Editors: Kini, Sudha R.

Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition

Copyright ©2008 Lippincott Williams & Wilkins

> Front of Book > Editors

Editor
Sudha R. Kini
Henry Ford Hospital

Department of Pathology

Division of Cytopathology

Detroit, Michigan
 P.iv
Contributors
J. MARTIN MILLER, MDKINI
Emeritus Consultant
Division of Endocrinology
Department of Internal Medicine
Henry Ford Hospital;+

Endocrinologist
Associated Endocrinologists
Southfield, Michigan;

Emeritus Clinical Associate Professor

University of Michigan
Ann Arbor, Michigan

MAX WISGERHOF, MD
Division of Endocrinology and Metabolism
Department of Internal Medicine
Henry Ford Hospital
Detroit, Michigan

VINOD NARRA, MD
Department of General Surgery
Henry Ford Hospital;

Clinical Assistant Professor

Wayne State University
Detroit, Michigan

OSAMA ALASSI, MD
Senior Staff Pathologist
Department of Pathologist
Henry Ford Hospital
Detroit, Michigan

MELINA CANKOVIC, PHD

Division Head, Molecular Pathology
Department of Pathology
Henry Ford Hospital
Detroit, Michigan

CLAIRE W. MICHAEL, MD
Associate Professor of Pathology
Director, Cytopathology
University of Michigan
Ann Arbor, Michigan
Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Front of Book > Acknowledgments

Acknowledgments

Permission to reproduce the following is gratefully acknowledged:

From Miller JM, Kini SR, Hamburger JI. Needle Biopsy of the Thyroid. New York:
Praeger Publishers; 1983 for Figures 2.2, 2.3, 2.4 and 2.5.

From Kini SR, Miller JM, Hamburger JI, et al. Cytopathology of follicular lesions of
the thyroid gland. Diagn Cytopathol. 1985;1:123–132, published by Igaku-Shoin,
New York for Figures 5.21 and 5.25.

From Cervino JM, Paseyro P, Grosso O, et al. La exploration citologic de la glandula

tirodes y sus correlaciones anatomoclinicas. An Facultad Med. 1962;47:128–143
for Figure 7.48.

From Crissman JD, Druzdowicz S, Johnson C, et al. Fine needle aspiration diagnosis
of hyperplastic and neoplastic follicular nodules of the thyroid. A morphometric
study. Anal Quant Cytol Histol. 1991;13:321–328 for Tables 7.15 to 7.18.

From Kini SR. Color Atlas of Differential Diagnosis in Exfoliative and Aspiration
Cytopathology. Philadelphia: Lippincott Williams & Wilkins;1999 for Figure 5.18.

The permission to photograph cases or reproduce the images is gratefully

acknowledged from:

Mariza de Peralta-Venturina, MD, William Beaumont Hospital, Royal Oak, Michigan

for Figures 6.22, 6.30A and 6.30B, 6.40, 6.45, 7.20A to 7.20E, 7.42A to 7.42D, 7.54A
to 7.54D, 8.21A and 8.21B, 9.14G, 9.17E, 9.19D, 9.36B, 17.11A to 17.11C, 18.12,
and 19.52.

Mithra Baliga, MD, University of Mississippi, Jackson, for Figures 7.13A and 7.13B,
7.56A to 7.56C, 8.14A to 8.14D, 8.20A to 8.20F, 10.19A to 10.19B, 11.27A to
11.27E, 12.49A and 12.49B, 16.14A and 16.14B.

David B. Kaminsky, MD, Palm Springs Pathology Associates, Palm Springs, California
for Figures 19.9 and 19.19.

Sedigheh-Keyhani, MD, FIAC, Professor of Clinical Pathology, Ohio State University

Hospital, Columbus, for Figures 13.3 and 13.18.

John F. Goellner, MD, formerly of Department of Pathology, Mayo Clinic Rochester,

Minnesota for Figures 12.54 and 19.20.

W. K. Ng, MBBS, Department of Pathology, University of Hong Kong, Queen Mary

Hospital, Hong Kong for Figure 19.46.

Rene? Gerhard, MD, Department of Pathology, Hospital das Clinicas, University of

Sao Paulo, Brazil for Figure 19.47.

Edward Bernecki, MD, William Beaumont Hospital, Royal Oak, Michigan for Figures
19.48A to 19.48C.

Claire Michael, MD, University of Michigan Hospital, Ann Arbor, for Figures 19.48D
to 19.48F.

Chris Jenson, MD, University of Iowa Hospitals, Iowa City, for Figure 19.49.

Ricardo Gonzalez-Campora, MD, FIAC, Department of Pathology, Faculty of

Medicine, University of Seville, for Figure 19.51.

A. Vodovnik, Calderdale Royal Hospital, HX3 OPW Halifax, England for Figures 12.69
and 19.63.

Fadi Abdul-Karim, MD, Institute of Pathology, University Hospitals of Cleveland, for

Figure 19.54.

Ms. I. Kikuchi, CT (IAC), Department of Pathology, Central Clinical Laboratory,

Iwate Medical University, Morioka, Japan for Figure 19.56.

A. Watts, MD, Cedar Sinai Hospital, Los Angeles, California for Figure 13.2.

Yun Gong, MD, University of Texas M.D. Anderson Cancer Center, Houston, for
Figure 16.19.

Ami J. Walloch, MD and Rashead Hammadeh, MD, Christ Hospital, Oaklawn, Illinois
for Figure 15.21.

DV. Trivedi, MD, Methodist Hospital, Peoria, Illinois for Figure 13.51.

Michael Glant, MD, Director, Diagnostic Cytology Clinic, Indianapolis, for Figures
21.4A to 21.4D.

Sajal Choudhary, MD, formerly of Mt. Carmel Mercy Hospital, Detroit, Michigan for
Figure 16.16.
Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Front of Book > Dedication

Dedication

To all the patients, for their thyroid biopsies and thyroidectomies, that provided
the invaluable learning opportunities and experience.

To all of my clinical colleagues in Endocrinology & EndocrineSurgery for their

confidence in my cytologic interpretations.

To my daughters, Sarita and Sunita, whose support I can always count on.

To my granddaughter Maya, for bringing immense joy in my life.

And

To the loving memory of my late husband, Ratnakar. I cannot ever forget

hisencouragement and the moral support that I enjoyed throughoutour married life.
The fond memories have and always will guide me in spirit.
Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Front of Book > Preface

Preface

This Atlas and Text on Cytopathology of the Thyroid Gland is essentially the third
edition of "Thyroid" Guides to Clinical Aspiration Cytology. It comes 12 years after
the second edition, in a new format and all in color.

The atlas has retained the organization of the second edition and also most of the
text, modified whenever necessary with additional information. Several hundred
images have been added to illustrate the wide spectrum of cytologic features for
each disease entity. I have attempted to include the usual and unusual patterns of
disease entities in each chapter, as well as their diagnostic pitfalls. A few images
have been repeated just to emphasize the characteristics. Familiarity with the
histopathologic features of various thyroid lesions is extremely important. I have
therefore included more images in this atlas than in the second edition. The urge to
illustrate more examples was irresistible and I thank the publishers for allowing me
to do so.

The contributions made by the late Dr. Martin Miller (Chapters 1, 2, and 23) in the
two editions of the "Thyroid" Guides to Clinical Aspiration Cytology are retained in
this atlas for several reasons. First of all, the credit for success of fine-needle
aspiration biopsy of thyroid in the United States goes to a large extent to the
efforts of Dr. Miller.1 He strongly believed that too many thyroid glands with benign
disease were being removed, and was willing to explore ways to differentiate
benign from malignant nodules. Dr. Miller's expertise in thyroidology, his deep
concern for patients, and his enthusiasm and persistence in carrying through the
biopsy project since it was launched are all testimony to the success of fine-needle
biopsy. I am indeed privileged to have had a long association with him. Dr. Miller's
observations and approach are still applicable, and in my opinion worth retaining.
Writing this atlas was not as easy a task as I had thought it would be. The target
audience now is more sophisticated (and opinionated), experienced, and
knowledgeable in thyroid cytopathology. This is in sharp contrast to the time, some
three decades ago, when most cytopathologists were inexperienced in thyroid
cytology, especially the author, who had to struggle her way through. As aspiration
biopsy of thyroid nodules has become a standard of practice, the literature has
been inundated with case reports, review articles, differential diagnosis and
ancillary diagnostic tests, chapters and textbooks. I have made every attempt to
review most of the publications and incorporate the important information.

The diagnostic criteria for various thyroid lesions described in previous editions
have not changed but are expanded in this atlas. The criteria are still valid,
applicable, and reproducible (if tried on Papanicolaou-stained preparations). The
old statistical data is also retained, as it has been a very important part of my
learning experience. The importance of cytohistocorrelations of misinterpreted
cases cannot be overemphasized.

One of the main reasons for the wide variations in interpretations in thyroid
cytology is the inconsistency and lack of standardization in cytopreparations.
Fixation of the cellular material, cytopreparatory techniques, and type of staining
vary considerably from laboratory to laboratory. Cytopathologic criteria based on
one type of preparation may not be applicable to the specimen processed by other
techniques and stains. The cytologic criteria described and illustrated in this atlas
are entirely based on spray-fixed material stained by the Papanicolaou method. I
firmly believe that the interpretation of a cytologic specimen not only requires
appreciation of the pattern but most importantly, the nuclear details such as
presented in the Papanicolaou-stained preparations. I am also not convinced that
liquid-based cytology is a good alternative. This may be due to my lack of
experience with the preparations for non-gynecologic cytology, specifically for
thyroid aspirates. But I make no apologies. Something that has worked wonderfully
for the last 30 years need not be changed unless there are striking advantages in
terms of diagnostic yield, accuracy, and cost containment. I see none with liquid-
based cytologic preparations. However, I have included images of the Romanowsky-
stained preparations and have added a section on liquid-based cytology for the
benefit of a wider audience.
I still believe that follicular and Hürthle cell neoplasms can be cytologically
differentiated from non-neoplastic lesions in a high proportion of cases, especially
with the Papanicolaou-stained preparations. Diagnostic accuracy of follicular and
Hürthle cell lesions cannot be judged fairly against the gold standard of surgical
pathology when there is no consistency in surgical pathology diagnoses of these
neoplasms. It is always taken for granted that the histologic diagnosis is accurate
when cytologic and histologic diagnoses in any given case are discordant. The fact
that histologic diagnoses could be in error is usually not taken into consideration
when the accuracy of cytologic diagnosis is measured. I have personally reviewed
several discordant cases where the diagnoses rendered by pathologists were
inaccurate (in my opinion). I have illustrated some examples in Chapter 9.

The diagnostic problems in follicular/Hürthle cell lesions of the thyroid gland

have served as an impetus for developing special markers either at the tissue level
or at the molecular level. This field has exploded with newer diagnostic techniques
in the hope of finding a magic tumor marker that would solve all the controversies
and differentiate the various follicular/Hürthle cell lesions. Chapter 22 barely
touches this subject.

I am extremely grateful to so many individuals for their participation. I sincerely

appreciate the contributions by my professional colleagues, Max Wisgerhof, MD,
Vinod Narra, MD, Osama Alassi, MD, and Melina Cancovic. PhD. I am
P.viii
very thankful to Clair Michael, MD, for contributing the section on liquid-based
cytology for thyroid aspirates.

The images are an essential part of any atlas and its success depends on the quality
of the images. I cannot thank enough our past supervisor of the Cytopathology
Laboratory, Mrs. M. Jane Purslow, CT (ASCP, MIAC), for taking thousands of images
of a wide variety of thyroid lesions during her years at Henry Ford Hospital, Detroit.
The quality of those images has always been superb. I am indebted to my past
fellows: Osama Alassi, MD, Songling Liang, MD, and Dongping Shi, MD, who were
always willing to photograph any new cases that I needed for this atlas. I had
requested several of professional colleagues from the United States and abroad for
the examples of interesting and rare lesions. I sincerely appreciate their generosity
and prompt response. In particular, I would like to thank Mariza dePeralta, MD and
Mithra Baliga, MD for several cases, especially of Romanowsky-stained preparations.

I am very grateful to Mrs. Linda Brandt for her secretarial assistance. Ms. Laure
Porzondek's help in retrieving the voluminous literature necessary to compile this
text is gratefully acknowledged. I would like to express my appreciation to Mrs.
Toni Klimowicz, our Cytopathology Laboratory supervisor, for providing the archival
data and to Ms. Dawn M. Webb for her input in cytopreparatory techniques.

Finally, I must acknowledge the efforts of the members of the Department of Media
Resources at Henry Ford Hospital, Detroit. Scanning hundreds of slides, merging the
files with digital images, color balancing, and keeping all in order (1,800 of them,
to be exact) has been a laborious process. I am grateful to Ms. Patricia Muldoon,
Ms. Reva Sayegh, Mr. John Grybas, Mr. Jeff Boni, and Mr. Ray Manning for their
diligence and prompt work.
Sudha R. Kini, MD

REFERENCE
1.Gharib H. Changing trends in thyroid practice: understanding nodular thyroid
disease. Endocr Pract. 2004;10:31–39.
Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Front of Book > Note to Readers

Note to Readers

STAINS
Most of the thyroid aspirates are wet-fixed, using spray fixatives and stained by the
Papanicolaou method. Any other stain used is so specified.

MAGNIFICATIONS
Unless otherwise specified, the photomicrographs are taken at 40 × (or high
power). All other magnifications are noted in the legends (low power at 4 × and
medium power at 10 ×).

All electron micrographs are taken on uranyl acetate and lead citrate preparations.
Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 1 - Introduction

1
Introduction
J. Martin MillerKINI
Max Wisgerhof
The approach to thyroid nodularity, as recounted in late Dr. Miller's introduction
to the second edition of Thyroid: Guides to Clinical Aspiration Biopsy, has not been
eclipsed. Instead, the attempt at a cytologic diagnosis of thyroid nodularity by
fine-needle aspiration has become the standard of care. The clinical purpose of
Thyroid Cytopathology: A Text and Atlas remains the same as that stated by the
late Dr. Miller in Thyroid: Guides to Clinical Aspiration Biopsy.*Deceased.

—Max Wisgerhof

Shortly after World War II, articles appeared in the medical literature stating that
the incidence of thyroid cancer in surgically removed thyroid nodules was 20% to
30%. These articles also suggested that these findings were representative of the
entire nodular goiter population.1, 2 Opponents of this point of view cited the low
incidence of thyroid cancer as a cause of death in autopsy material,3 and a
controversy was born regarding the true risk of a thyroid nodule. By the 1950s, it
was generally agreed that the morbidity and mortality of thyroid cancer did not
justify removal of all thyroid nodules4; today the controversy focuses on the means
of selection of patient nodules for surgical biopsy—that is, the method of
determining the risk of a given thyroid nodule.

During the 1960s and 1970s, it became evident to physicians in the United States
that radionuclide or ultrasound images of the thyroid were successful in eliminating
consideration of thyroid surgery for no more than 10% to 20% of thyroid nodules.
However, as early as 1950 in the Scandinavian countries, attention was focused on
the use of a fine needle to aspirate a cytologic sample from thyroid nodules5 and
thus determine the probable pathologic diagnosis. For 25 years, such reports
evoked little interest in North America. The reasons for this are speculative and
include dissatisfaction with the variably reported sensitivity of the European
studies, failure of authors to provide direction for use of biopsy data in avoiding
thyroid surgery, and the "certain knowledge" that cytology would not provide a
diagnosis of a lesion, often requiring many histologic sections for identification.
Overreaction to one reported case of subcutaneous tumor implant by needle
biopsy6 was also a factor, as was the use of Giemsa stain by the Europeans, a
cytologic stain not popular among American cytopathologists accustomed to
Papanicolaou staining techniques.

By the late 1970s, the Canadians had reported experience with fine-needle biopsy,7
and groups in Cleveland and Boston had evaluated large-needle biopsy.6, 8 The first
American study combining both was reported in 1979 by our group.9 Since that
time, numerous reports have appeared in the English-language literature on the
diagnosis of thyroid nodules by needle biopsy, mostly by the cytologic specimens
obtained by fine-needle aspiration. In spite of limited but definite advantages to
the combined use of large- and fine-needle biopsy in a biopsy program,10 the
universal application, simplicity, safety, ease of performance, and patient
acceptance of fine-needle biopsy account for its exclusive use in most reported
studies.11

Our experience with over 4,500 satisfactory biopsies spans the 10 years from 1975
to 1985 and has provided us with over 1,100 correlations with surgical specimens.
Our purpose has been twofold: (i) to provide diagnostic information for the
management of our patients and those of our referring doctors, and (ii) to record
our experience in obtaining and diagnosing thyroid needle biopsy specimens in such
a way that others might profit from our trials and errors. This book is our third
attempt to make available to our colleagues our total needle biopsy experience.
Unlike the first two attempts,12, 13 we have limited this work to fine-needle
biopsy. Its purpose is to assist the cytopathologist in the proper interpretation of
cytologic samples from the thyroid gland. Therefore, most of the text is concerned
with our experience in obtaining these samples by the fine needle and interpreting
them. If cytologic diagnosis was an exact science, and if there was a predictable
correlation between a particular diagnosis and tumor behavior, this information
would suffice. Such is not the case, and certain ancillary information is of value to
the interpreter of thyroid cytopathology. This includes the gross and histologic
anatomy of the lesion subjected to biopsy, the life history of benign and malignant
P.2
thyroid nodules, and the management of thyroid nodules with and without biopsy.

IMPORTANCE OF NEEDLE BIOPSY

The morbidity and mortality of thyroid cancer do not qualify it as an important
public health problem. The number of noninvasive diagnostic tests and surgical
lobectomies done to establish or exclude its presence, however, makes it a disease
of economic importance. Living in a society concerned with containment of medical
costs, we should carefully select the most cost-effective diagnostic tests. The
experience of our group is that needle biopsy is far more accurate for the selection
of patients with nodules for diagnostic lobectomy and is much cheaper than any
combination of noninvasive tests. Its use has halved the number of operations
prescribed and has doubled the number of cancers identified per 100 surgical
removals.14 Cutting surgical and hospital bills for nodule management in half is a
worthwhile achievement. Our figures also suggest that we are now identifying
cancers that were initially diagnosed as benign nodules, or we are making the
diagnosis of cancer at an earlier stage. Determining whether this too is
advantageous, and will favorably influence the morbidity and mortality of thyroid
cancer, will require many years of study.

In summary, most physicians agree that neither removing all thyroid nodules nor
removing no thyroid nodules is a sensible management approach. Therefore, they
employ some process of selection in prescribing surgical lobectomy. The most cost-
effective method of selection is needle biopsy.

REFERENCES
1.Cerise EJ, Randall S, Ochsner A. Carcinoma of the thyroid and nontoxic
nodular goiter. Surgery. 1952;31:552.
2.Cole WH, Majarakis JO, Slaughter OP. Incidence of carcinoma of the thyroid
in nodular goiter. J Clin Endocrinol. 1949;9:1007.

3.Rogers WF, Asper SP, Williams RH. Clinical significance of malignant

neoplasms of the thyroid gland. N Engl J Med. 1947;237:569.

4.Miller JM. Carcinoma and thyroid nodules. Problem in endemic goiter. N Engl
J Med. 1955;252:247–251.

5.Söderström N. Puncture of goiters for aspiration biopsy. A preliminary

report. Acta Med Scand. 1952;144:235–244.

6.Crile G Jr, Hawk WA Jr. Aspiration biopsy of thyroid nodules. Surg Gynecol
Obstet. 1973;136:241–245.

7.Crockford PM, Bain GO. Fine-needle aspiration biopsy of the thyroid. Can Med
Assoc J. 1974;110:1029–1032.

8.Wang C, Vickery AL Jr, Maloof F. Needle biopsy of the thyroid. Surg Gynecol
Obstet. 1976;143:365–368.

9.Miller JM, Hamburger JI, Kini SR. Diagnosis of thyroid nodules by fine needle
aspiration and needle biopsy. JAMA. 1979;241: 481–486.

10.Miller JM, Hamburger JI, Kini SR. Fine needle aspiration cytology, cutting
biopsy or both in the evaluation of thyroid nodules? In: Thompson NW, Vinik AI,
eds. Endocrine Surgery Update. New York: Grune & Stratton; 1983:23.

11.Ashcraft MW, Van Herle AJ. Management of thyroid nodules II. Scanning
techniques, thyroid suppression therapy and fine needle aspiration. Head Neck
Surg. 1981;3:297.
12.Hamburger JI, Miller JM, Kini SR. Clinical-pathological evaluation of thyroid
nodules. In: Handbook & Atlas, Part I. Southfield, MI: private publication;
1979;15.

13.Miller JM, Kini SR, Hamburger JI. Needle Biopsy of Thyroid. New York:
Praeger; 1983.

14.Miller JM, Hamburger JI, Kini SR. The impact of needle biopsy on the
preoperative diagnosis of thyroid nodules. Henry Ford Hosp Med J. 1980;28:145.
Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 2 - Techniques of Fine-Needle Aspiration Biopsy

2
Techniques of Fine-Needle Aspiration Biopsy
J. Martin MillerKINI
Max Wisgerhof
It is axiomatic that a pathologist must have an adequate biopsy specimen to make a
satisfactory interpretation. Obtaining an adequate cellular sample requires enough
capillary blood or tissue fluid to serve as a vehicle, but not so much as to cause a
problem by dilution. The sample must then be fixed and stained in such a way as to
permit the most accurate interpretation possible. Obtaining an adequate cytologic
sample from the thyroid is a simple procedure. However, the number of failures by
physicians with little experience suggests that matters of technique, although simple,
are indeed essential.*Deceased.

Before beginning the discussion of technique, we acknowledge the prerequisite of

experience in palpating thyroid nodules for the biopsy physician. Little experience is
needed to palpate a nodule of 4 to 5 cm in its greatest dimension, but the 1-cm
nodule on the posterior aspect of a lobe requires skillful palpation. Nodules felt by
single-digit palpation with the patient erect can always be felt with the patient in the
recumbent biopsy position. Most nodules felt by bidigital examination with the
patient seated can at least be localized with the patient supine.

PREPARATION
Mental
Proper mental preparation is the first step in the performance of a thyroid biopsy.
Most of the pain experienced by patients is minor discomfort magnified by anxiety.
The patient should be reassured as to the simplicity, painlessness, and brevity of the
procedure. The prick of the anesthetic needle and the sting of the local anesthetic
should be described immediately before they are felt by the patient. The patient
should be asked to not swallow while the needle is in the nodule, and should be
assured that this represents a small fraction of the total time involved in doing a
biopsy—that is, swallowing is minimally restricted. (Pain and even serious vascular
injury may result if the patient swallows when the needle has passed through the
nodule.) We find that anxiety is lessened by maintaining pleasant conversation with
the patient during the procedure.

Physical
With a few exceptions (we have performed biopsies on a few patients while they were
sitting), the patient assumes a supine position, with the head and neck extended over
a pillow. The degree of extension should not produce skin tension that interferes with
nodule palpation or partially obstructs vertebral artery blood flow in the elderly. The
site of the needle puncture is cleaned by firm application of an alcohol swab. We
attribute the total absence of infection in over 7,000 biopsy attempts to the adequacy
of normal body defense mechanisms rather than to the excellence of our sterile
technique.

ANESTHETIC: TO USE OR NOT TO USE?

If the operator can be certain that only one needle will be necessary, a local
anesthetic is superfluous. This assumes no bloody aspirates, no degenerated nodules,
no cystic lesions, and no grossly unsatisfactory specimens. It also assumes adequate
sampling by multiple passes of the same needle, as recommended by some Swedish
physicians.1, 2 We make none of these assumptions, so to limit patient discomfort to
one needle, we
P.4
use lidocaine. There are two possible disadvantages to the use of an anesthetic. First,
the patient may be allergic to lidocaine and may not be aware of it. We have had
several patients with known allergies to lidocaine for whom we have used either
mepivacaine (Carbocaine) or nothing, but we have not encountered a patient with a
lidocaine allergy of which he or she was unaware. Second, the anesthetic may obscure
the nodule. In such a situation, a little local massage will disperse the fluid.
Many physicians consider local anesthetic to be superfluous even when three or four
needles are used. We agree that most patients can tolerate this discomfort, but why
should they?

We use 1 to 2 mL of 1% lidocaine for the skin and subcutaneous tissues. Care is

exercised not to infiltrate the nodule, which might cause a "lidocaine aspirate."

SYRINGE
A 10-mL syringe provides ample negative pressure for obtaining cytologic specimens.

NEEDLES
The larger the needle, the larger the tissue sample, and the greater the possibility of
an unwanted volume of blood. We have found the 25-gauge, 1.5-inch needle to be
suitable for the majority of nodules. With less vascular nodules, a 22- or even a 20-
gauge needle gives better results. When we use a mechanical suction device, we
prefer the greater rigidity of a 22-gauge needle.

NEEDLE PLACEMENT
The right-handed physician fixes right-sided nodules between the second and third
digits of the left hand and inserts the needle with the right hand while standing behind
the patient. For left-sided nodules, it is more comfortable to perform nodule
immobilization while standing on the right side of the patient. For nodules 1.5 cm or
smaller, simply inserting the needle into the nodule is a reasonable goal. With larger
nodules, peripheral subcapsular parts of the nodule should be sampled rather than the
center. The periphery is more apt to be predictive of histologic behavior. The center
often is undergoing degenerative change.

SUCTION: HOW AND HOW MUCH

Suction is applied once, repetitively, or during maneuvers designed to further disrupt
the follicular epithelium. The total procedure should be sufficient to make aspirate
appear in the hub of the needle, but not in the barrel of the syringe. Aspirate within
the syringe must be removed by a washing procedure followed by a concentrating one,
both of which tend to distort cytologic features and add to the complexity and cost of
the problem.
Many pioneers in needle biopsy consider a mechanical device for producing suction
absolutely essential for this procedure (Fig. 2.1). Producing suction with this device
and maintaining it requires only one hand, and allows the operator to continuously fix
nodules with the left hand while suction is maintained with the right (Fig. 2.2). It also
allows the maximum possible suction from a 10-mL syringe.

Figure 2.1. Mechanical syringe holder; 10-mL plastic BD syringe; 22-gauge, 1.5-
inch needle; and 25-gauge, 1.5-inch needle.
 Figure 2.2. Aspiration using the mechanical device to produce suction. Tissue
disrupted by vertical movement.

We performed our first 3,000 satisfactory biopsies without recourse to, or even
knowledge of the existence of, this mechanical device. We find it simple to maintain
suction with one hand, with no mechanical assistance, once suction has been achieved
and the needle is in the nodule (Fig. 2.3). This requires reestablishing fixation, which
seems to be a disadvantage only in very small nodules. Among the disadvantages of the
mechanical suction device are its one-time expense of approximately $150, the more
remote "touch" occasioned by the hand being a greater distance from the needle, and
the fact that the needle cannot be twirled while suction is being applied (see "Tissue
Disruption," below).

P.5

Figure 2.3. Same maneuver shown in Figure 2.2, but without a mechanical
holder.

TISSUE DISRUPTION
Simple application of suction by pulling the plunger of the syringe back to 6 or 7 mL is
often unsatisfactory. Results may be improved if a pumping action is used, and
improved even more if the barrel of the syringe is rotated rapidly while the plunger is
held stationary as suction is maintained (Fig. 2.4). Moving the needle in and out (but
with the tip in the nodule) has much the same effect (Fig. 2.2 and Fig. 2.3). The
nodule must be fixed during this maneuver to prevent a small nodule from moving with
the needle, thus eliminating the motion of the needle within the nodule.

Figure 2.4. Rotation technique for fine-needle biopsy. Note that the index finger
of the right hand maintains suction while the left hand rotates the barrel of the
syringe.
The cutting action of any needle motion is improved by speed. It is our practice that if
nothing appears in the needle hub from maintained suction, we twirl and then move
the needle in and out until something appears.

ADDITIONAL TECHNIQUES
Two additional techniques, one major and one minor, can be added to those of the
late Dr. Miller as described above.

The minor additional technique is that of performing the thyroid aspiration by

inserting the needles—25, 22, or 20 gauge—for the six to eight smears, without a
syringe attached to the needle. The tissue disruption is as with the syringe attached,
although the hub of the needle, rather than the syringe, is held by the fingers to
produce the vertical and rotational movements of the needle in the thyroid. The
needle shaft and the needle hub fill by capillary action. The needle is withdrawn as
the hub is nearly filled with the aspirate, which is then expelled through the needle
and smeared as described below. This additional technique can lessen the amount of
obscuring blood, aspirated by suction, and the aspirate is expelled from the hub more
readily than when suction makes it adhere to the inner surface of the hub.

The major additional technique is the use of real-time thyroid ultrasound to identify
the thyroid nodule to be aspirated, particularly the incidentally detected, nonpalpable
nodule, and to guide the placement of the aspirating needle tip into the part of the
tissue or nodule most likely to yield a cytologic diagnosis. (It might well be that many
nodules thought not to be palpable targets for aspiration and identifiable only by
ultrasound could have been palpated and aspirated by those with considerable
experience in palpation of the thyroid. Also, it could be contended that palpable
nodules are those that have important potential for morbidity and will more likely
yield sufficient aspirate for cytologic diagnosis.) The technique of real-time ultrasound
guidance of thyroid aspiration has two major differences from aspiration by palpation.

The hand that fixed the nodule or tissue now holds and positions the ultrasound
probe against the skin over the nodule or tissue. A small amount of sterile gel
is applied to the probe and the skin to transmit the sound waves (care must be
taken not to include gel in the aspirate). The other
 P.6
hand guides the insertion of the needle alongside the probe, so that the course
of the needle tip is within the sound wave.

The person performing the aspiration looks at the real-time ultrasound image
displayed on the screen to guide the course of the needle tip immediately
after inserting the needle through the skin over the thyroid tissue or nodule.
The vertical and rotational movements of the needle tip are as in palpation
aspiration, and often can be visualized by the ultrasound image. The aspirate
sample is visualized in the hub, whether or not a syringe is attached to the
needle, as in palpation aspiration.

Proficiency and skill in ultrasound-guided thyroid aspiration is soon achieved if

aspirations are performed with frequency, as in palpation aspiration. A discussion of
thyroid ultrasound as a technique to distinguish benign from malignant thyroid lesions
is beyond the scope and purpose of this book. It is generally concluded that the
ultrasound characteristics of thyroid nodularity, including Doppler imaging, are not
reliable to diagnose benign or malignant thyroid disease.

SMEARS
After suction, the needle is removed and the plunger is withdrawn a couple of
milliliters. The needle is reaffixed, and the specimen is expressed onto the slide. This
procedure is the same with or without the use of a mechanical suction device. At this
point, an estimate is made as to whether the volume of the aspirate is suitable for
smearing on the slide. If it is not excessive, it may be either smeared with the edge of
another slide, as is usual with a blood smear (Fig. 2.5, method 1) or if particulate
matter or colloid is visibly present, the material may be compressed between two
slides and smeared (Fig. 2.5, method 2). If the volume of the specimen seems too
great for the slide, tilt it and remove the blood that flows to the low side by using an
absorbent tissue (Fig. 2.6). Smearing is then done as described above. Another
recommended technique for concentrating cellular material is shown in Figure 2.5,
method 3. The slide with the specimen may be tilted, frosted end down, to enlist the
aid of gravity while the edge of the smearing slide is drawn up. After the blood has
been separated, the smearing slide is flattened, and the smear is completed.
Figure 2.5. Three methods of smearing the fine-needle aspirate. See text for
details.
 Figure 2.6. To remove excess blood or fluid, the slide is tilted and a tongue of
absorbing tissue is touched to the dependent portion of the drop.

There have been elegant treatises on the exact hand and slide maneuvers necessary to
produce the best smears.3 It is sometimes difficult to determine whether the
experiences recounted are of those who perform biopsies only of the thyroid or those
who perform biopsies of many types of more cellular tumors. As 70% of thyroid
specimens will be from benign disease and will have minimal cell density, the
procedures suggested for transferring material to two or more slides are probably
unnecessary. Be that as it may, the simple instructions given here have served us very
well with fairly extensive experience.

Number of Smears
If a smear looks unsatisfactory, it usually is. If it looks satisfactory, it may be so. We
take six smears to ensure three good ones and adequate sampling.

FIXATION
Fixation must be matched to the staining technique employed. We use a modified
Papanicolaou staining technique and therefore fix immediately with alcohol as part of
a spray. If May–Grünwald–Giemsa stain is used, the smear is air dried and no
prompt fixation is necessary.

POSTBIOPSY CARE
If there has been no intranodular bleeding, we apply an elastic bandage and keep the
patient under surveillance for about 15 minutes. If there has been some bleeding into
the nodule, we ask the patient to maintain pressure for about 30 minutes. In either
instance, removal of the bandage after 1 hour is authorized.

REFERENCES
1.Willems JS, Löwhagen T. Fine needle aspiration cytology in thyroid disease. In:
Williams, ed. Clinics in Endocrinology and Metabolism. Vol 10. Philadelphia:
Saunders; 1981:247–266.

2.Löwhagen T, Willems JS, Lundell G, et al. Aspiration biopsy cytology in

diagnosis of cancer. World J Surg. 1981;5:61–73.

3.Abele JS, Miller TR, King EB, et al. Smearing techniques for the concentration of
particles from fine needle aspiration biopsy. Diagn Cytopathol. 1985;1:59–65.
Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 3 - Cytopreparatory Techniques

3
Cytopreparatory Techniques

The importance of optimal cytopreparatory technique and staining cannot be overemphasized.

Inferior cytologic preparation will not allow adequate cytopathologic evaluation. Several
methods exist for specimen collection, fixation, processing, and staining. The cytomorphology
varies according to the mode of fixation, type of fixative, and choice of staining technique.
Because of familiarity, convenience, or personal preference, every cytopathology laboratory has
its own guidelines for specimen collection, cytopreparation, and staining. Cytologic criteria
applicable to one preparation may not always apply to other types of preparation. The
diagnostic criteria for various thyroid lesions described in this chapter are based on cellular
details seen in the preparations from the cytopathology laboratory at Henry Ford Hospital in
Detroit, Michigan.1 The cytologic criteria used in differentiating certain thyroid neoplasms are
very subtle and are dependent on the cellular details that are best demonstrated in smears fixed
with spray fixative and stained by the Papanicolaou method. The architecture of the tissue
fragments, relationship of one cell to the other, cytoplasmic quality, cell borders, nuclear
chromatin, and nucleoli can all be appreciated very well in spray-fixed smears. The pros and
cons of different methods of collection, fixation, and staining will be discussed.

SPECIMEN COLLECTION
Specimens obtained by an aspiration biopsy procedure can be submitted in the following ways:

Specimen (aspirate) expelled on the slides and smears prepared at the site (direct
smears).

Specimen collected in a preservative (e.g., Saccomanno fixative).2

 Rinsing of the needle in balanced salt solution after the direct smears have been made.

Specimen collected in special collection medium for liquid-based cytology.

Cyst fluid with or without fixative.

METHODS FOR SMEAR PREPARATION

There are several methods of preparing smears, whether directly from the aspirates or from the
centrifuged sediments (cell spreads) of specimens (e.g., specimens collected in liquid medium
such as needle rinsing or in Saccomanno fixative). The method or methods employed in any given
laboratory reflect the preference, choice of fixative and stain, convenience, comfort level, and
the results. Whichever method is chosen, the goal should be same—to obtain a monolayer of
well-fixed, well-stained, and well-visualized cells. Every laboratory should set its own standards.
This chapter describes only a few methods, as it is beyond the scope of this text to describe
every available method.

Prior to cytopreparation, there are certain prerequisites that must be followed rigidly. Every
specimen container, every test tube in which any given specimen is processed, and every glass
slide used to prepare the smear must be labeled properly with the patient's name, unique
identifying number, and laboratory accession number. Cytopreparation must be performed under
the biologic hood and by following universal precautions. If the smears are prepared in the
clinic, the clinicians must be properly instructed as to the preferred way of making smears,
fixation, and most importantly, to identify the slides appropriately by labeling with patient's
name and unique identifying number.

The frequently used smear techniques for thyroid aspirates include:

Peripheral blood smear technique (see Fig. 2.5 , method 1).

Pull-apart method (see Fig. 2.5 , method 2).

We prefer and recommend using plain glass slides with frosted ends. In our experience, cellular
distortion is seen on smears prepared using fully frosted slides.

Peripheral Blood Smear Technique

The peripheral blood smear technique is routinely used for making peripheral blood or bone
marrow smears. However, it has provided excellent results with thyroid aspirates. It is
recommended that the specimen be fresh and in its normal state when the smears are made. If
possible, the smears should be made before any balanced salt solution or preservative is added
to the specimen. For reasons not very clear, cells from specimens to which a balanced salt
solution has been added tend to explode during air-drying. The smears are made in such a way
as to create a feathered edge where the nucleated cells migrate and produce the best example
of the monolayer.

P.8

Procedure

Label the slide.

Place a small drop of specimen on the glass slide a little distance away from the frosted
end.

Place another glass slide on the specimen drop at a 45-degree angle. Let the specimen
spread along the edge.

Smear the specimen on the labeled slide with a fast, single motion in the direction away
from the frosted edge.

Spray-fix for Papanicolaou stain or let air-dry for Romanowsky stain.

NOTE: Technique in creating a feathered edge is very important and requires practice.

Pull-Apart Method
The pull-apart method is used for preparing direct smears of a fine-needle aspirate or cell
spreads of fine-needle aspirates collected in a liquid medium, centrifuged with visible sediment.
It results in a monolayer, provided that not too much of the specimen is placed on the slide.

Procedure

Place a drop of aspirate or the sediment on a labeled glass slide.

Place another labeled glass slide face down on top.

 Allow the sediment to spread naturally.

Pull the slides apart, either vertically or horizontally.

Fix both the slides immediately. The canister of the spray fixative should be aimed at
least 12 inches away from the slide surface so as not to dislodge the cells.

Allow the slides to dry completely.

Pucker or bubble artifacts may occur when droplets of spray fixative impact the slide surface,
pushing aside any cellular material. The "hills and valleys" thus created may leave thick areas
alternating with clear thin ones, the former being quite tedious to screen. Tilting the slide back
and forth, spreading the material evenly, can prevent this problem.

The techniques for making smears vary in every laboratory. These are described in detail in the
literature.3 , 4 , 5

FIXATION AND FIXATIVES

The term "fixation" refers to a procedure whereby the cells to be examined are treated so as to
prevent autolysis (self-digestion) or degeneration by bacteria and fungi. Fixation is a means by
which the cells are permanently preserved and remain in the state they were at the time of
fixation. The process results in cells that are stabilized, maintaining their shape and structure.
The fixation process prevents the loss of cell contents, makes available the reactive sites for
linking with coloring agents (staining), and renders the cell membrane permeable by the dyes.
Smears may be air-dried if Romanowsky stains are used. This is the method of choice for
hematologic malignancies and is popular among some pathologists for rapid assessment of
specimen adequacy during fine-needle aspiration biopsy procedures.

Wet fixation is necessary for Papanicolaou stains or hematoxylin-eosin stains. The methods of
wet fixation include:

Spray fixative.

95% ethyl alcohol—universally accepted as the best fixative for Papanicolaou stain.

Isopropyl alcohol.

Buffered formalin for hematoxylin-eosin stain.

 Specimen collected in Saccomanno fixative.

Spray Fixative
The author's lab highly recommends spray fixative for thyroid aspirates. Several spray fixatives
are commercially available. The smears must be immediately flooded with the spray fixative.
The spray can should be held at least 12 inches from the slide. The slightest delay in fixing will
result in air-drying of the cells, which will stain poorly with the Papanicolaou method. Once
sprayed, the fixative on the slide must be completely dried (do not enclose the wet slides in a
cardboard folder, as cellular material will adhere to the cardboard folder and be lost forever). It
is subsequently removed by soaking the slides in 95% ethyl alcohol before staining. There are
several advantages to spray fixatives. They are inexpensive, less messy than other fixatives, and
easy to store. Cellular details are well preserved and are easy to interpret, and the red blood
cells in the background are not hemolyzed. The intact red blood cells serve as a guide in judging
the follicular nuclear size. The cytoplasm and the cell borders are preserved and nuclear
chromatin and nucleoli are beautifully displayed. There are no disadvantages to using spray
fixatives.

95% Ethyl Alcohol

The universally accepted, ideal fixative for Papanicolaou stain is 95% ethyl alcohol. Also, 80%
isopropyl alcohol is sometimes used as a fixative. These fixatives have the following
disadvantages:

The water content of 95% ethyl alcohol or the isopropyl alcohol causes lysis of the red
blood cells—that is, it is cytolytic—and it also destroys the cytoplasm of epithelial
cells. The relationship of one cell to the other is often lost. Aspiration biopsy specimens
are often bloody. The precipitate after hemolysis of red blood cells interferes with the
staining quality, producing eosinophilia.

The nuclei are also affected to some extent; they shrink, the chromatin stains darkly and
compact, and the nucleoli are not often visualized.

The thyroid aspirates generally do not adhere to the slides. There seems to be a "falloff"
of cellular material when smears are dropped in the fixative. Precoating the slides with
egg albumin to prevent falloff will impart diffuse eosinophilia to the slide and the cells.
 A ribbing effect is seen if the smears are not dropped swiftly into the alcohol container.

Alcohol is flammable.

Saccomanno Fixative
Saccomanno fixative (2% Carbowax or polyethylene glycol, in 50% ethyl alcohol) has been
recommended by some2 as an ideal method of collecting aspirates. The specimen can be
collected at any site away from the cytopathology laboratory. There is no fear of cell
deterioration or air-drying, and there is no need for others to make thin cell spreads. A cell
block can also be prepared if necessary. Saccomanno fixative has following disadvantages:

A longer period of time is needed for cytopreparation.

Lysis of red cells will precipitate in the background and cause nuclear shrinkage.

P.9
Rinsing of the needle in balanced salt solution is used as an adjunct after the smears are made.
Table 3.1 lists the advantages and disadvantages of fixation by air-drying and wet fixation.

Dependence on smearing
technique
Strong
Moderate
Moderate
Dependence on fixation
None
Strong; immediate wet fixation
is critical
Strong; immediate wet fixation
is critical
Cell loss during fixation
None
None with spray fixative; cell
loss may be considerable with
 95% ethyl alcohol
If smears are air-dried first and
then hydrated, cell loss may be
minimal; loss varies with liquid
fixative
Need for fixative to be
removed
Not applicable
Yes if spray-fixed or if smears
are prepared from prefixed
specimen
No
Length of time required
for staining
Up to 2 minutes
Longer time required for the
routine staining technique;
up to 2 minutes with rapid
staining technique
Up to 2 minutes
Coverslipping
Not required
Required
Required
Architecture of the tissue
fragments
Visualized if the smear is thin;
poor details with thick tissue
fragments
Well-visualized
Well-visualized
Cell and nuclear size
Flattened, appear larger
Comparable to that seen in
 tissues; smaller than seen in
air-dried smears
Comparable to that seen in
tissues; smaller than seen in
air-dried smears
Nuclear morphology
Not crisp, chromatin structure
not comparable to
Papanicolaou-stained cells;
micronucleoli difficult to
appreciate
Crisp; excellent nuclear details
as to chromatin structure,
nuclear membrane, and
nucleoli
Crisp; excellent nuclear details as
to chromatin structure, nuclear
membrane, and nucleoli
Cytoplasmic details
Variable; squamous differentiation
and keratinization cannot be
appreciated; oncocytic cells
resemble histiocytes and
sometimes difficult to identify
Cytoplasm clearly visualized,
squamous differentiation and
keratinization well
demonstrated; oncocytic cells
readily identified
Cytoplasm clearly visualized,
squamous differentiation and
keratinization well
demonstrated; oncocytic cells
readily identified
Psammoma bodies
Not well-visualized
Well-visualized; presents
variable morphology with
multiple colors
Well-visualized; basophilic
concentric lamellated structure
Colloid
Stains lavender to magenta
(metachromatic stain)
Cyanophilic to eosinophilic;
orange when mixed with blood
Eosinophilic
Use in hematologic
malignancies and
lymphoproliferative
disorders
Ideal stain
Not as specific as Romanowsky
stain
Usefulness in differentiating
follicular or Hürthle cell
lesions
Limited
Very useful
Very useful
Application for
immunostains
Useful for certain lymphoid
markers
Stained smears can be selected
for cellularity and processed
for immunostains
Not known
aWet fixation can be achieved with 95% ethyl alcohol, spray fixative, specimen collected in
Saccomanno fixative.
b Wetfixation for hematoxylin-eosin can be achieved with absolute or 95% ethyl alcohol, or
smears can be air-dried and then rehydrated for Papanicolaou stain.

Fixation by Air-Drying Wet Fixationa Wet Fixationb

Romanowsky-Type Stain Papanicolaou Stain Hematoxylin-Eosin Stain

TABLE 3.1 Comparison of Air-Dried Smears with

Romanowsky-Type Stain, Wet-Fixed Smears with
Papanicolaou Stain and Hematoxylin-Eosin Stain

Air-Dried Rehydration
Air-dried rehydration is a very useful method for utilizing air-dried smears for Papanicolaou
staining following rehydration.6

P.10

Procedure

Immerse the air-dried smears in balanced salt solution or preservative for 30 seconds.

Place in a jar of 95% ethyl alcohol for 30 seconds.

Stain by the Papanicolaou method.

LIQUID-BASED CYTOPREPARATION
Liquid-based cytopreparation is a newer cytopreparatory technique being utilized in several
laboratories. The author's laboratory has not adopted the liquid-based cytology for thyroid
aspirates. It is described in detail in Chapter 22 .

Procedure for Cyst Fluids

The gross quality of the cyst fluid determines the method for cytopreparation.
 If the specimen is clear, centrifuge it at 2,500 rpm for 10 minutes. If the sediment is
visible, make a wet-film preparation (see below). If the specimen is poorly cellular, a
cytospin preparation is preferred.

If the specimen or sediment is grossly bloody, the saponin technique may be used to
hemolyze red cells.

Toluidine Blue Wet-Film Preparation

The wet-film preparation of sediment from the centrifuged specimen allows rapid assessment of
its cellularity, as well as its cell type, that is, benign or malignant.7 This examination guides
cytotechnologists to follow a suitable method for processing the specimens and helps prevent
cross-contamination. The method consists of the following steps:

Place a drop of centrifuged sediment on the slide.

Place one drop of toluidine blue solution on the slide and mix.

Coverslip and examine.

SAPONIN TECHNIQUE FOR REMOVING BLOOD FROM THE

SPECIMEN
Saponin is an enzyme that lyses red blood cells. A saponin solution is extremely useful in
processing grossly bloody specimens.1 , 8 , 9 Caution must be exercised to avoid using excess
saponin, which may destroy the cellular component of the specimen. When saponin technique is
controlled, it selectively lyses red blood cells. The technique used consists of the following
steps:

Resuspend the sediment in 30 mL of balanced salt solution.

Add 5 drops of saponin solution and agitate gently for 1 minute.

Add 15 drops of calcium gluconate solution to stop the action of saponin enzyme and mix
well.

Centrifuge for 10 minutes at 2,500 rpm.

 If no sediment is visible, prepare by the membrane-filter technique.

If the sediment is visible and clear of blood, prepare direct smears, spray fix, and stain.
If the sediment is still very bloody, repeat the above procedure.

Saponin technique should not be used more than twice, as it may lyse the cells of diagnostic
importance. Any leftover sediment is further processed for a cell block (see below).

CYTOCENTRIFUGATION AND CYTOSPIN PREPARATION

Cytospin preparation is the method of choice for harvesting poorly cellular samples.
Cytocentrifugation allows the concentration of cells on a glass slide by way of collecting them
over a filter placed on the "well" etched on a special glass slide manufactured for the procedure.
It produces a monolayer of cells within a clearly defined area. The specimen should be non
mucoid or else it will clog the filter. The addition of Saccomanno fixative to the specimen when
Papanicolaou stain is used will prevent air-drying. The procedure recommended by the
manufacturer should be closely followed

CELL BLOCK TECHNIQUE

Cell block refers to the examination of sediment, blood clots, or grossly visible flecks of tissue
from cytologic specimens that are processed by paraffin embedding and staining by hematoxylin
and eosin. Small tissue flecks must be wrapped in tissue paper and then placed in the cassette.
Sediments can be embedded in either Histogel or agar.

Histogel Prepared Cell Blocks

Histogel is solid at room temperature. It must be liquefied before use by heating to 60°C ±
5°C by placing Histogel in a water bath to about 60°C.

Procedure
This method is suitable for sediments or smaller tissue fragments.

Place 2 to 3 drops of Histogel onto the bottom part of a labeled Petri dish.

Place sediment or tissue particles inside the Histogel button. Alternately, place 2 to 3
drops of Histogel over the specimen.
 Cover the Petri dish and refrigerate for 10 minutes for hardening.

Once the button hardens, trim off the excess Histogel.

Place the button in a cell block bag, to be transferred to a cassette.

Keep the cassette in formalin until ready for tissue processing.

Agar Method for Cell Block

The agar method for a cell block consists of the following steps:

Agitate the tube containing the sediment remaining after smears have been prepared.

Add 4 mL of 6% melted agar to the sediment and mix well.

Centrifuge for 10 minutes at 2,500 rpm to make a cell button.

P.11
Refrigerate the tube until the agar is completely solidified (approximately 30 minutes).

Gently pry the agar clot from the tube. Slice the visible material into thin sections and
process for paraffin embedding.

The author's laboratory does not routinely prepare cell blocks from thyroid aspirates. In our
experience, the cell block does not provide any additional information. However, they are
prepared from cyst aspirates if the sediment is visible and adequate for embedding. Several
laboratories do routinely prepare the cell blocks.

STAINING
Of the various stains in use, Papanicolaou is the most popular stain utilized in the practice of
cytopathology. Romanowsky-type stains are ideal for hematologic disorders. It is also popularly
used in rapid assessment of adequacy of fine-needle aspiration biopsies.10 Hematoxylin and
eosin stains are utilized for cell blocks, but can also be used for the smears. In addition to these
three routine stains, a host of special stains is available for specific purposes. Most are
performed in histology laboratories. Hence, only the Papanicolaou, hematoxylin-eosin, and
Romanowsky-type staining procedures will be described here.
Papanicolaou Stain
Papanicolaou stain is a polychrome stain containing multiple dyes to differentially stain the
various components of the cells. The smear must be wet fixed swiftly and rapidly. The slightest
air-drying will result in poor staining, rendering the smears unsatisfactory for cytologic
evaluation. The main components of Papanicolaou stain include a basic dye—hematoxylin,
which stains the nucleus; and three acid dyes—light green, eosin, and orange G, which stain
the cytoplasm. With the Papanicolaou stain, the nucleus stains deep blue, nuclear details are
sharp, the nucleolus stains red, and the cytoplasm stains eosinophilic, cyanophilic, or orange.
Keratin stains deep orange.

Romanowsky-Type Stain
Romanowsky-type stain is a combination of an acid dye and a basic dye in the same solution.10
The colored cation and anion may combine, forming a colored salt referred to as a neutral salt.
The latter can react with certain cell components. In addition, the acid component and the
basic component of the neutral salt can react with other cell elements. Thus all three—the
neutral salt, cation, and anion—can color different components of the cell. Because of this
threefold action, a neutral stain can produce a very useful differentiation of cell components in
one staining solution. The two components of the stain include methylene blue (basic dye) and
eosin Y (acid dye). The combination of these two dyes result in staining the nucleus purple, and
the nucleolus and cytoplasm blue. Any stain that contains a combination of these two dyes is
called Romanowsky-type stain, and the results are referred to as Romanowsky effect. There are
several modifications of Romanowsky stain. Romanowsky-type stains are also useful for
evaluating the background substances that stain metachromatically—mucin, colloid, and
chondroid tissue basement membrane-like material, all of which stain bright magenta pink.

Romanowsky-type stain is used for rapid assessment of adequacy of the fine-needle aspirate. It
is a preferred stain for hematologic malignancies. Some examples of Romanowsky stains include
May-Grunwald-Geimsa, Leishman, Diff-Quik, Heme-3, and Wright.

Hematoxylin and Eosin Stain

Hematoxylin and eosin is traditionally used for staining tissues processed by formalin fixation
and paraffin embedding, sections cut at 5 µm. Rapid hematoxylin and eosin stain used for
frozen sections is also applicable to cytologic specimens for on-site adequacy assessment.
Hematoxylin and eosin stain is used routinely in some laboratories.11 This stain provides
excellent nuclear details (please refer to Figs. 8.14 , 8.20 , 11.27 , and 11.31B ).

STAINING PROCEDURES
Papanicolaou Staining Procedure (As Used in the Henry Ford
Hospital Cytopathology Laboratory)
1. 95% ethyl alcohol (to soak off the
Carbowax from the spray fixative)
15 minutes
2. Deionized water
10 dips
3. Gill II hematoxylin
45 seconds
4. Deionized water
3 changes/10 dips each
5. Scott's water
1 minute
6. Deionized water
3 changes/10 dips each
7. 95% ethyl alcohol
10 dips
8. OG-6
3 minutes
9. 95% ethyl alcohol
10 dips
10. 95% ethyl alcohol
10 dips
11. EA-65
3 minutes
12. 95% ethyl alcohol
10 dips
13. 95% ethyl alcohol
10 dips
14. Absolute alcohol
10 dips
15. Absolute alcohol
10 dips
16. Absolute alcohol
10 dips
17. Xylene
1 minute

Reagent Time or Dips

It is absolutely essential to stain one or two test smears and check the staining quality before
staining the entire batch of prepared smears from specimens received in the laboratory. The
timing of each step must be recorded in a daily log as a quality control measure. This process
must be followed every single day.

Staining Procedure for Rapid Papanicolaou Stain (As Used in

the Henry Ford Hospital Cytopathology Laboratory)
Rapid Papanicolaou stain is used for on-site assessment of the aspirates.

P.12

1. Rinse in deionized water

10 dips
2. Gill's hematoxylin
10 seconds
3. Rinse in deionized water
10 dips
4. Scott's tap water
10 seconds
5. Rinse in deionized water
10 dips
6. 95% ethanol
10 dips
7. Cytostain
15 seconds
8. 95% ethanol
10 dips
9. 100% ethanol
10 dips
10. 100% ethanol
10 dips
11. Dip in xylene until slide is clear
12. Coverslip

Hematoxylin and Eosin Stain, Method 1, for FNA Smears (As

Used in the Henry Ford Hospital Histopathology Laboratory)
This stain is used for frozen sections. It is also suited for FNA smears or scrape preparations for
rapid assessment.

Fix the smear by swiftly immersing in absolute alcohol and remove it.

Hematoxylin 1 minute.

Rinse in water thoroughly.

Blue in lithium carbonate 5 times.

Rinse and wash thoroughly.

Stain with eosin for 20 seconds, agitating.

Dehydrate in absolute alcohol for 30 seconds.

Dehydrate in absolute alcohol for 30 seconds.

Dehydrate in absolute alcohol for 1 minute.

Clear with xylene for 30 seconds.

Clear with xylene for 30 seconds.

Clear with xylene for 1 minute.

 Coverslip.

Hematoxylin and Eosin Stain, Method 2, for FNA Smears

The prepared smears of the aspirate are air-dried. Rehydrate the smears first in normal saline
for 1 minute.

1
Fixative (Pen-Fix)
1 minute
2
Tap water
Rinse
3
Tap water
Rinse
4
Hematoxylin III
30 seconds
5
Tap water
Rinse
6
Tap water
Rinse
7
Clarifier
5 seconds
8
Tap water
Rinse
9
Bluing reagent
10 seconds
10
Tap water
Rinse
11
Tap water
Rinse
12
Eosin Y
15 seconds
13
Absolute ethyl alcohol
10 dips
14
Absolute ethyl alcohol
10 dips
15
Absolute ethyl alcohol
10 dips
16
Xylene
10 dips
17
Xylene
10 dips
18
Xylene
10 dips
Coverslip
*Courtesy of Mithra Baliga, MD, University of Mississippi, Jackson.

Step Solution Time/Dips*

Diff-Quik Stain
Reagents
Diff-Quik (American Scientific Products) staining kit includes:

Fixative: trimethane dye and methyl alcohol.

Solution I: xanthene dye.

Solution II: buffered solution of thiazine dyes.

Distilled water.

Procedure

Dip air-dried smears in fixative 5 times, 1 second each time; allow excess to drain.

Dip smears 5 times in solution I, 1 second each time; allow excess to drain.

Dip smears 5 times in solution II, 1 second each time; allow excess to drain.

Rinse the smears in distilled water.

Check the quality of the stain before coverslipping. If necessary, restain in Solutions I
and II for one or two seconds.

Allow the slides to dry.

Coverslip.

Heme-3 Stain
Reagents

Heme-3 fixative

Heme-3 solution I

Heme-3 solution II

Distilled water
Procedure

Dip air-dried smears in fixative 5 times, 1 second each time; allow excess to drain.

Dip smears 5 times in solution I, 1 second each time; allow excess to drain.

Dip smears 5 times in solution II, 1 second each time; allow excess to drain.

Rinse the smears in distilled water.

Check the quality of the stain before coverslipping. If necessary, restain in solutions I
and II for 1 or 2 seconds.

Allow the slides to dry.

Coverslip.

SUBMITTING THE SLIDES FOR IMMUNOSTAINS

Immunostains can be performed on smears prepared from cytologic samples. The smears may be
submitted as unstained and wet-fixed, Papanicolaou stained, or destained already stained by the
Papanicolaou method. Study has shown that destaining is not necessary and may even lower the
sensitivity of the immunostaining procedure.12 , 13 A Papanicolaou-stained smear can be
directly processed without destaining, and with good results. The advantage of using a
prestained slide is that the slide may be selected based on cellular material or number of
diagnostic cells. Although an unstained wet-fixed smear is considered slightly better than the
stained one, it is not known whether the given slide will have the cells in question.

P.13
A smear tested nonreactive to a particular antibody may be reprocessed to check another
antibody, especially when the cellular material is of limited amount. While choosing a smear for
immunostains, it is prudent to avoid one with excess blood, as it will result in background
staining, leading to nondiagnostic results. For surface immunoglobulins, air-dried smears are
preferred.

The laboratory must keep positive and negative controls by preparing wet-fixed scrape smears of
known lesions. The controls normally used are tissues that are fixed in formalin and may not be
ideally suited as controls for cytologic samples.
Cell blocks are preferred for immunostains, because multiple sections can be made available for
a large battery of stains.

APPENDIX*

FIXATIVES
Fix-Rite 2 (Spray Fixative)

Richard Allan Scientific

Kalamazoo, MI
(800) 522-7270
www.rallansci.com
Reorder # 76150
12 per case/4 oz (120 mL) each

Surgipath Cytology Fixative Nonaerosol

Surgipath Medical Industries, Inc.

5205 Route 12
P.O. Box 528
Richmond, IL 60071
800-225-3025
www.surgipath.com
Item # 01800
12 per case/4oz (188 mL) each

Saccomanno Fixative

Saccomanno fluid
Fisher Scientific
Kalamazoo, MI
1-800-522-7270
Cat # 751-054
1 gallon

Pen-Fix (for Hematoxylin and Eosin Stain)

Richard Allan Scientific

Kalamazoo, MI
1-800-522-7270
www.rallansci.com
Cat # 6101
1 gallon

SUBMITTING THE SPECIMEN FOR ELECTRON MICROSCOPY

Ultrastructural evaluation of the cytologic specimen is occasionally necessary. The sampling,
such as small flecks of tissue or sediment, can be collected in glutaraldehyde prior to processing.

SUBMITTING THE SPECIMEN FOR FLOW CYTOMETRY

The specimen should be fresh and unfixed. An ideal transport medium is a balanced salt
solution.

HENRY FORD HOSPITAL CYTOPATHOLOGY NONALCOHOLIC

PRESERVATIVE
This is a liquid medium for transporting the specimen and is meant for short-term preservation.
The solution contains several nutrients and broad-spectrum antibiotics. It is recommended that
the preservative be frozen in aliquots and thawed as needed.

Stock Solution
Balanced salt solution
400 mL
Fetal bovine serum
200 mL
Heparin
4,000 international units
Broad-spectrum antibiotics
(e.g., penicillin)
20,000 units

Method
Using aseptic techniques, reconstitute the antibiotics by injecting enough sterile water into each
vial of antibiotic. Shake vigorously until the powder is dissolved. Mix all the ingredients in a
1,000-mL sterile container. Divide in equal quantities in 50-mL tubes and freeze. Label all the
tubes with preparation and expiration dates (6 months).

Preparation of Working Preservative Solution from Stock

Solution
Inject 100 mL of thawed stock solution into a 1-L bag of balanced salt solution. Label the bag
with preparation and expiration dates (1 week). Keep the solution refrigerated.

REAGENTS FOR SAPONIN TECHNIQUE

Saponin Solution
P.14
Deionized water
100 mL
Saponin
1.0 g
P-hydroxybenzoic acid
sodium salt
0.2 g

Mix thoroughly. Filter twice through 5.0-millipore filter.

Saponin
 Acros

500 American Road

Morris Plains

New Jersey 07950

USA

1-800-ACROS-01

Cat # 41923-1000 100 g

P-Hydroxybenzoic Acid Sodium Salt

Pfaltz and Bauer, Inc.

172 East Aurora Street

Waterbury, CT 06708

Cat # 09910

CAUTION: Fungi grow rapidly in Saponin solution. The solution must be filtered every morning.

Calcium Gluconate
Deionized water
100 mL
Calcium gluconate powder
3.0 g
P-hydroxybenzoic acid sodium salt
0.2 g

Mix thoroughly. Filter twice through 5.0-millipore filter.

Calcium Gluconate Anhydrous Powder

 Mallinckrodt Baker, Inc.

Phillipsburg, NJ 08865

1-908-859-2151

www.jtbaker.com

Cat # 1272-01 500 g

REAGENTS FOR WET-FILM TECHNIQUE

Toluidine Blue Supravital Stain
Toluidine blue
0.5 g
95% ethyl alcohol
20.0 mL
Deionized water
80.0 mL

Dissolve toluidine blue in ethyl alcohol. Add water and store in a dark bottle. Refrigerate when
not being used.

Toluidine Blue O
Fisher Scientific

Fairlawn, NJ 07410

1-201-796-7100

Cat # 52040

PREPARATION OF SCOTT'S TAP WATER

Scott's tap water is used as a bluing agent for Gill's hematoxylin during the Papanicolaou staining
process.

Procedure
Carefully weigh out the required amount of magnesium sulphate and sodium bicarbonate
and add them to the container.

Add the appropriate quantity of deionized water and shake vigorously.

Label the container with date and contents.

Reagents
Hydrous magnesium sulphate
20 g
Sodium bicarbonate
2g
Deionized water
1,000 mL

OR

Anhydrous magnesium sulphate

10 g
Sodium bicarbonate
2g
Deionized water
1,000 mL

Sodium Bicarbonate

Fischer Scientific
 Fairlawn, NJ 07410

1-201-796-7100

Cat # S233-500 500 g

Magnesium Sulfate Heptahydrate

Fischer Scientific

Fairlawn, NJ 07410

1-201-796-7000

www. fischersci.com

Cat # M63-500 500 g

STAINS
Papanicolaou Stain
Gill 2 Hematoxylin

Richard Allan Scientific

Kalamazoo, MI

1-800-522-7270

www.rallansci.com

Reorder # 72511

1 gallon/3.8 L

Pap Stain EA 65

Richard Allan Scientific

 Kalamazoo, MI

1-800-522-7270

www.rallansci.com

Reorder # 75611

1 gallon/3.8 L

P.15

Pap Stain OG-6

Richard Allan Scientific

Kalamazoo, MI

1-800-522-7270

www.rallansci.com

Reorder # 75211

1 gallon/3.8 L

Cyto- Stain

Richard Allan Scientific

Kalamazoo, MI

1-800-522-7270

www.rallansci.com

Reorder # 7501R

1 gallon/3.8 L

Diff-Quik Stain
 Dade Behring Inc.

1717 Deerfield Road

Deerfield, IL

1-847-267-5300

www.dadebehring.com

Protocol Heme-3 Stain Set

Fisher Diagnostics

Fisher Scientific

8365 Valley Pike

Middle Town, VA 22645-0307

1-800-524-0294

Hematoxylin Eosin Stain (Used for Frozen Sections at Henry

Ford Hospital)
Harris' Hematoxylin
Anatech; cat # 842

Stock 1% Alcoholic Eosin

Eosin-Y, water soluble (C.I. 4538) dissolved in 20 mL distilled water

Add 80 mL 95% ethyl alcohol

Working Eosin Solution

Stock 1% alcoholic eosin
100 mL
80% ethenol
300 mL
Glacial acetic acid
2 mL

1% Acid Alcohol
Absolute ethyl alcohol
2,079 mL
Distilled water
891 mL
Concentrated hydrochloric acid
30 mL

Saturated Lithium Carbonate

Lithium carbonate
1g
Distilled water
100 mL

Hematoxylin Eosin Stain 2 (Used for Air-Dried FNA Smears)

Gill III Hematoxylin

Richard-Allen Scientific

4481 Campus Drive

Kalamazoo, MI 49008

1-800-522-7270
 Cat # 72604 (one gallon)

Eosin-Y

Richard-Allen Scientific

Cat # 7111 (one pint)

Bluing Agent

Richard-Allen Scientific

Cat # 7301 (one gallon)

Clarifier 2

Richard-Allen Scientific

Cat # 7402 (one gallon)

Histogel
Richard-Allen Scientific

4481 Campus Drive

Kalamazoo, MI 49008

1-800-522-7270

www.rallansci.com

Reorder # HG-4000-012

Cat # 904012

12 vials/10 mL each
HistoPrep Xylene
Fischer Scientific

Pittsburgh, PA 15275

1-201-796-7100

Cat # HC700

1 gallon

Agar
Nutrient Agar (Difco)

Fisher Scientific

4500 Turnberry Drive, Ste A

Hanover Parks, IL 60133

1-800-640-0640

www.fishersci.com

Cat No DF0001-17-0-(500 MG)

*The reagents listed in this appendix are those currently being used in the Cytopathology
Laboratory at the Henry Ford Hospital, Detroit. This is not an endorsement for any particular
product.

REFERENCES
1.Henry Ford Hospital. Cytopathology Laboratory Manual . Detroit: Henry Ford Hospital;
2006.

2.Jennings AS, Atkinson BF. Thyroid needle aspiration: collection and handling the specimen.
N Eng J Med . 1983;308:1602–1603.

P.16

3.Geisinger KR, Stanley MV, Raab SS, et al. Fine-needle aspiration: equipment, basic and
clinical techniques, and results reporting. In: Modern Cytopathology . Philadelphia:
Churchill-Livingstone; 2004;9–34.

4.Powers CN. Frable WJ. Fine needle aspiration biopsy of the head and neck . Boston:
Butterworth-Heinemann; 1996.

5.Able JS, Miller TR, Lowhagen T. Smearing techniques for the concentration of particles
from fine needle aspiration biopsy. Diagn Cytopathol . 1985:1:59–65.

6.Yang GC, Alvarez H. Ultrafast Papanicolaou stain: an alternative preparation for fine-
needle aspiration cytology. Acta Cytol . 1995;39:55–60.

7.Naylor B, Toivonem T. The use of toluidine blue-stained wet films in diagnostic cytology.
Cytopathol Ann . 1993;279–287.

8.Gill G. Personal communication.

9.Coughlin D, Lukeman JM. The use of saponin for hemolysis in effusion cytology. Acta Cytol
. 1982;26:739.

10.Boon ME, Drijver JS. RoutineCytologic Staining Techniques: Theoretical Background

Practice . London: MacMillan Education; 1986.

11.Baliga M. Personal communication.

12.Abendroth CS, Dabbs DJ. Immunocytochemical staining of unstained versus previously

stained cytologic preparations. Acta Cytol . 1995;39:379–386.
13.Dabbs DJ, Wang X. Immunocytochemistry on cytologic specimens of limited quantity.
Diagn Cytopathol . 1998;18:166–169.
Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 4 - Specimen Adequacy and Assessment, Reporting System

4
Specimen Adequacy and Assessment, Reporting
System

The ultimate result of an aspiration biopsy procedure should be smear(s) prepared and stained in
such a way as to enable a cytopathologist to give an accurate and meaningful cytopathologic
evaluation, one that is in the best interest of the patient. The specimen must be adequate in
terms of cellularity and the smear must be satisfactory in terms of quality—that is, thickness,
fixation, and staining. The final product should be an ideal smear that fulfills the criteria listed
in Table 4.1 and illustrated in Figure 4.1 . This chapter will deal with specimen adequacy and
our reporting system/scheme, including unsatisfactory and inadequate diagnoses.

Adequately cellularity and a thin, monolayered smear.

Adequately wet-fixed (for Papanicolaou staining).
Well-visualized, well-stained cellular material.
Must provide assessment of architectural patterns of tissue
fragments.
Must provide details of nuclear morphology.
Demonstrates cytoplasmic characteristics.
Psammoma bodies are well-visualized when present.
Stains colloid.

TABLE 4.1 CHARACTERISTICS OF AN IDEAL SMEAR OF

THYROID ASPIRATE
Figure 4.1. An Ideal smear. A. Low-power view of an aspirate of papillary thyroid carcinoma,
showing adequate cellularity. The architectural patterns of the tissue fragments are well
visualized. B. This tissue fragment presents a follicular growth pattern. The follicular cells are
well fixed and stained well. C. The nuclei demonstrate excellent morphology. The powdery
chromatin, nucleoli, grooves, and inclusions are well visualized. D. These anaplastic carcinoma
cells present clearly malignant nuclei. Diagnosis can be made based on small number of cells. E.
Psammoma bodies are well stained and readily identified. F. The colloid is stained in the
background.
ADEQUACY
It is very difficult to define an adequate cytologic specimen of a thyroid aspirate. The
assessment greatly depends on several factors, such as quality of the specimen (fixation and
cytopreparation), quantity or the number of diagnostic cells, the interpreter's skills, and the
comfort level. This comfort level is built on experience, not only with cytologic interpretations
but years of follow-up of cytologic specimens and their correlations with the histologic diagnoses
whenever available. Misinterpreted cytologic diagnoses are often an educational experience
when correlated with histologic findings. The reverse is also true.

Additional factors that impact both adequacy assessment and interpretation include the clinical
data, ultrasound findings, size of the nodule, and risk factors (if any).

An adequate specimen is one in which the cytologic material is sufficient to render a diagnosis,
benign or otherwise. A rare group of benign follicular cells should not be considered indicative of
a benign disease.

Our criteria of 8 to 10 tissue fragments of follicular cells (Fig. 4.2 ) on each of at least two
smears were subjectively derived from our experience with over 3,000 specimens.1 They have
been remarkably helpful in rendering a benign or non-neoplastic diagnosis. These criteria are
still applicable and are used in the author's laboratory. The requirement of 8 to 10 tissue
fragments may seem rigid and will raise the percentage of unsatisfactory results. For example,
because of this requirement, the rate of unsatisfactory results in our series was reported to be
20%.1 But such rigid criteria will minimize the risk of false-negative diagnoses. Most of our false-
negative diagnoses were encountered during the first few years of biopsy experience and on
retrospective review; the majority were based on inadequate specimens.2 Poor cellular yield
can be due to several factors (Table 4.2 ).
Figure 4.2. A. An adequately cellular aspirate of thyroid with at least 7 to 8 tissue fragments of
follicular epithelium in the background of colloid. B. This aspirate demonstrates several well-
preserved follicular cells in tissue fragments, with 8 to 10 cells in each fragment. C. Well-
preserved follicular cells forming regular follicles. Note thin colloid in the background.

1. Sclerotic lesions
Scarring in nodular goiter
Fibrous variants of Hashimoto's thyroiditis
Riedel's thyroiditis
Neoplasms with marked desmoplasia
2. Thick, fibrous, calcified capsule of the nodule in question
3. Large lesions with cystic degeneration
4. Long-standing cysts
5. Necrotic lesions
Abscess
Infarct

6.
 Necrosis of the tumor
6. Very vascular neoplasms
7. Sampling error: biopsy needle in tissue surrounding
the nodule
8. Faulty biopsy technique: too much or too little suction

TABLE 4.2 PROBABLE REASONS FOR INADEQUATE SPECIMENS

How strictly can these guidelines be followed? With a large nodule, 8 to 10 tissue fragments may
not be adequate. Does one need the same amount of cellularity to diagnose an anaplastic
carcinoma? Perhaps not. A few groups of clearly malignant cells, as depicted in Figure 4.1D , on
only one smear are sufficient and diagnostic for rendering an interpretation of anaplastic
carcinoma. This has to be done in context with the patient's clinical data and clinical diagnosis.
What if only one smear is very cellular and the rest are acellular? Does one need two smears for
a diagnosis of papillary carcinoma? A single smear of an overwhelmingly cellular aspirate, as
shown in Figure 4.1A , is diagnostic when all the criteria are visualized. However, with
marginally cellular aspirate, the presence of minimal criteria on at least one smear is critical
(see Chapter 9 ).

The adequacy criteria recommended by others vary.3 , 4 , 5 , 6 Goellner and associates3 and
Caruso and Mazzaferri4 require 5 or 6 groups of well-preserved follicular cells, each group
consisting of at least 10 to 15 cells. They have not specified the number of slides, and it is not
clear whether 6 tissue fragments or groups is a cumulative number from all of the smears.
Hamburger and Hussain5 recommended at least 6 aspirates of a nodule in question, with at least
two containing 6 clusters of benign cells (number of cells per group not specified). Nguyen and
colleagues6 require 10 clusters of follicular cells with at least 20 cells in each cluster. Again, the
number of smears is not specified.

Besides adequate cellularity, preservation of epithelial cells is also very critical in Papanicolaou-
stained material. An adequately cellular aspirate must also be satisfactory for cytopathologic
evaluation. Too much blood, cellular and
P.18
necrotic debris, thick smears, poor fixation, and suboptimal stain can all influence the final
product. An adequate cellular specimen can be unsatisfactory for cytopathologic evaluation due
to any of these causes. Guidelines for ensuring a satisfactory and adequate sample are presented
in Table 4.3 .

1. Multiple punctures of the nodule in question, so that several

areas are sampled (easily done if the aspiration biopsy is
performed under local anesthesia).
2. At least six properly prepared thin cell spreads.
3. Immediate wet fixation for Papanicolaou staining technique.
4. A minimum of 8 to 10 tissue fragments of well-preserved
follicular epithelial cells on at least 2 slides.

TABLE 4.3 RECOMMENDED GUIDELINES FOR ENSURING

ADEQUATE AND SATISFACTORY SPECIMENS

REPORTING SCHEME FOR THYROID ASPIRATES

A reporting system or scheme in cytopathology practice is a means of communicating the results
of cytologic evaluation and diagnostic interpretation to the clinician. The scheme should be
simple, succinct, and easily understood. The
P.19
patient management depends greatly on how the results are communicated. Ambiguous
terminology must be avoided at all costs.

In general, the reporting schemes in cytopathology vary, depending on the type of specimen as
well as the organ or site. The schemes for exfoliative cytopathology are generally simple,
consisting of four basic categories: unsatisfactory, negative, atypical/suspicious, and positive.
This simple scheme is broadened in aspiration cytology, because of the wide range of diagnostic
possibilities, which are often site specific.

In aspiration cytology of thyroid aspirates, the reporting of the cytologic evaluation and
interpretation (diagnosis) has caused considerable confusion over the years. Several formats
have been suggested or recommended in the literature and are currently in use.7 The
professional societies have published broad guidelines.8 Most published schemes7 , 9 are
individualized and customized to suit the respective institutions and are strongly dependent on
(i) the
 P.20
P.21
cytopathologists' interpretations based on specimen adequacy, cytopreparations, and
experience; (ii) institutional experience with the aspirates and the diagnostic accuracy; and (iii)
the management strategy of the endocrinologists and the surgical management. These schemes,
although practical for the particular institutions, may not be applicable in different settings.

No matter how the scheme and the algorithms are designed and recommended, the important
factor is the cytopathologic interpretation. For example, an aspirate interpreted as
nondiagnostic by one pathologist may be interpreted as negative, indeterminate, or suspicious
by another. The case illustrated in Figure 4.3 is such an example, where three cytopathologists
interpreted the aspirate differently. The suspicious diagnosis resulted in surgery, which was
confirmed as papillary carcinoma.

Figure 4.3. These four images represent the only cells present in a cytospin preparation of a
clear cyst fluid from the thyroid. The diagnostic impression by three cytopathologists were
inadequate/non-diagnostic, negative for malignant cells, and suspicious for papillary carcinoma.
Surgery confirmed the diagnosis of papillary carcinoma.
The customized reporting schemes may have three tiers, four tiers, or more.7 Stratification is
very essential in thyroid aspiration cytology because of the extremely wide range of possibilities
and multiple options open to the clinicians. It is critical that whichever scheme is chosen or
followed, there should be a clear communication between the cytopathologists,
endocrinologists, and surgeons.

The reporting scheme used in author's laboratory is listed in Table 4.4 . It varies from several
others in that (i) the acellular or unsatisfactory and inadequate categories are separate instead
of having one category, "nondiagnostic," that includes both; (ii) the follicular/Hürthle cell
neoplasms are reported as "abnormal"; and (iii) the suspicious diagnosis is a separate category,
at variance with the practice of other institutions of combining follicular/Hürthle cell
neoplasms and suspicious diagnosis as "indeterminate."

Unsatisfactory a

Inadequate a

Negative
(Benign)

Abnormal b

Suspicious b

Positive

Acellular smears; no follicular cells; bloody; smears too thick.

Adequate cellularity but poor cell preservation due to air-drying
in Papanicolaou-stained preparations.
Scant cellularity with or without mild nuclear atypia.
Abundant colloid with no or few follicular cells.
 Cyst fluids with only histiocytes and no or few follicular cells.
Nodular goiter: benign follicular cells, with or without colloid
and histiocytes.
Thyroiditis; chronic lymphocytic or Hashimoto's type.
Subacute or granulomatous thyroiditis.
Cellular features of follicular adenoma.
Cellular features of Hürthle cell neoplasms.
Cellular material inadequate but suggestive of malignancy.
Diagnostic criteria insufficient for a definite diagnosis of malignancy.
Malignant cells present.
(Malignancy to be typed.)

a Non-diagnostic. In some reporting schemes, this category includes acellular and inadequate
diagnoses.
b Indeterminate. In some reporting schemes, this category includes follicular neoplasms,

Hürthle cell
neoplasms, and suspicious diagnoses.
From Henry Ford Hospital, Detroit.

Category Observations

TABLE 4.4 REPORTING SCHEME FOR THYROID ASPIRATES

The management strategies based on above described reporting scheme are described in
Chapter 23 .

Explanation of the Diagnostic Terms Used in the Reporting

Scheme and Their Significance
Unsatisfactory
The specimen is unsatisfactory for cytologic evaluation due to lack of follicular cells. Presence of
only stromal cells and/or only lymphocytes is of no significance. The cytologic smears must be
properly prepared and wet-fixed promptly for Papanicolaou staining. The slightest delay in fixing
will result in poor cellular details, rendering the specimen unsatisfactory for cytologic
evaluation, regardless of the cellularity. Abundant venous blood and thick smears obscure the
cellular details and will also render the specimen unsatisfactory for evaluation.

Inadequate
The aspirate is considered inadequate for cytologic evaluation when the number of follicular
cells is small (see "Adequacy" earlier in this chapter). The inadequate category also includes (i)
abundant colloid with no follicular cells and with or without histiocytes or with few benign
follicular cells; (ii) cyst fluid aspirates with few or no follicular cells; and (iii) rare groups of
follicular cells with minimal nuclear atypia, not sufficient for any specific diagnosis, may be
included in this group, and may indicate degenerative/reactive changes.

Although cystic change and degeneration are frequent in nodular goiters, they are also seen in a
substantial number of papillary carcinomas. The presence of histiocytes alone cannot be taken
as a feature in favor of benign disease. The aspirate may be reported simply as cyst contents
without using the prefix "benign."

In some reporting schemes,3 , 4 the unsatisfactory and inadequate diagnoses are grouped
together in a nondiagnostic category, with an explanation that the term "nondiagnostic" does not
mean negative but warrants a repeat biopsy.9

The unsatisfactory and inadequate categories (nondiagnostic) together comprise roughly 10% to
21% of the fine-needle biopsy procedures.2 , 4 , 9 , 10 Results as low as 2%11 and as high as
31%12 are also reported in the literature. These numbers are dependant on adequacy criteria,
which vary considerably from institution to institution. The incidence of diagnostic results
following rebiopsy is reported to be 62%.13 Roughly 30% to 38% remain nondiagnostic due to
factors inherent to the lesions (e.g., fibrosis, increased vascularity, cystic change). The
malignancy yield in the nondiagnostic group is variably reported to be 2%,14 5%,15 and 9%16 ;
Chow and co-workers13 reported 7% overall malignancy in the nondiagnostic group, but the
percentage increased to 37% when only surgical cases were considered.

Negative
The specimen is representative of benign non-neoplastic diseases, either nodular goiter or any
type of thyroiditis. This is the most common diagnosis encountered, comprising 60% to 70% of the
diagnoses. Negative diagnosis means no malignancy in the aspirated samples and the patients
are managed conservatively.

Isolated groups of mildly atypical follicular cells in the background of nodular goiter may be
described in the microscopic description and their presence alluded to by using a phrase "see
comments" in the diagnosis. This type of diagnosis is usually followed by clinical observation
and/or repeat biopsy. The diagnostic term "abnormal/atypical" or "indeterminate" for these few
atypical cells will confuse the clinicians and often leads to unnecessary surgery. The same holds
true for Hashimoto's thyroiditis, where epithelial atypia is of common occurrence. If the atypia is
marked and a neoplasm is strongly considered, the suspicious category is recommended.

The incidence of malignancy in the benign group is very low, although a true incidence can
never be determined, because the majority of patients with benign diagnoses are managed
conservatively.

Abnormal
The abnormal category is used when the cytologic features indicate a benign neoplasm such as a
follicular adenoma or a Hürthle cell neoplasm.

An abnormal/atypical diagnosis corresponds to the indeterminate category of some reporting

schemes,9 and is followed by surgical excision. Usually, the decision for surgical excision and the
extent of surgery rests with the clinician, taking into account any risk factors and the patient.

If the specimen is inadequate but presents some features suggestive of a benign neoplasm, these
features may be included in
P.22
the inadequate category with specific comments in the microscopic description. Repeat biopsies
are usually indicated.

Suspicious for Malignancy

This category includes three cytologic patterns: (i) adequate cellularity and cytologic features
suggesting malignancy but lacking all the criteria for a definite diagnosis (e.g., cellular follicular
adenomas with a differential diagnosis of follicular carcinoma or a follicular variant of papillary
carcinoma); (ii) adequate cellularity, with most but not all the features of papillary carcinoma;
and (iii) inadequate cellularity but cellular features strongly favoring malignancy.

Many laboratories lump indeterminate and suspicious results into one category as
indeterminate/suspicious. The malignancy yield is apt to be different when each category is
considered separately. This group represents 11% to 21% of cytology results,4 , 9 , 17 , 18 and
surgical excision is recommended for all. Most are found to be benign. The surgical follow-up in
this group reports 20% to 40% malignant neoplasms, 30% to 40% follicular/Hürthle cell
adenomas, and 20% to 30% non-neoplastic diseases.4

Positive (Diagnostic of Malignancy)

Several malignant neoplasms of the thyroid offer accurate cytologic diagnosis with a high degree
of sensitivity and specificity, allowing proper management strategy. The malignant tumors that
can be diagnosed from cytologic samples include papillary carcinoma, Hürthle cell carcinoma,
poorly differentiated follicular carcinoma, insular carcinoma, medullary carcinoma, anaplastic
carcinoma, large cell malignant lymphoma, and metastatic carcinoma. The malignant diagnosis
in a compilation of 10 series ranged from 1% to 18%, with an average of 4%.4

False-negative diagnoses imply malignant diagnoses in surgical specimens from patients with a
benign diagnosis. The incidence is variable, ranging from less than 1% to 6%.4 The reasons
include unsatisfactory/inadequate samples or sampling errors and interpretation.

False-positive diagnoses imply no malignancy detected in surgically removed thyroids that had
positive fine-needle biopsy diagnosis. The reported incidence ranges from 0% to 7.7%.4 The
errors are always interpretative, due to overlapping features, degenerative changes, an
inadequate specimen, or simply inexperience. Papillary carcinoma is the most common false-
positive diagnosis.

The diagnostic accuracy is usually determined by sensitivity and specificity. The reported
sensitivity for thyroid fine-needle aspirates is 83%, with a range of 65% to 98%; the specificity is
92%, with a range of 72% to 100%.9

Table 4.5 lists several examples from the diagnostic categories of unsatisfactory and inadequate
(nondiagnostic).

P.23
Acellular, bloody;
no thyroid follicular cells;
Unsatisfactory for cytologic
evaluation
Faulty technique; vascular or cystic lesion;
desmoplasia (see Table 4.2); repeat the FNA.
Acellular, bloody;
no thyroid follicular cells;
 spindle cells of stromal origin
(Fig. 4.4)
Unsatisfactory for cytologic
evaluation
Stromal cells or tissue fragments may originate from
granulation tissue or fibrosis in nodular goiters or
Hashimoto's thyroiditis; rarely they may represent an
anaplastic carcinoma or a papillary carcinoma with
desmoplasia; review the smear(s) carefully; single
spindle cells with bizarre, pleomorphic nuclei may
represent an anaplastic carcinoma with marked
desmoplasia; repeat the FNA; clinical correlation
required.
Acellular, bloody;
no thyroid follicular cells; only
histiocytes with or without
hemosiderin (Fig. 4.5)
Unsatisfactory for cytologic
evaluation (nondiagnostic)
Probably represents cystic change in nodular goiter;
rarely, a cystic papillary carcinoma may present a
similar pattern; reaspirate if a residual is palpable or
if the cyst recurs; clinical correlation required.
Acellular, bloody;
no thyroid follicular cells;
only lymphocytes (Fig. 4.6)
Unsatisfactory for cytologic
evaluation
Confirm that the needle was in thyroid and not in the
adjacent lymph node; may represent late stages of
Hashimoto's thyroiditis; repeat the FNA; clinical
correlation required.
Acellular; abundant colloid;
no thyroid follicular cells
 (Fig. 4.7)
Unsatisfactory for cytologic
evaluation (nondiagnostic)
Probably represents a colloid nodule (hyperinvolution
in nodular goiter or a macrofollicular adenoma); clinical
correlation required; repeat FNA may be indicated.
Poor cellular preservation due to
improper fixation (air-drying)
(Fig. 4.8) for Papanicolaou-stained
preparations, thick smears,
excessive blood
Unsatisfactory for cytologic
evaluation (regardless of
cellularity)
Repeat the FNA.
Histiocytes with or without
hemosiderin; few follicular cells with
or without degenerative changes
(Fig. 4.9)
Inadequate for cytologic
evaluation due to scant
cellularity; (nondiagnostic)
Probably represents nodular goiter; clinical correlation
required; repeat FNA may be indicated based on
clinical and radiologic findings.
Histiocytes with or without hemosiderin;
few follicular cells with atypia; some
but not all the cytologic features of
papillary carcinoma (Figs. 4.10
and 4.11)
Suspicious for papillary
carcinoma
May represent either a nodular goiter with
degeneration or a cystic papillary carcinoma; repeat
 FNA or recommend surgery.
Abundant colloid, few benign follicular
cells; histiocytes ± (Fig. 4.12)
Negative for malignant cells;
colloid nodule,
(hyperinvoluted nodular
goiter) or a macrofollicular
adenoma
If the lesion is large, (>2 cm in diameter), adequate
sampling may be a problem; lesions yielding abundant
colloid and few benign-appearing cells are rarely
if ever malignant; differential diagnosis includes a
macrofollicular variant of papillary carcinoma; look for
syncytial architecture of the tissue fragments and
nuclear features of papillary carcinoma; repeat FNA
only if cytologic atypia is present.
Few (fewer than 6 to 8) well-preserved
tissue fragments of follicular cells,
honeycomb arrangement, and
regular follicles; small nuclei <9 µm
in diameter with compact chromatin;
absent or scant colloid (Fig. 4.13)
Inadequate for cytologic
evaluation due to scant
cellularity; (nondiagnostic)
Probably represents nodular goiter; nodule size must
be taken into consideration; repeat FNA based on
clinical judgment; sometimes clinically followed.
Rare group or tissue fragment of follicular
cells, syncytial arrangement, nuclei
with granular/powdery chromatin,
nucleoli (Fig. 4.14).
Suspicious for a neoplasm
Repeat FNA or recommend excision.
Few groups or tissue fragments of
atypical cells; poor preservation; some
features suggestive of papillary
carcinoma (Fig. 4.15)
Suspicious for papillary
carcinoma
Recommend surgery.

Cellular Features Interpretation/Diagnosis Explanation/Recommendations

TABLE 4.5 CRITERIA FOR ADEQUACY AND GUIDELINES FOR

REPORTING UNSATISFACTORY/INADEQUATE
(NONDIAGNOSTIC) SPECIMENS

Figure 4.4. The presence of only benign stromal cells in the absence of follicular cells is
inconsequential. The aspirate is unsatisfactory for evaluation.
 P.24

Figure 4.5. A. An aspirate of a thyroid cyst containing only histiocytes. Follicular cells are not
present. This aspirate is inadequate for cytologic evaluation. B. This cyst aspirate contained only
histiocytes in a hemorrhagic background. Because it recurred, a thyroidectomy was performed,
which revealed a cystic papillary carcinoma. Presence of histiocytes even in large numbers is not
diagnostic of a cyst. A cystic papillary carcinoma must always be considered in the differential.

Figure 4.6. Only lymphocytes are present in FNA of a documented case of Hashimoto's
thyroiditis. The aspirate is unsatisfactory for cytologic evaluation due to lack of follicular cells.

Figure 4.7. Abundant colloid. No follicular cells. Although this may represent a nodular goiter,
the aspirate is inadequate due to lack of follicular cells. A clinical correlation is required.

Figure 4.8. Poor cytopreparation will result in an unsatisfactory smear. A. This aspirate from a
papillary carcinoma is very cellular but air-dried, resulting in poor cellular details. The aspirate
is unsatisfactory in spite of the cellularity. B. This aspirate from Hashimoto's thyroiditis is air-
dried, resulting in pale nuclei, and misinterpreted as suspicious for papillary carcinoma. This
preparation should be addressed as unsatisfactory. Errors are apt to happen when a diagnosis is
rendered on a suboptimal preparation.

P.25

Figure 4.9. A cyst aspirate containing histiocytes and few benign follicular cells. This aspirate is
inadequate for cytologic diagnosis.
Figure 4.10. Cyst fluid. A. This image shows few follicular cells with poorly preserved nuclei
with high N/C ratios. There are histiocytes in the background. B. The syncytial tissue fragment
of follicular cells demonstrates high N/C ratios and well-defined cell borders with variable foamy
cytoplasm. Micronucleoli are occasionally seen. The N/C ratios are high. The variable cytoplasm
is bubbly and foamy. The cell borders are well defined. The aspirate shows some but not all the
features of papillary carcinoma.

Figure 4.11. This poorly cellular aspirate shows very few discrete follicular cells, pleomorphic in
size, and resembles histiocytes. The cell borders are well defined and the cytoplasm is variable
dense to vacuolated. The nuclei are enlarged with irregular chromatin along the nuclear
membrane. Micronucleoli are occasionally present. Experience is required to appreciate the
subtle atypical features that are suspicious for papillary carcinoma.
Figure 4.12. A. Abundant colloid and rare group of benign follicular cells (low power). B. Higher
magnification showing small follicular cells with pyknotic nuclei. Although in terms of quantity
this aspirate is inadequate, it probably represents a nodular goiter.

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Figure 4.13. Scant cellularity, minimal colloid, small numbers of well-preserved follicular cells.
This aspirate is inadequate for cytologic evaluation but may represent nodular goiter. Clinical
correlation required.
Figure 4.14. The aspirate is poorly cellular. The tissue fragments are syncytial with only a mild
increase in the nuclear size. Note intranuclear inclusions. This aspirate should be interpreted as
suspicious.
Figure 4.15. The cells are air-dried with suboptimal nuclear morphology. The syncytial
architecture of the tissue fragment and a sharp intranuclear inclusion are disturbing features
suggesting a diagnosis of papillary carcinoma. A suspicious diagnosis is justified in this case.

REFERENCES
1.Kini SR, Miller JM, Hamburger JI, et al. Cytopathology of follicular lesions of the thyroid
gland. Diagn Cytopathol . 1985; 1:123–132.

2.Miller JM, Kini SR, Hamburger JI. Needle Biopsy of the Thyroid. New York: Praeger; 1983.

3.Goellner JR, Gharib H, Grant CS, et al. Fine needle aspiration cytology of the thyroid, 1980
to 1986. Acta Cytol . 1987;31: 587–590.

4.Caruso D, Mazzaferri EL. Fine needle aspiration biopsy in the management of thyroid
nodules. Endocrinologist . 1991;1: 194–202.
5.Hamburger JI, Hussain M. Semiquantitative criteria for fine-needle biopsy diagnosis:
reduced false-negative diagnosis. Diagn Cytopathol . 1988;4:14–17.

6.Nguyen GK, Ginsberg J, Crockford PM. Fine-needle aspiration biopsy cytology of the
thyroid. Its value and limitations in the diagnosis and management of solitary thyroid
nodules. Pathol Ann . 1991;26–63.

7.Wang HH. Reporting thyroid fine-needle aspiration: literature review and a proposal. Diagn
Cytopathol . 2006;34:67–76.

8.Papanicolaou Society of Cytopathology Task Force on Standards of Practice. Guidelines of

the Papanicolaou Society of Cytopathology for the examination of fine-needle aspiration
specimen from thyroid nodules. Diagn Cytopathol . 1996; 15:84–89.

9.Gharib H, Goellner JR. Fine-needle aspiration biopsy of the thyroid: an appraisal. Ann Int
Med . 1993;118:282–289.

10.Hamburger JI. Extensive personal experience. Diagnosis of thyroid nodules by fine needle
biopsy: use and abuse. J Clin Endocrinol Metab . 1994;79:335–339.

11.Pepper GM, Zwickler D, Rosen Y. Fine needle aspiration biopsy of the thyroid nodule.
Results of a start-up project in a general teaching hospital setting. Arch Intern Med
1989;149:594–601.

12.Burch HB, Burman KD, Reed L, et al. Fine needle aspiration of thyroid nodules.
Determinants of insufficiency rate and malignancy yield at thyroidectomy. Acta Cytol .
1996;40: 1176–1183.

13.Chow LS, Gharib H, Goellner JR, et al. Nondiagnostic thyroid fine-needle aspiration
cytology: management dilemmas. Thyroid . 2001:11:1147–1151.
 14.MacDonald L, Yazdi HM. Nondiagnostic fine needle aspiration biopsy of the thyroid gland:
a diagnostic dilemma. Acta Cytol . 1996:40:423–428.

15.Schmidt T, Riggs MW, Speights VO Jr. Significance of nondiagnostic fine needle aspiration
biopsy of the thyroid. South Med J . 1997;90:1183–1186.

16.McHenry CR, Walfish PG, Rosen IB. Non-diagnostic fine needle aspiration biopsy. A
dilemma in management of nodular thyroid diseases. Am Surgeon . 1993;59:415–419.

17.Gharib H, Goellner JR, Johnson DA. Fine-needle aspiration cytology of the thyroid. A 12
year experience with 11,000 biopsies. Clin Lab Med . 1993;13:699–709.

18.Gharib H. Changing trends in thyroid practice: understanding nodular thyroid disease.

Endocr Pract . 2004;10:31–39.

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APPENDIX TO CHAPTER 4
Classification of Thyroid Tumors

The two classifications for thyroid neoplasms are the traditional classification recommended by
the World Health Organization1 and another classification modified by Rosai and associates.2
The author has followed the modified classification in this Atlas.

WHO HISTOLOGICAL CLASSIFICATION OF THYROID AND

PARATHYROID TUMORS1

Thyroid Carcinomas

Papillary carcinoma

Follicular carcinoma
 Poorly differentiated carcinoma

Undifferentiated (anaplastic) carcinoma

Squamous cell carcinoma

Mucoepidermoid carcinoma

Sclerosing mucoepidermoid carcinoma with eosinophilia

Mucinous carcinoma

Medullary carcinoma

Mixed medullary and follicular carcinoma

Spindle cell tumor with thymus-like differentiation

Carcinoma showing thymus-like differentiation

Thyroid Adenomas and Related Tumors

Follicular adenoma

Hyalinizing trabecular adenoma

Other Thyroid Tumors

Teratoma

Primary lymphoma and plasmacytoma

Ectopic thymoma

Angiosarcoma

Smooth-muscle tumors

Peripheral nerve-sheath tumors

Paraganglioma

Solitary fibrous tumor

 Follicular dendritic cell tumor

Langerhans cell histiocytosis

Secondary tumors

Parathyroid Tumors

Parathyroid carcinoma

Parathyroid adenoma

Secondary tumors

MODIFIED HISTOLOGICAL CLASSIFICATION OF THYROID TUMORS2

Primary Tumors
Tumors of Follicular Cells

Benign Follicular Adenoma

Conventional

Variants

Malignant: Carcinoma

Differentiated

Follicular carcinoma

Papillary carcinoma

Conventional

Variants
 Poorly Differentiated

Insular

Others

Undifferentiated (Anaplastic)

Tumors of C-Cells and Related Endocrine Cells

Medullary carcinoma

Others

Tumors of Follicular and C-Cells

Sarcomas

Malignant Lymphoma (and Related Hematopoietic Neoplasms)

Miscellaneous Neoplasms

Secondary Tumors
Cytologic features resulting in special tumor types and subtypes that cross lines in the above
classification for the tumors of follicular cells and, to a lesser extent of C–cells, include the
following.

Tumors with Oncocytic (Hürthle cell) Features

Oncocytic adenoma (Hürthle cell adenoma)

Onvocytic carcinoma (Hürthle cell carcinoma)

Papillary oncocytic (Hürthle cell) tumors

Tumors with Clear Cell Features

 Tumors with Squamous Features

Tumors with Mucinous Features

REFERENCES
1.DeLellis RA, Lloyd RV, Heitz PU, et al, eds. Pathology and Genetics of Tumors of Endocrine
Organs. World Health Organization Classification of Tumors . Lyon: IARC Press; 2004.

2.Rosai J, Carcangiu ML, DeLellis RA. Tumors of the thyroid gland. In: Rosai J, Sobin LH, eds.
Atlas of Tumor Pathology . Washington, DC: Armed Forces Institute of Pathology; 1993:
19–20.
Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 5 - Concepts Basic to Thyroid Cytopathology and Guidelines for
Evaluating Thyroid Fine-Needle Aspirates

5
Concepts Basic to Thyroid Cytopathology and
Guidelines for Evaluating Thyroid Fine-Needle
Aspirates

Aspiration biopsy is essentially a form of microbiopsy. The aspirated material consists

of minute tissue fragments (multicellular formations; Fig. 5.1), isolated cells (Fig. 5.2),
and cells in groups or aggregates. The tissue fragments usually retain the architectural
patterns of the lesion aspirated, even when smeared on the slide, and are very similar
to those seen in paraffin-embedded hematoxylin-and eosin-stained sections. The only
difference is that the thickness of the cellular material smeared on the slide is not
uniform or even, unlike a section cut by a microtome. What makes the aspiration
biopsy specimen so interesting is that both the nuclear morphology and cytoplasmic
differentiation can be appreciated in great detail, especially in Papanicolaou-stained
preparations. Thus, fine-needle aspiration biopsy is a blend of histopathology and
cytopathology, and interpretation of the architectural configuration of the tissue
fragments (pattern diagnosis), as much as cytomorphology of the component cells and
isolated cells (exfoliative cytopathology) is an integral part of the evaluation. Mere
pattern diagnosis or only cytomorphologic evaluation is inadequate. A sound
knowledge of surgical pathology and expertise in cytopathology are essential.
Figure 5.1. A multicellular formation (tissue fragment) in contrast to single cells.
 Figure 5.2. Single dispersed cells.

The tissue fragments present a wide range of architectural patterns. Similarly, the
individual cells demonstrate a broad array of features based on their size, shape, and
type.

How does one evaluate the architectural pattern of the tissue fragments in cytologic
preparations, and why is a given tissue fragment papillary or follicular? To appreciate
these patterns, certain expressions frequently used in cytopathology are described in
following sections.

TISSUE FRAGMENT
A tissue fragment (Fig. 5.1) is a multicellular tissue formation, in contrast to single
cells (Fig. 5.2).1

SHEET
A sheet (Fig. 5.3) is a monolayered tissue fragment in which the component cells are
regularly arranged in relation to one another and possess distinct cell boundaries.2 The
nuclear polarity is maintained, resulting in a honeycomb pattern. Sheets are two-
dimensional and display all the component cells in one plane of focus. Any structure
that is single layered will present as a sheet when viewed en face in both cytologic and
histologic preparations. The common examples are thyroid follicles, endocervical
glands, mammary or pancreatic ducts, or a mesothelium.

P.29

Figure 5.3. Sheet (honeycomb). Two-dimensional tissue fragment. The

component cells are visualized in one plane of focus. The cell borders are well-
defined, nuclei regularly placed in relation to one another, and nuclear polarity is
maintained. This pattern is seen when a structure composed of a single cell layer
is seen en face, as with a thyroid follicle, endocervical gland, mesothelium,
mammary duct, or pancreatic duct.
SYNCYTIUM OR SYNCYTIAL TISSUE FRAGMENT
A syncytium or syncytial tissue fragment (Fig. 5.4) is a tissue fragment consisting of
cells that are irregularly arranged with respect to one another and have indistinct cell
borders2 and nuclear polarity. Because of the nuclear crowding and the lack of well-
defined cell borders, the nuclei often appear to be in several planes of focus. Syncytial
architecture differentiates a neoplasm from a benign structure that presents as a
sheet. Depending on the growth pattern of the neoplasm, the tissue fragments may
demonstrate various configurations or patterns that allow recognition and typing of
the neoplasm. A given neoplasm may show more than one growth pattern, and
consequently the aspirate may demonstrate tissue fragments with different
configurations, as in a case of papillary carcinoma. Figures 5.3, 5.4, 5.5, 5.6, 5.7, 5.8,
5.9, 5.10, 5.11, 5.12, 5.13, 5.14 and 5.15 illustrate commonly encountered patterns of
tissue fragments in thyroid aspirates.
Figure 5.4. Syncytium. A syncytium can be two- or three-dimensional, with the
component cells often visualized in multiple planes of focus and with poorly
defined cell borders, crowded and overlapping nuclei, and altered polarity.
Syncytial architecture is indicative of a neoplasm (an exception being
pseudostratified epithelium).
Figure 5.5. Cluster. A tissue fragment exhibiting a syncytial architecture with
marked crowding and overlapping of nuclei, visualized in multiple planes of focus,
appearing three-dimensional.
Figure 5.6. A follicle. The cells are arranged around a central lumen. A follicle
can vary in size and be seen in cross-section or in its entirety. The term
"macrofollicular" is used when a large monolayered tissue fragment is present. A
large follicle or macrofollicle cannot be seen in its entirety in cytologic
specimens, unlike in a tissue section, and is best appreciated when seen en face.
Figure 5.7. Syncytial tissue fragment with follicular pattern.
Figure 5.8. Trabecular pattern. Straight or curved chords, two or more cells
thick.
Figure 5.9. Papillary. Finger-like slender tissue fragments with or without
branching; central core of fibrovascular stromal tissue; epithelial cells line the
cores.
Figure 5.10. Papillary-like. Finger-like slender tissue fragments of epithelial cells
with or without branching, lacking central core of fibrovascular stromal tissue.
Figure 5.11. A syncytial tissue fragment that is monolayered, lacking a
honeycomb pattern. Note the absence of well-defined cell borders. There is
minimal crowding and altered nuclear polarity.
Figure 5.12. Fascicle. A bundle. The spindle cells are arranged in a fascicle.
Figure 5.13. Onion-skin. A syncytial tissue fragment with cells/nuclei arranged in
concentric fashion.
Figure 5.14. Cartwheel. A tissue fragment with cells radiating from the center.
 Figure 5.15. A tissue fragment incorporating psammoma bodies. A psammoma
body is a calcific concretion with concentric lamellations, which always stains
basophilic in tissue sections with hematoxylene and eosin but takes multiple
stains with the Papanicolaou method. In cytologic specimens, a psammoma body
can have various appearances: concentric lamellations, refractile, starburst.

Besides the architecture of the tissue fragments, the nuclear characteristics are very
important, and include the nuclear size, shape, nuclear membrane, chromatin
pattern, parachromatin clearing, presence or absence of nucleoli, grooves or
inclusions, and mitoses (Figs. 5.16 and 5.17). The size of the
P.30
P.31
P.32
cell or the nucleus is usually compared against a known structure, such as a red blood
cell, an entire neutrophil, a histiocytic nucleus, or a resting lymphocyte. In thyroid
aspirates, the follicular cell nucleus is compared against the red blood cell, which is
roughly 7 µm in its longest dimension. Figure 5.18 describes the size range of the cell
when compared to a resting lymphocyte. For detailed description of various
morphologic characteristics of the cell, nuclei, stroma, and background features, the
reader is referred to the literature.3

Figure 5.16. Nuclei exhibiting malignant characteristics. Note the pleomorphic

size, nuclear membrane irregularities, irregular chromocenters separated by
excessively cleared parachromatin, and multiple and variable
micro/macronucleoli.
Figure 5.17. Nuclear morphology: round, oval, and oblong nuclei demonstrating
powdery chromatin, nucleoli, grooves, and intranuclear inclusions.
 Figure 5.18. Cell size. A. Small: 1 to 3 times the size of a resting lymphocyte. B.
Medium: 3 to 5 times the size of resting lymphocyte. C. Large: 6 to 10 times the
size of resting lymphocyte. D. Giant: 10 times or larger than the resting
lymphocyte.

Most thyroid cancers are differentiated carcinomas. Unlike the diagnosis of anaplastic
carcinoma, which can easily be made from bizarre pleomorphic cells presenting
glaringly malignant criteria (Fig. 5.16), differentiated cancers are identified from (i)
the architectural patterns of the tissue fragments (e.g., papillary or follicular) and (ii)
the cytomorphology of the component cells. The nuclear changes are generally very
subtle.

The various structural aberrations presented in aspirated specimens of thyroid lesions

can be best appreciated when the anatomy and histology of the thyroid, as well as the
basic concept of the thyroid follicle, are understood.

The normal thyroid gland is located in front of the neck, straddling the trachea. It
consists of two lobes joined by an isthmus (Fig. 5.19), and weighs approximately 15 g.
Each lobe consists of multiple lobules, and each lobule is composed of several follicles
(Fig. 5.20) supported by a delicate but very vascular connective tissue stroma. A
follicle represents a unit of thyroid parenchyma. It is a three-dimensional closed sac
(Fig. 5.21A) filled with colloid and lined by a single layer of
P.33
cuboidal epithelium resting on a basement membrane. The nuclei of these cells are
centrally located and round to oval, with finely granular chromatin. The cell borders
are well defined, and the cytoplasm is moderate. A follicle seen in cross-section
appears as a ringlet of cuboidal cells, with regularly spaced nuclei and an appreciable
amount of cytoplasm, around a central lumen (Fig. 5.21B). Viewed en face, it appears
as a monolayered sheet of cells with well-defined cell borders and centrally spaced
nuclei, giving a honeycomb pattern (Fig. 5.21C). This two-dimensional architecture
results from the follicles being lined by a single layer of cells. Thus, depending on how
the thyroid follicles are sectioned or smeared, they may appear as regular follicles or
honeycomb sheets. Such a pattern is seen in non-neoplastic thyroid lesions—such as,
nodular goiter—both cytologically and histologically (Figs. 5.22 and 5.23). A normal
or benign thyroid follicle if aspirated in its entirety will show a honeycomb
architecture in different planes (Fig. 5.24). A large, distended follicle is not seen in its
entirety in smears, as it gets ruptured. Instead it presents as a large monolayered
sheet, referred to as macrofollicle. The regular arrangement of cells of a normal
follicle is usually not seen in neoplastic lesions, whether benign or malignant. A
neoplastic follicle is irregular (Fig. 5.25A), and whether seen in a cross-section (Fig.
5.25B) or en face (Fig. 5.25C), it appears as a syncytial-type tissue fragment with
poorly defined cell borders and crowded, overlapping nuclei. These structural
aberrations are easily appreciated in aspirates of follicular neoplasms, both
cytologically and histologically (Figs. 5.26, 5.27 and 5.28). The exceptions are
adenomas with well-formed follicles that recapitulate the structure of normal thyroid.
Figure 5.19. Anatomy of the thyroid.

Figure 5.20. Histologic section of a normal thyroid showing follicles containing

colloid. The lining epithelium is low cuboidal.
Figure 5.21. A. Concept of normal thyroid follicle. B. Cross-section of the
follicle. C. Follicle seen en face presenting a honeycomb pattern.
Figure 5.22. Aspiration biopsy specimen of nodular goiter with regular follicles
and monolayered sheets of cells with a honeycomb pattern, similar to that seen
in Figure 5.23.
Figure 5.23. Histologic section of nodular goiter with regular follicles and a
monolayered sheet with a honeycomb pattern. Note the similarity to Figure 5.22.
Figure 5.24. A benign follicle aspirated in its entirety showing a honeycomb
arrangement of cells.
Figure 5.25. A. Concept of a neoplastic thyroid follicle. B. Cross-section of the
neoplastic follicle. A lumen may or may not be present. C. Neoplastic follicle seen
en face, showing syncytial-type tissue fragments with crowded, overlapped
nuclei.
Figure 5.26. A syncytial-type tissue fragment, with and without a follicular
pattern from a cellular follicular adenoma. Compare the disturbed architecture
to the uniform pattern of nodular goiter in Figure 5.22.
Figure 5.27. Syncytial-type tissue fragment of follicular carcinoma. Note the lack
of a two-dimensional configuration that is, a monolayered sheet and uniform
spacing of nuclei.
 Figure 5.28. Histologic section of a follicular carcinoma. Note the solid and a
follicular growth pattern of the neoplasm, with poorly developed follicles.

With this understanding of follicular structure, we can now focus on the papillary
architecture of the tissue fragments, both in papillary hyperplasia and in papillary
carcinoma of the thyroid. Papillary hyperplasia of the thyroid follicles involves an
infolding of the lining epithelium composed of tall columnar cells with basally located,
uniform nuclei (Fig. 5.29). There is usually no central core of fibrovascular tissue.4 In
contrast, papillary carcinoma has a central core of fibrovascular tissue usually covered
by one, and sometimes more than one, layer of cells with crowded nuclei at all levels.
The lining cells in papillary hyperplasia show basally located small nuclei containing
compact chromatin (Figs. 5.29 and 5.30A) and lack typical nuclear features of
conventional papillary carcinoma (Fig. 5.30B).

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Figure 5.29. Histologic section showing papillary hyperplasia. The infolding of the
lining epithelium has edematous stroma and mimics the fibrovascular cores of
true papillary fronds. The lining epithelium is cuboidal with basally located
uniform nuclei, containing compact chromatin.
 Figure 5.30. Composite of histologic sections showing (A) papillary hyperplasia
and (B) papillary carcinoma. Note the basally located, small, uniform nuclei with
compact chromatin in hyperplasia in contrast to the typical nuclear features of
conventional papillary carcinoma.

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GENERAL GUIDELINES FOR EVALUATION OF A SMEAR OF

A THYROID ASPIRATE
A prepared and stained smear of a thyroid aspirate is usually evaluated in three steps.
The initial step consists of scanning the smear using a 4× objective (low power). This
allows assessment of the following:

Quality of the cytopreparation (e.g., fixation, staining, evenness of the cellular

 material).

Cellularity (adequacy).

Concentration of the cellular material in any particular area/s of the

slide/smear.

Presentation such as dispersed pattern or an admixture of cells and tissue

fragments.

Architectural pattern(s) of the tissue fragments.

Background features, including absence or presence of colloid and its amount,

blood, diathesis, calcific debris, inflammatory infiltrate, and granuloma.

The next step involves examination using a 10× objective (medium power) to focus
on the architectural pattern of the tissue fragments—sheet versus syncytium, regular
or irregular follicular patterns, and cytomorphology. Most often, a diagnosis can be
made after this second step.

The last step involves examination under a 40× objective (high power) for assessment
of the nuclear features of the follicular cells as compared to intact red blood cells in
terms of size, shape, chromatin pattern, presence or absence of nucleoli, grooves, and
nuclear inclusions. The intact red blood cells are the best indicators of the size. This
helpful feature is lost if the smear is wet-fixed in ethyl alcohol or other liquid medium,
which results in lysis of red blood cells. The nuclear size is an important parameter in
interpretation of thyroid aspirates. Assess the cell borders and the amount and quality
of the cytoplasm.

Once the smear is evaluated and the diagnostic interpretation is made, the findings
are reported as per the reporting scheme presented in Table 4.4.

REFERENCES
1.Frost JK. Concepts Basic to General Cytopathology. Baltimore: Johns Hopkins;
1972.

2.Patten SF Jr. Diagnostic cytology of the uterine cervix. In: Weid GC, ed.
Monographs in Clinical Cytology, vol. 3. New York: S. Karger; 1969:5.

3.Kini SR. Atlas and Text of Differential Diagnosis in Exfoilative and Aspiration
Cytopathology. Philadelphia: Lippincott Williams & Wilkins; 1999.

4.Vickery AL Jr. Thyroid papillary carcinoma: pathological and philosophical

controversies. Am J Surg Pathol. 1983;7:797–807.
Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 6 - Nodular Goiter

6
Nodular Goiter

Nodular goiter—also referred to as "adenomatous" goiter, colloid goiter, nontoxic

nodular goiter, and multinodular goiter— is an enlargement of the thyroid caused by
intermittent or persistent hyperplasia in response to thyroid-stimulating hormone
(TSH) or thyroid-growth immunoglobulin. The compensatory rise in serum may be
caused by hypothyroxinemia related to iodine deficiency, environmental goitrogens, or
unknown factors. Nodular goiter is the most common benign condition mistaken for a
thyroid tumor.1

Initially, as the thyroid gland undergoes cycles of hyperplasia and

involution/hyperinvolution, the gland is diffusely enlarged and all of the lobules are
involved. As the cycles continue, they eventually lead to nodule formations. Because
the lobules do not respond in a uniform manner, the nodules vary in size. Some
nodules are appreciated only microscopically, while others are large enough to cause
clinical enlargement and may even cause pressure symptoms. One or more nodules
may become dominant. These nodules often undergo degeneration, resulting in
hemorrhage, necrosis, and granulation tissue leading to fibrosis and calcification. Cyst
formation is very frequent.

The nodules are usually cold on radionuclide imaging and cannot be differentiated
from a neoplasm.

RADIOLOGIC FINDINGS
The ultrasound findings of nodular goiter are variable.2, 3 Small, less than 1 cm
solitary or multiple fluid-filled nodules are often caused by thyroid nodular
hyperplasia. The cystic spaces represent either colloid-filled cysts or fluid from
degeneration and necrosis. A comet tail artifact may be visualized in colloid cysts, a
finding reported to have a sensitivity and specificity of 100% in predicting the benign
nature.4 Multiple cystic spaces separated by septations in a honeycomb pattern
strongly indicate benign non-neoplastic nodules.

GROSS AND HISTOLOGIC FEATURES

The thyroid with nodular goiter is variably enlarged. It may be massive, bulky with
asymmetric lobes and multiple nodules (Fig. 6.1). Nodules vary greatly in size, and
some may be fluid-filled cysts. The cut surface demonstrates a variegated pattern.
The nodules may be uniform, solid and fleshy, hemorrhagic, or cystic. Fibrotic areas
and calcification are often noted (Fig. 6.2). These changes are more frequent with the
larger nodules.
 Figure 6.1. Multinodular goiter. Both lobes of the thyroid show asymmetric
enlargement due to multiple nodules, some with cystic changes and hemorrhage.

Figure 6.2. Another example of multinodular goiter with asymmetric enlargement

of the lobes due to multiple nodules. The largest nodule, involving the left lobe,
is completely cystic.

The microscopic pathology varies widely (Figs. 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 6.10,
6.11, 6.12, 6.13, 6.14, 6.15 and 6.16), dominated by non-encapsulated, small to large
distinct nodules (Fig. 6.3) exhibiting changes ranging from hyperplasia, to involution,
to hyperinvolution. The hyperplastic nodules consist of closely packed small to
medium-sized follicles without colloid and are lined by tall columnar epithelium,
sometimes with papillary changes (Figs. 6.4 and 6.5). The follicular cell nuclei have a
vesicular chromatin pattern and sometimes appear ground-glass–like, similar to
those seen in papillary carcinoma (Fig. 6.6). Involution is characterized by variably
distended follicles with accumulation of colloid and low cuboidal epithelium (Fig. 6.7).
With hyperinvolution, the follicles are overdistended with colloid, resulting in
flattening of the lining epithelium containing pyknotic nuclei (Fig. 6.8). Hürthle cell
metaplasia of follicular cells is very common in nodular goiter. It can be focal or
generalized and may form large nodules (Figs. 6.9 and 6.10).

Figure 6.3. Histologic section of nodular goiter showing a distinct non-

encapsulated nodule.
Figure 6.4. Histologic sections demonstrating hyperplastic phase of nodular
goiter. The follicles are crowded and lined by cuboidal epithelium. Very few
follicles contain colloid. Aspirates from such areas may be misinterpreted as
follicular neoplasms.

Figure 6.5. Hyperplastic nodular goiter showing papillary hyperplasia. Aspirates

from such nodules may be misinterpreted as papillary carcinoma.
Figure 6.6. Nodular goiter. Pale nuclei with vesicular chromatin pattern bearing
some resemblance to the nuclei of papillary carcinoma.
Figure 6.7. Involution. Some follicles are distended with colloid. The lining
epithelium is low cuboidal.
Figure 6.8. Hyperinvolution. The thyroid follicles are over-distended with colloid
and lined by flattened epithelium.
Figure 6.9. Nodular goiter with Hürthle cell metaplasia. The follicles are lined
by large cells with abundant granular, eosinophilic cytoplasm. Note considerable
stromal fibrosis.
 Figure 6.10. Hürthle cell metaplasia. The follicles are lined by large cells with
abundant granular, eosinophilic cytoplasm.

Retrogressive changes in nodular goiter occur frequently and are characterized by

recent and/or old hemorrhage, degeneration of the follicular cells, cyst formation,
and accumulation of histiocytes with or without hemosiderin (Fig. 6.11). Nuclear
atypia may be pronounced (Fig. 6.12). Squamous metaplasia is occasionally present.
With cystic changes, the follicles get dilated; the follicular lining epithelium forms
papillary-like projections that are directed towards the center within the cystic cavity
(Fig. 6.13). With recent hemorrhage, granulation tissue may be present (Fig. 6.14).
Fibrosis eventually develops. It can be focal or extensive with broad bands of
collagenized tissue. Calcification may also be present. Occasionally, psammoma bodies
are identified in nodular goiters.
Figure 6.11. A. Nodular goiter. Histologic section showing degeneration with
dilated follicles, cyst formation, and an area of old hemorrhage. B. Higher
magnification showing follicular cells and histiocytes containing hemosiderin.

Figure 6.12. Histologic section of nodular goiter showing extreme nuclear

pleomorphism with pyknosis.
Figure 6.13. A. Nodular goiter with cystic change exhibiting a pseudopapillary
change. Note the central cystic cavity with papillary- like projections of the lining
epithelium, directed towards the center of the cavity. B. Another field showing
multiple follicles with papillary projections of the epithelium.
 Figure 6.14. Histologic section of nodular goiter showing granulation tissue with
proliferating fibroblasts and capillaries with plump endothelial lining cells. An
aspirate from such an area will yield spindle-shaped stromal cells with atypical
nuclei, causing diagnostic difficulties.

CYTOPATHOLOGIC FEATURES
The cytopathologic features of nodular goiter span a very wide spectrum (Figs. 6.15,
6.16, 6.17, 6.18, 6.19, 6.20, 6.21, 6.22, 6.23, 6.24, 6.25, 6.26, 6.27, 6.28, 6.29, 6.30,
6.31, 6.32, 6.33, 6.34, 6.35, 6.36, 6.37, 6.38, 6.39, 6.40, 6.41, 6.42, 6.43, 6.44, 6.45,
6.46, 6.47, 6.48, 6.49, 6.50, 6.51, 6.52, 6.53, 6.54, 6.55, 6.56 to 6.62, Table 6.1),
reflecting the various stages of the disease process: hyperplasia, involution/
hyperinvolution, and several of the secondary changes such as
 P.37
P.38
Hürthle cell metaplasia and recent or old hemorrhage and its
sequelae—degeneration, necrosis, granulation tissue, fibrosis, and calcification.
Fine-needle aspirates generally show an admixture of colloid and benign follicular cells
in varying proportions (Fig. 6.15). The colloid is abundant in hyperinvoluted goiters
(Fig. 6.16) while scant or absent from the hyperplastic areas (Fig. 6.17). These two
patterns represent two ends of the spectrum of cytopathologic features of nodular
goiter, with most cases exhibiting a pattern somewhere in between, with or without
secondary changes.

TABLE 6.1 CYTOPATHOLOGIC FEATURES OF NODULAR

GOITER

Presentation Admixture of colloid and follicular epithelial cells in

varying proportions; cells
isolated, in loosely cohesive groups and in tissue
fragments

Architectural Regular follicles with evenly spaced nuclei,

Patterns of the monolayered sheets with honeycomb arrangement;
Tissue Fragments papillary-like pattern in hyperplastic goiters with
component cells in a honeycomb arrangement

Follicular Cells Small, cuboidal to round with well to poorly defined

cell borders; degenerating or reactive/
regenerating follicular cells with enlargement and
spindle shapes

Nucleus Round to oval, 7–9 µm in diameter; smooth

nuclear membrane; uniformly distributed finely
granular to compact chromatin; pyknotic nuclei in
 hyperinvoluted goiters; nucleoli inconsistent
but may be present in hyperplastic goiters

Cytoplasm Scant to moderate, pale

Hürthle Cell Frequent, isolated and sheets of Hürthle cells with

Metaplasia well-defined cell borders, size variable, larger
than the normal follicular cells; moderate to
abundant granular cytoplasm; transition forms from
normal follicular cells to Hürthle cells within a
tissue fragment; nucleus similar to or larger than
the normal follicular cells; lack prominent
macronucleoli

Colloid Pale, thin film to thick, inspissated blobs with or

without cracks (fissures); cyanophilic to eosinophilic
in Papanicolaou-stained preparations, lavender to
purple with Romanowsky stain

Psammoma Bodies Rarely present; naked or incorporated in a tissue

fragment of benign follicular cells

Secondary Changes Histiocytes with or without hemosiderin;

multinucleated foreign body-type giant cells; stromal
cells, mostly in tissue fragments but isolated
spindle cells may be present; calcific debris;
frequent squamous metaplasia
Figure 6.15. FNA of a nodular goiter with an admixture of follicular cells and
colloid.
Figure 6.16. FNA of a nodular goiter with abundant colloid and sparse follicular
cells, a pattern characteristic of involution or hyperinvolution.
 Figure 6.17. FNA of a nodular goiter. Note the hypercellularity of the aspirate
and absence of colloid in the background.

The appearance of the colloid in Papanicolaou-stained preparations varies (Figs. 6.18,

6.19, 6.20 and 6.21). In its pure form, the colloid appears as a thin film of
homogeneous material staining pink or greenish-blue. It stains orange when mixed with
blood. After the colloid has been smeared on the glass slide, it retracts from the slide.
The inspissated colloid stains dense, appearing as droplets suggestive of follicular
luminal casts. Colloid also shows a tendency to crack in a linear fashion (Fig. 6.18),
occasionally simulating a psammoma body. Large lakes of colloid with multiple fissures
tend to give a mosaic pattern.5 Colloid stains light purple to blue-violet in air-dried
Romanowsky-stained preparations (Fig. 6.22). The presence of colloid in fine-needle
aspirates of thyroid nodules is taken
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P.40
 P.41
by some as presumptive evidence that the thyroid nodule is benign and not a true
neoplasm.6, 7

Figure 6.18. FNA of a nodular goiter. Note abundant colloid with linear cracks
forming a mosaic pattern.
Figure 6.19. FNA, nodular goiter. A few small groups of follicular cells with
pyknotic nuclei, floating in pools of colloid.
Figure 6.20. FNA nodular goiter. The abundant colloid is stained cyanophilic
showing a single follicle bordered by regularly spaced follicular cells with small
uniform nuclei. Note the chromatin is compact.
Figure 6.21. FNA, nodular goiter. The colloid is stained eosinophilic. The
follicular cell nuclei appear naked and resemble lymphocytes.
 Figure 6.22. FNA nodular goiter. The colloid stains purple to violet in
preparations stained by the Romanowsky method. (Courtesy of Dr. Mariza de
Peralta-Venturina, William Beaumont Hospital, Royal Oak, Michigan.)

The benign follicular cells in aspirates from nodular goiters are seen isolated, in
aggregates, or in tissue fragments, with and without a follicular pattern (Figs. 6.23,
6.24, 6.25, 6.26, 6.27, 6.28, 6.29, 6.30, 6.31, 6.32, 6.33 and 6.34). The follicles are
generally small, showing a central lumen bordered by cuboidal cells with regularly
spaced, small, uniform nuclei (Fig. 6.23). Colloid may be present within their lumina.
Occasionally, a follicle is seen in its entirety (Fig. 6.24) in a three-dimensional form.
The entire follicles exhibit a honeycomb arrangement in different planes of focus. The
tissue fragments without a follicular pattern appear as monolayered sheets, with a
resemblance to a honeycomb (see Chapter 4). The component cells have well-defined
cytoplasmic borders and contain regularly spaced, uniform nuclei that maintain their
polarity (Figs. 6.25, 6.26, 6.27, 6.28, 6.29 and 6.30). There is small amount of
P.42
P.43
clear to pale cytoplasm. The follicular cell nuclei are round, with diameters ranging
from 7 to 9 µm.8 The nuclear chromatin is finely granular and uniformly distributed
or compact. Nucleoli are generally not seen, but may be present in hyperplastic
follicular cells or with reparative/regenerative changes. Small, pyknotic, dense-
staining nuclei are characteristic of hyperinvoluted goiters, where the follicular cells
are seen singly or in small groups, floating in large lakes of colloid (Figs. 6.19, 6.20 and
6.21). Their scanty, pale cytoplasm fades away against the background of the colloid,
and their pyknotic nuclei appear bare and are difficult to differentiate from
lymphocytes. The aspirates of hyperplastic goiters show abundant cellular material
(Figs. 6.31, 6.32, 6.33 and 6.34) consisting of tissue fragments of benign follicular cells
with and without a follicular pattern. The cellularity can be overwhelming (Fig. 6.32).
The colloid is usually scant or absent, and the aspirates are often interpreted as
follicular neoplasms. The papillary hyperplasia yields papillary-like tissue fragments of
follicular epithelium with a branching pattern and smooth external contours (Figs.
6.32, 6.33 and 6.34). However, their component cells show well-defined borders in a
honeycomb pattern, a feature that
P.44
P.45
greatly helps distinguish hyperplasia from papillary carcinoma. They also lack the
nuclear features of papillary carcinoma.
Figure 6.23. Nodular goiter. A. Cellular aspirate with minimal colloid in the
background. The follicular cells are isolated or form small, regular follicles. The
nuclei are small; low power. B. Higher magnification showing the follicular cells
with uniform, small nuclei containing compact chromatin. Compare the nuclear
size with the red blood cells in the background.
Figure 6.24. Nodular goiter. Two follicles seen in their entirety and presenting a
three-dimensional pattern. Note uniform, small nuclei with compact chromatin
and well-defined cell borders. The honeycomb pattern is seen indifferent planes
of focus.
Figure 6.25. FNA of nodular goiter. A monolayered sheet of follicular epithelium
with well-defined cell borders and centrally located, uniform, small nuclei. The
honeycomb pattern is well demonstrated.
Figure 6.26. FNA, nodular goiter. A different case to illustrate the characteristic
monolayered sheet of follicular epithelium with well-defined cell borders and
centrally located, uniform small nuclei. The honeycomb pattern is well
demonstrated. Compare the nuclear size to the red cells in the background.
Figure 6.27. FNA, nodular goiter. Abundant cellular material and lack of colloid
in the background may suggest the diagnosis of follicular neoplasm. However, the
monolayered tissue fragments with a honeycomb pattern, and small, uniform
nuclei suggest the diagnosis of nodular goiter.
Figure 6.28. FNA, nodular goiter. Another example of a cellular aspirate
containing monolayered tissue fragments of follicular epithelium with a
honeycomb pattern, and small, uniform nuclei that suggest the diagnosis of
nodular goiter. Note dense-staining colloid.
Figure 6.29. Nodular goiter. A. Large, monolayered tissue fragment of follicular
epithelium. The honeycomb pattern is evident even at low magnification. B.
Higher magnification showing small, uniform nuclei with compact chromatin.
Figure 6.30. FNA, nodular goiter. A. Monolayered tissue fragment of follicular
cells with honeycomb arrangement. The nuclei are uniform and regularly spaced.
Also note a follicular pattern with colloid within the lumens. B. A different field
from the same case. Note a regular follicle bordered by uniform small nuclei.
Diff-Quik stain. (Courtesy of Dr. Mariza de Peralta-Venturina, William Beaumont
Hospital, Royal Oak, Michigan.)
Figure 6.31. FNA, nodular goiter. A. This hypercellular aspirate consisting of
several tissue fragments of follicular cells in the background of abundant colloid
may prompt a diagnosis of follicular neoplasm, low power. B. Higher
magnification showing the tissue fragments with a honeycomb architecture with
regularly spaced uniform nuclei. The chromatin is granular to compact. C. This
field shows several follicles, seen en face presenting a honeycomb pattern with
small uniform nuclei containing compact chromatin. D. Another field showing
microfollicles consisting of small nuclei with compact chromatin.
Figure 6.32. Hyperplastic goiter. A. This overwhelmingly cellular aspirate consists
of a large number of papillary-like and monolayered tissue fragments. Under low
magnification, this may be mistaken for a papillary carcinoma. B. Higher
magnification showing uniform, small nuclei and a honeycomb pattern, ruling out
neoplasia.

Figure 6.33. Hyperplastic goiter. A. Low power depicting a large tissue fragment
of follicular epithelium. B. Higher magnification shows several follicles with a
honeycomb arrangement and uniform small nuclei with compact chromatin.
 Figure 6.34. Hyperplastic goiter. A, B. Cellular aspirate with large tissue
fragments of follicular cells with papillary-like architecture. The nuclei appear
crowded and are slightly enlarged. A papillary carcinoma was suspected. C. A
core needle biopsy showing hyperplastic goiter with papillary change.

Hürthle cell metaplasia of follicular cells is a common occurrence in nodular goiters.

The metaplastic Hürthle cells are usually present in tissue fragments and less often
as discrete cells or in groups (Figs. 6.35, 6.36, 6.37, 6.38, 6.39 and 6.40). They vary in
size, ranging from medium-sized to large; are cuboidal, oval to polygonal; and contain
abundant granular or sometimes dense cytoplasm and slightly eccentric nuclei. Their
cell borders are usually well defined. The nuclei of the metaplastic Hürthle cells
tend to be pleomorphic in size with frequent giant forms. Their chromatin pattern is
variable from granular to pyknotic, structureless, and deep staining. The presence of
nucleoli is not common. Transition forms from regular follicular cells to
 P.46
P.47
Hürthle cells are often noted, serving as a feature in favor of metaplasia rather than
a neoplasm (Figs. 6.35, 6.36, 6.37, 6.38 and 6.39). A cellular aspirate from a nodular
goiter with a predominance of metaplastic Hürthle cells represents a potential
diagnostic pitfall and may be misinterpreted as a Hürthle cell neoplasm. The
differentiating features are discussed in Chapter 8.

Figure 6.35. Hürthle cell metaplasia. Benign follicular cells mixed with
metaplastic Hürthle cells (arrow) containing abundant granular cytoplasm and
pyknotic, variably sized nuclei.
Figure 6.36. Hürthle cell metaplasia, nodular goiter. The Hürthle cells are
large and pleomorphic with abundant cytoplasm. Their nuclei are likewise
pleomorphic with pyknotic nuclei.
Figure 6.37. This aspirate demonstrates two tissue fragments, one of benign
follicular cells and the other consisting of larger cells, pleomorphic in size, with
abundant granular cytoplasm, representing Hürthle cell metaplasia. Their nuclei
are slightly pleomorphic and occasionally pyknotic.
Figure 6.38. This large tissue fragment of follicular cells consists of benign
follicular cells with transition forms to metaplastic Hürthle cells.
Figure 6.39. This large tissue fragment of follicular cells consists of benign
follicular cells with transition forms to metaplastic Hürthle cells. Note abundant
eosinophilic granular cytoplasm.
 Figure 6.40. A group of Hürthle cells from a case of nodular goiter. Diff-Quik
stain. (Courtesy of Dr. Mariza de Peralta-Venturina, William Beaumont Hospital,
Royal Oak, Michigan.)

Hemorrhage and degeneration in a nodular goiter are common events initiating the
regressive changes in the follicular cells. These events eventually lead to cyst
formations, fibrosis, and calcifications. The aspiration biopsy may yield variable
amounts of clear to bloody fluid of varying consistency. The cytologic specimens
demonstrate degenerating follicular cells, which appear enlarged, with abundant
granular, foamy, or vacuolated cytoplasm, and sometimes with phagocytized
hemosiderin pigment (Fig. 6.41).9 Their nuclei remain normal-sized to slightly
enlarged, and may contain prominent nucleoli. These cells with prominent nucleoli
often cause concern8, 9, 10 and may be misinterpreted as neoplastic (Figs. 6.42, 6.43,
6.44 and 6.45). The degenerating follicular cells, because of expanded granular
cytoplasm containing hemosiderin, strongly resemble macrophages. The only
differentiating feature is that the follicular cells occur in tissue fragments, unlike
macrophages, which occur singly. The aspirates of nodular goiter that has undergone
degenerative changes may contain isolated groups or tissue fragments of cells with
varying degrees of nuclear atypia and represent diagnostic pitfalls (Figs. 6.46, 6.47,
6.48 and 6.49). Misinterpretation may lead to unnecessary surgery. The follicular cells
with regressive changes may assume spindle shape or undergo squamous metaplasia
(Figs. 6.48 and 6.49).

Figure 6.41. Degenerating follicular cells from nodular goiter. Note that the cells
are in a monolayered tissue fragment, large with abundant granular cytoplasm
and strongly resemble macrophages. Some even contain hemosiderin pigment.
Figure 6.42. Degenerating follicular cells from nodular goiter. Note that the
follicular cells are large, loosely cohesive, and in monolayered tissue fragments.
Their cytoplasm is moderate to abundant, and foamy to granular. The nuclei are
moderately enlarged with nucleoli; the N/C ratios are low.
Figure 6.43. Degenerating follicular cells from nodular goiter. The follicular cells
are mostly discrete, enlarged with abundant granular cytoplasm. The nuclei
contain prominent nucleoli. Note a multinucleated giant cell.
Figure 6.44. These follicular cells from nodular goiter contain enlarged nuclei
with prominent nucleoli and probably represent a reactive/regenerative
response. Such cells are usually few in number in the background features of
nodular goiter.
Figure 6.45. Degenerating follicular cells from nodular goiter. Note that the cells
are in a monolayered tissue fragment, large, with abundant granular, vacuolated
cytoplasm, and that they strongly resemble macrophages. Diff-Quik stain.
(Courtesy of Dr. Mariza de Peralta-Venturina, William Beaumont Hospital, Royal
Oak, Michigan.)
Figure 6.46. A large population of discrete follicular cells with foamy, vacuolated
cytoplasm. The nuclei have a uniform chromatin pattern and contain nucleoli.
These cells may represent either degenerating follicular cells or histiocytes. Note
the tissue fragment of follicular epithelium with pyknotic nuclei.
Figure 6.47. A, B. FNA of a thyroid nodule showing tissue fragments of follicular
cells with enlarged, pleomorphic nuclei, containing coarsely granular chromatin.
Although the background features were suggestive of nodular goiter, a suspicious
diagnosis was rendered. C. A core needle biopsy revealed a cystic nodular goiter
with papillary change (low power). D. Higher magnification highlighting the
atypia of the lining follicular cells.
Figure 6.48. Aggregate of round to spindle-shaped cells from an aspirate of a
nodular goiter. The nuclei are enlarged with coarsely granular chromatin. The
rounded cells with appreciable cytoplasm suggest the origin of these cells to be
follicular cells. These cells, when occurring in the background of nodular goiter,
have no significance.
 Figure 6.49. A. FNA of a nodular goiter showing fragments of spindle cells, low
power. B. Higher magnification showing varying sized follicular cells from normal
to enlarged ones with appreciable cytoplasm and slightly enlarged nuclei. Some
follicular cells appear spindle shaped. C. Different field showing enlarged
follicular cells with spindle shape and cytoplasmic processes. Note benign
follicular cells in the background. These were the only abnormal-appearing cells
in the background features of nodular goiter and are considered as a
reactive/reparative process.

With cystic change, the fine-needle biopsy will often yield fluid contents of variable
consistency. Their cytologic preparations show large numbers of histiocytes or
macrophages. Histiocytic aggregates occasionally may be mistaken for cells
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of papillary carcinoma.11 The cytoplasm of the macrophages contains large, coarse,
greenish-brown granules of hemosiderin pigment, indicating old hemorrhage in the
nodule (Figs. 6.50, 6.51 and 6.52). The cyst contents when examined fresh often show
cholesterol and oxalate crystals. Accompanying the histiocytes, are multinucleated
histiocytic foreign body-type giant cells (Fig. 6.53). The presence of such cells has no
practical significance. The same holds true for calcific debris (Fig. 6.54).

Figure 6.50. FNA of a nodular goiter. The presence of macrophages with and
without hemosiderin is a frequent finding and indicates old hemorrhage. Note
benign follicular cells in the background.
Figure 6.51. FNA of a nodular goiter. The benign follicular cells and macrophages
containing hemosiderin pigment.
Figure 6.52. FNA of a nodular goiter. A. This aspirate consisting of predominantly
histiocytes with and without hemosiderin probably represents a cystic nodular
goiter (low power). B. Higher magnification shows the histiocytes to be discrete.
No follicular cells are present. Lack of follicular cells will warrant an
unsatisfactory diagnosis.
Figure 6.53. FNA nodular goiter. Multinucleated foreign body-type giant cells, a
very common finding in the presence of degeneration and cystic change.
 Figure 6.54. FNA nodular goiter. Calcific debris.

Because of the old hemorrhage, granulation tissue, and fibrosis, the aspirates of
nodular goiter may also show stromal cells, either isolated or in tissue fragments.
Isolated stromal cells have large, elongated to spindle-shaped nuclei with nucleoli
(Figs. 6.55). Their uniform size and bland chromatin suggest their benign nature.
 Figure 6.55. FNA of a nodular goiter. A group of large spindle cells of stromal
origin. These are usually an isolated finding and are of no significance. Note low
N/C ratios and bland nuclear chromatin.

Rarely, aspirates of nodular goiter may show psammoma bodies,12 which may be
either naked or incorporated in tissue fragments of benign follicular cells (Fig. 6.56).
Their presence is a potential diagnostic pitfall. The differentiation between
psammoma bodies seen in nodular goiter and those seen in papillary carcinomas is
described in Table 9.24.

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 Figure 6.56. FNA nodular goiter. This psammoma body is incorporated in a tissue
fragment of benign follicular cells arranged in a honeycomb pattern, containing
small uniform nuclei with compact chromatin.

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DIAGNOSTIC ACCURACY AND POTENTIAL DIAGNOSTIC

ERRORS
The usual cytologic pattern of nodular goiter (Table 6.1) thus consists of benign
follicular cells and colloid in variable proportions. Hürthle cell metaplasia and
histiocytes with and/or without hemosiderin, multinucleated giant cells, and calcific
debris suggest secondary changes. All of these features may not be present in aspirates
of every nodular goiter,13 and it is not necessary to fulfill all the criteria listed in
Table 6.1 to make a cytologic diagnosis of nodular goiter. The presence of colloid
and/or histiocytes should not be a requirement for the diagnosis of nodular goiter.
Colloid reflects the functional activity of the follicular cells and does not indicate
whether the follicular cells are neoplastic or nonneoplastic. Likewise, histiocytes
represent a degenerative phenomenon. At the same time, hypercellularity is not a
feature that is diagnostic of neoplasia. The aspirates of hyperplastic goiters can yield
markedly cellular specimens. One needs to focus on the architecture of the tissue
fragments and nuclear morphology—size, shape, chromatin pattern, and the
presence or absence of nucleoli.

Variations in the usual pattern of nodular goiter, as described above, create settings
for potential errors that may lead to false-positive results.13, 14, 15, 16, 17, 18, 19,
20 Some of the listed criteria of nodular goiter, if present in excess and to the
exclusion of other features, may lead to interpretive traps, and a nodular goiter may
be mistaken for a neoplasm.13, 14, 15, 16, 17, 18, 19, 20, 21 Such cases with unusual
presentations of nodular goiter are infrequent, but they constitute important
diagnostic pitfalls and may lead to unnecessary surgery. In fact, cellular features from
nodular goiters can be misinterpreted as almost every type of thyroid neoplasm
including metastatic tumors, as listed in Table 6.2. The differentiation of nodular
goiter with atypical cytologic features from various neoplastic entities is best
understood when one is familiar with the cytopathologic features of thyroid
neoplasms. For this reason, and also not to repeat the contents, this is discussed in
great detail in subsequent chapters.

TABLE 6.2 DIFFERENTIAL DIAGNOSES OF NODULAR

GOITER

Diagnostic Entity Clues for

Cytopathologic Pattern Mistaken for Differentiation

Hypercellular aspirate Follicular neoplasm Honeycomb

with a large number (adenoma/carcinoma) arrangement,
of tissue fragments of regular follicles,
follicular cells with small
 or without a follicular evenly spaced
pattern; background nuclei, finely
clean with scant or granular,
absent colloid uniformly
dispersed
chromatin;
nucleoli
inconsistent;
folded
large tissue
fragments may
mimic syncytial
pattern

Hypercellular aspirate Papillary carcinoma Lack of syncytial

with several tissue arrangement and
fragments, absence of
either monolayered or minimal
and/or papillary-like criteriaa

Follicular cell nuclei Papillary carcinoma Lack of syncytial

with one or more but arrangement and
not all absence
of the following of minimal
features: enlarged, pale criteriaa
chromatin,
micronucleoli, nuclear
grooves,
intranuclear inclusions

Occasional psammoma Papillary carcinoma Lack of minimal

body, single or multiple; criteriaa in cells
either naked or forming tissue
incorporated in tissue fragments
fragments incorporating the
of follicular cells; psammoma body;
inspissated, dense- naked
staining psammoma bodies
colloid with cracks or are not diagnostic
fissures simulating a
psammoma body

A large Hürthle cell Hürthle cell neoplasm Hürthle cells in

population sheets with
transition forms;
pyknotic nuclei
with
pleomorphism;
lack
prominent
cherry-red
macronucleoli and
monomorphic
patterns of
Hürthle cell
neoplasm;
feature of
nodular goiter in
the background

Spindle-shaped cells Anaplastic carcinoma Lack of extreme

either stromal nuclear
or epithelial origin pleomorphism and
malignant
criteria; clinical
correlation is very
helpful
Spindle-shaped cells Medullary carcinoma Immunostain for
either stromal calcitonin is
or epithelial origin negative; spindle
cells
in medullary
carcinoma have
eccentric nucleoli
with coarser
chromatin;
nucleoli
inconsistent

Degenerating follicular Metastatic carcinoma Lack of obvious

cells containing malignant criteria;
pleomorphic features of
nuclei with nodular goiter in
micro/macronucleoli, the background;
cytoplasmic no history
vacuoles; in the of primary
background features of cancer
nodular
goiter; histiocytic
aggregates

Aggregates of histiocytes Papillary carcinoma Lack of dense

with foamy cytoplasm cytoplasm with
or degenerating well-defined cell
follicular cells with borders; minimal
bubbly, finely criteria absenta
vacuolated cytoplasm

aMinimal criteria for cytologic diagnosis of papillary thyroid carcinoma:

 syncytial arrangement with enlarged nuclei, dusty; powdery chromatin;
multiple micro/macronucleoli; nuclear grooves; pseudoinclusions (see Table
9.19).

The problem of atypical cells in nodular goiter is discussed in the present chapter and
in Chapters 9, 17, and 18. There are several reasons for this. The atypia are discussed
in a different context in each of these chapters. This has also provided an opportunity
for the author to present many examples of this difficult but very common problem in
thyroid cytopathology.

The important facts to remember are that the presence of colloid is not an absolute
requirement for the diagnosis of nodular goiter, and the absence of colloid is not an
absolute criterion for a neoplasm.

REFERENCES
1.Meissner WA, Warren S. Tumors of the thyroid gland. Fascicle four, second
series. Atlas of Tumor Pathology. Washington, DC: Armed Forces Institute of
Pathology; 1969.

2.Reading CC, Charboneau JW, Hay ID, et al. Sonography of thyroid nodules: A
"classic pattern" diagnostic approach. Ultrasound Q. 2005;2:1–19.

3.Khati N, Adamson T, Johnson KS, et al. Ultrasound of the thyroid and

parathyroid glands. Ultrasound Q. 2003;19:162–176.

4.Ahuja A, Chick W, King W, et al. Clinical significance of the comet tail artifact in
thyroid ultrasound. J Clin Ultrasound. 1996;24: 124–129.

5.Löwhagen T, Linsk JA. Aspiration biopsy cytology of the thyroid gland. Clinical
Aspiration Cytology. In: Linsk JA, Sixteen F, eds. Philadelphia: Lippincott;
1983:67–69.
6.Frable WJ. Thin Needle Aspiration Biopsy. Philadelphia: Saunders;
1983;152–182.

7.Friedman M, Shimaoka KC, Getaz P. Needle aspiration of 310 thyroid lesions.

Acta Cytol. 1979;23:196–203.

8.Cervino JM, Pasegro P, Grosso OT, et al. La exploration citologic de la glandula

tiroides y sus correlaciones anatomoclinices. Ann Facultad Med.
1962;47:1728–1743.

9.Droese M. Cytologic Aspiration Biopsy of the Thyroid Gland. Stuttgart: F.R.

Schattauer-Verlag; 1980;55–57.

10.Faqin WC, Cibas ES, Renshaw AA. Atypical cells in fine-needle aspiration biopsy
specimens of benign thyroid cysts. Cancer (Cancer Cytopathol). 2005;105:71–79.

11.Nassar A, Gupta PK, LiVolsi VA, et al. Histiocytic aggregates in benign nodular
goiters mimicking cytologic features of papillary thyroid carcinoma (PTC). Diagn
Cytopathol. 2003;29:243–245.

12.Riazmontazer N, Bedayat G. Psammoma bodies in fine needle aspirates from

thyroids containing nontoxic hyperplastic goiters. Acta Cytol. 1991;35:563–566.

13.Harach HR, Zusman SB, Day S. Nodular goiter: A histocytological study with
some emphasis on pitfalls of fine-needle aspiration cytology. Diagn Cytopathol.
1993;8:409–419.

14.Bakhos R, Selvaggi SM, De-Jong S, et al. Fine-needle aspiration of the thyroid:

Rate and causes of cytohistopathologic discordance. Diagn Cytopathol.
2000;23:233–237.

15.Sidawy MK, Del Vecchio DM, Knoll SM. Fine-needle aspiration of thyroid
nodules. Correlation between cytology and histology and evaluation of discrepant
cases. Cancer (Cancer Cytopathol). 1997;81;253–259.

16.Busseniers AE, Oertel YC. "Cellular adenomatoid nodules" of the thyroid:

Review of 219 fine-needle aspirates. Diagn Cytopathol. 1993;9:581–589.

17.Caraway NP, Sneige N, Samaan NA. Diagnostic pitfalls in thyroid fine-needle

aspiration. A review of 394 cases. Diagn Cytopathol. 1993;9:345–350.

18.Fiorella RM, Isky W, Miller L, et al. Multinodular goiter of the thyroid mimicking
malignancy. Diagnostic pitfalls in fine-needle aspiration biopsy. Diagn Cytopathol.
1993;9:351–354.

19.Anderson RJ, Pragasam PJ, Nazar T. Atypical, retrogressive and metaplastic

changes in nodular goiters. Potential pitfalls in aspiration cytology of the thyroid.
Acta Cytol. 1990;34:715–716.

20.Hall TL, Layfield LJ, Philippe A, et al. Sources of diagnostic error in fine needle
aspiration of the thyroid. Cancer. 1989;63:718–725.

21.Hsu C, Boey J. Diagnostic pitfalls in the fine needle aspirates of thyroid

nodules: A study of 555 cases in Chinese patients. Acta Cytol. 1987;31:69.
Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 7 - Follicular Adenoma and Follicular Carcinoma

7
Follicular Adenoma and Follicular Carcinoma

This chapter on the cytopathology of follicular adenoma and follicular carcinoma begins with a
brief commentary, unlike the other chapters (except Chapter 8 on Hürthle cell lesions). This
commentary is deemed necessary by the author because, in general, the role of cytopathology in
the diagnosis of follicular adenomas and follicular carcinomas is considered unclear and
questionable. The reasons for this are many. First of all, the histologic diagnosis of follicular
carcinomas is based strictly on demonstrating the invasive characteristics, which cannot be
assessed from cytologic samples. Hence the cytologic differentiation of follicular adenoma and
carcinoma is considered not possible, and the notion that the differentiation can be done
cytologically is totally unacceptable to surgical and many cytopathologists. The problem,
however, is compounded because of the continuing debate and controversies among surgical
pathologists on what constitutes the true invasion. The interpretation and the final histologic
diagnosis become subjective, leading to a marked interobserver variability and making the
cytohistologic correlation difficult. Also, many hyperplastic goiters are interpreted histologically
as follicular adenomas, because the criteria for differentiating them from follicular neoplasms
are not consistent. To avoid disparities, the Scandinavian cytopathologists1 , 2 recommended
that all thyroid aspirates containing abundant follicular cells be grouped into one category called
"follicular neoplasms," indicating that the cytologic differentiation between benign and
malignant follicular neoplasms is not possible. This approach suited most of the
pathologists/cytopathologists as well as the clinicians, including endocrinologists and surgeons
(with the exception of few), here in the United States. Pathologists in general do not like to
overdiagnose malignancy for the fear of over-treatment. At the same time, there is a fear of
missing a cancer. Consequently, the diagnostic category of "indeterminate/ suspicious," lumping
together of the aspirates that contained an abundance of follicular or Hürthle cells, became a
popular one, with recommendation for surgical excision.3 , 4 Interestingly enough, there have
been only a few studies reported in the literature on any attempt at the cytologic
differentiation of follicular adenomas and follicular carcinomas.5 , 6 , 7 , 8 , 9 Most of the
relevant literature emphasizes only an apparent limitation of cytology in discriminating follicular
adenomas from carcinomas. It is not clear how this conclusion was reached without documented
studies on cytologic analysis and cytohistologic correlations. The only study9 that attempted to
cytologically differentiate adenomas from carcinomas, and which concluded that the separation
of follicular neoplasms into adenoma and carcinoma was not possible, involved only a few cases
to make a judgment.

The author is at variance with the general sentiment that follicular lesions cannot be separated
cytologically. Unlike many pathologists/cytopathologists, the author has attempted to
differentiate hyperplastic goiters, follicular adenomas, and follicular carcinomas, initially at the
request of endocrinologists who were concerned with unnecessary surgeries for benign diseases.
With adequate specimen and proper cytopreparation, the majority of the hyperplastic goiters
can be differentiated from follicular adenomas. Likewise, most follicular adenomas can be
identified from cytologic samples. Poorly differentiated follicular carcinomas are readily
recognized. This leaves a small proportion of cellular follicular adenomas and well-differentiated
follicular carcinomas that are difficult to differentiate cytologically. These are interpreted as
either cellular adenomas or suspicious for follicular carcinomas. The criteria for differentiating
various follicular neoplasms were described in earlier publications,6 are time-tested, and are
still applicable. By attempting to cytologically differentiate hyperplastic goiters, follicular
adenomas and carcinomas, we are providing probabilities of malignancy that have greatly
influenced patient management. This chapter will describe the cytopathologic features of
follicular adenomas and carcinomas, their diagnostic accuracy, and differential diagnostic
features.

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FOLLICULAR ADENOMA
Follicular adenomas are encapsulated, follicular, cell-derived benign neoplasms of the thyroid
demonstrating a follicular growth pattern.10 , 11 , 12 , 13 They occur more commonly in women
over a wide age range but are frequent in the 5th to 6th decades. After nodular goiter, follicular
adenomas are the most common cause of nonfunctioning thyroid nodules. The true incidence of
follicular adenomas may not be known for two reasons: (i) many hyperplastic nodules may be
interpreted as adenomas10 and (ii) oncocytic or Hürthle cell tumors are often considered as
morphologic variants of follicular neoplasms.10 Adenomas are common in iodine-deficient
areas.13 Clinically they present as a painless neck mass of varying duration. Smaller lesions are
often detected as incidental findings. Adenomas are most often solitary, but multiple adenomas
in the same lobe or both lobes are not uncommon. Frequently of great size, they may undergo
degenerative changes, hemorrhage, necrosis, and infarction. Acute hemorrhage is usually
associated with painful, rapid enlargement. In larger adenomas, the central areas tend to be
edematous and with scarring.

Radiologic Findings
Thyroid imaging with radionuclide shows a hypofunctioning area or a "cold nodule." On
ultrasound, follicular adenomas appear as solitary hypoechoec areas.

Gross and Microscopic Features

Grossly, follicular adenomas are sharply circumscribed, discrete, solitary, expansile lesions (Figs.
7.1 and 7.2 ). Follicular adenomas vary greatly in size. Areas of degeneration and hemorrhage
are often present especially in larger lesions. Cystic change is reported in roughly 30% of
follicular adenomas.14 Solid neoplasms show a fleshy, bulging cut surface, while the colloid-rich
adenomas show minute cysts filled with glistening amber-colored colloid.
Figure 7.1. Gross photograph of a follicular adenoma involving the left thyroid lobe.
Figure 7.2. Gross photograph of a thyroid with follicular adenomas involving both lobes. Note
hemorrhage within the left lobe adenoma.

Microscopically, follicular adenoma is encapsulated (Fig. 7.3 A and B), a feature that
differentiates it from a nonneoplastic nodule of an adenomatous or nodular goiter (Fig. 7.3 C).
The thyroid parenchyma adjacent to the capsule is compressed and presents a different
morphology than the adenoma itself. The capsule is of varying thickness. Follicular adenomas
present an array of morphologic patterns based on their architecture (growth pattern), cell
morphology or types, and functional differentiation (amount of colloid), the common
denominator being total encapsulation and benign behavior.10 , 11 , 12 Recognition of any
morphologic variant carries no clinical significance. However, in cytopathology practice, it is
extremely useful in cytohistologic correlations, as well as in understanding the overlapping
cytopathologic patterns. The questions of why some nodular goiters cannot be differentiated
from follicular adenomas, and why some follicular adenomas have cytopathologic as well as
histopathologic patterns similar to those of follicular carcinomas, can only be appreciated if one
is familiar with the spectrum of morphologic patterns described below.
Figure 7.3. A. Low power showing complete encapsulation. B. The follicular adenoma is
encapsulated and shows large clear areas representing degeneration, low power. Aspirates from
such areas may result in poor cellularity. C. A non-encapsulated nodule of nodular goiter, low
power.

Follicular adenomas are classified into conventional types and several morphologic variants, the
former being more common (Table 7.1 ).

Conventional

Macrofollicular (colloid)

Normofollicular (simple)

Microfollicular (fetal)

Trabecular (embryonal)
Oncocytic (Hürthle cell) adenomaa
Hyalinizing trabecular
Adenoma with clear cell change
Adenoma with papillary hyperplasia
Atypical adenoma
Miscellaneous
a Oncocytic or Hürthle cell adenomas are described separately in Chapter 8.

TABLE 7.1 MORPHOLOGIC VARIANTS OF FOLLICULAR

ADENOMAS
The conventional type of follicular adenomas present four basic histomorphologic patterns:
colloid or macrofollicular, simple or normofollicular, fetal or microfollicular, and embryonal or
trabecular (Fig. 7.4 ).11 In a given adenoma, the pattern remains generally uniform, although a
combination of one or two patterns may be encountered, particularly when the lesion is large.
This factor must be taken into account when performing aspiration biopsy of a large nodule so
that several areas can be sampled.
Figure 7.4. Morphologic patterns of conventional follicular adenomas. A. Macrofollicular
adenoma consisting of varying-sized but large follicles distended with colloid. B. Simple or
normofollicular adenoma with normal-sized follicles. C. Microfollicular adenoma with small or
microfollicles. D. Trabecular adenoma consisting of trabeculae formed by follicular cells.

Colloid Adenoma
Colloid adenoma (also referred to as colloid nodule by some) represents the most differentiated
follicular adenoma (macrofollicular adenoma), with overdistended varying-sized but large
follicles containing abundant colloid (Fig. 7.5 A). The lining epithelium is flattened with pyknotic
nuclei. This adenoma virtually replicates the pattern of hyperinvoluted goiter, except for the
encapsulation.
Figure 7.5. Characteristics of macrofollicular adenoma. A. Histologic section, low power, to
demonstrate an encapsulated lesion. The large colloid-filled follicles are evident even at this
magnification. B. FNA consisting of abundant colloid and a large tissue fragment of benign
follicular cells forming a honeycomb sheet with uniform nuclei.

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Cytopathologic Features
Aspirates of colloid or macrofollicular adenoma exhibit abundant colloid and have a sparse
cellular component, with tissue fragments of follicular epithelium forming small follicles or a
honeycomb pattern. Nuclei are small; the chromatin is compact and deep-staining (Table 7.2 ,
Fig. 7.5 B). The presence of abundant colloid and absent or sparse cellular component may
render the aspirate inadequate or nondiagnostic.

Histology
Encapsulated; colloid filled varying-
sized but large follicles, distended
with colloid; lining follicular epithelium
flattened with pyknotic nuclei
Cytopathology
Abundant colloid; may be inspissated
with fissures and cracks; sparse
epithelial cells with pyknotic nuclei
Differential
Diagnosis
Nodular goiter; macrofollicular variant
 of papillary carcinoma
a Note that cytologically, macrofollicular adenomas cannot be differentiated from nodular

goiter. The diagnosis of an adenoma is histologically based on total encapsulation.

TABLE 7.2 MACROFOLLICULAR OR COLLOID TYPE

FOLLICULAR ADENOMAa
The cytologic pattern of colloid adenomas, indistinguishable from that of hyperinvoluted goiter,
rarely if ever represents a malignant process.15 The only malignant neoplasm that strongly
resembles a colloid adenoma or a hyperinvoluted goiter, both macroscopically and
microscopically, is the macrofollicular variant of papillary carcinoma. The distinguishing feature
is the typical nuclear morphology of papillary carcinoma.

Simple Adenoma
Simple adenoma (normofollicular) consists of well-developed follicles of approximately normal
size (Fig. 7.6 ). The lining epithelium is low cuboidal, with either normal-sized or slightly
enlarged nuclei. The amount of colloid within the follicles varies. Cellular areas consisting of less
well-developed follicles may be present, along with more well-developed follicles, especially in
very large adenomas.
Figure 7.6. Multiple morphologic patterns in a large follicular adenoma. A. This field depicts
both a macrofollicular pattern and a solid pattern (arrow). B. Higher magnification
demonstrating a solid pattern. C. Macrofollicular areas mixed with normal-sized follicles. The
cytologic presentation of an adenoma like this will vary, depending on the area sampled.

Cytopathologic Features
The cytopathologic pattern of simple adenoma depends on the histologic differentiation of the
areas sampled (Table 7.3 ).
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When the adenoma resembles a normal gland, the aspirates present cytologic features of a
nodular goiter—an admixture of colloid and benign follicular epithelium with honeycomb
sheets and regular follicles—and are often interpreted as such. The differentiation between
the nodular goiter and a simple follicular adenoma is often impossible, the final diagnosis
depending on the demonstration of encapsulation.

Histology
Encapsulated; resembles normal thyroid parenchyma, consisting of normal sized follicles
containing colloid;
lining epithelium low cuboidal with basally located uniform round nuclei
Cytopathology
A mixed pattern

1. Varying proportion of colloid and benign follicular cells forming regular follicles or
honeycomb sheets; uniform
or minimally enlarged, round nuclei with granular chromatin; nucleoli absent,
representing normofollicular pattern
2. Syncytial tissue fragments with or without a follicular pattern; uniform or minimally
enlarged, round nuclei with
granular chromatin; nucleoli absent, representing cellular areas.

a The aspirate may be interpreted as a nodular goiter.

TABLE 7.3 NORMOFOLLICULAR OR SIMPLE-TYPE FOLLICULAR

ADENOMAa
A varied morphologic pattern consisting of micro/macrofollicular areas will yield a combination
of cytologic patterns; sampling of cellular areas exhibits syncytial tissue fragments
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with and without a follicular pattern similar to that seen in cellular follicular adenomas
(microfollicular/trabecular). The cytologic diagnosis depends on the area sampled. A
combination of cytologic features of nodular goiter and cellular follicular adenoma strongly
supports the diagnosis of a follicular adenoma with mixed morphology. Such a varied pattern is
frequently seen in a large adenoma demonstrating more than one pattern (Figs. 7.7 and 7.8 ).
Figure 7.7. Simple follicular adenoma. A, B. FNA showing tissue fragments of follicular cells with
a honeycomb pattern and uniform small nuclei. This cytologic presentation is similar to that
seen with nodular goiter and may be interpreted as such. C. The tissue fragments of follicular
cells are syncytial type with a follicular pattern exhibiting crowding and overlapping of
minimally enlarged nuclei. The cytologic presentation is consistent with a cellular follicular
adenoma. D. Thyroidectomy showed a large, discrete encapsulated follicular adenoma with
multiple morphologic patterns. E. Low power showing capsule and varying sized follices. F. The
follicles are normal sized, lined by uniform nuclei.
Figure 7.8. FNA of a simple follicular adenoma. A. Note marginal cellularity with few large
follicles. B. The component cells have uniform nuclei with compact chromatin. The pattern is
consistent with nodular goiter. Thyroidectomy revealed a solitary encapsulated follicular
adenoma.

Microfollicular/Trabecular Adenoma (Cellular Follicular

Adenoma)
Microfollicular adenoma (or fetal adenoma), as the name implies, is composed of poorly
developed or maldeveloped follicles with little or no colloid, denoting poor architectural as well
as functional differentiation (Fig. 7.4 C). The lining epithelium is cuboidal, with nuclei that may
be variably increased in size (Fig. 7.9 C).
Figure 7.9. FNA of a cellular follicular adenoma. A. Cellular aspirate showing several tissue
fragments of follicular cells with follicular pattern, low power. B. Higher magnification to show
the syncytial architecture with a follicular pattern, crowded, overlapped, mildly but uniformly
enlarged nuclei. The background is clean with no colloid. Thyroidectomy revealed a
microfollicular adenoma. C. Histologic section of the microfollicular adenoma.

Trabecular adenoma (or embryonal adenoma) displays a trabecular growth pattern with
anastomosing ribbons or trabeculae of follicular epithelium (Fig. 7.4 D). There is neither a
follicular growth pattern nor the presence of colloid, indicating a lack of both architectural and
functional differentiation at the light-microscopic level in routinely stained material.

Because microfollicular and trabecular adenomas are cellular neoplasms, they will henceforward
be referred to as "cellular follicular adenomas."

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Cytopathologic Features
Unlike macrofollicular and simple adenomas, aspirates of cellular follicular adenomas (Figs. 7.9 ,
7.10 , 7.11 , 7.12 , 7.13 , 7.14 and 7.15 ) show a distinctly different cytopathologic pattern
(Table 7.4 ). The aspirate is usually very cellular and consists of syncytial-type tissue fragments
of follicular epithelium, with or without a follicular pattern. A follicular pattern is more
commonly seen in a microfollicular adenoma, whereas in the trabecular
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type, syncytial-type tissue fragments with broad trabeculae predominate. Discrete, varying-sized
follicles are often present. The presence and the significance of microfollicles in thyroid
aspirates has been over-emphasized and considered to be diagnostic of follicular neoplasms. It
should be noted that the microfollicles are also seen in aspirates of nodular goiters. The
differentiating feature is the nuclear size and arrangement and not the size of the follicle per
se. The microfollicles from goiter show regularly arranged small nuclei while those from cellular
adenomas demonstrate crowded, overlapped, and enlarged nuclei with altered polarity. It is
important to recognize this feature or else aspirates consisting of microfollicles will be
interpreted as follicular neoplasms/adenomas.

Cellularity
Variable; low to high
Presentation
Cells mostly in syncytial tissue fragments or in loosely cohesive groups; scant
or absent colloid
Architecture of Tissue Fragments
With or without follicular pattern; follicles may be discrete, vary in size, and may
contain small amount of colloid; trabeculae with or without branching and
anastomosis; considerable crowding and overlapping of nuclei
Cells
Poorly defined cell borders; N/C ratios favor the nucleus
Nucleus
Round, uniformly increased in size; smooth nuclear membranes; granular
chromatin; nucleoli, grooves, or inclusions absent
Cytoplasm
Scant; pale
Colloid
Absent or scant
Background
Clean

TABLE 7.4 CYTOPATHOLOGIC FEATURES OF

MICROFOLLICULAR/TRABECULAR-TYPE FOLLICULAR
ADENOMA (CELLULAR FOLLICULAR ADENOMA)

Figure 7.10. FNA of a cellular follicular adenoma. A. Hypercellular aspirate with several tissue
fragments of follicular cells in a clean background, with no colloid. B. Higher magnification
showing syncytial architecture with a follicular pattern, uniformly enlarged, crowded and
overlapped nuclei. The chromatin is granular, evenly dispersed. No nucleoli are present.

Figure 7.11. FNA of a cellular follicular adenoma. A. Hypercellular aspirate with several tissue
fragments of follicular cells in a clean background, with no colloid, low power. B. Higher
magnification showing syncytial architecture with a follicular pattern, uniformly enlarged,
crowded and overlapped nuclei. The chromatin is granular, evenly dispersed. No nucleoli are
present.

Figure 7.12. FNA of a cellular follicular adenoma. A. Hypercellular aspirate with several tissue
fragments of follicular cells in a clean background, with no colloid, low power. B. Higher
magnification showing syncytial architecture with a follicular pattern, uniformly and moderately
enlarged, crowded and overlapped nuclei. The chromatin is granular, evenly dispersed. No
nucleoli are present. The follicular cells contain scant, pale cytoplasm
Figure 7.13. FNA of a cellular follicular adenoma. A. Large syncytial tissue fragment of follicular
cells. The follicular architecture is not evident. The nuclei are moderately but uniformly
enlarged in size, crowded, and overlapped. No nucleoli are appreciated. The background is
clean, devoid of colloid. Thyroidectomy revealed a cellular follicular adenoma. B, C. FNA of a
follicular adenoma. Note syncytial architecture with a follicular pattern, Diff-Quik. (Courtesy of
Mithra Baliga, MD, University of Mississippi, Jackson, Mississippi.)
Figure 7.14. FNA of a cellular follicular adenoma. A. This aspirate is markedly cellular,
consisting of several syncytial, anastomosing tissue fragments of follicular cells with follicular
and trabecular pattern. Note the clean background and lack of colloid, low power. B. Higher
magnification to highlight the microfollicular pattern, marked crowding, and overlapping of
enlarged nuclei containing granular chromatin. An occasional nucleus contains micronucleoli,
which suggest the possibility of invasive characteristics and warrants a suspicious diagnosis.
Thyroidectomy showed an encapsulated microfollicular adenoma.

Figure 7.14. C. Low power of the encapsulated adenoma demonstrating a solid growth pattern.
The small extension of the tumor is not considered enough evidence by the surgical pathologist
for justifying a diagnosis of follicular carcinoma. D. Higher magnification depicting the
microfollicular adenoma.

Figure 7.15. FNA of a cellular follicular adenoma with a trabecular pattern. This aspirate is
markedly cellular, consisting of varying-sized, syncytial tissue fragments of follicular cells with a
trabecular pattern. The nuclei are considerably enlarged, crowded, and overlapped. Their
chromatin is granular and nucleoli are occasionally seen. Note the clean background, lacking
colloid. Thyroidectomy revealed a follicular adenoma with a trabecular growth pattern.

The nuclear size in cellular follicular adenomas remains uniform in a given case, but is variably
increased in size from tumor to tumor. The nuclei are crowded and overlapped. The cell borders
are indistinct. The nuclear chromatin is granular and rather coarse but evenly distributed.
Nucleoli are infrequent and the cytoplasm is variable but scanty, colorless to pale. Nuclear
pleomorphism and the presence of nucleoli should raise the suspicion of follicular carcinoma.

The background is usually clean, and colloid is rarely present but may be seen within the lumina
of the follicles.

Cellular follicular adenomas overlap with well-differentiated follicular carcinomas both

cytologically and histologically, and the distinction between the two may be difficult.
Additionally, the aspirates of cellular follicular adenomas present morphologic similarities with
parathyroid adenomas and medullary thyroid carcinomas. The differentiating features are
discussed in the respective chapters.

A summary of the cytopathologic features of conventional follicular adenomas is given in Table

7.5 .

Cellularity
Low
Moderate
Moderate to marked
Moderate to marked
Presentation
Abundant colloid with follicular
cells isolated appearing as
bare nuclei often resembling
lymphocytes or in loosely
cohesive groups or in tissue
fragments
Variable amounts of colloid;
follicular cells in tissue
fragments
Follicular cells in tissue
fragments, scant to
absent colloid
Follicular cells in tissue
fragments, scant to
absent colloid
Architecture
Small regular follicles or in
monolayered sheets with
honeycomb arrangement
Tissue fragments with both
honeycomb and syncytial
arrangement with or without
follicular patterns; follicles
small, some with evenly
spaced nuclei, some with
crowding and overlapping
Syncytial arrangement,
mostly with follicular
pattern; crowding and
overlapping of nuclei
Syncytial arrangement
mostly with trabecular
pattern, follicular pattern
infrequent, crowding
and overlapping of
nuclei
Nuclei
Small, pyknotic
Normal sized (7–9 µm) to
slightly enlarged, evenly
dispersed, finely granular
chromatin; nucleoli absent
Variably enlarged but
 uniformly in a given
neoplasm; fine to
coarsely granular
chromatin; nucleoli
generally absent
Variable enlarged,
occasionally pleomorphic,
fine to coarsely granular
chromatin; nucleoli
generally absent
Significance
Cannot be differentiated from
hyperinvoluted goiter
Difficult to differentiate from
nodular goiter
Difficult to differentiate
from minimally invasive
or well-differentiated
follicular carcinoma
Difficult to differentiate
from minimally invasive
or well-differentiated
follicular carcinoma

Colloid or Simple or
Macrofollicular Adenoma Normofollicular Microfollicular Trabecular

TABLE 7.5 COMPARISON OF CYTOPATHOLOGIC FEATURES OF

CONVENTIONAL FOLLICULAR ADENOMAS

Morphologic Variants of Follicular Adenoma

Hyalinizing Trabecular Adenoma
Hyalinizing trabecular adenoma, first described by Carney and associates16 and also referred to
as "paraganglioma-like adenoma of thyroid" (PLAT),17 is a distinctive but uncommon subtype of
follicular adenoma with a female preponderance. These tumors generally behave in a benign
fashion. Recurrence or metastasis is infrequent11 ; however, invasive hyalinizing trabecular
carcinomas have been reported.18

Gross and Microscopic Features

Grossly the tumors are discrete, circumscribed, and solid; they are tan to gray-pink in color,
with a granular texture.

Histologically, hyalinizing trabecular adenomas are characterized by encapsulation and an

alveolar or trabecular growth pattern (Figs. 7.16 and 7.17 ).11 , 16 , 17 , 18 , 19 , 20 , 21 , 22
The neoplastic cells are medium-sized, oval, polygonal to spindle-shaped, and either arranged in
solid masses or as trabeculae separated by dense hyaline stroma. The trabeculae are straight or
sinuous, two to three layers thick. The neoplastic cells adjacent to the stroma are often
mummified, and those within the trabeculae form a pseudofollicular pattern (Fig. 7.16 ), with or
without colloid.
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Another characteristic pattern consists of elongated neoplastic cells aligning with their bases
inserted vertically into the capillaries of the delicate fibrovascular stroma. The tumor cells
contain variable pale to granular cytoplasm with perinuclear clearing. Their nuclei are round and
mildly enlarged, with granular chromatin, micronucleoli, frequent inclusions, and grooves. The
nuclear/cytoplasmic ratio is low. The stroma is variable, often increased, and with dense hyaline
resembling amyloid. The stains for amyloid are negative.
Figure 7.16. Hyalinizing trabecular adenoma. Histologic section showing trabeculae formed by
elongated cells.
Figure 7.17. Histologic sections of hyalinizing trabecular adenoma. A. This field shows large
follicular cells forming trabeculae. Note focal area in the center, where nuclei appear very
clear, similar to that seen in papillary carcinoma. Also note stromal hyalinization. B. Another
field showing dense hyalinizing stroma separating the islands and trabeculae of neoplastic
follicular cells.

Immunohistochemical findings23 , 24 , 25 include a positive reaction to thyroglobulin, TTT-1,

cytokeratin, and vimentin; and a negative reaction to HBME-1, calcitonin, S-100 protein, and
neurofilament. Neuroendocrine differentiation has been reported by some.25 A distinctive
membrane staining with MIB-1 is described.23

Cytopathologic Features
Cytologically, hyalinizing trabecular adenomas show features common to both medullary and
papillary carcinomas (Table 7.6 , Figs. 7.18 , 7.19 and 7.20 ). 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33
, 34 , 35 The aspirates show oval to spindle-shaped cells, isolated, in loosely cohesive groups, or
in syncytial tissue fragments without any follicular or papillary architectural pattern. At times,
the neoplastic cells are arranged in a sinuous parallel array and appear to radiate from a central
hyaline, acellular area (Fig. 7.20 ).
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Bondeson and Bondeson32 have described neoplastic cells in a follicle-like or pseudofollicular
arrangement around acellular material that stains metachromatically purplish red in
May–Grünwald–Giemsa stain. The cytoplasm of these cells is pale to dense and variable,
sometimes filamentous, and not well visualized. Bipolar and triangular cells with long
cytoplasmic processes may be present. Yellow cytoplasmic bodies 3 to 5 µm have been
described both histologically and cytologically. Although Rothenberg and colleagues21 described
them in all 75 cases, the yellow cytoplasmic bodies are seen sparingly in any given case of
hyalinizing trabecular adenoma. The nuclei tend to be round, oval to elliptical, and mildly
pleomorphic in size have a smooth border and contain finely granular, evenly distributed
chromatin with micronucleoli. Intranuclear inclusions and nuclear grooving are frequent. 26 , 33
, 34 , 35 Goellner and Carney35 described chromocenters with halo-like, clear zones around
them. The perinuclear clearing appreciated in histologic sections may also be seen in cytologic
samples. The background may contain amorphous hyaline material similar to amyloid, staining
pink to gray-blue. Psammoma bodies have been described in both cytologic material and
histologic sections. 22 , 32 , 34

Cellularity
Variable
Presentation
Cells, discrete, in groups or in syncytial tissue fragments
Architecture of Tissue
Fragments
Syncytial without follicular pattern; papillary-like with branching; trabeculae; central cores
of acellular hyaline material
Cells
Variably increased in size; round, oval, polygonal to elongated; poorly defined cell borders;
N/C ratios low
Nucleus
Increased variably; often eccentric; round, oval to elongated, smooth nuclear membranes, finely
granular chromatin; micronucleoli present, intranuclear inclusions very frequent; grooves +
Cytoplasm
Abundant, pale, fibrillar to finely granular; long, tapered cytoplasmic processes ±; yellow
cytoplasmic bodies ±; perinuclear halo ±
Psammoma Bodies
±
Background
Hyaline material, staining metachromatically purplish-red with Romanowsky stain; colloid absent
Immunoprofile
Thyroglobulin, TTF-1, cytokeratin, and vimentin positive; distinctive cell membrane staining
pattern with MIB-1, calcitonin, and chromogranin negative

TABLE 7.6 CYTOPATHOLOGIC FEATURES OF HYALINIZING

TRABECULAR ADENOMA
Figure 7.18. FNA of hyalinizing trabecular adenoma. Low power view showing anastomosing
trabeculae. Hyaline stroma is seen between the follicular cells (arrows). B, C. Higher
magnification showing syncytial fragments of follicular cells with a trabecular pattern. Their
nuclei are enlarged with pale granular chromatin. Note the intranuclear inclusions (arrows) and
nuclear grooves. D. This field shows stromal hyaline material (arrow).
Figure 7.19. FNA of hyalinizing trabecular adenoma. A, B. The follicular cells are in syncytial
tissue fragments, forming trabeculae. Note the abundant granular cytoplasm. Their nuclei have
powdery chromatin, grooves and inclusions. C. The cells are discrete and loosely cohesive. They
are large and elongated, with some showing delicate filamentous cytoplasmic processes.
Figure 7.20. FNA of hyalinizing trabecular adenoma. A. Syncytial tissue fragments of follicular
cells without any architectural configurations. The nuclei have finely granular chromatin,
grooves, occasional micronucleoli, and frequent inclusions. B, C. These two images show
intercellular hyaline material (arrows). The nuclei have powdery chromatin, and inclusions. D.
Histologic section of the hyalinizing trabecular adenoma. E. Different field showing calcification
and possible psammoma bodies. (Courtesy of Marizza de Peralta-Venturina, MD, William
Beaumont Hospital, Royal Oak, Michigan.)

The cytologic recognition of hyalinizing trabecular adenomas is difficult because of the

morphologic overlap with papillary and medullary carcinomas. Most of the reported series concur
with this observation. The differentiating features are listed in Chapter 9 on papillary carcinoma
(Table 9.16 ) and Chapter 12 on medullary carcinoma (Table 12.7 ). Although very rare, primary
paraganglioma of the thyroid may be considered in the differential diagnosis.36

Follicular Adenoma with Clear Cell Change

Follicular adenoma with a clear cell change is of uncommon occurrence. Its demographics,
clinical presentation, and behavior are similar to the conventional-type adenomas.11 , 37 , 38 ,
39 , 40

Histologically, follicular adenoma with clear cell change shows an encapsulated tumor with a
follicular or solid growth pattern formed by benign follicular cells containing abundant clear,
empty-looking cytoplasm. The nuclei are small and uniform.

Cytologically, the clear cell pattern is difficult to recognize when the cytoplasmic borders are
indistinct or disrupted and the bare nuclei resemble lymphocytes (Fig. 7.21 ). The clear
cytoplasm is difficult to appreciate in cytologic preparations.
Figure 7.21. Follicular adenoma with clear cell change. A–C. FNA showing tissue fragments of
follicular cells with follicular pattern. Their cell borders are poorly defined and the nuclei
appear bare, resembling lymphocytes because of compact chromatin. D. Histologic section of
the resected follicular adenoma with a clear cell pattern.

The differential diagnosis includes metastatic renal cell carcinoma and intrathyroidal
parathyroid adenoma.41

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Follicular Adenoma, Oxyphil Cell Type

Follicular adenomas composed of oxyphil cells are considered by some as a morphologic variant
of follicular adenomas.10 , 12 , 42 Others refer to them as Hürthle cell tumors and consider
them a separate entity. They are described in detail in Chapter 8 .

Follicular Adenoma with Papillary Hyperplasia

Follicular adenomas with papillary hyperplasia or a papillary change are considered to be more
frequent in teenagers and young adolescents11 , 42 , 43 and are characterized by degenerative
changes with cyst formation and papillary change. The papillae are edematous, directed toward
the center of the cyst, and lined by benign follicular epithelium containing basally located nuclei
with compact chromatin (Fig. 7.22 A and B, and Fig. 7.23 C to E). They lack the typical nuclear
morphology of papillary carcinoma.

Figure 7.22. Follicular adenoma with papillary change. A. Histologic section of a follicular
adenoma with large dilated follicles showing infolding of the lining follicular cells, suggesting a
papillary pattern (low power). B. Higher magnification shows papillary-like pattern with
hyalinized stroma. The lining cells are single layered, lack stratification, have uniform nuclei,
and do not demonstrate nuclear features of papillary carcinoma. C. FNA of this lesion was
misinterpreted as papillary carcinoma because of highly cellular aspirate consisting of numerous
papillary-like tissue fragments. D. Higher magnification to highlight the honeycomb pattern and
uniform nuclei, a pattern not typical of papillary carcinoma.
Figure 7.23. Follicular adenoma with papillary change. A. FNA showing branching large tissue
fragments of follicular cell (low power). B. Higher magnification showing the large tissue
fragment of follicular cells, folded over giving an appearance of syncytial arrangement. Their
nuclei are slightly but uniformly enlarged with granular chromatin. Some contain micronucleoli.
Thyroidectomy revealed a follicular adenoma with cystic degeneration and papillary change. C.
Note the thick capsule and the papillary change. D. Different field showing papillary
architecture (low power). E. Higher magnification showing lack of nuclear criteria for papillary
carcinoma.

Cytologically, follicular adenomas with papillary hyperplasia may be misinterpreted as papillary

carcinoma (Fig. 7.22 C and D, and Fig. 7.23 A and B). The aspirates are usually cellular,
consisting of syncytial tissue fragments of follicular cells with a papillary-like pattern. The
typical nuclear features of conventional papillary carcinoma are lacking. The diagnostic
problems are discussed in detail in Chapter 9 .

Atypical Adenoma
Hazard and Kenyon44 coined the term "atypical adenoma" for those follicular adenomas that are
histologically characterized by (i) hypercellularity, (ii) closely packed follicles often lacking
lumina, (iii) back-to-back arranged trabeculae, (iv) solid areas, (v) areas with spindle-shaped
cells, (vi) mitotic figures, (vii) complete encapsulation and lack of invasive features, and (viii) a
favorable outcome. It is apparent from this description that the atypical adenomas have the
histomorphology of follicular carcinoma (Fig. 7.24 ) but lack invasive characteristics. The
incidence of atypical adenoma is reported to be 9% by Lang and co-workers.45 They included
cases with questionable invasive features.

Figure 7.24. Histologic sections of two examples of atypical follicular adenomas. The neoplasm
demonstrates a solid growth pattern with back-to-back follicles and trabeculae. The nuclei are
large with open chromatin and contain nucleoli. These tumors were confined to the capsule with
no evidence of capsular and vascular invasion.
Cytopathologic Features
Cytologically, the aspirates of atypical adenomas demonstrate marked cellularity, consisting of
syncytial tissue fragments of follicular epithelium (Figs. 7.25 and 7.26 ). They may exhibit a
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follicular or a trabecular pattern or show branching without any architectural configurations,
with marked crowding and overlapping of enlarged, pleomorphic nuclei containing nucleoli. This
cytologic pattern is similar to that seen in follicular carcinoma (see Table 7.8 ).45 These
aspirates are interpreted as follicular carcinomas and histologically diagnosed as atypical
adenomas due to lack of invasion. Atypical adenoma is thus a histologic diagnosis and is never
made from cytologic samples.

Figure 7.25. FNA of an atypical adenoma. A. The aspirate is markedly cellular, consisting of
several tissue fragments of follicular cells in a background that is devoid of colloid, low power.
B. Higher magnification showing syncytial tissue fragments, with and without a follicular
pattern. The cells are large, pleomorphic in size, with appreciable cytoplasm. Their nuclei are
large, round, with granular chromatin, parachromatin clearing, and contain nucleoli. The
pattern is consistent with follicular carcinoma. Thyroidectomy revealed an encapsulated
follicular adenoma with no invasive characteristics and was interpreted as atypical adenoma. C.
FNA of a histologically confirmed follicular carcinoma showing similar cytologic pattern.

Figure 7.26. Atypical follicular adenoma. A. Low power of an overwhelmingly cellular aspirate
consisting of large branching tissue fragments of follicular cells. B, C. Higher magnification
showing syncytial tissue fragments with a trabecular pattern. The nuclei are extremely crowded,
overlapped, and contain deep-staining, granular chromatin, and nucleoli. A diagnosis of
follicular carcinoma was made. Thyroidectomy revealed an encapsulated cellular follicular
adenoma with a thin capsule and no capsular or vascular invasion. E. The tumor showed a solid
growth pattern and occasional mitosis and was interpreted as an atypical adenoma.

The other variants listed in Table 7.1 are of uncommon occurrence. The author has no personal
experience with their cytologic features. The differential diagnoses of various types of follicular
adenomas are listed in Table 7.7

Macrofollicular Adenoma

Nodular goiter
Macrofollicular variant of papillary carcinoma

Simple or Normofollicular Adenoma

Nodular goiter

Microfollicular and Trabecular

Adenoma

Hyperplastic goiter (cellular adenomatoid nodule)

Follicular nodule from Hashimoto's thyroiditis
Well-differentiated follicular carcinoma
Follicular variant of papillary carcinoma
Medullary carcinoma
Parathyroid adenoma

Hyalinizing Trabecular Adenoma

Papillary carcinoma
Medullary carcinoma

Follicular Adenoma with Papillary

Change
 Papillary carcinoma
Nodular goiter

Follicular Adenoma with Clear Cell

Change

Metastatic renal cell carcinoma

Parathyroid adenoma

Atypical adenoma
Follicular carcinoma

TABLE 7.7 DIFFERENTIAL DIAGNOSIS OF FOLLICULAR

ADENOMAS
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FOLLICULAR CARCINOMA
Follicular carcinomas11 , 46 , 47 , 48 are reported to represent 13% to 17% of thyroid
carcinomas, although an incidence as low as 1% to 2% has been described.49 , 50 The reported
incidences vary depending on whether or not Hürthle cell carcinoma was included in the
group. Follicular carcinomas are several times more common in women than in men, but the age
distribution differs from that of papillary carcinoma, being more frequent in middle and older
age groups. A high incidence is reported in geographic areas with endemic goiters.13 Follicular
carcinomas can be distinguished from papillary carcinomas in several ways. They are solitary
lesions and rarely metastasize to cervical lymph nodes. They spread via the bloodstream to
distant organs such as lungs, bone, brain, and liver. The prognosis is generally good, depending
on the invasive characteristics of the tumor, but less favorable than for papillary carcinoma.11 ,
12 , 51 , 52 , 53 , 54 , 55 , 56 , 57

Gross and Microscopic Features

Like adenomas, follicular carcinomas grossly are well circumscribed and sharply demarcated
from adjacent parenchyma (Fig. 7.27 ). Poorly differentiated carcinomas are usually very large
and may replace the entire lobe. The cut surface shows a varied pattern, including a bulging cut
surface, fleshy areas, hemorrhage, necrosis, and calcification.
Figure 7.27. Follicular carcinoma, gross photographs. Follicular carcinomas are usually large,
bulky, and may involve the entire lobe. Their cut surfaces are fleshy, bulging with hemorrhage
and foci of necrosis.

The microscopic pattern is as varied as that of the adenomas, ranging from well-developed
follicles to a solid pattern with no evidence of follicular cell differentiation (Figs. 7.28 and 7.29
). The solid pattern may show trabeculae, alveoli, or large nests of carcinoma cells. Different
growth patterns may be seen in the same tumor. The follicular cells have larger nuclei with
coarsely granular chromatin, often separated by clear parachromatin. Nucleoli are frequent.
Mitoses may be seen, especially in poorly differentiated carcinomas.
Figure 7.28. Histologic sections of well-differentiated or low-grade follicular carcinomas. A, B.
Microfollicular growth pattern. C. Trabecular growth pattern. These carcinomas show histologic
growth patterns similar to those of cellular follicular adenomas. The cells have uniform but
enlarged nuclei. Cytologically, these low-grade carcinomas are difficult to differentiate from
cellular follicular adenomas unless micronucleoli are identified, which are present in carcinoma
cells and usually not seen in adenomas.
Figure 7.29. Spectrum of histologic patterns of poorly differentiated follicular carcinomas.
A–D. These four images depict a solid growth pattern. The cells have large, pleomorphic
nuclei with an open chromatin pattern and prominent nucleoli. Some show mitosis and focal
necrosis. E, F. This follicular carcinoma shows sheets of follicular cells with only focal follicular
pattern. Their nuclei are hyperchromatic and pleomorphic.

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Classification of follicular carcinomas may be based on differentiation (e.g., well differentiated
or poorly differentiated) or on the extent of invasion (e.g., capsular or blood vessel invasion, or
wide invasion of the surrounding parenchyma) regardless of the cytomorphology (Figs. 7.25 ,
7.26 and 7.27 ).11 , 12 , 42 , 46 , 47 , 48 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61
Usually well-differentiated carcinomas tend to be minimally invasive and the poorly
differentiated carcinomas tend to be widely invasive.

A histologic diagnosis of follicular carcinoma is based on the presence of invasive characteristics

such as capsular or vascular invasion or invasion of the parenchyma outside the capsule and the
extent of it. Although everyone agrees that the demonstration of invasive features is absolutely
essential for the diagnosis of follicular carcinoma, considerable confusion, controversy, and
debate exist over what constitutes a capsular or vascular invasion and how much invasion is
significant. Thus, the interpretation becomes subjective, and the diagnosis of encapsulated
follicular lesions varies greatly.58 , 59 , 60

Capsular Invasion
Some investigators feel that any degree of invasion of the capsule (Fig. 7.30 A to C) constitutes
the invasion qualifying for the diagnosis of follicular carcinoma.61 Others require complete
transgression of the capsule to qualify as an invasive process (Fig. 7.30 D).62 Small nubbins of
the tumor into the capsule beyond its interface with the tumor are considered a feature of
capsular invasion61 ; others totally discount it. Some consider this feature as a post–fine-
needle biopsy effect.
Figure 7.30. Follicular carcinoma with capsular invasion. A. These small foci of neoplastic cells
infiltrating the thick capsule but not completely penetrating it may not qualify for the diagnosis
of follicular carcinoma according to some pathologists. B. The tumor has split the thick and
fibrotic capsule. Again, this was not considered sufficient evidence for the diagnosis of follicular
carcinoma. C. The invasion in this image is seen as involving the entire capsule but not beyond
it. D. The invasion of the tumor is seen as complete transgression of the capsule and beyond.

Vascular Invasion
The presence of vascular invasion is regarded as a reliable feature in favor of carcinoma. The
problem is what constitutes a vascular invasion. Mere presence of tumor within a small blood
vessel is not sufficient. The tumor must be attached to the vessel wall, subendothelial in
location, and must be covered by the endothelium (Fig. 7.31 ). The invaded blood vessel must be
within the capsule or outside and not intralesional.
Figure 7.31. Follicular carcinoma. Vascular invasion. A. Tumor involving the small blood vessel
(arrow). There is capsular invasion as well. B. Follicular carcinoma with a larger blood vessel
containing the tumor.

Wide Invasion of the Parenchyma

The tumor invades the capsule and invades the adjoining parenchyma widely (Fig. 7.32 ). The
tumor may form pushing nodules and incite fibrosis and should not be considered as separate
nodules. Widely invasive tumors tend to be poorly differentiated.
Figure 7.32. Follicular carcinomas with moderate to marked invasion. A, B. The carcinoma
shows large islands of tumor outside the capsule, invading the thyroid parenchyma. C. The
carcinoma has extended to the thyroid capsule and invaded the surrounding soft tissues.

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Cytopathologic Features
The aspirates of follicular carcinomas present a spectrum of cytologic features (Table 7.8 ). At
one end of the spectrum, the cytologic pattern closely resembles that of cellular follicular
adenomas. The other end of the spectrum represents poorly differentiated follicular carcinomas
where the neoplastic cells are clearly malignant. The cytologic recognition of well-differentiated
or low-grade follicular carcinomas may offer considerable difficulties because of the overlapping
features with cellular adenomas. The poorly differentiated follicular carcinomas are readily
identified.

Cellularity
Variable; usually high
Presentation
Cells mostly in syncytial tissue fragments or in loosely cohesive groups; scant
or absent colloid
Architecture of Tissue Fragments
With or without follicular pattern; follicles may be discrete, irregular, vary in size, and may
contain small amount of colloid; trabeculae with or without branching and anastomosis;
marked crowding and overlapping of nuclei
Cells
Poorly defined cell borders; N/C ratios favor the nucleus
Nucleus
Round, considerably increased in size; smooth nuclear membranes; coarsely granular
chromatin; nucleoli, parachromatin clearing; grooves or inclusions absent; pleomorphic
size and clearly malignant in poorly differentiated carcinomas
Cytoplasm
Usually scant; pale but may be dense
Colloid
Absent or scant
Background
Usually clean, may show necrosis in poorly differentiated carcinomas

TABLE 7.8 CYTOPATHOLOGIC FEATURES OF FOLLICULAR

CARCINOMA

Well-Differentiated Follicular Carcinoma

The cytopathologic features of follicular carcinomas are usually not described separately from
follicular adenomas, although
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there are certain features that suggest the strong possibility, an observation made by Lang and
associates63 several years ago. Well-differentiated follicular carcinomas are usually minimally
invasive. Their aspirates tend to be generally very cellular, composed of varying-sized syncytial-
type tissue fragments of follicular epithelium, with or without a follicular pattern. Nuclei are
very crowded and overlapped, and their density within a given tissue fragment is much greater
than that seen
 P.76
in follicular adenomas (Figs 7.33 , 7.34 , 7.35 , 7.36 , 7.37 , 7.38 , 7.39 , 7.40 , 7.41 and 7.42 ).
The architecture of the follicles can be strikingly irregular (Fig. 7.33 ). The nuclei are
considerably increased in size, round to oval, and either uniform or pleomorphic. The nuclear
size is an important parameter and can be judged against an intact red blood cell in the
background. The nuclear chromatin is coarsely granular with parachromatin clearing. Micro-
and/or macronucleoli are almost always present, and intranuclear inclusions are almost never
seen, although Glant and associates64 reported one case in which they were present. The cells
of follicular carcinoma
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tend to have more cytoplasm than those of adenoma. Colloid is very rarely seen in the
background, but it may be present within the follicular lumina. The background is clean. The
cytologic features of well-differentiated follicular carcinomas are illustrated in Figures 7.33 to
7.42.
Figure 7.33. FNA of well-differentiated follicular carcinoma. A. Low power showing a
hypercellular aspirate with several tissue fragments of follicular cells in a background that is
clean and lacks colloid. B. Higher magnification showing syncytial tissue fragments of follicular
cells with a follicular pattern. The nuclei are large, round, and vary in size. The chromatin is
granular with micronucleoli, a feature that favors invasive characteristics. Thyroidectomy
confirmed the diagnosis of follicular carcinoma. C. Follicular carcinoma showing invasion outside
the capsule (low power). D. Higher magnification showing two patterns: a solid one on the right
and the normofollicular one on the left. E. Higher magnification of the solid tumor.
Figure 7.34. Well-differentiated follicular carcinoma. A. Low power of FNA showing a
hypercellular aspirate with several tissue fragments in a background that is clean and lacks
colloid. B. Higher magnification showing syncytial tissue fragments of follicular cells with
follicular pattern. The cells are larger. Their nuclei are large, round, and vary in size. The
chromatin is granular with micronucleoli, a feature that favors invasive characteristics.
Thyroidectomy confirmed the diagnosis of follicular carcinoma

Figure 7.35. Well-differentiated follicular carcinoma. A. Low power depicting a cellular

aspirate. B. Higher magnification showing anastomosing trabeculae of follicular cells with
syncytial arrangement. The nuclei are enlarged with granular chromatin and contain nucleoli. No
colloid is present in the background. The cytologic diagnosis of follicular carcinoma was
confirmed on histology.
Figure 7.36. Well-differentiated follicular carcinoma. A–C. These three images show syncytial
tissue fragments with extreme crowding and overlapping of moderately enlarged nuclei. Both
follicular and trabecular patterns are seen. The nuclear chromatin is coarsely granular and deep-
staining. Nucleoli are occasionally seen. The cytologic diagnosis of follicular carcinoma was
confirmed on thyroidectomy. D. The resected thyroid showing a large left lobe completely
replaced by the tumor. E. Histologic section of the carcinoma. F. The carcinoma has invaded the
capsule and beyond.
Figure 7.37. Well-differentiated follicular carcinoma. A, B. FNA showing syncytial tissue
fragments of follicular cells with extreme crowding and overlapping of enlarged nuclei,
pleomorphic in size. The nuclei are hyperchromatic with coarsely granular chromatin. The
cytologic diagnosis of follicular carcinoma was confirmed at surgery. C. Histologic section of the
carcinoma showing vascular invasion.
Figure 7.38. Well-differentiated follicular carcinoma. A, B. The aspirate is cellular, consisting of
syncytial tissue fragments of follicular cells with a follicular pattern. The nuclei are mildly
enlarged, uniform, and with granular chromatin. No nucleoli are seen. The background is clean.
The cytologic diagnosis was cellular follicular adenoma. However, thyroidectomy revealed a
follicular carcinoma with capsular invasion. C. Histologic section. This extent of invasion may
not be acceptable to some pathologists as enough evidence to justify a malignant diagnosis. In
that case, there will be a concordance between cytologic and histologic diagnoses.
Figure 7.39. Well-differentiated follicular carcinoma. Syncytial architecture, follicular pattern,
irregular follicles, large nuclei, pleomorphic in size, coarse chromatin with nucleoli, as depicted
here, are the cytologic features that favor the diagnosis of follicular carcinoma.

Figure 7.40. FNA of a follicular carcinoma. Syncytial architecture, extreme crowding and
overlapping of enlarged nuclei, coarsely granular chromatin with parachromatin clearing, and
nucleoli are diagnostic of follicular carcinoma. Such extreme crowding of nuclei is generally not
seen in adenomas. Note the discrete follicles in the background. They are irregular with extreme
crowding of nuclei.
Figure 7.41. FNA of a follicular carcinoma showing syncytial tissue fragments with and without
follicular pattern. The cells and their nuclei are pleomorphic, hyperchromatic, and contain
nucleoli.

Figure 7.42. A till D. FNA of a follicular carcinoma (Diff-Quik preparation). Nuclear morphology
is not as clear in Romanowsky-stained preparations as with Papanicolaou stain. (Courtesy of
Mariza de Peralta-Venturina, MD, William Beaumont Hospital, Royal Oak, Michigan.)

The cytopathologic features of well-differentiated follicular carcinomas overlap with those of

follicular adenomas, proliferating follicular nodules from Hashimoto's thyroiditis, and the
follicular variant of papillary carcinoma (see "Differential Diagnosis of Follicular Lesions and
Diagnostic Accuracy" later in the chapter, and Figs. 7.49 , 7.50 , 7.51 , 7.52 , 7.53 and 7.54 ).
They may also overlap morphologically with medullary carcinoma8 , 65 and parathyroid
adenoma.8
Figure 7.43. A–C. Poorly differentiated follicular carcinoma. FNA showing syncytial tissue
fragments of clearly malignant follicular cells. Follicular pattern is evident. The nuclei contain
granular chromatin with parachromatin clearing and prominent nucleoli. The thyroidectomy
showed a widely invasive follicular carcinoma.
Figure 7.44. FNA of a poorly differentiated follicular carcinoma demonstrating syncytial tissue
fragments of follicular cells without any architectural pattern. The malignant cell nuclei are
pleomorphic, hyperchromatic, and contain nucleoli.
Figure 7.45. A and B. FNA of a poorly differentiated follicular carcinoma showing syncytial
tissue fragments of follicular cells with and without a follicular pattern. The nuclei are enlarged,
hyperchromatic, pleomorphic, and contain nucleoli. The small cell size may represent an insular
component.

Figure 7.46. Poorly differentiated follicular carcinoma. A. FNA yielded an overwhelmingly

cellular sample with syncytial tissue fragments. The background is clean and lacks colloid. Low
power. B. Medium power to show the pleomorphic malignant cells.
Figure 7.46. C. Higher magnification depicting clearly malignant cells forming syncytia with
follicular pattern. Thyroidectomy confirmed a follicular carcinoma, which was widely infiltrating
the adjacent parenchyma. D, E. Histologic section showing marked invasion. F. Higher
magnification of the poorly differentiated carcinoma.
Figure 7.47. FNA of a poorly differentiated follicular carcinoma. The malignant cells are
pleomorphic and enlarged, containing granular chromatin and nucleoli. The tissue fragment is
syncytial with no architectural pattern.
Figure 7.48. A spectrum of follicular nuclear size and amount of colloid in follicular lesions of
the thyroid. (Modified from Cervino JM, Paseyro P, Grosso O, et al. La exploracion citologica de
la glandula tirodes y sus correlaciones anatomoclinicas. An Facultad Medicina.
1962;47:128–143.)
Figure 7.49. Differential diagnosis of follicular lesions. Histologic sections of follicular lesions
(follicular-patterned). The common denominator here is the follicular growth pattern of
follicular-derived cells. A. Nodular goiter. B. Follicular nodule in the background of Hashimoto's
thyroiditis. Note lymphoid cell infiltrate. C. Microfollicular adenoma. D. Follicular carcinoma. E.
Follicular variant of papillary carcinoma.
Figure 7.50. Differential diagnosis of follicular lesions. Cytologic features of follicular lesions
(follicular-patterned). The common denominators here are: the follicular growth pattern, lack of
colloid and hypercellularity. A. Nodular goiter. The follicular cells are small, forming honeycomb
sheets and regular follicles with evenly spaced small uniform nuclei, containing compact to
finely granular chromatin. B. Follicular nodule in Hashimoto's thyroiditis. The tissue fragment is
syncytial in architecture and resembles that of cellular follicular adenoma. Without lymphocytes
in the background, this will be interpreted as a follicular adenoma. C. Cellular follicular
adenoma with syncytial tissue fragments of follicular cells, crowded, overlapped, uniformly
enlarged nuclei. Their chromatin is granular and evenly distributed. There are no nucleoli. D.
Follicular carcinoma. Syncytial tissue fragments of clearly malignant cells. Note the follicular
pattern. E. Follicular variant of papillary carcinoma. The syncytial tissue fragments show a
follicular pattern. The component cells contain enlarged nuclei with pale, powdery chromatin,
micronucleoli, grooves, and inclusions, diagnostic of papillary carcinoma.

Figure 7.51. Differential diagnosis of follicular lesions. Cytologic features of follicular lesions
(follicular-patterned). The common denominators here are: the follicular growth pattern, lack of
colloid and hypercellularity. A. Nodular goiter. The follicular cells are small, forming honeycomb
sheets and regular follicles with evenly spaced small uniform nuclei, containing compact to
finely granular chromatin. B. Follicular nodule in Hashimoto's thyroiditis. The tissue fragment is
syncytial in architecture and resembles that of cellular follicular adenoma. Note a few
stretched-out lymphocytes that may serve as a clue for the diagnosis of Hashimoto's thyroiditis.
C. Cellular follicular adenoma with syncytial tissue fragments of follicular cells, crowded,
overlapped uniformly enlarged nuclei. Their chromatin is granular and evenly distributed. There
are no nucleoli. D. Follicular carcinoma. Syncytial tissue fragments of clearly malignant cells.
Note the follicular pattern. E. Follicular variant of papillary carcinoma. The syncytial tissue
fragments show a follicular pattern. The component cells contain enlarged nuclei with pale,
powdery chromatin, micronucleoli, and grooves. Inclusions are not identified. This pattern is
highly suggestive of papillary carcinoma.

Figure 7.52. Differential diagnosis of follicular lesions. Cytologic features of follicular lesions
(follicular-patterned). A. Nodular goiter. B. Cellular follicular adenoma. C. Follicular carcinoma.
D. Follicular variant of papillary carcinoma. Features that separate nodular goiter from the
remaining three include lack of syncytial architecture and small uniform nuclei. All the three
neoplasms depicted here, in B, C, and D, demonstrate syncytial architecture. Carcinoma cells in
C contain nucleoli. D. The follicular cell nuclei here demonstrate features of papillary
carcinoma.

Figure 7.53. Differential diagnosis of follicular lesions. Cytologic features of follicular lesions
(follicular-patterned). A. Nodular goiter. B. Cellular follicular adenoma. C. Follicular carcinoma.
D. Follicular variant of papillary carcinoma. All four lesions demonstrate a microfollicular
pattern. The presence of microfollicles by themselves is not indicative of a follicular neoplasm
unless the follicles are irregular; demonstrate crowded and overlapped nuclei, and syncytial
architecture.
Figure 7.54. Differential diagnosis of follicular lesions. Cytologic features of follicular lesions
(follicular-patterned). A. Hyperplastic goiter. B. Follicular adenoma. C. Follicular carcinoma. D.
Follicular variant of papillary carcinoma. The cytologic distinction of these various lesions is
difficult from this type of preparation. (Diff-Quik preparations.) (Courtesy of Mariza de Peralta-
Venturina, MD, William Beaumont Hospital, Royal Oak, Michigan.)

Poorly Differentiated Follicular Carcinoma

The aspirates of poorly differentiated follicular carcinomas pose no diagnostic problems. They
tend to be very cellular, consisting of large syncytial tissue fragments of malignant cells along
with loosely cohesive cells. The tissue fragments may exhibit a follicular pattern and often show
branching, with a solid growth pattern. The malignant cells tend to be larger than those seen in
well-differentiated carcinomas; are pleomorphic in size, with variable pale to dense cytoplasm;
and have large round nuclei with intensely stained coarsely granular chromatin and
parachromatin clearing. Nucleoli are easily identified. Colloid is generally not conspicuous. The
background may show necrosis. The cytologic features of poorly differentiated follicular
carcinomas are illustrated in Figures 7.43 to 7.47.

The morphologic variants of follicular carcinomas include carcinomas with clear cell changes,
with mucinous features, and with rhabdoid features.66 These are extremely uncommon. The
cytologic features of follicular carcinomas with clear cell and mucinous changes are described in
Chapter 19 .

Immunocytohistochemical Profile
The cells of follicular neoplasms, including follicular adenomas and their morphologic variants,
as well as follicular carcinomas, demonstrate positive reactivity to thyroglobulin, the intensity
depending on the differentiation. A positive reaction
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is also noted in the colloid. The neoplastic follicular cells also react to TTF-1 and to low-
molecular-weight keratin but not to high–molecular weight keratin. Vimentin is co-expressed
with keratin, and the cells show negative reactivity to carcinoembryonic antigen (CEA) and
calcitonin. Follicular carcinomas consistently react negatively to CK 19 galectin-3 and RAT-
oncogen.

Differential Diagnosis of Follicular Lesions and Diagnostic

Accuracy
The follicular cell-derived lesions of the thyroid presenting a follicular growth pattern are
referred to as follicular lesions or follicular-patterned lesions,67 and include the following.

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P.81

Non-Neoplastic Entities

Nodular goiters

Proliferating follicular nodules from Hashimoto's thyroiditis

Neoplasms
 Follicular adenomas

Follicular carcinomas

Follicular variant of papillary carcinoma

The above-mentioned follicular lesions share several morphologic features, both cytologically
and histologically, causing
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diagnostic difficulties. As noted in previous sections, the subject of cytopathology of follicular
lesions has raised some key issues:

Can the various follicular lesions be differentiated from cytologic samples? If so, what
are the differentiating features?

If the cytologic differentiation is attempted, what is the diagnostic accuracy?

For patient management, is the cytologic differentiation of follicular lesions better than
grouping all lesions into one category, "indeterminate/suspicious," and recommending
surgery?

Is the number of surgical removals of the thyroid for benign diseases reduced when
cytologic differentiation is attempted?

Issue #1: Can Follicular Lesions Be Differentiated from Cytologic

Samples? If So, What Are the Differentiating Features?
The answer to this question is yes. In most instances cytologic differentiation is achievable.

The common cytologic feature shared by the aspirates of follicular lesions is hypercellularity
with a large population of follicular cells, in a clear background containing little or no colloid
(Table 7.9 ). However, certain cytologic parameters are noticeable (Fig. 7.48 )68 and can also
be appreciated in
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histologic sections if one looks for them (Figs. 7.49 and 7.50 ). As Rosai and Carcangiu stated,69
"It is not generally recognized that one of the classic papers70 on encapsulated angioinvasive
carcinoma stated that microscopic atypia are nearly always present in these tumors." These
atypical features in cytologic samples are represented by alterations in architectural patterns of
the tissue fragments of follicular epithelium and their nuclear morphology. The following
observations are useful:

Cellularity
Usually cellular
Usually cellular
Usually cellular
Usually cellular
Usually cellular
Presentation
Follicular cells mostly in tissue
fragments
Follicular cells mostly in tissue
fragments; sparse to
abundant lymphoid cells
Mostly in tissue fragments
In tissue fragments, sometimes
in loosely cohesive groups
In tissue fragments and in
loosely cohesive groups
Architecture
Regular small follicles with
evenly spaced nuclei;
monolayered with honeycomb
pattern; infrequently papillary
configuration but with
honeycomb arrangement
of component nuclei
Tissue fragments with or
without follicular pattern;
nuclei often crowded and
overlapped; permeated by
mature lymphocytes
Syncytial tissue fragments with
or without follicular
pattern; follicles irregular with
crowding and overlapping of
nuclei; trabecular pattern ±
Syncytial tissue fragments with
or without follicular and
trabecular pattern; follicles
may be markedly irregular
with intense crowding and
overlapping of nuclei;
Syncytial tissue fragments with
or without follicular pattern
with crowding and
overlapping of nuclei
inspissated colloid within
follicular lumina
Nuclear Size
Normal to slightly increased;
uniform; 7–9 µm in diameter
Considerable variation in size
Variably enlarged but uniformly
in a given neoplasm
Considerably enlarged with
variation in size
Enlarged with variation in size
Chromatin
Finely granular, evenly
distributed, sometimes
compact; smooth nuclear
membrane
Fine to coarsely granular;
smooth nuclear membrane
Fine to coarsely granular;
 smooth nuclear membrane
Fine to coarsely granular;
parachromatin clearing;
nuclear membrane may be
irregular
Dusty, powdery to finely
granular
Nucleolus
Micronucleoli ±
Micronucleoli ±
Micronucleoli ±
Micronucleoli/macronucleoli
Micronucleoli ±
Intranuclear
Inclusions
Absent
Rarely present
Absent
On rare occasions
Usually present
(a diagnostic clue)
Nuclear
Grooves
Rare
Absent
Absent
Absent
Present
Cytoplasm
Variable, clear to pale
Variable, clear to pale
Scant, pale
Variable, generally scant,
pale to dense
Usually scant to pale
Colloid
Scant to absent
Scant to absent
Scant to absent, may be
present as droplets, within or
outside follicular lumina
Scant to absent, may be
present as droplets, within or
outside follicular lumina
Often
Multinucleated
Foreign Body
Type Giant
Cells
Absent
Rarely present
Absent
Absent
Present
Helpful
Features
Cytologic changes of nodular
goiter
Hürthle cell metaplasia and
lymphoplasmacytoid cells in
the background (high
antimicrosomal or
antithyroglobulin antibody
titers)
—
—
Cytologic features of papillary
carcinoma on other slides
 Follicular
Follicular Nodule Adenoma
Hyperplastic in Cellular Type Follicular Variant
Nodular Hashimoto's (Microfollicular Follicular of Papillary
Goiter Thyroiditis and Trabecular) Carcinoma Carcinoma

TABLE 7.9 DIFFERENTIAL DIAGNOSTIC OF FOLLICULAR

LESIONS

The amount of colloid decreases from macrofollicular adenoma to hyperplastic goiter to

cellular follicular adenoma and follicular carcinoma. Consequently, the cellularity in the
aspirated material is more noticeable. It is important to realize that the absence of
colloid does not rule out a diagnosis of nodular or hyperplastic goiter. Mere absence of
colloid is not a criterion in favor of neoplasm.

The architectural patterns of the tissue fragments of follicular epithelium differ in non-
neoplastic follicular lesions from follicular neoplasms. The former display monolayered
sheets with a honeycomb arrangement and regular follicles. The tissue fragments in
neoplastic lesions are characterized by syncytial architecture. If the architectural
pattern of the tissue fragments is disregarded and emphasis is placed on cellularity
alone, differentiation of follicular lesions is not possible. Hypercellularity of the aspirate
does not equate with neoplasia (Figs. 7.55 , 7.56 and 7.57 ).

Follicular cell nuclei gradually increase in size from nodular goiter to follicular adenomas
to follicular carcinomas.
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P.86
The difference of nuclear size between goiters and follicular carcinomas is considerable
and can easily be appreciated. There is certainly an overlap between some cases of
follicular adenomas and low-grade or well-differentiated carcinomas, where the nuclear
size approximates. The cytologic distinction in such cases is not possible.

The compact chromatin pattern of follicular cell nuclei in nodular goiter changes to
granular in cellular adenomas and to coarsely granular with the presence of nucleoli and
 parachromatin clearing in follicular carcinomas. The presence of nuclear pleomorphism
with oval, oblong nuclear shapes, powdery chromatin, micronucleoli, grooves, and
nuclear inclusions favors the follicular variant of papillary carcinoma. The nuclei in
follicular adenomas and the low-grade follicular carcinomas tend to be uniformly
enlarged in a given case.

The aspirates of poorly differentiated follicular carcinomas demonstrate clearly

malignant features and are not diagnostic problems.

Nodular proliferations of follicular epithelium in Hashimoto's thyroiditis will yield cellular

samples exhibiting morphology very similar to that displayed by cellular follicular
adenomas or follicular carcinomas. The presence of lymphocytes in the background
supports the diagnosis of Hashimoto's thyroiditis. If the lymphoid cells are sparse,
overlooked, or even absent, it is not possible to recognize the nature of the lesion as
Hashimoto's thyroiditis and it will be interpreted as a follicular neoplasm. This
constitutes an important diagnostic pitfall, causing a false-positive diagnosis.
Differentiation of follicular nodules from follicular neoplasms in the background of
Hashimoto's thyroiditis does not pose a problem in surgical pathology, where the entire
lobe or a gland is available for examination.

Figure 7.55. Hyperplastic goiter will yield a very cellular aspirate and no colloid in the
background. Hypercellularity is not synonymous with neoplasia. Tissue fragments with a
honeycomb architecture forming a two-dimensional sheets, regularly spaced, uniform small
nuclei with finely granular, evenly spaced or compact chromatin indicate a benign non-
neoplastic lesion. A. Low power of an aspirate from hyperplastic goiter. B. Higher magnification.
Figure 7.56. FNA of a hyperplastic goiter. The aspirate is very cellular, with no colloid in the
background. The cellularity may lead to a diagnosis of a follicular neoplasm. (Diff-Quik).
(Courtesy of Mithra Baliga, MD, University of Mississippi, Jackson.)

Figure 7.57. Simple type follicular adenoma, misinterpreted as nodular goiter. A. Low power of
FNA showing large tissue fragments of follicular epithelium. B. Medium power.

Figure 7.57. C, D. Higher magnification. The aspirate was interpreted as nodular goiter.
Thyroidectomy revealed a large follicular adenoma with cystic change and multiple growth
patterns. E, F. Encapsulated tumor with solid areas mixed with large colloid filled follicles (low
power). G. Higher magnification. Sampling is the major problem in discrepancies.

If the above-mentioned factors are used as guidelines, the majority of the benign non-neoplastic
diseases can be separated from neoplastic lesions. The differentiating features of various
cellular follicular lesions are listed in Table 7.9 and illustrated in Figures 7.51 , 7.52 , 7.53 , 7.54
, 7.55 , 7.56 to 7.57 .

Our observations and the criteria for separating various types of follicular lesions are echoed by
Suen71 and also supported by morphometric studies.5 , 72 , 76 Crissman and associates72
determined the morphometric parameters of the nuclear area (NA), the nuclear:cytoplasmic
ratio and nuclear roundness (NR) in single cells and cell aggregates, the percentage of nuclear
overlap (NO), and the percentage of the nuclear area of overlap (NAO) in cellular aggregates
(Tables 7.15 , 7.16 and 7.17 ), from the cytologic samples of 20 hyperplastic goiters, 21 follicular
adenomas, 5 encapsulated follicular carcinomas, and 22 invasive follicular carcinomas. All of the
cytologic diagnoses were subsequently confirmed by histologic examination. Cellular aggregates
provided the maximum diagnostic information. Stepwise discriminant analysis revealed that
nuclear size, nuclear roundness, and the percentage of nuclear area overlap (NAO) in syncytial
tissue fragments, allow optimum differentiation of hyperplasia, adenomas, and carcinoma. All of
the poorly differentiated carcinomas (large NA, low NR, high NO, and high NAO) could be readily
diagnosed. Discriminant analysis allowed the differentiation of carcinoma from adenoma in 20 of
22 cases (91%) and correct identification of 19 of 21 adenomas (Table 7.15 ). The two cases of
follicular carcinomas misdiagnosed as adenoma by discriminant analysis represent insular
carcinomas in which the malignant follicular cells are characteristically much smaller (see
Chapter 10 ).

An overlap of cell and nuclear size in hyperplastic goiters and in some follicular adenomas
explains the results of discriminant analysis in which two adenomas were incorrectly identified
as hyperplasia and three hyperplasias as adenomas.

The study by Crissman and co-workers,72 as summarized in Tables 7.15 , 7.16 and 7.17 ,
concluded that (i) nuclear size remains an important criterion in differentiating hyperplastic
nodules from follicular neoplasms, and is most important in separating follicular adenoma from
follicular carcinoma; and (ii) the nuclear area overlap (NAO) in syncytia demonstrates the
greatest observed differences in separating hyperplasias, adenoma, and carcinoma. Table 7.18
lists similar observations reported in other studies.73 , 74 , 75 The morphometric analyses by
DeSantis and colleagues76 on histologic sections were similar to those reported by Crissman and
co-workers.72 DeSantis and associates76 reported a mean nuclear area of 22.6 µm2 in normal
thyroid, 30.9 µm2 in goiters, 37.4 µm2 in follicular adenomas, and 59.3 µm2 in follicular
carcinomas. These studies strongly support the cytologic observations. However, most
cytopathologists are reluctant to attempt cytologic classification and separation of follicular
lesions.3 , 4 , 9 , 15 , 77 , 78 , 79 , 80

Issue #2: If Cytologic Differentiation Is Attempted, What Is the

Diagnostic Accuracy?
Our experience with cytohistologic correlation of all the follicular lesions and the incidence of
follicular carcinoma/follicular variant of papillary carcinoma during a 7-year period from 1976 to
19836 is listed in Table 7.10 . The first 3 years of data reflects a learning curve as we ventured
into fine-needle biopsy of the thyroid in late 1976. Using the criteria listed in Table 7.8 , at least
70% to 75% of the follicular carcinomas were identified accurately (Tables 7.11 and 7.12 ).6 The
detection
P.87
P.88
P.89
P.90
P.91
P.92
P.93
P.94
rate was substantially lower when no attempts were made to differentiate follicular carcinomas
from other follicular lesions. As we gained experience with an increasing number of aspirates
and their cytohistologic correlations, we attempted to separate various follicular lesions
cytologically, which resulted in improved accuracy of the cytologic interpretations, as noted in
Table 7.12 . Fifty-three percent of the follicular carcinomas were identified cytologically in the
first 3 years as against 75% during the second 4-year period, which represents a substantial
increase in the detection rate.

Nodular Goiter
107
2
1
3
—
4
45
52
—
Follicular Adenoma
158
14
4
9
2
5
83
37
4
Suspected FCA
46
11
—
—
—
5
18
10
2
FCA
37
25
—
—
—
4
6
1
1
Suspected FVPC
7
—
4
—
—
—
2
1
—
FVPC
24
—
24
—
—
—
—
—
—
Totals
379
52
33
12
2
18
154
101
7
AA, atypical adenoma; FAD, follicular adenoma; FCA, follicular carcinoma; FVPC, follicular
variant of papillary carcinoma; HASH, Hashimoto's thyroiditis; MT, medullary carcinoma of the
thyroid; NG, nodular goiter; PCA, papillary carcinoma.

Histologic Diagnosis

Cytologic No.
Diagnosis Cases FCA FVPC PCA MCT AA FAD NG HASH

TABLE 7.10 CYTOHISTOLOGIC CORRELATION OF

FOLLICULAR LESIONS OF THE THYROID (EXCLUDING
HÃœRTHLE CELL LESIONS)

Follicular carcinoma
25
70%
Suspected follicular carcinoma
11
Cellular follicular adenoma
14
Nodular goiter
2
TOTAL
52

TABLE 7.11 CYTOLOGIC DIAGNOSIS OF 52 HISTOLOGICALLY

CONFIRMED FOLLICULAR CARCINOMAS

Follicular carcinoma
7 (53%)
18 (75%)
Atypical adenoma
1
3
Nodular goiter
1
0
Follicular adenoma
3
3
Hashimoto's thyroiditis
1
—
TOTAL
13
24

Histologic Diagnosis First 3 Years Second 4 Years

TABLE 7.12 HISTOLOGIC DIAGNOSIS OF 37 CASES

CYTOLOGICALLY INTERPRETED AS FOLLICULAR CARCINOMA:
COMPARISON OF TWO TIME PERIODS
The incidence of follicular carcinoma among the cases cytologically interpreted as follicular
adenomas was 18% cumulative for 7 years, but was considerably lower (14%) during the second 4-
year period as compared to 21% during the first 3 years (Table 7.13 ), as experience was gained
in recognizing the cytologic patterns of papillary carcinoma and its follicular variant.

Papillary carcinoma
7
2
9
Follicular variant of
papillary carcinoma
4
0
4
Follicular carcinoma
6
8
14
Medullary carcinoma
1
1
2
Atypical adenoma
1
5
6
Follicular adenoma
31
44
75
Nodular goiter
28 (45%)
14 (19%)
42
Hashimoto's thyroiditis
6
—
6
TOTAL
84
74
158
PERCENt(%) carcinoma
21
14
18

Histologic First 3 Years Second 4 Years

Diagnosis (Oct. 1976–1979) (1980–1983) Total
 TABLE 7.13 HISTOLOGIC DIAGNOSIS OF 158 THYROID
NODULES CYTOLOGICALLY INTERPRETED AS CELLULAR
ADENOMA: COMPARISON OF FIRST 3 AND SECOND 4 YEARS
This trend has continued, as seen in a more recent review of follicular neoplasms during a period
of 10 years from 1990 to 2000 (Table 7.14 ).81 The follicular neoplasms were subclassified into
five categories: (i) follicular adenoma when the cytologic features presented a micro-
macrofollicular pattern, that is, a combination of cytologic features of nodular goiter as well as
features suggestive of cellular follicular adenomas; (ii) cellular adenoma when the pattern
indicated microfollicular/trabecular adenoma but lacked nuclear features of follicular
carcinoma; (iii) cellular follicular neoplasm that included a suspicious category; (iv) follicular
carcinoma; and (v) follicular variant of papillary carcinoma. It is noteworthy that the cumulative
incidence of carcinoma when the first three categories were combined, corresponding to the
indeterminate/suspicious group, was 16.5%. There was one follicular variant of papillary
carcinoma and no follicular carcinoma in the group cytologically interpreted as cellular follicular
adenoma. Of the 13 cases cytologically interpreted as follicular carcinoma, 10 were proven to be
malignant, 8 as follicular carcinoma, and 2 as the follicular variant of papillary carcinoma. Of
the 8 cases cytologically interpreted as the follicular variant of papillary carcinoma, 7 were
histologically confirmed (87% concordance), and 1 was proven to be a follicular carcinoma. The
presence of nuclear features of conventional papillary carcinoma allows the diagnosis of the
follicular variant of papillary carcinoma with high degree of accuracy (Table 7.13 ).

Follicular adenoma
21
2
16
2
1
Cellular adenoma
22
5
1
15
1
Cellular follicular neoplasm
30
5
16
3
5
1a
Follicular carcinoma
13
2
1
8
2
Follicular variant of
papillary carcinoma
8
1
7
a Sampling error.

NG, nodular goiter; CG, colloid goiter; HASH, Hashimoto's hyroiditis; FA, follicular adenoma;
FCA, follicular carcinoma; FVPC, follicular variant of papillary carcinoma; PC, papillary
carcinoma; AC, anaplastic carcinoma.
From Boboc L, Suterwala S, Kini SR, et al. Cytology can predict histology of follicular thyroid
neoplasm. Presented at 74th Annual meeting of the American Thyroid Association, October
10–13, 2002.

Cytologic Diagnosis NO NG/CG HASH FA FCA FVPC/PC AC

TABLE 7.14 CYTO-HISTO CORRELATIONS OF 94 CASES WITH

CYTOLOGIC DIAGNOSES OF FOLLICULAR NEOPLASTIC
LESIONS

Correctly Predicted
17
Hyperplasia
Hyperplasia
26.49
0.93
2.98
19
Adenoma
Adenoma
35.56
0.94
14.19
20
Carcinoma
Carcinoma
47.66
0.92
14.19
Incorrectly Predicted
3
Hyperplasia
Adenoma
31.94
0.94
4.93
2
Adenoma
Hyperplasia
26.33
0.94
6.25
2
Carcinoma
Adenoma
34.60
0.94
13.65
From Crissman JD, Drozdowicz S, Johnson C, et al. Fine needle aspiration diagnosis of
hyperplastic and neoplastic follicular nodules of the thyroid. Anal Quant Cytol Histol.
1991;13:321–328.

Discriminant Mean Nuclear Extent of Nuclear

No. Diagnosis Analysis Nuclear Area Roundness Area Overlap (%)

TABLE 7.15 MORPHOMETRIC PARAMETERS OF FOLLICULAR

LESIONS: DISCRIMINANT ANALYSIS

Hyperplasia (FH)
—
27.309
P value, FH vs. FA
<0.0001
Adenoma (FA)
41.007
35.584
P value, FA vs. EFC
-0.5842
-0.0035
Encapsulated
carcinoma (EFC)
43.591
44.112
P value, EFC vs. IFC
-0.3398
-0.6219
Invasive (IFC)
49.524
44.478
 P value, IFC vs. FA
41.007
35.584
Adenoma (FA)
41.007
35.584
aThe two-tailed, unpaired t test was used.
FH, follicular hyperplasia; FA, follicular adenoma; EFC, encapsulated follicular carcinoma; IFC,
invasive follicular carcinoma.
From Crissman JD, Drozdowicz S, Johnson C, et al. Fine needle aspiration diagnosis of
hyperplastic and neoplastic follicular nodules of the thyroid. Anal Quant Cytol Histol.
1991;13:321–328.

Mean Nuclear Area (µm2 )

Parameter Single Cells Sheets/Syncytia

TABLE 7.16 MORPHOMETRIC PARAMETERS OF FOLLICULAR

LESIONS: STATISTICAL EVALUATIONa

No. patients
20
21
5
22
% of nuclei with overlap
21.170
30.262
42.926
57.466
% of nuclear area with
overlap
3.316
6.575
13.325
16.749
From Crissman JD, Drozdowicz S, Johnson C, et al. Fine needle aspiration diagnosis of
hyperplastic and neoplastic follicular nodules of the thyroid. Anal Quant Cytol Histol.
1991;13:321–328.

Encapsulated Invasive
Parameter Hyperplasia Adenoma Carcinoma Carcinoma

TABLE 7.17 MORPHOMETRIC PARAMETERS OF FOLLICULAR

LESIONS: CELLS WITH NUCLEAR OVERLAP AND AN AREA OF
OVERLAP

Hyperplasia
25
56.1
35
43.6
—
27.3
Adenoma
74
66.4
42
50.1
41.0
35.6
Carcinoma
131
84.0
47
64.2
49.5
46.5
Measured only well-differentiated follicular carcinomas (five).
(a) From Crissman JD, Drozdowicz S, Johnson C, et al. Fine needle aspiration diagnosis of
hyperplastic and neoplastic follicular nodules of the thyroid. Anal Quant Cytol Histol.
1991;13:321–328.

Fixed, Papanicolaou-Stained Preparation (µm2

)

Air-Dried Cytology
Preparation (µm2 ) Current Study

Boon et Wright et Luck et Wright et

al.75 al.74 al.73 al.74 Single Syncytia
Disease (1980) (1987) (1982)a (1987) Cells (1990)

TABLE 7.18 MORPHOMETRIC PARAMETERS OF FOLLICULAR

LESIONS: MEAN NUCLEAR AREA—COMPARISON WITH DATA
FROM PUBLISHED STUDIES
Lately, the follicular variant of papillary carcinoma has generated considerable interest in the
pathology community. The literature has focused on the difficulty in the diagnosis of the
follicular variant of papillary carcinoma both cytologically and
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P.96
P.97
histologically.58 , 59 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 However,
there seems to be wide variance in cytologic recognition of the follicular variant of papillary
carcinoma. Some have reported very low sensitivity. Many cases of the follicular variant of
papillary carcinoma are interpreted cytologically as either nodular goiter or follicular neoplasms.
The diagnostic problems very often arise from the fact that in some cases of the follicular
variant of papillary carcinoma, the typical nuclear morphology may be limited to only a few
focal areas within a tumor, or even in only one area depending on the sections taken. The
surgical pathologist is often at a loss to make an unequivocal diagnosis of the follicular variant of
papillary carcinoma. Chan has recommended strict guidelines for histologic diagnosis of the
follicular variant of papillary carcinoma.96 The follicular neoplasms continue to cause great
diagnostic concerns. LiVolsi and Baloch59 feel that even if the areas showing features of
papillary carcinoma are focal, the neoplasm should be diagnosed as the follicular variant. If only
a single focus is identified, it should be referred to as follicular adenoma with a single focus of
papillary carcinoma. Williams and associates97 have proposed a scheme for addressing this issue
and recommend the term "well-differentiated tumor of uncertain malignant potential." The
same holds true for cytologic samples. The absence of typical nuclear features in the cytologic
samples in these cases may be related to sampling.

Issues # 3 and 4: For Patient Management, Is Cytologic

Differentiation of Follicular Lesions Better than Grouping All
Lesions into One Category ("Indeterminate/Suspicious") and
Recommending Surgery for All? Is the Number of Surgical Removals
of the Thyroid for Benign Disease Reduced when Cytologic
Differentiation Is Attempted?
The purpose of the fine-needle biopsy is defeated if no attempt is made to differentiate non-
neoplastic from neoplastic lesions. One must try to triage the hyperplastic goiters from follicular
neoplasms in order to avoid unnecessary surgeries. The incidence of benign non-neoplastic
lesions in the group cytologically interpreted as indeterminate is 20% to 30%.3 , 4 The yield of
malignancy from the indeterminate/suspicious group is reported to be roughly 20%, of which 9%
represent follicular carcinomas.3 The majority of the remaining cases have proven to be
follicular adenomas. These results parallel most other reported studies where all follicular
neoplasms are cytologically grouped into one category.

SUMMARY
In conclusion, the various follicular lesions can be differentiated from cytologic samples with a
fair degree of accuracy if an attempt is made. The prerequisites are an adequate specimen that
is wet-fixed and stained by the Papanicolaou technique, with the best results obtained by using
spray fixatives. An alternative is hematoxylin and eosin stain.

The cytologic differentiation between cellular follicular adenomas and some low-grade or well-
differentiated follicular carcinomas is difficult. Poorly differentiated follicular carcinomas are
easily recognized. Mere cellularity of the aspirate with abundance of follicular cells and lack of
colloid do not equate with neoplasia. Syncytial architecture of the tissue fragments and the
nuclear size are important parameters in differentiating hyperplastic goiters from follicular
neoplasms. Increase in the nuclear size of the follicular cells and the presence of nucleoli favor
follicular carcinoma, while powdery chromatin, nuclear inclusions, grooves, and nucleoli favor
the follicular variant of papillary carcinoma.

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2.Löwhagen T. Thyroid. In: Zajicek J, ed. Aspiration Biopsy Cytology. Part I: Cytology of
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3.Gharib H, Goellner JR. Fine-needle aspiration biopsy of the thyroid: An appraisal. Ann
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4.Caruso D, Mazzaferri EL. Fine needle aspiration biopsy in the management of thyroid
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6.Kini SR, Miller JM, Hamburger JI, et al. Cytopathology of follicular lesions of the thyroid
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10.Chan JKC, Hirokawa M, Evans H, et al. Follicular adenoma. In: De Lellis, RA, Lloyd R,
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13.Williams ED, Doniach I, Bjarnason O, et al. Thyroid cancer in an iodide rich area. Cancer
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14.Cusick EL, McIntosh CA, Krukowski ZH, et al. Cystic change and neoplasia in isolated
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16.Carney JA, Ryan J, Goellner JR. Hyalinizing trabecular adenoma of the thyroid gland. Am
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Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 8 - Hürthle cell Lesions

8
Hürthle cell Lesions

Hürthle cells—also called "oncocytes," "Askanazy cells," or "oxyphils"—are altered follicular cells
Although the cells described originally by Hürthle were probably parafollicular cells, the term
"Hürthle cell" has become established in the medical literature. They are large polygonal cells (Fig
8.1 and 8.2 ) with abundant granular cytoplasm, the granularity being the result of abundant
mitochondria (Fig. 8.3 ).1 , 2 Hürthle cells do not concentrate radioactive iodine.

FIGURE 8-1. Comparison of normal follicular cells and Hürthle cells in histologic sections of thyroi
The follicular cells are small, cuboidal, and single layered, lining the follicles; they have scant
cytoplasm and round nuclei with compact to finely granular chromatin. Nucleoli are usually not pres
B. The Hürthle cells are larger and variable in size with abundant granular cytoplasm due to
accumulation of large numbers of mitochondria.
FIGURE 8-2. Comparison of normal follicular cells and Hürthle cells in cytologic samples of thyroid
The follicular cells are small and cuboidal with scant cytoplasm. Their nuclei are round with compac
finely granular chromatin. Nucleoli are usually absent (× 1,000). B. The Hürthle cells are large an
polygonal with abundant granular cytoplasm and a slightly eccentric nucleus with a prominent
macronucleolus in neoplastic cells (× 1,000).
FIGURE 8-3. Ultrastructure of a Hürthle cell exhibiting abundant mitochondria in the cytoplasm.

The Hürthle cell metaplasia of follicular cells probably reflects a functional state labeled by
Friedman3 as a "cellular involution." It is seen in several conditions affecting the thyroid, such as
Hashimoto's thyroiditis, adenomatous goiter, Graves disease, and others (Table 8.1 ). This change ca
extensive, resulting in the formation of nodules that are either palpable, or detected on ultrasound.
They clinically cannot be differentiated from neoplasms, often necessitating fine-needle biopsies. T
chapter deals with the cytopathology of Hürthle cell neoplasms and non-neoplastic Hürthle cell
nodules, which together constitute Hürthle cell lesions of the thyroid (Table 8.2 ).

Hashimoto's thyroiditis
Adenomatous goiter
Graves disease
Radiation
Myxedema
Partial Thyroidectomy

TABLE 8.1 CONDITIONS ASSOCIATED WITH HÃœRTHLE CELL

(OXYPHILIC) CHANGE

Hürthle cell neoplasms

Non-neoplastic Hürthle cell nodules
Hashimoto's thyroiditis
Adenomatous (nodular) goiter
Graves disease

TABLE 8.2 DIFFERENTIAL DIAGNOSIS OF HÃœRTHLE CELL

LESIONS

HÃœRTHLE CELL NEOPLASMS

Hürthle cell neoplasms have generated considerable interest over the last several decades4 , 6 an
still do. The controversies and debates over almost every aspect of Hürthle cell neoplasms continu
To begin with, Hürthle cell neoplasms are considered by many pathologists as morphologic variant
follicular neoplasms; hence they are classified and referred to as "follicular adenoma, oxyphil cell ty
and "follicular cell carcinoma, oxyphil cell type." Proponents of this view believe that there is no
justification for isolating Hürthle cell adenomas or carcinomas, because their morphologic pattern
behavior parallel that of follicular adenoma or carcinoma, respectively. It is felt that the oncocytic
change is an inconsequential event that has no effect on the natural history.7 , 8 , 9 , 10 , 11 , 12 ,
14 , 15 , 16 , 17 , 18 In sharp variance with this viewpoint, was the study of Thompson, et al.19 The
authors reviewed 25 Hürthle cell neoplasms and found that their biological behavior was
unpredictable, and that the distinction between an adenoma and carcinoma was not easily made by
conventional criteria used. for follicular neoplasms. According to Thompson, et al.19 Hürthle cell
tumors followed an aggressive course with a frequent recurrence rate, distant metastasis, and a hig
incidence of fatal outcomes, regardless of their invasive characteristics. Therefore, they assigned th
term "Hürthle cell tumors" to all neoplasms comprising Hürthle cells and recommended total
thyroidectomy. Gundry, et al.20 confirmed this observation several years later. Rosai,2 Carcangiu, e
al.21 Grant , et al.22 Tollefsen, et al.23 and many others believe that although Hürthle cell adeno
behave in a benign fashion, Hürthle cell carcinomas represent an entity distinct from follicular
carcinomas, with an aggressive behavior, as supported by the study of Carcangiu, et al.21

The above-mentioned controversy extends to the cytologic interpretation as well. Reasons are same
that for follicular lesions. The histologic criteria for the diagnosis of malignant Hürthle cell carcino
parallel those of follicular carcinomas. Needless to say, their interpretations have become very
subjective, as already discussed in Chapter 7 . Many cytopathologists and therefore
endocrinologists/surgeons believe that the cytologic differentiation of Hürthle cell adenomas from
Hürthle cell carcinomas is not possible,24 , 25 , 26 , 27 , 28 , 29 , 30 because the diagnosis of
malignancy is made only from histologic examination. Along the same line, it is also believed by som
cytopathologists that non-neoplastic Hürthle cell nodules cannot be differentiated from Hürthle
neoplasms. Consequently, all aspirates composed of a Hürthle cell population are lumped togethe
Hürthle cell lesions and categorized as "indeterminate/suspicious" in the reporting scheme, thereb
recommending surgical excision.24 , 25 , 26 , 27 , 28 , 29 , 30

The author disagrees with this approach, and strongly feels that the cytologic triage of Hürthle ce
lesions into non-neoplastic and neoplastic, and benign and malignant, is possible.31 , 32 These
observations are supported by other investigators.33 , 34 , 35

The author's clinical colleagues (endocrinologists and surgeons) believed and still believe that Hürt
cell neoplasms are a separate entity from follicular neoplasms. Therefore, Hürthle cell neoplasms
were cytologically placed in a separate category as Hürthle cell tumors, but without separation in
adenoma and carcinoma, when the FNA project was launched in the author's institution in 1976. Thi
was in keeping with Thompson's recommendation.19 We gained the experience in cytologic
presentations of Hürthle cell neoplasms from their
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cytohistologic correlations as well as from misinterpreted cases. First, it became apparent that
Hürthle cell adenomas can be separated from their malignant counterparts; second, the non-
neoplastic Hürthle cell lesions present a different morphologic pattern, allowing their recognition
from cytologic samples.

As in cytopathology of any other diseases of the thyroid, or for that matter of any other site or orga
100% diagnostic accuracy cannot be achieved. Realizing this, we continue to triage Hürthle cell le
from the cytologic samples and offer the probabilities of neoplasia and malignancy with considerabl
success.
Hürthle Cell Adenoma
The synonyms for Hürthle cell adenoma are oncocytic-adenoma, oxyphilic-adenoma, and follicular
adenoma with oncocytic features.

Hürthle cell adenomas are benign thyroid neoplasms, exclusively or predominantly composed of
Hürthle cells, or oncocytes (over 75%).2 , 14 , 21 , 22 , 136 , 137 , 138 , 139 Their true incidence
cannot be assessed, because they are often considered as the morphologic variants of follicular
adenomas. Hürthle cell adenomas are more frequent in women, with a male:female ratio of 1:8.2
Although Hürthle cell adenomas can occur at any age, they are more common between the third a
fourth decades of life. The clinical presentation is same as follicular adenomas.

Gross and Histologic Features

Hürthle cell adenomas are usually solitary, discrete tumors that may reach a large size. Multiple
Hürthle cell tumors as well as bilaterality and the association with other diseases have been
reported.14 Their cut surfaces are bulging, and have characteristic mahogany-brown coloration (Fig
). Hürthle cell tumors are very vascular and have frequent hemorrhage and cystic changes.
FIGURE 8-4. Gross photograph of a Hürthle cell neoplasm. Note the characteristic mahogany-brow
color on cut surface.

Histologically, Hürthle cell adenomas are completely encapsulated. The capsule is variably thick.
tumor is composed entirely of large Hürthle cells with abundant, granular, consistently deep
eosinophilic cytoplasm (Figs. 8.5 and 8.6 ). The cell borders are distinct and well defined. Their nuc
are round, uniform containing finely granular chromatin with a prominent macronucleolus. The N/C
ratios are characteristically very low. The growth patterns of Hürthle cell adenomas vary from
follicular, solid, and trabecular to occasional papillary patterns (Figs. 8.5 , 8.6 and 8.7 ). The follicl
vary in size and may contain abundant colloid (Figs. 8.6B and 8.7C ). Cystic change is not uncommon
Psammoma bodies may be present in adenomas with a papillary growth pattern. Hürthle cell
adenomas may demonstrate nuclear pleomorphism. But the chromatin in these pleomorphic nuclei i
deep-staining, smudgy, and structureless, indicating degeneration; and the nuclei are not indicative
malignancy.

FIGURE 8-5. Histologic section of a Hürthle cell adenoma with a trabecular pattern, formed by lar
polygonal cells, containing abundant eosinophilic cytoplasm, and having uniform small nuclei with
prominent macronucleoli. The N/C ratios are low.

FIGURE 8-6. A . Histologic section of an encapsulated Hürthle cell adenoma, low power. B . Highe
magnification showing a follicular growth pattern. Note that the component cells are large with wel
defined cell borders. The cytoplasm is abundant, and deeply eosinophilic. The N/C ratios are low. T
nuclei are uniform. The follicles contain colloid. Aspirates of these lesions may contain a significant
amount of colloid.
FIGURE 8-7. A. Histologic section of an encapsulated Hürthle cell adenoma with a papillary growt
pattern, low power. B. Medium power view, showing papillary fronds lined by oncocytic cells, conta
round uniform nuclei with macronucleoli. Note the lack of characteristic nuclear morphology of a
conventional papillary carcinoma. C. Higher magnification. Note abundant colloid.

Cytopathologic Features of Hürthle Cell Adenoma

Hürthle cell adenoma cells present a very characteristic pattern on account of their abundant gran
cytoplasm and prominent cherry-red macronucleus (Table 8.3 ; Figs. 8.8 , 8.9 , 8.10 , 8.11 , 8.12 , 8
and 8.14 ).31 , 32 , 33 , 34 , 35 , 40 In general, the aspirates of Hürthle cell adenomas are very
cellular and demonstrate a strikingly monomorphic cell population. The neoplastic Hürthle cells te
to present themselves as isolated, in small groups, and in tissue fragments. A dispersed cell pattern
more commonly encountered. The tissue fragments are seen as sheets (two-dimensional) and as
follicles. Syncytial architecture is not a feature of Hürthle cell adenomas. A papillary pattern may
occasionally be present. The tissue fragments of Hürthle cells often demonstrate transgressing blo
vessels.41 , 42 , 43 Although we have noted this feature in Hürthle cell neoplasms, the frequency
been low in our experience. The cells of Hürthle cell adenomas are usually very large, polygonal,
round to oval, and with well-defined cell borders. Binucleation is frequent. The nuclei can be centra
eccentric. The cytoplasm is abundant and granular, resulting in very low N/C ratios. The staining of
cytoplasm is dependent on the fixative and the stains used. With spray-fixed smears and Papanicola
stain, the cytoplasm stains eosinophilic, cyanophilic, or amphophilic (Figs. 8.8 , 8.9 , 8.10 , 8.11 , 8
and 8.13 ) compared to smears wet-fixed with 95% alcohol; the Hürthle cells stain deep eosinophil
similar to an H&E stained specimen (Fig. 8.14D ). The Hürthle
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cell cytoplasm stains lavender with Romanowsky stain (Fig. 8.14C ). The nuclei of the Hürthle cell
adenomas cells are always round, with smooth, crisp, nuclear membranes containing finely granular
evenly dispersed chromatin. A single cherry-red macronucleolus is the hallmark of neoplastic Hürt
cells, a feature that often helps differentiate Hürthle cell neoplasm from other thyroid follicular/C
cell derived neoplasms and importantly from non-neoplastic Hürthle cell lesions. Intranuclear
inclusions are not the feature of Hürthle cell adenomas. In a given neoplasm, the nuclei of the
Hürthle cell adenoma cells tend to be of the same size and very uniform. Intracytoplasmic vacuole
lumina, have been described in neoplastic Hürthle cells.41 , 42 , 43 Rarely, psammoma bodies ma
identified.

Cellularity
Generally very cellular
Presentation
Monomorphic, cells isolated, in loose groups or in tissue fragments, either monolayered or forming
follicles; papillary configuration ±; dispersed pattern more common; transgressing blood vessels
within
the tissue fragments ±
Cells
Generally large, round, oval to polygonal; tend to be of uniform shape in a given tumor; well-define
cell
borders; low N/C ratios
Nucleus
Single or binucleated, rarely multinucleated; central to eccentric; round with smooth nuclear
membranes,
consistently uniform in size; finely granular, evenly dispersed chromatin, prominent, single cherry
macronucleolus; intranuclear cytoplasmic inclusions not present
Cytoplasm
Abundant, granular, may stain eosinophilic, cyanophilic, or amphophilic with Papanicolaou stain; de
eosinophilic with hematoxylin-eosin stain; light purple to lavender with Romanowsky stain; vacuol
±
Psammoma Bodies
Infrequently present
Background
Frequently bloody; colloid variable; usually clean; histiocytes ±
Ultrastructure
Large numbers of mitochondria
Immunoprofile
Immunoreactive to thyroglobulin, TTF-1 ±, low-molecular-weight keratin

TABLE 8.3 CYTOPATHOLOGIC FEATURES OF HÃœRTHLE CELL

ADENOMA
FIGURE 8-8. FNA of a Hürthle cell adenoma. The cellular aspirate shows large, round to polygonal
cells with well-defined cell borders, arranged in sheets. Note the abundant granular eosinophilic
cytoplasm. The nuclei are uniform, round, central to eccentric, and with finely granular chromatin.
cherry-red macronucleolus is the hallmark of neoplastic Hürthle cells. Note low N/C ratios. There
colloid in the background.
FIGURE 8-9. FNA of another Hürthle cell adenoma. The cellular aspirate shows large, round to
polygonal cells with well-defined cell borders, occurring singly or arranged in sheets. Note that the
abundant granular cytoplasm is stained cyanophilic. The nuclei are uniform, round, and central to
eccentric, with finely granular chromatin containing cherry-red macronucleolus.

FIGURE 8-10. This FNA of a Hürthle cell adenoma shows neoplastic cells with either (A) eosinophil
(B) cyanophilic cytoplasm. The cells are pleomorphic in size and shape, but contain abundant granu
cytoplasm with low N/C ratios. The nuclei are uniform.
FIGURE 8-11. A. The neoplastic cells in FNA of this Hürthle cell adenoma are round but large, and
seen isolated, in groups, or in sheets. The cytoplasm is abundant and granular. The nuclei are round
uniform, containing macronucleolus. Note the cytoplasmic vacuole. B. Histologic section of the exci
tumor showing a solid growth pattern with occasional follicular differentiation. Note the large cell s
and low N/C ratios.

FIGURE 8-12. A. FNA of a Hürthle cell adenoma depicting marked cellularity and a clean backgrou
(low power). B. Higher magnification highlighting the characteristic cytomorphology. The neoplastic
Hürthle cells are round to oval, containing amphophilic cytoplasm. Some cells are binucleated.
Macronucleoli are conspicuous. The background is clean with no colloid.
FIGURE 8-13. FNA of a Hürthle cell adenoma with follicular pattern. A. The aspirate is very cellula
with several tissue fragments in a clean background. B. Higher magnification demonstrating large, r
to oval Hürthle cells forming follicles. Their granular cytoplasm is stained cyanophilic. Note promi
nucleoli. Because of the high N/C ratios, malignancy was suspected. Thyroidectomy revealed an
encapsulated Hürthle cell adenoma.
FIGURE 8-14. FNA of a Hürthle cell adenoma. A , B . Papanicolaou-stained preparation showing la
round to polygonal cells with abundant cytoplasm. The nuclei are pleomorphic, with low N/C ratios.
Same aspirate, Diff-Quik preparation. D . Same aspirate, hematoxylin-eosin preparation. (Courtesy o
Mithra Baliga, MD, University of Mississippi, Jackson.)

The background is usually bloody. The amount of colloid is variable: it can be absent, scant, or
appreciable. The presence of colloid is not a feature against the diagnosis of Hürthle cell neoplasm
However, benign, regular-type, follicular cells are not present in the background. The occurrence o
histiocytes with or without hemosiderin indicates old hemorrhage within the tumor and does not rul
out a neoplasm.

Being very vascular, Hürthle cell adenomas are prone to postbiopsy infarction (see Chapter 20 ).44
The importance of knowing this lies in the fact that infarction may compromise the final histologic
diagnosis, in the event that the surgical pathologist is not informed of the cytologic diagnosis. In thi
case, the pathologist may overlook the viable tumor usually present as a thin rim at the periphery.
Spontaneous infarction can also occur in Hürthle cell adenomas.44

Hürthle Cell Carcinoma

Synonyms for Hürthle cell carcinoma are oncocytic carcinoma, oxyphilic carcinoma, and follicular
carcinoma with oncocytic features.

Hürthle cell carcinomas are predominantly or exclusively composed of Hürthle cells. Again, their
true incidence is not known, as they are often considered morphologic variants of follicular
carcinomas.7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 They are considered uncommon,
comprising 2% to 3% of all thyroid malignancies and 20% of follicular carcinomas.14 Hürthle cell
carcinomas are more common in women, and occur in the older age group, the mean age at the tim
presentation being 55 years.
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They present an aggressive clinical behavior, with a high degree of mortality.2 , 19 , 20 , 21 , 22 , 2
45 , 46 , 47 , 48 , 49 , 50 Hürthle cell carcinomas are locally invasive, frequently recur, and unlike
follicular-carcinomas, metastasize to the cervical lymph nodes. They also metastasize to the distant
organs such as lungs, bones, and liver. Hürthle cell carcinomas do not take up radioactive iodine.
Large tumor size (> 4 cm), extrathyroidal extension, and nodal metastasis are factors associated wit
the worst outcome.
Gross and Histologic Features
Grossly, Hürthle cell carcinomas are large and bulky, replacing the entire lobe (Figs. 8.15 and 8.25
with a fleshy, brown, cut surface, and frequently with areas of necrosis and hemorrhage. Histologica
Hürthle cell carcinomas may be completely encapsulated with capsular or vascular invasion, or the
can be widely invasive. Hürthle cell carcinomas are characterized by solid, alveolar, trabecular, o
papillary growth patterns (Figs. 8.16 , 8.17D , 8.18C , 8.19B , 8.20E , 8.20F , 8.22C , 8.22D , 8.24C ,
8.25F , 8.26C and 8.28B ). The malignant Hürthle cells are usually of much smaller size compared
their benign counterpart. The N/C ratios are high, and macronucleoli are very prominent. The
carcinoma demonstrates an increased proliferative activity with mitosis. Hürthle cell carcinomas a
demonstrate a poorly differentiated pattern with large, pleomorphic, malignant cells containing cle
malignant nuclei. The carcinoma frequently involves the perithyroidal soft tissues.

FIGURE 8-15. Gross photograph of a Hürthle cell carcinoma, involving the entire right lobe of the
thyroid. The tumor is bulky and fleshy with areas of hemorrhage and necrosis.
FIGURE 8-16. Histologic sections of a Hürthle cell carcinoma, showing a solid and a trabecular pat
formed by smaller neoplastic cells with very high N/C ratios.

FIGURE 8-17. FNA of Hürthle cell carcinoma. A. The aspirate is markedly cellular with neoplastic
forming a dissociated pattern. The background is clean and lacks colloid (low power). B , C . Higher
magnification showing much smaller cells, occurring singly, in loosely cohesive groups, or in syncytia
tissue fragments. Smaller cell size, scant but dense cytoplasm, relatively large nucleus with high N/
ratios, and prominent macronucleoli characterize malignancy in Hürthle cell neoplasms. Also, note
plasmacytoid cells, resembling medullary-carcinoma cells. Thyroidectomy confirmed a Hürthle cel
carcinoma. D . Histologic section showing a solid growth pattern with small to medium-sized cells an
high N/C ratios.
FIGURE 8-18. FNA of Hürthle cell carcinoma. A . The neoplastic Hürthle cells are present in
syncytial tissue fragments. The malignant cells are medium-sized, round, oval to columnar, and
containing scant cytoplasm with high N/C ratios. Note the prominent macronucleoli. B . Another fie
showing syncytial arrangement with crowding and overlapping of nuclei. Their chromatin is coarsely
granular, and single or multiple nucleoli are conspicuous. C . Histologic section of the carcinoma.

FIGURE 8-19. A . Another example of Hürthle cell carcinoma, showing a dispersed pattern formed
small to medium-sized uniform cells with high N/C ratios. Note the characteristic nuclear morpholog
with prominent macronucleoli. B . Histologic section of the excised tumor.

FIGURE 8-20. FNA of a Hürthle cell carcinoma. A, B . Papanicolaou-stained preparation showing

syncytial tissue fragments of small Hürthle cells with high N/C ratios. Note scant but granular to d
cytoplasm, round nuclei with macronucleoli. C . Smear stained with hematoxylin &eosin. The cells a
in syncytial arrangement, containing eosinophilic cytoplasm. The nuclei are uniform, but contain
prominent macronucleoli. D . Diff-Quik-stained preparation showing a syncytial tissue fragment of
Hürthle cells. Note prominent nucleoli. E . Histologic section showing capsular invasion. F. Higher
magnification to show the solid growth pattern. (Courtesy of Mithra Baliga, MD, University of Mississ
Jackson.)

The diagnosis of Hürthle cell carcinoma is entirely based on demonstrating invasive characteristics
such as capsular and vascular invasion and invasion of the surrounding parenchyma, as described for
conventional follicular carcinomas. The same diagnostic criteria are applicable and the same
controversies are also encountered.

Cytopathologic Features of Hürthle Cell Carcinoma

The aspirates of Hürthle cell carcinomas tend to be hypercellular and exhibit a spectrum of cytolo
features (Table 8.4 ; Figs. 8.17 , 8.18 , 8.19 , 8.20 , 8.21 , 8.22 , 8.23 , 8.24 , 8.25 , 8.26 , 8.27 , 8.
and 8.29 ), which vary from small to medium-sized, uniform round, cuboidal, plasmacytoid cells wit
high N/C ratios, to a very pleomorphic cell pattern. The latter is only infrequently encountered, wh
the small to medium-sized cell pattern is more commonly observed in our experience. The malignan
cells appear discrete, in loosely cohesive groups or in syncytial tissue fragments, the dispersed cell
pattern being more frequent. Malignant Hürthle cells are characterized by granular, sometimes de
variable but scant cytoplasm, and larger, round nuclei with high N/C ratios (Figs. 8.17 , 8.18 8.19 , a
8.22 , 8.23 , 8.24 ). In fact, a very cellular aspirate with a dispersed cell pattern formed by
monomorphic small to medium-sized Hürthle cells with prominent cherry-red macronucleoli makes
striking presentation, even at low power (Figs. 8.17A and 8.24A ). The neoplastic cells are often stri
of their cytoplasm, resulting in naked nuclei 34 seen in the background.
FIGURE 8-21. FNA of a Hürthle cell carcinoma stained by Diff-Quik. Note that nucleoli are not rea
visible. (Courtesy of Marizza de Peralta, MD, William Beaumont Hospital, Royal Oak, Michigan.)
FIGURE 8-22. FNA of a Hürthle cell carcinoma. A, B . The cellular aspirate is composed of small,
round to cuboidal cells, discrete and forming small syncytial tissue fragments. The cell borders are
poorly defined. N/C ratios are high, and macronucleoli are prominent. C . Histologic section of
carcinoma exhibiting a solid growth pattern. D . Invasion of the blood vessel.

FIGURE 8-23. Another example of a Hürthle cell carcinoma, demonstrating a dispersed cell patter
formed by small to medium-sized cells with high N/C ratios and containing a prominent macronucleo
FIGURE 8-24. Hürthle cell carcinoma. A . Low-power view of the cellular aspirate with a dispersed
pattern. The background is clean, lacking colloid. B . Higher magnification showing oval, uniform, sm
to medium-sized cells. The nuclei are eccentric. But for their macronucleoli, these cells resemble
medullary-carcinoma cells. C . Histologic section showing invasion of the parenchyma outside the
capsule.

Cellularity
Usually very cellular
Presentation
Monomorphic, cells isolated, in loosely cohesive groups or in syncytial tissue fragments with or witho
a follicular pattern; trabecular forms ±; papillary configuration ±; dispersed pattern more comm
transgressing blood vessels within the tissue fragments ±
Cells
Usually small to medium-sized, round, oval to cuboidal, increased N/C ratios, well to poorly defined
borders; cells tend to be uniform in size, but can be large and pleomorphic
Nucleus
Uniformly but slightly increased in size or can be pleomorphic; bimultinucleation ±; central to
eccentric;
round with smooth nuclear membranes; finely granular chromatin, parachromatin clearing ±;
micronucleoli or single to multiple macronucleoli; intranuclear cytoplasmic inclusions ±
Cytoplasm
Variable; scant, more than seen in cells of follicular adenoma, or carcinoma to appreciable cytoplas
generally much less compared to Hürthle cell adenoma cells, dense to granular; may stain
eosinophilic,
cyanophilic, or amphophilic with Papanicolaou stain; deep eosinophilic with hematoxylin-eosin sta
light purple to lavender with Romanowsky stain
Psammoma Bodies
May be present in papillary variant
Background
Usually bloody; colloid generally absent; necrosis ±
Ultrastructure
Large numbers of mitochondria
Immunoprofile
Positive reactivity to thyroglobulin, TTF-1 ± low-molecular-weight keratin

TABLE 8.4 CYTOPATHOLOGIC FEATURES OF HÃœRTHLE CELL

CARCINOMA
The syncytial tissue fragments may show no architectural configurations, or demonstrate follicular o
trabecular patterns. Papillary architecture is encountered in the papillary variant. Many investigato
have reported transgressing blood vessels in the tissue fragments of malignant cells to be considered
key feature in the cytologic diagnosis.28 , 33 , 38 , 39 , 40 The nuclei are uniformly round and only
slightly increased in size, compared to the benign counterpart (Fig. 8.37 ), with finely granular
chromatin and the characteristic macronucleolus. Hürthle cell carcinomas may also exhibit a very
pleomorphic pattern (Figs. 8.25 , 8.26 and 8.27 ). Multiple nucleoli are frequent,
P.108
P.109
P.110
P.111
P.112
 P.113
P.114
along with intranuclear inclusions (Fig. 8.25B ). The presence of intranuclear inclusions is not a
consistent or a specific feature of Hürthle cell carcinomas. They were encountered infrequently; b
if present should raise a high index of suspicion for malignancy.

FIGURE 8-25. This Hürthle cell carcinoma initially presented as a destructive lesion of the vertebr
Physical examination revealed a large thyroid nodule. Both lesions were biopsied which showed simi
cytologic pattern. A, B . FNA of the vertebral mass showing syncytial tissue fragments of Hürthle c
Their cytoplasm is scant, and. macronucleoli are conspicuous. C, D . FNA of the thyroid mass. The c
are clearly malignant, arranged in syncytial tissue fragments with pleomorphic nuclei, prominent
nucleoli, and intranuclear inclusion. E . Gross photograph of the excised thyroid showing a large ma
replacing the entire left lobe. F . Histologic section showing Hürthle cell carcinoma. Note the vasc
invasion.

FIGURE 8-26. FNA of a Hürthle cell carcinoma. A, B . The malignant cells are large, containing
abundant cytoplasm, and are arranged in syncytial fashion. However, note that their nuclei are enla
and very pleomorphic with prominent nucleoli. C . Histologic section of the carcinoma showing a sol
growth pattern formed by pleomorphic malignant cells.
FIGURE 8-27. A different example of Hürthle cell carcinoma, showing syncytial tissue fragments w
very pleomorphic nuclei.

FIGURE 8-28. FNA of a locally recurrent Hürthle cell carcinoma. A . The cells are small, occurring
singly, presenting a dispersed pattern. Note uniformity, scant cytoplasm, high N/C ratios and
macronucleoli. B . Histologic section of the excised tumor showing a solid growth pattern. The
neoplastic cells are smaller with high N/C ratios.

The background may be clean, necrotic, or bloody and devoid of colloid. The presence of histiocyte
with and without hemosiderin has been reported to be a feature against the diagnosis of Hürthle c
tumors.29 Our experience, and that of others, states otherwise. Degeneration and hemorrhage is qu
common in Hürthle cell neoplasms. Local recurrence is frequent with Hürthle cell carcinomas. T
aspirates present the characteristic small to medium-sized cell pattern (Figs. 8.28 and 8.29 ).
FIGURE 8-29. FNA of another example of locally recurrent Hürthle cell carcinoma, consisting of
dispersed small cells with scant but dense cytoplasm, and nuclei with prominent nucleoli.

P.115

Papillary Variant of Hürthle Cell Carcinoma

Papillary variants of Hürthle cell carcinoma are very uncommon, and are characterized by a papill
growth pattern.2 , 4 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 The papillary fronds are lined by cubo
to columnar oncocytic cells. Their nuclei contain granular chromatin and micronucleoli as well as
intranuclear inclusions. However, powdery, pale chromatin and nuclear grooves are not seen.
Psammoma bodies are frequently identified. The clinical behavior is considered to be similar to
conventional papillary carcinomas, as was suggested by Horn.4 Barbuto, et al.55 and others2 have
reported an aggressive behavior.

Cytologically, the aspirates are cellular, and composed of syncytial tissue fragments of Hürthle ce
with papillary configurations.57 , 58 , 59 The neoplastic cells are small to medium-sized with typica
Hürthle cell morphology. This includes variable granular cytoplasm and nuclei containing prominen
nucleoli. Intranuclear inclusions are frequent. Psammoma bodies are present within the syncytial tis
fragments, but can be seen as naked.

Histologically and cytologically, the papillary variant of Hürthle cell carcinoma is difficult to
differentiate from the oxyphilic, tall cell, and Warthin-like variants of papillary carcinomas.60 , 61
differentiating feature between the carcinomas is the lack of typical nuclear pattern with ground-gl
watery nuclei in Hürthle cell carcinomas (Figs. 8.30 , 8.31 , 8.32 and 8.33 ).

FIGURE 8-30. Hürthle cell carcinoma with a papillary growth pattern and psammoma bodies. A, B
FNA showing syncytial tissue fragments, with crowding and overlapping of nuclei with prominent
nucleoli. C . Histologic section of the excised tumor showing vascular invasion. D . The tumor also
showed a papillary growth pattern. E . Higher magnification of the papilla. Note that neoplastic
Hürthle cells lack the characteristic nuclear morphology of conventional papillary carcinoma. Inste
the cells demonstrate the characteristic morphology of a Hürthle cell neoplasm. Note the psammo
body.

FIGURE 8-31. FNA of a papillary Hürthle cell carcinoma. A . The Hürthle cells are smaller and
forming syncytial pattern. Note papillary-like architecture, with smooth external contours. Their nu
are crowded, overlapped, and contain macronucleoli. The cytoplasm is dense to granular, but scant
with high N/C ratios. B . These syncytial tissue fragments from a different field show multiple
psammoma bodies. Note the lack of fine powdery chromatin.
FIGURE 8-32. Papillary Hürthle cell carcinoma. A . The Hürthle cells are large, but in syncytial
arrangement and with altered nuclear polarity. B . This tissue fragment of Hürthle cells contains
psammoma bodies. C . Histologic section of the Hürthle cell carcinoma demonstrating papillary
architecture and psammoma bodies.
FIGURE 8-33. Locally recurrent papillary Hürthle cell carcinoma with psammoma bodies. The pati
had a lobectomy in the past, with a diagnosis of papillary carcinoma that was based solely on the
presence of psammoma bodies. The oncocytic pattern was not taken into consideration. The patien
developed a nodule in the area. A, B . FNA consisting of Hürthle cells, isolated and in syncytial tis
fragments. Note the smaller size and high N/C ratios. C, D . The excision revealed a Hürthle cell
carcinoma with a papillary growth pattern and multiple psammoma bodies.

IMMUNOCYTOHISTOCHEMICAL PROFILE AND SPECIAL STUDIES

The cells of Hürthle cell or oncocytic neoplasms react positively to thyroglobulin, but less intensiv
than their follicular counterparts. The cells show positive reactivity to TTF-1 in 30%, and to low-
molecular-weight keratin, but not to calcitonin. Although reactivity to carcinoembryonic antigen (C
is generally absent, Johnson, et al.62 reported consistent positivity to CEA. This observation was no
confirmed by Bronner and LiVolsi50 and Nesland et al.63 Galectin-3 is demonstrated in 95% of Hür
cell neoplasms, and reactivity to HBME-1 in 55%, with a specificity of 88% when both markers were
used.64 , 65 Erickson et al. have demonstrated increased proliferative activity and cyclin D1 expres
in Hürthle cell, or oncocytic-neoplasms.66 Ploidy analysis has proven to be of limited value in the
diagnosis of Hürthle cell-neoplasms.67 , 68

Chiappetta and co-workers69 demonstrated RET/PTC in a significant number of both Hürthle cell
adenomas and carcinomas, and its absence in cases with oncocytic hyperplasia. An unequivocal RET
gene rearrangement has also been demonstrated in papillary Hürthle cell carcinomas.70

DIAGNOSTIC ACCURACY AND DIFFERENTIAL DIAGNOSIS

Because of their characteristic cytomorphology, high diagnostic accuracy can be expected for Hür
cell neoplasms. However, in actual practice it is not so. The diagnostic accuracy cannot be assessed
from the available data. An important limiting factor is that most institutions group all aspirates
consisting of a large population of Hürthle cells as "Hürthle cell lesions" without an attempt to
differentiate non-neoplastic
P.116
entities from neoplastic ones, or benign from malignant lesions. In such an environment, the questio
concordance or discordance between cytology and histology does not exist, because all are Hürthl
cell lesions and the incidence of false-positive or false-negative diagnosis becomes irrelevant.

Many investigators believe that Hürthle cell carcinomas present a very aggressive behavior, and
recommend a total thyroidectomy. It makes sense, then, to provide the probabilities of neoplasia,
specifically that of malignancy, and to identify non-neoplastic Hürthle cell lesions from the aspira
Patients with the non-neoplastic diagnosis can be managed conservatively. In the author's experienc
as well as that of others,33 , 34 , 35 this is achievable with a considerable degree of success. This is
noted in Table 8.5 , which lists the cytohistologic correlations of 125 histologically proven Hürthle
neoplasms (81 adenomas and 29 carcinomas). Of the 81 Hürthle cell adenomas, 73 were cytologica
interpreted as Hürthle cell tumors (according to the recommendation of
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P.118
Thompson, et al.19 ; the distinction between adenoma and carcinoma was not attempted in the ear
part of the biopsy experience). Twenty of thirty-five Hürthle cell carcinomas were correctly diagn
from cytology, while only 3 of 17 cases cytologically suspected of carcinoma were confirmed. No no
neoplastic lesions were found in suspicious or positively diagnosed Hürthle cell cancer. One case o
Hürthle cell neoplasm in the background of Hashimoto's thyroiditis did exhibit transcapsular invasi
but was interpreted histologically as an atypical Hürthle cell nodule (an example of controversial,
surgical pathological interpretation). The incidence of false-positive diagnoses (nodular goiter and
Hashimoto's thyroiditis) was 12%. The majority of the misinterpretations occurred due to inexperien
Hürthle cell tumors
73
53
6
10
4
Suspected Hürthle cell carcinoma
17
14
3
0
0
Hürthle cell carcinoma
35
14
20
0
1a
TOTAL
125
81
29
10
5
88%
12%
a Final diagnosis was Hashimoto's thyroiditis with atypical Hürthle cell nodule.

Histologic Diagnosis

Hürthle Cell Hürthle Cell Nodular Hashimoto's

Cytologic Diagnosis Adenoma Carcinoma Goiter Thyroiditis
 TABLE 8.5 CYTOHISTOLOGIC CORRELATION OF HÃœRTHLE CEL
NEOPLASMS
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HÃœRTHLE CELL ADENOMA VERSUS HÃœRTHLE CELL CARCINOMA

Although we agree with the histologic criteria for Hürthle cell carcinoma, we have observed that i
most instances, the cytologic patterns seen in aspirates of adenomas are strikingly different than th
seen in carcinomas in Papanicolaou-stained preparations. The features are also appreciated in histo
sections, if one cares to look for them. Certain parameters are important in differentiating adenom
from carcinomas:

In terms of >cell size , cells of Hürthle cell adenomas are distinctly larger than in carcinom

>The nuclear size remains almost the same in adenomas and carcinomas, with minimal
variations in carcinomas. What is more striking is that the N/C ratios are markedly increased
carcinoma cells as supported by morphometry (see below).

Benign neoplastic cells are characterized by >abundant cytoplasm, in sharp contrast to the
scant cytoplasm of carcinoma cells.

The diagnostic criteria listed in Table 8.4 for Hürthle cell carcinomas are extremely helpfu
However, some cases of Hürthle cell carcinomas demonstrate larger cells with minimal
deviation from the usual cytologic pattern seen in adenomas. McIvor, et al.35 reported 3 of
cases of Hürthle cell carcinomas to contain a bland pattern; these were not identified as
carcinoma from the aspirates. One of our cases of Hürthle cell adenomas showed a cytolog
pattern indistinguishable from that seen in Hürthle cell carcinomas (Figs. 8.34 and 8.35 ).
FIGURE 8-34. A–C . FNA of a Hürthle cell adenoma cytologically interpreted as carcinom
The cells are smaller, discrete. The scant cytoplasm is granular. The N/C ratios are high, and
macronucleoli are conspicuous. A thyroidectomy revealed an encapsulated tumor with no
invasion. Histologic section of the resected mass showing the solid and trabecular growth
pattern with smaller cells.

FIGURE 8-35. Hürthle cell carcinoma, cytologically interpreted as adenoma. A . The neopl
Hürthle cells are discrete, large, and monomorphic, a pattern generally consistent with be
behavior, yet showed evidence of invasive characteristics in the excised thyroid. B . Histolog
section showing vascular invasion.

The cytohistomorphologic differences between Hürthle cell adenomas and carcinomas are
listed in Table 8.6 and illustrated in Figures 8.36 and 8.37 .

Cellularity
Cellular
Cellular
Presentation
Cells isolated, in loosely cohesive groups, or in two
dimensional sheets; follicle formation infrequent;
papillary tissue fragments in tumors with papillary
architecture; dispersed cell pattern common
Cells isolated, in loosely cohesive groups or syncytial,
usually without any architectural patterns; papillary
tissue fragments present in papillary variant; dispersed
cell pattern common
Cells
Large, well-defined cell borders; polygonal, round
to oval; low N/C ratios
Usually small to medium-sized; round, oval to cuboidal;
cytoplasmic borders well to poorly defined; very high
N/C ratios
Nucleus
Central to eccentric; frequent binucleation; round,
uniform, and monomorphic in a given case; thin,
crisp nuclear membrane, finely granular, uniformly
dispersed chromatin; single large cherry-red
macronucleolus is characteristic; nuclear
pleomorphism and pyknosis are rare
Central to eccentric; round, minimally pleomorphic in size;
usually same size as that of benign counterpart or slightly
enlarged; smooth nuclear membranes, finely granular
 chromatin with prominent cherry-red macronucleous;
nuclei may present clearly malignant features with coarse
chromatin; parachromatin clearing, intranuclear inclusions
in poorly differentiated, widely invasive tumors
Colloid
Variable
Absent

Hürthle Cell Adenoma Hürthle Cell Carcinoma

TABLE 8.6 DIFFERENTIATING FEATURES BETWEEN

HÃœRTHLE CELL ADENOMA AND CARCINOMA

FIGURE 8-36. Hürthle cell adenoma versus carcinoma. A . Histologic section of Hürthle c
adenoma showing a follicular pattern. Note abundant colloid. B . Histologic section of an
adenoma with a solid growth pattern. The cells are large with abundant cytoplasm and low N
ratios. C . Histologic section of a Hürthle cell carcinoma with a trabecular pattern. Note th
 small cell size and higher N/C ratios.

FIGURE 8-37. A, B . FNA of Hürthle cell adenomas. Note large discrete Hürthle cells, with low N
ratios.
FIGURE 8-37. C . FNA of a Hürthle cell carcinoma for comparison. The cells are smaller, with high
ratios. D . A different example of Hürthle cell carcinoma showing syncytial tissue fragments. Note
prominent cherry-red nucleoli. E . FNA of a Hürthle cell adenoma, consisting of large Hürthle ce
with abundant cytoplasm, small uniform nuclei with low N/C ratios. F . These small carcinoma cells
high N/C ratios appear strikingly different from adenoma cells.

Studies such as morphometric analysis have produced mixed results. Bondeson and co-workers,71 in
their morphometric study of 26 oxyphilic thyroid tumors (13 benign and 13 malignant), found no
difference between the nuclei of benign and malignant cells. Although mean nuclear size was larger
malignant neoplasms than in the benign group, there was considerable overlap. Bondeson et al.71
however, did not comment on the N/C ratios. Our experience with 29 Hürthle cell carcinomas sug
that although the nuclei do not show much enlargement, the nuclear/cytoplasmic ratio is altered in
favor of the nucleus in carcinomas. This is because the Hürthle cells in carcinomas are often
considerably smaller. This is an observation also made by Horn,4 and is confirmed by the study repo
by Benoit72 They performed morphometric analysis on fine-needle aspiration biopsy smears of 40
Hürthle cell lesions; 10 carcinomas, 10 adenomas, and 10 cases each of nodular proliferations in
chronic lymphocytic thyroiditis and nodular goiter. Their study proved that the cells of Hürthle ce
carcinomas were smaller,
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and had significantly higher nuclear/cytoplasmic ratios than those of adenomas or non-neoplastic
proliferations p <0.05 (Fig. 8.38 ). The difference in the nuclear areas was not significant, as report
by Bondesson, et al.71

FIGURE 8-38. Morphometric analysis of Hürthle cell lesions.72 A . Comparison of cytoplasmic and
nuclear areas (square micrometers) in benign and malignant Hürthle cell neoplasms and non-
neoplastic nodule proliferations. B . An illustration of the calculated mean nuclear and cytoplasmic
diameters in benign and malignant Hürthle cell neoplasms and non-neoplastic nodule proliferation
 P.121

HÃœRTHLE CELL ADENOMA/CARCINOMA VERSUS NON-NEOPLASTI

HÃœRTHLE CELL NODULES
Clinically palpable, or ultrasonically detected thyroid nodules formed entirely of Hürthle cells occ
nodular goiters, Hashimoto's thyroiditis, and sometimes following Graves disease. Clinically, and on
imaging, these nodules cannot be differentiated from a neoplasm and are subjected to aspiration
biopsy. A large population of Hürthle cells in cytologic samples has caused considerable diagnostic
difficulties in separating them from Hürthle cell neoplasms. Cytologically, these aspirates have be
interpreted as Hürthle cell lesions or as indeterminate/suspicious, which has often resulted in surg
excision. The incidence of benign non-neoplastic Hürthle cell lesions in these groups is reported in
range of 17% to 50%. The cytologic criteria for differentiating Hürthle cell neoplasms from Hürth
cell nodules are subtle, and recognizing them requires experience (Table 8.7 ).

Cellularity
Variable but generally high
Variable
Variable
Presentation
Neoplastic cells isolated, loosely
cohesive, in two-dimensional
sheets, follicular pattern ±;
small to large syncytial tissue
fragments; usually without any
architectural patterns; papillary
pattern infrequent;
monomorphic cell patterna
Hürthle cells usually in varying-
sized tissue fragments as sheets
with honeycomb arrangement,
follicular pattern may be present;
isolated cell pattern infrequent;
monomorphic cell pattern absent;
varying numbers of benign
 follicular cells
Hürthle cells isolated, or in
varying-sized tissue fragments,
syncytial architecture unusual,
monomorphic cell absent
Hürthle cells
Large, polygonal or oval in
adenomas; round to cuboidal,
small to medium-sized in
carcinomas; well to poorly
defined cell borders; N/C ratios
low in adenomas; high in
carcinomas
Very pleomorphic in size; transition
forms from normal benign
follicular cells characteristic
within a given tissue fragment;
well-defined cell borders; low
N/C ratios
Very pleomorphic in
size; well-defined cell borders;
low N/C ratios
Nucleus
Central to eccentric location,
frequently binucleated; round
with smooth nuclear
membranes; finely granular
chromatin; prominent, single
cherry-red nucleolus; size
uniform in a given case
Central location; bimultinucleation
infrequent; variable in size from
cell to cell with occasional giant
forms; chromatin finely granular
 to smudgy; may be pyknotic;
micronucleoli ±; cherry-red
macronucleolus not observed
Central location;
bimultinucleation infrequent;
variable in size from cell to cell
with occasional giant forms;
chromatin finely granular to
smudgy; may be pyknotic;
micronucleoli ±; cherry-red
macronucleolus very rare
Cytoplasm
Abundant, granular in adenomas;
stain eosinophilic, cyanophilic,
or amphophilic; scant in
carcinomas; intracytoplasmic
lumens ±
Variable, granular, and
eosinophilicto cyanophilic
Variable; granular; eosinophilic
to cyanophilic
Regular type
follicular cells
Absent
Present with transition forms
±
Lymphoplasmacytic and
germinal center cells
Absent
Absent
Present in variable numbers; may
be sparse; lymphoid tangles ±
Degenerative changes;
histiocytes with and
 without Hemosiderin
±
±
Absent
Regular type
follicular cells
Absent
Present with transition forms
±
Transgressing blood
vessels in tissue
fragments of Hürthle
cells
±; Can be appreciated if the
tissue fragments are large
—
—
a A pleomorphic cell pattern seen in poorly differentiated or high-grade Hürthle cell carcinomas, b

with clearly malignant nuclear features.

Hürthle Cell Hürthle Cell Nodules Hürthle Cell Nodules

Neoplasms in Nodular Goiter in Hashimoto's Thyroiditis

TABLE 8.7 CYTOPATHOLOGIC DIFFERENTIATION BETWEEN

HÃœRTHLE CELL NEOPLASMS AND NON-NEOPLASTIC
(PROLIFERATIVE) HÃœRTHLE CELL NODULES

HÃœRTHLE CELL ADENOMA/CARCINOMA VERSUS HÃœRTHLE CEL

METAPLASIA IN NODULAR GOITER
Hürthle cell metaplasia is an extremely common feature in nodular goiters (Fig. 8.39 ). A few
scattered Hürthle cells along with benign follicular cells are often present in aspirates from nodul
goiter. However, nodules entirely composed of Hürthle cells will yield a large population of Hürt
cells that may be difficult to differentiate from a true neoplasm. We have found the cytologic featu
described below, and in Table 8.7 , very helpful.
FIGURE 8-39. Hürthle cell metaplasia in nodular goiter. Histologic sections. A . Low power. B . Hig
power.

Hürthle cells aspirated from non-neoplastic Hürthle cell nodules tend to be cohesive and presen
sheets of epithelium
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with a honeycomb arrangement, well-defined cell borders, and abundant cytoplasm that is either d
or granular and contains centrally placed nuclei (Figs. 8.40 , 8.41 , 8.42 , 8.43 , 8.44 and 8.45 ). A
follicular pattern is not uncommon. Transitional forms from regular follicular cells to large, polygon
cells are usually present (Figs. 8.40 , 8.41 and 8.42 ) and serve as important diagnostic clue. The nu
are almost always pleomorphic in size, and generally do not show macronucleoli. The nuclear chrom
is coarsely granular and pyknotic forms are very frequent (Figs. 8.40 , 8.41 and 8.42 ). Colloid is pre
in the
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background, but it is variable and can be abundant. Groups and tissue fragments of regular type
follicular cells are often present in the background. Degenerative changes with histiocytes containin
hemosiderin are features that favor nodular goiter. Papillary change in a nodular goiter with extensi
Hürthle cell metaplasia is also a potential diagnostic pitfall (Fig. 8.45 ).
FIGURE 8-40. FNA of thyroid showing Hürthle cell metaplasia. The pleomorphic, large Hürthle ce
are admixed with benign follicular cells. They have abundant cytoplasm and small nuclei with comp
chromatin. Macronucleoli are absent.
FIGURE 8-41. Sheets of pleomorphic Hürthle cells with variable deep eosinophilic cytoplasm, and
of uniformity and absence of macronuclei are features of metaplasia.
FIGURE 8-42. A large tissue fragment of benign follicular cells with transition forms to Hürthle cel
metaplasia. Note abundant cytoplasm and large nuclei with smudgy chromatin.
FIGURE 8-43. Hürthle cell metaplasia. A . The cellular aspirate reveals several tissue fragments of
Hürthle cells. Abundant eosinophilic cytoplasm is evident even at this low power. B . Higher
magnification, demonstrating sheets of Hürthle cells with a honeycomb arrangement. The nuclei a
pleomorphic in size and lack macronucleoli. The cytoplasm is abundant. C . Another field, showing a
tissue fragment of metaplastic Hürthle cells. D . A tissue fragment of metaplastic Hürthle cells w
variable but abundant granular cytoplasm, and pleomorphic nuclei with compact chromatin. Note th
absence of macronucleoli.
FIGURE 8-44. Hürthle cell metaplasia in nodular goiter. The aspirate is showing tissue fragments o
metaplastic Hürthle cells with a honeycomb pattern. The cells are larger than their normal
counterpart (benign follicular cells). The nuclei have compact chromatin and lack macronucleoli.
FIGURE 8-45. Hürthle cell metaplasia in nodular goiter with papillary change. A . Large tissue
fragment of metaplastic Hürthle cells with appreciable, eosinophilic cytoplasm. Note the honeyco
pattern. B . Naked psammoma bodies in the background. C . Thyroidectomy revealed a multinodula
goiter with cystic and papillary change, low power. D . Higher magnification showing pseudo-papilla
pattern with lining of Hürthle cells. E . Another field showing Hürthle cell metaplasia with multi
psammoma bodies. The typical nuclear pattern of conventional papillary carcinoma is lacking.

HÃœRTHLE CELL ADENOMA/CARCINOMA VERSUS HÃœRTHLE CEL

NODULES IN HASHIMOTO'S THYROIDITIS
Hürthle cell metaplasia is considered a hallmark of Hashimoto's thyroiditis. Varying-sized nodules,
composed entirely of Hürthle cells, are a frequent histologic finding in
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Hashimoto's thyroiditis. These nodules may reach a significant proportion and be palpable, presentin
a cold nodule, necessitating an FNA biopsy. They are also detected as incidental findings on an
ultrasound performed for non-thyroid-related reasons. An aspirate of a cold nodule in the backgroun
a diffusely enlarged goiter showing many or predominantly Hürthle cells, with a few lymphocytes
plasma cells, can be interpreted as a non-neoplastic Hürthle cell lesion. Experience is helpful in
recognizing such lesions. A predominant Hürthle cell component in an aspirate will suggest a diagn
of a neoplasm (Figs. 8.46 , 8.47 , 8.48 and 8.49 ). A few stretched-out lymphocytes, and an admixtu
regular follicular cells with or without nuclear atypia and transition forms, serve as a clue to the
diagnosis of Hashimoto's thyroiditis (Table 8.7 ). The problem of misinterpreting Hürthle cells from
thyroiditis as a Hürthle cell neoplasm is shared by many investigators.73 , 74 , 75 , 76 , 77 This is
discussed in detail in Chapter 13 .
FIGURE 8-46. FNA of Hashimoto's thyroiditis, showing a large tissue fragment of Hürthle cells with
pleomorphic nuclei. The dispersed pattern of Hürthle cell neoplasms is lacking. The nuclei have
smudgy chromatin and lack micronucleoli. Rare lymphocytes in intimate contact with the Hürthle
are difficult to identify. This aspirate was cytologically interpreted as Hürthle cell neoplasm.
FIGURE 8-47. Another case of Hashimoto's thyroiditis with predominance of Hürthle cells. Note lar
cells, large pleomorphic nuclei, and abundant cytoplasm. These cells, however, lack the characteris
nuclear morphology of neoplastic Hürthle cells. Rare lymphocytes are present in the background.

FIGURE 8-48. A . FNA of a nodule from Hashimoto's thyroiditis, showing Hürthle cells in a tissue
fragment and discrete. Note pleomorphic nuclei. This case was interpreted as Hürthle cell tumor.
lymphocytes were present in the background but were overlooked. Note, however, that these cells
the characteristic nuclear morphology of Hürthle cell neoplasm. B. FNA of Hürthle cell tumor
demonstrating the characteristic morphology for comparison.

FIGURE 8-49. A . This bloody aspirate consisted of several tissue fragments of metaplastic Hürthle
cells, containing pleomorphic, large, hyperchromatic nuclei, and was interpreted as malignant. B .
Thyroidectomy revealed florid Hashimoto's thyroiditis. The interpretative error was due to inexperie

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P.126
P.127
P.128
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HÃœRTHLE CELL CARCINOMA VERSUS OTHER NEOPLASMS

Several different types of neoplasms share morphologic similarities with Hürthle cell adenomas an
carcinomas. These include medullary carcinoma; oncocytic parathyroid adenoma, either in an
intrathyroid location or in close proximity to the thyroid; and metastatic renal cell carcinoma

HÃœRTHLE CELL CARCINOMA VERSUS MEDULLARY CARCINOMA

Hürthle cell carcinomas share morphologic similarities with medullary thyroid carcinomas. Becaus
their small size, round to oval shape, and a monomorphic pattern, Hürthle cell carcinoma cells
strongly resemble medullary carcinoma when the latter presents a monomorphic pattern (Figs. 8.50
8.51 and 8.52 ). Medullary carcinoma cells occasionally demonstrate abundant deep-staining cytopla
and large pyknotic nuclei, a feature that is sometimes observed in Hürthle cell neoplasms. The
differentiating features include prominent cherry-red macronucleoli in Hürthle cell carcinomas, w
are characteristically absent in medullary-carcinoma cells. The nuclear chromatin is very coarse in
medullary carcinomas, unlike the finely granular pattern of Hürthle cell carcinoma cells. If the
cytologic preparations of Hürthle cell carcinoma fail to stain the macronucleoli, the differentiatio
between the two may be difficult. Immunostains for thyroglobulin and calcitonin are required to
confirm the diagnosis. The differentiating features are listed in Table 12.7.

FIGURE 8-50. Hürthle cell carcinoma versus medullary thyroid carcinoma. Hürthle cell carcinom
share morphologic similarity with medullary carcinomas, and may be interpreted as such. A . Extrem
cellular aspirate with predominantly dispersed cells (low power). B . Higher magnification showing
discrete cells, markedly pleomorphic in size with eccentric nuclei. Macronucleoli were not present.
differential diagnosis included Hürthle cell neoplasm and medullary carcinoma. Calcitonin stain w
negative. C . Thyroidectomy revealed minimally invasive Hürthle cell carcinoma with a solid growt
pattern. Note nuclear pleomorphism corresponding to the cytologic presentation. D . Compare with
of a medullary thyroid carcinoma, with a large cell, containing abundant cytoplasm and an enlarged
nucleus with smudgy chromatin.
FIGURE 8-51. A . FNA of a Hürthle cell carcinoma with uniform, plasmacytoid cells containing
eccentric nuclei strongly resembling medullary-carcinoma cells. Macronucleoli are only rarely presen
Calcitonin stain was negative. B . FNA of a medullary carcinoma for comparison.

FIGURE 8-52. These two images present very similar morphologic pattern. A . Hürthle cell carcino
B . Medullary carcinoma. Cytologic differentiation sometimes is not possible, and requires immunost
with thyroglobulin and calcitonin.

SUMMARY
Hürthle cell tumors with benign behavior (adenomas) often show large, loosely cohesive cells with
well-defined cell borders; abundant, granular cytoplasm with variable staining characteristics and
central or eccentric nuclei with prominent cherry-red macronucleoli and a monomorphic pattern.
Hürthle cell tumors with malignant behavior (carcinomas) can be recognized by their small cell siz
syncytial-type tissue fragments, and high nuclear/cytoplasmic ratios. Infrequent features include
intranuclear, cytoplasmic inclusions, and psammoma bodies. Hürthle cell carcinoma may be misty
as medullary thyroid carcinoma. Important diagnostic pitfalls include metaplastic Hürthle cell nod
in the background of nodular goiter or Hashimoto's thyroiditis.

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Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 9 - Papillary Carcinoma

9
Papillary Carcinoma

Papillary carcinoma, the most common differentiated malignant neoplasm of the thyroid,
comprises up to 80% of all thyroid carcinomas in the United States.1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ,
10 , 11 , 12 , 13 It occurs more frequently in women, with a female:male ratio of 3:1. Papillary
carcinomas are seen in all age groups, with a peak in the third to fourth decade. They have a
tendency for intraglandular spread, cervical lymph node metastasis, and local invasion, but
demonstrate fewer predilections for hematogenous spread than follicular carcinomas. Distant
metastases are uncommon and occur late in the disease. Relapses can occur as late as 30 years
after initial treatment.6 These tumors are slow growing, and follow an indolent course. The
prognosis for papillary thyroid carcinoma is generally considered favorable; however, it depends
on several risk factors such as the patient's age; the extension stage (e.g., occult, intrathyroidal,
or extrathyroidal), and the histologic differentiation. Mortality is very low—6.5% on long-term
follow-up.5 A higher incidence of poorly differentiated and sclerosing types has been reported in
children exposed to the radiation from Chernobyl studies.14 , 15 Risk factors for developing
papillary thyroid carcinoma include prior exposure to ionizing radiation, genetic factors, and
nodular disease of the thyroid.

RADIOLOGIC FINDINGS
Papillary carcinomas present as cold nodules on radionuclide imaging. On ultrasound, two
patterns are described: (i) presence of a solid hypoechoic nodule with discrete echogenic foci
and microcalcifications, and (ii) solid hypoechoic nodule with coarse echogenic foci.16

GROSS AND HISTOLOGIC FEATURES

The literature is rich in documentation of pathology of papillary thyroid carcinomas, with several
excellent reviews on morphology including the ultrastructural findings.1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ,
9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27

The gross appearance of papillary carcinoma varies with the size. Large tumors are typically
fleshy, velvety, fragile, and may extend to the capsule of the thyroid (Figs. 9.1 , 9.2 and 9.3 ).
They are usually invasive, but may be circumscribed. Papillary carcinomas are typically non-
encapsulated, but have a tendency to develop fibrosis that results in partial encapsulation.
Markedly desmoplastic carcinomas may appear like a scar tissue. Cystic changes due to
degeneration are very common (Fig. 9.2 ). This can be extensive, with a prominent unicystic or
multicystic pattern. Calcification is frequent.

Figure 9.1. Papillary carcinoma of the thyroid. The tumor is fleshy, with a bulging, variegated
cut surface, mottled by small cystic cavities and fibrosis.
Figure 9.2. Cystic papillary carcinoma. The tumor appears friable protruding into the cavity.
Figure 9.3. Papillary carcinoma of the left thyroid lobe with involvement of multiple lymph
nodes.

Microscopically, papillary carcinomas present varied patterns (Figs. 9.4 , 9.5 , 9.6 , 9.7 , 9.8 ,
9.9 , 9.10 , and 9.11 ). A typical papillary carcinoma is characterized by neoplastic epithelium
arranged on fibrovascular stalks (Figs. 9.4 and 9.5 ). The papillary fronds may be well developed,
with a complex branching pattern; or they may be rudimentary, without discernible
fibrovascular stalks. Some fronds may be broad and edematous, and may contain foamy
histiocytes. Generally, the covering epithelium is single-layered, although it may be
multilayered, and the nuclei are stratified. The neoplastic cells can be cuboidal, columnar, or
squamoid, with variable cytoplasm surrounding a central ovoid nucleus. These nuclei have pale
chromatin, with peripheral condensation that gives a ground- glass or watery appearance, so
typical of papillary carcinoma.28 , 29 Intranuclear inclusions are readily identified in sections of
conventional papillary carcinomas. Nuclear grooves are characteristic. Micronucleoli are almost
always seen, especially with pale watery chromatin.30 , 31 Mitoses are extremely rare.
Multifocal involvement of one or both lobes occurs in about 20% of cases,12 , 13 , 24 but can be
higher if the whole gland is sectioned.11

Figure 9.4. Histologic section. Papillary carcinoma with branching papillary fronds. The lining
epithelium is single-layered, with ground-glass nuclei.
Figure 9.5. A delicate papillary frond covered by epithelium with stratified, empty-looking
nuclei presenting "eggs in the basket" appearance.
Figure 9.6. A. Papillary carcinoma exhibiting a follicular pattern. B. These follicles from a
papillary carcinoma are elongated and are arranged in a parallel fashion (railroad tracks).
Figure 9.7. Papillary carcinoma with squamous metaplasia.

Figure 9.8. Multiple psammoma bodies in papillary carcinoma.

Figure 9.9. Papillary carcinoma with multinucleated foreign-body type giant cell (arrow ).
Figure 9.10. Papillary carcinoma with marked desmoplasia.
Figure 9.11. Papillary carcinoma with lymphocytic infiltrate.

Papillary carcinomas are often mixed, with areas of follicular differentiation in varying
proportions (Fig. 9.6A ). The follicles may be well developed, filled with colloid, or form closely
packed narrow tubules (Fig. 9.6B ). Areas of solid growth pattern may also be present. Squamous
metaplasia is quite common, present in up to 40% of cases.9 , 10 , 13 , 21 , 22 These foci of
squamous differentiation appear as morulae within the follicles or against the papillae (Fig. 9.7A
and B ). Spindle cell metaplasia has been described.32 Roughly 40% to 60% of papillary
carcinomas have lamellated calcific spherules, called "psammoma bodies," "microliths," or
"calcospherites" (Fig. 9.8 ).8 , 12 , 22 , 33 , 34 , 35 . These are basophilic, nonbirefringent, 5 to
100 µm in size, and seem to arise between epithelial cells. They are also found within
hyalinized stroma at the tip of a papilla. "Naked" psammoma bodies may be found in thyroid
tissue adjacent to, or even distant from, the cancer. The colloid in papillary carcinoma is dense
staining.21 Multinucleated giant cells are commonly seen (Fig. 9.9 ).

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Cystic degeneration is very common. Carcangiu, et al.7 in their series of 241 papillary
carcinomas, reported an incidence of 52.5%, with marked cystic changes in 9.1%. Cystic changes
also develop in nodal metastasis; 19.7% of papillary carcinomas may present clinically with nodal
metastasis.

The stroma in papillary carcinomas is often desmoplastic, which could be extensive (Fig. 9.10
).20 , 36 Spindle cell metaplasia in papillary carcinomas is described, but is encountered only
rarely.32

Lymphocytic infiltrate is frequent. Franssila9 reported this feature in 31% of his cases, and
Carcangiu, et al.20 reported it in 26.7% (Fig. 9.11 ). Whether this infiltrate represents
Hashimoto's thyroiditis or a reaction to the neoplasm is not certain.

Papillary carcinomas may coexist with poorly differentiated "insular" or undifferentiated areas.

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CYTOPATHOLOGIC FEATURES OF CONVENTIONAL PAPILLARY

CARCINOMA
The cytopathologic features of papillary carcinoma are amply reported in the literature.37 , 38 ,
39 , 40 , 41 , 42 , 43 , 44 , 45 Kini, et al. (43) described them in great detail.43

Because of the diversity of morphologic patterns, the cytopathologic criteria, as reflected in

cytologic samples, are numerous and complex (Table 9.1 ). The diagnosis of papillary carcinoma
cannot be based on just one criterion, because any feature listed in Table 9.1 can be seen in
benign diseases. It is important, therefore, to be familiar with the typical cytopathologic
features, in order to appreciate the variations and diagnostic pitfalls. For this reason, the usual
and typical cytopathologic features are first described individually, in detail, and then discussed
later in the chapter in terms of their significance.

Cellularity
Variable; overwhelmingly cellular to scant in tumors with desmoplasia, or with cystic change
Presentation
Neoplastic cells isolated, in loosely cohesive groups or in syncytial tissue fragments with various
architectural configurations
Architecture of the
tissue fragments
Papillary, with or without complex branching, containing central fibrovascular cores; papillary-
 like without visible central cores but appearing as finger-like processes; monolayered (two-
dimensional, but syncytial) with or
without branching; syncytial with follicular pattern; syncytial without architectural patterns or
appear as three-dimensional balls, onion-skin pattern or swirls;
nuclei variably crowded and overlapped
Cells
Wide range of size and shapes; small, medium-sized to very large; round, cuboidal, short
columnar,
elongated, polygonal, spindle-shaped, cell borders well to poorly defined; N/C ratios variable
Nucleus
Pleomorphic in size and shape; round, oval, oblong; nuclear membranes smooth to irregular;
chromatin
characteristically, pale, dusty, powdery to finely granular; multiple micro/macronucleoli;
longitudinal
grooves, single or multiple intranuclear inclusions; small to large occupying the entire nucleus,
bordered by condensed chromatin; mitosis rare to absent; degeneration may mask nuclear
features
Cytoplasm
Variable, insignificant in conventional types to abundant in some morphologic variants; pale
Squamous metaplasia
±
Psammoma bodies
Often present; naked or incorporated in syncytial tissue fragments of neoplastic cells displaying
nuclear
features of papillary carcinoma; single or multiple within any given tissue fragment;
concentric
lamellated to star-burst appearance; basophilic to combination of multiple colors: brown,
amber,
violet to purple; sometimes refractile; naked psammoma bodies not of diagnostic importance
Multinucleated foreign-
body-type
giant cells
Almost always present; variable in numbers and size, number of nuclei vary; round to oval with
finely granular chromatin and micronucleoli; grooves and inclusions not present; cytoplasm
 abundant, dense and not phagocytic
Background
Usually clean without necrosis; evidence of recent or old hemorrhage—histiocytes with or
without
hemosiderin; lymphocytic infiltrate ±; colloid variable; pale to dense, often stringy
Immunoprofile
Reactive to thyroglobulin, TTF-1; cytokeratin 19

TABLE 9.1 CYTOPATHOLOGIC FEATURES OF CONVENTIONAL

(USUAL TYPE) PAPILLARY CARCINOMA
Papillary carcinomas are generally soft, fragile, and when they have minimal stroma, they yield
very cellular aspirates. The cellularity is often overwhelming. A typical presentation at a very
low magnification includes a large number of tissue fragments with characteristic structural
patterns, mixed with a large population of pleomorphic, isolated, and groups of neoplastic cells
(Fig. 9.12 ). The architectural patterns of the tissue fragments of follicular cells seen in
aspirates of papillary carcinoma are multiple (Fig. 9.13 ). Their component cell nuclei present
the characteristic and diagnostic features. The carcinoma cells will be described first.
Figure 9.12. FNA. An overwhelmingly cellular aspirate of papillary carcinoma with many tissue
fragments exhibiting a complex branching pattern; some large ones appear monolayered. The
background is clean (low power).
Figure 9.13. General presentation. A: cellular aspirate showing papillary tissue fragments with
complex branching. B: Large numbers of papillary-like (without visible central cores) tissue
fragments. C: Varying-sized monolayered tissue (two-dimensional) fragments. D: Syncytial tissue
fragments with anastomosing trabeculae. E: A follicular pattern. F: Single cell pattern.

Cells of Papillary Carcinoma

Papillary carcinoma cells (Fig. 9.14 ) are so varied that practically any shape and size may be
encountered. They may be cuboidal, columnar, ovoid, polygonal, squamoid, and even spindle-
shaped.
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Papillary carcinoma cells may be medium-sized to large, sometimes exceeding 10 µm in
diameter. The cell borders in single cells tend to be well defined. The cytoplasm is variable,
scant to abundant, and may be pale, foamy, vacuolated, granular, or dense. The carcinoma cells
with abundant, dense cytoplasm appear Hürtheloid. Their nuclei are generally slightly
eccentric in position; round, oval to ovoid, often irregular in shape, and varied in size. In well-
developed papillary fronds, the nuclei appear small because they are closely packed together. In
monolayered tissue fragments, they appear considerably larger. The nuclear membranes are
sharp, and may show irregularities. The chromatin is so finely granular, and dusty to powdery,
that the nuclei appear clear, pale, or watery. Single or multiple micro- and or macronucleoli are
always seen. Although not diagnostic by itself, nuclear groove is a consistent feature. It is seen
as a chromatin ridge along the long axis of the nucleus, and is probably due to irregular infolding
of the nuclear membrane, as seen in electronmicrographs.25 Another characteristic aspect is
the presence of intranuclear cytoplasmic inclusions, a consistent feature in aspirates of papillary
carcinoma (Fig. 9.15 ), considered to be cytoplasmic invagination. They occur as sharply
defined, clear, round inclusions, bordered by condensed chromatin. Intranuclear inclusions may
be large
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and single, occupying the entire nucleus, or they may be small and multiple. The multiple
inclusions within a single nucleus present a "soap-bubble" appearance. According to Abele and
Miller,40 an intranuclear inclusion should take up at least 10% of the total nuclear surface area
to distinguish it from nonspecific vacuoles, which are often seen in air-dried preparations. Also,
the sharp border of these inclusions is a differentiating feature from the vacuoles seen in some
degenerating nuclei, where the vacuoles merge with the chromatin.
Figure 9.14. Cells of papillary carcinoma . A. Small, oval, and short columnar cells, poorly
defined cell borders; scant, indiscernible cytoplasm; powdery chromatin; intranuclear
inclusions. B. Medium-sized cuboidal cells. C. Medium-sized oval to plasmacytoid cells with
eccentric nuclei. D. Cells with dense cytoplasm resembling Hürthle cells. E. Tissue fragment of
very large cells with large, very pleomorphic nuclei and abundant dense cytoplasm. F.
Pleomorphic, elongated, spindle to columnar cells with abundant dense cytoplasm. G. Cells of
papillary carcinoma (Diff-Quik stain). (Part G Courtesy of Mariza de Peralta-Venturina, MD,
William Beaumont Hospital, Royal Oak, Michigan.)
Figure 9.15. Characteristic nuclear morphology of papillary carcinoma cells . A. Round to oval
nuclei with fine, dusty, powdery chromatin. B. Syncytial tissue fragment of cells. The nuclei are
oval or ovoid, many with irregular shapes. The chromatin is pale and powdery with multiple
micronucleoli, intranuclear inclusions (arrow ), and frequent grooves. C. Syncytial arrangement
of cells. Nuclei are large and oval and have dusty powdery chromatin, micronucleoli, grooves,
and intranuclear inclusions. D. These papillary carcinoma cells are pleomorphic and elongated.
Their nuclei demonstrate conspicuous inclusions that are sharp and bordered by condensed
chromatin. Some inclusions are single and some nuclei have multiple small inclusions like a soap
bubble. E. Medium-sized round to cuboidal cells. The nuclei are slightly pleomorphic with finely
granular chromatin, micronucleoli, grooves, and inclusions.

The nuclear characteristics of papillary carcinomas are diagnostic. In cytologic material, the
tetrad of pale, enlarged nuclei with dusty chromatin, nucleoli, a chromatin ridge or groove, and
intranuclear cytoplasmic inclusions are virtually pathognomonic of papillary carcinoma (Fig. 9.15
).

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Syncytial-Type Tissue Fragments

Cancer cells grow irregularly. In cytologic specimens, they present themselves as syncytial-type
tissue fragments (Fig. 9.16 ). The component cells may have ill-defined cell borders and altered
nuclear polarity with crowded, overlapped nuclei. Syncytial architecture is seen in any type of
malignancy, and papillary carcinoma is no exception. Syncytial tissue fragments show a spectrum
of architectural configurations in differentiated cancers, while in poorly differentiated
neoplasms only syncytial tissue fragments without any architectural patterns predominate. In
papillary carcinomas, the cells generally exhibit the typical nuclear morphology of conventional
papillary carcinoma.
Figure 9.16. Syncytial-type tissue fragments of papillary carcinoma without specific
architectural configurations . A. The tissue fragment is composed of carcinoma cells that have
poorly defined cell borders and marked crowding and overlapping of enlarged nuclei. The
nuclear chromatin is fine, dusty, and powdery. Note micronucleoli and grooves. B,C. Syncytial
tissue fragments with extreme crowding and overlapping of enlarged, round to oval nuclei. The
chromatin is fine, powdery, and is condensed irregularly along the nuclear membranes. Note
prominent micronucleoli and intranuclear inclusions. D. A syncytial tissue fragment of papillary
carcinoma cells (Diff-Quik stain).

Papillary Tissue Fragments

Papillary tissue fragments (Fig. 9.17 ) are syncytial, and have a simple or complex branching
pattern that is characterized by a smooth external contour and peripheral palisading of the
nuclei. The component cells are closely packed, have poorly defined cell borders, and their
cytoplasm is hardly visible. The nuclei are crowded, overlapped, and exhibit characteristic
morphology. The tips of the papillary fronds may be seen as three-dimensional clusters, with
smooth external boundaries. By definition, papillary tissue fragments must demonstrate central
fibrovascular cores. In well-fixed, well-stained preparations, the papillary tissue fragments
demonstrate central fibrovascular stroma containing capillary loops. Neoplastic cells arising from
such a stromal core are low cuboidal or columnar and give a feathery pattern to the papillary
fragment.

Figure 9.17. Papillary architecture . A. Tissue fragments with a complex branching pattern. B.
Branching papillary tissue fragments. The central fibrovascular cores are visible even at low
power. C. Higher magnification of tissue fragments in B showing a lining of columnar cells. Note
the fibrovascular stroma. D. A papillary frond with clearly visible blood-filled capillaries in the
fibrovascular core. E. Branching papillary tissue fragments with central stromal cores.
Intranuclear inclusions are seen in some of the cells. Diff-Quik preparation. (Part E is courtesy of
Mariza de Peralta-Venturina, MD, William Beaumont Hospital, Royal Oak, Michigan.)

Papillary-Like Tissue Fragments

When the central fibrovascular cores are not visualized, and the tissue fragments present finger-
like processes with or without branching, they are referred to as "papillary-like" (Fig. 9.18 ).

Figure 9.18. A. Branching papillary-like (without visible stromal core/cores) tissue fragment
with a syncytial pattern. Note the smooth external contour and peripheral palisading of the
nuclei. B. A single syncytial tissue fragment with marked crowding and overlapping of small
nuclei. The chromatin is finely granular to powdery. Nuclear grooves, inclusions, and
micronucleoli are visible. Note the smooth external contour. C. Multiple branching papillary-like
tissue fragments. D. Papillary-like tissue fragment from papillary carcinoma in a Diff-Quik
preparation. (Fig. 9.18.D is courtesy of Mariza de Peralta-Venturina, M.D., William Beaumont
Hospital, Royal Oak, Michigan.)

Syncytial Tissue Fragments with Follicular Pattern

These tissue fragments demonstrate multiple well-formed follicles, filled with colloid. The
component nuclei show typical features of papillary carcinoma (Fig. 9.19 ).

Figure 9.19. Syncytial-type tissue fragments with a follicular pattern . The nuclei have fine,
powdery chromatin with peripheral condensation, thus appearing pale or clear.

Syncytial Tissue Fragments with Three-Dimensional

Architecture
It is not unusual to encounter three-dimensional cell clusters in aspirates of papillary
carcinomas. They probably represent the tips of the papillary fronds (Fig. 9.20 ).
Figure 9.20. A syncytial tissue fragment from papillary carcinoma with extreme crowding of
nuclei, smooth external contour, and appearing three-dimensional.

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Monolayered (Two-Dimensional) Syncytial Tissue Fragments

The presence of monolayered tissue fragments (Fig. 9.21 ) is characteristic of papillary
carcinoma. These fragments probably represent the papillary fronds seen "en face" (see Chapter
5 ). This impression is supported by the fact that many fragments are large, with branching,
sweeping curves. They may aslo represent large neoplastic follicles seen "en face." The tissue
fragments are commonly referred to as "monolayered sheets," because they often show a two-
dimensional pattern—that is, the cells are in one plane of focus. The component cells usually
have poorly defined cell borders with a syncytial pattern. Nuclei are generally large and
pleomorphic, with altered polarity, and the nuclear chromatin is finely granular and powdery.
Micro- and macronucleoli are frequently present. The nuclei show morphology characteristic of
papillary carcinoma. Intranuclear cytoplasmic inclusions are conspicuous. The cytoplasm is
variable; generally abundant, pale, and foamy to dense, giving a Hürtheloid appearance.
Although, this dense cytoplasm is considered a diagnostic feature by Miller, et al.39 it is not one
of the requirements for the cytologic diagnosis of papillary carcinoma.

Figure 9.21. Monolayered tissue fragments . A. FNA of a papillary carcinoma showing

monolayered (two-dimensional) tissue fragments with branching, sweeping curves (low power).
B. Higher magnification. The cells are arranged in syncytial fashion with poorly defined cell
borders and altered polarity. The nuclei are round to oval, enlarged, and have smooth nuclear
membranes. The chromatin is fine, dusty, and powdery. Note micronucleoli, grooves, and
inclusions. C,D. A monolayered but syncytial tissue fragment of papillary carcinoma cells with
several nuclei containing inclusions, micronucleoli, and grooves. E. A monolayered tissue
fragment from papillary carcinoma (Diff-Quik stain).

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Miscellaneous Architectural Patterns

At times, the tissue fragments of papillary carcinoma show a concentric arrangement of cells,
referred to as swirls46 (Fig. 9.22A and B ), or an onion-skin pattern (Fig. 9.22C ).46 This pattern
is specially noted in cystic carcinomas. It is perhaps due to a fluid environment that the cells will
ball up. Another pattern noted in the aspirates from cystic carcinoma is a "cartwheel" pattern,
where the syncytial tissue fragment is composed of elongated cells, with one slender end
directed centripetally and the wider ends projecting outwards, extending from centralized
nuclei, giving a cartwheel appearance to the tissue fragment (Fig. 9.22D ).

Figure 9.22. Miscellaneous architectural patterns . A,B. Cellular swirls in an FNA of papillary
carcinoma with tightly and concentrically arranged cells of papillary carcinoma. C. Tissue
fragment of carcinoma cells with concentric arrangement like an onion-skin. D. Cartwheel
pattern with cells radiating from the center.

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Squamous Metaplasia
Although squamous metaplasia is frequently seen in histologic sections of papillary carcinomas,
it is encountered only rarely in cytologic samples. Squamous metaplasia presents as tissue
fragments of large cells with abundant cytoplasm, smaller, uniform nuclei, and a concentric
arrangement (Fig. 9.23 ).

Figure 9.23. Squamous metaplasia in papillary carcinoma. Note the concentric arrangement of
the cells.
Psammoma Bodies
Psammoma bodies (Fig. 9.24 ) are a diagnostic feature of papillary carcinoma22 but are present
in only 20% of the aspirates.43 They are easily recognized in histologic sections by their
basophilic, concentric lamellation. In Papanicolaou-stained preparations of fine-needle
aspirates, the psammoma
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bodies not only stain basophilic, but also stain lavender, golden brown, or amphophilic. The
architecture may also be different. In addition to concentric lamellation, they have a star-burst
and refractile appearance or may resemble a Maltese cross. The psammoma bodies vary in size
may be seen naked or incorporated within a tissue fragment of follicular cells. They may be
single or multiple within a given tissue fragment. Occasionally aspirates may contain a myriad of
psammoma bodies with a striking display of various colors in Papanicolaou-stained preparations.
The nuclei of the cells forming the tissue fragments that incorporate the psammoma body show
the typical morphology of papillary carcinoma.
Figure 9.24. Psammoma bodies. A. Syncytial tissue fragment of malignant papillary carcinoma
cells incorporating a single psammoma body. Note that concentric lamellation is not seen. The
psammoma body has a refractile center with a starburst appearance. B. Multiple psammoma
bodies with concentric lamellations. C. A syncytial tissue fragment incorporating three
psammoma bodies. The component cells demonstrate nuclear features of papillary carcinoma.
D. Psammoma bodies within this tissue fragment appear refractile. E. Myriad of psammoma
bodies with a striking display of colors.
Multinucleated Foreign Body-Type Giant Cells
Although giant cells are not generally described in the literature on the histopathology of
papillary carcinoma, their presence appears to be ubiquitous in cytologic and histologic material
(Fig. 9.25 ). They are seen in the absence of degeneration and do not seem to be phagocytic or
histiocytic in origin. These giant cells vary in size from small to enormous, and may fill an entire
high-power field. Their cytoplasm is dense and not dirty, granular, or vacuolated like that of the
histiocytic-type giant cells. The nuclei vary in number and often resemble those of carcinoma
cells. Giant cells are always intimately associated with papillary or monolayered fragments, a
feature appreciated in histologic material as well. Hidvegi et al.60 suggested that the giant cells
are perhaps derived from cancer cells.

Figure 9.25. Multinucleated giant cells in papillary carcinoma, often seen in association with
tissue fragments of carcinoma cells.

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Colloid Strands
As described by Löwhagen et al.44 , 45 ropy strands of colloid (Fig. 9.26A to C ) are often seen
in aspirates from papillary carcinoma. The colloid may also be dense staining and is frequently
observed as blobs or follicular luminal casts (Fig. 9.26C ).

Figure 9.26. Colloid in papillary carcinoma . A. Strands of dense sticky colloid alongside the
monolayered tissue fragments of papillary carcinoma. B. These spherical blobs of dense colloid
appear as luminal casts, typically seen in an aspirate of follicular variant of papillary carcinoma.
C. Thin, watery colloid in the background.

DEGENERATION
Degenerative changes with cyst formation (Fig. 9.27 ) are frequently observed in papillary
carcinomas. They are manifested in the aspirate by the presence of histiocytes, with or without
hemosiderin.
Figure 9.27. Papillary carcinoma cells with degeneration and hemorrhage. Such a pattern is
often seen with cystic degeneration.

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LYMPHOCYTIC INFILTRATE
The presence of lymphocytes indicates underlying or coexisting Hashimoto's thyroiditis, features
of which may be seen along with the cytologic features of papillary carcinoma (see Chapter 13 ).
According to some authors, papillary carcinomas elicit a host reaction characterized by a
lymphocytic infiltrate,3 although Carcangiu and co-workers20 have disputed that concept.

IMMUNOCYTOHISTOCHEMICAL PROFILE
The cells of papillary carcinoma demonstrate positive reactivity to thyroglobulin in a consistent
fashion, except for the columnar cell variant. Wenig, et al. in their review of 17 cases of the
columnar cell variant of papillary carcinoma, found reactivity to thyroglobulin in all their cases
but in variable intensity. The papillary carcinoma cells also react to both low- and high-
molecular-weight keratins, the latter indicating a tendency toward squamous metaplasia.
Positive reactivity is also noted with thyroid transcription factor-1 (TTF-1). Positive reactivity
has been documented with vimentin but not with carcinoembryonic antigen (CEA) or with
calcitonin. Strong reactivity to S-100 protein has also been reported.2 Other markers that have
been reported include CK-19, CD-15, HBME-1, and galectin-3.61 , 62 , 63 , 64 , 65 , 66

Molecular analysis has shown mutations in RAS proto-oncogenes, BRAF oncogenes, and RET/PTC
gene rearrangement in
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papillary carcinomas. The routine diagnostic application of these tests has not been established
as yet (see Chapter 22 for more information).

MORPHOLOGIC VARIANTS OF PAPILLARY CARCINOMA

Several histologic variants of papillary thyroid carcinomas have been described (Table 9.2 ).1 , 3
Some of the variants have a better prognosis than the conventional types, while others tend to
behave in an aggressive fashion, with a higher frequency of morbidity and mortality. Those with
aggressive behavior include the tall cell variant, diffuse sclerosing variant, diffuse follicular
variant, and papillary thyroid carcinomas with dedifferentiated areas. The morphologic variants
that are sometimes associated with an unfavorable outcome include the follicular variant, solid
variant, oncocytic variant, and those arising in the background of autoimmune thyroiditis.

Usual or conventional
Follicular
Macrofollicular
Diffuse follicular
Tall cell
Columnar cell
Oxyphil cell or oncocytic
Solid and trabecular
Diffuse sclerosing
Papillary carcinoma with nodular fasciitis-like stroma
Clear cell
Encapsulated
Warthin's-like tumor
Cribriform morular
Papillary microcarcinoma
 TABLE 9.2 MORPHOLOGIC VARIANTS OF PAPILLARY
CARCINOMA
The classification of the morphologic variants of papillary carcinomas is based on the
architectural (growth) patterns and the cell types. Any variant must have more than 75% of the
tumor composed of a specific morphologic pattern to qualify for a specific designation. The
common denominator for all the variants is the typical nuclear morphology characterized by pale
nuclei, nucleoli, nuclear grooves, and intranuclear cytoplasmic inclusions, the exception being
the columnar cell variant. These nuclear features allow an accurate diagnosis of papillary
carcinoma, both histologically and cytologically. It is very common to see multiple growth
patterns in a given papillary carcinoma. The cytologic diagnosis thus depends on the area
sampled and may not be representative of the major morphologic pattern.

Histologically, the morphologic variants of papillary thyroid carcinomas can be easily recognized,
but their identification from cytologic samples is generally not attempted, with the exception of
the follicular variant. Features that characterize some of the variants—including encapsulation
(encapsulated variant), diffuse involvement (diffuse macrofollicular variant), desmoplastic or
nodular fasciitis-like stroma and micro papillary carcinomas (microcarcinoma)—cannot be
appreciated in cytologic samples but only in histologic sections. Furthermore, the incidence of
most of these subtypes is low, and their cytopathologic features are documented only rarely.
With the exception of columnar cell carcinomas, all other subtypes have the same characteristic
nuclear features, and a generic diagnosis of papillary thyroid carcinoma is easily made with a
high degree of accuracy. Cytologic recognition of morphologic subtypes may be unwarranted,
and insignificant in terms of the patient management. A total thyroidectomy is routinely
performed with a diagnosis of papillary thyroid carcinoma, regardless of the morphologic
subtypes. Several studies have attempted to subtype cytologic samples of papillary carcinomas
to predict the histologic variants but were not entirely successful.67 , 68 , 69 , 70 , 71 , 72 , 73
, 74

Follicular Variant of Papillary Carcinoma

First described by Lindsay75 and subsequently reported in detail by Chan and Rosai,76 the
follicular variants comprise up to 12% of thyroid papillary carcinomas.2 , 13 , 76 The incidence
of cervical lymph node metastasis is stated to be high. Although the biologic behavior is usually
that of the conventional type, a few reports have indicated a somewhat aggressive course, with
a greater propensity to metastasize distally, especially to the lungs.2 , 3 , 7 , 77

The follicular variants of papillary carcinoma are completely or partially encapsulated or

nonencapsulated and infiltrative. They vary in size, from microcarcinomas to large.
Histologically, as the name implies, a predominantly or an exclusively follicular growth pattern
characterizes the follicular variant (Figs. 9.28 and 9.29 ). The follicles vary in size and shape
from round to elongated, many distended with colloid. The lining epithelium may show
infolding, forming rudimentary papillae. Their nuclei, however, exhibit the typical morphology
of conventional papillary carcinoma. The colloid within the follicles is often dense (Fig. 9.29B ),
deep-staining, and show peripheral scalloping. A clear cell pattern may be present (Fig. 9.30 ).
The follicular variant may contain desmoplastic stroma. Psammoma bodies can be identified
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in the interfollicular stroma, and the multinucleated foreign-body type giant cells are sometimes
present. The metastatic foci from the follicular variant often show the typical morphology of
conventional papillary carcinoma.

Figure 9.28. Histologic sections. A. An encapsulated neoplasm, medium power. B. Higher

magnification to show the follicular architecture. The lining epithelium shows typical nuclear
features of papillary carcinoma. C. The carcinoma cells in the right half of the section show lack
of clear nuclei. D. Higher magnification showing varying-sized follicles containing colloid. Note
the lining epithelium with dark hyperchromatic nuclei, resembling a follicular adenoma.
Sampling from this area will not allow a specific diagnosis of the follicular variant of papillary
carcinoma.

Figure 9.29. Follicular variant of papillary carcinoma. A. The carcinoma demonstrates a

follicular growth pattern. At low power, the nuclear chromatin appears darkly stained. An area
of typical papillary carcinoma cell nuclei is seen (arrows ). B. Higher magnification to show the
follicular epithelium with granular chromatin. Intranuclear inclusions are present. The follicular
lumens contain dense, deep eosinophilic colloid.
Figure 9.30. Follicular variant of papillary carcinoma. Histologic section showing clear
cytoplasm. The colloid in the lumens shows peripheral scalloping.

Cytopathologic Features
The aspirates of follicular variant of papillary carcinoma tend to be cellular (Figs. 9.31A and
9.32A ), but may be scanty in the presence of desmoplastic stroma. The typical cytologic
appearance includes small to moderately enlarged follicular cells, in loosely cohesive groups and
in syncytial tissue fragments, with and without a follicular pattern (Figs. 9.31 , 9.32 , 9.33 , 9.34
, 9.35 , 9.36 , 9.37 , 9.38 , 9.39 , 9.40 and 9.41 ). The neoplastic follicles may be seen discrete
(Fig. 9.34 ). Their enlarged, round to ovoid nuclei, containing pale, dusty, powdery chromatin,
micronucleoli, grooves, and inclusions, clinch the diagnosis of the follicular variant (Table 9.3 ).
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The cytoplasm of the cells of this variant is scant or barely visible and the cell borders are poorly
defined. The aspirates often show monolayered (two-dimensional), syncytial tissue fragments,
which are often misinterpreted as indicative of nodular goiter, especially in Romanowsky-stained
preparations. The colloid is usually present as dense, rounded casts within the follicular lumina,
as well as in the background (Figs. 9.31B , 9.32B , 9.39 ). Gallagher, et al. 78 described the
colloid in follicula variants of papillary carcinoma to be pink and dense. The dense-staining
colloid in the follicular variant of papillary carcinomas is a characteristic feature that is also
appreciated in histologic sections. Other cytologic features, such as papillary and papillary-like
tissue fragments, are generally not observed, unless the needle also samples the focal papillary
growth pattern if present within the tumor. Psammoma bodies and multinucleated giant cells
are sometimes present. The background is usually clean.
Figure 9.31. FNA. A. Follicular variant of papillary carcinoma. Note the hypercellularity and the
striking follicular pattern (low power). B. Higher magnification demonstrates syncytial tissue
fragments forming follicles. Their nuclei contain powdery chromatin and cytoplasmic inclusions.
The colloid within the follicles is dense.

Figure 9.32. A. Follicular variant of papillary carcinoma. Note the hypercellularity and the
striking follicular pattern (low power). B. Higher magnification. The lining cells of the follicles
present classic nuclear features of papillary carcinoma. Note that many nuclei have intranuclear
inclusions. The colloid within the follicular lumina is dense.
Figure 9.33. A syncytial tissue fragment with follicular architecture. The nuclei are enlarged,
round, and have finely granular to powdery chromatin. Nuclear inclusions and micronucleoli are
seen.
Figure 9.34. Angulated, curvaceous syncytial tissue fragment with component cells exhibiting
nuclear features of papillary carcinoma.
Figure 9.35. Discrete follicles lined by follicular cells. Their nuclei are enlarged, overlapped
with altered polarity and contain finely granular chromatin, micronucleoli, intranuclear
inclusions, and grooves.

Figure 9.36. A. This syncytial tissue fragment of follicular cells shows a vague follicular pattern.
The component nuclei are enlarged, with finely granular chromatin, micronucleoli, grooves, and
inclusions consistent with a follicular variant of papillary carcinoma. B. FNA of a follicular
variant of papillary carcinoma (Diff-Quik stain). (Part B is courtesy of Mariza de Peralta-
Venturina, MD, William Beaumont Hospital, Royal Oak, Michigan.)

Figure 9.37. The syncytial tissue fragment of follicular cells shows minimal follicular
architecture. Small amount of colloid is seen in the lumen. The nuclei, however, show typical
features of papillary carcinoma.
Figure 9.38. FNA of a follicular variant of papillary carcinoma. The cellular aspirate shows
syncytial tissue fragments with follicular pattern. The nuclei have fine powdery chromatin and
nucleoli. Nuclear grooves or inclusions are not present. A cytologic diagnosis of follicular variant
should be high on the list. Follicular neoplasms do not exhibit pale nuclei.
Figure 9.39. FNA of a follicular variant of papillary carcinoma. The syncytial tissue fragments
with a follicular pattern. The nuclei contain deep-staining granular chromatin. Lack of nucleoli,
grooves, and inclusions favors a follicular adenoma/carcinoma. A clue to the correct diagnosis
may be the presence of dense colloid.
Figure 9.40. A syncytial tissue fragment of follicular cells with a follicular pattern. The enlarged
nuclei are crowded and overlapped. The chromatin is deeply stained and granular. Grooves,
inclusions, and nucleoli are not seen. This aspirate was interpreted as cellular follicular
adenoma. It was histologically diagnosed as a follicular variant of papillary carcinoma.
Figure 9.41. These tissue fragments of follicular cells are syncytial without any follicular
pattern. The nuclei are uniformly enlarged, crowded, and overlapped. The chromatin is
granular. Nucleoli, grooves, and inclusions are not present. The background is clean. The
cytologic features are consistent with a cellular follicular adenoma. Thyroidectomy revealed a
follicular variant of papillary carcinoma.

Cellularity
Variable
Presentation
Neoplastic cells in loosely cohesive groups or in syncytial tissue fragments
Architecture of the tissue fragments
Syncytial tissue fragments with follicular pattern; varying sized individual follicles, empty or
containing dense-staining globules of colloid; monolayered tissue fragments with or without
branching; syncytial tissue fragments without any architectural patterns; twisted tubular
structures; papillary or papillary architecture not present
Cells
Round to cuboidal; medium-sized; poorly defined cell borders; N/C ratios high
Nucleus
Variably enlarged, pleomorphic, round, oval, ovoid; nuclear membrane irregularity ±; pale
nuclei with powdery to finely granular chromatin; occasionally coarsely granular chromatin;
micronucleoli, nuclear grooves, pseudoinclusions
Cytoplasm
Scant and pale
Psammoma bodies
±
Background
Dense-staining, stringy or globules of colloid, lymphocytes ±; histiocytes ±

TABLE 9.3 CYTOPATHOLOGIC FEATURES OF FOLLICULAR

VARIANT OF PAPILLARY CARCINOMA
P.150
P.151

DIFFICULTIES WITH CYTOLOGIC DIAGNOSIS OF FOLLICULAR

VARIANTS OF PAPILLARY CARCINOMA
This distinctive subtype of papillary carcinoma is correctly identified both histologically and
cytologically when classic features, that is, the typical nuclear morphology of conventional
papillary carcinoma, are present. However, recognition of these tumors has caused many
problems at multiple levels, including aspiration cytology, intraoperative frozen sections,79 and
histologic interpretations. Many feel that these variants are overdiagnosed both cytologically
and histologically.80 , 81 , 82

The typical nuclear morphology of conventional papillary carcinoma—such as powdery

chromatin, micronucleoli, nuclear grooves, and inclusions—may not be a universal feature in a
given case of the follicular variant of papillary carcinoma. If the fine needle targets the areas
lacking these classic nuclear features within a tumor, a correct diagnosis of the follicular variant
of papillary carcinoma is not possible. The follicular architecture and the lack of typical nuclear
morphology will lead to a diagnosis of a follicular lesion or a follicular neoplasm, especially in
the absence of intranuclear inclusions (Figs. 9.39 , 9.40 and 9.41 ; see also Figs. 7.50 , 7.51 ,
7.52 , 7.53 and 7.54 ). A follicular variant of papillary carcinoma must always be considered in
the differential diagnosis, when an aspirate suggestive of a follicular neoplasm demonstrates
some of the nuclear features of papillary carcinoma.

In the last two decades, there has been a surge of reports on the cytologic diagnosis of the
follicular variant of papillary carcinoma.78 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ,
94 , 95 , 96 , 97 Several reviews have attempted to analyze the cytologic features from
histologically confirmed cases of the follicular variant of papillary carcinoma. The diagnostic
accuracy of the follicular variant of papillary carcinoma reported varies from 40% to 86%.83 , 84
, 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 Many cases of follicular variants of papillary
carcinoma have been interpreted as nodular goiter or follicular neoplasms. The problem is
compounded by the fact that the histologic criteria used to identify this variant are also
inconsistent.79 , 81 There is considerable interobserver variation in the histologic diagnosis of
the follicular variant of papillary carcinoma, indicating difficulties in a precise classification.98

Because of the tendency to overdiagnose the follicular variant of papillary carcinoma, Chan81
has proposed strict guidelines for the histologic diagnosis: (i) nuclei are ovoid rather than round;
(ii) nuclei are crowded, often manifesting as lack of polarization in the cells lining the follicle;
(iii) nuclei show a clear or pale chromatin pattern (nuclear clearing should not be confined to
the central portion of the tumor, which can happen due to poor fixation) or they exhibit
prominent grooving; and (iv) psammoma bodies are found. If one of these four features is
lacking, four or more of the following subsidiary features have to be present for a diagnosis of
FVPC: (i) presence of abortive papillae, (ii) predominantly elongated or irregularly shaped
follicles, (iii) dark-staining colloid, (iv) presence of rare nuclear pseudoinclusions, and (v)
multinucleated histiocytes in the lumens of the follicles.

Numerous studies have been conducted on the possible role of immunochemistry and molecular
analysis. None of the tests so far have been conclusive. In the absence of acceptable criteria as
recommended by Chan,81 the diagnostic scheme proposed by the Chernobyl group99 may be
applicable: "Well-differentiated tumor of uncertain malignant potential" —an encapsulated
tumor composed of well-differentiated follicles with questionable nuclear features of papillary
carcinoma and no vascular invasion and either absent or questionable capsular invasion.

Livolsi and Baloch100 present a different opinion. They prefer to address an encapsulated lesion
with a follicular pattern but with multifocal distribution of nuclear features of papillary
carcinoma as a follicular variant of carcinoma. If the encapsulated lesion shows only one focus of
papillary carcinoma, these authors designate the lesion as "follicular adenoma with a single focus
of papillary carcinoma."
Tall Cell Variant of Papillary Carcinoma
First described by Hawk and Hazard,24 the tall cell variant comprises about 10% of papillary
carcinomas of the thyroid.101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 ,
113 , 114 These tumors tend to occur in elderly patients, with a male:female ratio of 1:5. The
tall cell variant is often large and bulky, frequently exceeding 6 cm in diameter, with areas of
necrosis, extrathyroidal extension, and vascular invasion (42%). The biologic behavior is more
aggressive101 than that of the conventional type, with a higher incidence of recurrences,
cervical lymph node metastasis (75%), and distant metastasis (17%). Death occurs in 25% of the
cases.1 , 2 , 101

Histologically, the growth pattern is papillary with complex branching (Fig. 9.42A and B ). The
follicles are elongated, often aligned in parallel lines referred to as "railroad tracks." The
hallmark of tall cell carcinoma is neoplastic cells that are twice as tall as wide, containing
abundant, eosinophilic, dense cytoplasm. Mitotic activity may be prominent. Colloid is scant,
and the carcinoma is frequently associated with lymphocytic infiltrate. Histologically, tall cell
carcinomas require at least 30% of the cell population to be of the tall cell type.101 , 104
Figure 9.42. Tall Cell Variant . A. Histologic sections of the tall cell variant demonstrating
branching papillae, lined by tall cells containing abundant eosinophilic cytoplasm. B. The
neoplastic follicles are elongated and arranged in a linear fashion (railroad tracks), separated by
stroma. The lining follicular cells are tall columnar. C. FNA of this case showing several tissue
fragments of malignant cells in a clean background. The elongated shapes of the cells are
evident even at this low power. D,E. Higher magnification. The pleomorphic cells are loosely
cohesive and discrete, large, elongated to columnar-shaped, with well-defined cell borders.
Their cytoplasm is abundant and dense. Several nuclei contain sharp cytoplasmic inclusions,
some with a "soap-bubble appearance" (arrows ).

Cytopathologic Features
Cytopathologic features have been described in the literature as case reports and as small series
(Table 9.4 ).109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 The aspirates
P.152
tend to be cellular, consisting of syncytial tissue fragments with various architectural
configurations, in loosely cohesive groups and as isolated cells. The neoplastic cells are
elongated, columnar, with well- defined cell borders, and containing abundant, oxyphilic to
cyanophilic cytoplasm, which is often dense and sometimes pale and granular (Fig. 9.42C to E ).
Their resemblance to Hürthle cells is striking on account of the abundant cytoplasm. The cells
may appear large and round instead of elongated when smeared in different planes (Figs. 9.43B
and 9.44 ). Their nuclei are large, but the N/C ratios remain low due to abundant cytoplasm,
and the nuclei are eccentric in elongated cells but may be central. The nuclei are round to oval
with smooth to irregular nuclear membranes, exhibiting typical cytologic features of
conventional papillary carcinoma. Intranuclear inclusions are seen much more frequently in
aspirates of tall cell variants of papillary carcinomas, an observation that was made by the
author a decade ago118 and also supported by Soloman and co-workers.109 The nuclear
inclusions can be multiple within any given nucleus, imparting a "soap-bubble appearance."109
Lymphoid infiltrate may be present (Fig. 9.45 ) Damiani and co-workers73 described the
cytologic features, such as large cell size, oxyphilic to amphophilic cytoplasm, and a high
nuclear/cytoplasmic ratio, as indicative of the tall cell variant. The differential diagnosis of the
tall cell variant of papillary carcinoma includes the oxyphilic variant of papillary or papillary
Hürthle cell carcinoma.
Figure 9.43. FNA of a different case of a tall cell variant of papillary carcinoma. The large,
malignant cells with abundant granular to dense cytoplasm form a monolayered but syncytial
tissue fragments. The nuclei demonstrate typical features of papillary carcinoma.

Figure 9.44. FNA of a tall cell variant of papillary carcinoma. The malignant cells are large, with
dense cytoplasm, forming a monolayered syncytial tissue fragment. Their nuclear morphology is
typical of papillary carcinoma. Cells of a tall cell variant sometimes appear round to polygonal
instead of columnar or elongated and strongly resemble a Hürthle cell neoplasm.
Figure 9.45. FNA of a tall cell variant of papillary carcinoma. The malignant cells are large, with
dense cytoplasm, forming a monolayered syncytial tissue fragment. Their nuclear morphology is
typical of papillary carcinoma. Lymphocytes are present in the background.

Cellularity
Usually very cellular
Presentation
Cells isolated, in loosely cohesive groups and in syncytial tissue fragments
Architecture of the tissue fragments
Predominantly papillary with or without branching, monolayered, follicular pattern
infrequent
Cells
Large, elongated to columnar, appear round to polygonal when seen on cross-section;
well-defined cell borders; N/C ratios lower than cells of conventional or follicular
variant carcinoma cells
Nucleus
Usually eccentric, may be central; large, round to oval, with smooth to irregular mem-
 branes; chromatin dusty, powdery to finely granular; micro-macronucleoli;
grooves; intranuclear inclusions present in larger numbers than other variants;
multiple inclusions within a single nucleus giving a "soap-bubble" appearance;
rare mitosis
Cytoplasm
Abundant, dense staining cyanophilic or oxyphilic; may be pale and granular and
amphophilic
Psammoma bodies
Very rare
Background
Colloid infrequent, lymphocytic infiltrate ±

TABLE 9.4 CYTOPATHOLOGIC FEATURES OF TALL CELL

VARIANTS OF PAPILLARY CARCINOMA

Columnar Cell Variant of Papillary Carcinoma

The columnar cell variant is an extremely rare, morphologically distinct type of papillary
carcinoma. First described by Evans119 and later by Sobrinho-Simoes et al.,120 the columnar cell
variant is considered to be an aggressive tumor. All of their patients died of the disease.
However, in a large series by Wenig et al.67 this view is contradicted. According to this report,
the behavior depends on the presence or absence of extrathyroidal extension rather than the
morphologic type alone. Literature on the columnar cell variant of papillary carcinoma is
limited,119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 with only a few case
reports on cytopathologic findings.125 , 126 , 127 , 128 , 129 , 130

The histologic features of the columnar cell variant of papillary carcinoma are characterized by
an extreme papillary growth pattern, tall columnar cells, and nuclear stratification, presenting a
strong morphologic resemblance to endometrioid carcinoma (Figs. 9.46A , 9.46B , 9.47G , 9.47H
). Also present are elongated follicles, arranged in parallel lines.67 Columnar cell papillary
carcinomas may be associated with other growth patterns. The neoplastic cells are twice as tall
as they are wide, and contain clear, vacuolated to eosinophilic cytoplasm, sometimes exhibiting
subnuclear vacuoles. The nuclei, aligned perpendicular to the surface, are darker and lack the
empty look of classic papillary carcinoma cells (Figs. 9.46C to 9.46E , 9.47A to 9.47D ). Increased
mitotic activity may be present, but necrosis is rare. The colloid is minimal to absent and
psammoma bodies are rare. The immunoprofile includes positive reactivity to cytokeratin.
Although all cases described by Wenig et al.67 showed positive reactivity to thyroglobulin, it was
inconsistent, varying from strong to weak to focally negative within a given tumor and was
absent in metastatic tumor. In the cases described by Evans,119 the carcinoma cells did not
react with antithyroglobulin antibodies. Two cases of columnar cell variants of papillary
carcinoma from the author's files showed negative reactivity.
Figure 9.46. Columnar cell variant of papillary carcinoma . A. Histologic section. The tumor
shows a complex papillary pattern with tall columnar cells and nuclear stratification and
resembles an endometroid adenocarcinoma. B. Higher magnification. Note the tall columnar
tumor cells with hyperchromatic, stratified nuclei. C–E. Fine-needle biopsy of this columnar
cell variant of papillary carcinoma. The tumor cells are delicate and columnar, with pale
cytoplasm and tapered ends, round to oblong nuclei with coarse chromatin, and micronucleoli.
Intranuclear inclusions or grooves are not identified. F. A large tissue fragment consisting of
closely packed cells with elongated nuclei with peripheral palisading. Nuclear details are
difficult to assess due to thickness of the tissue fragment. G. The syncytial tissue fragment
shows stratified elongated nuclei at the periphery. The chromatin is granular. Micronucleoli and
occasional inclusions are present (arrow ).
Figure 9.47. Columnar cell variant of papillary carcinoma . FNA of a massively enlarged thyroid
with multiple enlarged cervical lymph nodes. A. Overwhelmingly cellular aspirate consisting of
several papillary tissue fragments with complex branching. The background shows single cells
and groups of cells, low power. B. Higher magnification of the tissue fragment shows minimally
enlarged round nuclei with granular chromatin and micronucleoli; their cytoplasm is scant. C.
Different field showing a tissue fragment of malignant cells with papillary-like pattern. Their
nuclei have deep-staining coarsely granular chromatin. Some exhibit nucleoli. The cells
demonstrate variable cytoplasm. D. The neoplastic cells are small to medium-sized, are present
isolated and in syncytial tissue fragments. Their cell borders are poorly defined and the
cytoplasm is scant. The nuclei are round and uniform, containing granular chromatin and
micronucleoli. E. Core needle biopsy of the neck mass showing a papillary carcinoma. F.
Immunostain with thyroglobulin. The neoplastic cells are nonreactive. Thyroidectomy revealed a
columnar cell carcinoma, widely infiltrating the adjacent tissues and involving multiple cervical
lymph nodes.

Figure 9.47. G. Histologic section demonstrating typical architecture of the columnar cell
variant of papillary carcinoma, resembling an endometrioid carcinoma. H. Higher magnification
highlighting the columnar cells, stratification, and pale cytoplasm.

P.153

Cytopathologic Features
The aspirate of the columnar cell variant shows syncytial tissue fragments with a papillary
pattern comprised of elongated columnar cells that may show pale, tapering cytoplasm at one
end (Figs. 9.46 and 9.47 ). The nuclei show stratification and palisading at the periphery of the
tissue fragments. They are hyperchromatic, oval to oblong nuclei with micronucleoli, contrasting
sharply with the dusty, powdery chromatin of the cells seen in conventional or other
morphologic variants. Intranuclear inclusions or nuclear grooves are usually absent. The cells of
the columnar cell variant possess scant, pale to clear cytoplasm. The ancillary features—such
as psammoma bodies, multinucleated foreign-body–type giant cells, and colloid—are not
described or seen in these tumors.
 P.154
The lack of typical nuclear features of papillary carcinoma may lead to diagnostic difficulties
and may be mistyped as other neoplasms such as medullary carcinoma.125 The columnar cell
pattern was misinterpreted as possible contamination by respiratory columnar cells, in their
initial evaluation of the case reported by Jayaram.127 Columnar cell carcinoma morphologically
resembles tall cell carcinoma. But the cytoplasm in tall cell carcinomas is dense and eosinophilic
and the nuclei demonstrate typical features of papillary carcinoma.

Oncocytic or Oxyphil Cell Variant

The oncocytic variant of papillary carcinoma is uncommon, the reported incidence ranging from
3.5% to 11%.131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 There are two types of
oncocytic papillary carcinomas. Both have a papillary growth pattern.

The oncocytic variant of papillary carcinoma demonstrates typical nuclear features of

conventional papillary carcinoma such as powdery chromatin, micronucleoli, grooves, and
inclusions. These may also demonstrate a follicular growth pattern. These are usually
encapsulated and may or may not show capsular invasion. The biologic behavior of the oxyphilic
variant parallels that of a conventional papillary carcinoma.

The papillary Hürthle cell carcinomas demonstrate a papillary growth pattern, but lack some
nuclear features such as powdery chromatin and micronucleoli, yet show a prominent cherry-red
macronucleolus. Inclusions are present in both and do not serve as a differentiating feature.
These are more aggressive clinically with 16% mortality and are in keeping with Hürthle cell
carcinomas.

Cytologic specimens from the oncocytic variant of papillary carcinomas show a Hürthle cell
population (Figs. 9.48
P.155
and 9.49 ). The neoplastic cells are variable in size, may be discrete, and occur in loosely
cohesive groups and syncytial tissue fragments, with a papillary configuration; a follicular
pattern may be evident (Fig. 9.49 ). Their nuclei demonstrate nuclear features seen in papillary
carcinomas such as powdery, dusty chromatin, micronucleoli, grooves, and inclusions. The
oxyphilic cells contain abundant granular cytoplasm similar to that seen in cells of the tall cell
variant. Psammoma bodies may or may not be present in the background. A papillary Hürthle
cell carcinoma is illustrated in Figure 9.50 for comparison.
Figure 9.48. Oxyphilic variant of papillary carcinoma . A–D. FNA of a cystic thyroid nodule.
The syncytial tissue fragments consist of cells with abundant cyanophilic cytoplasm. The nuclei
contain finely granular chromatin, micronucleoli, grooves, and inclusions. Thyroidectomy
revealed a large cystic tumor with residual in the wall. E. Histologic section showing an oxyphilic
variant of papillary carcinoma with branching papillary fronds. F. Higher magnification of the
papillary frond. The lining cells are columnar with abundant eosinophilic cytoplasm. The nuclei
are uniform in size, round, and with granular chromatin containing nucleoli. Nuclear inclusions
are also seen.
Figure 9.49. Oxyphilic variant with a follicular pattern . A,B. Syncytial tissue fragments with a
follicular pattern. The nuclei are round with granular chromatin and nucleoli. Intranuclear
inclusions are easily identified. The appreciable amount of cytoplasm is dense. The cytologic
diagnosis was a follicular variant of papillary carcinoma. The oxyphilic nature of the cells was
not recognized. C. Histologic sections of the resected tumor showing a follicular growth pattern,
formed by oncocytic cells. D. Higher magnification. The follicles are lined by Hürthle cells with
uniform nuclei, some containing inclusions. Macronucleoli are not seen.
Figure 9.50. Hürthle cell carcinoma, papillary type . A. Markedly cellular aspirate with
syncytial tissue fragments exhibiting a papillary and monolayered patterns. B. Higher
magnification showing cells lining a papillary core demonstrating typical nuclear features of a
Hürthle cell tumor with prominent macronucleoli. C. Syncytial tissue fragments of small
Hürthle cells presenting with uniform round nuclei containing characteristic macronucleoli.
Nuclear grooves or inclusions are not seen. D,E. Histologic section showing a Hürthle cell
carcinoma with papillary growth pattern. F. Note the psammoma body. Note that the nuclear
pattern is that of a Hürthle cell carcinoma and not a conventional papillary carcinoma.
 P.156
P.157
P.158

Solid and Trabecular Variants

As the name implies, these subtypes are characterized by a solid growth pattern composed of
polygonal cells with abundant pink cytoplasm and nuclei with typical characteristics of
conventional papillary carcinoma (Fig. 9.51A ). The solid pattern comprising 70% of the tumor is
usually associated with common morphologic types and blends with the papillary and follicular
areas and with squamous metaplasia. These tumors with solid growth pattern must be
differentiated from poorly differentiated or undifferentiated carcinomas. The features that
favor papillary carcinoma include irregular fibrous trabeculae within the tumor and occasional
psammoma body and most important, the nuclear morphology.2 , 141

Figure 9.51. Solid variant of papillary carcinoma . A. Histologic section. The growth pattern is
solid with an attempt at follicle formation. B,C. FNA showing syncytial tissue fragments of large
cells without any architectural configurations. Their nuclei are large and show an occasional
intranuclear inclusion (arrow ).

Cytologically, these carcinomas contain malignant cells, isolated and in syncytial tissue
fragments, without any papillary or a follicular architecture However, the nuclear morphology is
characteristic (Fig. 9.51B and C).

Diffuse Sclerosing Variant

First reported by Vickery et al. 22 the diffuse sclerosing variant is more frequently seen in
children and adolescents.142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 It
accounts for 2.3% of all thyroid papillary carcinomas. The characteristic features include diffuse
involvement of one or both lobes rather than a dominant nodule, numerous small papillary
formations within cleft-like spaces, probably lymphatics, extensive squamous metaplasia, many
psammoma bodies, marked lymphocytic infiltration, and prominent fibrosis (Fig. 9.52 ). Chan et
al.148 and others145 described the presence of S-100 protein-containing cells in the stroma. This
variant shows a greater incidence of cervical lymph node involvement and pulmonary metastasis.
The metastatic deposits are not as distinctive as primary tumor and resemble classic-type
papillary carcinoma.148
Figure 9.52. Diffuse sclerosing variant of papillary carcinoma . A. Histologic section of the
diffuse sclerosing variant of papillary carcinoma with a heavy lymphoid infiltrate and numerous
psammoma bodies. B. Another field showing a solid growth pattern in the background of a
lymphocytic infiltrate. C. Higher magnification of part B, showing tumor cells in an endothelium-
lined space. The component cells are uniform appearing squamoid. D,E. Fine-needle biopsy from
the same case shown in parts A to C. The malignant cells are pleomorphic, with the
characteristic nuclear features of papillary carcinoma. Lymphocytes are present in the
background. F. A tissue fragment of malignant cells incorporating psammoma bodies.
Cytopathologic features of diffuse sclerosing variant are documented in only three case
reports.150 , 151 , 152 One personally examined
P.159
case showed syncytial tissue fragments of medium-sized cells containing nuclei with the typical
features of papillary carcinoma. Many psammoma bodies were conspicuous in the background of
heavy lymphocytic cells (Fig. 9.52 ). This morphologic variant cannot be detected from the
cytologic samples, since areas of fibrosis are not visualized and the samples will be interpreted
as papillary carcinoma in the background of lymphocytic thyroiditis. Abundant psammoma bodies
may be present.

P.160

Papillary Carcinoma with Exuberant Nodular Fascitis-Like

Stroma
Papillary carcinoma with nodular fasciitis-like stroma was first described by Chan et al. in
1991.153 Since then a few case reports have appeared in the literature on histologic and
cytologic presentations.154 , 155 , 156 , 157 , 158

This variant of papillary carcinoma is characterized by abundant fasciitis-like stroma consisting

of spindle cells arranged in fascicles in a background of vascularized fibrovascular stroma with
histiocytes and inflammatory cells (Fig. 9.53 ). The stromal spindle cells have plump nuclei with
a finely granular, bland chromatin pattern. The amount of stroma can be extensive and
exuberant. The papillary carcinoma may present follicles, papillae, and trabeculae separated by
variable stroma. The nuclear features are those of a typical conventional papillary carcinoma.
Psammoma bodies may occasionally be seen (Fig. 9.53C ). The spindle cell component is
immunoreactive to vimentin and negative to cytokeratin.
Figure 9.53. Papillary carcinoma with nodular fasciitis-like stroma. A. Histologic section of
papillary carcinoma with nodular fasciitis-like stroma. Note the exuberant proliferating stroma
with trapped neoplastic follicles and cells (arrows ). The follicles are lined by epithelium with
features of conventional papillary carcinoma. B. Proliferating stroma composed of spindle cells
with small nuclei presenting a bland chromatin pattern. A psammoma body is embedded in the
exuberant stroma. C. Exuberent stroma and a single follicle lined by cells with typical
morphology of papillary carcinoma. Because of the increased stroma, the fine-needle biopsies of
this variant will tend to be poorly cellular but will show features of either the conventional or
follicular variant of papillary carcinoma. FNA in this case was inadequate for cytologic
evaluation.

Cytopathologic Features
Because of the fibrous stroma, the aspirates tend to be paucicellular with minimal epithelial
component. Cytologic presentations are sparsely reported.157 , 158 This subtype cannot be
identified from cytologic samples due to the absence of the stromal component. The aspirates,
however, exhibit the typical cytopathologic features of the conventional or follicular variants of
papillary carcinoma. Most published reports highlight the diagnostic difficulties. Yang et al.157
reported a case of papillary carcinoma with nodular fasciitis-like stroma that was cytologically
interpreted as malignant neoplasm suggestive of myxoid sarcoma because of the large
population of spindle cells with a bland chromatin pattern. The diagnosis of papillary carcinoma
was established at open biopsy.

Macrofollicular Variant
As a morphologic variant of papillary carcinoma, macrofollicular papillary carcinoma was first
described by Albores-Saavedra and co-workers.159 It is characterized by the presence of large,
varying-sized colloid-filled macrofollicles mixed with the follicular variant of papillary carcinoma
(Fig. 9.54 ). The colloid within the follicles is often scalloped or vacuolated. The nuclei of the
cells lining the follicles may be hyperchromatic. The classic nuclear pattern of conventional
papillary
P.161
carcinoma is seen in foci scattered throughout the tumor. The large colloid-filled follicles may
also contain abortive papillae lined by atypical cells. Due to the presence of large, distended
follicles with abundant colloid, this variant may be easily confused with multinodular goiter or a
macrofollicular adenoma, both grossly and histologically. Albores-Saavedra et al.159 , 161 and
Ashfaq and co-workers160 have reported a higher incidence of insular component associated
with the macrofollicular variant of papillary carcinoma.

Figure 9.54. Macrofollicular variant of papillary carcinoma . Histologic section. A. The large,
varying-sized follicles distended with colloid present a deceptively bland pattern, strongly
resembling a nodular goiter or a macrofollicular adenoma. Focally the follicles are lined by
epithelium (arrows ) with typical nuclear features of conventional papillary carcinoma, which
can be appreciated only at high power. B. Higher magnification to highlight the nuclear
morphology. This carcinoma metastasized to the shoulder 4 years later with dedifferentiation
into an insular pattern (see Figure 15.10 in Chapter 15 ).

The cytologic features162 , 163 , 164 are similar to those of the conventional or follicular
variant, with abundant colloid in the background (Figs. 9.54 , 9.55 and 9.56 ). This variant must
be differentiated from a nodular goiter with abundant colloid or a macrofollicular adenoma.

Figure 9.55. Macrofollicular variant of papillary carcinoma . A. Marginally cellular specimen

with few tissue fragments in the background of abundant colloid, low power. B. Higher
magnification showing syncytial architecture with nuclei exhibiting typical feature of papillary
carcinoma.
Figure 9.56. Macrofollicular variant of papillary carcinoma . Different example showing small
monolayered tissue fragments with component nuclei containing powdery chromatin and
intranuclear inclusions. Note abundant colloid in the background.

P.162
P.163

Diffuse Follicular Variant

Originally described by Sobrinho-Simoes et al.165 the diffuse follicular variant occurs
predominantly in women who may be hyperthyroid and presents grossly as a goiter. The enlarged
thyroid gland is diffusely involved by a neoplasm showing the follicular pattern and nuclear
morphology of papillary carcinoma. The clinical course is described as aggressive, with distant
metastasis.166 Although the cytologic features have not been reported, they conceivably will
present the cytomorphology of papillary carcinoma.

Encapsulated Variant
The encapsulated variant is characterized by total encapsulation, with or without invasion of the
capsule by the tumor.167 , 168 , 169 Because of this encapsulation, it was referred to as
"papillary adenoma." The histomorphology may be typical of the conventional variant or the
follicular variant, with corresponding cytologic features.

This morphologic variant is strictly based on complete encapsulation identified only in a

surgically excised specimen, and hence can be interpreted only as papillary carcinoma from
cytologic samples.

Papillary Carcinoma with Clear Cell Change

Some consider papillary carcinomas with clear cell change as an expression of morphologic
variance.170 , 171 Rosai et al.2 state that this feature in papillary carcinomas is rare and
inconsequential. Meissner and Adler13 reported clear cell change in 28% of their 224 cases of
papillary carcinoma. The clear cytoplasm is a result of glycogen accumulation or vesicular
formation.172

Histologically, clear cell change is more frequent with the follicular variant (Fig. 9.57 A and B)
but can also be seen with the papillary pattern (Fig. 9.57D ). Cytologically, the cells with clear
change show poorly defined cell borders, tend to appear discrete, and frequently appear as
stripped nuclei. Their cytoplasm is barely discernible; the enlarged nuclei exhibit the typical
features of a papillary carcinoma. Because of the single cell pattern, these aspirates may be
misinterpreted as medullary carcinoma (Fig. 9.57C ).
Figure 9.57. Papillary carcinoma with clear cell change . Histologic section. A. Follicular
pattern with follicular cells exhibiting clear cytoplasm. B. Higher magnification. C. FNA. The
aspirated cells tend to be isolated and possess poorly defined cell borders. The nuclei
demonstrate typical features of papillary carcinoma. D. Histologic section of papillary carcinoma
with clear cell change.

Cribriform-Morular Variant
The cribriform-morular variant as a distinct variety of papillary carcinoma was first described by
Harach et al.173 in association with familial adenomatous polyposis syndrome. This association
has been confirmed in other studies.

Histologically, the cribriform-morular variant is characterized by an intricate blending of

cribriform, follicular, papillary, trabecular, and solid patterns with morular (squamoid) areas
(Fig. 9.58 ).173 , 174 , 175 , 176 , 177 The cribriform pattern is formed by anastomosing bars
and arches of cells without intervening stroma and resembles breast-duct carcinoma. Discrete
cribriform structures are scattered in sclerotic stroma. The follicular structures are usually
devoid of colloid. The neoplastic cells are tall with abundant eosinophilic cytoplasm and
frequent pseudostratification. Also present is a trabecular arrangement of spindle cells
reminiscent of hyalinizing trabecular adenoma.
Figure 9.58. Cribriform-morular variant. A. Histologic section (low power). Lobules of
neoplastic tissue surrounded by sclerotic stroma. Note the cribriform pattern and squamous
morula. B. Medium power view showing a cribriform pattern C. Extensive squamous metaplasia
seen as large morulae. D. Areas of conventional papillary carcinoma with squamous metaplasia.
E. FNA of this case. Tissue fragments of papillary carcinoma cells with a large morula of
squamous cells. F. Two large squamous morulae presenting with a typical whorled pattern. G.
Tissue fragments of carcinoma cells with typical cytomorphology of papillary carcinoma. H.
Tissue fragment of spindle cells and a squamous morula (arrow ).

Colloid is scant to absent. The cells vary from cuboidal to columnar and display typical nuclear
morphology of papillary thyroid carcinoma. The tumor is immunoreactive to thyroglobulin.

P.164

Cytologic Features
The cytologic findings of the cribriform-morular variant as described by Chuah and co-
workers,174 Kuma et al.,175 and Chong et al.176 include the usual features of papillary
carcinoma with typical nuclear characteristics. The syncytial tissue fragments may show a
cribriform pattern and cellular whirls or morulae may be present. Cytologic features of one case
from the author's laboratory are illustrated in Figure 9.58 .A to F.

Papillary Hürthle Cell Carcinoma with Lymphocytic Stroma

(Warthin's-Like Tumor of the Thyroid)
A recent addition to the long list of morphologic variants of papillary carcinoma, this variant is
characterized by papillary growth pattern, intimately mixed with heavy lymphoid infiltrate,
bearing a striking resemblance to Warthin's-like tumor of the salivary gland. Since first described
by Apel et al.,178 there have been several cases reported with histologic and cytologic
findings.179 , 180 , 181 , 182 , 183 , 184 , 185

Histologically, papillary Hürthle cell carcinoma with lymphocytic stroma consists of papillary
architecture formed by cuboidal to columnar Hürthle cells containing abundant eosinophilic
cytoplasm (Fig. 9.59 A to C). The fibrous stalks of the papillary fronds are packed with lymphoid
cells. The neoplastic cells demonstrate typical nuclear morphology of conventional papillary
carcinoma.

Figure 9.59. Papillary carcinoma with Warthin's tumor-like features . A. Histologic section
showing well-defined lobules of tumor, consisting of papillary fronds of epithelium with the
fibrovascular stalks densely infiltrated by lymphocytes, medium power. B,C. Higher
magnification. The papillary fronds and elongated tubules show oncocytic epithelium. There is
dense lymphocytic infiltrate. D. FNA of this case. Medium power showing a cellular aspirate with
branching tissue fragments. E. Higher magnification. The tissue fragments are monolayered and
long with small, uniform, crowded, and overlapped nuclei. The chromatin is finely granular with
micronucleoli. F. These syncytial tissue fragments show nuclei with micronucleoli and
intranuclear inclusions. Their cytoplasm is scant. The oxyphilic nature is not seen. Few
lymphocytes are present in the background.

Cytologic Features
There are four case reports documenting the cytologic findings.182 , 183 , 184 , 185 The
aspirates contain discrete and syncytial tissue fragments of Hürthle cells with or without
papillary architecture. The neoplastic cells exhibit typical features of conventional papillary
carcinoma. The background shows variable numbers of lymphoid cells. One personally
encountered case illustrated in Figure 9.59 did not contain Hürthle cells. The lymphoid
infiltrate was sparse. However, the cellular aspirate showed diagnostic features of conventional
papillary carcinoma (Fig. 9.59 D to F).

PAPILLARY MICROCARCINOMA AND OCCULT CARCINOMA

The terms "microcarcinoma" and "occult carcinoma" are frequently used synonymously, creating
considerable confusion among pathologists, endocrinologists, and surgeons alike.
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P.166
P.167
Papillary microcarcinoma is defined as tumor less than 10 mm in size (WHO).1 Lesions ranging
from 5 to 10 mm are visible to the naked eye; visualized by ultrasound, they can be palpated by
an endocrinologist (unless deeply situated) and even biopsied.

An occult carcinoma is refers to a carcinoma discovered subsequent to its presentation at a

metastatic site, which is more often to the cervical lymph nodes. An occult carcinoma is not
necessarily a microcarcinoma. Papillary thyroid carcinomas discovered incidentally in
thyroidectomy specimens or at autopsy should be considered latent carcinomas.18 Like occult
carcinoma, a latent carcinoma is not necessarily a microcarcinoma. A common incidental finding
in several series based on autopsy studies, the incidence of latent (incidental) carcinoma varies
from 4% to as high as 35% to 60%.186 , 187 , 188 , 189 , 190

Papillary occult carcinomas usually manifest as cervical lymph node metastases. The latter often
present as cystic lesions in the neck. Fine-needle biopsy is able to establish a correct diagnosis in
a majority of cases. Several studies on microcarcinomas have supported this observation.191 ,
192 , 193 , 194

Microcarcinoma may be solitary, multifocal, unilateral or bilateral, circumscribed, and well

defined with or without encapsulation. It may be infiltrative in the surrounding parenchyma, or
be sclerotic and sharply defined from the adjacent normal parenchyma.18 Very small
microcarcinoma may be missed on gross examination. A small microcarcinoma may resemble a
scar due to desmoplasia.

Histologically, microcarcinomas may present features of conventional papillary carcinoma or a

follicular variant (Fig. 9.60 ). They may be seen as microscopic foci formed by aggregates of few
follicles exhibiting typical nuclear features of papillary carcinoma (Fig. 9.58B ) and are
frequently observed in thyroidectomy specimens as incidental findings. Lymph node metastases
can occur with microcarcinoma (see Figure 15.8 in Chapter 15 ) and distant metastases are also
reported.195 , 196 , 197 , 198 , 199 Kasai and Sakamoto200 suggested subgrouping of
microcarcinoma as minute (0–5 mm) and tiny (5–10 mm), because of difference in the
incidence of lymph node metastases, 13% versus 59%, and extrathyroidal extension, 3% versus
10%. Fine-needle biopsy may be diagnostic if the carcinomas are accessible to aspiration and is
dependent on the size.201 , 202

As mentioned earlier, cytologic detection of the various morphologic variants depends upon the
sampled areas. Some variants may be identified while some do not lend themselves for typing.
Table 9.5 summarizes the cytologic features of some of the morphologic variants of papillary
carcinoma.

Cytopatho
logic features
Conventional
FVPC
Tall Cell
Diffuse
Sclerosing
Macrofollicular
Oxyphilic
Solid
Columnar
Papillary
Carcinoma
Cribriform-
Morular Typea
Warthin's-Like
Tumor of
Thyroida
Tissue fragments
Syncytial with
or without a
follicular
pattern
Syncytial with
or without a
follicular
pattern
Syncytial
without a
follicular
pattern
Syncytial
without a
follicular
pattern
Syncytial with
or without a
follicular
pattern
Syncytial with
or without a
 follicular
pattern
Syncytial
without a
follicular
pattern
Syncytial
without a
follicular
pattern
Syncytial with a
cribriform
pattern
Syncytial
without a
follicular
pattern
Papillary with
or without a
central core of
fibrovascular
tissue
Papillary
fragments
not present
Papillary
without
central cores
Papillary
uncommon
Not present
Papillary with
or without core
Not present
Papillary
without
a core
Papillary with
or without
central cores
Papillary
with or without
central cores
Monolayered
±
Monolayered
Monolayered
Monolayered
Monolayered
Rare
Not present
Monolayered
tissue fragments
not present
Monolayered
tissue
fragments ±
Cells
Pleomorphic
Round to
cuboidal
Large
polygonal,
squamoid or
Hürthleoid
Medium-sized,
round
Round to
 cuboidal
Round to
polygonal
Medium-sized,
round to
cuboidal
Columnar
Round to
cuboidal;
spindle cells
frequent
Round to
cuboidal
Cytoplasm
Variable in
quality and
quantity
Scanty, pale
Abundant,
dense
Variable
Scanty, pale
Abundant,
granular
Variable, pale
to dense
Clear with
cytoplasmic
tailing
Variable in
quality and
quantity
Variable in
quality and
 quantity;
abundant
eosinophilic
cytoplasm,
resembling
Hürthle cells
Nucleus size
Enlarged
Enlarged
Enlarged
Enlarged
Enlarged
Enlarged
Enlarged
Enlarged
Enlarged
Enlarged
Chromatin
Fine, powdery
to granular
Fine, powdery
to granular
Fine, powdery
to granular
Fine, powdery
to granular
Fine, powdery
to granular
Fine, powdery
to granular
Fine, powdery
to granular
Coarse
Powdery to finely
 granular
Powdery to
finely granular
Nucleoli
Micro/macro
Micro
Micro/macro
Micro/macro
Micro
Macro
Micro/macro
Micro
Micro/macro
Grooves
Present
Present
Present
Present
Present
Present
Present
Not present
Present
Present
Inclusions
Present
Present
Present
Present
Present
Present
Present
±
Present
Present
Squamous
Metaplasia
(Morulae)
±
±
Generally not
present
Marked
Generally not
present
Not present
±
Not present
Morulae
characteristic
Not present
Colloid
Ropy strands ±
Blobs of
dense viscous
colloid ±
Generally not
present
±
Abundant
Generally not
present
Not present
Not present
Not conspicuous
Absent
Psammoma
Bodies
±
±
±
Abundant
Rare
±
Rare
Not present
±
Not described
Lymphocytes
±
±
±
Abundant
Not present
Not present
Not present
Not present
Not present
Present in
variable
numbers
Differential
Diagnoses
Hyperplastic
nodular goiter;
papillary hyper
plasia in
follicular
adenoma;
Hashimoto's
thyroiditis
Follicular
 adenoma/
follicular
carcinoma
Hürthle cell
carcinoma
Hashimoto's
thyroiditis in
the absence of
psammoma
bodies
Nodular goiter;
follicular
adenoma/
follicular
carcinoma
Hürthle cell
carcinoma
Medullary
carcinoma;
follicular
carcinoma
Adenocarcinoma,
metastatic
Adenocarcinoma,
metastatic
Oxyphilic
variant;
papillary
Hürthle cell
carcinoma;
tall cell variant
These variants are rare, with sparse documentation of cytologic features.
 TABLE 9.5 CYTOPATHOLOGIC FEATURES OF SOME
MORPHOLOGIC VARIANTS OF PAPILLARY THYROID
CARCINOMA
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P.169
P.170

DIAGNOSTIC DIFFICULTIES IN PAPILLARY CARCINOMAS

An adequate cellular sample with the characteristic cytopathologic features of papillary
carcinoma facilitates a correct diagnosis in most instances. Diagnostic difficulties do arise in
several settings listed in Table 9.6 . The first two settings represent a typing problem. Some of
the subtypes of papillary carcinoma share morphologic similarities with other thyroid neoplasms,
both benign and malignant. The remaining three represent major diagnostic dilemmas and
constitute important reasons for both false-positive and false-negative diagnoses. Each of these
settings is discussed in detail below.

1. Morphologic subtypes
Follicular variant
Oxyphilic variant
Columnar cell variant
Macrofollicular variant
2. Papillary carcinoma with single cell pattern
3. Papillary carcinoma with cystic change
4. Papillary carcinoma coexistent with
Hashimoto's thyroiditis
5. Inadequate sample/unsatisfactory cytopreparation

TABLE 9.6 DIFFICULTIES IN CYTOLOGIC DIAGNOSIS OF

PAPILLARY CARCINOMA

Morphologic Subtypes PresentingDiagnostic Difficulties

The morphologic subtypes that present diagnostic problems include:
 The follicular variant, which may be interpreted as a follicular lesion or a follicular
neoplasm.

The oxyphil variant, typed as Hürthle cell tumor.

The columnar cell variant, where identification as thyroid in origin is difficult on a

routinely stained specimen.

The macrofollicular variant, which may be interpreted as nodular goiter or a colloid

adenoma.

The diagnostic problems with the follicular variant of papillary carcinoma are already discussed
in detail in Chapter 7 . The differentiating features are listed in Table 7.13 .

The cells of the oxyphilic variant lack powdery chromatin and micronucleoli but exhibit typical
features of Hürthle cell carcinoma (see Chapter 8 ). The exact designation, whether an
oxyphilic variant of papillary thyroid carcinoma or Hürthle cell carcinoma, is probably not
significant for patient management.

The cells of the columnar cell variant not only lack the nuclear features of papillary carcinoma
but may be nonreactive to thyroglobulin.119 This subtype is extremely rare and may be
interpreted cytologically as a carcinoma not otherwise specified.

The macrofollicular variant of papillary carcinoma can be a diagnostic problem because (both
grossly and microscopically) it resembles involuted goiter, except for the nuclei, which show
characteristics of conventional papillary carcinoma. The macrofollicular pattern may be seen in
parts of the tumor as well and may yield abundant colloid. Many believe that the abundance of
colloid is a diagnostic feature of nodular goiter. Thus, they consider it a feature of benignity;
consequently, the nuclear morphology is overlooked.

P.171

PAPILLARY CARCINOMA WITH A SINGLE CELL PATTERN

Papillary carcinomas often have solid areas with or without clear cell change. Aspirates from
these foci yield mostly single cells ranging from round to cuboidal to short columnar forms.
Architectural patterns of tissue fragments seen in the conventional type may not be present.
However, the neoplastic cells do exhibit powdery chromatin and intranuclear inclusions. Because
of a single cell dispersed pattern with intranuclear inclusions, a diagnosis of medullary thyroid
carcinoma may be rendered (Fig. 9.61 ).203 Immunostain for calcitonin is negative, while that
for thyroglobulin is positive.

Figure 9.60. Papillary microcarcinoma . A,B. Histologic sections. Papillary microcarcinoma less
than 2 mm. C. Microcarcinoma consisting of aggregates of follicles lined by cells typical of
papillary carcinoma.
Figure 9.61. FNA. Two separate examples of papillary carcinomas with a single cell pattern in
aspirates. The nuclear chromatin is finely granular with micronucleoli and inclusions. This
pattern may be mistaken for medullary thyroid carcinoma.

CYSTIC PAPILLARY CARCINOMA

The most common malignant neoplasm of the thyroid to undergo cystic change is papillary
carcinoma.7 In a study by Goellner and Johnson,204 16.6% of papillary carcinomas were cystic.
The carcinoma may be purely cystic or partially cystic, unilocular or multilocular, thin walled or
thick walled, and may contain residual in the wall (Figs. 9.61 , 9.62 , 9.63 and 9.64 ). Following
an aspiration biopsy of any cystic nodule, it is desirable to palpate for a residual mass in the wall
and aspirate it, if present. The reaspiration often provides a diagnostic specimen.

Figure 9.62. Gross photograph of a cystic papillary carcinoma.

Figure 9.63. Gross photograph of a unilocular cystic papillary carcinoma bordered by a thick
capsule.
Figure 9.64. The patient presented with a cystic neck mass that was aspirated and interpreted
as papillary carcinoma. A. Gross photograph of the excised multilocular cystic neck mass, which
histologically confirmed the lymph node metastasis. B. Thyroidectomy revealed a large cystic
papillary carcinoma.

Histologically, cystic carcinomas show papillary fronds projecting into the cystic cavity. The
latter is often filled with old and new blood, varying numbers of histiocytes, with and without
hemosiderin pigment, cellular and calcific debris, as well as detached papillary fronds (Figs. 9.65
, 9.66 and 9.67 ).

Figure 9.65. Histologic section of a cystic papillary carcinoma. Note the thick fibrotic capsule.
Figure 9.66. Histologic section of a cystic papillary carcinoma filled with detached papillae, and
psammoma bodies.
Figure 9.67. Histologic section of a cystic papillary carcinoma filled with inflammatory, cellular,
and calcific debris. An aspirate of such a lesion is apt to present diagnostic difficulties due to
degenerative changes and cellular debris obscuring the morphology.

The aspirates of the cystic carcinomas are often diagnostic problems.204 , 205 , 206 , 207 The
diagnosis of cystic papillary carcinoma will be accurate in the presence of cellular material with
classic cytologic features (Fig. 9.68 ). However, in cystic papillary carcinomas, the cytologic
features present a broad spectrum, which are to a great extent modified by the degenerative
changes occurring in the fluid milieu. Besides the typical pattern of conventional papillary
carcinoma, the cells in the cystic environment present a number of features that are not
commonly encountered in aspirates of noncystic papillary carcinomas (Figs. 9.68 , 9.69 , 9.70 ,
9.71 , 9.72 , 9.73 , 9.74 , 9.75 and 9.76 , Table 9.7 ):
Figure 9.68. Thyroid cyst fluid with diagnostic features of papillary carcinoma. Syncytial tissue
fragments with intranuclear inclusions.

Figure 9.69. FNA of a cystic papillary carcinoma. A–C. These tissue fragments are syncytial.
The cells are pleomorphic with well-defined cell borders and contain variable but abundant
cytoplasm that is bubbly and vacuolated as well as dense. The nuclei are pleomorphic in size,
containing deep-staining chromatin and prominent nucleoli. Grooves or inclusions are not
present. These cells are difficult to differentiate from the cells of nodular goiter. D. These two
syncytial tissue fragments appear three dimensional with scalloped borders. The nuclear
chromatin is intensely hyperchromatic and morphology is not visualized. The cells at the
periphery have bubbly vacuolated cytoplasm. E. This syncytial tissue fragment of follicular cells
show marked vacuolization of the cytoplasm (bubble-gum vacuoles). This feature should serve as
a red flag to examine the specimen more carefully. Thyroidectomy confirmed a cystic papillary
carcinoma.
Figure 9.69. F. Degenerating follicular cells from nodular goiter. Although the cytoplasm is
bubbly, the nuclei are small and very uniform. These histiocytoid cells may cause diagnostic
difficulties. G,H. Cystic papillary carcinoma. Note syncytial arrangement of cells and large
cytoplasmic vacuoles (Diff-Quik stain).
Figure 9.70. FNA of a cystic papillary carcinoma. The fluid was grossly blood-tinged. A. Against
the background of blood and a large number of histiocytes, these three syncytial tissue
fragments of follicular cells depict scalloped borders. Many cells at the periphery demonstrate
vacuolated cytoplasm. B,C. The syncytial tissue fragments are composed of elongated cells with
one slender end that is directed centripetally and the wider outer ends house the nuclei, giving
a cartwheel appearance to the tissue fragment. Some nuclei contain nucleoli. Inclusions and
grooves are not present and the chromatin appears dense. Although minimal criteria were not
observed, this aspirate was interpreted as suspicious for papillary carcinoma. Thyroidectomy
confirmed papillary carcinoma.

Figure 9.71. Cystic papillary carcinoma. These tissue fragments are composed of large cells with
abundant pale, vacuolated to dense cytoplasm. Their nuclei are large and round, many
containing nucleoli. No grooves or inclusions were seen. The syncytial architecture and high N/C
ratios, with nucleoli raised the possibility of papillary carcinoma and a suspicious diagnosis was
rendered. Papillary carcinoma was confirmed following thyroidectomy.
Figure 9.72. Cystic papillary carcinoma. A. The papillary carcinoma cells in a fluid medium
expand due to abundant vacuolated cytoplasm. These cells also demonstrate well-defined cell
borders and dense cytoplasm. The nuclei are large, pale, eccentric, and lack features of
papillary carcinoma. The presence of such cells should serve as a red flag for the possibility of
papillary carcinoma. B. These cells forming a syncytial tissue fragment show nuclear features of
papillary carcinoma. Note cytoplasmic vacuoles. The second tissue fragment contains a
psammoma body. C. Histologic section of the resected papillary carcinoma. Note the follicular
cells lining the papillary fronds show cytoplasmic vacuoles.
Figure 9.73. A. The fluid aspirated from this carcinoma was practically acellular except for a
single psammoma body incorporated in a tissue fragment. Note pale nuclear chromatin. B. A cell
block preparation of the sediment showed similar features suggesting the diagnosis of papillary
carcinoma.
Figure 9.74. A–C. The aspirated fluid from this cystic thyroid lesion was grossly clear. A
cytospin preparation salvaged few syncytial tissue fragments with scalloped borders. The nuclear
chromatin is pale with micronucleoli. Note dense cytoplasm and eccentric nuclei. These features
are suspicious for papillary carcinoma. D. Thyroidectomy confirmed a cystic papillary carcinoma.
Figure 9.75. The aspirated bloody fluid from a cystic thyroid nodule was marginally cellular and
showed groups and tissue fragments of moderately enlarged follicular cells. Common features
exhibited by all these cells include well-defined cell borders; variable, dense to vacuolated
cytoplasm; and round, moderately enlarged nuclei with micronucleoli. Inclusions and grooves are
rarely seen. These features are not seen in degenerating follicular cells of nodular goiter and
warrant a suspicious diagnosis. Thyroidectomy confirmed a cystic papillary carcinoma.

Figure 9.76. FNA of a cystic metastasis in neck from a papillary thyroid carcinoma. The cytologic
features of cystic metastases and primary cystic carcinoma were identical. A,B. FNA of the
cystic neck mass. The syncytial tissue fragments are composed of pleomorphic cells with
abundant foamy, vacuolated to dense cytoplasm and eccentric nuclei. The nuclear chromatin is
intensely basophilic due to degeneration and lacks the features of papillary carcinoma. Note the
scalloped borders of the tissue fragments. C. The cells reacted strongly to thyroglobulin,
confirming the thyroid origin.

Cellularity
Variable, but frequently marginal
Presentation
Biopsy may yield fluid contents; clear to bloody; cells isolated,
in loosely cohesive groups and in syncytial tissue
fragments, may be obscured by histiocytes and blood
Architecture of the
tissue fragments
Marked variation; syncytial tissue fragments; may present
all the architectural configurations; cells tend to form tight
groups in fluid medium, frequently forming a whorled
pattern; cartwheel pattern with nuclei along the
outer margin
Cells
Broad range of size; small to large; well-defined cell
borders; N/C ratios variable
Nucleus
Round to oval, variable in size; often eccentric; powdery
chromatin, micro/macronucleoli, grooves and inclusions
Cytoplasm
Scant to abundant; pale, vacuolated, bubbly; single to multiple
vacuoles; strongly resemble histiocytes (histiocytoid
carcinoma cells); must be differentiated from histiocytes
Psammoma bodies
±
Background
Clean to bloody; colloid absent; histiocytes with or
without hemosiderin

TABLE 9.7 CYTOPATHOLOGIC FEATURES OF CYSTIC

PAPILLARY CARCINOMA

The specimens are frequently poorly cellular, and inadequate for interpretation. The low
cellularity may be the result of failure of the needle to penetrate the thick, fibrous, and
often calcified capsule found in cystic carcinomas (Figs. 9.63 and 9.65 ).

The cellular and inflammatory debris resulting from hemorrhage and necrosis obscures
the cytomorphology of
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neoplastic cells (Fig. 9.67 ). Interpretation of scanty cellular material in the background
of extensive cellular debris can be very challenging (Figs. 9.65 , 9.65 , 9.66 , 9.67 , 9.73
, 9.74 , 9.75 ).

The tissue fragments of malignant cells ball up in the fluid medium, appearing three-
dimensional (Fig. 9.69D ), and often show an onion-skin pattern.

The tissue fragments of malignant cells often exhibit scalloped borders and also tend to
arrange themselves in a cartwheel pattern with nuclei at the outer perimeter (Fig. 9.70
B and C).

Degenerating carcinoma cells acquire abundant cytoplasm that can be bubbly or

vacuolated (Figs. 9.69A , 9.69B , 9.69E , 9.69H , 9.71 , 9.72 , 9.75 , 9.76 ). The vacuoles
may be small, multiple, or large occupying the entire cell and pushing the nucleus to the
periphery but not indenting it (Fig. 9.69 E and H).

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P.174
P.175
P.176
The degenerating papillary carcinoma cells may be discrete (Figs. 9.72 , 9.74A , 9.75D ),
in groups, or in syncytial tissue fragments. The single cells are difficult to differentiate
from the histiocytes. The diagnostic clues are well-defined, almost rigid cell borders and
dense cytoplasm (Figs. 9.72A , 9.74 , 9.75 , 9.76 ). The nuclear/cytoplasmic ratios are in
 favor of the nucleus. Also, histiocytes are never seen in tissue fragments, unlike
carcinoma cells. The foamy carcinoma cells referred to as histiocytoid carcinoma
cells204 may be misinterpreted as benign. On the other hand, the histiocytic aggregates
may be misinterpreted as carcinoma cells (Fig. 9.69F ).208 , 209 The carcinoma cells
with foamy cytoplasm must also be differentiated from degenerating cells from nodular
goiter (Fig. 9.69F ).

The chromatin of papillary carcinoma cell nuclei have a tendency to stain intensely due
to degeneration (Fig. 9.69C ). The characteristic fine powdery chromatin may not be
retained.

Long-standing cystic fluid may be clear and poorly cellular. Proper cytopreparation is
critical to salvage the few neoplastic
P.177
cells. The author's laboratory prefers to process clear fluids by cytocentrifugation (Fig.
9.74 ).

Cyst fluids are often bloody. Processing the specimen by removing the blood will assist in
proper cytologic evaluation.

Poorly cellular, clear fluids as well as bloody specimens are likely to result in both false-
negative208 , 209 , 210 and false-positive interpretations. Colloid is absent from aspirates of
cystic papillary carcinoma. Syncytial architecture with a follicular pattern is also unusual. The
presence of psammoma bodies
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favors a malignant diagnosis. However, care must be taken to evaluate the nuclear features of
the cells forming the tissue fragments. Naked psammoma bodies or calcific debris are of no
significance, except that careful examination of all the smears is in order when they are
encountered. Any visible sediment in a cyst fluid may be cell-blocked. Although routine cell-
block preparations of thyroid aspirates is not recommended, it can be of diagnostic help in cases
of cyst fluids (Fig. 9.73 ).

The cells from cystic nodular goiters mimic cytologic features of papillary carcinoma and may be
difficult to differentiate from carcinoma cells (Fig. 9.77 ). Table 9.8 lists the differences
between cells of papillary carcinoma and atypical cells in nodular goiter. This problem is also
addressed in Chapters 6 and 17 .
Presentations
Predominantly histiocytic
cell population mixed with
variable numbers of papillary
carcinoma cells; (malignant
cells rarely absent); malignant
cells discrete, in groups or in
syncytial tissue fragments
Predominantly histiocytic cell
population mixed with
variable numbers of benign
follicular cells, discrete, in
groups or in syncytial tissue fragments
Architecture of the
Tissue Fragments
Tissue fragments with varying
architectural configurations: papillary
or papillary-like, with scalloped
borders; swirls, cartwheel
pattern; three dimensional
Small regular follicles; loosely
cohesive groups or in varying
sized tissue fragments; large
papillary-like tissue fragments
unusual; when present demonstrate
honeycomb arrangement
Cells
Considerable pleomorphism in
size; small to large; well-defined
cell borders; N/C ratios variable
Follicular cells without
degenerative changes; small,
round to cuboidal; degenerating
cells larger in size; cell
 borders well to poorly defined
Nucleus
Variably enlarged; round with
smooth nuclear membranes;
often eccentric; nuclei located at
the periphery in tissue fragments
with cartwheel pattern; chromatin
granular; smudgy in degenerating
cells; nucleoli ±; grooves and
inclusions ±
Nucleus normal-sized to
minimally enlarged; round,
usually centrally located; smooth
nuclear membranes; granular
to smudgy chromatin;
nucleoli ±
Cytoplasm
Variable; pale, bubbly, finely
vacuolated to multiple small
vacuoles or a single large
bubble-gum type vacuole
pushing the nucleus to the
periphery but not indenting it;
dense cytoplasm is
characteristic; hemosiderin ±
Variable; scant to abundant, granular
in degenerating cells;
hemosiderin ±; nuclear
grooves and inclusions rare
Hürthle Cell
Metaplasia
Not present
±
Psammoma Bodies
±; Naked psammoma bodies not
diagnostic; must be incorporated
in tissue fragments
Very rare
Background
Often bloody; calcific debris ±;
colloid absent
May be bloody; colloid ±;
calcific debris rare

Cytologic Feature Cystic Papillary Carcinoma Cystic Nodular Goiter

TABLE 9.8 CYTOPATHOLOGIC FEATURES DIFFERENTIATING

CYSTIC PAPILLARY CARCINOMA AND CYSTIC NODULAR
GOITER
P.179
P.180
P.181

PAPILLARY CARCINOMA COEXISTENT WITH HASHIMOTO'S

THYROIDITIS
The differentiation of papillary hyperplasia from papillary carcinoma in the background of
lymphocytic (Hashimoto's) thyroiditis is often very difficult and challenging. The cells derived
from the hyperplastic process may present some of the nuclear features of papillary carcinoma.
Both false-positive and false-negative diagnoses may be rendered. Minimal cytologic criteria
must be demonstrated before interpreting an aspirate as diagnostic of papillary carcinoma. This
problem is discussed in the section on differential diagnosis, later in this chapter and also in
Chapter 13 on Hashimoto's thyroiditis.

Inadequate Sample
Inadequate samples and poor cytopreparation (Figs. 9.78 , 9.79 , 9.80 , 9.81 and 9.82 ) probably
account for most of the diagnostic errors. Attempting to provide an unequivocal diagnosis on the
basis of suboptimal preparations is risky. Partial or complete air-drying of cells in a Papanicolaou
preparation reveals very pale, clear nuclei mimicking those of papillary carcinoma (Fig. 9.78A ).

Figure 9.77. FNA of a cystic nodular goiter misinterpreted as suspicious for papillary carcinoma.
A,B. Monolayered tissue fragments with minimal nuclear overlapping and crowding. The nuclei
are slightly enlarged, with granular chromatin and micronucleoli. An occasional nucleus
suggested the presence of intranuclear inclusion. C. The background features were those of a
nodular goiter with abundant colloid. The aspirate was interpreted as atypical; papillary
carcinoma cannot be ruled out. Thyroidectomy showed cystic nodular goiter. D. Histologic
section of the thyroid showing features of nodular goiter with cystic degeneration. E. Higher
magnification showing mild nuclear atypia.

Figure 9.78. A. This aspirate shows partially air-dried cells with pale chromatin misinterpreted
as suggestive of papillary carcinoma. Thyroidectomy failed to confirm the malignancy. B. This
smear from a papillary carcinoma is hypercellular but totally air-dried, rendering the specimen
unsatisfactory for evaluation. C. This case represents a false-negative diagnosis due to sampling
error. The aspirate of the thyroid nodule revealed only lymphocytes. D. Repeat biopsy one year
later showed classic features of papillary carcinoma. Thyroidectomy confirmed the carcinoma in
a background of Hashimoto's thyroiditis.
Figure 9.79. An example of a true false-negative aspirate of papillary carcinoma. Three
attempts at the fine-needle biopsy yielded only hemorrhagic fluid containing histiocytes.
Thyroidectomy revealed a cystic papillary carcinoma.
Figure 9.80. This aspirate from a papillary carcinoma consisted of hemosiderin-containing
macrophages and extensive calcific debris. There were no well-preserved follicular cells. The
structure seen here (arrow ) suggests a formation of psammoma body. This aspirate was
interpreted as negative but should have been interpreted as inadequate. A repeat aspiration
biopsy was in order.
Figure 9.81. A hemorrhagic fluid from a cystic carcinoma, showing rare groups of atypical
follicular cells interpreted as benign. Note that they have features such as dense and vacuolated
cytoplasm and well-defined cell borders that should have raised the suspicion of papillary
carcinoma (refer to Figure 9.75).
Figure 9.82. This aspirate was poorly cellular and showed a rare group of large pleomorphic
cells that were interpreted as negative. Note that dense cytoplasm and pleomorphic nuclei with
nucleoli should have been reported as abnormal but scant, and a repeat biopsy requested. The
patient was biopsied again several years later only to confirm a papillary carcinoma.

DIAGNOSTIC ACCURACY
The diagnostic accuracy of papillary carcinoma should approach 90% to 94% (Table 9.9 ),
provided the aspirate obtained by fine-needle biopsy is adequate for cytologic interpretation.

Papillary carcinoma
303a
Suspected papillary carcinoma
18
Medullary carcinoma
2
Cellular follicular adenoma
13
Benign (nodular goiter)
4
Unsatisfactory
9
Total
349
a Two cases were initially benign (lymphocytic thyroiditis). However repeat biopsies revealed

papillary carcinoma in both. Sampling error was the reason for the discrepancy.

TABLE 9.9 CYTOLOGIC DIAGNOSIS OF 349 PAPILLARY

CARCINOMAS
Errors in the cytologic diagnosis of papillary carcinoma can be grouped into three categories:

False-negative results.

False-positive results.
 Typing errors.

False-Negative Results
The cytologic diagnosis of papillary carcinoma may be missed only if the specimen is acellular;
poorly cellular, demonstrating insufficient diagnostic criteria or if there is a sampling error
(Tables 9.9 and 9.10 ).

1
Cyst fluid; cellular debris;
histiocytes, calcospherites
No well-preserved follicular
epithelium present;
calcospherites, some
surrounded by cellular and
hemorrhagic debris
2
Few groups of follicular cells
Partially air-dried and scant
cellularity; intranuclear
inclusions overlooked;
inadequate but suspicious for
papillary carcinoma
3
Rare group of follicular cells
Inadequate for diagnosis; only
one syncytial tissue fragment
of follicular cells; large, atypical
nuclei not appreciated due to
inexperience
4
Bilateral nodules, both aspirated
with similar findings; few tissue
fragments with follicular cells
containing pale nuclei
Few groups of atypical follicular
cells in the background of
nodular goiter; possibly
sampling error
5
Hemorrhagic cyst fluid; only
histiocytes
True false-negative diagnosis
6–13
Acellular specimens
True false-negative diagnoses

Case No. Cytologic Findings Comments

TABLE 9.10 ANALYSIS OF 13 FALSE-NEGATIVE DIAGNOSES

OF PAPILLARY CARCINOMA
Acellular aspirates or a poor cellular yield on a fine-needle biopsy are inevitable in some
instances, such as large cystic
P.182
papillary carcinoma, marked desmoplasia, or a thick, fibrous, calcified capsule.

Three false-negative cases of papillary carcinoma in our series (Table 9.10 ) reflected a
combination of poorly cellular specimens and inexperience in recognizing certain cytologic
atypia as possibly indicative of papillary carcinoma. In one case of papillary carcinoma in which
repeated attempts at fine-needle biopsy were made—including one on a "residual" palpable
mass—only histiocytes were found. A large-needle biopsy on the residual mass confirmed the
diagnosis. Of 349 papillary carcinomas, 9 were acellular on fine-needle biopsy (2.5%) (Table 9.9
). If fine-needle biopsies on large nodules are unsuccessful and there are strong clinical
suggestions of carcinoma, a cutting-needle biopsy may be diagnostic.

A false-negative diagnosis may also occur as a result of sampling error. Two of our cases were
initially and correctly diagnosed as lymphocytic thyroiditis. One year later, repeat biopsy in both
cases showed all the criteria of papillary carcinoma coexistent with lymphocytic thyroiditis (Fig.
9.78 C and D). The initial biopsies had sampled the parenchyma adjacent to the carcinoma. For
this reason, a few unremarkable follicular cells aspirated from a thyroid containing a large
nodule should not be considered adequate and benign.

False-Positive Results
False-positive diagnoses of papillary carcinoma are common errors in the practice of thyroid
cytopathology and involve misinterpretation of aspirates from benign, non-neoplastic diseases of
the thyroid as malignant neoplasms when the cytologic features mimic some of the cytologic
criteria of papillary carcinoma (Table 9.11 ).215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 ,
224 , 225 , 226 , 227 , 228 , 229 The same problem occurs with cellular aspirates from a
follicular adenoma, especially with degeneration and pseudopapillary change. Most often, the
errors are made if too much emphasis is placed on just one cytologic feature, especially when
the aspirate is overwhelmingly cellular. Of 316 cytologic diagnoses of papillary carcinoma, 11
were false positive and 18 aspirates were interpreted as suspicious for papillary carcinoma
(Table 9.12 ).

Tissue Fragments
Papillary

Hyperplastic goiter
Papillary changes in follicular nodules
or follicular adenoma
Hashimoto's thyroiditis

Monolayered

Hyperplastic goiter
Follicular adenoma
Follicular hyperplasia in Hashimoto's thyroiditis

Nuclear Features
Powdery chromatin with
micronucleoli

Hyperplastic goiter or nodular goiter with

degeneration and cyst formation
Hashimoto's thyroiditis
Follicular adenoma
Pseudoinclusions

Hyalinizing trabecular adenoma

Hashimoto's thyroiditis
Nodular goiter

Grooves

Hyalinizing trabecular adenoma

Ancillary Features
Psammoma bodies

Hyalinizing trabecular adenoma

Nodular goiter
Hashimoto's thyroiditis
Follicular adenoma

Inspissated Colloid Simulating

psammoma body

Nodular goiter

Cytologic Findings Disease Entities Misinterpreted as PTC

TABLE 9.11 FALSE-POSITIVE DIAGNOSES OF PAPILLARY

CARCINOMA

Papillary carcinoma
303
Medullary carcinoma
2
Follicular adenoma
4
Nodular goiter
4
Hashimoto's thyroiditis
3
Total
316

TABLE 9.12 HISTOLOGIC DIAGNOSIS OF 316 CASESWITH

CYTOLOGIC DIAGNOSIS OF PAPILLARY CARCINOMA
A diagnosis of suspected papillary carcinoma (Figs. 9.83 , 9.84 , 9.85 , 9.86 and 9.87 ) is
generally given when:

Figure 9.83. This aspirate was poorly cellular but showed rare tissue fragments of follicular cells
that demonstrated atypical nuclear features. Note sharp intranuclear inclusions. The cytologic
interpretation was suspicious for papillary carcinoma. A repeat biopsy confirmed the diagnosis.
Figure 9.84. Air-dried cells in a syncytial arrangement with enlarged nuclei containing
intranuclear inclusions. The quantity was insufficient and was interpreted as suspicious for
papillary carcinoma, later confirmed on thyroidectomy.
Figure 9.85. This aspirate is adequately cellular but air-dried with poor cellular details. The
syncytial architecture and suggestion of intranuclear inclusions render this aspirate suspicious
for papillary carcinoma, confirmed on surgery.
Figure 9.86. A–C. An adequately cellular specimen with several syncytial tissue fragments of
follicular cells with hyperchromatic nuclei. The papillary-like architecture and pleomorphic
nuclei rendered this specimen suspicious for papillary carcinoma. Note that the minimal criteria
are not present. Thyroidectomy confirmed a cystic papillary carcinoma. D. The detached
fragments of papillary fronds were floating within the cystic cavity. E. Higher magnification.
Figure 9.87. The syncytial tissue fragments of follicular cells demonstrate all the nuclear
features of papillary carcinoma. Thyroidectomy showed a hyalinizing trabecular adenoma.

The aspirate is marginally cellular and exhibits atypical features suggestive, but not
diagnostic, of papillary carcinoma.

The aspirate is adequately cellular, with features of a benign disease (nodular goiter,
Hashimoto's thyroiditis, follicular adenoma) but in addition shows a few follicular cells
with atypia (Table 9.11 ).

The features that may be mistaken for papillary carcinoma are (i) an occasional monolayered
tissue fragment of follicular cells, with abundant dense cytoplasm and large, irregular nuclei
with powdery chromatin and nucleoli; (ii) an occasional follicular cell showing intranuclear
cytoplasmic inclusions; (iii) a rare papillary tissue fragment with crowded nuclei; (iv) tissue
fragments of spindle cells forming a whorled pattern, with atypical nuclei; or (v) a rare
psammoma body.
 P.183
These isolated findings, as listed in Table 9.11 , by themselves may be extremely worrisome, but
when present in the background of a benign disease, they should be judged with extreme
caution. Table 9.13 analyzes the cases with false-positive diagnoses of papillary carcinoma.

1
Single psammoma body; papillary
tissue fragments; background
features of nodular goiter; repeat
fine-needle biopsy; nodular goiter
Total thyroidectomy;
nodular goiter with
papillary hyperplasia
Diagnosis of papillary carcinoma
based on single psammoma
body, architectural pattern
(papillary) of the tissue fragment;
cells lacked typical cytomorphology
of papillary carcinoma
2
Single psammoma body; rare group
of atypical follicular cells; several
monolayered tissue fragments of
follicular epithelium with
honeycomb pattern
Total thyroidectomy;
multiple follicular
adenomas
Tissue fragment containing
psammoma body lacked typical
cytomorphology of papillary
carcinoma; other features of
papillary carcinoma not present;
tissue fragments of follicular epithe-
lium suggested diagnosis of
 nodular goiter
3
Cyst fluid; hemorrhagic, large
papillary tissue fragments;
psammoma bodies
Total thyroidectomy;
Hürthle cell adenoma
with cystic degeneration
Cytomorphology altered by the
hemorrhage; psammoma bodies
were atypical, perhaps colloid
4
Multiple psammoma bodies
Total thyroidectomy;
multiple follicular
adenomas
Inspissated colloid within
follicular simulated psammoma
bodies
5
Hypercellular aspirate; large
numbers of monolayered sheets
of follicular epithelium
Right lobectomy; simple
adenoma
Emphasis on cellularity and
architectural pattern of tissue
fragments without cytomorphology
of papillary carcinoma
6
Hypercellular aspirate; papillary
tissue fragments
Total thyroidectomy;
diffuse hyperplasia
Emphasis on cellularity and
architectural pattern;
cytomorphology of papillary
carcinoma lacking
7
Extremely cellular aspirate;
branching papillary tissue
fragments; crowded nuclei
with nucleoli
Total thyroidectomy;
follicular adenoma with
atypical papillary
change
Papillary fragments; crowded nuclei
with nucleoli, chromatin not
powdery; intranuclear inclusions
and chromatin ridge
8
Papillary tissue fragments
with powdery chromatin
Total thyroidectomy;
nodular goiter with
papillary hyperplasia,
one focus of atypical
hyperplasia
Marginal cellularity, partial
air-drying with suboptimal
cytomorphology; insufficient
criteria for diagnosis of
papillary carcinoma
9
Syncytial-type tissue fragments;
enlarged; crowded nuclei with
nucleoli; chromatin finely granular;
 features of lymphocytic thyroiditis;
history of lobectomy for
carcinoma papillary
Lobectomy; Hashimoto's
thyroiditis
Insufficient criterial for diagnosis
of papillary carcinoma; history
of carcinoma influenced the
diagnosis
10
Features of lymphocytic thyroiditis;
occasional papillary fragment of
follicular epithelium
Total thyroidectomy;
Hashimoto's thyroiditis
with papillary hyperplasia
Typical nuclear cytomorphology
absent
11
Features of lymphocytic thyroiditis;
occasional papillary fragment
of follicular epithelium
Total thyroidectomy;
Hashimoto's thyroiditis
with papillary hyperplasia
Typical nuclear cytomorphology
absent

Patient No. Cytologic Findings Surgery Commentss

TABLE 9.13 ANALYSIS OF 11 FALSE-POSITIVE DIAGNOSES OF

PAPILLARY CARCINOMA
Of 42 patients with suspected papillary carcinoma, 36 underwent surgery (Table 9.14 ). Eighteen
cases were confirmed. Two were follicular carcinomas and two were follicular adenomas,
indicating a typing error (see Chapter 7 ). Thirteen were benign, non-neoplastic diseases of the
thyroid. Surgery was not recommended for six patients because the cytologic features on repeat
biopsy were diagnostic of benign disease. As the diagnostic accuracy of papillary carcinoma with
an adequate aspirate is very high, it is advisable to have a definitive diagnosis before surgery.
The decision to recommend a surgical excision after a cytologic diagnosis of suspicious papillary
carcinoma depends on such factors as the age and sex of the patient, size of the nodule,
lymphadenopathy, and a history of radiation to the head and neck and unsatisfactory attempts
at repeat fine-needle biopsy.

Papillary carcinoma
18
Follicular carcinoma
2
Follicular adenoma
3
Nodular goiter
11
Hashimoto's thyroiditis
2
Total
36

TABLE 9.14 HISTOLOGIC DIAGNOSIS OF 36 CASES

CYTOLOGICALLY SUSPECTED OFPAPILLARY CARCINOMA

Typing Errors
Typing errors are not as consequential as false-positive results because surgery is recommended
for most thyroid neoplasms. Tumors that may be confused with papillary carcinomas include
follicular neoplasms—follicular adenoma and its special variant, the hyalinizing trabecular
adenoma, as well as follicular carcinoma. The cytologic features differentiating follicular
adenoma, follicular carcinoma, and the follicular variant of papillary carcinoma are listed in
Table 7.13 .
Hyalinizing trabecular adenoma is a subtype of follicular adenoma (see Chapter 7 ) that displays
almost all the nuclear features of papillary carcinoma (Fig. 9.87 ). Cytologic differentiation
between the two neoplasms is very difficult, (Table 9.15 ).213 , 215

Pattern
Cells mostly isolated, in loose aggregates
with cells radiating from acellular material;
syncytial tissue fragments without any
architectural patterns
Cells isolated, in loosely cohesive groups or in
syncytial tissue fragments with various
architectural pattern
Cells
Mildly pleomorphic in size; oval to spindle
shaped; bipolar and triangular forms;
cytoplasmic processes present
Marked variation in size and shape; spindle cells,
rare to absent; cytoplasmic processes not
present
Nucleus
Size & shape
Round, oval to elliptical; minimal variation
in size
Round to oval with marked variation in size
Chromatin
Finely granular, occasional prominent
chromocenter with clearing around
Dusty, powdery
Nucleoli
Micronucleoli
Micro/macronucleoli
Nuclear grooving
Frequent
Frequent
Intranuclear
 inclusions
Frequent
Frequent
Cytoplasm
Variable; pale to dense, sometimes
filamentous; intracytoplasmic hyaline
deposit
Variable; clear pale to dense, sometimes
vacuolated
Psammoma bodies
Absent
May be present
Background
Amorphous/Hyaline
material
Present in variable amount, stain purplish-pink
with Romanowsky stain
Absent
Colloid
Absent
Present
Multinucleated
giant cells
Absent
Present

Hyalinizing Trabecular Adenoma Papillary Carcinoma

TABLE 9.15 CYTOPATHOLOGIC DIFFERENTIATION BETWEEN

PAPILLARY CARCINOMAAND HYALINIZING TRABECULAR
ADENOMA
P.184
P.185
Papillary carcinoma is also mistyped as medullary carcinoma, especially when there is a single
cell pattern. Both of these malignant tumors have morphologic similarities (see Table 12.6 ).
Other uncommon lesions in the differential diagnosis include parathyroid adenoma and
metastatic bronchioloalveolar carcinoma.

A critical analysis of 16 cases cytologically suspected of papillary carcinoma is given in Table

9.16 .

1
Hypercellular aspirate; large,
monolayered sheets of follicular
epithelium; occasional papillary
pattern; multiple micronucleoli
Nodular goiter with
infarct
Emphasis on hypercellularity as well as
architectural pattern; lacked typical
cytomorphology of papillary carcinoma
2
Features of nodular goiter; few
groups of atypical follicular cells
with large nuclei and multiple
nucleoli
Nodular goiter
Few groups of atypical cells in a background of
nodular goiter, generally of no significance;
misinterpretation due to inexperience
3
Cyst fluid; histiocytes and
tissue fragments of follicular
epithelium with foamy
cytoplasm, enlarged nuclei
and nucleoli
Nodular goiter with
cyst
Degenerative changes in epithelium from cyst
fluid mimicking neoplasia; important
diagnostic pitfall
4
One group of pleomorphic
cells with atypical nuclei; one
psammoma body; one very
large monolayered sheet of
follicular epithelium; nucleoli
present
Nodular goiter
Marginal cellularity; cytomorphology of papillary
carcinoma not present
5
Hypercellular aspirate; many
monolayered sheets of
follicular epithelium
Simple adenoma
Emphasis on only one criterion, i.e.,
monolayered sheets; typical nuclear
morphology of papillary carcinoma absent
6
Hypercellular aspirate; many
monolayered sheets of
follicular epithelium
Simple adenoma
Emphasis on only one criterion, i.e.,
monolayered sheets; typical nuclear
morphology of papillary carcinoma absent
7
Occasional papillary tissue
fragment (?), psammoma body
Simple adenoma
Pseudopsammoma body (inspissated
 colloid simulating psammoma body)
8
Few tissue fragments of
atypical cells; spindle forms;
nucleoli; swirling arrangement
suggesting a papillary
configuration; background of
nodular goiter
Hyperplastic goiter
Adequate aspirate with features of nodular
goiter; only a few tissue fragments of atypical
cytomorphology; nuclei did not show
cytoplasmic inclusions; mostly coarse
chromatin
9
Few tissue fragments of
atypical follicular epithelium;
two psammoma bodies; many
histiocytes and giant cells
Nodular goiter
Psammoma bodies not surrounded by cells that
exhibit typical cytomorphology of papillary
carcinoma; features of papillary carcinoma not
present
10
Cystic hemorrhage with cellu-
lar debris; few fragments of
follicular epithelium; vacuo-
lated cytoplasm
Nodular goiter
Poorly cellular specimen; nuclear cytomorphol-
ogy not seen; degenerated follicular cells with
nuclear atypia
11
Psammoma bodies and
features of nodular goiter
Hyperplastic goiter
with single
psammoma
True psammoma body, but lacked nuclear
features of papillary carcinoma
12
Psammoma body; few groups
of atypical cells; occasional
monolayered tissue
fragments
Nodular goiter
Marginal cellularity; typical cytomorphology of
papillary carcinoma absent; emphasis only on
psammoma body
13
Features of nodular goiter;
calcific debris and multinu-
cleated giant cells; rare
psammoma body
Nodular goiter
Features of papillary carcinoma not present;
emphasis only on calcospherites
14
Cytologic features of lympho-
cytic thyroiditis; occasional
papillary tissue fragment
with overlapping nuclei
Hashimoto's
thyroiditis
Papillary tissue fragments; lacked typical
cytomorphology
15
Features of lymphocytic thy-
roiditis; occasional tissue
fragment with papillary con-
figuration; discrete cells with
intranuclear inclusions
Hashimoto's
thyroiditis
Except for intranuclear inclusions, papillary tissue
fragments lacked nuclear morphology of
papillary carcinoma
16
Cellular debris and hemor-
rhage; (?) syncytial-type
tissue fragments
Hypec goiter
Only (?) syncytial-tissue fragments; typical
nuclear cytomorphology not present

Patient No. Cytologic Findings Surgery Comments

TABLE 9.16 CRITICAL ANALYSIS OF 16 CASES

CYTOLOGICALLY SUSPECTED OF BEING PAPILLARY
CARCINOMA WITH HISTOLOGIC DIAGNOSES OF BENIGN
DISEASES FOLLOWING SURGERY

MINIMAL CRITERIA FOR CYTOLOGIC DIAGNOSIS

Cytologic preparations of papillary carcinoma have several diagnostic features, but not all may
be present in aspirates of every case. Some features are essential, whereas others are adjunct.
Their frequency also depends on the histologic pattern of the tumor.

P.186
In a review and analysis of cytopathologic features of 329 cases of papillary carcinoma, all of the
features listed in Table 9.1 were present in only 27 cases. Tables 9.17 and 9.18 indicate the
frequency of occurrence of various cytologic features of papillary carcinoma in adequately
cellular (329 cases) and marginally cellular specimens (65 cases), respectively. These Figures
differ somewhat from those reported in our earlier review of 87 cases of papillary carcinoma,43
perhaps because of better cytologic preparation in subsequent years and more careful review.
Usually one or two features predominated. The most consistent features were enlarged nuclei
containing fine, powdery, dusty chromatin that appeared pale or watery (100%); a linear
chromatin ridge or groove (88%); single or multiple micro- and/or macronucleoli (100%); and
intranuclear cytoplasmic inclusions (93%).

Syncytial tissue fragments

329
100
Papillary tissue fragments
283
86
Monolayered tissue fragments
198
60
Syncytial tissue fragments with
follicular pattern
174
50
Powdery chromatin
320
100
Micro- and/or macronucleoli
320
100
Nuclear inclusions
308
93
Nuclear grooves
290
88
Psammoma bodies
68
 20
Multinucleated foreign-body–type
giant cells
200
60
Colloid Strands
100
30

Cytologic Criteria No. Percent

TABLE 9.17 FREQUENCY OF OCCURRENCE OF VARIOUS

CYTOLOGIC CRITERIA IN 329 CASES OF PAPILLARY
CARCINOMA

Syncytial tissue fragments with or

without follicular pattern
65
100
Papillary tissue fragments
34
52
Monolayered tissue fragments
13
20
Powdery chromatin
65
100
Micro- and/or macronucleoli
65
100
Nuclear inclusions
55
84.5
Nuclear grooves
54
83
Psammoma bodies
15
23
Multinucleated foreign-body type
giant cells
19
29
Colloid strands
2
3

Cytologic Criteria No. Percent

TABLE 9.18 FREQUENCY OF OCCURRENCE OF VARIOUS

CYTOLOGIC CRITERIA IN 65 CASES OF PAPILLARY
CARCINOMA WITH MARGINAL CELLULARITY
P.187
The minimal criteria for the diagnosis of papillary carcinoma thus include a syncytial-type
tissue fragment of follicular epithelium that, regardless of the architectural pattern, shows a
typical nuclear morphology, that is, pale-appearing enlarged nuclei with fine, dusty, powdery
chromatin; a chromatin bar or ridge; single or multiple micro- and/or macronucleoli; and
intranuclear cytoplasmic inclusions (Fig. 9.88 , Table 9.19 ).
Figure 9.88. Minimal criteria. All six images show syncytial tissue fragments without any specific
architectural configuration. The cells display varied types, but their nuclei are enlarged and
contain fine, powdery chromatin with nucleoli, grooves, and inclusions.

1. Syncytial tissue fragments with or without any architectural

configurations
2. Enlarged nuclei with very fine, dusty powdery chromatin
3. Multiple micro- and/or macronucleoli
4. Intranuclear cytoplasmic inclusions
5. Nuclear grooves

TABLE 9.19 MINIMAL CRITERIA FOR THE CYTOLOGIC

DIAGNOSIS OF PAPILLARY CARCINOMA
The results of an analysis of cytologic preparations of 65 papillary carcinomas with marginal
cellularity (Table 9.18 ) were similar to those for the overall analysis of 329 cases, thus
substantiating the minimal criteria of the cytologic diagnosis of papillary carcinoma (Fig. 9.88 ).
Abele and Miller40 have subclassified cytopathologic features in primary and secondary groups.
Their primary features include intranuclear cytoplasmic inclusions (92%), cells with dense
cytoplasm (89%), and papillary fronds (92%). Their secondary features included septate
cytoplasmic vacuoles (64%), huge multinucleated giant cells (50%), psammoma bodies (36%),
P.188
P.189
P.190
monolayered sheets with atypical nuclei (36%), and "bubble-gum" colloid (14%).

No single cytopathologic feature is diagnostic of papillary carcinoma. A diagnosis based on one

feature will often prove to be a false-positive result (Tables 9.11 and 9.16 ). The cases where
the atypical cytologic features lead us to interpretive traps in all three categories are listed in
Tables 9.13 and 9.16 and illustrated in Figures 9.89 , 9.90 , 9.91 , 9.92 , 9.93 , 9.94 , 9.95 , 9.96
, 9.97 , 9.98 , 9.99 , 9.100 , 9.101 , 9.102 , 9.103 , 9.104 , 9.105 , 9.106 , 9.107 , 9.108 , 9.109 ,
9.110 and 9.111 .

Figure 9.89. Papillary tissue fragments in nodular goiter versus papillary carcinoma A.
Extremely cellular aspirate. The large numbers of tissue fragments with papillary-like and
monolayered architecture are very striking at this medium-power view. The background is clean
and devoid of colloid. B. The honeycomb arrangement of small cells with uniform round nuclei,
containing granular chromatin supports the diagnosis of hyperplastic goiter.

Figure 9.90. Papillary tissue fragments in nodular goiter versus papillary carcinoma. A.
Extremely cellular aspirate. The large numbers of tissue fragments with papillary and
monolayered architecture are highly suggestive of neoplasia at this low power. Note abundant
colloid in the background. B. At medium power, the tissue fragments show papillary-like
architecture. However, the honeycomb arrangement is quite evident. C. The honeycomb
arrangement of small cells with uniform round nuclei, containing compact chromatin supports
the diagnosis of hyperplastic goiter. D. FNA of a papillary carcinoma for comparison. The
extreme cellularity is formed by several large, branching tissue fragments of follicular cells in a
clean background (low power). E. Higher magnification shows a monolayered syncytial tissue
fragment with characteristic features of papillary carcinoma cell nuclei. Compare this with part
C.

Figure 9.91. Papillary tissue fragments in a cystic nodular goiter versus papillary carcinoma. A.
The cellular aspirate consists of several tissue fragments of follicular cells that appear to be in
syncytial arrangement with crowding and overlapping. The nuclei are round, with coarsely
granular chromatin and occasional nucleoli. B. These two tissue fragments of follicular cells
demonstrate similar morphology. The background is bloody. A large number of degenerating
follicular cells were present in the background (not illustrated). A suspicious diagnosis of
papillary carcinoma was rendered. Thyroidectomy revealed a cystic nodular goiter with papillary
hyperplasia. C. Histologic section at low power showing a cystic lesion. Papillary architecture is
readily apparent. D. Higher magnification showing edematous papillae lined by follicular cells
containing hyperchromatic nuclei and lacking the characteristics of conventional papillary
carcinoma.
Figure 9.92. Papillary tissue fragments in follicular adenoma with papillary change versus
papillary carcinoma. FNA of a thyroid nodule. A. The cellularity of this aspirate is impressive.
The tissue fragments appear papillary and monolayered. B. At medium power, the tissue
fragments appear monolayered and papillary-like, lacking central cores of fibrovascular tissue.
C. Higher magnification demonstrating a honeycomb arrangement of uniform, small round nuclei
with granular chromatin. The overwhelming cellularity and the architecture of the tissue
fragments lead to a positive diagnosis of papillary carcinoma. Thyroidectomy revealed a
follicular adenoma with papillary change. D. Histologic section with several dilated follicles
showing short papillae protruding in the lumen. E. Higher magnification of the papillae covered
by uniform follicular cells, lacking stratification and pale watery nuclei.

Figure 9.93. Papillary tissue fragments in follicular adenoma with papillary change versus
papillary carcinoma . Another example of a false-positive cytologic diagnosis. FNA of an isthmic
nodule. A,B. An adequately cellular aspirate showing tissue fragments of follicular epithelium
with papillary-like architecture. The honeycomb arrangement is apparent at this power. C. A
monolayered tissue fragment with honeycomb arrangement. The follicular cell nuclei are
uniform, small, and hyperchromatic. No grooves or inclusions are present. D. This tissue
fragment contains a psammoma body. Note that the component cells lack the characteristic
features of papillary carcinoma. Based on the architecture and psammoma body, papillary
carcinoma was diagnosed. Thyroidectomy confirmed an encapsulated cystic follicular adenoma.
E. Histologic section at low power to illustrate the nodule with arborizing papillae, directed
towards the center of the cavity. F. Higher magnification. Note the lack of typical features of
papillary carcinoma.

Figure 9.94. Nuclear atypia and papillary hyperplasia in the background of Hashimoto's
thyroiditis versus papillary carcinoma in the background of thyroiditis . A. This syncytial tissue
fragment shows a papillary-like configuration. The component cell nuclei are minimally
enlarged, round, and with granular chromatin. Besides the architecture, nuclear characteristics
of papillary carcinoma are lacking. B. Syncytial tissue fragment with small, minimally enlarged
nuclei and some suggestion of intranuclear inclusions. With a suspicious diagnosis for papillary
carcinoma, a thyroidectomy was performed, which failed to confirm a papillary carcinoma. C.
Histologic section showing features of Hashimoto's thyroiditis with papillary hyperplasia. D. The
lining epithelium is atypical, with nuclei containing pale chromatin.

Figure 9.95. Differential Diagnosis of monolayered tissue fragments . A. FNA of a hyperplastic

nodular goiter, low power. The aspirate is overwhelmingly cellular, consisting of several tissue
fragments of follicular cells. B. Medium-power view demonstrating monolayered tissue
fragments. C. Higher magnification highlights the lack of nuclear features of papillary
carcinoma. The cellularity by itself may tempt a diagnosis of follicular neoplasm. D–F. FNA of
a papillary carcinoma consisting of predominantly monolayered tissue fragments, for comparison
with the case illustrated in parts A to C. D. The cellular aspirate shows several tissue fragments.
This low-power view is very similar to part A. E. Medium-power view. F. Higher magnification.
The tissue fragment is syncytial, with altered polarity of enlarged nuclei. The chromatin is pale,
fine, and powdery. Note micronucleoli, grooves, and intranuclear inclusions.

Figure 9.96. Another example of hyperplastic goiter with a cellular aspirate consisting of a large
number of monolayered tissue fragments that may lead to a false-positive diagnosis of papillary
carcinoma. A. Low power to demonstrate the cellularity and large number of tissue fragments.
B. Medium power view to show the monolayered tissue fragments with honeycomb arrangement.
The nuclei are minimally but uniformly enlarged with granular chromatin. C. Higher
magnification highlights the lack of nuclear features of papillary carcinoma.
Figure 9.97. FNA of a papillary carcinoma consisting of predominantly monolayered tissue
fragments for comparison with the case illustrated in Figure 9.96. A. The cellular aspirate shows
several tissue fragments. This low-power view is very similar to Figure 9.96A. B. Medium-power
view to show the monolayered architecture. C. Higher magnification. The tissue fragment is
syncytial, with altered polarity of enlarged nuclei. The chromatin is pale, fine, and powdery.
Note micronucleoli, grooves, and intranuclear inclusions.
Figure 9.98. Follicular adenoma versus papillary carcinoma . A. FNA of a thyroid nodule showing
several large monolayered tissue fragments of follicular epithelim, low power. B. Higher
magnification showing a monolayered tissue fragment lacking features of papillary carcinoma.
The case was misinterpreted as suspicious for papillary carcinoma. C,D. Thyroidectomy revealed
an encapsulated simple-type follicular adenoma. E,F. Another example of cellular follicular
adenoma, interpreted as suspicious for papillary carcinoma. FNA showing syncytial tissue
fragments of follicular epithelium without any architectural pattern. The nuclei are enlarged.
Their chromatin appears pale with some suggestion of intranuclear inclusions (arrows ). Partial
air-drying has rendered the nuclei pale looking. G. Thyroidectomy showed an encapsulated
cellular follicular adenoma with a solid growth pattern. H. Higher magnification showing a
trabecular adenoma.

Figure 9.99. Papillary hyperplasia in Hashimoto's thyroiditis presenting monolayered tissue

fragments, misinterpreted as papillary carcinoma. A. The cellular aspirate shows several large
tissue fragments (low power). B. Higher magnification showing a monolayered tissue fragment
with syncytial arrangement. The cells are large, with abundant cytoplasm and appear
Hürtheloid. The nuclei are round and enlarged, with micro- and macronucleoli. The chromatin
is granular. Nuclear grooves or inclusions are not present. Lymphocytes are present in the
background. Thyroidectomy failed to show a papillary carcinoma. C. Histologic section showing
features of Hashimoto's thyroiditis with diffuse papillary hyperplasia. D. Higher magnification.
The follicular cells lining these short papillae lack nuclear characteristics of papillary carcinoma.
Figure 9.100. Squamous metaplasia in nodular goiter and papillary carcinoma. FNA of a nodular
goiter. A. A large tissue fragment with smooth external contour with papillary-like pattern,
medium power. B. Higher magnification showing the spindle cell architecture. The nuclei are
round and uniform, with granular chromatin and some containing nucleoli. C. Some tissue
fragments of follicular cells exhibited mild nuclear atypia. Grooves and inclusions are not
present. With a suspicious diagnosis of papillary carcinoma, a thyroidectomy was performed,
which showed nodular goiter with cystic change. D. Histologic section of the goiter, low power.
E. This image depicts degeneration of the follicular cells with spindle cell change (arrow ). F.
FNA of a papillary carcinoma to illustrate squamous metaplasia. Note the large tissue fragment
with cytomorphology similar to that seen in part A. Also note the monolayered tissue fragment
of papillary carcinoma in the field. G. Higher magnification of the tissue fragment with
squamous metaplasia.

Figure 9.101. Atypical nuclear changes in nodular goiter mimicking papillary carcinoma. A,B.
Poorly preserved tissue fragments of follicular epithelium with crowding and overlapping of small
hyperchromatic nuclei. There is some suggestion of intranuclear inclusions (arrow ). C. Features
of nodular goiter were present elsewhere in the aspirate. D. Thyroidectomy revealed cystic
nodular goiter with papillary change.
Figure 9.102. Atypical nuclear changes with post 131I therapy mimicking papillary carcinoma.
A. Low power showing a very large branching tissue fragment of follicular cells. B. Higher
magnification showing a monolayered tissue fragment. The nuclei are enlarged, mildly
pleomorphic with frequent micronucleoli and grooves. No inclusions are identified. C. These
cells are much larger, pleomorphic, and with abundant dense cytoplasm. Their nuclei are
enlarged with nucleoli. Also note the bubbly appearance of the chromatin due to radiation. A
psammoma body is also present. A papillary carcinoma was suspected. Thyroidectomy failed to
confirm the malignancy. History of prior radiation was not available at the time of biopsy.
Figure 9.103. Atypical nuclear changes in Hashimoto's thyroiditis mimicking papillary
carcinoma. A–C. All three tissue fragments are syncytial with marked crowding and
overlapping of nuclei. The chromatin is pale, and some suggest the presence of intranuclear
inclusions. No lymphocytes are present in the background. The aspirate was interpreted as
suspicious for papillary carcinoma. D. Thyroidectomy revealed Hashimoto's thyroiditis with
follicular cell atypia, mimicking changes of papillary carcinoma.
Figure 9.104. Reactive changes in nodular goiter or Hashimoto's thyroiditis with pale nuclei and
micronucleoli may lead to false-positive diagnosis. A. Histologic section of nodular goiter
showing focal area with pale, watery nuclei. B. FNA of a thyroid nodule showed marked
cellularity. The tissue fragments of follicular cells are large with branching. C,D. Higher
magnification to show nuclei with fine, powdery chromatin and prominent micronucleoli. A
papillary carcinoma was suspected. Thyroidectomy showed Hashimoto's thyroiditis with follicular
cell nuclear atypia. E. Histologic section showing features of Hashimoto's thyroiditis. F. Higher
magnification depicting follicular cells with pale chromatin and micronucleoli.
Figure 9.105. The presence of intranuclear inclusion by itself is not a diagnostic criterion for
papillary carcinoma. A. FNA of Hashimoto's thyroiditis with a papillary-like tissue fragment of
follicular cells. The nuclei are crowded and overlapped. B. A single cell containing an
intranuclear inclusion. A suspicious diagnosis resulted in a thyroidectomy, which showed only
Hashimoto's thyroiditis. C. FNA of Hashimoto's thyroiditis interpreted as suspicious for a follicular
variant of papillary carcinoma. Note the intranuclear inclusions (arrows ). Lymphoid cells are not
seen in this field. Papillary carcinoma was not confirmed. D. An intranuclear inclusion should be
sharp and bordered by condensed chromatin, as seen here. E. The follicular cell depicted in this
image shows a suggestion of intranuclear inclusion that blends with the peripheral chromatin
and probably represents a degenerative change.
Figure 9.106. Significance of psammoma bodies . A. FNA of a nodular goiter. This low-power
view shows abundant colloid, few groups of follicular cells, and a small psammoma body (arrow
), low power. B. Higher magnification highlighting the psammoma body. The follicular cell nuclei
are small with compact chromatin. Note another group of benign follicular cells (arrow ). C. A
different field from the same case showing a single psammoma body incorporated in a tissue
fragment of benign follicular cells. The background features were those of a nodular goiter and
the aspirate was considered benign. A regular follow-up and possibly a repeat biopsy should be
recommended.
Figure 9.107. A. FNA of a nodular goiter showing a tissue fragment of benign follicular cells
containing small nuclei with compact chromatin, incorporating three psammoma bodies. B. FNA
of a different case of nodular goiter depicting psammoma bodies incorporated in a tissue
fragment of benign follicular cells. C. Psammoma body from a papillary carcinoma for
comparison. The component cell nuclei exhibit features of papillary carcinoma.
Figure 9.108. An example of a false-positive diagnosis of papillary carcinoma that was based on
the presence of psammoma bodies. A,B. These two images depict degenerating follicular cells
containing hemosiderin pigment and psammoma bodies. Note the absence of nuclear features of
papillary carcinoma. C. A large tissue fragment of benign follicular cells with papillary-like
configuration. The component cells are arranged in honeycomb fashion and have small nuclei
with compact chromatin. A suspicious diagnosis for papillary carcinoma was rendered. D.
Thyroidectomy revealed a multinodular goiter with cystic degeneration. There was no papillary
carcinoma. E. Histologic section of the nodular goiter.
Figure 9.109. Psammoma body in aspirate of follicular adenoma. FNA of a follicular adenoma
with monolayered tissue fragments and psammoma bodies. A,B. These tissue fragments of
follicular epithelium are syncytial type with follicular pattern. The nuclei are enlarged with
granular chromatin and contain micronucleoli. Grooves or inclusions are not present. Note small
psammoma bodies (arrows ). C. Same aspirate showing a syncytial tissue fragment with a
psammoma body. Although micronucleoli are present, no grooves or inclusions are present. D.
Thyroidectomy revealed an encapsulated follicular adenoma with cystic change. E. Higher
magnification to demonstrate multiple small psammoma bodies surrounded by hemosiderin-
containing histiocytes. F. Histologic section of the follicular adenoma showing follicles lined by
epithelium and lacking features of papillary carcinoma.

Figure 9.110. Naked psammoma bodies are not diagnostic of papillary carcinoma. A. FNA of a
nodular goiter showing multiple naked psammoma bodies. B. FNA of a papillary carcinoma.
Naked psammoma bodies can also occur in papillary carcinoma. To be diagnostic, they must be
incorporated in tissue fragments with cells presenting nuclear features of papillary carcinoma.

Figure 9.111. Mimics of psammoma body. A. FNA of a nodular goiter with extensive Hürthle
cell metaplasia and cystic degeneration. This tissue fragment of follicular cells contains an
inspissated colloid-simulating psammoma body. The follicular cell nuclei contain micronucleoli
but lack grooves and inclusions, B. Dense colloid within a microfollicle mimicking a psammoma
body. C. Inspissated colloid with cracks resembling a naked psammoma body.

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 P.192

PAPILLARY CARCINOMA VERSUS PAPILLARY HYPERPLASIA;

DIFFERENTIAL DIAGNOSIS OF PAPILLARY TISSUE FRAGMENTS
Papillary or papillary-like architecture can be seen in several conditions affecting the thyroid
gland that present clinically as cold nodules (Figs. 9.89 , 9.90 , 9.91 , 9.92 , 9.93 and 9.94 ,
Table 9.20 ).215 Fine-needle aspirates of thyroid nodules of any of these diseases yield papillary
tissue fragments of follicular epithelium. Their occurrence in lesions other than papillary
carcinoma, however, is infrequent. The papillary tissue fragment is one of the most common
features in the cytologic material of papillary carcinoma. Of 329 papillary carcinomas, 283
aspirates showed either only papillary or predominantly papillary tissue fragments (Table 9.17 ).
Such a pattern was not appreciated in only 46 cases.

1. Papillary carcinoma
2. Papillary hyperplasia in nodular goiter
3. Papillary change in follicular adenoma
4. Hashimoto's thyroiditis
a Although papillary hyperplasia is seen in Graves disease, it is not included here as no fine-

needle biopsies were performed on functioning nodules.

TABLE 9.20 TISSUE FRAGMENTS WITH PAPILLARY OR

PAPILLARY-LIKE ARCHITECTURE IN CYTOLOGIC SAMPLESa
Despite its frequency, the diagnosis of papillary carcinoma based on papillary architecture alone
is difficult both cytologically and histologically. This problem is covered in several articles that
offer criteria helpful for differentiating between benign and malignant lesions on a histologic
basis.22 Carcangiu et al.20 stressed the cytologic criteria in the diagnosis of papillary
carcinoma. The cytomorphology of the cells forming the papillary tissue fragment is critically
important. Papillary hyperplasia occurring in follicular nodules or lymphocytic thyroiditis
contitutes an important diagnostic pitfall.215 , 216 , 217 , 218

Papillary Hyperplasia in Follicular Nodules

Papillary hyperplasia can occur in follicular adenoma or in an adenomatous nodule with
hyperplastic change. These hyperplastic nodules are well circumscribed, with or without
encapsulation (Figs. 9.89 , 9.90 , 9.91 , 9.92 , 9.93 and 9.94 ), and may show cystic change
centrally. The follicular epithelium is hyperplastic papillary, with the papillae directed toward
the center of the nodule. The papillae may be edematous and contain follicles. Their nuclei
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are basally located, round, and do not exhibit the cytologic criteria of papillary carcinoma. We
encountered 11 cases of follicular nodules with papillary hyperplasia, 5 interpreted cytologically
as diagnostic of papillary carcinoma and 6 as suspicious. The patients ranged from 14 to 51 years
of age; 10 were female and 1 was male. The aspirates yielded fluid in 4 cases.

The diagnosis of papillary carcinoma was based on the presence of one or more of the following
features: papillary or syncytial tissue fragments; mildly enlarged nuclei with powdery to granular
chromatin; and micronucleoli, intranuclear inclusions (1/11), nuclear grooves (1/11), and a
psammoma body (1/11). None of these cases showed the minimal criteria
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of papillary carcinoma. Furthermore, 5 specimens were only marginally cellular. Thyroidectomy
in all 11 patients failed to show papillary carcinoma. Four were follicular adenomas and 7 were
nodular goiter (Table 9.21 ).

Cystic (fluid aspirated)

4/11
Nuclear chromatin
Cellularity
Powdery
1/11
Hypercellular
1/11
Finely granular
7/11
Adequate
5/11
Coarsely granular
3/11
Marginal
5/11
Micronucleoli
11/11
Tissue fragments
Nuclear groove
1/11
Papillary
8/11
Monolayered
5/11
Intranuclear inclusion
1/11
Syncytial
4/11
Background
Follicular cells (round to cuboidal)
11/11
Histiocytes
8/11
Nuclei
Bloody
5/11
Mildly enlarged
7/11
Moderately enlarged
2/11

TABLE 9.21 CYTOLOGIC FEATURES IN 11 CASES OF

PAPILLARY HYPERPLASIA IN FOLLICULAR NODULES
The cytologic differentiation between benign and papillary fragments and papillary carcinoma is
listed in Table 9.22 .

Cellularity
Generally high
Generally high
Generally high
Presentation
Papillary tissue fragments
Papillary tissue fragments
Papillary tissue fragments
Architecture of tissue
fragments
Component cells with
honeycomb arrangement;
well-defined cell borders;
nuclear polarity maintained;
peripheral palisading of
nuclei present
Syncytial arrangement with
crowding and overlapping
of nuclei, altered polarity
peripheral palisading of
nuclei; central fibrovascular
core may be visible
Honeycomb arrangement; well-
defined cell borders; nuclear polarity
maintained, peripheral palisading of
nuclei may be present
Nucleus
size
Small uniform to slight
enlargement (7–9 µm) round;
finely granular chromatin
Enlarged, pleomorphic in size,
round, dusty powdery chromatin
Slightly enlarged; uniform, round,
finely granular chromatin
Nucleolus
Multiple micronucleoli
Multiple micro/macronucleoli
Miconucleoli
Groove
Rare in nodular goiter;
absent in adenoma
Present
Absent
Intranuclear
inclusions
Rare in nodular goiter;
absent in follicular
adenoma
Present
Rare
Psammoma Bodies
Rare
25% of the cases
Rare
Background
histiocytes with
±
±
-
or without
hemosiderin
Multinuclear
giant cells
-
Present
Present
lymphoid cells
-
±
+

Papillary Hyperplasia/
Papillary Change in
Nodular Goiter and Papillary Carcinoma
Follicular Adenoma Papillary Hyperplasia in Hashimoto's Thyroiditis

TABLE 9.22 CYTOPATHOLOGIC DIFFERENTIATION BETWEEN

PAPILLARY HYPERPLASIA AND PAPILLARY CARCINOMA

Papillary Carcinoma versus Follicular Hyperplasia:

Differential Diagnosis of Monolayered Tissue Fragments
Monolayered tissue fragments of carcinoma cells (Figs. 9.95 , 9.96 , 9.97 , 9.98 and 9.99 ) were
seen in 60% of the aspirates of papillary carcinoma in our series (Table 9.17 ). As described
earlier, they probably represent either the papillary fronds or large follicles seen en face. Being
single layered, they exhibit a two-dimensional pattern and share a morphologic similarity to
tissue fragments of nodular goiter. An overwhelmingly cellular aspirate of hyperplastic goiter
with a myriad of monolayered tissue fragments may be mistaken for papillary carcinoma,
especially when viewed under a low-power objective (Figs. 9.95A and 9.96A ). However, closer
examination will reveal a different cytomorphology. The monolayered tissue fragments of
nodular goiter have a honeycomb pattern, with well-defined cell borders; uniform, small nuclei
with regular polarity; and compact chromatin. They do not show all of the nuclear features
exhibited by monolayered tissue fragments of cancer cells seen in papillary carcinoma (Fig.
9.95C , Table 9.23 ).

Presentation
Large number of
monolayered tissue
fragments; scant or
absent colloid
Large numbers of
monolayered tissue
fragments; colloid
variable
Large numbers of
monolayered tissue
fragments; colloid variable
in blobs or strings
Large number of monolay-
ered tissue fragments; scant
to absent colloid, lymphoid
cells in the background
Component
follicular
cells
Honeycomb arrangement
with well-defined cell
borders; nuclear polarity
maintained
Honeycomb
arrangement with
well-defined cell
borders; some
crowding and
overlapping; with
nuclear polarity
maintained or
slightly altered
Lack of honeycomb
arrangement; some
crowding and overlapping;
cell borders may or may
not be well-defined;
altered nuclear polarity
Honeycomb arrangement
with well-defined cell
borders; nuclear polarity
either maintained or slightly
 altered
Cell size
Normal
Normal to slightly
increased
Slight to considerable
enlargement
Slightly enlarged
Nucleus
Normal, uniform 7–9 µm;
chromatin finely granular,
evenly distributed;
miconucleoli ±
Slightly enlarged
uniform; chromatin
finely granular,
evenly distributed;
miconucleoli ±
Considerably enlarged; dusty
powdery to finely granular
chromatin; single/multiple
micronucleoli/
macronucleoli
Slightly enlarged;
finely granular chromatin;
multiplemicronucleoli
Intranuclear
inclusions
Extremely rare
Extremely rare
Present
Rarely present
Nuclear grooves
±
Absent
Present
±
Cytoplasm
Variable, pale
Variable, generally
scant and pale
Variable, may be
abundant and dense
Variable, pale
Psammoma
bodies
Rarely present
Rarely present
Present in up to
25% of the cases
Rarely present
Background
Multinucleated
giant cells absent
Multinucleated
giant cells absent
Multinucleated giant
cells present
Multinucleated giant
cells may be present;
features of Hashimoto's
thyroiditis present

Hyperplastic Simple
Nodular Follicular Papillary
Goiter Adenoma Carcinoma Hashimoto's Thyroiditis
 TABLE 9.23 CYTOPATHOLOGIC DIFFERENTIATION BETWEEN
MONOLAYERED TISSUE FRAGMENTS IN THYROID ASPIRATES
Monolayered tissue fragments may also be seen in simple follicular adenomas or Hashimoto's
thyroiditis with papillary hyperplasia, but they lack the typical nuclear morphology of papillary
carcinoma (Figs. 9.98C and 9.99 ).

FALSE-POSITIVE DIAGNOSIS OF PAPILLARY CARCINOMA DUE TO

SQUAMOUS METAPLASIA
Squamous metaplasia in both papillary carcinoma and nodular goiters is not a frequent
occurrence in cytologic samples. When encountered in cytologic samples, this may cause a
diagnostic dilemma (Fig. 9.100 )

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FALSE-POSITIVE CYTOLOGIC DIAGNOSIS OF PAPILLARY

CARCINOMA DUE TO ATYPICAL NUCLEAR FEATURES
The nuclei of papillary carcinoma cells present a characteristic morphology consisting of
enlargement, pale to powdery chromatin, micro/macronucleoli, grooves, and inclusions. One or
more but not all of these features may be present in benign diseases and may lead to false-
positive interpretation. Nodular goiter is a prime example. Degeneration, hemorrhage, and
cystic changes result in retrogressive as well as reactive/reparative changes that mimic nuclear
morphology of papillary carcinoma cells. Hyperplasia in nodular goiters or Hashimoto's thyroiditis
may show micronucleoli as well as
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pale chromatin. Nuclear grooves are also rarely observed in nodular goiters. Intranuclear
inclusions may occasionally be seen in follicular cell nuclei in nodular goiters and in Hashimoto's
thyroiditis. These diagnostic difficulties are illustrated in Figures 9.101 , 9.102 and 9.103 .

SIGNIFICANCE OF INTRANUCLEAR INCLUSIONS

Intranuclear cytoplasmic inclusions were first noted by Söderström and Bjorklund52 to be an
important criterion of malignancy in fine-needle aspirate smears of papillary carcinoma of the
thyroid. They were present in 308 of 329 cases (93%) of papillary carcinoma in our series.
Löwhagen and Sprenger45 found them in 5 of 10 (50%), Christ and Haja48 in 20 of 22 (91%), and
Frable41 in 7 of 7 (100%). Intranuclear inclusions are often considered synonymous with the
ground-glass or "Orphan Annie" appearance of the nuclei of papillary thyroid carcinoma.
However, ground-glass or watery nuclei is more or less a generalized finding in papillary
carcinomas involving the entire nucleus due to finely granular, powdery chromatin. Intranuclear
inclusions are morphologically different, seen in both cytologic and histologic sections, but in a
small proportion of cells. Ultrastructurally, they are seen as membrane-bound, spheroidal
masses of cytoplasm intruding into the nuclei27 , 28 that contain cytoplasmic organelles.

Although a frequent feature of papillary carcinoma, intranuclear inclusions are also present in
other thyroid malignancies. They are a remarkably consistent finding in hyalinizing trabecular
adenomas, medullary carcinoma,43 and are sometimes seen in Hürthle cell carcinomas49 as
well as in anaplastic carcinoma. Glant et al.50 reported their presence in follicular neoplasms,
both adenoma and carcinoma, and Droese42 found them in benign, nonneoplastic conditions. We
have seen three aspirates from Hashimoto's thyroiditis with follicular cell nuclei containing
cytoplasmic
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P.201
inclusions (Fig. 9.105 ). Intranuclear cytoplasmic inclusions are not only present in cells of
thyroid neoplasms but are also observed in several different types of malignancies, including
malignant melanoma, liver cell carcinoma, adenocarcinoma of the lung, breast carcinomas, and
soft-tissue sarcomas.

Intranuclear cytoplasmic inclusions are diagnostically important only when present in a proper
setting. In thyroid aspirates, syncytial-type tissue fragments of any architectural pattern, with
nuclei containing powdery chromatin and cytoplasmic inclusions, may be diagnostic of papillary
carcinoma. On the other hand, aspirates showing only isolated cells with intranuclear inclusions
may be a medullary carcinoma203 of the thyroid, a papillary carcinoma (see Chapter 12 ), or a
benign lesion. For this reason, a diagnosis of papillary carcinoma should never be based on the
presence of intranuclear cytoplasmic inclusions alone.

SIGNIFICANCE OF PALE, WATERY NUCLEI

Hapke and Dehner29 described the incidence and discussed the significance of optically clear
nuclei in thyroid lesions, stating that they occur in a variety of nonneoplastic and neoplastic
conditions (Figs. 9.103 to 9.104 ). They concluded that the mere presence of optically clear
nuclei must not be considered diagnostic of papillary carcinoma. Aspirates from nodular goiter,
Hashimoto's thyroiditis, and follicular adenoma may all show a few groups of follicular cells with
dusty, powdery chromatin and micronucleoli resembling the cells of papillary carcinoma.
However, these pale nuclei lack the other features (e.g., grooves and inclusions) are not
diagnostic of papillary carcinoma.

SIGNIFICANCE OF NUCLEAR GROOVES

A nuclear groove or crease is a frequent finding in the cells of papillary carcinoma.30 , 54 , 55 ,
56 , 57 , 58 , 59 Seen as a linear crease or a fold along the long axis of the nucleus (Fig. 9.11 ),
it probably represents an irregular infolding of the nuclear membrane, as observed
ultrastructurally.27 , 28 Its presence is by no means diagnostic of papillary thyroid carcinoma,
even though some authors have reported it in 100% of their cases reviewed.57 Studies have
shown nuclear grooving in cells of other nonneoplastic and neoplastic thyroid lesions.57

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P.203

FALSE-POSITIVE CYTOLOGIC DIAGNOSIS OF PAPILLARY

CARCINOMA DUE TO THE PRESENCE OF PSAMMOMA BODIES
Psammoma bodies (Fig. 9.24 ) are considered a pathognomonic feature of papillary
carcinoma.22 The reported incidence in histologic material varies from 40% to 60%, but they are
not seen with such frequency in cytologic material (Table 9.16 ). We found them in 20% of the
aspirates from papillary carcinomas. Psammoma bodies are so rarely seen in benign disorders of
the thyroid35 , 225 , 226 , 227 , 228 , 229 that their presence in an otherwise normal-appearing
thyroid gland or even in a cervical lymph node should be regarded as evidence for the presence
of carcinoma until proved otherwise.13 Because of
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P.205
P.206
P.207
P.208
such views, the presence of psammoma bodies in aspirates of thyroid nodules causes a diagnostic
dilemma if other cytologic features of papillary carcinoma are not present. Can a diagnosis of
papillary carcinoma be made unequivocally in the above situations? Should a surgical procedure
be recommended to confirm the diagnosis of papillary carcinoma? As indicated earlier, minimal
criteria for the diagnosis of papillary carcinoma do not include a psammoma body. Initially, we
placed considerable emphasis on psammoma bodies alone in making a diagnosis of papillary
carcinoma, but later it was noted that they might not be of diagnostic importance in the
absence of other features of papillary carcinoma. "Naked" psammoma bodies (Fig. 9.110 ) or a
rare psammoma body incorporated in a tissue fragment without minimal criteria of papillary
carcinoma must be interpreted with
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P.210
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P.212
caution, as these may be seen in nodular goiter. Two of our false-positive cases fell in to this
category (Table 9.11 ). A diagnosis of suspected papillary carcinoma was given in nine cases
solely because of the presence of psammoma bodies. Five patients underwent surgery, with a
final diagnosis of adenomatous goiter. The other four cases had a diagnosis of nodular goiter
based on the results of a repeat fine-needle or large-needle biopsy. All nine cases had features
of nodular goiter in the background, and the typical cytomorphology of papillary carcinoma was
either lacking or insufficient. The cellular material exhibited insufficient criteria for the
diagnosis of papillary carcinoma (Table 9.13 ). A psammoma body is diagnostic only if it is
incorporated in a tissue fragment of follicular cells that exhibit minimal criteria of malignancy.
Table 9.24 lists the difference between psammoma bodies seen in papillary carcinoma and those
seen in nodular goiters.

Number of psammoma bodies

Generally an isolated finding or few
in numbers; multiple psammoma bodies
in a single tissue fragment uncommon
Usually in significant numbers
when present; multiple psammoma
bodies in a single tissue fragment common
Naked forms
Present
Present
Size
Usually small
Variable, small to large
Characteristics of tissue fragment
incorporating the psammoma
body(ies)
Component cells of the tissue
fragment have small uniform nuclei
with compact to finely granular
chromatin, lack the typical nuclear
features of papillary carcinoma;
syncytial arrangement absent.
Syncytial arrangement of cells
with enlarged nuclei demonstrating
the typical features of papillary carcinoma
Calcific Debris in the Background
±
±
Background
Background features of nodular goiter
Features of papillary carcinoma

Psammoma Bodies Psammoma Bodies

in Nodular Goiter in Papillary Carcinoma

TABLE 9.24 DIFFERENTIATING FEATURES BETWEEN

PSAMMOMA BODIES IN NODULAR GOITER AND PAPILLARY
CARCINOMA
A psammoma body can be mimicked by dense, inspissated colloid within a follicle or because of
its tendency to crack in a linear fashion (Fig. 9.111 ).

Having described in detail the cytopathologic features of papillary carcinoma, the diagnostic
difficulties, and analyzing the errors, the author would like to pose a philosophical question: Is
surgical pathology always the gold standard against which an accuracy of cytologic diagnosis of
papillary carcinoma is judged? Is it taken for granted that the histologic diagnosis rendered in
every case is accurate?

Figures 9.112 , 9.113 , 9.114 and 9.115 represent some such examples. The reader is requested
to make his or her own judgment.
Figure 9.112. Is surgical pathology always a gold standard? Positive cytology for papillary
carcinoma, histology interpreted as benign. A–D. FNA of a thyroid nodule. These four images
depict syncytial tissue fragments of follicular cells with psammoma bodies. The pleomorphic,
enlarged nuclei show features of papillary carcinoma. Note the intranuclear inclusions and
grooves. The background contains a large number of histiocytes, suggesting a cystic lesion. The
cytologic diagnosis was papillary carcinoma. Thyroidectomy at another hospital was interpreted
as Hashimoto's thyroiditis. E. Histologic section showing a cystic papillary carcinoma. F. Another
section revealing lymphoid infiltrate in the wall of the cystic cavity showing papillary carcinoma
lining the cyst. G. Higher magnification of the papilla with psammoma body. Lack of typical
nuclear features in this lining epithelium lead the pathologist to interpret this lesion as benign.
Is this lesion Hashimoto's thyroiditis or papillary carcinoma in the background of thyroiditis?

Figure 9.113. Is surgical pathology always a gold standard? Positive cytology for papillary
carcinoma, histology interpreted as benign. FNA of a thyroid nodule. A,B. FNA of a cold nodule.
These syncytial tissue fragments of follicular cells. The nuclear chromatin is granular with
occasional intranuclear inclusions and micronucleoli. Cytologic interpretation was suspicious for
papillary carcinoma. Thyroidectomy revealed a small cystic lesion in the background of nodular
goiter. C. Histologic section showing the cystic cavity containing a detached, small but complex
branching papillary structure. D. Higher magnification demonstrates pale, watery nuclei with
intranuclear inclusions. The final histologic diagnosis was nodular goiter. Does this lesion
represent a microcarcinoma?

Figure 9.114. Is surgical pathology always a gold standard? Positive cytology for papillary
carcinoma, histology interpreted as benign. A–C. Hypercellular aspirate showing syncytial
tissue fragments of follicular cells. The nuclear chromatin is pale with frequent intranuclear
inclusions. Papillary carcinoma was suspected. Thyroidectomy showed a massively enlarged
multinodular thyroid with features of nodular goiter. D,E. Histologic sections of the nodular
goiter. F. Cervical lymph nodes showed thyroid tissue and psammoma bodies. Typical nuclear
features of papillary carcinoma were not present. Was a papillary carcinoma overlooked on gross
examination of the thyroid and not sampled because of the large size of the thyroid? Was the
psammoma body considered insignificant and the thyroid tissue in the cervical nodes considered
as lateral aberrant thyroid valid?

Figure 9.115. Is the surgical pathology always a gold standard? Positive cytology for papillary
carcinoma, histology interpreted as benign . Fine-needle biopsy of a thyroid nodule from a 14-
year-old girl. A–C. FNA yielded several milliliters of hemorrhagic fluid. The cytospin
preparation was marginally cellular, with rare tissue fragments of follicular epithelium obscured
by blood and cellular debris. These tissue fragments show follicular cells with nuclei containing
powdery chromatin and prominent nucleoli. The aspirate was diagnosed as suspicious of
papillary carcinoma. A repeat fine-needle biopsy again yielded hemorrhagic fluid and very few
cells containing pleomorphic nuclei with pale chromatin. D. Thyroidectomy revealed a 2-cm
cystic lesion. E,F. Histologic sections were interpreted as nodular goiter with cystic change and
papillary hyperplasia. Is this a nodular goiter or a microcarcinoma?

P.213
P.214

SUMMARY
Papillary carcinoma of the thyroid is the most common differentiated thyroid malignancy. It is
also the least difficult to diagnose from cytologic samples, provided the aspirate is adequate. It
has a diagnostic accuracy of over 90%. Although there are several cytologic features, the
minimal criteria include a syncytial-type tissue fragment that, irrespective of the architectural
pattern, shows typical nuclear morphology of pale, watery nuclei due to powdery, dusty
chromatin; micro- and/or macronucleoli; a chromatin ridge; and intranuclear cytoplasmic
inclusions. False-positive diagnoses result from interpretations based on insufficient criteria
and/or placing emphasis on few but not all the described cytologic features of papillary
carcinoma.

P.215

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Encapsulated Follicular Variant

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Clear Cell Variant

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Microcarcinoma
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Cystic Carcinoma
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Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 10 - Poorly Differentiated "Insular" Carcinoma

10
Poorly Differentiated "Insular" Carcinoma

In 1984, Carcangiu et al.1 reported 25 cases of a distinctive type of thyroid carcinoma

characterized by the formation of solid masses or islands (insulae) of small monomorphic tumor
cells with aggressive clinical behavior, distant metastases, and death in most instances. The
authors believed that this carcinoma occupies a place intermediate between well-differentiated
follicular/papillary carcinomas and the usually fatal anaplastic carcinoma. They referred to this
morphologic type as poorly differentiated carcinoma, and coined the term "insular" because of
the characteristic histologic appearance.

Insular carcinomas are uncommon, comprising 4% to 7% of all thyroid malignancies, with a

male:female ratio of 1:2.2 Insular carcinoma usually occurs in older individuals, the mean age
being 55 years. But it has also been described in the pediatric age group.3 , 4 , 5 These tumors
follow an aggressive course and have a high mortality rate. Most patients demonstrate local and
distant metastases at the time of presentation.

Since the introduction of this aggressive subtype of thyroid carcinomas by Carcangiu and co-
workers,1 several small series and case reports have been published in the literature,3 , 4 , 5 , 6
, 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28
, 29 , 30 , 31 including a few on their cytologic presentations.21 , 22 , 23 , 24 , 25 , 26 , 27 , 28
, 29 , 30 , 31

GROSS AND HISTOLOGIC FINDINGS

Grossly, insular carcinomas are usually large and bulky, often exceeding 5 cm in dimension. They
are solid and grayish white, with foci of necrosis (Fig. 10.1 ). Gross extrathyroidal extension is
frequently present.
Figure 10.1. Gross photograph of an insular carcinoma involving the left lobe of the thyroid. The
tumor is large, bulky with areas of necrosis and is replacing almost the entire left lobe.

Insular carcinomas demonstrate a distinctive histologic appearance (Figs. 10.2 , 10.3 and 10.4 ),
characterized by a solid growth pattern consisting of well-defined nests or insulae of round to
oval, small follicular cells averaging up to 10 µm in diameter. The nests of the tumor cells are
well demarcated, vary in size, and are separated by thin connective-tissue septae containing
delicate blood vessels. The nests of tumor cells may be solid, or show a follicular pattern, often
with abortive follicles or a trabecular pattern. Large areas of necrosis are frequent (Fig. 10.4 ).
Sparing of malignant cells around the blood vessels imparts a peritheliomatous pattern. Mitoses
are frequent. Droplets of colloid may be present in the abortive follicles.
Figure 10.2 A. Histologic section of an insular carcinoma with a solid growth pattern and
prominent vascularization (low power). B. Higher magnification showing small uniform malignant
cells with scant cytoplasm and hyperchromatic nuclei.

Figure 10.3. Histologic sections of insular carcinoma. A. Note a solid growth pattern with large
islands of uniform malignant cells (insulae), delineated by delicate fibrous septae, low power. B.
Higher magnification highlighting the small uniform malignant cells. Note the abortive follicles
(arrows).
Figure 10.4. A. Histologic section of insular carcinoma showing a solid growth pattern with large
areas of necrosis (low power). B. Higher magnification highlighting the small monotonous cells
and abortive follicles (arrow), some containing colloid. C. Positive reactivity of the insular
carcinoma cells to thyroglobulin.

Insular carcinomas may be associated with well-differentiated follicular/papillary carcinomas or

anaplastic carcinomas.2 , 17 , 18 , 19 The macrofollicular variant of papillary carcinoma in
particular has been described as associated with an insular component.18 , 19 An insular pattern
is also observed in metastases from differentiated follicular/papillary carcinomas.

CYTOPATHOLOGIC FEATURES
The cytopathologic findings of insular carcinomas are sparsely documented.21 , 22 , 23 , 24 , 25
, 26 , 27 , 28 , 29 , 30 , 31 Their presentation varies, the common denominator being the
consistent small cell size. The aspirates are generally cellular, consisting of a large population of
small, very uniform malignant cells occurring singly, in loosely cohesive groups, and in syncytial
tissue fragments (Figs. 10.5 , 10.6 , 10.7 , 10.8 , 10.9 , 10.10 , 10.11 and 10.12 ). The latter
occur as nests, masses, or trabeculae with intense crowding and overlapping of nuclei. The nests
are often rounded and sharply defined, corresponding to the insulae seen in the histologic
sections. Some syncytial tissue fragments may demonstrate a microfollicular pattern, with their
lumens at times containing droplets of colloid (Fig. 10.10C ). A dispersed pattern is also
occasionally seen (Fig. 10.7 ). The cells of the insular carcinoma are round, with poorly defined
cell borders, and are much smaller than cells of the differentiated (follicular/papillary) thyroid
cancers, averaging 9 to 10 µm in diameter. Plasmacytoid features causing difficulties in
differentiating the tumor from medullary carcinoma have been described.22 Their cytoplasm is
scant, indiscernible, occasionally pale and vacuolated with extremely high N/C ratios. The
nuclear contours are smooth and the chromatin is coarsely granular and deep-staining. Excessive
parachromatin clearing is also appreciated and micronucleoli are usually conspicuous. Mitotic
figures may be present. Insular carcinomas, dedifferentiated from papillary carcinomas, may
demonstrate features of papillary carcinoma such as powdery chromatin, nuclear grooves, and
intranuclear
P.221
inclusions. Those dedifferentiated from follicular carcinomas may demonstrate a follicular
pattern. As mentioned in histologic findings, a metastatic carcinoma from a differentiated
thyroid cancer may present as an insular carcinoma (Figs. 10.10 and 10.11 ). The background
may be clean or necrotic. Mitosis may be a prominent feature. No colloid is appreciated in the
background. The cytologic features of insular carcinoma are listed in Table 10.1 and illustrated
in Figures 10.5 to 10.12 .
Figure 10.5. A,B. FNA of an insular carcinoma consisting of syncytial tissue fragments of small,
uniform, round cells with scant to indiscernible cytoplasm. Note the follicular pattern (arrow).
C,D. Scrape cytology of sternal metastasis of the insular carcinoma depicted in A and B, showing
similar cytomorphology. The patient initially presented with a pulsatile mass with destruction of
the sternum.
Figure 10.6. A,B. FNA of an insular carcinoma showing large syncytial tissue fragments of small
uniform malignant cells with extreme crowding and overlapping. Note a vague follicular pattern
(arrows). "Insular" nature may not be recognized from the cytologic samples and the carcinoma
may be interpreted as poorly differentiated follicular carcinoma. C. Histologic section of the
resected insular carcinoma.
Figure 10.7. A. FNA of another case of an insular carcinoma. The cellular aspirate consists of
small malignant cells, in syncytial tissue fragments with a follicular pattern. Note the dispersed
pattern (low power). B. Higher magnification showing small uniform malignant cells with scant
cytoplasm, high N/C ratios, and granular chromatin with micronucleoli. Note the clean
background. C. Histologic section of the insular carcinoma.
Figure 10.8. FNA of an insular carcinoma metastatic to the vertebra. Note the characteristic
insula formed by small uniform cells. There is an attempt at follicular growth pattern.

Figure 10.9. A. FNA of an insular carcinoma metastatic to the lung. Note syncytial tissue
fragments forming insulae with well-defined outlines (low power). B. Higher magnification
demonstrating monomorphic small follicular cells with high N/C ratios, presenting a follicular
pattern.
Figure 10.10. This case represents a macrofollicular papillary carcinoma, which metastasized 4
years later to the shoulder with dedifferentiation. FNA of the shoulder mass showed an insular
carcinoma that was confirmed on surgical excision. A. Histologic section of the macrofollicular
papillary carcinoma. Note large follicles distended with colloid. The lining epithelium
demonstrates classic nuclear features of a conventional papillary carcinoma. B. Higher
magnification to highlight the classic nuclear features of a conventional papillary carcinoma. C.
FNA of the shoulder mass showing small uniform malignant follicular cells. Note occasional
follicle formation and colloid in their lumens. D. Positive reactivity of the malignant cells to
thyroglobulin. E. Histologic section of the excised shoulder mass showing insular carcinoma.
Figure 10.11. This case represents a follicular carcinoma that metastasized 11 years later to the
lung as an insular carcinoma. A. FNA of the follicular carcinoma performed preoperatively. Note
syncytial tissue fragments with a follicular pattern. The component cells have intensely
hyperchromatic, enlarged nuclei. B. The thyroidectomy revealed a very large fleshy tumor
replacing the entire right lobe. C. Histologic section showed a widely invasive follicular
carcinoma. Note vascular invasion (arrow). D. Higher magnification of the follicular carcinoma.
E,F. FNA of the pulmonary metastasis showing a characteristic cytologic pattern of insular
carcinoma with a follicular pattern. Compare the cell size in this metastatic tumor with the
original tumor as depicted in A.
Figure 10.12. This case represents an anaplastic thyroid carcinoma with a coexistent insular
component. Both components were present in the fine-needle aspirates and were confirmed on
histologic examination following the excision. A. FNA showing a cellular aspirate with a large
population of small cells, isolated and in syncytial tissue fragments, some with a follicular
pattern. The follicular cell nuclei are uniformly round with finely granular chromatin,
parachromatin clearing, and contain micronucleoli. The cytologic pattern is consistent with
poorly differentiated carcinoma. An interpretation of insular carcinoma is difficult. B. Another
smear of the same aspirate showing spindle and giant malignant cells, characteristic of
anaplastic carcinoma. Recognition of both the components depends on sampling.

Cellularity and
presentation
Generally very cellular, malignant cells isolated, in loosely
cohesive groups or in syncytial tissue fragments;
a dispersed pattern is frequent
Architecture
Syncytial tissue fragments of small malignant cells with follicular
pattern, or forming insulae, nests or trabeculae; intense
crowding and overlapping of nuclei; peripheral palisading
not present in the tissue fragments
Cells
Small, monomorphic
Nucleus
Approximately 10 µm in diameter; round, deep-staining, granular
 chromatin with parachromatin clearing; single/multiple
micronucleoli; no nuclear molding; mitoses ±; no stretch artifacts
Cytoplasm
Scant, indiscernible; pale; vacuoles ±
Background
Clean to necrotic; features of pre-existing follicular or papillary
carcinoma ±
Immunocytochemical
profile
Usually react positively with antibodies to thyroglobulin and
TTF-1, occasionally negative; positive reactivity to cytokeratin;
negative reactivity to calcitonin, neuroendocrine markers,
leukocyte common antigen (LCA)

TABLE 10.1 CYTOPATHOLOGIC FEATURES OF POORLY

DIFFERENTIATED"INSULAR CARCINOMA"

IMMUNOPROFILE
The insular carcinoma cells usually react positively to thyroglobulin and TTF-1. Negative
reactivity to thyroglobulin is occasionally observed. Insular carcinomas also react positively to
cytokeratins.

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DIAGNOSTIC ACCURACY AND DIFFERENTIAL DIAGNOSIS

The diagnostic accuracy of insular carcinoma is difficult to assess. These are uncommon thyroid
neoplasms, and since first described over two decades ago in 1984, cytologic findings of insular
carcinoma have been described only infrequently, usually as individual case reports or as small
case series.21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 In most of these reports, the cases
were interpreted as poorly differentiated carcinomas, and the insular nature was appreciated
following the histologic examination. An accurate cytologic diagnosis of insular carcinoma is
difficult to make, unless the aspirate shows insulae formed by small, uniform malignant cells.21
, 25 Most cases of insular carcinomas are cytologically interpreted as poorly differentiated
follicular carcinoma because of the follicular architecture or papillary carcinomas if features of
papillary carcinoma are coexistent. Presence of insulae is not a very common feature.
Recognition
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also depends on the experience of the interpreter, as most cytopathologists have limited
experience with the cytologic presentation of this uncommon thyroid neoplasm. The small size
of the malignant cells, however, is the key to the diagnosis. Conventional follicular carcinoma
cells are much larger (Fig. 10.11 ). Also, many insular carcinomas are associated with
differentiated carcinomas of follicular cell origin, such as the follicular or papillary type. The
aspiration biopsy may sample only the differentiated component and the diagnosis of insular
carcinoma will be evident only following the surgical excision. On rare occasions however,
multiple sampling of the neoplasm may demonstrate the coexistence of both components (Fig.
10.12 ).

Differential Diagnosis
The differential diagnosis of insular carcinoma includes neoplasms composed of small malignant
cells such as medullary thyroid carcinoma with a small cell pattern, other neuroendocrine
tumors including carcinoid tumors or the recently described non–calcitonin-producing
neuroendocrine carcinoma,32 , 33 , 34 malignant lymphoma, metastatic malignancy such as
small cell carcinoma, or poorly differentiated metastatic malignancy composed of a small cell
pattern (Table 10.2 ). Immunostains are often required to establish a correct diagnosis. The
cytologic differentiating features are listed in Table 10.3 .

Medullary carcinoma with a small cell pattern

Other neuroendocrine tumors with small cells
Malignant lymphoma
Metastatic small cell malignancy
Small cell carcinoma
Basaloid squamous cell carcinoma
 TABLE 10.2 DIFFERENTIAL DIAGNOSIS OF INSULAR
CARCINOMA

Presentation
Dispersed cell pattern
or cells in syncytial
tissue fragments
forming nest, insulae
or trabeculae;
microfollicular
pattern ±; intense
crowding and over-
lapping of nuclei
Neoplastic cells dis-
crete, in loosely
cohesive groups,
infrequently in syn-
cytial tissue
fragments; pseudo-
follicular
pattern ±
Cells mostly isolated
with dispersed
pattern; rare syncytial
tissue fragment
Neoplastic cells iso-
lated, in loosely
cohesive groups and
in syncytial tissue
fragments without
any architectural
patterns
Neoplastic cells
 isolated, in
loosely cohe-
sive groups or
in syncytial tis-
sue fragments
without any
architectural
pattern
Cells
Small in size,
monomorphic,
round, poorly
defined cell borders;
high N/C ratios
Small, monomorphic
poorly defined cell
borders; high N/C
ratios
Small, monomorphic
poorly defined cell
borders; high N/C
ratios
Small pleomorphic in
size, poorly defined
cell borders; high
N/C ratios
Small, pleomor-
phic in size,
poorly defined
cell borders;
high N/C ratios
Nucleus
Approximately 10 µm
in diameter, round,
 smooth nuclear
membrane, finely
granular chromatin
with parachromatin
clearing; micronu-
cleoli ±; no nuclear
molding; no stretch
artifacts; mitosis ±;
intranuclear inclu-
sions ±; nuclear
groove ±; karyor-
rhexis not observed
round; smooth
nuclear membrane;
coarsely granular
chromatin; nucleoli ±;
nucleus often eccen-
tric; no nuclear
molding; no stretch
artifacts; mitosis -;
intranuclear inclu-
sions ±; nuclear
groove -; karyor-
rhexis -
Round; smooth to
irregular nuclear
membrane; finely
granular chromatin
with parachromatin
clearing; microncle-
oli +; no nuclear
molding; mitosis +;
stretch artifacts +;
intranuclear inclu-
 sions -; nuclear
groove -; karyor-
rhexis +
Round, oval, oblong
to short spindle
shape; smooth
nuclear membrane;
compact chromatin;
nucleoli not appreci-
ated; nuclear mold-
ing characteristics;
mitosis +; stretch
artifacts +; intranu-
clear inclusions -;
nuclear groove +;
karyorrhexis +
Rounds, oval to
oblong; smooth
nuclear mem-
brane; chromatin
coarsely granular
and deep stain-
ing; nucleoli ±;
no nuclear mold-
ing; mitosis -;
stretch artifacts
-; intranuclear
inclusions -;
nuclear grooves
-
Cytoplasm
Scant, insignificant;
may contain small
vacuoles
Scant, insignificant;
rudimentary cyto-
plasmic tailing
Scant, indiscernible
Scant, indiscernible
Scant; indiscernible
Colloid
Absent
Absent
Absent
Absent
Absent
Amyloid
Absent
±
Absent
Absent
Absent
Background
Clean or necrosis
Clean
Clean or necrotic
debris
Necrosis
Necrosis ±
Immunoprofile
Thyroglobulin
+
—
—
—
—
TTF-1
+
—
—
—
—
Cytokeratin
+
+
—
+
+
Calcitonin
—
+
—
—
—
Neuroendocrine
—
+
—
—
—
Markers
LCA
—
—
+
—

Medullary Metastatic
Carcinoma, Metastatic Basaloid
Insular Small Cell Malignant Small Cell- Squamous Cell
Carcinoma Type Lymphoma Carcinoma Carcinoma
 TABLE 10.3 DIFFERENTIAL DIAGNOSIS OF POORLY
DIFFERENTIATED "INSULAR" CARCINOMA

Insular Carcinoma versus Medullary Thyroid Carcinoma

The aspirate of a medullary carcinoma consisting of small uniform cells is very difficult to
distinguish from insular carcinoma of the thyroid without the help of immunostains (Figs. 10.13
and 10.14 ). Insular carcinomas often show necrosis and increased proliferative activity, a
feature generally not observed with medullary carcinomas. Calcitonin will be strongly positive
with medullary carcinoma cells. A rare primary neuroendocrine tumor referred to as calcitonin-
free oat cell carcinoma34 will be extremely difficult to differentiate from either a medullary
carcinoma or a metastatic small cell carcinoma. An example is illustrated in Figure 10.15 .

Figure 10.13. FNA of a medullary thyroid carcinoma depicting syncytial tissue fragments
composed of monomorphic small cells with hyperchromatic nuclei. In the absence of a typical
pleomorphic cell pattern of a medullary carcinoma, a diagnosis of insular carcinoma must be
considered. A positive calcitonin stain will establish the diagnosis.
Figure 10.14. A. Medium power view of an aspirate of a medullary thyroid carcinoma showing
small monomorphic malignant cells appearing discohesive and in syncytial tissue fragments
resembling insulae. B. Higher magnification. The malignant cells are small with insignificant
cytoplasm, high N/C ratios. Note pseudofollicular pattern (arrows). Such a pattern with small
cells may be mistaken for an insular carcinoma. C. Histologic section of the medullary carcinoma
showing nests of small, round to cuboidal cells. The tumor cells strongly reacted to calcitonin.

Figure 10.15. A. FNA of a thyroid mass. The aspirate is markedly cellular, consisting of several
syncytial tissue fragments as well as loosely cohesive cells (low power). B. Higher magnification
showing the syncytial tissue fragment of the malignant cells without any architectural pattern.
The malignant cells have scant undifferentiated cytoplasm. Their nuclei are slightly larger than
the usual insular carcinoma cells and bear a strong resemblance to neuroendocrine carcinoma
cells. C. The cell block of the aspirate showing several tissue fragments forming insulae. There is
marked necrosis in the background, medium power. D. Higher magnification demonstrating an
insular pattern. The tumor cells did not express thyroglobulin, TTF-1, calcitonin, or any
neuroendocrine markers. Only cytokeratin was positive. The neoplasm strongly resembles a small
cell neoplasm but the exact morphologic type remains undetermined. This may represent an
endocrine carcinoma (clinically serum calcitonin levels were not elevated).

Insular Carcinoma versus Malignant Lymphoma

A dispersed pattern of small malignant cells in an insular carcinoma of the thyroid may be
misinterpreted as malignant lymphoma (Figs. 10.16 and 10.17 ). Nuclear molding and stretch
artifacts are not present in either of the two malignancies. The presence of increased
proliferative activity, frequent mitotic figures, and necrotic background are features common to
both. Without immunostains such as thyroglobulin and lymphoid markers, their differentiation
may be very difficult.

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Figure 10.16. FNA of a primary malignant lymphoma of the thyroid. The monomorphic cell
population of poorly differentiated lymphoid cells closely resembles cells of insular carcinoma.
The malignant lymphoma cells will react positively with leukocyte common antigen (LCA).
Figure 10.17. FNA of a primary malignant lymphoma of the thyroid showing a syncytial tissue
fragment bearing morphologic resemblance to insular carcinoma.

Insular Carcinoma versus MetastaticSmall Cell Carcinoma

Small cell carcinomas of the lung often metastasize to the thyroid (Fig. 10.18 ). Not
infrequently, a rapidly growing thyroid mass may be the only initial presenting sign of lung
carcinoma. Although the common denominator for both entities is the small cell size, insular
carcinoma cells lack the nuclear molding and stretch artifacts, a hall mark of small cell
carcinomas; but extensive necrosis and frequent mitoses are common to both. Also, small cell
carcinoma cells usually have a pleomorphic nuclear pattern with round, oval, and oblong shapes,
while insular carcinoma cells are round. Insular carcinomas as well as small cell carcinomas are
TTF-1 and cytokeratin positive; however, thyroglobulin is strongly expressed by insular
carcinomas most of the time.
Figure 10.18. A. FNA of a metastatic small cell carcinoma of the lung that presented as a
thyroid mass. The malignant cells exhibit a typical cytologic pattern of small cell carcinoma.
Note round, oval, oblong nuclei with molding. The cytoplasm is insignificant. Also note stretch
artifacts and karyorrhexis. B. The cell block of the aspirate confirming small cell carcinoma.

Insular Carcinoma versus Poorly Differentiated Metastatic

Malignancy
Poorly differentiated malignancy such as basaloid squamous cell carcinoma may be extremely
difficult to differentiate from an insular carcinoma of the thyroid. Figure 10.19 gives an example
of such a case, where both the cytologic and histologic presentations appeared to closely
resemble those of an insular carcinoma. The diagnosis of insular carcinoma was not supported by
the negative reactivity to follicular cell markers such as thyroglobulin or TTF-1. An extensive
workup confirmed a basaloid squamous cell carcinoma arising in the esophagus that had invaded
the thyroid and presented itself as a thyroid mass.

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Figure 10.19. A. FNA of a metastatic basaloid squamous cell carcinoma of the esophagus that
presented as a rapidly growing thyroid mass. The aspirate is cellular, showing syncytial tissue
fragments of small uniform malignant cells with scant cytoplasm and high N/C ratios. Note
necrosis in the background. The pattern is highly suggestive of an insular carcinoma. B. The cell
block of the aspirate showed malignant cells presenting an insular pattern and considerable
necrosis. Note the peripheral palisading (arrows) of nuclei, which is not a feature of insular
carcinoma. The differential diagnosis included insular carcinoma, medullary carcinoma, and a
metastatic small cell carcinoma. The tumor cells expressed only cytokeratin. Further
investigations revealed an infiltrating basaloid squamous carcinoma of the esophagus that
infiltrated the thyroid presenting as a goiter. (Courtesy of Mithra Baliga, MD, University of
Mississippi, Jackson.)
SUMMARY
Insular carcinomas constitute a subset of poorly differentiated thyroid carcinomas with
aggressive behavior, and they present a characteristic cytopathologic pattern. Criteria helpful in
correct identification include small monomorphic cells with a high nuclear/cytoplasmic ratio,
syncytial tissue fragments with and without a follicular pattern, and granular chromatin with
micronucleoli.

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differentiated thyroid carcinomas. Am J Surg Pathol . 1999;23:205–211.

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10.Rodriguez JM, Parrilla P, Moreno A, et al. Insular carcinoma: an infrequent subtype of

thyroid cancer. J Am Coll Surg . 1998;187:503–508.

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of the thyroid. Pathol Int . 1996;45:663–668.

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19.Ashfaq R, Vuitgh F, Delgado R, et al. Papillary and follicular thyroid carcinomas with an
insular component. Cancer . 1994;73:416–423.

20.Papotti M, Micca FB, Favero A, et al. Poorly differentiated thyroid carcinoma with
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Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 11 - Anaplastic Carcinoma

11
Anaplastic Carcinoma

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, with a rapid
onset and fatal outcome in a short period of time.1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 It
comprises 2% to 5% of thyroid malignancies; however, a higher incidence is reported in areas
with endemic goiters.1 Anaplastic thyroid carcinomas are more frequent in women, with a
male:female ratio of 1:3 to 1:4. It commonly occurs in older individuals, with a median age of 60
years, although anaplastic carcinomas can occur in younger individuals. Some patients have a
long history of goiter or a thyroid nodule. Patients with anaplastic carcinomas present with a
rapidly growing, painful neck mass and pressure symptoms, such as dysphagia, dyspnea, and
hoarseness of voice. The thyroid gland is firm to hard and fixed. The tumor is widely infiltrative
locally and metastasizes to distant organs and is rapidly fatal.

GROSS AND HISTOLOGIC FEATURES

Grossly, anaplastic carcinomas are large, bulky tumors extensively infiltrating the thyroid. The
cut surfaces are soft, fleshy, and lobulated with areas of necrosis, hemorrhage, and cystic
degeneration (Figs. 11.1 and 11.2 ). The tumor often infiltrates the perithyroidal soft tissues and
neighboring organs.
Figure 11.1. Gross photograph of an anaplastic carcinoma. The tumor is large, bulky, replacing
the entire lobe of the thyroid. Note the fleshy cut surface with necrosis and hemorrhage.
Figure 11.2. Another example of an anaplastic carcinoma. The tumor is bulky and fleshy, with a
cystic change, and is infiltrating the surrounding soft tissues.

The histomorphology of anaplastic carcinoma varies widely from tumor to tumor and sometimes
within the same tumor (Figs. 11.3 , 11.4 , 11.5 , 11.6 , 11.7 , 11.8 , 11.9 , 11.10 , 11.11 and
11.12 ).6 , 8 Three basic patterns have been described: giant cell type, spindle cell type, and
squamoid.6 One of these patterns may predominate, although a combination of varied types is
frequent.

The giant cell type (Fig. 11.3 ) is characterized by a solid growth pattern consisting of markedly
pleomorphic round to oval, large to giant-sized malignant cells containing single to multiple
bizarre nuclei with prominent nucleoli. Normal as well as abnormal mitoses are commonly
observed (Fig. 11.4 ). Their cytoplasm is variable, scant to abundant, pale to dense to granular
or clear. The giant tumor cells are often mixed with smaller mononuclear tumor cells.
Figure 11.3. Histologic section of anaplastic carcinoma showing a giant cell pattern. Note the
pleomorphic tumor cells giant with bizarre nuclei.
Figure 11.4. Histologic section of anaplastic carcinoma. The pleomorphic malignant cells have
bizarre nuclei. Note the intranuclear inclusion and quadripolar mitosis. Inflammatory cells are
present in the background.

The squamoid type of anaplastic carcinoma is composed of large, round to polygonal cells,
resembling the cells of non-keratinizing, poorly differentiated squamous carcinoma, forming a
solid growth pattern (Fig. 11.5 ). They are more uniform, occasionally showing keratinization,
and lack the typical giant tumor cells. The squamoid type anaplastic carcinoma cells contain
abundant eosinophilic cytoplasm. Both giant cell and squamoid types show prominent
vasculature with curvaceous capillaries within the neoplasm.
Figure 11.5. Histologic section of anaplastic carcinoma depicting a squamoid cell pattern.

The spindle cell pattern strongly resembles a soft-tissue sarcoma and is composed of
pleomorphic spindle cells with bizarre nuclei. Fascicles of tumor cells, a storiform pattern,
scattered tumor giant cells, and inflammatory infiltrate mimic the pattern of malignant fibrous
histiocytoma (Fig. 11.6 ). Elongated spindle-shaped tumor cells separated by collagen resemble a
fibrosarcoma. Anaplastic carcinomas often consist of a mixed giant cell and spindle cell pattern
(Fig. 11.7 ). Squamous differentiation may be present (Fig. 11.8 ).
Figure 11.6 A and B. Histologic sections of anaplastic carcinoma with a spindle cell pattern,
reminiscent of a soft-tissue sarcoma.

Figure 11.7. Histologic section of anaplastic carcinoma showing a mixed spindle cell and giant
cell pattern.
Figure 11.8. Anaplastic carcinoma with focal squamous differentiation.

Hemorrhage, necrosis, and inflammatory cell infiltrate may be seen with all cell patterns.
Anaplastic carcinomas frequently contain osteoclast-like multinucleated giant cells (Fig. 11.9
).13 , 14
Figure 11.9. Numerous osteoclast-type giant cells in an anaplastic carcinoma.

Anaplastic carcinomas generally develop from differentiated follicular/papillary thyroid cancers.

Evidence of pre-existing follicular or papillary carcinoma may be seen (Figs. 11.10 and 11.11 ).15
, 16 , 17 Anaplastic carcinomas may develop from dedifferentiation of Hürthle cell carcinoma.
Coexistence of insular and anaplastic carcinomas is also described.
Figure 11.10. A. Histologic section of anaplastic carcinoma with remnants of pre-existing
follicular carcinoma. B. Higher magnification showing malignant cells with numerous abnormal
mitoses and malignant follicles containing colloid.

Figure 11.11. Anaplastic carcinoma showing a focal area consisting of typical nuclei of a
conventional papillary carcinoma, indicating a pre-existing papillary carcinoma.

Morphologic variants of anaplastic carcinoma include the paucicellular (Fig. 11.12 )18 and
rhabdoid types.19 The paucicellular variants are characterized by extensive desmoplasia with
wide areas of collagenized fibrous tissue. Malignant cells usually of the spindle cell type are few
in number, often seen scattered within the fibrous stroma. Areas of necrosis and infarction are
also present. The paucicellular variant clinically as well as grossly mimics Riedel's thyroiditis.
Extensive fibrosis is common in both lesions. Needle biopsies, both fine and large, tend to be
either acellular or poorly cellular due to fibrosis.
Figure 11.12. Histologic sections of a paucicellular variant of anaplastic carcinoma with
desmoplastic stroma. A. The malignant sells are pleomorphic and separated by collagen. B. The
carcinoma shows extensive fibrosis widely separating few malignant spindle cells.

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The rhabdoid type is a rare morphologic variant, with only a few cases reported in the
literature. The reported cases consisted of foci of papillary or follicular carcinomas.
Histologically, the rhabdoid variant of anaplastic carcinoma shows a solid growth pattern with a
uniform, large, round cell population containing eccentric nuclei. The cytoplasm of the
malignant cells contains eosinophilic globules that are shown to contain intermediate filaments
ultrastructurally. These also stain positively with desmin and muscle-specific actin. The small
cell variant of anaplastic carcinomas described in the literature probably represents malignant
lymphoma, medullary carcinoma, or poorly differentiated "insular" carcinomas.20 , 21 , 22 , 23 ,
24 , 25

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CYTOPATHOLOGIC FEATURES
The cytopathologic features of anaplastic carcinoma are usually diagnostic on account of
neoplastic cells that present obvious malignant criteria (Figs. 11.13 , 11.14 , 11.15 , 11.16 ,
11.17 , 11.18 , 11.19 , 11.20 , 11.21 , 11.22 , 11.23 , 11.24 , 11.25 , 11.26 , 11.27 , 11.28 , 11.29
, 11.30 , 11.31 , 11.32 , 11.33 and 11.34 ).

The cellularity of the aspirates of anaplastic carcinomas depends on the histologic type as well
as the presence and extent of tumor necrosis.26 , 27 , 28 , 29 , 30 , 31 Carcinomas with a
spindle cell pattern and abundant collagenous stroma tend to be paucicellular or even acellular,
while the giant cell and squamoid types yield overwhelmingly cellular aspirates. Carcinomas with
extensive necrosis may yield unsatisfactory samples. With adequate cellularity, the cytologic
diagnosis of anaplastic carcinoma is obvious even to a novice (Fig. 11.13 ). The spectrum of
cytologic features is extremely wide, although the anaplastic nature is conspicuously apparent.
Figure 11.13. FNA of an anaplastic carcinoma, giant cell type. The neoplastic cells are discrete,
markedly pleomorphic, and clearly malignant.
Figure 11.14. FNA of an anaplastic carcinoma. The malignant cells are discrete and widely
pleomorphic. Note multinucleation and an abnormal mitosis (arrow ).
Figure 11.15. FNA of a giant cell type anaplastic carcinoma. The malignant cells are discrete
and markedly pleomorphic (Diff-Quik Stain).

Figure 11.16. A. This cellular aspirate consists of a large population of discrete malignant cells.
The pleomorphic nature and the giant cell pattern are evident even at this low power. B. Higher
magnification showing giant malignant tumor cells with inflammatory cells in the background.
Figure 11.17. FNA of an anaplastic carcinoma showing loosely cohesive, pleomorphic malignant
cells. Note occasional cells with dense cytoplasm, rigid cell borders, and central nuclei
suggesting squamous differentiation.

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The malignant cells range in size from small to giant forms reaching enormous dimensions (Figs.
11.18 , 11.19 and 11.20 ). Their shape likewise demonstrates extreme variation from round,
oval, plasmacytoid, polygonal, caudate, racket shaped, to spindle type. The malignant cells are
usually discrete, in discohesive groups, or infrequently in syncytial tissue fragments without any
architectural patterns. Arborizing blood vessels may be seen in the background. A given aspirate
may present only one cell pattern or a combination of one or more patterns.
Figure 11.18. An admixture of malignant cells exhibiting wide variation in their size and shapes.
Some are multinucleated. The background is dirty due to proteinaceous material and amorphous
debris.
Figure 11.19. These anaplastic carcinoma cells are very pleomorphic in size and shape. Some
are multinucleated. Their cytoplasm is variable and abundant. Several malignant cells are
spindle shaped.
Figure 11.20. A and B. FNA of an anaplastic carcinoma showing an admixture of small, medium-
sized, and large to giant malignant cells.

The aspirates of giant cell anaplastic carcinomas show pleomorphic giant tumor cells containing
bizarre nuclei with irregular nuclear membranes with scalloping (Figs. 11.13 , 11.14 , 11.15 ,
11.16 , 11.17 , 11.18 , 11.19 , 11.20 , 11.21 , 11.22 , 11.23 and 11.24 ). The nuclei are large with
coarsely granular to clumped, deep-staining chromatin and excessively clear parachromatin.
Nucleoli are prominent and intranuclear inclusions are often present. Exuberant mitotic activity
is reflected by the presence of both normal and abnormal mitotic figures. Multilobulation and
multinucleation are very common. The malignant cells of the giant cell type contain abundant
pale to dense and sometimes clear cytoplasm and may demonstrate emperipolesis. The dense
cytoplasm imparts a Hürthaloid appearance (Figs. 11.24 and 11.25 ). However,
ultrastructurally, mitochondria are few or absent. An admixture of pleomorphic smaller
malignant cells is often noted (Fig. 11.20A and B ).
Figure 11.21. A. The aspirate is overwhelmingly cellular, consisting of large tissue fragments of
malignant cells with dispersed cells in the background (low power). B. Higher magnification.
Note large round to spindle malignant cells with high N/C ratios. The nuclei are intensely
hyperchromatic, and irregular with multiple nucleoli.

Figure 11.22. FNA of a squamoid-type anaplastic carcinoma showing discrete large, round
malignant cells with variable cytoplasm.

Figure 11.23. FNA of a squamoid-type anaplastic carcinoma showing a syncytial tissue fragment
of malignant cells containing large nuclei and variable cytoplasm.
Figure 11.24. These malignant cells from an anaplastic carcinoma are giant sized and contain
abundant dense cytoplasm with a Hürtheloid appearance.
Figure 11.25. Another example of anaplastic carcinoma cells with dense cytoplasm presenting a
Hürtheloid appearance.

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The squamoid type of anaplastic carcinomas yield cellular aspirates composed of medium to
large, malignant cells occurring discrete, in loosely cohesive groups, or in syncytial tissue
fragments without any architectural patterns (Figs. 11.22 and 11.23 ). The malignant cells are
round to polygonal with appreciable pale to dense cytoplasm. Squamous differentiation and
keratinization may be focally evident.

The carcinoma cells in the spindle cell type of anaplastic carcinoma vary in numbers and may
present as discrete cells, in aggregates, or as syncytial tissue fragments occasionally forming
fascicles (Figs. 11.26. , 11.26. and 11.28 ). The cell borders may be poorly to well defined. The
nuclei vary from round, oval, and elongated to spindle shape, often with irregular nuclear
membranes. The nuclear features are similar to those seen in the giant cell type. With marked
desmoplasia, the aspirate may yield fragments of collagenized stroma in which discrete
malignant cells are embedded and may be difficult to recognize (Fig. 11.27C and D ).
Figure 11.26. A. This marginally cellular aspirate from a spindle cell–type anaplastic
carcinoma showed only a few tissue fragments of malignant cells (low power). B. Higher
magnification demonstrating malignant spindle cells varying widely in size. Note bizarre nuclear
pattern, variable cytoplasm and cytoplasmic processes. The cytomorphologic pattern is
reminiscent of a soft-tissue sarcoma.
Figure 11.27. A. FNA of a spindle cell anaplastic carcinoma consisting of several tissue
fragments of malignant cells. B. Higher magnification depicting pleomorphic malignant cells
with numerous spindle forms (Diff-Quik stain). C. Same aspirate stained by Papanicolaou stain,
depicting several large tissue fragments of stromal tissue with spindle-shaped malignant cells
embedded in the collagenized tissue. D,E. Different fields showing more cellular areas with
pleomorphic malignant spindle cells. F. Same aspirate stained by hematoxylin and eosin. Note
collagen separating the neoplastic spindle cells with bizarre nuclei. (Courtesy of Mithra Baliga,
MD, University of Mississippi, Jackson.)

Figure 11.28. FNA of a poorly cellular aspirate of a spindle cell anaplastic carcinoma. The
malignant cells are pleomorphic with long cytoplasmic processes. The nuclei are clearly
malignant.

Osteoclast-type multinucleated giant cells have been described in some anaplastic carcinoma
(Fig. 11.29 ).32 , 33 , 34 , 35 The background usually shows necrosis, inflammation, and tumor
diathesis with cellular debris. Extensive necrotic debris may obscure the isolated malignant cells
and result in a false-negative diagnosis (Fig. 11.34 ).
Figure 11.29. A–C. FNA of an anaplastic carcinoma depicting osteoclast-like multinucleated
giant cells. Note that their nuclei are small, round to oval, uniform, with finely granular
chromatin, and appearing very bland. D. Histologic section of the anaplastic carcinoma showing
the osteoclast-like multinucleated giant cells.

The clear cell variant (Fig. 11.30 ) demonstrates malignant cells with cytologic features of giant
cell type anaplastic carcinoma with clear cytoplasm, appreciated better in histologic sections
than in cytologic preparations. Their nuclei are often seen as naked due to disruption of the cell
membranes and cleared cytoplasm. The cytoplasm is abundant and often very pale.

Figure 11.30. A. Histologic section of an anaplastic carcinoma with a clear cell pattern. B–D.
FNA of this carcinoma. The malignant cells contain variable, pale to clear cytoplasm with bizarre
nuclei. Because of the clear cytoplasm, some cells appear as bare nuclei.
The paucicellular variant, because of the extensive desmoplastic stroma, tends to yield poorly
cellular aspirate, predominantly consisting of pleomorphic spindle-shaped malignant cells (Fig.
11.31 ).36 The rhabdoid type shows undifferentiated malignant cells containing abundant
cytoplasm with vimentin-positive globules (Fig. 11.32 ), which ultrastructurally contain whorls of
filaments (Fig. 11.32D and E ).37 The aspirates may also include cellular features of a pre-
existing follicular/ Hürthle cell, papillary carcinoma, or an insular carcinoma (Fig. 11.33 ).17 ,
18 , 37 , 38
Figure 11.31. Anaplastic carcinoma, rhabdoid variant. A. Cellular aspirate depicting discrete
malignant cells with large pleomorphic eccentric nuclei and variable dense cytoplasm. B. Scrape
cytology of the resected tumor showing medium to large-sized plasmacytoid malignant cells with
dense cytoplasm. The cells appear uniform. H&E stain. C. Histologic section of the resected
tumor. Medium-power view, showing a solid growth pattern. D. Higher magnification. The
malignant cells are medium sized, round to polygonal, with an appreciable amount of
eosinophilic cytoplasm. Note eosinophilic cytoplasmic globules (arrows ). E. Ultrastructure
showing cytoplasmic globule of filaments (arrows ). F. Higher magnification showing
intermediate filaments with a whorled pattern.

Figure 11.32. Paucicellular variant of anaplastic carcinoma. Three attempts at fine-needle

biopsy of the hard, fixed enlarged thyroid in a 41-year-old male failed to yield an adequate
aspirate. From over 40 smears from three aspirates, rare but pleomorphic spindle and giant cells
were identified that raised a question of anaplastic carcinoma. The surgical resection showed a
paucicellular anaplastic carcinoma with considerable desmoplasia, explaining the difficulties in
obtaining an adequate aspirate. A–D. The malignant cells are discrete, highly pleomorphic
with variable cytoplasm, spindle to giant forms. E. An aggregate of pleomorphic spindle cells
was the only finding in one of the aspirates. Histologic section of the resected tumor confirmed
anaplastic carcinoma with marked desmoplasia (please refer to Fig. 11.12 ).

The cytologic features of anaplastic carcinoma are listed in Table 11.1 and illustrated in Figs.
11.13 , 11.14 , 11.15 , 11.16 , 11.17 , 11.18 , 11.19 , 11.20 , 11.21 , 11.22 , 11.23 , 11.24 , 11.25
, 11.26 , 11.27 , 11.28 , 11.29 , 11.30 , 11.31 , 11.32 , 11.33 and 11.34 .
Cellularity
Variable; usually very cellular; low in paucicellular variant or
necrotic tumors
Presentation
Malignant cells isolated, in loosely cohesive groups, or in syncytial
tissue fragments without any architectural patterns
Cells
Extremely pleomorphic in size and shape; small to giant forms;
round, polygonal, spindle shaped, caudate, tadpoles; well to
poorly defined cell borders; N/C ratios variable, usually high
Nucleus
Large to giant sized; round, elongated to spindle shaped;
bizarre forms; bi-multinucleation frequent; deep staining
coarsely granular to clumped chromatin with excessive
parachromatin clearing; multiple micro-macronucleoli;
intranuclear cytoplasmic inclusions; mitotic figures +
Cytoplasm
Variable; scant to abundant; clear, pale, vacuolated to dense;
emperipolesis frequent
Background
Cellular and necrotic debris; acute inflammatory cells ±;
osteoclast-like giant cells ±
Features of pre-existing
papillary, follicular, or
insular carcinoma
May be present, depending on the sampling
Immunoprofile
Almost always negative reactivity to thyroglobulin and TTF-1;
positive reactivity to cytokeratin and vimentin

TABLE 11.1 CYTOPATHOLOGIC FEATURES OF ANAPLASTIC

CARCINOMA
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IMMUNOPROFILE
Several studies on reactivity of various antibodies have indicated that anaplastic carcinoma cells
fail to react to thyroglobulin in almost all cases.39 , 40 , 41 , 42 , 43 , 44 Keratin is the most
useful marker, as it is consistently positive. Carcinoembryonic agent (CEA) and epithelial
membrane antigen (EMA) are of limited diagnostic value. Anaplastic carcinoma cells are also
non-reactive to calcitonin and leukocyte common antigen (LCA). However, all these stains are
useful in differentiating anaplastic carcinomas from several other poorly differentiated
neoplasms.

DIAGNOSTIC ACCURACY AND DIFFERENTIAL DIAGNOSIS

With adequate cellularity, the cytologic presentation of anaplastic carcinomas in fine-needle
aspirates usually offers no diagnostic challenge. The diagnostic accuracy is reported in the range
of 85% to 90%.26 False-negative diagnosis results from inadequate aspirate usually from
paucicellular spindle cell variants containing excessive collagenized stroma.45 Extensive necrosis
may also result in a false-negative diagnosis, as the single malignant cells obscured by the
inflammatory and cellular debris preclude the diagnosis. Sampling of only a pre-existing
differentiated cancer in anaplastic carcinoma is another reason for a missed diagnosis. Up to 71%
of anaplastic carcinomas arise as dedifferentiation of an existing differentiated carcinoma,
either follicular or papillary.7 , 16 , 17 The cytologic samples may or may not contain both
components (Fig. 11.33 ).16 , 37 , 38 Unlike a surgically resected specimen that allows careful
inspection and examination of multiple areas, cytologic interpretation is based only on the area
sampled by the biopsy needle, an important limitation of fine-needle biopsy.
Figure 11.33. FNA of an anaplastic carcinoma that de-differentiated from a follicular
carcinoma. The aspirate contained both components, which were correctly identified. A. Low-
power view of the overwhelmingly cellular aspirate showing large tissue fragments of malignant
cells with branching and anastomosing. The spindle cell nature is apparent at this magnification.
B. A different field from the same case showing a syncytial tissue fragment of large
undifferentiated malignant cells. C. Yet another field showed a very different cytologic pattern.
Note a very cellular field containing smaller cells, discrete and in syncytial tissue fragments with
a follicular pattern. Their enlarged, crowded, and overlapped nuclei contain granular chromatin
and nucleoli. The background is clean. The cytologic presentation is consistent with follicular
carcinoma. The surgical resection showed an anaplastic carcinoma with varied histologic
patterns that included follicular carcinoma, an insular pattern, and anaplastic carcinoma with a
mixed spindle cell and giant cell pattern.
Figure 11.34. A. FNA of a rapidly growing thyroid mass in an elderly woman with a history of
long-standing goiter, contained predominantly inflammatory and cellular debris obscuring rare
pleomorphic malignant cells (arrows ) (low power). B. Two malignant cells with cytoplasm
distended with neutrophils referred to as emperipolesis. The neutrophils have completely
masked the nuclei. C. A discrete racket-shaped malignant cell in the background of
inflammatory cells. D. An isolated giant tumor cell with abundant dense cytoplasm and rigid cell
border. The surgical excision confirmed an anaplastic carcinoma with extensive necrosis.

In general, the characteristic cytomorphology of anaplastic carcinoma with extreme

pleomorphism of the malignant cells containing bizarre nuclei lends itself to accurate diagnosis
and cannot be misinterpreted as any other neoplasm. The converse is not true. Several types of
benign cells46 as well as some malignant neoplasms may be misinterpreted as anaplastic
carcinoma (Table 11.2 ). Benign cells that can be misinterpreted as anaplastic carcinoma include
proliferating fibroblasts and stromal tissue fragments in Riedel's as well as subacute thyroiditis
(see Chapter 18 for a detailed discussion on spindle cells in thyroid aspirates). Degenerative
changes in the benign follicular cells in nodular goiters, or radiation-induced changes, may also
mimic anaplastic carcinoma cells.
Thyroiditis
Acute thyroiditis with abscess
Subacute or granulomatous thyroiditis
Fibrous variant of Hashimoto's thyroiditis
Riedel's thyroiditis
Nodular goiter
Proliferating fibroblasts from granulation tissue
Degenerating follicular cells in nodular goiter
Radiation-induced changes
Megakaryocytes from ossified cartilage
Medullary thyroid carcinoma
Poorly differentiated primary squamous cell carcinoma
Poorly differentiated metastatic carcinomas
Malignant lymphoma
Malignant melanoma
Soft-tissue sarcomas (primary and secondary)

TABLE 11.2 DIFFERENTIAL DIAGNOSIS OF ANAPLASTIC

CARCINOMA
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Acute infections with abscess are uncommon examples that masquerade clinically as anaplastic
carcinoma. Rarely, megakaryocytes aspirated from the laryngeal or thyroid cartilage may be
mistaken for anaplastic carcinoma. Malignant neoplasms mistyped as anaplastic carcinoma
include medullary thyroid carcinoma, malignant lymphoma, poorly differentiated primary
squamous carcinoma, poorly differentiated metastatic carcinomas, metastatic malignant
melanoma, and soft-tissue tumors. The cytologic features of various diagnostic entities in the
differential diagnosis of anaplastic carcinoma are listed in Table 11.3 .

Acute thyroiditis
Acute inflammatory (neutrophilic) exudate; histiocytes;
 cellular and necrotic debris
11.35
Subacute (granulomatous
thyroiditis)
Large numbers of multinucleated foreign-body type giant
cells, some enormously large with multiple, uniform
nuclei in tens and hundreds; often seen in the vicinity
of blobs of colloid, forming granuloma, epithelioid
cells ±; varying numbers of spindle cells with bland
nuclei, tissue fragments of stroma; benign follicular and
Hürthle cells with or without nuclear atypia; lymphocytes
in the background; neutrophils and cellular debris in
acute phase
11.36
Riedel's thyroiditis
Acellular aspirate; no follicular cells; stromal tissue
fragments; spindle cells, lymphocytes
Nodular goiter
Degenerating follicular cells with marked nuclear atypia,
11.39
with pyknosis; spindle shaped cells with bland nuclear
chromatin; nuclear inclusions and grooves ±
11.40
Radiation-induced
Pleomorphic follicular cells with spindle shapes; stromal
11.41
changes
spindle cells, bland nuclear chromatin or with
degenerative changes with pyknosis; bare nuclei in
the background
11.42
Megakaryocytes
Pleomorphic, large with multilobulated (not multinucleated)
nuclei with clumped chromatin; hematopoietic cells in
 the background
11.43
Medullary thyroid
Pleomorphic cell pattern with spindle and large polygonal
11.44
carcinoma
cells; spindle cells may be in fascicles; high N/C ratios;
dense cytoplasm; coarsely granular chromatin; nuclear
inclusions +; nucleoli inconsistent; grooves –; mitotic
activity not present; background clean; amyloid +;
neoplastic cells reactive to calcitonin
11.45
Poorly differentiated
primary squamous
carcinoma
Medium to large malignant cells, isolated, in loosely
cohesive groups and in syncytial tissue fragments;
undifferentiated cytoplasm; clearly malignant nuclei
with nucleoli; mitotic activity +; cellular and necrotic
debris ±; negative reactivity to thyroglobulin; positive
reactivity to cytokeratin
11.46
Poorly differentiated metastatic
carcinomas
Malignant cells pleomorphic; clearly malignant nuclei;
mitotic activity +; cytoplasm with no differentiating
features; immunostains necessary to identify the origin
11.47 to 11.49
Malignant large cell
lymphoma
Medium-sized round cells with scant cytoplasm; round
nuclei with granular chromatin, parachromatin clearing,
multiple nucleoli; mitotic activity brisk; karyorrhexis +;
LCA +
11.53
Malignant melanoma
Pleomorphic malignant cell population; fine to coarsely
granular chromatin; macronucleoli; mitosis +, nuclear
inclusions +; melanin pigment in the cytoplasm ±; HMB
45-positive reactivity
11.52
Soft-tissue sarcomas (primary
or secondary)
Spindle cell population, cells discrete or in fascicles;
pleomorphism common; nuclear morphology depending
on the type of neoplasm and range from bland to clearly
malignant; mitotic activity ±; negative reactivity
to thyroglobulin and cytokeratin; positive to vimentin
and soft-tissue tumor markers (muscle-specific actin,
HHF 35, Desmin)
11.54
Anaplastic carcinoma
Extremely pleomorphic malignant cell population, ranging
11.13
from medium-sized to large and giant forms; round,
11.16
polygonal, to spindle shape; discrete, in groups, or in
11.17
syncytial tissue fragments with no architectural patterns;
large nuclei, often with irregular outlines; coarsely granular
chromatin with excessive parachromatin clearing; multiple
micro/macronucleoli; mitotic activity +; intranuclear inclusions +
11.26

Diagnostic Entity Cytopathologic Features See Fig(s).

TABLE 11.3 DIFFERENTIAL DIAGNOSIS OF ANAPLASTIC

CARCINOMA CYTOLOGIC FEATURES
Anaplastic Carcinoma versus Acute Thyroiditis with Abscess
Acute infection of the thyroid with an abscess formation is not a common occurrence. Both
acute infection, as well as anaplastic carcinoma may be extremely painful and especially in
older individuals anaplastic carcinoma is certainly a consideration. FNA biopsy will show acute
inflammatory exudate and must be differentiated from a necrotic anaplastic carcinoma with
inflammatory and cellular debris (Fig. 11.35 ). The aspirate of the abscess will not contain any
epithelial cells. However, the plump histiocytes may offer some diagnostic difficulties. Actively
proliferating fibroblasts from the granulation tissue in these cases may also be a diagnostic
problem.

Figure 11.35. Anaplastic carcinoma versus an acute abscess . A,B. FNA of a painful thyroid mass
showing heavy neutrophilic infiltrate and a large multinucleated cell, and histiocytes. C. The
surgical excision revealed an abscess and granulation tissue.

Anaplastic Carcinoma versus Riedel's Thyroiditis

The paucicellular variant of anaplastic carcinoma with excessive collagenized stroma will mimic
Riedel's thyroiditis. Both are hard to palpate and fixed to the deeper and surrounding tissues.
Aspirates of both lesions may yield only fragments of fibrous tissue. The stromal spindle cells
from Riedel's thyroiditis will show a bland nuclear pattern in contrast to anaplastic carcinoma
cells.18

Anaplastic Carcinoma versus Subacute or Granulomatous

Thyroiditis
Subacute or granulomatous thyroiditis, a self-limiting condition, presents with severe discomfort
in the thyroid area. The onset is usually sudden. When the condition occurs in an elderly
patient, a fine-needle biopsy may be performed to exclude an anaplastic carcinoma. Fascicles of
spindle cells of stromal origin (Fig. 11.36 ) may be misleading, and the multinucleated foreign-
body type giant cells may be interpreted as osteoclast-type giant cell, thus supporting the
diagnosis of spindle cell type anaplastic carcinoma. The benign stromal cells do not possess the
bizarre nuclei that are so characteristic of anaplastic carcinoma.

Figure 11.36. Anaplastic carcinoma versus subacute or granulomatous thyroiditis . FNA of a

painful, extremely tender, diffusely enlarged thyroid in a 70-year-old woman. A. The large
anastomosing bundles of spindle cells suggested anaplastic carcinoma. The large multinucleated
giant cell (arrow ) was overlooked. B. The bland nuclear pattern is inconsistent with the
diagnosis of anaplastic carcinoma. Higher magnification. Two weeks following the biopsy, the
thyroid enlargement subsided and the tenderness disappeared.

Anaplastic Carcinoma versus Degenerating Follicular Cells

from Nodular Goiter
Degenerating follicular cells in nodular goiters may exhibit conspicuous cellular changes that
include cytokaryomegaly with bizarre nuclear pattern (Figs. 11.37 and 11.38 ). These changes
are usually focal and occur in the background features of nodular goiter.
Figure 11.37. Anaplastic carcinoma versus nodular goiter . A. Degenerating follicular cells may
exhibit cellular and nuclear enlargement with micronucleoli and may appear worrisome. Such
cells are usually small in numbers and occur in the background of benign follicular cells. B. The
anaplastic carcinoma cells for comparison. Note the morphologic similarity to the degenerating
follicular cells. Anaplastic carcinomas do not show features of nodular goiter in the background.
C. FNA of a nodular goiter showing an isolated group of large round cells with atypical nuclei.
Some contain intranuclear inclusions. Their cytoplasm is abundant and foamy.
Figure 11.38. Anaplastic carcinoma versus nodular goiter . A. FNA of an enlarged nodular
thyroid lobe in a 70-year-old woman with a history of contralateral thyroid lobectomy in the
remote past for a nodular goiter. The aspirate was paucicellular, consisting of a few groups of
pleomorphic cells. Note small to large cells with an occasional giant form. Their nuclei are
likewise pleomorphic, ranging from round, oval, and oblong to short and spindle shaped with
some exhibiting nuclear notches. The chromatin is granular and nucleoli can be appreciated. The
exact origin of these cells is uncertain but may represent an admixture of reactive follicular
cells and stromal cells. B. Another group from the same smear is more consistent with stromal
cells. With a cytologic diagnosis of anaplastic carcinoma, lobectomy was performed, which failed
to confirm the diagnosis. C. An aspirate of anaplastic carcinoma for comparison.

Anaplastic Carcinoma versus Proliferating Fibroblasts from

Granulation Tissue in a Nodular Goiter with Hemorrhage
The actively proliferating spindle-shaped fibroblasts sometimes present an alarming cytologic
appearance that may lead to a malignant diagnosis such as anaplastic carcinoma of spindle cell
type. Their nuclei, however, contain finely granular chromatin and contain micronucleoli. The
cytoplasm of fibroblasts is usually abundant with low N/C ratios. Anaplastic carcinoma cells are
more pleomorphic with clearly malignant features (Figs. 11.39 and 11.40 ).

Figure 11.39. Anaplastic carcinoma versus proliferating granulation tissue . A. FNA of painful
solitary thyroid nodule with rapid enlargement. Note very pleomorphic cells highly suggestive of
anaplastic carcinoma. B. The presence of benign follicular cells in the background should have
been a clue for exercising caution in rendering a malignant diagnosis. C. Thyroidectomy revealed
hemorrhage, organization with proliferating fibroblasts, in a nodular goiter. D. Anaplastic
carcinoma with a spindle cell pattern for comparison. Hemorrhage within a nodule is a frequent
cause for painful thyroid.

Figure 11.40. Anaplastic carcinoma versus proliferating granulation tissue . A. FNA of a nodular
goiter representing another example of actively proliferating fibroblasts. The spindle-shaped
cells are in fascicles, containing round to oval nuclei with finely granular chromatin and
micronucleoli. The N/C ratios are low. Note the uniformity, clean background. The other smears
from the same aspirate showed features of nodular goiter. B. Anaplastic carcinoma for
comparison. The malignant cells are round to spindle shaped, less cohesive, and with larger
nuclei and high N/C ratios. The chromatin is coarsely granular and hyperchromatic. Note the
inflammatory background.

Anaplastic Carcinoma versus Radiation-Induced Changes in

Benign Follicular Cells
Radioactive iodine used for treating Grave disease may have residual effect on the follicular
cells. These changes include cytokaryomegaly, with clumped chromatin, intranuclear inclusions,
presence of nucleoli, and leukophagocytosis (Figs. 11.41 and 11.42 ). These changes may be
pronounced, mimicking anaplastic carcinoma.
Figure 11.41. Anaplastic carcinoma versus radiation induced changes . Pleomorphic follicular
cells with bizarre nuclei. The patient had131 I therapy for Graves disease. Without taking the
clinical information into account, these cells may be interpreted as anaplastic carcinoma.
Figure 11.42. Anaplastic carcinoma versus radiation-induced changes . Another example of
radiation-induced changes. The naked nuclei of the follicular cells are enlarged and contain
smudgy chromatin. They appear similar to the bare nuclei seen in an aspirated anaplastic
carcinoma with clear cell change (Fig. 11.30 D).

Anaplastic Carcinoma versus Megakaryocytes

On rare occasions, the needle may inadvertently target the ossified thyroid cartilage containing
hematopoietic tissue. The dispersed megakaryocytes with their giant size and lobulated nuclei
mimic anaplastic carcinoma cells (Fig. 11.43 ). The megakaryocytes, however, lack the
malignant criteria exhibited by anaplastic carcinoma cells (Fig. 11.43 ). Also, the clinical data
and the presenting symptoms are not consistent with the diagnosis of anaplastic carcinoma.
Figure 11.43. Anaplastic carcinoma versus hematopoietic cells . A,B. An FNA of a large thyroid
mass in an 80-year-old man yielded a marginally cellular aspirate predominantly consisting of
varying-sized large to giant cells with single to multilobulated nuclei. These are megakarycytes,
inadvertently aspirated from ossified thyroid cartilage, which has developed foci of
hematopoietic tissue. These megakaryocytes are easily interpreted as anaplastic carcinoma in a
right clinical setting as in this case. C,D. Discrete anaplastic carcinoma cells for comparison.
Note the nuclei are clearly malignant with coarsely granular chromatin, excessive parachromatin
clearing and macronucleoli.

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Anaplastic Carcinoma Versus Medullary Thyroid Carcinoma

Medullary carcinoma of the thyroid presents a characteristic cytologic pattern allowing an easy
recognition. The nuclei of the medullary carcinoma cells have a typical neuroendocrine
chromatin pattern that is rather uniform. Occasionally, medullary carcinoma cells may be very
pleomorphic, simulating a pattern of anaplastic carcinoma (Figs. 11.44 and 11.45 ).39
Immunostains are required for establishing a correct diagnosis.

Figure 11.44. Anaplastic carcinoma versus medullary carcinoma . FNA of a medullary carcinoma
depicting a very pleomorphic cell pattern that can be misinterpreted as anaplastic carcinoma.

Figure 11.45. Anaplastic carcinoma versus medullary carcinoma . A. FNA of an irregularly and
massively enlarged thyroid in an 80-year-old man showing pleomorphic cell pattern with spindle
and large round cells suggesting the diagnosis of anaplastic carcinoma. The differential diagnosis
included anaplastic and medullary carcinomas. B. Another field from the same case revealed the
malignant cells with eccentric nuclei, intranuclear inclusions, and appreciable cytoplasm, raising
the possibility of a medullary carcinoma. C. A strongly positive calcitonin stain on the aspirate
smear confirmed the diagnosis of medullary carcinoma. D. Histologic section of the resected
thyroid with medullary carcinoma demonstrating a round cell pattern (arrows ) and a
predominant spindle cell pattern (arrowheads ). E. Histologic section with strong positive
reactivity to calcitonin.

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Anaplastic Carcinoma versus Poorly Differentiated Primary

Squamous Carcinoma
Primary squamous carcinomas of the thyroid are very uncommon. However, when they do occur,
an accurate typing is difficult especially when squamous differentiation is not apparent in the
malignant cells (Fig. 11.46 ). Immunostains are not helpful in differentiating the two neoplasms,
because both will be strongly reactive to cytokeratin and anaplastic thyroid carcinomas are
usually nonreactive to thyroglobulin.1
Figure 11.46. Anaplastic carcinoma versus primary poorly differentiated squamous carcinoma .
FNA of a primary poorly differentiated squamous cell carcinoma of the thyroid showing
pleomorphic malignant cells that do not exhibit any architectural or cytoplasmic squamous
differentiation. These cannot be differentiated from an anaplastic carcinoma.

Anaplastic Carcinoma versus Metastatic Poorly

Differentiated Carcinomas
Metastatic poorly differentiated carcinomas, whether squamous or adenocarcinomas, may pose a
diagnostic dilemma, especially when a primary site is not known (Figs. 11.47 and 11.48 ). Poorly
differentiated carcinomas arising from the neighboring organs such as esophagus or larynx may
clinically present as thyroid masses and may be misinterpreted as anaplastic carcinomas (Figs.
11.49 , 11.49 and 11.51 ). Differentiation between the two is not possible from cytomorphology
alone.
Figure 11.47. Anaplastic carcinoma versus metastatic malignancy . FNA of a poorly
differentiated metastatic adenocarcinoma of the lung presenting as a thyroid nodule. In the
absence of benign follicular cells in the background, these cells must be differentiated from an
anaplastic thyroid carcinoma.
Figure 11.48. Anaplastic carcinoma versus metastatic malignancy . Another example of a poorly
differentiated adenocarcinoma of the lung metastatic to the thyroid.
Figure 11.49. Anaplastic carcinoma versus metastatic malignancy . Poorly differentiated
metastatic squamous cell carcinoma presenting as a solitary nodule. From cytology alone, these
poorly differentiated malignant cells cannot be differentiated from anaplastic thyroid
carcinoma. The patient had a history of squamous carcinoma of the upper aerodigestive tract.
Figure 11.50. Anaplastic carcinoma versus metastatic malignancy . Poorly differentiated
squamous carcinoma of the esophagus extending into and infiltrating the thyroid clinically
presenting as a thyroid mass. FNA biopsy depicting pleomorphic malignant cells with no
cytoplasmic differentiation.
Figure 11.51. Anaplastic carcinoma versus metastatic malignancy . FNA of a carcinosarcoma of
the esophagus infiltrating into the thyroid, presenting primarily as a thyroid mass. A combination
of spindle-shaped and large round malignant cells suggested the diagnosis of anaplastic thyroid
carcinoma. Further workup identified the esophageal primary.

Anaplastic Carcinoma versus Malignant Melanoma

Malignant melanoma commonly metastasizes to the thyroid. Melanin pigment and a history of
melanoma allow accurate diagnosis. The problem arises when the melanoma cells are
amelanotic and cytologically difficult to separate from anaplastic thyroid carcinomas (Fig. 11.52
).
Figure 11.52. Anaplastic carcinoma versus metastatic malignant melanoma . FNA of metastatic
melanoma to the thyroid. Melanoma cells can be very pleomorphic with bizarre nuclei. In the
absence of melanin pigment, melanoma cells cannot be differentiated from anaplastic
carcinoma cells without the aids of ancillary tests.

Anaplastic Carcinoma versus Malignant Lymphoma

Anaplastic carcinomas are known for their wide spectrum of cytomorphology. One of the
patterns include small to medium-sized cells with scant cytoplasm and high N/C ratios,
P.254
a pattern difficult to differentiate from that of a large cell malignant lymphoma (Fig. 11.53 ).
Shvero and co-workers39 reclassified 3 of 26 anaplastic carcinomas as malignant lymphomas.
Ancillary tests such as immunostains and flow cytometry are necessary to establish a correct
diagnosis.
Figure 11.53. Anaplastic carcinoma versus malignant lymphoma . A,B. Two separate examples
of large cell malignant lymphomas of the thyroid. These discrete large lymphoma cells must be
differentiated from anaplastic carcinoma by immunostains and flow cytometry.

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Anaplastic Carcinoma versus Soft-Tissue Sarcomas (Primary

and Secondary)
Anaplastic carcinomas with a spindle cell pattern simulate cytologic features of soft-tissue
malignancy, both primary and secondary. Shvero et al.39 reclassified 1 of 26 cases of anaplastic
carcinoma as hemangioendothelioma. Primary soft-tissue sarcomas of the thyroid are extremely
rare. A history of sarcoma is helpful for proper cytologic evaluation (Figs. 11.54 and 11.55 ).

Figure 11.54. Anaplastic carcinoma versus soft-tissue tumors (primary and metastatic) . FNA of
a metastatic retroperitoneal malignant fibrous histiocytoma. The isolated spindle-shaped cells
mimic the cytologic pattern of a paucicellular anaplastic carcinoma.
Figure 11.55. Anaplastic carcinoma versus soft-tissue tumors (primary and metastatic) . FNA of
a laryngeal chondrosarcoma clinically presenting as a thyroid nodule. A. Delicate spindle cells in
a myxoid stroma. B,C. Bizarre, pleomorphic giant malignant cells with dense cytoplasm strongly
resemble an anaplastic carcinoma. The excision confirmed a chondrosarcoma.

SUMMARY
Anaplastic or undifferentiated carcinoma of the thyroid is one of the most lethal malignancies,
which follows a rapid, aggressive course with fatal outcome. The cytologic features are easily
recognized, causing no diagnostic problems. However, many other poorly differentiated
neoplasms and non-neoplastic disease entities may be cytologically mistaken for anaplastic
carcinoma. Anaplastic carcinomas usually do not react to thyroglobulin antibodies, but do react
to cytokeratin.

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13.Esmaili JM, Hafez GR, Warner TFCS. Anaplastic carcinoma of the thyroid with osteoclast-
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anaplastic thyroid tumors. J Clin Pathol . 1985;38: 893–896.

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Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 12 - Medullary Carcinoma

12
Medullary Carcinoma

Medullary carcinoma of the thyroid arises from the calcitonin-producing "C-cells," "parafollicular
cells," or "clear cells."1 In 1951, Horn2 recognized this thyroid carcinoma as a distinct and
separate entity from other differentiated carcinomas by noting the differences in histologic
patterns and their biologic behavior. Hazard et al.3 identified the amyloid in the stroma of this
neoplasm and coined the term medullary carcinoma . Williams,1 later in 1965, identified the
cell of origin. A considerable interest in this tumor, leading to extensive studies and advances in
understanding the pathogenesis of medullary carcinoma, followed this observation.4 , 5 , 6 , 7 ,
8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18

Medullary carcinoma comprises 3% to 10% of all thyroid malignancies.4 , 5 , 6 It occurs in two

forms; roughly 20% are familial forms and the remaining are sporadic forms. The hereditary form
of medullary carcinoma, transmitted as an autosomal dominant trait, includes three types: MEN
IIA, MEN IIB, and non-MEN familial type. The MEN II syndromes are associated with tumors of the
other endocrine organs.4 , 5 , 6 , 15 , 16 , 17

The sporadic form of medullary carcinoma occurs more commonly in women, primarily in the
older individuals with the mean age of 5 to 6 decades. They clinically present as a unilateral
palpable nodule and have a high incidence (up to 50%) of cervical lymph node metastases.6
Distant metastases via hematogenous spread to liver, lungs, bone, and occasionally to brain
occur in roughly 15% of the cases. Occult medullary carcinomas with local metastatic disease
involving the cervical lymph nodes have been described.7

The familial forms are common in males and occur at a younger age. The non-MEN familial
medullary carcinoma is slightly more common in women.5 Medullary carcinomas in general
project good clinical outcome, especially in sporadic forms. Aggressive clinical behavior with
fatal outcome is described in some hereditary forms.

Medullary carcinomas arise from C-cells, which originate from the neural crest via migration
through the ultimobranchial body.1 The ultimobrancial body is located in the middle and upper
thirds of the lateral lobes, and so medullary carcinomas are only found in these locations and
not in the isthmus or the extreme uppe r or lower thirds of the lateral lobes. C-cells are not
visualized in routinely stained histologic or cytologic preparations.

The main secretory product of the C-cells is the hormone calcitonin, increased levels of which
serve as a sensitive marker for the presence of medullary carcinomas.1 , 18 C-cell hyperplasia is
considered a precursor lesion for medullary carcinomas (Fig. 12.4 ).
Figure 12.4. A. Histologic section of a thyroid demonstrating C-cell hyperplasia. Note well-
defined nests of cuboidal to polygonal cells in between the thyroid follicles. There was no grossly
visible tumor. The patient had several members of the family with hereditary-type medullary
carcinoma. B. Higher magnification. These cells have abundant eosinophilic cytoplasm. C.
Imprint of the surgically resected specimen showing discrete C-cells with plasmacytoid
appearance.

RADIOLOGIC FINDINGS
Medullary carcinomas present as hypofunctioning cold nodules. The plain x-rays of the neck may
show dense calcification. Ultrasound shows hypoechoic mass. Imaging with ultrasonography
using131 I metaiodobenzylguanidine (MIBG) demonstrates a positive uptake and is a useful
diagnostic tool.5

Gross and Histologic Features

The sporadic form of medullary carcinoma occurs as a unilateral, well-defined, nonencapsulated
solitary nodule variable in size, ranging from less than 1 cm to several centimeters and may
replace the entire lobe (Figs. 12.1 and 12.2 ). Its cut surface is tan-white to gray or pink, usually
flat. The consistence is soft to firm, at times gritty, and without areas of hemorrhage and
necrosis. Calcification may be present. The hereditary forms are usually multifocal and bilateral
(Fig. 12.3 ).

Figure 12.1. A gross photograph of a nonfamilial (sporadic) form of medullary thyroid carcinoma
located in the middle third of the lobe and lymph node metastasis.
Figure 12.2. This nonfamilial medullary carcinoma is large, replacing the entire right lobe. The
tumor presents a flat cut surface.
Figure 12.3. An example of hereditary medullary carcinoma. Note that the tumor is located in
the middle third of the lobe and bilateral.

The histologic spectrum of medullary carcinoma is extremely wide and varies from tumor to
tumor and within the same tumor, often mimicking other types of follicular cell–derived
tumors such as follicular, papillary, insular, Hürthle–cell, or anaplastic carcinomas (Figs.
12.5 , 12.6 , 12.7 , 12.8 , 12.9 , 12.10 , 12.11 , 12.12 , 12.13 , 12.14 , 12.15 , 12.16 , 12.17 ,
12.18 , 12.19 , 12.20 and 12.21 ).4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19
, 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 The histologic patterns are similar in both the
familial type and the sporadic type. Medullary carcinoma shows multiple growth patterns such as
lobular, insular, trabecular, solid, and rarely follicular or papillary. The spindle cells form
fascicles, simulating a sarcomatous pattern. The nests of tumor cells vary in size, separated by
stromal tissue, imparting an organoid pattern. The cell types vary as well, and include small
round to oval carcinoid-like cells, polygonal, or epithelioid, plasmacytoid to spindle shape, and
vary considerably in size from small to large with occasional giant forms. Their cell borders are
well to poorly defined, and the cytoplasm varies from scant to abundant, clear,
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pale to dense. Some may contain mucin.5 , 6 , 28 The nuclei are pleomorphic, round, oval,
oblong to spindle shape with stippled to coarsely granular chromatin and sometimes contain
cytoplasmic inclusions. Hemorrhage, necrosis, and mitotic activity are infrequent findings. A
given tumor may show a predominant cell type or pattern; mixed patterns are more frequent
with several cell types. However, a monomorphic pattern is also encountered.

Figure 12.5. Medullary carcinoma showing a lobular growth pattern and is composed of small
round cells.
Figure 12.6. Medullary thyroid carcinoma showing a predominantly uniform, cuboidal cell
pattern. The neoplastic cells have appreciable eosinophilic cytoplasm.
Figure 12.7. Medullary carcinoma is composed of large polygonal cells with abundant
eosinophilic cytoplasm bearing a morphologic resemblance to oncocytes.
Figure 12.8. Medullary thyroid carcinoma. The left half of the section shows tumor composed of
large polygonal cells with abundant eosinophilic cytoplasm, while the rest consists of smaller
round to cuboidal cells.
Figure 12.9. Histologic section of a medullary carcinoma showing a lobular pattern. The lobules
vary in size, separated by bands of fibrous tissue septae. Also note clear change in the
cytoplasm.
Figure 12.10. Medullary carcinoma exhibiting a trabecular growth pattern. The trabeculae vary
in thickness from slender to broad and are interdigitating, medium power.
Figure 12.11. FNA of a medullary carcinoma showing broad trabeculae consisting of very
pleomorphic, round to short spindle-shaped cells.
Figure 12.12. This medullary carcinoma is composed of cells forming small nests with a
follicular growth pattern.
Figure 12.13. A solid growth pattern of medullary carcinoma. The cells contain scant to
indiscernible cytoplasm
Figure 12.14. Medullary carcinoma with a spindle cell pattern. The spindle cells are forming
large nests, separated by fibrous tissue septae.
Figure 12.15. The histologic pattern of this medullary carcinoma with nests of elongated spindle
cells resembles a paraganglioma.
Figure 12.16. Histologic section of medullary carcinoma exhibiting a pleomorphic cell pattern
with amyloid in the stroma.
Figure 12.17. Medullary carcinoma with abundant amyloid in the stroma.
Figure 12.18. Histologic section of medullary carcinoma, showing apple green birefringence of
amyloid stained with Congo red.
Figure 12.19. Bright green fluorescence of amyloid when stained with thioflavin T and viewed
under ultraviolet light.
Figure 12.20. Medullary carcinoma demonstrating a strong positive reactivity with calcitonin
stain.
Figure 12.21. Electron micrograph of medullary carcinoma showing membrane-bound, spherical
neurosecretory granules with an electron-dense core (arrows ). Uranyl acetate and lead citrate
preparation (42,000).

Medullary carcinoma is characterized by the presence of amyloid deposits in the stroma in up to

80% of cases (Figs. 12.16 and 12.17 ). The amyloid shows green birefringence under crossed
polarized light when stained by Congo red (Fig. 12.18 ) and green fluorescence under ultraviolet
light when stained by thioflavin T (Fig. 12.19 ). The carcinoma may also contain a significant
amount of collagenous stroma, with or without calcification.

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Several morphologic variants have been described.19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ,
29 , 30 These include follicular or tubular, papillary, small cell, giant cell, clear cell, melanotic
(pigmented), oncocytic, squamous, amphicrine (composite calcitonin and mucin-producing), and
paraganglioma-like.

Histochemistry
Argyrophilia as demonstrated by silver stain (Grimelius) is present in 90% of medullary
carcinomas.6 The stroma shows PAS and Alcian blue positivity. Both intra- and extracellular
mucin is demonstrated by mucicarmine stain in a high proportion of cases.6 , 28

Ultrastructure
Ultrastructurally, medullary carcinoma cells demonstrate characteristic membrane-bound
secretory granules (Fig. 12.21 ).

Cytopathologic Features
The cytopathologic features of medullary carcinoma are documented in several publications.31 ,
32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 They encompass a broad spectrum
(Table 12.1 ; Figs. 12.22 , 12.23 , 12.24 , 12.25 , 12.26 , 12.27 , 12.28 , 12.29 , 12.30 , 12.31 ,
12.32 , 12.33 , 12.34 , 12.35 , 12.36 , 12.37 , 12.38 , 12.39 , 12.40 , 12.41 , 12.42 , 12.43 , 12.44
, 12.45 , 12.46 , 12.47 , 12.48 , 12.49 and 12.50 ), depending on the histomorphology:
monomorphic if only one pattern is evident and pleomorphic if a combination of different
morphologic patterns is seen. The pleomorphic pattern is more frequently observed.

Cellularity
Usually very cellular
Presentation
Cells mostly isolated, in aggregates and rarely in tissue fragments forming nests and
trabeculae; follicular or papillary architecture not present; pseudofollicular pattern
rarely present; dispersed pattern characteristic; aggregates of spindle cells may
present a "fish-school" pattern or occur in fascicles
Cells
Uniform to markedly pleomorphic; size ranging from small to large with frequent
giant forms; varied shapes: round, cuboidal, plasmacytoid, polygonal, caudate,
racket-shaped, triangular, short to elongated spindle shaped; unipolar cells;
admixture of various types is characteristic; cell borders well to poorly defined;
variable N/C ratios
Nucleus
Location
Always eccentric with extreme marginal location
Numbers
Bi-multinucleation frequent
Shape
Round, oval, oblong to spindle shaped; smooth nuclear
membranes
Chromatin
Deep-staining, coarsely granular to chunky
Parachromatin clearing
Not common
Nucleoli
±
Nuclear grooves
Not observed
Intranuclear inclusions
Almost always present
Mitotic activity
Generally absent
Cytoplasm
Variable; scant, indiscernible to abundant; clear, pale, granular to dense; drawn into
cytoplasmic processes; rudimentary tailing to delicate intertwining processes;
azurophilic cytoplasmic granules in Romanowsky-stained preparations
Psammoma bodies
Rare
Background
Hyaline, amorphous, fluffy acellular material staining positive for amyloid (Congo red
or thioflavin T); strongly resembles colloid; usually clean; necrosis generally absent
Histochemistry
Argyrophilic granules in the cytoplasm
Immunoprofile
Positive reactivity to: calcitonin, low-molecular-weight keratin, CEA, neuroendocrine
markers (chromogranin A, synaptophysin, somatostatin, neuron-specific enolase)
 and TTF-1; negative reactivity to thyroglobulin
Ultrastructure
Electron dense, membrane-bound neurosecretory granules

TABLE 12.1 CYTOPATHOLOGIC FEATURES OF MEDULLARY

CARCINOMA

Figure 12.22. A. FNA of a medullary thyroid carcinoma showing the characteristic dispersed cell
pattern (low power). B. Higher magnification showing the discrete, medium-sized, pleomorphic
and plasmacytoid neoplastic cells.

Figure 12.23. A. FNA of a medullary carcinoma depicting a dispersed cell pattern formed by
spindle-shaped cells (low power).B. Higher magnification. Note eccentric nuclei.
Figure 12.24. The presence of syncytial tissue fragments in FNA of medullary carcinoma is not
very common. A. Low power showing several tissue fragments. B,C. Higher magnification. The
tissue fragments are syncytial. Note that the component cells are pleomorphic.

Figure 12.25. A. Medullary carcinoma cells exhibiting marked pleomorphism in cell size and
shape. Note the admixture of small, round carcinoid-type cells, plasmacytoid cells, polygonal
cells, and triangular cells. The nuclei are consistently eccentric. Also note the multinucleation.
B. Pleomorphic cell pattern with intranuclear inclusions.
Figure 12.26. A. FNA of a medullary carcinoma. These cells are very small with scant cytoplasm
and compact nuclei. Note rudimentary cytoplasmic processes, × 1,000. B. These medullary
carcinoma cells are very small with hyperchromatic nuclei and indiscernible cytoplasm. The
larger cells have scant cytoplasm with thin and rudimentary cytoplasmic processes.

Figure 12.27. FNA of a medullary carcinoma. The neoplastic cells are spindle shaped, with
cytoplasmic processes. Note the salt-and-pepper chromatin pattern of the nuclei.
Figure 12.28. Another case of medullary carcinoma. The carcinoma cells are loosely cohesive
and discrete. They are round, cuboidal to spindle shaped. The cytoplasm is moderate in amount
and dense. The background is clean.

Figure 12.29. A. Medullary carcinoma cells exhibiting the nuclear chromatin pattern so
characteristic of a neuroendocrine tumor. The nuclei are round, ovoid to spindle shaped, with
salt-and-pepper chromatin. Note that nucleoli are not seen. The cells possess delicate
cytoplasmic processes. B. Smear stained for calcitonin showing positive reactivity to calcitonin.

Figure 12.29. C. Reactivity to calcitonin is usually very strong as demonstrated by these

medullary carcinoma cells.
Figure 12.30. FNA of medullary carcinoma showing a monomorphic cell pattern of plasmacytoid
cells. Note intranuclear inclusions (arrow ).
Figure 12.31. A pleomorphic cell pattern as seen here is the hallmark of medullary carcinoma.
Figure 12.32. Medullary carcinoma cells with pleomorphic spindle cells, eccentric bland nuclei,
and fibrillar cytoplasm with processes.
Figure 12.33. Medullary carcinoma with a dominant spindle cell pattern. The carcinoma cells
are discohesive and possess delicate cytoplasmic processes.

Figure 12.34. Medullary carcinoma cells are medium-sized, cuboidal, with a modest amount of
cytoplasm. Lack of pleomorphism may cause typing difficulties. This pattern may be mistaken
for a follicular neoplasm.
Figure 12.35. Medullary carcinoma with a small cell pattern. The carcinoma cells have scant to
indiscernible cytoplasm and deep-staining nuclei. This pattern may be misinterpreted as a small
cell carcinoma.

Figure 12.36. A. FNA of a medullary thyroid carcinoma showing marked cellularity with a
dispersed cell pattern (low power). B. The isolated neoplastic cells are small, round, and slightly
pleomorphic in size. The cell borders are well defined and the cytoplasm is scant, indiscernible
to dense, with cyanophilic thin rim (arrows ). The nuclei are round with coarsely granular
chromatin. There is no nuclear molding. With a monomorphic pattern of small cells, malignant
lymphoma must be considered in the differential diagnosis.

Figure 12.37. A. The carcinoma cells are spindle shaped and in fascicles. Note the acellular
cyanophilic material in close association with carcinoma cells, which probably represents
amyloid. B. A different field showing pleomorphic malignant cells. Note multinucleation and
intranuclear inclusion. The background shows abundant dense acellular material that probably
represents amyloid. In Papanicolaou-stained smears, amyloid resembles colloid. C. The cell
block of the aspirate showing a very pleomorphic, diagnostic cell pattern of medullary
carcinoma.
Figure 12.38. FNA of a medullary carcinoma showing a giant tumor cell with bizarre nucleus.
Figure 12.39. The medullary carcinoma cells are small, discrete, and in tissue fragments. They
are monomorphic with eccentric, bland nuclei and contain modest amount of cytoplasm. This
pattern may be mistaken for a follicular neoplasm.
Figure 12.40. The medullary carcinoma cells in this aspirate are compactly arranged in a tissue
fragment and offer no clue as to their type. This pattern may be mistaken for a follicular
neoplasm.
Figure 12.41. These medullary carcinoma cells are pleomorphic but contain abundant dense
cytoplasm.
Figure 12.42. These medullary carcinoma cells resemble oncocytes because of their abundant
dense cytoplasm.
Figure 12.43. Medullary carcinoma. The aspirate is poorly cellular and partially air-dried. The
only clue to the diagnosis of medullary carcinoma is the pleomorphic nuclei. A medullary
carcinoma with abundant amyloid may yield a poorly cellular aspirate.
Figure 12.44. A. FNA of a medullary carcinoma cells with extremely pleomorphic cells
containing large nuclei resembling anaplastic carcinoma. B. Another field showing similar cells.
Note large intranuclear cytoplasmic inclusion.
Figure 12.44. C,D. The aspirate also revealed aggregates of spindle-shaped cells. The calcitonin
stain was strongly positive.

Figure 12.45. Spindle-shaped cells from an aspirate of medullary carcinoma. Note the typical
salt-and-pepper nuclear chromatin.
Figure 12.46. A,B. FNA of a medullary thyroid carcinoma, with an exclusive spindle cell pattern
raising the possibility of a soft-tissue tumor. Calcitonin stain was positive. Medullary carcinoma
was confirmed on thyroidectomy. C. Spindle cells in fascicles from another case of medullary
carcinoma.

Figure 12.46. D. Positive reactivity to calcitonin.

Figure 12.47. FNA of a medullary carcinoma stained with Romanowsky stain. A. The cells are in
syncytial tissue fragments. B. Pleomorphic medullary carcinoma cells. Some contain azurophilic
granules in their cytoplasm (arrow ).
Figure 12.48. These medullary carcinoma cells contain the characteristic azurophilic granules in
their cytoplasm Romanowsky stain.
Figure 12.49. A–C. FNA of a medullary carcinoma presenting a very pleomorphic cell pattern.
Many cells are plasmacytoid. Romanowsky stain.
Figure 12.49. D. Same aspirate with Papanicolaou stain. (Courtesy of Mithra Baliga, MD,
University of Mississippi, Jackson.)

Figure 12.50. A. Dense acellular material in FNA of medullary carcinoma, probably representing
amyloid. Note the resemblance to colloid. B. Cell block of an aspirate of medullary carcinoma
stained with thioflavin T, to demonstrate bright green fluorescence under ultraviolet light.

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P.265
P.266
P.267
P.268
P.269
P.270
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P.272
The aspirates are usually cellular; scant cellularity is encountered with carcinomas containing
extensive amyloid deposits and calcification.

The smear of an aspirate from medullary carcinoma of the thyroid generally shows malignant
cells, either isolated or in loosely cohesive groups (Figs. 12.22 and 12.23 ) presenting a dispersed
cell pattern. Syncytial-type tissue fragments are infrequent (Fig. 12.24 ) and a papillary or
follicular pattern is not identified. However, a pseudofollicular pattern may rarely be seen (see
Fig. 12.56 ). The spindle cells may be present in fascicles, dispersed, or in aggregates with
intertwining cytoplasmic processes (Figs. 12.27 , 12.32 , 12.33 , 12.45 , and 12.46 ).

Medullary carcinoma cells are very pleomorphic; any size or shape may be present (Figs. 12.25 ,
12.26 , 12.27 , 12.28 , 12.29 , 12.30 , 12.31 , 12.32 , 12.33 , 12.34 , 12.35 , 12.36 , 12.37 , 12.38
, 12.39 , 12.40 , 12.41 , 12.42 and 12.43 ). The carcinoma cells can be small, round to cuboidal,
reminiscent of carcinoid cells, or oval to plasmacytoid. They may be triangular, polyhedral,
racket-shaped, or spindle-shaped. Their size also varies: the small, round cells are slightly larger
than the follicular cells, and the larger cells are several microns in their largest dimension. A
cellular aspirate with a dispersed cell pattern formed by pleomorphic cells is virtually
pathognomonic of medullary carcinoma (Figs. 12.25 , 12.26 , 12.27 , 12.28 and 12.29 ), whereas
a monomorphic pattern comprising only one type of cell is not frequently observed (Figs. 12.30 ,
12.39 , and 12.40 ). The latter does cause typing difficulties.

The nuclei of medullary carcinoma cells are always eccentric, regardless of the cell shape, cell
size, or number of nuclei. Extreme marginal location of the nucleus is characteristic of the
plasmacytoid cell type, and bi- and multinucleation occur very frequently (Fig. 12.25 ). The
nuclei are round, sometimes oval and occasionally oblong or elongated in spindle-shaped cells.
Their chromatin is coarse, stippled with a salt-and-pepper pattern, so characteristic of
neuroendocrine tumors (Figs. 12.27 , 12.28 and 12.29 ). The presence of nucleoli is not a
consistent finding. Bizarre nuclei, such as those seen in anaplastic
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carcinomas, are rare. A remarkable and consistent feature is the presence of intranuclear
cytoplasmic inclusions (Figs. 12.25 , 12.30 , and 12.37 ).40

The cytoplasm of medullary carcinoma cells is variable. In small round cells, it is very scant and
hardly discernible (Figs. 12.26 , 12.35 , and 12.36 ), whereas in plasmacytoid or large polyhedral
cells it is abundant (Figs. 12.25 , 12.41 , and 12.42 ). It generally stains pale and has a fibrillar
quality (Fig. 12.25 ). The cytoplasm is often drawn out in a delicate process, which may be
rudimentary in cuboidal cells (Fig. 12.26 A). Söderström et al.43 called these "dendritic
processes." The spindle cells of medullary carcinoma are usually and characteristically unipolar
with eccentric nuclei. A group of spindle cells with delicate intertwined cytoplasmic processes is
a characteristic finding in smears from medullary carcinoma (Fig. 12.33 ).

Another feature of diagnostic importance is the presence of azurophilic granules in the

cytoplasm of medullary carcinoma cells which are seen only in air-dried preparations stained by
the Romanowsky method (Figs. 12.48 and 12.49 ), and not in Papanicolaou-stained preparations.
These granules are present in about 5% to 10% of the neoplastic cell population and probably
represent cytoplasmic calcitonin.

One of the characteristic features of medullary carcinoma is the presence of stromal amyloid. It
can be seen in cytologic preparations as fluffy, finely granular, or dense acellular material in the
background (Figs. 12.37 and 12.50 A). The amyloid has the same staining characteristics as the
colloid in Papanicolaou-stained preparations and cannot be differentiated from it without
special stains such as Congo red or thioflavin T (Fig. 12.50 B). Although the presence of
intracellular cytoplasmic amyloid has been described by Söderström et al.,43 it is not
appreciated by Papanicolaou stain. The use of special stains to identify amyloid in cytologic
preparations is time-consuming and not recommended. It is best performed on cell-block
preparations.

Immunocytohistochemical Profile of Medullary Carcinoma

Positive reactivity to calcitonin is very specific,6 , 45 , 46 although rare negative reactivity has
been reported.6 , 45 The stain works well on alcohol-fixed cytologic preparations. In our
experience, medullary thyroid carcinomas reveal positive reactivity to calcitonin on cytologic
smears and have correlated 100% with increased serum calcitonin levels and histologic findings.
Goellner et al.45 however, reported a positive reaction in 60% of their cytologic preparations but
in 93% of histologically proven medullary carcinomas. Bose et al.37 found positive reactivity in
55% of their cases. Medullary carcinoma cells show positive reactivity to low-molecular-weight
cytokeratin but very rarely to high-molecular-weight keratin. Reactivity to vimentin is variable.
The carcinoma cells react positively to a host of antibodies such as chromogranin and
synaptophysin, aimed at neuroendocrine differentiation (Table 12.2 ).

Calcitonin
Positive
Low-molecular-weight cytokeratin
Positive
High–molecular-weight cytokeratin
Rarely expressed
Vimentin
Variable
Neuron-specific enolase
Positive
Synaptophysin
Positive
Chromogranin
Positive
Carcinoembryonic antigen
Positive
Thyroglobulin
Negative
Thyroid transcription factor-1
Positive

Antibodies Reactivity

TABLE 12.2 IMMUNOPROFILE OF MEDULLARY CARCINOMA

Diagnostic Accuracy
The cytologic typing of medullary carcinoma can be achieved with a high degree of accuracy.
However, it can be mistyped as various different types of thyroid cancers, both histologically
and cytologically.

In our first 9 years of experience with fine-needle aspirates of the thyroid nodules, 571 cases
were diagnosed as primary thyroid malignancies by surgery, of which 27 (4.5%) were medullary
carcinomas. Of these 27 cases, 20 were accurately typed from cytologic specimens. Three were
interpreted as undifferentiated carcinoma, one as a follicular variant of papillary carcinoma,
and two as cellular follicular adenomas (Table 12.3 ). Typing errors are generally due to
inexperience and unfamiliarity with the varied cytopathologic features of medullary carcinoma.
Our errors were made within the first 2 years of our experience in interpreting biopsy
specimens. In the largest study of cytologic features of medullary carcinomas, Papaparaskeva et
al.32 reviewed fine-needle aspiration biopsy specimens from 91 histologically confirmed
medullary carcinomas. Accurate cytologic typing of medullary carcinoma was reported in 89% of
the cases (81 of 91). Five cases were cytologically mistyped as follicular neoplasms, and 4 cases
were typed as papillary carcinoma, 4 as neuroendocrine carcinoma, 4 as carcinoma NOS, and 4
as spindle cell tumor. There was one false-negative case, interpreted as follicular hyperplasia.

Medullary carcinoma
20
8
6
1
Hürthle cell carcinoma
0
0
0
0
Undifferentiated carcinoma
3
0
0
0
Papillary carcinoma
1
0
0
0
Follicular adenoma
2
0
0
0
Acellular
 1
0
0
0

Histologic Diagnosis

Cytologic Diagnosis Medullary Hürthle Cell Papillary Nodular

Carcinoma Carcinoma Carcinoma Goiter
(n = 27) (n = 8) (n = 8) (n =1)

TABLE 12.3 CYTOHISTOLOGIC CORRELATION OF MEDULLARY

CARCINOMA OF THE THYROID
Medullary carcinoma also tends to be over diagnosed cytologically. The monomorphic cell
population of Hürthle cell carcinomas, the single cell pattern in papillary carcinomas, and the
spindle cells in anaplastic carcinomas all may be mistaken for medullary carcinoma. In our
series, 33 cases were typed cytologically as medullary carcinoma, of which 20 were confirmed, 8
were diagnosed as Hürthle cell carcinoma, 4 as papillary carcinoma, and 1 as nodular goiter
(Table 12.3 ). In the series reported by Papaparaskeva et al.,32 14 cases cytologically typed as
diagnostic or suspicious for medullary carcinoma were histologically proven to be follicular
neoplasms (4), papillary carcinoma (4), metastatic carcinoid tumor (2), paraganglioma (2),
metastatic renal cell carcinoma (1), and nodular goiter (1).

A cytologic diagnosis of medullary carcinoma must be confirmed by other means, such as:

Immunostain for calcitonin.

Serum calcitonin levels.

Large-needle biopsy (size of the thyroid nodule permitting).47 , 48

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Poor cellularity is likely to result in a false-negative diagnosis (Fig. 12.43 ). A diligent search is
necessary in poorly cellular specimens with abundant amyloid to identify medullary carcinoma
cells. Immunostains for calcitonin, as well as serum calcitonin levels, should help confirm the
diagnosis.

Differential Diagnosis
The pleomorphic cell pattern is characteristic and diagnostic of medullary carcinoma. It is more
frequently encountered, allowing an accurate cytologic diagnosis. A monomorphic cell pattern,
comprised of only one cell type such as small round cells, plasmacytoid cells, or spindle-shaped
cells, is not common and may be mistaken for other types of thyroid neoplasms, and vice versa
(Table 12.4 ).51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 Neoplasms such as
Hürthle cell carcinomas are often confused with medullary carcinoma because of the
plasmacytoid cells. Bourtsos et al.63 reported a case of primary plasmacytoma of the thyroid
that was interpreted as medullary carcinoma. Follicular neoplasms (e.g., hyalinizing trabecular
adenoma and follicular adenomas and carcinomas) have been misinterpreted as medullary
carcinomas. Extreme pleomorphism with bizarre nuclei or a spindle cell pattern may be
mistaken for anaplastic carcinoma. A spindle cell pattern can also be confused with soft-tissue
tumors. Medullary carcinomas demonstrate morphologic overlap with other neuroendocrine
tumors such as carcinoid tumors,23 paragangliomas,19 , 20 , 21 or the rare "oat- cell carcinoma"
of the thyroid.57 The small cell pattern may also be mistyped as poorly differentiated "insular"
thyroid carcinoma, metastatic small cell carcinoma, or a malignant lymphoma. Benign conditions
may also cause diagnostic pitfalls. The presence of benign spindle cells of stromal origin in cases
of nodular goiters when present in large numbers may mimic the cytologic pattern of medullary
carcinoma. The rare cases of amyloid goiter in patients with systemic amyloidosis are another
example of diagnostic pitfall. Hyperplastic nodular goiters were interpreted as medullary
carcinoma as reported by Papaparaskeva,32 Forrest,33 and their colleagues.

Nodular goiter
Follicular cell hyperplasia
Spindle-shaped stromal cells
Amyloidosis or amyloid goiter
Follicular neoplasms
Hyalinizing trabecular adenoma
Cellular follicular adenoma
Follicular carcinoma
Hürthle cell carcinoma
Papillary carcinoma
Poorly differentiated "insular carcinoma"
Anaplastic (undifferentiated) carcinoma
Other neuroendocrine tumors
Carcinoid tumor
Paraganglioma
Calcitonin-free oat cell carcinoma (neuroendocrine
carcinoma)
Soft-tissue tumors (primary or metastatic)
Malignant lymphoma
Malignant melanoma

TABLE 12.4 DIFFERENTIAL DIAGNOSIS OF MEDULLARY

CARCINOMA

Medullary Carcinoma versus Stromal Cells in Nodular Goiter

Occasionally, in a nodular goiter, the fibroblasts from the supporting stroma or the granulation
tissue from an old hemorrhage appear very similar to the spindle cells of medullary carcinoma
(Figs. 12.51 , 12.52 and 12.53 ). Features of nodular goiter, if present in other areas of the
smears, should aid in correct interpretation. Also, the stromal fibroblasts are bipolar with
central nuclei while medullary carcinoma cells are unipolar with eccentric nuclei.
Figure 12.51. Medullary carcinoma versus nodular goiter . Spindle-shaped stromal cells from a
nodular goiter may be mistaken for medullary carcinoma. The delicate, slender spindle cells
bear a strong resemblance to medullary carcinoma cells. The stromal cells, however, are few in
number and occur in the background of nodular goiter. The spindle-shaped stromal cells are
bipolar while the medullary carcinoma cells are unipolar.
Figure 12.52. Medullary carcinoma versus nodular goiter . Another example of pleomorphic
stromal cells from an aspirate of nodular goiter. Note that the stromal cells are bipolar with
central nuclei, unlike medullary carcinoma cells, which are usually unipolar with eccentric
nuclei.
Figure 12.53. FNA of a medullary carcinoma showing unipolar spindle-shaped cells for
comparison.

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Medullary Carcinoma versus Hyperplastic Nodular Goiter

Follicular hyperplasia in a nodular goiter has been misinterpreted as medullary thyroid
carcinoma.32 , 33 The hypercellular specimens composed of round to cuboidal follicular cells
may be responsible for mistyping.

Medullary Carcinoma versus Amyloid Goiter

Systemic amyloidosis involving the thyroid gland rarely presents as a goiter (Fig. 12.54 ).49 , 50
Extensive amyloid deposits in a cellular sample may be misinterpreted as medullary carcinoma,
as reported by Kapila and Verma.49
Figure 12.54. Medullary carcinoma versus amyloid goiter . FNA of amyloid goiter. The aspirate
is poorly cellular, consisting of predominantly acellular material that is proven histochemically
as amyloid. (Courtesy of John F. Goellner, MD, Previously of Department of Pathology, Mayo
Clinic, Rochester, Minnesota.)

Medullary Carcinoma versus Hyalinizing Trabecular Adenoma

Hyalinizing trabecular adenoma is an infrequent subtype of follicular adenoma that strongly
resembles medullary carcinoma both cytologically and histologically (Fig. 12.55 ).51 , 52 , 53 ,
54 , 55 , 56 The distinction between the two may be very difficult without the aid of
immunocytohistochemical stains for calcitonin and thyroglobulin. Table 12.5 lists the cytologic
features of both medullary carcinoma and hyalinizing trabecular adenoma.
Figure 12.55. Medullary carcinoma versus hyalinizing trabecular adenoma . A. FNA of a
hyalinizing trabecular adenoma. The cells are elongated, spindle-shaped, and have bland nuclei.
The pattern has a strong resemblance to medullary thyroid carcinoma cells and is interpreted as
such. B. Histologic section of the lesion showing a characteristic pattern of hyalinizing
trabecular adenoma. C. FNA of a hyalinizing trabecular adenoma showing a pseudofollicular
pattern. The collagen seen in the center may be mistaken for amyloid. (Part C is courtesy of
Marizza de Peralta-Venturina, MD, William Beaumont Hospital, Royal Oak, Michigan.)

Cellularity
Variable, usually cellular
Variable
Presentation
Cells mostly isolated or in loosely cohesive
groups with a dispersed pattern; syncytial tissue
fragments not common; no architectural
 configurations
Cells isolated, in loosely cohesive groups and in
syncytial tissue fragments, some with central
acellular hyaline material with cells springing
from it; trabecular with branching
Cells
Monomorphic to markedly pleomorphic; round,
plasmacytoid, spindle shaped with unipolar cyto-
plasmic processes; well-defined to poorly defined
cell borders; N/C ratios variable
Round, oval, elongated, spindle shape with bipo-
lar cytoplasmic processes; well to poorly
defined cell borders; N/C ratios low
Nucleus
Eccentric with extreme marginal location; bi- and
multinucleation frequent; giant forms ±; pleomor-
phic, round, oval, oblong to spindle shaped,
smooth nuclear membranes; salt-and-pepper type
granular chromatin, sometimes chunky; nucleoli
usually not seen; intranuclear inclusions always
present; grooves not appreciated
Central to eccentric; round to oval, smooth
nuclear membranes; bi- and multinucleation not
seen; finely granular chromatin; micronucleoli;
perinucleolar halo +; intranuclear inclusions
always present; nuclear grooves +
Cytoplasm
Variable; scant to abundant; pale, granular to dense;
intracytoplasmic azurophilic granules with
Romanowsky stain
Abundant, pale
Background
Clean; amorphous, acellular, hyaline material con-
firmed as amyloid with Congo red stain or
 thioflavin T
Clean; amorphous, acellular, hyaline material; neg-
ative staining for amyloid; hyaline material of
basement membrane origin
Immunoprofile
Positive reactivity to calcitonin; negative reactivity to
thyroglobulin
Negative reactivity to calcitonin; positive reactivity
to thyroglobulin

Medullary Carcinoma Hyalinizing Trabecular Adenoma

TABLE 12.5 DIFFERENTIATING FEATURES BETWEEN

MEDULLARY CARCINOMA AND HYALINIZING TRABECULAR
ADENOMA

Medullary Carcinoma versus Follicular Adenoma/Carcinoma

A common cytologic presentation of medullary carcinoma is that of isolated or loosely cohesive
cells. The infrequent cytologic presentation of syncytial-type tissue fragments with a
pseudofollicular pattern and small, round to cuboidal cells with nuclei containing coarse
chromatin may be mistyped as
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follicular adenoma or carcinoma. The presence of intranuclear cytoplasmic inclusions favors a
diagnosis of medullary carcinoma or a follicular variant of papillary carcinoma. Recognition of
medullary carcinoma may be extremely difficult unless cytoplasmic processes are identified
(Table 12.6 , Figs. 12.56 , 12.57 , 12.58 and 12.59 ). Appropriate immunostains will confirm the
diagnosis.

Cellularity
Usually cellular
Variable
Presentation
Cells mostly isolated or in loosely cohesive
groups with a dispersed pattern; syncytial tissue
 fragments not common; no architectural
configurations; pseudofollicular pattern ±
Cells arranged in syncytial tissue fragments with
and without follicular pattern; isolated and
loosely cohesive groups less frequent
Cells
Small, round to cuboidal; ill-defined to well-defined
cell borders; high N/C ratios
Small, round to cuboidal; ill-defined cell borders;
high N/C ratios
Nucleus
Eccentric; round, oval; smooth nuclear membranes;
salt-and-pepper type granular chromatin,
sometimes chunky; nucleoli usually not seen;
intranuclear inclusions always present
Central location; round with smooth nuclear mem-
branes; coarsely granular chromatin; micronu-
cleoli ±; intranuclear inclusions absent
Cytoplasm
Scant, pale to dense; cytoplasmic tailing (rudimentary
process) ±
Scant indiscernible cytoplasm; no cytoplasmic
processes
Amyloid
±
Absent
Colloid
Absent
±; May be present in the background or within
the follicular lumens
Immunoprofile
Positive reactivity to calcitonin; negative reactivity to
thyroglobulin
Negative reactivity to calcitonin; positive reactivity
 to thyroglobulin

Medullary Carcinoma Follicular Adenoma/Carcinoma

TABLE 12.6 DIFFERENTIATING FEATURES BETWEEN

MEDULLARY CARCINOMA WITH ROUND CELL PATTERN AND
FOLLICULAR ADENOMA/FOLLICULAR CARCINOMA

Figure 12.56. Medullary carcinoma versus follicular adenoma/carcinoma . A. This cellular

aspirate showed a monomorphic population of small to medium-sized cells, discrete and in small
tissue fragments with a pseudofollicular pattern (medium power). B. Higher magnification
demonstrated eccentric nuclei and minimal pleomorphism. Note the pseudofollicular pattern
(arrows ). The aspirate was interpreted as a cellular follicular adenoma. C. Thyroidectomy
revealed a medullary carcinoma, confirmed by positive calcitonin stain.
Figure 12.57. Medullary carcinoma versus follicular adenoma/carcinoma . Another example of
medullary carcinoma cytologically interpreted as cellular follicular adenoma. The syncytial
arrangement of cuboidal cells favored the diagnosis of follicular neoplasm. The short spindle
cells, rudimentary cytoplasmic processes, and intranuclear inclusions were not appreciated at
the time of examination. Thyroidectomy revealed a medullary carcinoma.

Figure 12.58. Medullary carcinoma versus follicular adenoma/carcinoma . This cellular aspirate
consisted of syncytial tissue fragments of round to cuboidal cells with scant cytoplasm. The
nuclear chromatin was uniform and bland, lacking the coarse granularity of medullary carcinoma
cell nuclei. Absence of pleomorphism led to the diagnosis of a follicular neoplasm.
Thyroidectomy revealed a medullary carcinoma.
Figure 12.59. Medullary carcinoma versus follicular adenoma/ carcinoma . Uniform, medium-
sized cells in syncytial tissue fragment with coarsely granular chromatin, can be misinterpreted
as a follicular neoplasm.

Medullary Carcinoma versus Hürthle Cell Carcinoma

In our experience, cells aspirated from some Hürthle cell carcinomas exhibit a morphologic
resemblance to plasmacytoid cells of medullary carcinoma. This observation is shared by Forrest
et al.33 and Söderström and co-workers,43 but not by Geddie et al.41 However, Söderström
et al.43 believe that the distinction between a Hürthle cell neoplasm and a medullary thyroid
carcinoma could be made easily by the dusty blue granulation of Hürthle cells in Romanowsky-
stained preparations and the cytoplasmic pink granules of medullary carcinoma cells. A
prominent cherry-red macronucleolus favors the diagnosis of Hürthle cell carcinoma.
Whenever an aspirate shows a monomorphic pattern of oval to plasmacytoid cells with no other
cytologic features of medullary carcinoma or Hürthle cell carcinoma, it is prudent to
recommend tests to rule out medullary carcinoma (Table 12.7 , Figs. 12.60 , 12.61 and 12.62 ).
Cellularity
Highly cellular
Highly cellular
Pattern
Cells mostly discrete, in groups, rarely in
syncytial tissue fragments; without any architec-
tural patterns, dispersed pattern frequent and
characteristic
Cells discrete, in groups, or in syncytial tissue
fragments; a dispersed pattern is frequent
Cells
Medium-sized, round, oval, plasmacytoid, mildly
pleomorphic; cell borders well-defined to poorly
defined; N/C ratios variable
Medium-sized, round, oval to plasmacytoid, uni-
form in a given case; cell borders well defined in
discrete cells; N/C ratios very high
Nucleus
Almost always eccentric, binucleation frequent;
round, variably sized; smooth nuclear membranes,
coarsely granular chromatin to salt-and-pepper
type chromatin; nucleoli not conspicuous; intranu-
clear inclusions frequent
Central to eccentric; binucleation frequent; round,
mostly uniform with little variation in size;
smooth nuclear membranes, finely granular
chromatin; macro nucleoli conspicuous; intranu-
clear inclusions ±
Cytoplasm
Variable; pale, lacy to dense; azurophilic granules
in Romanowsky-stained preparations
Variable, usually scant; granular to dense;
azurophilic granules in Romanowsky-stained
preparations not present
Background
Colloid absent; amyloid present;
clean with no necrosis
Colloid ±; amyloid absent; necrosis ±
Immunoprofile
Calcitonin +; Thyroglobulin
Calcitonin -; thyroglobulin +
Ultrastructure
Neurosecretory granules
Abundant mitochondria

Medullary Carcinoma Hürthle Cell Carcinoma

TABLE 12.7 DIFFERENTIATING FEATURES BETWEEN

MEDULLARY CARCINOMA WITH MONOMORPHIC ROUND, OVAL
TO PLASMACYTOID CELLS AND HÃœRTHLE CELL CARCINOMA

Figure 12.60. Medullary carcinoma versus Hürthle cell carcinoma . A. FNA of a Hürthle cell
carcinoma. The cells are monomorphic with eccentric nuclei. A differential diagnosis of
Hürthle cell carcinoma and medullary carcinoma was considered. Immunostain for
thyroglobulin was positive and negative for calcitonin. Thyroidectomy confirmed a Hürthle cell
carcinoma. B. FNA of a medullary carcinoma demonstrating cytomorphology similar to a
Hürthle cell neoplasm.
Figure 12.61. Medullary carcinoma versus Hürthle cell carcinoma . A. FNA of a Hürthle cell
carcinoma showing plasmacytoid cells resembling the cells of medullary carcinoma.
Macronucleoli in some cells suggested the diagnosis of Hürthle cell neoplasm. A calcitonin stain
was nondiagnostic. Thyroidectomy revealed a Hürthle cell carcinoma. B. FNA of a medullary
carcinoma showing cells with morphology similar to Hürthle cell carcinoma.

Figure 12.62. FNA of a Hürthle cell carcinoma. A. The aspirate is very cellular consisting of
discrete, pleomorphic cells (low power). B. Higher magnification showing plasmacytoid shapes
with eccentric nuclei. The chromatin is coarsely granular and macronucleoli are not
appreciated. C. A different field showing a syncytial tissue fragment of similar cells with
abundant dense cytoplasm; some cells are short spindle shaped. A differential diagnosis of
Hürthle cell neoplasm and medullary carcinoma was considered. A calcitonin stain was
negative while the cells were reactive to thyroglobulin. Thyroidectomy confirmed a Hürthle
cell carcinoma.

Medullary Carcinoma versus Papillary Carcinoma

Most papillary carcinomas of thyroid are easily recognized by the varied architectural patterns of
the tissue fragments and the characteristic nuclear morphology. Very infrequently, aspirates
from papillary carcinomas present a single cell pattern with a large population of cuboidal, short
columnar, or spindle-shaped cells similar to those seen in medullary carcinomas. Other
diagnostic features of papillary carcinoma may not be
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P.278
P.279
P.280
present in the aspirated sample. Intranuclear cytoplasmic inclusions are seen in both carcinomas
and are not helpful in differentiating the two. Powdery nuclear chromatin, micronucleoli, and a
chromatin ridge or the groove, if present, suggests papillary carcinoma (Table 12.8 , Figs. 12.63
, 12.64 and 12.65 ).

Cellularity
Highly cellular
Highly cellular
Pattern
Cells mostly discrete, in groups, rarely in syncytial tis-
sue fragments; without any architectural patterns,
dispersed pattern frequent and characteristic
Cells mostly discrete, in groups, rarely in syncytial
tissue fragments without any architectural pat-
terns, dispersed pattern
Cells
Small, round to cuboidal; ill-defined to well-defined
 cell borders; high N/C ratios
Small, round to cuboidal, to short columnar; ill-
defined to well-defined cell borders; high N/C
variable
Nucleus
Eccentric; round, oval; smooth nuclear membranes;
salt-and-pepper type granular chromatin, some-
times chunky; nucleoli usually not seen. binucle-
ation frequent; intranuclear inclusions always
present
Eccentric to central; round, oval; smooth nuclear
membranes; salt-and-pepper type granular
chromatin; nucleoli usually not seen; binucle-
ation not a feature; intranuclear inclusions
always present
Cytoplasm
Scant, pale to dense; cytoplasmic tailing (rudimentary
process) ±; azurophilic granules in Romanowsky-
stained preparations
Variable, pale clear or vacuolated; azurophilic
granules in Romanowsky-stained preparations
not present
Background
Colloid absent; amyloid present
Colloid ±; amyloid absent
Immunoprofile
Calcitonin +; thyroglobulin -
Calcitonin -; thyroglobulin +

Medullary Carcinoma Papillary Carcinoma

TABLE 12.8 DIFFERENTIATING FEATURES BETWEEN

MEDULLARY CARCINOMA AND PAPILLARY CARCINOMA WITH
A SINGLE CELL PATTERN
Figure 12.63. Medullary carcinoma versus papillary carcinoma . FNA of a papillary thyroid
carcinoma showing a single cell pattern. The neoplastic cells are pleomorphic, round to spindle
shaped, and with cytoplasmic processes. Note the intranuclear inclusions. The differential
diagnosis in this case includes papillary carcinoma, hyalinizing trabecular adenoma, and
medullary carcinoma. Immunostains are necessary for the diagnosis. Thyroidectomy confirmed a
papillary carcinoma.
Figure 12.64. A. Medullary carcinoma versus papillary carcinoma . FNA of a papillary carcinoma
composed of large polygonal cells with abundant cytoplasm and eccentric nuclei. The coarse
thready chromatin favored medullary carcinoma. Other smears from the same aspirate showed
features suggestive of papillary carcinoma and were confirmed on thyroidectomy. B. FNA of a
medullary thyroid carcinoma showing similar cytomorphology to that seen in part A.

Figure 12.65. Medullary carcinoma versus papillary carcinoma . Another example of papillary
carcinoma with a single cell pattern. The round, cuboidal, and plasmacytoid cells with eccentric
nuclei containing intranuclear inclusions raise the possibility of medullary carcinoma. When in
doubt, immunostains for calcitonin will confirm the diagnosis of medullary carcinoma.

Medullary Carcinoma versus Insular Carcinoma

The small cell variant of medullary carcinoma shows morphologic overlap with other small cell
malignancies such as poorly differentiated or insular carcinoma of the thyroid as well as
malignant lymphoma and metastatic small cell carcinoma. The aspirate of medullary carcinoma
consisting of small uniform cells is very difficult to distinguish from insular carcinoma of the
thyroid without the help of immunostains (Fig. 12.66 ). Insular carcinomas often show necrosis
and increased proliferative activity, a feature generally not observed with medullary
carcinomas. Calcitonin will be strongly positive with medullary carcinoma cells. A rare primary
neuroendocrine
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P.282
P.283
tumor referred to as calcitonin-free oat cell carcinoma will be extremely difficult to
differentiate from either a medullary carcinoma or a metastatic small cell carcinoma. The
differential diagnosis of thyroid aspirates with small cells is discussed in Chapter 10 and listed in
Table 10.3 .
Figure 12.66. Medullary carcinoma versus insular carcinoma . A. FNA of a medullary carcinoma.
A small cell pattern forming sharply defined tissue fragments resembling insulae of insular
carcinoma. B. Thyroidectomy confirmed medullary carcinoma. Histologic section showing a
lobular pattern formed by small round cells and is reminiscent of an insular carcinoma.

Medullary Carcinoma versus Carcinoid Tumor

The small cell pattern of medullary thyroid carcinoma with salt-and-pepper nuclear chromatin
morphologically resembles a carcinoid tumor. Fine-needle aspirates of carcinoid tumor
metastatic to the thyroid may be interpreted as medullary carcinoma.32 There have been
isolated case reports of metastases from extra-thyroidal carcinoid tumor to the thyroid gland
that may be confused with medullary carcinomas.

Medullary Carcinoma versus Anaplastic Carcinoma

The monomorphic spindle cell pattern of medullary carcinoma may be mistyped as anaplastic
carcinoma, particularly when occasional nuclei appear bizarre (Fig. 12.67 ). On the other hand,
in the absence of the usual cytopathologic features, such as pleomorphic and bizarre nuclei and
tumor diathesis, the aspirate of anaplastic carcinoma may be mistyped as medullary carcinoma.
Intranuclear cytoplasmic inclusions are seen in both types of cancer cells. The presence of other
features of medullary carcinoma, as described earlier, is helpful in making a correct diagnosis.
Intertwining cytoplasmic processes are not a feature of anaplastic carcinoma (Table 12.9 ).
Immunostains for calcitonin are necessary to confirm the diagnosis of medullary carcinoma.

Figure 12.67. Medullary carcinoma versus anaplastic carcinoma . A,B. FNA of a medullary
carcinoma showing syncytial tissue fragments of markedly pleomorphic cells, which reacted
strongly to calcitonin. Thyroidectomy confirmed the medullary carcinoma. C. Histologic section
of the medullary carcinoma. D. Strong positive reaction to calcitonin.

Cellularity
Generally high
Generally high, can be low with markedly desmo
plastic cancer
Pattern
Cells mostly discrete, in groups, presenting a
fish-school pattern; rarely in fascicles
Isolated, loosely cohesive; in syncytial tissue
fragments;
Cells
Variably sized, spindle shaped; delicate slender;
well-defined cell borders; N/C ratios variable
Variably sized, slender to plump spindle shaped,
well-defined cell borders; N/C ratios variable;
giant forms frequent
Nucleus
Eccentric, round to oval, short spindle shaped; pleo-
morphism may be pronounced; smooth nuclear
membranes; coarsely granular chromatin; nucleoli
not conspicuous; intranuclear inclusions present;
mitosis -
Central to eccentric; very pleomorphic; multinucle-
ation +; coarsely granular chromatin with exces-
sively cleared parachromatin; smooth to irregular
nuclear membranes; bizarre forms frequent; mul-
tiple micro/macronucleoli with irregular forms;
intranuclear inclusions +; mitotic activity + with
normal and abnormal mitoses
Cytoplasm
Variable; pale lacy to dense; unipolar with delicate
cytoplasmic processes often intertwining
Variable, can be abundant and dense; cytoplasmic
processes rare
Background
Clean; amyloid +; necrosis absent; stromal tissue
fragments not present
Amyloid +; necrosis frequent; stromal tissue
fragments ±
Immunoprofile
Calcitonin +; thyroglobulin -
Calcitonin -; thyroglobulin usually negative
Ultrastructure
Electron dense, membrane-bound; neurosecretory
granules
No neurosecretory granules

Medullary Carcinoma Anaplastic Carcinoma

TABLE 12.9 DIFFERENTIATING FEATURES BETWEEN

MEDULLARY CARCINOMA AND ANAPLASTIC CARCINOMA

Medullary Carcinoma versus Malignant Lymphoma

Medullary carcinomas may consist predominantly of small cells that present a dissociated
pattern (Fig. 12.68 ). With uniform, small, round cells, scant cytoplasm, and high N/C ratios, a
malignant lymphoma must be considered in the differential diagnosis. Cytoplasmic tailing, lack
of nucleoli, and coarsely granular chromatin are the features that help differentiate medullary
carcinomas from malignant lymphomas. The latter exhibit malignant cells with nucleoli, high
proliferative activity, karyorrhexis, and necrosis. Ancillary diagnostic tests are required for
accurate diagnosis. Please refer to Chapter 10 , Table 10.3 , on cytologic features of small cell
neoplasms of the thyroid gland.
Figure 12.68. Medullary carcinoma versus malignant lymphoma . FNA of a medullary thyroid
carcinoma consisting of discrete small to medium-sized cells with high N/C ratios and scant
cytoplasm. These cells strongly resemble large cell lymphoma.

Medullary Carcinoma versus Paraganglioma

Medullary carcinomas with a histologic pattern similar to that of a paraganglioma has been
described in the literature.19 , 20 , 21 It is possible to misinterpret the cells of primary
paraganglioma of the thyroid as a medullary carcinoma (Fig. 12.69 ), as reported by Vodvnik58
and Papaparaskeva et al.32
Figure 12.69. Medullary carcinoma versus paraganglioma . FNA of a histologically confirmed
primary paraganglioma of the thyroid. The marginally cellular aspirate demonstrates medium-
sized to large cells with poorly defined cell borders. The nuclei are moderately pleomorphic,
large, round to oval, and with evenly dispersed chromatin. Nucleoli are only occasionally
present. These cells have insignificant to scant, pale, bluish cytoplasm. A cytologic diagnosis of
paraganglioma is not possible from this morphology alone, as the cells also bear similarities to
medullary carcinoma cells. Romanowsky stain. (Courtesy of A. Vodovnik, MD, Calderdale Royal
Hospital, HX3 OPW Halifax, England.)

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Medullary Carcinoma versus Soft-Tissue Tumors

An exclusive spindle cell pattern is unusual for medullary carcinoma and when present may be
mistyped as soft-tissue tumor (Fig. 12.70 ). Medullary carcinoma cells tend to be discohesive and
unipolar. Spindle cells running in fascicles like the ones seen in leiomyoma or fibrous
histiocytomas are very unusual. Again, a differential diagnosis must be rendered, and
appropriate ancillary tests need to be performed for accurate typing.
Figure 12.70. Medullary carcinoma versus soft-tissue tumors . An exclusive spindle cell pattern
as seen here in an FNA of medullary carcinoma is unusual. Also, the neoplastic cells in medullary
carcinomas tend to be discohesive and unipolar. Spindle cells running in fascicles like the ones
seen in leiomyoma or fibrous histiocytomas are very unusual. A differential diagnosis must be
rendered and appropriate ancillary tests need to be performed for accurate typing.

Medullary Carcinoma versus Plasmacytoma

The medullary carcinoma cells may be predominantly plasmacytoid in shape and resemble a
plasmacytoma. A case of plasmacytoma of the thyroid interpreted as medullary carcinoma was
reported by Bourtsas et al. (63).

Medullary Carcinoma versus Malignant Melanoma

Malignant melanoma is a great mimicker and must always be considered in any differential
diagnosis. With a broad spectrum
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of morphologic patterns, it is conceivable that a melanoma may be diagnosed as medullary
carcinoma in thyroid aspirates. On the other hand, medullary carcinoma will be typed as
melanoma if such a past history is available.

Mixed Medullary, Follicular, and Composite Carcinomas

These tumors show both parafollicular and follicular differentiation in the same tumor.64 , 65 ,
66 , 67 , 68 , 69 Two types are described, mixed carcinoma and composite carcinoma.64

Mixed tumors demonstrates both medullary (C-cell) and follicular cell differentiation, the latter
with a follicular or papillary growth pattern. The tumor cells express reactivity to both
calcitonin and thyroglobulin.

The composite tumors of the thyroid show two distinct cell populations, thyroglobulin reactive
papillary carcinoma and calcitonin reactive medullary carcinoma. Composite tumors differ from
mixed tumors in that the parafollicular and follicular cell origin can be demonstrated in two
distinct cell populations rather than within the same tumor of mixed type.64

These tumors are uncommon, and only three reports document their cytologic features,70 , 71 ,
72 This author has no personal experience with them.

SUMMARY
Medullary thyroid carcinoma presents a characteristic cellular pattern with a wide variety of cell
shapes and sizes. The eccentric nuclear position, intranuclear cytoplasmic inclusions, fibrillar
cytoplasm, cytoplasmic processes, and azurophilic granules in the cytoplasm (by Romanowsky
stain) are diagnostic. The cytologic interpretation can be confirmed by demonstrating positive
reactivity to calcitonin, and by serum calcitonin levels.

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Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 13 - Thyroiditis

13
Thyroiditis

Thyroiditis, an inflammatory condition of the thyroid, can be classified according to its etiology, dur
classification by morphology and duration is accepted by most (Table 13.1).7

TABLE 13.1 CLASSIFICATION OF THYROIDITIS

Acute thyroiditis

Subacute or granulomatous thyroiditis

Chronic thyroiditis

Infectious thyroiditis

Fibrosing thyroiditis (Riedel's thyroiditis)

Hashimoto's thyroiditis (chronic

lymphocytic thyroiditis)
Any type of thyroiditis can be mistaken clinically for a neoplasm. Clinical and gross features such as
both inflammation and neoplasms. Without a biopsy, the distinction between thyroiditis and tumor

INFECTIOUS THYROIDITIS
Infectious diseases of the thyroid gland are rare. A detailed review was reported by Berger et al. in
infectious processes is attributed to its unique anatomic location and its rich system of drainage for

Acute bacterial thyroiditis is rapid in onset, with fever, pain, and tenderness; is most common in wo
suppurative thyroiditis is very uncommon in the cytopathology practice of thyroid aspirates. In the a
bacterial thyroiditis were encountered. Fine-needle biopsy is useful in the diagnosis of acute suppur
the differential diagnosis includes anaplastic carcinoma as well as granulomatous thyroiditis.

CHRONIC INFECTIOUS THYROIDITIS

Among the types of chronic infectious thyroiditis, mycobacterial and fungal infections and, with the
Pneumocystis carinii infections have been reported. Parasitic infestations, such as with Wucheria ba

Tuberculosis of the thyroid is extremely rare.6, 8, 12, 13, 14 Das et al.13 reported eight cases amon
lymphadenitis, one had pulmonary tuberculosis, and four had no known focus. Involvement of the th
lesions presenting as a cold abscess. The aspirates show necrotic acellular debris and granulomas co
special stains.

MYCOTIC INFECTIONS
Among the fungal diseases involving the thyroid gland, infection caused by Aspergillus sp. is reporte
approximately 20% of patients, the thyroid gland is infected with disseminated aspergillosis based on
17, 18, 19, 20

We have encountered one case of Aspergillus thyroiditis in an immunosuppressed patient with a ren
identified by aspiration biopsy and later confirmed following thyroidectomy (Fig. 13.1).
Figure 13.1. A. Aspiration biopsy specimen of a cold nodule in an immunosuppressed patient yiel
smear showing calcium oxalate crystals when viewed under crossed polarized light. C. Thyroidect
granulomatous inflammation.
 Figure 13.1. E. Higher magnification showing Aspergillus hyphae within a granuloma (arrows). F.

Other mycotic infections of the thyroid reported in the literature include Candida and cryptococcos

HIV INFECTION
Opportunistic infections involve the thyroid in patients with human immunodeficiency virus (HIV) inf
gland involved by HIV infection shows multiple cysts.32, 33

PNEUMOCYSTIS CARINII INFECTIONS OF THE THYROID

Thyroid gland involvement by P. carinii infection has generally been reported in immunosuppressed
infection.24, 25, 26, 27, 28, 29, 30, 31

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Patients with Pneumocystis carinii infection may present with a tender unilateral thyroid mass or di
Aspiration biopsies showed large amounts of granular, frothy material associated with bland spindle
silver stain demonstrated the presence of Pneumocystis carinii organisms in the frothy material (Fig
Figure 13.2. A. Fine-needle biopsy of a thyroid nodule in a patient with AIDS. There is granular, f
through them. B. Methenamine silver stain on the smear showed organisms with morphology cons
 Figure 13.3. A cell block preparation from an aspirate of a thyroid nodule in a patient with AIDS.
pattern. (Courtesy of Sedigheh-Keyhani-Rafagha, MD, FIAC, Professor of Clinical Pathology, Ohio S

PARASITIC INFESTATION
In developing countries with endemic infestation by Wucheria bancrofti, microfilaria has been occas
echinococcal cyst involving the thyroid is reported by Sodhani and co-workers.39

SARCOIDAL THYROIDITIS
Sarcoidosis of thyroid is rare and usually presents as a manifestation of a generalized disease.2, 3, 6
related to the thyroid disease, such as a diffuse asymmetrical enlargement or nodular goiter, or hyp

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Histologically, there are interfollicular non-caseating granulomas consisting of epithelioid cells and m
contain asteroids or Schaumann bodies.

Fine-needle aspiration biopsy is not a diagnostic modality for sarcoidosis of the thyroid. The findings
sarcoidosis. The cytologic presentation is that of characteristic non-caseating granulomas of sarcoid
 Figure 13.4. A. FNA of a thyroid nodule from a patient with a history of sarcoidosis. The smear sh
granulomas. C. Higher magnification showing aggregates of epithelioid cells, forming a non-casea

SUBACUTE GRANULOMATOUS THYROIDITIS

Subacute or granulomatous thyroiditis is a spontaneously remitting inflammatory disease considered
pseudotuberculous thyroiditis, viral thyroiditis, nonsuppurative thyroiditis, struma granulomatosa, a
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cell thyroiditis. It is reportedly common in women from the second to the fifth decades. Patients pr
the thyroid gland to an abrupt onset with chills, fever, severe neck pain, and symptoms of hyperthy
blood cell count, and low radioiodine level. There may be increased blood levels of thyroxine and tr
although recurrence is common. However, it is self-limiting, and thyroid functions gradually return t

Usually the entire gland is involved, but initially the disease may be focal. In such circumstances, a
nodular involvement. The characteristic
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microscopic features show destruction of the thyroid parenchyma with foreign body-type giant cells
infiltrate consists of neutrophils and eosinophils, as well as lymphocytes and plasma cells. Lymphoid

Figure 13.5. A. Histologic section of a thyroid involved by subacute (granulomatous) thyroiditis. T

granulomas with large multinucleated foreign body-type giant cells.

Cytopathologic Findings
Fine-needle biopsy as a diagnostic technique is not routinely used to confirm the diagnosis of subacu
Biopsies are performed in patients with an unusual presentation to rule out suppurative thyroiditis o
one rarely encounters a case in routine cytopathology practice; our experience is limited to less tha
review is presented by Chang et al.52

The cytopathologic features of subacute thyroiditis (Figs. 13.6, 13.7, 13.8) are presented in Table 13
the aspirate is cellular, characterized by several
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large multinucleated foreign body-type giant cells containing up to several hundred nuclei (Fig. 13.6
generally uniform, small, round to oval, with sharp nuclear membranes, finely granular chromatin, a
often seen in the vicinity of either follicular epithelial cells or colloid droplets (Fig. 13.6D). Distinct
cells (Fig. 13.7).
Figure 13.6. FNA from subacute (granulomatous) thyroiditis. A. Cellular aspirate with inflammato
Higher magnification highlighting the multinucleated foreign body-type giant cells. C. A Langhans
giant cells surrounding a blob of colloid.
Figure 13.7. A. Subacute (granulomatous) thyroiditis. A granuloma formed by epithelioid cells is

Figure 13.8. FNA of a painful thyroid mass in an older individual. A. Several fragments of stromal
showing stromal spindle-shaped cells and multinucleated giant cell.
 TABLE 13.2 CYTOPATHOLOGIC FEATURES OF SUBACUTE (GRANU

Cellularity Variable; can be highly cellular

Presentation Varying numbers of large multinucleated foreign-body-type giant cells somet

propor-
tions; contain large numbers of nuclei scattered throughout the cytoplasm
perimeter;
multinucleated cells discrete or in groups, often around colloid forming gr
usu-
ally identified; epithelioid cells ±; lymphocytes in varying numbers; germ
tingible
body histiocytes not present; neutrophils in acute stages

Epithelial Follicular and Hürthle cells with or without nuclear atypia in varying numb
cells

Background Spindle cells of stromal origin; stromal tissue fragments may be seen in late
inflammatory
debris in acute stages

Other inflammatory cells include spindle-shaped and/or plump epithelioid cells, lymphocytes, and p
be seen, along with cellular and inflammatory debris. Stromal cells are often aspirated, especially in
absent during the healing phase.

Differential Diagnosis
The cytologic pattern of an aspirated sample from subacute or granulomatous thyroiditis has charac
also be seen in several conditions affecting the thyroid gland (see "Multinucleated Giant Cells in Thy
thyroiditis and subacute (granulomatous) thyroiditis are discussed later in this chapter, in the sectio

Anaplastic carcinoma is important as a differential diagnosis clinically because both diseases presen
Occasionally, proliferating stromal fibroblasts may be mistaken for spindle cell-type anaplastic carci
Anaplastic Carcinoma versus Granulomatous Thyroiditis).

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SUBACUTE LYMPHOCYTIC THYROIDITIS

This relatively recently recognized entity is also referred to as "painless thyroiditis."56, 57, 58 Some
lymphocytic infiltrate. This type of thyroiditis is very common in the United States and is frequently
debatable. More information can be found in the literature.

RIEDEL'S THYROIDITIS (INVASIVE FIBROUS THYROIDITIS)

Invasive fibrous thyroiditis, the rarest form of thyroiditis,1, 2, 3, 59, 60, 61, 62, 63 primarily affects
struma. Originally described by Riedel in 1896, it is a progressive disease characterized by complete
process causes pressure symptoms in the neck, with fixation of the neck organs. Clinically, this form
granulomatous thyroiditis.

Grossly, the thyroid is rock-hard in consistency. The cut surface shows a loss of normal reddish-brow
is total destruction of the thyroid parenchyma, which is replaced by dense collagenized fibrous tissu
 Figure 13.9. A. Gross photograph of Riedel's thyroiditis. The cut surface of the right lobe shows a
lobulation. A fine-needle biopsy from such a lesion is likely to be unsatisfactory. B. Core-needle b
infiltrate. C. Higher magnification to show dense fibrosis.

Fine-needle biopsy yields no thyroid follicular cells. Rare documented cases with fine-needle biopsy
65, 66

CHRONIC LYMPHOCYTIC (HASHIMOTO'S) THYROIDITIS

Hashimoto's thyroiditis, first described in 1912, is the most common form of thyroiditis.1, 2, 3, 4, 5,
goiter, autoimmune thyroiditis, and chronic lymphocytic thyroiditis. It commonly occurs in females,
reported occurrence of this disease a decade earlier in areas of endemic goiter. Hashimoto's thyroid
are at risk of developing malignant lymphoma, stated to be 67- to 80-fold.76, 77

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Clinically, the disease is characterized by a diffuse firm, nontender goiter with or without nodularit
thyroiditis is an autoimmune disease with high titers of antithyroglobulin antibodies, antimicrosoma
Hashimoto's thyroiditis may be progressive, and it is an important cause of hypothyroidism.

Radiologic Findings
Imaging quite often shows patchy uptake or cold defects. Innumerable tiny hypoechoic nodules in bo

Gross and Histologic Features

Grossly, the thyroid is symmetrically enlarged, 2 to 4 times the normal size (Fig. 13.10), and both lo
also occur. The capsule is smooth and tense. The gland feels firm and rubbery. The cut surface is pa

Figure 13.10. Gross photograph of a thyroid with both lobes involved by Hashimoto's thyroiditis.

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Microscopically (Figs. 13.11, 13.12, 13.13, 13.14, 13.15, 13.16, 13.17, 13.18, 13.19, 13.20, 13.21), a
tissue. Progressive destruction of the thyroid parenchyma is seen, along with interlobular and interf
82, 83 The lymphoid infiltrate varies significantly from gland to gland and within the same gland. It
The lymphoplasmacytic infiltrate may obscure the thyroid follicles.
Figure 13.11. Histologic sections of Hashimoto's thyroiditis. A. Low power showing heavy inflamm
lymphoid follicles with expanded germinal centers. C. Higher magnification to show interfollicula
Figure 13.12. Hashimoto's thyroiditis. Heavy inflammatory infiltrate, lymphoid follicles with germ
Figure 13.13. Hashimoto's thyroiditis with prominent Hürthle cell metaplasia and lymphoid infi
Figure 13.14. Hashimoto's thyroiditis. A. Low power. Note multiple epithelial nodules and lymph
lymphoid infiltrate. FNA biopsy of such an area is likely to show a predominant or an exclusive HÃ

Figure 13.15. Hashimoto's thyroiditis medium-power view demonstrating varying-sized follicular n

Figure 13.16. Hashimoto's thyroiditis. Histologic section highlighting extensive Hürthle cell met
likely to show an admixture of Hürthle cells and lymphoplasmacytic cells. The nuclear atypia ca
typical change in Hashimoto's thyroiditis.
Figure 13.17. Another example of Hashimoto's thyroiditis with irregular follicles, some dilated an
significant perifollicular fibrosis.
Figure 13.18. Hashimoto's thyroiditis. An infrequent finding, showing dilated follicles filled with d
Figure 13.19. Hashimoto's thyroiditis. Embedded in the pools of lymphoplasmacytic infiltrate are
resembling the nuclei of conventional papillary carcinoma.
 Figure 13.20. A. Hashimoto's thyroiditis with extensive fibrosis, separating large areas of lympho

Figure 13.21. Fibrous variant of Hashimoto's thyroiditis with extensive fibrosis. The thyroid was g

The epithelial changes are varied and are characterized by oxyphilic change in the follicular epithel
formations. Oxyphilic change in the epithelium is considered a hallmark of Hashimoto's disease. The
However, these nodules are non-encapsulated. Papillary hyperplasia is also present. The follicles ma
regular follicular epithelium often show considerable atypia. The follicular cell nuclei may present a
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changes of papillary carcinoma. In some instances, the thyroid may contain aggregates of three to f
carcinoma (Fig. 13.19)81, 82 Multinucleated foreign-body-type giant cells may be seen infrequently.
part of the lobe may be seen. In later stages, there may be marked fibrosis with considerable atroph
infrequent occurrence. Still more rarely, thyroids may show squamous lined cysts referred to as lym

The intensity of the changes described above varies from lobe to lobe, as well as within a lobe. Vari
prominent feature, but the lymphocytic infiltration is diffuse and extensive. This is referred to as th

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FIBROUS VARIANT OF HASHIMOTO'S THYROIDITIS

The fibrous variant of Hashimoto's thyroiditis represents approximately 10% of cases.2 It occurs in sl
pressure symptoms. Grossly the gland is more fibrotic, larger. Histologically, it maintains the norma
Features such as lymphoid follicles with germinal centers, and Hürthle cell metaplasia, are readily
thyroiditis.

Cytopathologic Features
Aspirates of the thyroid gland involved by Hashimoto's disease show an admixture of polymorphic inf
13.26, 13.27, 13.28, 13.29, 13.30, 13.31, 13.32, 13.33, 13.34, 13.35, 13.36, 13.37).55, 84, 85, 86, 8
of involvement. Usually the inflammatory cells are comprised of lymphocytes, plasma cells, and lym
transforming lymphocytes, including immunoblasts and histiocytes with phagocytic debris (Fig. 13.25
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distorted and are seen as stretched fibers, frequently in dark, tangled masses (Fig. 13.24B).53 Aspir
centrifuged blood. Cytologic preparations of such aspirates show a dense population of lymphoid cel
aspirated may remain as tight groups of cells and may mimic a tissue fragment of follicular cells (Fig
discrete lymphocytes are not visualized. The author has encountered this problem on two occasions
lymphoid cells (Fig. 13.27C and 13.27D). The inflammatory infiltrate in Hashimoto's thyroiditis repre
are polyclonal for heavy-and light-chain immunoglobulins.
Figure 13.22. A. FNA of Hashimoto's thyroiditis, showing a mixture of inflammatory and epithelia
background of lymphoplasmacytic cells. C. These Hürthle cells demonstrate considerable nuclea
Figure 13.23. FNA of Hashimoto's thyroiditis. A. A characteristic pattern with cellular aspirate co
magnification. C. Diff-Quik stain.
Figure 13.24. A. This smear from an FNA of Hashimoto's thyroiditis shows loosely cohesive groups
identified. B. Another field from the same case showing several tissue fragments of Hürthle cell
lymphocytes.
Figure 13.25. A. Hashimoto's thyroiditis, lymphoid variety, showing a heavy inflammatory compo
of the lymph node. B. Higher magnification depicting polymorphic cell population representing th
Figure 13.26. FNA of Hashimoto's thyroiditis. This large aggregate of tightly packed lymphoid cell
follicular neoplasm. This may represent lymphocytes totally obscuring the follicular cells. Note di

Figure 13.27. A,B. FNA of Hashimoto's thyroiditis showing a large aggregate of tightly packed lym
pattern. This was misinterpreted as a follicular neoplasm. Thyroidectomy revealed typical change
these cells raised the possibility of being lymphoid cells. C. Immunostain for leukocyte common a
fragment shows central follicular cells, not reacting to leukocyte common antigen (LCA), and is su
Figure 13.28. A. Low-power view of a cellular aspirate from a case of Hashimoto's thyroiditis, con
neoplasm. B. Higher magnification demonstrating Hürthle cells with atypical but markedly pleo
diagnosis of thyroiditis. These Hürthle cells lack the typical nuclear morphology of Hürthle cel

Figure 13.29. A. Hashimoto's thyroiditis showing a large tissue fragment of Hürthle cells withou
contain prominent nucleoli. Hürthle cell neoplasm was suspected. B. The core-needle biopsy co
Figure 13.30. A. This aspirate from a case of Hashimoto's thyroiditis contained several tissue frag
magnification showing a monolayered sheet of Hürthle cells with uniform nuclei, lacking macron
Hürthle cells with bizarre nuclei. Such a presentation is not consistent with a Hürthle cell neo
Figure 13.31. FNA of Hashimoto's thyroiditis showing a syncytial tissue fragment of follicular cells
to be interpreted as a follicular neoplasm.
Figure 13.32. FNA of a thyroid nodule. The aspirate is cellular, with syncytial tissue fragments of
few lymphocytes are present in the background, suggesting Hashimoto's thyroiditis.
Figure 13.33. FNA of another case of Hashimoto's thyroiditis showing tissue fragments of follicula
cells in the background were overlooked and a diagnosis of follicular neoplasm was rendered. A co
Figure 13.34. FNA of a thyroid, with a clinical diagnosis of Hashimoto's thyroiditis. Note follicular

Figure 13.35. A. FNA of Hashimoto's thyroiditis showing multinucleated foreign-body-type giant c

seen only infrequently in aspirates of Hashimoto's thyroiditis. D. A stromal tissue fragment.
Figure 13.36. Hashimoto's thyroiditis versus subacute (granulomatous) thyroiditis. A. FNA of a c
significance. The presence of multinucleated giant cell alone does not favor the diagnosis of gran
demonstrate multinucleated giant cells.
Figure 13.37. Hashimoto's thyroiditis versus Hürthle cell neoplasm. A. FNA of a thyroid nodule
The background is clean. B,C. Higher magnification showing Hürthle cells lacking macronucleoli
Hürthle cell tumor was rendered. D. A large-needle biopsy revealed Hashimoto's thyroiditis. E. D
lymphoid tangles such as these in different smears should have suggested the diagnosis of Hashim
TABLE 13.3 CYTOPATHOLOGIC FEATURES OF CHRONIC LYMPHO

Cellularity Variable, generally highly cellular; paucicellular in late stages due to at

Presentation An admixture of inflammatory and epithelial cells in varying proportions

Epithelial cells

Hurthle cells Isolated, in loosely cohesive groups and in tissue fragments (in sheets an
size;
well-defined cell borders; abundant granular cytoplasm; nuclei round,
granular
chromatin; the characteristic macronucleoli seen in Hurthle cell neop
infrequently;
tissue fragments may be permeated and/or obscured by lymphoplasm

Follicular cells In loosely cohesive groups and in tissue fragments (in sheets and in sync
infrequent;
papillary-like pattern ±; nuclei round, variable in size; fine to coarse
micronucleoli ±;
intranuclear inclusions rare; nuclear grooves ± tissue fragments may
by lymphoplasmacytic infiltrate

Inflammatory Lymphocytes, plasma cells, and the entire range of transforming lympho
cells plasma
cells; tingible body histiocytes; lymphoid tangles and stretched out ly
packed aggre-
gates of lymphocytes difficult to differentiate from follicular cells; mu
giant cells ±
 Background Clean; scant or absent colloid; stromal cells, tissue fragments of fibrous

Epithelial cells, generally seen in tissue fragments, can also occur isolated and in aggregates. They r
component cells of the follicular or Hürthle cell tissue fragments are very cohesive and rather stic

The Hürthle cells are pleomorphic in size and shape (Figs. 13.22B, 13.22C, 13.24A, 13.24C, 13.28,
cherry-red nucleolus, a feature so characteristic of Hürthle cell neoplasms, is usually not seen.

The follicular cells may be their usual size or hyperplastic and are aspirated in tight clusters. When
aggregates of lymphocytes (Figs. 13.26 and 13.27). Tissue fragments of follicular epithelium rarely s
pleomorphism in size and hyperchromasia with the occasional presence of grooves and nuclear inclu
nuclear pattern of both Hürthle cells and regular follicular cells is more common in Hashimoto's th
even obscured by them. On the other hand, the follicular and/or Hürthle cells may predominate w
disease with increasing
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fibrosis, the aspirate is often acellular or poorly cellular, showing only a few lymphocytes.

Other nonspecific findings include the presence of multinucleated foreign body–type giant cells, w
occasionally seen (Fig. 13.35D).

There are frequent deviations from the usually encountered patterns described above that may resu
of this chapter.

Diagnostic Accuracy and Differential Diagnosis

Hashimoto's thyroiditis as a disease entity presents complex diagnostic problems, not only because t
mimic various types of neoplasia, but also because benign and malignant thyroid neoplasms occur fr
nodularity of the thyroid gland are seen in Hashimoto's thyroiditis, with or without a coexisting neop
of Hashimoto's thyroiditis with coexisting neoplasm from those that do not harbor any tumors. The d
unique and specific problem in cytologic specimens from Hashimoto's thyroiditis, because in a surgic
presence or absence of Hashimoto's disease does not appear as a problem. The cytologic evaluation

The incidence of neoplasia in the background of Hashimoto's thyroiditis is variably reported from les
number of patients with thyroiditis were subjected to surgery110, 111 because of high
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incidence of malignancy in surgical specimens. Hashimoto's thyroiditis, with its characteristic clinica
In doubtful cases, aspiration biopsy is very useful.

It is most difficult to judge the diagnostic accuracy of Hashimoto's thyroiditis because, in our practic
thyroiditis, an aspiration biopsy is performed primarily to rule out a neoplastic process under the fol
imaging defects; and (iii) enlarging tender goiter.

Also, some patients are asymptomatic and present with clinically palpable or ultrasonically detected
cytologic basis after an aspiration biopsy has been performed, and subsequently confirmed by routin

Cytologic errors in Hashimoto's thyroiditis can be grouped into two main categories:

False-positive diagnoses: diagnoses of neoplastic disease made when the cytologic changes o

False-negative diagnoses: failure to identify a neoplastic process coexistent with thyroiditis.

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Our initial experience in this field revealed many false-positive as well as false-negative results, ref
features. In later years, errors have been considerably minimized. Thus the statistics presented here

TABLE 13.4 CYTOHISTOLOGIC DATA ON 117 PATIENTS

 Cytologic Diagnosis

Lymphocytic thyroiditis

Lymphocytic thyroiditis and papillary carcinoma

Lymphocytic thyroiditis and cellular adenoma

Lymphocytic thyroiditis and

possible lymphoma

Cellular adenoma

Hürthle cell tumor

Suspected follicular carcinoma

Total

aOne patient developed malignant lymphoma 7 years after the diagnosis of lymphocytic
thyroiditis.

The first period includes 117 cases (Table 13.4) in which aspiration biopsy was performed because o
histologically. Thirteen cases were misinterpreted as follicular or Hürthle cell neoplasms. Three ca
thyroiditis was identified easily and accurately.
During the second period (Table 13.5), 398 patients had a cytologic diagnosis of Hashimoto's thyroid
a small number of patients (Table 13.5). It is noteworthy that coexistent diagnoses of follicular neop
lymphoma or papillary carcinoma in the presence of Hashimoto's thyroiditis was made more frequen

TABLE 13.5 CYTOHISTOLOGIC DATA ON 398 PATIENTS WITH HA

No. Patients No.

with Patients
No. Large-Needle with
Cytologic Diagnosis Patients Biopsy Surgery

Lymphocytic thyroiditis 307 45

Lymphocytic thyroiditis and 18 18 16

papillary thyroiditis

carcinoma 2

Lymphocytic thyroiditis and 9 1 3 1

suspected thyroiditis

papillary carcinoma 3

Lymphocytic thyroiditis and 21 21 18 18

malignant thyroiditis

lymphoma 1

2
Lymphocytic thyroiditis and 10 9 4 3
suspected thyroiditis

malignant lymphoma 6

Lymphocytic thyroiditis and 1 1

cellular

adenoma 1
thyroiditis

Lymphocytic thyroiditis and (? 15 4 2

) cellular

adenoma 2

Lymphocytic thyroiditis and 2 2 2 1

follicular thyroiditis

carcinoma 1
thyroiditis

Lymphocytic thyroiditis and (? 11 2 1

) Hürthle

cell tumor 1

Lymphocytic thyroiditis and 1 1 1

Hürthle cell
 carcinoma 1
Hürthle cell n

Lymphocytic thyroiditis and 1 1 1 1

carcinoma,

type unknown

Cellular adenoma 1 1 1

Hürthle cell tumor 1 1 1

Total 398

False-negative diagnoses of epithelial neoplasms in the background of thyroiditis are more often due
and may be missed (Table 13.4).

HASHIMOTO'S THYROIDITIS VERSUS OTHER DISEASES

Diagnostic difficulties can occur when Hashimoto's thyroiditis is mistaken for other diseases.56, 91,
presents lymphoplasmacytic cells along with epithelial cells and both components are present in fai
predominates, and the usual presentation is absent. Thus, cytologic changes of Hashimoto's thyroidi
differentiating features are summarized in Table 13.7.
TABLE 13.6 DIFFERENTIAL DIAGNOSIS OF HASHIMOTO'S THYROID

Subacute or granulomatous thyroiditis

Hürthle cell neoplasms

Follicular neoplasms (adenoma/carcinoma)

Papillary carcinoma

Malignant Lymphoma

TABLE 13.7 DIFFERENTIAL DIAGNOSIS OF HASHI

Chronic Lymphocytic Granulomatous

Thyroiditis (Subacute)
(Hashimoto's type) De Quervain Thyroiditis Hürthle Cell T

Cellularity Variable Variable Variable, generally

moderate to
marked

Presentation Admixture of Admixture of lymphoid Neoplastic cells iso

lymphoid and cells, in loosely
epithelial cells in epithelioid, cohesive groups,
varying histiocytes, large tissue frag-
proportions; multinucleated ments
follicular cells foreign-body-
 isolated, in loosely type giant cells,
cohe- epithelial
sive groups, and in cells in varying
tissue proportions;
fragments follicular cells
isolated, in
loosely cohesive
groups, and
in tissue fragments

Architecture of Mostly in In monolayered sheets In monolayered sh

tissue monolayered occasionally
fragments sheets, occasionally follicular pattern
with
syncytial
arrangement

Epithelial cell Either regular Either regular follicular Monomorphic (roun

follicular cell cell oval to
type or Hürthle type or Hürthle cell polygonal) in a g
cell type; type; neoplasm
pleomorphic in size pleomorphic in size

Epithelial cell Pleomorphic in size; Round, uniform in a Round to oval, var

nuclei round; given neo- enlarged but
fine to coarsely plasm; finely to niform; smooth n
granular granular chro- membrane;
chromatin; smooth matin; prominent finely granular
nuclear cherry-red chromatin; nucleo
membrane; nucleoli macronucleoli; inconsistent;
±; rare intranuclear intranuclear inclus
intranuclear inclusions absent; absent; generall
inclusions; generally absent (present in
 nuclear grooves absent (present in carcinoma); nuc
absent carcinoma); grooves absent
nuclear grooves
absent

Psammoma Exceptionally rare Absent Rare

bodies

Lymphoid cells With germinal center Mature lymphocytes; Absent

cells plasma
and plasma cells cells absent

Foreign-body- Occasionally present; Hallmark of the disease, Absent

type granu- enor-
giant cells lomas absent mous size with several
nuclei or Langhans
type

Epithelioid-type Absent Present, especially —

histiocytes around
blobs of colloid-
forming
granuloma

Hashimoto's Thyroiditis versus Granulomatous Thyroiditis

Multinucleated foreign-body-type giant cells are seen infrequently in aspirates of Hashimoto's thyroi
cells, granulomatous thyroiditis may be suspected. In the latter, giant cells are enormous in size and
fewer nuclei (Fig. 13.36). Lymphocytes are present in both, but germinal center cells are not presen
data are necessary to corroborate the cytologic findings.

Hashimoto's Thyroiditis versus Hürthle Cell Neoplasm

A pronounced Hürthle cell change in Hashimoto's thyroiditis can give rise to palpable nodules that
13.37 and 13.38). Aspiration biopsy specimen of such nodules will show a large population of Hürth
pitfall sometimes extends to histologic specimens as well.

Hürthle cells in aspirates of Hashimoto's thyroiditis are more often seen in cohesive groups or in ti
lacking the prominent macronucleolus of neoplastic Hürthle cells. The monomorphic pattern chara
exceptions do occur (Fig. 13.38). Hürthle cell neoplasms, on the other hand, have been interprete
 Figure 13.38. Hashimoto's thyroiditis versus Hürthle cell neoplasm. A. Low-power view of a ve
These Hürthle cells with high nuclear/cytoplasmic ratios and prominent macronucleoli were hig
needle biopsy specimen was equally indicative of Hürthle cell carcinoma. D. Higher magnificatio
with multiple Hürthle cell nodules. F. This Hürthle cell nodule was encapsulated with tumor e
that seen in the core biopsy with a solid growth pattern and forming trabeculae. Final diagnosis b

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Hashimoto's Thyroiditis versus Follicular Neoplasm

Follicular hyperplasia in Hashimoto's thyroiditis often results in nodule formation (Figs. 13.39, 13.40
infiltrate in these nodules may be focal or sparse, and the fine-needle biopsy specimens of such nod
cells appear very cohesive and are architecturally difficult to differentiate from syncytial-type tissu
presence of any inflammatory cells, such as lymphocytes or plasmacytes, suggests a nonneoplastic n
identification of the aspirate as that of Hashimoto's thyroiditis.

Figure 13.39. Hashimoto's thyroiditis versus follicular neoplasm. FNA of thyroid nodule. These sy
No lymphocytes are appreciated in the background. A cytologic diagnosis of follicular neoplasm w
Figure 13.40. Hashimoto's thyroiditis versus follicular neoplasm. Another example of Hashimoto'
tissue fragments of enlarged follicular cells with pleomorphic nuclei. The cytologic interpretation
failed to show any neoplasm but revealed Hashimoto's disease. D. Histologic section showing a lar
Figure 13.40. E. Medium power view showing a proliferative nodule. Note lymphoid aggregates. F

Figure 13.41. A,B. Hashimoto's thyroiditis versus follicular neoplasm. FNA of a thyroid nodule. T
and overlapping of mildly but uniformly enlarged nuclei. No Hürthle cells or lymphocytes are se
thyroiditis.
Figure 13.42. Hashimoto's thyroiditis versus follicular neoplasm. A,B. Aspirate showing tissue fra
cannot be differentiated from a follicular neoplasm.
Figure 13.42. C,D. Thyroidectomy showed features of Hashimoto's thyroiditis. There were multip
as a non-neoplastic lesion. It is not clear whether the biopsy sampled this nodule.

Figure 13.43. Hashimoto's thyroiditis versus follicular neoplasm. FNA of a thyroid nodule with cl
show marked nuclear atypia leading to a diagnosis of follicular carcinoma. The presence of lymph
on the part of the interpreter led to the misinterpretation. C. Thyroidectomy revealed Hashimoto
 Figure 13.44. Hashimoto's thyroiditis versus papillary carcinoma. A,B. An example of aspirate fro
lobe of thyroid from a patient who had undergone left thyroid lobectomy and right subtotal lobec
syncytial tissue fragments of follicular cells with enlarged and pleomorphic nuclei in the backgrou
these cells do not exhibit minimal cytologic criteria of papillary carcinoma, the clinical history inf
surgery. C. Histologic section of the resected lobe, showing Hürthle cell proliferation. D. Higher

One of the diagnostic clues for differentiating non-neoplastic proliferation of Hürthle cells or follic
unlike with a neoplasm.

Hashimoto's Thyroiditis versus Papillary Carcinoma

Epithelial changes in Hashimoto's thyroiditis may be misinterpreted as papillary carcinoma from cyto
changes include syncytial tissue fragments of follicular epithelium with papillary-like or monolayere
carcinoma. Berbo and Suster82 reported cases of Hashimoto's thyroiditis with microscopic foci of aty
case where few tissue fragments in the aspirated sample were interpreted as papillary carcinoma. H
papillary carcinoma, but there was no discrete tumor. It is not unusual to see occasional nuclear gro
giant cells must not be considered a feature of papillary carcinoma, in the absence of minimal crite
papillary carcinoma are not met. This diagnostic problem is discussed in detail in Chapter 9.

Figure 13.45. Hashimoto's thyroiditis versus papillary carcinoma. Another example of a misinterp
of the tissue fragments and the presence of multinucleated giant cells. The nuclei did not presen
thyroiditis.
Figure 13.46. Hashimoto's thyroiditis versus malignant lymphoma. FNA of a massively enlarged,
showing a diffuse lymphoid infiltrate. B. Higher magnification showing a monomorphic small cell
 lymphoid infiltrate with tingible body histiocytes. D. Some smears demonstrated a typical cytolog
background of lymphoid cells. E. This syncytial tissue fragment of follicular cells show enlarged p
performed. The thyroid was massively enlarged, the left lobe larger than the right. The cut surfac
right lobe shows a nodule in the upper pole. G. Histologic sections showed florid, lymphoid infiltr
magnification showing a heterogenous cell population. No papillary carcinoma was identified. Thi
Hashimoto's thyroiditis.

Hashimoto's Thyroiditis versus Malignant Lymphoma

Aspiration biopsy of the lymphoid variety of Hashimoto's thyroiditis will yield an aspirate containing
differentiation between the two disease entities is not possible without ancillary testing (Fig. 13.46)

Hashimoto's Thyroiditis and Associated Neoplasms

There is considerable controversy over the causal relationship between Hashimoto's thyroiditis and o
thyroiditis and other thyroid neoplasms (Table 13.8).104 The controversy stems from several inconsi
among pathologists.

TABLE 13.8 INCIDENCE OF NEOPLASMS IN HASHIMOTO'S

Hashimoto's
Thyroiditis Hashimoto's
plus Hashimoto's Thyroiditis
Benign and Thyroiditis plus
Hashimoto's Malignant plus Malignant
Reference (Year) Thyroiditis Neoplasms Carcinoma Lymphoma

Dailey et al.109 278 73 35

(1954) (36.2%) (17.7%)

Woolner et al.73 605 18 (3%) 12 (2%)

(1959)
Schlicke et al.107 103 9 (8.7%)
(1960)

Shands108 (1960) 44 18 (32%) 3 (7%)

Chesky106 (1962) 432 48 43 (10%) 5 (1.1%)

Hirabayashi and 752 169 (22.5%)

Lindsay105 (1965) (22.5%)

Holmes et al.76 60 10 (6.6%) 2 (3.3%) (3.5%)

(1977)

Crile104 (1978) 373 1

(0.37%)

Ott et al.103 (1985) 146 47 (32%)

Pollock and 52 6 5 (10%) (1.2%)

Sprang110 (1985) (11.5%)

Ott et al.101 (1987) 161 61 (38%)

Sclafani et 48 8 (17%)
al.109(1993)

McKee et al.99 115 16 (14%) 5 (4 %) 7 (6%)

(1993)
 Carson et al.98 90 7 (4%) 1 (1%)
(1996)

Nguyen et al.92 134 7 2 (1.5%)

(1997)

In a review of 1,150 surgical pathology reports on thyroidectomies from our series, a lymphocytic in
thyroiditis, chronic lymphocytic thyroiditis, nonspecific lymphocytic infiltrate, or nonspecific thyroid
concluded that the disease process can be diffuse or focal and that Hürthle cell change may not b
diagnosis of Hashimoto's thyroiditis. Because antibody titers from all patients who undergo thyroid s
correlated. LiVolsi and Marino112 have justly remarked that adequate serologic and clinical docume
direct correlation of the clinical level of thyroid-stimulating hormone, free thyroxine index (FTI), an
in papillary thyroid carcinomas to the host response, but Carcangiu and co-workers113 have questio

Although a detailed discussion of this debate is beyond the scope of this monograph, suffice it to say
is to identify the coexistence of two disease processes. Although we believe that malignant lymphom
we cannot say the same about Hürthle cell neoplasm or follicular cell neoplasm. The latter are dif
component of thyroiditis are almost identical to those seen in follicular/Hürthle cell neoplasms. T
hand, papillary carcinoma presents specific diagnostic criteria that can be appreciated even in the b
the basis of insufficient criteria (see Chapter 9). A malignant lymphoma, large cell type can be accu
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thyroiditis if sampled. The cytologic features and diagnostic pitfalls are described in Chapter 14.

The apparent ease with which a papillary carcinoma or diffuse large B-cell lymphoma can be diagno
by follicular or Hürthle cell neoplasms, is understandable and may be explained by the model pres
neoplastic processes (Fig. 13.47A). Involvement is, at times, diffuse and multicentric. Thus the aspir
of papillary carcinoma allow easy recognition of both or coexistent disease processes. On the other
Aspiration biopsy will sample only the lesion bordered by the capsule, not the adjacent parenchyma
identified only in surgically removed specimens. Metaplastic Hürthle cell nodules or hyperplastic f
and large. They almost always contain a lymphocytic infiltrate and even germinal centers. Thus aspi
be few in number and easily overlooked. Hence, we recommend extreme caution in the diagnosis of
practice to alert the clinician and suggest additional investigations. These include laboratory studies
Because thyroid neoplasms are slow-growing, it is not necessary to hasten surgical intervention.

Figure 13.47. A model to demonstrate the significance of lymphoid cells when follicular or Hür
A. Hashimoto's thyroiditis coexistent with discrete encapsulated neoplasms, such as follicular ade
papillary carcinoma. The aspirates will represent only the neoplasm, not the surrounding thyroid
external to the capsule is not sampled. Thyroiditis is diagnosed only after thyroidectomy. B. Hash
these appear discrete and palpable when enlarged, they are non-encapsulated and often have a l
shows a large population of epithelial cells (follicular or Hürthle) and a few lymphoplasmacytic
with malignant lymphoma or papillary carcinoma. The neoplastic process is quite often diffuse an
processes.
 Figure 13.48. A. Gross photograph of a thyroid involved by Hashimoto's disease. The right lobe is
confirmed as an encapsulated microfollicular adenoma. This corresponds to Figure 13.47A of the m
surrounding parenchyma.

Figure 13.49. A. Gross photograph of a thyroid involved by Hashimoto's thyroiditis and a papillary
Figure 13.47C of the model. B. Histologic section of papillary carcinoma on a core-needle biopsy.

Hashimoto's Thyroiditis and Papillary Carcinoma

Of the malignant neoplasms associated with Hashimoto's thyroiditis, papillary carcinoma (Figs. 13.49
author's laboratory, lymphocytic infiltration was noted cytologically in 36 cases (10%), and
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histologically in 92 cases (28%). This disparity is explained by the fact that the parenchymal involvem
needle biopsy (Fig. 13.47A). With adequate cellularity showing several of the cytologic features of p
Figure 13.50. Papillary carcinoma coexistent with Hashimoto's thyroiditis. A. FNA showing a mon
cytoplasmic inclusions (arrow), and lymphocytes in the background. B. Characteristic psammoma
background of lymphocytes,
 Figure 13.51. Anaplastic carcinoma arising in the background of Hashimoto's thyroiditis. A. FNA s
magnification to demonstrate marked nuclear atypia and is consistent with malignancy. The aspir
neoplastic epithelial type, seen in Hashimoto's thyroiditis. Thyroidectomy confirmed an anaplastic

Hashimoto's Thyroiditis and Malignant Lymphoma

The association between these two diseases has been recognized by most authors. Cytologic identifi
differentiated lymphoid cells without a mixture of polymorphic germinal center cells should alert th
features of Hashimoto's thyroiditis. Diagnosis of MALT lymphoma may be extremely difficult.

Other types of malignant neoplasms associated with Hashimoto's thyroiditis are not well documente
the background of Hashimoto's thyroiditis (refer to Chapter 19). We have seen one case of anaplasti
Hashimoto's Thyroiditis and Benign Neoplasms
Most of the literature has focused on the association between Hashimoto's thyroiditis and malignant
adenoma or Hürthle cell tumors.90, 91, 94

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We find it difficult to diagnose follicular or Hürthle cell neoplasms cytologically in the presence of
neoplasm. Without clinical or laboratory data, the association between the neoplasm and lymphoid

SUMMARY
Hashimoto's thyroiditis is a clinical disease entity that presents with a diffusely enlarged goiter acco
may be seen in conditions other than Hashimoto's thyroiditis, cytologically the aspirates may be repo
Not only is it a great imitator of various neoplasms, but the latter are frequently present in its back

Hashimoto's thyroiditis is a common disease entity, characterized by progressive destruction of thyro

varying degrees of nuclear atypia and heavy lymphoplasmacytic infiltrate with germinal centers. An

The aspiration biopsies are performed to identify co-existant neoplasms that occur with high inciden
malignant neoplasms.

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Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 14 - Malignant Lymphoma

14
Malignant Lymphoma

Primary malignant lymphomas of the thyroid are considered to be uncommon malignant

neoplasms of the thyroid. The reported incidence varies from 2% to 5% of all thyroid
malignancies.1 , 2 , 3 , 4 , 5 , 6 , 7 A higher incidence of 8% to 10% has been reported.8 , 9
Primary malignant lymphomas of the thyroid almost always arise in the background of
Hashimoto's thyroiditis1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 and are of B-cell
lineage. The relative risk of developing malignant lymphomas in patients with Hashimoto's
thyroiditis is reported to be up to 67 to 80 times higher than with a normal individual.15 , 16 It
takes on an average of 20 to 30 years for lymphoma to develop after the onset of lymphocytic
thyroiditis.17 Primary malignant lymphomas have attracted considerable interest.1 , 2 , 3 , 4 , 5
, 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ,
28 , 29 , 30 , 31 , 32 , 33 , 34 Over the last few decades there have been substantial advances in
our understanding of the development of primary lymphomas of the thyroid. A great deal of
information is now available in the literature, and it is beyond the scope of this monograph to
include the details. Some salient features are described below that may help understand the
mechanism of development of primary lymphomas in the thyroid, their cytohistologic patterns,
diagnostic features, limitations, and the use of ancillary tests in aid of diagnosis.

Primary lymphomas of the thyroid are basically of two types, referred to as extranodal marginal
zone B-cell lymphoma (ENMZBL) and diffuse large B-cell lymphoma (DBCLL). Isaacson and Wright
in 198435 noted the morphologic similarity between low-grade lymphomas of the stomach, lung,
salivary glands and thyroid (organs lacking native lymphoid tissue), which recapitulated those of
mucosa-associated lymphoid tissue (MALT), typified by Peyer patches in the intestine. They
coined the term MALT lymphoma to describe this group of extranodal lymphomas. Subsequently
it was appreciated that the common denominator for these extranodal lymphomas is that they
arise from the acquired lymphoid tissue in the setting of autoimmune disorders and demonstrate
features of MALT, which include lymphoid follicles and adjacent epithelium referred to as
lymphoepithelium.

MALT lymphomas are low-grade lymphomas, remain localized for a long period of time, and may
show progression to high grade. They have a tendency to involve the "mucosal" (extranodal) sites
and spare the bone marrow. It is felt by some5 that lymphomas of the thyroid referred to as
follicular lymphoma, diffuse small cleaved lymphoma, lymphocytic lymphoma, monocytoid B-cell
lymphoma, and plasmacytoma, that arise in the setting of Hashimoto's thyroiditis indeed
represent variants MALT lymphoma. The Revised European-American Classification of Lymphoid
Neoplasms (REAL)36 and the World Health Organization (WHO) Classification for Neoplastic
Diseases of the Lymphoid Tumors37 have referred to primary thyroid lymphomas as marginal
zone B-cell lymphoma of MALT type (MZBL) and diffuse large B-cell lymphoma (DLBCL).

Primary malignant lymphomas occur in elderly individuals in the sixth to seventh decades of life,
and are more frequent in women, with a female:male ratio of 4:1 although this differs in
younger age groups.8 , 26 The youngest patient reported was 11 years old,33 but the average
age is 63 to 65 years. Patients generally give a history of pre-existing goiter of variable duration.
Presenting symptoms include a rapidly enlarging, tender mass in the neck, often with pressure
symptoms such as dysphagia, hoarseness, or tracheal compression. These symptoms clinically
mimic those of anaplastic carcinomas.

Patients often have a history of Hashimoto's thyroiditis with a goiter. Derringer et al.3 reported
evidence of Hashimoto's thyroiditis in 94% of their cases. Antithyroid antibody levels are often
elevated.

RADIOLOGIC FINDINGS
Imaging shows cold nodules, cold areas in diffuse goiters, or patchy uptake.

GROSS AND HISTOLOGIC FEATURES

The lymphomas are often large, bulky, and involving a single lobe or both lobes of the thyroid,
but may present as a solitary nodule (Figs. 14.1 , 14.2 , 14.3 and 14.4 ). The gland is enlarged,
often several centimeters in the longest dimensions. The cut surface is
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bulging, smooth, homogeneous, pale, and pearly-white to pink with a "fish-flesh" appearance,
and may show areas of hemorrhage and necrosis (Fig. 14.4 ). They feel firm and rubbery on
palpation. Malignant lymphomas may extend beyond the thyroid capsule, involving the
surrounding soft tissues and skeletal muscle.

Figure 14.1. Gross photograph of thyroid with massive enlargement of the right lobe due to
involvement by malignant lymphoma. The tumor is bulky with a bulging cut surface presenting a
fish-flesh appearance.
Figure 14.2. Gross photograph of the thyroid with both lobes involved by malignant lymphoma.
Figure 14.3. This malignant lymphoma presented grossly as a discrete nodule.
Figure 14.4. Gross photograph of malignant lymphoma with areas of hemorrhage and necrosis.

Histologically, malignant lymphomas of the thyroid are grouped into two types:

Marginal zone B-cell lymphoma (MZBL).

Diffuse large B-cell lymphoma or DLBCL.

All thyroid primary lymphomas arise in the setting of Hashimoto's thyroiditis, features of which
may be identified in the biopsy specimens or excised glands depending on the extent of
involvement by lymphoma.

MARGINAL ZONE B-CELL LYMPHOMA (MZBL)

Histologically, extranodal marginal zone B-cell lymphoma (MZBL) shows either focal or diffuse
areas of confluent dense lymphoid infiltration with effacement of thyroid follicles. Reactive
lymphoid follicles are always present and may be extremely prominent. The lymphomatous
infiltrate is seen in between the lymphoid follicles replacing and pushing the thyroid
parenchyma peripherally (Fig. 14.5A ). This infiltrate is heterogenous or polymorphic,
characterized by an admixture of predominantly small lymphoid cells with variable proportions
of centrocyte-like cells, monocytoid B-cells, plasma cells, and dispersed large transformed
lymphocytes or immunoblasts (Figs. 14.5B ). Another feature of these lymphomas is the
colonization of the germinal centers of the lymphoid follicles by the lymphoma cells, often
completely replacing them. This colonization mimics the follicular pattern of reactive lymph
nodes (Fig. 14.6 ). However, they lack the starry-sky pattern of the germinal centers.

Figure 14.5. MALT lymphoma. Core-needle biopsy of thyroid. A. The malignant lymphoma cells
are infiltrating the interfollicular area (medium power). Note the darker area represents
lymphoid cells of the marginal zone. B. Higher magnification showing a heterogenous cell
population representing a mixture of lymphocytes, centrocyte-like cells, monocytoid B–cells,
and plasma cells.
Figure 14.6. Histologic section of MALT lymphoma. A. Low power showing a nodular pattern due
to colonization of the germinal center. B. Note the loss of starry-sky pattern. The lymphoma
cells are infiltrating the thyroid parenchyma extensively (medium power). C. Higher
magnification highlighting the polymorphic nature of the lymphoma cells.

Lymphoepithelial lesions are always present and are characteristic of MALT lymphoma. Two
types of lymphoepithelial lesions are described, one where the lymphoma cells are infiltrating
and growing into the thyroid follicles (Fig. 14.7A ) and the other consisting of lymphoma cells
filling the lumens and expanding the follicles, referred to as "MALT balls" (Fig. 14.7B ). Plasma
cell differentiation is more frequent in thyroid MZBL. It may be so pronounced as to suggest the
diagnosis of plasmacytoma.
Figure 14.7. MALT lymphoma, lymphoepithelial lesions. A. The thyroid parenchyma is diffusely
infiltrated by lymphoma cells involving the follicles, forming a lymphoepithelial lesion (arrow ).
B. The lymphoma cells are packed in the follicular lumen, referred to as "MALT balls" (arrow ).

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DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)

The diffuse large B-cell lymphomas are high-grade lesions and occur more commonly than
marginal-zone B-cell lymphomas, showing massive replacement of thyroid parenchyma by sheets
of poorly differentiated lymphoid cells representing the variants of large B-cell lymphomas,
including centroblast-like cells, immunoblasts, monocytoid B-cells, and plasma cell
differentiation. Focal Reed–Sternberg-like cells or Burkitt-like cells with brisk mitotic activity,
apoptosis, and starry sky pattern may be seen (Fig. 14.8 ). Lymphoepithelial lesions are usually
not present. Morphologic evidence of Hashimoto's thyroiditis is present in existing thyroid tissue
(Fig. 14.9 ). Some malignant lymphomas present prominent sclerosis (Fig. 14.10 ).
Figure 14.8. Histologic section of diffuse large B-cell lymphoma. A. The lymphoma cells are
large, monomorphic with an open chromatin pattern and contain nucleoli. B. Diffuse large B-cell
lymphoma (× 1,000).

Figure 14.9. A. Histologic section of malignant lymphoma of the thyroid, in the background of
Hashimoto's thyroiditis seen in the right half of the field. B. Higher magnification, to highlight
homogeneous population of large lymphoma cells.
Figure 14.10. Malignant lymphoma with sclerosis.

Lymphoma cells have a tendency to invade the walls of the blood vessels and extend into the
perithyroidal soft tissues and skeletal muscles (Fig. 14.11 ).3 , 11 Areas of progression to diffuse
large B-cell lymphoma from MALT lymphomas may be identified.
Figure 14.11. Malignant lymphoma of the thyroid, infiltrating the skeletal muscles of the neck.

Cytopathologic Features of Marginal Zone B-Cell Lymphoma

(MZBL)
The MALT-type malignant lymphomas are not very common and their cytopathologic features are
sparsely documented (Table 14.1 , Figs. 14.12 , 14.13 , 14.14 and 14.15 ).36 , 37 , 38 , 39 , 40 ,
41 , 42 , 43 , 44 , 45 The aspirates of marginal-zone B-cell lymphoma of MALT type consist of
heterogenous population of lymphoid cells characterized by an admixture of centrocyte-like
cells, monocytoid B-cells and plasma cells. The centrocyte-like cells are medium-sized lymphoid
cells (1.5 times the small lymphocyte), have deep-staining nuclei with condensed chromatin and
with irregular outlines. The monocytoid B-cells are larger and contain appreciable amounts of
pale cytoplasm. Plasma cells may be present in large numbers. Features suggestive of
lymphoepithelial lesions cannot be appreciated in cytologic samples.
Figure 14.12. MALT lymphoma. FNA of a diffusely enlarged thyroid. A. Polymorphic small
lymphoid cell infiltrate, lacking tingible body histiocytes. A malignant lymphoma can only be
suggested. B. Core biopsy of the thyroid showing a fragment of thyroid parenchyma heavily
infiltrated by lymphoid cells, low power. C. Medium power to show the effacement of thyroid
parenchyma by the lymphoid infiltrate. D. Higher magnification highlighting the cell composition
representing a heterogenous lymphoid population including some immature forms (× 1,000).

Figure 14.13. MALT lymphoma. A. FNA of an enlarged thyroid. This infiltrate composed of small
lymphoid cells was interpreted at an outside hospital as Hashimoto's thyroiditis. Note that the
cells are heterogenous, consisting of small lymphocytes some larger and occasional monocytoid
B-cells. A diagnosis of lymphoma can only be suggested as no tingible body histiocytes or
follicular/Hürthle component were present. B. Core-needle biopsy showed heavy lymphoid
infiltrate, low power.
Figure 14.13. C. Higher magnification showing diffuse lymphoid infiltrate replacing the thyroid
parenchyma. D. Histologic section of the thyroid confirming malignant lymphoma. Note
lymphoepithelial lesions (arrows ). E. Higher magnification to highlight the cell composition.
Figure 14.14. MALT lymphoma. An FNA of a 5-cm thyroid mass, enlarging over a period of 1 year
in an 80-year-old woman. Antibody titers were extremely high. A. The aspirate shows
predominantly immature lymphoid cells with karyorrhexis. Thyroidectomy confirmed MALT
lymphoma. B. Histologic section showing diffuse lymphoid infiltrate replacing the thyroid
parenchyma. Lymphoepithelial lesions can be identified (arrow ). C. Higher magnification
showing heterogenous lymphoid cell population (× 1,000).
Figure 14.15. MALT lymphoma developed 7 years after the diagnosis of Hashimoto's thyroiditis.
A. FNA showing massive lymphoid infiltrate. No epithelial component is identified. B. Higher
magnification showing germinal center cells including tingible body histiocytes. A diagnosis of
Hashimoto's thyroiditis was rendered. The patient was lost to follow-up for 7 years and was seen
at an outside facility for rapidly enlarging thyroid, where an FNA was interpreted as Hashimoto's
thyroiditis. The patient was referred for a cutting needle biopsy. C. Core needle biopsy at low
power shows a dense lymphoid infiltrate. D. Higher magnification showing lymphoid cells
infiltrating and destroying the thyroid parenchyma. Note lymphoepithelial lesions. E.
Heterogeneous cell population consistent with MALT Lymphoma (× 1,000).
Cellularity
Variable, usually very cellular
Presentation
Heavy lymphoid cell population, with or without epithelial cell component
Characteristics of lymphoid cell population
Heterogenous population representing an admixture of small lymphocytes,
centrocyte-like cells (1.5 times the size of resting lymphocyte) with deep-staining
chromatin and irregular nuclear membranes; monocytoid B-cells with appreciable
pale cytoplasm; plasma cells; scattered centroblasts and immunoblasts; mitotic
activity insignificant; karyorrhexis ±; lymphoglandular bodies ±
Features of Hashimoto's thyroiditis
May be present in the same smear or in smears representing different sampled areas
Background
Usually clean
Immunoprofile
CD 20 +, CD 79a +, CD 5 -, CD 10 -; occasional coexpression of CD43 with
CD 20; express IgM, less often than IgA or IgG with light-chain restriction
Flow cytometry
Monoclonal

TABLE 14.1 CYTOPATHOLOGIC FEATURES OF MARGINAL

ZONE B-CELL LYMPHOMA (MZBL)
The aspirates of marginal zone B-cell lymphoma may also demonstrate features of underlying
Hashimoto's thyroiditis, specifically an epithelial cell component characterized by Hürthle cells
and follicular cells along with lymphoplasmacytic
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cells. This polymorphic lymphoid infiltrate of Hashimoto's thyroiditis is practically impossible to
differentiate from the heterogenous neoplastic infiltrate of MZBL without the aid of ancillary
diagnostic techniques. Identification of fair numbers of transformed lymphocytes may serve as a
diagnostic clue.
Cytopathologic Features of Diffuse Large B-Cell Lymphoma
(DLBC)
Diffuse large B-cell lymphomas are more common than MALT-type lymphomas, and so the
cytologic features have been reported more frequently.39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ,
48 Aspirates of DLBCL tend
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to be very cellular (Table 14.2 , Fig. 14.16 ). The cell spreads show a dense and homogeneous
population of poorly differentiated lymphoid cells, larger than the normal lymphocytes. Their
morphology depends on the morphologic variant (Figs. 14.16 , 14.17 , 14.18 , 14.19 , 14.20 ,
14.21 , 14.22 , 14.23 and 14.24 ). The lymphoma cells are usually discrete and round, with
scanty, pale cytoplasm. The nuclei are large, with high N/C ratios and contain finely granular
chromatin that gives an open pattern, in contrast to the compact nuclei of the mature
lymphocytes. Nucleoli are always present, either small and multiple in a marginal location
(centroblast), or large in a central position (immunoblast). Mitotic activity is frequent.
Karyorrhexis is a common feature of high-grade malignant lymphoma. Fragmented nuclei are
often seen in the background and also as phagocytized debris in the histiocytes. Another
characteristic feature seen only in Romanowsky-stained preparations is the presence of
detached fragments of the cytoplasm of lymphoma cells, about the size of platelets. They stain
basophilic and are referred to as "lymphoglandular
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bodies." In exfoliative cytology, lymphoma cells are characterized by a discrete pattern. But in
the material obtained by an aspiration biopsy, it is not unusual to find a tissue fragment of
lymphoma cells (Figs. 14.19B and 14.24 ). These fragments of small, round cells with scanty
cytoplasm should not be mistaken for carcinoma. Tumor diathesis is often seen in the
background. Lymphoma cells are usually seen in large aggregates or masses. Being very fragile,
they may appear as lymphoid tangles (Fig. 14.22C ). In such areas, features of Hashimoto's
disease (germinal center cells or epithelial cells) are conspicuously absent.
Figure 14.16. A. FNA of malignant lymphoma showing a dense population of lymphoid cells
(medium power). B. Higher magnification to depict the monomorphic population of poorly
differentiated lymphoid cells (× 1,000). C. Histologic section of thyroid showing malignant
lymphoma, diffuse large cell type.
Figure 14.17. FNA of a diffuse large B-cell lymphoma (Diff-Quik stain).

Figure 14.18. FNA of a diffuse large B-cell lymphoma. A. Monomorphic population of poorly
differentiated lymphoid cells. B. Imprint of the lymphoma stained by hematoxylin and eosin.
Figure 14.19. FNA of diffuse large B-cell lymphoma. A. Discrete large, poorly differentiated
lymphoid cells with scanty cytoplasm, large nuclei with an open chromatin pattern, and multiple
nucleoli (× 1,000). B. Another field from the smear showing mitosis and karyorrhexis (×
1,000). Thyroidectomy confirmed malignant lymphoma, Burkitt type, and associated Hashimoto's
thyroiditis. C. Histologic section of the lymphoma, showing a typical "starry-sky" pattern. D.
Higher magnification.
Figure 14.20. Aspiration biopsy specimen of malignant lymphoma, signet ring cell type. A. Note
the cytoplasmic secretions (× 1,000). B. Romanowsky-stained preparation (× 1,000).
Thyroidectomy revealed a signet ring cell lymphoma in the background of Hashimoto's
thyroiditis.

Figure 14.20. C. Section of the thyroid showing signet ring cell lymphoma (× 1,000).
Figure 14.21. A. FNA of malignant lymphoma with extreme plasmacytic differentiation
(plasmacytoma of the thyroid) with a large population of poorly differentiated plasma cells (×
1,000). B. Large-needle biopsy specimen confirmed plasmacytoma.
Figure 14.22. A. Diffuse large B-cell lymphoma with histiocytes containing karyorrhectic debris.
These are not indicative of tingible body histiocytes as seen in germinal centers. The background
cell population is monomorphic and represents poorly differentiated lymphoid cells. An open
biopsy specimen revealed diffuse large cell lymphoma infiltrating the soft tissues of the neck. B.
Another example of diffuse large B-cell lymphoma with histiocytes containing karyorrhectic
debris. C. This aspirate of a large cell lymphoma is partially air-dried and poorly preserved. Note
lymphoid tangles. Such a preparation will not allow the diagnosis of malignant lymphoma.

Figure 14.23. Malignant lymphoma large cell type. A. The tumor diathesis and large nuclear size
suggested the differential diagnosis of poorly differentiated carcinoma and malignant lymphoma.
Thyroidectomy confirmed diffuse large cell lymphoma and associated Hashimoto's thyroiditis. B.
Section of the thyroid showing large cell lymphoma (× l,000).
Figure 14.24. FNA of malignant lymphoma with tissue fragments of lymphoma cells. A diagnosis
of poorly differentiated carcinoma was also considered (× 1,000). Thyroidectomy revealed
diffuse, large cell lymphoma and associated Hashimoto's thyroiditis.

Cellularity
Variable, usually very cellular
Presentation
Sheets of homogeneous cell population; cells discrete but rare
tissue fragments may be present
Characteristics of lymphoid
cell population
Poorly differentiated lymphoid cell (transformed lymphocytes)
with features of specific morphologic variant: centroblastic;
immunoblastic; plasmacytoma; Burkitt type; signet-ring type,
anaplastic; brisk mitotic activity; lymphoglandular bodies in
Romanowsky-stained preparations; karyorrhexis; histiocytes
with karyorrhectic debris
Features of Hashimoto's
thyroiditis
May be present in smears representing other sampled areas
Background
Often dirty with cellular and necrotic debris
Immunoprofile
CD 20 + , CD 79a + , CD 5 - , CD 10 -; express IgM, less often
IgA or IgG with light-chain restriction
Flow cytometry
Monoclonal

TABLE 14.2 CYTOPATHOLOGIC FEATURES OF DIFFUSE

LARGE B-CELL LYMPHOMA (DLBCL)
Dependent on the sampling, however, cytologic features of Hashimoto's thyroiditis may be
present, either separately from lymphoma cells on the same smear or on different smears
representing other areas of the thyroid. Such a varied pattern is not infrequent when the thyroid
is focally involved or when the malignant lymphoma is of the nodular type. Thyroid epithelial
neoplasms, especially papillary carcinoma, can occur in the background of thyroiditis and
malignant lymphoma (refer to "Multiple Neoplasms in the Thyroid" in Chapter 19 ).

IMMUNOCYTOHISTOCHEMICAL PROFILE
Cytologic diagnosis of malignant lymphoma can be confirmed by immunocytochemical stains on
the smears.1 , 2 , 3 , 4 , 28 , 39 , 45 , 49 If a diagnosis of malignant lymphoma is clinically
suspected, and if an immediate diagnosis is available on-site, additional cellular material can be
obtained for the ancillary diagnostic techniques to further type the malignant lymphoma.

Malignant lymphoma cells are positive for leukocyte common antigen, which helps differentiate
lymphoma from carcinoma. Cytokeratin can be used for the same purpose because of its
negative reactivity in malignant lymphoma cells. However, antibodies to cytokeratin will
highlight the epithelial remnants in the lymphoepithelial lesions.

Because primary thyroid lymphomas are B-cell derived, pan B-cell markers are useful.28
Malignant lymphomas can be confirmed by their positive reactivity to light-chain
immunoglobulins, either kappa or lambda, and establish the clonality. B-cell lymphomas are
reactive to CD20 and or CD79a. Coexpression of CD43 with CD20 is seen in a small percentage of
marginal zone B-cell lymphomas. They are nonreactive to CD5, CD10, and CD23.

The histologic and cytologic recognition of diffuse large B-cell lymphoma is facilitated because
of the homogeneous and diffuse population of poorly differentiated lymphoid cells, unlike that
of MALT lymphoma. Their cytohistologic differentiating features are listed in Table 14.3 .

FNA: Cellularity
Variable
Usually high
Cell population
Heterogenous, composed of small lymphocytes,
centrocyte-like cells, monocytoid B-cells, plasma
cells, scattered centroblasts and immunoblasts in
varying proportions; mitotic activity -
Homogeneous population of poorly differentiated
lymphoid cells, dependant on the morphologic
type; high mitotic activity; karyorrhexis; lym-
phoglandular bodies in Romanowsky-stained
smears
Histology:
Location of the infiltrate
In the marginal zone of reactive B-cell follicles,
extending into the interfollicular region, and
involve parenchyma; effacement of the architec-
ture ±; colonization of the germinal centers,
eventually replacing it entirely with lymphoma
cells resembling nodular lymphoma; transition to
large cell lymphoma may be present
Diffuse sheets and islands of malignant cells with
effacement of the architecture; necrosis ±; high
mitotic rate
Lymphoepithelial
lesions

1.
2.
 1. Involvement of the follicles
2. Formation of "MALT" balls

Not present
Vascular invasion
±
Easily identified
Evidence of Hashimoto's
disease in the thyroid
Present
Present in the remnants
Extrathyroidal extension
±
Frequent
Immunoprofile
CD 20 + , CD 79a + ,
CD 5 - , CD 10 -
CD 20 + , CD 79a + ,
CD 5 - , CD 10 -
Immunoglobulin
Express IgM, less often IgA or
IgG with light-chain restriction
Express IgM, less often IgA or
IgG with light-chain restriction
Flow cytometry
Monoclonal
Monoclonal
Differential diagnosis
Hashimoto's thyroiditis
Neoplasms composed of small cells:
Anaplastic carcinoma
Medullary thyroid carcinoma with small pattern
Insular carcinoma
Metastatic small cell carcinoma
Clinical behavior
Indolent, slow to recurrences, may involve
other extranodal sites
Very aggressive

Extranodal Marginal Zone B-Cell Lymphoma Diffuse Large B-Cell Lymphoma

TABLE 14.3 CYTOHISTOLOGIC FEATURES OF PRIMARY

MALIGNANT LYMPHOMAS OF THE THYROID

DIAGNOSTIC ACCURACY
Accuracy of cytopathologic diagnosis of primary malignant lymphoma of the thyroid depends on
several factors, such as adequacy of the specimen and proper cytopreparatory technique, as
well as the interpreter's familiarity with their cytopathologic patterns. Lymphoma cells are very
fragile and dry quickly unless wet-fixed immediately for Papanicolaou stain. Drying artifacts
prevent proper cytopathologic evaluation. The literature on the cytologic features of primary
malignant lymphomas of the thyroid
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and their diagnostic pitfalls is very limited. 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48
Inadequate specimens and/or inexperience are prime reasons for false-negative results. Due to
inexperience, our first three cases of malignant lymphoma were interpreted as lymphocytic
thyroiditis (Table 14.4 ).7 The polymorphic lymphoid infiltrate of MALT is extremely difficult to
differentiate from the infiltrate of Hashimoto's thyroiditis, both histologically and cytologically.
Hyjek et al.,14 in a retrospective review of Hashimoto's thyroiditis, identified five out of 21
cases as MALT lymphoma. Saangalli et al.40 interpreted three out of 10 MALT lymphomas as
Hashimoto's thyroiditis. Others have reported similar experience.7 , 26 , 43 , 49 , 50 , 51 , 52 ,
53 , 54 , 55 , 56 , 57

Malignant lymphoma
23
20
2
1
(?) Malignant lymphoma,
(?) carcinoma
2
2
—
—
Suspicious malignant
lymphoma
10
3
—
7

Histologic Diagnosis

Atypical

Cytologic Malignant Lymphoid Hashimoto's

Diagnosis No. Lymphoma Hyperplasia Thyroiditis

TABLE 14.4 HISTOLOGIC DIAGNOSES OF 35 CASES OF

CYTOLOGICALLY DIAGNOSED MALIGNANT LYMPHOMA OR
SUSPECTED MALIGNANT LYMPHOMA
In the author's laboratory, 35 cases were cytologically interpreted as either diagnostic or
suspicious for lymphoma. Of 23 cases cytologically interpreted as diagnostic of malignant
lymphoma, 20 were confirmed by large-needle biopsy, thyroidectomy, or both. Two were
difficult to interpret histologically, but had a final diagnosis of atypical lymphoid hyperplasia;
and one was Hashimoto's thyroiditis. Of the 10 cases of suspected malignant lymphoma, only
three were confirmed (Table 14.4 ). Ancillary tests were either not available or not performed,
which would have been immensely helpful.

Of 32 histologically confirmed malignant lymphomas, 20 cases were correctly interpreted from

fine-needle aspirates (Table 14.5 ). Typing errors are occasionally involved between large cell
lymphomas and poorly differentiated carcinomas. Two cases had a differential diagnosis of
malignant lymphoma and poorly differentiated carcinoma (Table 14.5 ).

Malignant lymphoma
2
Malignant lymphoma and lymphocytic thyroiditis
18
Suspected malignant lymphoma and lymphocytic thyroiditis
3
(?) Carcinoma, (?) malignant lymphoma, lymphocytic thyroiditis
2
Lymphocytic thyroiditisa
3
Unsatisfactory (acellular)a
4
Total
32
a Diagnosis of malignant lymphoma based on large-needle biopsy specimen.

TABLE 14.5 CYTOLOGIC DIAGNOSES OF 32 PRIMARY NON-

HODGKIN'S MALIGNANT LYMPHOMA OF THE THYROID
Some false-positive results must be anticipated in the cytologic diagnosis of malignant lymphoma
if false-negative results are to be avoided, and in order to maintain a high sensitivity for its
diagnosis. With the aid of immunocytochemistry and flow cytometry, the diagnosis of malignant
lymphoma can be readily established.

DIAGNOSTIC DIFFICULTIES AND DIFFERENTIAL DIAGNOSIS

Just as the diagnosis of malignant lymphoma of the thyroid is difficult histologically, either by
large-needle biopsy specimen50 or in surgically excised specimens, cytologic diagnosis51 , 52 ,
53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 may pose similar problems, for the following reasons:

The aspirates from MALT lymphomas show heterogenous population of small

lymphocytes, centrocyte-like cells, monocytoid B-cells, and plasma cells with variable
numbers of transformed lymphocytes. These cells are difficult to differentiate from
 lymphoid cells of Hashimoto's thyroiditis. A large number of transformed lymphocytes as
well as very heavy lymphoid infiltrate should raise the suspicion of MALT lymphoma. Any
diagnostic concern should be followed by ancillary tests. A repeat aspiration biopsy is in
order if the initial specimen is inadequate. A large-needle biopsy can be quite helpful.7 ,
26 , 50

Lymphomas, when involvement is focal, multiple samples may show lymphoma cells on
some cell spreads and evidence of Hashimoto's thyroiditis on others. Such a diverse
pattern is often present. A cytologic pattern of Hashimoto's disease on one of the
specimens should not be a deterrent to rendering a diagnosis of lymphoma.

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Phagocytic histiocytes with karyorrhectic debris are seen frequently in large cell
lymphomas (Fig. 14.22B ). These should not be mistaken for germinal-center cells.

Lymphoma cells, especially of the large cell type, are large and may be mistaken for
carcinoma

Aspiration biopsy may yield a few tissue fragments of neoplastic lymphoid cells. The
traditional diagnostic criteria of malignant lymphoma in exfoliative cytopathology
include a single cell pattern; the presence of a tissue fragment should not be considered
a feature contradicting the diagnosis of malignant lymphoma (Fig. 14.24 ).

The differential diagnoses of MALT lymphoma include Hashimoto's thyroiditis with florid
lymphoid infiltrate (lymphoid verity) (Table 14.7 ). The diffuse large B-cell lymphoma may be
typed as anaplastic carcinoma or poorly differentiated insular carcinoma of the thyroid,
medullary carcinoma with small cell pattern, and a metastatic small cell carcinoma (Table 14.6
and Table 14.8 ; also refer to Table 10.3 and Figures 10.15 , 10.16 , 10.17 , 10.18 and 10.19 ).

Extranodal marginal zone B-cell lymphoma

Hashimoto's thyroiditis
Diffuse large B-cell lymphoma
Anaplastic carcinoma
Insular carcinoma
Medullary carcinoma, small cell type
Metastatic small cell carcinoma
 TABLE 14.6 DIFFERENTIAL DIAGNOSIS OF PRIMARY
MALIGNANT LYMPHOMA OF THE THYROID

Cellularity
Variable, generally highly cellular; paucicellular in
late stages due to atrophy and fibrosis
Variable, usually very cellular
Presentation
An admixture of inflammatory and epithelial cells in
varying proportions
Heavy lymphoid cell population; epithelial cells ±
Characteristics of
lymphoid cell
population
Heterogenous cell population, consisting of lympho-
cytes, plasma cells, and the entire range of trans-
forming lymphocytes (germinal center cells);
plasma cells; tingible body histiocytes; lymphoid
tangles and stretched out lymphocytes; large
closely packed aggregates of lymphocytes diffi-
cult to differentiate from follicular cells;
Heterogenous population representing an admix-
ture of small lymphocytes, centrocyte-like cells
(1.5 times the size of resting lymphocyte) with
deep-staining chromatin and irregular nuclear
membranes; monocytoid B-cells with apprecia-
ble pale cytoplasm; plasma cells; scattered cen-
troblasts and immunoblasts; mitotic activity
insignificant; karyorrhexis ±;
Characteristics of
epithelial component
(follicular and Hürthle
cells)
In variable proportions; one type may predominate;
in groups or in tissue fragments, with or without
nuclear atypia; may be obscured by lymphocytes
Same as Hashimoto's thyroiditis if present in the
aspirated sample
Background
Clean; multinucleated foreign body-type giant cells
±; scant or absent colloid; stromal cells, tissue
fragments of fibrous tissue ±; endothelial cells
Clean; no colloid; no multinucleated foreign-body
type giant cells; stromal cells or tissue frag-
ments of stroma ±
Flow cytometry
Polyclonal
Monoclonal

Extranodal Marginal Zone

B-Cell Lymphoma
Hashimoto's Thyroiditis (MALT Lymphoma)

TABLE 14.7 DIFFERENTIATING FEATURES BETWEEN

HASHIMOTO'S THYROIDITIS AND MARGINAL ZONE B-CELL
LYMPHOMA (MALT LYMPHOMA)

Large B-cell lymphoma

Dispersed cell pattern; syncytial tissue fragment very rare; monomorphic population of
immature
lymphoid cells; poorly defined cell borders; high N/C ratios; large nucleus with smooth to
irregular
nuclear membrane, finely granular chromatin; parachromatin clearing, nucleoli +; mitosis ±;
karyorrhexis +; nuclear molding absent; scant cytoplasm; lymphoglandular bodies in
Romanowsky-
stained preparations; LCA +; thyroglobulin, TTF-1, and calcitonin negative
Anaplastic Carcinoma
 (Small round cell type)
Variable cellularity; malignant cells isolated and in tissue fragments; size variable; high N/C
ratios;
nucleus round with smooth to irregular membranes; granular chromatin with parachromatin
clearing;
single to multiple nucleoli; mitosis with atypical forms ±; karyorrhexis +; lymphoglandular
bodies
absent; leukophagocytosis +/-; scant, nondescript cytoplasm; cytokeratin +; negative
reactivity
to LCA, thyroglobulin, TTF-1, calcitonin, and neuroendocrine markers
Medullary carcinoma with
a small cell pattern
Neoplastic cells discrete, in loosely cohesive groups; syncytial tissue fragments infrequent;
pseudofol-
licular pattern ±; small size, monomorphic, poorly defined cell borders; high N/C ratios;
eccentric
nuclei; round with smooth nuclear membranes; coarsely granular to chunky chromatin;
nucleoli usu-
ally absent; mitosis unusual; karyorrhexis -; no nuclear molding; no stretch artifacts;
intranuclear
inclusions ±; nuclear grooves -; scant cytoplasm with rudimentary cytoplasmic tailing; colloid
absent in the background; amyloid ±; positive reactivity to calcitonin, neuroendocrine
markers,
cytokeratin; negative reactivity to LCA, thyroglobulin, TTF-1
Metastatic small cell
carcinoma
Marked cellularity; small cells; round to oval; indiscernible cytoplasm; poorly defined cell
borders; high
N/C ratios; coarse, deep-staining chromatin; nucleoli absent or not appreciated; mitosis
frequent;
nuclear molding characteristic; mitosis frequent; stretch artifacts +; karyorrhexis -; positive
reac-
tivity to cytokeratin, TTF-1, and neuroendocrine markers; negative reactivity to LCA and
calcitonin
 Tumor Type Cytopathologic Features

TABLE 14.8 DIFFERENTIAL DIAGNOSIS OF DIFFUSE LARGE B-

CELL LYMPHOMA

Malignant Lymphoma versus Hashimoto's Thyroiditis

In the lymphoid variety of Hashimoto's thyroiditis, the aspirates generally exhibit a dense
population of lymphoid cells, without an admixture of epithelial cells. The presence of
polymorphic germinal center cells favors the diagnosis of Hashimoto's thyroiditis. However, it is
sometimes very difficult to rule out a malignant lymphoma from the cytologic or histologic
specimens without the aid of immunocytohistochemistry and flow cytometry. These cases are
interpreted as atypical lymphoid hyperplasia. Whether atypical lymphoid hyperplasia represents
an early stage in the evolution of malignant lymphoma in the background of thyroiditis is a
subject beyond the scope of this text. Compagno and Oertel11 have also referred to this
problem. Cytologically, such cases may be diagnosed as malignant lymphoma or suspected
malignant lymphoma and must be followed by ancillary testing. Figures 14.25 and 14.26
illustrate two examples of such cases from our experience.
Figure 14.25. A. FNA showing a dense population of lymphoid cells. No follicular/Hürthle cells
are seen (low power). B. Higher magnification showing a mixed cell population with many
plasma cells.

Figure 14.25. C. This field shows a tingible body histiocyte. Because of the dense lymphoid
infiltrate, malignant lymphoma was suspected. Thyroidectomy showed florid Hashimoto's
thyroiditis and no malignant lymphoma. Immunostains and flow cytometry would have been
helpful in confirming or ruling out malignant lymphoma.
Figure 14.26. Another example of atypical lymphoid infiltrate on cytology suspected of
malignant lymphoma. A large-needle biopsy did not confirm the cytologic diagnosis.

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P.340

Malignant Lymphoma versus Anaplastic Carcinoma

Malignant lymphomas have been mistyped as anaplastic carcinomas both histologically and
cytologically.41 , 61 The large size of the lymphoma cells (Figs. 14.23A and 14.27 ), as well as
the presence of tissue fragments (Fig. 14.24 )—a feature common to epithelial neoplasms,
were reasons for mistyping the malignant lymphoma as anaplastic carcinoma.
Immunocytochemical stains and flow cytometry are required to confirm the diagnosis.

Figure 14.27. Fine-needle aspiration biopsy of a rapidly enlarging thyroid in a 51-year-old male.
A,B. The aspirate showed a homogeneous population of medium-sized, pleomorphic discrete
cells with high N/C ratios. Note the mitotic figures. Anaplastic carcinoma and malignant
lymphoma were considered in the differential diagnoses. Thyroidectomy confirmed a diffuse
large B-cell lymphoma.

Figure 14.27. C. Histologic section of the lymphoma. D. Higher magnification (× 1,000).

Malignant Lymphoma versus Metastatic Undifferentiated

Small Cell Carcinoma
On rare occasions, small cell carcinoma of the lung metastatic to the thyroid may be mistaken
for malignant lymphoma. The clinical history and other diagnostic studies, including a large-
needle biopsy, are necessary for establishing a diagnosis.

Plasmacytoma
Plasmacytomas are rare in thyroid.59 , 60 , 61 It is suggested that these lesions probably
represent MALT lymphomas with predominant plasma cell differentiation.

Secondary Involvement of Thyroid by Malignancy of

Hematopoietic System
The thyroid gland is reported to be frequently involved by malignancies of the lymphoid tissue.
In a series of 300 autopsies on patients dying of lymphomas, of either the Hodgkin's or non-
Hodgkin's type, Naylor62 found that leukemias and multiple myelomas formed an overall
incidence of thyroid involvement in 17.7%. None of the patients in Naylor's series experienced
thyroid enlargement during life; the secondary involvement was identified only on microscopic
examination. However, on occasion, secondary involvement does present as thyroid nodules,
which are biopsied, as illustrated in Figures 14.28 , 14.29 and 14.30 .
Figure 14.28. FNA of a large cell lymphoma, metastatic to the thyroid. The patient had
generalized lymphadenopathy and a large retroperitoneal mass (× 1,000).
Figure 14.29. Hodgkin's lymphoma metastatic to thyroid. A. FNA showing Reed–Sternberg
cells, obscured by heavy lymphoid cell population.
Figure 14.29. B. Diff-Quik stain.
Figure 14.30. Aspiration biopsy specimen of thyroid involved by generalized malignant
histiocytosis. A,B. Large, malignant histiocyte with erythroleukophagocytosis. C. Histologic
section of the cervical lymph node showing sinusoids filled with malignant histiocytes exhibiting
erythroleukophagocytosis.

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SUMMARY
The increasing incidence of primary malignant lymphomas of the thyroid has been recognized
only in recent years. An early diagnosis of this disease made possible by aspiration cytology, can
certainly accomplish the goals of early cancer detection, i.e., effective treatment and control of
the disease. This is one of the greatest contributions of aspiration cytology of the thyroid.

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57.Droese M. Cytological Aspiration Biopsy of the Thyroid Gland . Stuttgart: Schattauer-

Verlag; 1980.

58.Shvero J, Gal R, Avidor I, et al. Anaplastic thyroid carcinoma. A clinical histologic and
immunohistochemical study. Cancer . 1988;62:319–325.

59.Lopez M, DiLauro L, Marolla P, et al. Plasmacytoma of the thyroid gland. Clin Oncol .
1983;9:61–66.

60.Bourtsos EP, Bedrossian CW, De Frias DV, et al. Thyroid plasmacytoma mimicking
medullary carcinoma: a potential pitfall in aspiration cytology. Diagn Cytopathol .
2000;23:354–358.

61.Kovacs CS, Mant MJ, Nguyen GK, et al. Plasma cell lesions of the thyroid: report of a case
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62.Naylor B. Secondary lymphoblastomatous involvement of the thyroid gland. Arch Pathol .

1959;67:432–437.
Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 15 - Thyroid Carcinomas Metastatic to Other Body Sites

15
Thyroid Carcinomas Metastatic to Other Body
Sites

Thyroid carcinomas are infrequent compared to malignancies arising in other body sites
or organs, comprising less than 1% of all cancers diagnosed in the United States.1 , 2 Most
primary thyroid carcinomas are low-grade, well-differentiated, and follow a protracted
clinical course with excellent prognosis. Although cervical lymph node metastases are
common with papillary carcinomas, distant metastases of differentiated thyroid cancer
are infrequent and reported to be in the range of 7% to 23%.3 , 4 , 5 , 6 The great
majority of metastatic thyroid cancers offer few diagnostic difficulties, but on occasion
may cause a diagnostic dilemma.

The pattern of spread differs with the type of thyroid cancer. They also have different
predilections for metastatic sites. For example, anaplastic carcinomas are known for
extensive local as well as widespread involvement of multiple organs and sites.1 , 7
Metastasis to distant organs such as lungs, bones, liver, and brain are more frequent with
follicular, poorly differentiated or insular, medullary, and Hürthle cell carcinomas, and
less frequent with papillary carcinomas.1 , 7 , 8 , 9 , 10 , 11 On the other hand, cervical
lymph node metastases are extremely common with papillary carcinomas1 , 12 but can
also occur with Hürthle cell, medullary, and anaplastic carcinomas.1 Involvement of
the serous membranes with effusions are associated with papillary and anaplastic
carcinomas and not documented with other types of thyroid cancers.

The metastatic involvement of different body sites by primary thyroid carcinomas can be
observed in one of the several settings described next.
A known history of thyroid cancer with a clinical diagnosis of local or distant
metastasis at a later date. A new disease process or a neoplasm in the organ
suspected of involvement by the metastatic thyroid cancer is often a possibility,
which must be ruled out (Fig. 15.1 ).

Figure 15.1. A,B. Recurrence/metastasis versus a different neoplastic process .

Metastatic papillary carcinoma. Smears of bronchial brushings from a patient with
a past history of papillary thyroid carcinoma, who presented with hemoptysis 4
years later. The morphology of these malignant cells is consistent with metastatic
papillary carcinoma. Since both carcinomas will be reactive to TTF-1,
immunostain with thyroglobulin is recommended to rule out primary
adenocarcinoma of the lung. C,D. Bronchial brushings from a woman in her 30s
with a history of papillary thyroid carcinoma resected several years earlier, who
now presented with obstructive pulmonary symptoms. Bronchoscopy was done to
rule out metastatic carcinoma. A lesion was found in the bronchus. The
neoplastic cells are forming syncytial tissue fragments. Their cytoplasm is scanty,
and the nuclear chromatin is very granular. A cytologic diagnosis of carcinoid
tumor was made and confirmed by lobectomy. E. FNA of a mediastinal mass
suspected of metastatic carcinoma, in a 56-year-old woman with thyroidectomy,
6 years earlier for papillary carcinoma. The aspirate shows a large population of
immature plasma cells, suggesting a diagnosis of multiple myeloma, which was
later confirmed.

Patients present with a palpable thyroid mass associated with cervical

lymphadenopathy. This pattern is more frequent with papillary and medullary
thyroid carcinomas. Sometimes both sites are biopsied simultaneously, with the
thyroid biopsy offering nondiagnostic results. In such instances the thyroid origin
must be determined (Fig. 15.2 ).
Figure 15.2. Simultaneous aspiration biopsies of thyroid nodule and cervical
lymph node. This patient had a palpable thyroid nodule and cervical
lymphadenopathy. Fine-needle aspiration biopsy of the thyroid was
unsatisfactory. A,B. Aspiration biopsy of the cervical lymph node showing cells
with cytomorphology consistent with medullary carcinoma. C. Histologic section
of the thyroidectomy showing medullary carcinoma. Metastases were present in
the lymph nodes.

Recurrent thyroid cancer at the thyroidectomy site, a frequent occurrence with

Hürthle cell carcinomas (Fig. 15.3 ).
Figure 15.3. A. FNA of mass in the thyroid area in a patient with a history of
thyroidectomy for Hürthle cell carcinoma. The aspirate is cellular, consisting of
discrete and syncytial tissue fragments of small Hürthle cells with high N/C
ratios and prominent macronucleoli, consistent with the recurrent Hürthle cell
carcinoma. B. Gross photograph of the resected large, bulky tumor.

Figure 15.3. C. Histologic section of Hürthle cell carcinoma.

The patient presents with metastatic thyroid malignancy at a distant site with
subsequent discovery of a palpable thyroid nodule. These thyroid cancers are
generally silent. The patient presents with signs and symptoms related to the site
of metastasis, such as bone pain, weakness hemoptysis and cough (Figs. 15.4 ,
15.5 , 15.6 and 15.7 ).

Figure 15.4. Silent thyroid malignancy presenting with distant metastases . Fine-
needle biopsy of a lytic lesion involving the cervical vertebra in a 47-year-old
man. The malignant cells are small and closely packed. Their nuclei have coarse
chromatin showing a follicular pattern (arrows ). Although the cytomorphology is
strongly suggestive of a thyroid neoplasm, other sources, such as the lung or
prostate, must be ruled out. Immunostain for thyroglobulin was strongly positive.
A thyroidectomy confirmed an insular carcinoma.
Figure 15.5. Silent thyroid malignancy presenting with distant metastases . Fine-
needle biopsy of a lytic lesion of the vertebra with a paraspinal mass showing
pleomorphic malignant cells with prominent macronucleoli. The cytomorphology
resembles that of a malignant melanoma or a liver cell carcinoma. The patient
was found to have a large thyroid nodule. Fine-needle aspiration biopsy showed
Hürthle cell carcinoma. The malignant cells are forming syncytial tissue
fragments with and without a follicular pattern. The nuclei are large, with
prominent macronucleoli.
Figure 15.6. Silent thyroid malignancy presenting with distant metastases.
Poorly differentiated "insular" carcinoma presenting as a pulsatile mass involving
the sternum in a 69-year-old woman. The patient was later found to have a large
thyroid mass. A. FNA of the thyroid showing a syncytial-type tissue fragment of
small follicular cells with enlarged, crowded nuclei consistent with the diagnosis
of insular carcinoma. B. Imprint of the resected sternal mass with cells similar to
those seen in thyroid carcinoma.
Figure 15.7. Silent thyroid malignancy presenting with distant metastases .
Sixty-five-year-old male with a low-grade prostate adenocarcinoma, was found to
have multiple lung nodules and a large pleural effusion on CT scan during the
follow up examination. The scan also revealed a superior mediastinal mass
extending superiorly and involving the left lower pole of the thyroid. The serum
PSA levels were within normal limits. A. These smears from the aspirated pleural
fluid show malignant cells in syncytial tissue fragments with an acinar patten. B.
These malignant cells demonstrate large cytoplasmic vacuoles. Note the
intranuclear inclusions (arrows ). C. Positive reactivity to TTF-1 supports both the
lung adenocarcinoma and thyroid papillary carcinoma. D. Positive reactivity to
thyroglobulin confirms thyroid origin. E. Histologic section of a 1-cm papillary
carcinoma that infiltrated the extrathyroidal soft tissues.

Initial presentation of thyroid malignancy at a metastatic site, either local or

distant. The thyroid shows no palpable nodules. The cancers are occult and may
or may not be detected by ultrasonography or imaging.13 , 14 , 15 , 16 , 17 , 18 ,
19 , 20 , 21 , 22 , 23 This presentation is more frequently associated with
papillary carcinomas and is usually associated with cervical lymphadenopathy
with extensive cystic change (Fig. 15.8 ). The cystic metastasis may be
misinterpreted clinically as branchial cleft cysts. Occult thyroid carcinomas with
distant metastases are rare.24 , 25 , 26 , 27 , 28 , 29 , 30
Figure 15.8. Metastatic carcinoma in cervical lymph node with occult papillary
carcinoma. A. Fluid aspirated from a lateral neck cyst. The tissue fragments of
epithelial cells are syncytial. The cells are pleomorphic, with vacuolated
cytoplasm. Their nuclei show degenerative changes and appear compact.
Immunostain for thyroglobulin was positive. B. Excision of the neck mass revealed
a thin-walled, multiloculated cystic lesion. C,D. Histologic section showing
metastatic papillary thyroid carcinoma. No nodule was palpated in the thyroid or
detected by imaging. E. Thyroidectomy showed a 2-mm papillary
microcarcinoma.
 Previous needle biopsy or surgery for a thyroid lesion misinterpreted as benign
and metastasis occurring at a later date (Fig. 15.9 ).

Figure 15.9. Distant metastasis in a patient with thyroidectomy for an apparent

benign disease. A. Fine-needle aspiration biopsy of a large shoulder mass with
lytic lesions of the humerus. The patient had a history of large (200-g)
multinodular goiter resected 4 years earlier. The cellular aspirate shows small
malignant cells in syncytial tissue fragments with and without a follicular pattern.
The chromatin is powdery. The nuclei contain grooves, inclusions, and nucleoli.
Immunostain for thyroglobulin was strongly positive, confirming metastatic
thyroid carcinoma. B. Review of the thyroidectomy specimen showed a
macrofollicular variant of papillary carcinoma.

The metastasis from a differentiated thyroid cancer may dedifferentiate into

insular or anaplastic types (Fig. 15.9 ) and may require extensive workup to
determine the primary source.

The following paragraphs describe cytologic features of metastatic thyroid cancer in

different organs or sites.

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LYMPH NODES
Papillary carcinomas show a great propensity for cervical lymph node involvement,
reported to be in the range of 46% to 47%.1 , 2 This involvement may be ipsilateral,
contralateral, or bilateral. The metastatic process may also involve the mediastinal
lymph nodes. A lateral neck mass or cervical lymphadenopathy is the initial presenting
sign in about 21% of papillary thyroid carcinomas.12 , 13 , 31 , 32 Many are associated
with occult lesions a few mm in size, neither palpable nor detectable on imaging or
ultrasound (Fig. 15.8 ). Fine-needle biopsy of the enlarged lymph nodes involved by
papillary carcinoma offers an accurate diagnosis, especially when the lesion is solid, but
tends to be a diagnostic problem with cystic degeneration. Clinically cystic lesions in the
lateral neck are often diagnosed as branchial cleft cysts.33 With extensive cystic
degeneration, the cyst fluid consists of predominantly or solely histiocytes with or
without hemosiderin pigment. The
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carcinoma cells when present show pronounced degenerative changes, precluding an
accurate diagnosis. Immunostains with thyroglobulin are often confirmatory. False-
negative diagnoses are frequent with extensive cystic degeneration.

It must be realized, however, that not all papillary carcinomas in cervical lymph nodes
are thyroidal in origin. The differential diagnosis for metastatic papillary carcinomas
includes primary sites such as lungs, kidneys, or ovaries. Homan et al. (15) reported three
cases of metastatic renal cell carcinomas in cervical lymph nodes interpreted as papillary
thyroid carcinoma from the cytologic samples obtained by fine-needle biopsy.
Immunostains for thyroglobulin in all three cases were nondiagnostic and thyroidectomies
in all three cases failed to show papillary carcinomas. Our experience with metastatic
papillary cystadenocarcinoma of the ovary to the cervical lymph nodes, histologically
misinterpreted as metastatic papillary thyroid cancer, is illustrated in Figure 15.10 .
Thyroidectomy had failed to confirm the papillary carcinoma. The tumor subsequently
recurred in the neck and was aspirated which showed cytologic pattern inconsistent with
the primary thyroid. A past history of ovarian cystadenocarcinoma was later made
available. Bronchogenic or bronchioloalveolar adenocarcinomas metastatic to the
cervical lymph nodes also present a cytologic pattern identical to that of papillary
thyroid carcinomas, including psammoma bodies.34 Both papillary thyroid carcinomas
and pulmonary adenocarcinomas react positively to TTF-1; however, papillary thyroid
carcinomas will react to thyroglobulin.
Figure 15.10. A. Aspiration biopsy specimen of a lateral neck mass in a 67-year-old
woman with a history of ovarian adenocarcinoma, showing large, branching papillary
tissue fragments. B. Higher magnification showing secretory vacuoles in the cytoplasm
filled with neutrophils (arrows ). This suggested a mucin-producing carcinoma not
originating in the thyroid.

Medullary thyroid carcinomas frequently metastasize to the cervical lymph nodes (Fig.
15.2 ). Occasionally, cervical lymphadenopathy may be the presenting sign. A
characteristic pleomorphic cell pattern in cytologic samples obtained by fine-needle
biopsy offers correct diagnosis (see Chapter 12 ). However, a monomorphic pattern with
small cells may mimic a small cell carcinoma. Cervical paraganglioma must also be
considered with large polyhedral cells. Positive immunostains for calcitonin and
increased serum calcitonin levels will support the diagnosis of medullary carcinoma. The
involvement of cervical lymph nodes by follicular carcinoma is an exceptional event.

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Hürthle cell carcinomas may involve the cervical lymph nodes but rarely present as an
initial sign. Local recurrences are very frequent with Hürthle cell carcinomas (Fig. 15.3
).1 Poorly differentiated or insular carcinoma and anaplastic thyroid carcinoma do
metastasize to the cervical lymph nodes and are not diagnostic problems.

RESPIRATORY SYSTEM
With generalized widespread involvement, lungs are frequent sites for metastatic
anaplastic carcinomas, and less frequently for insular carcinomas, Hürthle cell
carcinomas, and medullary carcinomas. Pulmonary involvement in differentiated thyroid
cancers (follicular and papillary) is reported to be 10% for follicular carcinomas and 2% to
14% for papillary carcinomas.5 , 6 Metastases to the lungs denote advanced disease.
Rarely do thyroid carcinomas initially manifest with signs and symptoms of pulmonary
involvement.22 , 24 , 35 These range from cough, hemoptysis, fever, and pleural effusion
to opacities in lung fields on chest x-rays. Both miliary infiltrates36 and macronodular
densities have been described. Direct extension into the trachea may occur. Metastatic
thyroid cancer can be identified from cytologic samples such as sputum, bronchial
brushings and washings, transbronchial or transthoracic percutaneous fine-needle biopsy
(Figs. 15.11 , 15.12 and 15.13 ), and pleural fluid (Fig. 15.7 ). Primary lung cancer must
be ruled out when papillary carcinoma is identified from the respiratory specimens, since
primary lung cancers are more common than metastatic thyroid cancers. Follicular
carcinomas also spread to the lungs (Fig. 15.14 ), and with poorly differentiated types
ancillary studies are needed to confirm the diagnosis. Hürthle cell carcinomas are
known to involve the lungs. When occurring as an endobronchial lesion (Fig. 15.15A ),
Hürthle cell carcinomas may be difficult37 , 38 to differentiate from granular cell
tumors since both show cells with abundant granular cytoplasm (Fig. 15.15 ).

Figure 15.11. Sputum preparation from a woman in her 60s who presented with
hemoptysis. The large papillary tissue fragments of malignant cells, with crowded and
overlapped nuclei containing powdery chromatin and multiple micronucleoli, are
diagnostic of adenocarcinoma. The patient was subsequently found to have multiple lung
lesions and a thyroid nodule, which harbored a papillary carcinoma. Immunostains with
thyroglobulin and TTF-1 will both be positive and diagnostic in this case.
Figure 15.12. A. Bronchial brushings from a patient with a history of papillary thyroid
carcinoma and a lung mass on chest x-ray. The malignant cells have large nuclei, some
with irregular contours, very fine powdery chromatin, and prominent nucleoli.
Intranuclear inclusions or grooves are not present. The differential diagnosis includes
metastatic papillary thyroid carcinoma and bronchogenic adenocarcinoma. Immunostain
for thyroglobulin was positive. B. Bronchial brushings of a metastatic follicular variant of
papillary carcinoma. These cells must be differentiated from pulmonary adenocarcinoma.
Figure 15.13. FNA of a metastatic papillary thyroid carcinoma to the lung. The syncytial
tissue fragment is composed of crowded nuclei with powdery chromatin, grooves,
micronucleoli, and inclusions. These features are also shared by bronchioloalveolar
carcinoma. Immunostains with thyroglobulin and TTF-1 are required to establish a
diagnosis. Both will be positive with papillary thyroid carcinoma.

Figure 15.14. FNA of a metastatic follicular carcinoma to the lung. The patient had
thyroidectomy for a follicular carcinoma 9 years prior to the development of metastasis.
Figure 15.15. A,B. Bronchial brushings showing a metastatic Hürthle cell carcinoma.
The differential diagnosis includes granular cell tumor. C. Bronchial brushings of a
granular cell tumor. Note the morphologic similarities.

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Medullary carcinomas may metastasize to the lungs (Fig. 15.16A ). With a spindle cell
pattern, medullary carcinoma must be differentiated from a spindle cell carcinoid tumor
of the lung (Fig. 15.16B ).
Figure 15.16. A. FNA of a metastatic medullary thyroid carcinoma to the lung. Note the
intranuclear cytoplasmic inclusions in malignant cells (arrows ). B. FNA of a spindle cell
carcinoid tumor of the lung demonstrating morphologic similarity to the medullary
carcinoma cells.

BODY CAVITY FLUIDS

Metastatic thyroid cancers are rarely encountered in body cavity fluids.39 , 40 , 41
Among the thyroid cancers, anaplastic and papillary carcinomas tend to metastasize to
the pleural cavities (Figs. 15.7 and 15.17 , 15.18 and 15.19 ). Their cytologic presentation
may cause some diagnostic difficulties, as the fluid medium may initiate regressive
changes such as marked cytoplasmic vacuolization, resulting in considerable deviation
from the usual cytologic patterns. Also papillary carcinoma in pleural cavities must be
differentiated from either primary lung adenocarcinomas or papillary carcinomas from
other body sites.
Figure 15.17. Anaplastic carcinoma metastatic to the pleura. A–D. Bizarre isolated
malignant cells in pleural fluid. E. Cell block preparation of the pleural fluid showing
similar malignant cells.

Figure 15.18. Papillary carcinoma metastatic to the pleura. The carcinoma cells in
pleural fluid have bizarre nuclei and marked cytoplasmic vacuolization, resembling
mucin-producing adenocarcinoma. The Alcian blue stain on the cell block preparation did
not reveal the presence of mucin, indicating that the cytoplasmic vacuoles represent
degenerative changes in the fluid medium.

Figure 15.19. A. Metastatic papillary carcinoma in pleural fluid showing a syncytial

tissue fragment with a psammoma body. B. Different example of metastatic papillary
carcinoma in pleural fluid from a patient with a history of thyroid carcinoma. Note
marked cytoplasmic vacuolization and intranuclear cytoplasmic inclusion.
SKELETAL SYSTEM
The skeletal system is a frequent site for metastatic thyroid cancer, especially follicular,
Hürthle cell, insular and anaplastic types.1 , 9 , 42 The incidence is reported to be 9%.
The osseous lesions are often osteolytic, involving long bones as well as flat bones such as
the pelvis and sternum. Pulsatile lesions are described as a characteristic feature of
metastatic follicular carcinomas to the bones. The presenting signs and symptoms include
bone pain, weakness, and pathologic fractures may occur. The metastatic tumor may
extend into the adjacent soft tissues. Fine-needle biopsy is a helpful diagnostic
technique (Figs. 15.4 , 15.5 and 15.6 , 15.20 ) but may present interpretative difficulties
if the tumor is less differentiated.

Figure 15.20. FNA of metastatic follicular carcinoma to the bone. A. Low power showing
a cellular aspirate composed of syncytial tissue fragments of malignant cells with a
follicular pattern. B. Higher magnification highlighting the neoplastic follicles with
enlarged nuclei. Romanowsky stain.

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MISCELLANEOUS SITES
Other organs or sites involved less frequently by thyroid cancer include breast,43 , 44
liver,45 , 46 , 47 and central nervous system.48 , 49 Single case reports have appeared of
various types of thyroid cancers involving rare and uncommon sites such as uvea,50
skin,51 , 52 , 53 , 54 spleen,55 parotid gland,56 and urinary bladder.57 A case of
metastatic medullary carcinoma metastasizing to the thigh seen in consultation is
illustrated in Figure 15.21 .
Figure 15.21. Metastatic medullary thyroid carcinoma to the thigh. (Courtesy of Ami J.
Walloch, MD and Rashead Hammadeh, MD, Christ Hospital, Oaklawn, Illinois.)

SUMMARY
The majority of thyroid cancers are of the differentiated type and metastasize to distant
organs only infrequently. Cervical lymph node involvement is common with papillary
carcinomas. A history of thyroid cancer is necessary for correct identification of a
metastatic tumor and can be confirmed by immunostains such as thyroglobulin, TTF-1, or
calcitonin, especially in the presence of overlapping patterns.

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Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 16 - Metastatic Malignancyto the Thyroid

16
Metastatic Malignancyto the Thyroid

The thyroid gland is a rare site for metastatic malignancy. Clinically significant
metastatic disease is not commonly encountered,1, 2, 3, 4, 5, 6, 7, 8, 9 but the
incidence of thyroid involvement in patients with extensive malignant disease is
reported to be in the range of 0.19% to 24.2% as discovered at autopsy.10, 11, 12, 13
At the Mayo Clinic,14 only 30 cases of metastatic thyroid cancers were reported from a
series of 1,161 thyroid cancers over a period of 25 years. Our own series15 included 22
cases of 593 thyroid cancers over a period of 9 years. Chacho et al.16 reported 8
metastatic tumors out of 61 malignant thyroid lesions, while the incidence of 0.1% or
25 metastatic cancers out of 25,000 aspiration biopsies reported by Schmidt et al.17 is
extremely low.

A thyroid nodule occurring in a patient with a history of extrathyroidal cancer may be

a diagnostic problem, because it could represent a metastasis from an extrathyroidal
malignancy, a primary thyroid cancer, or a benign thyroid lesion. Fanning and Katz18
reported 63 extrathyroidal cancer patients with thyroid nodules over a period of 8
years who had fine- needle biopsy procedures. Their data revealed 46 benign lesions, 4
primary malignancies, 11 metastases, and 2 inconclusive results. This study not only
revealed a higher incidence of metastatic disease in patients with a history of
extrathyroidal malignancy, but also that the primary thyroid cancer occurs in a
significant number of these patients.

Metastases to the thyroid are most often multifocal and variable in size in autopsy
series. In clinical series, they are more commonly solitary and present as a nodule, and
may attain large dimensions. Malignancy originating in neighboring organs tends to
involve a single lobe and tend to present as a large mass.1 The great majority of the
patients with metastatic disease to the thyroid are asymptomatic. Rarely, a metastatic
malignancy may masquerade as primary thyroid cancer or present with symptoms of
hyperthyroidism or subacute thyroiditis.19, 20, 21, 22, 23, 24, 25, 26, 27 The thyroid
gland can harbor metastatic tumor from any part of the body, but four primary sites
are listed as the most common source: kidney, 28, 29, 30, 31, 32, 33, 34 lung,35
breast,36, 37 and melanoma.38, 39, 40 The other sites42, 43, 44, 45, 46, 47, 48, 49
include the gastrointestinal tract, especially the colon41, 42; genital and urothelial
malignancies salivary glands43; neuroendocrine tumors44, 45, 46; malignant
lymphomas47; and soft- tissue sarcomas.48 The incidence of these primary sources
involving the thyroid varies considerably in different studies. The thyroid gland may
also be involved by direct spread from the cancers originating in the neighboring
organs such as esophagus, larynx, pharynx, or trachea.1 These are usually squamous
carcinoma or its morphologic variants. FNA has been valuable in the diagnosis of
metastatic disease and the management, especially when the patients have had a
history of extrathyroidal cancer and an advanced disease.49, 50, 51, 52, 53

MICROSCOPIC FEATURES
Willis13 described three histologic patterns of metastatic tumors to the thyroid: (i)
multiple small but discrete foci less than 2 mm, (ii) a single discrete clinically palpable
nodule; and (iii) diffuse widespread parenchymal involvement.

CYTOPATHOLOGIC FEATURES
The cytologic pattern of a metastatic tumor depends upon the manner in which the
thyroid is involved by the secondary neoplasms (Table 16.1, Figs. 16.1, 16.2 and 16.3)
and on the histologic type of the tumor as well as their stage of differentiation (Figs.
16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 16.10, 16.11, 16.12, 16.13, 16.14, 16.15, 16.16,
16.17, 16.18, 16.19 and 16.20). The aspirated sample reveals two basic cytologic
patterns. With metastatic foci less than 2 mm in size, the cytologic samples show an
admixture of malignant cells and benign follicular cells (Fig. 16.1) Tumor diathesis is
rare or absent. With a single, discrete, large palpable nodule or with diffuse
widespread involvement, the aspirate shows only malignant cells (Figs. 16.2 and 16.3).
The thyroid follicular cells are not present in the background and tumor diathesis is
frequent, particularly in large tumors. Necrosis is also a characteristic of metastatic
colon carcinomas.

TABLE 16.1 CYTOHISTOLOGIC PATTERNS OF

METASTATIC MALIGNANCY TO THE THYROID AND
THEIR DIFFERENTIAL DIAGNOSIS

Histologic Pattern Cytologic Pattern Differential Diagnosis

A. Multiple small Admixture of Degenerating follicular cells

foci of metastatic malignant cells and in nodular goiter
tumor, less benign
than 2 mm follicular cells;
tumor diathesis
absent

B. Single large Large population of

discrete nodule malignant cells; no
thy-
roid follicular
cells in the
background;
tumor diathesis
frequent;

I. Malignant cells Consistent with metastatic

with squamous or malignancy
glandu
lar
differentiation

II. Medium- sized to 1. Anaplastic thyroid

large, round to
2.
Histologic Pattern Cytologic Pattern Differential Diagnosis
1. Anaplastic thyroid
large, round to carcinoma
polyg- 2. Poorly
onal malignant differentiated
cells with no primary or metasta-
functional tic squamous cell-
or architectural carcinoma
differentiation 3. Poorly
differentiated
adenocarcinoma
4. Malignant melanoma
5. Malignant large cell
lymphoma

III. Small malignant 1. Anaplastic thyroid

cells carcinoma with
small
cell pattern
2. Medullary thyroid
carcinoma
3. Basaloid squamous
cell carcinoma
4. Metastatic
neuroendocrine
carcinomas
including small cell
carcinomas
5. Malignant lymphoma
6. Malignant melanoma

III. Spindle cell 1. Anaplastic thyroid

pattern carcinoma, spindle cell
pattern
Histologic Pattern Cytologic Pattern Differential Diagnosis
pattern
2. Medullary thyroid
carcinoma
3. Soft- tissue sarcoma
3. Metastatic
carcinosarcoma
4. Malignant melanoma

IV. Clear cell 1. Anaplastic thyroid

pattern carcinoma
2. Metastatic renal cell
carcinoma

C. Diffuse and Same as above Same as above

widespread
involvement
Figure 16.1. Metastatic squamous cell carcinoma of the lung infiltrating in the
form of multiple foci less than 2 mm. Note intact thyroid follicles in between the
infiltrating tumor.
Figure 16.2. Cytologic pattern of the metastases, smaller than 2 mm, generally
includes an admixture of cancer cells and the benign follicular cells. Note very
pleomorphic malignant cells with benign follicular cells in the background.
Figure 16.3. A. Metastatic tumor occurring as a distinct large, palpable nodule.
Fine- needle biopsy is utilized to differentiate between a benign thyroid lesion,
primary thyroid cancer, or metastasis. This is a metastatic malignant melanoma
in a young male with a history of melanoma. B. The histologic section of the
resected thyroid showing a solid growth pattern of poorly differentiated
malignant cells, consistent with malignant melanoma. C. FNA of the mass showing
amelanotic melanoma cells. Without a history of primary malignancy, these
undifferentiated malignant cells must be differentiated from a primary anaplastic
carcinoma.
Figure 16.4. A. Metastatic carcinoma diffusely involving the thyroid parenchyma.
This pattern will yield only malignant cells in FNA biopsy. B. FNA of the above
thyroid mass showing small cell carcinoma cells originating from the lung. This
tumor first presented as a thyroid nodule.
Figure 16.5. A and B. Well- differentiated squamous carcinomas of the lung,
metastatic to the thyroid. A cytologic pattern of well- differentiated squamous
cancer cells with keratinization is more consistent with the diagnosis of
metastasis because a primary squamous cancer of the thyroid is very uncommon.
A history of primary cancer elsewhere is critical.

Figure 16.6. FNA of a poorly differentiated squamous cell carcinoma of the

esophagus masquerading as goiter. These malignant cells must be differentiated
from anaplastic carcinoma of the thyroid.
Figure 16.7. FNA of a poorly differentiated squamous carcinoma of the esophagus
that infiltrated the thyroid and clinically presented as goiter.

Figure 16.8. FNA of a solitary thyroid nodule in a patient with a history of

squamous carcinoma of the upper aerodigestive tract, showing poorly
differentiated malignant cells. There was no evidence of tumor metastasis
anywhere else in the body. This case is difficult to differentiate from a primary
squamous cell carcinoma.
Figure 16.9. FNA of a metastatic pulmonary adenocarcinoma. The malignant cells
are extremely pleomorphic. The architecture of the tissue fragments with acinar
pattern (arrows) suggests an adenocarcinoma.
Figure 16.10. FNA of a metastatic adenocarcinoma of the colon to the thyroid.
A. The syncytial type tissue fragment of malignant cells containing elongated
nuclei in a picket fence arrangement is characteristic of colonic adenocarcinoma.
Note benign follicular cells in the background. B. Another field showing syncytial
tissue fragments of malignant cells with acinar pattern. Note cytoplasmic
vacuoles. C. Histologic section of the excised tumor confirming colonic origin.

Figure 16.11. Metastatic renal cell carcinoma. The carcinoma is clear cell type,
as noted by pale cytoplasm and disrupted cell borders resulting in bare nuclei
that are small and uniform.
Figure 16.12. A,B. Another example of metastatic renal cell carcinoma to the
thyroid. The history of nephrectomy for renal cell carcinoma, in the remote past,
was not available at the time of FNA biopsy of the solitary thyroid nodule. The
malignant cells are in syncytial arrangement and have appreciable granular
cytoplasm with uniform nuclei. Note the morphologic resemblance to Hürthle
cell tumors. C. FNA of a Hürthle cell carcinoma for comparison.

Figure 16.13. A. FNA of a small cell carcinoma of the lung clinically presenting as
goiter. The aspirate is cellular, demonstrating the typical cytomorphologic
pattern of small cell carcinoma. Note oval to oblong nuclei with dense chromatin,
nuclear molding, and karyorrhexis. B. Cell block preparation of the aspirate
confirming the cytologic diagnosis of small cell carcinoma.
Figure 16.14. A. FNA of a rapidly growing large thyroid mass. The malignant cells
are small with very high N/C ratios and scant indiscernible cytoplasm. There is
necrosis in the background. The differential diagnoses include: Insular carcinoma,
metastatic small cell carcinoma, medullary carcinoma and malignant lymphoma.
A large panel of immunostain performed was nondiagnostic except for
cytokeratin. A surgical exploration revealed a large malignant neoplasm of the
esophagus extending into the thyroid. B. Histologic section of the tumor showing
basaloid squamous carcinoma. (Courtesy of Mithra Baliga, MD, University of
Mississippi, Jackson.)
Figure 16.15. FNA of a thyroid nodule showing metastatic malignant non-
Hodgkin's lymphoma. The aspirate shows poorly differentiated lymphoid cells
consistent with the diagnosis of large cell lymphoma. Patient was subsequently
found to have a generalized lymphadenopathy and an abdominal mass. Thyroid is
more often involved by secondary lymphoma than a primary one.
Figure 16.16. A patient with a history of leiomyosarcoma of the inferior vena
cava and a mastectomy for duct adenocarcinoma of the breast developed a cold
thyroid nodule. A. Histologic section of the leiomyosarcoma. B. FNA of the
thyroid nodule showing large tissue fragments of spindle- shaped cells. C. Higher
magnification highlighting the spindle cells in fascicles consistent with
leiomyosarcoma. D. These malignant cells from the same aspirate appear
epithelial in origin and suggest metastatic breast adenocarcinoma. The patient
also had cutaneous metastases from leiomyosarcoma. Whether this case
represents double metastases is not known, because histologic confirmation is not
available and no ancillary tests were performed on cytologic material.
Figure 16.17. A. FNA of a metastatic malignant fibrous histiocytoma of the
retroperitoneum to the thyroid. B. Histologic section of the resected thyroid
showing a spindle cell tumor consistent with malignant fibrous histiocytoma.
Figure 16.18. Metastatic carcinosarcoma of the esophagus infiltrating the
thyroid, masquerading as goiter. A. Syncytial tissue fragment of malignant cells
with glandular differentiation. B. A different field from the same case showing
spindle- shaped malignant cells, suggesting sarcomatous differentiation. C.
Histologic section of the excised tumor showing carcinosarcoma exhibiting both
glandular and stromal components.

Figure 16.19. FNA of a metastatic carcinoma of the breast, metaplastic type to

the thyroid. The cytologic pattern consists of a pleomorphic cell population with
spindle cells. Positive reactivity to cytokeratin confirmed the epithelial nature of
the tumor. (Courtesy of Yun Gong, MD, University of Texas, M.D. Anderson Cancer
 Center, Houston.)

Figure 16.20. A,B. FNA of a thyroid nodule in an elderly woman. These

degenerating follicular cells with atypical nuclei were considered to be
metastatic carcinoma. Thyroidectomy did not confirm the diagnosis. C.
Metastatic breast adenocarcinoma (arrow) in a background of benign follicular
cells and hemosiderin- containing macrophages.

Metastatic squamous carcinomas are easily recognized when the malignant cells
exhibit evidence of functional differentiation
P.359
P.360
such as keratin (Fig. 16.4) but the poorly differentiated ones must be distinguished
from primary anaplastic carcinomas (Figs. 16.5, 16.6 and 16.7). Similarly, the acinar
pattern and the presence of cytoplasmic vacuoles (Fig. 16.8) are diagnostic of
adenocarcinomas. The presence of melanin pigment supports the diagnosis of
malignant melanoma. However, amelanotic melanomas must be differentiated from
primary anaplastic thyroid carcinomas (Fig. 16.2). The typical architectural patterns
displayed by the tissue fragments of malignant cells, such as palisading or picket fence
arrangement of nuclei, are highly indicative of colonic carcinomas (Fig. 16.9). Renal
cell carcinomas are the most common malignant tumor to involve the thyroid
secondarily (Figs. 16.10 and 16.11). Their cytologic presentation may pose problems if
the history is not available.

P.361
P.362
P.363
The characteristic cytomorphology of small cell carcinoma of the lung depicting small
cell size; round to oval nuclei; molding; compact chromatin; frequent mitotic figures;
and karyorrhexis in the background allows easy identification of the primary source
(Fig. 16.12). In fact, small cell carcinomas of the lung are known to present clinically
as thyroid nodules before the primary malignancy is clinically evident. Small cell
carcinomas should be differentiated from small cell medullary carcinomas, insular
carcinomas, metastatic basaloid squamous carcinoma (Fig. 16.13), and malignant
lymphomas (Fig. 16.14).

Soft- tissue sarcomas very rarely involve the thyroid gland. Since primary sarcomas of
the thyroid are extremely rare, a primary spindle cell- type anaplastic thyroid
carcinoma must be first ruled out when a spindle cell tumor is encountered. Metastatic
sarcomas occur more frequently than the primary lesions (Figs. 16.15, 16.16, 16.17 and
16.18).

In general, metastatic tumors to the thyroid offer diagnostic difficulties when (i) the
malignant cells are undifferentiated, (ii) the primary tumor is unknown, (iii) the
primary cancer is remote or the history is unknown, or (iv) when there is
cytomorphologic overlap between the metastatic tumor and primary thyroid cancers.

If the distinguishing cytologic features are absent, as is the case in most poorly
differentiated cancers, their separation from primary anaplastic carcinoma of the
thyroid may cause a diagnostic dilemma (Figs. 16.3, 16.6, 16.7 and 16.8, 16.18).
Ancillary diagnostic techniques such as histochemical or immunocytohistochemical
stains are necessary to establish the diagnosis.54

The cytohistologic patterns of metastatic tumors and their differential diagnoses are
listed in Table 16.1 and illustrated in Figures 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 16.10,
16.11, 16.12, 16.13, 16.14, 16.15, 16.16, 16.17, 16.18, 16.19 and 16.20. The features
that help differentiate primary from secondary tumors are listed in Table 16.2. When
the history of prior non- thyroidal malignancy is available, a review of previous
cytologic/surgical material is extremely useful.

TABLE 16.2 DIFFERENTIATING FEATURES FOR

PRIMARY VERSUS SECONDARY THYROID TUMORS

History of primary cancer elsewhere in the body

Presence of unremarkable thyroid follicular cells mixed with cancer cells
favors a metastatic
process
Functional differentiation of cytoplasm of cancer cells (e.g., keratin or
mucin secretions, melanin)
Characteristic cytomorphology of ceratin types of neoplasms:
Small cells with compact nuclear chromatin, molding, frequent mitoses,
and karyorrhexis (small cell carcinoma)
Small cells, uniform, round nuclei, with open chromatin pattern and
nucleoli, high N/C ratios,
and scant cytoplasm favor malignant lymphoma
Salt- and- pepper nuclear chromatin
Architectural patterns of the tissue fragments of malignant cells:
Acinar or glandular pattern
Palisading of elongated nuclei with a picket- fence pattern

Metastatic tumors to the thyroid that share morphologic similarities with primary
thyroid cancers include renal cell carcinoma, neuroendocrine tumors, and malignant
lymphomas. Renal cell carcinomas are known to metastasize several years
P.364
P.365
P.366
P.367
after the initial detection. Without the clinical history, the neoplasm may be
mistyped. For example, cells of metastatic renal cell carcinoma with granular and
clear cytoplasm morphologically resemble Hürthle cell carcinoma (Fig. 16.12).

A metastatic bronchioloalveolar carcinoma of the lung to the thyroid is very difficult

to differentiate morphologically from a primary thyroid papillary carcinoma without
appropriate immunostains.35 Likewise, metastases from neuroendocrine tumors to the
thyroid gland, although rare, may be misinterpreted as medullary carcinoma.42, 43

False- positive diagnosis of metastatic malignancy is a possibility when the

degenerating follicular cells containing atypical nuclei in nodular goiter mimic the
cytologic presentation of small metastatic foci, as with benign follicular cells and
malignant cells (Fig. 16.20).

P.368

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Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 17 - Cysts and Cystic Lesions of the Thyroid

17
Cysts and Cystic Lesions of the Thyroid

The term "cysts" or "cystic" implies a fluid-filled, epithelium-lined space; those without epithelial
lining are referred to as "pseudocysts." True cysts occur as a result of dilatation of the ducts or
tubules lined by epithelium, although the latter may be denuded secondary to inflammation.
Pseudocysts lack epithelial lining. They develop following degeneration, necrosis, and
hemorrhage into the parenchyma or soft tissues with fluid accumulation. In the thyroid gland,
the term "cyst" is used loosely to denote any fluid-containing lesion, usually detected by
ultrasound or during the aspiration biopsy procedure when the fluid is aspirated. The incidence
of cysts in solitary thyroid nodules removed surgically is reported to be as high as 37%.1 Various
types of cystic lesions are identified in the thyroid gland (Table 17.1 ), the most common being
cystic degeneration in nodular goiters.

Simple cyst
Lymphoepithelial cyst in Hashimoto's thyroiditis
Intrathyroidal thyroglossal duct cyst or branchial cleft cyst
Colloid-filled giant mMacrofollicle in nodular goiter or a
macrofollicular adenoma
Cystic degeneration in nodular goiter
Degenerating neoplasms
Follicular or Hürthle cell adenomas
Malignant neoplasms
Papillary carcinoma
Anaplastic Carcinoma
 TABLE 17.1 CYSTS OF THYROID: MORPHOLOGIC TYPES
The majority of the thyroid cysts are benign. The incidence of malignancy in thyroid cysts
reported in various series ranges from 0% to 33% (Table 17.2 ).1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ,
11 , 12 , 13 , 14 , 15 Cystic change is more frequent with thyroid lesions greater than 4 cm.2 , 4
,5,6,7,8

Crile15 (1966)
0/5
0
Miller et al.14 (1974)
2/303
0.6
Ma and Ong13 (1975)
1/62
1.6
Jensen and Rasmussen12 (1976)
0/288
0
Walfish et al.11 (1977)
3/13
23.0
Goellner and Johnson9 (1982)
9/158
5.6
Hammer et al.10 (1982)
16/48
33.0
Suen and Quenville8 (1983)
2/59
3.0
Rosen et al.7 (1986)
15/60
25.0
Cusick et al.1 (1988)
15/106
14.0
Sarda et al.1 (1988)
5/78
6.4
de las Santos et al.5 (1990)
10/71
14.0
Mecko et al.4 (1995)
39/90
29.0
McHenry et al.3 (1999)
6/70
8.6
Abbas et al.2 (2001)
4/34
12.0

Author (Year) No. Percent

TABLE 17.2 INCIDENCE OF CARCINOMA IN CYSTS OF

THYROID
Clinically, thyroid cysts can be suspected by a rounded nodule that appears tense or taut on
palpation.15 The sudden appearance of a rapidly enlarging thyroid nodule, causing discomfort, is
nearly always a cyst with acute hemorrhage.15

RADIOLOGIC FINDINGS
Ultrasound has been helpful in identification of the cystic lesions.16 , 17 , 18 , 19 , 20 , 21 , 22
The high-resolution ultrasonography can determine the characteristics of the nodule such as the
size, whether solid or cystic or complex, although distinguishing benign from malignant is not
possible.
Ultrasound findings that favor benign non-neoplastic nodules include small cystic nodules, with
or without internal echogenic foci; multiple cystic spaces separated by thin septations in a
"honeycomb" pattern; and a large cyst.16 Papillary carcinomas with cystic component rarely
reach the dimensions of a large benign cyst.

GENERAL CHARACTERISTICS OF CYSTIC LESIONS

The most commonly encountered cystic lesions are nodular goiters. Benign cysts such as those
arising from the nodular goiters collapse after being drained. A small number may re-accumulate
or bleed immediately following an aspiration biopsy necessitating re-aspiration. Recurrence with
hemorrhagic contents should be a warning of the possibility of malignancy.

Aspiration biopsy has been found to be very useful for (i) identifying the lesion as a cyst, and (ii)
differentiating between benign and malignant cysts based on cytologic examination of the cyst
fluids.23 , 24

The volume of the aspirated fluid varies from a few milliliters to 20 mL or more. The gross
characteristics of the fluid reflect the duration as well as the nature of the cystic lesion. Soon
after the hemorrhage into the nodule, the specimen resembles the venous blood. Subsequently,
the cyst contents change from a chocolate-colored fluid to opaque to an olive, translucent and
ultimately to yellow, amber-colored transparent fluid. A nodule that has undergone
degeneration and necrosis may yield a small amount of turbid, thick fluid. The gross
characteristics have no bearing on the nature of the lesions. Rehak et al.25 performed
biochemical analysis of thyroid cyst fluids for several analytes. They did not identify any analyte
that would differentiate between benign and malignant cysts.

The cytopreparation of the cyst contents varies according to the gross characteristics of the cyst
fluid. The cytopathologic features of the aspirated fluid specimen depends on several factors,
including the type of cyst; whether non-neoplastic or neoplastic; whether it is hemorrhagic, and
if so, recent or old hemorrhage; and the extent of necrosis. The cytologic evaluation too
depends greatly on the quality of the cytopreparation (see Chapter 3 ). A poor cytopreparation
of a bloody specimen is likely to be unsatisfactory and nondiagnostic, even if the lesion is
malignant, unless the blood is removed prior to making the smears. At the same time, a clear,
transparent fluid
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from a cystic papillary carcinoma is likely to be poorly cellular and may result in a false-negative
diagnosis and must be processed by the cytocentrifugation method to salvage the few malignant
cells (see Fig. 17.23 ). The fluid medium to which
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the exfoliated cells are exposed may initiate retrogressive changes that simulate neoplasia in
benign cells, thereby constituting an important diagnostic pitfall. Conversely, true neoplasia can
be masked by retrogressive changes, resulting in false-negative diagnoses.2 , 4 , 11 , 14

Figure 17.23. A,B. Cytospin preparation of a clear fluid aspirated from a cystic papillary
carcinoma. The aspirate is poorly cellular with a rare syncytial tissue fragment of enlarged
follicular cells with scalloped margin and with well-defined cell borders. The nuclei are enlarged
with finely granular chromatin with prominent nucleoli. Their cytoplasm is foamy to vacuolated.
The morphology is suspicious for papillary carcinoma. The thyroidectomy confirmed a cystic
papillary carcinoma. C. The cyst lining composed of a single layer of atypical follicular cells is
not typical of papillary carcinoma. D. A conventional papillary carcinoma was present focally in
the cyst wall.

SIMPLE CYSTS
Simple epithelium-lined cysts are extremely rare and their etiology is uncertain.26 , 27 , 28 , 29
The epithelial lining may be squamous type. The case illustrated in Figure 17.1 represents an
example of a simple cyst with squamous lining. The aspirated sample showed atypical cells,
which were interpreted as suspicious for malignancy. The thyroidectomy revealed a simple
squamous epithelium-lined cyst with atypical features.

Figure 17.1. A. The smears prepared from the aspirated cyst fluid were almost acellular except
for this syncytial tissue fragment of cells with large, atypical nuclei containing nucleoli. The
cells were interpreted as suspicious for papillary carcinoma. B. Thyroidectomy revealed a fibrous
walled cyst and no papillary carcinoma. C,D. Higher magnification showing lining epithelium
with nuclear atypia, which is the source of atypical cells in the cyst fluid.
Figure 17.1. E. A tissue fragment of atypical squamoid cells floating in the cystic cavity.

LYMPHOEPITHELIAL CYSTS
Small cysts lined by squamous epithelium have been described in Hashimoto's thyroiditis,26 and
are referred to as lymphoepithelial cysts or lymphoepithelial-like cysts as they bear resemblance
to
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lymphoepithelial cysts encountered in parotid glands. They are extremely rare and only a few
cases are reported in the surgical pathology literature (Fig. 17.2 ).30 , 31 , 32 , 33 Louis et al.30
described two cases of multiple cysts in patients with Hashimoto's thyroiditis. These cysts, lined
mostly by squamous epithelium and focally by columnar epithelium, were surrounded by
lymphoid tissue with follicles and germinal centers and contained a fibrous capsule. They
referred to these as branchial cleft-like cysts. Apel et al.31 reported 6 cases of intrathyroidal
lymphoepithelial cysts, all associated with Hashimoto's thyroiditis. The cysts were lined by
squamous epithelium and contained heavy lymphoid tissue in their walls. In 5 of their cases,
solid cell nests (please refer to Chapter 19 ) were found in the vicinity of the cysts. The authors
postulated that these branchial cleft-like cysts may have resulted from squamous metaplasia and
degeneration or may have been derived from cystic change within the solid cell nests. The
squamous lining of these cysts may demonstrate cytologic atypia leading to a malignant diagnosis
(Fig. 17.2 ). Rys?ks et al.35 reported 2 cases of intrathyroidal lymphoepithelial cysts that were
not associated with Hashimoto's thyroiditis. Carney28 reported 2 cases of branchial cleft-like
cysts in thyroid, not associated with Hashimoto's thyroiditis. In both instances, the cysts were
single and the extra cyst parenchyma showed islands and strands of basaloid epithelium,
associated with lymphoid infiltrate as seen with lymphoepithelial lesions. Lymphoepithelial cysts
of thyroid have also been documented in patients with HIV infection,33 , 34 with one report
describing the cytologic findings on aspiration biopsy.34

Figure 17.2. A. Histologic sections of a thyroid with Hashimoto's disease. Note multiple cystic
spaces, some within lymphoid follicles, low power. B. Higher magnification of the cyst within
the lymphoid follicle, lined by squamous epithelium. C. A different field showing a cystic cavity
lined by stratified squamous epithelium. Note squamous metaplasia within the lymphoid tissue
(arrow ). D. Higher magnification of C highlighting the squamous metaplasia.

INTRATHYROIDAL THYROGLOSSAL DUCT CYST AND

INTRATHYROIDAL BRANCHIAL CLEFT CYST
Both thyroglossal duct cysts36 , 37 , 38 and branchial cleft cysts39 , 40 have been described in
the intrathyroidal location as discrete cystic structures within the thyroid parenchyma and lined
by stratified squamous epithelium. No other disease process in the surrounding thyroid
parenchyma, such as thyroiditis, was described. Aspiration biopsy of the above-reported
intrathyroidal cysts showed only benign squamous cells. The cytohistologic features were
consistent with both thyroglossal duct cysts and branchial cleft cysts. We recently came across 3
such cases of intrathyroidal cysts (confirmed by ultrasound). Their aspirates contained mature
squamous cells with and without keratinization, and large numbers of anucleated squames (Figs.
17.3 , 17.4 and 17.5 ). One cyst aspirate also contained benign follicular cells along with
squamous cells (Fig. 17.5 ). The cytologic patterns strongly resembled those of branchial cleft
cyst or thyroglossal duct cysts. Since the benign cytologic features of these cases did not warrant
surgical excision, there was no surgical follow-up and their etiology remains unknown.
Figure 17.3. Case #1. Cyst aspirate of an intrathyroidal cyst with mature squamous cells and
anucleated squames.
Figure 17.4. Case #2. Cyst aspirate of an intrathyroidal cyst with mature squamous cells and
anucleated squames. Note some cells with keratinization.
Figure 17.5. Case #3. Cyst aspirate of an intrathyroidal cyst with mature squamous cells and
anucleated squames. Note a group of benign follicular cells, suggesting the diagnosis of
thyroglossal duct cyst.

COLLOID CYST OR GIANT COLLOID-FILLED FOLLICLE

It is not uncommon to aspirate several milliliters of watery to viscous colloid during the
aspiration biopsy procedure of thyroid nodules. The prepared smears generally demonstrate
abundant colloid with no or rare small follicular cells containing
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pyknotic nuclei (Fig. 17.6 ). The colloid stains dense and shows cracks or fissures and tends to
fall off the slide during the fixation (in 95% ethyl alcohol) and processing. These aspirates with
abundant colloid generally represent hyperinvoluted goiter or a macrofollicular adenoma.
Figure 17.6. Fine-needle aspiration biopsy of a colloid cyst (nodule), showing abundant colloid
with a few benign follicular cells.

CYSTIC DEGENERATION IN NODULAR GOITER

Cyst formation is a frequent occurrence in nodular goiters. The cysts vary in size and can attain
large dimensions (Fig. 17.7 ). Depending on their duration, the fine-needle biopsy of these cysts
will yield varying amounts of fluid, from frankly hemorrhagic to thick, sticky contents, referred
to by one of our endocrinologists as "gruel." The fluid from a long-standing cyst is usually thin,
clear, transparent, and practically acellular. The absence of well-preserved follicular cells seems
to be the rule in such cases rather than an exception.
Figure 17.7. A gross photograph of a large cystic nodular goiter.

Generally, the smears prepared from the sediment of the cyst fluid almost always contain
variable numbers of histiocytes with or without hemosiderin pigment (Fig. 17.8 ). These
histiocytes or macrophages possess abundant, granular to foamy cytoplasm, and round nuclei
that are central to slightly eccentric. Their N/C ratios are low and their cell borders are well
defined but not rigid or sharp, unlike the discrete papillary carcinoma cells (see Fig. 17.23 ). The
nuclear chromatin is finely granular and micronucleoli may be present. Multinucleated
histiocytic foreign-body-type giant cells are frequent; some contain hemosiderin pigment.
Cholesterol crystals are often identified (Fig. 17.9 ) in a toluidine blue-stained preparation of
the fresh fluid sediment (wet mount; see Chapter 3 ). A paraffin cell block preparation of the
sediment is highly recommended. On rare occasions, it will provide a diagnostic result. The cyst
fluid may
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contain follicular cells, their numbers as well as their morphology dependent on the duration of
the cyst.
Figure 17.8. Usual cytopathologic pattern of cyst fluid showing several hemosiderin-containing
histiocytes.

Figure 17.9. Cyst fluid from a degenerated nodular goiter with cholesterol crystals and
hemosiderin-containing histiocytes. Wet mount, Toluidine blue preparation.

Degenerating follicular cells exhibit various morphologic alterations. They may enlarge and
acquire abundant granular cytoplasm, resembling histiocytes, and they may even be phagocytic,
containing hemosiderin. Although they resemble histiocytes, follicular cells are almost always in
tissue fragments (Fig. 17.10 ) unlike the macrophages.
Figure 17.10. A tissue fragment of degenerating follicular cells with hemosiderin pigment.

In long-standing cysts, the follicular cell nuclei demonstrate variable degrees of atypia (Figs.
17.11 , 17.12 , 17.13 , 17.14 , 17.15 and 17.16 ).41 , 42 , 43 The nuclei show enlargement and
may contain prominent nucleoli. Nuclear grooves are occasionally present as are intranuclear
inclusions. Their cytoplasm may be vacuolated or may even contain a single vacuole.
Figure 17.11. FNA of a cystic nodule.A. Degenerating follicular cells and histiocytes. B,C. Tissue
fragments of follicular cells with mild nuclear enlargement. The nuclear atypia suggesting a
neoplasm, possibly papillary carcinoma.. Thyroidectomy showed nodular goiter. Diff-Quik
preparation. (Courtesy of Mariza de Peralta-Venturina, MD, William Beaumont Hospital, Royal
Oak, Michigan.)
Figure 17.12. FNA of cystic nodular goiter. A. This group of follicular cells has assumed spindle
shape with nuclear enlargement. Note hemosiderin-containing macrophages. B. A different
group exhibiting similar morphology. A small number of these types of cells in a background of
nodular goiter are usually of no significance.

Figure 17.13. FNA of a cystic nodular goiter. Tissue fragments of enlarged follicular cells with
pleomorphic and enlarged nuclei with granular to compact chromatin and occasional
micronucleoli. Nuclear grooves or inclusions are not appreciated. These cells were few in
numbers, in the background of typical features of cystic nodular goiter and do not justify a
surgical procedure.
Figure 17.14. FNA of a cystic nodule showing a single group of enlarged follicular cells with
markedly pleomorphic, hyperchromatic nuclei and high N/C ratios, in the background features of
nodular goiter.
Figure 17.15. A. Cytospin preparation of clear cyst fluid showing several large tissue fragments
of follicular cells, low power. B,C. Higher magnification demonstrating follicular cells in tissue
fragments with follicular pattern and in loosely cohesive groups. Their cell borders are poorly
defined and the cytoplasm is pale, vacuolated to dense. The nuclei are enlarged, crowded
nuclei, some containing micronucleoli. The cytologic diagnosis was suspicious for papillary
carcinoma. D. The thyroidectomy confirmed nodular goiter with cystic change. E. The cystic
cavity is filled with hemosiderin-containing histiocytes. No papillary carcinoma was identified.
Figure 17.16. Different example of a cystic nodular goiter that was cytologically interpreted as
"atypical cells, papillary carcinoma cannot be ruled out." A,B. These two images depict tissue
fragments of follicular cells with pleomorphic nuclei, granular chromatin, and occasional nuclear
grooves. C. The thyroidectomy revealed a cystic nodular goiter. No papillary carcinoma was
identified. D. The follicular cells in focal areas demonstrated nuclear atypia, representing the
source of atypical cells.

Large tissue fragments of benign follicular cells within the cystic cavity exposed to the fluid
environment may resemble syncytial-type tissue fragments from papillary carcinoma. The
atypical follicular cells in a cystic nodular goiter may acquire a spindle shape and abundant
cytoplasm, and may present a directional flow similar to that seen in repair squamous
metaplasia.44

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The morphologic alterations in follicular cells in cystic nodular goiters represent a frequent
source of diagnostic problems as they mimic malignant cells and constitute a major cause for the
false-positive diagnosis of papillary carcinoma.

Various examples of disturbing morphologic alterations in follicular cells in cyst fluids are
illustrated in Figures 17.11 , 17.12 , 17.13 , 17.14 , 17.15 , 17.16 . The diagnostic difficulties of
differentiating atypical follicular cells of the cystic nodular goiters from cystic papillary
carcinoma cells are discussed in detail in Chapter 9 and listed in Table 9.8 .

CYSTIC DEGENERATION IN NEOPLASMS

The cystic degeneration may also occur in both benign and malignant thyroid neoplasms. The
larger the size of the neoplasm, the greater the chances of degeneration, necrosis, and cyst
formation. Large follicular and Hürthle cell adenomas
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are frequently cystic. The incidence of cystic change in follicular adenomas is reported to be as
high as 37% (Fig. 17.17 ).1 De las Santos et al.5 reported 25% of 71 cystic lesions to be follicular
adenomas and 3% Hürthle cell adenomas. The cyst fluid show features of the respective benign
neoplasm in the background of histiocytes and foreign-body-type multinucleated giant cells (Fig.
17.18 ).
Figure 17.17. Gross photograph of a large cystic follicular adenoma.
Figure 17.18. FNA of a cystic follicular adenoma consisting of a syncytial tissue fragment of
follicular cells with a follicular pattern. The nuclei are mildly enlarged. Note macrophages in the
background.

CYSTIC PAPILLARY CARCINOMA

The most common malignant neoplasm of the thyroid to undergo cystic change is papillary
carcinoma.45 In a study reported by Goellner,9 16.6% of papillary carcinomas were cystic. The
carcinoma may be purely cystic or partially cystic and may contain residual in the wall (Fig.
17.19 ). The diagnosis of
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P.379
P.380
cystic papillary carcinoma will be accurate in the presence of cellular material with classic
cytologic features (Fig. 17.20 ). However, considerable diagnostic difficulties are faced with the
cytologic diagnosis of cystic papillary carcinoma due to a poorly cellular sample, regressive
changes in the neoplastic cells masking the malignant criteria, and the cellular debris, blood,
and large numbers of macrophages in the background (Figs. 17.21 , 17.22 , 17.23 , 17.24 , 17.25
and 17.26 ). Their differentiation from reactive/reparative follicular cells in cystic nodular
goiter is a major diagnostic problem. Castro-Gomez46 described the features helpful in
identifying papillary carcinoma cells that included tridimensional tissue fragments,
anisonucleosis, nuclear bars, powdery chromatin, metaplastic cytoplasm, and cytoplasmic
vacuoles.

Figure 17.19. Gross photograph of a cystic papillary carcinoma. The cystic cavity is large with a
thick wall. Note residual tumor in the wall (arrow ). After aspirating a cystic lesion, the residual
tumor if palpable should be aspirated.
Figure 17.20. A. Fine-needle aspirate of a cystic papillary carcinoma may be diagnostic as seen
here with branching papillary tissue fragments. B. Higher magnification showing features of
papillary carcinoma.

Figure 17.21. This aspirate from a cystic papillary carcinoma consists of tissue fragments of
malignant cells obscured by hemosiderin-containing macrophages. Note a psammoma body. Poor
cellular details will preclude an unequivocal diagnosis of papillary carcinoma.
Figure 17.22. Another example of degenerating carcinoma cells from a cystic papillary
carcinoma. Their cytoplasm is markedly vacuolated. The nuclei have smudgy chromatin with a
suggestion of intranuclear inclusions (arrows ). An unequivocal diagnosis of papillary carcinoma
cannot be given from this cytologic pattern.
Figure 17.24. A. Fine-needle biopsy of cystic papillary carcinoma. The smear shows a large
number of degenerating follicular cells and histiocytes (low power). B,C. Higher magnification.
The follicular cells are large and pleomorphic, with cytoplasmic vacuoles. The nuclear chromatin
appears smudgy, but pseudoinclusions are seen (arrows ). D. Thyroidectomy confirmed a cystic
papillary carcinoma.
Figure 17.25. FNA of a surgically proven cystic papillary carcinoma showing hemorrhagic
background and tissue fragments of enlarged follicular cells containing abundant finely
vacuolated cytoplasm. Their nuclei present degenerative changes and are difficult to evaluate.
Note a suggestion of intranuclear inclusion (arrow ). These cells appear histiocytoid but are
suspicious for papillary carcinoma.
Figure 17.26. FNA of a cystic papillary carcinoma. A. The aspirate is bloody and the smear is
practically acellular, containing few histiocytes. B. This field shows a naked psammoma body.
The smear is nondiagnostic. C. The cell block, however, revealed fragments of papillary
carcinoma. Thyroidectomy confirmed the papillary carcinoma.

We rely very heavily on minimal criteria for the cytologic diagnosis of papillary carcinoma (see
Chapter 9 ), which are similar to those described by Castro-Gomez et al.46

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Cystic change is unusual in follicular carcinomas but may be pronounced in anaplastic
carcinomas due to extensive necrosis (Fig. 17.27 ). The cellular and necrotic debris obscures the
malignant cells and may preclude a correct diagnosis.
Figure 17.27. Cystic anaplastic carcinoma showing inflammatory and necrotic background. The
malignant cells (arrows ) have poorly defined cell borders and are obscured by the cellular
debris.

Very rarely a branchial cleft cyst (Fig. 17.28 ) or a parathyroid cyst enters the differential
diagnosis. Unless clinically and radiologically suspected, the cytologic differentiation of a
parathyroid cyst from a cystic nodular goiter is not possible without ancillary tests (see Chapter
21 ). The differential diagnostic features of various cystic thyroid lesions are listed in Table 17.3

Simple cyst
Usually squamous epithelial lined cyst; variable cellularity; epithelial cells
may be atypical
17.1
Lymphoepithelial cyst
Uncommon multiple cysts in the background of Hashimoto's thyroiditis;
may be present without underlying disease process; lined by squamous
epithelium with or without atypia; associated squamous
metaplasia
17.2
Intrathyroidal thyroglossal
duct cyst or branchial
cleft cyst
Squamous or columnar epithelial lining; aspirated specimen with benign,
mature squamous cells; metaplastic squamous cells ±; anucleated
squames; thyroid follicular cells ±
17.3 to 17.5
Colloid cyst
Abundant colloid; absent or few follicular cells with small pyknotic nuclei
17.6
Cystic nodular goiter
Aspirated fluid variable in quantity; thin, clear to amber colored, or thick,
turbid, "gruel-like"; or hemorrhagic to chocolate colored; variable cellularity,
usually few or no well-preserved follicular cells; occasionally large tissue
fragments; degenerative changes in follicular cells, with cellular and nuclear
enlargement, granular to compact chromatin; micronucleoli ±; appreciable
cytoplasm, with or without hemosiderin; repair/regenerative changes with
atypical features such as nuclear grooves, intranuclear inclusions, squamous
metaplasia., spindle forms; Hürthle cells ±; variable numbers of macrophages
with and without hemosiderin; multinucleated foreign-body-type giant
cells; calcific debris, stromal cells; oxalate crystals with supravital stain
(wet mount)
17.8 to 17.16
Cystic follicular adenoma
Syncytial tissue fragments of follicular cells with or without follicular pattern,
with mild to moderately enlarged nuclei, containing granular chromatin;
histiocytes with and without hemosiderin in the background
17.18
Cystic Hürthle cell tumor
Neoplastic Hürthle cells discrete, in groups, or in tissue fragments, uniform
nuclei with prominent macronucleoli; transition forms not present; follicular
cells or colloid not present in the background; histiocytes with and without
hemosiderin
Cystic papillary carcinoma
Aspirated contents may be clear to turbid, grossly hemorrhagic to chocolate
colored; cellularity variable; carcinoma cells well-preserved and clearly
diagnostic of papillary carcinoma or with degenerative changes such as
cytoplasmic vacuoles, foamy, bubbly cytoplasm appearing histiocytoid,
hemosiderin ±; psammoma body ±; histiocytes with and without
hemosiderin in large numbers; may obscure carcinoma cells; colloid
absent
17.20 to 17.26
Anaplastic carcinoma with cystic
degeneration and necrosis
Profuse inflammatory infiltrate, obscuring carcinoma cells; identification of
malignant cells may be difficult
17.27
Branchial cleft cyst in the neck
Aspirated fluid clear to turbid; polymorphic cell population composed of
benign squamous cells with frequent anucleated forms; ciliated columnar
cells ±; thyroid follicular cells ±; mucoid background; inflammatory cells ±;
macrophages ±; cholesterol crystals ±
17.28
Parathyroid cyst
Clear fluid, acellular to poor cellularity; small cuboidal epithelial cells with
uniform, round nuclei; coarsely granular chromatin; difficult to
differentiate from thyroid follicular cells; macrophages ±; positive
immunoreactivity to parathyroid antibody; high levels of parathyroid
hormone
See Fig. 21.4
(Chapter 21)

Disease Entity Cytopathologic Features See Fig(s).

TABLE 17.3 DIFFERENTIAL DIAGNOSIS OF CYSTIC LESIONS OF

THE THYROID
Figure 17.28. A. Branchial cleft cyst fluid showing benign mature squamous cells anucleated
squames and cellular debris in the background. B. Histologic section of a branchial cleft cyst
lined by stratified squamous epithelium.

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SUMMARY
The most common cystic lesion of the thyroid is cystic nodular goiter. The follicular cells in a
cystic background often demonstrate degenerative and/or reparative-regenerative changes and
cause diagnostic difficulties. They are often misinterpreted as suspicious or diagnostic of
papillary carcinoma, leading to unnecessary surgical procedures. It is prudent not to render a
cytologic diagnosis of papillary carcinoma unless minimal cytologic criteria are present.
Degenerative changes may also result in a false-negative diagnosis. Clinically suspicious cysts are
those that recur or those with a residual mass by palpation or by ultrasonography after
aspiration. Repeat aspiration or excision of suspicious cysts is indicated because of the risk of
cancer.

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31.Apel RL, Asa SL, Chalvardlian A, et al. Intrathyroidal lymphoepithelial cysts of probable
branchial origin. Hum Pathol . 1994;25:1238–1242.

32.Watanabe I, Kobayashi K, Yamaguchi M, et al. Multilocular lymphoepithelial cyst in the

thyroid accompanied with a minute thyroid carcinoma. Patholgy Int . 1995;45:965–970.

33.Mittledorf CATS, de Oliveira Misiara AC, de Carvalho IE. Multicystic autoimmune

thyroiditis-like disease associated with HIV infection. A case report. Acta Cytol .
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34.Mishalani SH, Lones MA, Said JW. Multilocular thyroid cyst. A novel thyroid lesion
associated with human immunodeficiency virus infection. Arch Pathol Lab Med .
1995;119:467–470.

35.Ry?sks A, Vokurka J, Michal M, et al. Intrathyroidal lymphoepithelial cyst. A report of two

cases not associated with Hashimoto's thyroiditis. Pathol Res Pract . 1997;193:777–781.

36.North JH Jr. Foley AM, Hamill RL. Intrathyroid cysts of thyroglossal duct origin. Am Surg .
1998;64:886–888.

37.Hatada T, Ichii S, Sagayama K, et al. Intrathyroid thyroglossal duct cyst simulating a

thyroid nodule. Tumori . 2000;86:250–252.

38.McHenry CY, Danish r, Murphy T, et al. Atypical thyroglossal duct cyst: a rare cause for a
solitary thyroid nodule in childhood. Am J Surg . 1993;59:223–228.

39.Desmet J, DeWolf-Oeeters C, Cappelle L, et al. Branchial cleft-like cysts of the thyroid.

Am J Surg Path ol. 1990;14:1165–1171.

40.Lim-Tio SW, Judson R, Busmanis I, et al. An intra-thyroidal branchial cyst: a case report.
Aust NZ J Surg . 1992;62:826–828.

41.Nassar A, Gupta PK, LiVolsi VA, et al. Histiocytic aggregates in benign nodular goiters
mimicking cytologic features of papillary thyroid carcinoma (PTC). Diagn Cytopathol .
2003;29:243–245.

42.Faqin WC, Cibas ES, Renshaw AA. Atypical cells in fine-needle aspiration biopsy
specimens of benign thyroid cysts. Cancer (Cancer Cytopathol) . 2005;105:71–79.

43.Renshaw AA. Histiocytoid cells in fine needle aspirates of papillary carcinoma of the
thyroid: frequency and significance of an under-diagnosed cytologic pattern. Cancer (Cancer
Cytopathol) . 2002; 96:240–243.
44.Ohashi H, Sato A, Tanagbe Y, et al. Cystic goiter with squamous cell metaplasia–-case
report and comment on origin of squamous cell cyst. Acta Pathol Jpn . 1976;26:503–508.

45.Carcangiu ML, Zampi G. Pupi A, et al. Papillary carcinoma of the thyroid: a

clinicopathological study of 241 cases treated at the University of Florence, Italy. Cancer .
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46.Castro-Gomez L, Cordova-Ramirez S, Duarie-Torres R, et al. Cytologic criteria of cystic

papillary carcinoma of the thyroid. Acta Cytol . 2003;47:590–594.
Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 18 - Spindle Cells in Thyroid Aspirates

18
Spindle Cells in Thyroid Aspirates

The normal thyroid gland contains limited stromal component. The presence of spindle-shaped
cells of mesenchymal origin in fine-needle aspirates of epithelial lesions of the thyroid is not a
common occurrence. Infrequently, the epithelial cells, in non-neoplastic as well as both benign
and malignant neoplastic lesions acquire spindle shape. The stromal and epithelial spindle cells
originate from diverse sources (Table 18.1 ). They present considerable diagnostic difficulties
when encountered in aspirated specimens from thyroid nodules, and may result in false-positive
diagnosis of malignancy because of several cytologic abnormalities. The problem caused by the
presence of spindle cells in thyroid aspirates has not received much attention and only a few
reports document the diagnostic difficulties.1 , 2 , 3 This chapter describes various conditions in
which spindle cells are present in the thyroid aspirates including their diagnostic pitfalls and
cytologic features differentiating benign spindle cells from malignant ones (Table 18.2 ).

Stromal
Non-neoplastic
Nodular goiter
Chronic lymphocytic thyroiditis
Granulomatous thyroiditis
(subacute and infectious)
Riedel's thyroiditis (extremely rare)
Post131I therapy
Proliferating granulation tissue with
fibroblastic and endothelial proliferation
Leiomyocytes (blood vessel)
Desmoplastic stroma of papillary or
anaplastic carcinoma
Neoplastic
Soft-tissue neoplasms, primary
or metastatic
Epithelial
Non-neoplastic
Reparative/regenerative follicular cells in
nodular goiter
Squamous metaplasia
Nodular goiter
Hashimoto's thyroiditis
Papillary carcinoma
Neoplastic
Hyalinizing trabecular adenoma
Papillary carcinoma
Medullary thyroid carcinoma
Anaplastic carcinoma
Poorly differentiated squamous carcinoma
(sarcomatoid type)
Spindle cell thyroid tumor with thymus-like
elements (SETTLE)
Spindle cell type, intrathyroidal thymoma
Metastatic carcinosarcoma

TABLE 18.1 SPINDLE CELLS IN THYROID ASPIRATES

Presentation
In tissue fragments or loosely cohesive groups; iso-
lated cells infrequent
In tissue fragments, loosely cohesive groups or isolated cells; may be in fascicles
Arrangement
In fascicles with palisading of nuclei, directional
flow to the cytoplasm; swirling arrangement;
 cells may be separated by collagen
May be in fascicles, swirling arrangement or stori
form pattern ±
Cells
Large, mildly pleomorphic
Markedly pleomorphic
Cytoplasm
Abundant, pale
Variable with high N/C ratios
Nuclei
Round, oval, oblong, spindle to cigar-shaped, uni
form to mildly pleomorphic, smooth nuclear mem
branes, notch on the membrane ± , compact to
evenly dispersed, finely granular chromatin; multi
ple micro- macronucleoli ±; intranuclear inclusions
±; mitosis regular ±
Marked anisonucleosis with bizarre shapes,
irregular nuclear membranes, coarsely granular
chromatin with excessive parachromatin clear
ing; multiple, irregular, micro-macronucleoli;
intranuclear inclusions ±; mitosis regular and
irregular ±
Background
Clean to inflammatory; features of nodular goiter or
Hashimoto's thyroiditis
Clean to necrotic

Benign Spindle Cells Malignant Spindle Cells

TABLE 18.2 DIFFERENTIATING FEATURES BETWEEN BENIGN

AND MALIGNANT SPINDLE CELLS

NON-NEOPLASTIC SPINDLE CELLS OF MESENCHYMAL ORIGIN

Benign spindle cells of mesenchymal or stromal origin are encountered in nodular goiters, in
Hashimoto's thyroiditis, and from desmoplastic stroma in papillary or anaplastic carcinomas
(Table 18.1 , Figs. 18.2 , 18.3 , 18.4 , 18.5 and 18.6 ). In nodular goiters they may be derived
from fibrosis occurring as a result of episodes of hemorrhage, necrosis and subsequent
organization of the granulation tissue (Figs. Figs. 18.1 and 18.2 ). They may also be derived from
reparative processes especially in cases of cystic degeneration. The cystic change and the
fibrotic lesions are a frequent source of stromal cells in thyroid aspirates. Anderson et al.3
reported an incidence of 49% of nodular goiters with retrogressive changes to contain
fibroblastic proliferations. Van Hooven et al.2 described 3 cases with fibrotic nodules that
resulted in surgery because of significant population of spindle cells. Fibrosis has also been
described in large follicular adenomas,2 although it is not very common. The thyroid
parenchyma along the needle biopsy track or from the infarcted lesions (Figs. Fig. 18.3 ) may
show fibroblastic proliferation and may be seen in aspirated samples. Desmoplastic stroma in
papillary or anaplastic carcinoma is yet another source of benign spindle cells (Figs. Figs. 18.4
and 18.5 ).

Figure 18.1. Histologic section of a fibrotic nodule from a case of nodular goiter. Note the
collagenized stroma. Aspirate of such a lesion will be paucicellular with few stromal cells.
Figure 18.2. Histologic section showing granulation tissue with actively proliferating fibroblasts.
FNA of this lesion may yield spindle cells with atypical nuclei.
Figure 18.3. Histologic section of granulation tissue along the perimeter of an infarcted tumor.
Figure 18.4. Histologic section of a papillary carcinoma with marked desmoplasia. FNA of these
areas may be poorly cellular with only stromal cells leading to a false negative diagnosis.
Figure 18.5. Histologic section of a paucicellular variant of anaplastic carcinoma with
desmoplastic stroma. FNA of these areas may be poorly cellular, and may contain only stromal
cells, leading to a false-negative diagnosis.
Figure 18.6. Histologic section of a thyroid involved by Hashimoto's disease demonstrating
parenchymal atrophy and increased fibrosis.

Tissue fragments of connective tissue stroma may also be seen in aspirates of Hashimoto's
thyroiditis (Fig. 18.6 ), especially in late stages of the disease.

Cytopathologic Features
The spindle cell of stromal origin in thyroid aspirates present a diverse morphology (Figs. 18.7 ,
18.8 , 18.9 , 18.10 , 18.11 , 18.12 , 18.13 , 18.14 , 18.15 , 18.16 , 18.17 , 18.18 , 18.19 , 18.20 ,
18.21 , 18.22 , 18.23 and 18.24 ). The latter depends on whether the area biopsied is an old
fibrotic nodule, or an actively organizing stroma with proliferating fibroblasts and capillaries.
The spindle cells from the fibrotic nodule usually are few in numbers and have bland nuclei,
while those from organizing stroma show atypical nuclei with pleomorphism and nucleoli. The
spindle cells by their sheer presence cause diagnostic concern, more so with atypical
morphology, and are often misinterpreted as neoplastic.
Figure 18.7. FNA of a nodular goiter showing several elongated spindle-shaped stomal cells
separated by collagen. Note the nuclei are oblong to spindle shaped, containing bland
chromatin.

Figure 18.8. FNA of a nodular goiter showing a string of elongated stromal fibrocytes with long
cytoplasmic processes. The spindle-shaped nuclei have a bland chromatin pattern.
Figure 18.9. This aspirate from a case of nodular goiter shows a large population of spindle
cells, isolated and in aggregates. The cells appear monomorphic with bland nuclei. This pattern
may be misinterpreted as a soft-tissue tumor or a medullary carcinoma.
Figure 18.10. A group of delicate stromal spindle cells with long cytoplasmic processes and
spindle-shaped nuclei. A small number of these types of cells in the background of nodular goiter
should cause no concern.
Figure 18.11. A fascicle of spindle-shaped stromal cells identified in an aspirate of nodular
goiter. These stromal cells have abundant pale cytoplasm and impart a directional flow similar
to that seen in repair. The nuclei are plump but with uniformly distributed finely granular
chromatin.
Figure 18.12. FNA of nodular goiter showing a branching stromal tissue fragment. Note benign
follicular cells and colloid in the background (Diff-Quik stain). (Courtesy of Mariza de Peralta-
Venturina, MD, William Beaumont Hospital, Royal Oak, Michigan.)
Figure 18.13. FNA of a nodular goiter showing a group of spindle-shaped cells with atypical
nuclei. The background showed features of nodular goiter.

Figure 18.14. FNA of a nodular goiter showing few tissue fragments of elongated spindle-shaped
stromal cells with abundant cytoplasm and varying-sized enlarged nuclei. Note prominent
nucleoli and intranuclear inclusions (arrows ).

Figure 18.15. FNA of a cystic nodular goiter. A. This fascicle of spindle cells was present in a
background of benign follicular cells and histiocytes containing hemosiderin. Note that their
nuclei are elongated with bland chromatin and contain intranuclear inclusion (arrow ). B.
Different field showing a fascicle of spindle cells with elongated nuclei. These strongly resemble
medullary carcinoma cells.
Figure 18.16. FNA of Hashimoto's thyroiditis. Note spindle-shaped stromal cells in a background
of inflammatory cells.

Figure 18.17. Another example of a tissue fragment of stromal cells from Hashimoto's
thyroiditis.
Figure 18.18. A. FNA of an anaplastic carcinoma showing a tissue fragment of benign stroma.
Note that the nuclei are uniform, small, containing granular chromatin and lack malignant
features. B. Malignant cells of anaplastic carcinoma from the same case as A. Compare the
benign stromal cells to these malignant cells, which appear clearly malignant. It is not unusual
to aspirate benign stromal tissue from malignant lesions. C. FNA of a spindle cell type anaplastic
carcinoma. Note occasional malignant cell (arrows ) embedded in this dense fibrous tissue.
Figure 18.19. FNA of a mass considered being of thyroid origin. A. Spindle-shaped, actively
proliferating fibroblasts with delicate cytoplasmic processes. The nuclei are uniform with finely
granular chromatin. B. A different field showing round, plump histiocytes with nuclei containing
a notch (arrow ) as well as intranuclear inclusion. Note spindle-shaped fibroblasts and
inflammatory cells. A malignant diagnosis was suspected. C. Excision of the mass revealed
granulation tissue in the region of prior neck surgery unrelated to the thyroid.

Figure 18.20. FNA of a cold thyroid nodule. A,B. The cells are spindle shaped, with very
pleomorphic, atypical nuclei. Malignant diagnosis was rendered.
Figure 18.20. C,D. The thyroidectomy revealed the nodule to be totally composed of
proliferating granulation tissue, probably representing an organizing hematoma. Note the
actively proliferating fibroblasts and capillaries.

Figure 18.21. FNA of a nodular goiter. A. One of the passes of needle biopsy contained these
large anastomosing tissue fragments of spindle cells (low power). B. Higher magnification
depicted stromal cells with abundant cytoplasm, low N/C ratios, and uniform nuclei. These
stromal cells probably represent proliferating granulation tissue. Most of the cellular material in
this case was diagnostic of nodular goiter. C. FNA of an anaplastic thyroid carcinoma for
comparison. Note that the nuclei are clearly malignant with high N/C ratios.
Figure 18.22. A,B. Another example of very atypical stromal cells from nodular goiter with
morphologic similarity to medullary carcinoma cells. C. FNA of a medullary thyroid carcinoma
demonstrating discrete spindle-shaped carcinoma cells. Compare these with the benign stromal
cells in A and B.
Figure 18.23. FNA of subacute (granulomatous) thyroiditis depicting fascicles of stromal spindle
cells. Note a multinucleated giant cell (arrow ).

Figure 18.24. A. FNA of a nodular goiter showing longitudinally sectioned blood vessel (low
power). B,C. Higher magnification showing palisading, uniform cigar-shaped nuclei consistent
with leiomyocytes.
Figure 18.24. B,C. Higher magnification showing palisading, uniform cigar-shaped nuclei
consistent with leiomyocytes. D. FNA of thyroid showing malignant smooth-muscle cells from a
metastatic leiomyosarcoma, for comparison.

In thyroid aspirates of nodular goiters or Hashimoto's thyroiditis, the stromal cells or fibrocytes
are generally present in small numbers, isolated, in groups, or in tissue fragments separated by
collagen (Figs. Fig. 18.7 ). They have elongated, spindle-shaped nuclei with pale, uniformly
distributed finely granular chromatin, occasionally containing micronucleoli (Figs. 18.7 , 18.8 ,
18.9 , 18.10 , 18.11 , 18.12 , 18.13 , 18.14 , 18.15 , 18.16 , 18.17 and 18.18 ). The nuclear
membrane is smooth, thin, and may show a notch as well as intranuclear inclusions (Figs. 18.14
and 18.15 ). The stromal cells or fibrocytes are bipolar with variable, pale cytoplasm that may
extend into processes. The N/C ratios are low. At times, the stromal cells are displayed in small
fascicles that appear flat with a directional flow to the cytoplasm (Fig. 18.11 ). The collagen
appears fibrillar or homogeneous in Papanicolaou-stained preparations (Fig. 18.7 ), while it
appears as ragged, membranous fragments staining metachromatically red in air-dried
Romanowsky-stained preparations.4 The background often shows hemosiderin-containing
histiocytes and inflammatory cells.

The benign spindle cells of stromal origin are frequently present in aspirates from Hashimoto's
thyroiditis (Figs. 18.16
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P.387
P.388
and 18.17 ). Again, the morphology of these cells is very similar to that seen in stromal cells
from nodular goiters.

It is not uncommon to find benign stromal tissue fragments in aspirates from papillary carcinoma
or anaplastic carcinomas. They originate from the desmoplastic stroma (Fig. 18.18 ).
Morphologically, the benign stromal cells are distinctly benign as compared to the malignant
cells from the same aspirate, which demonstrate obvious malignant features.

The aspirate from an actively organizing granulation tissue yields proliferating fibroblasts and
endothelial lining cells of the proliferating capillaries. These present as elongated, or large,
round cells that are loosely cohesive, sometimes arranged in fascicles that may interdigitate
(Figs. 18.19 , 18.20 , 18.21 , 18.22 and 18.23 ). Their elongated to oblong nuclei are enlarged
with a moderate increase in the N/C ratios. The nuclear membrane is smooth, thin and crisp,
the chromatin finely granular and evenly distributed. The micronucleoli may be conspicuous.
These spindle cells have abundant pale cytoplasm, with distinct long cytoplasmic processes.
Because of the increased N/C ratios and prominent nucleoli, the proliferating fibroblasts or
endothelial lining cells may be misinterpreted as malignant, especially anaplastic thyroid
carcinoma, or medullary carcinoma or a soft-tissue tumor. Anderson et al.3 reported 299 cases
of nodular goiters of which 73 (24%) of cases displayed atypical, retrogressive, or metaplastic
changes.
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Of these, 36 (49%) contained fibroblastic proliferations characterized by elongated to round or
bizarre cells with atypical nuclei.

Systemic administration of radioactive iodine (131 I) can induce changes in both the follicular
cells and the stromal tissue of the thyroid. Aspiration biopsy shows both epithelial and stromal
type spindle cells with karyocytomegaly and deep-staining smudgy, structureless chromatin with
occasional intranuclear inclusions.5 Their cytoplasm is variable, sometimes abundant and
vacuolated, and may contain neutrophils. Bare, pleomorphic, but pyknotic nuclei are also seen
frequently (see "Radiation-Induced Cellular Changes" in Chapter 19 ).

Another source of benign spindle cells is granulomatous or subacute thyroiditis. Aggregates of

epithelioid and stromal spindle cells may be present with or without accompanying
multinucleated giant cells (Fig. 18.23 ).4 , 6 Cytologic identification is generally easy especially
when considered in context with the clinical features, laboratory data, and radionuclide imaging
findings. Riedel's thyroiditis, or fibrosing thyroiditis, an extremely rare condition of the thyroid,
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P.392
P.393
will yield scant aspirate on needle biopsy, represented by only stromal cells.4 , 7

Spindle cells in thyroid aspirates may also originate from the smooth-muscle wall of the blood
vessels. The smooth-muscle cells are arranged in a palisading fashion and are aligned in parallel
rows. Their nuclei are cigar shaped with blunt ends and a bland chromatin pattern (Fig. 18.24 ).

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NEOPLASTIC SPINDLE CELLS OF MESENCHYMAL ORIGIN

The spindle cell pattern is one of the morphologic characteristics of both benign and malignant
soft-tissue tumors. These primary soft-tissue neoplasms8 , 9 , 10 , 11 , 12 , are very rare in the
thyroid gland. The reported cases include schwannoma, leiomyosarcoma, liposarcoma,
hemangioendothelioma, synovial sarcoma,8 and osteosarcoma, to mention a few. The thyroid
gland may also be the site of metastatic sarcoma (Fig. 18.24D ).13 Soft-tissue tumors in the neck
may clinically simulate thyroid nodules and be aspirated.

NON-NEOPLASTIC SPINDLE CELLS OF EPITHELIAL ORIGIN

Non-neoplastic spindle cells of epithelial origin include reactive/reparative follicular cells in
nodular goiters and squamous cell metaplasia. The reactive follicular cells in nodular goiters
with degeneration may acquire a spindle shape, enlarge in size, and may contain pleomorphic
nuclei. These cells usually occur in small numbers, seen either isolated or in loosely cohesive
groups (Figs. 18.25 , 18.26 , 18.27 , 18.28 , 18.29 and 18.30 ). Their nuclei have finely granular
chromatin and micronucleoli, and also exhibit occasionally inclusions and grooves, causing a
great deal of concern. Faquin et al.1 described atypical cells from 75 benign cysts of the thyroid
associated with nodular goiter with histologic follow-up. The cytologic features of the atypical
cells included flat tissue fragments, distinct cell borders, nuclear enlargement, nuclear grooves,
dense granular cytoplasm, small distinct micronucleoli, fine chromatin, and elongation to
spindle cytomorphology. These cells were immunoreactive to cytokeratin and thyroglobulin
while negative for CD68 and smooth-muscle actin, suggesting a follicular origin.
Figure 18.25. FNA of a nodular goiter with retrogressive changes, showing an admixture of
reactive, enlarged follicular cells with spindle and round forms. A papillary carcinoma was
suspected. The thyroidectomy revealed multinodular goiter.
Figure 18.26. A group of very abnormal-appearing spindle and round cells with enlarged nuclei
containing finely granular chromatin. Note intranuclear inclusion (arrows ). A malignant
diagnosis was rendered. Thyroidectomy showed nodular goiter.
Figure 18.27. FNA of a nodular goiter with retrogressive changes. This group of spindle and
round cells probably represents reactive/reparative follicular cells and may offer diagnostic
difficulties. A hemosiderin-containing macrophage is present in the background.
Figure 18.28. Squamous metaplastic cells occurring in the background of nodular goiter often
display spindle shape. They may be present as isolated cells.
Figure 18.29. A. An excellent example of squamous metaplasia in FNA of nodular goiter. This
tissue fragment of follicular cells exhibit enlarged nuclei, containing coarsely granular
chromatin. Note the transition to spindle and polygonal forms with cytoplasmic processes
resembling spider cells (arrow ) described for metaplastic squamous cells. B. A different field
from the same case showing squamous metaplasia. The follicular cells are large, with abundant
pale cytoplasm. C. A different field showing several spindle-shaped and round cells in the same
aspirate. The morphology resembles that of stromal cells. It is not unusual to see spindle cells of
both stromal and epithelial origin in the same aspirate. D. Same aspirate showing tissue
fragments of benign follicular cells consistent with nodular goiter.
Figure 18.30. A. FNA of a nodular goiter showing large tissue fragments of metaplastic
squamous cells (low power).

Figure 18.30. B,C. Higher magnification demonstrating spindle shapes with abundant cytoplasm,
smaller nuclei with low N/C ratios, and finely granular chromatin.

The metaplastic squamous cells are sometimes encountered in the aspirates of thyroid lesions,
such as with nodular
 P.395
goiter, especially with cystic change; in thyroids subjected to 131 I therapy; and in chronic
lymphocytic thyroiditis of the Hashimoto's type. Squamous metaplasia is also reported in 10% to
50% of papillary carcinomas14 , 15 and may be present in cytologic specimens from papillary
carcinomas. The metaplastic squamous cells occur as tight groupings of cells forming morulae, or
with a whirled arrangement (see Figs. 19.29 and 19.30 ), or as loosely cohesive, elongated cells
with abundant cytoplasm and tapered ends (Figs. 18.28 , 18.29 and 18.30 ). Occasionally,
squamous metaplasia presents as large monolayered tissue fragments (Fig. 18.30 ). The nuclei
are centrally located, containing granular chromatin and low N/C ratios. The presence of
micronucleoli is not consistent. The metaplastic squamous cells are large, polygonal to spindle
shaped, with well-defined cell borders. Multiple cytoplasmic processes referred to as spider cells
as described in cervical smears may also be encountered (Fig. 18.29A ). Their cytoplasm is
variable but abundant and pale to dense.

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NEOPLASTIC SPINDLE CELLS OF EPITHELIAL ORIGIN

Neoplastic spindle cells of epithelial origin may be seen in benign neoplasms such as hyalinizing
trabecular adenoma,16 or in malignant neoplasms, that is, papillary carcinomas17 (Fig. 18.31 ),
medullary carcinoma (Fig. 18.32 ), or anaplastic carcinoma (Fig. 18.33 ). Some very infrequent
examples of thyroid epithelial neoplasms with a spindle cell pattern include intrathyroidal
thymomas, referred to as thyroid carcinoma showing thymus-like element (CASTLE), and spindle
epithelial tumor of thyroid with thymus-like elements (SETTLE) (see "Unusual and Uncommon
Neoplasms of the Thyroid" in Chapter 19 ). Other rare examples include primary or metastatic
poorly differentiated squamous carcinomas, sarcomatoid type, and metastatic carcinosarcoma.
Figure 18.31. Three separate cases of papillary thyroid carcinomas with spindle-shaped
carcinoma cells with their nuclei demonstrating features of papillary carcinoma.
Figure 18.32. FNA of a medullary thyroid carcinoma showing spindle-shaped cells. Their nuclear
chromatin is typical salt-and-pepper type.
Figure 18.33. FNA of an anaplastic thyroid carcinoma, exhibiting spindle-shaped malignant
cells.

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SUMMARY
The presence of few spindle-shaped cells in thyroid aspirates originating from stromal tissue or
altered follicular cells may cause a great concern. Usually, they are of no diagnostic
significance. The background features of the aspirate are generally those of nodular goiter with
retrogressive changes. It is important to recognize them as benign and of stromal origin or
reactive/reparative follicular cells so that over-diagnosis and unnecessary surgery is avoided.

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specimens of benign thyroid cysts. Cancer (Cancer Cytopathol) . 2005;105:71–79.
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fibrotic nodule. Diagn Cytopathol . 1996;14:362–366.

3.Anderson RJ, Pragasam PJ, Nazeer T. Atypical retrogressive and metaplastic changes in
nodular goiter: potential pitfalls in aspiration cytology of the thyroid. Acta Cytol .
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4.Droese M. Cytological Aspiration Biopsy of the Thyroid Gland. Stuttgart: Schattauer

Verlag; 1980:57,62,81–85.

5.Centeno BA, Szyfelbein WM, Daniels GH, et al. Fine needle aspiration biopsy of the thyroid
gland in patients with prior Grave's disease treated with radioactive iodine: Morphologic
findings and potential pitfalls. Acta Cytol . 1996;40:1189–1197.

6.Ofner C, Hittmair A, Kroll I, et al. Fine needle aspiration cytodiagnosis of subacute (de
Quervain's) thyroiditis in an endemic goiter area. Cytopathology . 1994;5:33–40.

7.Clark DP, Faquin WC. Thyroid Cytopathology . New York: Springer Verlag; 2005:40–41.

8.Kikuchi I, Anbo J, Nakamura S, et al. Synovial sarcoma of the thyroid. Report of a case
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9.Jayaram G. Neurilemmoma (schwannoma) of the thyroid diagnosed by fine needle

aspiration cytology. Acta Cytol . 1999;47:743–744.

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10.Andrion A, Mazzucco G, Torchio B. FNA cytology of thyroid neurilemmoma (schwannoma).

Diagn Cytopathol . 1992;8:311–312.

11.Andrion A, Bellis D, Delsedime L, et al. Leiomyoma and neurilemmoma: report of two

unusual non-epithelial tumors of the thyroid gland. Virchows Arch . 1988;413:367A–372A.
12.Andrion A, Gaglio A, Dogliani N, et al. Liposarcoma of the thyroid gland. Fine needle
aspiration cytology, immunohistology and ultrastructure. Am J Clin Pathol .
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13.Wojcik EM. Fine needle aspiration of metastatic malignant schwannoma to the thyroid.
Diagn Cytopathol . 1997;16:94–95.

14.LiVolsi VA. Papillary neoplasms of the thyroid: pathologic and prognostic features. Am J
Clin Pathol . 1992;97:426–434.

15.Carcangiu ML, Zampi G, Pupi A, et al. Papillary carcinoma of the thyroid: a

clinicopathologic study of 241 cases treated at the University of Florence, Italy. Cancer .
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16.Casey MB, Sebo TJ, Carney JA. Hyalinizing trabecular adenoma of the thyroid gland.
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17.Woyke S, Al-Jassar AK, Al-Jarallah M, et al. Papillary carcinoma of the thyroid with
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Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 19 - Miscellaneous Lesions of the Thyroid

19
Miscellaneous Lesions of the Thyroid

This chapter is a potpourri of cytopathologic features of a broad range of uncommon and unusual to
rare neoplastic and non-neoplastic lesions of the thyroid. They represent some unexpected
cytopathologic patterns encountered in aspiration biopsy specimens of thyroid nodules or neck
lesions that masquerade as thyroid nodules.1 Some are related to the thyroid gland; others are non-
thyroidal. Interestingly enough, lesions that occur in the lateral neck not only masquerade as
thyroid lesions but can also occur within the thyroid, although on extremely rare occasions (that is,
soft-tissue tumors and Hodgkin's lymphoma). With increasing use of fine-needle biopsy procedures,
these patterns may be encountered more frequently. The cytopathologist needs to be cognizant of
the diverse lesions that can occur in the thyroid gland and adjacent region so that their recognition
can be easy or at least differential diagnoses can be offered. Every attempt is made to include and
illustrate cytologic presentations of uncommon, unusual, and rare lesions. Several case reports
describing rare entities in thyroid aspirates can be found in the current literature. An illustration of
every example is beyond the scope of this book. The reader may refer to the literature for further
information.

NON-NEOPLASTIC CELLS OF NON-THYROID ORIGIN

Aspiration biopsy of the thyroid gland may yield cells that are non-thyroidal in origin (Table 19.1 ).
Most often these include fragments of epidermis, skeletal muscle, or subcutaneous fibroadipose
tissue (Figs. 19.1 and 19.2 ). An inadvertently placed needle in the trachea may aspirate respiratory
columnar cells, dust cells, carbon-containing multinucleated histiocytes, and mucus (Figs. 19.3 and
19.4 ). The presence of respiratory columnar cells has no significance and represents a minor
complication of the biopsy procedure. Jayaram2 reported an incidence of 0.2% of thyroid aspirates
(42/18,847) containing respiratory columnar cells, while the incidence reported by Kumar3 was 0.1%
of the thyroid aspirates (3/339). The biopsy needle may also aspirate the chondrocytes originating
from the laryngeal cartilage1 (Fig. 19.5 ). The laryngeal cartilage may get ossified and develop
hematopoietic tissue.4 , 5 Aspiration biopsy of these foci may contain megakaryocytes in the
background of other hematopoietic cells.4 , 5 The large to giant-sized multilobated megakaryocytes
are an important source of diagnostic pitfalls as they can be misinterpreted as cells of anaplastic
carcinoma (Figs. 19.6A to C and 19.7 ; see also Fig. 11.43 ). Rarely, the thyroid gland may be
involved by agnogenic myeloid metaplasia,6 , 7 , 8 , 9 and may clinically present as a thyroid
nodule. The aspiration biopsy findings in such a case with the presence of megakaryocytes have
been documented.6 The cytologic diagnosis in these cases was assisted by the clinical information
of an existing disease.

Epidermis
Adipose tissue
Skeletal muscle
Tracheal contents
Respiratory columnar cells
Dust cells and macrophages
Chondrocytes
Hematopoietic cells including megakaryocytes
(from the hematopoietic tissue developed in ossified
laryngeal cartilage) or agnogenic myeloid metaplasia
involving the thyroid

TABLE 19.1 NON-NEOPLASTIC CELLS OF NON-THYROID ORIGIN

Figure 19.1. Strips of epidermis as seen here are sometimes present as contaminants in thyroid
aspirates, and are easily recognized.
Figure 19.2. Fragments of skeletal muscle may also be present.
Figure 19.3. Ciliated respiratory columnar cells from trachea are rarely encountered if needle
enters the trachea.
Figure 19.4. During the biopsy procedure the needle inadvertently entered the trachea and
aspirated mucus along with dust cells. A. Mucus and dust cells (low power). B. Higher magnification
showing the dust cells.

Figure 19.5. Normal chondrocytes may also be aspirated.

Figure 19.6. Hematopoietic cells in a thyroid aspirate from a 30-year-old woman with a solitary
cold nodule. A–C. Large, giant cells with multilobated nuclei. These cells were not recognized as
megakaryocytes at the time of biopsy. Follicular cells were absent. A cytologic diagnosis of
anaplastic carcinoma was made. D. A repeat FNA biopsy showed features of a cellular follicular
adenoma. The follicular cells are in syncytial tissue fragment with moderately enlarged nuclei
containing granular chromatin. The megakaryocytes were not present in the repeat biopsy sample.
E. Histologic section of the surgically excised thyroid nodule confirming a cellular follicular
adenoma.
Figure 19.7. Another example of hematopoietic cells in thyroid aspirate. FNA of a large thyroid
nodule with cervical lymphadenopathy. A to D. The smears showed only megakaryocytes in the
background of other hematopoietic cells. Follicular cells were not present. E. A megakaryocyte in
the background of other hematopoietic cells (arrow ). Thyroidectomy subsequently revealed a
papillary carcinoma with metastasis to cervical lymph nodes.

MULTINUCLEATED GIANT CELLS IN THYROID ASPIRATES

The presence of multinucleated giant cells is a frequent but a nonspecific finding in fine-needle
aspirates of the thyroid. These multinucleated giant cells originate from a wide variety of disease
processes10 (Table 19.2 ). Their cytomorphology differs in different conditions.11 , 12 Some
multinucleated giant cells present characteristic features that are highly suggestive of the
disease—for example, subacute (granulomatous) thyroiditis; while the majority of multinucleated
giant cells present nonspecific features (Table 19.3 , Figs. 19.8 , 19.9 , 19.10 , 19.11 , 19.12 , 19.13
, 19.14 , 19.15 , 19.16 and 19.17 ).

Multinucleated foreign-body-type histiocytic giant cells

Nodular goiter and neoplasms with degeneration
Multinucleated foreign-body-type giant cells
Subacute or granulomatous thyroiditis
Hashimoto's thyroiditis
Chronic infectious granulomatous thyroiditis
Sarcoidosis
Foreign-body giant cells (e.g., Teflon granuloma)
Associated with radiation induced changes
Multinucleated giant cells associated with papillary carcinoma
Multinucleated malignant tumor giant cells
Anaplastic thyroid carcinoma and poorly differentiated
carcinomas (primary and secondary)
Hodgkin's lymphoma
Osteoclast-type multinucleated giant cells associated with
anaplastic carcinoma
Megakaryocyte

TABLE 19.2 MULTINUCLEATED GIANT CELLS IN THYROID

ASPIRATES
Figure 19.8. Multinucleated foreign body-type histiocytic giant cells in FNA of nodular goiter with
degeneration. Similar giant cells may be seen in benign and malignant neoplasms of thyroid with
cystic degeneration.
Figure 19.9. Multinucleated foreign-body giant cells from Teflon granulomas of the thyroid. Note
refractile foreign material in the giant cells. (Courtesy of David B. Kaminsky, MD, Palm Springs
Pathology Associates, Palm Springs, California.)
Figure 19.10. Multinucleated giant cell from a sarcoid granuloma.
Figure 19.11. Multinucleated giant cells from FNA of a case of subacute or granulomatous
thyroiditis.
Figure 19.12. Nondescript multinucleated giant cells from FNA of a case of chronic lymphocytic
thyroiditis of the Hashimoto's type.
Figure 19.13. Multinucleated giant cells in FNA of a papillary carcinoma.
Figure 19.14. A multinucleated malignant cell with bizarre nuclei in FNA of an anaplastic
carcinoma.
Figure 19.15. An osteoclast type giant cell in anaplastic carcinoma.
Figure 19.16. Multinucleated Reed–Sternberg cell from Hodgkin's lymphoma.
Figure 19.17. Megakaryocytes with multilobulated nucleus. Note the compact smudgy chromatin.

Foreign body
histiocytic type
Nodular goiter or thyroid
neoplasms with degeneration
and with cystic change
Variable in size; nuclei uniform and usually
small in numbers; cytoplasm dirty, granular,
with or without hemosiderin
19.8
Multinucleated foreign-
body type
Subacute or granulomatous
thyroiditis
Considerable variation in size; may be present
in large numbers; the giant cells can be
 enormous in size with multiple, uniform
nuclei in tens and hundreds; often seen
in the vicinity of blobs of colloid, forming
granuloma, epithelioid cells ±; associated
features—spindle-shaped stromal cells
19.11
Multinucleated giant cell
Hashimoto's thyroiditis
Infrequent occurrence; nondescript
morphology; fewer nuclei, associated
features of Hashimoto's thyroiditis; of no
diagnostic significance
19.12
Multinucleated giant cell
Papillary carcinoma
Variable in size; can be very large, often
angulated; abundant, dense cytoplasm; no
phagocytosis; isolated or in the vicinity of
follicular tissue fragments; rare intranuclear
inclusions and grooves
19.13
Multinucleated tumor
giant cell
Anaplastic carcinoma; poorly differ-
entiated metastatic carcinomas
Bizarre nuclei with malignant criteria
19.14
Osteoclast-type
Anaplastic carcinoma
Rarely present in anaplastic carcinomas,
variable numbers of uniform small nuclei
19.15
Multinucleated
foreign-body giant cells
Infectious granulomatous lesions;
sarcoidosis
Langhans-type giant cells characteristic in
tuberculous granulomas; associated with
epithelioid cells and granulomas
19.10
Megakaryocytes
Inadvertent aspiration of
thyroid or thyroid cartilage
Variable in size; multilobulated nuclei;
smudgy chromatin, abundant dense
cytoplasm; other hematopoietic cells in
the background; may be mistaken for
malignant cells
19.17
Multinucleated foreign
body giant cells
Teflon granuloma
Varying-sized multinucleated foreign-body
giant cells containing refractile Teflon
19.11
Multinucleated giant
cells in Hodgkin's
lymphoma
Hodgkin's lymphoma
Varying-sized, large to giant forms; mirror-
image nuclei or multinucleated with
prominent nucleoli
19.16

Type of Giant Cell Present In Cytologic Characteristics See Fig.

TABLE 19.3 MULTINUCLEATED GIANT CELLS IN THYROID

ASPIRATES: DIFFERENTIATING FEATURES
The multinucleated giant cells associated with degeneration and cystic change in nodular goiters
usually occur in smaller numbers, are not significantly enlarged, and contain fewer nuclei. Their
cytoplasm is dirty, granular to foamy, and phagocytic, often containing hemosiderin (Fig. 19.8 ).
The multinucleated giant cells in foreign-body granulomas often contain foreign bodies, for
example, Teflon granuloma in thyroid aspirates (Fig. 19.9 ). Infectious granulomatous inflammation
of the thyroid is also associated with the presence of multinucleated giant cells. Sarcoidosis rarely
involves the thyroid gland. The multinucleated giant cells in sarcoidosis are often associated with
epithelioid granulomas and may resemble Langhans-type giant cells or be nonspecific (Fig. 19.10 ).
They have been reported to contain Schumann bodies or asteroid bodies.

In subacute or granulomatous thyroiditis, the multinucleated giant cells are enormous in size and
contain tens and hundreds of nuclei11 , 12 , 13 (Fig. 19.11 ). Multinucleated giant cells are also
seen in aspirates of Hashimoto's thyroiditis14 (Fig. 19.12 ).

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The presence of multinucleated giant cells is a nonspecific but a consistent finding in aspirates of
papillary carcinomas (Fig. 19.13 ).15 , 16 , 17 , 18 , 19 , 20 The origin of the giant cells in papillary
carcinomas is uncertain. Anaplastic carcinomas demonstrate tumor giant cells with obvious
malignant criteria (Fig. 19.14 ). Anaplastic carcinomas may also be associated with osteoclast-type
multinucleated giant cells (Fig. 19.15 ).20 , 21 , 22

Multinucleated tumor giant cells (Reed–Sternberg cells) are also encountered in aspirates from
Hodgkin's lymphoma (Fig. 19.16 ). The presence of megakaryocytes in thyroid aspirates is a rare
occurrence. They are inadvertently aspirated from the ossified laryngeal cartilage that has
developed hematopoiesis. The megakaryocytes resemble multinucleated giant cells. However, their
nuclei are multilobulated rather than multiple in numbers and the chromatin is smudgy. The
multiple lobulations and smudgy chromatin should aid the identification (Fig. 19.17 ; see also "Non-
Neoplastic Cells of Non-Thyroid Origin" earlier in the chapter).

BLACK THYROID ASSOCIATED WITH MINOCYCLIN THERAPY

Certain drugs such as minocyclin are known to cause black pigmentation of the thyroid. Minocycline
is an antibiotic related to the tetracycline group, used for bacterial infection and acne. Its long-
term use has been associated with black pigmentation of the skin, nails, teeth, and rarely the
thyroid gland.23 , 24 There is uncertainty as to the nature of the black
P.403
pigment.25 , 26 , 27 , 28 , 29 Thyroid involvement is uncommon. So far, only 62 cases are reported
in the literature, of which 15 cases had fine-needle aspiration biopsies.30 Most cases of black
thyroid have been diagnosed as incidental findings either at autopsy or at surgical resection. The
brown to jet black pigmentation involves the thyroid parenchyma (Fig. 19.18A and B). However,
pigmentation of the nodular lesions is not consistent. Cases reported by Oertel et al. ,30 Jennings
et al.,31 and Pastolero et al.32 did not show pigmentation of the nodular lesions, either in fine-
needle biopsy specimens or in their histologic sections. Keyhani-Rofagha et al.33 reported a case
where the aspirate of the thyroid nodule showed follicular cells containing dark brown pigment in
their cytoplasm, which was also observed in macrophages (Fig. 19.18C and D). The black
pigmentation is of no clinical significance.

Figure 19.18. A,B. FNA of a thyroid nodule in a patient with a long history of minocycline therapy.
The follicular cells contain abundant cytoplasmic black granules. C. Thyroidectomy revealed a jet
black discrete nodule. D. Histologic section of the nodule showing jet-black pigment in the follicular
cells. (Courtesy of Sedigheh-Keyhani, MD, FIAC, Professor of Clinical Pathology, Ohio State
University Hospital, Columbus.)
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TEFLON GRANULOMA OF THE THYROID

Polytef (polytetrafluoroethylene), or Teflon, is sometimes injected into the larynges of patients
with unilateral vocal cord paralysis to improve phonation. Teflon particles are known to migrate
into the soft tissues and to distinct sites including the thyroid gland, eliciting a granulomatous
reaction.34 The granulomas show refractile, irregular, angular particles ranging from 4 to 100 µm.
This reaction can cause nodularity of the thyroid.35 , 36 , 37 Wilson and Gartner35 reported a case
of fine-needle biopsy of a thyroid nodule containing Teflon granuloma that was initially
misinterpreted as suspicious for malignancy. The author has seen one case in consultation,
illustrated in Figure 19.19 .

Figure 19.19. A. FNA of a thyroid involved by Teflon granuloma. Low-power view showing multiple
granulomas. The refractile Teflon granules can be appreciated even at low power. B. Higher
magnification showing the refractile Teflon granules in the multinucleated foreign–body- type
giant cells. (Courtesy of David B. Kaminsky, MD, Palm Springs Pathology Associates, Palm Springs,
California.)

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AMYLOID GOITER
Amyloid goiter is a rare condition and occurs as a result of amyloid deposits in the thyroid of
patients with primary or secondary systemic amyloidosis.38 , 39 Amyloid deposits produce a
progressive enlargement of the thyroid gland that may be clinically misdiagnosed as carcinoma.
Diagnosis of amyloid by fine-needle aspiration biopsy has been reported in several reports.40 , 41 ,
42 , 43 Gharib and Goellner43 described two cases of amyloid goiter diagnosed by fine-needle
biopsy; one patient presented with diffuse goiter, not responding to the treatment, and the other
one with a firm, discrete nodule. In both cases, rectal biopsies confirmed systemic amyloidosis.
Nijhwan et al.42 reported 4 cases of amyloid goiter and Lucas et al.42 reported 2 cases, all
correctly diagnosed by cytology.

The aspirates of amyloid goiters are sparsely cellular consisting predominantly of large deposits of
acellular material in the background of spindle-shaped stromal cells and few lymphocytes (Fig.
19.20 ). Multinucleated foreign-body-type giant cells may be present. Presence of follicular cells is
unusual. Mature fat has been described in fine-needle aspirates of amyloid goiters.40
Figure 19.20. A. FNA of an amyloid goiter. Medium-power view showing large deposits of acellular
material. B. Higher magnification showing the hyaline quality of the amyloid deposit with few
spindle-shaped stromal cells. The presence of amyloid must be confirmed by special stains.
(Courtesy of John F. Goellner. MD, formerly of Department of Pathology, Mayo Clinic, Rochester,
Minnesota.)

The amyloid appears as irregular deposits of pale cyanophilic to eosinophilic, amorphous material,
more solid and hyaline than colloid with artifactually stretched and distorted nuclei of the stromal
cells. Amyloid may be confirmed with special stains such as Congo red, which shows apple-green
birefringence or with thioflavin T, which demonstrates bright green fluorescence under ultraviolet
light. The differential diagnosis of amyloid deposits in thyroid aspirates includes medullary
carcinoma. Kapila and Verma41 described a case of amyloid goiter that was cytologically diagnosed
as medullary thyroid carcinoma.

RADIATION-INDUCED CELLULAR CHANGES

Morphologic alterations in thyroid parenchyma secondary to radioactive iodine (131 I) therapy used
in the treatment of Graves disease or secondary to external radiation are well described in the
literature.44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52

Histopathologic changes in thyroid parenchyma following radioactive iodine 131 I are varied,
depending on the dose of radiation and the duration of the treatment. The morphologic changes
include initially a neutrophilic infiltrate, necrosis of follicular cells, and a giant cell reaction,
followed by parenchymal atrophy and fibrosis, loss of colloid, oxyphilia of the follicular cells,
cytoplasmic degeneration, and variable degree of nuclear atypia. The latter is characterized by a
pleomorphism in nuclear size and shape and chromatin pattern (Fig. 19.21 ). Morphologic changes
similar to those of Hashimoto's thyroiditis and development of adenomatous nodules have also been
described. Hürthle cell change is often pronounced, leading to nodule formations. A detailed
description of histologic changes can be found in the literature.44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ,
52 High-dose external radiation (greater than 1,500 rad) to the head and neck area has been
reported to cause significant morphologic changes in thyroid.47
Figure 19.21. A. Histologic section of the thyroid from a patient with history of 131 I therapy.
There is marked parenchymal atrophy, distorted follicles lined by variably enlarged cells, with
considerable nuclear atypia. Note extensive interfollicular fibrosis (medium power). B. Higher
magnification highlighting the marked nuclear atypia and the fibrosis. C. Histologic section of a
different thyroid gland, treated with 131 I for Graves disease. Note extensive Hürthle cell change
with nuclear atypia.

Cytopathologic Features
The cytologic findings are variable but can be significant enough to cause diagnostic difficulties
that have resulted in malignant diagnoses.53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 A wide spectrum of
cellular changes is noted in fine-needle aspirates (Table 19.4 , Figs. 19.22 , 19.23 , 19.24 and 19.25
). The aspirates show tissue fragments of follicular epithelium with varying degrees of cellular and
nuclear atypia. The follicular cells are enlarged and may contain abundant cytoplasm that may be
vacuolated and contain neutrophils. Their nuclei are enlarged, pleomorphic in size, with a deep-
staining, often smudgy, structure less chromatin. Similar but varyiably sized, bare nuclei may be
present in the background (Fig. 19.22 ). Large tissue fragments of follicular cells with papillary-like
configurations have been described in the literature (Fig. 19.24 ), leading to misinterpretation of
papillary carcinoma. Intranuclear inclusions and nuclear grooves may be present (Fig. 19.23 ),
further causing diagnostic difficulties. Stromal cells are often seen, either isolated or in tissue
fragments, and may demonstrate nuclear atypia. The background often shows inflammatory cells
and occasionally psammoma bodies.

Cellularity
Variable, scant in cases with increased fibrosis
Composition
Admixture of follicular cells and spindle cells of
stromal origin
Follicular Cells
Discrete, in groups or in tissue fragments with or without
Hürthle cell metaplasia, markedly pleomorphic
in size and shape; round to spindle shaped; enlarged
nuclei with deep-staining, smudgy chromatin; may
contain prominent nucleoli and intranuclear inclusions;
nuclear grooves; varying-sized, bare nuclei containing
structureless chromatin scattered throughout;
cytoplasm may be abundant with intracytoplasmic
neutrophils, vacuolated, or disintegrated; and the
Hurthle cell metaplasia
Stromal Cells
Pleomorphic, isolated, or in fascicles; atypical nuclei with
variation in size; granular chromatin; prominent nucleoli ±
Background
Colloid scant to absent; inflammatory cells +; neutrophils
in early stages; lymphocytes and macrophages with or
without hemosiderin; karyorrhexis, cellular and calcific
debris; psammoma bodies ±

TABLE 19.4 CYTOLOGIC FEATURES OF RADIATION-ASSOCIATED

CHANGES
Figure 19.22. A. FNA of a thyroid subjected to 131 I therapy. A low-power view showing tissue
fragments of pleomorphic follicular cells. The background shows proteinaceous debris,
macrophages, and pyknotic bare follicular cell nuclei. B. Higher magnification, showing many
varying-sized bare follicular cell nuclei. Note the structureless dense-staining chromatin.

Figure 19.23. FNA of a thyroid subjected to 131 I therapy. A. The follicular cells are in a tissue
fragment, and contain abundant granular cytoplasm. The nuclei are likewise enlarged and contain
nucleoli. B. The cells here are large, pleomorphic, predominantly spindle shaped, and may be of
stromal origin. Their nuclei have coarse chromatin and are round to spindle shaped. Also present
are intranuclear cytoplasmic inclusions (arrow ). C. These cells are probably stromal in origin and
present bizarre shapes. They have abundant cytoplasm and enlarged pleomorphic, hyperchromatic
nuclei.

Figure 19.24. A. Another example of radiation-induced changes in thyroid with a history of 131 I
therapy for Graves disease. This low-power view shows a cellular aspirate consisting of large
branching tissue fragments of follicular cells. B. Higher magnification showing a syncytial
arrangement with crowded and enlarged nuclei, suggesting a diagnosis of a follicular neoplasm.
Figure 19.25. FNA of a thyroid nodule in a patient with a history of Graves disease treated with 131
I. The aspirate was very cellular consisting of a tissue fragment of Hürthle cells with a honeycomb
arrangement.

The varied cytologic changes induced by 131 I therapy for Graves disease can be significantly
abnormal, leading to diagnosis of malignant neoplasms. Centeno et al.57 reported cytologic changes
in 6 cases with 131 I therapy. One case was interpreted as diagnostic of papillary carcinoma and the
other
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P.410
was suspected of papillary carcinoma. Saqi et al.53 and Sturgis54 reported similar findings. De la
Roza et al.55 reported a case of post-131 I therapy where the severe atypia lead to a diagnosis of
anaplastic carcinoma. Without a clinical history of such a therapy, the cytologic interpretation may
lead to a false-positive diagnosis. Extensive Hürthle cell change with nodule formation may be
interpreted as Hürthle cell neoplasm (Fig. 19.25 ).
"INCLUSIONS" IN THE THYROID
The thyroid gland may be a seat for branchial and pharyngeal pouch-derived endodermal and
mesodermal structures, such as parathyroid tissue, thymic tissue, and salivary gland tissue. It may
also contain remnants of ultimobranchial body (Table 19.5 ).61 , 62 , 63 , 64 , 65 , 66 , 67 The
embryologic remnants are incidental findings in the histologic sections of the thyroid and are easily
identified but are not expected to be present in aspirates of the thyroid lesions. However,
"inclusions" are discussed here briefly, because some of the lesions of the thyroid originate from
such inclusions.

Intrathyroidal islands of ectopic thymus

Intrathyroidal parathyroid
Intrathyroidal salivary gland tissue
Ultimobranchial body
Mesenchyme-derived structures: adipose tissue
skeletal muscle, cartilage, bone

TABLE 19.5 INCLUSIONS IN THYROID

Thymic tissue can be seen in 1.8% of thyroid glands (Fig. 19.26 ).63 Occasionally these thymic rests
may give rise to neoplasms (thymoma). Similarly, parathyroid gland hyperplasia and adenoma also
arise in an intrathyroid location.
Figure 19.26. Histologic section of intrathyroidal thymic rests with Hassall's corpuscles.

The ultimobranchial thyroid solid cell nests (SCNs) are irregular structures roughly 1 mm in the
longest dimension, usually found in the middle third of the thyroid lateral lobes. SCN are found in
20% to 30% of thyroids.64 They are composed of nonkeratinizing polygonal to elongated squamous
cells, which lack intercellular bridges and are arranged in solid clusters or nests. Their nuclei are
uniform centrally located round to oval or short and spindle-shaped (Fig. 19.27 ). These cell nests
often have cystic spaces that may contain mucinous material. SCN may be associated with
lymphocytic aggregates. The cells of SCN are immunoreactive to high and low molecular weight
cytokeratins, as well as to CEA and calcitonin, and are negative to thyroglobulin. The SCN may be
misinterpreted as medullary carcinoma, C cell hyperplasia or nodules, foci of squamous cells, or
occult papillary carcinoma. SCN is less likely to be encountered in cytologic material. The cytologic
presentation of cells of ultimobranchial body cyst is illustrated by Clark and Faquin.67
Figure 19.27. A. Histologic section of the thyroid showing an ultimobranchial body or solid cell
nests (SCN) (low power). B. Higher magnification. The cells of SCN are round, oval to short spindle
shaped with uniform nuclei. Note multiple small cystic structures (arrows ).

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FAT IN THE THYROID

Synonyms for fat in the thyroid are hamartomatous adiposity and adenolipomatosis.

Rarely, mature adipose tissue is found within the thyroid gland under normal conditions as well as
associated with pathologic conditions such as amyloid goiter, lymphocytic thyroiditis, thyroid
atrophy, follicular adenoma (adenolipoma), papillary carcinoma, follicular carcinoma, and rarely
diffuse hyperplasia and dyshormonogenetic goiter.61 The presence of adipose tissue within the
thyroid parenchyma is an incidental finding. The normal or benign adipose tissue varies in amount
and is found intimately admixed with the thyroid tissue (Fig. 19.28 ). The mature adipocytes appear
as fairly uniform cells with some variation in size and shape. They are characterized by the
presence of a clear to vacuolated cytoplasm that compresses and eccentrically displaces the cell
nucleus. The nuclei have bland chromatin.
Figure 19.28. FNA of a thyroid nodule showing small tissue fragments of benign follicular cells
admixed with adipose tissue.

The other mesenchymal derived inclusions include skeletal muscle and cartilage and bone.61

SQUAMOUS CELLS, SQUAMOUS METAPLASIA, AND SQUAMOUS

CARCINOMA
Squamous Cells in Thyroid
The squamous cells in thyroid occur in several different settings such as developmental rests,
inflammatory conditions, and neoplasms.68 , 69 , 70 , 71

The developmental rests associated with squamous cells include thymic remnants, thyroglossal duct
remnants, and ultimobranchial body rests or solid cell nests (see "'Inclusions'in the Thyroid" earlier
in the chapter).
 P.412

Squamous Metaplasia
Squamous metaplasia is a benign process whereby the follicular cells change and acquire features of
squamous epithelium. It occurs in a wide variety of situations. Squamous metaplasia is most
common with chronic lymphocytic thyroiditis of the Hashimoto's type71 and in nodular goiters with
retrogressive changes. Squamous metaplasia is also encountered in thyroids subjected to fine-
needle aspiration biopsies, in the vicinity of the needle track. Among the neoplasms, squamous
metaplasia is seen in papillary carcinomas (20% to 40%), either conventional types or in the diffuse
sclerosing and cribriform-morular types.72

Histologically and cytologically, squamous metaplasia appears as nests of round to oval cells often
appearing as "morulae" (Figs. 19.29 , 19.30 , 19.31 and 19.32 ). The metaplastic squamous cells are
characteristically arranged in whorls. The squamous cells have abundant cytoplasm with low N/C
ratios; keratinization and intercellular bridges may occasionally be seen. The nuclei are uniform
with a bland chromatin pattern. Metaplastic squamous cells often assume a spindle shape,
appearing elongated. They usually contain nuclei with bland chromatin pattern.
Figure 19.29. FNA of a nodular goiter showing squamous cells in a whorled pattern. The
metaplastic cells have abundant cytoplasm and bland nuclei.
Figure 19.30. Another example of squamous metaplasia in a case of nodular goiter. The cells are
arranged in a whorled pattern.
Figure 19.31. Histologic section of Hashimoto's thyroiditis with squamous metaplasia.
Figure 19.32. A. Histologic section of papillary carcinoma with squamous metaplasia. B. FNA of
papillary carcinoma showing cells with squamous metaplasia.

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Primary Squamous Carcinoma of the Thyroid

Primary squamous carcinomas of the thyroid are rare, accounting for 1% of all thyroid
malignancies.72 Very few cases with histologic and cytologic findings are documented in the
literature.72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 It occurs in elderly individuals and is more common in
females. Squamous carcinomas arise from the squamous epithelium present in the normal gland,
which is derived from developmental remnants such as ultimobranchial body or thyroglossal duct
remnant. It may also arise from metaplastic squamous cells, seen in nodular goiter, and Hashimoto's
thyroiditis as well as papillary and follicular carcinomas.

Squamous carcinoma clinically presents as a rapidly growing mass with pressure symptoms and
follows an aggressive course. Imaging studies are necessary to exclude a metastatic process from
primary squamous carcinoma occurring at other sites and to study the extent of the disease. The
tumor grows rapidly, spreading locally, and metastasizes widely. The prognosis is poor.

Gross and Microscopic Features

Squamous cell carcinomas are typically large bulky tumors, grayish-white in color, with areas of
necrosis. Histologically, the carcinoma is exclusively the squamous type, predominantly poorly
differentiated with focal keratinization. Squamous carcinomas may occur in combination with
papillary carcinomas, follicular carcinomas, or anaplastic carcinomas

Immunoprofile
Squamous carcinomas are strongly immunoreactive to CK-19 but negative for CK1, CK4, CK10/13,
and CK20, and focally positive for CK7 and CK18. They are negative for thyroglobulin.73

Cytopathologic Features
The cytopathologic features of primary squamous carcinomas are no different than their metastatic
counterpart from other sources. The aspirates of squamous carcinomas are usually very cellular,
consisting of a large population of malignant squamous cells, isolated, in loosely cohesive groups
and in syncytial tissue fragments (Figs. 19.33 , 19.34 , 19.35 and 19.36 ). The malignant cells are
usually large with appreciable cytoplasm that occasionally shows keratinization. Necrosis is
frequent and the malignant cells may be obscured by the cellular and necrotic debris (Figs. 19.35
and 19.36 ).
Figure 19.33. A. FNA of primary squamous cell carcinoma of the thyroid. The malignant cells are in
a syncytial tissue fragment and are poorly differentiated. There is focal squamous differentiation
with keratinization (arrow ). B. A different field from the same case showing poorly differentiated
malignant cells with no squamous differentiation. C. Histologic section of the excised tumor
confirming the squamous cell carcinoma.
Figure 19.34. A. FNA of a thyroid mass showing a large population of undifferentiated malignant
cells suggesting a diagnosis of anaplastic carcinoma. B. The malignant cells reacted strongly to
cytokeratin but not to thyroglobulin. C. Thyroidectomy revealed a poorly differentiated carcinoma
with focal squamous differentiation.
Figure 19.35. A,B. FNA of a primary squamous carcinoma of the thyroid with extensive necrosis.
Note scattered keratinized individual squamous cells obscured by inflammatory and necrotic debris.
C. Thyroidectomy showed a poorly differentiated squamous cell carcinoma. Note isolated cells with
keratinization (arrows ).
Figure 19.36. A. FNA of a large cystic mass of the thyroid that yielded a large amount of straw-
colored fluid. The smears showed necrosis and a rare syncytial tissue fragment of poorly
differentiated malignant cells. B. There were individual cells scattered in the background, some
exhibiting keratinization. Thyroidectomy confirmed a primary squamous carcinoma.

The metastatic squamous carcinomas are more common in thyroid and must be ruled out before
rendering the diagnosis of a primary squamous carcinoma, especially in the event of a remote
primary cancer elsewhere (Fig. 19.37 ). Poorly differentiated squamous carcinomas are also very
difficult to differentiate from anaplastic carcinomas. The primary thyroid squamous carcinoma cells
are non-reactive to thyroglobulin and the anaplastic carcinomas tend to be negative in majority of
the cases. Both display positive reactivity to cytokeratin. The differential diagnosis also includes
poorly differentiated metastatic adenocarcinomas, malignant melanomas, and high-grade
mucoepidermoid carcinoma.
Figure 19.37. FNA of a solitary thyroid nodule showing poorly differentiated malignant cells.
Squamous differentiation with keratinization was focally present suggesting the diagnosis of poorly
differentiated squamous carcinoma. Since there were no other lesions detected anywhere else in
the body, a diagnosis of primary squamous carcinoma was suggested. The thyroidectomy confirmed
a squamous cell carcinoma. It was later found out that the patient had a remote history of
squamous cell carcinoma of the upper aerodigestive tract. In the light of the history, this lesion
must be considered as a metastatic cancer.

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ECTOPIC THYROID
The presence of thyroid tissue in abnormal locations as a result of developmental anomaly is
referred to as "thyroid ectopia."80 , 81 , 82 Thyroid tissue can be found at the base of the tongue
(lingual thyroid), beneath the tongue (sublingual thyroid), in and around the hyoid bone (as part of
the thyroglossal duct cyst), and in the mediastinum. Other locations for ectopia include the
trachea, larynx, aortic arch, heart and diaphragm, lateral neck ("lateral aberrant thyroid"), or the
ovary ("struma ovarii").
These ectopic foci may be the seat of non-neoplastic as well as neoplastic lesions similar to those
arising in the thyroid gland. Fine-needle biopsy is useful in identifying these lesions.83 , 84 , 85 , 86
, 87

THYROGLOSSAL DUCT CYSTS

Thyroglossal duct cyst results from the failure of obliteration of the thyroglossal duct following the
descent of the thyroid in the early fetal life and cystic dilatation.88 , 89 , 90

Thyroglossal duct cysts can occur at any age from the first to eighth decades of life, and are
frequent in childhood.91 They are slightly more common in males, with a male to female ratio of
1.4:1. Most often they presents as a painless, midline mass, in front of the neck, that moves upward
with swallowing. The thyroglossal duct cyst is always connected to the hyoid bone. Thyroglossal
duct cysts typically occur in the midline but can occur laterally and rarely within the thyroid.88 , 89
, 90 , 91 , 92 , 93 , 94

Radiologic findings include a solitary, well-defined thin-walled anechoic cystic lesion in the midline
just under the hyoid bone.

Gross and Microscopic Features

Grossly, the thyroglossal duct cysts are cystic structures with a smooth lining and range from 1.5 to
5 cm in diameter. The cyst contents range from clear, mucinous to turbid, to thick and purulent in
infected cysts. Histologically, the cyst wall is lined by columnar, simple cuboidal, or squamous
epithelium (Fig. 19.38 ). The epithelium may be denuded as a result of acute and chronic
inflammation (Fig. 19.39 ). Lymphoid tissue or thyroid follicular cells may be present in the cyst
wall, which is often fibrotic. Chow and Lee95 described cholesterol granulomas in the wall of the
cyst.
Figure 19.38. Histologic section of a thyroglossal duct cyst, lined by stratified squamous
epithelium. The lining is focally denuded with inflammation of the cyst wall (arrow ).
Figure 19.39. Histologic section of a thyroglossal duct cyst showing a fibrous wall, which is
inflamed.

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Cytopathologic Features
The cytologic findings are variable depending on whether the cyst is infected.95 , 96 , 97 , 98 , 99
The aspiration biopsy of the cyst yields variable amounts of thin, clear, and watery to viscid and
mucoid contents, ranging from a few to several milliliters. The contents may be purulent if the cyst
is infected. The cellularity of the cyst fluid is variable but usually sparse, consisting of a
predominantly inflammatory cell component comprised of neutrophils, lymphocytes, and histiocytes
with or without hemosiderin (Fig. 19.40 ). The epithelial component is represented by ciliated and
nonciliated columnar cells and squamous cells (Figs. 19.41 and 19.42 ). Benign thyroid follicular
cells (Fig. 19.41 ) are reported to be present in 3% to 20% of cases.96 , 97 The squamous cells are
usually of mature type with frequent anucleated as well as keratinized forms. Metaplastic squamous
cells are also encountered. The background shows cellular debris, thick mucoid material, sometimes
inspissated colloid, and only occasionally cholesterol crystals.95 Lymphoid cells are generally few in
numbers because the lymphoid tissue is in the subepithelial area. They may be present in large
numbers if the epithelial lining gets ulcerated (Fig. 19.43 ). Also described are the presence of
foamy histiocytes and multinucleated foreign-body-type giant cells originating from cholesterol
granulomas (Fig. 19.43F ). The usual cytologic features of thyroglossal duct cysts, described in
detail in two large series, are summarized in Table 19.6 .

Figure 19.40. FNA of thyroglossal duct cyst showing sparse cellularity. Note rare squamous cells
(arrows), histiocytes, and inflammatory cells. The background shows cellular debris.
Figure 19.41. This aspirate from a different case of thyroglossal duct cyst shows benign thyroid
follicular cells, mature squamous cells, and anucleated squames.

Figure 19.42. A and B . FNA of a thyroglossal duct cyst showing mature squamous cell population.
Note the keratinized squamous cells with mildly atypical nuclei.
Figure 19.43. A–C. An aspirate from a 2.5-cm cyst in the isthmus in a 31-year-old woman with
hypothyroidism. The smears showed a large population of lymphoid cells with focal aggregates of
immature forms, raising the suspicion for a malignant lymphoma in the background of Hashimoto's
thyroiditis. A repeat aspirate with flow cytometry did not confirm the diagnosis of malignant
lymphoma. An MRI requested by the surgeon, following the FNA diagnosis of possible lymphoma,
suggested the lesion as a possible thyroglossal duct cyst. D,E. The surgical excision confirmed a
thyroglossal duct cyst. There is extensive lymphoid tissue containing prominent germinal centers, in
the wall of the cyst. The cyst lining is of squamous type. This case illustrates the fact that the
diagnosis of thyroglossal duct cyst can be accurately made only in the right clinical context. F. The
cyst wall also contained cholesterol granulomas.

Macrophages, with or without hemosiderin

85
89
Colloid
68
61
Squamous epithelial cells including anucleated
and metaplastic and keratinized forms
65
88
Neutrophils
56
61
Lymphocytes
—
72
Cholesterol crystals
50
—
Mucoid or proteinaceous debris
44
16
Ciliated columnar cells
18
33
Thyroid follicular cells
3
11
a Shaffer M, Ortel Y. Thyroglossal duct cysts: criteria by fine needle aspiration. Am J Clin Pathol.

1994;102:52(A).
b Shahin A, Burroughs FH, Kirby JP, et al. Thyroglossal duct cyst: a cytopathologic study of 26 cases.

Diagn Cytopathol. 2005;33:365–369.

Shaffer et al.a Shahin et al.b

Cytomorphologic Feature % %

TABLE 19.6 CYTOPATHOLOGIC FEATURES OF FLUID

ASPIRATED FROM THYROGLOSSAL DUCT CYSTS
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The differential diagnosis of thyroglossal duct cysts includes branchial cleft cyst, thyroid cysts,
cystic papillary carcinomas, and metastatic squamous carcinoma.

Neoplasms Arising in Thyroglossal Duct Cysts

Both benign and malignant neoplasms can occur in the thyroglossal duct cysts.88 , 89 , 90 , 100 ,
101 , 102 , 103 Their occurrence, however, is rare. Benign neoplasms include follicular and
Hürthle cell adenomas.104 , 105 Of the various types of malignant neoplasms reported to arise
from thyroglossal duct cysts, papillary carcinomas (Fig. 19.44 ) are the most common, comprising
87% to 94%.105 , 106 , 107 , 108 , 109 Other malignancies include Hürthle cell carcinoma,110
anaplastic carcinoma,111 , 112 and squamous carcinomas.113 , 115 Fine-needle biopsy is effective
in the preoperative diagnosis of malignancy, although the origin from a thyroglossal duct cyst is
determined only after excision.
Figure 19.44. A gross photograph of a papillary carcinoma arising in a thyroglossal duct cyst, which
was correctly diagnosed as papillary carcinoma from the aspirated specimen. However, the origin
was determined only after the surgery.

UNUSUAL AND UNCOMMON NEOPLASMS OF THE THYROID

The thyroid gland can be a seat for several unusual and uncommon primary neoplasms, which are
rarely encountered in fine-needle aspirates of the thyroid. Because of the rarity
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and unusual cytopathologic features, they do cause diagnostic difficulties. This section will describe
some of these neoplasms.

THYROID CARCINOMA SHOWING THYMUS-LIKE ELEMENT

(CASTLE)
Chan and Rosai116 introduced the term CASTLE for thyroid carcinomas showing thymus-like
differentiation. This tumor was described as an intrathyroidal thymoma by Miyachi et al.117 The
other terms used for this tumor include lymphoepithelioma-like carcinoma of the thyroid gland,
intrathyroid epithelial thymoma, and primary thyroid thymoma. This unusual thyroid neoplasm is
sparsely documented in the literature.116 , 117 , 118 , 119 , 120 , 121 , 122 , 123

CASTLE usually arises in the middle to lower third of the thyroid and occurs in adults 40 to 50 years
of age. It often extends into the extrathyroidal soft tissues. The tumors are circumscribed, well
demarcated from the surrounding thyroid, and show a lobulated firm and gray cut surface (Fig.
19.45A ).
Figure 19.45. A. Gross photograph of an intrathyroidal thymoma or CASTLE. The left thyroid lobe is
totally replaced by a white fleshy lobulated tumor. B. Histologic section of the tumor showing large
masses of tumor cells separated by strands of lymphoid cells. C. Higher magnification showing
medium-sized cells with poorly defined cell borders, amphophilic cytoplasm, and large vesicular
nuclei containing nucleoli. D. Ultrastructurally, the neoplastic cells showed features of thymoma.
This electron micrograph shows a group of squamous epithelial cells invested by a basement
membrane (B ). The cells have numerous perinuclear bundles of tonofilaments (T ) and desmosomes
(arrows). Uranyl acetate and lead citrate preparation ∞ 43,2000. E–G. FNA of the above
illustrated thyroid tumor. The aspirate is cellular showing syncytial tissue fragments of malignant
cells with no architectural patterns. The component cells are medium-sized with poorly defined cell
borders, scant pale to dense cytoplasm, and round to oval nuclei. Note lymphocytes in the
background. These malignant cells offer no clue as to their differentiation. A diagnosis of thymoma
or CASTLE is difficult from cytologic samples.

Histologically, CASTLE closely resembles thymic carcinoma by histologic features and

immunoprofile. The tumor shows a solid growth pattern consisting of sheets and lobules of poorly
differentiated malignant cells intermingled with mature lymphocytes (Fig. 19.45B and C). The
tumor lobules are separated by fibrous septae. The malignant cells contain large nuclei and a finely
granular, open chromatin pattern with prominent nucleoli. They have abundant cytoplasm. Mitoses
are sparse. Focal squamous differentiation may be present. The tumor cells are positive for
cytokeratin, and negative for thyroglobulin and calcitonin as well as CD5 antibody, similar to thymic
tumors. Positivity to bcl-2 and mcl-1 has been recorded in both thymic carcinomas and CASTLE.119
Ultrastructurally (Fig. 19.45D ), thymoma cells demonstrate prominent, multiple desmosomes and
tonofilaments, often in bundles arranged in garland-like fashion around the nucleus.

Cytopathologic Features
The cytologic findings of CASTLE are sparsely documented.123 , 124 , 125 Our experience with one
case of CASTLE is illustrated in Figure 19.45 . Cytologically, the lymphoid cells mixed with
malignant epithelial cells (Fig. 19.45E to G) suggested a carcinoma in the background of
lymphocytic thyroiditis. The malignant cells exhibited no architectural or cytoplasmic
differentiation precluding accurate typing.

Most cases described in the literature represent CASTLE with lymphoepithelioma-like pattern (Fig.
19.46 ). Gerhard et al.125 described a case of intrathyroidal thymoma with a predominant spindle
cell pattern (Fig. 19.47 ).
Figure 19.46. A,B. FNA of a different case of CASTLE of thyroid, showing undifferentiated
malignant cells. Lymphocytes are not easily appreciated in the background. C. Surgical excision
showed a malignant neoplasm with features of CASTLE. Note that the morphology resembles a
lymphoepithelial carcinoma. (Courtesy of W.K. Ng, MD, Department of Pathology, University of
Hongkong, Queen Mary Hospital, Hong Kong.)
Figure 19.47. A. FNA of a left lower lobe thyroid mass showing interdigitating fascicles of spindle
cells (low power). B. Higher magnification showing spindle cells with bland nuclei. The pattern is
suggestive of a spindle cell neoplasm and the diagnosis of medullary thyroid carcinoma was
considered. C. Same aspirate stained by Diff-Quik. The tissue fragment is composed of spindle cells
with some suggestion of epithelioid forms. D. Histologic section of the excised thyroid tumor
confirming spindle cell thymoma. (Courtesy of René Gerhard, MD, Department of Pathology,
Hospital das Clinicas, University of Sao Paulo, SP, Brazil.)

Differential Diagnosis
The epithelial predominant tumors must be differentiated from lymphoepitheliomas, poorly
differentiated squamous carcinomas. and malignant lymphomas. The spindle cell type thymoma
(CASTLE) must be differentiated from medullary carcinoma or spindle epithelial tumor with thymus-
like differentiation (SETTLE) and soft-tissue tumors.
SPINDLE EPITHELIAL TUMOR WITH THYMUS-LIKE
DIFFERENTIATION (SETTLE)
The term spindle epithelial tumor with thymus-like differentiation (SETTLE) was first coined by
Chen and Rosai126 to describe malignant neoplasms occurring in children and young adults with a
distinctive histologic pattern consisting of a biphasic cellular composition and featuring spindle-
shaped epithelial cells that merge into glandular structures.126 , 127 , 128 These tumors are also
referred to as thyroid spindle cell tumors with mucus cysts, malignant teratoma, and thyroid
thymoma in childhood.129 , 130 , 131 , 132 SETTLE is an extremely uncommon neoplasm of the
thyroid with very few cases being reported in the literature.132 , 133 , 134 , 135 The cytologic
features are documented still more rarely.133 , 136 , 137

SETTLE usually affects children, adolescents, and young adults with a mean age of 19 years and a
range of 4 to 59 years. Male predominance is reported. They present as solitary thyroid mass and
are characterized by slow growth, late local recurrences, and distant metastases.126

Histologically, the tumor shows a lobular growth pattern, with lobules encircled by thick sclerotic
bands. The neoplasm demonstrates a mixture of spindle cells and epithelial cells, the former
predominating. The spindle cells occur in fascicles
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forming a whorled or storiform pattern. They usually have bland chromatin pattern. The epithelial
cells show glandular, papillary, trabecular, or solid growth patterns (Figs. 19.48D to F and 19.49D ).
Occasionally, squamous differentiation reminiscent of Hassall's corpuscles can be seen. Cystic
changes can be seen both grossly and microscopically. The cysts are small, lined by squamous or
columnar epithelium or goblet cells. Interstitial mucin can be demonstrated in the majority of the
cases.
Figure 19.48. A. FNA of a thyroid mass from a 15-year-old. The aspirate is cellular showing tissue
fragments of closely packed spindle cells. Discrete spindle cells are seen dispersed in the
background (low power). B. Higher magnification showing the spindle cells to be very uniform,
monotonous with scant to indiscernible cytoplasm. Their nuclei are elongated with bland
chromatin. C. The aspirate also contained tissue fragments of cuboidal epithelial cells with an
acinar pattern, suggesting glandular differentiation. The cytoplasm is vacuolated and some cells
appear to be the goblet cell type. D. The surgically excised mass was lobulated and multicystic. The
cysts contained greenish to white turbid fluid. The tumor showed a biphasic pattern consisting of
spindle cells with varying-sized cysts, lined by goblet cells (low power). E. Higher magnification
highlighting the spindle cell component and the goblet cell-lined cysts. F . Another section
demonstrating the monomorphic spindle cells. Note a rudimentary glandular structure merging
imperceptibly with the spindle cells (arrow ). (A to C are courtesy of Edward Bernecki, MD, William
Beaumont Hospital, Royal Oak, Michigan. D to F are courtesy of Claire Michael, MD, University of
Michigan Hospital, Ann Arbor.)

Figure 19.49. A. FNA of another case of SETTLE. A low-power view showing a very cellular aspirate
consisting of tissue fragments, loosely cohesive groups and dispersed cells, the spindle forms being
apparent even at this power. Diff-Quik stain. B. Medium power showing the monomorphic, delicate
small spindle cells presenting a dispersed pattern. Diff-Quik stain. C. Same aspirate, stained with
Papanicolaou. A tissue fragment of monomorphic small to medium-sized spindle cells. D. Histologic
section of the excised tumor showing a biphasic pattern with a spindle cell component forming
fascicles and a glandular component. (Courtesy of Chris Jenson, MD, University of Iowa Hospitals,
Iowa City.)

The spindle cells stain positive with cytokeratins, smooth-muscle actin, and muscle-specific actin,
and stain negative with thyroglobulin and calcitonin.119 Ultrastructurally, the neoplastic cells are
encased by well-defined basal lamina and the cytoplasm contains tonofilaments and few
desmosomes.

Cytologically, SETTLE is characterized by spindle cells with scant cytoplasm present in tissue
fragments or in dispersed fashion. They contain scant cytoplasm, uniform nuclei with finely granular
chromatin, and indistinct nucleoli (Figs. 19.48 and 19.49 ). The epithelial component is present as
tissue fragments of mucin-producing columnar cells.136 , 137

Differential diagnosis of SETTLE includes intrathyroid thymoma and mesenchymal tumors of the
thyroid, especially synovial sarcoma, medullary thyroid carcinoma, and anaplastic carcinoma.126

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PRIMARY MUCOEPIDERMOID CARCINOMA OF THE THYROID

Primary mucoepidermoid carcinoma, first described in 1977,138 is a malignant tumor of the thyroid
with only a few cases reported in the literature.139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 It is
characterized by a combination of squamous and mucin-secreting features. Mucoepidermoid
carcinomas have been also reported to be associated with papillary carcinomas.145 , 146 , 147 ,
148 It is more common in females, with an age range of 10 to 56 years.

Histologically, both low-grade and high-grade mucoepidermoid carcinomas have been reported. The
mucoepidermoid carcinomas are comprised of solid islands and sheets of malignant squamous cells.
The glandular component is seen as mucin-producing cells lining duct-like formations. Both types of
cells are intimately associated. Cyst formations are present in the low-grade tumors.
Intracytoplasmic and intraluminal mucin stains positive with mucicarmine and is PAS diastase
resistant. Immunoprofile includes positivity to cytokeratin and often to thyroglobulin. The mucin-
secreting component reacts positively to CEA.

Cytopathologic Features
The cytologic findings of mucoepidermoid carcinomas of the thyroid are identical to those occurring
in salivary glands149 or
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other extrasalivary gland sites. The cytologic features are dependent on the grade. The low-grade
tumor shows tissue fragments of squamous to intermediate cells with mucin-producing cells and
must be differentiated from metastatic mucoepidermoid carcinoma originating in salivary glands
(Fig. 19.50 ).

Figure 19.50. A,B. FNA of a thyroid nodule from a patient with the history of mucoepidermoid
carcinoma of the minor salivary glands at the base of the tongue. The syncytial tissue fragments are
composed of malignant cells with hyperchromatic nuclei and variable but scant cytoplasm. C.
Another field showing syncytial tissue fragment of malignant cells. Lack of architectural pattern and
scant, indiscernible cytoplasm does not allow typing. D. The malignant cells show negative
reactivity to thyroglobulin, ruling out the possibility of a thyroid follicular cell-derived neoplasm.
The cytomorphology is similar to primary mucoepidermoid carcinoma of the minor salivary glands.
The high-grade tumors show clearly malignant cells but offer difficulties in typing, since they must
be differentiated from squamous, anaplastic or metastatic carcinoma (Fig. 19.51 ). A low-grade
mucoepidermoid carcinoma cannot be differentiated from a metastatic mucoepidermoid carcinoma
without a clinical history. A high-grade carcinoma needs to be differentiated from a poorly
differentiated primary or metastatic squamous carcinoma.

Figure 19.51. A,B. FNA of a high-grade histologically confirmed primary mucoepidermoid

carcinoma of the thyroid. The malignant cells are large, round, and polygonal with hyperchromatic
nuclei and abundant dense cytoplasm. Note occasional cells containing cytoplasmic vacuoles. C.
Same aspirate stained with Romanowsky stain. (Courtesy of Ricardo Gonzalez-Campora, MD,
Department of Pathology, Faculty of Medicine, University of Seville.)

SCLEROSING MUCOEPIDERMOID CARCINOMA WITH EOSINOPHILIA

Sclerosing mucoepidermoid carcinoma with eosinophilia is a morphologically distinctive malignant
neoplasm of the thyroid showing epidermoid and glandular differentiation, sclerosis with prominent
eosinophilia and lymphocytic infiltrate. The tumor occurs in adults and affects women almost
exclusively. It occurs in the background of Hashimoto's thyroiditis, often of the fibrous type.150 ,
151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159

Histologically, sclerosing mucoepidermoid carcinoma with eosinophilia is characterized by a

sclerotic stroma extensively infiltrated by eosinophils, lymphocytes, and plasma cells. The tumor
cells form anastomosing cords and nests of polygonal
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cells with mild to moderate nuclear atypia and distinct nucleoli. Also present are mucinous cells
and small pools of mucin. The background almost always shows Hashimoto's thyroiditis.

The tumor is immunoreactive to cytokeratin, and negative for thyroglobulin and calcitonin. Roughly
50% of the cases have demonstrated immunoreactivity to TTF-1. The mucin-containing cells may be
positive to CEA.

Cytologic Features
The cytologic features of sclerosing mucoepidermoid carcinoma with eosinophilia are sparsely
documented and correspond to the histologic pattern. They are characterized by tissue fragments
of squamous cells with varying degrees of differentiation, intimately associated with glandular or
mucin-producing cells. The background shows prominent eosinophilia and lymphoid cells (Fig. 19.52
).
Figure 19.52. A,B. FNA of a sclerosing mucoepidermoid carcinoma with eosinophilia, depicting a
syncytial tissue fragment of small malignant cells without any architectural pattern. Their cell
borders are poorly defined and the cytoplasm is scant to indiscernible. The nuclei are large with
high N/C ratios, crowded, and overlapped. The chromatin is coarsely granular. Note several
eosinophils in the background. C. These syncytial tissue fragments of malignant cells demonstrate
an acinar pattern (arrow ). Note mucin in the lumen (m). There are many lymphocytes in the
background. D. The malignant cells in this syncytial tissue fragment contain appreciable pale,
foamy cytoplasm. The cells at the periphery appear columnar (arrows ). The malignant cells within
this syncytial tissue fragment show cytoplasmic vacuoles (arrow ). Occasional goblet cells are also
present (gb). E. The surgical excision revealed a multicystic tumor in the background of Hashimoto's
thyroiditis. F. Higher magnification showing glandular structures lined by goblet cells and islands of
squamoid cells in the background of lymphoid cells and marked eosinophilia. Note mucin within the
glandular space. G. Note stromal sclerosis (Courtesy of Mariza de Peralta-Venturina, MD, William
Beaumont Hospital, Royal Oak, Michigan.)

PRIMARY PARAGANGLIOMA OF THE THYROID

Primary paragangliomas of the thyroid are extremely rare and very few cases are documented in
the surgical pathology literature.160 , 161 , 162 , 163 , 164 , 165 , 166 Morphologically they present
a pattern typically seen in paragangliomas at the other sites. Only one
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case of cytologic findings from fine-needle aspirate of primary paraganglioma of the thyroid is
documented in the literature (Fig. 19.53 ).166

The differential diagnosis of paraganglioma includes hyalinizing trabecular adenoma, which has a
morphologic similarity to paraganglioma. In fact, hyalinizing trabecular adenomas are sometimes
referred to as paraganglioma-like follicular adenoma. Other possible differential diagnostic entities
include medullary carcinoma, metastatic neuroendocrine neoplasms, Hürthle cell carcinoma, and
insular carcinoma.
Figure 19.53. FNA of a histologically confirmed primary paraganglioma of the thyroid. The
marginally cellular aspirate demonstrates tissue fragments of medium-sized to large cells with
poorly defined cell borders. The neoplastic cells are also present as discrete and in loosely cohesive
groups. The nuclei are moderately pleomorphic, large, round to oval, and with evenly dispersed
chromatin. Nucleoli are only occasionally present. These cells have insignificant to scant, pale
bluish cytoplasm. A cytologic diagnosis is of paraganglioma is not possible from this morphology as
they also bear similarities to medullary carcinoma cells. Romanowsky stain. (Courtesy of A.
Vodovnik, MD, Calderdale Royal Hospital, HX3 OPW Halifax, England.)

LANGERHANS' CELL HISTIOCYTOSIS (HISTIOCYTOSIS X)

Langerhans' cell histiocytosis is an uncommon disorder affecting children and adolescents, and
involves multiple systems in the body, such as skin, bone, lung, lymph nodes, and the central
nervous system. Involvement of thyroid is rare, and the isolated involvement presenting as a thyroid
nodule or goiter is still rarer.167 , 168 , 169 , 170 , 171 Cytologic diagnoses of Langerhans' cell
histiocytosis by fine-needle aspiration biopsy in such cases have been described.172 , 173 , 174 ,
175 , 176 A clinical history of Langerhans' cell histiocytosis and the presence of characteristic
Langerhans' cells allow an accurate diagnosis and can be confirmed by immunostains. The
Langerhans' cells are round to polygonal, with poorly defined cell borders, and contain abundant
pale to granular cytoplasm. The nuclei are oval to kidney-shaped with characteristic deep grooves
(Fig. 19.54A ). Nucleoli are often present. The Langerhans' cells are often associated with
eosinophils, lymphocytes, multinucleated foreign-body-type giant cells, and macrophages.
Ultrastructurally, Langerhans' cells demonstrate characteristic Birbeck granules. Their
immunoprofile includes positive reactivity to S100 protein (Fig. 19.54B ), CD1, CD 11, and CD14.

Figure 19.54. A. FNA of the thyroid. The aspirate is cellular, consisting of numerous Langerhans'
cells with abundant granular cytoplasm and low N/C ratios. Their nuclei have prominent grooves
and indentations. B. Same case as above showing positive immunoreactivity of Langerhans'
histiocytosis cells with S-100 protein. (Courtesy of Fadi Abdul-Karim, MD, Institute of Pathology,
University Hospitals of Cleveland.)

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PRIMARY SOFT-TISSUE TUMORS OF THE THYROID

Both benign and malignant soft-tissue and mesenchymal tumors arise in the thyroid gland, although
very rarely.177 , 178 The benign tumors include vascular tumors such as hemangioma or
lymphangioma, schwannoma,177 , 178 , 179 , 180 , 181 leiomyoma,181 lipoma,182 and solitary
fibrous tumors.183 , 184 , 185 An aspirate of hemangioma may yield only blood, resulting in an
unsatisfactory aspirate and the diagnosis established only after surgical excision (Fig. 19.55 ).
Figure 19.55. A. Histologic section of a cavernous hemangioma of the thyroid. The fine-needle
aspiration biopsy of this lesion was bloody and acellular. The section shows anastomosing thin-
walled blood spaces, some filled with blood. B. Higher magnification highlighting the structure of
hemangioma.

The malignant mesenchymal tumors of the thyroid are extremely rare and include
angiosarcomas,186 , 187 leiomyosarcomas,188 , 189 malignant peripheral nerve-sheath tumors,
synovial sarcoma,190 liposarcoma, fibrosarcoma, osteosarcoma, and chondrosarcoma. The cytologic
presentation of these extremely rare primary neoplasms is almost non-existent. A case of synovial
sarcoma is illustrated in Figure 19.56 . Metastatic soft-tissue sarcomas may be more frequently
encountered than the primary ones.
Figure 19.56. FNA of a primary synovial sarcoma of the thyroid. A. The cellular aspirate consists of
branching tissue fragments of delicate spindle cells. These spindle cells are also present in a
dispersed fashion. B. Higher magnification showing the spindle cells with uniform round to
elongated nuclei with a finely granular, bland chromatin. The cell borders are poorly defined with
scant cytoplasm. C. Another field showing a tissue fragment of spindle cells in the background of
discrete round cells. D. These tumor cells appear epithelioid. E. Histologic section of the synovial
sarcoma showing fascicles of spindle cells. F. Higher magnification of the synovial sarcoma showing
spindle cells with uniform elongated nuclei. (Courtesy of Ms. I. Kikuchi, CT (IAC), Department of
Pathology, Central Clinical Laboratory, Iwate Medical University, Morioka, Japan.)

PRIMARY HODGKIN'S LYMPHOMA OF THE THYROID

Primary extranodal Hodgkin's disease of the thyroid gland is extremely rare. Cases so diagnosed are
generally found to be a secondary involvement. Some bona fide cases have been
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reported in the surgical pathology literature.191 , 192 , 193 , 194 However, only 2 cases have been
described with a cytologic diagnosis made following aspiration biopsy.192 , 193

CLEAR CELL CHANGE IN THYROID NEOPLASMS

Clear cell change can occur in several types of thyroid neoplasms. Carcangiu et al.195 presented an
excellent review of 38 cases including 10 cases of Hürthle cell tumors, 17 cases of follicular
neoplasms, 7 cases of papillary carcinomas, and 4 cases of anaplastic carcinomas. All of these cases
exhibited extensive clear cell change involving over 50% of the tumor. In the past, clear cell change
had prompted a separate category of the tumors such as clear cell carcinoma. Carcangiu et al.195
claim from their study that the clear cell change is a secondary event in different types of tumors
and a separate designation of clear cell carcinoma is not indicated.196 , 197 , 198 The clear
cytoplasmic change occurs due to a variety of reasons, including (i) formation of medium-sized
vesicles, many of mitochondrial derivation, a common cause in
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Hürthle cell and follicular neoplasms; (ii) glycogen accumulation in papillary and anaplastic
carcinomas; and (iii) deposition of intracellular thyroglobulin in a subgroup of follicular neoplasms
with a signet ring or lipoblast-like appearance. The clear cell change is also described in medullary
carcinomas.199

Cytologic Features
The cytologic findings of clear cell change in thyroid tumors are reported infrequently.200 , 201 ,
202 , 203 , 204 , 205 The characteristic clearing of the cytoplasm seen in histologic sections stained
by hematoxylin and eosin is not replicated in cytologic preparations stained by the Papanicolaou
method. The cytoplasm of the clear cells stains very pale to granular, cyanophilic to eosinophilic.
Their cell borders are often poorly defined and the cells appear as naked nuclei (Figs. 19.57 , 19.58
and 19.59 ) due to rupture of the cell membranes. The pale eosinophilic granular cytoplasm of the
cells may lead to a diagnosis of Hürthle cell neoplasm.201

Figure 19.57. A,B. FNA of a follicular adenoma with clear cell change. The follicular cells are in
syncytial arrangement and have poorly defined cell borders and are probably ruptured. The nuclei
are crowded and overlapped and appear naked. C. Histologic section of the thyroid tumor showing a
follicular adenoma with a clear cell pattern.
Figure 19.58. A,B. FNA of a poorly differentiated follicular carcinoma showing syncytial tissue
fragments without any follicular pattern. The nuclei are considerably enlarged, pleomorphic in size,
and with granular chromatin and nucleoli. The moderate amount of cytoplasm is pale to clear. C.
The surgical excision showed a poorly differentiated follicular carcinoma with extensive clear cell
change.
Figure 19.59. A–C . FNA of an anaplastic carcinoma. Note that the variable but abundant
cytoplasm is very pale and some nuclei appear bare. D . Histologic section of the anaplastic
carcinoma showing clear cell change.

The differential diagnosis tumors with clear cell change include metastatic clear cell carcinoma of
the kidney to the thyroid. El-Sahrigy et al.203 reported a signet-ring-type follicular adenoma that
was interpreted as metastatic adenocarcinoma on fine-needle aspiration biopsy.

THYROID TUMORS WITH MUCINOUS FEATURES

The presence of cytoplasmic mucin in thyroid tumors is not uncommon.206 , 207 , 208 , 209 , 210 ,
211 , 212 It has been described in follicular adenomas of the signet ring type, follicular carcinomas
(Fig. 19.60 ), mucoepidermoid carcinoma, sclerosing mucoepidermoid carcinoma with eosinophilia,
and spindle epithelial tumor with thymus-like differentiation (SETTLE). Other malignant thyroid
neoplasms associated with mucin production include papillary carcinomas, where Chan210
described the presence of mucin in 17% of the cases; anaplastic carcinomas; medullary carcinomas;
and metastatic adenocarcinomas.
Figure 19.60. A,B. FNA of a follicular carcinoma with mucinous features. The aspirate was very
cellular, consisting of several syncytial tissue fragments of follicular cells with and without follicular
pattern. Their nuclei are considerably enlarged in size, pleomorphic, crowded, and overlapped,
containing coarsely granular chromatin and nucleoli. The cytoplasm is variable and occasionally
abundant and foamy. C. Thyroidectomy revealed a large follicular carcinoma with a solid growth
pattern. D. Several areas of the carcinoma showed abundant mucin. E. Strongly positive alcian blue
stain, 2.5 pH confirmed the mucin. F . The mucin was present within the malignant cells and in
between the cells. Alcian blue, 2.5 pH. G. Strong positive reactivity to thyroglobulin.

P.432
P.433
The mucin can be demonstrated by histochemical stains such as alcian blue or mucicarmine. The
documentation of cytologic findings of thyroid tumors with mucin production is sparse, limited to
very few reports.213 , 214 , 215 A case of mucin-producing follicular carcinoma from the author's
files is illustrated in Figure 19.60 .

MULTIPLE NEOPLASMS IN THE THYROID

The presence of multiple tumors, benign and malignant, occult or apparent, in the same thyroid is
not uncommon,216 , 217 , 218 , 219 , 220 , 221 , 222 but the incidence is not known due to the
sparsity of literature on the subject. O'Neill and Lomas218 and Lamberg et al.221 reported
concurrent medullary carcinoma and papillary carcinoma. Ayala et al.222 described a case of
Hashimoto's thyroiditis with follicular carcinoma and malignant lymphoma. These reported cases
were identified following surgery. Cytologic diagnosis of multiple malignancies has not been
reported. Our experience includes 2 cases of Hashimoto's thyroiditis with papillary carcinoma and
malignant lymphoma (Fig. 19.61 ) and one case of Hürthle cell carcinoma and papillary carcinoma
identified in cytologic samples (Fig. 19.62 ).
Figure 19.61. FNA of a diffusely enlarged thyroid with nodularity, from a 30-year-old woman. A. A
homogeneous population of immature lymphoid cells, low power. B. Higher magnification,
consistent with malignant lymphoma. C. Smears from other areas of the thyroid showing features of
lymphocytic (Hashimoto's) thyroiditis. D,E. Aspirate also showed syncytial-type tissue fragments
with typical nuclear morphology of papillary carcinoma. F. Total thyroidectomy revealed both lobes
enlarged and replaced by a white, fleshy tumor. Note the discrete nodule in the right lobe (arrow ).
G. Histologic section confirming malignant lymphoma, diffuse mixed lymphocytic and large cell
type. H. Section of the discrete nodule showing a papillary carcinoma.

Figure 19.62. A. Aspirate of a cold thyroid nodule showing small Hürthle cells, discrete and in
tissue fragments, suggesting a diagnosis of Hürthle cell carcinoma. B. Another field from the same
smear as in a showing syncytial-type tissue fragments, with nuclei exhibiting typical morphology of
papillary carcinoma. Note the intranuclear cytoplasmic inclusions. Thyroidectomy confirmed both
Hürthle cell carcinoma and papillary carcinoma.

NON-THYROID MASSES PRESENTING AS THYROID NODULES

Lesions in front of the neck, or those that move with deglutition, are not necessarily thyroidal in
origin.223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 Enlarged cervical lymph nodes, soft-
tissue tumors along the lateral borders of the thyroid, lesions of the larynx and trachea,
thyroglossal duct cysts, branchial cleft cysts, parathyroid lesions, and dermal adnexal tumors may
all appear clinically to originate in the thyroid gland. Lesions of the tail of the parotid gland may
clinically appear to be a thyroid nodule at its upper pole. Anterior mediastinal masses extending
proximally into the neck may also appear to arise from the thyroid gland. Clinically, radiologically,
and even on radionuclide scanning, these lesions may simulate cold thyroid nodules. The FNA
biopsies of such lesions present wide-spectrum cytologic patterns representing a host of lesions.
Some are illustrated in the following sections.

MALIGNANT LYMPHOMA, HODGKIN'S AND NON-HODGKIN'S TYPE,

INVOLVING THE CERVICAL LYMPH NODES
Because cervical lymph nodes often move with the thyroid, they are sometimes clinically and even
on imaging (Fig. 19.63A ) mistaken for thyroid nodules. The same holds true for an anterior
mediastinal mass that extends into the neck, covering the thyroid. An aspiration biopsy specimen
provides an accurate diagnosis in such instances. We have diagnosed 5 cases of Hodgkin's lymphoma
that presented clinically as thyroid masses (Figs. 19.63B and C and 19.64 ). One case of poorly
differentiated lymphocytic lymphoma arising from the anterior mediastinum, extended in front of
the neck, and presented as goiter. It was correctly identified following an aspiration biopsy (Fig.
19.65 ).
Figure 19.63. A. Radionuclide scan showing an area of decreased uptake in the left lobe of the
thyroid. B–E. FNA of the mass showing typical Reed–Sternberg cells. The surgical excision
confirmed Hodgkin's lymphoma involving the cervical lymph node.
Figure 19.64. A,B. Bizarre tumor giant cells from an aspirate of massively enlarged cervical lymph
node. C. Histologic section of the excised lymph node confirmed Hodgkin's lymphoma.

Figure 19.65. FNA of a mediastinal non-Hodgkin's malignant lymphoma poorly differentiated

lymphocytic type. The mediastinal mass extended proximally in the neck and presented as a goiter.
The smear shows a homogeneous population of poorly differentiated lymphoid cells.

TUMORS OF THE LARYNX AND TRACHEA

Rarely, tumors of the larynx or trachea may involve the thyroid and clinically present as thyroid
nodules. Aspiration biopsies of these lesions may cause diagnostic difficulties because of the
unsuspected cytologic features in "thyroid" aspirates. A case of low-grade chondrosarcoma of the
larynx, an uncommon neoplasm223 , 224 presenting as a thyroid nodule, is illustrated in Figure
19.66 .
Figure 19.66. A. Radionuclide imaging of a thyroid nodule, present for 2 years in a 70-year-old
male with recent enlargement. Note the area of decreased uptake at the right upper pole, which
corresponded to the palpable mass. B. FNA of this "thyroid" nodule showing tissue fragments of
large round cells with chondroid stroma (arrows ) (medium power). C. Higher magnification showing
clusters of markedly enlarged neoplastic chondrocytes, containing more than one, atypical nucleus.
D. Histologic section of the core needle biopsy of the mass showed this mass to be a low-grade
chondrosarcoma.

Natarajan et al.225 reported cytologic findings of a case of adenoid cystic carcinoma of the larynx
that mimicked a thyroid mass. Na et al.226 also reported primary adenoid cystic carcinoma of the
trachea mimicking thyroid tumor.

SOFT-TISSUE TUMORS IN THE NECK

Soft-tissue tumors in the neck in close proximity to the thyroid gland may mimic thyroid nodules
both clinically and on radionuclide imaging. Fine-needle aspiration biopsy will present unusual
cytologic patterns that often present a diagnostic challenge.

Butler and Oertel reported lipomas that simulated thyroid nodules (Fig. 19.67 ).227 We encountered
2 cases of cervical schwannomas that presented as thyroid nodules. One case had an unsatisfactory
fine-needle biopsy but the core-needle biopsy was diagnostic for schwannoma (Fig. 19.68 ). The
second case showed a cellular aspirate consisting of spindle cells in anastomosing fascicles. Their
nuclei were pleomorphic. The surgical excision confirmed a peripheral malignant nerve-sheath
tumor (Fig. 19.69 ). A spindle cell pattern in a thyroid aspirate must always be differentiated from a
medullary thyroid carcinoma.228
Figure 19.67. FNA of a neck mass clinically appeared to be a thyroid nodule. FNA consisted of only
mature adipose tissue, consistent with lipoma.
Figure 19.68. A. Thyroid scan from a 16-year-old female, who was found to have a 2-cm firm
nodule that seemed to be located at the right upper pole of the thyroid. Note the area of
decreased function in the upper pole of the right lobe. The fine-needle biopsy was acellular. B.
Large-needle biopsy showed a typical histologic pattern of schwannoma with fascicles of delicate
spindle cells separated by collagenized stroma.
Figure 19.69. A. Fine-needle aspiration biopsy of a nodule, felt to be thyroidal in origin. The
aspirate is cellular, showing several interdigitating tissue fragments of spindle-shaped cells (low
power). B. Higher magnification showing spindle cells with pleomorphic nuclei with low
nuclear/cytoplasmic ratios and variable cytoplasm. C. Another field showing a mixture of round and
spindle-shaped cells, some with delicate cytoplasmic processes. Exploration of the neck revealed a
nodule in the soft tissues. Histologic examination showed features of a neurogenic tumor.

Some other lesions in the neck reported as masquerading as thyroid nodules include cervical
chordoma229 and cervical thymoma.230 , 231 , 232

DERMAL ADNEXAL TUMORS OVER THE THYROID AREA, MIMICKING

A THYROID LESION
Chondroid Syringoma (Mixed Tumor) of the Skin in the Thyroid
Area
Lesions involving the skin overlying the thyroid gland move with deglutition and may be diagnosed
clinically as thyroid nodule. Aspiration biopsy may be of value in recognizing the exact nature of the
lesion. Our experience with a case of chondroid syringoma arising in the skin over the thyroid
isthmus is illustrated in Figure 19.70 . The nodule was clinically felt to be thyroidal. The fine-needle
aspiration biopsy revealed loosely cohesive groups of delicate small spindle cells that suggested the
diagnosis of medullary thyroid carcinoma. The neoplastic cells were nonreactive to calcitonin and
to thyroglobulin. Surgical excision proved to be a chondroid syringoma.
Figure 19.70. A. FNA of a nodule in the thyroid isthmic region that moved with swallowing and was
thought to be thyroidal in origin. The aspirate is cellular, showing very uniform short spindle cells
with oval to spindle-shaped bland nuclei. The cytologic pattern was suggestive of medullary thyroid
carcinoma. The calcitonin stain performed on the smear was negative. B. Surgical excision showed
a benign mixed tumor (chondroid syringoma) of the dermal adnexa.

P.434
P.435
P.436
P.437
P.438
P.439

Salivary Gland Lesions Mimicking Cytologic Patterns of Thyroid

Neoplasms
Based on their cytologic features, some salivary gland lesions may occasionally be interpreted as of
thyroid origin. We had misinterpreted a case of Warthin's tumor of the parotid gland that was
submitted by an endocrinologist as an aspirate from a nodule, located in the upper pole of the
thyroid. The presence of oncocytic cells and the clinical data led to the diagnosis of Hürthle cell
tumor and the patient was referred to the surgeon for the excision (Fig. 19.71A ). Immunostains
performed at the request of the surgeon, since he clinically questioned the thyroid origin, were
nonreactive to thyroglobulin (Fig. 19.71B ). Surgical exploration resulted in a superficial
parotidectomy for Warthin's tumor (Fig. 19.71C ).
Figure 19.71. A,B. Fine-needle biopsy of a mass in the lateral neck submitted by an endocrinologist
as being of thyroidal origin. These oncocytic cells, some in a sheet with a low nuclear/cytoplasmic
ratio and few lymphocytes in the background, were interpreted as a Hürthle cell nodule. The
patient was referred to an endocrine surgeon who doubted the site of the lesion as thyroid.
Immunostain for thyroglobulin was performed which was negative. C. Surgical exploration of the
area revealed a lesion at the lower pole of the parotid gland. Histologic examination showed a
Warthin's tumor. Note the oncocytic papillary structure and the lymphoid stroma.

Another case of a mucoepidermoid carcinoma of the submandibular gland was interpreted as a

metastatic papillary carcinoma of the thyroid. The specimen was submitted as FNA of the
submandibular lymph node. The smears of the aspirate revealed several monolayered syncytial
tissue fragments of neoplastic cells with enlarged nuclei, powdery chromatin, nucleoli, and
intranuclear inclusions (Fig. 19.72A to C). A diagnosis of metastatic papillary carcinoma was
rendered. The mucoid background was overlooked (Fig. 19.72A ). The thyroid gland failed to show
any lesion either on palpation or imaging. Surgical exploration showed a mucoepidermoid carcinoma
of the submandibular salivary gland (Fig. 19.72D and E).

Figure 19.72. A. Fine-needle aspiration of a mucoepidermoid carcinoma of the submandibular

gland. The specimen was submitted as that of a submandibular lymph node. Note the tissue
fragments of neoplastic cells in the background of abundant mucin (low power). B. Another field
from this case with several monolayered tissue fragments of neoplastic cells (low power). C. Higher
magnification showing a monolayered but syncytial tissue fragment. The nuclei are enlarged with
finely granular chromatin, nucleoli, and intranuclear inclusions. A diagnosis of metastatic papillary
thyroid carcinoma was given. D. Surgical exploration revealed a mass involving the submandibular
salivary gland. Histologic sections revealed a low-grade cystic mucoepidermoid carcinoma. E.
Higher magnification showing a mucinous component.

COLD THYROID NODULES IN CHILDREN AND ADOLESCENTS

The prevalence of nodular thyroid disease in the adult population is high, reported to be about 7%
by palpation, up to 35% by ultrasound, and almost 50% at autopsy. However, its prevalence in
children and adolescents (age up to 18 years) is considerably lower. Towbridge et al.233 found
goiters in 6% of 7,785 children aged 9 to 16 years, while Rallison et al.234 detected goiters in 1.8%
of 5,179 children aged 11 to 18 years. The incidence of diffuse and nodular goiters was found with
equal frequency in the Rallison et al.234 study. Most diffusely enlarged thyroid glands during
adolescence are due to Hashimoto's thyroiditis, Graves disease, and multinodular goiter.235 The
solitary cold nodules of the thyroid are still infrequent in the pediatric and adolescent age
groups.233 , 235 This incidence could be higher if the age group was extended to 21 years.237

The incidence of cancer in solitary nodules in this age group is considerably higher as compared to
the adults and is reported to be anywhere from 2% to 50%.234 , 235 , 236 , 237 , 238 , 239 , 240 ,
241 , 242 , 243 , 244 , 245 , 246 , 247 , 248 As in adults, clinical evaluation, laboratory data, or
imaging techniques are not very helpful in differentiating non-neoplastic from neoplastic and
benign from malignant thyroid nodules. Fine-needle biopsy, an indispensable diagnostic tool in the
evaluation of cold nodules in adults, is underutilized in pediatric population. The management of
cold nodules in children without a preoperative diagnosis is a subject of controversy.243 , 249 , 250
, 251 Some authors suggest surgical removal of all solitary nodules, whereas others recommended a
somewhat conservative approach, based on clinical, laboratory, and imaging data. In recent years,
FNA biopsy has been utilized more frequently in pediatric patients with a high degree of
accuracy.238 , 239 , 240 , 242 , 252 , 253 , 254 , 255 , 256 , 257 , 258 Ultrasound guidance has been
of particularly great help in performing the fine-needle biopsy. A study by Amrikachi et al.252
concluded that only FNA significantly contributed in detecting thyroid malignancies in childhood
and adolescence, offering the best sensitivity, specificity, and accuracy in detecting malignancy,
compared to other conventional methods. Their observation is supported by other studies as
well.238 , 239 , 240 , 242 , 252 , 253 , 254 , 255 , 256 , 257 , 258 Some have used large-needle
biopsy of the thyroid nodules with success.259
Our experience with 175 children and adolescents aged 9 to 21 years with cold thyroid nodules
proved that the fine-needle biopsy is as useful in this age group as it is in adults
P.440
(Table 19.7 ).242 Nonsurgical diseases, such as nodular goiter or chronic lymphocytic thyroiditis
(Hashimoto's thyroiditis), are readily identified by aspiration-biopsy specimen. Nodular goiters
constituted 36% while lymphocytic thyroiditis represented 12% of the aspirates. A study by Rabb et
al.240 reported a higher incidence of benign diagnosis (77%). These results are at variance with
ours, where the incidence of neoplasia was higher. Table 19.8 lists the cytohistologic correlation of
69 patients from our study who underwent surgery.

Nodular goiter
64
Lymphocytic thyroiditis
21
Cellular follicular adenoma
14
Hürthle cell tumor
5
Papillary carcinoma
45
Suspected papillary carcinoma
2
Medullary carcinoma
1
Follicular carcinoma
1
Abscess
1
Unsatisfactory
21
TOTAL
175
 TABLE 19.7 CYTOLOGIC DIAGNOSES OF 175 PATIENTS AGE 9
TO 21 YEARS WITH COLD NODULES
Hashimoto's thyroiditis is the most common cause of thyroid enlargement in the pediatric age
group.260 , 261 Fine-needle biopsy is also very useful in differentiating nodular goiters from chronic
lymphocytic thyroiditis. The risk of developing hypothyroidism is higher with the latter, and the
cytologic diagnosis is complimentary to the other diagnostic procedures. It is also associated with a
higher incidence of papillary carcinoma.262

The information on benign thyroid neoplasms in the pediatric age group is limited. We encountered
17 cases that included 12 follicular adenomas and 5 Hürthle cell neoplasms among 69
thyroidectomies (Table 19.8 ), an incidence of 24%.

Nodular goiter
1
1
Cellular adenoma
14
12
1
1
Hürthle Cell tumor
5
5
Suspected papillary
carcinoma
2
1
1
Papillary
carcinoma
45
1
44
Follicular
carcinoma
1
1
Medullary
carcinoma
1
1
Total
69

Histologic Diagnosis

Medullary
Cytologic No. Nodular Follicular Follicular Hürthle Papillary Carcinoma
Diagnosis Patients Goiter Adenoma Carcinoma Tumor Carcinoma of Thyroid

TABLE 19.8 CYTOHISTOLOGIC CORRELATION OF 69 PEDIATRIC

PATIENTS WITH COLD NODULES
Thyroid cancer is the third most common solid malignant tumor in children and adolescents.263 The
incidence of neoplasia in our series was 36% and that of malignancy was 25% (Table 19.8 ). The
majority of thyroid carcinomas in childhood are of the differentiated type, with papillary thyroid
carcinomas the most common malignant tumor in this age group, followed by follicular
carcinomas.264 , 265 , 266 , 267 , 268 , 269 , 270 , 271 , 272 , 273 , 274 , 275 The risk factors for
developing carcinomas include radiation exposure.

P.441
P.442
Papillary carcinomas top the list among childhood thyroid cancers. Although most are conventional-
type papillary carcinomas, a higher incidence of poorly differentiated and sclerosing types have
been reported in children exposed to the radiation from Chernobyl studies.277 , 278 , 279
Coexistence of Hashimoto's thyroiditis and papillary carcinomas is frequent.262 Fifteen of 45
papillary carcinomas in our series were associated with Hashimoto's thyroiditis, an incidence of 40%.
Cervical lymph node metastasis is more frequent in children (87.7%) than in adults (34.7%), although
postoperative node recurrence and distant metastasis are seen with equal frequency in children and
adults.268 , 273 Survival is comparable to that of adults up to 30 years of age. Other differentiated
cancers include follicular carcinomas and medullary carcinomas.277 Most children with thyroid
cancers fare well, with rare fatalities.272 , 274 , 276

Poorly differentiated malignancies such as insular carcinomas in the pediatric age group have been
documented.280 , 281 Other rare malignancies in this age group include the spindle epithelial
tumor with thymus like differentiation (SETTLE)282 , 283 and teratomas.284

DYSHORMONOGENETIC GOITER
Dyshormonogenetic goiters are genetically determined thyroid hyperplasias due to enzyme defects
in thyroid hormone synthesis.285 , 286 The resulting negative feedback to the pituitary is
responsible for hypersecretion of TSH leading to continuous stimulation and hyperactivity. It is seen
in newborns to adults with a median age of 16 years. Patients present with goiters and are clinically
diagnosed as hypothyroid. The thyroid glands are enlarged, multinodular, and weigh up to 600 gms.
Histologically, dyshormonogenetic goiters are characterized by cellular nodules with various growth
patterns and nuclear atypia, mimicking various types of thyroid neoplasms. Fibrosis is common. An
excellent morphologic review is presented by Ghossein et al.285

Fine-needle biopsy is not a recommended test for dyshormonogenetic goiters. A single case report
describes cytologic findings.287

P.443

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Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 20 - Infarction of Thyroid Neoplasms Following Fine-Needle Biopsy

20
Infarction of Thyroid Neoplasms Following Fine-
Needle Biopsy

Necrosis along the needle tract is not unusual following a cutting needle biopsy of a thyroid
neoplasm with Vim-Silverman or Tru-Cut needles (Fig. 20.1 ), whereas fine-gauge needles used
for aspiration biopsy procedures are generally atraumatic.1 Considering the widespread use of
the fine-needle aspiration biopsy in evaluating thyroid nodules, tissue damage is an infrequent
occurrence. However, a wide range of morphologic changes in thyroids with preoperative FNA
biopsy has been described in the recent literature,1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13
, 14 , 15 , 16 partial or complete infarction of the neoplasms being one of them. LiVolsi and
Merino5 compiled an impressive list of post–fine-needle biopsy changes in 300 thyroidectomies
from a total of 3,000 cases, an incidence of 10%. The authors referred the changes as "worrisome
histologic alterations following fine needle aspiration biopsy (WHAFFT)" and grouped them into
two categories, acute and chronic.
Figure 20.1. Follicular adenoma of the thyroid showing a needle tract caused by the Tru-Cut
needle (arrows ). Note the linear fibrosis and hemorrhage.

The acute changes were observed within 3 weeks of fine-needle aspiration biopsy and included
hemorrhage, granulation tissue, giant cells and siderophages, mitoses and necrosis, nuclear
clearing, poorly formed granuloma, capsular distortion, and, rarely, infarction. The chronic
changes included linear fibrosis near siderophages, metaplasia (oncocytic, spindle cell, and
squamous types), infarction, pseudo-invasion of the capsule, significant random nuclear atypia,
cyst formation, papillary degeneration, and calcification.

The etiology of such changes can only be speculated on. Reasons offered include interruption of
the microvascular supply, compromised vascular supply from the extraction of large amounts of
tissue, traumatic venous thrombosis, rough needle use, and multiple passes with vigorous
aspiration.4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18

Of the changes described above, infarction, either partial or complete, is the most dramatic
(Fig. 20.2 ). The incidence of infarction, previously published in our series,13 was 1.4% (22 of
1,150 thyroidectomies). However, an incidence as high as 10% (8 of 82) was reported by Gordon
et al.6

Figure 20.2. Gross photograph of the thyroid showing an acutely infarcted papillary carcinoma
(case 4 in Table 20.2 ).

Our initial experience with a total of 28 cases of thyroid neoplasms that showed partial to total
infarction was reported in 1996.14 Their cytologic diagnoses were 15 Hürthle cell tumors, 8
papillary carcinomas, and 5 follicular neoplasms; 10 of these also had large-needle biopsy
procedures, 2 concurrent and the remaining 8 within 3 weeks of fine-needle aspiration biopsy.
Three showed infarction, one within 24 hours of the biopsy, indicating that infarction could
occur within a short period. Since our last publication,14 we have encountered 13 additional
cases of post-fine needle biopsy infarction of the thyroid neoplasms, which included 9 Hürthle
cell tumors, 2 papillary carcinomas, 1 follicular carcinoma, and 1 follicular adenoma, bringing
the total to 41 cases (Table 20.1 ). None of these additional 13 cases had large-needle biopsy
procedures. However, one case had a repeat fine-needle biopsy, which revealed infarcted cells.
The time period between the fine-needle biopsy and the surgical resection varied from 1 week
to 7 months (case 38 in Table 20.2 ). The higher incidence of infarction of Hürthle cell
neoplasms (24/41) after fine-needle aspiration biopsy, is perhaps due to their increased
vascularity. Table 20.2 lists the cytologic diagnosis of all 41 cases, large-needle biopsy diagnosis
if performed, the time period between the two biopsy procedures, time between fine/large-
needle biopsy and thyroidectomy, and the histologic diagnoses rendered by the surgical
pathologists. Some examples of infarction are illustrated in Figures 20.3 , 20.4 , 20.5 , 20.6 ,
20.7 , 20.7 , 20.8 , 20.9 , 20.10 and 20.11 . Pathologists, if not aware of the cytologic diagnosis,
may overlook the thin rim of viable-appearing tumor at the periphery.

Hürthle cell neoplasms

24
Papillary carcinomas
10
Follicular neoplasms
7
Total
41

TABLE 20.1 CYTOLOGIC DIAGNOSIS OF 41 CASES OF

INFARCTED THYROID NEOPLASMS

1
6/27/78
Hürthle cell
tumor
6/28/78
Hürthle-
cell
tumor
1
7/25/98
Hürthle cell tumor
with total necrosis
in the center
28
2
5/17/79
Follicular
carcinoma
5/31/79
Consistent with
follicular
neoplasm
14
8/9/79
Infarcted nodule
with fibrosis; no
specific diagnosis
90
3
8/22/79
Hürthle cell
tumor
9/21/79
Marked degeneration;
histologic evaluation
difficult
30
4
6/22/80
Papillary
carcinoma
6/27/80
Papillary
carcinoma
Concurrent
7/7/80
Almost total
infarction with
organizing
 hematoma;
papillary
carcinoma at
the periphery
10
5
6/30/80
Hürthle-
cell tumor
7/9/80
Degeneration and
necrosis of the
nodule; no specific
diagnosis
9
6
12/10/81
Hürthle cell
carcinoma
1/10/81
Infarcted nodule; no
specific diagnosis
30
7
1/20/81
Hürthle-
cell
tumor
2/4/81
Hürthle-
cell
tumor
14
3/19/81
Follicular adenoma
with infarction,
recent and
organizing
hemorrhage;
Hürthle cells along
the tract
60
8
4/22/81
Hürthle-
cell
carcinoma
5/21/81
Benign necrotic nodule
(review diagnosis:
a thin rim of Hürthle cell
tumor at the periphery)
28
9
5/26/81
Papillary
carcinoma
10/22/81
Necrotic papillary
carcinoma
30
10
9/1/81
Hürthle-
cell tumor
9/23/81
Necrotic tissue
22
10/12/81
Infarcted nodule; no
specific diagnosis
35
11
6/17/81
Cellular
follicular
adenoma
8/7/87
Follicular adenoma,
partial infarction
50
12
2/8/82
Papillary
carcinoma
2/22/82
Infarcted nodule
(revised diagnosis:
PTC with infarction
and metastasis to
cervical lymph node)
14
13
6/4/82
Hürthle cell
tumor
9/15/82
Extensive necrosis
and hemorrhage, no
recognizable tumor
90
14
6/8/82
Papillary
carcinoma
7/14/82
Degenerating nodule
(revised diagnosis:
papillary carcinoma
with extensive
necrosis)
35
15
9/28/82
Hürthle cell
tumor
11/5/82
Extensive area of
degeneration
colloid nodule with
areas of Hürthle-
cell differentiation
50
16
6/25/82
Hürthle cell
tumor
8/11/82
Encapsulated nodule
with diffuse
coagulative necrosis
(review diagnosis—a
thick rim of Hürthle-
cell tumor of the
periphery)
45
17
1/21/82
Cellular
follicular
adenoma
1/12/83
Infarcted
tissue
11
No surgical follow-up
18
3/21/83
Hürthle-
cell tumor
3/31/83
Infarcted Hürthle-
cell tumor
10
19
5/11/83
Hürthle-
cell
tumor
5/18/83
? Follicular
adenoma
7
6/9/83
Extensive hemorrhage
and necrosis, no
specific diagnosis
28
20
3/11/85
Suspicious for
follicular
carcinoma
4/2/85
Partial infarction;
follicular
adenoma
22
21
9/3/85
Hürthle-
cell
tumor
9/12/85
Necrotic
tissue
9
10/15/85
Hürthle cell tumor
with massive
infarction
35
22
4/30/86
Papillary
carcinoma
4/30/86
Papillary
carcinoma
Concurrent
6/5/86
Totally infarcted
nodule, metastatic
PTC in lymph
 nodes
35
23
2/2/87
Papillary
carcinoma
3/24/87
Total infarction with
rim of PTC at the
periphery
50
24
5/4/87
Hürthle cell
tumor
5/25/87
Infarcted adenoma
compatible with
Hürthle cell type
21
25
5/29/87
Hürthle cell
tumor
6/19/87
Infarcted nodule
(review diagnosis:
Hürthle cell tumor

of the periphery)
21
26
7/8/87
Suspicious for
 PTC papillary
carcinoma
9/10/87
Infarcted nodule and
fibrosis; no specific
diagnosis
60
27
7/11/91
Cellular
adenoma
7/18/91
Follicular adenoma,
partial infarction
17
28
3/23/92
Follicular
variant of
papillary
carcinoma
4/30/92
Infarction, fibrosis
squamous metaplasia
(revised diagnosis:
focal PTC)
35
29
10/10/96
Hürthle cell
tumor
12/6/96
Hürthle cell tumor,
almost total infarction
56
30
1/22/99
Suspicious for
follicular
carcinoma
3/17/99
Minimally invasive
follicular carcinoma,
partial infarction
25
31
4/14/99
Hürthle-
cell tumor
5/19/99
Hürthle cell tumor,
partial infarction
35
32
1/3/00
Hürthle-
cell tumor
1/10/00
Hürthle cell tumor,
acute infarction
7
33
Not
known
Hürthle-
cell tumor
Hürthle cell tumor,
almost total
 infarction
35
34
Not
known
Papillary
carcinoma
Papillary carcinoma,
almost total
infarction
Not
known
35
7/16/01
Hürthle-
cell tumor
8/3/01
Hürthle cell tumor
almost total
infarction
7
36
2/6/03
Hürthle cell
tumor under-
going infarction
(repeat
biopsy?
1 week
between
two FNBs)
12/22/03
No surgical
follow-up
35
37
11/17/03
Scant,
nondiagnostic
12/22/03
Follicular adenoma
with infarction
35
38
1/13/04
Hürthle-
cell tumor
8/9/04
Hürthle cell neoplasm,
extensive infarction
210
39
1/26/06
Suspicious for
Hürthle cell
carcinoma
2/21/06
Minimally invasive
Hürthle cell carcinoma,
massive infarction
36
40
4/4/06
Hürthle-
cell
carcinoma
5/12/06
Total infarction; few
 foci of Hürthle
cells, suggestive
of neoplasia
38
41
5/18/06
Papillary
carcinoma
6/22/06
Total infarction of
papillary carcinoma;
metastasis to lymph
nodes
40

Fine-Needle Biopsy (FNB) Large-Needle Biopsy (LNB) Surgery

Days Days
between between
Cytologic Histologic FNB and Histologic FNB and
Case Date DX Date DX LNB Date DX Surgery

TABLE 20.2 CYTOHISTOLOGIC CORRELATION OF 41 CASES

OF INFARCTED THYROID NEOPLASMS
Figure 20.3. A. This aspirate, characteristic of Hürthle cell neoplasm (adenoma), shows large,
discrete Hürthle cells with eccentric nuclei and prominent macronucleoli. B. A total
thyroidectomy was performed. The 1.5-cm tumor is almost completely infarcted (low power). C.
Higher magnification showing only a thin rim of Hürthle cell tumor at the periphery, bordering
the granulation tissue (arrows ) around the infarcted tumor (case 16 in Table 20.2 ).

Figure 20.4. A. FNA presenting the characteristic cytopathologic pattern of papillary carcinoma
with branching papillary tissue fragments, medium power. B. Higher magnification showing a
syncytial tissue fragment of follicular cells with enlarged, pleomorphic nuclei, finely granular
chromatin, micronucleoli, intranuclear inclusions, and nuclear grooves. C. Total thyroidectomy
revealed an almost totally infarcted hemorrhagic nodule, interpreted as such. Subsequent
examination of the thyroid gland showed tumor extending beyond the capsule (arrow ). D.
Section of the hemorrhagic nodule showing the ghost appearance of papillary fronds (arrows ).
E. Section of tumor beyond the capsule demonstrating the papillary carcinoma. Note also the
extension of the carcinoma into the lymph node (see part A), which was overlooked by the
pathologist (case 12 in Table 20.2 ).
Figure 20.5. A. FNA showing monolayered tissue fragments of follicular cells with enlarged
nuclei, finely granular chromatin, micronucleoli, nuclear grooves, and nuclear inclusions,
diagnostic of papillary carcinoma. B. A total thyroidectomy revealed a hemorrhagic nodule that
represented almost total infarction of the papillary carcinoma with a peripheral, narrow rim of
viable tumor (arrow ). C. Higher magnification of the viable papillary carcinoma. The histologic
diagnosis initially was a cyst, but later amended after a second review (case 14 in Table 20.2 ).
Figure 20.6. A. FNA of a thyroid nodule demonstrating syncytial tissue fragments of follicular
cells with and without follicular pattern. Their nuclei are moderately enlarged, crowded, and
overlapped. The chromatin is granular and nucleoli are not appreciated. The cytologic pattern is
that of a cellular follicular adenoma. B. A core-needle biopsy performed 11 days after the FNA
biopsy revealed several fragments of infarcted tissue with no recognizable pattern or structure
(case 17 in Table 20.2 ).
Figure 20.7. A. FNA of a thyroid nodule consisting of syncytial tissue fragments of follicular cells
with and without a follicular pattern. The nuclei are enlarged, crowded, containing granular
chromatin and micronucleoli. A cytologic diagnosis of follicular carcinoma was rendered.

Figure 20.7. B. A total thyroidectomy performed 25 days later, revealed a minimally invasive
follicular carcinoma with over 90% of the infarction with organization. C. Note the biopsy track
and cholesterol crystals (arrow ) (case 30 in Table 20.2 ).

Figure 20.8. A. Fine-needle aspiration biopsy of a papillary carcinoma showing syncytial tissue
fragments of follicular epithelium with enlarged nuclei, finely granular chromatin, and
intranuclear inclusions (arrows ) (case 28 in Table 20.2 ). B and C. A total thyroidectomy
performed 35 days post-FNA showed a fibrotic nodule with considerable squamous metaplasia.
There were a few trapped dilated follicles, lined by follicular cells with features of papillary
carcinoma cells (case 28 in Table 20.2 ).
Figure 20.9. An example of a totally fibrotic nodule with no residual tumor. A,B. FNA showing
syncytial tissue fragments of follicular cells with enlarged, mildly pleomorphic nuclei, containing
finely granular chromatin, micronucleoli, and some suggestion of intranuclear inclusions. The
cytologic diagnosis was suspicious for papillary carcinoma. The repeat aspirate was
unsatisfactory. C. A total thyroidectomy performed 60 days later revealed a large (3 cm),
encapsulated, totally fibrotic nodule with no identifiable neoplasm. Note several dilated blood
vessels. D. Rarely, few trapped follicles were noted. E. Higher magnification highlighting the
lining follicular epithelium. No histologic diagnosis of a neoplasm was rendered in this case (case
26 in Table 20.2 ).

Figure 20.10. Another example of a nondiagnostic thyroidectomy. A. FNA of a thyroid nodule

consisting of enlarged cells containing very pleomorphic nuclei with nucleoli. Note an
intranuclear inclusion. The cells have variable, dense cytoplasm. B. A different field showing
syncytial tissue fragment of follicular cells with enlarged nuclei, containing granular chromatin
and micronucleoli. A cytologic diagnosis of carcinoma was rendered. C. Thyroidectomy 90 days
later revealed a fibrotic nodule with no features suggestive of malignancy. D. A focal area within
the fibrotic area showed these trapped follicular cells with oncocytic features. No histologic
diagnosis of a neoplasm was rendered on this case (case 2 in Table 20.2 ).
Figure 20.11. Spontaneous infarction. A. Fine-needle biopsy specimen of a Hürthle cell tumor.
Note the characteristic cytomorphology with large polygonal, loosely cohesive cells, with
abundant granular cytoplasm and uniform nuclei with prominent macronucleoli. B. A different
smear from the same case showing infarcted cells. Hürthle cell tumor was confirmed on
surgery.

The long-term sequelae, such as fibrosis, endothelial proliferation, atypical nuclei along the
needle tract, metaplasias, and entrapment of neoplastic tissue in the capsule, are worrisome
changes that may offer diagnostic difficulties in histopathologic evaluation.2 , 3 , 4 , 5 , 6 , 7
Completely infarcted neoplasm may undergo total fibrosis, which would prevent a surgical
pathologist from rendering a meaningful diagnosis. These events are encountered with a long
time span between the fine-needle biopsy and the surgical excision. The prolonged interval
between the procedures allows sufficient time for the development of fibrosis. Two such cases
are illustrated in Figures 20.9 and 20.10 . The case of spontaneously disappearing Hürthle cell
adenoma reported by Bauman and Strawbridge17 probably represents an extreme example of
the late effect of an infarcted neoplasm.

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The importance of these post-fine-needle biopsy sequelae is that extensive necrosis and
infarction will obscure the true nature of the neoplasm, and the cytologic diagnosis of the
neoplasm may not be confirmed histologically. Widespread necrosis/infarction in a neoplasm
should alert the histopathologist to evaluate the specimen more carefully. The accuracy of the
cytologic diagnoses of papillary carcinomas, Hürthle cell tumors, and follicular neoplasms is
quite high. An unequivocal cytologic diagnosis of neoplasia, especially of malignancy, should not
be taken lightly in the presence of hemorrhage and necrosis of the neoplasm (Fig. 20.5 ). It is
imperative that the surgical pathologist be provided with the information on preoperative fine-
needle aspiration biopsy diagnosis. Lack of information or the knowledge on the part of the
surgical pathologist may result in a benign diagnosis. In
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the light of positive cytologic results, and a careful examination of both the gross and
microscopic specimens, a neoplasm can be usually be recognized in focal areas along the
perimeter of the lesion. Judkins et al.18 performed immunohistochemical studies on infarcted
neoplasms. Their study demonstrated that the infarcted tissue of the thyroid neoplasm reacted
positively to thyroglobulin and not to cytokeratin.

It must be noted, however, that spontaneous hemorrhage, necrosis, organization, fibrosis, and
cyst formation do occur in nodular goiters and also in neoplasms. Fine-needle biopsy will
demonstrate necrotic debris with ghost cells in the background (Fig. 20.5 ). Spontaneous
necrosis/infarction is also reported in several other organs, and readers may refer to the
literature for their review.19 , 20 , 21 , 22 , 23 , 24

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SUMMARY
In summary, partial or complete infarction of the thyroid neoplasm is an infrequent complication
following fine/large-needle biopsies. Of the various types of benign and malignant neoplasms,
Hürthle cell tumors are more prone to post-biopsy infarction. The final histologic diagnosis of
the infarcted neoplasm may be compromised, resulting in non-confirmation of the cytologic
diagnosis if the cytologic diagnosis is not taken into consideration.

REFERENCES
1.Miller JM, Kini SR, Hamburger JI. Needle Biopsy of the Thyroid . New York: Praeger; 1983.
2.Baloch ZW, LiVolsi VA. Post fine-needle aspiration histologic alterations of thyroid
revisited. Am J Clin Pathol . 1999;112:311–316.

3.Baloch ZW, LiVolsi VA. Post FNA spindle cell nodules of the thyroid (PSCNT). Am J Clin
Pathol . 1999;111:70–74.

4.Ersoz C, Soylu L, Erkocak E, et al. Histologic alterations in the thyroid gland after fine-
needle aspiration. Diagn Cytopathol . 1997;16:230–232.

5.LiVolsi VA, Merino MJ. Worrisome histologic alterations following fine needle aspiration of
thyroid. Pathol Ann . 1994;29:99–120.

6.Gordon DL, Gattuso P, Castelli M, et al. Effect of fine needle aspiration biopsy on the
histology of thyroid neoplasms. Acta Cytol . 1993;37:651–654.

7.Tsang K, Duggan MA. Vascular proliferation of the thyroid: a complication of fine-needle

aspiration. Arch Pathol Lab Med . 1992;116:1404–1042.

8.Us-Krasovec M, Golauth R, Auesperg M, et al. Tissue damage after fine needle aspiration
biopsy. Acta Cytol . 1992;36:456–457.

9.Axiots AC, Merino MJ, Ain K, et al. Papillary endothelial hyperplasia in the thyroid
following fine-needle aspiration. Arch Pathol Lab Med . 1991;115:240–242.

10.Kini SR. Post fine needle biopsy infarction of thyroid neoplasms. A review of 28 cases.
Diagn Cytopathol . 1996;15:211–220.

11.Layfield LJ, Lones MA. Necrosis in thyroid nodules after fine needle aspiration biopsy.
Report of two cases. Acta Cytol . 1991;35:427–430.

12.Alejo M, Matias-Guiu X, de las Heras Duran P. Infarction of a papillary thyroid carcinoma

after fine needle aspiration. Acta Cytol . 1991;35:478–479.

13.Keyhani-Refagha S, Kooner DS, Keyhani M, et al. Necrosis of a Hürthle cell tumor of the
thyroid following fine needle aspiration. Case report and literature review. Acta Cytol .
1990;34: 805–808.

14.Kini SR, Miller SM, Abrash MP, et al. Post-fine needle aspiration biopsy infarction in
thyroid nodules. Mod Pathol . 1988;1:14A.

15.Jayaram G, Aggarwal S. Infarction of thyroid nodule: a rare complication following fine

needle aspiration. Acta Cytol . 1989:33:940–941.

16.Jones JD, Pittman DL, Sander LR. Necrosis of thyroid nodules after fine needle aspiration.
Acta Cytol . 1985;29:29–32.

17.Bauman A, Strawbridge HTG. Spontaneous disappearance of an atypical Hürthle cell

adenoma. Am J Clin Pathol . 1983;80: 399–402.

18.Judkins AR, Roberts SA, LiVolsi VA. Sensitivity of antibodies on necrotic thyroid nodules.
Mod Pathol . 1998;11:57A.

19.Tsang WYW, Chan JKC. Spectrum of morphologic changes in lymph nodes attributable to
fine needle aspiration. Hum Pathol . 1992;23:562–565.

20.Layfield LJ, Reznick M, Low M, et al. Spontaneous infarction of a parotid gland

pleomorphic adenoma. Acta Cytol . 1992;36: 381–385

21.Dekmezian RH, Sneige N, Katz RL. The effect of fine needle aspiration of lymph node
morphology in lymphoproliferative disorders. Acta Cytol . 1989;33:732–733.

22.Davies JD, Webb AJ. Segmental lymph node infarction after fine needle aspiration. J Clin
Pathol . 1982;35:855–857.

23.Kern SB. Necrosis of a Warthin's tumor following fine needle aspiration. Acta Cytol .
1988;32:207–208.

24.Lucey JJ. Spontaneous infarction of the breast. J Clin Pathol . 1975;28:937–943.

Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 21 - Lesions of the Parathyroid Glands

21
Lesions of the Parathyroid Glands

Fine-needle aspiration biopsy is not routinely performed in evaluation of the parathyroid gland
lesions. Consequently, information on their cytopathologic findings is limited. The literature
includes mostly individual case reports, small case series, and very few reviews of large number
of cases. The cytologic criteria for parathyroid cysts, hyperplasia, and adenoma described in this
chapter are based on limited personal experience and also culled from the literature.1 , 2 , 3 , 4
, 5 , 6 , 7 , 8 , 9 , 10 , 11

Although specimens from the parathyroid lesions are not received in routine cytopathology
practice, it is important to be familiar with their cytologic presentations. This is because the
parathyroid glands, either in their usual or in ectopic locations, may clinically and/or
radiologically appear to be of thyroidal origin.12 , 13 , 14 , 15 , 16 , 17 Thus specimens
submitted as thyroidal lesions may indeed be parathyroidal in origin. Furthermore, the
specimens from these parathyroid lesions are difficult to recognize accurately because of the
morphologic overlap between thyroid and parathyroid lesions, which constitutes a common
diagnostic problem.

Some reasons for the infrequent use of fine-needle biopsy in the diagnosis of parathyroid lesions
may be as follows:

Functioning parathyroid lesions are subjected to surgical exploration following a clinical

diagnosis supported by the laboratory data. Preoperative fine-needle biopsies are not
performed or required in these instances.

Although ultrasonography is popularly used10 , 11 , 18 , 19 , 20 in localizing the

parathyroid lesions, its sensitivity varies widely, ranging from 34% to 92%, while the
specificity is reported to be high, up to 97%. But the difficulties in differentiating
between thyroid nodules, parathyroid glands, and lymph nodes still exist (Fig. 21.2 ).

Figure 21.2. Thyroid radionuclide image. The large, discrete, clear area (arrow) was
interpreted as a cold nodule of the right lobe of the thyroid. A fine-needle biopsy
specimen was diagnosed as carcinoma but was not typed (see Fig. 21.14 ).
Thyroidectomy revealed a large, encapsulated nodule grossly thought to be involving the
right thyroid lobe. Only the histologic examination confirmed the parathyroid adenoma.
This is an example of a parathyroid lesion being mistaken for a thyroid nodule on
radionuclide scan.

Small functioning parathyroid lesions may not be detected by ultrasonography.

Accurate cytologic identification of parathyroid glands offers difficulties because of the

 morphologic overlap between thyroid and parathyroid lesions.

Fine-needle biopsies of parathyroid gland lesions have been performed in following situations:

Enlarged parathyroid glands visualized during routine ultrasonography of the neck for
thyroid.21

Patients with hyperparathyroidism with ultrasound localization of the parathyroid

glands.5 , 10 , 11

Ultrasonography of thyroid bed following thyroidectomy.22

Suspected parathyroid lesion following unsuccessful parathyroid exploration, under

ultrasound guidance.4 , 23 , 24

NORMAL PARATHYROID GLANDS

The parathyroid glands are small red-brown, flattened, ovoid structures generally measuring 4 to
6 mm in length, 2 to 4 mm in width, and 1 to 2 mm in thickness. The average combined weight is
120 ± 3.5 mg in males and 142 ± 5.2 mg in females.25 Most normal adults have four
parathyroid glands, the superior pair located about 1 cm above the intersection of the recurrent
laryngeal nerve and the inferior thyroid artery. The inferior parathyroids are typically found
inferior, posterior, or lateral to the lower pole of the thyroid and sometimes high up on the
anterior aspect of the thyroid lobe. Due to their intimate anatomic location in thyroid area,
lesions of the parathyroid may masquerade as thyroidal lesions. The parathyroid glands are
highly vascularized and thinly encapsulated. Histologically, the parathyroid gland shows a
mixture of parenchyma and adipose tissue (Fig. 21.1A ). The parathyroid parenchyma consists of
chief cells, varying numbers of oncocytic cells, and transitional oncocytic cells (Fig. 21.1B ). The
parenchymal cells are often arranged in a lobular pattern. The chief cells are polyhedral, 8 to 10
µm in diameter,26 with round central nuclei containing sharp nuclear membrane with coarse
chromatin. Their cytoplasm is eosinophilic to amphophilic and often appears clear or vacuolated
in formalin-fixed tissues. The cells are rich in glycogen and contain variable amounts of neutral
lipid in the form of two or three sudanophilic fat droplets per cell.25 The chief cells may form
solid sheets, branching anastomosing cords, and sometimes small acinar structures. Eosinophilic
periodic acid–Schiff (PAS)–positive material resembling colloid may be present within these
acinar structures. The oncocytic cells
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measure 12 to 20 µm in diameter and contain deep eosinophilic cytoplasmic granules. Their
nuclei are slightly larger than those of chief cells. The stroma contains mature fat cells, blood
vessels, and varying amounts of connective tissue, the proportion of which changes with age.
The immunoprofile of parathyroid parenchymal cells includes positive reactivity to
parathormone and chromogranin.
Figure 21.1. A. Histologic section of the normal parathyroid gland with a mixture of parenchyma
and adipose tissues (low power). B. Higher magnification showing islands of chief cells with
intervening adipose tissue.

The parathyroid cells secrete parathyroid hormone, which along with the hormones calcitriol
(produced in the kidney) and calcitonin (produced in the thyroid), regulates calcium and
phosphorus levels.25

RADIOLOGIC FINDINGS
Several imaging modalities are used to localize parathyroid gland lesions. These include
ultrasonography, CT scanning, magnetic resonance imaging (MRI), thallium substation scanning,
and the recent technetium-99m sestamibi imaging. Ultrasonography is the most frequently used
modality for primary parathyroidism. A normal parathyroid gland is typically not seen with
ultrasound. A parathyroid adenoma or a carcinoma is seen as a round, elliptical, or oblong
hypoechoic mass. These may contain cysts and calcifications. Hyperplastic glands are usually
much smaller than adenomas. Ultrasound cannot localize ectopic parathyroids. Thyroid nodules
and lymph nodes may be mislabeled as parathyroids.

PARATHYROID CYSTS
Parathyroid cysts are rare,25 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ,
41 with fewer than 300 cases reported to date in the literature. The incidence of parathyroid
cysts among cystic neck lesions is stated to be less than 1% of patients undergoing neck
exploration for parathyroid and thyroid lesions.

Most parathyroid cysts are located in the lower cervical neck region in proximity to the inferior
parathyroid glands; 13% are found in the anterior superior mediastinum.13 , 25 , 30 , 36
Parathyroid cysts are generally asymptomatic, but the larger ones may cause symptoms due to
compression of the trachea, esophagus, or recurrent laryngeal nerve. Up to 11% of parathyroid
cysts may be associated with hyperparathyroidism.25 Nonfunctional cysts are more common in
women. Clinically, the parathyroid cysts may present as cervical nodules often mistaken for
those of thyroidal origin. The results of radionuclide thyroid imaging are often misleading in the
diagnosis of parathyroid cysts.6 , 7 , 9 , 10 , 11 However, ultrasonography has been quite
successful in detecting parathyroid cysts, allowing for the fine-needle biopsy procedures.2 , 4 , 5
, 6 , 7 , 10 , 11 , 35 , 43 The origin of parathyroid cysts includes:
 Embryologic remnants of the third and fourth branchial clefts.

Coalescence of microcysts.

Degeneration in a hyperplastic gland or in an adenoma.

Gross and Microscopic Features

Grossly, parathyroid cysts vary in size and may be as large as 10 cm in diameter. They are
loosely attached to the thyroid (Fig. 21.3A ). They can be uni- or multilocular. The cyst walls are
typically thin, translucent, membranous, and gray-white.
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Histologically, the wall is fibrous and lined by flattened epithelial cells, some containing clear
cytoplasm and resembling chief cells. Trapped islands of chief cells may also be present in the
wall (Figs. 21.3B and C ).

Figure 21.3. A. Gross photograph of a thin-walled parathyroid cyst. B. Low-power view of the
histologic section of a multiloculated parathyroid cyst with thin walls. C. Higher magnification
showing an island of parathyroid cells in the wall.
Cytopathologic Features
Aspirated cyst fluid can measure up to several milliliters; and is characteristically clear, watery,
and occasionally golden brown, in contrast to thyroid cyst fluid, which is straw-colored, amber,
hemorrhagic, dark brown, or viscous. The fluid is often acellular2 or poorly cellular, consisting of
tissue fragments of small cuboidal cells with round nuclei containing granular to compact
chromatin (Fig. 21.4 ). The cells are arranged in regular microfollicles or honeycomb sheets.
Oncocytic cells and histiocytes are rarely seen, and colloid is absent. The background shows
proteinaceous debris. The
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parathyroid hormone levels in cyst fluids are always elevated, supporting their parathyroid origin
and serving as a differentiating feature from thyroid cysts.2 , 4 , 33

Figure 21.4. Parathyroid cyst fluid. A,B. Monolayered tissue fragments of small cuboidal cells in
a honeycomb arrangement. The nuclei are small and uniform, with compact chromatin. Note
their strong resemblance to thyroid follicular cells. The empty spaces within the tissue fragment
probably represent fat cells.
Figure 21.4. C. A tissue fragment of tightly packed small parathyroid cells with scant cytoplasm
and high N/C ratios. D. A group of histiocytes. Heme-3 stain. E. Same specimen as A to D,
stained by Papanicolaou stain. Tissue fragments of small cuboidal cells with crowding and
overlapping of small, uniform, nuclei with compact chromatin. Note their strong resemblance to
thyroid follicular cells. The background shows proteinaceous precipitate. (Courtesy of Michael
Glant, MD, director, Diagnostic Cytology Clinic, Indianapolis.)

Diagnostic Accuracy and Differential Diagnosis

Both clinically and cytologically, parathyroid cysts are often mistaken for thyroidal cysts of
degenerating nodular goiters (Figs. 21.5 and 21.6 ). Parathyroid cells resemble thyroid follicular
cells in size and in architectural configurations. The main differentiating features between these
two cysts include the gross characteristics of the parathyroid cyst fluid and the elevated
parathormone levels. The parathyroid cells will react positively to parathyroid antibody and
negatively to thyroglobulin.42 , 43 Table 21.1 lists the differentiating features between
parathyroid cysts and cysts of nodular goiter. The other differential diagnostic entities include
cystic lesions of the neck such as branchial cleft, thymic, or thyroglossal duct cysts.
Figure 21.5. FNA of a nodular goiter. The tissue fragment of benign follicular cells with a
honeycomb pattern, lacking extreme crowding and overlapping of nuclei. The nuclear size is
slightly larger than the parathyroid cells. Note the morphologic overlap between thyroid
follicular cells and parathyroid cells.
Figure 21.6. FNA of a cystic nodular goiter showing macrophages and benign follicular cells. The
cytologic pattern is indistinguishable from that of a parathyroid cyst.

Presentation
Aspirated fluid water: clear, thin, occasionally straw-
colored or red-brown
Clear, straw-colored, amber, red-brown to hemor-
rhagic, to thick, sticky
Cellularity
Acellular to poorly cellular
Variable
Epithelial cells
Rare group or a tissue fragment of very small round
to cuboidal cells; microfollicular pattern or sheets,
poorly defined cell borders; scant cytoplasm with
high N/C ratios; round nuclei with deep-staining
compact chromatin
Follicular epithelial cells in varying numbers; regu-
lar follicles or honeycomb sheets with well-
defined cell borders; uniform round nuclei with
compact to granular chromatin; degenerative
changes frequent
Hürthle Cell metaplasia
Absent
±
Histiocytes
±
Usually present in variable numbers; with or with-
out hemosiderin; multinucleated foreign-body-
type giant cells ±
Colloid
Absent
Variable
Immunoprofile
Positive reactivity to parathyroid hormone and
chromogranin
Positive reactivity to thyroglobulin
Parathyroid hormone
levels
High
Nil

Parathyroid Cyst Thyroid Cyst (Nodular Goiter)

TABLE 21.1 CYTOPATHOLOGIC FEATURES OF PARATHYROID

CYSTS AND THYROID CYSTS IN NODULAR GOITER
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PARATHYROID HYPERPLASIA AND ADENOMA

Parathyroid hyperplasia and adenoma may be associated with primary hyperparathyroidism
characterized by excess production of parathyroid hormone and hypercalcemia, along with
certain bone changes.25 Solitary adenoma is the most frequent cause (80% to 85% of cases) of
hyperparathyroidism. Primary hyperplasia accounts for up to 15% of primary
hyperparathyroidism. It can also be associated with the dominantly inherited multiple endocrine
neoplasia (MEN) syndrome. The incidence of primary hyperparathyroidism has increased over the
last several years,25 , 27 primarily because of the improved radiologic modalities and
sophisticated laboratory studies.

Secondary hyperplasia of the parathyroid glands occurs as a result of certain systemic

disorders.25

PARATHYROID HYPERPLASIA
Gross and Microscopic Features
Proliferation of parenchymal cells of the parathyroid is referred to as hyperplasia,25 , 27 and
often takes the form of nodules. Generally, all four parathyroid glands are involved but not
uniformly. The size and weight of each enlarged gland are variable features, and not all glands
are visualized by ultrasound. Histologically, the hyperplasia involves chief cells as well as
oncocytic cells (Figs. 21.7 and 21.8 ). It can be diffuse or nodular and sometimes can form
glandular patterns. The stromal adipose tissue is reduced or absent.

Figure 21.7. A. Histologic section of a hyperplastic parathyroid gland with reduced amount of
adipose tissue (low power). B. Higher magnification showing chief cell hyperplasia with a
follicular growth pattern.
Figure 21.8. A. Scrape preparation of a hyperplastic parathyroid gland. The parathyroid cells
are small with poorly defined cell borders, scant cytoplasm, and containing round nuclei. The
chromatin is compact. The cells are in aggregates or small tissue fragments and are separated by
fat cells. B. Histologic section of the excised hyperplastic parathyroid gland revealing
hyperplasia of both chief and oncocytic cells.

Cytopathologic Features
The smears are variably cellular, showing tissue fragments of small parathyroid cells with round,
uniform nuclei, containing finely granular chromatin. The cytoplasm of the chief cells is scant,
pale, or may be finely vacuolated. The oncocytic cells are slightly larger and contain appreciable
slightly denser cytoplasm. The stromal fat if identified in the aspirate will favor the diagnosis of
hyperplasia (Fig. 21.8 ).

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PARATHYROID ADENOMA
Gross and Microscopic Features
In contrast to hyperplasia, parathyroid adenoma involves a single gland. A typical parathyroid
adenoma is a thinly encapsulated, tan to reddish brown neoplasm, homogeneous in consistency,
with a smooth external surface. Adenomas vary considerably in size and shape. They may be
round, ellipsoid, bean- or kidney-shaped, or flattened and elongated (Fig. 21.9 ).18 , 19 Larger
adenomas may undergo cystic change and the aspiration biopsy may yield fluid contents.
Figure 21.9. Gross photograph of a large parathyroid adenoma.

Histologically, adenomas are encapsulated neoplasms with compressed normal parenchyma

outside the capsule. The dominant cell type is chief cells often larger than their normal
counterpart. The cell outlines are indistinct. Their cytoplasm ranges from faintly eosinophilic to
clear, and contains abundant
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glycogen deposits. The nuclei are round and central, with dense chromatin and occasional
nucleoli. A few cells may contain large, hyperchromatic nuclei. The growth patterns consist of
closely packed chief cells arranged in anastomosing cords, nests, glandular formations, and
sheets separated by a delicate network of sinusoids (Fig. 21.10 ).
Figure 21.10. Histologic sections demonstrating various cell types and growth patterns of
parathyroid adenomas. A. Parathyroid adenoma showing nests and insulae of cells. B.
Trabecular growth pattern of chief cells. Note the rich sinusoidal network. C. Follicular growth
pattern. D. Clear cell pattern. E. Oncocytic cell pattern. F. Note marked nuclear atypia that is
sometimes present in parathyroid adenomas.
Figure 21.10. G. Higher magnification of an adenoma composed of chief cells depicting a
follicular pattern, small cuboidal cells with uniform nuclei.

The adenomas frequently contain cystic structures, which may be empty or filled with PAS-
positive, eosinophilic, homogeneous material that strongly resembles colloid. The cells contain
glycogen and fat. Argyrophilic granules in the cytoplasm of adenoma cells have been
described.10

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Immunoprofile
The cells of parathyroid hyperplasia or adenoma exhibit positive reactivity to parathyroid
hormone, chromogranin A, and low-molecular-weight cytokeratin; and negative reactivity to
thyroglobulin and vimentin.2 , 4 , 25 , 42 , 43

Cytopathologic Features
Cytologically, a parathyroid adenoma cannot be distinguished from parathyroid hyperplasia
because both present similar cytologic features.8 When adequate, the cytologic material
consists of a large population of small round to cuboidal epithelial cells displayed singly, in
loosely cohesive groups, or in thick syncytial-type tissue fragments (Figs. 21.11 , 21.12 , 21.13 ,
21.14 and 21.15 ). A dispersed cell pattern is also characteristic (Fig. 21.13 ). The tissue
fragments present various architectural configurations. They may be monolayered (two-
dimensional), trabecular with branching and interdigitating to enclose spaces (Fig. 21.11 ). The
tissue fragments may present a follicular pattern (Fig. 21.11E ) or appear papillary-like with
complex branching and frayed edges. Frequently, the extreme crowding and overlapping of
nuclei within a tissue fragment result in a three-dimensional pattern (Figs. 21.11 and 21.12 ).

Figure 21.11. Scrape smears of a parathyroid adenoma. A. The syncytial tissue fragment
consists of small cells with extreme crowding and overlapping of uniform, round nuclei with
granular chromatin. The N/C ratios are very high. The cell borders are indistinct and the
cytoplasm is pale, scant but variable. B. The syncytial tissue fragments of small cells present a
trabecular pattern. C. Syncytial tissue fragments with a follicular pattern. D. Positive reactivity
to parathyroid hormone antibody.
Figure 21.11. E. Histologic section of the resected specimen showing a variegated growth
pattern such as insular, trabecular, and follicular. Medium power. F. Higher magnification
showing chief cells.
Figure 21.12. A,B. FNA of a parathyroid gland adenoma. The specimen was submitted as that
from a thyroid nodule and interpreted as a cellular follicular adenoma. The parathyroid cells are
in syncytial tissue fragments forming anastomosing chords and trabeculae, enclosing spaces. The
component cells demonstrate extreme crowding and overlapping of small uniform nuclei with
finely granular chromatin. The background is clean. C,D. Some of the neoplastic cells contain
scant, pale cytoplasm. Their nuclei are uniform with granular chromatin. E. Histologic sections
of the parathyroid adenoma composed of chief cells presenting a follicular growth pattern. Low
power. F. Higher magnification.

Figure 21.13. A. Low-power view of a cellular aspirate from parathyroid adenoma, showing a
dispersed cell pattern and tissue fragments. B. Higher magnification showing loosely cohesive
and discrete epithelial cells with poorly defined cell borders. The nuclei are mildly pleomorphic
and many appear to be stripped of their cytoplasm.
Figure 21.14. Fine-needle biopsy of a parathyroid adenoma submitted as thyroid nodule, seen
as a defect on imaging studies (Fig. 21.2 ) A. The aspirate is very cellular consisting of large,
branching tissue fragments of epithelial cells, and fibrovascular stroma (low power) B. Another
field showing very large tissue fragments of epithelial cells. C,D. Higher magnification. The
syncytial tissue fragments of epithelial cells demonstrate no architectural configurations. The
nuclei are round, with granular chromatin, and contain nucleoli. The cell borders are poorly
defined, and the cytoplasm is scant.

Figure 21.14. E. The neoplastic cells show a characteristic perivascular location. F. Note the
branching capillaries. The neoplastic cells are aligned along the capillaries. G. Histologic section
of the encapsulated parathyroid adenoma (low power) demonstrating a thick capsule (C ). H.
Higher magnification showing a solid growth pattern composed of uniform cells. Note that the
tumor is richly vascular.
Figure 21.15. An example of intrathyroidal parathyroid adenoma. A,B. This aspirate, submitted
as that from a thyroid nodule, was marginally cellular, consisting of syncytial tissue fragments of
small cells with uniform nuclei containing finely granular chromatin. The cell borders are
vaguely appreciated. The cytoplasm is scant and appears pale to foamy.
Figure 21.15. (continued ) C,D. These cells are slightly larger and possess granular cytoplasm
and probably represent an oncocytic component. The aspirate was interpreted as
nondiagnostic/unsatisfactory due to poor cellularity. E. Total thyroidectomy revealed a 2-cm
encapsulated nodule with compressed normal parathyroid parenchyma external to the capsule.
F. The neoplasm is predominantly composed of chief cells and showed areas with clear cells and
oncocytic cells. G. The neoplasm showed positive reactivity to parathyroid hormone antibody. H.
The neoplastic cells exhibited negative reactivity to thyroglobulin.

Another characteristic feature of parathyroid adenomas is the branching network of capillaries

and the neoplastic cells often seen along the capillaries (Fig. 21.14A ). The parathyroid adenoma
cells are round to cuboidal, slightly smaller than normal thyroid follicular cell nuclei, measuring
6 to 7 µm in diameter. Their nuclei are round, uniform, containing coarsely granular chromatin
and micronucleoli. Nuclear pleomorphism is occasionally present. Nuclear molding has been
described as a hitherto undescribed but diagnostic feature2
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but not documented by others. The parathyroid chief cells have scanty, pale cytoplasm with ill-
defined cell borders and are frequently displayed as stripped nuclei, presenting a lymphocyte-
like pattern. Occasionally single vacuoles are noted within the cytoplasm. The oncocytic cells
contain appreciable amounts of granular cytoplasm. Although a monomorphic pattern is
commonly seen in adeno-mas, pleomorphic size and shapes may occasionally be encountered.
Mitoses or karyorrhexis is not present. The background contains delicate, branching,
vascularized stromal tissue fragments. Histiocytes are rarely present, and fat globules are not
identified. The presence of fat globules favors hyperplasia. The background may contain
proteinaceous fluid or colloid-like material. The cytologic features of parathyroid
hyperplasia/adenoma are summarized in Table 21.2 .

Cellularity
Generally hypercellular
Presentation
Cells isolated or discrete, in loosely cohesive groups or in tissue fragments; dispersed
cell pattern frequent; network of branching capillaries with tissue fragments of
epithelial cells in perivascular location; lymphocyte-like pattern due to naked
nuclei of chief cells
Architecture of the tissue fragments
Syncytial tissue fragments, without any architectural patterns with extreme crowd-
ing and overlapping of nuclei, often appearing three dimensional; trabecular
arrangement with branching and interdigitating, enclosing varying sized spaces,
 mimicking acinar pattern; monolayered small to large tissue fragments; microfol-
licular pattern; papillary-like architecture
Cells
Small, round to cuboidal; poorly defined, indistinct cell borders; 7–9 µm in
diameter
Nucleus
Usually round, with high N/C ratios; smooth nuclear membranes; coarsely granular
to compact, deep-staining chromatin; micronucleoli ±; usually uniform but occa-
sionally pleomorphic; size slightly larger than the normal counterpart; intranu-
clear inclusions extremely rare
Cytoplasm
Insignificant to moderate; clear, pale to granular, single cytoplasmic vacuole ±
Background
Usually clean; naked nuclei; colloid-like material ±; fat globules ± in hyperplasia
but absent in adenoma; lymphocytes rare; macrophages with or without hemo-
siderin ±
Histochemistry
Argyrophilic granules in the cytoplasm
Immunoprofile
Positive reactivity to parathyroid hormone, chromogranin A, and low-molecular-
weight cytokeratin; negative to thyroglobulin

TABLE 21.2 CYTOPATHOLOGIC FEATURES OF PARATHYROID

HYPERPLASIA AND ADENOMA
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Diagnostic Accuracy and Differential Diagnosis

Recognition of parathyroid lesions from cytologic samples has historically presented difficulties.2
, 3 , 9 , 12 , 15 , 29 , 44 , 45 , 46 , 47 , 48 , 49 The diagnostic difficulties are compounded when
the location is intrathyroidal (Fig. 21.14 ) or if the specimen is submitted as a thyroid nodule
(Figs. 21.12 , 21.13 and 21.14 ). Cytologically, many aspirates from parathyroid lesions are
interpreted as thyroid neoplasms, only to find parathyroid pathology on surgically excised
specimens. There is considerable cytomorphologic overlap between thyroid lesions and
parathyroid lesions. There are no definite cytologic criteria that help accurately identify the
parathyroid lesions without the help of ancillary diagnostic techniques, coupled with clinical and
radiologic data. However, some authors have claimed that cytologic differentiation between
thyroidal and parathyroidal lesions is possible.11 , 24 , 50

Löwhagen and Sprenger46 reported 5 cases of parathyroid adenomas cytologically diagnosed as

follicular neoplasms. Friedman et al.47 described a case of parathyroid adenoma with the
cytologic diagnosis of papillary carcinoma. The presence of oncocytic cells in large numbers is a
potential diagnostic pitfall and will lead to misinterpretation of the aspirates as thyroidal
lesions.15 , 45 Auger et al. reported a case of intrathyroidal parathyroid adenoma that was
interpreted as lymphocytic thyroiditis. The naked nuclei of the chief cells with the clumped
chromatin along with oncocytic-type cells lead to the diagnosis of lymphocytic thyroiditis.
Lymphoid infiltrate has been described in parathyroid adenomas.15

The small cell size of parathyroid adenoma cells, and their presentation in tight, three-
dimensional clusters, resembles the cytologic pattern of insular carcinoma of the thyroid and is a
potential diagnostic pitfall. The same holds true for medullary thyroid carcinoma with a small
cell pattern.

Differentiation of parathyroid lesions from thyroid lesions may be attempted based on the
current knowledge of parathyroid cytopathologic features of hyperplasia/adenomas, as listed in
Tables 21.1 and 21.2 , and the special stains. Parathyroid cells contain glycogen and argyrophil
granules that can be demonstrated by the PAS reaction and the sliver stain, respectively.7

Immunoreactivity to parathyroid hormone will confirm the origin of the cells.4 , 42 , 43 Ryska et
al.44 reported high levels of parathyroid hormone in the needle rinsing of the aspirate. Also, the
morphometric analysis of parathyroid cells and thyroid cells has been reported to be helpful.48
Presence of fat cells will favor parathyroid origin and a hyperplastic lesion. The accuracy of
diagnosing parathyroid lesions from cytologic specimens is low in general, but can be maximized
if the parathyroid location is known or suspected, in which case ancillary tests will offer
conclusive results.

Parathyroid adenomas may also on occasion be difficult to differentiate from oncocytic, or clear
cell, neoplasms of the thyroid; they also share morphologic similarities with metastatic renal cell
carcinoma.

PARATHYROID HYPERPLASIA/ADENOMA VERSUS FOLLICULAR

ADENOMA/CARCINOMA
In cytologic samples, follicular neoplasms of the thyroid—follicular adenoma and follicular
carcinoma—share morphologic similarities with parathyroid lesions (Table 21.3 , Fig. 21.16 ).
Syncytial-type tissue fragments and coarse nuclear chromatin are characteristic of both
parathyroid hyperplasia/adenoma and follicular neoplasms (adenoma/carcinoma). However, the
thyroid follicular cell nuclei in adenoma/carcinoma are considerably enlarged. Colloid is usually
scant or absent in cellular follicular neoplasms. The differentiation between parathyroid lesions
and thyroid follicular neoplasms is extremely difficult. The diagnostic dilemma may be solved by
immunostains with either thyroglobulin or parathyroid hormone.

Cellularity
Generally hypercellular
Generally hypercellular
Generally hypercellular
Pattern
Cells isolated, in loose aggre-
gates, or in syncytial tissue
fragments; bare nuclei fre-
quent
Cells isolated, in loosely cohe-
sive groups and in syncytial
tissue fragments with various
different architectural patterns,
bare nuclei is not a feature
Cells in syncytial tissue frag-
ments; bare nuclei is not a
feature
Architecture of the
tissue fragments
Small to large tissue fragments
 with or without branching; tra-
becular pattern frequent; fol-
licular pattern ±; extreme
crowding and overlapping of
nuclei; perivascular arrange-
ment of neoplastic cells;
branching network of delicate
capillaries characteristic
Architectural patterns include
papillary with or without
branching, papillary-like, with
or without follicular pattern,
monolayered, three- dimen-
sional clusters; swirls
Syncytial with or without follicular
patterns; slim to broad trabec-
ulae, with or without branch-
ing; crowding and overlapping
of nuclei, intense in carcinomas
Cells
Small, round to cuboidal, poorly
defined cell borders; 6–9 µm
in diameter
Variable size; pleomorphic;
larger than parathyroid cells;
well to poorly defined cell
borders
Larger than parathyroid cells;
variable in size; poorly defined
cell borders
Nucleus
Round; smooth nuclear mem-
branes; coarsely granular chro-
matin; micronucleoli; high N/C
 ratios
Enlarged; demonstrate nuclear
criteria of papillary carcinoma
(powdery to pale granular
chromatin; micro/macronucle-
oli; nuclear grooves and
intranuclear inclusions)
Variably enlarged, smooth
nuclear membranes; fine to
coarsely granular chromatin;
nucleoli ± in adenomas but
present in carcinomas
Cytoplasm
Scant, indiscernible to modest;
clear, granular, occasionally
oxyphilic
Variable
Scant
Psammoma bodies
Absent
May be present
Absent
Background
Clean to proteinaceous material;
fat globules in hyperplasia
No proteinaceous material or fat
globules; macrophages ±
No proteinaceous material or fat
globules
Colloid
Absent
Colloid ±; dense blobs to
stringy
Colloid ±; may be present in fol-
 licular lumens
Immunoprofile
Parathyroid
hormone
+
-
-
Thyroglobulin
-
+
+
Chromogranin
+
-
-

Thyroid Cellular
Follicular
Parathyroid Papillary Thyroid Adenoma/Follicular
Hyperplasia/Adenoma Carcinoma Carcinoma

TABLE 21.3 CYTOPATHOLOGIC FEATURES OF PARATHYROID

HYPERPLASIA, PAPILLARY THYROID CARCINOMA, AND
FOLLICULAR NEOPLASMS

Figure 21.16. Parathyroid adenoma versus follicular neoplasm. A. FNA of a cellular follicular
adenoma. Note the cellularity and large tissue fragments of follicular cells. B. Higher
magnification showing syncytial architecture, with and without a follicular pattern. The cells are
slightly larger than those seen in parathyroid adenoma. The chromatin is granular. This cytologic
presentation is very similar to that of parathyroid adenoma.

PARATHYROID HYPERPLASIA/ADENOMA VERSUS PAPILLARY

THYROID CARCINOMA
Aspirates of parathyroid adenoma have been misinterpreted as papillary thyroid carcinoma (PTC)
(Table 21.3 ). The latter presents a wide spectrum of cytologic features with several
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characteristics that are not seen in parathyroid lesions. Branching tissue fragments of epithelial
cells with a papillary-like pattern alone, which are seen in cytologic specimens of parathyroid
adenomas, must not be considered a diagnostic feature of PTC unless accompanied by nuclear
features (e.g., enlargement, powdery chromatin, micronucleoli, nuclear grooves, and
intranuclear inclusions; Fig. 21.17 ). Positive immunostains for parathyroid hormone will confirm
the parathyroid origin.
Figure 21.17. Parathyroid adenoma versus papillary carcinoma. A. FNA of a papillary thyroid
carcinoma depicting large monolayered tissue fragments. B. Higher magnification showing a
syncytial arrangement with enlarged nuclei, powdery chromatin, micronucleoli, nuclear grooves,
and intranuclear inclusions. C. FNA of a parathyroid adenoma depicting large monolayered tissue
fragments. D. Higher magnification showing the syncytial arrangement of uniform nuclei, lacking
minimal criteria for papillary carcinoma.

PARATHYROID CARCINOMA
The cytopathologic features of parathyroid carcinoma are sparsely documented as individual
case reports.50 , 51 , 52 , 53 , 54 The cytologic features described are extremely variable,
ranging from uniform small cells with regular nuclei to a pleomorphic cell pattern; evenly
dispersed chromatin to coarsely granular; single to multiple macronucleoli; and dispersed
pattern to syncytial tissue fragments. It is a general opinion
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that parathyroid hyperplasia/adenoma and carcinoma are difficult to separate cytologically.
SUMMARY
Fine-needle aspiration biopsy may be helpful in recognizing parathyroid lesions in the following
circumstances: (i) size sufficient for ultrasonic localization, (ii) adequate cytologic material, (iii)
clinical data favoring parathyroid dysfunction, and (iv) familiarity with the cytologic features.

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Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 22 - Ancillary Diagnostic Techniques

22
Ancillary Diagnostic Techniques
Osama Alassi
Sudha R. Kini
Milena Cankovic
Claire W. Michael

Ancillary diagnostic techniques have become an integral part of pathology practice and
are utilized to confirm or support the diagnostic impression made on routinely stained
(H&E or Papanicolaou-stained) preparations or to identify a lesion from several
diagnostic possibilities. These tests range from simple histochemical stains to
immunochemistry, electron microscopy, tissue cultures, flow cytometry, and image
analysis. Some of these tests are sparingly used because of their limited application;
some have only historical value, while technique such as immunochemistry has become
an indispensable diagnostic tool. The quest for more information beyond the diagnosis,
in terms of better understanding of the disease process, improving the diagnostic
abilities, expanding the therapeutic options, and improving prognostication, has led to
the development of more sophisticated tests at molecular level.

APPLICATION OF ANCILLARY TECHNIQUES IN THE

DIAGNOSIS OF THYROID DISEASES
Most of the thyroid lesions are relatively easy to interpret. But as alluded to earlier
(Chapters 7 to 9), the histologic diagnoses of certain thyroid lesions continue to cause
difficulties because the interpretation of the criteria established for various follicular
and Hürthle cell lesions has turned out to be very subjective, at times causing
controversies in the diagnoses and patient management. The controversies hover
around separation of hyperplastic nodular goiter from follicular and Hürthle cell
neoplasms, and follicular adenomas from follicular carcinomas. The diagnostic
difficulties involve both cytopathology and histopathology. Another major problem is
differentiating the follicular variant of papillary carcinoma (FVPC) from follicular
lesions, especially when the FVPC demonstrates nuclear morphology of conventional
papillary carcinoma only in focal areas. The cytologic diagnoses of follicular lesions
rendered are often ambiguous and grouped into one broad category as
"indeterminate." Most of these diagnostic difficulties affect the management decisions
and the extent of surgical procedures. The inability to make a precise diagnosis of a
follicular lesion has led the investigators to seek the assistance of ancillary diagnostic
techniques. It is also hoped that the newer techniques would offer more information
regarding the biologic behavior, including the prognosis of the disease, and help in
patient management. The ancillary diagnostic techniques applicable to thyroid lesions
include histochemical and immunocytohistochemical stains, flow cytometry, and
image analysis. Currently the attention is focused on molecular testing, which has
generated a great deal of interest, with several studies being conducted for possible
routine use in thyroid lesions.1, 2, 3, 4, 5, 6, 7, 8

This chapter will briefly describe the application of these ancillary tests in the
diagnosis of thyroid disease. A detailed discussion is beyond the scope of this chapter.
The interested reader is requested to refer to the vast literature available on the
subject. Also included in this chapter is a section on liquid-based cytology, since many
laboratories currently process the aspirates by using liquid-based preparations in
addition to the conventional methods.

Simple histochemical stains have been to a large extent replaced by immunostains.

Their application in thyroid pathology has been limited and will not be further
discussed.

IMMUNOCHEMISTRY
The technique of detecting tissue antigens by utilizing specific antibodies and tagging
them with chromogens so as to visualize the antigen–antibody reaction, referred to
as immunochemistry, is a major milestone in surgical pathology. That it has
revolutionized the practice of surgical/cytopathology is an understatement. Practice
without the use of immunochemistry is now unimaginable. Hundreds of antibodies are
currently available for any diagnostic workup. Only a few are applicable to thyroid
diseases. The stains can be performed on tissues as well as on fine-needle aspirates,
both on smears and cell blocks.

In immunocytochemistry, as in any other technical procedure, strict qualitative and

quantitative controls are required.9, 10, 11
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Results may vary and greatly depend on proper fixation, processing, and
immunocytochemical methods. Interpretative variability in agreement on the pattern
of staining (e.g., cytoplasmic or nuclear, cutoff level of positivity, and what part of
the tumor) may also affect the test results. Attention must be paid to nonspecific
staining due to diffusion of the antigens as well as coexpression by tissues other than
the intended lesion.

Immunochemical stains for thyroid lesions are useful in following situations:

To differentiate follicular cell-derived tumors from C cell derived neoplasms

such as medullary carcinoma. The use of thyroglobulin and calcitonin are
diagnostic.

To differentiate parathyroid lesions, either in intrathyroidal location or in close

proximity of thyroid, simulating thyroid origin ( e.g., parathyroid hormone).

To distinguish poorly differentiated primary thyroid cancer from a poorly

differentiated metastatic cancer to the thyroid of known extrathyroidal
malignancy.

To confirm metastatic malignant neoplasm of thyroid origin to other body

sites.

To differentiate non-neoplastic lesions from the neoplastic ones; e.g.,

thyroiditis from malignant lymphoma.

As additional prognostic markers in thyroid carcinoma.

Besides the traditional markers such as thyroglobulin, TTF-1, and calcitonin, several
new markers have been studied in order to differentiate non-neoplastic lesions from
neoplastic ones, follicular adenomas from follicular carcinomas, and follicular
carcinomas from papillary carcinomas, as described in the following sections.

Thyroglobulin
The thyroglobulin antibody is specific for follicular cell-derived lesions and is
extremely useful in confirming the thyroid origin of a metastatic lesion, or in
distinguishing a poorly differentiated carcinoma in aspirates of the thyroid from extra-
thyroidal malignancy. The frequency and intensity of thyroglobulin positivity in thyroid
carcinomas depends on the degree of tumor differentiation and the histologic
subtype.10 Generally, poorly differentiated carcinomas contain less thyroglobulin than
better-differentiated tumors. Most anaplastic carcinomas do not express
thyroglobulin.12, 13 Poorly differentiated thyroid carcinoma of the insular type is
usually thyroglobulin positive, although the extent of cellular staining is usually weak
and focal.13

Thyroid Transcription Factor-1

Thyroid transcription factor-1 (TTF-1) is expressed in the thyroid, diencephalon, and
lung. TTF-1 regulates the expression of thyroperoxidase and thyroglobulin genes in the
thyroid. TTF-1 immunoreactivity has been reported in almost all follicular-derived
neoplasms: 96% of papillary, 100% of follicular, 20% of Hürthle cell, 100% of insular,
and 90% of medullary carcinomas16 and about 34 % of anaplastic carcinoma.14, 15, 16

Cytokeratin Subtypes
Cytokeratins are intermediate filaments of different molecular weights, present in
thyroid follicular cells.10 CK1, CK4, CK10, and CK13 are high-molecular-weight
cytokeratins, detected in the stratified squamous epithelium. The normal follicular
cells react positively to low-molecular-weight cytokeratins such as CK7, CK8, CK18,
and CK19, which are present in the simple or glandular epithelium, but not to high-
molecular-weight keratins.10, 17, 18 Broad-spectrum keratin antibodies such as
AE1/AE3 and CAM5.2 react with normal and hyperplastic follicular cells, chronic
thyroiditis, and all tumor types.10 High molecular-weight keratins are positive in 100%
of papillary carcinomas. CK19, a low-molecular-weight keratin, is especially useful in
the diagnosis of papillary carcinoma, including the follicular variant.10, 17, 18, 19, 20,
21, 22, 23, 24, 25, 26 Studies have shown that strong, diffuse staining with CK19 is
characteristic of papillary carcinoma including the follicular variant. It is also found to
be positive in follicular carcinomas. The reactivity is weak and focal in nodular goiter
and other benign lesions.19 Follicular adenoma may have some immunoreactivity,
although it tends to be focal and weaker than in papillary carcinoma.19 Although
reactivity to CK19 is reported to be 92% to 100% for papillary carcinomas by some
investigators,21, 23 others recommend caution in interpretation because some
reactivity is noted in other thyroid lesions as well.24, 25

HBME-1
HBME-1 is one of the most useful markers to differentiate benign thyroid lesions from
carcinoma, either follicular or papillary. This antibody recognizes an unknown epitope
present on the microvilli of mesothelial cells. Most of the studies are done on paraffin-
embedded histologic sections and few are on cell blocks from fine-needle
aspiration.27, 28, 29, 30, 31 Both follicular (up to 40%) and papillary carcinomas (85%
to 100%) show diffuse positive staining. Benign lesions, (nodular goiter and follicular
adenoma) may show focal positive staining (20% to 60%). There are few studies that
questioned the ability of this stain to diagnose follicular carcinoma.28 A negative
reactivity, however doesn't rule out carcinoma.27, 28, 29, 30, 31, 32

Galectin 3
Galectin 3 is a beta galactosil-binding protein involved in regulating cell cycle and
apoptosis, thyroid cell transformation, and tumor progression. Many studies have
reported encouraging results with this marker.33, 34, 35, 36, 37, 38, 39, 40, 41, 42,
43, 44, 45, 46, 47 Others, however, found this marker to be of no or limited use in
differentiating benign from malignant thyroid nodules. Aron et al.33 found galectin 3
to be strongly expressed in papillary carcinomas; however, they also found it to be
expressed in 60% of benign nodules, and therefore its role as a presurgical marker for
differentiating benign from malignant thyroid nodules is limited.32, 36 Mills et al.35
concluded that galectin 3 does not reliably distinguish benign from malignant nodules
and also many thyroid aspirates are of low cellularity and are not suitable for reliable
immunohistochemical stain. Nascimenti et al.44 reported positive reactivity in 59% of
Hürthle cell carcinomas as against 7.1% of adenomas, indicating that galectin 3 may
be used to differentiate adenoma from carcinoma. On the other hand, studies by
Saggiorato et al.36 and Maruta et al.38 indicated that galectin 3 and HBME-1 do not
appear to be useful in differentiating adenoma from carcinoma in oncocytic cell
tumors.

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Carcinoembryonic Agent (CEA)

CEA is generally absent from follicular cell-derived lesions.10, 48, 49 Medullary
carcinoma cells demonstrate positive reactivity to CEA.10 With the availability of
calcitonin as a specific marker for medullary carcinoma, the utility of CEA is limited.

Calcitonin and Neuroendocrine Markers

Calcitonin is a specific marker for medullary carcinoma cells with a high degree of
sensitivity and specificity in both histologic and cytologic samples. Other routinely
used endocrine markers include chromogranin, synaptophysin, and neuron-specific
enolase, which are useful in the workup of medullary carcinoma and other
neuroendocrine tumors of the thyroid.10

Vimentin is often coexpressed with cytokeratins.10 S-100 protein has been reported in
100% of papillary carcinomas, 75% of follicular carcinomas, 37.5% of follicular
adenomas, and 28.5% of papillary hyperplasias.10 Parathyroid hormone is diagnostic in
identifying intraparathyroidal parathyroid lesions.

CD15 (Leu-M1)
CD15 (Leu-M1) is a marker for adenocarcinomas. It is expressed in a significant number
of cases of papillary carcinomas.50 The cellular distribution of reactivity is largely
cytoplasmic, with some cases demonstrating membranous accentuation. The
immunoreactivity of CD15 appears similar to HBME-1, although with less frequency and
strength in papillary carcinomas (30%).

CD57 (Leu-7)
CD57, also known as Leu-7, a marker of NK lymphocytes and glucose transporter-1, is a
facilitative cell-surface transport protein expressed in a wide variety of epithelial
malignancy. Ghali et al.51 reported strong CD57 positivity in 100% of papillary and
follicular carcinomas, whereas focal and weak staining was present in 25% of colloidal
goiters and 21% of follicular adenomas. Other authors, however, have questioned the
specificity of CD57 as a marker for malignancy in thyroid tumors.52, 53, 54

CD44
CD44, also known as Hermes antigen, H-CAM, Pgp-1, and ECM-III, is a glycosylated
cartilage-linked protein associated with extracellular matrix adhesion and lymphocyte
homing.55, 56, 57, 58 Chhieng et al.56 described intense staining in 14 of 16 papillary
carcinomas and only 1 case of nonpapillary carcinoma (Hürthle cell tumor) displayed
focal weak staining.

The preferential expression of CD44 antigen in papillary carcinomas was demonstrated

by Ross et al. in aspiration biopsy specimens57 and by Figge et al.58 in tissue sections.
Positive immunostaining is characterized by cytoplasmic staining.

Some other markers studied for thyroid neoplasms include CA15-3, CA19-9, CA125, and
lectoferrin. CA15-3 is present in 100% of papillary carcinomas while CA19-9 has been
reported in 70% of the papillary carcinomas but absent in follicular carcinomas.59
CA125 has been reported in 40% of papillary carcinomas.60 Lectoferrin is suggested to
be useful in differentiating benign from malignant lesions in cytologic smears.61
Steroid receptors are variably expressed with 21% in papillary carcinomas and none in
Hürthle cell neoplasms. Reactivity to progesterone was described in 33% of papillary
carcinomas, 40% of follicular neoplasms (adenomas and carcinomas), and 53% of
Hürthle cell neoplasms.62

Proliferation Markers (Ki-67, p-27kip1, Bcl-2)

The proliferative activity in tumors is considered an important prognostic indicator.
Many antibodies raised against various antigens present in proliferating cells have been
developed over the years. Antibodies tested include KI-67 (MIB-1), p-27kip1, and Bcl-2,
with variable results.63, 64, 65, 66

Lymphoid Markers
The lymphoid markers used in other areas of pathology are also applicable with the
thyroid, in differentiating Hashimoto's thyroiditis from malignant lymphoma. Flow
cytometry is the technique of choice.

p53
The mutations of the p53 tumor-suppression gene play an important role in carcinomas
of the colon, breast, and urinary bladder. However, its role has been examined in
cases of thyroid carcinoma. In the series reported by Soares et al.,67p53 was absent
from 14 cases of goiter and follicular adenomas and from 12 cases papillary
carcinomas. p53 was present in 20% of follicular carcinomas (predominantly of the
widely invasive type), 16% of poorly differentiated carcinoma, and 67% of
undifferentiated carcinoma. In the series reported by Holm and Nesland,68 6 of 32
(19%) of papillary carcinomas, 5 of 29 (17%) of follicular carcinomas, and 18 of 24 (75%)
of undifferentiated carcinoma were p53 positive; in contrast, the retinoblastoma (Rb)
gene product was present in all thyroid carcinomas.71

A wealth of literature is available on the application of newer markers to thyroid

lesions with variable degrees of success. The reported sensitivities and specificities of
the above-described new markers vary from study to study. To date, none of the
recently introduced makers are considered as diagnostically specific for any particular
thyroid lesion. As a result, many investigators have recommended a panel of three or
more markers to increase the specificity.30, 32, 39, 69, 70, 71, 72

FLOW CYTOMETRY
Flow cytometry measures different cellular parameters73 of cells in suspension, as
they flow in a single file, in a controlled space with application of laser light.
Currently, the computer-interfaced flow cytometers are very sophisticated, capable of
six or more simultaneous measurements on each of the cells in the sample. There are
two important clinical applications: (i) measuring the DNA content of tumor cells to
distinguish diploid from aneuploid tumors and to display tumor cell-cycle distribution,
that is, proliferative activity; and (ii) diagnosis and classification of leukemias and
lymphomas by expression of cellular antigens.63 An excellent review on technical as
well
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as practical aspects of flow cytometry is provided by Melamed73 and is highly
recommended.

Application of Flow Cytometry to Thyroid Lesions

The application of flow cytometry to thyroid lesions is very limited as reported by
several studies.74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88 Tsuchiya et
al.74 found the majority of thyroid carcinomas (92%) to be diploid and 7.4%,
aneuploid. Nodular goiters were found to be aneuploid in 13% by Castro et al.75 and in
10% by Mizukami et al.76 Many thyroid adenomas were found to be aneuploid.77, 78,
79 On the other hand, several investigators found various thyroid malignancies to be
diploid.75, 78, 80 In addition, the presence of aneuploidy does not signify malignant
potential. Cuscik et al.81 found similar proportions of benign and malignant follicular
lesions to be aneuploid. Some studies, however, have shown an improvement in
diagnostic accuracy when combining the use of flow cytometric determination with
fine-needle aspiration biopsy cytology. Sturgis et al.82 and Yamashita et al.83 found
significant association between aneuploidy and death from the disease in cases of
papillary carcinomas. Joensuu et al.84 also detected aneuploidy more frequently in
the recurrent (40%) and in the deceased (33.3%) groups than in the nonrecurrent group
(4.3%).

Schelfhout85 found a high frequency and degree of aneuploidy in undifferentiated

carcinomas, which is in agreement with the very poor survival rate in these patients.
However, the occurrence of highly aneuploid adenomas and (near)-diploid
undifferentiated carcinomas does not point to a direct causal relationship between
DNA-ploidy changes and clinical behavior of these thyroid tumors.

Aneuploidy increases with undifferentiated carcinomas and is more common with

advancing age, which may explain why carcinomas in the elderly tend to have a worse
prognosis. From the diagnostic point of view, poorly differentiated thyroid carcinoma
is easy to diagnose on a morphologic basis, and using DNA ploidy, other than for
academic interest, seems redundant.

As part of a nationwide study of thyroid carcinoma in Iceland, Jonasson and

Hrafnkelsson86 measured DNA ploidy in 424 tumors and found aneuploid populations in
approximately 10% of papillary carcinoma, 24% of follicular carcinoma, 43% of
medullary carcinoma, and 79% of anaplastic carcinomas. They also measured S-phase
fraction, which was somewhat lower in papillary carcinoma than in other histologic
classes. When taking into account known prognostic variables of thyroid carcinoma in a
multivariate analysis, however, neither ploidy status nor S-phase value proved
significant. They concluded that neither DNA ploidy nor S phase fraction were of
independent prognostic significance. In this large study, and other studies, the
controversial results indicate that ploidy has no prognostic significance in thyroid
carcinomas.

Studies on Hürthle cell tumors did not show surprising results either. El-Naggar et
al.80 found that nuclear DNA ploidy alone does not distinguish benign from malignant
Hürthle cell tumors; however, aneuploid Hürthle cell carcinoma had a more
aggressive clinical course and a worse outcome. Therefore, ploidy studies are not
helpful in diagnosis, but may give an insight on clinical outcome.

MORPHOMETRY OR IMAGE ANALYSIS

Static cytometry, or morphometry in contrast to flow cytometry, is performed on a
variety of cell preparations, including cytologic smears, touch imprints, and
cytocentrifuge processed preparations of nuclei disaggregated from tissue paraffin
blocks as well as paraffin tissue sections. The instrument consists of an optical light
microscope, a video camera that captures the image, an image frame buffer, and a
computer system for analysis. The absorption values are represented as a range of
"gray levels" and digitized into a series of tiny squares called "pixels." The system is
known as digital image analysis.

In contrast to flow cytometry, static image analysis does not necessarily require single
cell suspensions, and has the added advantage that direct cell identification is
possible. The major drawback of image analysis is that only a small number of cells are
examined, and the procedure is slow and cumbersome. It can also suffer from an
inadequate selection of cells to examine, with poor randomization and selection of
subgroups by the operator. The quality of DNA histograms obtained in image analysis,
in comparison to flow cytometry, is not as refined. This limitation is secondary to the
small numbers of cells evaluated. Therefore, in contrast to flow cytometric analysis,
examination of the different cell-cycle phases is not possible. In a prospective
comparative study of DNA quantitation by image and flow cytometry performed by
Baur et al.,88 a relatively good correlation between both methods was reported, with
only a few aneuploid peaks missed by image analysis or flow cytometry.

From the cytologic viewpoint, image analysis can also be used to quantify
micromorphometric data on nuclear and cellular details. These include nuclear
volumes, areas, contours, shapes, nuclear:cytoplasmic ratios, and chromatin texture
(see Chapters 7 and 8).
MOLECULAR TECHNIQUES
Milena Cankovic

Cancer is a complex disease that occurs as a result of progressive accumulation of

genetic aberrations and epigenetic modification that enables cancer cells to escape
from normal control mechanisms. Cancer cells may have many acquired genetic
abnormalities such as chromosomal rearrangements, amplifications, deletions, and
point mutations, which result in gain of function or loss of function in affected genes.
Additionally, epigenetic modifications in certain genes act to promote tumor growth.
The genetic alterations in oncogenes generally lead to an increased function of the
protein product, while tumor-suppressor genes are inactivated during carcinogenesis
with apparent loss of function of the protein product.

Molecular genetic testing is well established as an ancillary method in surgical

pathology. It encompasses well-established technologies such as immunohistochemistry
and flow cytometry. In recent years, nucleic acid-based techniques have become an
integral part of surgical pathology practice. The use of genetic biomarkers relevant to
each of the main cancer types is helping to better define individual cancer types,
provide information for more accurate diagnosis and staging, give a measure of risk
assessment, and aid in therapy monitoring.
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Molecular genetic techniques can be divided in two types: (i) hybridization-based
technologies and (ii) amplification-based technologies. The commonly used
hybridization techniques in clinical settings include fluorescent in situ hybridization
(FISH) and Southern blot analysis. Microarray techniques, which are currently used
mainly in research settings, include gene profiling and comparative genomic
hybridization (CGH). Hybridization-based technologies use signal amplification as a
method of detection.

Amplification-based technologies rely on copy number amplification of the gene of

interest. Well established in the clinical arena are techniques such as polymerase
chain reaction (PCR), where isolated genomic DNA is used as a target; and reverse
transcriptase PCR (RT-PCR), which uses RNA as an amplification target. PCR and RT-
PCR products can be detected by a variety of methods such as gel electrophoresis,
capillary electrophoresis, real-time quantitative PCR, and DNA sequencing. Some of
the detection methods include use of fluorescent primers and probes that enhance the
sensitivity of detection.

Thyroid Cancer
Thyroid cancer is the most common malignant tumor of the endocrine system and
accounts for approximately 1% of all newly diagnosed cancer cases.89 When diagnosed
early, thyroid cancer is generally curable. Consequently, accurate differentiation of
malignant from benign thyroid nodules is very important. This is currently
accomplished by cytologic evaluation of thyroid needle aspirated materials. While
cytologic assessment is diagnostic in the majority of patients, approximately 15% to
20% of biopsies have an insufficient amount of tissue for assessment, and an additional
15% to 20% have indeterminate cytologic findings.90 Identification of more aggressive
tumors preoperatively would permit more extensive surgery when indicated. Over the
past few years, a number of laboratories have started using genomic approaches to
address issues in thyroid pathology, such as understanding pathogenesis and improving
diagnosis and prognosis.91 Molecular diagnostic techniques, while still lacking the
sensitivity and specificity needed to make them an effective preoperative screening
tool, nevertheless offer additional help in characterizing difficult to diagnose thyroid
nodules.

Papillary Thyroid Carcinoma

Papillary thyroid carcinoma (PTC) accounts for about 80% of all thyroid malignancies.
With PTC, prognosis is generally dependent on the patient's age and tumor stage at the
time of diagnosis. However, the aggressiveness of individual tumors cannot always be
predicted from the initial clinical features, making it difficult to consistently identify
patients who will die from their disease. While the traditional morphologic
classification of thyroid neoplasms into follicular, papillary, medullary, and anaplastic
subtypes remains valid for most lesions, subclassification, particularly of variant
papillary lesions and lesions showing mixed morphology, can be problematic.

Papillary carcinomas frequently have genetic alterations that lead to the activation of
the mitogen-activated protein kinase (MAPK) signal pathway. These include two
general types of mutations: (i) chromosomal rearrangements of the tyrosine kinase
proto-oncogenes RET (located on chromosome 10q11.2) and NTRK (located at 1q22)92,
93 and (ii) point mutations of the serine-threonine kinase BRAF (located at 7q34)94, 95
and RAS on multiple genes.96 Mutations of one of these genes are found in over 70% of
papillary carcinomas, and they rarely overlap in the same tumor.97 The RET/RAS/BRAF
mitogen-activated protein kinase signal transduction pathway is central to PTC
development via mitogenic signaling to the nucleus and uncontrolled cell division.

BRAF
Point mutations of the BRAF gene are found in about 45% of thyroid papillary
carcinomas.94, 97 Most of them involve nucleotide 1,799 and result in a valine to
glutamate substitution at residue 600 (V600E).95, 98 In addition to papillary
carcinomas, BRAF mutations are found in thyroid anaplastic and poorly differentiated
carcinomas, typically in those tumors that also contain areas of well-differentiated
papillary carcinoma.99, 100, 101

BRAF mutations are highly prevalent in classical papillary carcinomas and in the tall
cell variant, but are rare in the follicular variant.102, 103 Mutant BRAF has been
shown to play a role in tumor dedifferentiation. Mutant BRAF is also likely to be
associated with tumor recurrence and resistance to conventional radioactive therapy.
In some studies, the presence of BRAF mutation has been associated with an older age
of patients, advanced tumor stage at presentation, and tumor recurrence. BRAF
mutations have also been associated with the decreased ability of tumors to trap I-131
and treatment failure of the recurrent disease.104, 105

Most recent efforts in developing targeted therapy for papillary thyroid carcinomas
have focused on BRAF inhibitors. Several new drugs that act as RAF kinase inhibitors
are currently undergoing clinical trials for use as potential targeted therapeutic
agents. The initial results with these agents have been encouraging.106 Assuming that
further studies demonstrate the efficacy of these therapeutic agents, and provided
that a link between BRAF V600E and clinical outcome does exist, BRAF mutational
analysis may become a routine part of the evaluation of papillary thyroid
carcinomas.107

RET/PTC
The RET tyrosine kinase is involved in rearrangements with a number of different
partner genes in PTC.92, 108, 109 At least 11 types of RET/PTC have been reported to
date.93, 110 The two most common rearrangement types are RET/PTC1 and
RET/PTC3, which account for the majority of all rearrangements found in papillary
carcinomas. RET/PTC1 is formed by fusion of RET with the H4 (D10S170) gene, and
RET/PTC3 by fusion of RET with the NCOA4 (ELE1) gene.111, 112 The RET/PTC fusion
products act as oncoproteins that activate the RAS-RAF-MAPK cascade.113, 115

NTRK
A much smaller subset of papillary thyroid carcinomas shows rearrangements in the
NTRK1 gene,116 and the percentage of tumors that harbor NTRK1 rearrangements does
not seem to be increased in Chernobyl-associated tumors.117

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RAS
The RAS genes (H-RAS, K-RAS, and N-RAS) encode highly related G-proteins that are
located at the inner surface of the cell membrane and play a central role in the
intracellular transduction of signals arising from tyrosine kinase and G-protein-coupled
cell-surface receptors.

In many human neoplasms, point mutations occur in the discrete domains of the RAS
gene, which result in either an increased affinity for GTP or inactivation of the
autocatalytic GTPase function. As a result, the downstream signaling pathways become
permanently activated.

In papillary carcinomas, activating RAS mutations are relatively infrequent, being

detected in 10% to 15% of these tumors.93, 118 Papillary carcinomas with RAS
mutations almost always have the follicular variant histology. This mutation also
correlates with significantly less prominent nuclear features, more frequent
encapsulation, and a low rate of lymph node metastases.103, 119 Some studies have
reported the association between RAS mutations and more aggressive behavior of
papillary carcinoma and a higher frequency of distant metastases.120, 121

Morphologic Variants of Papillary Thyroid Carcinoma

Between 3% and 25% of cases of the follicular variant of PTC contain RET/PTC1 or
RET/PTC3 mutations,119, 122 and a larger group of 20% to 43% of cases harbors RAS
mutations.119, 123 The tall cell variant of PTC typically harbors the RET/PTC3 variant,
which has been demonstrated in 100% of cases.122

BRAF mutations have been detected in about 40% of cases of the oncocytic variant of
PTC, and in about 75% of cases of Warthin-like PTC.102

Follicular Thyroid Carcinoma

Follicular thyroid carcinoma (FTC), the second most common thyroid malignancy,
accounts for 5% to 15% of malignant thyroid neoplasms, depending on the criteria used
for diagnosis. FTC is an aneuploid tumor with a high loss of heterozygosity (LOH) and
high frequency of RAS mutations and PAX8-PPARγ rearrangement.124

PAX8-PPARγ
PAX8-PPARγ fusion gene rearrangement results from t(2;3)(q13;p25) translocation.
The PAX8 gene at 2q13 encodes a transcription factor that is essential for development
of the thyroid follicular epithelial cell lineage,125 and the PPARγ1gene at 3p25
encodes a ligand-dependent nuclear transcription factor that is a member of the
perioxysome proliferator-activator receptor family.126

Functionally, the PAX8-PPARγ1 fusion protein is a dominant negative suppressor of

wild-type PPARγ1 function,127 but the mechanism by which suppression of PPARγ
promotes follicular carcinoma formation is not well understood.

RAS
In follicular thyroid carcinoma, RAS mutations are found in 40% to 50% of tumors,128,
129, 130 and they may also correlate with tumor dedifferentiation and a less favorable
prognosis.120

Molecular Testing in Thyroid Cancer

With the completion of the Human Genome Project and recent advances in
technology, it is now possible to examine a person's entire genome in order to provide
individualized risk predictions and treatment decisions. With the advances in
molecular diagnostics, we are now in a position to characterize health and disease
states by molecular fingerprinting and to develop meaningful stratification for patient
populations to elucidate mechanistic pathways based on genome-wide data, and to
develop new preventive, diagnostic, and therapeutic strategies that will completely
shift patient care from reactive to proactive. Several tasks lie ahead in molecular
technologies. First, correlation of genetic testing with diseases needs to be validated.
Most of the molecular signatures are based on retrospective studies, and additional
prospective studies are needed to fully understand the connection between molecular
markers and disease. Second, consideration should be given to whether a new marker
meets the criteria for being a valuable and practical clinical tool. To have utility in
general usage, a biomarker should be detected relatively easily, reproducibly, and
reliably, and should have value in guiding patient treatment decisions.

Real-Time Quantitative RT-PCR

There are several issues to consider, such as RNA quality issues, clinicopathologic
correlates, cellular heterogeneity even in small tissue samples, and microarray data
validation by other available molecular methods.

Validation of select genes by quantitative RT-PCR is often performed to validate

microarray data. Giordano et al.131 studied PPARG and four additional genes
(ANGPTL4, AQP7, ENO3, and PGF) with increased expression in the PPFP(+) follicular
carcinomas. Overall, their study demonstrated that the RT-PCR results validated the
microarray data.

Microarrays
Application of microarray technology to analysis of tumor biology has provided new
opportunities to study and understand cancer biology, including the identification of
new genes involved in carcinogenesis. Based on their individual gene expression
profiles, tumors can be classified as high risk or low risk.

Many studies have examined the potential of molecular profiling for thyroid cancer.
While none of the studies have resulted in a clinically available and validated
diagnostic assay, the results are generally encouraging.

A cluster analysis study of a group of 62 samples was performed to determine whether

molecular profiling can discriminate between benign and malignant thyroid
nodules.132 The study group included 11 papillary thyroid carcinomas, 13 of the
follicular variant of papillary thyroid carcinomas, 9 follicular thyroid carcinomas, and
26 benign tumors. Hierarchical cluster analysis of oligonucleotide microarray data
reliably distinguished between benign and malignant follicular thyroid tumors, as well
as benign thyroid nodules and papillary thyroid carcinomas. Additionally, the study
demonstrated that molecular profiling of thyroid nodules can be used to classify
tumors as high risk or low risk, indicating that microarray-based expression profile
analysis is a powerful tool
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that can distinguish benign from malignant thyroid tumors, as well as risk-stratify
carcinomas into high and low risk.

Using commercially available oligonucleotide microarrays, a gene expression data set

was generated that corresponded to the common types of benign and malignant
thyroid tumors.133 The investigators applied various clustering methods to the study
set and were able to show that the clustering studies provided molecular classification
that recapitulated the overall morphologic classification of thyroid tumors.
Examination of the papillary thyroid carcinoma cohort revealed a molecular
classification that was a reflection of both tumor morphology and an underlying
activating mutation. They found a large degree of heterogeneity within the papillary
thyroid carcinoma cohort, consistent with the numerous morphologic variants
associated with papillary thyroid carcinoma and with several different activating
mutations (BRAF, RET/PTC, and RAS). Examination of the papillary thyroid carcinoma
cohort revealed a molecular classification that was a reflection of tumor morphology
as well as underlying activation mutation.

The study further showed that the clustering divided the study cohort into tumors with
papillary architecture and follicular architecture. Additionally, papillary thyroid
carcinoma follicular variants formed two subclusters within the follicular-patterned
tumors, and these tumors had a predominance of RAS mutations.

Follicular thyroid carcinoma (FTC) with the PAX8-PPARγ translocation formed a

distinct subcluster within the follicular patterned lesions.131 Other studies confirmed
the finding that these tumors display a characteristic gene expression profile, where
FTC with PAX8-PPARγ translocation has a gene expression profile that is a function of
the activity of the fusion protein PPFP.134 These studies imply the role of the PPFP
fusion protein in the pathogenesis of FTC with PAX8-PPARγ and suggest that this fusion
protein might present an important therapeutic target.

In terms of using gene expression profiling in the clinical laboratory, it has to be kept
in mind that microarray data contains biological information imbedded in a lot of
technical and biological noise. Methods of experimental design and data analysis must
be carefully selected in order to reliably identify biological effects of interest while at
the same time removing extra noise. One drawback of moving this technology into the
clinical arena is the fact that only fresh and frozen tissues can be used for analysis.
Additionally, since expression profiling of a large numbers of genes gets evaluated, this
necessitates a large amount of isolated RNA. Both of these requirements make the
microarray technology unsuitable for analysis of archival specimens, as well as fine-
needle biopsies, where only a small amount of tissue is available for analysis.

Comparative Genomic Hybridization (CGH)

Comparative genomic hybridization (CGH) is a technique for analyzing genomic
information by focusing on the differences in DNA copy numbers between tumor and
normal tissue.

MicroRNA Profiling
The discovery of microRNAs (miRNAs) and the growing appreciation of the importance
of miRNAs in the regulation of gene expression are driving increasing interest in miRNA
expression profiling. MicroRNA profiling represents a complimentary approach to
messenger RNA profiling.

MicroRNAs are small RNA molecules that are thought to function as negative regulators
of gene expression.135, 136 Early studies have suggested prominent roles for these
genetically encoded regulatory molecules in a variety of normal biological processes
and diseases, particularly cancer.137, 138, 139, 140 MicroRNA profiling represents a
complimentary approach to gene expression profiling using messenger RNA. Microarray
experiments studying miRNA expression changes in thyroid cancers hold an interesting
promise.141, 142, 143, 144 Studies have shown that these small-molecular-weight
RNAs play a regulatory role in both papillary and follicular thyroid carcinoma.

Methylation Profiles in Thyroid Cancer

DNA methylation is another potential marker for thyroid cancer, and real-time
quantitative methylation-specific PCR techniques on blood samples preoperatively
have been found to differentiate benign from malignant lesions. When five genes were
analyzed, this method of detecting aberrant DNA methylation had a preoperative
sensitivity for detecting thyroid cancer of 68%, specificity of 95%, accuracy of 77%,
positive predictive value of 96%, and negative predictive value of 60%.145

SUMMARY
Of the several ancillary diagnostic techniques utilized in the practice of pathology,
only a few are of diagnostic value in thyroid. Immunochemistry is indispensable in
confirming thyroid follicular cell origin. Similarly, calcitonin is a very specific marker
for medullary thyroid carcinoma. Of the large number of newly introduced markers
aimed at differentiating follicular lesions, none has shown the diagnostic sensitivity
and specificity to be used in the routine practice. Flow cytometry has only a limited
application, especially in the diagnosis of lymphoproliferative disorders. DNA
measurements have not been helpful in differentiating benign from malignant thyroid
lesions. Molecular diagnostics have shown a lot of promise. Currently, molecular
testing is performed in research settings with limited practical application.

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APPENDIX TO CHAPTER 22
Liquid-Based Cytopathology for Thyroid
Aspirates
Claire W. Michael

The liquid-based preparation (LBP) technique for cytopathology samples has been
gaining popularity in the last decade, particularly for cervical specimens and selected
non-gynecologic specimens. However, its utilization for fine-needle aspirations (FNA)
has been controversial, particularly thyroid FNA, where architecture and colloid play a
significant role in diagnostic accuracy. Despite that concern, LBP assumed a significant
role in our cytopathology practice, especially in small private practices, community
hospitals, or large reference laboratories that sought an opportunity to improve the
specimen quality and preservation without investing in the resources needed for on-
site adequacy assessment or technical support. To date, two of the preparations that
received FDA approval, ThinPrep and SurePath, are widely used for non-gynecologic
specimens. While both represent LBP, they are completely different in methodology.
ThinPrep harvests the cells through filtration while SurePath relies on sedimentation of
cells at one times gravity (1 g) on a lysine-coated slide. For more detailed comparison
of the two procedures, please refer to Michael et al.1 The author has more extensive
experience with ThinPrep, and with the exception of few publications1, 2 all the
literature has focused on ThinPrep for FNA. Therefore, while the following discussion
will focus on ThinPrep, SurePath will be cited whenever possible for completion of the
discussion.

ADVANTAGES OF LIQUID-BASED PREPARATIONS (LBP)

 The slides are easier to examine due to the elimination of many of the
obscuring elements such as blood, mucous and obscuring inflammation.

The immediate wet fixation allows for optimal cellular preservation and
eliminates air-drying artifacts.

Lack of manual spreading results in elimination of crushing artifact that may

obscure examination.

During the cell- transfer stage, the cells are evenly deposited on the slide
within a defined circular area, which allows more efficient screening.

Decrease in number of unsatisfactory specimens.3 This is a result of the

elimination of obscuring elements and the cellular concentration achieved by
filtration in the case of ThinPrep and cell enrichment by SurePath.

Reduced number of slides needed to prepare per specimen.4, 5

METHODOLOGY
ThinPrep (Cytyc Corporation, Boxborough, MA)6, 7
The needle is rinsed in CytoLyt solution (20% buffered methanol-based solution), which
acts as the collecting medium. At the laboratory, the specimen in centrifuged, the
supernatant is discarded, and 3 to 5 drops of the cell pellet are transferred to
PreservCyt (50% methanol-based fixative, Cytyc Corporation, Boxborough, MA) and
should be fixed for at least 20 minutes. If the pellet is small, it can be transferred in
its entirety to PreservCyt. The vial is then introduced into the Cytyc 2000 in which
processing is done.

Processing
Cell Dispersion
A cylinder with attached TransCyt filter is inserted into the vial and rotated to create
currents within the fluid that disperse mucuos and cell debris.

Cell Collection
A gentle vacuum is created within the filter, thus collecting the cells on its exterior
surface. The processor software monitors the rate of cell flow and collection.
Collection stops when the filter saturation reaches a preset density set by the machine
software, or in scantly cellular specimens, when the specimen is depleted.

Cell Transfer
The TransCyt filter is inverted and pressed against the slide. A slight positive pressure
through the cylinder ensures optimal transfer of cells and adherence within a defined
circular area in a thin layer.

Slide Staining
The slides are then dropped in 95% ethanol and stained by the Papanicolaou stain
based on the laboratory protocol of staining, whether automated or manual. The slides
can also be spray fixed and stained at a later time. While in the United States
Papanicolaou staining for ThinPrep is the standard of practice, in Europe, May-
Grünwald-Giemsa staining has been
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practiced with success on air dried ThinPrep, where the 95% ethanol fixation step is
bypassed.8

ThinPrep-Related Issues7
Filtration induces concentration of the sample, allowing easier identification of
the different components. However, this also alters the ratio of these
components in relation to one another (e.g., the ratio of colloid to follicular
cells cannot be relied on to favor hyperplasia versus neoplasia).

Blood undergoes hemolysis during processing, leaving behind scattered fibrin

fragments and inflammatory cells in the background. Few red blood cells
(RBCs) may still be detected in significantly bloody samples.

Small cells such as lymphocytes and neutrophils may be considerably reduced

in number. Remaining lymphocytes may migrate towards the periphery of the
ring.

Colloid is altered in both quality and quantity. Watery colloid does not
 withstand processing well and becomes difficult to recognize or distinguish
from fibrin. Hard colloid tends to survive processing better and presents as
small droplets.

There is a uniform decrease in cellular size when compared to conventional

smears as a result of wet fixation in methanol.

Large and complex cellular fragments such as papillae tend to break into
smaller and simpler groups.

Nuclear features are well preserved; however, intranuclear pseudo-inclusions

are markedly reduced in number.

The nucleoli appear more prominent than their counterpart on conventional

smears

The cytoplasm acquires a denser quality due to the wet fixation.

Filters may get clogged by highly inflamed or bloody specimens resulting in an

empty prep in the center with a peripheral ring of red blood cells or
neutrophils, the "halo effect."

SurePath (TriPath Imaging, Burlington, NC)9

Specimen Concentration
Mix the specimen well and remove any large visible blood clots or mucous. Transfer to
50-mL centrifuge tube, centrifuge for 10 minutes at 600 g, and decant supernatant.

Specimen Fixation
Add 30 mL CytoRich Red and centrifuge for 10 minutes at 600 g, then decant
supernatant and vortex.

Specimen Washing
In a 12-mL tube containing 10 mL water, transfer the entire pellet if not visible or
small. Otherwise, add a representative sample (1 to 5 drops) and centrifuge the tube
for 5 minutes at 600g. Decant the supernatant and vortex to homogenize the specimen
Processing and Staining
Load the labeled 12-mL tubes onto the PrepStain. The cells are allowed to settle on
the slide at 1g and stained by Papanicolaou stain within the same cycle.

TriPath-Related Issues1
Blood, inflammatory cells, and colloid are usually adequately represented regardless of
their original amount.

Cellular preservation is excellent and with minimal shrinkage. Cells will ball up
as a result of liquid fixation and may appear smaller.

Large complex fragments retain their complex architecture and assume a

three-dimensional configuration that may be pronounced at times and
interfere with examination of such clusters. In those cases, smaller groups with
more spread-out cells may be easier to evaluate.

Cells and clusters are in different planes of focus. This is a result of

sedimentation with gravity without applied pressure.

Specimen Adequacy
Two issues are worthy of consideration when discussing thyroid aspirates in the setting
of liquid base cytology. The first is what constitutes an adequate sample? The second
is how many preps are needed to achieve adequacy? Recently we evaluated these two
questions in our institution. In one study we reviewed 218 thyroid aspirates prepared
by one ThinPrep each; all had a surgical pathology correlation. The number of cells
and clusters were counted, and each case was given a definitive diagnosis based on a
standardized classification developed by the group and modified from that of the
Papanicolaou Society Guidelines.11 Based on statistical analysis of the data, samples
with 180 cells or less had an agreement rate of 50% or less. The agreement rate
increased to 80% when the cellularity was 180 to 320. Therefore we now require a
minimum of 200 cells to establish a definitive diagnosis. While most adequacy
guidelines on conventional smears are based on a minimum number of clusters, we
were surprised that the total number of clusters per case/prep did not play an
independent role in explaining diagnostic agreement. However, we found that the
number of cells per cluster had a significant correlation and that a 25-cell increase in
average cells per cluster increased the odds of diagnostic agreement by 65%.12

Knowing that the ThinPrep is a random representative sample, and that frequently
additional material is left behind after the first ThinPrep is prepared, we wanted to
test whether additional preps possibly containing additional clusters would improve
diagnostic accuracy. We reviewed 100 consecutive aspirates prepared by two
ThinPreps. Each ThinPrep was reviewed separately and then together. We found that
in 97 of 100 cases the two preps were similar. In only three scantly cellular cases, the
second prep contained a few atypical cells that were lacking in the first prep;
however, they were not sufficient to achieve adequacy or establish a definitive
diagnosis.5 In our laboratory we choose to do ThinPrep in cases that we do not provide
immediate assessment for. In such cases we vortex the CytoLyt vial well and divide the
sample in two 50- mL tubes. One tube is used to prepare the ThinPrep and the other
for a cell block. In another study,4 where four ThinPreps were initially prepared for
each case; the authors concluded that 1.4 preps were adequate to achieve diagnostic
accuracy.

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Benign Cystic Lesions

Simple Thyroid Cysts
The aspirate usually consists of variable number of foamy histiocytes in a clear
background. Hemorrhagic cysts may present with numerous hemosiderin-laden
macrophages, and the background may be surprisingly clear except for scattered fibrin
fragments and few red blood cells either trapped within the fibrin or singly scattered.

Thyroglossal Duct Cyst

These aspirates are usually clear and contain few columnar cells and few anucleated
squamous cells. Ciliated cells are easily recognized when present.

Autoimmune Thyroiditis
Hashimoto's Thyroiditis-HT (Chronic Lymphocytic
Thyroiditis)
Chronic lymphocytic thyroiditis (CLT) and nonspecific lymphocytic thyroiditis (NSLT)
were the lesions mostly reported to be missed by ThinPrep. Cochand-Priolellet et al.8
reported missing 2 cases, diagnosing them as suspicious for malignancy; while Frost et
al.4 reported missing 10 out of 26 cases by ThinPrep compared to only 2 out of 26 by
direct smears. Meanwhile, 9 of the 85 adenomatoid nodules in their series were
misdiagnosed as CLT. Tulecke et al.10 reported predicting the correct diagnosis in 3 of
19 cases with CLT on follow-up resection (2 HT and 1 NSLT), while falsely diagnosing
HT/ NSLT in 11 cases. Malle et al.3 correctly classified 3 out of 9 cases and
misdiagnosed the remaining 6 cases as follicular/Hürthle neoplasms. It has also been
our experience that CLT could be misclassified or not recognized, particularly if the
reviewer is not familiar with the ThinPrep presentation.

ThinPrep Features (Fig. 22.1)

Figure 22.1. Chronic lymphocytic thyroiditis. A. Low power showing singly
scattered lymphocytes in the background, mostly away from the epithelial
clusters. Some lymphocytes appear as aggregates when entrapped by fibrin. B. A
tight cluster of Hürthle cells with infiltrated lymphocytes. The cells are tightly
cohesive with overcrowded pleomorphic nuclei, coarse chromatin, and prominent
nucleoli.C. Aggregated polymorphous population of lymphocytes admixed with
plasmacytoid cells (ThinPrep).

As the blood undergoes hemolysis during processing, some of the white blood
cells (WBCs) left behind appear as scattered cells in the background or are
entrapped within the fibrin, giving the false impression that inflammatory cells
are increased. However, upon closer examination it is clear that those cells are
not associated with the epithelial clusters and are composed of a mixture of
lymphocytes and
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neutrophils. Few red blood cells may be retained if the aspirate was bloody,
giving a clue to the cells origin.

By its nature, the ThinPrep was designed to filter obscuring inflammatory cells.
Consequently, it had been our experience that in the majority of CLT,
lymphocytes are markedly decreased when compared with conventional
smears. When present, the lymphocytes tend to pool away from the epithelial
clusters or migrate to the periphery of the ring, especially when present as
single cells.

Background giant cells are easily detected.

At low magnification, most cases present with scattered small clusters of

follicular/Hürthle cells, some of which may be infiltrated by lymphocytes.
The background may vary widely from one case to another. Rarely, there would
be numerous lymphocytes but most commonly the lymphocytic component is
scant to moderate. The lymphocytes tend to pool together away from the
clusters or get entrapped within the fibrin fragments.
SurePath Features (Fig. 22.2)

Figure 22.2. Hashimoto's thyroiditis showing sheets of Hürthle cells surrounded

by numerous singly scattered lymphocytes. Notice the three-dimensional
appearance and presence of cellular components at different planes of focus,
medium power (SurePath).

Lymphocytes are usually adequately represented throughout the Prep making them
easier to recognize. However, similar to ThinPrep, inflammatory cells from hemolyzed
blood could also be present and should be distinguished from the polymorphous
lymphocytic population characteristic of CLT.

The diagnostic pitfalls and clues for chronic lymphocytic thyroiditis are listed in Table
22.1.

TABLE 22.1 DIAGNOSTIC PITFALLS AND CLUES FOR

HASHIMOTO'S THYROIDITIS (HT)/CHRONIC
LYMPHOCYTIC THYROIDITIS

Diagnostic Pitfalls Diagnostic Clues

Subtle lymphocytic infiltrate Look for lymphocytes infiltrating or close

to epithelial clusters; lymphocytes may
pool as small aggregates away from
clusters
Look for lymphocytes towards the
periphery of the ring

Bare follicular nuclei or white Polymorphous population of lymphocytes

blood cells and plasma cells
from hemolyzed blood can
be confused
with lymphocytes

Follicular/Hürthle cells are Hürthle cells in HT appear as small,

increased in cohesive, syncytial aggregates
number and can be
mistaken for nodular
hyperplasia or neoplasia

Cells are enlarged and may exhibit

cytologic atypia

Chromatin pattern is not as crisp as that of

 Hürthle cell neoplasms and single
cells are rare

Nodular Colloid Goiter (NCG)

In a comparison between conventional smears (CS) and ThinPrep of 41 surgical bench
aspirates, Biscotti et al.13 accurately diagnosed 19 of 25 goiters by ThinPrep versus 20
of 25 cases by CS. On the other hand, Frost et al.,4 in their study of split samples,
reported missing 10 of 85 of their goiter cases, contributing to half of their discrepant
cases. Low cellularity and cystic degeneration accounted for these errors. Almost all
studies described colloid as markedly diminished and appearing as small dense droplets
rather than a diffuse layer or film. Tulecke et al.10 described two forms of colloid, the
dense droplets and tissue-paper-like material corresponding to abundant watery
colloid on correlating histology. It is worth noting that in their 37 goiters on surgical
follow-up, 2 were accurately diagnosed by cytology as goiters, 11 diagnosed as benign,
24 cases were considered indeterminate, and 4 were diagnosed as follicular/Hürthle
cell neoplasm on ThinPrep. Of the 23 cases they diagnosed as benign by ThinPrep, only
11 were goiters, and 12 were follicular adenomas on surgical follow-up. While I agree
that some of the watery colloid may appear as thin tissue-like sheets, I found it very
difficult to reliably distinguish that type of colloid from fibrin fragments in many
cases.

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ThinPrep Features (Fig. 22.3)

Figure 22.3. Multinodular goiter. A. Cluster of follicular cells with uniform,
orderly arranged cells adjacent to small droplets of dense colloid. B. Thin colloid
appearing as a thin folded tissue paper with semi-translucent quality. This
appearance can be difficult to distinguish from fibrin produced by hemolyzed
blood. C. Fibrin fragments seen in a ThinPrep from cerebrospinal fluid. Notice the
similarity to watery colloid (medium power). D. Transmission gel may mimic
colloid. However, it has a purple color and more transparent quality (ThinPrep).

Small sheets of follicular/Hürthle cells in a honeycomb arrangement. The

cells have well-defined cell borders, no crowding or overlapping of cells, and
the nuclei are equally spaced.
 Large fragments and spherules are less frequent.

Some follicular cells exhibit degenerative changes.

Scattered histiocytes, some may contain hemosiderin.

Small droplets of thick colloid.

Thin paper-like sheets with homogeneous transparent quality (not commonly

found).

SurePath Features (Fig. 22.4)

The honeycomb arrangement is easily visualized despite the three-dimensional

appearance. Colloid is easier to identify and adequately represented. Thin colloid
acquires a denser quality than that seen on CS.
 Figure 22.4. Multinodular goiter showing several clusters of follicular cells and
easily identifiable colloid fragments presented in a range of sizes (SurePath).

The honeycomb arrangement is easily visualized despite the three-dimensional

appearance. Colloid is easier to identify and adequately represented. Thin colloid
acquires a denser quality than that seen on CS.

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The diagnostic pitfalls and clues for nodular colloid goiter are listed in Table 22.2.

TABLE 22.2 DIAGNOSTIC PITFALLS AND CLUES FOR

NODULAR COLLOID GOITER (NCG)

Diagnostic Pitfalls Diagnostic Clues

Colloid is markedly reduced Appears as small dense cyanophilic

droplets; sometimes thick droplets acquire
two-tone staining

Ultrasound transmission gel Gel has a purplish hue and has a more
mimic colloid transparent texture

Cellularity of follicular cells Watch out! Ratio of colloid to cells is not

may be exaggerated accurate and may be reversed
Diagnosis should depend on the
organization of follicular cells within the
aggre-
gates (i.e., honeycomb arrangement
rather than syncytial sheets)
Follicular Cell Neoplasms (FCN)
The high cellularity, disturbed architecture, and numerous microfollicles are
characteristic of these lesions. Caution should be exercised when reviewing the
literature regarding follicular/Hürthle cell lesions, since the reporting criteria varied
among the studies. Some studies included macrofollicular adenomas with benign
lesions,8 while others included in this differential all follicular/Hürthle cell rich
lesions mainly including floridly hyperplastic nodular goiters, adenomas, and
carcinomas. In our institution we diagnose FCN when we are considering adenoma or
carcinoma. Generally the rates of false negative in this category by ThinPrep is less
than that of CS,3 and in all reported studies, neoplastic lesions, including follicular
adenomas (FCA) and carcinomas (FCca), were correctly classified as neoplastic or
suspicious for malignancy.4, 10, 13 However, there were some false-positive cases in
several studies, where multinodular goiters were erroneously classified as
hypercellular follicular lesions/neoplasia. In the study by Tulecke et al.,10 almost 60%
of the nodular goiters were misclassified as indeterminate or neoplastic. It has also
been our experience that this error is particularly prevalent among new reviewers who
are not very familiar with changes unique to ThinPrep and that it declines with
experience.

ThinPrep Features (Figs. 22.5 and 22.6)

Figure 22.5. Follicular cell adenoma. A. Cellular prep containing numerous
variably sized clusters of follicular cells, numerous scattered microfollicles and
some single cells, medium power. B. Syncytium of follicular cells showing
irregularly spaced cells with no distinct cell borders. The nuclei are relatively
larger and hyperchromatic when compared with those seen in Figure 22.3A. C.
Several microfollicles appearing as an aggregate with irregular borders or singly
scattered. Small droplets of inspissated colloid may sometimes be seen within the
microfollicles (ThinPrep).
Figure 22.6. Follicular cell carcinoma showing small scattered microfollicles and
single cells. The nuclei are large with coarse chromatin and prominent nucleoli
(ThinPrep).

Cellular preps with small syncytial sheets, exhibiting loss of orderly

arrangement, crowding of cells, irregular spacing of nuclei, and lack of well-
defined cell borders.

Numerous microfollicles (a small flower-like arrangement of follicular cells

with or without inspissated colloid) and small clusters with scalloped contours.

Variable number of colloid droplets but usually few and small in microfollicular
neoplasms.
 Follicular carcinomas may show more nuclear enlargement, nuclear
pleomorphism, predominantly microfollicular pattern, and numerous singly
scattered cells. The cells may appear relatively more crowded.

SurePath Features (Fig. 22.7)

Figure 22.7. Follicular cell adenoma. A. Cellular prep containing numerous

sheets, clusters, and microfollicles appearing in several focal planes and three-
dimensional configuration.
 Figure 22.7. B. Microfollicles with inspissated colloid and discohesive follicular
cells with enlarged nuclei and small nucleoli (SurePath). (Courtesy of Paul
Wakely, MD, Ohio State University, Columbus.)

Generally, the cytologic presentation is very similar to that of ThinPrep. The SurePath
is highly cellular and is comprised of a mixture of small sheets, clusters, and some
microfollicles in a background of numerous singly scattered and evenly distributed
cells. Fragments of very dense colloid may also be seen.

The diagnostic pitfalls and clues for follicular cell neoplasm are listed in Table 22.3.
 TABLE 22.3 DIAGNOSTIC PITFALLS AND CLUES FOR
FOLLICULAR CELL NEOPLASM (FCN)

Diagnostic Pitfalls Diagnostic Clues

Exaggerated cellularity and Diagnosis is based on organization of

reduced colloid may cells within sheets or aggregates
result in mistaking NCG for (i.e., honeycomb versus syncytium)
FCN Follicular clusters have irregular or
scalloped contours rather than the
smooth surface seen in intact follicles
Look for microfollicles singly scattered or
within the cellular clusters

Microfollicular pattern tend to Numerous microfollicles that do not

be overestimated (3) exceed 10-15 cells are not a charac-
teristic feature of NCG
When present in FCN colloid droplets are
usually smaller and fewer
against a highly cellular background.

Papillary carcinoma Although the syncytial arrangement may

misclassified as FCN be a common feature and micro
follicles may be seen in the follicular
variant, the chromatin is almost
always coarser in FCN

Hürthle Cell Neoplasms (HCN)

This category includes Hürthle cell adenoma (HCA) and carcinoma (HCca). The
numbers of these cases are very few in ThinPrep reported literature, and most studies
reported no problems with correctly recognizing them. Cochand-Priollet et al.8
reported that 50% (2 of 4 cases) were missed by ThinPrep. Similar to FCN, false-
negative cases are not common for these neoplasms in our experience; however, false-
positive cases do occur. As with CS, aspirates rich in Hürthle cells from hyperplastic
nodules within Hashimoto's thyroiditis or extensive Hürthle cell change in NCG could
be misdiagnosed as HCN.3, 8 FCA and papillary carcinomas with considerable Hürthle
cell change may be misclassified as HCN.

ThinPrep Features (Figs. 22.8 and 22.9)

Figure 22.8. Hürthle cell adenoma showing a predominantly discohesive and

monotonous cell population and occasional microfollicle. The cells are enlarged
and contain abundant granular cytoplasm. Despite the enlarged nuclei, the N/C
ratio remains relatively low (ThinPrep).

Figure 22.9. Hürthle cell carcinoma showing a predominantly single cell

population with uniform size. The nuclei are enlarged and the nucleoli are very
prominent (ThinPrep).

Cellular Preps consisting predominantly of small clusters or single cells. Few

microfollicles may be detected.

The cells are markedly enlarged and monomorphic in size and appearance
 within the same sample.

The cells are widely spaced by their abundant granular or slightly vacuolated
cytoplasm.

The nuclei are large with prominent frequently cherry red nucleoli. They are
slightly eccentric and the nuclear to cytoplasmic ratio (N/C) is usually low,
particularly in adenomas.

HCca may present with larger fragments and prominent nuclear atypia such as
coarse chromatin and irregular or multiple nucleoli.

SurePath Features (Fig. 22.10)

Figure 22.10. Hürthle cell adenoma showing small clusters of monotonously

 enlarged cell with abundant cytoplasm, large nucleoli, and prominent nucleoli
(SurePath). (Courtesy of Paul Wakely, MD, Ohio State University, Columbus.)

The features on SurePath are very similar to those described above. The extent of
discohesion may, however, be less prominent.

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The diagnostic pitfalls and clues for Hürthle cell neoplasm are listed in Table 22.4.

TABLE 22.4 DIAGNOSTIC PITFALLS AND CLUES FOR

HÃœRTHLE CELL NEOPLASM (HCN)

Diagnostic Pitfalls Diagnostic Clues

Hyperplastic Hürthle cell Clusters are tightly cohesive and

nodules within HT may commonly infiltrated by lymphocytes
dominate the aspirate and Cytologically atypical with nuclear
mimic HCN variation and pleomorphism
Nuclei centrally located and frequently
show degenerative changes

Papillary carcinoma with Nuclear grooves and powdery chromatin

Hürthle cell change lack are present
nuclear crowding and
overlap

FCN with considerable FCN presents predominantly as

Hürthle cell change exhibits microfollicles in contrast to the sheets or
many overlapping features single cells seen in HCN
 Hyperplastic NCG with Sheets of Hürthle cells admixed with
Hürthle cell change sheets of follicular cells, colloid
droplets, and histiocytes
Cells are orderly arranged in a honeycomb
pattern with centrally located
nuclei and small nucleoli
The granular cytoplasm is far less
abundant than in FCN

Granular cell tumor (GCT) in Be aware that the loose background

the vicinity of thyroid granules commonly seen in the CS
gland may mimic HCN15 are absent in ThinPrep
Cells of GCT show some spindling, less
defined cytoplasm, and relatively
inconspicuous nucleoli
Cells of GCT are reactive to neuro specific
enolase and nonreactive to
pancytokeratin

Papillary Carcinoma (PCA)

Two studies correctly identified all 7 PCA in their reports,4, 8 and one identified 5 out
of 6 cases and diagnosed the sixth case as a hypercellular follicular neoplasm.13 In a
study dedicated to PCA by ThinPrep, Zhang et al.14 statistically analyzed 40 cases of
PCA and 17 cases of other lesions for 10 characteristics with assigned scores. They
found that high cellularity, presence of papillary clusters and large sheets, nuclear
grooves, nuclear molding, powdery chromatin, and small nucleoli were significant.
However, none of these features could absolutely predict PCA by itself. Not
surprisingly, intranuclear inclusions had the highest predictive power while cellularity
and small nucleoli had the least predictive power. They found that the presence of
intranuclear inclusions is essential to achieve 100% specificity, and recorded many
inclusions in 12 of 40 cases and rare inclusions in 18 of 40 cases. In a pilot study in our
institution, we accurately diagnosed 22 of 38 adequately cellular cases with surgical
follow-up. Fifteen of these 22 cases showed inclusions, but it is worth noting that in 10
of 15 cases, the intranuclear inclusions were rare and only detected after scrutiny
under high magnification. In our experience, the presence of numerous nuclear
grooves within crowded irregular nuclei is highly correlated with PCA.

ThinPrep Features (Fig. 22.11)

Figure 22.11. Papillary carcinoma. A. Cellular prep with small cellular clusters
and simple papillae. The nuclei are densely packed within the clusters when
compared to those of nodular goiter, medium power. B. Uniformly enlarged cells
that are slightly crowded. Notice the marked wrinkling of the nuclear membrane.
The nuclear chromatin is evenly distributed and several nuclear grooves can be
 detected. C. A sheet of monotonous more or less orderly arranged cells with
smooth nuclear membranes can be mistaken for hyperplasia. However, notice the
powdery chromatin, small nucleoli, and numerous nuclear grooves. D.
Intranuclear pseudoinclusions are occasionally detected (ThinPrep).

Cellular preps containing numerous sheets and clusters.

Papillary architecture may need some experience to recognize, since papillae

may be broken down into finger-like clusters and rarely retain the complex
architecture seen on CS.

The cells are crowded and nuclear molding could be prominent.

Uniformly enlarged nuclei with powdery chromatin and small nuclei.

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Nuclear grooves and coffee-bean-like nuclei. Nuclear membranes may be
markedly wrinkled.

Intranuclear inclusions are not easily visualized and may be absent.

Hard colloid appears as very thick fragments.

Squamous metaplasia may be focally present as small clusters or single cells

with larger nuclei and thick cyanophilic cytoplasm.

Psammoma bodies when present are well preserved.

SurePath Features (Fig. 22.12)

 Figure 22.12. Papillary carcinoma. A. Papillary clusters with central psammoma
bodies. B. Evenly spread cluster of enlarged cells with oval nuclei, powdery
chromatin, nuclear grooves, and small nucleoli (SurePath). (Courtesy of Michael
Henry, MD, Mayo Clinic, Rochester, Minnesota.)

The complex papillae are usually preserved and assume a three-dimensional

architecture. About 50% of cases manifest intranuclear inclusions (personal
communication). Examination of cells lining the periphery of these three-dimensional
papillae and clusters reveals all the characteristic nuclear features. Psammoma bodies
are well preserved.

The diagnostic pitfalls and clues in papillary carcinoma are listed in Table 22.5.
 TABLE 22.5 DIAGNOSTIC PITFALLS AND CLUES IN
PAPILLARY CARCINOMA (PCA)

Diagnostic Pitfalls Diagnostic Clues

Monolayer sheets can be The aspirate is usually very cellular with

deceptively uniform with large sheets
subtle nuclear features; this The nuclei are crowded and wrinkled
could be mistaken for when viewed at higher magnification
NCG, especially in cases with The chromatin is pale and finely granular
cystic degeneration Colloid fragments are relatively larger
and denser than those of NCG

PCA with Hürthle cell change Characteristic nuclear features such as

lack the nuclear grooves and membrane irregularity
crowding and overlap and Powdery, finely granular chromatin
may be mistaken for Present predominantly as sheets or
HCN clusters and not as single cells as in
FCN

Follicular variant may mimic Characteristic nuclear changes

FCN

Some FCA may manifest focal Focal changes are not sufficient for
nuclear crowding unequivocal diagnosis of PCA
and groves

Anaplastic Carcinoma
Only one study reported 9 anaplastic carcinoma cases, all correctly diagnosed by
ThinPrep.3 In the several cases we have seen in our institution, mostly of the giant cell
type, all cases were easily identified.

ThinPrep Features of Giant Cell Type (Fig. 22.13)

Figure 22.13. Anaplastic carcinoma. Gigantic cells with markedly large nuclei,
high N/C ratio, course clumpy chromatin and macronucleoli. Phagocytosis of
neutrophils by the malignant cells is prominent (ThinPrep).

Predominantly single cells and few small cell aggregates.

Extremely pleomorphic cells with wide variation of size and shape.

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 P.498
Bizarre nuclei with prominent nucleoli and irregular nuclear membranes

Fibrin fragments with entrapped cellular debris represent background necrosis

Cytoplasmic leukophagocytosis

Nuclear inclusions are rarely detected unlike those on conventional smears.

ThinPrep Features of Spindle Cell Type

Aspirates are usually scant in cellularity

Singly scattered or small groups of spindled cells with variable degree of

pleomorphism. Some may mimic medullary carcinoma with spindle cell
features and require confirmation by immunostains.

Medullary Carcinoma
Only 2 cases were reported by ThinPrep.7, 8 Over the years we have encountered
several cases with variable amounts of amyloid. Congo red stain can be performed on a
cell block or on an additional ThinPrep with success. We have also routinely applied
thyrocalcitonin with excellent results. However, we have encountered occasional
Hürthle cell lesions collected in CytoLyt that would falsely react to calcitonin and
therefore recommend that it is interpreted in conjunction with thyroglobulin as a
negative control.

ThinPrep Features (Fig. 22.14)

 Figure 22.14. Medullary carcinoma. A. Loosely cohesive clusters of cells with
eccentric nuclei, slight nuclear membrane irregularity, evenly distributed
chromatin and small nucleoli. B. Loosely cohesive clusters and single
plasmacytoid cells. Two dense fragments with waxy quality are consistent with
amyloid (ThinPrep).

Small singly scattered and in small cohesive groups, cells are cuboidal,
columnar, polygonal, or plasmacytoid in shape.

Cells may vary from monomorphic to pleomorphic, and occasional bizarre cells
are not unusual.

Eccentric nuclei, coarsely granular chromatin and small nucleoli.

Cytoplasm is moderate in amount, dense, with well-defined borders.

Amyloid when present appears as small dense fragments with waxy quality.

REFERENCES
1.Michael CW, McConnell J, Pecott J, et al. Comparison of the ThinPrep and
AutoCyte liquid based preparations in non-gynecologic specimens. Diagn
Cytopathol. 2001;25:177–184.
2.Nicol TL, Kelly D, Reynolds L, et al. Comparison of TriPath thin-layer technology
with conventional methods on non-gynecologic specimens. Acta Cytol.
2000;44:567–575.

3.Malle D, Valeri RM, Panajiotou, et al. Use of a thin-layer technique in thyroid

fine needle aspiration. Acta Cytol. 2006;50:23–17.

4.Frost AR, Sidawy MK, Ferfelli M, et al. Utility of thin-layer preparations in

thyroid fine needle aspiration. Diagnostic accuracy, cytomorphology and optimal
sample preparation. Cancer Cytopathol. 1998;84:17–25.

5.Hasteh F, Pang Y, Pu RT, et al. Do we need more than one ThinPrep to obtain
adequate cellularity in fine needle aspirates? Cancer Cytopathol. 2006;108:424A.

6.CYTYC Corporation. Operator's Manual. ThinPrep Processor. Marlborough, MA:

CYTYC; 1992.

7.Michael CW, Hunter B. Interpretation of fine needle aspirates processed by the

ThinPrep technique: cytologic artifacts and diagnostic pitfalls. Diagn Cytopathol.
2000;23:6–13.

8.Cochand-Priollet B, Prat JJ, Polivka M, et al. Thyroid fine needle aspiration: the
morphological features on ThinPrep slide preparations. Eighty cases with
histological control. Cytopathology. 2003;14:343–349.

9.TriPath Imaging Inc. Operator's Manual. General Non-Gynecologic Procedure.

Burlington, NC: TriPath Imaging; 2006.

10.Tulecke MA, Wang HH. ThinPrep for cytologic evaluation of follicular thyroid
lesions: Correlation with histologic findings. Diagn Cytopathol. 2004;30:7–13.
11.The Papanicolaou Society of Cytopathology Task Force on Standards of
Practice. Guidelines of the Papanicolaou Society of Cytopathology for examination
of fine-needle aspiration specimens from thyroid nodules. Diagn Cytopathol.
1996;15:84–89.

12.Michael CW, Pang Y, Pu RT, et al. Cellular adequacy for thyroid aspirates
prepared by ThinPrep: how many cells are needed? Mod Pathol. 2006;19:292A.

13.Biscotti CV, Hollow JA, Toddy SM, et al. ThinPrep versus conventional smear
cytologic preparations in the analysis of thyroid fine-needle aspiration specimens.
Am J Clin Pathol. 1995;104: 150–153.

14.Zhang Y, Fraser JL, Wang HH. Morphologic predictors of papillary carcinoma on

fine-needle aspiration of thyroid with ThinPrep preparations. Diagn Cytopathol.
2001;24:378–383.

15.Kintanar BK, Giordano TJ, Thompson NW, et al. Granular cell tumor of trachea
masquerading as Hürthle cell neoplasm on fine needle aspirate: a case report.
Diagn Cytopathol. 2000;22:379–382.
Editors: Kini, Sudha R.
Title: Thyroid Cytopathology: A Text and Atlas, 1st Edition
Copyright ©2008 Lippincott Williams & Wilkins

> Table of Contents > 23 - Application of Needle Biopsy Data to Management Decisions

23
Application of Needle Biopsy Data to Management
Decisions

A PHILOSOPHICAL APPROACH
J. Martin MillerKINI

Deceased.

The primary consideration in the application of needle biopsy data to the management of
thyroid nodules is the perception of thyroid cancer by the responsible physician. When thyroid
nodules were selected for lobectomy by noninvasive means, it was recognized that some cancers
were missed. (Just how many were missed was not appreciated until we began doing thyroid
biopsies.) The problem, however, was not failure to identify cancers that later proved lethal,
but a plethora of operations for removal of benign disease. Simply stated, in the minds of most
physicians, the consequences of observing some cancerous thyroid nodules did not justify the
removal of all thyroid nodules. Consider this example of a translation of this perception of
thyroid cancer into aspiration biopsy language: A cytologic diagnosis that admits to a small (10%)
chance of a nodule's being a mini-invasive thyroid cancer is not synonymous with a surgical
mandate. Under certain circumstances, even a definite diagnosis of carcinoma might not be a
surgical mandate. For example, a 65-year-old man with congestive heart failure, previous
myocardial infarction, and a 1-cm isthmus nodule diagnosed as papillary carcinoma by fine-
needle biopsy is probably not a surgical candidate.

The cytopathologist and the thyroidologist must understand each other's objectives.

The former has been justifiably trained never to miss a diagnosis of cancer. The thyroidologist,
however, places maximum emphasis on being certain that the morbidity and mortality of the
thyroid lesion in question exceed those of the anesthesia and surgery for a particular patient.
The cytopathologist appreciates that a diagnosis other than outright malignancy may represent a
very small chance of a lethal cancer. When the cytopathologist perceives that the clinician
favors conservative management, he or she is free to note the presence of small numbers of
abnormal cells or to vacillate between a diagnosis of benign tumor and adenoma without
provoking early, and usually unnecessary, surgery. The clinician will respond to such a diagnosis
by prescribing observation with thyroid-stimulating hormone suppression, repeat biopsy after 3
to 12 months, or a large-needle biopsy before considering lobectomy. For the clinician, a
definitive diagnosis is not required. A needle biopsy diagnosis is needed that is more accurate on
the average than that from noninvasive diagnostic methods. The needle biopsy diagnosis must
identify all cancers with proximate lethal potential and, utilizing previous biopsy diagnoses
correlated with surgical data, provide a statement of the probability of a nodule's being a less
aggressive differentiated cancer. It must also reliably select nodules that may be safely
observed; if this is at variance with clinical judgment, selection must be almost 100% accurate.
When clinical and biopsy data both suggest a diagnosis of benign disease but both are in error,
the delay in making a proper diagnosis should not prove catastrophic. When the physical
description or behavior of a nodule suggests malignancy and the diagnosis by needle biopsy is
benign, the tissue diagnosis must be correct or a therapeutic opportunity may be lost. It is the
responsibility of the physician who correlates the biopsy diagnosis and the clinical findings to
make sure that the biopsy diagnosis adequately explains the total clinical picture. This has been
our guideline for 10 years of needle biopsy use. Abele and Miller1 have expressed this philosophy
very well.

The approach of many physicians to nodule management is quite simple. If the biopsy diagnosis
is benign, observe it or treat it by thyroid-stimulating hormone suppression. If the biopsy
diagnosis is anything else (and, therefore, does not exclude cancer), remove the nodule. As
clinicians, our opinion is that such a therapeutic philosophy results in too many diagnostic
surgical lobectomies. If the pathologist member of the biopsy team is aware that all nodules
diagnosed as non-benign will be removed anyway, much of the incentive for attempting specific
diagnoses has been eliminated. This applies mostly to follicular lesions for which the specificity
of the diagnosis is less than that for papillary lesions. The specificity varies with
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the exact cytologic diagnosis made. Therefore, we encourage the cytopathologist to make as
accurate a diagnosis as possible on all lesions and for selective removal to be employed. If the
presence of cancer is highly probable, surgery is usually advised. If it is only possible, other
factors are considered.

In our experience, 10% to 15% of fine-needle biopsy specimens are diagnosed as cellular
adenoma. Perhaps 25% of these are false-positive results, as the correct pathologic diagnosis is
nodular goiter. If the nodule is 2 cm or larger, a large-needle biopsy is done, and the histologic
specimen often enables us to screen out the nodular goiters. If the fine-needle biopsy diagnosis
of cellular adenoma is confirmed, or if the nodule is too small for large-needle biopsy, the
decision for or against surgery is based on several factors. These include the length of time at
risk (the patient's age), the presence of diseases that increase the operative risk, the perception
of risk based on the cytopathology, and the perception of risk based on the clinical features of
the nodule. It is important to note that follicular cancers identified by the diagnosis of cellular
adenoma have consistently been mini-invasive, in our experience. All aggressive cancers have
been easily diagnosed as such.

Different cytopathologists have different classifications for fine-needle biopsy diagnoses based
on different microscopic criteria. Therefore, decisions made by one biopsy team may not be
applicable to the experience of another team. Consider the differences in diagnoses made on
the first 2,000 satisfactory fine-needle biopsy specimens interpreted at the Mayo Clinic2 in
Rochester, Minnesota, and the first 2,000 diagnoses made from a combination of fine- and large-
needle biopsy specimen interpretations at the Henry Ford Hospital in Detroit. Table 23.1
summarizes the percentage of diagnoses in each diagnostic classification.

Malignant
5
Malignant or suspected
malignancy
15
Suspected
17
Abnormal; cellular
adenoma or Hürthle cell adenoma
18
Benign
78
Benign
 67

Mayo Clinic Percent Henry Ford Hospital Percent

TABLE 23.1 PERCENTAGE OF DIAGNOSES BY DIAGNOSTIC

CLASSIFICATION AT THE MAYO CLINIC AND THE HENRY FORD
HOSPITAL
When the middle categories are compared, nonequivalence of microscopic criteria is suggested
by the number and type of cancers identified. At the Mayo Clinic, 253 of 333 patients were
operated on who had a diagnosis of suspected malignancy. Of these, 60 cancers were
found—32 papillary, 14 follicular, 4 medullary, 1 anaplastic, 2 metastatic, and 7 assorted
cancers including malignant lymphoma. Among the Henry Ford Hospital group diagnosed as
abnormal (possible cancer), 224 of 354 nodules underwent operation. Only 20 were cancer—8
Hürthle cell variant of follicular carcinoma, 6 follicular, 5 papillary, and 1 medullary
carcinoma. It appears that the management of a diagnosis of suspected malignancy in Minnesota
and a diagnosis of possible cancer in Michigan should not be the same.

It is appropriate to close the discussion of needle biopsy management of thyroid nodules with a
restatement of the goals of such management. They are, first, to remove all potentially lethal
thyroid cancers and, second, to remove as few benign nodules as possible in achieving the first
goal. Continued refinement of diagnostic biopsy criteria is necessary for maximum
approximation of these objectives.

AN ENDOCRINOLOGIST'S PERSPECTIVE
Max Wisgerhof

The endocrinologist is ever more dependent upon the skill and experience of the cytopathologist
for the diagnostic assessment of thyroid nodularity, because the aspiration of thyroid nodules is
rapidly increasing, in large part as a result of the detection, incidentally, of nodules by
ultrasound, computerized tomography, and magnetic resonance imaging, performed for
indications not related to the thyroid.

The characteristics of thyroid nodularity shown by imaging are not sufficiently reliable to
distinguish cancerous from benign nodularity. Assessment by molecular genetic markers holds
promise, but one that has not as yet been fulfilled. Immunostaining, excepting in medullary
thyroid cancer, has not been helpful.

Defining Ambiguities in the Management of Thyroid

Nodularity
Clinical recommendations for the management of thyroid nodularity can be linked to the results
of the cytological examination of the aspirates, and those links are made in the next section.

Two challenges can be highlighted in attempting to link a cytologic report and a clinical
recommendation:

The inadequate aspirate.

The cytopathology report for an abnormal or indeterminate thyroid nodule.

For the inadequate cytologic specimen, the endocrinologist faces a dilemma—was the sample
inadequate because of the nature of the nodule or the technique of the aspiration? Ultrasound
guidance has enhanced aspiration technique (and tempted aspiration of small nodules with
problematic cytologic yield), and the endocrinologist often falls back on the
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premise that neoplastic thyroid nodules should yield sufficient cells for cytopathologic
evaluation—"no (few) cells, no cancer." This is plagued with risk, and clinical suspicion trumps
the premise. Whatever, thyroid surgery can usually await a cytological diagnosis, or suspected
diagnosis, from repeated aspiration(s) of nodules initially inadequate cytologically, or can wait
upon clinical acumen.

For the cytopathology report for an abnormal or indeterminate nodule, the endocrinologist has
little room to maneuver by judgment. If the cytology interpretation cannot be more specific,
there are few—really no—reliable clinical or ultrasound characteristics to place the abnormal
follicular nodule in the benign or malignant camp. Thus, the value of the labored experienced
interpretation cytologically of the follicular-patterned lesions to reach the diagnosis of follicular
adenoma, or follicular carcinoma.

These two highlighted ambiguities are included in Table 23.2 , linking clinical recommendations
and cytopathology reports, and in the next section.

Unsatisfactory for cytologic evaluation

Consider whether thyroid follicular cells were not obtained because of:
• Aspiration technique, or
• Characteristics of the nodule or tissue.
Reaspiration can resolve this, although clinical monitoring is often appropriate
because the technique is straightforward, readily learned, and usually not faulty;
and morbid follicular nodules are expected to yield cells
Consider the presence of:
• Colloid nodularity (frequent), or
• Cystic papillary carcinoma
Reaspiration to resolve this is indicated, particularly if colloid is scant; ultrasound
guidance for placement of the needle tip in tissues can be helpful.
Inadequate for cytologic evaluation
Attempt to obtain the findings to support not proceeding to thyroid surgery
(no finding itself is reliable):
• Soft, homogeneous by palpation
• "Benign" ultrasound characteristics (full "halo," not vascular, homogeneous,
ovoid, smooth, regular borders)
• Small size, less than 2 cm
• Absence of radiation exposure, autoimmune thyroid disease, and family history of
thyroid cancer, or
• Upon review with the cytopathologist, malignant cells are not suggested
Reaspirate if some or all of the above not obtained, or if the patient or physician
requires diagnosis
Monitor nodule size for rapid growth, which would indicate reaspiration; or thyroid
surgery, to detect more serious thyroid cancer
Negative for malignant cells (Benign)
Set aside considerations for thyroid surgery or reaspiration, unless:
• Nodularity is markedly vascular
• Neither colloid goiter nor chronic thyroiditis present clinically
• Nodularity is large (greater than 2 cm; "sampling error"), and/or
• Apparently rapidly enlarging
Abnormal cytology
follicular adenoma
Monitor for rapid growth, an indication for surgery; use clinical factors t• recom-
mend monitoring:
• Small size (less than 2 cm)
• Older patient age
• Patient and physician preference
This conundrum requires discussion among patient, physician, cytopathologist,
endocrinologist, and surgeon
Strongly consider thyroid surgery, because the natural history of this thyroid disease
cannot be reliably predicted
Hürthle Cell neoplasm
Review with the cytopathologist the diagnosis for degree of certainty, because
though unusual, it is challenging diagnostically and therapeutically
Suspicious for malignancy
Recommend thyroid surgery, accepting that:
• Predictability of papillary thyroid carcinoma can be as low as 50%
• The potential for morbidity and mortality for other types of thyroid cancer is
greater than the risks from thyroid surgery, anesthesia, and resulting hypothy-
roidism
• Reaspiration cannot reasonably set aside this report
• Monitoring suspected Hürthle cell cancer or lymphoma, for positive indicators, is
not helpful because such do not exist
Positive for or diagnostic of malignancy
differentiated thyroid cancers
Thyroid surgery (unless the patient's surgical risk is great, and then there would have
been little indication for the aspiration)
• Consider that the false-positive incidence is low (less than 5%)
Thyroidectomy is the opportunity for cure, and is important for palliation
Poorly differentiated or anaplastic thyroid
cancers

Thyroidectomy and tumor excision-for cure and palliation

Medullary thyroid cancer
Malignant lymphoma
Attempt confirmation of diagnosis by flow cytometry, and consider nonsurgical
 intervention

Metastasis from nonthyroid cancer

Consider staging for the primary cancer to direct interventions, unless palliation indi-
cated, to protect the airway, for example

For cystic thyroid nodules:

Inadequate (nondiagnostic)
Nodular goiter
Suspicious or diagnostic of papillary
cancer
For follicular-patterned thyroid lesions with
cystic degeneration

Monitor for recurrence or enlargement, and reaspirate

Reevaluate if symptomatic
Total thyroidectomy

Review the cytology with the cytopathologist to attempt a specific diagnosis and/or
estimate of risk of cancer. Otherwise, offer for discussion close monitoring to
detect suspicion for cancer or its progression, though no finding is sensitive

Cytopathology Report Clinical Recommendation

TABLE 23.2 PROPOSALS FOR CLINICAL MANAGEMENT

Refining the Ambiguity

In an attempt to refine the clinical ambiguity that can reside in management decisions about
thyroid nodularity, the endocrinologist can propose, to the patient or the patient's physician,
reasonable links between the cytopathology report and a clinical recommendation. Some links
are based on sound experience, and others on sound communication among the
cytopathologist(s), endocrinologist, surgeon, physician, and most importantly, the patient.

The proposals for clinical management in Table 23.2 are organized by the reporting categories
for the cytopathology result from thyroid aspirate (see "Reporting Scheme for Thyroid Aspirates"
in Chapter 4 ).

Accepting the Ambiguity

The value of these clinical recommendations is fundamentally dependent upon the
cytopathologic interpretation and the clarity of the report. Frequent collegial discussion and
review of the cytology are essential, among the cytopathologist, endocrinologist, and surgeon,
for recommendations to approach success. With that, the inherent ambiguity in predicting
histology or clinical outcome from cytology can be tolerable for all.

A SURGEON'S PERSPECTIVE
Vinod Narra

In 1973 there were approximately 7,500 cases of thyroid cancer reported whereas in 2007, based
on the Surveillance Epidemiology and End Result (SEER) database, there will be 30,000.3 With
this unprecedented rise in the incidence of thyroid cancer over the last 30 years and with little
indication that this steady increase will cease, our ability to accurately diagnose these lesions
preoperatively is critical to formulation of an appropriate treatment plan. It remains unclear
whether the true incidence has increased or increase is associated with greater awareness of the
disease and/or an increased detection of subclinical nodules. Regardless of the reason, the need
for an accurate evaluation differentiating benign from malignant lesions is required.

In the management of thyroid nodules, the interaction between the endocrinologist,

cytopathologist, and surgeon is critical to the achievement of an optimal treatment plan. While
there is tremendous reliance on the expertise of the endocrinologist to clinically categorize
thyroid nodules based on history, physical, and radiographic appearance, it is the precision and
adequacy of the fine-needle aspirate and the subsequent cytopathologist's interpretation of the
fine-needle aspirate that drives not only the decision to operate but also the extent of surgery.
Any uncertainty or vacillation can lead to suboptimal treatment, potentially exposing the
patient to unnecessary harm.

Interpretation of the Fine-Needle Aspirate and Its

Therapeutic Implications—Minimizing Risk and Maximizing
Benefit
Papillary thyroid cancer, including its variants, accounts for 85% to 90% of all thyroid cancers, is
more prevalent in iodine-rich areas, and is often multifocal with regional lymph node
involvement. Follicular thyroid cancers are often solitary, arise in iodine-deficient areas, and
show minimal extension to the regional lymph nodes. Hürthle cell carcinomas, like papillary
carcinoma, are often multifocal, and to a lesser extent than papillary thyroid cancers, they
spread to regional lymph nodes; but in contrast they rarely trap iodine. Medullary thyroid
cancers are sporadic 70% of the time, multifocal, and also have a propensity for regional nodal
involvement.

When a diagnosis of cancer can be established, we advocate a total thyroidectomy. In

experienced hands, the risk of recurrent laryngeal nerve injury ranges from 0.5% to 1.5% and the
risk of hypoparathyroidism is 2% to 4% for a total thyroidectomy. The benefits of total
thyroidectomy include the following.

Improves the ability to perform postoperative radioiodine scanning and ablation.

Allows for the initiation of hormone-suppression therapy. When performing a

hemithyroidectomy, there is an assumption that replacement hormone therapy is not
necessary. However, there is a risk of hypothyroidism leading to a rise in thyroid-
stimulating hormone (TSH), which is mitogenic.

Permits the use of thyroglobulin levels to detect persistent or recurrent disease. This is
particularly important in the case of Hürthle cell carcinomas, which infrequently trap
iodine.

Eliminates the risks of an undetected or untreated contralateral lesion.

The adjuvant treatment options for thyroid cancer remain limited. Therefore, the primary mode
of cure remains surgical. If a clear diagnosis of malignancy can be established preoperatively,
then a central neck dissection can be advantageous both for staging purposes and cytoreduction,
when metastases are present. The lymphatic clearance of the central or lateral neck can be
particularly valuable in the case of Hürthle cell carcinoma, where radioiodine uptake is poor
and there is a need for surgical extirpation of all thyroid tissue.

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With accurate preoperative assessment, the need for reoperation and subjecting the patient to
an unnecessary second operation can be limited. We find intraoperative frozen section only of
benefit in cases when fine-needle aspiration is deemed inadequate or unsatisfactory and
suspicion remains for malignancy based on the nodule's growth or ultrasound characteristics.
Particularly with follicular or Hürthle cell neoplasms, there is a need for multiple sections, and
this generally is not practical in the settings of frozen section. In addition, postbiopsy changes
that may occur within the lesion can mimic cytologic changes of malignancy as well as invasion
of the capsule. These changes may mislead to a malignant diagnosis at frozen section.

By stringently applying our center's reporting scheme (Table 4.4 ) to each fine-needle aspirate,
the uncertainty of certain cytopathology reports as recommended in other reporting schemes is
eliminated. Our reporting scheme does not include the phrase "favor goiter but cannot rule out
neoplasm." This latter terminology is exceedingly confusing and lacks any standardization. An
unanticipated consequence of our reporting schema has been the significant decrease in the
number of surgical specimens consisting of nodular goiter when there was concern for
malignancy. Our experience with nodular goiters is mainly isolated to those patients with large
nodular goiters exhibiting compressive symptoms. We continue to advocate that surgical
management of large multinodular goiters requires a total thyroidectomy even with a unilateral
enlargement because of the risk for hypertrophy of the contralateral side, the incidence of
hypothyroidism developing despite sparing adequate thyroid tissue, and particularly in younger
individuals there is a significant risk for recurrent disease or occult and latent papillary
microcarcinomas.

SUMMARY
A multidispiciplinary approach to the management of thyroid nodules—involving an
experienced endocrinologist, cytopathologist, and surgeon, in which constant feedback and
evaluation of the efficacy and quality of the fine-needle aspirates as well as the interpretation
of the fine-needle aspirate with respect to the surgical pathology—should be followed to
improve outcome. The classification schema as discussed in earlier sections has improved the
positive predictive value of fine-needle aspirate diagnosis and final surgical specimens,
minimizing unnecessary operations or the need to perform completion thyroidectomies. When
total thyroidectomy can be done with minimal morbidity, it should be the treatment of choice
for patients with thyroid cancer, because persistent or recurrent disease can be readily detected
using serum thyroglobulin levels and localized with either radioiodine or FDG-PET. This is
predicated on the center's ability to identify suspicious nodules, obtain adequate fine-needle
aspirates, and appropriately distinguish the characteristic features within the samples.
REFERENCES
A Philosophical Approach
1.Abele JS, Miller TR. Fine needle aspiration of the thyroid nodule: clinical application. In:
Clark OH, ed. Endocrine Surgery of the Thyroid and Parathyroid Glands. St Louis:
Mosby;1985:293.

2.Gharib H, Goellner JR, Zinsmeister AR, et al. Fine-needle aspiration biopsy of the thyroid:
the problem of suspicious cytological findings. Ann Intern Med . 1984;101:25.

A Surgeon's Perspective
3.Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States,
1973–2002. JAMA . 2006;296:2164–2167.

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APPENDIX TO CHAPTER 23
Observations on Pathophysiology of the Thyroid
J. Martin MillerKINI

Deceased.

The raison d'ětre for needle biopsy of the thyroid is the palpable nodule of uncertain nature.
The term "nodule" is defined for our purposes as an area within or adjacent to a thyroid lobe
that has a consistency other than that of normal thyroid tissue. Theoretically, a portion of a lobe
different from the remaining tissue should be included only because of its increased thickness.
The palpatory differences may be related to the cellularity, vascularity, amount of fluid or
colloid, or any combination of these factors.

There is no perfect experimental model for studying the pathogenesis of thyroid nodules. Using
the rat as an imperfect experimental model, it seems that most thyroid nodules appear as a
result of thyroid-stimulating hormone or thyroid-growth immunoglobulin stimulation, remittent
or intermittent. The nodule represents an area of hyperinvolution remaining after the remainder
of the thyroid-stimulating hormone–stimulated hyperplastic tissue has returned to normal; or
it begins as a group of follicles that partially or totally escapes from thyroid-stimulating hormone
control and grows and/or functions independently of the trophic hormone. In many instances
these nodules are multiple, although one may be dominant and palpable and the others small or
microscopic and not felt.

The hyperinvolution hypothesis of nodule formation was well described by Marine1 based on
material from patients with endemic goiter. A diffuse enlargement of the gland preceded the
formation of palpable nodules. Miller et al.2 observed, by autoradiographic studies, single
follicles or groups of follicles that escaped thyroid-stimulating hormone control as the genesis
for autonomous functioning nodules.

When a nodule enlarges to approximately 1 cm, an important classification can be made by

radionuclide imaging. About 10% of nodules will appear to be functioning. On a second study,
with the patient taking triiodothyronine to suppress thyroid-stimulating hormone, the nodule
will continue to function whereas the extranodular tissue will suppress and take up less
radionuclide. This identifies the nodule as a true functioning tumor of the thyroid. These tumors
are composed of a spectrum of histologic structures ranging from large, colloid-filled follicles to
small, hyperplastic follicles. The latter may have nuclear chromatin patterns that can be
confused with those of malignant neoplasia. Of the thousands of these tumors surgically
removed, only two of those reported in the literature were probably well-differentiated
carcinomas.3 , 4 Most patients with thyroid nodules have radionuclide imaging before biopsy,
and the autonomous functioning tumors are not evaluated cytologically. The possibility of
interpretive error must be kept in mind when looking at the cytology of patients whose nodules
have not been imaged.

On radionuclide image, 90% of thyroid nodules localize to an area of decreased function. At least
two-thirds of these are involutional nodules, or have been diagnosed as nodular goiter rather
than follicular adenoma (a true tumor) by a thyropathologist. The other one-third is usually
grossly solitary tumors, with a well-defined capsule, composed of follicular cells of varying
patterns. Autoradiographically, these nodules collect little radioactive iodine, which accounts
for their appearance on scintiphoto.

As most nodules subject to biopsy do not trap or bind pertechnetate or iodine radionuclide, the
epithelium that the pathologist calls "benign" or "nodule goiter" is composed of functionally
inactive cells, as judged by iodine metabolism. Nuclei of normal follicles appear much more
active. This difference might prove confusing, except that normal thyroid follicles are rarely
aspirated through a fine needle. The evidence for this is circumstantial. We routinely make six
separate slides from each nodule using six different needles. In studies of over 6,000 nodules, we
have virtually never found tumor on one slide and diagnostic numbers of normal-appearing cells
on another. As most of the 1- to 2-cm tumor nodules are at least partially surrounded by normal
tissue, this is a remarkable observation. We have, however, diagnosed Hashimoto's thyroiditis on
one slide and tumor on another when the paranodular tissue had features of autoimmune
thyroiditis. We hypothesize, therefore, that we usually get an unsatisfactory aspirate and an
acellular smear when the fine needle is placed in normal thyroid tissue. It is probable that the
structural integrity of normal tissue is far greater than that of tumor. This is in keeping with the
observation we have made on 16-gauge aspirations of follicular tumors: The ease of sample
aspiration is inversely proportional to the follicular size.

Hashimoto's thyroiditis, generally recognized as an autoimmune process, is of concern in several

different ways to the pathologist interpreting biopsies. If the cytotoxic antibodies destroy the
follicular epithelium without producing a hyperplastic reaction, or if thyroid-stimulating-
hormone–blocking antibodies prevent the formation of a goiter, the associated hypothyroidism
is of concern only to the clinician. If compensatory hyperplasia of the damaged epithelium and
the lymphocytic infiltrate combine to produce palpable thyroid enlargement, then it is possible
that the needle biopsy specimen will supply information of value for the physician making
management decisions. Diffuse thyromegaly is not usually considered an indication for needle
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biopsy, but in the following instances, biopsy may follow a clinical diagnosis of Hashimoto's
thyroiditis:

Thyromegaly does not regress with thyroid-stimulating hormone suppression.

Thyromegaly increases despite thyroid-stimulating hormone suppression, either in the

initial treatment period or after a period of stable gland size.

Diffuse thyroid enlargement or abnormality is accompanied by an area different enough

in size or consistency to be described as a nodule.

In each instance, the original diagnosis may be questioned as to correctness or completeness: Is

the enlargement either totally or partially from lymphocytic thyroiditis? If it is partial, what is
the other pathologic entity?
Two diseases coexist in the thyroid with lymphocytic thyroiditis often enough to recommend
their inclusion in its differential diagnosis. The first disease is papillary carcinoma. Carcinoma
has been reported as occurring in as many as 3% of thyroids operated on for Hashimoto's
thyroiditis.5 The majority of these tumors are papillary. The tumor may present as a nodule, and
may be palpable or may present with multiple microscopic foci throughout a lobe. These add to
the lobe's size but are not individually identifiable. Our series of 593 cancers did not include a
follicular carcinoma in a palpable, diffusely abnormal gland of lymphocytic thyroiditis.

The second disease associated with lymphocytic thyroiditis is malignant lymphoma. In our
practice, we have noted an increase in the occurrence of malignant lymphoma of the thyroid.6
Although malignant lymphoma is rare in patients with lymphocytic thyroiditis, about 75% of
patients with malignant lymphoma have an underlying lymphocytic thyroiditis.7 As malignant
lymphoma of the thyroid is easily curable when diagnosed early and almost incurable when
diagnosed late, it behooves the clinician and the cytopathologist to have a high index of
suspicion for this disease in patients with Hashimoto's thyroiditis. For the clinician, this means
abandoning the picture of malignant lymphoma of the thyroid as a massive, rapidly enlarging
goiter in an elderly female and substituting any suspicious enlargement (or lack of regression) in
patients with Hashimoto's thyroiditis, regardless of their age or sex. For the cytopathologist, this
means reporting any suspected coexisting malignant lymphoma and determining false-positive
results by histologic examination of a large-needle biopsy specimen.

The occurrence of medullary carcinoma of the thyroid has special significance for the physician
interpreting or performing biopsies. This tumor may be sporadic (80%) or familial (20%). The
familial variety may be associated with a parathyroid adenoma or pheochromocytoma, and the
presence of either will alter surgical planning. Therefore, a specific biopsy diagnosis is of great
importance. A good cytologic specimen should rarely be interpreted as other than cancer, and if
there is any suspicion that this might be a medullary carcinoma, immunoperoxidase and serum
calcitonin studies should be done. This will ensure proper determination of the presence or
absence of ancillary tumors.

Most of the statistics concerning cancer metastatic to the thyroid are based on autopsy material.
In our 10 years of biopsy experience, we have observed cancer of the lung, esophagus, colon,
kidneys, sebaceous glands, and breast, as well as malignant melanoma presenting as a thyroid
nodule. Most were not the primary site of identification of the tumor, although the metastatic
nature was sometimes unsuspected.

Undifferentiated cancer of the thyroid may occur in an otherwise normal gland, and even
modest growth makes the patient aware of its presence. (In such situations, dedifferentiation of
a papillary or follicular cancer may be present, which might have been prevented by early
biopsy, identification, and removal of the differentiated cancer.) Undifferentiated cancer of the
thyroid may also arise in a multinodular goiter that has been present for many years. This
possibility presents two caveats for the biopsy physician. First, the physician must remember the
very limited information provided by fine-needle biopsy of large multinodular goiters and must
perform repeat biopsy of any areas of anatomic change. Second, the physician must carefully
avoid giving the patient the impression that carcinoma has been ruled out by a benign biopsy.

CYSTIC NODULES
The number of thyroid nodules that are partially or totally cystic at the time of presentation has
been estimated to be about 20%.8 The thin-walled veins in many nodules are susceptible to
minor trauma, with subsequent hemorrhage, tissue necrosis, and cyst formation. The potential
for such change depends on the vascularity of the lesion. Most thyroid cancers are less vascular
than benign lesions; this accounts for the unusual presentation of cancer as a cystic lesion. At
the other end of the spectrum is the autonomous functioning thyroid nodule, which frequently
presents with partial cystic change. The degree of vascularity apparently relates to the degree
of metabolic activity. Judging from our experience4 with cyst aspiration, hemorrhagic cysts
present in two different ways. In one, following bleeding, hemoglobin is absorbed. At initial
aspiration, straw-colored fluid is found. In the other, it is hypothesized that partial reabsorbtion
of the cyst contents decreases the pressure on the vein from which the original bleeding took
place, and hemorrhage recurs. At initial aspiration, the cyst content is always that of recent
bleeding. Although cytologic examination of most cyst aspirates identifies only histiocytes, the
recent bloody contents are more apt to contain viable follicular cells than are straw-colored
residue from bleeding that occurred at least 6 to 8 weeks previously.

Some thyroid cysts contain viscous, clear material that has the same appearance as aspirates
from a tendon sheath cyst or ganglion. This material stains like colloid with Papanicolaou stain
and may well be colloid. Rare lesions of this sort that have been removed have been endothelial-
lined cavities (simple cysts).

Hemorrhagic cysts are turgid and quite firm on palpation, as bleeding has been stopped by the
pressure of the capsule. Cysts that are spongy or soft almost invariably contain water-clear or
gray-opalescent fluid. These are parathyroid cysts, and their etiology is established by a level of
cyst fluid parathormone at least three times that of blood serum.
We do not routinely examine cyst fluid for either thyroxine or parathormone, as neither
contributes to management decisions. Patients with parathyroid cysts diagnosed from the above
description are routinely checked for hyperparathyroidism.

P.506
Certain clinical observations are relevant for pathologists interpreting or performing thyroid
biopsies. Even with palpable residual after initial aspiration, obtaining a satisfactory fine-needle
biopsy specimen is difficult. Efforts made at the second or third aspiration are more apt to be
rewarding. Partial or complete recurrence of the cyst is considered presumptive evidence of
existence of part of the original nodule. Aspiration biopsy may be attempted in the suspected
area, as well as in palpable residual tissue. On second and third biopsies of nonpalpable or
barely palpable residuals of small cysts, we have identified four papillary carcinomas.

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2.Miller JM, Horn RC, Bloch MA. The autonomous functioning thyroid nodule in the evolution
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4.Hopwood NJ, Carrol RG, Kinney FM, et al. Functioning thyroid masses in children and
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