhage, edema, and
They may respond to TSH and may even produce ex- fibrosis, especially in the central portions of the tu-
cessive amounts of thyroid hormones or, if medullary mor [35]. Calcification may be seen. Lesions that have
carcinoma, release abnormal quantities of calcitonin undergone fine-needle aspiration biopsy may show
or other hormones [34]. Localization of thyroglobu- necrosis, increased mitotic activity, and cellular atypia
lin or calcitonin by immunohistochemistry aids in in the area of the needle tract [144].
the classification of unusual thyroidal tumors and in Whether or not some solitary follicular nodules
providing definite identification of metastatic thyroid have the biologic potential to become carcinoma is
carcinomas [37]. unknown; the findings of aneuploid cell populations
in 27% of such lesions suggest that some of these may
represent carcinoma in situ [145,146]. The solitary
10.7.1 Benign Neoplasms follicular lesion that is removed by lobectomy and
when adequately studied shows no evidence of inva- Adenomas and Adenomatous Nodules sion, will neither recur nor metastasize [35]. (Enucle-
ation of follicular adenomas or nodulectomy should
A follicular adenoma or solitary adenomatous or ad- be condemned as a surgical procedure and considered
enomatoid nodule is defined as a benign encapsulated suboptimal care. The pathologic evaluation of these
mass of follicles, usually showing a uniform pattern lesions requires analysis of the tumor capsulethyroid
throughout the confined nodule [35,37]. Follicular interface [143].)
adenomas with papillary hyperplasia (some of which
are functional) should not be classified as papillary
adenomas [141], but as papillary hyperplastic nod- Hyalinizing Trabecular
ules [142]. Adenomas are solitary; indeed, if there Adenoma/Neoplasm of the Thyroid
are multiple nodules in a lobe or a thyroid gland, it is
probably more appropriate to diagnose multinodular The hyalinizing trabecular adenoma is a distinct pat-
goiter with adenomatous change (adenomatous hy- terned follicular-derived lesion of the thyroid; i.e., it
perplasia). The features that distinguish histologically expresses thyroglobulin, thyroid transcription factor
between adenoma and adenomatous nodules included (TTF1) and not calcitonin [147]. Microscopically,
encapsulation, uniformity of pattern within the ad- these adenomas grow in nests that are surrounded
enoma, and compression of the surrounding gland by by dense hyaline stroma. The nested histology of the
the adenoma and its capsule (Fig. 10.5) [143]. tumor cells is reminiscent of that seen in paraganglio-
Descriptive terms that have been used to delineate mas (thus termed by some authors as paraganglioma-
the patterns seen in follicular adenomas include mac- like adenoma of thyroidPLAT) [148]. The nuclear
rofollicular, simple, microfollicular, fetal, embryonal, features of the follicular cells are similar to those seen
10 Thyroid Pathology 117

malignant diseases, with the exception that autoim-

mune thyroiditis may predispose to malignant lym-
phoma [37]. Anaplastic carcinomas have often arisen
in goitrous thyroids, and careful examination of the
resected tissues has frequently demonstrated benign
tumors or well-differentiated carcinomas in close as-
sociation with the anaplastic neoplasm. Such findings
have led to suggestions that the benign tumor or low-
grade carcinoma can transform into the anaplastic
carcinoma [155]. Papillary Carcinoma

Fig. 10.6 Hyalinizing trabecular neoplasm. Tumor mainly of
elongated cells (inset) and hyalinized stroma This is the most common malignant tumor of the
gland in countries having iodine-sufficient or iodine-
excess diets, and comprises about 80% of thyroid
in papillary carcinoma (Fig. 10.6) [149]. By immu- malignancies in the United States [156158]. Papil-
nohistochemistry, the cells of hyalinizing trabecular lary thyroid carcinoma (PTC) clinically behaves in
adenoma stain positive for thyroglobulin and cyto- an indolent fashion and carries an excellent prognosis
keratin 19 and negative for calcitonin, although the (>90% survival at 20 years) [158]. It invades lymphat-
presence of other neuroendocrine markers has been ics leading to multifocal lesions and to regional lymph
described [150]. node metastases [156,158]. Venous invasion rarely
Some authors have proposed that these adenomas occurs and metastases outside the neck are unusual
actually represent a variant of papillary carcinoma. (57% of cases) [159].
This is due to similar nuclear cytology, immunopro- Papillary thyroid carcinoma can occur at any age
file, and RET oncogene rearrangements in both tu- and rarely has been diagnosed as a congenital tumor
mors [151]. However, a benign behavior has so far [160]. Most tumors are diagnosed in patients in the
been described in all cases of hyalinizing trabecular third and fifth decades. Women are affected more
adenoma. Therefore, we believe until metastatic be- than men in ratios of 2:1 to 4:1 [161].
havior is described in a case of hyalinizing trabecular
adenoma with classic histology, these tumors can be
designated as hyalinizing trabecular neoplasm as pro- Etiologic Factors
posed by the World Health Organization [149].
Etiologic factors for PTC are not well established;
various cellular and genetic mechanisms/targets have
Atypical Follicular Adenoma been studied in the development of PTC.

The term atypical follicular adenoma includes those

follicular tumors that show pathologically disturbing Iodide
features (spontaneous necrosis, infarction, numerous
mitoses, or unusual cellularity), but do not show inva- The addition of iodine to the diet in endemic goiter
sive characteristics on careful examination. The over- areas in Europe has been associated with a decreased
whelming majority of the atypical adenomas behave incidence of follicular cancer and an increase in PTC
in a benign fashion clinically [152154]. [162,163].

10.7.2 Malignant Neoplasms External Radiation

The most common malignant neoplasms of the thy- External radiation probably plays a role in the de-
roid origin are the well-differentiated carcinomas velopment of PTC [164,165]. The average time from
of follicular epithelial origin: up to 80% of these are radiation exposure to tumor development has clas-
papillary carcinomas [35]. Most non-neoplastic dis- sically been reported as 20 years; however, develop-
eases of the thyroid do not seem to be precursors of ment time can be variable [130,165]. The Chernobyl
118 Zubair W. Baloch and Virginia A. LiVolsi

nuclear accident has induced a great increase in the (APC) gene. PTC (>95% of cases) occurs in 12% of
incidence of PTC in Belarus, Russia, and Ukraine patients with FAP; all these patients do show germline
[130]. The increased incidence is seen predominantly mutations of the APC gene, however, somatic muta-
in young children. Most reported tumors following tions or loss of heterozygosity for the APC gene are
this nuclear disaster have been PTC, some of which not found in thyroid tumors. Interestingly, a majority
show aggressive features including extracapsular ex- of these tumors do show activation of ret/ptc1 in thy-
tension and vascular invasion; however, mortality is roid tumors suggesting a possible association between
extremely low [130,166]. APC and ret/ptc in the development of this particular
subset of familial papillary carcinoma [172177].
Cowdens syndrome is characterized by formation
Autoimmune Disease of hamartomas in several organs and a high risk of
developing breast and thyroid cancer. The genetic lo-
Many studies indicate that up to one third of PTCs cus for Cowdens syndrome has been mapped to chro-
arise in the setting of chronic thyroiditis. Follow-up mosome 10q23.3 and is also known as PTEN, which
studies of patients with documented thyroiditis indi- is a protein tyrosine phosphatase and exerts its tumor
cate that the tumor that arises much more frequently suppressor effects by antagonizing protein tyrosine
in these glands is malignant lymphoma, not PTC (see kinase activity. Interestingly, PTEN mutation or gene
below) [167]. Since papillary cancer and thyroiditis deletion is noted in 26% of benign tumors but only in
are both common conditions, the possibility of coin- 6.1% of malignant tumors of the thyroid [178,179].
cidental coexistence is more likely than an etiologic
relationship [167,168]. However, loss of heterozygos-
ity for various tumor suppressor genes has been dem- Thyroid/Parathyroid Adenomas
onstrated in the cytologically atypical areas/nodules
in chronic lymphocytic thyroiditis [169]. Thus, a link Occasionally, papillary cancers arise in benign nod-
may exists between chronic lymphocytic thyroiditis ules or adenomas. It is believed that this is likely to
and PTC. be a random event of location and does not indicate
a casual relationship [143]. Several authors have de-
scribed the association of PTC and parathyroid ad-
Hormonal and Reproductive Factors enoma and/or hyperplasia [180,181]. Both types of
lesions are associated with a history of low-dose ex-
Papillary thyroid carcinoma is more common in ternal radiation to the neck.
women than men. Some studies have suggested the
role of various hormonal factors in the development
of PTC; these include increased parity, late age at the Pathology
onset of first pregnancy, fertility problems, and oral
contraceptives [170]. However, studies of steroid hor- The gross appearance of PTC is quite variable. The
mone receptors have been disappointing since about lesions may appear anywhere within the gland. By
50% of normal thyroid, and benign and malignant definition, clinical papillary carcinomas are >1.0 to
nodules can contain estrogen and/or progesterone 1.5 cm in size often averaging 23 cm, although le-
receptors and smaller numbers of androgen recep- sions may be quite large. The lesions are firm and
tors. No correlation with age or gender has been usually white in color with an invasive appearance.
identified [171]. Tumoral calcification is a common feature. Because
of extensive sclerosis, the tumor may grossly resemble
a scar. In addition, cyst formation may be observed
Genetic Syndromes [34,35,156].
Microscopically, PTC displays papillae contain-
Papillary carcinomas have been described in patients ing a central core of fibrovascular tissue lined by one
with familial adenomatous polyposis coli (FAP), or occasionally several layers of cells with crowded/
Cowdens syndrome, non-polyposis colon cancer overlapping oval nuclei. The nuclei of papillary can-
syndrome (HNPCC), Peutz Jeghers syndrome, and cer have been described as clear, ground glass, empty,
ataxia telangiectasia [172174]. or Orphan Annie eyed. These nuclei are larger and
Familial adenomatous polyposis coli is caused by more oval than normal follicular nuclei and contain
germline mutations of adenomatous polyposis coli hypodense chromatin. Intranuclear inclusions of
10 Thyroid Pathology 119

by molecular biology techniques that papillary car-

cinomas are clonal proliferations [190]. In view of
these studies it is believed that multifocality of pap-
illary carcinoma must be due to intrathyroidal lym-
phatic spread rather than multifocal primary tumors
[64,190]. Recent RET/PTC and LOH studies have
shown that multifocal papillary microcarcinomas can
be separate primaries instead of intraglandular spread
from one tumor source [191,192].
Venous invasion can be identified in up to 7% of
papillary cancers [193]. Whether this finding alone
is predictive of a more aggressive behavior is unclear
Fig. 10.7 Papillary carcinoma, classic type. Tumor cells ar- Regional lymph node metastases are extremely
ranged in papillary groups and showing chromatin clearing, common (50% or more) at initial presentation of usual
intranuclear grooves, and inclusions (arrow) papillary cancer (Fig. 10.8) [158]. Some patients will
present with cervical node enlargement and will have
no obvious thyroid tumor [196]. Not infrequently the
cytoplasm are often found. Another characteristic nodal metastasis will involve one node that may be
of the papillary cancer nucleus is the nuclear groove cystic. The histology of the nodal metastases in papil-
(Fig. 10.7) [37,156,157]. Nuclear grooves may be seen lary cancer may appear papillary, mixed, or follicu-
in other thyroid lesions including Hashimotos dis- lar. This feature does not adversely affect long-term
ease, adenomatous hyperplasia, and diffuse hyper- prognosis [156,157]. Hence, attempts at staging of
plasia as well as in follicular adenomas (particularly papillary carcinoma may have minimal clinical sig-
hyalinizing trabecular neoplasm) [182]. Hence, the nificance.
mere presence of nuclear grooves is not diagnostic for Tumor grading is of no use in this tumor since
papillary carcinoma. over 95% of these lesions are grade 1 [194]. In some
Psammoma bodies are lamellated round to oval tumors, either in the primary site or in recurrences,
structures that represent the ghosts of dead papil- areas of poorly differentiated cancer characterized
lae and are formed by focal areas of infarction of the by solid growth of tumor, mitotic activity, and cyto-
tips of papillae attracting calcium that is deposited logic atypia can be found. Such lesions have a much
upon the dying cells. These are seen within the cores more guarded prognosis [197]. Anaplastic change in
of papillae or in the tumor stroma [35,156]; only a papillary cancer can occur, although it is uncom-
rarely are psammoma bodies found in benign condi- mon [155].
tions in the thyroid [183,184]. Psammoma bodies are Distant metastases of papillary carcinoma to lungs,
found in about 4050% of cases, but their presence in bones, and brain occur in 57% of cases [198]. Despite
thyroid tissue indicates that a papillary carcinoma is the presence of multiple metastases, however, survival
most likely present somewhere in the gland [35,37].
The finding of psammoma bodies in a cervical lymph
node is strong evidence of a papillary cancer in the
thyroid [185].
Scattered lymphocytes are common at the invasive
edges of the tumor [186,187]. Cyst formation may oc-
cur and in fact may be so striking that the diagnosis
of PTC is difficult to make particularly if the lesion
has metastasized to neck lymph nodes making the
distinction clinically from a branchial cleft cyst dif-
ficult [34,188,189].
Papillary thyroid carcinoma early in its develop-
ment invades the glandular lymphatics [34], which
accounts for the high incidence of regional node me-
tastases [156]. The tumors can also present multifo-
cally within the same gland [156]. It has been shown Fig. 10.8 Lymph node with metastatic papillary carcinoma
120 Zubair W. Baloch and Virginia A. LiVolsi

may still be prolonged, especially if the metastases can RET is only expressed in C cells and not follicular
be treated with radioiodine [199]. In ordinary papil- cells. RET/PTC seen in papillary carcinomas occurs
lary carcinoma, death is uncommon [199]. due to fusion of the tyrosine kinase domain of RET
to the 5 portion of the various genes. To date more
than ten novel types of rearrangements have been
Immunohistochemistry described in papillary carcinoma. RET/PTC1 and 3
are the most common forms that occur in sporadic
Immunostaining shows that most papillary cancers papillary carcinoma. RET/PTC1 is formed by fusion
express thyroglobulin, TTF1, and not calcitonin [37]. of RET to H4 and RET/PTC3 occurs due to fusion of
Several reports have been published regarding the use RET to ELE1 gene [214216].
of various immunohistochemical markers that can RET/PTC expression in thyroid follicular cells of
differentiate papillary carcinoma from other follicu- transgenic mice leads to development of thyroid tu-
lar-derived lesions of the thyroid. From an extensive mors with histologic features of papillary thyroid
list of these markers the ones that have shown some carcinoma [217]. Similarly, transfection of follicular
promise include cytokeratin 19, HBME1, and galec- cells in tissue culture by RET/PTC causes the cells to
tin 3 [200205]. However, none of these have proven demonstrate nuclear features of papillary carcinoma
to be specific since all can be expressed in some be- [218]. The prevalence of RET/PTC in papillary carci-
nign lesions of the thyroid. Therefore, some authors noma varies significantly among various geographic
have proposed that diagnosis of PTC by immunohis- regions; in the United States it ranges from 11%
tochemistry should be carried out by using the mark- to 43% [216]. In sporadic tumors RET/PTC1 is the
ers mentioned above in an immunopanel [202,206]. most common form of rearrangement (6070%) fol-
The other markers that have been explored in the lowed by RET/PTC3 (2030%) [216,219]. The other
diagnosis of PTC include: S100 protein, blood group rare forms of RET/PTC rearrangements have been
antigens, estrogen receptors, CD10, CD15, and CD57. mainly found in radiation-induced papillary carcino-
The proliferation of markers indicates that no one mas. Several studies have shown a strong association
of them is useful for the daily practice of pathology between radiation-induced papillary carcinoma and
[207210]. expression of RET/PTC; in papillary carcinoma in
children affected by the Chernobyl nuclear accident,
RET/PTC3 was found to be the commonest form of
Flow Cytometry rearrangement followed by RET/PTC1 [220,221].
Recently it has been shown that RET/PTC expres-
Although the great majority of papillary thyroid can- sion can also occur in some benign lesions. These in-
cers are diploid, the literature suggests up to 20% may clude hyalinizing trabecular neoplasm [151], Hashi-
show aneuploid or at least non-diploid subpopu- motos thyroiditis [222,223], and hyperplastic nodules
lations. It has been shown that aneuploid tumors and follicular adenoma [224].
are often associated with a more aggressive clinical Several authors have suggested an association be-
course; however, multivariate analysis has not shown tween Hashimotos thyroiditis and PTC; however,
that ploidy is an independent prognostic factor others have suggested that this association is most
[146,157,211]. likely incidental since both are common. Recently
two independent studies have shown high prevalence
of RET/PTC in histologically benign thyroid tissue af-
Molecular Pathology fected by Hashimotos thyroiditis; these studies con-
cluded that thyroiditic glands harbor multiple foci of
In the decade since 1995 the literature on thyroid has papillary carcinoma that are not identified by histo-
been focused mainly on the role of various biologic logic examination only [222,223]. However, a more
events and genetic determinants in the pathogen- recent study failed to reproduce these results [168].
esis of various thyroid tumors. Rearrangements of RET/PTC has been identified in benign thyroid
RET gene, known as RET/PTC have been identified nodules, especially the ones that are seen in patients
in papillary carcinoma of the thyroid [212,213]. The with a history of external radiation [224]. However,
RET protooncogene is normally expressed in cells of this still remains controversial and needs to be further
neural crest origin and plays a role in kidney and gas- elucidated by examination of a large cohort of cases.
trointestinal neuronal development. It is located on Activation of the ras oncogene-signaling pathway
chromosome 10q11.2 and cell membrane receptor ty- is considered to be an important mechanism by which
rosine kinase [212,214]. In normal thyroid wild-type human cancer develops. Ras has been shown to regu-
10 Thyroid Pathology 121

late several pathways that contribute to cellular trans- Subtypes of Papillary Carcinoma
formation including the Raf/MEK/ERK pathways.
Numerous studies confirm that the Raf/MEK/ERK Papillary Microcarcinoma
pathway is a significant contributor to the malignant (Occult Papillary Carcinoma)
phenotype associated with deregulated Ras signaling
[225,226]. According to the WHO, papillary microcarcinoma
Recently, an activating mutation in the serine/thre- is defined as tumor measuring 1 cm or less; however,
onine kinase BRAF was described of human PTCs. some experts have also defined tumors measuring up
BRAF-activating mutations in thyroid cancer are to 1.5 cm as microcarcinomas (Fig. 10.9) [239,240].
almost exclusively the BRAF V600E mutation, and These lesions are quite common as incidental findings
have been found in 2969% of papillary thyroid can- at autopsy or in thyroidectomy for benign disease or
cers, 13% of poorly differentiated cancers, and 10% of in completion thyroidectomies in patients with a his-
anaplastic cancers [226229]. These data identify that tory of carcinoma involving the opposite thyroid lobe
BRAF is an oncogene in human cancer. The high fre- [241]. The incidence of these lesions has varied signif-
quency of BRAF mutations in thyroid cancer suggests icantly with the study, but papillary microcarcinoma
that inhibition of BRAF activity may represent an im- has been reported in up to 36% of carefully sectioned
portant new strategy in the treatment of patients with thyroid specimens [241]. Lymph node metastases
thyroid cancer. from papillary microcarcinoma can occur; metasta-
ses from lesions less than 0.5 cm have been reported
[240,241]. Distant metastases, although very rare, are
Prognostic Factors also documented [242]. Histologically, the tumors
may be totally follicular or show papillary areas as
Poor prognostic factors in papillary carcinoma in- well. Sclerosis may be prominent; the lesions infil-
clude older age at diagnosis, male sex, large tumor trate the surrounding thyroid [34]. A familial form
size, and extrathyroidal growth [158,199]. Pathologic of papillary microcarcinoma has been recognized;
variables associated with a more guarded prognosis these tumors are characterized by multifocality with
include less differentiated or solid areas, vascular in- increase tendency toward vascular and lymphatic in-
vasion, and aneuploid cell population [194]. Some au- vasion, distant metastasis, and even death [243,244].
thors have found varying prognostic factors in males It is important to recognize that the incidentally
and females. In men, age and presence of gross lymph found microcarcinoma confined within the thyroid is
node metastases were important, while in females age, probably of no clinical importance and should not be
presence of gross lymph node metastases, tumor size, overtreated.
and the number of structures adhered to the gland
were important [199,230].
Some studies have shown that RET/PTC expres- Follicular Variant of Papillary Cancer
sion in papillary carcinoma can be associated with ag-
gressive biologic behavior; conversely, others have re- The follicular variant of papillary carcinoma is a dis-
ported that its expression is more commonly seen in tinctive papillary carcinoma variant that shows follic-
slow growing and clinically indolent tumors [231,232].
It is also suggested that different rearrangements of
RET/PTC are associated with different biologic be-
havior. Nikiforov et al. found a significant difference
in local recurrence and distant metastases between
tumor with RET/PTC1 and RET/PTC3 expression
[216]. Cetta et al. reported similar findings [233]. Be-
sides RET/PTC, several other biologic markers have
been suggested as prognostic predictors in papillary
carcinoma; these include p53, Ki67, cell cycle pro-
teins, proliferating cell nuclear antigen (PCNA), bcl2,
cathepsin D, and topoisomerase II [234238].

Fig. 10.9 Papillary microcarcinoma

122 Zubair W. Baloch and Virginia A. LiVolsi

Fig. 10.10 Follicular variant of papillary carcinoma. Variably Fig. 10.11 Tall cell variant of papillary carcinoma. Enlarged
sized follicles lined by cells showing nuclear features of papil- tumor cells with oncocytic cytoplasm and nuclear features of
lary carcinoma papillary carcinoma

ular growth pattern and diagnostic nuclear features of Tall Cell Variant
papillary carcinoma (Fig. 10.10) [245,246]. The inci-
dence of this variant is difficult to determine since in The tall cell variant is an aggressive variant of papil-
the past some of these lesions have been classified as lary carcinoma that tends to occur in elderly patients.
follicular carcinomas or adenomas [247]. Grossly and These tumors are usually large (>6 cm), extend ex-
histologically, the tumor may appear encapsulated trathyroidally, and show mitotic activity and vascu-
[248]. The prognosis of the follicular variant is appar- lar invasion more often than usual papillary cancer.
ently similar to usual papillary cancer although there The tall cell variant of PTC consists of tumor cells
may be a greater risk for this variant to metastasize twice as tall as they are wide and shows eosinophilic
outside the neck and for vascular invasion; regional cytoplasm; because of this these tumors are referred
nodal metastases are less common than in classic to as the pink cell variant of papillary carcinoma
papillary cancer [249,250]. (Fig. 10.11) [255,256]. Dedifferentiation to squamous
Two distinct types of follicular variant are the dif- cell carcinoma has been described in the tall cell vari-
fuse and the encapsulated follicular variants. In the ant of PTC [257]. The prognosis for this variant is less
diffuse follicular variant, the gland is diffusely re- favorable than for usual papillary cancer, although it
placed by tumor [251]. Lymph node and distant me- is believed that the poor outcome is secondary to the
tastases are common in these patients. The prognosis fact that these tumors are often associated with poor
appears to be poor in these patients, although only a prognostic variables such as older age, extrathyroidal
handful of cases have been described [252,253]. spread, necrosis, high mitotic rate, and distant metas-
The encapsulated follicular variant refers to the fol- tases [258260].
licular variant that is characterized by the presence
of a capsule around the lesion. These lesions are as-
sociated with an excellent prognosis [251]. In some Columnar Cell Variant
cases the diagnosis of this particular variant of papil-
lary carcinoma can be difficult due to the presence of The columnar cell variant is a rare form of papillary
multifocal rather than diffuse distribution of nuclear carcinoma [261]. (Some authors believe it is so un-
features of papillary thyroid carcinoma. Because of usual a tumor that it deserves its own category and
this peculiar morphologic presentation, these tumors should not be placed in the papillary group. The tu-
can be misdiagnosed as adenomatoid nodule or fol- mor needs to be distinguished from other papillary
licular adenoma [143,251]. Some authors have sug- carcinomas since this lesion is associated with an ex-
gested that these tumors be classified as tumors of tremely poor outcome with most deaths occurring
undetermined malignant potential due to their ex- within 5 years of diagnosis. Extrathyroidal extension
cellent prognosis [254]; however, others have shown is common as are distant metastases [261263]. En-
that some cases belonging in this category can lead to capsulated variants, which may have a better progno-
distant metastasis [249]. sis, have been described [264].
10 Thyroid Pathology 123

Warthin-like Variant although it may occur as a sporadic tumor. It is over-

whelmingly common in women [175,282].
By light microscopy these tumors resemble Warthins
tumor of the salivary gland. These tumors usually
arise in a background of lymphocytic thyroiditis and Follicular Carcinoma
show papillary architecture. Limited follow-up has
shown that these tumors in their pure form follow a Follicular carcinoma comprises about 5% of thyroid
clinical course similar to conventional papillary carci- cancers; however, in iodide-deficient areas, this tumor
noma [265,266]. is more prevalent making up 2540% of thyroid can-
cers [283,284]. The true incidence of follicular carci-
noma is difficult to determine since the follicular vari-
Diffuse Sclerosis Variant ant of papillary carcinoma may still be placed into this
category [247]. Risk factors include iodine deficiency,
The diffuse sclerosis variant of papillary carcinoma is older age, female gender, and radiation exposure (al-
rare; it most often affects children and young adults, though the relationship of radiation to follicular car-
and may present as bilateral goiter. The tumor perme- cinoma is far less strong than with papillary cancer)
ates the gland outlining the intraglandular lymphat- [162,285]. Clinically, follicular carcinoma usually
ics. The lesions tend to recur in the neck and have a presents as a solitary mass in the thyroid [283].
somewhat more serious prognosis than usual child- Follicular carcinoma has a marked propensity for
hood papillary cancer. These lesions appear to repre- vascular invasion and avoids lymphatics; hence, true
sent 10% of the papillary carcinomas seen in children embolic lymph node metastases are exceedingly rare.
exposed to the radioactive iodine released following Follicular carcinoma disseminates hematogenously
the Chernobyl accident. While the tumors often show and metastasizes to bone, lungs, brain, and liver
extracapsular extension, distant and nodal metastases, [283,286,287].
and a decreased disease-free survival when compared Patients who have follicular carcinoma that is
to the usual type of papillary carcinoma, mortality is widely invasive fare poorly [284,288]; however,
low [267270]. those individual with encapsulated follicular tumors
confined to the thyroid enjoy a prolonged survival
(greater than 80% at 10 years) [289292]. Studies
Solid Variant of Papillary Carcinoma using multivariate analysis have identified age >45,
extrathyroidal extension, distant metastases, and tu-
The solid variant of PTC is most commonly seen in mor size >4 cm as independent prognostic factors in
children and has been reported in greater than 30% follicular carcinoma [286,291,293]. An extremely sig-
of patients with papillary carcinoma following the nificant complication that may occur in patients with
Chernobyl nuclear accident [271,272]. It is important follicular cancer is transformation into anaplastic
to recognize these lesions as papillary carcinomas and cancer; this may occur de novo in an untreated fol-
not to classify them as more aggressive tumors such as licular lesion, or in metastatic foci [294].
insular carcinoma (discussed below). The prognosis The widely invasive follicular carcinoma is a tumor
is controversial with some studies showing outcomes that is clinically and surgically recognized as a cancer;
similar to typical papillary carcinoma and other stud- the role of the pathologist in its diagnosis is to confirm
ies showing more aggressive behavior [271,273]. that it is of thyroid origin and is a follicular neoplasm.
Up to 80% of the patients with widely invasive can-
cers can develop metastases, and a 50% fatality rate
Other Variants of Papillary Carcinoma for widely invasive tumors compared with only 3%
for those with minimal invasion has been reported.
Rare variants of papillary cancer in which prognos- The pathologist can only diagnose the minimally
tic data are not well established include the spindle invasive follicular carcinoma by examining well-fixed
cell variant [274], the clear cell type [275], the oxy- histologic sections. These lesions are not diagnosable
philic (Hrthle cell) variant [275,276], papillary car- by fine-needle aspiration cytology since the diagnosis
cinoma with lipomatous stroma [277,278], papillary requires the demonstration of invasion at the edges
carcinoma with fasciitis-like stroma [279], and the of the lesion; therefore, sampling of the center, as in
cribriform variant [280281]. The last of these is often obtaining a cytologic sample, cannot be diagnostic
seen in patients with familial adenomatous polyposis [283287,295297].
124 Zubair W. Baloch and Virginia A. LiVolsi

The minimally invasive follicular carcinoma is an nition of capsular invasion is controversial [143,254].
encapsulated tumor that grossly resembles a follicu- Some authors require penetration of the capsule to
lar adenoma and only on microscopic examination diagnose a follicular tumor as carcinoma, while oth-
shows evidence of capsular and/or vascular invasion ers need tumor invasion through the capsule into the
(Figs. 10.12, 10.13). On microscopic examination, surrounding normal thyroid [254,292]. Is capsular in-
follicular carcinomas most often have a microfollicu- vasion insufficient for the diagnosis of follicular can-
lar pattern and resemble a cellular follicular adenoma. cer? Distant metastases have been reported in follicu-
Trabecular or solid patterns are fairly common and of- lar carcinoma diagnosed only on the basis of capsular
ten accompany the microfollicular pattern [143,291]. and not vascular invasion, however, in some cases,
What are the minimum criteria for making this di- metastases were already present at initial diagnosis
agnosis? Invasion of the capsule, invasion through the [290,298]. The presence of vascular invasion is also
capsule, and invasion into veins in or beyond the cap- indicative of malignancy in a follicular tumor. Inva-
sule represent the diagnostic criteria for carcinoma in sion of vessels within or beyond the lesional capsule
a follicular thyroid neoplasm [143,247,291]. The cri- is necessary for a definitive diagnosis of vascular inva-
terion for vascular invasion applies solely and strictly sion [35]. The lesions with vascular invasion should
to veins in or beyond the capsule, whereas, the defi- be separated from the minimally invasive follicular
carcinomas that show capsular invasion only, because
angioinvasive lesions have a greater probability of re-
currence and metastasis [251].
In our practice, we use the terms minimally inva-
sive and angioinvasive carcinoma. The former is ap-
plied to those cases that show only capsular or trans-
capsular invasion, while the latter is used for tumors
in which vascular invasion is found with or without
capsular invasion. As mentioned above, we propose
this distinction based on the belief that angioinvasive
tumors have a greater propensity toward distant me-
Similar problems exist in evaluating such lesions by
frozen section [299,300]. Some authors recommend
that intraoperative assessment of such lesions in-
volves the examination of frozen sections from three
Fig. 10.12 Follicular carcinoma. Thickly encapsulated follicu- or four separate areas of the nodule [301]. This wastes
lar and solid patterned lesion invading into the capsule in a resources and rarely gives useful diagnostic informa-
mushroom-shaped growth tion. The surgeon should have removed the lobe in-
volved by the nodule and if it is a follicular carcinoma
that is only minimally invasive, the appropriate ther-
apy has probably already been accomplished. Since a
only small number of these lesions will show evidence
of invasion at the time of permanent section, i.e., the
majority of them are benign, and since overdiagno-
sis is more dangerous for the patient than is the delay
in making a definitive diagnosis [299], we discourage
frozen section evaluation of these nodules.
None of the ancillary techniques assist in defin-
ing benign from malignant follicular tumors. Ul-
trastructural, morphometric, and flow cytometric
analyses have not helped in distinguishing these le-
sions [145,302]. About 60% of follicular carcinomas
will show aneuploid cell populations [145]. Backdahl
analyzed 65 follicular thyroid tumors (26 benign and
Fig. 10.13 Follicular carcinoma. Tumor embolus within a cap- 39 carcinomas). He noted that of the 20 patients with
sular vessel cancer who survived, 19 had diploid tumors, whereas
10 Thyroid Pathology 125

17 of 19 patients who died of carcinoma had tumors Oncocytic (Hrthle Cell) Tumors
with aneuploid DNA patterns [303].
All follicular carcinomas express thyroglobulin and Hrthle cells are derived from follicular epithelium
show a similar cytokeratin profile to normal thyroid and are characterized morphologically by large size,
parenchyma. Some authors have shown that HBME1 distinct cell borders, voluminous granular cytoplasm,
is exclusively expressed in 90100% of follicular car- large nucleus, and prominent nucleolus. Ultrastruc-
cinomas and not adenomas. However, others have tural studies have shown that the cytoplasmic granu-
reported HBME1 expression in adenomatoid nodules larity is produced by huge mitochondria filling the
and follicular adenomas [204,210,304,305]. cell [314,315]. Hrthle cells can be found in a number
of conditions in the thyroid [nodular goiter, non-spe-
cific chronic thyroiditis, longstanding hyperthyroid-
Molecular Biology of Follicular Carcinoma ism, and chronic lymphocytic thyroiditis (Hashimo-
tos disease)] [19].
A specific translocation t(2;3) leads to the expression Perhaps no thyroid neoplasm has elicited more
of PAX8 peroxisome proliferator activated recep- confusion or debate than Hrthle cell (oncocytic)
tor gamma (PPAR gamma) chimeric protein; initial neoplasms. Clinicians and pathologists alike have
studies by Kroll et al. demonstrated that this trans- considered that such tumors do not follow the rules
location is specific to follicular carcinoma [306]. for histopathologic diagnosis of malignancy. Some
However, follow-up studies employing immunohis- authors cite 80% or more of these lesions as benign,
tochemistry and molecular biology have shown that whereas others consider all such lesions malignant
PPAR gamma expression can occur in some cases of [316,317]. Over the decade since 1995, studies from
follicular adenoma, follicular variant of papillary thy- numerous institutions throughout the world have
roid carcinoma, and even benign thyroid parenchyma shown that oncocytic or Hrthle cell tumors can be
[307,308]. Ras mutations are more frequent in fol- divided into benign and malignant categories by care-
licular carcinoma as compared to follicular adenoma; ful adherence to strict pathologic criteria [318,319].
some authors have found an association between ras Since most Hrthle cell neoplasms are follicular in
mutations and clinically aggressive follicular carci- pattern, the criterion for distinguishing benign from
nomas [309311]. Loss of heterozygosity on chromo- malignant is the same as for follicular neoplasms, i.e.,
somes 10q and 3p can be seen in follicular carcinoma the identification of capsular and/or vascular invasion
suggesting a role of tumor suppressor genes in its [318,319]. However, the pathologic criterion for ma-
pathogenesis [312,313]. lignancy is met more frequently for tumors composed
of Hrthle cells than for their non-Hrthle counter-
parts. Thus, whereas 23% of solitary encapsulated
Well-differentiated Follicular Tumors follicular tumors of the thyroid show invasive char-
of Undetermined Malignant Potential acteristics, 3040% of such lesions showing Hrthle
cell cytology will show such features [315,318,320].
This designation has been recently proposed in thy- In addition, whereas true follicular carcinomas of
roid pathology for follicular patterned encapsulated the thyroid rarely, if ever, metastasize embolically to
tumors that have been controversial and difficult to lymph nodes, about 30% of Hrthle cell carcinomas
diagnose due to: (1) questionable or minimal nuclear do [34,321].
features of papillary thyroid carcinoma or (2) ques- Most Hrthle cell neoplasms of the thyroid are
tionable or one focus of capsular invasion that is solitary mass lesions that show complete or par-
confined to tumor capsule and does not traverse the tial encapsulation. They are distinguished from the
entire thickness of capsule and lacks any nuclear fea- surrounding thyroid by their distinctive brown to
tures of papillary thyroid carcinoma [254]. mahogany color [34,35,318]. Rarely, a Hrthle cell
This terminology may be extremely helpful to pa- neoplasm may undergo spontaneous infarction. Ex-
thologists in the diagnoses of certain follicular pat- tensive infarction may also be seen following fine-
terned lesions; however, these terms are proposed on needle aspiration biopsy.
the basis of data that lack complete clinical follow-up. The claim that all Hrthle cell neoplasms should
Therefore, clinicians may find it problematic to estab- be considered malignant or potentially malignant, es-
lish treatment strategies [143]. pecially if 2 cm or greater in size, is no longer consid-
ered valid. Many studies from the United States and
Europe indicate that benign Hrthle cell neoplasms
126 Zubair W. Baloch and Virginia A. LiVolsi

exist. Size, nuclear atypia, multinucleation, cellular but that have moderate to high rates of mitotic ac-
pleomorphism, mitoses, or histologic pattern of the tivity, are composed of solid masses or trabeculae of
lesion are not predictive of behavior [315,318,319]. relatively uniform epithelial cells, have tiny follicles
By immunohistochemistry, Hrthle cell lesions are present in varying numbers, may contain regions of
positive for thyroglobulin. Carcinoembryonic antigen acute necrosis, and are more aggressive than the usual
(CEA) expression has been described in some, but well-differentiated carcinomas [197]. Included among
not all series. Hrthle cell lesions are positive for S100 these lesions are insular carcinoma, columnar cell,
protein [318,322]. tall cell, and trabecular types of papillary cancer, and
DNA ploidy studies have shown aneuploid DNA poorly differentiated carcinoma of Sakamoto [330].
patterns in biologically and histologically benign Insular carcinoma or poorly differentiated thyroid
Hrthle tumors of the thyroid. These findings do not carcinoma is a follicular-derived carcinoma with a
indicate malignant behavior, however, about 2050% prognosis between well-differentiated thyroid carci-
of Hrthle cell tumors that are histologically malig- nomas (papillary or follicular) and anaplastic thyroid
nant and aneuploid are more aggressive biologically carcinoma. The term insular is used to describe the
and clinically than diploid Hrthle cell cancers [323]. lesions histologic growth pattern, which is somewhat
carcinoid-like. The incidence of this tumor appears
to vary with differing geographic locations with inci-
Molecular Biology of Hrthle Cell Tumors dence as high as 5% described in Italy, while the inci-
dence in the United States is much lower [331].
Hrthle cell tumors are biologically different from The lesions are often large, gray-white in color,
other follicular-derived tumors. H-ras mutations infiltrative, and show extensive necrosis. Microscop-
are more frequent in Hrthle cell carcinoma than ically the tumor is composed of small nests of cells
follicular carcinoma [324,325], and a high percent- that have a neuroendocrine growth pattern. Necrosis,
age of allelic alterations occur as compared to other vascular invasion, and mitoses are prominent features.
follicular-derived tumors. A study by Maximo et al. By immunohistochemistry the tumor cells express
showed that Hrthle cell tumors display a relatively thyroglobulin and not calcitonin. Insular carcinoma
higher percentage of common deletions of mitochon- is associated with a worse prognosis than well-dif-
drial DNA as compared to other follicular-derived ferentiated thyroid carcinomas, but is significantly
tumors. In addition, Hrthle cell tumors also showed better than anaplastic thyroid carcinoma [331333].
germline polymorphisms of ATPase 6 gene, which is The extent of the poorly differentiated component
required for the maintenance of mitochondrial DNA in a well-differentiated thyroid tumor can affect the
[326]. prognosis; tumors with >10% of the poorly differ-
entiated component are associated with frequent
regional recurrences, distant metastases, and poor
Clear Cell Tumors prognosis [334].

Clear cell change of the cytoplasm can occur in many

follicular-derived lesions of the thyroid, thyroiditis, Anaplastic Thyroid Tumors
nodules, and neoplasms [278,327,328]. Of greatest
importance is the differentiation of clear cell change Anaplastic carcinomas are a group of high-grade
in follicular thyroid lesions from clear cell renal cell thyroid carcinomas that are usually undifferentiated
carcinomas metastatic to the thyroid [329]. Immu- histologically and advertently have a lethal outcome
nostains for thyroglobulin are usually helpful in sort- [155,335]. Synonyms for anaplastic carcinoma in-
ing out this diagnostic problem. clude: undifferentiated, dedifferentiated, and sarco-
matoid carcinoma. These tumors have represented
approximately 10% of thyroid malignancies in older
Poorly Differentiated Carcinoma/ publications [155,336]. The tumor is more commonly
Insular Carcinoma seen in elderly females who present with a rapidly en-
larging mass that often results in dyspnea. Risk fac-
This heterogeneous group of malignant thyroid tu- tors are largely unknown but may include history of
mors includes carcinomas that are recognizable as radiation and iodine deficiency [155]. A precursor
originating from follicular epithelium (often with evi- well-differentiated thyroid carcinoma (papillary, fol-
dence of coexistent papillary or follicular carcinoma), licular, or Hrthle cell) may be observed [337].
10 Thyroid Pathology 127

[344,346]. Clinically, the affected patients resemble

those with anaplastic carcinoma. By gross and histo-
logic examination these tumors resemble angiosar-
comas of soft tissue. These tumors generally lack the
usual histologic features and exceptional aggressive-
ness of anaplastic carcinomas, but they are neither
typical follicular nor papillary carcinomas. Squamous Cell Carcinoma,

Mucoepidermoid Carcinoma,
and Intrathyroidal Thymoma-like
Fig. 10.14 Anaplastic carcinoma. Pleomorphic spindle-shape
and epitheloid tumor cells Squamous cell carcinoma in thyroid occurs usually
in association with papillary or anaplastic carcinoma
[257]. Rarely, squamous cell carcinoma appears as an
Grossly, the tumors are large with extensive intra- entity independent of any other form of thyroid can-
thyroidal and extrathyroidal invasion. Surgical resec- cer and behaves in an aggressive fashion with poor
tion is often not performed because of the lesions prognosis [347]. The major differential diagnosis is
extent and diagnosis is commonly made on biopsy. metastatic squamous carcinoma, especially from the
Necrosis, vascular invasion, and mitoses are quite head and neck, lungs, or esophagus.
prominent [337]. Histologically, a variety of pat- Mucoepidermoid carcinoma is a distinctive variant
terns have been described. The tumors are usually of thyroid carcinoma. It is composed of solid masses
made up of a variety of cell types (Fig. 10.14). Most of squamoid cells and mucin-producing cells, some-
tumors are composed of giant cells and spindle cells times forming glands [348]. Some authors consider
although squamoid differentiation is seen in about that this lesion is a variant of papillary carcinoma; all
one third of cases [338]. Osteoclast-like giant cells are cases show thyroglobulin expression [108,349]. The
a common feature [339]. A paucicellular variant of prognosis of thyroid mucoepidermoid carcinoma is
anaplastic carcinoma has been described; it is charac- quite good. Lesions may metastasize to regional nodes
terized by dense fibrosis, calcification, and a poor pa- and rarely distantly. Death from disease is rare [108].
tient outcome [340]. Spindle cell squamous anaplastic Sclerosing mucoepidermoid carcinoma with eosino-
carcinoma may be the result of transformation of tall philia is usually seen in a background of lymphocytic
cell papillary carcinoma [257]. Carcinosarcoma of the thyroiditis and is characterized by tumor cells ar-
thyroid has been described [341,342]. ranged in small sheets, anastomosing trabeculae, and
Electron microscopic and immunohistologic stud- narrow strands associated with dense fibrosis and nu-
ies have indicated that almost all anaplastic thyroid merous eosinophils. While these lesions may metas-
tumors are indeed epithelial in nature [338,343]. By tasize to lymph nodes and show extracapsular spread,
immunohistochemistry, anaplastic thyroid carcino- vascular invasion, and perineural invasion, death due
mas should be positive for cytokeratin. Thyroglobulin to disease is uncommon. The tumor cells stain nega-
immunostaining is often negative and thyroid tran- tive for thyroglobulin and calcitonin and positive for
scription factor can be rarely positive in anaplastic cytokeratin [108,350,351].
carcinoma [343]. There is no consensus regarding the origin of these
tumors. Some studies have suggested that on the ba-
sis of immunoprofile both these tumors have different Thyroid Sarcoma origins; mucoepidermoid carcinoma shows follicular
derivation, and sclerosing mucoepidermoid carci-
Sarcomas of the thyroid are rare; fibrosarcomas, noma is derived from ultimobranchial body nests/
leiomyosarcomas, and angiosarcomas have been de- solid cell nests [108].
scribed [344,345]. Angiosarcoma of thyroid has been Rare thyroid tumors composed of spindled epi-
most commonly described from the mountainous thelial cells arranged in nests, sometimes associated
regions of the world (Alpine regions of Europe, the with mucous microcysts, and resembling thymomas
Andes in South America, and the Himalayas in Asia) (spindled and epithelial tumor with thymus-like dif-
128 Zubair W. Baloch and Virginia A. LiVolsi

ferentiation; SETTLE) have been reported [352,353]. carcinomas and the MEN type 2 syndromes [373
Neoplasms resembling thymic carcinomas have also 375]. Mutations in specific codons have been corre-
been described (carcinoma with thymus-like differen- lated with clinical behavior and symptomatology in
tiation; CASTLE) in thyroid. These lesions may origi- some families [374]. MEN type 2B consists of medul-
nate from branchial pouch remnants within and adja- lary thyroid carcinoma and C cell hyperplasia, pheo-
cent to the thyroid [352,354356]. chromocytoma and adrenal medullary hyperplasia,
mucosal neuromas, gastrointestinal ganglioneuro-
mas, and musculoskeletal abnormalities [376379]. Medullary Carcinoma These patients may have familial disease (over 50%
do), and some cases arise apparently as spontaneous
Medullary thyroid carcinoma comprises less than mutations. These patients have biologically aggressive
10% of all thyroid malignancies [357361]. This tu- medullary carcinoma and may succumb to metastases
mor is of great diagnostic importance because of its at an early age. MEN2B shows similarity to von Reck-
aggressiveness, its close association with multiple en- linghausens disease since in neurofibromatosis simi-
docrine neoplasia syndromes (MEN2A and 2B), and lar lesions are found in the gastrointestinal tract, and
a relationship to a C cell hyperplasia, a probable pre- pheochromocytomas are common [378,379]. Nerve
cursor lesion [362]. While the majority of medullary growth factor has been identified in some medullary
carcinomas are sporadic, about 1020% are familial carcinomas of these patients; it has been postulated
[362]. Since these familial cases have been identified, that this product of the tumor may be responsible for
a gene associated with medullary carcinoma has been the neural lesions seen in the MEN type 2B patients
identified on chromosome 10 and involves mutations [380]. However, the neural lesions often precede by
in the RET oncogene [363365]. many years the development of medullary cancer. In
Medullary carcinoma can affect patients of any MEN type 2B, the tumors and germline mutations in
age; most affected individuals are adults with an aver- RET are found on codon 918an intracellular focus
age age of about 50 years. However, in familial cases, of the RET oncogene [381,382].
children can be affected; also in these instances the Medullary carcinoma is usually located in the area
age of diagnosis tends to be younger (mean age about of highest C cell concentration, i.e., the lateral upper
20 years) [361,366]. Although sporadic medullary two thirds of the gland. In familial cases, multiple
carcinomas are seen more commonly in women, fa- small nodules may be detected grossly and, rarely,
milial cases have a slight female to equal sex ratio, lesions may be found in the isthmus. The tumors
since an autosomal dominant mode of inheritance is range in size from barely visible to several centime-
present [367,368]. ters. Many medullary carcinomas are grossly circum-
Clinically sporadic medullary carcinoma will pres- scribed but some will show infiltrative borders. The
ent with a thyroid nodule that is painless but firm. typical medullary carcinoma may be microscopically
In up to 50% of cases, obvious nodal metastases will circumscribed or more likely will be infiltrating into
be present at the time of diagnosis. Distant metasta- the surrounding thyroid. The pattern of growth is of
ses, such as to lung, bone, or liver, may also be noted tumor cells arranged in nests separated by varying
initially in about 1525% of cases. When the tumor amounts of stroma. The tumor nests are composed of
produces excess hormone other than calcitonin, the round, oval, or spindle-shaped cells; often there is iso-
presenting symptoms may be related to that hor- lated cellular pleomorphism or even multinucleated
mone hypersecretion [adrenocorticotropic hormone cells (Fig. 10.15) [383,384]. The tumor stroma char-
(ACTH), prostaglandin] [369,370]. acteristically contains amyloid although this is not
In the familial lesions there are associated endo- necessary for the diagnosis as about 25% of medul-
crine and/or neuroendocrine lesions. Sipples syn- lary carcinomas do not contain amyloid (Fig. 10.15)
drome [multiple endocrine neoplasia (MEN) type 2A] [361,385,386]. The amyloid is most likely derived
[371] consists of medullary thyroid cancer and C cell from procalcitonin and indeed immunohistochemical
hyperplasia, adrenal pheochromocytoma and adrenal stains for calcitonin often stain the amyloid [37,386].
medullary hyperplasia, and parathyroid hyperplasia Calcifications in areas of amyloid deposition are char-
[372]. Studies have shown that the gene responsible acteristically present. The tumors commonly invade
for familial medullary carcinoma is RET [373,374]; lymphatics and veins [384].
mutations in RET (different from the RET transloca- Several variants of medullary carcinoma on the
tion in papillary carcinoma) are found in the tumors basis of growth pattern have been described. These
and the germline of patients with familial medullary include: papillary variant, follicular variant, encap-
10 Thyroid Pathology 129

as a medullary carcinoma, it should arise in a familial

setting or occur in a thyroid with unequivocal C cell
hyperplasia [398]. Immunoreactivity for calcitonin
gene-related peptide would add proof to the histoge-
netic nature of such a lesion.

Prognostic Factors

From the clinical standpoint, stage is the most im-

portant variable for prognosis [399401]. A tumor
confined to the thyroid without nodal or distant me-
tastases is associated with prolonged survival. Several
Fig. 10.15 Medullary carcinoma. Tumor cells arranged in nests workers have found that younger patients (under age
and round nuclei with finely granular chromatin (inset) in a 40), especially women, fare somewhat better than the
background of stroma and amyloid (arrow) whole group of medullary cancer patients [399,402].
Patients who are discovered by screening because
they are members of affected families often have very
small tumors and can be cured by thyroidectomy.
Patients with Sipples syndrome tend to have less ag-
gressive tumors than the sporadic group whereas the
patients with MEN type 2B have aggressive lesions
[401,403,404]. Pathologic features that have been
related to prognosis include tumor pattern, amyloid
content, pleomorphism, necrosis, mitotic activity,
and DNA aneuploidy [405].

Mixed Follicular and Medullary Carcinoma

These controversial tumors show thyroglobulin and

Fig. 10.16 Medullary carcinoma showing positive immuno- calcitonin immunoreactivity and ultrastructural evi-
staining with calcitonin antibody. The tumor is staining dark, dence of differentiation along two cell lines. Some of
and light staining is seen in the background amyloid the series of these tumors may have been confusing,
with trapping of follicles at the invading edge of the
medullary carcinoma and diffusion of thyroglobulin
sulated variant, small cell variant, giant cell variant, into the medullary carcinoma; this may result in diag-
oncocytic variant, and clear cell variant [389391]. nosis of mixed tumors showing immunostaining for
By immunohistochemistry, the majority of medul- both hormones. Caution should be taken when mak-
lary carcinomas express low molecular weight cyto- ing the diagnosis of mixed medullary and follicular-
keratin, calcitonin (Fig. 10.16), calcitonin gene-related derived carcinomas [406409].
peptide, and thyroid transcription factor (TTF1). In
addition, many tumors express CEA, which may also
be elevated in the serum [392394]. A variety of other Micromedullary Carcinoma
peptides may be found in tumor cells including so-
matostatin, vasoactive intestinal peptide, and synap- A few medullary carcinomas are discovered inciden-
tophysin [395,396]. Some studies have also identified tal to thyroid operations for other conditions, at au-
polysialic acid (neural cell adhesion molecule) in topsy, or because of an elevated serum calcitonin. The
medullary carcinomas but not in other thyroid tu- so-called micromedullary carcinomas (equivalent to
mors [397]. micropapillary carcinoma and defined as tumors of
Occasional lesions (and often these are small cell 1 cm or less) have an excellent prognosis if confined
type) do not contain immunoreactive calcitonin. In to the gland [410,411]. Some of the micromedullary
order to accept a calcitonin-free tumor of the thyroid cancers arise in the background of chronic thyroiditis
130 Zubair W. Baloch and Virginia A. LiVolsi

and may be associated with C cell hyperplasia even in When the diagnosis of thyroglossal cyst-associ-
the absence of familial disease [412]. Some of these ated thyroid cancer is made, the question of its origin
patients have hypothyroidism and elevated TSH arises. Does this tumor represent a metastasis from a
levels. Hence this type of C cell hyperplasia and mi- primary lesion in the gland, or is the primary site in
cromedullary carcinoma may represent a secondary the region of the gland, or is the primary site in the
reactive phenomenon leading to early neoplastic region of the cyst? In rare cases in which the thyroid
change [410,412414]. The non-tumoral parenchyma was examined pathologically, areas of papillary carci-
should be examined for evidence of C cell hyperpla- noma were found in the gland [30,423]. Most authors
sia in a thyroid removed for a medullary carcinoma. studying this problem conclude that the thyroglossal
Occasionally, the gland contains moderate to severe carcinoma is a primary tumor arising in remnants of
autoimmune thyroiditis, adenomatoid nodules, or thyroid associated with the duct; in those few cases
another follicular-derived thyroid cancer [414416]. where intrathyroidal tumor has been found, this was
considered a separate primary [30,421] although mo-
lecular analyses have not yet been reported to settle
10.7.3 Lymphoma this question.
Malignant tumors arising in thyroid tissue located
Secondary involvement of the thyroid by lymphoma within the trachea or larynx are very rare, but have
has been reported in 20% of patients dying from gen- been reported [424].
eralized lymphoma. Primary lymphoma of the thy- Carcinomas, usually papillary subtype, and lesions
roid is uncommon but not rare. Most patients may that resemble carcinoid tumors can arise in struma
have a history of diffuse goiter (probably the result of ovarii [425427].
autoimmune thyroiditis) that has suddenly increased
in size.
Most thyroid lymphomas are diffuse in type. Vir- 10.7.5 Metastatic Neoplasms
tually all examples are B cell types; many may be ex-
tranodal lymphomas that arise in mucosa-associated Tumors metastasize to the thyroid via direct exten-
lymphoid tissue (MALT) especially in the gastrointes- sion from tumors in adjacent structures, by retro-
tinal tract. Some patients have typical plasmacytomas grade lymphatic spread, or hematogenously. Carcino-
and these have a good prognosis. Hodgkins disease is mas of the larynx, pharynx, trachea, and esophagus
extremely rare. Malignant lymphoma should be dif- can invade the thyroid directly. In these cases the
ferentiated from advanced autoimmune thyroiditis; distinction from a thyroid primary is usually not dif-
this distinction requires assessment of lymphocyte ficult. Retrograde extension via lymphatic routes into
clonality by special studies (e.g., flow cytometry, gene the thyroid is unusual. In theory, at least, any tumor
rearrangement) [106,107,417419]. involving cervical lymph nodes could extend into the
thyroid by this mechanism. Hematogenous metasta-
ses to the thyroid vary according to tumor type [329].
10.7.4 Thyroid Tumors in Unusual Locations Carcinomas of the kidney, lung, and colon and mela-
noma are most commonly found [329]. Such lesions
Although clinically significant lingual thyroid is an are often solitary, circumscribed masses; they may ap-
unusual disorder, and microscopic remnants of thy- pear quite compatible with a primary tumor. Resem-
roid tissue have been described in 9.8% of tongues blance to colonic adenocarcinoma, breast cancer, or
examined at autopsy. Rare cases of thyroid carcinoma pigmented melanoma reassures that this is a metas-
arising in lingual thyroid are recorded [420]. tasis. However, clear cell carcinoma of the kidney, as
Neoplasms arising in association with the thyro- noted above, may present a problem [329,428430].
glossal duct might be expected to be squamous car-
cinomas, but these are extremely rare; indeed, most
tumors occurring in this setting have been thyroid 10.8 Frozen Section Diagnosis
carcinomas and most are described as papillary. Med- and the Thyroid
ullary carcinoma has not been described; since the
parafollicular cells are not found in the median thy- Before the advent of fine- and large-needle biopsy, the
roid, this is not unexpected. The clinical presentation method most often used in diagnosis of thyroid nod-
of thyroglossal duct carcinoma is identical to that of ules was intraoperative frozen section. The nodule or
benign thyroglossal duct cysts, i.e., a swelling in the preferably the thyroid lobe was excised and a repre-
anterior neck [27,421,422]. sentative portion (preferably encompassing nodule
10 Thyroid Pathology 131

capsulethyroid interface) was prepared for frozen 5. Zampi G, Bianchi S, Amorosi A, Vezzosi V (1994) [Thy-
section and interpretation by a pathologist. In those roid cancer: anatomy and pathologic histology]. Chir Ital
cases in which the diagnosis of papillary, medullary, 46:47
or anaplastic cancer was given, appropriate surgery 6. Kondalenko VF, Kalinin AP, Odinokova VA (1970) [Ul-
was immediately undertaken. trastructure of the normal and pathologic human thyroid
Even with frozen section, however, despite recom- gland]. Arkh Patol 32:2534
mendations of sampling two or even four different ar- 7. Nesland JM, Sobrinho-Simoes M, Johannessen JV (1987)
eas, the diagnosis of follicular carcinomas was notori- Scanning electron microscopy of the human thyroid gland
ously difficult. In many cases, the diagnosis rendered and its disorders. Scanning Microsc 1:17971810
8. Sugiyama S (1971) The embryology of the human thyroid
is follicular lesion diagnosis deferred to permanent
gland including ultimobranchial body and others related.
sections [299,300,431].
Ergeb Anat Entwicklungsgesch 44:3111
Several studies have evaluated frozen section and
9. Kovalenko AE (1999) [Contemporary concepts of em-
fine-needle aspirate (FNA) diagnostic results for thy-
bryology and surgical anatomy of the thyroid gland]. Klin
roid nodules [432434]. Although frozen section di- Khir 1999:3842
agnosis may be specific (9097%), it is not sensitive 10. Gibson W, Peng T, Croker B (1980) C-cell nodules in adult
(60%). In addition, deferred diagnoses at frozen sec- human thyroid: a common autopsy finding. Am J Clin
tion do nothing to alter the operative procedure or Pathol 73:347351
guide the surgeon [299]. Frozen section results influ- 11. Wolfe H, DeLellis R, Voelkel E, Tashjian A (1975) Distri-
enced the surgical approach in only a small percent- bution of calcitonin containing cells in the normal neona-
age of cases. Also, in the era of cost containment, it tal human thyroid gland: a correlation of morphology with
does not seem justified to perform frozen sections for peptide content. J Clin Endocrinol Metab 41:10761081
the intraoperative diagnosis of thyroid nodules; the 12. Baschieri L, Castagna M, Fierabracci A, Antonelli A, Del
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rendered on FNA is definitely malignant, the surgeon and in Hashimotos thyroiditis. Appl Pathol 7:99104
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a quantitative autopsy study. J Clin Endocrinol Metab
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16. Harach H (1986) Solid cell nests of the human thy-
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tion. Surgery 108:964967; discussion 970971

11 Surgery for Medullary Thyroid Cancer

Oliver Gimm

Contents The management of hyperparathyroidism in pa-

tients with multiple endocrine neoplasia (MEN2A)
11.1 Introduction . . . 147 will be discussed in Chapter 24 Multiglandular Para-
11.2 Diagnosis . . . 147
thyroid Disease and MEN Syndromes.
11.2.1 Further Diagnostic Investigation . . . 148
11.2.2 The Proto-oncogene RET . . . 149
11.3 Multiple Endocrine Neoplasia Type 2 . . . 149
11.3.1 Diagnosis . . . 150
11.2 Diagnosis
11.3.2 Prophylactic Thyroidectomy . . . 151
11.4 Therapy . . . 152
In many patients with MTC, thyroid nodules are the
11.4.1 Surgery . . . 152 first clinical sign. Since MTC metastasizes early to the
11.4.2 Technique of Lymph Node Dissection . . . 153 locoregional lymph nodes (by the time of diagnosis,
11.4.3 Cervicocentral Lymph Node Dissection . . . 154 more than 50% of patients with sporadic MTC have
11.4.4 Cervicolateral Lymph Node Dissection . . . 154 lymph node metastases), lymph node metastases may
11.4.5 Mediastinal Lymph Node Dissection . . . 155 also be the first clinical sign. The parafollicular C cells
11.4.6 Distant Metastases . . . 155 synthesize and secrete calcitonin which can be used
11.4.7 Non-surgical Treatment Options . . . 155 as a sensitive tumor marker. Calcitonin secretion can
11.5 Follow-up and Prognosis . . . 155 be stimulated by both calcium (2 mg/kg body weight
References . . . 155 of 10% Ca2+ injected intravenously in 1 min) and pen-
tagastrin (0.5 g/kg body weight, diluted in 510 ml
sterile saline, injected intravenously in 515 s), the
latter of which should preferably be used if available.
11.1 Introduction Calcitonin levels are considered pathologic when the
basal level is above normal range or when stimulation
Medullary thyroid cancer (MTC) is a rare type of of calcitonin leads to an increase of calcitonin more
thyroid cancer which derives from the parafollicular than two to three times the basal level [47]. While
C cells. C cells produce calcitonin which can be used other conditions (e.g., neuroendocrine pancreatic
as a tumor marker. The real incidence of MTC is un- tumors, carcinoids, small cell lung cancers, renal or
known. Based on epidemiologic studies from Scan- hepatic insufficiency, treatment with proton pump
dinavia, its prevalence was estimated to be roughly inhibitors) have been found to be associated with el-
34% of all thyroid malignancies [9,37]. Those stud- evated basal calcitonin levels [33,46,50], an increase
ies, however, analyzed data from the 1960s and 1970s, of at least two- to threefold after stimulation seems to
i.e., shortly after MTC was identified as a distinct en- be pathognomonic for both sporadic and hereditary
tity by Hazard [32]. Hence, the real incidence of MTC MTC.
was assumed to be higher. More recent studies that Routine preoperative measurement of basal cal-
emphasize the need to determine calcitonin routinely citonin in patients with thyroid nodules has been
in any patient with nodular thyroid disease found shown to enable identification of MTC preoperatively
an unsuspected high prevalence (1640%) of MTC [62,67,78]. This preoperative workup (Fig.11.1) of
[62,67,78]. This prevalence, however, appeared to be thyroid nodules is not recommended by all endo-
too high. Today, it is assumed that MTC accounts for crinologists and endocrine surgeons but has become
510% of all thyroid malignancies. MTC exists in a more and more accepted [43]. In a large recent study
sporadic (about 75%) and a hereditary (about 25%) of more than 10,000 patients, routine measurement
form [66] associated with several biological features of calcitonin in patients with nodular thyroid disease
that necessitate a particular surgical approach in or- significantly improved the 5-year (97% versus 81%)
der to offer a high chance of cure. and 10-year (86% versus 43%) long-term survival of
148 Oliver Gimm

patients with MTC in comparison with historical re- formed. Of note, ultrasound and other imaging tech-
sults [19]. Of note, the routine measurement of calci- niques may miss metastatic lymph nodes and small
tonin in patients with nodular thyroid disease has not (microscopic) disease. When imaging techniques fail
only increased the rate of preoperatively diagnosed to distinguish between scar tissue and MTC, the use
MTC but also may cause a diagnostic dilemma. Stim- of fine-needle aspiration may be helpful. If locally
ulated calcitonin levels below 100 pg/ml are rarely advanced tumor extension (e.g., infiltration of the
caused by MTC [43] but may be due to sporadic esophagus and/or trachea) is suspected, endoscopic
C cell hyperplasia as seen in various benign diseases examination is mandatory.
of the thyroid [1,8,31]. In these patients, immediate Hematogenous tumor spread occurs predomi-
total thyroidectomy is not advised unless the nodule nantly to the lung, liver, and bone. Various imaging
is otherwise suspected to be malignant (Fig. 11.1). techniques have been used to determine the extension
Instead, reevaluation after 36 months is recom- of distant metastases: computed tomography, mag-
mended. In patients with stimulated calcitonin levels netic resonance imaging, octreotide scintigraphy, and
>100 pg/ml, total thyroidectomy is advised. In rare in- positron emission tomography with various tracers
stances with high serum calcitonin levels, symptoms (e.g., FDG, DOPA) [13,22,35,54]. In addition, selec-
may arise from diarrhea [3] not responding well to tive venous catheterization has been used successfully
common anti-diarrheic drugs. Since MTC may syn- [22]. If none of these techniques enables the localiza-
thesize and secrete other hormones, for example cor- tion of distant metastases but if basal calcitonin levels
ticotropin (ACTH), paraneoplastic syndromes, such are above 500 pg/ml, laparoscopy is advised [77]. If
as Cushings syndrome, may occur [73]. laparoscopy does not reveal hepatic metastases, tho-
racoscopy may be helpful to assess the presence of
lung metastases. Typically, multiple micrometastases
11.2.1 Further Diagnostic Investigation can be found in these instances.
Advanced tumor stages can only be prevented by
Once MTC is diagnosed, local tumor extension (pri- early diagnosis of MTC. Concerning sporadic MTC,
mary tumor and lymph node metastases) may be as- this can only be achieved by routine measurement
sessed by ultrasonography. In particular in patients of calcitonin in patients with thyroid nodules [43].
with recurrent or persistent MTC, computed tomog- However, routine measurement in these patients is
raphy or magnetic resonance imaging should be per- not uniformly accepted. Regarding hereditary MTC,

Fig. 11.1 Work-up recommendations in patients with nodular goiter. CCH C cell hyperplasia, MTC medullary thyroid carcinoma
11 Surgery for Medullary Thyroid Cancer 149

11.3 Multiple Endocrine

Neoplasia Type 2
Hereditary MTC is part of the multiple endocrine neo-
plasia type 2 (MEN2) syndromes. Clinically, MEN2
has been divided into three subgroups: familial MTC
(FMTC), MEN2A, and MEN2B. MTC is the conditio
sine qua non of all three subgroups (Table 11.1). In
addition, patients with MEN2A may develop pheo-
chromocytoma and/or primary hyperparathyroid-
ism (pHPT). Primary hyperparathyroidism as part of
MEN2 is usually milder than primary hyperparathy-
roidism as part of multiple endocrine neoplasia type 1
(MEN1) or their sporadic counterpart. Hence, routine
subtotal or total parathyroidectomy plus autotrans-
plantation as recommended in MEN1 is not necessary
[12]. In the presence of MEN2-pHPT, parathyroid-
ectomy may be limited to the enlarged parathyroid
Fig. 11.2 Work-up recommendation in patients with inciden- gland. Alternatively, like patients with MEN2A and in
tally found MTC addition to MTC, patients with MEN2B may develop
pheochromocytoma (Table 11.1). Further, they de-
it can be achieved by screening at-risk family mem- velop neuromas of the tongue, ganglioneuromatosis
bers after identification of the family-specific RET of the intestine, and/or medullated corneal nerve fi-
mutation [18,80]. Hence, once MTC is diagnosed, the bers. A marfanoid habitus may also be present. None
patient must undergo germline RET mutation anal- of the latter phenotypes must be present in patients
ysis, irrespective of his/her age [71] or the presence with MEN2B nor are they pathognomonic [28,29,65].
of any other features suggestive for hereditary MTC Clinically symptomatic primary hyperparathyroid-
(Fig. 11.2). ism is not part of MEN2B. By definition, patients with
FMTC develop MTC only (Table 11.1). Of note, there
is no reliable diagnostic tool to distinguish patients
11.2.2 The Proto-oncogene RET with FMTC from those with MEN2A, i.e., members
of families with FMTC are always at risk of develop-
The proto-oncogene RET was initially found to be re- ing pheochromocytoma or, even though less likely,
arranged during transfection of NIH 3T3 cells [75]. primary hyperparathyroidism. For instance, in the
Later, somatic RET rearrangements were identified in past, several RET mutations (e.g., V804L, S891A) [36]
patients with papillary thyroid carcinoma [30]. These were believed to be associated with FMTC only. How-
mutations were somatic, i.e., only found in the thy- ever, pheochromocytomas have also been diagnosed
roid tumor. In 1993, RET mutations were also found in these patients [42,61]. It appears that the develop-
in patients with MTC [14,60]. In contrast to papillary ment of pheochromocytomas is rather a matter of
thyroid carcinoma, these mutations were found in pa- time. Hence, no patient with an FMTC/MEN2-spe-
tients with hereditary MTC and the mutations were cific RET mutation should be excluded from screen-
germline (i.e., present in every nucleus-containing cell ing for pheochromocytoma. Since FMTC is only a
of the human body) not somatic. The identification of clinical term based on the phenotype of the patient,
RET as the disease-causing gene of hereditary MTC the use of the term FMTC/MEN2A is recommended.
enabled identification of at-risk family members by MEN2 has also been named multiple endocrine
DNA analysis of blood leukocytes. Already in 1994, adenomatosis (MEA) type 2 but this term should no
the first clinical experience was reported [47,80]. For longer be used. MEN2A is also known as Sipples syn-
the first time, indication for surgery was solely based drome [72]. However, Sipple did not realize the as-
on the result of molecular analysis and RET became sociation of pheochromocytomas and the medullary
the paradigm of molecular medicine [18,20]. Despite type of thyroid carcinoma. Steiner and coworkers
the fact that RET is a large gene, mutation analysis is described a kindred with pheochromocytoma, MTC,
comparably simple since mutations found so far are and hyperparathyroidism and proposed the term
limited to a few exons (Table 11.1). multiple endocrine neoplasia (MEN) type 2A [74].
150 Oliver Gimm

Table 11.1 Genotype-phenotype correlation in MEN2. ( Disease/finding absent or frequency observed not higher that in the gen-
eral population, + disease/finding present in most cases but neither required nor pathognomonic [28,29,65])
8 533 533
10 609 609 609
611 611 611
618 618 618
620 620 620
11 630 630
634 634 634
13 768 768
790 790 790
791 791 791
14 804 804 804 b 804 c
844 844
15 883 883
891 891 891
16 912 912 e
918 918
Mean age at diagnosis (years) 4555 2535 1020
Medullary thyroid carcinoma (MTC) 90100% g 90100% g 100%
Pheochromocytoma 4060% 4060%
Primary hyperparathyroidism 1030%
Ganglioneuromatosis +
Multiple mucosal neuromas +
Marfanoid habitus +
Thickened corneal fibers +

Based on one publication [11]
Based on one report with MTC and adrenal and extra-adrenal pheochromocytoma [61]
Based on several reports with additional germline RET mutation [44,53,55]; however, it appears that the phenotype is rather
MEN2B-like than typical MEN2B
Based on one report with MTC and adrenal pheochromocytoma [42]
Based on one publication [41]
The age at diagnosis has become younger since the identification of RET
Since the identification of RET, many patients undergo surgery before MTC occurs

MEN2B has also been named MEN3 which should The female to male ratio is thought to be about 1:1
also no longer be used. Even less common is the term with a slight predominance of the female gender in
Wagenmann-Froboese syndrome [23,79]. some studies.
The incidence of MEN2 is not known. About one
fourth of all MTCs are thought to be hereditary [66].
Since thyroid cancer has been assumed to have an 11.3.1 Diagnosis
incidence of 13/100,000 per year, MEN2 may have
an incidence of 1.257.5/10,000,000 per year. This The diagnosis of MTC in the index patients of a
would fit with its estimated prevalence of 1/35,000. given family with MEN2 does not differ from that
11 Surgery for Medullary Thyroid Cancer 151

in sporadic MTC. Most patients present with ei- 11.3.2 Prophylactic Thyroidectomy
ther thyroid nodules or lymph node metastases or
both. Hence, once MTC is diagnosed, the patient In patients with hereditary MTC, biochemical pene-
should undergo phenotype-depending RET muta- trance, i.e., pathologic basal and/or stimulated calcito-
tion analysis (Table 11.1, Fig. 11.2). This can be most nin levels, reaches almost 100% by the age of 35 years.
easily done by analyzing leukocyte DNA of a venous Based on studies in the pre-RET era, it is known that
blood sample. If no RET mutation is found, the risk about 70% of patients with MEN2A develop clinically
of these patients having MEN2 is less than 1% un- apparent MTC by the age of 70 years [64].
less other features suggestive for MEN2 are present. Since every thyroidal C cell inherits the risk of be-
In the case of a proven RET mutation, the mutation coming malignant, total thyroidectomy is advised in
needs to be confirmed by analyzing a second, inde- any patient with FMTC/MEN2. MTC metastasizes
pendently drawn blood sample. If confirmed, the early to locoregional lymph nodes and beyond. Once
patient should undergo screening for accompany- lymph node metastases are present, the chance of bio-
ing diseases of MEN2. Further, his/her at-risk family chemical cure, i.e., normal basal and stimulated calci-
members should undergo analysis for this particular tonin levels, decreases [25]; once MTC is spread be-
RET mutation. In family members with proven RET yond the locoregional lymph nodes, biochemical cure
mutation, a thorough work-up is necessary and total is impossible. This is the rationale to offer timely ther-
(prophylactic) thyroidectomy should be advised. In apy. Hence, surgery should preferably be performed
rare instances (<10%), pheochromocytoma precedes before the development of MTC (prophylactic thy-
the development of MTC [7]. Hence, RET mutation roidectomy), at the latest before the development of
analysis is also recommended in patients with pheo- lymph node metastases, which means in some cases at
chromocytoma. Even less likely is the development of the age of 5 years and below. It is obvious that surgery,
primary hyperparathyroidism prior to the develop- in particular for these cases but also for MTC in gen-
ment of MTC. Routine RET mutation analysis is not eral, should be performed by experienced surgeons.
recommended in patients with primary hyperpara- Timing and extent of this prophylactic approach is
thyroidism. based on several parameters (Fig. 11.3). First, it has

Fig. 11.3 Recommendations for timing of prophylactic surgery in patients with FMTC/MEN2 according to stimulated calcitonin
levels and codon mutation. LND Lymph node dissection
152 Oliver Gimm

been shown that a genotype-phenotype correlation in order to minimize morbidity. In patients with he-
exists [20,48]. Some RET mutations (e.g., codons 634 reditary MTC, the coexistence of pheochromocytoma
and 618) are associated with an early onset of the dis- should be excluded in order to prevent intraopera-
ease while others (e.g., codons 768 and 791) appear tive life-threatening hypertension crisis. In patients
later at a greater age. Interestingly, this clinical aggres- with sporadic MTC, multifocal tumors are less com-
siveness somewhat correlates with the transforming mon (1020%) but total thyroidectomy has also been
activity of RET caused by this particular mutation recommended since C cells do not take up radioio-
[38,39]. Second, basal and stimulated calcitonin levels dine. Nevertheless, subtotal resections have been
are helpful in assessing the extent of the disease. In performed successfully [56] (Fig. 11.2). However, if
the case of hereditary MTC, C cell hyperplasia [CCH; calcitonin remains elevated after subtotal resection, a
increased number of thyroidal C cells, i.e., >50 cells completion (total) thyroidectomy is mandatory. Since
per low power field (100) on histological examina- lymphogenous spread is often (>50%) found in both
tion] precedes the development of MTC. Soon after, patients with sporadic MTC and index patients with
lymph node metastases may occur. Actually, lymph hereditary MTC, at least lymph node dissection of
node metastases have been found in the case of pri- the cervicocentral compartment (C1) (Fig. 11.4a) is
mary tumors less than 5 mm in size. While calcitonin recommended, in particular if stimulated calcitonin
levels can not reliably distinguish between CCH and level is >200 pg/ml (Fig. 11.1) [43]. Of note, lymph
intrathyroidal MTC, lymph node involvement can be node metastases are often not limited to the cervi-
assumed to be absent in the case of both basal and cocentral compartment (Table 11.2). Hence, bilateral
stimulated normal calcitonin levels. Third, MTC de- cervicolateral lymph node dissection (compartments
velopment has been shown to be age dependent [52]. C2 and C3; Fig. 11.4a) should be considered in all pa-
tients with MTC, both sporadic and hereditary [70].
The only exception may be patients who undergo
11.4 Therapy prophylactic thyroidectomy (see above and Fig. 11.3).
The level of basal of stimulated calcitonin level is not
11.4.1 Surgery helpful in determining the necessary extent of lymph
node dissection [26]. Primary tumor size and ex-
Total thyroidectomy is the treatment of choice. Pa- trathyroidal tumor extension correlate with lymph
tients should be referred to an experienced surgeon, node involvement (Table 11.3) but individually reli-

Fig. 11.4 a Compartment classification (described by Dralle et al. [16]). b Skin incisions according to the dissected compartment:
* cervicocentral compartment (1a right; 1b left), # cervicolateral compartment (2 right; 3 left), mediastinal compartment (4a right;
4b left)
11 Surgery for Medullary Thyroid Cancer 153

Table 11.2 Frequencies of nodal metastases (%) within different compartments in patients with primary MTC according to various
references. (n/a Not assessed)
Reference Patients Lymph node compartment, node positive (%)
Central Lateral Mediastinal
Ipsilateral Contralateral
Fleming et al. [21] 40 80 78 25 n/a
Moley et al. [57] 73 79 75 47 n/a
Scollo et al. [70] 101 48 49 24 n/a

Table 11.3 Frequencies of nodal metastases (%) within different compartments in patients with primary MTC according to tumor
Tumor size Patients Lymph node compartment, node positive (%)
Ipsilateral Contralateral Mediastinal
Central Lateral Central Lateral
Gimm et al. [25]
Intrathyroidal, 10 mm 3 33 33 0 0 0
Intrathyroidal, >10 mm 18 56 44 17 11 0
Extrathyroidal, any size 6 83 100 17 0 50
Machens et al. [51]
Intrathyroidal, 10 mm 35 14 11 3 0 0
Intrathyroidal, >10 mm 19 26 32 21 16 11
Extrathyroidal, any size 14 71 93 64 57 50

able parameters do not exist. Also, at reoperation, a common type of thyroid cancer, are often believed to
tumor size-dependent approach does not seem to be be of minor importance [5] even though their prog-
justified since bilateral compartment involvement is nostic significance is controversial [69]. In contrast,
very frequent [24]. The chance to cure the patient is the prognostic significance of lymph node metasta-
unrealistic if more than two compartments contain ses in patients with MTC is well documented [2,45]
lymph node metastases [51]. Even though mediastinal and lymphogenous spread is often found. However,
(compartment C4; Fig. 11.4a) lymph node metastases MTC is rather rare (510% of all thyroid carcinomas)
have been found quite frequently [25], prophylactic and only a few centers have experience in treating
dissection of the upper mediastinum is not recom- this disease. Therefore, it may not be surprising that
mended [49]. The reason is that nodal involvement a standardized concept of lymph node dissection for
of the mediastinum is often associated with hematog- thyroid cancer is lacking. The degree of lymph node
enous tumor spread and, hence, biochemical cure dissection varies from selective node removal (berry
is unlikely. Still, if tumor spread to the mediastinum picking) to radical neck dissection, a procedure orig-
has been proven, dissection of this compartment is inally developed for squamous cell carcinoma of the
advised to prevent local complications (e.g., tracheal head and neck.
infiltration). Lymph node metastases derived from MTC may
be very small in size and neither pre- nor intraop-
eratively detectable. Hence, selective node dissection
11.4.2 Technique of Lymph Node Dissection (berry picking) is not recommended in patients
with MTC. Instead, an en bloc systematic dissec-
In contrast to other epithelial cancers, lymph node tion of lymph nodes together with their surround-
dissection in thyroid cancer has not been well stan- ing adipose tissue while preserving nerves and ves-
dardized. One reason may be that lymph node me- sels should be performed. This systematic approach
tastases in papillary thyroid carcinoma, the most achieves an improved biochemical cure rate [24,58].
154 Oliver Gimm

The compartment-oriented approach advocated by very helpful to offer good access and should be per-
Dralle (Fig. 11.4a) has several advantages [16]. It is formed without hesitation. Following identification
based on the microdissection technique described by of the inferior thyroid artery, the recurrent laryngeal
Tisell and Moley [59,76]. The compartments are lim- nerve should be identified. The dissection in between
ited by major anatomical structures, are therefore well the carotid artery (lateral border) and the trachea
defined, and take into account the pattern of lym- (medial border) may preferably be performed in a
phogenous spread [25]. caudal-to-cranial fashion starting from the innomi-
The compartment model distinguishes four dif- nate artery up to the hyoid bone. The lower parathy-
ferent compartments (Fig. 11.4a). The cervicocentral roid glands can often not be preserved and should be
compartment (C1) reaches from the submandibular autotransplanted after histologic exclusion of tumor
gland down to the brachiocephalic vein and is later- involvement. The upper parathyroid glands should
ally limited by the carotid sheath. It contains the sub- be identified and preserved or, alternatively, auto-
mandibular, submental, paratracheal, and paraesoph- transplanted. Autotransplantation into both the right
ageal lymph nodes (level I+VI as defined by Robbins sternomastoid muscle and the forearm work well. The
and coworkers [68]) and is further subdivided into a location should be marked with a non-absorbable
right (C1a) and a left (C1b) compartment. Lateral of suture. Preparation on the first side is completed by
compartment C1 lie the cervicolateral compartments total mobilization of the thyroid lobe or remnant. Af-
C2 (right) and C3 (left) (levels II, III, IV, and V as ter complete preparation on one side, the same proce-
defined by Robbins and coworkers [68]). They reach dure is performed on the contralateral side. Follow-
from the mandible down to the subclavian vein and ing complete mobilization on both sides, the thyroid
are limited medially by the carotid sheath and laterally gland and the connective adipose tissue are removed
by the trapezoid muscle. Caudal of compartment C1 en bloc.
lies the mediastinal compartment (C4) which reaches
from the brachiocephalic vein down to the tracheal
bifurcation. It is laterally limited by the pleura and, 11.4.4 Cervicolateral Lymph Node Dissection
like compartment C1, is subdivided into a right (C4a)
and a left (C4b) compartment. It has been shown that For technical details refer also to Chapter 9 Modi-
involvement of these compartments follows a specific fied Radical Neck Dissection. Like dissection of the
pattern with the ipsilateral cervicocentral compart- cervicocentral compartment, lymph node dissection
ment and the ipsilateral cervicolateral compartment of the cervicolateral compartment is performed in a
being the first regions affected [25,51]. systematic way, i.e., all lymph nodes within that com-
In accordance with the various compartments, partment are removed together with the connective
the following procedures can be distinguished [17]: adipose tissue while muscles, nerves, and vessels are
cervicocentral lymph node dissection, cervicolateral preserved. In the case of cervicolateral lymph node
lymph node dissection, and mediastinal lymph node dissection, the Kocher incision is extended laterally
dissection. These dissections should always be per- along the anterior (medial) border of the sternomas-
formed using ocular magnifying devices and bipolar toid muscle (Fig. 11.4b). Thereafter, the carotid sheath
coagulation forceps. should be identified. Separation of its content (carotid
artery, internal jugular vein, vagus nerve) is not nec-
essary, however, the vagus nerve should be identified
11.4.3 Cervicocentral Lymph Node in order to preserve function of the recurrent laryn-
Dissection geal nerve. General incision of the sternomastoid
muscle is not necessary but may be helpful in the case
Dissection of the cervicocentral lymph node com- of multiple lymph node involvement. If performed,
partment may be performed together with total thy- the muscle should be anastomosed after completion
roidectomy. In many cases, however, cervicocentral of the dissection using absorbable sutures. Like in the
lymph node dissection is part of completion thyroid- cervicocentral compartment, dissection may prefera-
ectomy. The skin incision should be done like a Ko- bly be performed in a caudal-to-cranial fashion start-
cher incision in between the sternomastoid muscles ing at the medial border and continuing to the lateral
(Fig. 11.4b). Following exposure of the first thyroid border. Branches of the thoracic duct are ligated, and
lobe (usually the dominant side), the middle thyroid the external jugular vein should be preserved. Re-
vein (Kochers vein) should be ligated. Transection of moval of the connective adipose tissue containing the
the sternothyroid muscle and sternohyoid muscle is lymph nodes should be performed en bloc preserving
11 Surgery for Medullary Thyroid Cancer 155

the nerves of the brachial plexus and cervical plexus. metastases, and external radiation. External radia-
The accessory nerve, the phrenic nerve, and the sym- tion to the neck should be avoided as long as possible
pathetic trunk are preserved. since it causes scarring which may make both assess-
ment of local recurrence and reoperation difficult.
More recently, tyrosine kinase inhibitors have been
11.4.5 Mediastinal Lymph Node Dissection shown to inhibit RET tyrosine kinase activity [6,10].
Clinical studies are underway but results have not yet
In the case of extended lymph node involvement, been published.
lymphogenous spread is rarely limited to the cervical
compartment [51]. Actually, at reoperation, routine
dissection of the upper mediastinum has identified 11.5 Follow-up and Prognosis
lymph node metastases in up to 36% of cases [24].
However, biochemical cure is rare (<10%) in these The overall 5-year survival and 10-year survival rates
instances. Currently, dissection of the upper medias- have been reported to be 8090% and 6070%, re-
tinum is recommended in the case of proven lymph spectively [2,34]. Several factors have been identified
node metastases using imaging techniques. Dissec- to correlate with long-term prognosis. Early postop-
tion of the upper mediastinum should also be con- erative normalization of calcitonin levels, i.e., normal
sidered if the presence of lymph node metastases is basal and stimulated calcitonin levels (biochemical
very likely (e.g., contralateral or bilateral cervical cure) is strongly associated with a long-term disease-
lymph node metastases, extrathyroidal tumor exten- free survival [15,27,63]. Since the presence of lymph
sion) [52]. Dissection of this compartment requires node metastases has been shown to lower the cure
complete splitting of the sternum (Fig. 11.4b). Fol- rate from 100% to 33% [25], lymph node metastases
lowing sternotomy, the thymus and the adipose tissue themselves are strong predictors of a worse long-term
surrounding the thymus are prepared in a caudal-to- prognosis [2,45]. Of note, calcitonin levels may rise
cranial fashion starting down at the azygos vein and years after primary surgery despite initial normaliza-
going up to the brachiocephalic vein (left side) or tion [40]. Hence, regular follow-up is necessary in all
innominate artery (right side). Retrovascular, para- patients. Also, a subgroup of patients seem to have
tracheal, and paraesophageal lymph nodes are often a delayed normalization that may take up to a few
involved and must be removed in the case of a medi- weeks [4,27]. The meaning of this phenomenon is not
astinal lymph node dissection. Special care should be known.
taken to preserve the phrenic nerve.

11.4.6 Distant Metastases
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