An imprint of Elsevier Inc.

FINE NEEDLE ASPIRATION CYTOLOGY

© 2007, Elsevier Inc. All rights reserved.

ISBN-13: 978-0-443-06731-0
ISBN-10: 0-443-06731-7

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any
form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the
prior permission of the Publishers. Permissions may be sought directly from Elsevier’s Health
Sciences Rights Department, 1600 John F. Kennedy Boulevard, Suite 1800, Philadelphia, PA
19103–2899, USA: phone: (+1) 215 239 3804; fax: (+1) 215 239 3805; or, e-mail: healthpermissions@
elsevier.com. You may also complete your request on-line via the Elsevier homepage (http://www.
elsevier.com), by selecting ‘Support and contact’ and then ‘Copyright and Permission’.

NOTICE

Medical knowledge is constantly changing. Standard safety precautions must be followed, but as
new research and clinical experience broaden our knowledge, changes in treatment and drug
therapy may become necessary or appropriate. Readers are advised to check the most current
product information provided by the manufacturer of each drug to be administered to verify the
recommended dose, the method and duration of administration, and contraindications. It is the
responsibility of the practitioner, relying on experience and knowledge of the patient, to
determine dosages and the best treatment for each individual patient. Neither the Publisher nor
the author assume any liability for any injury and/or damage to persons or property arising
from this publication.
The Publisher

First published 2007

British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library

Library of Congress Cataloging in Publication Data

A catalog record for this book is available from the Library of Congress

Commissioning Editor: Michael Houston

Project Development Manager: Claire Bonnet
Project Manager: Cheryl Brant
Design Manager: Louis Forgione
Marketing Manager(s) (USA/UK): Kathleen Neely/Leontine Treur Working together to grow
libraries in developing countries
Printed in China www.elsevier.com | www.bookaid.org | www.sabre.org

Last digit is the print number: 9 8 7 6 5 4 3 2 1

FM-F06731.indd iv 10/26/2006 10:18:19 AM

 List of Contributors

Fadi W Abdul-Karim, MD Shahla Masood, MD

Professor of Pathology Professor and Associate Chair
Department of Pathology University of Florida
University Hospitals of Cleveland Chief of Pathology
Cleveland, OH Department of Pathology
USA Shands Jacksonville Medical Center
Jacksonville, FL
Syed Z Ali, MD USA
Associate Professor of Pathology and Radiology
Associate Director, Division of Cytopathology Ritu Nayar, MD
Johns Hopkins University School of Medicine Associate Professor and Director of Cytopathology
Baltimore, MD Department of Pathology
USA Feinberg School of Medicine
Northwestern University
Ema A Berbescu, MD Chicago, IL
Assistant Professor of Pathology
USA
Division of Anatomic Pathology
Medical College of Virginia Marlo M Nicolas, MD
Virginia Commonwealth University Health System Genitourinary Fellow
Richmond, VA Department of Pathology
USA University of Texas, MD Anderson Cancer Center
Houston, TX
Katherine Berezowski, MD USA
Assistant Professor
Department of Pathology Anil V Parwani, MD, PhD
The George Washington University Assistant Professor
Washington, DC Department of Pathology
USA University of Pittsburgh Medical Center
Pittsburgh, PA
Martha Bishop Pitman, MD USA
Associate Professor of Pathology
Harvard Medical School Celeste N Powers, MD, PhD
Assistant Director of Cytopathology Professor and Chair
Director of the Fine Needle Aspiration Biopsy Service Division of Anatomic Pathology
Massachusetts General Hospital Medical College of Virginia
Boston, MA Virginia Commonwealth University Health System
USA Richmond, VA
USA
Yener S Erozan, MD
Professor of Pathology Natasha Rekhtman, MD, PhD
Department of Pathology Assistant, Department of Pathology
The Johns Hopkins University School of Medicine Division of Surgical Pathology
Baltimore, MD Johns Hopkins University
USA Baltimore, MD
USA
Michael O Idowu, MD
Assistant Professor of Pathology Mary K Sidawy, MD
Division of Anatomic Pathology Professor of Pathology, Director of Anatomic Pathology
Medical College of Virginia Georgetown University
Virginia Commonwealth University Health System Washington, DC
Richmond, VA USA
USA
Sana O Tabbara, MD
Igor Jovanovic, MD, PhD Professor of Pathology
Cytopathology Fellow The George Washington University
Department of Pathology Washington, DC
George Washington University USA
Washington, DC
USA

FM-F06731.indd v 10/26/2006 10:18:19 AM

 vi LIST OF CONTRIBUTORS

Paul E Wakely Jr, MD Maureen F Zakowski, MD

Department of Pathology Attending Pathologist
The Ohio State University Department of Pathology
College of Medicine Memorial Sloan-Kettering Cancer Center
Columbus, OH New York, NY
USA USA

FM-F06731.indd vi 10/26/2006 10:18:19 AM


The study and practice of anatomic pathology is both
exciting and overwhelming. Surgical pathology, with
all of the subspecialties it encompasses, and cytopathol-
ogy have become increasingly complex and sophisti-
cated, and it is not possible for any individual to master
the skills and knowledge required to perform all of
these tasks at the highest level. Simply being able to
make a correct diagnosis is challenging enough, but the
standard of care has far surpassed merely providing a
diagnosis. Pathologists are now asked to provide large
amounts of ancillary information, both diagnostic and
prognostic, often on small amounts of tissue, a task
that can be daunting even to the most experienced
pathologist.
Although large general surgical pathology textbooks
are useful resources, they by necessity could not possi-
bly cover many of the aspects that pathologists needs to
know and include in their reports. As such, the concept
behind Foundations in Pathology was born. This series
is designed to cover the major areas of surgical and
cytopathology, and each edition is focused on one major
topic. The goal of every book in this series is to provide
the essential information that any pathologist, whether
general or subspecialized, in training or in practice,
would find useful in the evaluation of virtually any type
of specimen encountered.
Dr. Mary Sidawy from Georgetown and Dr. Syed Ali
from Johns Hopkins Hospital, both outstanding and
renowned cytopathologists, have edited what I believe
to be an outstanding state-of-the-art book covering the
essential aspects of fine needle aspiration cytology. This
book cuts to the essentials of what all pathologists
who practice the art of cytopathology need to know
about this challenging field. The list of contributors is
truly impressive and includes authors who have not
FM-F06731.indd vii
Foreword
only written extensively in these areas, but, more
importantly, have been practicing cytopathologists with
vast practical experience. As with other editions in the
Foundations in Diagnostic Pathology series, the informa-
tion is presented in a straightforward and accessible
manner, including numerous practical tables and
impressive photomicrographs. Where appropriate, the
authors seamlessly integrate ancillary diagnostic
techniques including immunohistochemistry, electron
microscopy and molecular techniques, which are also
an important part of the cytopathologist’s diagnostic
armamentarium.
This edition is organized into ten chapters covering
the full spectrum of fine needle aspiration cytology in
an organ-by-organ fashion. The first three chapters
focus on aspiration cytology of salivary glands, thyroid
and lymph nodes. Drs. Abdul-Karim and Massood
provide superb discussions on the finer points of fine
needle aspiration of soft tissue tumors and tumors
of the breast. Separate chapters covering the lung,
mediastinum, liver, pancreas, kidney and adrenal
gland are also provided. The chapters are uniformly
well organized, concisely written and beautifully
photomicrographed.
I wish to extend my sincerest gratitude to Drs. Sidawy
and Ali for leading this outstanding effort. Clearly, they
poured their heart and soul into this edition of the
Foundations in Diagnostic Pathology series, and for this
I am truly grateful. I would also like to extend my appre-
ciation to the authors who took time from their busy
schedules to contribute their expertise and knowledge.
I sincerely hope you enjoy this volume of Foundations
in Diagnostic Pathology.
John R. Goldblum, M.D.
10/26/2006 10:18:19 AM
 To our families,
Tony, Michelle, and Nicholas
Tehmina, Adeel, and Sabeen

FM-F06731.indd viii 10/26/2006 10:18:19 AM


In 1930, Martin and Ellis, recognizing the value of
cytologic sampling, published a cornerstone article
entitled “Biopsy by Needle Puncture and Aspiration.”
Fine needle aspiration (FNA) began gaining momen-
tum in Europe in the 1950s; however, it was not until
the 1980s when it became widely accepted in the United
States. FNA of palpable and deep-seated lesions has
quickly grown to become a powerful diagnostic tool in
the diagnosis of neoplastic, reactive, and infectious pro-
cesses. But as we acquired more experience and knowl-
edge we developed a better appreciation of the pitfalls
and limitations in interpreting cytologic samples.
There is no paucity of published scientific material
on aspiration cytopathology; we have seen an exponen-
tial growth in the cytopathology literature paralleling its
widespread success as a medical discipline. This volume
in the series Foundations in Diagnostic Pathology, offers
several notable features. FNA of most commonly
sampled sites are presented in ten chapters authored by
experts in the field. The template format throughout the
book provides a high degree of consistency in style and
presentation. Furthermore, the use of Facts and Fea-
tures boxes allows easy access to key information. High
resolution images are the cornerstone of morphologic
discussion of any given entity with the text revolving
around issues of practical diagnostic and clinical impor-
tance. Differential diagnoses, potential pitfalls, and the
use of ancillary techniques are emphasized. Cross
FM-F06731.indd ix
Preface
referencing the histopathologic characteristics with the
cytologic features reflects our conviction that the two
disciplines are complementary.
Cytopathologists enjoy a position at the forefront of
diagnostic anatomic pathology; we intimately interact
with many disciplines of clinical medicine. Therefore,
emphasis was placed on the interpretation of morpho-
logic findings in the proper clinicoradiologic context
leading to a more meaningful and valid list of differen-
tial diagnoses of FNA interpretation.
The book is aimed primarily at pathology residents
and fellows, as well as practicing pathologists looking
for a practical overview of FNA cytopathology. Our
ultimate goal is the best patient care based on timely and
accurate FNA interpretation. It is our hope that this
book will further the understanding of FNA and its role
in patient management. We would like to thank whole-
heartedly the authors that contributed time and effort to
this project; our mentors who inspired us, and our resi-
dents and fellows for constantly challenging us at the
microscope. We sincerely hope that this book will
convey our enthusiasm to the discipline of cytopathol-
ogy, an area that we find exciting, challenging and
fulfilling in our daily practice and teaching.
Mary K. Sidawy, M.D.
Syed Z. Ali, M.D.
October 2006
10/26/2006 10:18:19 AM
 1 Salivary Glands
Sana O Tabbara
INTRODUCTION
Fine needle aspiration (FNA) of salivary glands is
widely used in the initial diagnosis of salivary gland
swellings. It is a simple procedure with limited compli-
cations that provides rapid and valuable information
for the subsequent planning of patient management.
The cytologic features of common salivary gland neo-
plasms and inflammatory processes are well recog-
nized, and accurate diagnosis is possible in most cases.
Salivary gland lesions involve most commonly the
parotid glands, followed by the submandibular glands
and the minor salivary glands. FNA of masses in the
salivary gland area serves multiple purposes: it helps
determine the origin of the mass (salivary versus non-
salivary), it sorts neoplastic from non-neoplastic pro-
cesses, and in most neoplastic cases it distinguishes
benign from malignant tumors. Reported sensitivity for
presence of tumor and specificity for absence of neo-
plasm are >90%, but accuracy for a specific diagnosis
is lower. False negative diagnoses result mostly from
sampling errors and inadequately sampled cystic lesions,
whereas false positive diagnoses are encountered mostly
in benign neoplasms with cytologic atypia and in basa-
loid lesions. In FNAs of salivary gland neoplasms where
a specific diagnosis cannot be reached, it is important to
indicate if the tumor is a low- or a high-grade neoplasm
in order to guide surgical management.
Non-neoplastic salivary gland lesions range between
50% and 60% in some large series. FNA truncates
patient management in such instances and prevents
unnecessary surgery, resulting in a 30% decrease of
surgical excisions of salivary gland lesions. Eventually,
10–15% of non-neoplastic cases on FNA will require
surgery for definitive diagnosis.
FNA of a normal salivary gland tissue yields a sparsely
cellular smear that contains a mixture of acinar cells,
ductal cells, mature adipose tissue, and scattered small
acinar bare nuclei (Fig. 1-1). Serous acinar cells are seen
in FNAs from all salivary glands. They are pyramidal-
shaped and have abundant granular or finely vacuolated
cytoplasm containing periodic acid–Schiff (PAS)-
positive diastase-resistant zymogen granules, and a
small eccentric round nucleus with an inconspicuous
nucleolus. Outside the parotid, acinar cells show both
serous and mucinous differentiation. Mucinous acinar
cells are columnar and have a pale vacuolated cyto-
Ch001-F06731.indd 1
plasm. Acinar cells are arranged in acinar clusters that
appear to have a grape-like configuration and are some-
times attached to sheets of ductal cells. Ductal cells are
less numerous than acinar cells. They are small, bland
cuboidal cells with scant dense cytoplasm and are orga-
nized in small honeycomb sheets or occasionally branch-
ing tubules.
This chapter will address mass-producing lesions of
the salivary gland that are evaluated by FNA. These
lesions will be presented according to their line of
differentiation.
NON-NEOPLASTIC LESIONS
SIALADENOSIS
Sialadenosis is a condition associated with malnutri-
tion, diabetes, bulimia, alcoholism, cirrhosis, and some
drugs such as antihypertensives. Sialadenosis occurs
mostly in the parotid and is often bilateral. Typically,
smears are cellular and comprise normal salivary gland
elements. The features differentiating such from normal
salivary gland tissue are the hypertrophic, enlarged
acinar cells; however, the size difference from normal
acinar cells is usually difficult to appreciate. When
normal tissue without an inflammatory background
is aspirated from an enlarged gland, a sampling error
should be entertained, unless the patient is proven to
have no mass lesion by additional evaluations, includ-
ing re-aspiration, radiographic evaluation, and clinical
follow-up. If all evaluations are negative, the diagnosis
of sialadenosis should be considered.
SIALADENITIS
CLINICAL FEATURES
Acute sialadenitis is usually related to infection (viral,
bacterial, fungal) and may develop as a postoperative
complication or in relation to sialolithiasis. It presents
with diffusely enlarged, tender glands, most frequently
the parotids.
1
10/26/2006 10:19:23 AM
 2 FINE NEEDLE ASPIRATION CYTOLOGY
SIALADENITIS – DISEASE FACT SHEET
Clinical Features
៉ Acute sialadenitis: infectious (viral, bacterial, fungal); enlarged
tender gland
៉ Chronic sialadenitis: duct stricture, obstruction, trauma; diffuse
gland enlargement or mass; exacerbations and remissions
៉ Granulomatous sialadenitis: infectious, systemic autoimmune
disease, rarely neoplasms
Treatment
៉ Variable, treat etiology
Chronic sialadenitis is more commonly found in the
submandibular glands and is often associated with
duct stricture, obstruction (e.g. sialolithiasis), or trauma.
Clinically, it is characterized by exacerbations and
remissions associated with eating. Chronic sialadenitis
typically presents with a diffuse gland enlargement
but may produce a mass (Kuttner tumor) that must be
differentiated from a neoplastic process. Granuloma-
tous sialadenitis may result from a variety of infections,
including mycobacterial, fungal, cat scratch, and toxo-
plasmosis, or may be associated with systemic diseases
such as sarcoidosis. Rarely, granulomatous sialadenitis
is a manifestation of malignant neoplasms such as
Hodgkin or T-cell lymphoma or metastatic carcinoma.
CYTOPATHOLOGIC FEATURES
FNA smears of acute sialadenitis contain neutrophils,
fibrin, and necrotic debris. Material for special stains
Ch001-F06731.indd 2
FIGURE 1-1
Normal salivary gland. An aggregate
of salivary gland acini surrounds
a portion of ductal epithelium
arranged as a branching tubular
structure. Acinar cells have abun-
dant granular or finely vacuolated
cytoplasm, and small, regular, round
nuclei located peripherally within
the individual cell. The ductal epi-
thelium consists of uniform cuboi-
dal cells with bland round nuclei
arranged in orderly pattern. Alcohol-
fixed, Papanicolaou stain, medium
power.
SIALADENITIS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Acute sialadenitis: neutrophils, fibrin, necrotic debris
៉ Chronic sialadenitis: variable with duration of disease; mixed
mononuclear infl ammatory cells; salivary gland epithelium,
predominantly ductal; fibrous stroma; squamous and mucous cell
metaplasias; crystalline material
៉ Granulomatous sialadenitis: epithelioid histiocytes,
multinucleated giant cells, possible necrosis
Differential Diagnosis and Pitfalls
៉ Predominance of lymphoid cells, lack of epithelium: intraparotid
lymph node
៉ Lymphocyte-rich lesions: lymphoepithelial lesion, Warthin
tumor, malignant lymphoma
៉ Epithelial metaplasia: mucoepidermoid carcinoma (SCC not
discussed)
and cultures must be obtained and may identify the
causative organisms. In chronic sialadenitis, the cellu-
lar composition of the FNA material varies with the
duration of the disease. Smears contain a heteroge-
neous population of lymphocytes admixed with benign
salivary gland tissue. Both acinar and ductal epithe-
lium may be present. In disease of long duration, the
acinar epithelium may atrophy, decreasing the number
and size of the acinar cells and making the ductal
component more prominent (Fig. 1-2). The smear back-
ground may contain mucus, debris, and/or various
crystalloids (Fig. 1-3). Spindle-shaped fibroblasts and
collagenous stromal fragments may also be noted
(Fig. 1-4). Duct obstruction may cause squamous or
mucinous metaplasia (Fig. 1-5). Granulomatous sialad-
enitis is characterized by the presence of aggregates of
10/26/2006 10:19:24 AM
 CHAPTER 1 Salivary Glands 3

FIGURE 1-2
Chronic sialadenitis. Numerous lym-
phocytes and scattered epithelial
and stromal fragments are compat-
ible with chronic sialadenitis. Typi-
cally there is a decrease in acinar
cells and a predominance of ductal
epithelium. Alcohol-fixed, Papani-
colaou stain, low power.

FIGURE 1-3
Chronic sialadenitis. Rhomboid-
shaped crystalloids are present in a
background of mononuclear infl am-
matory cells including lymphocytes
and histiocytes. Fibrin and cellular
debris are also noted. Alcohol-fixed,
Papanicolaou stain, medium power.

Ch001-F06731.indd 3 10/26/2006 10:19:24 AM

 4 FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 1-4
Chronic sialadenitis. A collagenous stromal fragment containing bland
spindle cells is a common finding in long-standing chronic sialadenitis.
A rare acinar structure is noted in the vicinity. Alcohol-fixed, Papani-
colaou stain, high power. Courtesy of Ms Jamie L Covell, The University
of Virginia Health Sciences Center.
epithelioid histiocytes and associated multinucleated
giant cells (Fig. 1-6). Epithelioid histiocytes are recog-
nized by their elongated, finely vacuolated cytoplasm
and bland, occasionally bent nuclei. Their presence is
an indication for the performance of special stains or
culture for the identification of microorganisms.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis for chronic sialadenitis
includes other patterns of sialadenitis and other sali-
vary gland lesions containing lymphocytes.
Autoimmune sialadenitis or lymphoepithelial sialad-
enitis (LESA) is most commonly related to Sjögren
syndrome. The diagnosis is usually made by the unique
clinical presentation of bilateral enlargement of the
salivary glands (parotid and, in a minority of cases,
Ch001-F06731.indd 4
submandibular) and lacrimal glands. FNA smears
consist of an abundant mixed population of lympho-
cytes, plasma cells, and tingible-body macrophages with
rare epithelial elements arranged in cohesive clusters
and infiltrated by lymphocytes, forming the characteris-
tic lymphoepithelial islands. Because these lesions have
a propensity to develop into lymphomas, immunophe-
notypic studies and flow cytometry may be useful in
selected cases.
Aspirate smears from glands with patchy involve-
ment by chronic sialadenitis may look normal, with
benign salivary gland epithelial cells and little or no
inflammation.
Extensive squamous and mucinous metaplasia in
chronic sialadenitis may produce atypical cells that can
mimic necrotizing sialometaplasia or mucoepidermoid
carcinoma. Necrotizing sialometaplasia occurs almost
exclusively in the minor salivary glands, particularly the
palate, in contrast to the typical submandibular gland
presentation of chronic sialadenitis. Moreover, the rela-
tively low cellularity of the epithelial component and
the presence of an inflammatory background in sialad-
enitis should aid in its distinction from low-grade muco-
epidermoid adenocarcinoma. Radiation sialadenitis can
result in the presence of atypical epithelial cells, but the
cellularity of these aspirates is low, in contrast to the
high cellularity of malignant neoplasms.
Intraparotid lymph nodes yield a cellular aspirate
containing a polymorphous population of lymphoid
cells with large and small lymphocytes and immuno-
blasts with few or no epithelial cells and no stromal
fragments. Aspirate from Warthin tumors that are poor
in epithelium may mimic chronic sialadenitis. Care
must also be taken to distinguish sheets of oncocytes
from sheets of squamous metaplastic cells that can be
seen in chronic sialadenitis. Lastly, malignant lym-
phoma, if suspected, can be identified by ancillary
testing.
NON-NEOPLASTIC CYSTIC LESIONS
A cystic lesion is encountered in about 5% of FNAs of
salivary glands. A cystic component in a salivary gland
mass may be neoplastic or non-neoplastic in nature.
The two most common non-neoplastic cystic lesions
encountered are HIV-associated cystic lymphoepi-
thelial lesions and mucocele/retention cysts. HIV-
associated cystic lymphoepithelial lesions may be one
of the presenting criteria for the HIV-related complex.
They occur almost exclusively in the parotid glands of
both adults and children and, in contrast to simple
lymphoepithelial cysts that are solitary and unilateral,
they are commonly multiple and bilateral. The patho-
genesis of these cysts may be due to duct obstruction,
lymphoid hyperplasia, or duct destruction related to
cell-mediated immunity. FNA produces clear to turbid,
yellow–brown fluid.
Mucocele/retention cysts are common in the sub-
mandibular and sublingual glands. A mucocele lacks a
10/26/2006 10:19:26 AM
 CHAPTER 1 Salivary Glands 5

FIGURE 1-5
Chronic sialadenitis. Long-standing
infl ammation and metaplastic
changes may produce cytologic
atypia of the ductal epithelium
represented as nuclear enlarge-
ment, hyperchromasia, and nucleoli.
The isolated nature of the change
should preclude from making a
malignant diagnosis. Air-dried, Diff-
Quik stain, high power.

FIGURE 1-6
Granulomatous sialadenitis. In a
background of lymphocytic infil-
trate, clusters of epithelioid histio-
cytes and a multinucleated giant
cell are the highlights of granulo-
matous sialadenitis. The differen-
tial diagnosis includes infectious,
autoimmune, and, less likely, neo-
plastic diseases. Alcohol-fixed,
Papanicolaou stain, high power.

lining, whereas a retention cyst may have a mixture of
squamous, columnar and oncocytic epithelial lining.
They both result from obstruction associated with
sialolithiasis.
CYTOPATHOLOGIC FEATURES
The cytologic findings in aspirates of HIV-associated
cystic lymphoepithelial lesions include a mixed popula-
tion of lymphoid cells, vacuolated and multinucleated
histiocytes, lymphohistiocytic aggregates, and scattered
mature or anucleated squamous cells in a thick protein-
aceous background (Fig. 1-7). Some cases may show
squamous metaplastic cells or glandular cells, some cili-
ated or mucinous. Normal salivary gland tissue is scant
and degenerated or absent. Cholesterol crystals have
been noted in some cases. FNA of mucus-containing
cysts are usually scantly cellular and contain scattered
histiocytes and inflammatory cells in an abundant
mucinous background. Extracellular mucin may be
recognized as pale-green (Papanicolaou stain) to pink–
red hyaline material (Romanowsky stain). Occasional
mucinous/metaplastic cell or normal salivary gland
elements may be present (Fig. 1-8). A ruptured cyst
can incite a fibroblastic reaction that shows numerous

Ch001-F06731.indd 5 10/26/2006 10:19:27 AM

 6 FINE NEEDLE ASPIRATION CYTOLOGY
elongated spindle-shaped cells associated with abun-
dant thick mucoid material.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis for benign non-neoplastic
cystic lesions includes both non-neoplastic conditions
such as LESA and chronic sialadenitis with cyst forma-
tion, as well as neoplastic diseases such as Warthin
tumor. Typically, aspirates from neoplasms are highly
Ch001-F06731.indd 6
FIGURE 1-7
HIV-associated cystic lymphoepi-
thelial lesion. Numerous small lym-
phocytes, histiocytes, some with
multinucleation, and a thick pro-
teinaceous and granular background
dominate the smears. Scattered
mature or anucleated squamous
cells are also present. Alcohol-fixed,
Papanicolaou stain, medium power.
Courtesy of Ms Jamie L Covell, The
University of Virginia Health Sci-
ences Center.
FIGURE 1-8
Mucocele/retention cyst. Abundant
thick mucoid material contains only
a rare, if any, group of benign epi-
thelial cells. Alcohol-fixed, Papani-
colaou stain, low power.
cellular; however, in scanty aspirates, these tumors
may be difficult to differentiate from non-neoplastic
conditions based on cytomorphology alone. The correct
diagnosis of a neoplastic lesion relies on the identifica-
tion of the characteristic cell type. Lymphoepithelial
cysts are lymphocyte-rich and a malignant lymphoma
may enter the differential diagnosis. Flow cytometric
analysis will resolve that differential. Lymphangioma
can produce a lymphocyte-rich fluid on aspiration. The
clinical presentation for this lesion is essential in its
recognition.
Retention cysts/mucoceles yield abundant mucoid
material with very few cells. This pattern can overlap
10/26/2006 10:19:29 AM
 CHAPTER 1 Salivary Glands
with that of an inadequately sampled mucoepidermoid
carcinoma. A residual mass and the identification of
an occasional cluster of intermediate and squamous
cells may distinguish low-grade mucoepidermoid
carcinoma.
Clinical correlation and follow-up are essential in the
management of these lesions. Furthermore, surgical
excision may be recommended to exclude malignancy
in the event of an unresolving residual mass.
TUMORS WITH STROMAL/MESENCHYMAL
DIFFERENTIATION
BENIGN MIXED TUMOR
CLINICAL FEATURES
Benign mixed tumor is the most common salivary
gland neoplasm and accounts for up to 75% of the
neoplasms in some series. They are benign, slow-
growing tumors that occur predominantly in the super-
ficial lobe of the parotid (90%), involving the tail or the
anterior portion. The submandibular gland and minor
salivary glands are less frequently affected. Benign
mixed tumor occurs in all age groups, including chil-
dren, but are seen more frequently in women (M : F =
1 : 4) in their fourth and fi fth decades. Benign mixed
tumors are treated with superficial parotidectomy with
a good margin of normal salivary gland, since enucle-
ation may leave small tumor extensions behind and
may lead to recurrences (0–4%). Recurrences are slow
growing, require a lengthy follow-up, and may be diffi-
cult to eradicate. With deep-seated tumors, multifocal
tumors, and scarring, the facial nerve may be compro-
mised, resulting in injuries. If not excised, benign
mixed tumors may reach an enormous size and poten-
tially undergo malignant transformation.
BENIGN MIXED TUMOR – DISEASE FACT SHEET
Incidence and Location
៉ Most common salivary gland neoplasm (75%)
៉ Parotid (90%) > submandibular > minor salivary glands
Gender and Age Distribution
៉ Male to female ratio is 1 : 4
៉ Age: 40 years
Prognosis and Treatment
៉ Slow growing, may reach enormous size if not removed
៉ Potential for malignant transformation if not excised
៉ Surgical excision with good margins
៉ Enucleation associated with high recurrence rate
Ch001-F06731.indd 7
7
CYTOPATHOLOGIC FEATURES
The cytologic image of benign mixed tumor is varied
and the smear appearance may differ from one FNA
pass to another, emphasizing the importance of
adequate sampling of these tumors. Typically, highly
cellular smears contain variable combinations of bland
epithelial cells, fibrillar stroma, and myoepithelial cells
(Figs 1-9 & 1-10). Epithelial cells are cuboidal, usually
arranged in honeycomb sheets and clusters; ducts,
trabeculae, glands, and papillae can be identified (Fig.
1-11). Fragments of chondromyxoid stroma, intensely
metachromatic in Diff-Quik-stained smears, and pale
blue–green in Papanicolaou-stained smears, are fibril-
lar with frayed and irregular borders and are the clue
to the diagnosis. Spindle or stellate myoepithelial cells
are embedded within the stroma. Epithelial-stromal
interdigitation and transition from spindle to epithelial
cells are characteristic features of benign mixed tumor.
Single myoepithelial cells may be present in the back-
ground and may be plasmacytoid in appearance. Single,
clear or epithelioid myoepithelial cells are typically
difficult to distinguish from single epithelial cells.
Minor variations may occur in a tumor with the
typical background and include isolated cytologic atypia,
mucinous, squamous, and, less frequently, oxyphilic
and sebaceous metaplasia (Fig. 1-12) of ductal epithe-
lium, and variability in the stromal cellularity and
appearance from myxoid to fibrocollagenous, chondroid,
or osteoid. Crystal and crystalloid deposition and intra-
nuclear inclusions may be seen. Occasionally, mixed
tumor may harbor a cystic component (7%). The cystic
BENIGN MIXED TUMOR – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Interdigitating ductal epithelial cells, some with metaplastic
changes
៉ Myoepithelial cells
៉ Chondromyxoid stroma
Histopathologic Findings
៉ Gross: rubbery, bosselated, well-circumscribed mass with small
extensions into the surrounding normal tissue
៉ Microscopic: biphasic appearance with varied epithelial and
stromal components in variable proportions
Ancillary Studies
៉ Immunoreactivity with glial fibrillary acidic protein (GFAP) is
useful in differentiating benign mixed tumor from adenoid
cystic carcinoma and basal cell adenoma
Differential Diagnosis and Pitfalls
៉ Cylindromatous areas: adenoid cystic carcinoma
៉ Scant stroma: basal cell adenoma
៉ Squamous and/or mucinous metaplasia: mucoepidermoid
carcinoma
៉ Cytologic atypia: carcinoma ex-pleomorphic adenoma
10/26/2006 10:19:30 AM
 8 FINE NEEDLE ASPIRATION CYTOLOGY
proteinaceous background is thin and should not be
misinterpreted as mucin.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Cellular mixed tumors account for about 30% of mixed
tumors and FNA may sample the predominant epithe-
lial/myoepithelial component but not the scant stromal/
mesenchymal component, leading to misclassifying
the tumor as basal cell adenoma. These cellular mixed
Ch001-F06731.indd 8
FIGURE 1-9
Benign mixed tumor. Cellular smears
show the characteristic biphasic
cellular component. Epithelial and
stromal elements interdigitate with
each other. The stroma is pale blue–
green and has irregular edges and
a fibrillar nature. Courtesy of Ms
Jamie L Covell, The University of
Virginia Health Sciences Center.
Alcohol-fixed, Papanicolaou stain,
low power.
FIGURE 1-10
Benign mixed tumor. The stroma
appears metachromatic and can
vary from dense to more diffuse in
the smear background. A number of
single epithelial and myoepithelial
cells are typically present and are
not a sign of malignancy. Air-dried,
Diff-Quik stain, low power.
tumors have a distinctive low-power pattern composed
predominantly of loosely cohesive branching and arbo-
rizing groups of cells having indistinct community
borders. Frequently, the stroma associated with cellular
mixed tumor is fibrocollagenous, dense, and courses
within the branching epithelial clusters (Fig. 1-13). The
cells have scant cytoplasm, oval to round nuclei with
finely granular chromatin, and lack distinct nucleoli.
Occasional spindling of the cells is observed (Fig. 1-14).
Nuclear overlap and haphazard arrangement is a
common finding. Scattered plasmacytoid single cells
with moderate amount of cytoplasm are seen in most
cases.
10/26/2006 10:19:31 AM
 CHAPTER 1 Salivary Glands 9

FIGURE 1-11
Benign mixed tumor. Bland epithe-
lial cells are embedded into the
fibrillar mesenchymal stroma and
there is gradual transition into
spindle and stellate mesenchymal
cells that also populate the stroma.
Alcohol-fixed, Papanicolaou stain,
high power.

FIGURE 1-12
Benign mixed tumor. Sebaceous
metaplasia is rare in salivary gland
neoplasms. The metaplastic cells
resemble histiocytes. Round uniform
nuclei are centrally located in an
abundant vacuolated cytoplasm.
The vacuoles are small and punched
out and distend the cytoplasm.
Single myoepithelial cells and a
stromal fragment are present in
the background. Air-dried, Diff-Quik
stain, high power.

Increased cellularity coupled with focal cytologic
atypia is encountered in about 20% of tumors and
should not be considered a sign of malignancy when the
overall picture is that of benign mixed tumor. A cylin-
dromatous pattern occurs in 5% of mixed tumors and
should not elicit a diagnosis of adenoid cystic carcinoma
if occasional (Fig. 1-15); and scattered squamous and
mucinous metaplasia should not result in a diagnosis
of mucoepidermoid carcinoma. In some tumors, these
metaplastic changes may be present in association with
a highly myxoid background mimicking a mucinous
background, which may further confound the situation.
A predominant plasmacytoid/hyaline cell population
may mimic the intermediate cells of mucoepidermoid
carcinoma. Mucoepidermoid carcinoma is a difficult
diagnosis to make in FNA and requires the identifica-
tion of squamous, intermediate polygonal cells and
vacuolated mucinous cells, in an acellular mucinous
stringy background.
Tumors rich in plasmacytoid/hyaline myoepithelial
cells may also be interpreted as myoepitheliomas, acinic
cell carcinoma, or oncocytic. Predominance of spindle
myoepithelial cells elicits the differential diagnosis of
spindle cell proliferation including benign reactive pro-
cesses such as nodular fasciitis, pseudotumors, periph-
eral nerve sheath tumors, and spindle cell sarcomas.

Ch001-F06731.indd 9 10/26/2006 10:19:32 AM

 10
Myoepithelial cells have a characteristic immunoprofile
that allows their recognition and helps in the classifica-
tion of such tumors.
MALIGNANT MIXED TUMOR
Carcinoma ex-pleomorphic adenoma is rare and devel-
ops in up to 10% of cases of benign mixed tumor.
Malignant changes are suggested by sudden rapid
growth, pain, and facial paralysis in a patient with a long-
Ch001-F06731.indd 10
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 1-13
Cellular mixed tumor. Branching and
arborizing clusters of epithelial
cells are found amidst numerous
single cells. The stroma appears
dense, fibrocollagenous rather than
the typical fibrillar stroma seen in
benign mixed tumor, and courses
within the epithelial clusters.
Alcohol-fixed, Papanicolaou stain,
medium power.
FIGURE 1-14
Cellular mixed tumor. Single cells in
the background show variability in
shape and size. Some are plasmacy-
toid in appearance, while others are
more spindled, suggesting myo-
epithelial differentiation. The pres-
ence of variable nuclear atypia
including dark but smudgy chroma-
tin is not sufficient for a diagnosis
of carcinoma. Alcohol-fixed, Papani-
colaou stain, high power.
standing, slow-growing mass. The malignant changes
occur in a background of mixed tumor, and the diagno-
sis requires microscopic documentation of previous
benign mixed tumor. The malignant tumor is usually
a high-grade carcinoma, and could show differentiation
toward any of the usual primary carcinomas of the
salivary gland. The carcinoma is characterized by high
cellularity with cellular groups or sheets, and papillary
clusters of large cells with pleomorphic nuclei, promi-
nent nucleoli, and finely vacuolated cytoplasm domi-
nating the smears. Necrosis may be prominent in the
background and mitoses are increased (Fig. 1-16). As
opposed to the focal nature of metaplasia and atypia
10/26/2006 10:19:34 AM
 CHAPTER 1 Salivary Glands 11

FIGURE 1-15
Benign mixed tumor. A focal cylin-
dromatous pattern in this tissue
fragment is characterized by the
small metachromatic globules of
extracellular matrix embedded
within the epithelial group. These
findings overlap with those of basal
cell adenoma and resemble archi-
tectural features of adenoid cystic
carcinoma. The background protein-
aceous material reflects the cystic
nature of this lesion. Air-dried,
Diff-Quik stain, medium power.

A B

FIGURE 1-16
Malignant mixed tumor. A, Superimposed on findings of mixed tumor is a carcinoma with atypical discohesive cells with hyperchromatic pleomorphic
nuclei, coarsely granular chromatin, and a high N/C ratio. Alcohol-fixed, Papanicolaou stain, high power. B, Similar malignant cytologic features
are noted in addition to a mitotic figure. Air-dried, Diff-Quik stain, high power.

Ch001-F06731.indd 11 10/26/2006 10:19:35 AM

 12 FINE NEEDLE ASPIRATION CYTOLOGY

A B

FIGURE 1-17
Carcinosarcoma. A, A malignant epithelial cluster consists of crowded overlapping cells with cytologic atypia. B, Mesenchymal cells with atypical
nuclei are embedded in a chondromyxoid matrix material and establish the presence of a biphasic malignant neoplasm. Alcohol-fixed, Papanicolaou
stain, high power.

associated with cellular mixed tumor, features of malig- ponent is ductal and the mesenchymal component is
nancy are cytologically obvious in malignant mixed chondrosarcomatous. These tumors are highly aggres-
tumor. These tumors have a good prognosis if the sive and rapidly fatal.
changes are confined to the pre-existing mixed tumor.
The prognosis depends on the histologic type, grade,
proliferative index, and extent of invasion beyond the
capsule of the pre-existing tumor. MYOEPITHELIAL NEOPLASMS

CARCINOSARCOMA Myoepithelioma may be considered a variant of pleo-

True malignant mixed tumor is extremely rare and
has a biphasic composition of malignant epithelial
and mesenchymal elements. The aspirate is cellular
and contains large cell clusters and dissociated cells
with marked atypia and a background amorphous sub-
stance (Fig. 1-17). The diagnosis can be established on
cytology only if both sarcomatous and carcinomatous
elements are sampled. Frequently, the epithelial com-
morphic adenoma and is thought to consist solely of
myoepithelial cells. Myoepithelial cells have three dif-
ferent appearances to include plasmacytoid or hyaline
cells with dense, moderate to abundant, well-
demarcated cytoplasm, glycogen-rich clear cells, and
spindle cells. Myoepitheliomas can display a mixture
of those cell types. Most hyaline cell-type tumors occur
in minor salivary glands such as in the palate, whereas
spindle and clear cell myoepitheliomas are primarily
encountered in the parotid gland. Most hyaline cell

Ch001-F06731.indd 12 10/26/2006 10:19:38 AM

 CHAPTER 1 Salivary Glands 13

FIGURE 1-18
Myoepithelioma. A loosely cohesive
sheet and single cells with plasma-
cytoid features have eccentrically
placed nuclei and a moderate
amount of dense well-demarcated
cytoplasm. Mild nuclear variability
is noted. Courtesy of Ms Jamie L
Covell, The University of Virginia
Health Sciences Center. Alcohol-
fixed, Papanicolaou stain, high
power.

myoepitheliomas will behave as benign neoplasms,
whereas some spindle and clear cell tumors will present
with malignant infi ltrative features and may have
malignant potential with possible local recurrence,
metastases, and tumor-related death.
Cytologically, myoepitheliomas differ from mixed
tumors by the absence of stroma and epithelial cells and
by the presence of a dominant myoepithelial cell popula-
tion arranged in loose groups and single cells (Fig. 1-18).
Hyaline cell myoepithelioma can be distinguished from
plasma cell neoplasm by the nuclear chromatin pattern
and lack of perinuclear Hoff and plasma cell markers
(CD79a and CD138). Spindle cell neoplasms such as
peripheral nerve sheath tumors and low-grade spindle
cell sarcomas should be considered in the differential
diagnosis of spindle cell myoepitheliomas. Lastly, clear
cell myoepithelioma enters the differential diagnosis of
other clear cell neoplasms occurring in the salivary
glands, such as acinic cell carcinoma, mucoepidermoid
carcinoma, epithelial-myoepithelial carcinoma, and
metastatic renal cell carcinoma. The myoepithelial
nature of such tumors can be confirmed by the demon-
stration of staining with one or more of the following:
S-100 protein, smooth muscle actin, calponin, cytokera-
tin, and glial fibrillary acidic protein (GFAP). Addition-
ally, a myoepithelial-rich mixed tumor should always
be considered in the evaluation of an aspirate from a
myoepithelial-dominant tumor.
Epithelial-myoepithelial carcinomas are low-grade
myoepithelial-rich tumors that are locally aggressive.
They consist of two cell populations: the small dark
ductal cells arranged in tight clusters and the larger clear
myoepithelial cells with moderate to abundant cyto-
plasm, vesicular nuclei, and conspicuous nucleoli, which
predominate. The clear cells are large, polygonal, and
glycogen-rich, with mildly atypical nuclei and small
nucleoli, and demonstrate S-100 positivity characteris-
tic of myoepithelial differentiation. Some tumor cell
clusters may be surrounded by amorphous hyaline
material. Cellular arrangements with acellular basement
membrane material reminiscent of adenoid cystic carci-
noma may also be found (Fig. 1-19). These tumors may
share features with both mixed tumors and basaloid
neoplasms, as they consist of basaloid cells and stroma
that forms spherules or has an irregular, somewhat
fibrillar appearance.
ONCOCYTIC NEOPLASMS
WARTHIN TUMOR
CLINICAL FEATURES
Warthin tumors occur almost exclusively in the parotid
and are thought to arise from entrapped salivary duct
remnants within intra- or periparotid lymph nodes.
They are more common in men in the sixth decade and
older. The incidence in women is on the rise, as this
tumor shows a statistical relationship with smoking.
Warthin tumors are commonly multicentric (10–15%),
and bilateral; they constitute 70% of all bilateral sali-
vary gland neoplasms. The treatment is surgical exci-
sion, and recurrences may occur but are uncommon.
Malignant transformation in Warthin tumors is a rare
event, and may occur in either the epithelial or
lymphoid component.

Ch001-F06731.indd 13 10/26/2006 10:19:39 AM

 14 FINE NEEDLE ASPIRATION CYTOLOGY

A B

FIGURE 1-19
Myoepithelial carcinoma. A, Metachromatic stromal fragment with features similar to those seen in benign mixed tumor contains a large number
of basaloid cells. Air-dried, Diff-Quik stain, high power. B, Oval hyperchromatic nuclei with finely granular chromatin and scant cytoplasm with
short tapered cytoplasmic ends suggest a myoepithelial rather than epithelial differentiation of the basaloid cells. Courtesy of Ms Jamie L Covell,
The University of Virginia Health Sciences Center. Alcohol-fixed, Papanicolaou stain, high power.

WARTHIN TUMOR – DISEASE FACT SHEET WARTHIN TUMOR – PATHOLOGIC FEATURES

Incidence and Location Cytopathologic Findings

៉ Second most common salivary gland neoplasm (5–10%) ៉ Mixed population of lymphocytes
៉ Most common bilateral salivary gland neoplasm (70%) ៉ Small sheets of oncocytes
៉ Exclusively in the parotid ៉ Granular proteinaceous background
៉ Multicentric ៉ Metaplastic cells

Gender and Age Distribution Histopathologic Findings

៉ Male to female ratio is 5 : 1 ៉ Gross: lobulated mass, multicystic with fl uid-filled spaces
៉ Age >50 years separated by grayish septae; hemorrhagic infarcts post FNA are
common
Prognosis and Treatment ៉ Microscopic: typically, cystic lesion with prominent lymphoid
៉ Surgical excision with good margins tissue containing frequent germinal centers covered by
៉ Potential for recurrence oncocytes arranged in two layers, resulting in a papillary-like
architecture

Differential Diagnosis and Pitfalls

CYTOPATHOLOGIC FEATURES
Characteristically, Warthin tumors are multicystic and
yield a turbid brown fluid. Microscopically, a classic
dirty proteinaceous background (Fig. 1-20), and a
mixed but maturing population of lymphocytes and
scattered groups of oncocytes characterize these tumors
(Fig. 1-21). The lymphoid population is comprised pre-
dominantly of small lymphocytes and fewer larger cells
showing an ordered maturational sequence and por-
tions of germinal centers. A variable amount of uniform
oncocytic epithelium is present in small sheets without
crowding. The oncocytes have abundant granular cyto-
plasm, round uniform nuclei, even chromatin, and con-
spicuous nucleoli (Fig. 1-22). Frequently, the two cell
populations are intermixed within the same cellular
៉ Cystic lesions: lymphoepithelial cyst, branchial cleft cyst,
papillary cystadenoma
៉ Lesions with lymphoid component: chronic sialadenitis, benign
lymphoepithelial cyst, lymph node, lymphoma, acinic cell
carcinoma
៉ Oncocytic neoplasms
៉ Intraductal papilloma
៉ Other neoplasm such as squamous carcinoma or mucoepidermoid
carcinoma in association with epithelial metaplasia
៉ Infarct-like necrosis: malignant neoplasms
groups. Occasionally, pseudopapillary arrangements
may be present, consisting of two oncocytic cell layers
surrounding lymphoid aggregates.
Cytologic variants may include the presence of
focal squamous or mucinous metaplasia similar to that
seen in benign mixed tumor. Granulomas formed by

Ch001-F06731.indd 14 10/26/2006 10:19:40 AM

 CHAPTER 1 Salivary Glands 15

FIGURE 1-20
Warthin tumor. Large pools of
thick proteinaceous material are
easily identified among numerous
lymphocytes and scattered small
epithelium groups. The protein-
aceous material, which may have
some similarity to mucin pools, cor-
responds to the aspirated cyst
fluid. Air-dried, Diff-Quik stain,
high power.

FIGURE 1-21
Warthin tumor. Small fl at sheets of
oncocytes and lymphocytes in all
stages of maturation are the two
cell populations characteristic of
this tumor. Alcohol-fixed, Papanico-
laou stain, medium power.

both epithelioid histiocytes and multinucleated giant
cells (sarcoid type) can be seen in some cases. The
pathogenesis of granulomas is unknown, and could be
related to a toxic effect of the cyst content. Non-tyrosine
crystalloids similar to those seen in sialolithiasis and
sialadenitis, as well as corpora amylacea have been
described in association with Warthin tumors, and are
found in highest concentration in cystic and luminal
spaces.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Potential sources of diagnostic pitfalls in Warthin
tumors may be caused by the presence of dominant
morphologic features or atypical features. Such factors
may involve the epithelial component or the lymphoid
component. A scanty lymphoid component with a pre-
dominance of oncocytic cells may suggest a neoplasm

Ch001-F06731.indd 15 10/26/2006 10:19:41 AM

 16
such as oncocytoma or a bland oncocytic carcinoma. In
oncocytic neoplasms, oncocytes are organized in large
sheets rather than in the small clusters seen in Warthin
tumors; there is also a lack of the background protein-
aceous material. Intraductal papilloma of the salivary
gland is another cystic neoplasm that may have a pre-
dominance of oncocytic epithelium. In these rare cases,
the oncocytes are arranged in a striking papillary con-
figuration with a total absence of lymphocytes in the
background.
Squamous metaplasia can occur in Warthin tumors.
Such metaplastic changes have been reported in patients
with a previous history of FNA and in patients with
spontaneous infarction of a Warthin tumor. Infarcted
Warthin tumors may yield necrotic material that may
suggest a malignant neoplasm.
Also included in the differential diagnosis are lesions
of the salivary glands with lymphoid component. Benign
lymphoepithelial cysts overlap with Warthin tumors.
The lymphoid population is similar in both lesions.
Separating the two entities requires focusing on the
epithelial component, and identifying oncocytes for
Warthin tumor, or occasional mature and parakeratotic
squamous cells or columnar cell ghosts for lymphoepi-
thelial cysts. Variants of chronic sialadenitis or benign
lymphoepithelial lesions may mimic Warthin tumor but
are typically characterized by an intense inflammatory
response and a different mix of epithelial cells, includ-
ing ductal and some acinar epithelium. Lymph nodes
present within salivary glands constitute another diag-
nostic pitfall, but may be easily recognized when an
almost complete absence of an epithelial component is
noted. Acinic cell carcinoma with lymphoid component
will also enter the differential diagnosis. Acinic cell car-
cinoma will typically have a more abundant epithelial
component. The cytoplasm in acinic cell carcinoma will
Ch001-F06731.indd 16
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 1-22
Warthin tumor. Uniform oncocytes
are orderly arranged in this sheet
and appear to line up at the edge,
suggesting a papillary configura-
tion. The cells have the character-
istic round nuclei with conspicuous
nucleoli and abundant dense but
granular cytoplasm. Air-dried, Diff-
Quik stain, high power.
show vacuolization and granularity and will be more
delicate than the cytoplasm of oncocytes. Architectur-
ally, attempt at acinar formation can be found in acinic
cell carcinoma, whereas acini or glandular aggregates
are lacking in Warthin tumors.
Patients with Warthin tumors are at increased risk
of developing malignant lymphoma. When malignant
lymphoma is suspected, clonality of the cytologic
material can be proven by immunocytochemistry, flow
cytometry, or molecular studies to demonstrate gene
rearrangement.
ONCOCYTOMA AND ONCOCYTIC
CARCINOMA
Oncocytoma is a rare benign neoplasm that involves
mainly the parotid gland in patients over 70 years of
age. Oncocytomas produce a well-defined, solid, par-
tially encapsulated mass and yield a pure population of
oncocytes by FNA. Oncocytes have abundant dense
granular cytoplasm, central round nuclei, and conspic-
uous nucleoli. They occur in large sheets in a clean
background devoid of lymphocytes and proteinaceous
material. The differential diagnosis of oncocytoma is
oncocytosis and Warthin tumor. The malignant coun-
terpart of oncocytoma is oncocytic carcinoma, which
may not always be easy to diagnose based on cytologic
features alone. Oncocytic carcinoma is a diagnosis of
exclusion after ruling out oncocytic variants of other
more common tumors such as mucoepidermoid carci-
noma. Oncocytic carcinoma may be suspected in cyto-
logic preparations in the presence of atypia, mitosis,
and necrosis.
10/26/2006 10:19:42 AM
 CHAPTER 1 Salivary Glands 17

BASALOID NEOPLASMS BASAL CELL ADENOMA – DISEASE FACT SHEET

Location
៉ Parotid
This section addresses a group of salivary gland neo-
plasms that share cytologic features and cellular compo-
Gender and Age Distribution
sition, therefore resulting in overlapping findings on
៉ Slight predilection for females
FNA and creating diagnostic dilemmas and pitfalls.
៉ Age >50 years
These tumors consist of epithelial and myoepithelial
cells with bland nuclear features and scant cytoplasm,
Clinical Features
giving them a basaloid appearance. They also have vari-
៉ Presentation similar to benign mixed tumor
able amounts of extracellular matrix that may be hyalin-
ized, forming globules and cylinders enrobed within the
Prognosis and Treatment
cells. This group of tumors includes basal cell adenoma,
៉ Surgical excision with good margins
basal cell adenocarcinoma, adenoid cystic carcinoma,
៉ Potential for malignant transformation to adenoid cystic
polymorphous low-grade adenocarcinoma, and some carcinoma or basal cell adenocarcinoma
myoepithelial neoplasms. As a result of their shared
features, they also share their differential diagnoses.

BASAL CELL ADENOMA CYTOPATHOLOGIC FEATURES

CLINICAL FEATURES Smears are moderately cellular and consist of variably

Basal cell adenomas are tumors of the parotid gland
that have a slight female predilection. Their clinical
presentation is similar to that of benign mixed tumors,
although they tend to occur in an older age group.
Specific subtypes have been recognized, such as the
membranous type for its more aggressive clinical course
and association with skin tumors (cylindromas), and
the canalicular type for its location in the upper lip.
Treatment of these tumors is by complete excision.
sized, dark-appearing, densely packed clusters of mono-
morphic basaloid cells. Some clusters may display irreg-
ular branching and trabecular patterns. Peripheral
palisading of basaloid cells may be noted. A variable
number of single cells and naked nuclei are present in
the background (Fig. 1-23). The basaloid cells are
uniform with round nuclei, scant cytoplasm, well-
defined cell borders, and a high nuclear to cytoplasmic
(N/C) ratio. The chromatin is bland and nucleoli are
inconspicuous. Single basaloid cells lack the character-
istic plasmacytoid appearance of single myoepithelial

FIGURE 1-23
Basal cell adenoma. Single basaloid
cells with bland uniform oval nuclei
and scanty well-defined cytoplasm
lack the plasmacytoid appearance
of myoepithelial cells of benign
mixed tumor. Some cells are
arranged in a pseudoacinar forma-
tion surrounding the extracellular
matrix. Courtesy of Ms Jamie L
Covell, The University of Virginia
Health Sciences Center. Air-dried,
Diff-Quik stain, high power.

Ch001-F06731.indd 17 10/26/2006 10:19:43 AM

 18
BASAL CELL ADENOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Monomorphic bland basaloid cells
៉ Variably sized clusters, branching and trabecular pattern
៉ Peripheral palisading
៉ Single cells and bare nuclei
៉ Small hyaline globule and cylinders of extracellular matrix
៉ Thick ribbon of extracellular matrix around nests and tubules
(membranous type)
៉ Poorly defined stromal–epithelial interface
Histopathologic Findings
៉ Gross: encapsulated, often cystic
៉ Microscopic:
៉ Tubular, trabecular, or solid
៉ Peripheral palisading of cells at the edge of epithelial nests
៉ Abundant extracellular matrix at periphery and within nests
(cylindromatous pattern) in membranous type (unclear)
cells seen in pleomorphic adenoma. Within the clus-
ters, metachromatic/clear (Romanowsky/Papanicolaou
stains) stromal hyaline globules and cylinders sur-
rounded by basaloid cells are easily identified. Typi-
cally, the globules are small and the stromal edge is
poorly defined and interdigitates with the surrounding
cells (Fig. 1-24). Irregularly shaped stromal fragments
may be focally encountered within or at the periphery
of the clusters and represent the fibrous supporting
stroma. The fibrillar stroma of benign mixed tumor is
absent.
The cytologic findings in the membranous type of
basal cell adenoma are distinctive and allow for its
Ch001-F06731.indd 18
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 1-24
Basal cell adenoma. Cluster of basa-
loid cells containing small uniform
metachromatic stromal globules of
extracellular matrix. The globule
edges are poorly defined and
interdigitate with the surrounding
cells. Air-dried, Diff-Quik stain,
high power.
identification by FNA. Solid nests and tubular struc-
tures formed by basaloid cells are surrounded by a
thick ribbon of hyalinized basement membrane-
like material. The neoplastic cells show peripheral
palisading at the periphery of the clusters (Fig. 1-25).
Scattered hyaline globules can be seen within the cell
groups.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
See page 22.
BASAL CELL ADENOCARCINOMA
Basal cell adenocarcinoma is a rare, recently recog-
nized entity. It affects patients in the sixth decade of
life and occurs predominantly in the parotid. It is cyto-
logically similar to basal cell adenoma. The presence of
mitoses and nuclear atypia including prominent nucle-
oli may point to the malignant nature of the tumor.
However, the malignant nature of the process may be
difficult to ascertain, as it is impossible to determine
from FNA material the invasive nature of the tumor.
Invasion is primarily a histologic feature that sets it
apart from basal cell adenoma. Basal cell adenocarci-
noma is associated with perineural invasion and tends
to overexpress p53, bcl2, and EGFR. Its clinical course
may include local recurrences, and lymph node and
distant metastases, primarily to the lung. For the dif-
ferential diagnosis, see page 22.
10/26/2006 10:19:44 AM
 CHAPTER 1 Salivary Glands 19

FIGURE 1-25
Basal cell adenoma. Basaloid cells
show peripheral palisading at the
edge of this large solid cluster of
monomorphic cells. A ribbon of
stroma is noted surrounding the
cluster, a feature that suggests a
membranous pattern of basal cell
adenoma. Alcohol-fixed, Papanico-
laou stain, medium power.

ADENOID CYSTIC CARCINOMA
CLINICAL FEATURES
Adenoid cystic carcinoma is rare, and occurs with less
frequency than mucoepidermoid and acinic cell carci-
noma in the parotid gland. It is, however, the most
common malignancy in minor salivary glands. Adenoid
cystic carcinoma occurs more frequently in women in
the fi fth to sixth decade and has a slow, relentless
growth. It may present with a painful mass or facial
nerve paralysis. Radical resection is the treatment of
choice, and cure following recurrence is difficult to
ADENOID CYSTIC CARCINOMA – DISEASE FACT SHEET
achieve. Radiation therapy is not curative but may
produce temporary regression in unresectable cases.
Prognostic factors include tumor grade and stage, status
of surgical margins, anatomic site, and tumor size.
Adenoid cystic carcinoma has a high recurrence rate
even in well-differentiated tumors and is associated
with frequent lung and bone metastases. It has a pro-
tracted course and a low 15–20-year survival.
CYTOPATHOLOGIC FEATURES
Well-differentiated tumors are composed of small
basaloid cells, both ductal and myoepithelial, in solid

ADENOID CYSTIC CARCINOMA – PATHOLOGIC FEATURES

Incidence
៉ Rare in major salivary glands
Cytopathologic Findings
៉ Most common malignancy in minor salivary gland
៉ Small basaloid cells
៉ Solid clusters, spherules, cylinders
Gender and Age Distribution
៉ Hyalinized, acellular, large stromal fragments
៉ More frequent in women in the 5th and 6th decade ៉ Well-defined stromal edges
៉ Sharp stromal–epithelial interface
Clinical Features
៉ Slow relentless growth Histopathologic Findings
៉ Pain and facial nerve paralysis ៉ Gross: solid mass, infiltrative borders
៉ Microscopic:
Prognosis and Treatment ៉ Cribriform nests with pseudocysts
៉ Radical surgical excision with clear margins ៉ Tubular and solid patterns
៉ High recurrence rate and metastases to lung and bone ៉ Perineural invasion
៉ Low survival rate ៉ Strong staining with CD117 (c-kit protein)

Ch001-F06731.indd 19 10/26/2006 10:19:45 AM

 20
clusters, spherules, and cylinders, or in cribriform
groups (Fig. 1-26). The cells are uniform with round to
oval, sometimes angulated nuclei, scant cytoplasm, and
a high N/C ratio. The chromatin varies from fine to
coarse and nucleoli are small but conspicuous (Fig.
1-27). The basaloid cells surround intensely metachrom-
atic (Romanowsky stain) or pale and glassy (Papanico-
laou stain) stromal spheres and cylinders. The stromal
fragments are larger than those seen in monomorphic
adenoma; they are variably sized, acellular, and sharply
demarcated with smooth rounded edges (Fig. 1-28). In
some cases, the predominant finding is that of spherical
Ch001-F06731.indd 20
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 1-26
Adenoid cystic carcinoma. Large
variably sized metachromatic stro-
mal globules and small clusters of
bland basaloid cells are the classic
finding. Some of the stromal glob-
ules are rimmed by a row of basaloid
cells that are barely touching the
stromal fragment. Note the size dif-
ference of the stromal globules and
the lack of cell/stroma interdigita-
tion in comparison with basal cell
adenoma. Air-dried, Diff-Quik stain,
medium power.
FIGURE 1-27
Adenoid cystic carcinoma. The cells
are uniform with a high N/C ratio,
round to oval nuclei, and an occa-
sional angulated nuclear membrane.
Chromatin is fine and even, and
nucleoli are small but conspicuous.
ThinPrep, Papanicolaou stain, oil.
or cylindrical stromal fragments lying bare or sur-
rounded by a single discontinuous rim of basaloid
cells that seem to hardly touch the stromal surface.
Conversely, the poorly differentiated or solid form of
adenoid cystic carcinoma will have few stromal glob-
ules, a predominance of basaloid cells, and more promi-
nent nuclear atypia (Fig. 1-29). Special stains and
immunocytochemistry do not provide significant dif-
ferentiating features, except for CD117 (c-kit), which is
strongly immunoreactive in adenoid cystic carcinoma
in comparison with other basaloid tumors and may be
of diagnostic consideration.
10/26/2006 10:19:46 AM
 CHAPTER 1 Salivary Glands 21

DIFFERENTIAL DIAGNOSIS AND PITFALLS

See page 22.

POLYMORPHOUS LOW-GRADE
ADENOCARCINOMA

Polymorphous low-grade adenocarcinoma is a neoplasm

of minor salivary glands. It has rarely been reported in
the parotid gland and affects women more often than
men. Its most common location is the palate, where it
follows adenoid cystic carcinoma in frequency. Smears
are characterized by the presence of tubules, cords,
linear groupings, and branching papillary sheets and

POLYMORPHOUS LOW-GRADE ADENOCARCINOMA –

DISEASE FACT SHEET

Incidence and Location

៉ Second most common salivary gland neoplasm in palate
៉ Minor salivary glands, palate

Gender and Age Distribution

៉ More common in females
៉ Age: adult

Prognosis and Treatment

FIGURE 1-28
Adenoid cystic carcinoma. A bare stromal fragment may be the predominant
finding. Note the dense hyalinized appearance of the stroma and the sharply
demarcated contour. Globules, as well as cylindrical and more complex
structures, are common. Air-dried, Diff-Quik stain, medium power.
៉ Comprehensive surgical excision with clear margins
៉ Potential for recurrence and lymph node metastases
៉ No distant metastases

FIGURE 1-29
Adenoid cystic carcinoma. Poorly
differentiated tumors consist of
densely packed basaloid cells with
more obvious nuclear atypia and a
scant stromal component. The lack
of nuclear molding and neuroendo-
crine chromatin pattern helps dif-
ferentiate this tumor from a small
cell undifferentiated carcinoma.
Air-dried, Diff-Quik stain, medium
power.

Ch001-F06731.indd 21 10/26/2006 10:19:47 AM

 22
clusters (Fig. 1-30). Hyaline globules are identified
within the sheets of basaloid epithelium. Cytologic
uniformity or monomorphism is key; the tumor is com-
posed of basaloid, bland, uniform cells with round to
oval nuclei, dispersed chromatin, inconspicuous or
absent nucleoli, and scant cytoplasm (Fig. 1-31). Mild
nuclear variability can be seen, and mitoses are absent.
Treatment is by surgical excision with clean margins,
as recurrences are difficult to eradicate. Like adenoid
cystic carcinoma, this tumor has a predilection for
perineural invasion; however, it typically is a favor-
able actor, with local recurrences and regional lymph
nodes metastases described, but overall absent distant
metastases.
Ch001-F06731.indd 22
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 1-30
Polymorphous low-grade adenocar-
cinoma. Large tissue fragments
composed of monotonous uniform
cells display a branching papillary
architecture, one of the patterns
encountered in this tumor. Air-
dried, Diff-Quik stain, low power.
FIGURE 1-31
Polymorphous low-grade adenocar-
cinoma. Within the sheet of uniform
basaloid-appearing cells are small
stromal globules that bear resem-
blance to those seen in basal cell
adenoma and adenoid cystic carci-
noma and help differentiate this
lesion from other papillary neo-
plasms. Air-dried, Diff-Quik stain,
high power.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Tumors comprised of basaloid cells, such as basal cell
adenoma, adenoid cystic carcinoma, polymorphous
low-grade adenocarcinoma, and basal cell adenocarci-
noma, share cytologic features, and therefore all enter
the same differential diagnosis. Distinction between
basal cell adenoma and cellular mixed tumor may be
difficult, but is of no significant consequence since both
are benign tumors that are treated in a similar fashion.
Cells of basal cell adenoma show a uniform orderly cel-
lular arrangement with no loss of polarity, as opposed
to the haphazard arrangement in cellular pleomorphic
10/26/2006 10:19:49 AM
 CHAPTER 1 Salivary Glands
POLYMORPHOUS LOW-GRADE ADENOCARCINOMA –
PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Monomorphous bland basaloid cells
៉ Tubules, cords, linear groupings, and branching papillary sheets
៉ Hyaline globules within sheets of epithelial cells
Histopathologic Findings
៉ Uniformity of cell type
៉ Architectural variability: tubular, cribriform, papillary, solid,
and fascicular
៉ Infiltrative border
៉ Perineural invasion
Differential Diagnosis and Pitfalls (for all basaloid neoplasms)
៉ Basal cell adenoma
៉ Cellular pleomorphic adenoma
៉ Adenoid cystic carcinoma
៉ Polymorphous low-grade adenocarcinoma
៉ Basal cell adenocarcinoma
៉ Myoepithelial carcinoma
៉ Metastatic basal cell carcinoma
adenoma. The individual cells in basal cell adenoma
have a small rim of cytoplasm and lack the plasma-
cytoid appearance of myoepithelial cells seen in benign
mixed tumor.
Basal adenoma closely resembles adenoid cystic carci-
noma and may be difficult to distinguish from it cytologi-
cally in the individual case. The unique appearance of the
cell–stroma interface is useful in distinguishing between
basal adenomas and adenoid cystic carcinoma. In basal
cell adenoma the collagenous stroma interdigitates with
the adjacent cells, whereas in adenoid cystic carcinoma
there is a sharp demarcation of cells and stroma. The
spherules in basal cell adenoma are small and somewhat
uniform in size, whereas in adenoid cystic carcinoma
they are large and variable in size and shape. The stroma
of basal adenoma may contain some spindle cells and
capillaries, whereas the stroma of adenoid cystic carci-
noma is acellular. The stroma of solid adenoid cystic
carcinoma may mimic that seen in cellular mixed tumor.
It, however, represents a desmoplastic stroma. Any
abnormality of the chromatin and the presence of promi-
nent nucleoli favor a diagnosis of adenoid cystic carci-
noma over basal cell adenoma. The solid variant of
adenoid cystic carcinoma may also resemble small cell
undifferentiated carcinoma or basaloid squamous carci-
noma. Basal cell adenocarcinoma, as previously stated,
cannot be differentiated cytologically from basal cell
adenoma since presence of invasion is the determining
factor. Polymorphous low-grade adenocarcinoma may
be suspected because of its location and the detection
of architectural patterns that are not characteristic of
adenoid cystic carcinoma, such as papillary features.
Although less common, other tumors such as myoepithe-
lial carcinoma and metastatic basal cell carcinoma should
also be considered in the differential diagnosis. The major
dilemma in this group of tumors is to separate, on cyto-
Ch001-F06731.indd 23
23
logic grounds, and with a high degree of certainty, the
benign from the malignant neoplasms. In the individual
case, it is important to recognize the limitation of the
technique and classify the difficult lesions as ‘salivary
gland neoplasm’, listing a differential diagnosis, and
deferring classification to histologic examination.
MUCOEPIDERMOID CARCINOMA
CLINICAL FEATURES
Mucoepidermoid carcinoma comprises 5–10% of all
salivary gland neoplasms. It is the second most common
primary neoplasm of the salivary glands in adults
(30%), and the most common primary malignancy in
children. It is mostly located in the parotid, but may
also involve other major and minor salivary glands.
In adults, these tumors typically occur in the third to
fifth decades. Mucoepidermoid carcinomas are divided
according to grade and are most often classified as
low-grade and high-grade tumors, although some clas-
sification schemes include an intermediate grade. Their
presentation, treatment, and prognosis are dependent
on grade. Low-grade tumors tend to develop slowly over
a period of years. They may recur locally, but distant
metastases are rare. The 5-year survival for low-grade
tumors approaches 98%. The tumors tend to be well
circumscribed and may become cystic, containing
mucinous material. These tumors are treated and may
be cured with limited excision. High-grade tumors
grow rapidly, recur locally, and metastasize to regional
lymph nodes, lung, and bone. Their 5-year survival rate
is around 56%. High-grade tumors are infi ltrative and
tend to be solid. They are treated aggressively with
surgery, and possible lymph node dissection and
radiation therapy. Most of these tumors manifest their
poor behavior within the first year after surgery.
MUCOEPIDERMOID CARCINOMA – DISEASE FACT SHEET
Incidence and Location
៉ Most common salivary gland malignancy in children and adults
៉ Predominantly parotid
Age Distribution
៉ 20–40 years
Clinical Features
៉ Slow-growing mass for low-grade tumors, rapidly growing for
high-grade tumors
Treatment
៉ Wide local excision, regional node dissection if nodes clinically
involved
10/26/2006 10:19:50 AM
 24 FINE NEEDLE ASPIRATION CYTOLOGY

Extraglandular extension, vascular invasion, necrosis,

and high mitotic rate are poor prognostic features. MUCOEPIDERMOID CARCINOMA – PATHOLOGIC FEATURES

CYTOPATHOLOGIC FEATURES
The FNA diagnosis of mucoepidermoid carcinoma is
one of pattern recognition. Aspirates from these tumors
contain a variety of cell types: mucin-producing, squa-
mous, intermediate, and clear. Intermediate cells are
small and bear resemblance to squamous metaplasia.
In low-grade mucoepidermoid carcinoma, extracellular
stringy mucin is seen in the smear background of a
majority of cases. The cellular components are quanti-
tatively variable and include epithelial cell groups that
are multilayered with overlapping nuclei, mucin-
containing cells, intermediate cells without identifiable
keratin, squamous cells, and finely vacuolated clear
cells. In cellular clusters, a gradual transition from
intermediate to mucus-producing cells is readily iden-
tifiable (Fig. 1-32). The nuclei of these cells are gener-
ally small, uniform, round or oval, and not overtly
malignant. Mucin-producing cells typically predomi-
nate. They may have a columnar or signet-ring appear-
ance or may resemble histiocytes when present singly.
Aspirates from high-grade tumors demonstrate poorly
differentiated cells with frankly malignant features
including pleomorphic nuclei, hyperchromasia, coarse
chromatin, and prominent nucleoli; glandular/mucous
cells may be few in number and difficult to recognize,
requiring a special stain for mucin for identification
(Fig. 1-33). The squamous cells are more easily recog-
nized and, together with intermediate cells, predomi-
nate. Predominant bizarre forms of squamous cells,
pearl formation, extensive necrosis, and frequent
mitoses are not classic features of high-grade muco-
epidermoid carcinoma.
Cytopathologic Findings
៉ Variable combination of mucous, intermediate, squamous, and
clear cells
៉ Low grade: abundant mucoid background with predominance of
bland mucous and intermediate cells
៉ High grade: predominance of squamous and intermediate cells,
sparse mucous cells, overtly malignant features
Histopathologic Findings
៉ Gross:
៉ Low grade: well circumscribed, cystic
៉ High grade: solid, infiltrative growth pattern
៉ Microscopic:
៉ Low grade: cysts containing mucinous material, lined by well-
differentiated mucinous cells
៉ High grade: solid, infiltrative sheets of squamous intermediate
and clear cells with scattered mucin-producing cells
Differential Diagnosis and Pitfalls
៉ Low grade: mucocele, Warthin tumor with squamous/mucinous
metaplasia, pleomorphic adenoma with squamous/mucinous
metaplasia
៉ High grade: salivary duct carcinoma, carcinoma ex-pleomorphic
adenoma, adenosquamous carcinoma, oncocytic carcinoma,
metastatic squamous cell carcinoma
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Low-grade mucoepidermoid carcinoma is commonly
cystic, and may be difficult to diagnose by FNA. Ade-
quate sampling of these tumors is critical to accuracy
in interpretation.

A B

FIGURE 1-32
Mucoepidermoid carcinoma, low grade. A, Intermediate and mucin-producing cells are mingled within the same cluster. Intermediate cells, centrally
located in the cluster, are small with round uniform nuclei and moderate to scant cytoplasm, whereas mucinous cells have similar nuclear features
but ample vacuolated mucin-containing cytoplasm and are noted at the periphery of the cluster. Cells are multilayered and overlapping, a clue to
their neoplastic nature, and display a gradual transition from intermediate to mucous cells. Wisps of mucinous material are present in the back-
ground. Alcohol-fixed, Papanicolaou stain, medium power. B, A sheet of streaming, elongated cells with moderate amount of cytoplasm suggests
squamous differentiation. Alcohol-fixed, Papanicolaou stain, medium power.

Ch001-F06731.indd 24 10/26/2006 10:19:50 AM

 CHAPTER 1 Salivary Glands
FIGURE 1-33
Mucoepidermoid carcinoma, high
grade. Nuclear pleomorphism, hy-
perchromasia, nucleoli, cellular
crowding, and discohesion are easily
recognizable features of malignancy.
An occasional mucin-producing cell
is identified within the cluster.
Alcohol-fixed, Papanicolaou stain,
medium power.
Aspiration of these tumors may yield mucoid cyst
fluid containing inflammatory cells, histiocytes (which
may mimic glandular cells), and few epithelial cells.
This presentation must be distinguished from a mucous
retention cyst or mucocele, which is typically less cel-
lular and lacks the intermediate or squamous cell com-
ponent seen in low-grade mucoepidermoid carcinoma.
Another clue in separating a benign cyst from a neo-
plasm is the persistence in neoplastic processes of a
mass post FNA. Squamous and mucinous metaplasia
accompanied by inspissated mucus or thick protein-
aceous fluid can be seen in chronic sialadenitis, sialo-
lithiasis, and Warthin tumor, and may mimic the cells
seen in low-grade mucoepidermoid carcinoma. These
cells are usually found focally and do not constitute the
predominant cell population. Rarely, mucoepidermoid
carcinoma may present with oncocytic features that
renders its distinction from Warthin tumor or onco-
cytoma problematic.
The thick mucoid material in the smear background
of low-grade mucoepidermoid carcinoma may be meta-
chromatic with Diff-Quik staining and resemble the
myxoid matrix characteristic of benign mixed tumor.
This material, however, lacks the spindle cells seen in
the stroma of mixed tumors.
High-grade mucoepidermoid carcinoma shows
obvious cytologic features of malignancy and can mimic
other poorly differentiated primary or metastatic tumors
such as carcinoma ex-pleomorphic adenoma, salivary
duct carcinoma, adenosquamous carcinoma, and meta-
static squamous cell carcinoma. The correct diagnosis
of mucoepidermoid carcinoma relies on the identifica-
tion of both squamous and glandular components. In
high-grade tumors, squamous differentiation is more
easily recognized, but the mucous glandular cells are
few in number or difficult to identify without the use
of special stains for mucin. The only indication of
Ch001-F06731.indd 25
25
glandular differentiation may be scattered mucin vacu-
oles in sheets of intermediate and squamous cells. Sali-
vary duct carcinoma has extensive necrosis and may
have a papillary architecture. The presence of extensive
keratinization and prominent pearl formation favors
the diagnosis of squamous cell carcinoma over muco-
epidermoid carcinoma. Finally, the clinical history is
helpful in excluding a metastasis or identifying a pre-
existing mass such as in carcinoma ex-pleomorphic
adenoma. In the final evaluation, all primary high-grade
carcinomas of the salivary gland are treated similarly
and a definitive classification is not essential for appro-
priate therapy.
ACINIC CELL CARCINOMA
CLINICAL FEATURES
Acinic cell carcinoma is an uncommon neoplasm, com-
prising only 1–6% of all salivary gland neoplasms.
However, it is the second most common primary sali-
vary gland malignancy, occurs mostly in the parotid
gland, and can be bilateral in approximately 3% of
cases. It is most frequently encountered in the third to
fourth decade, and shows prevalence in women. Acinic
cell carcinoma forms a well-circumscribed, mobile,
slowly growing mass, and although it appears as a low-
grade malignancy, it often demonstrates a protracted
course and has a propensity for local recurrence and
regional and distant metastases. Treatment requires
wide local excision with regional node dissection if
necessitated by the presence of clinically involved
10/26/2006 10:19:51 AM
 26
ACINIC CELL CARCINOMA – DISEASE FACT SHEET
Incidence and Location
៉ Uncommon salivary gland neoplasm (1–6%)
៉ Predominantly parotid
Gender and Age Distribution
៉ Female predominance
៉ 30–40 years
Clinical Features
៉ Slow-growing mass
៉ Occasionally painful
Treatment
៉ Wide local excision, regional node dissection if nodes clinically
involved
lymph nodes. The role of radiation therapy is contro-
versial. Markers of poor prognosis include pain or fi xa-
tion, gross invasion, desmoplasia, cytologic atypia, and
increased mitotic activity.
CYTOPATHOLOGIC FEATURES
Aspiration smears are cellular and contain cell frag-
ments with vague, irregular acinar configurations.
Occasionally, a papillary configuration may be present.
Some tissue fragments will include portions of vascular
structures surrounded by neoplastic cells, reflecting the
vascular nature of the neoplasm. Within sheets and
clusters, cell borders are not distinct. When well dif-
ferentiated, the tumor cells resemble normal acinar
cells. They have a bland appearance with abundant
A B
FIGURE 1-34
Acinic cell carcinoma. A, A loose cellular aggregate consists of bland-appearing cells with delicate granular and finely vacuolated cytoplasm. Cyto-
plasmic borders are indistinct and true acinar formation is absent. Bare nuclei of neoplastic cells are present in the background. Alcohol-fixed,
Papanicolaou stain, medium power. B, Irregular acinar formation, lack of ductal epithelium, and granular nature of the cytoplasm are characteristic
features. Air-dried, Diff-Quik stain, high power.
Ch001-F06731.indd 26
FINE NEEDLE ASPIRATION CYTOLOGY
ACINIC CELL CARCINOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Sheets and tissue fragments with loose acinar formation
៉ Polygonal cells with bland nuclei and abundant granular/
vacuolated cytoplasm, indistinct cell border
៉ Background bare nuclei
៉ Vascular component
៉ Possible lymphoid background
Histopathologic Findings
៉ Gross: encapsulated round mass, solid, friable, grey–white cut
surface; occasionally cystic
៉ Microscopic: variable growth patterns (solid microcystic,
papillary cystic, follicular) and variable appearance of
neoplastic cells (acinic, intercalated duct, vacuolated, clear,
glandular NOS)
Differential Diagnosis and Pitfalls
៉ Non-neoplastic salivary gland
៉ Cytoplasmic granularity: oncocytic neoplasms
៉ Lymphoid background: Warthin tumor
៉ Clear/vacuolated cytoplasm: mucoepidermoid carcinoma,
epi-myoepithelial carcinoma, metastatic renal cell carcinoma,
sebaceous neoplasms
៉ Cytologic atypia: other high-grade carcinomas
granular to foamy cytoplasm, small dark nuclei, and
small nucleoli (Fig. 1-34). The cytoplasmic granules
(zymogen granules) are variable in quantity and char-
acteristically PAS-positive, diastase-resistant. Ductal
structures are absent. Cells with foamy cytoplasm have
few, if any, granules and have a clear cell appearance.
Although usually bland, nuclei can show variable
degrees of atypia, including a more granular chromatin
pattern and prominent nucleoli. The smear background
contains numerous bare nuclei that must be differenti-
ated from lymphocytes. Lymphocytes are usually
10/26/2006 10:19:52 AM
 CHAPTER 1 Salivary Glands
absent; however, in approximately 10% of acinic cell
carcinomas (follicular variant), the stroma is rich in
lymphoid cells with germinal centers. These tumors
produce aspirates with abundant lymphoid elements in
addition to the tumor cells. Poorly differentiated acinic
cell carcinoma is uncommon and demonstrates easily
recognizable features of malignancy and may be diffi-
cult to differentiate from other high-grade malignan-
cies involving the parotid. The papillary cystic variant
may present with sheet or papillary clusters of neoplas-
tic cells resembling ductal epithelium. They will also
be associated with material from cyst content, such as
debris and histiocytes, and may yield laminated, calci-
fied structures that resemble psammoma bodies. This
variant may be diagnostically challenging and difficult
to recognize as acinic cell carcinoma.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Well-differentiated acinic cell carcinoma must be dif-
ferentiated from normal salivary gland tissue or sialad-
enosis. The absence of ductal structures and associated
adipose tissue seen in normal salivary gland tissue
can help in the diagnosis of neoplasia. In acinic cell
carcinoma, there is discohesion of neoplastic cells, the
acinar-like arrangements are loose, the groups are
poorly formed, and crowded sheets are seen. The grape-
like arrangement of acini in association with ductal
structures seen in normal salivary gland tissue and the
orderly array of cells within acini showing basally
located nuclei are lacking. Acinic cell carcinoma with
lymphocyte-rich stroma must be differentiated from
Warthin tumor. Although cells from both lesions have
FIGURE 1-35
Acinic cell carcinoma. Punched-out
small vacuoles are similar to those
seen in cells with sebaceous differ-
entiation and are present in asso-
ciation with cytoplasmic granularity.
Courtesy of Ms Jamie L Covell, The
University of Virginia Health Sci-
ences Center. Air-dried, Diff-Quik
stain, high power.
Ch001-F06731.indd 27
27
abundant cytoplasm, the cytoplasm of oncocytes in
Warthin tumor is very dense in comparison to the
granular, foamy cytoplasm of acinic cell carcinoma
cells. This distinction would also aid in the differential
diagnosis with oncocytic neoplasms. The cytoplasmic
granularity of oncocytes results from the abundance
of mitochondria which stain positively with phospho-
tungstic acid–hematoxylin (PTAH).
The presence of clear cells can raise the possibility of
clear cell tumors, both primary and metastatic, espe-
cially mucoepidermoid carcinoma and metastatic renal
cell carcinoma. Although aspirates from mucoepider-
moid carcinoma can contain cells with abundant foamy
cytoplasm resembling acinar cells, the presence of back-
ground mucin and mucin-producing cells would exclude
a diagnosis of acinic cell carcinoma, which is negative
for mucin. Metastatic renal cell carcinoma is charac-
terized by the presence of clear cells showing nuclear
pleomorphism and prominent nucleoli. This tumor may
show numerous small vessels within the tissue frag-
ments, a finding that is compatible with the diagnosis
of acinic cell carcinoma. Specific immunomarkers
for renal cell carcinoma, such as CD10, and clinical
correlation will help resolve this differential. The rare
epithelial-myoepithelial carcinoma will present with
clear cells; however, it may be distinguished by the iden-
tification of a biphasic cell population. The presence
of small ductal cells forming tubules within sheets of
clear cells is a useful clue to the correct diagnosis. Acinic
cell carcinoma with vacuolated cytoplasm may
mimic tumors with sebaceous differentiation, such as
sebaceous lymphadenoma and sebaceous carcinoma
(Fig. 1-35).
The absence of acinar structures typical of acinic cell
carcinoma in all of the tumors considered in the differ-
ential diagnosis can aid in the accurate interpretation.
10/26/2006 10:19:53 AM
 28
SALIVARY DUCT CARCINOMA
CLINICAL FEATURES
Salivary duct carcinoma is an uncommon and highly
aggressive neoplasm that arises in Stensen’s duct of the
parotid gland or in the submandibular gland, and has
a predilection for men (M : F = 8 : 1). Although it can
occur at any age, patients are usually older and range
in age from 62 to 89 years (median, 69 years). Treat-
ment consists of surgical excision followed by radiation
therapy. The prognosis of this tumor is dependent on
the proportion of invasive and in-situ component and
on the histologic grade. Overall, the tumor has a poor
prognosis, and approximately two-thirds of the patients
die within 4 years of initial diagnosis. Tumor size,
presence of distant metastases, and c-erbB-2 amplifica-
tion are independent prognostic parameters in patients
with salivary duct carcinoma. Salivary duct carcino-
ma’s immunophenotypic profi le is more closely related
to prostate carcinoma. A rare case report describes
its association with elevated serum prostate-specific
antigen (PSA) levels.
CYTOPATHOLOGIC FEATURES
Smears are variably cellular but obviously malignant.
The most characteristic features of salivary duct carci-
noma are broad flat and branching sheets of cells with
a cribriform, papillary, or gland-like pattern in a vari-
ably necrotic background (Fig. 1-36). Dense fibrous
fragments may also be seen in the background. The
tumor cells are large and polygonal with round to oval,
pleomorphic, eccentric or centrally placed nuclei, and
SALIVARY DUCT CARCINOMA – DISEASE FACT SHEET
Incidence and Location
៉ Uncommon salivary gland neoplasm
៉ Parotid > submandibular
Gender and Age Distribution
៉ Male to female ratio is 8 : 1
៉ Wide age range, more often 60–90 years
Clinical Features
៉ Aggressive growth
Prognosis and Treatment
៉ Regional and distant metastases frequent, 70% mortality
៉ Surgical excision and radiation therapy
Ch001-F06731.indd 28
FINE NEEDLE ASPIRATION CYTOLOGY
SALIVARY DUCT CARCINOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Branching and cribriform sheets and clusters of cells
៉ Background necrosis
៉ Frequent marked cytologic atypia: polygonal cells with granular
or vacuolated cytoplasm and prominent nucleoli
៉ Rare low-grade cytologic features
Histopathologic Findings
៉ Similar to ductal carcinoma of the breast, comedo
៉ Solid, cribriform, papillary, mucinous, infiltrating, and
sarcomatoid patterns
Ancillary Studies
៉ Immunoreactivity for low and high molecular weight
cytokeratins, GCDFP-15, and androgen receptor (>90%)
៉ Moderate positivity for PAP and PSA
៉ Rare positivity for ER and PR
៉ Overexpression of p53 and c-erbB-2
Differential Diagnosis and Pitfalls
៉ High-grade cytologic features: high-grade mucoepidermoid
carcinoma, carcinoma ex-pleomorphic adenoma, adenosquamous
carcinoma, intraductal papillary adenocarcinoma, metastatic
squamous cell carcinoma, malignant melanoma
៉ Low-grade cytologic features: oncocytoma, Warthin tumor
prominent nucleoli (Fig. 1-37). The cytoplasm varies
from dense granular to vacuolated. Cases with bland or
mildly pleomorphic nuclei are reported. Salivary duct
carcinoma mostly resembles breast carcinoma in all its
variable patterns and features, but shares an immuno-
phenotypic profi le with both ductal-type adenocarci-
noma and prostatic adenocarcinoma. Malignant cells
are diffusely immunoreactive for low and high molecu-
lar weight cytokeratins. Salivary duct carcinoma will
show positivity for estrogen receptor (ER) and proges-
terone receptor (PR) in a minority of cases only – 1.3%
and 6%, respectively – but immunoreactivity to GCDFP-
15 is present in most cases. Androgen receptor, a marker
expressed in prostate carcinoma, is expressed in over
90% of salivary duct carcinomas, whereas 60% of cases
show scattered moderate positivity for prostatic acid
phosphatase (PAP), and 17% diffuse moderate positiv-
ity for PSA. Overexpression of p53 is reported in 53%
of cases and c-erbB-2 in 63%.
A rare sarcomatoid variant has been described in
association with usual-type salivary duct carcinoma. It
presents as a spindle and anaplastic cell tumor. Another
rare variant of salivary duct carcinoma is small cell
undifferentiated carcinoma. While some immunohisto-
chemical studies have demonstrated luminal, basal, and
myoepithelial differentiation compatible with origin of
the tumor from the salivary duct, other studies have
demonstrated neuroendocrine differentiation of this
tumor.
10/26/2006 10:19:53 AM
 CHAPTER 1 Salivary Glands 29

FIGURE 1-36
Salivary duct carcinoma. Broad
complex epithelial sheets with a
branching papillary and cribriform
appearance usually occur against a
necrotic background. Courtesy of Ms
Jamie L Covell, The University of
Virginia Health Sciences Center. Air-
dried, Diff-Quik stain, low power.

FIGURE 1-37
Salivary duct carcinoma. Large
polygonal cells with pleomorphic
round nuclei, prominent nucleoli,
and abundant dense granular cyto-
plasm are crowded in this duct-
like structure with central debris.
Although the cytologic features are
somewhat similar to those of onco-
cytes, the nuclear atypia and necro-
sis should preclude a benign
diagnosis. Courtesy of Ms Jamie L
Covell, The University of Virginia
Health Sciences Center. Air-dried,
Diff-Quik stain, high power.

dominate, an intraductal papillary adenocarcinoma

DIFFERENTIAL DIAGNOSIS AND PITFALLS
FNAs of salivary duct carcinoma are difficult to inter-
pret because of the morphologic spectrum of this tumor.
In high-grade tumors where pleomorphism is evident,
other high-grade malignant tumors enter the differen-
tial diagnosis. Such group of malignant tumors includes
high-grade carcinoma not otherwise specified (NOS),
high-grade mucoepidermoid carcinoma, and carcinoma
ex-pleomorphic adenoma. If papillary structures pre-
should be considered. Intraductal papillary adenocarci-
noma, a low-grade carcinoma and the malignant coun-
terpart of intraductal papilloma, shows cytologic atypia
and microinvasion, and has a better prognosis than
salivary duct carcinoma. Metastatic tumors such as
squamous cell carcinoma and malignant melanoma
should also be excluded. Low-grade tumors are a source
of false negative diagnoses. When bland features are
present, the neoplastic cells may show similarities to
oncocytes, and the tumor may be mistaken for onco-
cytoma or Warthin tumor.

Ch001-F06731.indd 29 10/26/2006 10:19:53 AM

 30
MALIGNANT LYMPHOMA
CLINICAL FEATURES
Most patients with malignant lymphoma will present
with a unilateral salivary gland mass. Primary malig-
nant lymphoma can arise in the gland itself, mostly
involving the parotid gland, and occasionally the
submandibular gland. In the area of the parotid gland,
malignant lymphoma also arises in intra- or periparotid
lymph nodes and has the features or clinical course of
a nodal lymphoma. Salivary glands may also be second-
arily involved by lymphoma as an expression of dis-
seminated disease. Most malignant lymphomas in the
salivary gland are of B-cell lineage, and Hodgkin lym-
phoma is unusual. Malignant lymphoma is known to
MALIGNANT LYMPHOMA – DISEASE FACT SHEET
Incidence
៉ 2–5% of salivary gland neoplasms
Clinical Features
៉ Primary or secondary
៉ Unilateral mass, most commonly involving parotid or lymph nodes
within area
៉ Behavior and treatment similar to that of nodal lymphoma
Ch001-F06731.indd 30
FINE NEEDLE ASPIRATION CYTOLOGY
arise in a background of LESA, Sjögren syndrome, or
Warthin tumor. The MALT/marginal zone lympho-
mas, frequently encountered in the salivary glands,
have an indolent clinical course and an excellent
prognosis.
CYTOPATHOLOGIC FEATURES
Most commonly, salivary glands are involved by B-cell
lymphomas, which in the majority of cases comprise
small lymphocytes and belong to the extranodal mar-
ginal zone B-cell lymphoma of MALT type. Typically
in such cases, smears show a population of small to
intermediate lymphocytes with round to slightly angu-
lated nuclei, and occasional larger cells with features
of immunoblasts (Fig. 1-38).
Follicular lymphomas occur in the salivary gland
with a high frequency as well (35–50%) and are com-
posed of small and large cleaved cells and large non-
cleaved cells that impart a polymorphous appearance to
the aspirate material. Conversely, diffuse large B-cell
lymphomas consist of large centroblastic and immuno-
blastic lymphoid cells that are overtly malignant.
T-cell lymphoma in the salivary gland is rare and
cannot be distinguished from a B-cell tumor on a mor-
phologic basis only. Another rare entity is plasma-
cytoma that can present as a salivary gland mass with
cytologic features varying from mature to anaplastic
plasma cells, similar to those seen in other sites (Fig.
1-39). Patients with plasmacytoma can later develop
multiple myeloma.
FIGURE 1-38
Malignant lymphoma, marginal
zone. Small to intermediate cell
lymphocytes with round to slightly
angulated nuclei are the predomi-
nant cell population. Scattered
larger cells and a mitotic figure are
present. Air-dried, Diff-Quik stain,
high power.
10/26/2006 10:19:55 AM
 CHAPTER 1 Salivary Glands 31

FIGURE 1-39
Plasmacytoma. Mature plasma cells
with round eccentric nuclei, clock-
face chromatin, and a moderate
amount of cytoplasm may resemble
hyaline myoepithelial cells. The
chromatin pattern and perinuclear
Hoff are distinguishing features.
Alcohol-fixed, Papanicolaou stain,
medium power.

flow cytometry is necessary to support the diagnosis of

MALIGNANT LYMPHOMA – PATHOLOGIC FEATURES lymphoma. A predominantly lymphoid infi ltrate can be
aspirated from neoplasms such as Warthin tumor, seba-
Cytopathologic Findings ceous lymphadenoma, and acinic cell carcinoma in
៉ Single discohesive cells which the epithelial cells have not been sampled. A
៉ Monotonous population of lymphocytes thorough search for epithelial cells or identification of
៉ Variable cell size and degree of atypia, dependent on cell type such cells by immunocytochemistry may be helpful in
៉ B-cell lymphomas most common identifying a non-lymphoid neoplasm. Lymphoepithe-
lial carcinoma that consists of a mixture of large
Pathologic Findings
anaplastic-appearing cells in a background of small
៉ Follicular diffuse or sclerosing growth pattern lymphocytes is also a consideration in the differential
៉ Commonly, cleaved or small cells
diagnosis of large cell lymphoma. Malignant melanoma
៉ Immunoblastic, plasma cell, or T-cell less frequent
៉ T-cell associated with prominent lymphoepithelial lesions
may need to be excluded if the lymphoma is immuno-
៉ Hodgkin lymphoma rare blastic in nature. The last two non-lymphoid malignant
neoplasms can be identified by immunocytochemical
Ancillary Studies staining for cytokeratin and for S-100 protein, Melan
៉ Flow cytometric studies
A, or HMB-45, respectively.

Differential Diagnosis and Pitfalls

៉ Chronic sialadenitis
៉ Lymphoepithelial lesion
៉ Poorly sampled lymphocyte-rich lesions (Warthin tumor,
sebaceous lymphadenoma)
៉ Lymphoepithelial carcinoma in large cell lymphoma
៉ Malignant melanoma in immunoblastic lymphoma
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis of malignant lymphoma in
the salivary gland includes a number of lymphocyte-
rich conditions, both neoplastic and non-neoplastic.
Low-grade lymphomas have to be differentiated from
chronic sialadenitis, LESA, lymphoepithelial cysts,
and intraparotid lymph nodes. Immunophenotyping by
RARE TUMORS
The following section addresses in brief both benign
and malignant tumors that are only exceptionally
encountered.
Benign tumors such as vascular tumors, lymphangi-
oma, lipomas, schwannomas, skin adnexal-type tumors
such as pilomatrixoma, and solitary fibrous tumors have
all been described in the salivary glands. Malignant
neoplasms include the following:
Primary small cell carcinoma of the salivary gland is
extremely rare and can be diagnosed only after exclud-
ing other primary sources. It affects predominantly men
in their sixth decade and has morphologic and cytologic
features similar to small cell undifferentiated carcinoma
in other locations. It also has a similar aggressive course

Ch001-F06731.indd 31 10/26/2006 10:19:55 AM

 32
and poor prognosis. Cellular smears contain poorly
cohesive clusters and syncytia of small blue cells with a
high N/C ratio. The nuclei are angulated and molding,
the chromatin is granular, and nucleoli are inconspicu-
ous (Fig. 1-40). Mitotic figures are easily found. Ultra-
structurally, it is characterized by neurosecretory
granules and demonstrates neuroendocrine features by
immunocytochemistry, including dot-like positivity for
cytokeratin and staining with chromogranin, synapto-
physin, neuron-specific enolase, and CD56. Similar to
Merkel cell tumors and unlike lung primaries, small cell
carcinoma of salivary gland origin is positive for CK20.
The main differential diagnostic consideration in the
salivary gland, apart from a metastasis from lung or
skin, is a solid variant of adenoid cystic carcinoma.
Adenocarcinoma not otherwise specified is a diagnostic
category that is used for high-grade tumors without
recognizable specific features.
Squamous cell carcinoma as a primary tumor in the
salivary gland is unusual. Some squamous-appearing
tumors may represent adenosquamous carcinoma, as
demonstrated by scattered mucin-containing cells.
These tumors are highly aggressive and are treated with
radical surgery and radiation therapy. More commonly,
squamous carcinoma results from secondary involve-
ment of the salivary gland either by direct extension or
by metastasis to an intra- or periglandular lymph node
from a head and neck or skin primary. Cystic metastases
are frequently aspirated and show keratinizing and
non-keratinizing atypical squamous cells in a necrotic
background (Fig. 1-41).
Lymphoepithelial carcinoma of the salivary gland
has an incidence of less than 0.5% of salivary gland
neoplasms, and occurs predominantly in Greenlanders,
Inuits, and Southern Chinese. It presents as a solitary
mass of the parotid or submandibular gland, and, like
its nasopharyngeal counterpart, is associated with
Epstein-Barr virus, which can be demonstrated by
Ch001-F06731.indd 32
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 1-40
Small cell undifferentiated carci-
noma. Poorly cohesive clusters and
syncytia of small blue cells with a
high N/C ratio. The nuclei are angu-
lated and molded, the chromatin is
granular, and nucleoli are incon-
spicuous. Alcohol-fixed, Papanico-
laou stain, high power.
in-situ hybridization or by serology. Cytologically, it
consists of syncytial sheets of large, highly pleomorphic
cells with vesicular chromatin, prominent nucleoli, and
delicate poorly defined cytoplasm, in an abundant back-
ground of mixed lymphocytes and plasma cells (Fig.
1-42). The main differential diagnosis is malignant lym-
phoma and can be resolved by a positive cytokeratin
immunostain in the large atypical cells of lymphoepithe-
lial carcinoma.
Clear cell carcinomas do not constitute a homoge-
neous group of tumors but comprise tumors with abun-
dant cytoplasmic glycogen, lipid, or mucin. Such tumors
include clear cell myoepitheliomas, neoplasms with
sebaceous differentiation or oncocytic features, muco-
epidermoid carcinoma, acinic cell carcinoma, and meta-
static renal cell carcinoma. If all such possibilities are
excluded, the diagnosis of hyalinizing clear cell carci-
noma should be considered, particularly in a tumor
occurring in the oral cavity.
Sarcomas may arise in salivary glands. In adults,
those are malignant spindle cell neoplasms that should
be distinguished from metaplastic carcinomas, myo-
epithelial tumors, or spindle cell melanoma. Sarcomas
described in that location include malignant peripheral
nerve sheath tumor, synovial sarcoma, Kaposi sarcoma,
malignant fibrous histiocytoma, primitive neuroectoder-
mal tumors/Ewing sarcoma, and, in children, embryo-
nal rhabdomyosarcoma.
SECONDARY TUMORS
Metastatic tumors to the region of the salivary glands
occur not infrequently, and involve intraparotid and
submandibular lymph nodes. If metastasis is suspected,
10/26/2006 10:19:56 AM
 CHAPTER 1 Salivary Glands 33

FIGURE 1-41
Squamous cell carcinoma. Keratin-
izing and non-keratinizing atypical
squamous cells in a necrotic back-
ground are compatible with a cystic
tumor of the head and neck primary.
The definite nuclear atypia and
cellularity separate this lesion from
non-neoplastic branchial cleft cysts
and cystic lymphoepithelial lesions.
Alcohol-fixed, Papanicolaou stain,
high power.

FIGURE 1-42
Lymphoepithelial carcinoma. Syncy-
tial sheets of large highly pleomor-
phic cells with vesicular chromatin,
prominent nucleoli, and delicate,
poorly defined cytoplasm in an
abundant background of mixed
lymphocytes and plasma cells may
mimic a large cell malignant
lymphoma. Courtesy of Ms Jamie
L Covell, The University of Virginia
Health Sciences Center. Alcohol-
fixed, Papanicolaou stain, high
power.

a clinical history of a primary tumor elsewhere, and
comparison of aspirate to pathology material from the
primary are always helpful. Most frequently, head and
neck squamous cell carcinoma forms a cystic necrotic
mass that may mimic some of the primary benign
squamous-lined cystic lesions. Identifying atypia
within the squamous cell is the way to a correct
diagnosis. Malignant melanoma metastasizes to the
salivary gland and may mimic some of the primary
high-grade carcinomas or lymphomas. Malignant mela-
noma consists of large polygonal cells arranged in
loosely cohesive clusters and single cells. Cells typically
have a moderate to abundant amount of dense cyto-
plasm, eccentrically placed nuclei, and prominent
nucleoli. A pronounced discohesive pattern, intra-
nuclear pseudoinclusions, binucleation, and melanin
pigment are diagnostic clues. In the absence of melanin
pigment, positive immunostaining for S-100 protein,
HMB-45, and Melan A confirms the diagnosis.
Tumors in the lung, kidney, breast, and, to a lesser
extent, prostate and colon metastasize to the salivary
glands. Lung, breast, and prostate carcinomas may
mimic high-grade adenocarcinomas arising in the sali-
vary gland. However, these metastases may be distin-
guished from salivary gland primaries by a thorough
clinical history and immunostains that are site-specific.

Ch001-F06731.indd 33 10/26/2006 10:19:57 AM

 34
TTF-1 stains a significant number of lung adenocarci-
noma; PSA and PAP, and ER and PR may help detect
prostate and breast carcinoma, respectively. A tall
columnar glandular population associated with mucin
production or a necrotic background may suggest a
colonic primary. Immunostains for the main mucin
protein cores (MUC1, MUC2, MUC3, MUC5AC), CDX2,
and villin may help confirm the site of origin of the
tumor. Metastases from renal cell carcinoma may pose
a challenge to the cytopathologist, as they mimic acinic
cell or mucoepidermoid carcinoma. Neoplastic cells are
large with abundant translucent, granular or vacuolated
cytoplasm. Nuclei are large, round, and may display
prominent nucleoli. Renal cell carcinoma is rich in
vessels that may be easily visualized in the FNA
material (Fig. 1-43).
A positive CD10 immunostain will help support the
renal origin of the tumor.
SUGGESTED READINGS
Non-neoplastic Lesions
Sialadenosis
Henrey-Stanley MJ, Beneke J, Bardales HR, Stanley MW. Fine-needle
aspiration of normal tissue from enlarged salivary glands: sialosis or
missed target? Diagn Cytopathol 1995;13:300–303.
Young NA, Mody DR, Davey DD. Misinterpretation of normal cellular ele-
ments in fine-needle aspiration biopsy specimens: observations from
the College of American Pathologists Interlaboratory Comparison
Program in Non-Gynecologic Cytopathology. Arch Pathol Lab Med 2002;
126:670–675.
Sialadenitis
Allen EA, Ali SZ, Mathew S. Lymphoid lesions of the parotid. Diagn
Cytopathol 1999;21:170–173.
Chai C, Dodd LG, Glasgow BJ, Layfield LJ. Salivary gland lesions with a
prominent lymphoid component: cytologic findings and differential
Ch001-F06731.indd 34
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 1-43
Renal cell carcinoma. Large neo-
plastic cells with abundant translu-
cent, granular, or vacuolated
cytoplasm have large round cen-
trally located nuclei and are
arranged around and in between
capillaries. These findings may
overlap with those of an acinic cell
carcinoma; however, cells of renal
cell carcinoma may be larger and
display a more abundant delicate
and vacuolated cytoplasm. Air-
dried, Diff-Quik stain, medium
power.
diagnosis by fine-needle aspiration biopsy. Diagn Cytopathol 1997;17:
183–190.
Cheuk W, Chan JK. Kuttner tumor of the submandibular gland: fine-needle
aspiration cytologic findings of seven cases. Am J Clin Pathol 2002;
117:103–108.
Lopez-Rios F, Diaz-Bustamante T, Serrano-Egea A, Jimenez J, de Agustin
P. Amylase crystalloids in salivary gland lesions: report of a case with
a review of the literature. Diagn Cytopathol 2001;25:59–62.
Cystic Lesions
Chhieng DC, Argosino R, McKenna BJ, Cangiarella JF, Cohen JM. Utility of
fine-needle aspiration in the diagnosis of salivary gland lesions in
patients infected with human immunodeficiency virus. Diagn Cytopathol
1999;21:260–264.
Elliot JN, Oertel YC. Lymphoepithelial cysts of the salivary glands –
histologic and cytologic features. Am J Clin Pathol 1990;93:39–43.
Layfield LJ, Gopez EV. Cystic lesions of the salivary glands: cytologic
features in fine-needle aspiration biopsies. Diagn Cytopathol 2002;27:
197–204.
Stewart CJR, MacKenzie K, McGarry GW, Mowatt A. Fine-needle aspiration
cytology of salivary gland: a review of 341 cases. Diagn Cytopathol
2000;22:139–146.
Tumor with Mesenchymal Differentiation
Benign Mixed Tumor
Chhieng DC, Cohen JM, Cangiarella JF. Fine-needle aspiration of spindle
cell and mesenchymal lesions of the salivary gland. Diagn Cytopathol
2000;23:253–259.
Das DK, Anim JT. Pleomorphic adenoma of salivary gland: to what extent
does fine needle aspiration cytology reflect histopathological features?
Cytopathology 2005;16:65–70.
Elsheikh TM, Bernacki EG. Fine needle aspiration cytology of cellular
pleomorphic adenoma. Acta Cytol 1996;40:1165–1175.
McLeod CB, Frable WJ. Fine-needle aspiration biopsy of the salivary gland:
problem cases. Diagn Cytopathol 1993;9:216–225.
Mooney EE, Dodd LG, Layfield LJ. Squamous cells in fine-needle aspiration
biopsies of salivary gland lesions: potential pitfalls in cytologic diag-
nosis. Diagn Cytopathol 1996;15:447–452.
Viguer JM, Vicandi B, Jimenez-Heffernan JA, Lopez-Ferrer P, Limeres MA.
Fine needle aspiration of pleomorphic adenoma. An analysis of 212
cases. Acta Cytol 1997;41:786–794.
10/26/2006 10:19:59 AM
 CHAPTER 1 Salivary Glands
Malignant Mixed Tumor
Anand A, Brockie ES. Cytomorphologic features of salivary duct carcinoma
ex-pleomorphic adenoma: diagnosis by fine needle aspiration biopsy
with histologic correlation. Diagn Cytopathol 1999;20:375–378.
De la Torre M, Larsson E. Fine-needle aspiration cytology of carcinosar-
coma of the parotid gland: cytohistological and immunohistochemical
findings. Diagn Cytopathol 1995;12:350–353.
Nigam S, Kumar N, Jain S. Cytomorphologic spectrum of carcinoma ex
pleomorphic adenoma. Acta Cytol 2004;48:309–314.
Pitman MB. Mucoepidermoid carcinoma ex-pleomorphic adenoma of the
parotid gland. Acta Cytol 1995;39:604–606.
Myoepithelial Neoplasms
Darvishian F, Lin O. Myoepithelial cell-rich neoplasms: cytologic features
of benign and malignant lesions. Cancer 2004;102:355–361.
Das DK, Haji BE, Ahmed MS, Hossain MN. Myoepithelioma of the parotid
gland initially diagnosed by fine needle aspiration cytology and immuno-
cytochemistry: a case report. Acta Cytol 2005;49:65–70.
Gupta RK, Naran S, Dowle C, Simpson JS. Coexpression of vimentin, cyto-
keratin and S-100 in monomorphic adenoma of salivary gland; value of
marker studies in the differential diagnosis of salivary gland tumors.
Cytopathology 1992;3:303–309.
Kumar PV, Sobhani SA, Monabati A, Hashemi SB, Eghtadari F, Hamidi SA.
Myoepithelioma of the salivary glands. Fine needle aspiration biopsy
findings. Acta Cytol 2004;48:302–308.
Ng W, Choy C, Ip P, Shek W, Collins RJ. Fine needle aspiration cytology
of epithelial-myoepithelial carcinoma of salivary gland – a report of
three cases. Acta Cytol 1999;43:675–680.
Schultenover SJ, McDonald EC, Ramzy I. Hyaline-cell pleomorphic adenoma:
diagnosis by fine needle aspiration biopsy. Acta Cytol 1984;28:593–
597.
Warthin Tumor/Oncocytic Neoplasms
Allen EA, Ali SZ, Mathew S. Lymphoid lesions of the parotid. Diagn Cyto-
pathol 1999;21:170–173.
Ballo MS, Shin HJ, Sneige N. Sources of diagnostic error in fine-needle
aspiration diagnosis of Warthin’s tumor and clues to a correct diagnosis.
Diagn Cytopathol 1997;17:230–234.
Chai C, Dodd LG, Glasgow BJ. Salivary gland lesions with a promi-
nent lymphoid component: cytologic findings and differential diagnosis
by fine-needle aspiration biopsy. Diagn Cytopathol 1997;17:183–
190.
Chhieng DC, Cangiarella JF, Cohen JM. Fine-needle aspiration cytology of
lymphoproliferative lesions involving the major salivary glands. Am J
Clin Pathol 2000;113:563–571.
Klijanienko J, Vielh P. Fine-needle sampling of salivary gland lesions II.
Cytology and histology correlation of 71 cases of Warthin’s tumor
(adenolymphoma). Diagn Cytopathol 1997;16:221–225.
Mooney EE, Dodd LG, Layfield LJ. Squamous cells in fine-needle aspiration
biopsies of salivary gland lesions: potential pitfalls in cytologic diag-
nosis. Diagn Cytopathol 1996;15:447–452.
Parwani AV, Ali SZ. Diagnostic accuracy and pitfalls in fine-needle aspira-
tion interpretation of Warthin tumor. Cancer 2003;99:166–171.
Ryska A, Seifert G. Adenolymphoma (Warthin’s tumor) with multiple
sarcoid like granulomas. Pathol Res Pract 1999;195:835–839.
Sherman ME, Magro C, Berry Y, Syzyfelbein WM. Oncocytic nodule. An
unusual case of a submaxillary gland mass in an elderly patient. Acta
Cytol 1990;34:827–830.
Williamson JD, Simmons BH, EL-Naggar A, Medeiros LJ. Mucoepidermoid
carcinoma involving Warthin tumor. A report of five cases and review
of the literature. Am J Clin Pathol 2000;114:564–570.
Basaloid Neoplasms
Basal Cell Adenoma/Basal Cell Adenocarcinoma
Pisharodi LR. Basal cell adenocarcinoma of the salivary gland. Diagnosis
by fine-needle aspiration. Am J Clin Pathol 1995;103:603–608.
Stanley MW, Horwitz CA, Bardales RH, Stern SJ, Korourian S. Basal cell
carcinoma metastatic to the salivary glands: differential diagnosis in
fine-needle aspiration cytology. Diagn Cytopathol 1997;16:247–252.
Ch001-F06731.indd 35
35
Stanley MW, Horwitz CA, Henry MJ, Burton LG, Lowhagen T. Basal cell
adenoma of the salivary gland: a benign adenoma that cytologically
mimics adenoid cystic carcinoma. Diagn Cytopathol 1988;4:342–
346.
Stanley MW, Horwitz CA, Rollins SD, et al. Basal cell (monomorphic) and
minimally pleomorphic adenomas of the salivary glands. Distinction
from the solid type of adenoid cystic carcinoma in fine-needle aspira-
tion. Am J Clin Pathol 1996;106:35–41.
Adenoid Cystic Carcinoma
Nagel H, Hotze HJ, Laskawi R, Chilla R, Droese M. Cytologic diagnosis of
adenoid cystic carcinoma of salivary glands. Diagn Cytopathol 1999;20:
358–366.
Stanley MW, Horwitz CA, Rollins SD, et al. Basal cell (monomorphic) and
minimally pleomorphic adenomas of the salivary glands. Distinction
from the solid type of adenoid cystic carcinoma in fine-needle aspira-
tion. Am J Clin Pathol 1996;106:35–41.
Yu GH, Caraway NP. Poorly-differentiated adenoid cystic carcinoma: cyto-
logic appearance in fine-needle aspirates of distant metastases. Diagn
Cytopathol 1996;15:296–300.
Polymorphous Low-Grade Adenocarcinoma
Frierson HF Jr, Covell JL, Mills SE. Fine-needle aspiration cytology of ter-
minal duct carcinoma of minor salivary gland. Diagn Cytopathol 1987;3:
159–162.
Gibbons D, Saboorian MH, Vuitch F, Gokaslan ST, Ashfaq R. Fine-needle
aspiration findings in patients with polymorphous low grade adenocar-
cinoma of salivary glands. Cancer 1999;87:31–36.
Saenz, Santmaria J, Catalina-Fernandez I. Polymorphous low grade adeno-
carcinoma of the salivary gland. Diagnosis by fine needle aspiration
cytology. Acta Cytol 2004;48:52–56.
Mucoepidermoid Carcinoma
Al-Khafaji BM, Nestok BR, Katz RL. Fine-needle aspiration of 154 parotid
masses with histologic correlation: ten-year experience at the Univer-
sity of Texas M.D. Anderson Cancer Center. Cancer (Cancer Cytopathol)
1998;84:153–159.
Cajulis RS, Gokaslan ST, Yu GH, Frias-Hidvegi D. Fine needle aspiration
biopsy of the salivary glands – a five-year experience with emphasis on
diagnostic pitfalls. Acta Cytol 1997;41:1412–1420.
Chan MKM, McGuire LJ, King W, Li AKC, Lee JCK. Cytodiagnosis of 112
salivary gland lesions – correlation with histologic and frozen section
diagnosis. Acta Cytol 1992;36:353–363.
Cohen MB, Fisher PE, Holly EA, Ljung BM, Lowhagen T, Bottles K. Fine
needle aspiration biopsy diagnosis of mucoepidermoid carcinoma –
statistical analysis. Acta Cytol 1990;34:43–49.
Jakobson PA , Blanck C, Eneroth C-M. Mucoepidermoid carcinoma of the
parotid gland. Cancer 1968;22:111–124.
Klijianienko J, Vielh P. Fine-needle sampling of salivary gland lesions.
IV. Review of 50 cases of mucoepidermoid carcinoma with histologic
correlation. Diagn Cytopathol 1997;17:92–98.
Kumar N, Kapila K, Verma K. Fine needle aspiration cytology of mucoepi-
dermoid carcinoma. A diagnostic problem. Acta Cytol 1991;35:357–
359.
Layfield LJ, Glasgow BJ. Aspiration cytology of clear-cell lesions of the
parotid gland: morphologic features and differential diagnosis. Diagn
Cytopathol 1993;9:705–712.
MacLeod CB, Frable WJ. Fine-needle aspiration biopsy of salivary gland:
problem cases. Diagn Cytopathol 1993;9:216–225.
Palombini L. Challenges in the interpretation of FNAs from the salivary
glands. Diagn Cytopathol 1997;17:417–421.
Acinic Cell Carcinoma
Ali SZ. Acinic-cell carcinoma, papillary-cystic variant: a diagnostic dilemma
in salivary gland aspiration. Diagn Cytopathol 2002;27:244–250.
Al-Khafaji BM, Nestok BR, Katz RL. Fine-needle aspiration of 154 parotid
masses with histologic correlation: ten-year experience at the Univer-
sity of Texas M.D. Anderson Cancer Center. Cancer (Cancer Cytopathol)
1998;84:153–159.
10/26/2006 10:19:59 AM
 36
Baccato P, Altavilla G, Blandamura S. Fine-needle aspiration of salivary
gland lesions – a reappraisal of pitfalls and problems. Acta Cytol
1998;42:888–898.
Cajulis RS, Gokaslan ST, Yu GH, Frias-Hidvegi D. Fine needle aspiration
biopsy of the salivary glands – a five-year experience with emphasis on
diagnostic pitfalls. Acta Cytol 1997;41:1412–1420.
Klijanienko J, Vielh P. Fine-needle sampling of salivary gland lesions V:
cytology of 22 cases of acinic cell carcinoma with histologic correlation.
Diagn Cytopathol 1997;17:347–352.
Layfield LJ, Glasgow BJ. Aspiration cytology of clear-cell lesions of the
parotid gland: morphologic features and differential diagnosis. Diagn
Cytopathol 1993;9:705–712.
Lewis JE, Olsen KD, Weiland LH. Acinic cell carcinoma – clinicopathologic
review. Cancer 1991;67:172–179.
Nagel H, Laskawi R, Buter JJ, Schroder M, Chilla R, Droese M. Cytologic
diagnosis of acinic-cell carcinoma of salivary glands. Diagn Cytopathol
1997;16:402–412.
Palombini L. Challenges in the interpretation of FNAs from the salivary
glands. Diagn Cytopathol 1997;17:417–421.
Sheyn I, Yassin R, Seiden A, Nestok BR. Papillary-cystic variant of acinic
cell carcinoma of the salivary gland diagnosed by fine needle aspiration
biopsy. A case report. Acta Cytol 2000;44:1073–1076.
Salivary Duct Carcinoma
Dee S, Masood S, Isaacs JH Jr, Hardy NM. Cytomorphologic features of
salivary duct carcinoma on fine needle aspiration biopsy. A case report.
Acta Cytol 1993;37:539–542.
Domson KK, Wakely PE Jr. Aspiration and imprint cytopathology of salivary
duct carcinoma. Cancer 1997;81:281–286.
Elsheikh TM, Bernacki EG, Pisharodi L. Fine-needle aspiration cytology of
salivary duct carcinoma. Diagn Cytopathol 1994;11:47–51.
Ersoz C, Cetik F, Aydin O, Cosar EF, Talas DU. Salivary duct carcinoma ex-
pleomorphic adenoma: analysis of the findings in fine needle aspiration
cytology and histology. Diagn Cytopathol 1998;19:201–204.
Fyrat P, Cramer H, Feczko JD, et al. Fine needle aspiration biopsy of
salivary duct carcinoma: report of five cases. Diagn Cytopathol 1997;16:
526–530.
Gilcrease MZ, Guzman-Paz M, Froberg K, Pambiccian S. Salivary duct
carcinoma. Is a specific diagnosis possible by fine needle aspiration
cytology? Acta Cytol 1998;42:1389–1396.
James GK, Pudek M, Berean KW, Diamandis EP, Archibald BL. Salivary duct
carcinoma secreting prostate-specific antigen. Am J Clin Pathol 1996;
106:242–247.
Kapadia SB, Barnes L. Expression of androgen receptor, gross cystic
disease fluid protein, and CD44 in salivary duct carcinoma. Mod Pathol
1998;11:1033–1038.
Khurana KK, Pitman MB, Powers CN, Korourian S, Bardales RH, Stanley
MW. Diagnostic pitfalls of aspiration cytology of salivary duct carci-
noma. Cancer 1997;81:373–378.
Moriki T, Ueta S, TakahashiT, Mitani M, Ichien M. Salivary duct carcinoma:
cytologic characteristics and application of androgen receptor immuno-
staining for diagnosis. Cancer 2001;93:344–350.
Lymphoproliferative Disorders
Allen EA, Ali SZ, Mathew S. Lymphoid lesions of the parotid. Diagn Cyto-
pathol 1999;21:70–73.
Ch001-F06731.indd 36
FINE NEEDLE ASPIRATION CYTOLOGY
Chhieng DC, Cangiarella JF, Cohen JM. Fine-needle aspiration cytology of
lymphoproliferative lesions involving the major salivary glands. Am J
Clin Pathol 2000;113:563–571.
Crapanzano JP, Lin O. Cytologic findings of marginal zone lymphoma.
Cancer 2003;99:301–309.
MacCallum PL, Lampe HB, Cramer H, Matthews TW. Fine-needle aspiration
cytology of lymphoid lesions of the salivary gland: a review of 35 cases.
J Otolaryngol 1996;25:300–304.
Ustun MO, Ekinci N, Payzin B. Extramedullary plasmacytoma of the
parotid gland. Report of a case with extensive amyloid deposition
masking the cytologic and histopathologic picture. Acta Cytol 2001;45:
449–453.
Rare Tumors
Chhieng DC, Cohen JM, Cangiarella JF. Fine-needle aspiration of spindle
cell and mesenchymal lesions of the salivary glands. Diagn Cytopathol
2000;23:253–259.
Gnepp DR, Wick MR. Small cell carcinoma of the major salivary glands: an
immunohistochemical study. Cancer 1990;66:185–192.
Mair S, Philips JI, Cohen R. Small cell undifferentiated carcinoma of the
parotid gland. Cytologic, histologic, immunohistochemical and ultra-
structural features of a neuroendocrine variant. Acta Cytol 1989;33:
164–168.
Milchgrub S, Vuitch F, Saboorian MH, Hameed A, Wu H, Albores-Saavedra
J. Hyalinizing clear-cell carcinoma of salivary glands in fine-needle
aspiration. Diagn Cytopathol 2000;23:333–337.
Nagao T, Sugano I, Matsuzaki O, Hara H, Kondo Y, Nagao K. Intra-
ductal papillary tumors of the major salivary glands: case reports of
benign and malignant variants. Arch Pathol Lab Med 2000;124:
291–295.
Thompson MB, Nestok BR, Gluckman JL. Fine needle aspiration cytology
of lymphoepithelioma-like carcinoma of the parotid gland. A case
report. Acta Cytol 1994;38:782–786.
Toyosawa S, Ohnishi A, Ito R, et al. Small cell undifferentiated carcin-
oma of the submandibular gland: immunohistochemical evidence of
myoepithelial, basal and luminal cell features. Pathol Int 1999;49:887–
892.
Secondary Tumors
Hughes JH, Jensen CS, Donnelly AD, et al. The role of fine-needle aspira-
tion cytology in the evaluation of metastatic clear cell tumors. Cancer
1999;87:380–389.
Lussier C, Klijanienko J, Vielh P. Fine-needle aspiration of metastatic
nonlymphomatous tumors to the major salivary glands: a clinicopatho-
logic study of 40 cases cytologically diagnosed and histologically
correlated. Cancer 2000;90:350–356.
Stanley MW, Bardales RH, Farmer CE, et al. Primary and metastatic high-
grade carcinomas of the salivary glands: a cytologic-histologic study of
twenty cases. Diagn Cytopathol 1995;13:37–43.
Yang B, Ali SZ, Rosenthal DL. CD10 facilitates the diagnosis of metastatic
renal cell carcinoma from primary adrenal cortical neoplasm in adrenal
fine-needle aspiration. Diagn Cytopathol 2002;27:149–152.
Zhang C, Cohen JM, Cangiarella JF, Waisman J, McKenna BJ, Chhieng
DC. Fine-needle aspiration of secondary neoplasms involving the
salivary glands. A report of 36 cases. Am J Clin Pathol 2000;113:21–
28.
10/26/2006 10:19:59 AM
 2 Thyroid
Katherine Berezowski
Mary K Sidawy
INTRODUCTION
Clinically detectable thyroid nodules occur in 4% to
10% of the population, of which only 5% are malig-
nant. Fine needle aspiration (FNA) is a powerful diag-
nostic tool recognized to have the best predictive value
in the presurgical evaluation of the thyroid. FNA is
regarded as a screening test aimed at distinguishing
nodules that require surgery from those that do not. Its
introduction has resulted in a decrease in the number
of thyroidectomies performed on ‘cold’ nodules, and
an increase in the yield of malignancy for excised
nodules.
The sensitivity of thyroid FNA ranges from 83% to
99%, and its specificity from 70% to 91%. The reported
false negative rate ranges from 1% to 8%, but its true
frequency is difficult to assess, since only 10% of
patients with benign cytologic findings undergo
surgery.
Since FNA is considered a screening test, particular
attention should be given to minimize false negative
results at the expense of accepting some false positive
diagnoses. Repeat FNA of benign lesions and periodic
clinical follow-up are advocated to decrease the false
negative diagnoses.
Accurate diagnostic interpretation depends upon an
adequate sample and optimally prepared slides. Although
it is difficult to define what constitutes an adequate
specimen, proposed criteria require five to ten groups of
well-visualized follicular cells with each group contain-
ing 10–20 cells. Rendering a definite diagnosis on sub-
optimal samples that barely meet the adequacy criteria
is a source of pitfall.
A good aspiration technique is paramount. The pro-
cedure is performed using a 23- or 25-gauge needle. The
thyroid is a vascular organ, thus a few milliliters or no
suction is recommended. The needle is moved rapidly
in the same needle track, and the procedure is stopped
as soon as the sample begins to fill the clear hub of the
needle. Three or four passes are usually necessary to
obtain an adequate sample. When cyst fluid is obtained,
the cyst is drained. If any palpable lesion remains, re-
aspiration should be performed. Ultrasonographic guid-
ance is necessary for sampling non-palpable nodules.
The smears may be air-dried and stained with the
Diff-Quik stain, alcohol-fixed and stained with the
Papanicolaou method, or prepared using a liquid-based
Ch002-F06731.indd 37
• Igor Jovanovic •
technology. Each method offers different advantages,
and the choice depends upon the familiarity and per-
sonal preference of the cytopathologist. The advantages
of air-dried smears include enhancement of background
and cytoplasmic features and they are ideal for evaluat-
ing lymphoid infiltrates. Alcohol-fixed smears are better
for preserving nuclear details, showing the chromatin
distribution and delineating nucleoli.
Liquid-based preparations are advocated as an adjunct
to conventional smears. Their exclusive use has not
gained popularity. Following each pass, one or two con-
ventional smears are prepared and the remaining sample
is rinsed in the appropriate liquid-based medium.
The main advantages of liquid-based cytology are the
decrease in the number of slides to be screened, the
ability to perform immunocytochemical and other
special stains, and the enhancement of nuclear details
and irregularities in papillary carcinoma. Limitations of
liquid-based preparation include loss of colloid during
processing, impacting the ability to assess the colloid to
cell ratio (Fig. 2-1). In addition, the diagnosis of Hashi-
moto’s thyroiditis may be missed due to the dispersed
appearance of lymphoid cells in these preparations
(Fig. 2-2).
CHRONIC LYMPHOCYTIC
(HASHIMOTO’S) THYROIDITIS
CLINICAL FEATURES
Chronic lymphocytic (Hashimoto’s) thyroiditis is the
most prevalent form of autoimmune thyroid disease,
and is considered to be the most common cause of
goitrous hypothyroidism in areas of the world in which
dietary iodine is sufficient. In the United States, Hashi-
moto’s thyroiditis affects approximately 3% to 4% of
the population, has a female to male ratio of 8–20 : 1,
and is most frequently diagnosed between the third and
fi fth decade of life. Although primarily a disease of
middle-aged women, it also occurs in children. Genetic
predisposition is a risk factor. Hashimoto’s thyroiditis
occurs in clusters within families, and is associated
with HLA-DR3 and HLA-DR5 major histocompatibil-
ity antigens.
37
10/26/2006 10:21:09 AM
 38 FINE NEEDLE ASPIRATION CYTOLOGY

A B

FIGURE 2-1
Adenomatoid nodule: colloid to cell ratio in conventional versus liquid-based preparations. A, Conventional smear demonstrating abundant colloid
with only few scattered clusters of follicular cells (high colloid to cell ratio). Diff-Quik stain, low power. B, Liquid-based preparation of the same
case, illustrating loss of colloid during processing and concentration of the follicular cells. The colloid to cell ratio is relatively low as compared
to the conventional smear. Papanicolaou stain, low power.

A B

FIGURE 2-2
Hashimoto’s thyroiditis: lymphoid cells in conventional versus liquid-based preparations. A, A cellular streak of lymphoid cells composed of a poly-
morphous population of lymphoid cells, tingible-body macrophages, germinal centers, and plasma cells. Diff-Quik stain, high power. B, Liquid-based
preparation from the same case, showing the dispersed nature of the lymphoid cells. A close-up evaluation of the cells is necessary to distinguish
the polymorphous lymphoid nature from follicular epithelial cells and peripheral blood elements. Papanicolaou stain, high power.

The thyroid gland is diffusely slightly enlarged, non-

HASHIMOTO’S THYROIDITIS – DISEASE FACT SHEET tender to palpation, and has a rubbery to firm consis-
tency. Although the disease affects the entire gland, the
Incidence process may accentuate any asymmetry of the normal
៉ Affects 3–4% of the US population thyroid, and some patients present with an asymmetri-
cally enlarged, nodular thyroid. The majority of the
Gender, Race, and Age Distribution patients are either euthyroid or hypothyroid. In some
៉ Female predominance cases, however, the disease may present with a transient
៉ More prevalent in Caucasians hyperthyroidism.
៉ Affects adults and children Patients with Hashimoto’s thyroiditis are at increased
risk of developing non-Hodgkin B-cell lymphomas, par-
Clinical Features ticularly large B-cell type. Also, of note is the association
៉ Diffusely enlarged gland, occasionally nodular of Hashimoto’s thyroiditis and papillary carcinoma of
៉ Painless the thyroid; however, the causal relationship between
៉ Transient hyperthyroidism, euthyroid, or hypothyroid
the two has not been established.
៉ Increased risk for non-Hodgkin B-cell lymphoma

Ch002-F06731.indd 38 10/26/2006 10:21:10 AM

 CHAPTER 2 Thyroid
CYTOPATHOLOGIC FEATURES
FNA is a reliable technique in the initial diagnosis of
Hashimoto’s thyroiditis. It is also instrumental in
establishing the diagnosis in patients with negative or
low autoantibody titers, which occurs in up to 10% of
cases, and in investigating potentially neoplastic domi-
nant nodules.
The aspirates are typically cellular and contain an
admixture of lymphoid and epithelial cells in variable
proportions depending on sampling and the stage of the
disease (Fig. 2-3). The follicular cells demonstrate a
spectrum of nuclear and cytoplasmic changes ranging
from regular follicular cells to Hürthle cells. They are
arranged in aggregates, sheets, and occasionally in a
microfollicular pattern. Hürthle cells are characterized
by abundant granular, dense cytoplasm with well-
HASHIMOTO’S THYROIDITIS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Moderately to highly cellular aspirates
៉ Mixture of Hürthle cells and regular follicular cells
៉ Polymorphous population of lymphoid cells
៉ Germinal center, tingible-body macrophages, lymphohistiocytic
aggregates, plasma cells, multinucleated giant cells
Ancillary Studies
៉ Antithyroid autoantibodies in the serum
Differential Diagnosis and Pitfalls
៉ Lymphoma
៉ Hürthle cell neoplasm
FIGURE 2-3
Hashimoto’s thyroiditis. A polymor-
phous lymphoid population admixed
with Hürthle cells. Diff-Quik stain,
high power.
Ch002-F06731.indd 39
39
defined cytoplasmic borders. Their nuclei are enlarged
with variable degrees of pleomorphism. Nucleoli vary
from inconspicuous to prominent (Fig. 2-4). The lym-
phoid cell population is polymorphous, consisting of
small, mature lymphocytes, centroblasts, centrocytes,
and immunoblasts. Germinal centers, tingible-body
macrophages, plasma cells, and multinucleated giant
cells may be present (Fig. 2-5). Epithelioid histiocytes
may be seen in small aggregates and may resemble gran-
ulomas. They occasionally exhibit mitoses. Lymphoid
cells are delicate and may appear as crushed tangles of
twisted chromatin material – ‘lymphoid tangles’ (Fig.
2-6). Blue cytoplasmic fragments (lymphoglandular
bodies) derived from the breakdown of lymphoid cells
are noted in the background. It is important to distin-
guish bare follicular cell nuclei from lymphocytes. The
latter retain a rim of blue cytoplasm, while the follicular
cells appear as well-preserved stripped nuclei. The
amount of colloid is variable. When fibrosis occurs, the
aspirates tend to be dry and hypocellular.
ANCILLARY STUDIES
The diagnosis of Hashimoto’s thyroiditis is confirmed
by the presence of antithyroid autoantibodies (antithy-
roglobulin and antithyroid peroxidase) in the serum.
Antithyroid peroxidase is more specific.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis of Hashimoto’s thyroiditis
depends on the cellular composition of the smears. In
10/26/2006 10:21:11 AM
 40
cases where the lymphoid component predominates,
lymphoma needs to be considered. Lymphomas yield a
monotonous population of lymphoid cells, unlike the
heterogenous population of Hashimoto’s thyroiditis.
Whenever the cytologic distinction is in question, flow
cytometric analysis should be performed. The sample
can be obtained by simply rinsing the needle in the
appropriate medium.
When the aspirates show a predominance of Hürthle
cells, the distinction between Hashimoto’s thyroiditis
Ch002-F06731.indd 40
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 2-4
Hashimoto’s thyroiditis. Follicular
cells with Hürthle cell change. The
cells are arranged in sheets and
display abundant granular cyto-
plasm and nuclear pleomorphism.
Diff-Quik stain, high power.
FIGURE 2-5
Hashimoto’s thyroiditis. Liquid-
based preparation illustrating a
multinucleated giant cell. Note the
scattered lymphocytes in the back-
ground. The presence of giant cells
is a useful clue to the diagnosis of
Hashimoto’s in liquid-based prepa-
rations, since the lymphoid popula-
tion is dispersed. Papanicolaou
stain, high power.
and a Hürthle cell neoplasm may be problematic.
Multiple passes increase the chance of sampling the
lymphoid component. Moreover, the relatively
cohesive nature of the Hürthle cells and the nuclear
pleomorphism are features more in keeping with Hashi-
moto’s thyroiditis. The presence of uniform, loosely
cohesive Hürthle cells with macronucleoli favors a
neoplasm.
10/26/2006 10:21:12 AM
 CHAPTER 2 Thyroid
FIGURE 2-6
Hashimoto’s thyroiditis. Lymphoid
tangles that represent twisted chro-
matin of crushed lymphocytes, and
a cluster of Hürthle cells. Diff-Quik
stain, high power.
NODULAR GOITER
CLINICAL FEATURES
Goiter is a clinical term that denotes enlargement of
the thyroid, which occurs due to impaired synthesis
of thyroid hormones. Clinically, goiter presents in a
nodular or diffuse form, and is divided by the func-
tional activity of the thyroid into the non-toxic and
toxic variants. Non-toxic nodular goiter is the most
common form in the United States, affecting approxi-
mately 5% of the population. In essence, it is a com-
pensatory response of the gland for a decrease in
hormone secretion. The specific cause of this form of
goiter is usually unknown. The basic mechanism
NODULAR GOITER (ADENOMATOID NODULE) –
DISEASE FACT SHEET
Incidence
៉ Affects 5% of population
Gender and Age Distribution
៉ Female predominance
៉ Occurs in adults
Clinical Features
៉ Asymptomatic, euthyroid
៉ Slow growing
៉ Sudden growth as result of hemorrhage
៉ Compressive symptoms
Ch002-F06731.indd 41
41
involves stimulation of the thyroid by TSH due to low
levels of the thyroid hormones, which leads to follicular
cell hyperplasia and involution. Nodular goiter is the
end-stage of a diffuse goiter and is caused by the cyclic
changes taking place during hyperplasia and
involution.
Nodular goiter is a disease of adults and shows a
female predominance. Most patients are asymptomatic
and, by definition, euthyroid. Multinodular goiter devel-
ops over many years and is detected on routine physical
examination or by the patient noticing an enlargement
in the neck. If the goiter is large enough, it can lead to
compressive symptoms. Patients may complain of
sudden pain caused by hemorrhage into a nodule.
CYTOPATHOLOGIC FEATURES
Cytologic nomenclature of nodular goiter includes
adenomatoid, cellular adenomatoid, adenomatous,
hyperplastic, and non-neoplastic nodule. The aspirates
from nodular goiter are of low to moderate cellularity.
They demonstrate an admixture of colloid and follicu-
lar cells in variable proportion, reflecting the different
phases of evolution of the disease. During the hyper-
plastic stage, follicular cells are abundant and colloid is
scant. As the disease progresses to the involutional
stage, follicular cells become fewer and colloid becomes
abundant.
The presence of abundant colloid and a high colloid
to cell ratio are extremely helpful in the cytologic diag-
nosis of goiter. Macroscopically, smeared unstained
colloid resembles varnish. Microscopically, colloid can
appear as thick amorphous material with sharply cir-
cumscribed edges or as a thin translucent film in the
background, often with folds and cracks. When diluted
10/26/2006 10:21:13 AM
 42
NODULAR GOITER (ADENOMATOID NODULE)–
PATHOLOGIC FEATURES
Cytopathologic Findings
៉ High colloid to cell ratio
៉ Follicular cells arranged in honeycomb sheets, spherules, tissue
fragments, or singly
៉ Small round nuclei, naked nuclei, delicate cytoplasm
៉ Hürthle cells
៉ Cystic change: macrophages (pigmented, multinucleated),
cyst-lining cells
Differential Diagnosis and Pitfalls
៉ Cystic papillary carcinoma
៉ Follicular neoplasm
៉ Follicular variant of papillary carcinoma
៉ Parathyroid cyst
by blood, its appearance overlaps with serum. Colloid
may be lost during processing, particularly with liquid-
based preparations (see Fig. 2-1).
Follicular cell nuclei are 1.5–2 times the size of
mature lymphocytes. The chromatin is finely granular
and uniformly dispersed, with inconspicuous nucleoli.
The nuclei are round and may show enlargement and
variability in size. The cytoplasm is delicate with indis-
tinct borders (Fig. 2-7). The follicular cells are arranged
in groups, honeycomb sheets, spherules, and tissue frag-
ments. A spherule represents an intact non-neoplastic
macrofollicle with its basement membrane. It appears
as a round structure, with smooth borders and evenly
spaced nuclei. A spherule may mimic a giant cell, but
the latter can be differentiated by its irregular outline
Ch002-F06731.indd 42
FINE NEEDLE ASPIRATION CYTOLOGY
and unevenly spaced, elongated nuclei (Fig. 2-8). Tissue
fragments with supporting vascular stroma may be mis-
taken for papillary structures and suggest papillary car-
cinoma. However, attention to the arrangement of the
follicular cells within the tissue fragments (spherules
and honeycomb sheets with maintained nuclear polar-
ity) should prevent such a pitfall (Fig. 2-9). The follicu-
lar cells may also be found dispersed singly and stripped
of their cytoplasm (Fig. 2-10). Hürthle cells with
enlarged nuclei showing variable degrees of pleomor-
phism are seen in nodular goiter.
In Diff-Quik-stained smears, the follicular cells may
reveal abundant intracytoplasmic blue granules, which
can obscure the nuclei. These granules are seen in cystic
and hemorrhagic lesions, and represent hemosiderin
pigments. They are not specific and may be seen in
goiter, as well as in benign and malignant neoplasms
(Fig. 2-11). These non-specific granules should be dis-
tinguished from a different type of granules, ‘paravacu-
olar granules’ (Fig. 2-12). The latter consist of small
blue granules grouped within a vacuole close to the
nucleus. They are frequently observed in non-lesional
thyroid tissue and occasionally in Hashimoto’s thyroid-
itis. When the majority of aspirated follicular cells
display paravacuolar granules, the cytopathologist needs
to consider that the targeted lesion (especially when
small) was missed and only adjacent non-lesional
thyroid tissue was sampled.
Hemorrhage and cystic change are quite common in
aspirates from nodular goiters. Cytologically, they mani-
fest by the presence of histiocytes and hemosiderin-
laden macrophages (many multinucleated), cholesterol
crystals, and cyst-lining cells (Figs 2-13 & 2-14). Cyst-
lining cells appear as flat sheets of spindled to polygonal
(squamoid) cells with abundant, dense cytoplasm,
enlarged pleomorphic nuclei, and prominent nucleoli
(Fig. 2-15). Bi- and multinucleation are common.
FIGURE 2-7
Adenomatoid nodule. Follicular
cells arranged in a honeycomb
sheet. The cells are evenly spaced,
with uniform round nuclei and
fine evenly dispersed chromatin.
The cytoplasm is delicate with ill-
defined borders. Papanicolaou stain,
high power.
10/26/2006 10:21:14 AM
 A B

FIGURE 2-8
Adenomatoid nodule: spherule. A spherule represents an intact non-neoplastic macrofollicle with its basement membrane. It is a tridimensional
round structure with smooth borders and evenly spaced nuclei. The latter feature helps distinguishing a spherule from a giant cell (see Fig. 2-5).
A, Diff-Quik stain, high power. B, Papanicolaou stain, high power.

FIGURE 2-9
Adenomatoid nodule. Tissue frag-
ment with supporting vascular
stroma. Note the presence of intact
macrofollicles (spherules). Their
presence along with the maintained
nuclear polarity are helpful clues
for the diagnosis of adenomatoid
nodule. Diff-Quik stain, low power.

FIGURE 2-10
Adenomatoid nodule. Follicular
epithelial cells dispersed singly and
stripped of their delicate cyto-
plasm. The absence of a small rim
of blue cytoplasm helps distinguish
follicular cells from lymphocytes.
Diff-Quik stain, high power.

Ch002-F06731.indd 43 10/26/2006 10:21:15 AM

 44 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 2-11
Adenomatoid nodule. Follicular
cells displaying non-specific intra-
cytoplasmic blue granules. These
granules are seen in cystic and
hemorrhagic lesions and represent
hemosiderin pigments. Diff-Quik
stain, high power.

FIGURE 2-12
Paravacuolar granules. Small blue
granules clustered within a vacuole
adjacent to the nucleus. These
granules are frequently seen in
aspirates of non-lesional thyroid
and in Hashimoto’s thyroiditis. Diff-
Quik stain, high power.

Ch002-F06731.indd 44 10/26/2006 10:21:17 AM

 CHAPTER 2 Thyroid 45

FIGURE 2-13
Adenomatoid nodule with hemor-
rhage and cystic change. Liquid-
based preparation illustrating
regular follicular cells and hemo-
siderin-laden macrophages (some
multinucleated). Papanicolaou stain,
high power.

FIGURE 2-14
Cholesterol crystals. Cholesterol
crystals in a Diff-Quik-stained prep-
aration appear as negative images.
Diff-Quik stain, high power.

Ch002-F06731.indd 45 10/26/2006 10:21:19 AM

 46
ANCILLARY STUDIES
Ancillary techniques including morphometry, image
analysis, DNA measurements by flow cytometry, telom-
erase activity (by polymerase chain reaction [PCR]),
and immunocytochemistry for a variety of antigens
have been advocated for discriminating between benign
and malignant nodules; however, none of these methods
is sufficiently reliable.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis of nodular goiter depends on
the stage of the disease. Cystic nodules must be differ-
entiated from cystic papillary carcinomas, while the
differential diagnosis of cellular adenomatoid (hyper-
plastic) nodules includes follicular neoplasms and
follicular variant of papillary carcinomas.
CYSTIC PAPILLARY CARCINOMA
Thirty per cent of thyroid nodules are cystic, most of
which are nodular goiter. It is also important to point
out that a third of papillary carcinomas are cystic, while
cystic degeneration is rare in follicular, medullary, and
anaplastic carcinomas. The gross appearance of the
fluid (yellow or hemorrhagic) is not reliable in distin-
guishing goiter from papillary carcinoma. To the unini-
tiated, the prominent cytologic atypia and squamoid
appearance of the cyst-lining cells of nodular goiter
Ch002-F06731.indd 46
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 2-15
Adenomatoid nodule: cyst-lining
cells. Flat sheet of polygonal cells
with abundant dense cytoplasm,
enlarged pleomorphic nuclei, and
distinct nucleoli. These cells are a
source of false positive diagnosis;
they can be mistaken for ‘squamoid
cells’ seen in papillary carcinoma.
Papanicolaou stain, high power.
may lead to the erroneous diagnosis of papillary
carcinoma.
FOLLICULAR NEOPLASMS
The cytologic features of cellular adenomatoid
nodules overlap with those of follicular neoplasms,
making the distinction between the two entities unreli-
able. High cellularity, scant colloid, and follicular cells
arranged in acini and occasional microfollicles are
shared features of both entities. When the distinction is
difficult, the aspirates fall in the indeterminate category
and are classified as ‘cellular follicular lesions’. The risk
of malignancy with indeterminate thyroid cytology is
reported as 15–20%.
FOLLICULAR VARIANT OF PAPILLARY CARCINOMA
This is a well-known pitfall, and one of the major
sources of false negative diagnoses in thyroid FNA. This
variant of papillary carcinoma reveals neoplastic cells
arranged in syncytial clusters and microfollicles, and
should be considered in the differential diagnosis
of cellular follicular lesions. Attention to the nuclear
features may help in establishing the correct diagnosis,
or at least including papillary carcinoma in the differ-
ential diagnosis.
PARATHYROID CYST
When crystal-clear fluid is aspirated, the possibility of
a parathyroid cyst should be considered. Measuring the
level of C-terminal/midmolecule parathyroid hormone
in the fluid helps in confirming the diagnosis.
10/26/2006 10:21:20 AM
 CHAPTER 2 Thyroid
FOLLICULAR NEOPLASMS
CLINICAL FEATURES
Follicular neoplasms include follicular adenomas and
carcinomas. Follicular adenoma is defined as a benign
thyroid neoplasm showing follicular cell differentia-
tion, which is completely encapsulated and lacks cap-
sular and vascular invasion. Follicular adenoma is the
most common thyroid neoplasm and may be found in
up to 4% of thyroid glands at autopsy. It occurs in
adults and shows female predominance. It presents as
a painless, solitary thyroid nodule, rarely greater than
3 cm. Most appear as ‘cold’ nodules on radionuclide
scanning, but functioning or ‘hot’ adenomas do occur.
Follicular carcinoma is the second most common
form of thyroid malignancies. It accounts for 5% to
15% of all thyroid carcinomas. Follicular carcinomas
are divided histologically into two groups: minimally
invasive (encapsulated type) and widely invasive. Fol-
licular carcinoma has a predilection for women, with a
peak incidence in the fifth decade of life. It is more
common in iodine-deficient areas. Exposure to radiation
FOLLICULAR NEOPLASMS – DISEASE FACT SHEET
Definition
៉ Term includes follicular adenomas and carcinomas
Incidence
៉ Adenoma: most common thyroid neoplasm
៉ Carcinoma: 5–15% of thyroid carcinomas
Gender and Age Distribution
៉ Female predominance
៉ Adenoma: middle age
៉ Carcinoma: older age
Risk Factors for Carcinoma
៉ Iodine deficiency
៉ Exposure to radiation
៉ Activating RAS mutations
Clinical Features
៉ Solitary ‘cold’ nodule
៉ Carcinoma: hematogenous spread (lungs, bones)
Prognosis
៉ Minimally invasive carcinoma: excellent prognosis
៉ Widely invasive carcinoma: mortality rate 80%
៉ Poor prognostic indicators of carcinoma:
៉ Poorly differentiated
៉ Age >45 years
៉ Tumor >4.0 cm
៉ Extrathyroid extension
៉ Distant metastases
Ch002-F06731.indd 47
47
and RAS mutations are also known risk factors. This
disease commonly presents as a painless thyroid nodule
which appears ‘cold’ on radionuclide scanning. Com-
pressive symptoms such as dyspnea, dysphagia, hoarse-
ness, and cough are rare at presentation and may occur
in patients with the widely invasive type. Follicular
carcinoma spreads hematogenously, to the lungs and
bones most commonly.
Prognosis is related to the tumor grade, stage, and
clinical presentation. Poor prognostic indicators are
high histologic grade (poorly differentiated carcinoma),
age above 45 years, tumors more than 4.0 cm in size,
extrathyroid extension, and distant metastases. Well-
differentiated follicular carcinomas that are confined to
the thyroid have an excellent prognosis, with a 10-year
survival rate approaching 90%, whereas widely inva-
sive, poorly differentiated follicular carcinomas with
distant metastases have a much worse prognosis, with
a 10-year survival rate of approximately 50%.
CYTOPATHOLOGIC FEATURES
FNA cannot separate follicular adenomas from well-
differentiated follicular carcinomas. Both entities
display similar cytologic features, and the diagnosis of
malignancy relies on the histologic demonstration of
either capsular or vascular invasion. Thus, the inclu-
sive term follicular neoplasm is recommended in the
cytologic literature. The cytologic features of follicular
neoplasms are variable, reflecting their histologic types.
However, they have in common high cellularity, scant
or absent colloid, and follicular cells with enlarged
nuclei arranged in syncytial groups displaying nuclear
crowding and overlapping. The cytoplasm varies from
ill-defined to dense. A prominent repetitive microaci-
nar arrangement is a reliable (although non-diagnostic)
FOLLICULAR NEOPLASMS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellular aspirates
៉ Low colloid to cell ratio
៉ Repetitive acinar arrangement
៉ Microfollicles
៉ Cytoplasm delicate, ill-defined, or dense
៉ Nuclei:
៉ Enlarged, round
៉ Loss of polarity with crowding and overlapping
៉ Prominent nucleoli
Differential Diagnosis and Pitfalls
៉ Cellular adenomatoid nodule versus adenoma/encapsulated
carcinoma
៉ Adenomatoid nodule versus macrofollicular adenoma
៉ Follicular variant of papillary carcinoma
៉ Insular carcinoma versus poorly differentiated follicular
carcinoma
10/26/2006 10:21:21 AM
 48 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 2-16
Follicular neoplasm (histologically
confirmed follicular adenoma).
Repetitive microacinar pattern.
Note the nuclear crowding and
overlapping. The smear is cellular
with no colloid in the background.
Diff-Quik stain, high power.

FIGURE 2-17
Follicular neoplasm. Microfollicular
arrangement characterized by the
presence of acini with central drops
of colloid. Note the nuclear enlarge-
ment, crowding, and overlapping.
Diff-Quik stain, high power.

criterion for a neoplasm (Fig. 2-16). Acini with a central chromatin, prominent nucleoli, and the presence of
lumen containing a drop of colloid represent microfol- mitotic figures. Adenomas very rarely reveal mitoses.
licles and are characteristic of follicular neoplasms
with a microfollicular growth pattern (Figs 2-17 &
2-18). A trabecular pattern is represented by parallel
rows of follicular epithelial cells. ANCILLARY STUDIES
Poorly differentiated follicular carcinoma may be
recognized as malignant cytologically. Cytologic features
that should alert the pathologist to the possibility of There are currently no ancillary tests or markers
malignancy include nuclear pleomorphism, marked that can reliably distinguish follicular adenomas
crowding and overlapping, hyperchromasia, coarse from follicular carcinomas. Though showing initial

Ch002-F06731.indd 48 10/26/2006 10:21:21 AM

 CHAPTER 2 Thyroid 49

FIGURE 2-18
Follicular neoplasm. Liquid-based
preparation illustrating microacinar
arrangement with nuclear enlarge-
ment, crowding, and overlapping.
Note the similarities with Fig. 2-16.
Based on cytologic features, this
case cannot be further classified
as benign or malignant. Surgical
follow-up demonstrated a follicular
carcinoma with capsular invasion.
Papanicolaou stain, high power.

promising results, telomerase activity (detected by

PCR), and immunostains for RET/PTC, CK19, galec- HÜRTHLE CELL NEOPLASMS
tin-3, HBME-1, and thyroid-specific transcription
factors have limited predictive value in distinguishing
follicular-patterned lesions owing to a lack of sensitiv- CLINICAL FEATURES
ity and/or specificity.

Hürthle cell neoplasms, also known as oncocytic or

oxyphilic thyroid neoplasms, are comprised exclusively
DIFFERENTIAL DIAGNOSIS AND PITFALLS or predominantly (more than 75%) of follicular cells

Overlapping cytologic features limit the distinction

between follicular neoplasms and cellular adenomatoid
(hyperplastic) nodules. Up to 15–25% of FNAs reported HÜRTHLE CELL NEOPLASMS – DISEASE FACT SHEET
as follicular neoplasms correlate with hyperplastic
nodules in subsequent thyroidectomies. Definition
Macrofollicular follicular neoplasms are difficult to ៉ Term includes Hürthle cell adenomas and carcinomas
recognize as neoplastic and may be misinterpreted as
adenomatoid nodules. The cytologic features of both Incidence
entities overlap and are characterized by the presence ៉ Accounts for 5–10% of thyroid neoplasms
of abundant colloid and regular follicular cells arranged
in honeycomb sheets. Fortunately, this misclassification Gender and Age Distribution
bears no negative impact on patient management, ៉ Female predominance
since most macrofollicular follicular neoplasms are ៉ Occurs in adults
adenomas.
Follicular variant of papillary carcinomas may be Clinical Features
misdiagnosed as follicular neoplasms. The syncytial ៉ Solid nodule
arrangement and microfollicular architectural pattern ៉ ’Cold’ on radionuclide scan
are shared by both entities. Attention to the nuclear ៉ Carcinomas: cervical lymph nodes and hematogenous spread
features, i.e. elongated nuclei with irregular nuclear
membranes and powdery chromatin, is key and should Prognosis
alert the pathologist to the possibility of papillary ៉ Poor prognostic indicators of carcinoma:
៉ Age >45 years
carcinoma.
៉ Tumor >4.0 cm
Poorly differentiated follicular carcinoma may be dif-
៉ Extrathyroid extension
ficult to distinguish from insular carcinoma. Both tumors ៉ Lymph node and visceral metastases
are positive for thyroglobulin and thyroid transcription
factor 1 (TTF-1).

Ch002-F06731.indd 49 10/26/2006 10:21:23 AM

 50
displaying cytoplasmic granularity due to the accumu-
lation of mitochondria. Hürthle cell neoplasms account
for 5% to 10% of all thyroid neoplasms, and include
Hürthle cell adenomas and carcinomas. According
to the World Health Organization classification, they
are considered as a variant of follicular thyroid
neoplasms.
Hürthle cell neoplasms occur in adults, and have a
female predilection, with a female to male ratio of 2–
7 : 1. Hürthle cell adenomas have a peak incidence in the
late forties and early fifties, whereas carcinomas tend to
affect a slightly older patient population, with a peak
incidence in the late fifties. The disease presents as a
painless thyroid nodule which appears ‘cold’ on radio-
nuclide scanning. Compared with conventional follicu-
lar carcinomas, Hürthle cell carcinomas show a more
aggressive clinical course. Extrathyroid extension, and
cervical lymph node and distant metastases are com-
monly seen at the time of diagnosis. Local recurrence
and distant metastases occur in up to 50% of patients.
Prognosis is related to the stage and clinical presenta-
tion. Poor prognostic indicators are: age above 45 years,
size of the tumor (more than 4.0 cm), extrathyroid
extension, and lymph node and visceral metastases. The
10-year survival rate ranges from 56% to 88%.
CYTOPATHOLOGIC FEATURES
Similar to follicular neoplasms, FNA cannot separate
Hürthle cell adenomas from carcinomas, since the diag-
nosis of malignancy is based on the histologic demon-
stration of either capsular or vascular invasion.
Hürthle cell neoplasms yield cellular aspirates with
scant or no colloid. The smears are composed of a
Ch002-F06731.indd 50
FINE NEEDLE ASPIRATION CYTOLOGY
HÜRTHLE CELL NEOPLASMS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellular aspirates
៉ Scant to absent colloid
៉ Monomorphic neoplastic cells
៉ Loosely cohesive and dispersed cells
៉ Polygonal and ovoid cells
៉ Large round nuclei with prominent macronucleoli
៉ Abundant granular cytoplasm with distinct borders
Ancillary Studies
៉ Positive for thyroglobulin, TTF-1
៉ Negative for calcitonin
Differential Diagnosis and Pitfalls
៉ Dominant Hürthle cell nodule in Hashimoto’s thyroiditis
៉ Dominant Hürthle cell nodule in nodular goiter
៉ Papillary carcinoma
៉ Medullary carcinoma
monotonous population of Hürthle cells arranged in
loosely cohesive clusters or dispersed singly (Fig. 2-19).
A microfollicular pattern may be seen. The cells are
polyhedral and have abundant granular cytoplasm with
well-defined cell borders. The nuclei are round to oval,
enlarged, and have fine chromatin and a central promi-
nent macronucleolus. Binucleation is seen frequently.
Although enlarged, the nuclei appear monotonous with
relatively little pleomorphism (Fig. 2-20). Lymphoid
cells and an admixture of regular follicular cells are
notably absent.
FIGURE 2-19
Hürthle cell neoplasm. Cellular
smear composed of a monotonous
population of Hürthle cells arranged
in loosely cohesive clusters and
singly. Compare the relatively
monotous nuclei to nuclear pleo-
morphism noted in non-neoplastic
conditions (Fig. 2-4). Diff-Quik
stain, high power.
10/26/2006 10:21:23 AM
 CHAPTER 2 Thyroid 51

A B

FIGURE 2-20
Hürthle cell neoplasm. Loosely cohesive Hürthle cells with abundant granular cytoplasm, uniformly enlarged nuclei, and prominent macronucleoli.
Binucleation is frequently seen. Surgical follow-up demonstrated Hürthle carcinoma. A, Liquid-based preparation, Papanicolaou stain, high power.
B, Diff-Quik stain, high power.

ANCILLARY STUDIES
PAPILLARY CARCINOMA

Hürthle cell neoplasms are immunoreactive for thyro-

globulin and TTF-1, and negative for calcitonin. CLINICAL FEATURES

Papillary carcinoma is the most common thyroid malig-

nancy, accounting for up to 80% of malignant thyroid
DIFFERENTIAL DIAGNOSIS AND PITFALLS

PAPILLARY CARCINOMA – DISEASE FACT SHEET

The differential diagnosis of Hürthle cell neoplasms
includes non-neoplastic Hürthle cell nodule in the
Incidence
setting of Hashimoto’s thyroiditis and nodular goiter,
៉ Most common malignant thyroid neoplasm
papillary carcinoma, and medullary carcinoma. In
Hashimoto’s thyroiditis, the Hürthle cells are cohesive,
Gender and Age Distribution
usually forming sheets, and reveal nuclear pleomor-
៉ Female predominance
phism. In addition, the aspirates typically contain a
៉ Peak incidence 35–40 years; occurs in children
mixture of Hürthle cells, regular follicular cells, and
a polymorphous population of lymphoid cells. Similar Risk Factors
to Hashimoto’s thyroiditis, aspirates from nodular
៉ Exposure to radiation
goiter yield cohesive Hürthle cells arranged in ៉ Activating BRAF mutations
clusters and sheets. Nuclear pleomorphism and ៉ RET/PTC gene rearrangement
prominent nucleoli are present, but distinct macro-
nucleoli are not present in every cell. An admixture of Clinical Features
regular follicular cells and colloid also favors the diag- ៉ Slow growing
nosis of nodular goiter. Papillary carcinoma is an ៉ Solid or cystic
important differential diagnostic consideration, since ៉ ’Cold’ on radionuclide scanning
the granular cytoplasm and the well-defined cytoplas- ៉ Cervical lymph node metastases
mic borders of Hürthle cells may easily be confused ៉ Hematogenous dissemination uncommon
with the dense cytoplasm of papillary carcinoma.
However, in contrast to papillary carcinomas, a fine Prognosis
powdery chromatin pattern, intranuclear cytoplasmic ៉ Overall prognosis excellent
inclusions, nuclear grooves, and irregular nuclear mem- ៉ Less favorable prognostic factors:
branes are not features of Hürthle cell neoplasms. ៉ Age >40 years
៉ Tumor size >4.0 cm
Medullary carcinoma is also a consideration, since a
៉ Extrathyroid extension
dispersed cellular pattern is a feature seen in both
៉ Distant metastases
neoplasms. The nuclei of medullary carcinomas display ៉ Male gender
coarsely granular, ‘salt and pepper’ chromatin and lack
macronucleoli.

Ch002-F06731.indd 51 10/26/2006 10:21:24 AM

 52
neoplasms. It occurs in adults, with a peak incidence
between 35 and 40 years. It also occurs in children, and
accounts for 90% of all childhood thyroid malignan-
cies. Papillary carcinoma is more common in women,
with a female to male ratio of 3–4 : 1. Its predisposing
risk factor is exposure to radiation.
Papillary carcinoma presents as a solid or cystic,
slow-growing, ‘cold’ thyroid nodule. It spreads via lym-
phatics, resulting in a high incidence of cervical lymph
node metastases and multifocal involvement of the
gland. Cervical lymphadenopathy may be the initial
manifestation of the disease. The involved lymph nodes
may be cystic. The incidence of lymph node metastases
is inversely related to age, being more common in
younger patients. The presence of lymph node metasta-
ses does not correlate with a worse outcome, but is
associated with an increased risk of recurrences. Infre-
quently, papillary carcinoma disseminates hematoge-
nously to the lungs, bones, and central nervous
system.
The overall prognosis is excellent, with a 10-year
survival rate exceeding 90%. Less favorable prognostic
indicators are: age above 40 years, tumor size more than
4.0 cm, extrathyroid extension, distant metastases, and
male gender.
CYTOPATHOLOGIC FEATURES
With adequate sampling, the diagnostic accuracy of
papillary carcinoma by FNA is over 90%. The aspi-
rates are highly cellular. The neoplastic cells are
arranged in papillary clusters, flat/folded monolayered
sheets, cohesive groups with finger-like projections,
syncytial clusters, microfollicles, or dispersed singly.
The distinctive papillary architecture may be difficult
to recognize cytologically, since the classic papillae
with accompanying fibrovascular cores is not frequently
present. Features of papillary architecture include
branching groups of cells with or without fibrovascular
cores, three-dimensional dome-shaped aggregates,
finger-like projections, densely cohesive follicular cells
with smooth external contour or peripheral palisading
(Figs 2-21 & 2-22). It is important to note that a tissue
fragment with central branching vascular stroma does
not necessarily mean that the architecture is papillary.
Nodular goiter and follicular neoplasms frequently
yield tissue fragments that display central branching
vascular stroma.
The nuclei are enlarged, ovoid, and crowded with
small nucleoli adherent to the nuclear membrane. They
display longitudinal grooves and intranuclear cytoplas-
mic pseudoinclusions. The latter are the result of cyto-
plasmic invaginations; they have well-defined margins
and occupy two-thirds of the nucleus (Fig. 2-23). Pseu-
doinclusions must be distinguished from artifactual
vacuoles and red blood cells overlying nuclei. Nuclear
membrane irregularities, an important characteristic
feature, are best appreciated in liquid-based prepara-
tions (Fig. 2-24). Chromatin is pale and powdery. The
Ch002-F06731.indd 52
FINE NEEDLE ASPIRATION CYTOLOGY
PAPILLARY CARCINOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellular aspirates
៉ Architectural features:
៉ Papillary with/without fibrovascular cores
៉ Monolayers
៉ Cytologic features:
៉ Enlarged, elongated nuclei
៉ Nuclear pseudoinclusions, grooves
៉ Marginated micronucleoli
៉ Nuclear membrane irregularity
៉ Pale, powdery chromatin
៉ Dense cytoplasm, septate vacuoles
៉ Background features:
៉ ‘Bubble-gum’, ropy colloid, pink ‘blobs’
៉ Multinucleated giant cells
៉ Psammoma bodies
Ancillary Studies
៉ Immunostains: positive for TTF-1, thyroglobulin, CK19, galactin-
3, and HMBE-1
Differential Diagnosis and Pitfalls
៉ Cystic adenomatoid nodule
៉ Adenomatoid nodule
៉ Papillary hyperplasia
៉ Follicular neoplasm
៉ Hürthle cell neoplasm
៉ Hyalinizing trabecular adenoma
ground-glass appearance of the nuclei seen in histologic
sections is an artifact of formalin fixation and is not
recognized in cytologic preparations. The cytoplasm is
dense with well-defined borders, and may have a squa-
moid appearance (Fig. 2-25). In some cases, the cyto-
plasm contains septate vacuoles, which appear as multiple
small vacuoles and resemble soap bubbles (Fig. 2-26).
Colloid is dense, stringy, and intimately associated with
the neoplastic cells, with the so-called ‘bubble-gum’
appearance (Fig. 2-27). Variably sized, round pink blobs
of colloid may be noted. In about half of cases, multi-
nucleated giant cells are present; they contain few or
numerous nuclei and their cytoplasm contains no pig-
ments or vacuoles (Fig. 2-28). Their presence in the
absence of cystic degeneration should raise the suspi-
cion for papillary carcinoma. Psammoma bodies, defined
as non-polarizable concentric calcified laminations, are
seen in one-third of cases (Fig. 2-29). Dystrophic calci-
fications need to be distinguished from psammoma
bodies, since they do not carry the same diagnostic
significance.
It is important to emphasize that none of the above-
described architectural and cytomorphologic or back-
ground features are unique to or diagnostic of papillary
carcinoma, since they may be present in various non-
neoplastic and neoplastic thyroid diseases. The defini-
tive diagnosis should be based on a constellation of
features, rather than on an individual cytologic
criterion.
10/26/2006 10:21:24 AM
 CHAPTER 2 Thyroid 53

FIGURE 2-21
Papillary carcinoma. Papillary struc-
ture with branching central fibro-
vascular core. A characteristic
finding, but not necessary for the
diagnosis of papillary carcinoma.
Diff-Quik stain, low power.

FIGURE 2-22
Papillary carcinoma. Three-
dimensional cohesive group of fol-
licular cells with smooth external
contour and peripheral palisading,
representing a papillary tip or ‘cap’
in papillary carcinoma. Papanico-
laou stain, high power.

Ch002-F06731.indd 53 10/26/2006 10:21:25 AM

 54 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 2-23
Papillary carcinoma. The nuclei are
enlarged, round to oval, and display
intranuclear cytoplasmic pseudo-
inclusions. The cytoplasm is dense
with well-defined borders. Diff-Quik
stain, high power.

FIGURE 2-24
Papillary carcinoma. Neoplastic fol-
licular cells arranged in a fl at mono-
layered sheet. This arrangement
must be distinguished from the
honeycomb sheet of adenomatoid
nodule. Note the presence of nuclear
grooves and nuclear membrane
irregularities, features helpful in
establishing the correct diagnosis
of papillary carcinoma. The latter
feature is well appreciated in this
liquid-based preparation. Papanico-
laou stain, high power.

Ch002-F06731.indd 54 10/26/2006 10:21:26 AM

 CHAPTER 2 Thyroid 55

FIGURE 2-25
Papillary carcinoma. The neoplastic
cells in papillary carcinoma have
dense cytoplasm with a squamoid
appearance. These cells share simi-
larities and must be distinguished
from cyst-lining cells in adenoma-
toid nodules (Fig. 2-15). Diff-Quik
stain, high power.

A B

FIGURE 2-26
Septate vacuoles. Best seen in Diff-Quik stain, septate vacuoles are small multiple intracytoplasmic vacuoles that resemble soap bubbles. They are
seen in papillary carcinoma, as well as in benign conditions. A, Papillary carcinoma with septate vacuoles. Diff-Quik stain, high power. B, Septate
vacuoles in a histologically confirmed case of papillary hyperplasia. Attention to the nuclear features is paramount in differentiating benign lesions
from papillary carcinomas. Diff-Quik stain, high power.

Ch002-F06731.indd 55 10/26/2006 10:21:28 AM

 56 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 2-27
Papillary carcinoma. Dense, stringy
colloid with a metachromatic ‘bubble-
gum’ appearance is characteristic of
papillary carcinoma. Note the inti-
mate association of colloid with the
neoplastic cells. Diff-Quik stain,
low power.

FIGURE 2-28
Papillary carcinoma. Multinucleated
giant cell with unusual shape, dense
cytoplasm, and numerous nuclei.
Note the lack of cytoplasmic pig-
ments or vacuoles. Finding giant
cells in the absence of cystic degen-
eration or Hashimoto’s thyroiditis
should raise the suspicion for papil-
lary carcinoma. Diff-Quik stain,
high power.

Ch002-F06731.indd 56 10/26/2006 10:21:29 AM

 CHAPTER 2 Thyroid 57

FIGURE 2-29
Papillary carcinoma. Psammoma
bodies are refractile concentric cal-
cified laminations. Diff-Quik stain,
high power.

FIGURE 2-30
Cystic papillary carcinoma. Three-
dimensional clusters of ‘histiocyt-
oid’ cells with scalloped borders.
The abundant hypervacuolated cyto-
plasm imparts a histiocytic appear-
ance to these neoplastic cells. Note
the presence of psammoma bodies
within the center of each group.
Liquid-based preparation, Papani-
colaou stain, high power.

Cystic papillary carcinomas comprise 25–30% of pap-
illary carcinomas. They are diagnostically challenging,
and a well-recognized source of false negative results.
Aspirates contain numerous macrophages, some pig-
mented, some multinucleated, but few or no diagnostic
neoplastic cells. If the aspirated fluid contains no follicu-
lar epithelial cells, a diagnosis of ‘cystic lesion, not
further classified’ must be rendered, with the recom-
mendation to repeat the procedure. In hypocellular
samples, the presence of three-dimensional clusters of
cells with enlarged nuclei, vacuolated cytoplasm, and
scalloped borders, ‘histiocytoid cells’, may be the only
clue to the diagnosis (Fig. 2-30). These cells can easily
be dismissed and misclassified as macrophages. It is also
important to emphasize that the cyst-lining cells of
cystic papillary carcinoma may be difficult to distin-
guish for those seen in cystic nodular goiter. Recogniz-
ing the risk of false negative diagnoses in cystic lesions,
a benign diagnosis should be rendered only when
follicular epithelial cell lacking atypia are adequately
sampled.
Follicular variant of papillary carcinoma also poses a
diagnostic challenge. The smears may be misdiagnosed
as cellular adenomatoid nodules or follicular neoplasms.
The aspirates reveal neoplastic cells arranged in
monolayers, syncytial clusters, and microfollicular

Ch002-F06731.indd 57 10/26/2006 10:21:30 AM

 58
architectural pattern. Nuclear features (elongated nuclei
with irregular nuclear membranes) are the key in estab-
lishing the correct diagnosis or at least raising suspicion
for papillary carcinoma.
The Hürthle cell variant of papillary carcinoma is
composed of neoplastic Hürthle cells with nuclear and
architectural features of papillary carcinoma.
Aggressive variants of papillary carcinoma are rarely
encountered by FNA. Tall cell variant is distinguished
by neoplastic cells that are twice as tall as they are
wide. The cells are characterized by oncocytic cyto-
plasm, distinct cells borders, and ‘soap-bubble-like’
intranuclear inclusions. Columnar cell variant is com-
posed of columnar cells with scant cytoplasm. The
nuclei are elongated, crowded, and stratified. Diffuse
sclerosing variant yields fibrotic stromal fragments,
psammoma bodies, squamoid cells, and a prominent
lymphoid infiltrate.
ANCILLARY STUDIES
CK19, HMBE-1, and galectin-3 are helpful in the diag-
nosis of papillary carcinoma, but lack specificity and
sensitivity to be reliable discriminators. For example,
the low molecular weight CK19, strongly positive in
papillary thyroid carcinoma, is shown to be also posi-
tive in follicular adenoma, follicular carcinoma, and
Hürthle cell carcinoma. In addition, CK19 is strongly
positive in benign follicular epithelium of Hashimoto’s
thyroiditis.
RET/PTC gene translocation and BRAF mutations
are common genetic alterations in papillary carcinomas.
RET/PTC expression by immunostains or molecular
Ch002-F06731.indd 58
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 2-31
Papillary hyperplasia. Papillary
tissue fragment with finger-like
projections and branching central
vascular stroma, a finding that may
lead to the erroneous diagnosis of
papillary carcinoma. The clue to the
correct diagnosis rests on the bland
nuclear features. Diff-Quik stain,
low power.
methods is a valuable adjunct in the diagnosis of papil-
lary carcinoma, but it has also been reported in insular
carcinoma, and follicular and Hürthle cell adenoma and
carcinoma.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis of papillary carcinoma varies
with each histologic variant. Cystic papillary carcino-
mas must be distinguished from cystic adenomatoid
nodules. The possibility of papillary carcinomas is
higher in cysts larger than 4.0 cm, hemorrhagic cysts,
and cysts that recur rapidly or repeatedly following
FNA. Hypocellular cystic samples should be carefully
examined with particular attention to any cytologic
evidence of papillary carcinoma. Psammoma bodies
and intranuclear pseudoinclusions should be
searched for.
Papillary hyperplasia is a source of pitfall. The pres-
ence of unequivocal papillary elements is not pathogno-
monic of malignancy. Papillary hyperplasia shares many
cytologic features with papillary carcinoma, including
high cellularity, papillary fragments with branching
fibrovascular cores, septate vacuoles, and occasional
psammoma bodies (Figs 2-26B & 2-31). The clues to the
correct diagnosis rest on the small, round, uniform
nuclei and finely dispersed chromatin seen in
hyperplasia.
Follicular variant of papillary carcinoma displaying
monolayered sheets may be misdiagnosed as adenoma-
toid nodule, since the flat sheets can be interpreted as
honeycomb arrangements indicative of goiter. Atten-
tion to the nuclear features (elongated and irregular
10/26/2006 10:21:31 AM
 CHAPTER 2 Thyroid 59

FIGURE 2-32
Hyalinizing trabecular adenoma.
The neoplastic follicular cells are
associated with fibrillar metachro-
matic stroma. Diff-Quik stain, high
power.

FIGURE 2-33
Hyalinizing trabecular adenoma.
Loosely cohesive neoplastic cells
with enlarged elongated nuclei and
intranuclear pseudoinclusion. This
neoplasm needs to be distinguished
from papillary and medullary carci-
noma. Diff-Quik stain, high power.

versus round) is essential in distinguishing the two enti-
ties. On the other hand, follicular variant of papillary
carcinoma displaying syncytial arrangements with a
microfollicular pattern may be misdiagnosed as a follic-
ular neoplasm.
The dense cytoplasm with well-defined borders of
papillary carcinoma may be also be confused with the
appearance of Hürthle cells.
Hyalinizing trabecular adenoma of the thyroid shares
cytologic features with papillary carcinoma. Aspiration
of these tumors yields cellular aspirates comprised of
neoplastic cells arranged in loose aggregates, micro-
follicles, or dispersed singly. The neoplastic cells are
typically elongated or spindle-shaped. The nuclei are
enlarged, ovoid, with pale chromatin, intranuclear cyto-
plasmic inclusions, and longitudinal nuclear grooves.
Psammoma bodies may be present. A clue to the diag-
nosis is the presence of metachromatic stromal material,
which is found as deposits between the neoplastic cells
(Figs 2-32 & 2-33). It differs from colloid by its distin-
guishable finely fibrillar appearance and fringed rather
than sharp edges.

Ch002-F06731.indd 59 10/26/2006 10:21:32 AM

 60
MEDULLARY CARCINOMA
CLINICAL FEATURES
Medullary carcinoma is a neuroendocrine malignancy
arising from calcitonin-secreting C cells. It accounts
for 5% to 10% of all thyroid malignancies and occurs
sporadically and in familial forms. The sporadic form
accounts for 80% of all cases. The remainder occurs in
the setting of the multiple endocrine neoplasia (MEN)
syndromes MEN IIA and MEN IIB, or as an isolated
familial medullary thyroid carcinoma. The familial
forms are characterized by an autosomal dominant
mode of inheritance and are associated with germline
point mutations in the RET proto-oncogene, which is
localized on chromosome 10. Medullary carcinoma
shows no particular sex predilection and can occur at
any age. The sporadic and isolated familial forms pri-
marily affect middle-aged adults, with a peak incidence
in the forties and fi fties. The MEN II-associated forms
affect younger patients, and may even occur during
childhood. MEN-associated forms occur either in asso-
ciation with adrenal pheochromocytoma and parathy-
roid chief cell hyperplasia (MEN IIA – Sipple syndrome)
MEDULLARY CARCINOMA – DISEASE FACT SHEET
Definition
៉ Neuroendocrine malignancy arising from calcitonin-secreting
C cells
Incidence
៉ 5–10% of thyroid malignancies
៉ Sporadic in 80%
Gender and Age Distribution
៉ Affects both sexes equally
៉ Occurs in children and adults
Risk Factors
៉ Familial forms: autosomal dominant inheritance; associated with
germline point mutations in the RET proto-oncogene
Clinical Features
៉ Sporadic form: solitary firm, ‘cold’ nodule, paraneoplastic
syndrome
៉ Familial forms: asymptomatic, discovered by screening
៉ Aggressive course: cervical lymph node and distant metastases,
local recurrence
Prognosis
៉ Poor prognostic indicators:
៉ Extrathyroid extension
៉ Age >40 years
៉ Sporadic form
៉ Five-year survival is 50–80%
Ch002-F06731.indd 60
FINE NEEDLE ASPIRATION CYTOLOGY
or in association with adrenal pheochromocytoma,
mucosal neuromas, gastrointestinal ganglioneuromas,
and skeletal abnormalities (MEN IIB – mucosal
neuroma syndrome, Gorlin syndrome).
Patients with the sporadic form present with a soli-
tary, firm, ‘cold’ nodule. In some cases, it is accompa-
nied by intractable diarrhea or Cushing syndrome
secondary to the paraneoplastic secretions of hormones
and prostaglandins. Only rarely this form is clinically
occult. In contrast, in the familial setting, despite being
multifocal and bilateral, medullary carcinoma is usually
asymptomatic and is discovered by screening of rela-
tives of patients with the disease for elevated calcitonin
levels.
Medullary carcinoma is an aggressive tumor with
metastases to cervical lymph nodes and to distant organs,
particularly the lungs, liver, and bones. Local recur-
rence occurs in up to 35% of patients. Prognosis is
related to the stage and clinical presentation. Poor prog-
nostic indicators are extrathyroid extension, age above
40 years, and sporadic form. The 5-year survival rate
ranges from 50% to 80%.
CYTOPATHOLOGIC FEATURES
The aspirates from medullary carcinoma are highly
cellular. Neoplastic cells are dispersed singly and
arranged in loose syncytial aggregates. Their cytologic
appearance varies. The cells may be oval with eccentric
nuclei (plasmacytoid), large polygonal, spindle, trian-
gular, or small round with scant cytoplasm (Fig. 2-34).
The cytoplasm is abundant and well-preserved. Spindle
cells have a centrally placed elongated nucleus and
indistinct cytoplasm. Nuclear pleomorphism, binucle-
MEDULLARY CARCINOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellular aspirates
៉ Single cells, loose syncytial aggregates
៉ Plasmacytoid, spindle, small cells
៉ Coarsely granular, ‘salt and pepper’ chromatin pattern
៉ Intranuclear cytoplasmic inclusions
៉ Inconspicuous nucleoli
៉ Cytoplasmic granules
៉ Amyloid
Ancillary Studies
៉ Immunoreactive for calcitonin, chromogranin, TTF-1, and
monoclonal CEA
៉ Negative for thyroglobulin
Differential Diagnosis and Pitfalls
៉ Hürthle cell neoplasm
៉ Papillary carcinoma
៉ Anaplastic carcinoma
៉ Hyalinizing trabecular adenoma
10/26/2006 10:21:33 AM
 CHAPTER 2 Thyroid 61

FIGURE 2-34
Medullary carcinoma. Highly cellu-
lar aspirate characterized by
dispersed neoplastic cells with
round–oval nuclei and plasmacytoid
appearance. Note the presence
of intranuclear pseudoinclusions.
Nuclear pleomorphism, binucle-
ation, and multinucleation are
frequently seen in aspirates of med-
ullary carcinoma. Diff-Quik stain,
high power.

FIGURE 2-35
Medullary carcinoma. Cellular smear
composed of spindle cells with the
characteristic ‘salt and pepper’
chromatin. Papanicolaou stain, high
power.

ation, and multinucleation are present. The nuclei have (Fig. 2-37). Congo red stain examined under polarized
a coarsely granular, ‘salt and paper’ chromatin pattern light confirms the diagnosis of amyloid.
and inconspicuous nucleoli (Fig. 2-35). Intranuclear
cytoplasmic inclusions are present in up to one-half of
cases. Intranuclear grooves are infrequently seen. Red
cytoplasmic neurosecretory granules are seen in scat- ANCILLARY STUDIES
tered cells and only appreciated in air-dried smears
(Fig. 2-36).
The presence of amyloid is variable. Amyloid appears Medullary carcinoma is negative for thyroglobulin, and
as amorphous, cotton-like, acellular material that is immunoreactive for calcitonin (Fig. 2-38), monoclonal
metachromatic in Diff-Quik and grayish-green in carcinoembryonic antigen (CEA), TTF-1, low molecu-
Papanicolaou stain. It may be confused with colloid lar weight cytokeratin, and chromogranin.

Ch002-F06731.indd 61 10/26/2006 10:21:33 AM

 62
The detection of germline mutations in the RET
oncogene in the serum is highly specific and sensitive
in identifying patients who have or will develop familial
forms of medullary carcinoma. It is replacing calcitonin
stimulation testing as a screening method.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis of medullary carcinoma
includes Hürthle cell neoplasm, papillary carcinoma,
Ch002-F06731.indd 62
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 2-36
Medullary carcinoma. Conventional
air-dried smear illustrating red
cytoplasmic neurosecretory gran-
ules. Multinucleation and nuclear
pleomorphism are present. Diff-
Quik stain, high power.
FIGURE 2-37
Medullary carcinoma. Amyloid
appears as amorphous, acellular
metachromatic material. Congo red
and crystal violet stains can be con-
firmatory of its presence. Diff-Quik
stain, high power.
anaplastic carcinoma, and hyalinizing trabecular
adenoma. In contrast to Hürthle cell neoplasms, macro-
nucleoli are not a feature of medullary carcinoma. High
cellularity, cellular discohesion, and intranuclear inclu-
sions are shared features with papillary carcinoma, but
other architectural, background, and nuclear features
help distinguish between the two. Anaplastic carci-
noma is a consideration when medullary carcinoma is
composed of spindle cells. The spindle cell variant of
medullary carcinoma yields a more uniform population
of neoplastic cells and lacks necrosis. Hyalinizing
trabecular adenoma and medullary carcinoma are
both characterized by high cellularity, poor cellular
10/26/2006 10:21:35 AM
 CHAPTER 2 Thyroid 63

FIGURE 2-38
Medullary carcinoma. Calcitonin
immunocytochemical stain per-
formed on a liquid-based prepara-
tion demonstrates positive staining
in the neoplastic cells. Calcitonin
immunostain, high power.

cohesion, spindle cells, and intranuclear inclusions.

Moreover, the stromal material in hyalinizing trabecu- INSULAR CARCINOMA – DISEASE FACT SHEET
lar adenoma may be misinterpreted as amyloid. A nega-
tive Congo red and calcitonin immunostain should Definition
assist in excluding medullary carcinoma. ៉ Poorly differentiated malignancy of follicular cell origin

Incidence
៉ Very rare in the United States

INSULAR CARCINOMA Gender and Age Distribution

៉ Female predominance
៉ Peak incidence 55 years
CLINICAL FEATURES
Risk Factors
៉ History of papillary or follicular carcinoma
Insular carcinoma is classified as a variant of poorly
differentiated carcinomas. It is a thyroid malignancy of Clinical Features
follicular cell origin with a biologic behavior between ៉ Aggressive malignancy
well-differentiated carcinoma (papillary, follicular car- ៉ Enlarging, ‘cold’ thyroid mass
cinoma) and anaplastic carcinoma. Insular carcinoma ៉ Extrathyroid extension, cervical lymph node and distant
has a distinct histologic appearance with neoplastic metastases
cells arranged in well-formed nests or islands (‘insulae’). ៉ Local recurrences
Its prevalence varies among different geographic ៉ Poor prognosis
regions. The highest prevalence, 5% of all thyroid
malignancies, has been reported from Italy, whereas in
the Unites States it is very low. The disease presents in
middle-aged and elderly patients, with a mean age of 55
years, and is more common in women, with a female The median survival is 3.9 years, and the 5-year sur-
to male ratio of 2 : 1. vival rate is 40–50%.
Insular carcinoma arises de novo or transforms from
well-differentiated thyroid carcinomas. It presents as an
enlarging thyroid mass which appears ‘cold’ on radio-
nuclide scanning. Extrathyroid extension, and cervical CYTOPATHOLOGIC FEATURES
lymph node and distant metastases are commonly
present at the time of diagnosis.
Insular carcinoma is an aggressive malignancy with The aspirates from insular carcinomas are highly
a poor prognosis. Recurrences develop in 60% of cases. cellular, revealing neoplastic cells arranged in loose

Ch002-F06731.indd 63 10/26/2006 10:21:36 AM

 64
INSULAR CARCINOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellular aspirates
៉ Loose clusters, microfollicles, single cells
៉ Hyperchromatic small neoplastic cells
៉ Increased N/C ratio
៉ Mild to moderate anisokaryosis
៉ Mitoses, necrosis
Differential Diagnosis and Pitfalls
៉ Follicular carcinoma
៉ Medullary carcinoma
៉ Anaplastic carcinoma
៉ Metastatic carcinoma
clusters, trabeculae, microfollicles, or dispersed singly.
The cells are relatively small and monomorphic, but
scattered large pleomorphic cells can also be present.
They display an increased nuclear to cytoplasmic
(N/C) ratio, irregular nuclei, hyperchromasia, and
inconspicuous nucleoli (Figs 2-39 & 2-40). Intranuclear
cytoplasmic pseudoinclusions and intranuclear grooves
are occasionally seen. The cytoplasm is pale and poorly
defined, and occasional intracytoplasmic vacuoles are
present. Mitotic figures and necrosis are present.
ANCILLARY STUDIES
Insular carcinoma is immunoreactive for thyroglobulin
and TTF-1, and negative for calcitonin, chromogranin,
and monoclonal CEA.
Ch002-F06731.indd 64
FINE NEEDLE ASPIRATION CYTOLOGY
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The diagnosis of malignancy is easy to establish in
FNA of insular carcinoma. The differential diagnosis
includes poorly differentiated follicular carcinoma,
anaplastic carcinoma, medullary carcinoma, and meta-
static carcinoma. The microfollicular architecture of
insular carcinoma is a feature shared with follicular
carcinoma. The high nuclear grade, mitotic figures, and
necrosis may suggest anaplastic carcinoma, but insular
carcinoma lacks the spindle cells, osteoclast-like giant
cells, and bizarre-appearing neoplastic cells of ana-
plastic carcinoma. Medullary carcinoma may show
striking morphologic overlap, but can be distinguished
by immunocytochemical stains (calcitonin-positive/
thyroglobulin-negative). Metastatic carcinoma to the
thyroid should be also considered. The patient’s clini-
cal history and comparison with previous cytologic or
histologic material are recommended.
ANAPLASTIC CARCINOMA
CLINICAL FEATURES
Anaplastic carcinoma is a highly malignant, undiffer-
entiated thyroid neoplasm that accounts for up to 5%
of all thyroid malignancies. It is a disease of older
adults, with a peak incidence in the sixth and seventh
decades, and is more common in women, with a female
to male ratio of 2–3 : 1.
Anaplastic carcinoma tends to arise in a background
of thyroid disease. A history of pre-existing goiter or
FIGURE 2-39
Insular carcinoma. Atypical follicu-
lar cells forming microacini and
showing nuclear crowding and over-
lapping. Note the enlarged nuclei
as compared to adjacent red blood
cells. Diff-Quik stain, high power.
10/26/2006 10:21:37 AM
 CHAPTER 2 Thyroid 65

FIGURE 2-40
Insular carcinoma. A crowded
cluster of neoplastic cells with
a high N/C ratio and hyperchromatic
nuclei. Papanicolaou stain, high
power.

the majority of patients are inoperable due to extensive

ANAPLASTIC CARCINOMA – DISEASE FACT SHEET local disease. The median survival is 3 to 4 months, and
the 5-year survival rate ranges from 5% to 10%.
Definition
៉ Undifferentiated thyroid neoplasm

Incidence CYTOPATHOLOGIC FEATURES

៉ 5% of thyroid malignancies

Gender and Age Distribution The cytologic features of anaplastic carcinoma vary,
៉ Female predominance
reflecting the histologic diversity of this malignancy.
៉ Occurs in the elderly The smears are variably cellular, and display neoplastic
cells that are unequivocally malignant. The cells are
Risk Factors arranged in large fragments, small clusters, or dispersed
៉ Pre-existing goiter singly. Spindle-shaped cells admixed with polygonal
៉ Well-differentiated thyroid carcinoma and giant cells are typically seen (Fig. 2-41). Some
anaplastic carcinomas contain large numbers of
Clinical Features osteoclast-like giant cells (Fig. 2-42); in others, the
៉ One of the most aggressive malignancies neoplastic cells demonstrate squamous differentiation.
៉ Rapidly enlarging, widely invasive
៉ Compression symptoms due to extrathyroid extension and invasion
of adjacent tissues present at the time of diagnosis
៉ Cervical lymph node and distant visceral metastases
ANAPLASTIC CARCINOMA – PATHOLOGIC FEATURES
៉ Prognosis extremely poor

Cytopathologic Findings
៉ Variably cellular aspirates
៉ Spindle, polygonal cells
well-differentiated (papillary or follicular) thyroid car- ៉ Osteoclast-like giant cells
cinoma is common. The disease presents as a rapidly ៉ Squamous differentiation
enlarging thyroid mass which appears ‘cold’ on radio- ៉ Marked nuclear pleomorphism, mitotic figures
៉ Background necrosis and acute infl ammation
active iodine scan. The carcinoma spreads beyond the
thyroid capsule into the adjacent neck structures,
Differential Diagnosis and Pitfalls
causing compression and invasion symptoms such as
៉ Granulomatous infl ammation
dyspnea, dysphagia, hoarseness, and cough. Metastases
៉ Medullary carcinoma
to neck lymph nodes and distant organs, particularly the
៉ Metastases
lungs and liver, are common. ៉ Sarcoma
Anaplastic carcinoma is a fatal disease. It does not
respond well to either radiation or chemotherapy, and

Ch002-F06731.indd 65 10/26/2006 10:21:38 AM

 66
The nuclei are very large, have irregular membranes,
and display coarsely granular chromatin and macro-
nucleoli. The cytoplasm varies in appearance and it
can be dense, granular, or vacuolated. Mitotic figures
including bizarre forms are readily identified. The
background reveals necrosis and acute inflammation
(Fig. 2-43).
The cytologic diagnosis is not always straightfor-
ward. Extensive desmoplasia yields hypocellular samples
with marked crush artifact which are therefore not diag-
nostic. Necrosis and marked inflammation may also
obscure the neoplastic cells, making the interpretation
of the aspirate difficult. Nevertheless, when an aspirate
Ch002-F06731.indd 66
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 2-41
Anaplastic carcinoma. Highly atypi-
cal spindle and polygonal cells with
bizarre nuclei and prominent nucle-
oli. Diff-Quik stain, high power.
FIGURE 2-42
Anaplastic carcinoma. Osteoclast-
like giant cells can be numerous
in anaplastic carcinoma. Diff-Quik
stain, high power.
of a rapidly enlarged thyroid in an older patient reveals
rare pleomorphic cells in a necroinflammatory back-
ground, the diagnosis of anaplastic carcinoma must be
considered.
ANCILLARY STUDIES
Cytokeratin positivity is observed in some anaplastic
carcinomas, and the vast majority are negative for
TTF-1 and thyroglobulin.
10/26/2006 10:21:39 AM
 CHAPTER 2 Thyroid 67

FIGURE 2-43
Anaplastic carcinoma. Necrotic
background with no viable tumor
cells. Diff-Quik stain, low power.

FIGURE 2-44
Metastatic colonic adenocarcinoma.
The tumor cells are columnar, and
display nuclear palisading and
stratification. Glandular arrange-
ment is prominent. Colloid is absent.
Diff-Quik stain, high power.

DIFFERENTIAL DIAGNOSIS AND PITFALLS immunoreactivity for calcitonin, chromogranin, and

The smears are usually diagnostic of malignancy;
however, the presence of giant cells associated with
necrosis may be misinterpreted as granulomatous
inflammation. The differential diagnosis of anaplastic
carcinoma includes medullary carcinoma, metastatic
carcinoma, and sarcoma. Medullary carcinoma
displays a lesser degree of cellular pleomorphism;
moreover, the readily identifiable mitoses and necro-
inflammatory background seen in anaplastic carcinoma
are absent. In addition, the presence of amyloid and
monoclonal CEA support the diagnosis of medullary
carcinoma. Metastases to the thyroid are rarely encoun-
tered by FNA. Malignant melanoma, lung, breast,
kidney, pancreas, and colon are the most common
primary sites. Fig. 2-44 illustrates a case of metastatic
colonic carcinoma. The differential diagnosis rests on
the patient’s clinical history, comparison with any
available previous cytologic or histologic material,
and performing the appropriate immunocytochemical
panel. Sarcoma, although rare in the thyroid, should be
considered, and can be excluded by the demonstration
of cytokeratin positivity.

Ch002-F06731.indd 67 10/26/2006 10:21:40 AM

 68
LYMPHOMA
CLINICAL FEATURES
Lymphoma may involve the thyroid as part of systemic
lymphoma (secondary thyroid lymphoma) or may arise
primarily in the gland (primary thyroid lymphoma).
Primary lymphomas of the thyroid are rare, and account
for up to 2% of thyroid malignancies, whereas second-
ary involvement of the thyroid occurs more frequently.
More than 90% of primary thyroid lymphomas are
non-Hodgkin B-cell lymphomas. Diffuse large B-cell
lymphoma (DLBL), extranodal marginal zone B-cell
lymphoma of mucosa-associated lymphoid tissue
(MZBL), and mixed MZBL/DLBL are the most common
variants. Primary thyroid T-cell lymphomas are rare.
Hodgkin lymphoma involving the thyroid is almost
always by direct extension from a lymph node or
thymus.
Primary thyroid lymphoma is a disease of older
adults, with a mean age of presentation of 65 years, and
is more common in women, with a female to male ratio
of 3–7 : 1. Its major risk factor is Hashimoto’s thyroid-
itis. The disease classically presents as a noticeably
enlarging thyroid mass which appears ‘cold’ on radio-
active iodine scan. Compressive symptoms such as
dyspnea, dysphagia, hoarseness, and cough due to extra-
thyroid extension are present in about one-third of
patients at the time of diagnosis. Because of the strong
association with Hashimoto’s thyroiditis, patients may
present with hypothyroidism.
The prognosis primarily depends on the stage and
histologic type of the disease. Patients with MZBL and
LYMPHOMA – DISEASE FACT SHEET
Definition
៉ Primary lymphoid thyroid malignancy
៉ >90% are non-Hodgkin lymphoma
Incidence
៉ 2% of malignant thyroid neoplasms
Gender and Age Distribution
៉ Female predominance
៉ Mean onset: 65 years
Risk Factor
៉ Hashimoto’s thyroiditis
Clinical Features
៉ Rapidly enlarging thyroid mass
៉ Compression symptoms due to extrathyroid extension
Prognosis
៉ Depends on stage and histologic type
Ch002-F06731.indd 68
FINE NEEDLE ASPIRATION CYTOLOGY
with early stage tumors confined to the gland have a
good prognosis, with a 5-year survival rate approaching
80%, whereas patient whose tumors either are of high
stage or have a DLBL component have a significantly
poorer prognosis.
CYTOPATHOLOGIC FEATURES
The aspirates are highly cellular and comprised of
atypical lymphoid cells (Fig. 2-45). The cytologic fea-
tures depend on the type of lymphoma. DLBL yield
cellular aspirates comprised of numerous monomor-
phic, large, atypical lymphoid cells with large nuclei,
either cleaved or non-cleaved, displaying a vesicular
chromatin pattern and conspicuous marginated nucle-
oli. Large, abnormal plasmacytoid lymphocytes with
single macronucleoli may be seen. Extensive karyor-
rhexis is present in the background. MZBL aspirates
are comprised of a polymorphous lymphocytic popula-
tion which includes atypical small and intermediate
size lymphocytes, monocytoid B cells, immunoblasts,
and plasma cells. Mixed DLBL/MZBL lymphomas
show features of both.
ANCILLARY STUDIES
Immunocytochemical staining for leukocyte common
antigen (CD45) and CD20, as well as flow cytometry
and molecular studies are recommended to confirm the
diagnosis.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The main differential diagnosis is Hashimoto’s
thyroiditis. DLBL is usually not a diagnostic challenge
LYMPHOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ DLBL: monotonous population of large lymphoid cells
៉ MZBL: centrocytes, monocytoid B cells, immunoblasts, plasma
cells
៉ Mixed DLBL/MZBL: features of DLBL and MZBL
Ancillary Studies
៉ Flow cytometry
៉ Molecular studies
៉ Immunocytochemistry: LCA, CD20+
Differential Diagnosis and Pitfalls
៉ Hashimoto’s thyroiditis
៉ Metastatic small cell carcinoma
10/26/2006 10:21:41 AM
 CHAPTER 2 Thyroid
FIGURE 2-45
Diffuse large B-cell lymphoma. Cel-
lular aspirate illustrating a monoto-
nous population of atypical large
lymphoid cells. Tingible-body mac-
rophages are present. Diff-Quik
stain, high power.
and can be easily distinguished. However, distinguishing
MZBL from Hashimoto’s thyroiditis can be difficult on
cytologic grounds alone. Flow cytometric analysis, im-
munocytochemistry, and molecular diagnostic methods
are very helpful in establishing the diagnosis.
Metastatic small cell carcinoma of the lung should
also be considered as a differential diagnosis. Small cell
carcinoma of the lung yields aspirates composed of
loosely cohesive clusters of small to intermediate-sized
cells with little or no cytoplasm, and nuclei displaying
hyperchromasia, inconspicuous nucleoli, and promi-
nent molding. Lymphoglandular bodies are absent from
the background.
SUGGESTED READINGS
Introduction
Cibas ES. Thyroid. In: Cibas ES, Ducatman BS, eds. Cytology: Diagnostic
Principles and Clinical Correlates, 2nd ed. Philadelphia: WB Saunders,
2003.
DeMay RM. Thyroid. In: The Art and Science of Cytopathology. Chicago:
ASCP Press, 1996.
Frost AR, Sidawy MK. Thyroid aspiration cytopathology. In: Atkinson BF,
Silverman JF, eds. Atlas of Difficult Diagnoses in Cytopathology, 1st ed.
Philadelphia: WB Saunders, 1998.
Frost AR, Sidawy MK, Ferfelli M, Tabbara SO, Bronner N, Sherman ME.
Utility of thin-layer preparations in thyroid fine-needle aspiration:
diagnostic accuracy, cytomorphology, and optimal sample preparation.
Cancer (Cancer Cytopathol) 1998;84:17–25.
Kini SR. Thyroid. In: Kline TS, ed. Guides to Clinical Aspiration Biopsy,
2nd edn. New York: Igaku-Shoin, 1996.
Merino MJ, Sidawy MK. The thyroid gland. In: Silverberg SG, DeLelllis RA,
Frable WJ, eds. Principles and Practices of Surgical and Cytopathology,
3rd ed. New York: Churchill Livingstone, 1997.
Miller JM, Hamburger JI, Kini SR. The impact of needle biopsy on the
preoperative diagnosis of thyroid nodules. Henry Ford Hosp Med J
1980;28:145–148.
The Papanicolaou Society of Cytopathology Task Force on Standards of
Practice. Guidelines of the Papanicolaou Society of Cytopathology for
the examination of fine-needle aspiration specimens from thyroid
nodules. Mod Pathol 1996;9:710–715.
Ch002-F06731.indd 69
69
Powers CN, Frable WJ. Thyroid and parathyroid. In: Fine Needle Aspiration
Biopsy of the Head and Neck, 1st ed. Boston: Butterworth-Heinemann,
1996.
Hashimoto’s Thyroiditis
Holm LE, Blomgren H, Lowhagen T. Cancer risks in patients with chronic
lymphocytic thyroiditis. N Engl J Med 1985;312:601–604.
Guarda LA, Baskin HJ. Inflammatory and lymphoid lesions of the thyroid
gland. Cytopathology by fine-needle aspiration. Am J Clin Pathol
1987;87:14–22.
McDonald L, Yazdi HM. Fine needle aspiration biopsy of Hashimoto’s
thyroiditis. Sources of diagnostic error. Acta Cytol 1999;43:400–406.
Nguyen GK, Ginsberg J, Crockford PM, Villanueva RR. Hashimoto’s thyroid-
itis: cytodiagnostic accuracy and pitfalls. Diagn Cytopathol 1997;16:
531–536.
Nodular Goiter
Abbas G, Heller KS, Khoynezhad A, Dubner S, Sznyter LA. The incidence
of carcinoma in cytologically benign thyroid cysts. Surgery 2001;
130:1035–1038.
Caraway NP, Sneige N, Samaan NA. Diagnostic pitfall in thyroid fine needle
aspiration: a review of 394 cases. Diagn Cytopathol 1993;9:345–350.
Dwarakanathan AA, Staren ED, D’Amore MJ, Kluskens LF, Martirano M,
Economou EG. Importance of repeat fine-needle biopsy in the manage-
ment of thyroid nodules. Am J Surg 1993;166:350–352.
Faquin WC, Cibas ES, Renshaw AA. ‘Atypical’ cells in fine-needle aspiration
biopsy specimens of benign thyroid cysts. Cancer (Cancer Cytopathol)
2005;105:71–79.
Frost AR, Sidawy MK. The effect of suppressive therapy on thyroid fine
needle aspiration cytology. Acta Cytol 1995;39:402–408.
Greaves TS, Olvera M, Florentine BD, et al. Follicular lesions of the thyroid:
a 5-year fine-needle aspiration experience. Cancer (Cancer Cytopathol)
2000;90:335–341.
Harach HR, Zusman SB, Saravia Day E. Nodular goiter: a histo-cytological
study with some emphasis on pitfalls of fine-needle aspiration cytology.
Diagn Cytopathol 1992;8:409–419.
Nassar A, Gupta P, LiVolsi VA, Baloch Z. Histiocytic aggregates in benign
nodular goiter mimicking cytologic features of papillary thyroid carci-
noma. Diagn Cytopathol 2003;29:243–245.
Sidawy MK, Costa M. The significance of paravacuolar granules of the
thyroid. A histologic, cytologic and ultrastructural study. Acta Cytol
1989;33:929–933.
Sidawy MK, Del Vecchio DM, Knoll SM. Fine needle aspiration of
thyroid nodules: correlation between cytology and histology and
10/26/2006 10:21:41 AM
 70
evaluation of discrepant cases. Cancer (Cancer Cytopathol) 1997;81:
253–259.
Follicular Neoplasms
Baloch ZW, LiVolsi VA. Follicular-patterned lesions of the thyroid: the bane
of the pathologist. Am J Clin Pathol 2002;117:143–150.
Baloch ZW, LiVolsi VA. The quest for a magic tumor marker. Continuing
saga in the diagnosis of the follicular lesions of the thyroid (Editorial).
Am J Clin Pathol 2002;118:165–166.
Cerilli LA, Mills SE, Rumpel CA, Dudley TH, Moskaluk CA. Interpretation of
RET immunostaining in follicular lesions of the thyroid. Am J Clin Pathol
2002;118:186–193.
DeMay RM. Follicular lesions of the thyroid. W(h)ither follicular carci-
noma? Am J Clin Pathol 2000;114:681–683.
Kroll TG. Molecular rearrangements and morphology in thyroid cancer. Am
J Pathol 2002;160:1941–1944.
LiVolsi VA, Asa SL. The demise of follicular carcinoma of the thyroid gland.
Thyroid 1994;4:233–236.
Segev DL, Clark DP, Zieger M, Umbricht C. Beyond the suspicious thyroid
fine needle aspirate. A review. Acta Cytol 2003;47:709–722.
Shaha AR, Loree TR, Shah JP. Prognostic factors and risk group analysis
in follicular carcinoma of the thyroid. Surgery 1995;118:1131–1136.
Umbricht CB, Conrad GT, Clark DP, et al. Human telomerase reverse tran-
scriptase gene expression and the surgical management of suspicious
thyroid tumors. Clin Cancer Res 2004;10:5762–5768.
Hürthle Cell Neoplasms
Chen KTK. Fine-needle aspiration cytology of papillary Hurthle-cell tumors
of thyroid: a report of three cases. Diagn Cytopathol 1991;7:53–56.
Gonzalez JL, Wang HH, Ducatman BS. Fine-needle aspiration of Hurthle
cell lesions: a cytomorphologic approach to diagnosis. Am J Clin Pathol
1993;100:231–235.
Lopez-Penabad L, Chiu AC, Hoff AO, et al. Prognostic factors in patients
with Hurthle cell neoplasms of the thyroid. Cancer 2003;97:1186–
1194.
McIvor NP, Freeman JL, Rosen I, Bedard YC. Value of fine-needle aspiration
in the diagnosis of Hurthle cell neoplasm. Head Neck 1993;15:
335–341.
Stojadinovic A, Ghossein RA, Hoos A, et al. Hurthle cell carcinoma: a
critical histopathologic appraisal. J Clin Oncol 2001;19:2616–2625.
Stojadinovic A, Hoos A, Ghossein RA, et al. Hurthle cell carcinoma: a
60-year experience. Ann Surg Oncol 2002;9:197–203.
Papillary Carcinoma
Baloch ZW, Abraham S, Roberts S, et al. Differential expression of cyto-
keratins in follicular variants of papillary carcinoma: an immunohisto-
chemical study and its diagnostic utility. Hum Pathol 1999;30:
1166–1171.
Chan JKC. Strict criteria should be applied in the diagnosis of encapsu-
lated follicular variant of papillary thyroid carcinoma. Am J Clin Pathol
2002;117:16–18.
Goellner JR, Carney JA. Cytologic features of fine-needle aspirates of
hyalinizing trabecular adenoma of the thyroid. Am J Clin Pathol 1989;
91:115–119.
Goodell WM, Saboorian MH, Ashfaq R. Fine-needle aspiration diagnosis of
the follicular variant of papillary carcinoma. Cancer 1998;84:349–354.
Lin JS, Komisar A, Opher E, Blaugrund SM. Follicular variant of papillary
carcinoma: the diagnostic limitations of preoperative fine-needle
aspiration and intra-operative frozen section evaluation. Laryngoscope
2000;110:1431–1436.
LiVolsi VA. Unusual variants of papillary thyroid carcinoma. Adv Endocrinol
Metab 1995;6:39–54.
Renshaw AA. ‘Histiocytoid’ cells in fine-needle aspirations of papillary
carcinoma of the thyroid: frequency and significance of an under-
recognized cytologic pattern. Cancer (Cancer Cytopathol) 2002;96:240–
243.
Shaha AR, Shah JP, Loree TR. Risk group stratification and prognostic
factors in papillary carcinoma of thyroid. Ann Surg Oncol 1996;3:
534–538.
Solomon A, Gupta PK, LiVolsi VA, Baloch ZW. Distinguishing tall cell
variant of papillary thyroid carcinoma from usual variant of papillary
Ch002-F06731.indd 70
FINE NEEDLE ASPIRATION CYTOLOGY
thyroid carcinoma in cytologic specimens. Diagn Cytopathol 2002;27:
143–148.
Tabbara SO, Acoury N, Sidawy MK. The origin of multinucleated foreign-
body-type giant cells in thyroid neoplasms: a cytologic, histologic and
immunohistochemical study. Acta Cytol 1996;40:1184–1188.
Medullary Carcinoma
Bhattacharyya N. A population-based analysis of survival factors in dif-
ferentiated and medullary thyroid carcinoma. Otolaryngol Head Neck
Surg 2003;28:115–123.
Bose S, Kapila K, Verma K. Medullary carcinoma of the thyroid: a cytologi-
cal, immunocytochemical, and ultra-structural study. Diagn Cytopathol
1992;8:28–32.
Collins BT, Cramer JM, Tabatowski K, Hearn S, Raminhos A, Lampe H. Fine
needle aspiration of medullary carcinoma of the thyroid. Cytomorphol-
ogy, immunocytochemistry and electron microscopy. Acta Cytol
1995;39:920–930.
Forrest CH, Frost FA, de Boer WB, Spagnolo DV, Whitaker D, Sterrett BF.
Medullary carcinoma of the thyroid: accuracy of diagnosis of fine-needle
aspiration cytology. Cancer 1998;84:295–302.
Kini SR, Miller JM, Hamburger JI, Smith MJ. Cytopathologic features of
medullary carcinoma of the thyroid. Arch Pathol Lab Med 1984;108:
156–159.
Insular Carcinoma
Guiter GE, Auger M, Ali SZ, Allen EA, Zakowski MF. Cytopathology of insular
carcinoma of the thyroid. Cancer 1999;87:196–202.
Layfield LJ, Gopez EV. Insular carcinoma of the thyroid: report of a case
with intact insulae and microfollicular structures. Diagn Cytopathol
2000;23:409–413.
Pietribiasi F, Sapino A, Papotti M, Bussolati G. Cytologic features of poorly
differentiated ‘insular’ carcinoma of the thyroid, as revealed by fine-
needle aspiration biopsy. Am J Clin Pathol 1990;94:687–692.
Pilotti S, Collini P, Mariani L et al. Insular carcinoma: a distinct de novo
entity among follicular carcinomas of the thyroid gland. Am J Surg
Pathol 1997;21:1466–1473.
Sironi M, Collini P, Cantaboni A. Fine needle aspiration cytology of insular
thyroid carcinoma. A report of four cases. Acta Cytol 1992;36:435–439.
Anaplastic Carcinoma
Berry B, MacFarlane J, Chan N. Osteoclastomalike anaplastic carcinoma of
the thyroid. Diagnosis by fine needle aspiration cytology. Acta Cytol
1990;34:248–250.
Brooke PK, Hameed M, Zakowski M. Fine-needle aspiration of anaplastic
thyroid carcinoma with varied cytologic and histologic patterns: a case
report. Diagn Cytopathol 1994;11:60–63.
Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data
Base report on 53,856 cases of thyroid carcinoma treated in the U.S.,
1985–1995. Cancer 1998;83:2638–2648.
Peterson CE, Hall W, Baskin HJ. Anaplastic thyroid carcinoma: cytomor-
phology and clinical implications of fine-needle aspiration. Diagn
Cytopathol 1991;7:63–67.
Venkatesh YS, Ordonez NG, Schultz PN, et al. Anaplastic carcinoma of the
thyroid. A clinicopathologic study of 121 cases. Cancer 1990;66:
321–330.
Lymphoma
Das DK, Gupta SK, Francis IM, Ahmed MS. Fine-needle aspiration cytology
diagnosis of non-Hodgkin lymphoma of thyroid: a report of four cases.
Diagn Cytopathol 1993;9:639–645.
Derringer GA, Thompson LD, Frommelt RA, Bijwaard KE, Heffess CS, Abbon-
danzo SL. Malignant lymphoma of the thyroid gland: a clinicopathologic
study of 108 cases. Am J Surg Pathol 2000;24:623–639.
Detweiler RE, Katz RL, Alapat C, El-Naggar A, Ordonez N. Malignant lym-
phoma of the thyroid: a report of two cases diagnosed by fine-needle
aspiration. Diagn Cytopathol 1991;7:163–171.
Skacel M, Ross CW, Hsi ED. A reassessment of primary thyroid lymphoma:
high-grade MALT-type lymphoma as a distinct subtype of diffuse large
B-cell lymphoma. Histopathology 2000;37:10–18.
10/26/2006 10:21:43 AM
 3 Lymph Nodes
Paul E Wakely Jr
Lymph nodes (or masses suspected to represent a lymph
node) rival the thyroid gland and the breast as the most
frequent sites for application of fine needle aspiration
(FNA) biopsy. FNA often unequivocally represents the
most direct and cost-effective diagnostic path to explain
an enlarged lymph node. Principal indications are to
exclude or confirm a benign, malignant (primary or
metastatic), or infectious process when the reason is
not clinically apparent to the physician.
REACTIVE LYMPHOID HYPERPLASIA
CLINICAL FEATURES
Non-specific reactive lymphoid hyperplasia is a common
cause of lymphadenopathy in children and young
adults, but much less so in older individuals, being very
infrequent beyond the fourth decade. Males and females
are equally affected. Reactive lymphoid hyperplasia
REACTIVE LYMPHOID HYPERPLASIA – DISEASE FACT SHEET
Definition
៉ A benign proliferation of cells in the lymph node cortex, medulla,
and/or paracortex caused by a variety of antigenic stimuli
Incidence
៉ Very common cause of lymphadenopathy in children and young
adults; much less so in adults
៉ Males = females
Clinical Features
៉ Usually solitary node enlargement; less commonly produces
multiple enlarged nodes
៉ Soft to palpation, non-tender, not fixed to soft tissue
៉ Typically involves cervical, axillary, or inguinal nodes; rarely
supraclavicular nodes
Prognosis and Treatment
៉ Completely benign and reversible
៉ Self-limited; surgical excision often occurs if node is >1 cm in
dimension and does not regress after a certain duration
Ch003-F06731.indd 71
manifests as a clinically enlarged lymph node that may
or may not be painful upon palpation. It may be due to
a variety of antigenic stimuli including organisms,
foreign material (drugs, environmental pollutants,
altered tissue components), altered immune status, and
enlargement in the drainage pathway of a neoplasm
without actually harboring neoplastic cells. In the vast
majority of instances, a specific etiology remains
unknown.
Prognosis of reactive lymphoid hyperplasia is excel-
lent, with most examples resolving on their own or after
a course of antibiotic therapy. The utility of FNA is
particularly noticeable with persistent lymphadenopa-
thy, since the patient, parents, and clinician begin to
consider a more ominous cause if an enlarged node is
present for more than 3 weeks.
CYTOPATHOLOGIC FEATURES
Two consistent findings in cytologic smears of
lymphoid tissue regardless of a benign or malignant
nature are: a) dispersion of cells predominantly as
REACTIVE LYMPHOID HYPERPLASIA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ A spectrum of lymphocytes ranging from small round forms
(7–8 μm) to transformed centrocytes and centroblasts to larger
immunoblasts
៉ Dendritic/lymphocytic aggregates
៉ Follicular center fragments consisting of a syncytium of
dendritic cells populated by a range of lymphocytes, tingible-
body macrophages, and short capillary segments
Ancillary Studies
៉ Immunophenotyping shows a polyclonal population of B and T
lymphocytes
Differential Diagnosis and Pitfalls
៉ Any ‘small cell’ non-Hodgkin lymphoma
៉ Small cell neuroendocrine carcinoma
៉ Certain benign causes of lymphadenopathy, e.g. progressive
transformation of germinal centers, Castleman disease,
toxoplasma lymphadenitis, HIV lymphadenopathy
71
10/26/2006 10:22:48 AM
 72 FINE NEEDLE ASPIRATION CYTOLOGY

A B

FIGURE 3-1
Reactive lymphoid hyperplasia. A, A polymorphous population of lympho-
cytes is present in a dissociated (single cell) pattern. Small lymphocytes
with rounded nuclei are most numerous, but large and intermediate-size
lymphocytes are also present. Note the blue globular lymphoglandular
bodies scattered between cells. Romanowsky stain, high power. B, A
centrally placed immunoblast looms over the remaining smaller lympho-
cytes in this field. Note the single nucleolus and the zone of deeply
basophilic staining at the immunoblast periphery. Romanowsky stain,
high power. C, Three tingible-body macrophages are easily recognized
because of their large size, and the presence of phagocytosed cellular
debris. A heterogeneous cell mixture is seen in the background. Papani-
colaou stain, high power.

non-clustered, individual forms – the so-called single
cell/dissociated cell pattern; and b) presence of
individual small globular or flake-like fragments of
cytoplasm that have been termed lymphoglandular
bodies. Lymphoglandular bodies are best seen with
a Romanowsky-type stain (Giemsa, Wright-Giemsa,
May-Grünwald-Giemsa, or Diff-Quik), where they
stain a pale blue or blue–gray, are about the size of a
red cell, and may contain small vacuoles; their size can
vary somewhat. Their presence, particularly in large
numbers, is assurance that lymphoid tissue has been
aspirated, but it does not guarantee that the lesion
on the slide is lymphoid. It merely states that a lym-
phoid population exists on the smear (e.g. metastatic
seminoma and undifferentiated nasopharyngeal carci-
noma typically contain lymphocytes as part of the
neoplasm).
Because little stroma exists in reactive lymphoid
hyperplasia to retain lymphoid cells during the back-
and-forth cutting action of an aspirating needle, rela-
tively large numbers of cells can be obtained, resulting
in moderately to highly cellular smears. Degree of cel-
lularity has no correlation with benignancy or malig-
nancy. Even if reactive lymphoid hyperplasia is
subdivided into various stages (early, mid, and late
phases), small round lymphocytes predominate with
variation in the percentage of other lymphocytes. It is
important to remember that the spatial relationships
visible in tissue sections of lymph node are lost in aspi-
rates. Thus, follicular, diffuse, sinusoidal, or marginal
zone architecture cannot be recognized with FNA.
Since the reactive node undergoes expansion of corti-
cal, medullary, and/or paracortical zones, the hallmark
of reactive lymphoid hyperplasia is the structural poly-
morphism/heterogeneity typical of sampling the normal
cellular elements from various parts of a normal but
expanded node. These constituents include small
lymphocytes, centrocytes, centroblasts, dendritic cells,
tingible-body macrophages, immunoblasts, plasmacytoid
monocytes, plasma cells, and, less often, capillaries,
eosinophils, and endothelial cells. Small round lympho-
cytes prevail in aspirate smears, followed by centrocytes
and centroblasts in examples of follicular reactive
lymphoid hyperplasia (Fig. 3-1). Centrocytes are similar
in size to or slightly larger than small lymphocytes,
having slight nuclear contour irregularity. Centroblasts
are non-cleaved lymphocytes (almost twice the diameter
of mature lymphocytes) with coarser chromatin, slightly
more cytoplasm, and may contain visible nucleoli.
Plasmacytoid lymphocytes/monocytes are small to

Ch003-F06731.indd 72 10/26/2006 10:22:49 AM

 CHAPTER 3 Lymph Nodes 73

intermediate in size with eccentrically placed nuclei, This can be accomplished either by rinsing the aspirat-
smudged chromatin, a variable perinuclear clear zone, ing needle in the media after cells are expressed onto
and a small amount of slightly basophilic cytoplasm. glass slides or by directly placing cells into such a
Immunoblasts are large cells (20–25 μm) with open fine medium from one of the FNA passes. The most impor-
chromatin, one or more distinct nucleoli, and moderate tant ancillary test for reactive lymphoid hyperplasia is
to abundant pale to basophilic cytoplasm. A perinuclear immunophenotyping. Immunophenotyping should be
clear zone may be seen. Tingible-body macrophages are performed on all lymph node aspirates that contain
large cells, with rounded nuclei, finely granular chroma- only a lymphoid population, to help assure that a
tin, a small distinct nucleolus, and a copious debris- non-Hodgkin lymphoma is excluded. Those aspirates
laden cytoplasm. Dendritic cells have oval hypochro-
matic nuclei, indistinct or absent nucleoli, and long
cytoplasmic processes; they are commonly binucleated
(Fig. 3-2). Cell processes are paradoxically better seen in
Papanicolaou-stained smears. Thus, it is not so critical in
reactive lymphoid hyperplasia that one tries to identify
each cell on the smear, rather to recognize that a range
of different lymphoid tissue cellular elements exists.
An exception to the single cell pattern in a normal
but reactive node is the presence of dendritic/lympho-
cytic aggregates and/or follicular center cell fragments.
Dendritic/lymphocytic aggregates are loose collections
(50–120 μm) of small lymphocytes and larger dendritic
cells devoid of tingible-body macrophages or capillaries
(Fig. 3-3A). The cytoplasmic processes of dendritic cells
are best seen in these aggregates. Follicular center cell
fragments contain the additional embellishments of
branching capillaries and tingible-body macrophages,
and are most often observed in examples of florid fol-
licular reactive lymphoid hyperplasia (Fig. 3-3B).

ANCILLARY STUDIES
All lymph node FNA biopsies should obtain cells in a
liquid medium that preserves cells for ancillary testing.
FIGURE 3-2
Reactive lymphoid hyperplasia, dendritic cells. A grouping of dendritic
cells displays the web-like cytoplasmic extensions that emanate from
the cell body. Cell borders are indistinct, creating a syncytium. Nuclei
are hypochromatic with smooth nuclear contours and small nucleoli.
Note the binucleated dendritic cell at the bottom of this group whereby
the two nuclei partially overlap. Papanicolaou stain, high power.

A B

FIGURE 3-3
Reactive lymphoid hyperplasia. A, Dendritic/lymphocytic aggregate. A discrete cluster of dendritic cells and heterogeneous lymphocytes is present.
The former are distinguished by their larger nuclear size and abundant amphophilic cytoplasm that creates a syncytium. Note that the large number
of lymphocytes partially obscures these cells. B, Follicular center cell fragment. A branching capillary traverses an aggregate of heterogeneous
lymphocytes and partially hidden dendritic cells. Tingible-body macrophages are embedded within the aggregate or closely associated with it (lower
center). Romanowsky stain, high power.

Ch003-F06731.indd 73 10/26/2006 10:22:49 AM

 74
containing a metastatic cancer do not necessarily
require immunophenotyping unless the clinical cir-
cumstances dictate otherwise. For reactive lymphoid
hyperplasia and all non-Hodgkin lymphomas, immuno-
phenotyping is best accomplished using flow cytometry
(FCM). FCM is the current standard for immunologic
analysis of lymphoid tissue/cells. Its advantages include
the ability to evaluate numerous lymphoid antigenic
markers on a smaller number of cells, an objective
assessment of clonality, the ability to detect small
monoclonal cell populations, and a rapid turnaround
time. A more time-consuming and less frequently used
method is immunocytochemistry of cytospin prepared
slides. With immunocytochemistry, an objective mea-
surement of clonality is lost, it is more laborious, and
fewer markers are utilized. Its major advantage is the
preservation of cell morphology, but this is offset by its
disadvantages, except in cases of presumptive Hodgkin
lymphoma.
In reactive lymphoid hyperplasia, FCM demonstrates
a polyclonal population of T and B lymphocytes. The
FCM result combined with the appropriate morphology,
and the proper clinical context are diagnostic of reactive
lymphoid hyperplasia. FCM is, however, imperfect.
Some lymph node aspirates contain too few cells to
evaluate, some B-cell lymphomas are immunoglobulin-
negative, and some lymphomas have such a high cell
turnover rate that an insufficient number of viable lym-
phocytes exist for immunophenotyping. In these cases,
molecular studies can be employed to further identify
the lesion.
Molecular and genetic tests can be applied to sus-
pended cells in a liquid medium or directly to cells
smeared on a glass slide. One method uses the poly-
merase chain reaction (PCR) that amplifies the DNA of
lymphocytes, and can determine if the heavy chain
immunoglobulin genes of B cells or the T-cell receptor
genes of a T-cell lymphoma have been rearranged.
Another method is fluorescence in situ hybridization
(FISH), whereby commercially available probes are
used to label parts of a chromosome to determine
whether a cytogenetically abnormal rearrangement has
occurred. Specific examples are addressed under certain
disease states.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Some benign lymphadenopathies have distinctive archi-
tectural features and spatial relationships in tissue sec-
tions that allow for a specific diagnosis. However, these
features are not readily transferable to smears. Thus,
benign lymphadenopathies such as Castleman disease,
toxoplasma lymphadenitis, HIV-associated lymph-
adenopathy, progressive transformation of germinal
centers, and some examples of dermatopathic lymph-
adenopathy for the most part are morphologically
similar to reactive lymphoid hyperplasia smears, and
are rarely distinguishable with absolute certainty by
using FNA.
Ch003-F06731.indd 74
FINE NEEDLE ASPIRATION CYTOLOGY
The principal diagnostic pitfall is confusing reactive
lymphoid hyperplasia with a small cell type of non-
Hodgkin lymphoma (NHL). The major morphologic
feature that separates these two categories is the pres-
ence of a range of lymphocytes in the former and its
relative absence in the latter. Most small cell lymphomas
are composed of monotonous (or nearly monotonous)
lymphocytes. Follicular lymphoma, marginal zone lym-
phoma, and some T-cell lymphomas, however, show a
degree of cell heterogeneity that allows them to be con-
fused with reactive lymphoid hyperplasia. Grade II
follicular lymphoma in particular often has a two-cell
population of small and large lymphocytes, but a true
spectrum of lymphoid cells is absent. This can be diffi-
cult to appreciate. Thus, immunophenotyping is manda-
tory in all aspirates of presumptive reactive lymphoid
hyperplasia.
Small cell neuroendocrine carcinoma may be mis-
taken infrequently with reactive lymphoid hyperplasia.
It is more apt to be confused with small cell forms of
NHL, and thus is discussed in detail in that section. A
cytologic diagnosis (regardless of what tissue or organ
is aspirated) of reactive lymphoid hyperplasia must fit
with the overall clinical context of the patient’s problem.
If it does not, then the cytologic diagnosis must be vali-
dated using another method, usually surgical biopsy. In
the example of an individual with a large, fixed node
whose combined aspirate morphology and immunophe-
notyping shows reactive lymphoid hyperplasia, a cyto-
logic diagnosis has been made that does not correlate
with the clinical scenario. Partial involvement of a node
by a malignant process is a potential reason why a diag-
nosis of reactive lymphoid hyperplasia, although techni-
cally correct, may be invalid in the overall clinical
circumstance.
GRANULOMATOUS LYMPHADENOPATHY
CLINICAL FEATURES
Granulomatous lymphadenopathy is very common and
is due to various etiologies. Most examples are second-
ary to infectious disease, but granulomas may appear
as a consequence of placement of foreign material,
immune-related disease, environmental toxins and
dust, or neoplasms. Sarcoidosis is a common cause of
granulomatous lymphadenopathy. In the United States,
the incidence is 40 per 100,000 in black individuals,
which is 8–10 times more common than in whites. All
ages can be affected, but peak incidence is in the third
to fi fth decade, with a female predominance (2 : 1). In
addition to peripheral adenopathy, enlargement of
pulmonary hilar nodes is common. Patients may also
display signs and symptoms of uveitis, sinusitis, ery-
thema nodosum, and joint lesions, along with elevated
angiotensin-converting enzyme, erythrocyte sedimen-
tation rate, and serum calcium.
10/26/2006 10:22:51 AM
 CHAPTER 3 Lymph Nodes
GRANULOMATOUS LYMPHADENOPATHY – DISEASE FACT SHEET
Definition
៉ The presence of granulomas with or without inflammation and
necrosis in a lymph node; etiology may be infectious or
non-infectious
Incidence
៉ Sarcoidosis: 40 per 100,000 in black population; 8–10 times less
common in whites
៉ Infectious causes: common in children and immunosuppressed
patients
Gender and Age Distribution
៉ Sarcoidosis: 20–40 years of age; women > men
៉ Infectious causes: any age, with equal male/female ratio;
dependent on immunologic status
Clinical Features
៉ Enlarged node or group of nodes
៉ Usually firm to palpation in non-infectious causes
៉ May be tender to palpation with cutaneous erythema in infectious
causes
Prognosis and Treatment
៉ Usually excellent prognosis
៉ Antibiotic, antifungal, antimycobacterial therapy, dependent on
etiology
Patients with fungal or mycobacterial lymphadenitis
often contain granulomas within enlarged nodes. These
can occur at any age, and are often associated with a
deficient immune status in the host. Patients may
present with non-specific lymphadenopathy, or may
have the constitutional signs and symptoms of dissemi-
nated infection. Some fungal infections such as Crypto-
coccus and Histoplasma are endemic to certain areas
of the United States. Tuberculous and non-tuberculous
(M. avium and M. intracellulare) lymphadenitis are
particularly common in AIDS patients and others with
poor immune function, and in the under-developed
world. Atypical mycobacteria lymphadenitis is often a
childhood disease with enlarged cervical nodes mimick-
ing a bacterial infection. Cat-scratch disease is a lymph-
adenitis secondary to Bartonella henselae. The incidence
is 9 per 100,000 in the United States, and most patients
are less than 20 years of age. Although a high proportion
of patients are in contact with a cat, only about 50%
report actually being scratched.
Prognosis of patients with infectious granuloma-
tous lymphadenitis depends on response to antimi-
crobials, and correction of immune status. Children
with atypical mycobacteria recover fully in nearly all
cases. Cat-scratch disease is self-limited in immuno-
competent patients. Sarcoidosis remits spontaneously
in a large percentage of cases; many are treated with
steroids.
Ch003-F06731.indd 75
75
CYTOPATHOLOGIC FEATURES
Regardless of cause, the cytopathology of granuloma-
tous lymphadenopathy is similar with minor differ-
ences. Granulomas appear in smears as either loose or
tightly clustered collections of epithelioid histiocytes of
variable number and size. The key feature of an epithe-
lioid histiocyte (which allows its distinction from a
macrophage or dendritic cell) is an elongated, almost
elliptical or spindle-shaped nucleus. A slight smooth
indentation of the nuclear contour is present on one
side, producing an outline that has been variously
described as ‘footprint-, boomerang-, or banana-shaped’.
Not all nuclei in a collection of epithelioid histiocytes
will have this shape, but enough will to allow recogni-
tion as a granuloma. These nuclei are hypochromatic
and may have small nucleoli or no visible nucleoli (Fig.
3-4). Nuclei may project away from a granuloma center
in a ‘starburst’ pattern. Epithelioid histiocytes have a
moderate to abundant amount of finely granular, non-
vacuolated cytoplasm. Multinucleated giant cells are
variably present in slides of granulomatous lymphade-
nopathy; their presence is not necessary for the
diagnosis.
Infectious causes, particularly cat-scratch disease,
atypical mycobacteria, and some examples of tubercu-
lous lymphadenitis, have an added neutrophilic cellular
component on the smear, and may mimic an abscess
(Fig. 3-5). Mycobacterial lymphadenitis has a variety of
appearances, with some cases displaying no granulo-
mas, only necrosis with or without acute inflammation,
or foamy macrophages containing cytoplasmic stria-
tions. The latter represent ingested mycobacterial
organisms (Fig. 3-6).
GRANULOMATOUS LYMPHADENOPATHY – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Granulomas: syncytial clusters of epithelioid histiocytes
characterized by oval and elongated, indented nuclei in loose or
tight clusters
៉ Variable number of multinucleated giant cells
៉ Variable necrosis and acute infl ammation; acute infl ammation is
common in cat-scratch disease and mycobacterial infection;
absent in sarcoid
Ancillary Studies
៉ Histochemical stains for fungi and/or acid-fast bacilli
៉ Microbiologic testing
Differential Diagnosis and Pitfalls
៉ Dendritic/lymphocytic aggregates
៉ Suppurative lymphadenitis
៉ Spindle cell neoplasm
10/26/2006 10:22:51 AM
 76
FIGURE 3-4
Granulomatous lymphadenopathy: sarcoidosis. This syncytial cluster of
epithelioid histiocytes forms a granuloma. Some hypochromatic nuclei
are oval, but many have a markedly elongated spindled quality. Indenta-
tion of the nuclear contour varies from subtle to dramatic, particularly
so in the bottom half of the image. Nucleoli are indistinct. Papanicolaou
stain, high power.
FIGURE 3-5
Granulomatous lymphadenopathy: cat-scratch disease. This well-formed
granuloma has frayed edges. It is infiltrated and surrounded by numer-
ous polymorphonuclear leukocytes that partly obscure histiocyte nuclei.
All areas of the smear are covered with neutrophils. Papanicolaou stain,
high power.
ANCILLARY STUDIES
The primary study for any infectious cause should be
microbiologic testing for an organism. Some of the aspi-
rate can be submitted in a culture tube for fungal, bac-
terial, or mycobacterial testing. Direct histochemical
staining of the slide for fungi and mycobacterial bacilli
using conventional silver and acid-fast stains is the
Ch003-F06731.indd 76
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 3-6
Granulomatous lymphadenopathy: mycobacterial lymphadenitis. This
smear from an immunosuppressed patient contained no granulomas,
only macrophages and lymphocytes, whose nuclei are seen. The striking
feature in this image is the randomly arranged and overlapping unstained
lines that exist extracellularly. These represent the acid-fast bacilli
whose lipid coat prevents them from taking up the stain, thus creating
the so-called ‘negative’ image. Romanowsky stain, high power.
FIGURE 3-7
Granulomatous lymphadenopathy: mycobacterial lymphadenitis. Same
case as seen in Fig. 3-6, now stained with an acid-fast stain highlight-
ing the innumerable red rod-shaped bacilli. Culture proved to be M.
avium-intracellulare. Fite stain, high power.
most direct path toward organism identification (Fig.
3-7). The diagnosis of sarcoidosis is based on ancillary
serologic tests, and clinicoradiologic examination.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The cytologic morphology of a granuloma in a well-
made smear is so characteristic that other entities rarely
10/26/2006 10:22:51 AM
 CHAPTER 3 Lymph Nodes
enter into the diagnosis. Follicular dendritic cells or
dendritic/lymphocytic aggregates could potentially be
mistaken for granulomas; however, the round to oval
nuclear shape that is universal to these cells allows
their distinction from epithelioid histiocytes. A sup-
purative bacterial lymphadenitis may mimic cat-scratch
disease because of the neutrophilic background, but
will lack the granulomas that exist in the latter. Rarely,
the spindle cell nature of epithelioid histiocytes is
exaggerated, and mimics a spindle cell proliferation.
However, not all granuloma clusters are affected, and
one finds more typical granuloma morphology in other
areas of the smear.
INFECTIOUS MONONUCLEOSIS
CLINICAL FEATURES
Infectious mononucleosis is a disease caused by the
Epstein-Barr virus (EBV). It is spread through person-
to-person contact, and occurs most commonly in ado-
lescents and young adults. The estimated incidence is
50 per 100,000 individuals in the United States, equally
affecting males and females. The classic clinical triad
includes fever, pharyngitis, and peripheral lymphade-
nopathy that is always bilateral in the cervical chain.
Axillary and inguinal adenopathy may also occur.
Occasionally, unusual features will exist that mislead
the physician, resulting in delayed diagnosis. Lymph
nodes are often tender upon palpation, and movable.
Splenomegaly is common, and splenic rupture a poten-
INFECTIOUS MONONUCLEOSIS – DISEASE FACT SHEET
Definition
៉ A lymphadenopathy due to Epstein-Barr viral infection
Incidence
៉ About 50 per 100,000 in the US
Gender and Age Distribution
៉ Most frequent in adolescents and young adults; rare in middle-
aged or elderly
Clinical Features
៉ Pharyngitis, fever, splenomegaly
៉ Local or generalized lymphadenopathy
៉ Peripheral blood lymphocytosis
៉ Positive heterophile antibodies
Prognosis and Treatment
៉ Self-limited; death in <1% of cases owing to complications of
EBV infection
៉ Treatment is supportive in most instances
Ch003-F06731.indd 77
77
tial complication. Infectious mononucleosis is a self-
limited condition lasting from 3 to 4 weeks, and
supportive medical treatment is the rule. Less than 1%
of affected patients develop serious complications from
the viral infection resulting in death.
CYTOPATHOLOGIC FEATURES
Aspiration smears typically contain many lymphocytes
in a dispersed pattern. Although a range of cells is
present, somewhat mimicking a reactive lymphoid
hyperplasia smear, some crucial differences exist. A
marked increase in the percentage of immunoblasts (a
consequence of the host response to EBV), centroblasts,
plasmacytoid monocytes, and plasma cells is noted
along with a diminution or absence of follicular center
cell fragments. This abnormal proliferation of immu-
noblasts results in a skewed elevated percentage of large
lymphocytes that can be misinterpreted easily for a
large cell lymphoma (Fig. 3-8). Immunoblasts display
enlarged nuclei, finely granular chromatin, one to three
nucleoli (that are indistinct in Romanowsky-stained
smears), and a moderate amount of basophilic cyto-
plasm (Fig. 3-9). EBV also induces infected B cells to
transform into plasmacytoid forms with eccentrically
placed nuclei, basophilic cytoplasm, and a minimal
perinuclear clear zone.
ANCILLARY STUDIES
The primary role of FNA is to suggest, confirm, or
exclude infectious mononucleosis in a patient who has
either not undergone serologic testing or has negative
serologic results. Laboratory findings include periph-
eral blood atypical lymphocytosis, and a positive mono-
spot (heterophile) test. IgM heterophile antibodies are
INFECTIOUS MONONUCLEOSIS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ A range of lymphocytes but with a noticeable increase in the
percentage of immunoblasts, plasmacytoid lymphocytes/
monocytes, and plasma cells
៉ Few dendritic/lymphocytic aggregates and follicular center cell
fragments
Ancillary Studies
៉ Flow cytometry is polyclonal with a reversed T4/T8 ratio
៉ Serologic testing for heterophile antibodies
Differential Diagnosis and Pitfalls
៉ Reactive lymphoid hyperplasia
៉ Large cell non-Hodgkin lymphoma
៉ Hodgkin lymphoma
10/26/2006 10:22:53 AM
 78
FIGURE 3-8
Infectious mononucleosis. A nearly monotonous population of immuno-
blasts mimicking a large cell lymphoma is present. These cell nuclei are
enlarged with slight irregularity of their nuclear outline. Nucleoli are
not particularly obvious with the Romanowsky stain. Note the two much
smaller plasmacytoid lymphocytes in the center of the field and one at
9 o’clock with focal perinuclear clearing and eccentric nuclear position-
ing. Romanowsky stain, high power.
FIGURE 3-9
Infectious mononucleosis. A mixture of immunoblasts, plasmacytoid
lymphocytes, and small lymphocytes is seen. There is marked basophilia
of the immunoblast cytoplasmic periphery. The intermediate-sized
plasmacytoid lymphocytes display small zones of perinuclear clearing.
Romanowsky stain, high power.
the principal diagnostic serologic test for infectious
mononucleosis. These are present in almost 70% of
patients after the first week of symptom onset. Almost
20% of patients, however, have a negative heterophile
test; this percentage is even higher in children less
than 5 years of age. FCM is the principal ancillary
study that should be performed from the FNA-captured
cells. This will demonstrate a polyclonal lymphocyte
Ch003-F06731.indd 78
FINE NEEDLE ASPIRATION CYTOLOGY
population, and a reversed CD4 : CD8 ratio with an
increase in cytotoxic CD8 suppressor T cells.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Distinguishing infectious mononucleosis from reactive
lymphoid hyperplasia requires recognition of the
increased number of immunoblasts and plasmacytoid
monocytes coupled with the clinical picture. Unlike
reactive lymphoid hyperplasia, tingible-body macro-
phages and follicular center cell fragments are only a
minor component of the infectious mononucleosis
smear, if present at all. However, very early in the
course of infectious mononucleosis, lymphadenopathy
may demonstrate only a florid reactive lymphoid hyper-
plasia type of smear, without the large population of
immunoblasts and centroblasts, making infectious
mononucleosis indistinguishable from an early phase
reactive lymph node. Other causes of nodal immuno-
blast proliferation such as anticonvulsant-induced
lymphadenopathy, herpes simplex lymphadenitis, and
drug hypersensitivity are cytologically identical to
infectious mononucleosis. Clinical and serologic data
combined with the cytopathology are therefore neces-
sary to establish a specific diagnosis.
Infectious mononucleosis may be confused for large
cell NHL cytologically and clinically, since a small
number of lymphoma patients may present with infec-
tious mononucleosis-like clinical symptoms. Smears of
large cell lymphoma exhibit greater cell monotony, do
not show the range of lymphocyte types seen in infec-
tious mononucleosis, and uncommonly possess the
prominent plasmacytoid cell population. With FCM,
large B-cell lymphoma will demonstrate monoclonality.
Since a small number of proliferating immunoblasts
in infectious mononucleosis may exhibit binucleation,
Hodgkin lymphoma may enter into the differential diag-
nosis. True Reed-Sternberg cells have pale cytoplasm
rather than the basophilic cytoplasm of B immunoblasts,
and their enlarged nucleoli are much larger than those
seen in the immunoblasts of infectious mononucleosis.
HODGKIN LYMPHOMA
CLINICAL FEATURES
Hodgkin lymphoma (HL) is considered a B-cell lym-
phoma defined by its unique pathologic features. The
incidence is 2–4 per 100,000 in the United States, with
a broad age range, peaking in the second to fourth
decades. A smaller spike occurs in the elderly, but this
may be artificial. HL comprises up to 35% of all lym-
phomas in Caucasians, but only 5–10% of all lympho-
mas that develop in Orientals. HL is slightly more
common (1.5 : 1) in males. Clinically, patients present
10/26/2006 10:22:54 AM
 CHAPTER 3 Lymph Nodes
HODGKIN LYMPHOMA – DISEASE FACT SHEET
Definition
៉ A lymphoma composed of cytologically abnormal cells termed
Reed-Sternberg (R-S) cells and Hodgkin cells residing in a
polymorphous mixture of lymphocytes and other inflammatory
cells
Incidence
៉ A wide variation globally
៉ 2–4 per 100,000 in the US and western Europe; uncommon in
Asian populations
Gender and Age Distribution
៉ Peak age is 15–35 years with a smaller peak in the 60s; rare
before 10 years in the US
៉ Slightly more common in males
Clinical Features
៉ Peripheral lymphadenopathy (cervical nodes most common) with
single or multiple matted nodes above or below the diaphragm
and mediastinum; extranodal involvement rare
៉ Node(s) often firm to palpation
៉ Symptoms: fever, night sweats, weight loss, pruritus
Prognosis and Treatment
៉ Curable in >90% with stage I–II disease
៉ Multiagent chemotherapy, radiotherapy, or both
with painless enlargement of cervical or mediastinal
lymph nodes. A single node or group of nodes may be
encountered. About 10% also have constitutional
symptoms of fever, weight loss, pruritis, and drenching
night sweats. No clinical laboratory test is specific for
HL. Prognosis is related to clinical stage; overall 5-year
survival is >95% for stage I and II disease with chemo-
therapy or radiotherapy regimens.
CYTOPATHOLOGIC FEATURES
Aspirates may be hyper- or hypocellular depending on
the degree of sclerosis in the affected node. Smears
mimic those of reactive lymphoid hyperplasia at low-
power examination with a range of various types of
lymphocytes present. Key to this diagnosis is the ability
to identify Reed-Sternberg (R-S) cells. The classic binu-
cleated R-S cell is, in most instances, not easily found.
Rather, one must be able to appreciate the presence of
enlarged mononuclear R-S variants in a heterogeneous
lymphocytic milieu that simulates reactive hyperplasia
(Fig. 3-10). These mononuclear so-called Hodgkin cells
(typically readily identifiable at medium power) are
markedly enlarged (20–30 μm) with rounded smooth
or lobated nuclear contours and a moderate amount of
pale, i.e. non-basophilic, cytoplasm. Hodgkin cells have
Ch003-F06731.indd 79
79
HODGKIN LYMPHOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Spectrum of lymphocytes with classic mirror-image Reed-
Sternberg (R-S) cells or mononuclear variants
៉ R-S cell: enlarged (≥20 μm), binucleated or mononucleated,
enlarged nucleus, polylobated nucleus, enlarged misshapen
nucleolus, meager to moderate amount of pale cytoplasm
៉ Acute infl ammation and necrosis infrequent
៉ Small granulomas possible
Ancillary Studies
៉ Classical Hodgkin lymphoma: R-S cells positive for CD15, CD30,
and fascin; negative for CD20
៉ Nodular lymphocyte-predominant Hodgkin lymphoma: R-S cells
positive for CD20, CD45, and EMA; negative for CD15 and CD30
Differential Diagnosis and Pitfalls
៉ Reactive lymphoid hyperplasia
៉ Large cell non-Hodgkin lymphoma
៉ Infectious mononucleosis
single macronuclei and macronucleoli. Nucleoli are
often comparable to the diameter of red cells in the
same field, and are often misshapen rather than smooth
and round (Fig. 3-11). Various combinations of nuclear
number and appearance can be seen (Fig. 3-12). The
classic R-S cell is binucleated with the same nuclear and
cytoplasmic characteristics as the mononuclear form
(Fig. 3-13). In some cases, only bare R-S nuclei are seen,
making the diagnosis much more challenging. These
abnormal cells are randomly scattered in a hetero-
geneous background of lymphocytes. Plasma cells and
eosinophils may be increased in these smears, and
necrosis is also possible. Small, poorly formed clusters
of epithelioid histiocytes typical of granulomas are very
infrequent. A very small number of HL cases are asso-
ciated with neutrophilic inflammation. These examples
of so-called suppurative HL contain R-S cells admixed
with acute inflammatory cells.
ANCILLARY STUDIES
FCM has no role to play in the diagnosis of HL itself,
but has if one is also strongly considering large cell
lymphoma in the differential diagnosis. One should
attempt to collect cells for a paraffin-embedded cell
block or cytospin preparation from aspirated cells, so
immunostaining is possible. Classical HL, which com-
prises 90% of HL cases, has a completely different
phenotype than nodular lymphocyte-predominant HL
(Table 3-1). Without such immunophenotyping, the
ability to separate HL into its two major subtypes using
cytology alone is compromised.
10/26/2006 10:22:55 AM
 80 FINE NEEDLE ASPIRATION CYTOLOGY

A B

FIGURE 3-10
Hodgkin lymphoma, mononuclear Reed-Sternberg (R-S) cells. A, Two mononuclear R-S variants (center) are nearly hidden in this polymorphous lym-
phocytic focus. At this power, their recognition depends primarily on their size in relation to the lymphocytes surrounding them. Nuclear streaking
is most likely secondary to the sclerosis that was present in this case of classical Hodgkin lymphoma, nodular sclerosis type. Romanowsky stain,
medium power. B, This image is almost identical to (A), except for the stain. Note how much more obvious the macronucleoli appear, even though
the cells are partially obscured by the smeared nuclear chromatin of small lymphocytes. Papanicolaou stain, medium power.

TABLE 3-1
Immunophenotyping of Classical and Nodular
Lymphocyte-Predominant Hodgkin Lymphoma

R-S cells Classical HL NLP HL

CD45 Negative Positive

CD15 Positive/negative Negative
CD30 Positive (may be weak) Negative/positive
EMA Negative Positive/negative
Fascin Positive Negative
CD20 Negative/positive Positive

R-S, Reed-Sternberg; HL, Hodgkin lymphoma; NLP, nodular

lymphocyte-predominant; EMA, epithelial membrane
antigen.

FIGURE 3-11
Hodgkin lymphoma, mononuclear Reed-Sternberg (R-S) cell. A mononu-
clear R-S cell is just to the right of center. The macronucleus is very
faintly lobated, and contains an enlarged rounded nucleolus. Note the
pale cytoplasm that lacks vacuoles. Small lymphocytes predominate in
this field, but an eosinophil lies directly to the left of the R-S cell, and
a vacuolated histiocyte is at the lower left. Romanowsky stain, high
power.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis of HL includes large cell lym-
phoma, reactive lymphoid hyperplasia, and infectious
mononucleosis. Failure to capture R-S cells in the aspi-
rate, and secondarily the inability to identify them
in a polymorphous lymphocyte background are the
principal sources of error. Since most examples of HL
belong to the nodular sclerosis subtype, FNA of scle-
rotic nodes may lead to an absence or insufficient
number of R-S cells. A way to avoid this is to aspirate
not just the firm large node, but also a smaller node in
the same field. The latter often will have much less
sclerosis, and therefore enough R-S cells are extracted
for identification.
Some cases of HL will have R-S cells in clusters rather
than as isolated randomly dispersed structures, thus
invoking a possible diagnosis of large cell NHL. Large
cell lymphoma aspirates do not exhibit the reactive lym-
phoid hyperplasia-type of accompanying cell types seen
in HL. Rather, large cells most often populate smears,
sometimes with a minor population of small lympho-

Ch003-F06731.indd 80 10/26/2006 10:22:55 AM

 CHAPTER 3 Lymph Nodes 81

A B

FIGURE 3-12
Hodgkin lymphoma, Reed-Sternberg (R-S) variants. A, This enlarged cell with voluminous pale chromatin contains a dual set of mirror-image macro-
nuclei and macronucleoli. Romanowsky stain, high power. B, Enlarged reddish nucleoli in this trinucleated R-S variant display an asymmetric rect-
angular shape, unlike the rounded edges in the prior image. Note the marked size difference between this R-S cell and the background lymphocytes.
Papanicolaou stain, high power.

immunoblasts, dendritic cells, plasmablasts, malignant

melanocytes, and, less often, the cells of a sarcoma or
large cell carcinoma (Fig. 3-14).

NON-HODGKIN LYMPHOMA,
SMALL CELL TYPES

CLINICAL FEATURES

The major small cell types of NHL include follicular

FIGURE 3-13
Hodgkin lymphoma, classic Reed-Sternberg (R-S) cell. Of the three R-S
cells in this field, only the one on the far right shows the classic ‘owl’s
eye’ binucleation with round macronucleoli. The one in the middle is a
typical mononuclear so-called ‘Hodgkin cell’, and the cell at the far left
is multilobated with macronucleoli that are out of the focal plane.
Neutrophils are common in this field. Papanicolaou stain, high power.
cytes. The malignant cells in large cell NHL also do not
typically display the marked macronucleoli typical of
R-S cells. FCM can be used to demonstrate light chain
restriction in large B-cell NHL or an aberrant T-cell
phenotype in T-cell NHL.
A binucleated cell(s) with mirror-image nucleo- and
nucleolomegaly is not diagnostic of an R-S cell. This cell
must exist in the proper milieu of a polymorphous lym-
phocyte background to be considered an R-S cell. Binu-
cleated cells that can be confused as R-S cells include
lymphoma, small lymphocytic lymphoma, mantle cell
lymphoma, and marginal zone lymphoma (Table 3-2).
Nearly all types appear in middle-age or older individu-
als, and are rare in children. Gender preference is
dependent on NHL subtype. Men are affected more
often (5 : 1) with mantle cell lymphoma, almost equal
incidence occurs with follicular lymphoma and small
lymphocytic lymphoma, and a slight female predomi-
nance exists with marginal zone lymphoma. With the
exception of mantle cell lymphoma, these lymphomas
are biologically indolent, but persistent. About 50,000
newly diagnosed patients (includes all types of NHL)
in all age groups present yearly in the United States
(16 per 100,000). Of these pathologic subtypes, follicu-
lar lymphoma is commonest (20–25% of cases), with
mantle cell lymphoma (6%), small lymphocytic lym-
phoma (6%), and marginal zone lymphoma (7%) occur-
ring less often. Most patients present with asymptomatic
peripheral lymphadenopathy. Localized (stage I) disease
is uncommon for this group, with the exception of
marginal zone lymphoma, which is most commonly
an extranodal disease (lymphoma of mucosa-associated

Ch003-F06731.indd 81 10/26/2006 10:22:56 AM

 82 FINE NEEDLE ASPIRATION CYTOLOGY

A B

C D

FIGURE 3-14
Reed-Sternberg (R-S) cell look-alikes. A, Plasma cell myeloma. A large binucleated cell with nuclear sameness and equally sized nucleoli is sur-
rounded by a single cell pattern of smaller cells. These smaller forms are the key to the diagnosis. They are relatively monotonous (unlike the milieu
of Hodgkin lymphoma) with cytologic features of plasma cells. Papanicolaou stain, high power. B, Non-small cell carcinoma, metastatic. A binucle-
ated cell with nucleo- and nucleolomegaly has the typical morphologic features of an R-S cell. Yet, the surrounding cells are not lymphocytes, but
large epithelial cells in a single cell pattern. Papanicolaou stain, high power. C, Malignant melanoma, metastatic. An imitation R-S cell exists in
the setting of monotonous cells with plasmacytoid features typical of melanoma. Note the enlarged and misshapen nucleoli in the R-S look-alike.
Papanicolaou stain, high power. D, Small lymphocytic lymphoma. A binucleated immunoblast in the center of this image is surrounded by monoto-
nous rather than polymorphic lymphocytes. Note the absence of marked nucleolomegaly in this immunoblast. Romanowsky stain, high power.

NON-HODGKIN LYMPHOMA, SMALL CELL TYPE – Clinical Features

DISEASE FACT SHEET ៉ Localized or diffuse lymphadenopathy
៉ Peripheral blood and/or bone marrow involvement possible
Definition ៉ Extranodal presentation (parotid, periorbital, thyroid) typically
៉ A lymphoma composed of relatively monotonous ‘small MALT lymphoma
lymphocytes’; vast majority are B-cell ៉ Node(s) rubbery or firm

Incidence Prognosis and Treatment

៉ 16 per 100,000 in the US and Australia; much less in Asia, Africa, ៉ Aggressive to indolent, depending on subtype and International
and South America Prognostic Index
៉ Follicular lymphoma, marginal zone lymphoma, small lymphocytic ៉ Multiagent chemotherapy
lymphoma, and mantle cell lymphoma types are the most
common

Gender and Age Distribution

៉ Median age is 50–70 years
៉ Slight male predominance overall, but varies with subtype

Ch003-F06731.indd 82 10/26/2006 10:22:57 AM

 CHAPTER 3 Lymph Nodes
TABLE 3-2
WHO Classification of Lymphoid Tissue,
B-Cell Neoplasms*
• Precursor B-cell lymphoblastic leukemia/lymphoma
• Mature B-cell neoplasms
B-cell CLL/small lymphocytic lymphoma
B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma
Mantle cell lymphoma
Follicular lymphoma
Marginal zone B-cell lymphoma of mucosa-associated
lymphoid tissue (MALT) type
Nodal marginal zone lymphoma with or without
monocytoid B-cells
Splenic marginal zone B-cell lymphoma
Hairy cell leukemia
Diffuse large B-cell lymphoma
Subtypes: mediastinal (thymic), intravascular, primary
effusion
Burkitt lymphoma
Plasmacytoma
Plasma cell myeloma
*More common entities are in bold font.
lymphoid tissue, i.e. MALT lymphoma). The Inter-
national Prognostic Index, which factors in patient age,
performance status, serum LDH level, number of extra-
nodal sites, and clinical stage, is commonly used to
predict survival.
CYTOPATHOLOGIC FEATURES
Except for marginal zone lymphoma, a morphologic
feature common to this group is highly cellular smears
with an almost monotonous population of small lym-
phocytes, that is, cells with small rounded or irregular
nuclei, no visible nucleoli, fine or coarse nuclear chro-
matin, and meager, attenuated cytoplasm. A dispersed
single cell pattern is the rule (with the exception of
dendritic/lymphocytic aggregates), and lymphoglandu-
lar bodies are numerous. Differences are listed for each
subtype.
FOLLICULAR LYMPHOMA
Follicular lymphoma smears are composed of monot-
onous small lymphocytes, or a mixture of small lympho-
cytes and larger transformed centrocytes and centroblasts.
Indentations, grooves, and small projections are markers
of nuclear irregularity which is common to follicular
lymphoma; some grooves/clefts appear to bisect the
nucleus (Fig. 3-15). Dendritic/lymphocytic aggregates
are common also in follicular lymphoma smears, as
are follicular center cell fragments, but the latter are
Ch003-F06731.indd 83
83
NON-HODGKIN LYMPHOMA, SMALL CELL TYPE –
PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Relatively monotonous small lymphocyte population lacking
cellular heterogeneity
៉ Evenly dispersed nucleoplasm with small or indistinct nucleoli,
smooth or irregular nuclear contour, sparse cytoplasm in small
lymphocytes
៉ Minor population of slightly larger ‘transformed’ lymphocytes
depending on subtype
៉ Dendritic/lymphocytic aggregates most common in follicular
lymphoma; uncommon in other subtypes
៉ Tingible-body macrophages are uncommon
Ancillary Studies
៉ Light chain restriction; surface Ig+
៉ CD5+ = small lymphocytic lymphoma (CD23+) or mantle cell
lymphoma (CD23−)
៉ CD5− = follicular lymphoma (CD10 ±, bcl-6+) or marginal zone
lymphoma (CD10−)
Differential Diagnosis and Pitfalls
៉ Distinction among various subtypes of small cell non-Hodgkin
lymphoma requires ancillary studies
៉ Reactive lymphoid hyperplasia.
៉ Small cell neuroendocrine carcinoma
៉ Myeloid (granulocytic) sarcoma
typically lacking tingible-body macrophages. Dendritic
cells can be particularly prominent. Some examples of
follicular lymphoma show pronounced plasmacytoid
differentiation. Attempts to grade follicular lymphoma
by counting the percentage of large centrocytic/centro-
blastic cells have been made.
M ANTLE CELL LYMPHOMA
These are highly cellular smears with almost a pure
population of small to intermediate-sized rounded lym-
phocytes. Nuclear notches and grooves are uncommon,
or at least much less exaggerated than seen in follicular
lymphoma, but some cases have nuclear contour irregu-
larity (Fig. 3-16). Plasmacytoid monocytes, tingible-
body macrophages, dendritic/lymphocytic aggregates,
follicular center cell fragments, and larger lymphocytes
such as centroblasts are often not seen. A blastoid
variant mimics the cytologic morphology of lympho-
blastic lymphoma (see below).
SMALL LYMPHOCYTIC LYMPHOMA
Small lymphocytic lymphoma is the nodal counter-
part of chronic lymphocytic leukemia (CLL). The cyto-
pathology overlaps with follicular lymphoma and mantle
cell lymphoma, due to a predominance of small lympho-
cytes and the near exclusion of other types of lympho-
cytes. The nuclei of small lymphocytic lymphoma have
a clumped chromatin pattern, and are smooth or mini-
mally irregular (Fig. 3-17). A small population of large
10/26/2006 10:22:59 AM
 84 FINE NEEDLE ASPIRATION CYTOLOGY

A B

FIGURE 3-15
Follicular lymphoma. A, The focus of these matching small lymphocytes is the irregular shape of their nuclear membrane. In some there is only a
minimal indentation (almost reniform), while others show deep clefts in the nucleus. Nucleoplasm is evenly dispersed without visible nucleoli, and
only a meager amount of cytoplasm is seen. Romanowsky stain, high power. B, A two-cell population of very darkly stained small lymphocytes, and
larger lymphocytes with small to intermediate amounts of cytoplasm is present. However, a true range of lymphocytes is absent. This dual popula-
tion of small–intermediate-size lymphocytes is common in grades I and II follicular lymphoma. A dendritic/lymphocytic aggregate is noticeable at
the lower right corner. Romanowsky stain, high power.

FIGURE 3-16 FIGURE 3-17

Mantle cell lymphoma. These small, almost identical lymphocytes have
such a high N/C ratio that they appear to be bare nuclei, but an
extremely attenuated rim of cytoplasm is present. Lymphoglandular
bodies are not well seen with this stain. Note the tingible-body
macrophage in the upper left corner. Papanicolaou stain, high power.
Small lymphocytic lymphoma. Small morphologically equivalent lympho-
cytes show some nuclear molding, and focal perinuclear clearing sug-
gesting plasmacytoid differentiation. Note the abundant lymphoglandular
bodies. Romanowsky stain, high power.

M ARGINAL ZONE LYMPHOMA

transformed cells corresponding to pseudofollicular Aspirates, particularly those of extranodal tissue,

growth centers is present. These large lymphocytes
represent prolymphocytes and paraimmunoblasts. In
smears, it is difficult to distinguish them from each
other; however, it is not necessary to do so. Both are
two to three times the diameter of small lymphocytes,
and have a visible nucleolus and a moderate amount of
pale or basophilic cytoplasm.
show variable cytomorphology. In some cases, a more
or less monomorphous lymphocyte population is seen,
while in others the composition is one of lymphocytic
heterogeneity that imitates a reactive condition. Mixed
small and large lymphocytes having round, smooth or
irregular nuclei can be seen. Follicular dendritic cells,
plasmacytoid monocytes, follicular center cell fragments,

Ch003-F06731.indd 84 10/26/2006 10:22:59 AM

 CHAPTER 3 Lymph Nodes 85

Unfortunately, lymphomas do not exhibit strict immu-

nologic fidelity, nor are lymphocyte markers present
and absent in 100% of cases. Molecular methods have
been introduced recently to overcome this handicap.
Mantle cell lymphoma has a t(11;14)(q13;q32) trans-
location in almost 75% of patients that produces an
upregulation of the bcl-1(PRAD1) gene, which in turn
leads to overexpression of a protein termed cyclin D1.
Follicular lymphoma is characterized by a t(14;18)
translocation with rearrangement of the bcl-2 gene in
over 75% of cases. These cytogenetic abnormalities are
currently being exploited by interphase FISH using
commercially available probes to detect abnormal
nuclear fusion signals from FNA specimens, thus
improving diagnostic specificity.

FIGURE 3-18 DIFFERENTIAL DIAGNOSIS AND PITFALLS

Marginal zone lymphoma, nodal. These monocytoid lymphocytes contain
slightly more visible cytoplasm, but their cellular sameness mimics that
of other small cell forms of lymphoma. The extranodal form of marginal Without doubt, the most important differential deci-
zone lymphoma is typically more heterogeneous. Romanowsky stain, sion is to accurately separate any small cell lymphoma
high power. from reactive lymphoid hyperplasia. In most cases, this
is readily accomplished by light microscopy alone, due
to the lymphocyte monotony of the former and hetero-
geneity of the latter. However, since small cell lym-
TABLE 3-3 phoma populations are not pure, those having any
Immunophenotyping of Small Cell B-Cell Lymphomas variation in cell size and type can cause confusion with
reactive lymphoid hyperplasia. This problem is most
Marker SLL MtCL FL MZL acute with follicular lymphoma, where a mixture of
small and large lymphocytes in nearly equal numbers
CD5 Pos Pos Neg Neg is possible, and not uncommon. If one looks carefully
CD10 Neg Neg/pos Pos/neg Neg at each of these forms of small cell lymphoma (except
CD20 Pos/neg Pos Pos Pos for marginal zone lymphoma), it is rare indeed for them
CD23 Pos Neg Neg/pos Neg to show a true range of lymphocyte forms (immuno-
FMC-7 Neg Pos Pos Pos blasts, plasmacytoid monocytes, and tingible-body mac-
CD43 Pos Pos Neg Neg/pos rophages) as occurs in a reactive lymphoid hyperplasia
Tdt Neg Neg Neg Neg smear. That said, these different cell types can be
present in small cell lymphoma smears, but only as a
SLL, small lymphocytic lymphoma; MtCL, mantle cell minor population, and even more importantly it is rare
lymphoma; FL, follicular lymphoma; MZL, marginal zone for all the various cell elements to exist in similar per-
lymphoma; pos/neg, majority of cases are positive, small centages as they do in reactive lymphoid hyperplasia.
percentage negative; neg/pos, majority of cases are
negative, small percentage positive.
Thus, immunophenotyping is currently the best pro-
tection the cytopathologist has in not confusing a small
cell type of NHL for reactive lymphoid hyperplasia.
Small cell neuroendocrine carcinoma consists of cells
that are about three times the size of small lymphocytes,
immunoblasts, tingible-body macrophages, and plasma
and show no range in cell types. Instead, because of
cells are all possible. Monocytoid lymphocytes, those
their high cell turnover, a two-cell population of viable
having smooth rounded nuclei and a moderate amount
intact cells and apoptotic cells characterized by pyk-
of pale cytoplasm, are variable in number (Fig. 3-18).
notic, karyorrhectic nuclei exists (Fig. 3-19). This
invariably creates smears having abundant background
necrosis. Necrosis can be seen in small cell lymphomas,
ANCILLARY STUDIES but is distinctly unusual. Smearing or streaking of nuclei
is non-specific, since it is present in both lymphoma and
carcinoma. Although small cell neuroendocrine carci-
Because a large degree of morphologic overlap exists noma cells have a high nuclear to cytoplasmic (N/C)
among this group of NHL, it is imperative to phenotype ratio and may superficially resemble small lymphocytes,
these aspirates for specific subclassification. This is they display clustering, crowding, and ‘molding’ of their
best accomplished using FCM whereby the application nuclei into one another. This is not to say that
of various surface markers is employed (Table 3-3). nuclear molding is completely absent in all small cell

Ch003-F06731.indd 85 10/26/2006 10:23:01 AM

 86
A B
FIGURE 3-19
Small cell neuroendocrine carcinoma, metastatic. A, Although a few dissociated cells are found, most are arranged in these small compressed
aggregates leading to angulated distortion of nuclear shapes. Romanowsky stain, high power. B, Markedly hyperchromatic nuclei cling together
loosely. Note that some of these have an angulated or spindle shape. The abundant necrosis creates numerous lymphoglandular body look-alikes,
particularly with this stain. Papanicolaou stain, high power.
lymphomas, but when present is less florid than that
seen in carcinoma. A search for lymphoglandular bodies
in small cell neuroendocrine carcinoma will uncover
cell debris fragments, but not the globular, vacuolated
structures that are common to lymphoma.
Myeloid (granulocytic) sarcoma is a rare tumor of
myeloid precursors that can arise in extramedullary
sites prior to (rare) or concurrent with acute myeloid
leukemia. Skin and soft tissue are preferred sites. The
blastic immature types have features of small or
intermediate-size lymphoma with a single cell pattern,
high N/C ratio, and minimal cytoplasm. Lymphoglandu-
lar bodies can be present. The more differentiated forms
of myeloid sarcoma show a spectrum of myeloid differ-
entiation with granulated promyelocytes, metamyelo-
cytes, or band forms seen. Immunophenotyping shows
expression of myeloid markers CD13, CD33, CD43, and
myeloperoxidase.
NON-HODGKIN LYMPHOMA,
LARGE CELL TYPES
CLINICAL FEATURES
Large cell lymphomas encompass malignancies derived
from B, T, or NK cells. Of these, diffuse large B-cell
lymphoma is most common, constituting about 35–
40% of all adult lymphomas in Western Europe and
North America (about 25,000 new cases annually) and
about one-third of pediatric lymphomas. A higher inci-
dence of large cell lymphoma exists in developing coun-
Ch003-F06731.indd 86
FINE NEEDLE ASPIRATION CYTOLOGY
NON-HODGKIN LYMPHOMA, LARGE CELL TYPES –
DISEASE FACT SHEET
Definition
៉ A lymphoma composed of relatively monotonous ‘large
lymphocytes’; majority are B-cell, 10–12% are T-cell
Incidence
៉ 30–40% of all adult lymphomas
៉ T-cell lymphomas are more common in Asians
Gender and Age Distribution
៉ Broad age range, from children to elderly; peak age in 7th decade
in adults
៉ Slightly more common in men
Clinical Features
៉ Localized or diffuse adenopathy, extranodal disease
៉ Symptoms: fever, night sweats, weight loss, pruritus
៉ Node(s) often firm to palpation
Prognosis and Treatment
៉ Aggressive, potentially curable
៉ Multiagent chemotherapy
tries and in immunosuppressed patients. In the T-cell
group, anaplastic large cell lymphoma and peripheral
T-cell lymphoma are most common (Table 3-4). T-cell
lymphomas comprise about 10% of all NHL in North
America, and about twice that percentage in Asia. The
median age in adults of large cell lymphomas is 70
years, but there is a broad age range. Anaplastic large
10/26/2006 10:23:01 AM
 CHAPTER 3 Lymph Nodes
TABLE 3-4
WHO Classification of Lymphoid Tissue,
T-Cell Neoplasms*
• Precursor T-cell lymphoblastic leukemia/lymphoma
• Mature T-cell and NK-cell neoplasms
T-cell prolymphocytic leukemia
T-cell large granular lymphocytic leukemia
NK-cell leukemia
Extranodal NK-/T-cell lymphoma, nasal type
Mycosis fungoides
Sézary syndrome
Angioimmunoblastic T-cell lymphoma
Peripheral T-cell lymphoma
Adult T-cell leukemia/lymphoma (HTLV1)
Systemic anaplastic large cell lymphoma (T- and
null-cell types)
Primary cutaneous anaplastic large cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Enteropathy-type intestinal T-cell lymphoma
Hepatosplenic γ/δ T-cell lymphoma
*More common entities are in bold font.
cell lymphoma and diffuse large B-cell lymphoma, for
example, are the two most common forms of childhood/
young adult large cell lymphoma. Men are affected
slightly more than women in diffuse large B-cell lym-
phoma, but there is a marked male predominance (6 : 1)
for anaplastic large cell lymphoma. A rapidly enlarging
mass, either nodal or extranodal, is the usual present-
ing complaint. Extranodal sites include the gastrointes-
tinal tract (most common), skin, mediastinum, soft
tissue, bone, central nervous system, and salivary
gland. Disseminated disease at the time of diagnosis is
common. The International Prognostic Index is predic-
tive of survival. Only about 40% of patients with
diffuse large B-cell lymphoma are cured with polyche-
motherapy. Gene expression profi ling has recently been
introduced to develop molecularly distinct portraits of
diffuse large B-cell lymphoma (and, parenthetically,
follicular lymphoma also) to predict survival and thus
target patients for various types of chemotherapy
regimens.
In anaplastic large cell lymphoma, a relatively homo-
geneous group defined by a specific cytogenetic abnor-
mality has emerged. These patients develop systemic
disease in the first three decades of life, and their lym-
phomas are associated with a specific translocation,
t(2;5)(p23;q35), which fuses the ALK gene with the
NPM gene, thereby producing a protein (anaplastic
large cell lymphoma kinase) to which antibodies have
been developed. These patients have a much improved
prognosis (70% 5-year survival) than their anaplastic
large cell lymphoma kinase-negative counterparts (30%
5-year survival).
Ch003-F06731.indd 87
87
CYTOPATHOLOGIC FEATURES
Common to all forms of large cell lymphoma is an aspi-
rate smear containing a predominance of large lympho-
cytes. These range from two to five times the diameter
of small mature lymphocytes. In some examples, large
lymphocytes are the only cell type found, but in most
cases there is a minor population of small lymphocytes.
In diffuse large B-cell lymphoma, centroblastic-type
cells are most commonly seen, with a smaller number
of cases having immunoblastic features. Nuclei vary
from smooth rounded structures to those with irregu-
lar contours, finely dispersed or coarse chromatin, and
variable presence of nucleoli; single macronucleoli are
characteristic of the immunoblastic variant of diffuse
large B-cell lymphoma (Fig. 3-20). Binucleated, multi-
nucleated, multilobated, and reniform nuclei can be
seen, particularly with anaplastic large cell lymphoma
(Fig. 3-21). A greater amount of cytoplasm is present
when compared with the small cell lymphoma group.
It is often deeply basophilic in Romanowsky-stained
smears, and small cytoplasmic vacuoles are not uncom-
mon. Tingible-body macrophages and individual cell
necrosis are also more frequent in large cell lymphomas
than in the small cell category; there is a paucity of
follicular center cell fragments. As in all examples of
lymph node aspirates, nuclear streaking and smearing
are not uncommon; this is particularly evident in those
large cell lymphomas associated with sclerosis.
Although peripheral T-cell lymphoma aspirates are
discussed in this section of large cell lymphoma, their
NON-HODGKIN LYMPHOMA, LARGE CELL TYPES –
PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Relatively monotonous large lymphocytes
៉ Nuclear size equal to or exceeds that of macrophage; 2–5 times
larger than mature lymphocyte
៉ Nucleoli common, but not universal
៉ Nuclear pleomorphism with lobulated, indented nuclei and
multiple nuclei common in anaplastic large cell lymphoma
៉ Cytoplasm moderate to abundant; can be vacuolated
៉ Variable tingible-body macrophages and necrosis
Ancillary Studies
៉ Immunophenotyping best accomplished using flow cytometry
៉ B-cell: light chain restriction; positive for CD20 and CD19;
variable CD10, surface Ig, aberrant CD43 expression
៉ T-cell: aberrant phenotype with loss of CD7, CD5, or CD2;
positive for CD3, CD43, and CD30
៉ PCR: clonally rearranged T-cell receptor genes
Differential Diagnosis and Pitfalls
៉ Infectious mononucleosis
៉ Hodgkin lymphoma
៉ Non-lymphoid large cell malignancies
10/26/2006 10:23:02 AM
 88
FIGURE 3-20
Diffuse large B-cell lymphoma. Large lymphocytes contain one or more
nucleoli in hypochromatic vesicular nuclei. A second population of
darkly stained small lymphocytes is not uncommon in large cell lym-
phoma. Papanicolaou stain, high power.
FIGURE 3-21
Anaplastic large cell lymphoma. All lymphocytes in this field are large,
with some more anaplastic than others. Several nuclei have reniform
configurations which are typical, but not pathognomonic, of this lym-
phoma. Romanowsky stain, high power.
cytomorphology is much more heterogeneous than that
of diffuse large B-cell lymphoma or anaplastic large cell
lymphoma. These smears may be composed of an over-
whelmingly monomorphous population of large cells
similar to any large cell NHL. However, many examples
exhibit a mixture of small, intermediate-sized, and large
lymphocytes reminiscent of reactive lymphoid hyper-
plasia (Fig. 3-22). A variable number of plasma cells,
eosinophils, and histiocytes can be present. Follicular
center cell fragments and tingible-body macrophages are
uncommon to rare in peripheral T-cell lymphoma, and
Ch003-F06731.indd 88
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 3-22
Peripheral T-cell lymphoma, unspecified. A mixture of lymphoid cells
is present, including an immunoblast (right of center), several large
lymphocytes harboring visible nucleoli, plasmacytoid lymphocytes, and
even an eosinophil (far left). This cytomorphology is not specific, but
is typical of this lymphoma. Romanowsky stain, high power.
their absence could be a clue that one is not dealing with
a normal population of lymphocytes.
ANCILLARY STUDIES
Immunophenotyping using FCM is the most efficacious
method for determining light chain restriction, and
thus B-cell monoclonality. Nearly all are positive for
surface Ig and CD19, with variable expression of CD10,
CD22, CD23, and FMC-7.
For T-cell lymphomas, immunophenotyping will
show an absence of B-cell markers and a variable panel
of T-cell marker (CD1a, CD2, CD3, CD4, CD5, CD7,
CD8) positivity. Typically, a loss of one or more of these
markers, particularly CD7, or combined absence of
CD4/CD8 is seen. The term anaplastic large cell lym-
phoma is currently restricted to CD30-positive T- and
null-cell lymphomas. CD30 is typically added to an FCM
panel if a large lymphocyte population is observed. PCR
analysis of T-cell receptor (TCR) beta gene rearrange-
ment is the most specific test to determine clonality of
a T-cell lymphoma. This can be accomplished using
PCR fragment size analysis of the FNA material, for
which instruments are commercially available.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The high percentage of immunoblasts makes infectious
mononucleosis a mimicker of large cell lymphoma.
Close examination of the infectious mononucleosis
smear will show a subpopulation of plasmacytoid
10/26/2006 10:23:02 AM
 CHAPTER 3 Lymph Nodes
FIGURE 3-23
Nasopharyngeal carcinoma, metastatic. A discrete tight cluster of epi-
thelial cells to the right of center is surrounded and infiltrated by small
lymphocytes. Note that epithelial cell nuclei lack discrete nucleoli, but
are about three times larger than the lymphocyte population. Papani-
colaou stain, high power.
lymphocytes, and some plasma cells. Immunopheno-
typing will demonstrate the polyclonality typical of
infectious mononucleosis. HL has occasionally been
mistaken as a large cell lymphoma also. Cells having
the morphologic features of R-S cells have been seen in
all forms of large cell lymphoma. The key to avoiding
this trap of mistaking such cells as true R-S cells lies
in examination of all components that exist in the
smear. With HL, the smear background simulates that
of reactive lymphoid hyperplasia, whereas in large cell
lymphomas it lacks this lymphocytic heterogeneity.
The two principal non-small cell carcinomas meta-
static to lymph nodes, metastatic squamous cell carci-
noma and adenocarcinoma, are rarely mistaken as
large cell lymphoma, since they typically lack lympho-
glandular bodies and nearly always display some cell
aggregation. Metastatic nasopharyngeal carcinoma,
undifferentiated type, however, can be misdiagnosed as
lymphoma for several reasons. First, patients frequently
present with an enlarged cervical node like lymphoma,
bypassing the usual clinical scenario where an individ-
ual is known to have cancer and only then develops
lymphadenopathy. Also, lymphocytes are a normal
constituent of this tumor; therefore, lymphoglandular
bodies are present. A range of lymphocytes often com-
mingles with and can sometimes obscure the clusters of
malignant epithelial cells (which may be few), and epi-
thelial cells can be dispersed in loose aggregates. Epithe-
lial cells have large nuclei, may or may not have visible
nucleoli, and have a small amount of cytoplasm that
lacks keratinization due to their undifferentiated state
(Fig. 3-23). Cytokeratin staining of the smear may be
necessary to fully characterize these cells.
Metastatic seminoma should also be considered if the
clinical setting is suggestive, such as mediastinal/hilar
adenopathy or retroperitoneal lymphadenopathy in a
Ch003-F06731.indd 89
89
FIGURE 3-24
Seminoma, metastatic. A mixture of large germ cells and smaller lym-
phocytes are set in a distinctive background of reticulated cytoplasm
(so-called ‘tigroid background’). Some of the germ cells contain one
or more visible nucleoli and a moderate amount of cytoplasm. Bare
germ cell nuclei are also present (lower right). Romanowsky stain, high
power.
young adult male. A second population of lymphocytes
accompanies the large germ cells. Thus, smears will
contain lymphoglandular bodies. Germ cells having
large rounded nuclei with enlarged nucleoli are distrib-
uted singly or in clusters, bare nuclei are common, and
cell cytoplasm is smeared in a reticular pattern, or as
short strips, giving the appellation ‘tigroid’ to this pattern
(Fig. 3-24). It is important to remember that this pattern
is not universally present, nor is it seen well in
Papanicolaou- or hematoxylin and eosin (H&E)-stained
smears.
Malignant melanoma is probably the most frequent
mimic of lymphoma since it commonly involves lymph
nodes, displays a monomorphic population of cells, has
a single cell pattern, is habitually amelanotic, and may
present in a patient without a known primary malig-
nancy. Smears lack lymphoglandular bodies. Character-
istically, cells are often binucleated with mirror-image
nuclei, have intranuclear cytoplasmic inclusions, and
cell nuclei eccentrically displaced toward the cyto-
plasmic edge, giving them a plasma cell-like appearance
(Fig. 3-25).
PEDIATRIC NON-HODGKIN LYMPHOMAS
CLINICAL FEATURES
The principal lymphomas of childhood include precur-
sor T- and B-cell lymphoblastic, Burkitt, and large cell
lymphoma, comprising 30–40%, 40–50%, and 15–25%
of cases, respectively. Burkitt lymphoma is rare in the
10/26/2006 10:23:04 AM
 90
FIGURE 3-25
Malignant melanoma, metastatic. A polymorphous population of epi-
thelioid cells is seen. Note that two of these cells have mirror-image
nuclei, and three have distinct intranuclear cytoplasmic inclusions.
Eccentric nuclear placement in some gives them a plasmacytoid look.
Compare the size of these to the small lymphocytes and neutrophils in
the background. Papanicolaou stain, high power.
PEDIATRIC NON-HODGKIN LYMPHOMAS – DISEASE FACT SHEET
Definition
៉ Lymphoblastic: lymphoma of precursor lymphocytes, 85–90% T-cell
៉ Burkitt: lymphoma of medium-size B cells with translocation
involving c-myc gene
Incidence
៉ Lymphoblastic lymphoma and Burkitt lymphoma each account for
30–40% of pediatric lymphomas
៉ Burkitt: endemic in equatorial Africa, sporadic in North America/
Europe
Gender and Age Distribution
៉ Male to female ratio about 2 : 1
៉ Peak in 2nd and 3rd decades of life for both
Clinical Features
៉ Lymphoblastic: cervical, supraclavicular, or axillary
lymphadenopathy, 50–80% with anterior mediastinal mass, pleural
effusion, dyspnea, wheezing
៉ Burkitt: abdominal visceral disease most common in North
America/Europe, head and neck masses less common; associated
with EBV infection, AIDS
Prognosis and Treatment
៉ 90% survival for stage I and II disease, about 70–80% for stages
III and IV
៉ Multiagent chemotherapy for both types
Ch003-F06731.indd 90
FINE NEEDLE ASPIRATION CYTOLOGY
United States, with only 100–150 new cases annually,
compared with in equatorial Africa, where 0.01% of
children develop it. Other lymphoma subtypes are
exceedingly rare in this age group. Large cell lympho-
mas can be B-cell, T-cell, or null-cell types; this group
is discussed in the section above.
In lymphoblastic lymphoma, the male to female
ratio is about 2 : 1, with the majority occurring in the
older child–adolescent years. Lymphoblastic lymphoma
almost always presents as supra-diaphragmatic lymph-
adenopathy. An anterior mediastinal mass is found in
up to 80% of patients. This mass may induce symptoms
of bronchial asthma, persistent cough, cyanosis, syncope,
or superior vena cava syndrome, and tracheal compres-
sion. Burkitt lymphoma is also a neoplasm of adoles-
cence and young adulthood, with a male predominance
(2–3 : 1). In developed countries, Burkitt lymphoma
presents primarily as an intra-abdominal mass. Some
individuals present with signs and symptoms of acute
appendicitis. In children, precursor T-cell lymphoblastic
lymphoma has a good prognosis, with 70–90% 5-year
disease-free survival. The prognosis is worse in adults,
with a 5-year disease-free survival of 45–55%. Burkitt
lymphoma patients with localized disease or with com-
pletely resected abdominal disease can have a long-term
survival rate of 90% or more.
CYTOPATHOLOGIC FEATURES
Smears of lymphoblastic lymphoma are hypercellular
with uniform lymphoid blasts about twice the size of
small lymphocytes, having round to convoluted nuclei,
finely granular so-called ‘dusty’ chromatin, inconspicu-
ous or small nucleoli, and extremely meager, rarely
vacuolated cytoplasm. Tingible-body macrophages may
be present (Fig. 3-26). Aspirates of Burkitt lymphoma
PEDIATRIC NON-HODGKIN LYMPHOMAS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Lymphoblastic: monomorphic intermediate-size cells, round or
convoluted nuclei, finely granular chromatin, indistinct nucleoli,
infrequently vacuolated sparse cytoplasm
៉ Burkitt: monomorphic intermediate-size cells, coarse chromatin,
2–5 nucleoli, commonly vacuolated sparse cytoplasm
៉ Numerous tingible-body macrophages
Ancillary Studies
៉ Lymphoblastic: Tdt-positive in both B- and T-cell types; 85–90%
express T-cell antigens
៉ Burkitt: B-cell, Tdt-negative, monoclonal light chain; positive
for surface Ig, CD10, CD19, and CD20; FISH: c-myc translocation
Differential Diagnosis and Pitfalls
៉ Blastoid variant of mantle cell lymphoma
៉ Myeloid (granulocytic) sarcoma
៉ Malignant small round cell tumors of childhood
10/26/2006 10:23:05 AM
 CHAPTER 3 Lymph Nodes
FIGURE 3-26
Precursor T-cell lymphoblastic lymphoma. An identical population of
lymphocytic blasts display delicate, evenly dispersed chromatin without
discrete nucleoli, and minimal cytoplasm. Some nuclei show slight
unevenness. Smaller, more darkly stained nuclei represent apoptotic
cells. Romanowsky stain, high power.
FIGURE 3-27
Burkitt lymphoma. The prominent feature in these blasts is the coarse
chromatin with one to several small nucleoli. Cytoplasmic vacuoles are
barely visible in this image (center cell). Mitotic figures are an expected
finding in Burkitt lymphoma smears. Romanowsky stain, high power.
show nuclei with coarse chromatin, small nucleoli, and
variable cytoplasmic vacuoles. Tingible-body macro-
phages are more frequent in Burkitt lymphoma smears,
but this too is variable (Fig. 3-27).
ANCILLARY STUDIES
Most lymphoblastic lymphomas are T-cell (85–90%),
all Burkitt lymphomas are B-cell, and large cell lympho-
Ch003-F06731.indd 91
91
mas may be either. Lymphoblastic lymphoma is defined
by the near universal presence of Tdt (terminal deoxy-
nucleotidyl transferase), which exists in both T- and
B-cell types, and can be analyzed using FCM. A con-
sistent non-random translocation, t(8;14), that involves
the c-myc gene occurs with Burkitt lymphoma.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
In pediatric patients, the principal diagnostic problem
for either lymphoblastic lymphoma or Burkitt lym-
phoma is to exclude other entities that exist in the
category of ‘malignant small round cell tumor’. These
include rhabdomyosarcoma, Ewing sarcoma, desmo-
plastic small round cell tumor, and, less often, neuro-
blastoma or Wilms tumor. This is often accomplished
merely by clinical and radiologic evaluation. The single
cell pattern combined with background lymphoglandu-
lar bodies will usually suffice to allow categorization
of the aspirate as a lymphoma since these two features
are absent in the other lesions in this category. A poten-
tial pitfall exists if an anterior mediastinal mass is
aspirated. Since benign thymocytes are Tdt-positive,
one must ensure that cells have a blast morphology.
The blastoid variant of mantle cell lymphoma can
mimic lymphoblastic lymphoma. Clinically, these
patients are not in the same age group as those with
lymphoblastic lymphoma. The morphology, however,
can be very similar with intermediate to large cells;
immunotyping is required. All mantle cell lymphomas
are B-cell and lack Tdt.
Myeloid sarcoma may occur in children prior to a
leukemic phase. The undifferentiated forms can mimic
a blastic morphology. FCM shows lack of lymphocytic
markers and expression of myeloid markers, as dis-
cussed above.
SUGGESTED READINGS
Reactive Lymphoid Hyperplasia
Flanders E, Kornstein MJ, Wakely PE Jr, Kardos TF, Frable WJ. Lympho-
glandular bodies in fine needle aspiration cytology. Am J Clin Pathol
1993;99:566–569.
Geisinger KR, Stanley MW, Raab SS, Silverman JS, Abati A. Lymph nodes
and spleen. In: Modern Cytopathology. Philadelphia: Churchill-
Livingstone, 2004:643–687.
Glant MD. Cytopathology of lymph nodes in nonspecific reactive hyper-
plasia: prognostication and differential diagnosis. Am J Clin Pathol
1997;108:S31–S55.
Wakely PE Jr. Aspiration and touch preparation of lymph nodes. In:
Atkinson BF, ed. Atlas of Diagnostic Cytopathology, 2nd ed. Philadelphia:
Saunders, 2004:411–458.
Wakely PE Jr, Cibas ES. Lymph nodes. In: Cibas ES, Ducatman BS, eds.
Cytology: Diagnostic Principles and Clinical Correlates, 2nd ed. Edinburgh:
Elsevier, 2003:307–344.
Granulomatous Lymphadenopathy
Das DK, Bhambhani S, Pant JN, et al. Superficial and deep-seated tuber-
culous lesions: fine-needle aspiration cytology diagnosis of 574 cases.
Diagn Cytopathol 1992;8:211–215.
10/26/2006 10:23:06 AM
 92
DeMay RM. Lymph node. In: The Art and Science of Cytopathology.
Chicago: ASCP Press, 1996:779–846.
Ellison E, Lapuerta P, Martin SE. Fine needle aspiration diagnosis of
mycobacterial lymphadenitis. Sensitivity and predictive value in the
United States. Acta Cytol 1999;43:153–157.
Stanley MW, Horwitz CA, Burton LG, Weisser JA. Negative images of bacilli
and mycobacterial infection: a study of fine-needle aspiration smears
from lymph nodes in patients with AIDS. Diagn Cytopathol 1990;6:
118–121.
Stastny JF, Wakely PE Jr, Frable WJ. Cytologic features of necrotizing
granulomatous inflammation consistent with cat scratch disease. Diagn
Cytopathol 1996;15:108–115.
Infectious Mononucleosis
Kardos TF, Kornstein MJ, Frable WJ. Cytology and immunocytology of
infectious mononucleosis in fine needle aspirates of lymph nodes. Acta
Cytol 1988;32:722–726.
Stanley MW, Steeper TA, Horwitz CA, Burton LG, Strickler JG, Borken S.
Fine needle aspiration of lymph nodes in patients with acute infectious
mononucleosis. Diagn Cytopathol 1990;6:323–329.
Wakely PE Jr. Aspiration and touch preparation of lymph nodes. In:
Atkinson BF, ed. Atlas of Diagnostic Cytopathology, 2nd ed. Philadel-
phia: Saunders, 2004:411–458.
Hodgkin Lymphoma
Chhieng DC, Cangiarella JF, Symmans WF, Cohen J-M. Fine-needle aspira-
tion cytology of Hodgkin disease. A study of 89 cases with emphasis
on the false-negative cases. Cancer (Cancer Cytopathol) 2001;93:52–
59.
Fulciniti F, Vetrani A, Zeppa P, et al. Hodgkin’s disease: diagnostic accu-
racy of fine needle aspiration; a report based on 62 consecutive cases.
Cytopathology 1994;5:226–233.
Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. World Health Organization
Classification of Tumours. Pathology and Genetics of Tumours of Hae-
matopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001.
Kardos TF, Vinson JH, Behm FG, Frable WJ, O’Dowd GJ. Hodgkin’s disease:
diagnosis by fine needle aspiration biopsy. Analysis of cytologic criteria
from a selected series. Am J Clin Pathol 1986;86:286–291.
Tani E, Ersoz C, Svedmyr E, et al. Fine needle aspiration cytology and
immunocytochemistry of Hodgkin’s disease – suppurative type. Diagn
Cytopathol 1998;18:437–440.
Non-Hodgkin Lymphoma, Small Cell Types
Caraway NP, Gu J, Lin P, et al. The utility of interphase fluorescence in
situ hybridization for the detection of the translocation t(11;14)(q13;32)
in the diagnosis of mantle cell lymphoma on fine-needle aspiration
specimens. Cancer (Cancer Cytopathol) 2005;105:110–118.
Chhieng DC, Cohen J-M, Cangiarella JF. Cytology and immunophenotyping
of low- and intermediate-grade B-cell non-Hodgkin’s lymphomas with
a predominant small-cell component: a study of 56 cases. Diagn Cyto-
pathol 2001;24:90–97.
Crapanzano JP, Lin O. Cytologic findings of marginal zone lymphoma. A
study of 14 specimens. Cancer (Cancer Cytopathol) 2003;99:301–309.
Ch003-F06731.indd 92
FINE NEEDLE ASPIRATION CYTOLOGY
Meda BA, Buss DH, Woodruff RD, et al. Diagnosis and subclassification of
primary and recurrent lymphomas. The usefulness and limitations of
combined fine needle aspiration cytomorphology and flow cytometry.
Am J Clin Pathol 2000;113:688–699.
Rassidakis GZ, Tani E, Svedmyr E, Porwit A, Skoog L. Diagnosis and sub-
classification of follicle center and mantle cell lymphomas on fine-
needle aspirates. A cytology and immunocytochemical approach based
on the revised European-American lymphoma (REAL) classification.
Cancer (Cancer Cytopathol) 1999;87:216–223.
Suh YK, Shin HJ. Fine-needle aspiration biopsy of granulocytic sarcoma:
a clinicopathologic study of 27 cases. Cancer (Cancer Cytopathol) 2000;
90:364–372.
Young NA, Al-Saleem T. Diagnosis of lymphoma by fine-needle aspiration
cytology using the revised European-American classification of lym-
phoid neoplasms. Cancer (Cancer Cytopathol) 1999;87:325–345.
Zeppa P, Marino G, Troncone G, et al. Fine-needle cytology and flow
cytometry immunophenotyping and subclassification of non-Hodgkin
lymphoma: a critical review of 307 cases with technical suggestions.
Cancer (Cancer Cytopathol) 2004;102:55–65.
Non-Hodgkin Lymphoma, Large Cell Types
Al Shanqeety O, Mourad WA. Diagnosis of peripheral T-cell lymphoma by
fine-needle aspiration biopsy: a cytomorphologic and immunopheno-
typic approach. Diagn Cytopathol 2000;23:375–379.
Dong HY, Harris NL, Preffer FI, Pitman MB. Fine-needle aspiration biopsy
in the diagnosis and classification of primary and recurrent lymphoma:
a retrospective analysis of the utility of cytomorphology and flow
cytometry. Mod Pathol 2001;14:472–481.
Ng W-K, Ip P, Choy C, Collins RJ. Cytologic and immunocytochemical
findings of anaplastic large cell lymphoma. Analysis of ten fine-needle
aspiration specimens over a 9-year period. Cancer (Cancer Cytopathol)
2003;99:33–43.
van Heerde P. Lymph nodes. In: Orell SR, Sterrett GF, Walters MN-I,
Whitaker D, eds. Manual and Atlas of Fine Needle Aspiration Biopsy.
London: Churchill-Livingstone, 1999:74–108.
Yao JL, Cangiarella JF, Cohen J-M, Chhieng DC. Fine-needle aspiration
biopsy of peripheral T-cell lymphomas. A cytologic and immunopheno-
typic study of 33 cases. Cancer (Cancer Cytopathol) 2001;93:151–
159.
Pediatric Non-Hodgkin Lymphomas
Geisinger KR, Silverman JF, Wakely PE Jr. Pediatric Cytopathology. Chicago:
ASCP Press, 1994:201–228.
Jacobs JC, Katz RL, Shabb N, et al. Fine needle aspiration of lymphoblastic
lymphoma. A multiparameter diagnostic approach. Acta Cytol 1992;36:
887–894.
Stastny JF, Almeida MM, Wakely PE Jr, Kornstein MJ, Frable WJ. Fine
needle aspiration biopsy and imprint cytology of small non-cleaved cell
(Burkitt’s) lymphoma. Diagn Cytopathol 1995;12:201–207.
Tani E, Maeda S, Frostad B, et al. Aspiration cytology with phenotyping
and clinical presentation of childhood lymphomas. Diagn Oncol
1993;3:294–301.
Wakely PE Jr, Kornstein MJ. Aspiration cytopathology of lymphoblastic
lymphoma and leukemia: the MCV experience. Pediatr Pathol Lab Med
1996;16:243–252.
10/26/2006 10:23:07 AM
 4 Soft Tissue
Marlo M Nicolas Ritu Nayar
Fadi W Abdul-Karim
INTRODUCTION
Fine needle aspiration biopsy (FNAB) is a safe and
reliable method for the assessment of soft tissue tumors
and tumor-like lesions. Many of these entities have
distinctive clinical attributes such as specific age ranges
and predilection for certain body sites, so that a limited
list of differential diagnoses or a definitive diagnosis
can be rendered after cytologic evaluation and clinical
correlation. The line of communication between the
cytopathologist, radiologist, and clinician should always
be open to assure an optimal interpretation of the avail-
able material.
Familiarity with the various spectra of the histo-
pathologic features of soft tissue lesions is important for
interpretation of the FNAB specimens. The cytomor-
phology of these lesions often reflects the histologic
features by which most of these entities are defined. An
accompanying cell block (CB) may prove useful in some
instances due to the approximation to the native histo-
logic architecture of the lesion. A needle core biopsy
(NCB) can establish the histologic specific subtype of
a lesion, especially when a diagnosis of sarcoma, not
otherwise specified is rendered from FNAB materials.
Nevertheless, surgeons are often satisfied with the
diagnosis of a low- or high-grade sarcoma, and further
subclassification may not be necessary in the immediate
management. NCBs are most effective in establishing
the diagnosis of soft tissue lesions when employed in
instances where the FNAB is unsatisfactory. In the
setting of a non-diagnostic NCB or FNAB, an open or
excisional biopsy should be obtained for further
evaluation.
Performance of the FNAB by an experienced pathol-
ogist with immediate assessment of adequacy will reduce
the number of unsatisfactory specimens and results in
better material for interpretation. The pathologist can
also, following rapid assessment, triage the specimens
for ancillary studies such as DNA ploidy, cytogenetics,
and electron microscopy (EM). In selected cases, the
judicious application of immunohistochemical stains
done on the CB or NCB will aid in narrowing down the
differential diagnosis.
FNAB is most useful for documenting recurrence
or metastases in a patient previously diagnosed with
sarcoma. Recurrent and metastatic sarcomas, however,
may show significant variations in cell morphology
• •
when compared to the primary tumor. Radiation and
chemotherapy can induce changes that mimic recurrent
disease. In addition, many non-neoplastic, rapidly pro-
liferating or exuberant reactive lesions can have cyto-
logic atypia that approximates that seen in higher-grade
sarcomas. Awareness of these changes helps avoid
overdiagnosis.
This chapter focuses on the cytologic features of soft
tissue tumors and tumor-like lesions that are most com-
monly encountered in the practice of cytopathology.
ADIPOSE TISSUE TUMORS
LIPOMA
CLINICAL FEATURES
Lipomas are composed of mature adipose tissue and
are the most common benign soft tissue tumors. They
usually occur in older adults and have a male predilec-
tion. Lipomas present as a painless mass in the head
and neck region, shoulder, back, and extremities. Com-
plete excision is usually curative.
The admixture of other mesenchymal elements
results in several variants: spindle cells (spindle cell
lipoma), capillaries (angiomyolipoma), smooth muscle
(myolipoma), and giant ‘floret’ cells (pleomorphic
lipoma). In addition to subcutaneous tissue, lipomas
may arise in skeletal muscle (muscular lipoma) and
synovial connective tissue (lipoma arborescens).
LIPOMAS – DISEASE FACT SHEET
Incidence and Location
៉ Most common soft tissue tumor
៉ Trunk, proximal extremities, and head and neck
Gender, Race and Age Distribution
៉ Male predominance
៉ No racial predilection
៉ Adult (more than 40–60 years)
93
94 FINE NEEDLE ASPIRATION CYTOLOGY

PATHOLOGIC FEATURES

Histologically, lipomas are typically composed of

mature adipose tissue indistinguishable from non-
neoplastic fatty tissue.
FNAB of lipomas consists of mature adipocytes,
usually as tissue fragments and rarely as singly dis-
persed cells (Fig. 4-1). The adipocytes are round or
ovoid and have a dominant cytoplasmic vacuole that
does not indent the eccentrically located nucleus. Capil-
laries may be seen separating clusters of adipocytes. In
addition to the mature adipose tissue, spindle cells and
large multinucleated tumor cells are seen in aspirates
of spindle cell and pleomorphic lipomas, respectively.
FNAB of intramuscular lipomas and angiolipomas can
FIGURE 4-1
yield other mesenchymal elements, such as skeletal
Lipoma: FNAB. The aspirated adipocytes are cohesively clustered. The
muscle and excessive amounts of capillaries, cells have abundant cytoplasm and peripherally located small nuclei.
respectively. Papanicolaou stain, high power.

ANCILLARY STUDIES DIFFERENTIAL DIAGNOSIS AND PITFALLS

The tumor cells of lipomas are positive for vimentin
and S-100 protein. Up to 75% of lipomas can have
an abnormal karyotype, the most common of which
involves the long arm of chromosome 12.
LIPOMAS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Aspirated material consists of fatty droplets when extruded on to
the slide; fairly cellular to hypocellular smears; mature adipose
cells have a dominant cytoplasmic vacuole, nuclei are small and
eccentrically placed
៉ Spindle cell lipomas: spindle cells admixed with mature adipose
cells
៉ Pleomorphic lipomas: multinucleated cells and mature adipose
cells
៉ Other variants may consist of other types of mesenchymal tissue
admixed with mature adipose cells: skeletal muscle (intramuscular
lipoma), chondroid matrix (chondrolipoma), bone marrow elements
(myelolipoma), and smooth muscle (myolipoma)
Immunohistochemistry
៉ Adipocytes are positive for vimentin and S-100 protein; spindle
cells of spindle cell lipomas are positive for CD34
៉ Tumor cells are negative for epithelial, smooth muscle, skeletal
muscle, and neuroendocrine markers
Genetics
៉ Approximately 55–75% have an abnormal karyotype; 66% involve
12q13–15
Differential Diagnosis and Pitfalls
៉ Atypical lipomatous tumor/well-differentiated liposarcoma
៉ Normal subcutaneous adipose tissue (adjacent normal adipose
tissue is sampled and needle missed the lesion)
The cytologic features of lipomas may be indistinguish-
able from those of atypical lipomatous tumor (ALT)/
well-differentiated liposarcoma (WDLS), which may
consist predominantly of mature adipose tissue. Lipo-
blasts and atypical adipocytes are expectedly rare in
these aspirates and are often difficult to recognize.
Cytogenetic studies may assist in recognizing these
tumors.
The cells of lipomas are identical to those of non-
neoplastic subcutaneous fat. The possibility of sampling
the subcutaneous fat should be entertained when the
aspirates yield mature adipocytes, especially if detailed
clinical information is not provided or the FNAB is
performed by health professionals other than the cyto-
pathologist interpreting the case.
LIPOSARCOMA
CLINICAL FEATURES
Liposarcomas are malignant mesenchymal tumors with
fatty differentiation.
Four histologic types are recognized: atypical lipoma-
tous tumor (ALT)/well-differentiated liposarcoma
(WDLS), dedifferentiated liposarcoma (DDLS), myxoid
liposarcoma (MLS)/round cell liposarcoma (RCLS), and
pleomorphic liposarcoma (PLS).
Liposarcomas are tumors of adults and infrequently
occur in children. More than 90% of the liposarcomas
are ALTs/WDLSs and MLSs/RCLSs. PLSs and DDLSs
account for less than 10% of liposarcomas. PLSs are
quite rare.
ALTs and WDLSs are composed of mature adipose
tissue with scattered atypical cells. Superficial tumors of
CHAPTER 4 Soft Tissue
LIPOSARCOMA – DISEASE FACT SHEET
Incidence
៉ Atypical lipomatous tumor(ALT)/well-differentiated liposarcoma
(WDLS): 50% of liposarcomas
៉ Myxoid liposarcoma (MLS)/round cell liposarcoma (RCLS): 30–40%
of liposarcomas
៉ Dedifferentiated liposarcoma (DDLS): 5% of liposarcomas
៉ Pleomorphic liposarcoma (PLS): <5% of liposarcomas
Location
៉ ALT: superficial trunk and extremities
៉ WDLS: deep soft tissue of thigh, retroperitoneum, paratesticular
area, and mediastinum
៉ MLS/RCLS: lower extremities (70% in thigh)
៉ DDLS: Retroperitoneum, mediastinum, and paratesticular region
៉ PLS: lower extremities, less often retroperitoneum and
mediastinum
Gender, Race, and Age Distribution
៉ No sex or race predilection
៉ ALT/WDLS: middle-aged adults (peak – 6th decade)
៉ MLS/RCLS: young and middle-aged adults (peak – 4th decade)
៉ DDLS: middle-aged adults
៉ PLS: elderly patients (>50 years)
the trunk or extremities are designated as ALTs, while
WDLSs apply to similar tumors in deep-seated locations
such as the retroperitoneum, paratesticular region, and
mediastinum. A liposarcoma is categorized as a dedif-
ferentiated type when an area of non-lipogenic sarcoma
is present in a newly diagnosed ALT/WDLS (de novo),
in a local recurrence of an ALT/WDLS, or in a distant
metastasis following or with a concurrent diagnosis
of ALT/WDL. DDLSs have a significant potential for
metastasis.
MLSs and RCLSs have identical cytogenetic abnor-
malities. Histopathologically, RCLSs are considered a
less differentiated type of MLSs. The presence of an
RCLS component imparts a more aggressive behavior.
PLSs are highly malignant tumors characterized by an
early onset of metastasis and a high mortality rate.
PATHOLOGIC FEATURES
Histologically, ALTs/WDLSs are composed mainly of
mature adipose tissue with fibrous septae containing
atypical cells. Lipoblasts may be present. The foci of
DDLSs are usually high grade and are indistinguish-
able from other sarcomas. MLSs/RCLSs have charac-
teristic branching capillaries and uniform tumor cells.
RCLSs are considerably more cellular than MLSs. PLSs
are characterized by extremely atypical cells and lipo-
blasts of the pleomorphic (mulberry) type.
Smears of ALTs/WDLSs consist predominantly
of mature adipose tissue indistinguishable from non-
neoplastic fatty tissue and lipoma. The atypical cells may
be sparse and difficult to recognize. Multivacuolated
95
LIPOSARCOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Atypical lipomatous tumor(ALT)/well-differentiated liposarcoma
(WDLS): variably cellular smears of mature adipose tissue
indistinguishable from non-neoplastic fat; scattered atypical
cells; lipoblasts are scarce
៉ Myxoid liposarcoma (MLS)/round cell liposarcoma (RCLS): uniform
round or oval cells; myxoid matrix appears as purple or magenta
in Romanowsky-stained smears; branching capillary network;
signet-ring lipoblasts
៉ Dedifferentiated liposarcoma (DDLS): clusters of spindle or
pleomorphic cells without intervening mature adipose tissue;
no lipoblasts; may have cells similar to ALT/WDLS
៉ Pleomorphic liposarcoma (PLS): highly cellular aspirate with
pleomorphic or bizarre-appearing tumor cells; pleomorphic
(mulberry) lipoblasts
Immunohistochemistry
៉ ALT/WDLS: atypical cells are positive for S-100 protein
៉ MLS/RCLS: tumor cells are positive for vimentin and S-100
protein
៉ DDLS: dedifferentiated areas usually express antibodies
expected of the morphology; residual ALT/WDLS is positive for
S-100 protein
៉ PLS: tumor cells are positive for vimentin and S-100 protein;
epithelioid variant may be positive for cytokeratin
Genetics
៉ ALT/WDLS: supernumerary ring and giant marker chromosomes;
amplified sequences of 12q14–15 and, less frequently, 12q21–22
and 1q21–25
៉ MLS/RCLS: t(12;16)(q13;p11) in 90% of cases; t(12;22)(q13;q12)
in 10% of cases
៉ DDLS: supernumerary ring and giant marker chromosomes;
amplified sequences of 12q14–15 and, less frequently, 12q21–22
and 1q21–25
៉ PLS: complex cytogenetic aberrations
Differential Diagnosis and Pitfalls
៉ ALT/WDLS: lipoma, fat necrosis, and non-neoplastic fat
៉ MLS/RCLS: extraskeletal myxoid chondrosarcoma and low-grade
fibromyxoid sarcoma; small round cell tumors in pure or
predominantly RCLS
៉ DDLS: may be indistinguishable from other sarcomas including
malignant fibrous histiocytoma, malignant peripheral nerve
sheath tumor, and leiomyosarcoma if ALT/WDLS areas are not
sampled
៉ PLS: malignant fibrous histiocytoma, other pleomorphic
sarcomas and carcinomas
lipoblasts are rarely present. The diagnosis of ALT/
WDLS usually necessitates a biopsy. DDLSs are recog-
nized by the presence of a high-grade non-lipomatous
component in a background of ALT/WDL (Fig. 4-2).
MLSs/RCLSs consist mainly of uniform round or ovoid
tumor cells with a high nuclear to cytoplasmic (N/C)
ratio and occasionally signet-ring lipoblasts in a back-
ground of abundant myxoid matrix (Figs 4-3 & 4-4).
Branching capillaries are conspicuously present. Bizarre
tumor cells and a variable number of pleomorphic
lipoblasts typify PLSs (Fig. 4-5).
96
FIGURE 4-2
Dedifferentiated liposarcoma: touch preparation. The dedifferentiated
foci are cellular and usually densely aggregated. These tumor cells are
indistinguishable from other high-grade sarcomas. Demonstration of
such cells in a patient with a previous or concurrent diagnosis of atypi-
cal lipomatous tumor/well-differentiated liposarcoma suggests trans-
formation of the tumor to dedifferentiated liposarcoma. Diff-Quik stain,
high-power.
FIGURE 4-3
Myxoid liposarcoma: FNAB. The aspirate is moderately cellular. The
tumor cells are round or oval and of uniform size. The stromal back-
ground is myxoid. Prominent branching capillaries are present in the
middle of the tumor clusters. Diff-Quik stain, medium power.
ANCILLARY STUDIES
The mature adipocytes and lipoblasts are positive for
vimentin and S-100 protein. With the exception of
some epithelioid variants of PLSs, all types of liposar-
comas are negative for cytokeratins (CK). Dedifferen-
tiated foci other than malignant fibrous histiocytoma
are reactive to antibodies expected for the morphology,
e.g. rhabdomyosarcomatous areas are MyoD1- and
myogenin-positive.
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 4-4
Myxoid liposarcoma: needle core biopsy. Signet-ring lipoblasts are
randomly scattered. Note the relative uniformity of the lesional cells
without unusually large or bizarre tumor cells. H&E stain, medium
power.
ALTs/WDLSs and DDLSs have similar genetic
abnormalities. Both tumors have supernumerary ring
and giant cell marker chromosomes mostly derived from
the 12q14–15 karyotypic abnormality. The majority of
MLSs/RCLSs have t(12;16)(q13;p11) and about 10% of
these tumors show t(12;22)(q13;q12). PLSs do not show
a specific genetic aberration, and the cytogenetic make-
up of these tumors is complex.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
ALTs/WDLSs may consist predominantly of mature
adipose tissue and can be indistinguishable from
normal fat or lipoma. Aspirates of mature-appearing
adipose tissue in deep-seated locations should be
examined carefully for any atypical fibroblast-like cells.
In general, a biopsy is necessary to establish this diag-
nosis. Necrotic non-neoplastic fat may harbor histio-
cytes with large nuclei which simulate the atypical cells
of ALTs/WDLSs. DDLS components are indistinguish-
able from those of high-grade sarcomas such as malig-
nant fibrous histiocytoma, malignant peripheral nerve
sheath tumor, and leiomyosarcoma. The diagnosis of
DDLS can only be established when foci of ALT/WDLS
are demonstrated in the current specimen or a previous
history of ALT/WDLS is elicited.
The presence of vascular channels and limited atypia
of tumor cells, in a myxoid background is not unique
for MLS/RCLS and may be observed in other neoplasms
such as low-grade fibromyxoid sarcoma and extra-
skeletal chondromyxoid sarcoma. A biopsy is necessary
to discriminate these lesions.
In the absence of mulberry-type lipoblasts, PLSs
are indistinguishable from other poorly differentiated
mesenchymal and epithelial malignancies.
CHAPTER 4 Soft Tissue
A B
FIGURE 4-5
Pleomorphic liposarcoma: touch preparation. Pleomorphic cells and lipoblasts are shown here. The cytoplasmic vacuoles indent the peripherally
displaced nuclei. Due to variable numbers of lipoblasts, these may not be demonstrated in FNAB. Diff-Quik stain, high power.
FIBROBLASTIC AND FIBROHISTIOCYTIC
TUMORS
NODULAR FASCIITIS
CLINICAL FEATURES
Nodular fasciitis (NDF) usually arises in the subcuta-
neous tissue of the extremities, head and neck, or trunk
regions. The mass lesion often abuts the underlying
adjacent fascia. NDF may develop within blood vessels
(intravascular NDF), skeletal muscle (intramuscular
NDF), skull (cranial NDF), and, rarely, in visceral
organs. The typical presentation is that of a rapidly
growing painful mass in a young adult. A history of
antecedent trauma is often reported.
PATHOLOGIC FEATURES
Histologically, NDF is composed of spindly and wavy
cells haphazardly arranged or in short fascicles (tissue
NODULAR FASCIITIS – DISEASE FACT SHEET
Incidence and Location
៉ Not uncommon
៉ Upper and lower extremities, head and neck, and trunk; rarely
within skeletal muscle, vessels, and skull/scalp
Gender, Race, and Age Distribution
៉ No sex or race predilection
៉ Peak incidence between 2nd and 5th decades
97
NODULAR FASCIITIS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellular aspirate; the mildly atypical tumor cells are spindle or
plump cells; stellate or ganglion-like cells may be present; small
but sometimes prominent nucleoli; infl ammatory infiltrates and
mitotic figures are variably present
៉ Myxoid or collagenous stroma
៉ Depending on the site of lesion, degenerated tissue such as fat
necrosis or skeletal muscle may accompany the lesional cells
Immunocytochemistry
៉ Positive for vimentin, smooth muscle actin, and muscle-specific
actin, and rarely for desmin
៉ Negative for S-100 protein, CD34, bcl-2, and cytokeratin
Genetics
៉ Diploid by DNA ploidy analysis
៉ t(15;15)(q13;q22 or q25) was described in three cases
Differential Diagnosis and Pitfalls
៉ Benign and malignant spindle cell and myxoid tumors including
solitary fibrous tumor, low-grade fibromyxoid sarcoma,
fibrosarcoma, malignant peripheral nerve sheath tumor, and
leiomyosarcoma
៉ Spindle cell carcinoma
culture pattern). The stromal background is characteri-
stically myxoid and patchy in distribution. Mitotic
figures can be readily found. Older lesions are less
mitotically active with more fibrocollagenous stroma.
The FNAB smears of NDF are cellular and composed
of tightly clustered and singly scattered spindle, poly-
gonal, or stellate cells in a myxoid background (Fig.
4-6). The tumor cells are relatively uniform round or
spindled with a smooth outline. They have cytoplasmic
processes, and centrally located nucleoli reminiscent of
a ganglion cell are sometimes identified (proliferative
98
A B
FIGURE 4-6
Nodular fasciitis: FNAB. The aspirated materials are often cellular. The lesional cells are spindle or stellate with a moderate N/C ratio, inconspicu-
ous nucleoli, and abundant cytoplasm. Myxoid stroma often predominates. A few fragments of skeletal muscle are also present. Papanicolaou stain,
medium power.
fasciitis). A variable number of inflammatory cells
including neutrophils, eosinophils, and mononuclear
cells may be seen. Mitotic figures are usually present.
ANCILLARY STUDIES
The tumor cells are usually positive for vimentin,
smooth muscle actin (SMA), and muscle-specific actin
(MSA). Desmin may also be focally expressed. There
is no immunoreactivity with S-100 protein, melanoma
markers (HMB-45 and Melan A), CK, CD34, or bcl-2.
The tumor cells are diploid by flow cytometry. Cytoge-
netic analysis performed on a few reported cases
showed t(15;15)(q13;q22 or q25).
DIFFERENTIAL DIAGNOSIS AND PITFALLS
NDFs are perhaps the most common benign tumors to be
mistaken for malignancy on FNAB. An important clue
to their diagnosis is the clinical information of a rapidly
growing mass. Cytologically, several benign and malig-
nant spindle cell neoplasms can have similar features to
those of the cells of NDFs. Oftentimes, a definitive diag-
nosis can not be made on smear preparations, and biopsy
or excision is necessary for definitive diagnosis.
FIBROMATOSIS
CLINICAL FEATURES
Fibromatoses (FMs) are locally infi ltrative tumors
composed of spindle cells with fibroblastic and myo-
FINE NEEDLE ASPIRATION CYTOLOGY
FIBROMATOSIS – DISEASE FACT SHEET
Incidence
៉ Superficial: common among those of northern and eastern
European descent; 20% of 65 years or older
៉ Desmoid-type (aggressive): 2–4 per million population per year
Location
៉ Superficial: palmar and plantar regions
៉ Desmoid-type (aggressive): abdominal wall, retroperitoneum, trunk,
shoulder and proximal extremities
Gender, Race, and Age Distribution
៉ Superficial:
៉ Palmar fibromatosis: 3–4 times more common in men,
particularly those of northern or eastern European descent;
rare in non-Caucasians
៉ Plantar fibromatosis: slight male predilection; 35% of cases
are 35 years or younger
៉ Desmoid-type (aggressive):
៉ Children: no sex or race predilection; extra-abdominal
location is more common
៉ Child-bearing age: female predilection; abdominal location is
more common
៉ Older age: no sex predilection; equal distribution (abdominal
and extra-abdominal locations)
fibroblastic differentiation. They are usually divided
based on their location into superficial (palmar or
Dupuytren FM, and plantar or Ledderhose disease)
and desmoid types (aggressive FM).
Palmar FMs often present as subcutaneous nodules
with flexion contractures of the fingers. The overlying
skin of the palm and fingers may be dimpled. In most
instances, the subcutaneous nodules of plantar FMs
are asymptomatic. Pain on pressure from standing or
CHAPTER 4 Soft Tissue 99

A B

FIGURE 4-7
Fibromatosis: FNAB. (A) The aspirates are usually paucicellular in tumors with collagenous stroma. The tumor cells are spindle-shaped. Groups of
tumor cells (B) are held by fibrocollagenous stroma. Singly scattered nuclei are often devoid of their cytoplasm. Papanicolaou stain, medium
power.

walking may be the initial presentation. These lesions

are usually clinically diagnosed and not subject to
FNAB.
Desmoid-type FMs are further subdivided into
abdominal, intra-abdominal, and extra-abdominal types.
These tumors have a tendency for local recurrence,
either from multicentricity or residual tumor. Although
they do not have the capacity for distant spread, signifi-
cant morbidity through local destructive invasion may
result.
Abdominal FMs often present as asymptomatic
abdominal wall mass lesions following previous surgery
such as caesarian section. Owing to their location,
intra-abdominal FMs are symptomatic if vital structures
are compromised. Extra-abdominal FMs present as
palpable masses in the neck, shoulder, trunk, and
pelvic girdle.
FIBROMATOSIS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellularity depends on the stroma: myxoid lesions tend to
aspirate better than collagenous lesions
៉ Clusters or singly scattered cells; tumor cells have ovoid or
round nuclei with a smooth nuclear membrane and fine
chromatin material; elongated cytoplasm
Immunohistochemistry
៉ Positive for vimentin, smooth muscle actin, muscle-specific
actin, and β-catenin; may be positive for desmin
៉ Negative for S-100 protein, CD34, and cytokeratin
Genetics
៉ No specific karyotypic abnormality
៉ No specific genetic abnormality
៉ Patients with familial polyposis and, rarely, sporadic
fibromatosis may have APC gene inactivation

Differential Diagnosis and Pitfalls

PATHOLOGIC FEATURES ៉ Benign and malignant spindle cell tumors such as
myofibroblastoma, neurofibroma, solitary fibrous tumor,
leiomyoma, benign fibrous histiocytoma, dermatofibrosarcoma
Histologically, the bland-appearing spindle cells are protuberans, and low-grade fibromyxoid sarcoma
arranged in longitudinal fascicles with a collagenous or
myxoid background.
The superficial FMs have a typical clinical presenta-
tion and are excised without preoperative cytologic
evaluation. Desmoid-type FMs are clinically indistin-
guishable from other soft tissue tumors, and FNAB may
be performed as part of the initial evaluation. The col- ANCILLARY STUDIES
lagenous stroma may lead to paucicellular aspirates with
only singly scattered spindle cells often stripped of their
cytoplasm (Fig. 4-7). Clusters of these bland-appearing The tumor cells are immunoreactive for vimentin,
spindle cells are commonly seen. The tumor cells have SMA, MSA, and β-catenin. Rarely, desmin is also
oval and uniform nuclei with a smooth outline, and a expressed. The tumor cells are usually negative for
moderate amount of cytoplasm. If present, the myxocol- S-100, CD34, and CK. There are no known genetic
lagenous stroma is characteristically metachromatic on aberrations in FMs, although patients with familial
Romanowsky-based stains. polyposis (FP) may have APC gene inactivation.
100
DIFFERENTIAL DIAGNOSIS AND PITFALLS
On FNAB, the spindle cells of FMs are morphologically
indistinguishable from many spindle cell lesions includ-
ing myofibroblastoma, neurofibroma, solitary fibrous
tumor, benign fibrous histiocytoma, dermatofibrosar-
coma protuberans, and low-grade fibromyxoid sarcoma.
More aggressive tumors such as desmoplastic mela-
noma and spindle cell carcinoma may also have a
similar appearance. Immunohistochemical work-up
can assist in the differential. The diagnosis of FM is
usually strongly suspected on clinical and radiologic
grounds. NCB or excisional biopsy may be necessary
for a definitive diagnosis.
DERMATOFIBROSARCOMA PROTUBERANS
CLINICAL FEATURES
Dermatofibrosarcoma protuberans (DFSP) presents as
a slow-growing, pink or erythematous skin plaque or
as a subcutaneous mass. The tumors occur most fre-
quently in the trunk and proximal extremities in
middle-aged patients without sex predilection. DFSPs
are locally aggressive tumors with a high recurrence
rate following excision. Transformation to fibrosar-
coma is rare but well-documented. Rare cases of meta-
static DFSPs have been reported, typically following
multiple recurrence and prolonged follow-up.
PATHOLOGIC FEATURES
Histologically, DFSPs are composed of spindle cells
arranged in short interlacing fascicles forming a stori-
form or cartwheel pattern. The neoplastic cells are
relatively uniform and show minimal pleomorphism.
Infi ltrative tumor cells in the deep subcutaneous tissue
often surround individual or groups of fat cells.
The aspirated material is usually cellular. The tumor
cells are either individually dispersed or in small
DERMATOFIBROSARCOMA PROTUBERANS – DISEASE FACT SHEET
Incidence and Location
៉ 1.8% of soft tissue tumors
៉ Trunk, proximal portion of the extremities, and head and neck
Gender, Race, and Age Distribution
៉ No sex or race predilection
៉ Peak incidence: young and middle-aged adults
FINE NEEDLE ASPIRATION CYTOLOGY
DERMATOFIBROSARCOMA PROTUBERANS –
PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Fairly cellular aspirates composed of tightly clustered spindle
cells and scattered single cells devoid of cytoplasm; tumor cells
are spindly with ovoid, smooth-outlined nuclei, inconspicuous
nucleoli, and bipolar cytoplasmic processes
៉ Myxocollagenous stroma
Immunohistochemistry
៉ Positive for vimentin and CD34
៉ Negative for S-100 protein, actins, desmin, cytokeratin, and
epithelial membrane antigen
Genetics
៉ Ring chromosomes from chromosome 17 and 22
៉ t(17;22)(q22;q13) resulting in COL1A–PDGFB fusion transcript
Differential Diagnosis and Pitfalls
៉ Benign and malignant spindle cell tumors such as
myofibroblastoma, neurofibroma, benign fibrous histiocytoma,
fibromatosis, low-grade fibromyxoid sarcoma, and fibrosarcoma
aggregates with ill-defined boundaries (Fig. 4-8). The
spindled tumor cells have elongated or ovoid nuclei
with fine chromatin and inconspicuous nucleoli. Their
cytoplasm may demonstrate bipolar cytoplasmic pro-
cesses. The background stroma may be myxoid, collag-
enous, or fibrillary, and exhibits metachromasia with
Romanowsky-based stains. Mast cells and Touton-type
giant cells may be seen. Aspirated fragments of DFSPs
may display the characteristic storiform pattern. Trans-
formation to a higher-grade sarcoma (e.g. fibrosarcoma)
may not be possible to establish on FNAB specimens
due to lack of distinctive cytologic features unless
frankly atypical tumor cells are present.
FIGURE 4-8
Dermatofibrosarcoma protuberans: touch preparation. The tumor cells
have fine chromatin and are devoid of nucleoli. Significant pleomor-
phism of tumor cells is not demonstrated. Diff-Quik stain, high power.
CHAPTER 4 Soft Tissue
ANCILLARY STUDIES
The tumor cells of DFSPs are positive for vimentin and
CD34, and negative for S-100 protein, SMA, MSA,
desmin, CK, and epithelial membrane antigen (EMA).
The main reported cytogenetic abnormality in DFSPs
is a ring chromosome derived from chromosomes 17
and 22. This translocation, t(17;22)(q22;q13), results
in a chimeric transcript, COL1A-PDGFB (collagen
type 1–platelet-derived growth factor beta), which can
be detected by reverse transcriptase-polymerase chain
reaction (RT-PCR) or fluorescence in situ hybridization
(FISH). The same genetic abnormality is seen in giant
cell fibroblastoma, a closely related entity.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The spindle cell lesions listed under fibromatosis are
included in the differential diagnosis of DFSP. The
typical immunophenotype of DFSP, however, is not
observed in these entities. The presence of areas that
are negative for CD34 together with the appropriate
cellular morphology suggests transformation to FS.
When available, molecular studies can assist in the
diagnosis of DFSPs.
FIBROSARCOMA
CLINICAL FEATURES
Fibrosarcomas most often arise in the upper trunk,
proximal extremities, and head and neck region of
adults. They tend to be slow growing, and may be asso-
ciated with pain or paresthesia secondary to mass
effect. A preceding diagnosis of DFSP may be extracted
from the history.
PATHOLOGIC FEATURES
The characteristic feature of fibrosarcomas is the pres-
ence of spindly tumor cells forming long sweeping
FIBROSARCOMA – DISEASE FACT SHEET
Incidence and Location
៉ Rare tumors (other histologically similar tumors should be ruled
out)
៉ Deep soft tissue of lower extremities, trunk, head and neck
Gender, Race, and Age Distribution
៉ No sex or race predilection
៉ Middle-aged and older adults
101
FIBROSARCOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellular aspirate; uniform spindle tumor cells; considerable
cellular atypia in poorly differentiated tumors
៉ Myxocollagenous stroma
Immunohistochemistry
៉ Positive for vimentin; may be focally positive for smooth
muscle actin; fibrosarcoma arising from dermatofibrosarcoma
protuberans is positive for CD34
៉ Negative for epithelial markers (cytokeratin and epithelial
membrane antigen), muscle markers (MyoD1, myogenin, and
calponin), and neural/melanoma markers (S-100, HMB-45,
Melan A)
Genetics
៉ Complex karyotype
Differential Diagnosis and Pitfalls
៉ Benign and malignant spindle cell tumors such as
myofibroblastoma, neurofibroma, benign fibrous histiocytoma,
fibromatosis, low-grade fibromyxoid sarcoma, and
leiomyosarcoma
៉ Pleomorphic areas of fibrosarcoma are indistinguishable from
other high-grade sarcomas
fascicles that pull towards opposite directions (herring-
bone pattern). A collagenous background is variably
present. Fibrosarcomas have become a diagnosis
of exclusion after entities (e.g. synovial sarcoma) of
overlapping histology are classified under separate
categories.
The aspirated material is often cellular. Tissue frag-
ments often show fibrocollagenous stroma in which
tumor cells are embedded (Fig. 4-9). Individually
scattered neoplastic cells are spindle-shaped and often
devoid of cytoplasm. When intact, the cytoplasmic pro-
cesses are elongated at both ends of the cell. Consider-
able pleomorphism may be appreciated in tumors with
less differentiated components.
ANCILLARY STUDIES
FSs express vimentin but none of the more specific
antibodies. Epithelial, neural, and melanoma markers
are negative. At present, a specific genetic abnormality
has not been described.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The entities in the differential diagnosis of fibrosarco-
mas are similar to those listed under fibromatoses. A
more pleomorphic fibrosarcoma is difficult to distin-
guish from high-grade sarcomas. A more definitive
102
A B
FIGURE 4-9
Fibrosarcoma: FNAB. FNAB often yields cellular material. Tumors cells are spindled and show variable, moderate pleomorphism. The stroma may
be prominent or entirely non-existent. Component cells are indistinguishable from those in other spindle cell tumors such as synovial sarcomas.
Papanicolaou stain, high power.
diagnosis requires NCB or open biopsy. Expression of
an antibody or set of antibodies known to more or
less define an entity should exclude fibrosarcoma from
consideration.
MALIGNANT FIBROUS HISTIOCYTOMA
CLINICAL FEATURES
Two types of malignant fibrous histiocytomas (MFHs)
are considered here: pleomorphic MFH (PMFH), and
myxoid MFH (MMFH) or myxofibrosarcoma. PMFHs
usually present as a rapidly growing deep-seated mass.
The common locations are the proximal extremities,
trunk. and retroperitoneum. Pain, swelling, and loss of
MALIGNANT FIBROUS HISTIOCYTOMA – DISEASE FACT SHEET
Incidence
៉ Pleomorphic MFH: 1–2 cases per 100,000 per year
៉ Myxoid MFH: common sarcoma in elderly patients
Location
៉ Pleomorphic MFH: lower extremity and trunk (deep or cutaneous)
៉ Myxoid MFH: lower and upper extremities (proximal part)
Gender, Race, and Age Distribution
៉ Slight male predilection
៉ No race predilection
៉ Pleomorphic MSH: most common sarcoma in persons aged 40 years
or older
៉ Myxoid MSH: most common in elderly patients
FINE NEEDLE ASPIRATION CYTOLOGY
function are secondary to mass effect or tumor infi ltra-
tion. Metastasis to the lungs may be present at the time
of diagnosis. MMFHs are slow-growing subcutaneous
tumors that frequently arise from the extremities;
ulceration of the overlying skin from tumor infi ltration
may be present. Lower-grade MMFHs may have an
indolent behavior.
PATHOLOGIC FEATURES
Malignant fibrous histiocytomas (MFHs) are malig-
nant soft tissue tumors composed of tumor cells
without definitive morphologic, immunohistochemical,
and ultrastructural evidence of specific tissue differen-
tiation. The tumor cells are closely related to fibro-
blasts/myofibroblasts.
Histologically, PMFHs are hypercellular with mark-
edly atypical tumor cells and brisk mitotic activity. An
admixture of spindle and polygonal cells is common and
a storiform pattern is typically present. MMFHs have
variable cellularity composed of spindle cells with few
scattered pleomorphic cells in a myxoid background.
Relatively thick-walled vessels associated with fibrosis
are usually recognized.
FNAB of PMFHs consists of a pleomorphic popula-
tion of spindle, polygonal, and multinucleated cells (Fig.
4-10). The tumor cells may cling to vascular structures,
giving a pseudopapillary appearance. Erythrophagocy-
tosis can be identified. The neoplastic cells do not show
cytomorphologic evidence of specific tissue differentia-
tion. Mitoses are easily recognized. FNAB of MMFHs
shows hypocellular or moderately cellular aspirates
composed of a relatively less pleomorphic population
of tumor cells (usually spindly) with randomly inter-
spersed bizarre cells (Fig. 4-11). A copious myxoid
stroma is characteristic.
CHAPTER 4 Soft Tissue 103

A B

FIGURE 4-10
Malignant fibrous histiocytoma, pleomorphic type: FNAB. The hypercellular aspirates are composed of pleomorphic tumor cells without specific
cytomorphologic differentiation. Mitotic figures are easy to find. Diff-Quik stain, high power.

MALIGNANT FIBROUS HISTIOCYTOMA – PATHOLOGIC FEATURES

Cytopathologic Findings
៉ Pleomorphic MFH: cellular aspirates, bizarre tumor cells, mitotic
figures abound; fibrocollagenous or myxoid stroma
៉ Myxoid MFH: moderately cellular aspirates, spindle and polygonal
tumor cells, nuclear to cytoplasmic ratio is lower than in
pleomorphic MFH; prominent myxoid stroma

Immunohistochemistry
៉ Pleomorphic MFH: positive for vimentin; rare cells positive for
epithelial (cytokeratin and epithelial membrane antigen),
muscle (actin, desmin, MyoD1, and myogenin), and other
markers of specific tissue differentiation
៉ Myxoid MFH: positive for vimentin; rare cells positive for
epithelial (cytokeratin and epithelial membrane antigen),
muscle (actin, desmin, MyoD1, and myogenin), and other
markers of specific tissue differentiation
FIGURE 4-11
Malignant fibrous histiocytoma, myxoid type: FNAB. The tumor cells are
Genetics
spindle, stellate, or polygonal cells and less pleomorphic compared with
៉ Complex karyotype the pleomorphic type of MFH. The tumor cells are usually drawn toward
៉ No specific genetic abnormality the immediate periphery of the vascular channels. Note the prominent
myxoid stroma. Diff-Quik stain, high power.
Differential Diagnosis and Pitfalls
៉ Pleomorphic MFH: pleomorphic variants of other sarcomas
including liposarcoma, rhabdomyosarcoma, and leiomyosarcoma
៉ Myxoid MFH: malignant myxoid tumors (low-grade fibromyxoid
sarcoma, myxoid malignant peripheral nerve sheath tumor, and DIFFERENTIAL DIAGNOSIS AND PITFALLS
myxoid liposarcoma)

FNAB of high-grade sarcomas including liposarcoma,

ANCILLARY STUDIES
MFH does not exhibit a specific immunophenotype.
Rare scattered tumor cells may express epithelial and
muscle markers, and S-100 protein. The cytogenetic
abnormality is complex.
rhabdomyosarcoma, and leiomyosarcoma, and poorly
differentiated carcinomas can be morphologically
indistinguishable from PMFHs. Similarly, aspirates of
MMFHs may resemble myxoid malignant peripheral
nerve sheath tumor and myxoid liposarcoma. Diligent
search for isolated cells or clusters of cells that demon-
strate specific differentiation (lipoblasts, rhabdomyo-
blasts, keratinization, and mucin production) can
exclude the diagnosis of MFH.
104
NEURAL TUMORS
NEUROFIBROMA AND SCHWANNOMA
(NEURILEMMONA)
CLINICAL FEATURES
NEUROFIBROMA
Peripheral neurofibromas often present as visible and
palpable subcutaneous nodules. Neurofibromas of the
spinal roots may be incidentally discovered or manifest
symptoms from neural impingement. Neurofibromas
occur in two settings, either as a sporadic case or in a
background of neurofibromatosis type 1 (NF1). Patients
with NF1 usually have other stigmata of the syndrome,
including café-au-lait spots, skin freckling (usually in
the axillary and inguinal areas), iris hamartomas (Lisch
nodules), and other neoplasms (somatostatinoma,
pheochromocytoma). An increased incidence of trans-
formation to malignant peripheral nerve sheath tumor
(MPNST) is seen in the setting of NF1.
SCHWANNOMA
The distribution of schwannomas is similar to that
of neurofibromas, with few exceptions, including intra-
cranial locations and the propensity to arise from the
8th cranial nerve. The tumors are asymptomatic unless
there is impingement on a nerve, and compression of
the spinal cord or other vital structures.
PATHOLOGIC FEATURES
Histologically, neurofibromas show spindle tumor cells
with buckled nuclei in a variably myxoid and collage-
NEURAL TUMORS – DISEASE FACT SHEET
Incidence
៉ Neurofibroma: common tumors
៉ Schwannoma: common tumors; may be multiple in
neurofibromatosis type 2
Location
៉ Neurofibroma: skin and subcutaneous tissue, spinal and peripheral
nerves but not cranial nerves
៉ Schwannoma: peripheral nerves, spinal and cranial nerves,
particularly 8th cranial nerve
Gender, Race, and Age Distribution
៉ No sex or racial predilection
៉ Neurofibroma: affects all ages
៉ Schwannoma: affects all ages (peak – 4th to 6th decades)
FINE NEEDLE ASPIRATION CYTOLOGY
NEURAL TUMORS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Neurofibroma: hypocellular to fairly cellular aspirates; spindle
tumor cells; fibrocollagenous or myxoid stroma
៉ Schwannoma: fairly cellular aspirates; spindle tumor cells, tight
clusters sometimes predominate; atypical cells representing
degenerative changes may be prominent; fibrocollagenous or
myxoid stroma
Immunohistochemistry
៉ Neurofibroma: positive for S-100 (less staining intensity
compared with schwannoma); negative for cytokeratin and
epithelial membrane antigen
៉ Schwannoma: positive for S-100 (strong and diffuse); negative
for cytokeratin and epithelial membrane antigen
Electron Microscopy
៉ Neurofibroma: admixture of Schwann cells and fibroblasts
៉ Schwannoma: Luse bodies (compact fibrous long spacing
collagen), long cytoplasmic processes and basal lamina
surrounding Schwann cells
Genetics
៉ Neurofibroma: neurofibromatosis type 1 (NF1) syndrome; loss of
wild-type NF1 allele
៉ Schwannoma: loss of chromosome 22; loss of wild-type NF2
allele
Differential Diagnosis and Pitfalls
៉ Benign and malignant spindle cell tumors such as
myofibroblastoma, neurofibroma, benign fibrous histiocytoma,
fibromatosis, low-grade fibromyxoid sarcoma, and
dermatofibrosarcoma protuberans
nous stroma. The histology of NF1-associated neuro-
fibromas is similar to that of sporadic cases. Plexiform
neurofibromas, seen almost exclusively in NF1 patients,
consist of thickened nerve trunks and branches.
Schwannomas are encapsulated tumors. Alternating
cellular (Antoni A) and hypocellular (Antoni B) foci are
usually identified. The nuclei of schwannoma cells may
line up, forming a palisading pattern referred to as
Verocay bodies. The intratumoral blood vessels typi-
cally have thick and hyalinized walls.
In both neurofibromas and schwannomas, a sharp
pain or a tingling sensation extending to the immediate
distribution of the involved nerve may be felt by the
patient during the FNAB procedure.
The cytomorphologic features of neurofibromas and
schwannomas are generally similar (Figs 4-12–4-14).
Aspirates from both tumors are variably cellular. The
tumor cells are arranged in clusters and rarely are indi-
vidually scattered. The tumor cells are spindle-shaped
or, rarely, epithelioid. The nuclei are uniformly wavy
and devoid of nucleoli. When tissue fragments are
obtained, tumor cells of schwannomas lie in a homoge-
neous or fibrillary myxocollagenous stroma. Occasion-
ally, palisades of cellular nuclei (Verocay bodies) may
be appreciated in schwannomas. The patchy areas of
hypercellularity and rarity of single cells also suggest a
CHAPTER 4 Soft Tissue 105

FIGURE 4-12
Neurofibroma: FNAB. FNAB yield is variably cellular. The spindle tumor
cells are often held together by fibromyxoid stroma. Diff-Quik stain, high
power.

A B

FIGURE 4-13
Neurofibroma: needle core biopsy. The tumor cells display tapered and buckled nuclei and ample cytoplasm with abundant intervening fibrocollage-
nous or fibromyxoid stroma. The tumor cells express S-100 protein (B). A, H&E stain, high-power. B, S-100 protein, high power.

A
B

FIGURE 4-14
Schwannoma: FNAB. The aspirates are variably cellular. Tumors with a thick fibrocollagenous background may yield only a few cell clusters. Tumor
cells have a plump or epithelioid appearance. A, Diff-Quik stain, high power. B, Papanicolaou stain, high power.
106
diagnosis of a schwannoma rather than a neurofibroma.
Ancient schwannomas may have a few large atypical
cells which represent degenerative atypia and do not
necessarily signify transformation to malignancy. These
atypical cells are not mitotically active.
ANCILLARY STUDIES
Immunohistochemically, anti-S-100 protein stains
neurofibromas in a patchy distribution and schwan-
nomas in a diffuse and relatively strong manner.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Neurofibromas and schwannomas may be mistaken for
other benign spindle cell tumors and low-grade spindle
cell sarcomas, particularly in small samples. S-100
protein expression is very helpful in confirming a diag-
nosis of neurofibromas and schwannomas. Immuno-
histochemical staining for CD34 and smooth muscle
markers can assist in excluding solitary fibrous tumor
and smooth muscle and fibroblast/myofibroblast-derived
neoplasms such as fibromatosis, low-grade fibromyxoid
sarcoma, and dermatofibrosarcoma protuberans. A
recent increase in the size of a pre-existing nerve sheath
tumor warrants a careful assessment for the presence
of atypical cells that may signify transformation to
MPNST.
GRANULAR CELL TUMOR
CLINICAL FEATURES
Granular cell tumors (GCTs) arise commonly in the
tongue, subcutaneous tissue of the extremities and
GRANULAR CELL TUMOR – DISEASE FACT SHEET
Incidence and Location
៉ Relatively common
៉ Usual location is the subcutis of the extremities, breast and
trunk, and submucosa of the aerodigestive tract; rarely, the
lesion(s) may be multiple
Gender, Race, and Age Distribution
៉ Slight female predilection
៉ More common in Blacks
៉ Any age bracket; rare in children <5 years; peak – 4th to 6th
decades
FINE NEEDLE ASPIRATION CYTOLOGY
trunk, breast, and aerodigestive tract. The clinical
manifestations of GCTs are site-dependent. In the skin
and aerodigestive tract, the tumor is often discovered
as an asymptomatic subcutaneous or submucosal slow-
growing nodule, usually mistaken for a more serious
lesion. GCTs can be multicentric.
PATHOLOGIC FEATURES
Histologically, the tumor cells are polygonal or spindle-
shaped with abundant granular cytoplasm and small
round nuclei. The cell borders are usually distinct.
Infi ltration into adjacent tissue is common and not
indicative of a more aggressive behavior. Typically, S-
100 protein and CD68 are positive, and smooth muscle
markers are negative.
FNAB of GCTs is usually cellular and composed of
clusters and dispersed tumor cells with abundant granu-
lar cytoplasm (Figs 4-15 & 4-16). Fragmentation of the
granular cytoplasm may impart a hazy background on
low magnification. The cells have centrally located
round nuclei. Naked round or oval nuclei with a smooth
outline and devoid of prominent nucleoli may be
observed. Pseudonuclear inclusions may be present.
Cytologic atypia including hyperchromasia, pleomor-
phism and prominent nucleoli, necrosis, and mitotic
activity are not identified in clinically benign GCTs.
GRANULAR CELL TUMOR – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Aspirates are usually cellular; tumor cells have abundant and
granular cytoplasm
៉ Disintegrated cytoplasm may impart a necrotic background;
closer examination will show fragments of granular cytoplasm
៉ Naked nuclei are round and uniform with small but sometimes
prominent nucleoli
Immunohistochemistry
៉ Positive for vimentin, S-100 protein, CD68, laminin, and myelin
proteins
៉ Negative for cytokeratin, smooth muscle actin, neurofilament,
and glial fibrillary acidic protein
Electron Microscopy
៉ Numerous lysosomes
Genetics
៉ No specific karyotypic abnormality
៉ No specific genetic abnormality
Differential Diagnosis and Pitfalls
៉ Oncocytic neoplasms and paraganglioma
៉ Alveolar soft part sarcoma, renal cell carcinoma, and
rhabdomyosarcoma
CHAPTER 4 Soft Tissue 107

A B

FIGURE 4-15
Granular cell tumor: FNAB. The aspirates are moderately cellular. The tumor cells are spindle or polygonal with round nuclei and ample, granular
cytoplasm. A, Papanicolaou stain, medium power. B, Diff-Quik stain, high power.

A B

FIGURE 4-16
Granular cell tumor: cell block. The tumor cells typically have granular cytoplasm and a low N/C ratio. The tumor cells are strongly positive for
S-100 protein (B). Note the absence of staining in gastric epithelial cells. A, H&E stain, low power. B, S-100 protein, low power.

chemistry readily differentiates GCT from these neo-

ANCILLARY STUDIES
GCTs stain with S-100 protein (Fig. 4-16B), CD68, and
myelin proteins. GCTs do not stain for CK, SMA,
neural fi lament, and glial fibrillary acidic protein
(GFAP). Similar to neurofibroma and schwannoma,
GCTs can also express laminin. The cytoplasm is fi lled
with numerous lysosomes on EM.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
GCTs may be mistaken for oncocytic neoplasms that
are known to arise in several organs, including the
salivary gland, thyroid, and kidney. Immunohisto-
plasms, GCT being positive for S-100 protein and CD68,
and negative for epithelial markers. Ultrastructural
studies demonstrate the abundance of lysosomes in
GCTs and mitochondria in oncocytic neoplasms.
Paragangliomas may resemble GCTs. The absence of
cytoplasmic granularity and expression of CK and neu-
roendocrine markers are more in keeping with para-
ganglioma. In rare instances, alveolar soft part sarcoma,
renal cell carcinoma (RCC), and rhabdomyosarcoma
(RMS) may be difficult to separate from GCTs, particu-
larly in small biopsies. The immunophenotypes of
GCTs, RCCs, and RMSs should be relied upon in such
instances.
Gingival GCTs of the newborn, although morpho-
logically similar to GCTs of other sites, do not express
S-100 protein and the immunohistochemical profile sug-
gests a smooth muscle differentiation.
108
MALIGNANT PERIPHERAL NERVE
SHEATH TUMORS
CLINICAL FEATURES
Malignant peripheral nerve sheath tumors (MPNSTs)
present as an enlarging mass with pain or with symp-
toms from neural impingement. MPNSTs are most
commonly located in the proximal extremities and
paraspinal region. Approximately 50% of MPNSTs
arise in NF1 patients. Progressive enlargement of an
existing neurofibroma may herald transformation to
malignancy.
PATHOLOGIC FEATURES
Histologically, MPNSTs are hypercellular. Most tumors
are composed of spindle cells with buckled nuclei. A
transition to a rounded or epithelioid tumor cell popu-
lation is noted in a minority of tumors. Malignant glan-
dular (glandular MPNST) and rhabdomyosarcomatous
(malignant Triton tumor) elements may be present.
The aspirates are usually very cellular with predomi-
nance of spindle cells in tight clusters and myxocollage-
nous stroma (Figs 4-17 & 4-18). The tumor cells may
also be epithelioid, glandular, or rhabdoid forms. Cellular
evidence of malignancy including hyperchromasia,
pleomorphism, nucleolar prominence, and brisk mitotic
activity are usually evident. Sampling of MPNSTs arising
in a background of neurofibromas might yield benign-
appearing spindle tumor cells typical of neurofibromas.
ANCILLARY STUDIES
MPNSTs typically express S-100 protein in a patchy
and faint distribution, in contrast to neurofibromas
MALIGNANT PERIPHERAL NERVE SHEATH TUMORS –
DISEASE FACT SHEET
Incidence
៉ 5% of soft tissue tumors
៉ 66% arise from neurofibromas of NF1 patients and less frequently
in sporadic neurofibromas
Location
៉ Large nerve trunk of the proximal extremities and spinal nerve
roots
Gender, Race, and Age Distribution
៉ Slight predilection for females
៉ No race predilection
៉ Peak at 3rd to 6th decades
FINE NEEDLE ASPIRATION CYTOLOGY
MALIGNANT PERIPHERAL NERVE SHEATH TUMORS –
PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellular aspirates; tumor cells are spindle and polygonal cells;
less frequently, epithelioid cells or pleomorphic cells may be
present
៉ Cellular atypia and mitotic figures are readily appreciated:
hyperchromasia, coarse chromatin, pleomorphism, and
prominence of nucleoli
៉ Myxocollagenous stroma
Immunohistochemistry
៉ Positive for vimentin; foci of rhabdomyosarcomatous
differentiation are positive for muscle markers
៉ Epithelioid MPNST and epithelial components are positive for
cytokeratin
៉ 50–70% are positive for S-100 protein (faint/patchy)
៉ Negative for CD34, HMB-45, and tyrosinase
Genetics
៉ Complex karyotype
៉ May have deletion of the INKA/CDK2A gene (9p)
Differential Diagnosis and Pitfalls
៉ Spindle cell MPNSTs: fibrosarcoma, synovial sarcoma,
gastrointestinal stromal tumor, and desmoplastic melanoma
៉ Glandular MPNSTs: biphasic synovial sarcoma and carcinosarcoma
៉ Epithelioid MPNSTs: carcinoma, epithelioid sarcoma, and
melanoma
and schwannomas, which are strongly reactive.
MPNSTs with epithelioid morphology may be positive
for epithelial markers. The glandular epithelial compo-
nents (glandular MPNST) are expectedly CK-positive.
Foci of rhabdomyosarcomatous differentiation (Triton
tumors) are immunoreactive to skeletal muscle markers
(MyoD1 and myogenin).
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Spindle cell MPNSTs may be indistinguishable from
other spindle cell tumors. Remnants of neurofibroma
or schwannoma in the sampled material may indicate
origin of the malignancy. The stromal cells of synovial
sarcoma (SS) are spindle and uniform, in contrast to
the more pleomorphic mesenchymal components of
MPNSTs. The glandular MPNSTs may be mistaken for
biphasic SS. The epithelial components of glandular
MPNSTs are bland-appearing compared to their
counterpart in biphasic SSs. The malignant epithelial
components of carcinosarcoma are considerably more
pleomorphic than the glandular elements of MPNSTs.
Epithelioid MPNSTs may have components that are
morphologically similar with carcinoma, melanoma,
and other sarcomas with epithelioid/epithelial compo-
nents, including epithelioid sarcoma.
CHAPTER 4 Soft Tissue
A B
FIGURE 4-17
Malignant peripheral nerve sheath tumor: touch preparation. The tumor is hypercellular and composed of spindle and epithelioid cells. Considerable
cytologic atypia is usually demonstrated. Note the prominent nucleoli. Diff-Quik stain, high power.
FIGURE 4-18
Malignant peripheral nerve sheath tumor: FNAB. The tumor cells are
predominantly spindled with elongated cytoplasmic processes. Note the
presence of necrotic debris in the background. Papanicolaou stain, high
power.
SKELETAL MUSCLE TUMORS
RHABDOMYOSARCOMA
CLINICAL FEATURES
Rhabdomyosarcomas (RMSs) are generally divided
into three types: embryonal (ERMS), alveolar (ARMS),
and pleomorphic (PRMS). RMSs are rapidly growing
tumors and present with symptoms secondary to mass
effect.
ERMSs are the most common RMS in children. They
occur predominantly in the head and neck (50%),
followed by the genitourinary tract (30%) and the
109
RHABDOMYOSARCOMA – DISEASE FACT SHEET
Incidence
៉ Embryonal rhabdomyosarcoma (ERMS): most common sarcoma in
children
៉ Alveolar rhabdomyosarcoma (ARMS): less common than ERMS
៉ Pleomorphic rhabdomyosarcoma (PRMS): rare
Location
៉ ERMS: most common sites are the head and neck, and
genitourinary tract; spindle cell variant arises in scrotal area, and
head and neck; botryoid variant arises in the urinary bladder,
biliary tract, and pharynx
៉ ARMS: most common in the extremities, perineum, paraspinal
area, and paranasal sinuses
៉ PRMS: most common in the lower extremities
Gender, Race, and Age Distribution
៉ ERMS: slight male predilection; incidence is higher in Caucasians;
most common variant of rhabdomyosarcoma in children less than
15 years of age (45% occur in those less than 5 years of age)
៉ ARMS: no sex predilection; no racial predilection; more common
in adolescent and young adults
៉ PRMS: male predilection; no race predilection; adult population
(6th decade); very rare in children
extremities (10%), and less commonly in other sites
(10%). Head and neck ERMSs usually present as pro-
ptosis, diplopia, or hearing loss. Botryoid ERMSs repre-
sent a distinct subtype arising in a submucosal location,
mostly from the urinary bladder, vagina, and bile ducts.
In these organs, the patients may present with hematu-
ria, obstructive uropathy, or jaundice.
ARMSs occur more frequently in the extremities or
paranasal sinuses of adolescents and young adults and
may have similar manifestation as ERMSs. On occasion,
widespread dissemination of the tumor is noted at the
time of diagnosis.
110
The rare PRMSs arise from the lower extremities of
adults.
PATHOLOGIC FEATURES
Histologically, rhabdomyoblasts range from round to
stellate and are usually identified in either paucicellular
myxoid foci or densely populated aggregates of primi-
tive cells. Botryoid ERMSs are characterized by the
presence of a cambium layer which is a cellular band
of neoplastic cells beneath the mucosal surface.
ARMSs are composed of relatively small round cells
devoid of prominent nucleoli, aggregating as nests sepa-
rated by thin vascularized septae. The cellular nests may
undergo degenerative changes and fixation artifact
resulting in the formation of a central ‘cavity’ filled with
detached tumor cells. The solid variants of ARMSs have
a nested pattern of tumor cells separated by fibrocollag-
enous septa. PRMSs are high-grade pleomorphic sarco-
mas composed of bizarre tumor cells showing morphologic
or immunohistochemical evidence of skeletal muscle
differentiation.
FNAB of RMSs is usually markedly cellular, consist-
ing of tissue fragments and dissociated cells. ERMSs
(Fig. 4-19) tend to have an admixture of primitive-
appearing round cells and variable forms of rhabdomyo-
blasts including ‘spider’ cells or ‘strap’/‘tadpole’ cells
with occasional demonstrable striations. The latter cells
are also seen in PRMSs and, to a lesser extent, in
ARMSs. A myxoid and collagenous stroma may be
exceptionally abundant in any of the RMS subtypes.
Uniform round cells with pink cytoplasm and eccentri-
cally located nuclei are the typical findings in ARMSs
(Fig. 4-20). The presence of such cells helps to distin-
guish ARMSs from other differential diagnostic consid-
erations of small round cell tumors. Spindle ERMSs
consist principally of elongated slender cells, some with
A B
FIGURE 4-19
Rhabdomyosarcoma, embryonal type: FNAB. Aspirates are usually cellular. The tumor cells are predominantly round cells with a high N/C ratio.
Tumor cells may have eccentrically placed nuclei and a scant eosinophilic cytoplasm. Papanicolaou stain, high power.
FINE NEEDLE ASPIRATION CYTOLOGY
RHABDOMYOSARCOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Embryonal rhabdomyosarcoma (ERMS): admixture of round cells
and rhabdomyoblasts (spider cells, tennis-racket cells, or strap
cells) with demonstrable striations; elongated cells are common
in the spindle cell variant
៉ Alveolar rhabdomyosarcoma (ARMS): relatively monomorphic
population of round cells with eccentrically located nuclei;
cytoplasmic vacuoles may be present
៉ Pleomorphic rhabdomyosarcoma (PRMS): bizarre tumor cells with
demonstrable striations in some cells; mitotic figures are easy
to find
Immunohistochemistry
៉ ERMS: positive for vimentin, MyoD1, myogenin, desmin, actin,
and myoglobin; rare expression of cytokeratin, S-100, Leu7,
neuron-specific enolase, neurofilament, CD99, and B-cell markers
(CD20)
៉ ARMS: same immunophenotype; may be negative for myogenin
៉ PRMS: same immunophenotype
Genetics
៉ ERMS: complex karyotype; allelic loss in chromosomal region
11p15
៉ ARMS: about 90% of cases, t(2;13)(q35;q14); less common,
t(1;13)(p36;q14); PAX3/FKHR and PAX7/FKHR fusion transcripts
៉ PRMS: complex karyotype
Differential Diagnosis and Pitfalls
៉ ERMS: carcinoma, melanoma, ARMS, and epithelioid sarcoma
៉ Spindle ERMS: spindle cell tumors including fibrosarcoma,
synovial sarcoma, leiomyosarcoma, malignant peripheral nerve
sheath tumor, and melanoma
៉ ARMS: alveolar soft part sarcoma, renal cell carcinoma,
epithelioid sarcoma, and melanoma
៉ PRMS: pleomorphic sarcomas, and carcinomas
CHAPTER 4 Soft Tissue
A B
FIGURE 4-20
Rhabdomyosarcoma, alveolar type: FNAB. The tumor cells are round and uniform in size, indistinguishable from other entities under the ‘small round
blue cell tumor’ category. Cells with more abundant cytoplasm (B, arrow) are rare, but, when present, they suggest a skeletal muscle differentia-
tion. Papanicolaou stain, high power.
demonstrable striations. The tumor cells of PRMSs are
expectedly large with great variation in size and
shape.
ANCILLARY STUDIES
All variants of RMSs share a similar immunopheno-
type. MyoD1 and myogenin (nuclear stain) are highly
specific for skeletal muscle differentiation, and about
90% of RMSs express these antibodies. Myoglobin is
not commonly used due to high background staining
and may not stain less differentiated RMSs. RMSs
also stain with desmin and actins (SMA and MSA).
Ultrastructural studies may reveal diagnostic features
including thick and thin fi laments and rudimentary
sarcomeres.
Of the three histologic types, ARMSs have the most
consistent cytogenetic abnormality: t(2;13)(q35;q14) and
t(1;13)(p36;q14). Usually, these translocations are part
of a more complex karyotype. The fusion transcripts
(PAX3/FKHR and PAX7/FKHR) act as transcriptional
activators and can be demonstrated by RT-PCR. It has
been reported that allelic loss in chromosomal region
11p15 is common among ERMSs. The karyotype of both
ERMSs and PRMSs is often complex.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis of ARMSs encompasses
other small round cell tumors including lymphoma,
111
Ewing/peripheral nerve sheath tumor (PNET), neuro-
blastoma, and desmoplastic small round cell tumor.
Pulmonary small cell carcinoma, poorly differentiated
squamous cell carcinoma, and Merkel cell carcinoma
are also included in the cytologic differentials; however,
these neoplasms are only encountered in adults. When
an alveolar pattern is prominent, alveolar soft part
sarcoma may be difficult to discriminate from ARMSs
in small tissue biopsies; desmin may be positive in both
tumors, further compounding the dilemma. Additional
tumors with a prominent alveolar pattern such as
renal cell carcinoma, epithelioid sarcoma, and mela-
noma may resemble ARMSs.
Other spindle cell tumors such as synovial sarcoma,
rhabdomyoma, and even reactive conditions (postopera-
tive spindle cell nodules) should be differentiated from
ERMSs in the urinary bladder and scrotal area. Poorly
differentiated variants of other sarcomas and carcino-
mas are indistinguishable from PRMSs except for the
presence of scattered rhabdomyoblasts.
In all three types of RMSs, demonstration of rhabdo-
myoblasts is supportive of the diagnosis. Antibodies
against skeletal muscle differentiation (MyoD1 and
myogenin) are quite specific and often essential for
diagnosis. Triton tumors have true rhabdomyoblastic
differentiation and have to be taken into consideration
in the evaluation. Prudence should be exercised not to
mistake entrapped and regenerating non-neoplastic
skeletal muscle fibers as rhabdomyoblasts. Other anti-
bodies including epithelial, smooth muscle, hematolym-
phoid, and other markers directed to the entities in the
differential diagnosis may be necessary. When adequate
tissue is available, samples for cytogenetic, molecular,
and ultrastructural examinations should be submitted
to assist in problematic cases.
112
SMOOTH MUSCLE TUMORS
LEIOMYOSARCOMA
CLINICAL FEATURES
The common sites of leiomyosarcomas (LMSs) are
the uterus, deep large vessels (pulmonary vessels,
inferior vena cava, and vessels of the extremities), and
dermis. The latter tend to have a more indolent behav-
ior. Symptoms secondary to obstruction of large vessels,
such as Budd–Chiari syndrome, superior vena cava
syndrome, renal hypertension, or leg edema, may be
the initial manifestation of the deep-seated LMSs.
LEIOMYOSARCOMA – DISEASE FACT SHEET
Incidence and Location
៉ Most common in the uterus
៉ In the soft tissue, leiomyosarcomas (LMSs) account for 10–15% of
soft tissue tumors; most common in the retroperitoneum
Gender, Race, and Age Distribution
៉ Soft tissue LMSs: female predilection for retroperitoneal and
inferior vena cava LMS; other sites including large vessel or
dermal LMS, no sex predilection; most common in middle-aged
but also affects children
៉ Uterine LMSs: more common in black women; more common in
middle-aged or elderly patients (median age, 50–55 years)
A
FIGURE 4-21
Leiomyosarcoma: FNAB. The aspirated materials are usually cellular. The tumor cells are typically spindled with cigar-shaped nuclei. A fascicular
arrangement may be suggested by tight cohesion of cells (B). A, Diff-Quik stain, high power. B, Papanicolaou stain, high power.
FINE NEEDLE ASPIRATION CYTOLOGY
PATHOLOGIC FEATURES
Histologically, LMSs are composed of spindle-shaped
tumor cells forming short fascicles that intersect at
right angles. The tumor cells have rounded ends, and,
occasionally, epithelioid variants may be encountered.
Mitotic activity may be brisk. The stroma is usually
fibrocollagenous. The histologic criteria applied for the
diagnosis of LMSs may differ according to the site of
origin.
Uterine LMSs are not sampled by fine needle aspira-
tion. Primary LMSs of the large vessels and, less com-
monly, dermal LMSs may be aspirated. Most aspirated
LMSs are from tumors metastatic to the lungs or other
visceral organs. The aspirates of LMSs are usually
cellular and consist of cohesive spindle-shaped tumor
cells arranged in fascicles (Figs 4-21 & 4-22). The
cytoplasm may have fine granules. The spindle cells
typically have cigar-shaped (blunt-ended) nuclei. Less
differentiated forms of LMSs may consist of atypical
poorly cohesive polygonal cells. Bizarre pleomorphic
tumor cells may be present. Epithelioid LMSs consist
predominantly of uniform or markedly pleomorphic
tumor cells with hyperchromasia, pleomorphism, mitotic
figures, and prominent nucleoli. Necrosis may be
present. The stroma in all types of LMSs can be fibro-
collagenous or myxoid.
ANCILLARY STUDIES
LMSs are invariably positive for SMA (Fig. 4-22B) and
MSA, and less frequently for desmin, particularly in
poorly differentiated types. Caldesmon and calponin
are two other antibodies expressed by smooth muscle-
derived neoplasms. LMSs may be positive for CK and
B
CHAPTER 4 Soft Tissue 113

A B

FIGURE 4-22
Leiomyosarcoma: needle core biopsy. A, The tumor cells form short fascicles characteristically intersecting at right angles. H&E stain, low-power.
B, Smooth muscle actin is invariably expressed. Smooth muscle actin, low power.

There is no specific karyotypic aberration, and chro-

LEIOMYOSARCOMA – PATHOLOGIC FEATURES mosomal analysis usually shows multiple and complex
abnormalities.
Cytopathologic Findings
៉ Fairly cellular aspirates composed of predominantly spindle
cells; cigar-shaped nuclei; occasionally, epithelioid cells and
pleomorphic cells predominate
DIFFERENTIAL DIAGNOSIS AND PITFALLS
៉ Spindle tumor cells have elongated cytoplasm
៉ Stroma is myxocollagenous
Other spindle cell tumors such as dermatofibrosarcoma
protuberans (DFSP), fibrosarcoma, malignant periph-
Immunohistochemistry
eral nerve sheath tumor, synovial sarcoma (SS), angio-
៉ Positive for smooth muscle actin, caldesmon, desmin, and
sarcoma, gastrointestinal stromal tumors (GIST), and
calponin
៉ May be positive for cytokeratin and epithelial membrane
mesenteric fibromatosis enter the differential diagno-
antigen sis. Tumors originating from a vessel wall suggest a
៉ Negative for CD34, S-100, CD117, and β-catenin smooth muscle origin. Expression of muscle markers
(SMA, MSA, caldesmon, calponin, and desmin) sup-
Electron Microscopy ports the diagnosis of LMSs. The immunohistochemi-
៉ Actin filaments with focal densities, cell junctions, pinocytotic cal panel should include S-100 protein, CD34, CD117,
vesicles, and basement membrane and β-catenin to assist in the differential diagnosis.
Rarely, cytogenetic and ultrastructural studies are
Genetics resorted to in the confirmation of the diagnosis.
៉ Complex karyotype Although there is no specific cytogenetic abnormality
៉ RB1 gene abnormality may be detected of LMSs, entities with specific aberrations, including
SS and DFSP, can be detected by genetic analysis.
Differential Diagnosis and Pitfalls
៉ Spindle cell sarcomas including dermatofibrosarcoma
protuberans, fibrosarcoma, synovial sarcoma, malignant
peripheral nerve sheath tumor, and angiosarcoma VASCULAR TUMORS
៉ Gastrointestinal stromal tumors (GIST), mesenteric fibromatosis
៉ Presence of pleomorphic cells broadens the differential
diagnosis
ANGIOSARCOMA

EMA in up to 30% of cases. LMSs do not express S-100 CLINICAL FEATURES

and CD117, and rarely CD34. Whereas uterine LMSs
are positive for estrogen and progesterone receptors,
LMSs from other organs are negative. Ultrastructur-
ally, presence of actin fi laments with focal densities in
the cytoplasm, suggestive of smooth muscle differentia-
tion, may be demonstrated.
Angiosarcomas (ASs) may arise sporadically, associated
with syndromes (neurofibromatosis, Klippel–Trenaunay
syndrome, and Maffucci syndrome), or related to expo-
sure to chemicals including therapeutic and diagnostic
114
ANGIOSARCOMA – DISEASE FACT SHEET
Incidence
៉ Rare tumor
Location
៉ Sporadic angiosarcoma: deep soft tissue of extremities, head and
neck, trunk, and visceral organs
៉ Postradiation angiosarcoma: chest wall and breast tissue, and any
tissue in the field of exposure
Gender and Age Distribution
៉ Sporadic angiosarcoma: more common in elderly patients, without
sex predilection
៉ Postradiation angiosarcoma: middle-aged to elderly women
agents (radiation, Thorotrast, foreign body implants,
arsenic-containing insecticides, and vinyl chloride).
The common locations for sporadic AS are the scalp
and deep soft tissue. Postradiation ASs, most commonly
seen in patients treated for breast carcinoma, often
arise in the chest wall and breast tissue. ASs may
present as cutaneous plaques, subcutaneous nodules, or
soft tissue mass lesions. Non-specific symptoms related
to visceral organ involvement, such as gastrointestinal
bleeding or obstruction, may precede the discovery of
visceral AS. Epithelioid and poorly differentiated ASs
are aggressive tumors and may rapidly metastasize.
PATHOLOGIC FEATURES
Histologically, the spectrum of ASs varies from well-
differentiated innocuous vessel-forming lesion to
high-grade malignant tumor that mimics carcinoma. A
A
FIGURE 4-23
Angiosarcoma: FNAB. The aspirates are variably cellular, often in a hemorrhagic background. High-grade angiosarcomas usually exhibit an epithelioid
cytomorphology. Intracytoplasmic lumina are not regularly demonstrated. Note prominent nucleoli in (B). A, Papanicolaou stain, high power.
B, Diff-Quik stain, high power.
FINE NEEDLE ASPIRATION CYTOLOGY
ANGIOSARCOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Variable cellularity; predominantly spindle cells, rarely
epithelioid (polygonal) and plasmacytoid cells; intracytoplasmic
lumen containing red blood cells may be seen
៉ Hemorrhagic background
Immunohistochemistry
៉ Positive for vimentin, CD31, CD34, and factor VIII-related
antigen
៉ 50% are positive for cytokeratin and epithelial membrane
antigen
Electron Microscopy
៉ Weibel-Palade bodies are definitive for angiosarcomas but rarely
demonstrated
Genetics
៉ Complex karyotype
៉ No specific genetic defect
Differential Diagnosis and Pitfalls
៉ Spindle angiosarcomas: other vascular tumors including
hemangioma and Kaposi sarcoma, and other spindle cell
sarcomas including fibrosarcoma, leiomyosarcoma, and malignant
peripheral nerve sheath tumor
៉ Epithelioid angiosarcomas: epithelioid hemangioendothelioma,
carcinoma, and epithelioid mesenchymal tumors (epithelioid
sarcoma, synovial sarcoma, malignant peripheral nerve sheath
tumor)
helpful clue to the correct diagnosis is the presence of
intracytoplasmic lumina containing red blood cells.
Aspirates from ASs are often bloody with a variable
number of tumor cells (Fig. 4-23). The tumor cells may
be spindle-shaped, polygonal (epithelioid), or plasma-
B
CHAPTER 4 Soft Tissue
cytoid cells. Epithelioid AS may mimic carcinoma or
other mesenchymal lesions with epithelioid features.
Sheets of pleomorphic tumor cells are seen in poorly dif-
ferentiated ASs. Mitoses may be frequent, and intracyto-
plasmic hemosiderin pigment may be seen. Identification
of intracytoplasmic lumina with red blood cells is an
important feature of ASs; however, this feature may be
more difficult to appreciate in cytologic preparations.
ANCILLARY STUDIES
Most ASs express commonly used endothelial markers
(CD31, CD34, and factor VIII-related antigen). Some
ASs, particularly the epithelioid variants, are also
immunoreactive to CK and EMA. EM can demonstrate
Weibel-Palade bodies, which are regarded as specific
organelles for endothelial cells; however, these are
rarely identified in proven cases of ASs.
The karyotype of ASs is usually complex and without
specific genetic abnormalities.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis depends on the degree of
differentiation of an AS. Well-differentiated ASs can be
mistaken for hemangioma or Kaposi sarcoma. Less dif-
ferentiated ASs may present with solid sheets of spindle
cells that may be indistinguishable from other spindle
cell sarcomas such as fibrosarcoma, malignant fibrous
histiocytoma, and leiomyosarcoma. Epithelioid variants
of AS can resemble any epithelial/epithelioid neoplasms.
CK and EMA expression of ASs can further add to the
difficulty in the differential diagnosis. In general,
unusually bloody aspirates should suggest possibility of
a vascular lesion. Cytologically, the presence of cyto-
plasmic lumina with red blood cells, and intracyto-
plasmic hemosiderin are also suggestive of endothelial
differentiation. In the right clinical background and cell
morphology, expression of CD31, CD34, and/or factor
VIII-related antigen confirms the diagnosis of ASs.
GASTROINTESTINAL STROMAL TUMOR
CLINICAL FEATURES
Gastrointestinal stromal tumors (GISTs) arise from the
wall of the GI tract and occasionally in adjacent tissues
such as the omentum and mesentery. The stomach is
most frequently affected, followed in order of frequency
by the small intestine, colon, and esophagus. A common
presentation is mucosal ulceration which may lead to
hemorrhage, intestinal obstruction or perforation, and
other non-specific abdominal symptoms secondary to
115
GASTROINTESTINAL STROMAL TUMOR – DISEASE FACT SHEET
Incidence
៉ 7–14.5 per million population per year
Location
៉ Stomach – 51%
៉ Small intestine – 36%
៉ Colon and rectum – 12%
៉ Esophagus – 1%
៉ Mesentery, omentum, and extra-abdominal sites – rare
Gender, Race, and Age Distribution
៉ Slight male predilection
៉ Black women are affected six times more frequently than white
women
៉ Mean age – 63 years
mass effect. However, in some instances, the fi rst pre-
sentation is a metastasis, usually within the peritoneal
cavity, liver, or mesentery. The diagnosis of GIST is
usually established by endoscopic ultrasound-guided or
percutaneous FNAB.
PATHOLOGIC FEATURES
The histology of GISTs ranges from spindle cells in
fascicles to nested epithelioid cells to patternless clus-
tering of pleomorphic cells.
GASTROINTESTINAL STROMAL TUMOR – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellular aspirates; admixture of clustered or singly scattered
tumor cells; tumor cells form three-dimensional clusters
៉ Myxocollagenous stroma
Immunohistochemistry
៉ Positive for CD117 (almost all cases), CD34 (60–70%), smooth
muscle actin (30–40%), and, rarely, desmin and S-100 protein
(<5%)
៉ CD117 negative cases are positive for PDGFRA mutation
Genetics
៉ Common losses in chromosomes 14 and 22
៉ Mutation in exons 11, 9, or 13 of c-kit gene
៉ Mutation of PDGFR in c-kit-negative GISTs
Differential Diagnosis and Pitfalls
៉ Spindle GISTs: smooth muscle tumors, infl ammatory fibroid
polyp, infl ammatory myofibroblastic tumor, fibromatosis, solitary
fibrous tumor, dedifferentiated liposarcoma, malignant
peripheral nerve sheath tumor, spindle cell carcinoma,
melanoma, and reactive nodular fibrous pseudotumor
៉ Epithelioid GISTs: carcinoma and melanoma
៉ Pleomorphic GISTs: malignant fibrous histiocytoma, carcinoma,
and pleomorphic sarcomas
116 FINE NEEDLE ASPIRATION CYTOLOGY

A B

FIGURES 4-24
Gastrointestinal stromal tumor: FNAB. The aspirates are usually cellular. The component cells may have spindle (A), oval/round (B), epithelioid, or
pleomorphic cytology, and usually with abundant myxocollagenous stroma. A, Diff-Quik stain, low power. B, Diff-Quik stain, high power.

A B

FIGURE 4-25
Gastrointestinal stromal tumor: cell block. A, The spindle tumor cells are arranged in short fascicles with moderate fibrocollagenous stroma. H&E
stain, medium power. B, The tumor cells are strongly positive for CD117. Note the adjacent gastric epithelium. CD117, medium power.

FNAB smears are usually cellular (Fig. 4-24). Cell
block preparation may exhibit typical fascicular arrange-
ment of cells (Fig. 4-25). The tumor cells appear as
clusters, often in three-dimensional forms or palisades
admixed with single cells. The individually scattered
cells are often devoid of their cytoplasm. Where intact
cells are demonstrated, the cytoplasmic processes are
often delicate. Generally, the nuclei are relatively
uniform, ovoid to spindled, and often wavy with blunt
or tapered ends. Nuclear grooves and intranuclear inclu-
sions have been reported, particularly in epithelioid
variants. A combination of spindle and epithelioid
lesional cells may be encountered. The background
usually consists of myxocollagenous stroma.
ANCILLARY STUDIES
Approximately 95% of GISTs express c-kit (CD117) by
immunohistochemistry (Fig. 4-25B). The c-kit negative
GISTs have been shown to be immunoreactive for
PDGFRA (platet-derived growth factor receptor-α). Up
to 90% of these neoplasms also react with CD34, which
appears to be influenced by the site of the tumor.
Esophageal and rectal GISTs are known to have a
higher incidence of CD34 expression compared with
gastric and small intestine GISTs. Less than one-third
of GISTs are SMA-positive and much less frequently
(5%) desmin-positive. GISTs often express caldesmon.
CHAPTER 4 Soft Tissue
The genetics of GISTs have been extensively studied.
There is a gain-of-function mutation of c-kit, a growth
factor transmembrane receptor, leading to activation of
proteins in the signal transduction pathway and result-
ing in cell proliferation. C-kit mutations often involve
exons 11 and 9. Some of the c-kit-negative GISTs have
been shown to have mutation of PDGFRA, another
tyrosine kinase receptor. Common cytogenetic abnor-
malities include loss of chromosomes 14, 15, and 22.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
There is a long list of entities that cytologically resem-
ble GISTs. These include true smooth muscle tumors
of the GI tract, inflammatory myofibroblastic tumor,
inflammatory fibroid polyp, fibromatosis, solitary
fibrous tumor, dedifferentiated liposarcoma, malignant
peripheral nerve sheath tumor, carcinoma, and meta-
static melanoma. Pleomorphic GISTs are indistinguish-
able from other pleomorphic tumors of both epithelial
and mesenchymal origin. The importance of accurate
diagnosis lies in the good response of GISTs to imatinib
mesylate (Gleevae), a selective inhibitor of tyrosine
kinases including c-kit and PDGFRA.
Melanoma may express CD117, so other antibodies
(S-100 protein, HMB-45, and Melan A) should be
included in the laboratory work-up if melanoma is sus-
pected. Although some of the neoplasms listed above are
CD34-positive, none consistently express CD117. Car-
cinomas with small cell component may be positive for
CD117, but CK expression is rarely observed in GISTs.
More problematic cases are the CD117-negative GIST.
PDGFRA may be of help in some of these tumors. Muta-
tional analysis in most of these cases will show c-kit or
PDGFRA mutations. In the right histomorphology and
site of origin (most c-kit-negative GISTs arise from the
peritoneum and omentum), these tumors should be con-
sidered as GISTs. A recently described lesion, reactive
nodular fibrous pseudotumor, is CD117-positive and
may be difficult to discriminate from GISTs without the
benefit of clinical history and ancillary studies.
TUMORS OF UNCERTAIN HISTOGENESIS
MYXOMA
CLINICAL FEATURES
Myxomas are subclassified into three clinicopathologic
types: intramuscular myxomas (IMs), juxta-articular
myxomas ( JMs), and cutaneous myxomas (CMs) or
superficial angiomyxomas. IMs often arise in the thigh
muscles as a painless, soft and fluctuant mass. JMs are
usually located close to a large joint, most commonly
117
MYXOMA – DISEASE FACT SHEET
Incidence
៉ Intramuscular myxoma (IM): relatively common tumor
៉ Juxta-articular myxoma (JM): rare
៉ Cutaneous myxoma (CM) or superficial angiomyxoma: rare;
association with Carney syndrome
Location
៉ IM: thigh, buttocks, shoulder, and trunk
៉ JM: near knee, shoulder, elbow, and ankle joints
៉ CM: trunk, thigh, and head and neck
Gender, Race, and Age Distribution
៉ IM: female predilection; no race predilection; middle-aged to
elderly patients
៉ JM: male predilection; no race predilection; middle-aged patients
៉ CM: no sex predilection; no race predilection; young and middle-
aged patients
the knee joint, but can occur in the shoulder or elbow.
CMs may be multiple and are distributed in the trunk,
head and neck, and extremities. When CMs are multi-
ple, Carney complex (familial myxoma syndrome)
should be suspected.
PATHOLOGIC FEATURES
Histologically, the tumor cells are usually scant with
abundant myxoid stroma. The tumor vascularity is
often minimal to non-existent in IMs and JMs, but CMs
may have focally prominent capillaries.
MYXOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Low cellularity and abundant myxoid stroma; tumor cells are
spindle-shaped with a low N/C ratio; cytoplasm is bipolar with
elongated processes; absence of vascular channels
Immunohistochemistry
៉ Positive for vimentin
៉ May be positive for CD34, desmin, and smooth muscle actin
៉ Negative for S-100 protein
Genetics
៉ Intramuscular myxoma: mutation in GNAS1 gene
៉ Juxta-articular myxoma: no specific genetic abnormality; GNAS1
gene mutation is absent
៉ Cutaneous myxoma: association with Carney complex; mutation
in 17q22–24 locus (PRKAR1A gene)
Differential Diagnosis and Pitfalls
៉ Scar, and benign and malignant tumors with myxoid stroma
(benign fibrous histiocytoma, fibromatosis, dermatofibrosarcoma
protuberans, myxoid liposarcoma, low-grade fibromyxoid
sarcoma, and myxoid malignant fibrous histiocytoma)
118
A B
FIGURE 4-26
Myxoma: touch preparation. The tumor is often hypocellular and composed mainly of thin myxoid stroma. The bland-appearing tumor cells are
elongated with long cytoplasmic processes. Vascular channels are usually not identified. Diff-Quik stain, high power.
Aspirates from these tumors yield clear viscous fluid.
The smears are generally paucicellular with profuse
myxoid material in the background (Fig. 4-26). The
tumor cells are elongated and bland with long cytoplas-
mic processes. The N/C ratio is low and nucleoli are
not conspicuous. Aspirated capillary channels are quite
rare. Other entrapped or surrounding mesenchymal ele-
ments such as skeletal muscle, fat, or fibrocollagenous
tissue may be present in the aspirates.
ANCILLARY STUDIES
The lesional cells of myxoma may be positive for CD34,
desmin, and SMA. S-100 protein is not expressed.
Point mutation of the GNAS1 gene appears to be a
consistent abnormality of IMs but not JMs and CMs.
CMs associated with Carney complex may have muta-
tion of the suppressor gene – protein kinase A type I-α
(PRKAR1A) gene.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Several sarcomas may have spindle cells and myxoid
stroma, including malignant fibrous histiocytoma, low-
grade fibromyxoid sarcoma, and liposarcoma, particu-
larly the myxoid variant. Other benign and low-grade
sarcomas with myxoid component in the differential
diagnosis are fibromatosis, benign fibrous histiocy-
toma, and dermatofibrosarcoma protuberans.
The presence of bland-appearing spindle cells with
elongated cytoplasmic processes and absent or minimal
vascular channels in the aspirate support the diagnosis
of myxoma and exclude most of the entities listed in the
differential diagnosis. The malignant neoplasms with
FINE NEEDLE ASPIRATION CYTOLOGY
myxoid stroma invariably contain markedly atypical
cells and, in most occasions, moderate amount of
vascular channels.
Immunohistochemistry is of limited use in myxoma
owing to the absence of specific antibody associated
with the tumor; however, absence of expression of anti-
bodies known to be positive in other tumors (e.g. S-100
protein expression of myxoid liposarcoma) assists in the
differential diagnosis. Mutational analysis directed to
GNAS1 (for IMs) and PRKAR1A (for CMs) genes may
help establish the diagnosis.
EPITHELIOID SARCOMA
CLINICAL FEATURES
Epithelioid sarcomas commonly affect young and
middle-aged male patients. The distal types often
EPITHELIOID SARCOMA – DISEASE FACT SHEET
Incidence and Location
៉ Rare tumors
៉ Associated with tendons and aponeurosis of the distal extremities
(distal type) and deep soft tissue of the proximal extremities
(proximal type)
Gender, Race, and Age Distribution
៉ Male predilection
៉ No race predilection
៉ Young and middle aged adults for distal type; older age for
proximal type
CHAPTER 4 Soft Tissue 119

present as slow-growing subcutaneous nodules in the

fingers, palm, and wrist. The proximal types often
arise from the buttocks or thigh as deep-seated mass
lesions. The mode of spread is through regional lymph
nodes. Frequently, the tumor tracks along the tendon
and aponeurosis before reaching the lymph nodes.
Distant metastases are usually to the lungs.
PATHOLOGIC FEATURES
Histologically, the tumor cells form nests separated
by fibrocollagenous stroma. The most characteristic
feature of epithelioid sarcomas is the presence of central
necrosis surrounded by palisading tumor cells. The
tumor cells are spindle or polygonal with eosinophilic
cytoplasm, moderately pleomorphic nuclei, and small
nucleoli.
The aspirated material is usually highly cellular (Fig.
4-27). Due to the fibrocollagenous elements of some
tumors, occasional paucicellular aspirates can be
expected. The tumor cells are usually round or poly-
gonal. Infrequently, spindle-shaped cells may predomi-
nate. The neoplastic cells may also assume a rhabdoid
or plasmacytoid appearance. Moderate to severe atypia,
abundant mitotic figures, necrosis, and prominent
nucleoli are common in the proximal types of epitheli-
oid sarcomas. Loosely cohesive clusters of polygonal and
epithelioid cells and a background of necrosis may
recapitulate a granulomatous histology.
ANCILLARY STUDIES
Aside from vimentin, epithelioid sarcomas also con-
sistently express CK and EMA. Approximately 50%
EPITHELIOID SARCOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Spindle and polygonal cells with moderately pleomorphic nuclei
and variable nucleolar prominence; necrosis may be present;
palisading of aspirated tumor cells and necrosis may resemble
granulomas
៉ Proximal-type epithelioid sarcomas appear more undifferentiated
with a high N/C ratio and round or polygonal tumor cells
Immunohistochemistry
៉ Positive for cytokeratin, epithelial membrane antigen, and V-
cadherin; 50% are positive for CD34; variable expression of
desmin, muscle-specific actin (HHF-35), and smooth muscle
actin
៉ Negative for E-cadherin and S-100
Genetics
៉ No consistent karyotypic abnormality
Differential Diagnosis and Pitfalls
៉ Granuloma annulare, carcinoma, melanoma, rhabdomyosarcoma,
alveolar soft part sarcoma, synovial sarcoma, malignant
peripheral nerve sheath tumor, and epithelioid angiosarcoma
are positive for CD34. Epithelioid sarcomas may
stain with muscle markers including desmin, MSA
(HHF-35), and SMA. The tumor is consistently nega-
tive for S-100 protein, but may occasionally express
HMB-45.
The ultrastructural features of tumor cells range
from epithelial to fibroblast-like mesenchymal cells.
There is no specific chromosomal or genetic abnormal-
ity identified so far.

A
B

FIGURE 4-27
Epithelioid sarcoma: FNAB. FNAB materials are often cellular. The tumor cells are round or polygonal and indistinguishable from other epithelial
malignancies. Necrosis may be apparent on the aspirated material (A). A, Papanicolaou stain, medium power. B, Diff-Quik stain, high power.
120
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Epithelioid sarcomas can mimic granuloma annulare
(GA), carcinoma, and other epithelioid-appearing
sarcomas including alveolar soft part sarcoma (ASPS),
synovial sarcoma (SS), and epithelioid angiosarcoma
(AS). The frequent location of the tumor on the hand
and the presence of prominent central necrosis may be
interpreted as representing GA. Attention to the cyto-
logic atypia in the surrounding cells should prompt a
consideration of epithelioid sarcoma. The typical
location of the tumor, pure epithelioid lesional cells,
and expression of epithelial markers substantiate the
diagnosis.
Immunohistochemical stains are usually necessary
mainly to rule out other entities in the differential diag-
nosis: expression of CD31 and factor VIII-related antigen
for AS, CD68 for GA. Other ancillary studies are
intended to exclude other entities with specific ultra-
structural or genetic features, such as rhomboid crystals
and t(X;17) of ASPS, Weibel-Palade bodies of AS, or
t(X;18) of SS.
ALVEOLAR SOFT PART SARCOMA
CLINICAL FEATURES
Alveolar soft part sarcomas (ASPSs) are rare neoplasms
that present as slow-growing deep-seated tumors in the
lower extremities, particularly the thigh, usually in
young males. Other reported sites for ASPSs are the
orbit and tongue in children. ASPSs may also present
as metastatic lesions, particularly in the lungs, bone,
and brain.
A B
FIGURE 4-28
Alveolar soft part sarcoma: touch preparation. The tumor is usually cellular and composed of round or polygonal cells with abundant finely granular
cytoplasm, imparting a deceptively low N/C ratio. The nuclei, some devoid of cytoplasm, are round and smooth-outlined. Diff-Quik stain, high
power.
FINE NEEDLE ASPIRATION CYTOLOGY
ALVEOLAR SOFT PART SARCOMA – DISEASE FACT SHEET
Incidence and Location
៉ Rare tumor: 0.5–0.9% of soft tissue tumors
៉ Lower extremities (41% in thigh or buttocks); orbit and tongue in
children
Gender, Race, and Age Distribution
៉ Female predilection before age of 30 years; slight male
predilection after 30 years
៉ No race predilection
PATHOLOGIC FEATURES
The characteristic histology of ASPSs is that of a nested
pattern of tumor cells forming a central cavity partially
fi lled with dissociated tumor cells and thin septae
separating each nest. The tumor cells are polygonal
with ample eosinophilic cytoplasm and eccentrically
placed nuclei.
The aspirated material is cellular and composed of
tight aggregates or singly dispersed tumor cells (Fig.
4-28). The lesional cells are composed of relatively large
round cells with a low N/C ratio. Binucleation and
multinucleation are frequently seen with the nuclei
exhibiting conspicuous nucleoli. The nuclei are round
with smooth outline, and of variable size. The abundant
cytoplasm is finely granular. Due to the fragility of the
cytoplasm, scattered naked nuclei are often prominent
in the background. Branching capillaries may be associ-
ated with clusters of tumor cells. Myxocollagenous
stroma is rarely prominent.
CHAPTER 4 Soft Tissue
ALVEOLAR SOFT PART SARCOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellular aspirates; relatively large round cells with eosinophilic
and granular cytoplasm; nuclei are round and nucleoli are small;
mitotic figures are rare
៉ Stroma is usually scant
Immunohistochemistry
៉ No specific immunophenotype
៉ May be positive for desmin and S-100
៉ Negative for synaptophysin, chromogranin, cytokeratin, and
epithelial membrane antigen
Electron Microscopy
៉ Rhomboid crystals, free or membrane-bound
Genetics
៉ der(17) t(X;17) (p11.2;q25)
៉ ASPL/TFE3 fusion product
Differential Diagnosis and Pitfalls
៉ Paraganglioma, epithelioid sarcoma, renal cell carcinoma,
alveolar rhabdomyosarcoma, and melanoma
ANCILLARY STUDIES
The only antibody that ASPSs consistently express is
vimentin. ASPSs are variably reactive to desmin, and
occasionally reactive to SMA, MSA, and S-100 protein.
The tumor is non-reactive to MyoD1 and myogenin.
Epithelial and neuroendocrine markers are negative.
The characteristic intracytoplasmic crystals can be
appreciated as periodic acid–Schiff (PAS)-positive
needle-shaped crystals in tumor cells. These membrane-
bound or free rhomboid crystals can be demonstrated
by EM. A non-balanced translocation, t(X;17)(p11;q25),
resulting in fusion of TFE3 (Xp11) with ASPL (17q25)
appear to be specific for ASPS. The fusion product
(TFE3/ASPL) can be demonstrated by PCR analysis.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The distinctive alveolar pattern of ASPSs and its mod-
erate, sometimes clear cytoplasm are shared by other
tumors including alveolar rhabdomyosarcoma (ARMS),
paraganglioma, renal cell carcinoma (RCC), and granu-
lar cell tumor (GCT). Immunohistochemistry is often
performed to exclude other tumors in the differential
diagnosis. ARMSs are consistently positive for MyoD1
and myogenin; paraganglioma, for neuroendocrine
markers; RCC, for CK and vimentin; and GCT, for
S-100 protein and CD68. On occasions, ASPSs may
express desmin and S-100 protein, so a complete panel
of antibodies should be run to effectively exclude other
121
tumors. It is prudent to submit a portion of the tumor,
when adequate material is available, for EM, cyto-
genetic, and/or molecular studies.
SYNOVIAL SARCOMA
CLINICAL FEATURES
The majority of synovial sarcomas (SSs) are usually
slow-growing tumors which arise from soft tissue of
the extremities, often in the thigh. Less common sites
include the upper extremities, trunk, and head and
neck region. Patients may complain of pain, numbness,
paresthesia, or some loss of function of the involved
extremity. Incompletely excised tumor may locally
recur. Metastasis is usually to the lungs.
PATHOLOGIC FEATURES
Histologically, three types are currently recognized:
biphasic type, monophasic type, and poorly differenti-
ated type. The biphasic SSs consist of spindle cells and
epithelial cells often with glandular differentiation.
The monophasic SSs are composed purely of spindle
cells or plump cells with foci of cellular evidence of
epithelial differentiation manifested immunohisto-
chemically by expression of CK. Poorly differentiated
SSs (PDSSs) are composed of rather round or oval cells
that are indistinguishable from other small round cell
tumors. Immunohistochemical stains and molecular
studies are necessary to establish the diagnosis of
PDSSs.
FNAB of SSs is usually hypercellular (Figs 4-29 &
4-30). Singly dispersed lesional cells and tumor
tissue fragments, sometimes branched, are frequently
obtained. Myxofibrous stroma accompanies aggregates
of spindle cells or chunks of tumor. Singly dispersed
neoplastic cells are often stripped of their cytoplasm.
The tumor cell nuclei have fine chromatin and
inconspicuous nucleoli. The cytoplasm is elongated
with bipolar processes. Spindle-shaped tumor cells
SYNOVIAL SARCOMA – DISEASE FACT SHEET
Incidence and Location
៉ ∼10% of soft tissue tumors
៉ Extremities, trunk, and neck and head regions
Gender, Race, and Age Distribution
៉ Slight male predilection
៉ No race predilection
៉ Young adults and children (median age, 30–35 years)
122 FINE NEEDLE ASPIRATION CYTOLOGY

predominate even in biphasic SSs. Epithelial elements

SYNOVIAL SARCOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Biphasic SS: cellular aspirates; spindle cells predominate; scant
or absent epithelial cells; myxocollagenous stroma
៉ Monophasic SS: cellular aspirates; spindle cells with comma-
shaped nuclei; myxocollagenous stroma
៉ Poorly differentiated SS: cellular aspirates; oval or round cells;
spindle and epithelial cells may be present; myxocollagenous
stroma
of biphasic SSs may stand out as three-dimensional
clusters or gland-forming cuboidal or polygonal cells
associated with mucinous material. Squamous epithelial
elements are infrequent. The neoplastic cells of mono-
phasic SSs appear as ‘comma’-shaped cells and are
indistinguishable from spindle cells of biphasic SSs. The
tumor cells of PDSSs are round or oval, and relatively
small sized, with a high N/C ratio. In all three variants
of SSs, markedly pleomorphic cells are uncommon.

Immunohistochemistry
៉ Biphasic SS:
៉ Epithelial cells: positive for cytokeratin (CK), epithelial
membrane antigen (EMA), vimentin, HBME1 and calretinin,
and, less frequently, CD99; negative for bcl-2
៉ Stromal cells: positive for vimentin and bcl-2, CD99 (60%),
S-100 protein (30%); negative for desmin and smooth muscle
actin; scattered CK-positive cells
៉ Monophasic SS: phenotype is similar to the stromal cells of biphasic
SS; patchy areas are positive for CK, EMA, CD99, and calretinin
៉ Poorly differentiated SS: phenotype is similar to the stromal
cells of biphasic SS; negative for WT1; patchy areas are positive
for CK, EMA, CD99, and calretinin
Genetics
៉ t(X;18)(p11.2;q11.2)
៉ SYT/SSX fusion transcript
Differential Diagnosis and Pitfalls
៉ Biphasic SS: malignant peripheral nerve sheath tumor (MPNST)
with glandular component and carcinosarcoma
៉ Monophasic SS: neurofibroma, fibromatosis, solitary fibrous
tumor, fibrosarcoma, low-grade fibromyxoid sarcoma, MPNST,
leiomyosarcoma and other spindle cell soft tissue tumors, and
carcinoma
៉ Poorly differentiated SS: small round cell tumors (Ewing sarcoma/
primitive neuroectodermal tumor, rhabdomyosarcoma, non-
Hodgkin lymphoma, desmoplastic small round cell tumor, and
other small round cell tumors in children; small cell carcinoma,
Merkel cell carcinoma, and non-Hodgkin lymphoma in adults)
ANCILLARY STUDIES
CK (Fig. 4-30B), EMA, and, less frequently, mesothelial
markers (HBME1 and calretinin) highlight the epithe-
lial cells of biphasic SSs, and some areas of monophasic
SSs and PDSSs. The stromal cells of biphasic SSs, and
the majority of lesional cells of monophasic SSs and
PDSSs are positive for vimentin, bcl-2, and CD99. CK-
and EMA-positive foci of PDSSs may be minimal.
PDSSs are negative for WT1. SSs occasionally express
S-100 protein.
All variants of SSs exhibit t(X;18)(p11.2;q11.2), a
genetic abnormality not seen in other tumors. The chi-
meric transcript (SYT/SSX) results from fusion of the
SYT gene in chromosome 18 and SSX1, SSX2, or SSX4
in the X chromosome. The translocation can be demon-
strated by karyotyping, FISH, and RT-PCR.
The epithelial cells have ultrastructural characteris-
tics of glandular cells: desmosomal junctions and short
microvilli. Spindle cells have non-specific ultrastruc-
tural features. There is no transition from epithelial to
mesenchymal cells.

A B

FIGURE 4-29
Synovial sarcoma: FNAB. FNAB usually yields cellular smears. The tumor cells are spindled or round (poorly differentiated type), with a variable
amount of stroma. The epithelial component of the biphasic type is infrequently recognized in aspirates. A, Diff-Quik stain, low power.
B, Diff-Quik stain, high power.
CHAPTER 4 Soft Tissue
A B
FIGURE 4-30
Synovial sarcoma: cell block. Spindled stromal cells and strips of epithelial cells are identified in this cell block preparation. The epithelial cells
may be morphologically indistinguishable from the stromal cells, but are readily highlighted by cytokeratin stain (B). A, H&E stain, low power.
B, Cytokeratin stain, low power.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The spindle cells in biphasic SSs predominate and the
list of differential diagnoses is similar to that of mono-
phasic SS, including benign and malignant spindle cell
mesenchymal neoplasms such as neurofibroma, fibro-
matosis, fibrosarcoma, and glandular MPNST.
When the epithelial component of biphasic SS is rep-
resented in the aspirated material, other biphasic tumors
including MPNST and carcinosarcoma may be con-
sidered. The main cytomorphologic feature that favors
SS is the uniformity of the malignant stromal cells. In
contrast, the sarcomatous elements of MPNST and
carcinosarcoma are more pleomorphic.
PDSSs fall under the category of small round cell
tumors and the set of differential diagnoses vary with
the patient’s age. Neuroblastoma, non-Hodgkin lym-
phoma (NHL), Ewing sarcoma/primitive neuro-
ectodermal tumor (PNET), rhabdomyosarcoma, and
desmoplastic small round cell tumor should be consid-
ered in children. NHL, small cell carcinoma, and Merkel
cell carcinoma are the most frequently encountered
small round cell tumors in adults. Immunohistochemis-
try, flow cytometry, cytogenetic and/or molecular
studies are essential in arriving at a definitive
diagnosis.
SUGGESTED READINGS
General
Soft Tissue Tumors
Enzinger FM, Weiss SW, Goldblum JR. Enzinger and Weiss’s Soft Tissue
Tumors, 4th ed. St Louis, Mosby, 2001.
Fletcher CDM, Unni KK, Mertens F, eds. World Health Organization Classi-
fication of Tumors. Pathology and Genetics. Tumors of Soft Tissue and
Bone. Lyon, France: IARC Press, 2002.
Miettinen M. Diagnostic Soft Tissue Pathology. Philadelphia, Churchill
Livingstone, 2003.
123
Cytology of Soft Tissue
Abdul-Karim FW, Rader AE. Fine needle aspiration of soft-tissue lesions.
Clin Lab Med 1998;18:507–540.
Bennert KW, Abdul-Karim FW. Fine needle aspiration cytology vs. needle
core biopsy of soft tissue tumors. A comparison. Acta Cytol 1994;38:
381–384.
Das K, Hameed M, Heller D, et al. Liquid-based vs. conventional smears
in fine needle aspiration of bone and soft tissue tumors. Acta Cytol
2003;47:197–201.
Gonzalez-Campora R. Fine needle aspiration cytology of soft tissue tumors.
Acta Cytol 2000;44:337–343.
Gonzalez-Campora R. Cytoarchitectural findings in the diagnosis of primary
soft tissue tumors. Acta Cytol 2001;45:115–146.
Guiter GE, Gatscha RM, Zakowski MF. ThinPrep vs. conventional smears in
fine-needle aspirations of sarcomas: a morphological and immunocyto-
chemical study. Diagn Cytopathol 1999;21:351–354.
Jones C, Liu K, Hirschowitz S, et al. Concordance of histopathologic and
cytologic grading in musculoskeletal sarcomas: can grades obtained
from analysis of the fine-needle aspirates serve as the basis for thera-
peutic decisions? Cancer 2002;96:83–91.
Kilpatrick SE, Cappellari JO, Bos GD, et al. Is fine-needle aspiration biopsy
a practical alternative to open biopsy for the primary diagnosis of
sarcoma? Experience with 140 patients. Am J Clin Pathol 2001;115:
59–68.
Kilpatrick SE, Geisinger KR. Soft tissue sarcomas: the usefulness and limi-
tations of fine-needle aspiration biopsy. Am J Clin Pathol 1998;110:
50–68.
Kilpatrick SE, Ward WG, Cappellari JO, Bos GD. Fine-needle aspiration
biopsy of soft tissue sarcomas. A cytomorphologic analysis with empha-
sis on histologic subtyping, grading, and therapeutic significance. Am
J Clin Pathol 1999;112:179–188.
Kilpatrick SE, Ward WG, Chauvenet AR, Pettenati MJ. The role of fine-
needle aspiration biopsy in the initial diagnosis of pediatric bone and
soft tissue tumors: an institutional experience. Mod Pathol 1998;11:
923–928.
Maitra A, Ashfaq R, Saboorian MH, et al. The role of fine-needle aspiration
biopsy in the primary diagnosis of mesenchymal lesions: a community
hospital-based experience. Cancer 2000;90:178–185.
Mathur S, Kapila K, Verma K. Accuracy of cytological grading of spindle-
cell sarcomas. Diagn Cytopathol 2003;29:79–83.
Nagira K, Yamamoto T, Akisue T, et al. Reliability of fine-needle aspiration
biopsy in the initial diagnosis of soft-tissue lesions. Diagn Cytopathol
2002;27:354–361.
Palmer HE, Mukunyadzi P, Culbreth W, Thomas JR. Subgrouping and
grading of soft-tissue sarcomas by fine-needle aspiration cytology: a
histopathologic correlation study. Diagn Cytopathol. 2001;24:307–
316.
124
Powers CN, Berardo MD, Frable WJ. Fine-needle aspiration biopsy: pitfalls
in the diagnosis of spindle-cell lesions. Diagn Cytopathol 1994;10:
232–240.
Sapi Z, Antal I, Papai Z, et al. Diagnosis of soft tissue tumors by fine-
needle aspiration with combined cytopathology and ancillary tech-
niques. Diagn Cytopathol 2002;26:232–242.
Wakely PE Jr, Kneisl JS. Soft tissue aspiration cytopathology. Cancer
2000;90:292–298.
Weir MM, Rosenberg AE, Bell DA. Grading of spindle cell sarcomas in fine-
needle aspiration biopsy specimens. Am J Clin Pathol 1999;112:784–
790.
Lipoma and Liposarcoma
Akerman M, Rydholm A. Aspiration cytology of lipomatous tumors: a 10-
year experience at an orthopedic oncology center. Diagn Cytopathol
1987;3:295–302.
Bassett MD, Schuetze SM, Disteche C, et al. Deep-seated, well differenti-
ated lipomatous tumors of the chest wall and extremities: the role of
cytogenetics in classification and prognostication. Cancer 2005;103:
409–416.
Domanski HA, Carlen B, Jonsson K, et al. Distinct cytologic features of
spindle cell lipoma. A cytologic-histologic study with clinical, radio-
logic, electron microscopic, and cytogenetic correlations. Cancer 2001;
93:381–389.
Kapila K, Ghosal N, Gill SS, Verma K. Cytomorphology of lipomatous tumors
of soft tissue. Acta Cytol 2003;47:555–562.
Klijanienko J, Caillaud JM, Lagace R. Fine-needle aspiration in liposar-
coma: cytohistologic correlative study including well-differentiated,
myxoid, and pleomorphic variants. Diagn Cytopathol 2004;30:307–
312.
Vicandi B, Jimenez-Heffernan J, Lopez-Ferrer P, et al. Cytologic features
of round cell liposarcoma: a report on five patients. Cancer 2003;99:
28–32.
Walaas L, Kindblom LG. Lipomatous tumors: a correlative cytologic and
histologic study of 27 tumors examined by fine needle aspiration cytol-
ogy. Hum Pathol 1985;16:6–18.
Nodular Fasciitis
Aydin O, Oztuna V, Polat A. Three cases of nodular fasciitis: primary diag-
noses by fine needle aspiration cytology. Cytopathology 2001;12:
346–347.
Dahl I, Akerman M. Nodular fasciitis a correlative cytologic and histologic
study of 13 cases. Acta Cytol 1981;25:215–223.
Dodd LG, Martinez S. Fine-needle aspiration cytology of pseudosarcoma-
tous lesions of soft tissue. Diagn Cytopathol 2001;24:28–35.
Kong CS, Cha I. Nodular fasciitis: diagnosis by fine needle aspiration
biopsy. Acta Cytol 2004;48:473–477.
Plaza JA, Mayerson J, Wakely PE. Nodular fasciitis of the hand. A potential
diagnostic pitfall in fine-needle aspiration cytopathology. Am J Clin
Pathol 2005;123:388–393.
Willen H, Akerman M. Fine needle aspiration of nodular fasciitis – no need
for surgery. Acta Orthop Scand Suppl 1995;265:54–55.
Fibromatosis
Hayry P, Reitamo JJ, Totterman S, et al. The desmoid tumor. II. Analysis
of factors possibly contributing to the etiology and growth behavior.
Am J Clin Pathol 1982;77:674–680.
Raab SS, Silverman JF, McLeod DL, et al. Fine needle aspiration biopsy of
fibromatoses. Acta Cytol 1993;37:323–328.
Reitamo JJ, Scheinin TM, Hayry P. The desmoid syndrome. New aspects in
the cause, pathogenesis and treatment of the desmoid tumor. Am J Surg
1986;151:230–237.
Zaharopoulos P, Wong JY. Fine-needle aspiration cytology in fibromatoses.
Diagn Cytopathol 1992;8:73–78.
FINE NEEDLE ASPIRATION CYTOLOGY
Dermatofibrosarcoma Protuberans
Domanski HA, Gustafson P. Cytologic features of primary, recurrent, and
metastatic dermatofibrosarcoma protuberans. Cancer 2002;96:351–
361.
Klijanienko J, Caillaud JM, Lagace R. Fine-needle aspiration of primary and
recurrent dermatofibrosarcoma protuberans. Diagn Cytopathol
2004;30:261–265.
Klijanienko J, Caillaud JM, Lagace R. Fine-needle aspiration of primary and
recurrent benign fibrous histiocytoma: classic, aneurysmal, and myxoid
variants. Diagn Cytopathol 2004;31:387–391.
Mendenhall WM, Zlotecki RA, Scarborough MT. Dermatofibrosarcoma pro-
tuberans. Cancer 2004;101:2503–2508.
Malignant Fibrous Histiocytoma
Kilpatrick SE, Ward WG. Myxofibrosarcoma of soft tissues: cytomorphologic
analysis of a series. Diagn Cytopathol 1999;20:6–9.
Kilpatrick SE, Ward WG, Bos GD. The value of fine-needle aspiration biopsy
in the differential diagnosis of adult myxoid sarcoma. Cancer (Cancer
Cytopathol) 2000;90:167–177.
Klijanienko J, Caillaud JM, Lagace R, Vielh P. Comparative fine-needle
aspiration and pathologic study of malignant fibrous histiocytoma:
cytodiagnostic features of 95 tumors in 71 patients. Diagn Cytopathol
2003;29:320–326.
Merck C, Hagmar B. Myxofibrosarcoma: a correlative cytologic and histo-
logic study of 13 cases examined by fine needle aspiration cytology.
Acta Cytol 1980;24:137–144.
Neurofibroma and Schwannoma
Dahl I, Hagmar B, Idvall I. Benign solitary neurilemoma (schwannoma).
A correlative cytological and histological study of 28 cases. Acta Pathol
Microbiol Immunol Scand [A] 1984;92:91–101.
Ferretti M, Gusella PM, Mancini AM, et al. Progressive approach to the
cytologic diagnosis of retroperitoneal spindle cell tumors. Acta Cytol
1997;41:450–460.
Kong CS, Cha I. Nodular fasciitis: diagnosis by fine needle aspiration
biopsy. Acta Cytol 2004;48:473–477.
Mooney EE, Layfield LJ, Dodd LG. Fine-needle aspiration of neural lesions.
Diagn Cytopathol 1999;20:1–5.
Resnick JM, Fanning CV, Caraway NP, et al. Percutaneous needle biopsy
diagnosis of benign neurogenic neoplasms. Diagn Cytopathol 1997;16:
17–25.
Slagel DD, Powers CN, Melaragno MJ, et al. Spindle-cell lesions of the
mediastinum: diagnosis by fine-needle aspiration biopsy. Diagn Cyto-
pathol 1997;17:167–176.
Stelow EB, Lai R, Bardales RH, et al. Endoscopic ultrasound-guided fine-
needle aspiration cytology of peripheral nerve-sheath tumors. Diagn
Cytopathol 2004;30:172–177.
Granular Cell Tumor
Husain M, Nguyen GK. Cytopathology of granular-cell tumor of the lung.
Diagn Cytopathol 2000;23:294–295.
Liu K, Madden JF, Olatidoye BA, Dodd LG. Features of benign granular cell
tumor on fine needle aspiration. Acta Cytol 1999;43:552–557.
Liu Z, Mira JL, Vu H. Diagnosis of malignant granular cell tumor by fine
needle aspiration cytology: Acta Cytol 2001;45:1011–1021.
Wieczorek TJ, Krane JF, Domanski HA, et al. Cytologic findings in granular
cell tumors, with emphasis on the diagnosis of malignant granular cell
tumor by fine-needle aspiration biopsy. Cancer 2001;93:398–408.
Malignant Peripheral Nerve Sheath Tumor
Ferretti M, Gusella PM, Mancini AM, et al. Progressive approach to the
cytologic diagnosis of retroperitoneal spindle cell tumors. Acta Cytol
1997;41:450–460.
Klijanienko J, Caillaud JM, Lagace R, Vielh P. Cytohistologic correlations
of 24 malignant peripheral nerve sheath tumor (MPNST) in 17 patients:
the Institut Curie experience. Diagn Cytopathol 2002;27:103–108.
Mooney EE, Layfield LJ, Dodd LG. Fine-needle aspiration of neural lesions.
Diagn Cytopathol 1997;16:17–25.
CHAPTER 4 Soft Tissue
Resnick JM, Fanning CV, Caraway NP, et al. Percutaneous needle biopsy
diagnosis of benign neurogenic neoplasms. Diagn Cytopathol 1997;16:
17–25.
Vendraminelli R, Cavazzana AO, Poletti A, et al. Fine-needle aspiration
cytology of malignant nerve sheath tumors. Diagn Cytopathol 1992;8:
559–562.
Rhabdomyosarcoma
Brahmi U, Rajwanshi A, Joshi K, et al. Role of immunocytochemistry and
DNA flow cytometry in the fine-needle aspiration diagnosis of malignant
small round-cell tumors. Diagn Cytopathol 2001;24:233–239.
de Jong AS, van Kessel-van Vark M, van Heerde P. Fine needle aspiration
biopsy diagnosis of rhabdomyosarcoma. An immunocytochemical study.
Acta Cytol 1987;31:573–577.
Lussier C, Klijanienko J, Vielh P. Fine-needle aspiration of metastatic
nonlymphomatous tumors to the major salivary glands: a clinicopatho-
logic study of 40 cases cytologically diagnosed and histologically cor-
related. Cancer 2000;90:350–356.
Pohar-Marinsek Z, Anzic J, Jereb B. Topical topic: value of fine needle
aspiration biopsy in childhood rhabdomyosarcoma: twenty-six years of
experience in Slovenia. Med Pediatr Oncol 2002;38:416–420.
Pohar-Marinsek Z, Bracko M. Rhabdomyosarcoma. Cytomorphology, subtyp-
ing and differential diagnostic dilemmas. Acta Cytol 2000;44:
524–532.
Seidal T, Walaas L, Kindblom LG, Angervall L. Cytology of embryonal rhab-
domyosarcoma: a cytologic, light microscopic, electron microscopic, and
immunohistochemical study of seven cases. Diagn Cytopathol
1988;4:292–299.
Valencerina Gopez E, Dauterman J, Layfield LJ. Fine-needle aspiration
biopsy of alveolar rhabdomyosarcoma of the parotid: a case report and
review of the literature. Diagn Cytopathol 2001;24:249–252.
Leiomyosarcoma
Barbazza R, Chiarelli S, Quintarelli GF, Manconi R. Role of fine-needle
aspiration cytology in the preoperative evaluation of smooth muscle
tumors. Diagn Cytopathol 1997;16:326–330.
Ferretti M, Gusella PM, Mancini AM, et al. Progressive approach to the
cytologic diagnosis of retroperitoneal spindle cell tumors. Acta Cytol
1997;41:450–460.
Giuntoli RL II, Metzinger DS, DiMarco CS, et al. Retrospective review of
208 patients with leiomyosarcoma of the uterus: prognostic indicators,
surgical management, and adjuvant therapy. Gynecol Oncol 2003;89:
460–469.
Hornick JL, Fletcher CD. Criteria for malignancy in nonvisceral smooth
muscle tumors. Ann Diagn Pathol 2003;7:60–66.
Hummel P, Cangiarella JF, Cohen JM, et al. Transthoracic fine-needle
aspiration biopsy of pulmonary spindle cell and mesenchymal lesions:
a study of 61 cases. Cancer 2001;93:187–198.
Ito E, Saito T, Suzuki T, et al. Cytology of vaginal and uterine sarcomas.
Acta Cytol 2004;48:601–607.
Klijanienko J, Caillaud JM, Lagace R, Vielh P. Fine-needle aspiration of
leiomyosarcoma: a correlative cytohistopathological study of 96 tumors
in 68 patients. Diagn Cytopathol 2003;28:119–125.
Lin O, Olgac S, Zakowski M. Cytological features of epithelioid mesen-
chymal neoplasms: a study of 21 cases. Diagn Cytopathol 2005;32:
5–10.
Otano-Joos M, Mechtersheimer G, Ohl S, et al. Detection of chromosomal
imbalances in leiomyosarcoma by comparative genomic hybridization
and interphase cytogenetics. Cytogenet Cell Genet 2000;90:86–92.
Tao LC, Davidson DD. Aspiration biopsy cytology of smooth muscle tumors.
A cytologic approach to the differentiation between leiomyosarcoma
and leiomyoma. Acta Cytol 1993;37:300–308.
Angiosarcoma
Boucher LD, Swanson PE, Stanley MW, et al. Cytology of angiosarcoma.
Findings in fourteen fine-needle aspiration biopsy specimens and one
pleural fluid specimen. Am J Clin Pathol 2000;114:210–219.
Klijanienko J, Caillaud JM, Lagace R, Vielh P. Cytohistologic correlations
in angiosarcoma including classic and epithelioid variants: Institut
Curie’s experience. Diagn Cytopathol 2003;29:140–145.
Lin O, Olgac S, Zakowski M. Cytological features of epithelioid mesenchy-
mal neoplasms: a study of 21 cases. Diagn Cytopathol 2005;32:5–10.
125
Liu K, Layfield LJ. Cytomorphologic features of angiosarcoma on fine
needle aspiration biopsy. Acta Cytol 1999;43:407–415.
Mullick SS, Mody DR, Schwartz MR. Angiosarcoma at unusual sites. A report
of two cases with aspiration cytology and diagnostic pitfalls. Acta Cytol
1997;41:839–844.
Wakely PE Jr, Frable WJ, Kneisl JS. Aspiration cytopathology of epithelioid
angiosarcoma. Cancer. 2000;90:245–251.
Gastrointestinal Stromal Tumor
Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal
stromal tumors: a consensus approach. Hum Pathol 2002;33:459–
465.
Heinrich MC, Rubin BP, Longley BJ, Fletcher JA. Biology and genetic
aspects of gastrointestinal stromal tumors: KIT activation and cyto-
genetic alterations. Hum Pathol 2002;33:484–495.
Rader AE, Avery A, Wait CL, et al. Fine-needle aspiration biopsy diagnosis
of gastrointestinal stromal tumors using morphology, immunocytochem-
istry, and mutational analysis of c-kit. Cancer 2001;93:269–275.
Rossi G, Valli R, Bertolini F, et al. PDGFRA expression in differential
diagnosis between KIT negative gastrointestinal stromal tumours and
other primary soft-tissue tumours of the gastrointestinal tract. Histo-
pathology 2005;46:522–531.
Wieczorek TJ, Faquin WC, Rubin BP, Cibas ES. Cytologic diagnosis of gastro-
intestinal stromal tumor with emphasis on the differential diagnosis
with leiomyosarcoma. Cancer 2001;93:276–287.
Yantiss RK, Nielsen GP, Lauwers GY, Rosenberg AE. Reactive nodular fibrous
pseudotumor of the gastrointestinal tract and mesentery: a clinico-
pathologic study of five cases. Am J Surg Pathol 2003;27:
532–540.
Myxoma
Akerman M, Rydholm A. Aspiration cytology of intramuscular myxoma. A
comparative clinical, cytologic and histologic study of ten cases. Acta
Cytol 1983;27:505–510.
Caraway NP, Staerkel GA, Fanning CV, et al. Diagnosing intramuscular
myxoma by fine-needle aspiration: a multidisciplinary approach. Diagn
Cytopathol 1994;11:255–261.
Fornage BD, Romsdahl MM. Intramuscular myxoma: sonographic appear-
ance and sonographically guided needle biopsy. J Ultrasound Med
1994;13:91–94.
Gonzalez-Campora R, Otal-Salaverri C, Hevia-Vazquez A, et al. Fine needle
aspiration in myxoid tumors of the soft tissues. Acta Cytol 1990;34:
179–191.
Silver WP, Harrelson JM, Scully SP. Intramuscular myxoma: a clinicopatho-
logic study of 17 patients. Clin Orthop Relat Res 2002;(403):
191–197.
Wakely PE Jr, Geisinger KR, Cappellari JO, et al. Fine-needle aspiration
cytopathology of soft tissue: chondromyxoid and myxoid lesions. Diagn
Cytopathol 1995;12:101–105.
Epithelioid Sarcoma
Cardillo M, Zakowski MF, Lin O. Fine-needle aspiration of epithelioid
sarcoma: cytology findings in nine cases. Cancer 2001;93:246–251.
Gonzalez-Peramato P, Jimenez-Heffernan JA, Cuevas J. Fine-needle aspira-
tion cytology of ‘proximal-type’ epithelioid sarcoma. Diagn Cytopathol
2001;25:122–125.
Kitagawa Y, Ito H, Sawaizumi T, et al. Fine needle aspiration cytology of
primary epithelioid sarcoma. A report of 2 cases. Acta Cytol 2004;48:
391–396.
Lin O, Olgac S, Zakowski M. Cytological features of epithelioid mesenchymal
neoplasms: a study of 21 cases. Diagn Cytopathol 2005;32:5–10.
Zeppa P, Errico ME, Palombini L. Epithelioid sarcoma: report of two cases
diagnosed by fine-needle aspiration biopsy with immunocytochemical
correlation. Diagn Cytopathol 1999;21:405–408.
Alveolar Soft Part Sarcoma
Lopez-Ferrer P, Jimenez-Heffernan JA, Vicandi B, et al. Cytologic features
of alveolar soft part sarcoma: report of three cases. Diagn Cytopathol
2002;27:115–119.
126
Shabb N, Sneige N, Fanning CV, Dekmezian R. Fine-needle aspiration cytol-
ogy of alveolar soft-part sarcoma. Diagn Cytopathol 1991;7:293–
298.
Synovial Sarcoma
Akerman M, Ryd W, Skytting B; Scandinavian Sarcoma Group. Fine-needle
aspiration of synovial sarcoma: criteria for diagnosis: retrospective
FINE NEEDLE ASPIRATION CYTOLOGY
reexamination of 37 cases, including ancillary diagnostics. A Scandina-
vian Sarcoma Group study. Diagn Cytopathol 2003;28:232–238.
Ewing CA, Zakowski MF, Lin O. Monophasic synovial sarcoma: a cytologic
spectrum. Diagn Cytopathol 2004;30:19–23.
Klijanienko J, Caillaud JM, Lagace R, Vielh P. Cytohistologic correlations
in 56 synovial sarcomas in 36 patients: the Institut Curie experience.
Diagn Cytopathol 2002;27:96–102.
 5 Breast
Shahla Masood
MASTITIS, ABSCESS, AND FAT NECROSIS
Inflammation of the breast as the result of lactation,
infection, or trauma often presents as a palpable breast
lesion with varying degrees of pain and tenderness.
Acute supportive mastitis is typically seen in 1% to
3% of lactating women in the postpartum period. The
most common organisms are staphylococci and strep-
tococci. When inflammation localizes, acute mastitis
often results in an abscess and rarely leads to chronic
mastitis with periductal inflammation, duct ectasia,
fibrohistiocytic reaction, and mononuclear chronic
inflammatory infi ltrate.
Cytologically, smears are cellular and contain abun-
dant numbers of inflammatory infiltrates, histiocytes
with evidence of cytophagocytosis and nuclear debris.
Isolated and clusters of epithelial cells with reactive
atypia are also present (Fig. 5-1). The differential
diagnosis includes subareolar abscess, granulomatous
mastitis, and fat necrosis with organized hematoma.
Subareolar abscess is a specific clinicopathologic
entity, which was first described by Zuka et al as a low-
grade infection in the lactiferous duct or sinus with
subsequent abscess formation, chronic recurrent infec-
tion, and fistula formation at the base of the nipple.
Suggestion has been made that squamous metaplasia of
columnar epithelial cells of the lactiferous ducts is the
cause of this lesion. The breast aspirate shows rich
cellularity with abundant inflammatory cells and many
anucleated squamous cells, and keratinous material
(Fig. 5-2).
MASTITIS, ABSCESS, AND FAT NECROSIS – DISEASE FACT SHEET
Clinical Features
៉ Inflammatory conditions of the breast account for 5–10% of all
breast diseases
៉ Primary causes of inflammatory conditions of the breast are
lactation, infection, and trauma
៉ Approximately 70% of abscesses are non-lactational and only 30%
are related to puerperium
៉ Clinically, they present as a generalized cellulitis or a localized
mass which may be associated with pain and tenderness
៉ Clinically and mammographically, they may mimic carcinoma
៉ FNAB may serve as a diagnostic and therapeutic procedure
Ch005-F06731.indd 127
MASTITIS, ABSCESS, AND FAT NECROSIS –
PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellular aspirates
៉ Abundant infl ammatory cells
៉ Cytophagocytosis and granular debris in the background
៉ Epithelial cells with nuclear enlargement and prominent nucleoli
៉ Occasional multinucleated cells
៉ Macrophages
Ancillary Studies
៉ Microbiologic examination
៉ Culture and sensitivity
Differential Diagnosis and Pitfalls
៉ Subareolar abscess: cellular aspirate; abundant acute
infl ammatory cells; anucleated squamous cells and keratinous
material; macrophages and foreign body type giant cells
៉ Granulomatous mastitis: cellular aspirate; abundant chronic
infl ammatory cells, mostly lymphocytes and plasma cells;
granulomatous reaction and giant cells; fibroblasts and reactive
atypical epithelial cells
៉ Fat necrosis and organized hematoma: cellular aspirate; necrotic
background with granular debris; lipid and hemosiderin-
containing macrophages; multinucleated giant cells;
mononuclear infl ammatory cells; small, newly formed vessels;
reactive atypical epithelial cells; cholesterol crystals
Granulomatous mastitis is characterized by the
presence of granulomatous reaction and giant cell
formation. This entity is an inflammatory lesion of an
unknown etiology or may be the result of tuberculosis,
fungal infection, epidermal inclusion cyst, or foreign
body reaction such as suture and leakage from silicone
implants (Fig. 5-3).
Fat necrosis and organized hematoma are trauma-
induced inflammatory conditions that predominantly
present with foamy or hemosiderin-containing macro-
phages, lymphocytes, plasma cells, fibroblasts, fragments
of fibrous tissue, and newly formed vessels (Fig. 5-4).
Reactive epithelial atypia associated with fat necrosis
has resulted in false positive diagnosis of cancer. Mam-
mographically, fat necrosis with subsequent calcifica-
tion may also mimic a neoplastic process.
In the above-mentioned inflammatory conditions,
surgery can be avoided by the use of fine needle
127
10/26/2006 10:25:43 AM
 128
FIGURE 5-1
Direct smear of breast abscess: cellular aspirate containing abundant
acute infl ammatory infiltrate and a few isolated and clusters of epithe-
lial cells with infl ammatory atypia.
FIGURE 5-2
Direct smear of subareolar abscess: cellular aspirate with abundant
acute infl ammatory cells and squamous and anucleated cells.
aspiration biopsy (FNAB). In conjunction with micro-
biologic studies of the aspirated material, FNAB can
provide valuable information about the etiology of an
inflammatory condition of the breast. It can also serve
as a therapeutic modality.
TREATMENT-INDUCED CHANGES
Recent interest in breast cancer conservative therapy
and neoadjuvant chemotherapy has brought a new
diagnostic challenge for pathologists/cytopathologists.
The distinction between recurrent breast carcinoma
Ch005-F06731.indd 128
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 5-3
Direct smear of a granulomatous infl ammation: non-caseating granu-
loma with epithelioid cells, mononuclear infl ammatory cells, and giant
cells.
FIGURE 5-4
Direct smear of fat necrosis: cellular aspirate with amorphous material
in the background, acute infl ammatory cells, abundant macrophages,
and newly formed vessels.
TREATMENT-INDUCED CHANGES – DISEASE FACT SHEET
Clinical Features
៉ Patients often present with thickening and/or a skin nodule at
the site of previous operation or following radiation therapy
៉ Cytologic distinction between a reactive process and a recurrent
tumor is critical in further management
៉ Radiation-induced angiosarcoma can also present as a nodule
following conservation therapy
10/26/2006 10:25:44 AM
 CHAPTER 5 Breast 129

FIGURE 5-5 FIGURE 5-6

Direct smear of recurrent breast carcinoma following radiation therapy, Direct smear of recurrent breast carcinoma following radiation therapy:
characterized by isolated and clusters of highly pleomorphic epithelial higher magnification of the case seen in Fig. 5-5, highlighting necrosis
cells, macrophages, and necrosis in the background. and macronucleoli of neoplastic cells.

TREATMENT-INDUCED CHANGES – PATHOLOGIC FEATURES

Cytopathologic Findings
៉ Poor cellularity
៉ Granulation tissue
៉ Fat necrosis
៉ Epithelial atypia
៉ Granulatomous reaction
៉ Fibroblastic/spindle cell reaction
៉ Lymphoplasmacytic infiltration

Ancillary Studies
៉ Positive immunostaining reaction with endothelial cell markers

Differential Diagnosis and Pitfalls

៉ Recurrent tumor: rich cellularity; similar cytonuclear features to
the original tumor; conspicuous anisonucleosis with distinct
FIGURE 5-7
cell borders
៉ Angiosarcoma: moderate to rich cell yield; epithelioid and Direct smear of radiation-induced angiosarcoma: isolated, clustered,
and neoplastic spindle cells.
spindle cell pattern; various-sized nuclei with multiple nucleoli;
arborizing vessels and rosette-like structures

diagnosis of recurrent carcinoma in a sparsely cellular

and treatment-induced atypia is a difficult task, since
these entities present with overlapping features. It is
suggested that radiation-induced changes in the breast
exhibit three different patterns in FNAB smears. These
include epithelial atypia, fat necrosis, and poor cellular-
ity. In contrast, malignancy in an irradiated breast
presents with a cellular aspirate featuring loss of
cellular cohesion, arrangement of cells in small
clusters, anisonucleosis, conspicuous nucleoli, an irreg-
ular nuclear membrane, and necrosis (Figs 5-5 & 5-6).
In our own experience, the most important feature
in distinction between a radiation-induced change and
recurrent malignancy is the rich cellularity of the
aspirate. It may be advisable to refrain from making a
aspirate from an irradiated breast.
Radiation-induced angiosarcoma may also present as
a skin or subcutaneous nodule. This entity can easily be
mistaken for a recurrent carcinoma. Typically, patients
present with a discrete skin nodule several years after
breast conservation therapy. Cytologically, breast aspi-
rates yield moderate to high cellularity with a variable
cell pattern. Tumor cells are spindly and show positive
reaction for endothelial markers by immunocytochem-
istry. Often, a network of thin, arborizing vessels is seen
in the background. Tumor cells may form pseudo-
rosettes and have large nuclei with multiple nucleoli
(Figs 5-7 & 5-8). A high index of clinical suspicion is
the key factor in rendering an accurate diagnosis of
angiosarcoma by FNAB.

Ch005-F06731.indd 129 10/26/2006 10:25:46 AM

 130
FIGURE 5-8
Cell block preparation of same case as Fig. 5-7, a radiation-induced
angiosarcoma. Positive immunostaining with factor VIII.
FIGURE 5-9
Direct smear of treatment-induced changes following surgery, charac-
terized by the granulation tissue, new vessel formation, abundant
infl ammatory cells, and giant cell reaction.
Preoperative chemotherapy in locally advanced breast
carcinomas may also produce tissue reaction with and
without residual tumor. These tissue reactions are
similar to those with other forms of therapy, such as
granulomatous reaction, necrosis, and epithelial atypia.
In addition, the presence of a lymphoplasmacytic reac-
tion may be conspicuous.
Surgery-induced fibrosis and suture granulomas also
present with reactive inflammatory atypia that should
be separated from recurrent cancer. The typical form of
suture granuloma is characterized by the presence of
granulation tissue, granulomatous inflammation, histio-
cytes, mononuclear inflammatory cells, blood vessels,
and giant cells (Figs 5-9 & 5-10). Occasionally, retract-
able suture material can also be seen. However, exces-
sive amount of granulation tissue, atypical fat necrosis,
and atypical immature fibroblasts in surgery-induced
changes may be misinterpreted as a malignant tumor.
Ch005-F06731.indd 130
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 5-10
Direct smear of treatment-induced changes following surgery, showing
an ill-defined granuloma characterized by epithelioid cells, infl amma-
tory cells, and granular fibers.
Lack of cytologic similarity to the primary tumor and
predominance of spindle cells are important diagnostic
clues to exclude a recurrent tumor. Therefore it is criti-
cal to review the original pathology slides of each patient
for comparison.
HORMONAL CHANGES: SECRETORY,
PREGNANCY, AND LACTATIONAL CHANGES
The recognition of the spectrum of changes that reflect
the biologic attractions in normal mammary epithelial
cells is essential for the accurate interpretation of
various entities in breast pathology. The breast is a
hormone-dependent organ which undergoes puberty,
pregnancy, lactation, and involution and is influenced
by exogenous hormone effect. These changes may
introduce cytonuclear alterations that may be confused
with real disease process. The normal breast is a glan-
dular tissue with various amount of mammary adipose
tissue. During prepubertal and involutionary phases,
the aspirates are often hypocellular with a few ductal
HORMONAL CHANGES: SECRETORY, PREGNANCY, AND
LACTATIONAL CHANGES – DISEASE FACT SHEET
Clinical Features
៉ Pregnancy-associated lesions may present as galactocele,
lactating adenoma, and fibroderma
៉ The distinction between pregnancy in cancer and pregnancy-
associated changes is critical in evaluation of pregnant patients
with a palpable breast lesion
10/26/2006 10:25:46 AM
 CHAPTER 5 Breast
FIGURE 5-11
Direct smear of a pregnancy-associated change: cellular aspirate with
bubbly background, dispersed cell pattern, and a few macrophages.
HORMONAL CHANGES: SECRETORY, PREGNANCY, AND
LACTATIONAL CHANGES – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellular aspirate
៉ Proteinaceous background with bubbly appearance
៉ Dispersed cells and loosely arranged cell clusters
៉ Large epithelial cells with uniform nuclei and prominent
nucleoli
៉ Cytoplasmic vacuolization with fraying of cytoplasmic borders
៉ Bipolar naked nuclei, foamy macrophages, and occasional
multinucleated giant cells
Ancillary Studies
៉ Immunostain for myoepithelial cell markers
Differential Diagnosis and Pitfalls
៉ Cancer in pregnancy: high cellular yield; dispersed cell pattern
with intact cell borders; marked anisonucleosis and prominent
nucleoli; proteinaceous background
epithelial cells and fragments of fibroadipose tissue.
Secretory changes in mammary epithelial cells occur
in normal breast or in association with other entities
such as fibroderma, proliferative breast disease and in
association with a neoplastic process.
Pregnancy results in an increased number of acini
per lobule, with accumulation of secretory material in
the lobular epithelial cells. These changes occur de novo,
as a lactating adenoma or due to the enlargement of
pre-existing tumors such as tubular adenoma and fibro-
adenomas. Fine needle aspirates of pregnancy and
lactational changes are rich in cellularity with a bubbly
appearance and proteinaceous background. The cells
contain several secretory vacuoles with fraying of
cytoplasmic borders (Figs 5-11 & 5-12). Pregnancy-
Ch005-F06731.indd 131
131
FIGURE 5-12
Direct smear of a pregnancy-associated change: dispersed cell pattern
with enlarged cells, prominent nucleoli, granular debris in the back-
ground, and fraying of cytoplasmic borders.
FIGURE 5-13
Direct smear of a galactocele characterized by a cluster of epithelial
cells surrounded by abundant lipid-laden macrophages.
associated changes present as galactocele, lactating
adenoma, or fibroderma.
Galactoceles often present as a discrete and mobile
mass, which may increase in size during breastfeeding.
The mass regresses following FNAB. The smears show
low to moderate cellularity with numerous foamy cells,
proteinaceous background, and a few epithelial cells
with vacuolated cytoplasm (Fig. 5-13).
Lactating adenomas are initially noticed during preg-
nancy. Aspirates from lactating adenomas are cellular
and show grape-like clusters of epithelial cells similar to
expanded acini, attached to terminal ductules. The cells
and the background have all the features of hormone-
induced changes.
Fibrodermas become more conspicuous in size during
pregnancy. The cytologic features are similar to those
of lactating adenoma. In fibroadenomas there are
bipolar stripped nuclei, more stromal fragments, less
10/26/2006 10:25:47 AM
 132
FIGURE 5-14
Direct smear of primary breast cancer in pregnancy: isolated and clus-
ters of neoplastic epithelial cells with an intact cell membrane.
proteinaceous material, and lipid droplets in the back-
ground. They may contain a few giant cells. Pregnancy
and lactational changes often present with loosely
cohesive cellular aspirates with enlarged cells with con-
spicuous nucleoli. Those features mimic primary breast
carcinoma. This distinction is a diagnostic challenge,
particularly since pregnancy-associated changes can
also be seen in non-lactating women.
Primary breast carcinoma occurs in 1 out of 1000
pregnancies. Aside from anisonucleosis and chromatin
clumping, the most important cytologic feature in favor
of carcinoma is the presence of intact cell membrane in
the aspirated smears (Fig. 5-14).
FNAB is an effective initial tool in the evaluation of
pregnant women with a palpable mass. This approach
reduces the delay in the diagnosis of cancer in pregnant
and lactating women. Further follow-up and manage-
ment of a pregnant breast cancer patient depend on the
stage of pregnancy and the choice of the patient.
FIBROADENOMAS
Fibroadenomas are slow-growing tumors that are under
the influence of unopposed estrogen. They are the most
common tumor in young women and often present as
FIBROADENOMAS – DISEASE FACT SHEET
Clinical Features
៉ Most common benign tumor of the breast
៉ Often presents as a mobile breast mass
៉ Mammographically presents as a well-defined lesion
Ch005-F06731.indd 132
FINE NEEDLE ASPIRATION CYTOLOGY
FIBROADENOMAS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Highly cellular aspirate
៉ Biphasic pattern of stromal component and epithelial/
myoepithelial cells
៉ Sheets of monolayered ductal epithelial cells forming antler
horns
៉ Bipolar naked nuclei
៉ Occasional apocrine cells
៉ Rare multinucleated cells
Ancillary Studies
៉ Immunostain for myoepithelials cell markers
Differential Diagnosis and Pitfalls
៉ Proliferative breast disease: lack of stromal component; lack of
antler-horn pattern; lack of naked nuclei in the background
៉ Papillary lesions: presence of fibrovascular core; abundance of
macrophages; conspicuous columnar cell differentiation
៉ Low-grade carcinoma: absence of naked nuclei in the
background; absence of discrete stromal components; absence
of myoepithelial cells
៉ Phyllodes tumor: cellular stromal component; variable degree of
atypicality and mitosis
a small, solitary and painless nodule. Mammographi-
cally, they appear as well-defined lesions, and in 7% to
16% of cases, they may show evidence of multiplicity.
Carcinoma, often of lobular type, rarely occurs in fibro-
adenomas. Giant fibroadenomas are rapidly growing
fibroadenomas that occur in adolescent girls and they
may become as large as 19 cm.
Cytologically, fibroadenomas yield cellular aspirates
showing a biphasic pattern of epithelial and stromal
elements. The cell population displays two cell types:
epithelial and myoepithelial. The epithelial component
forms sheets of monolayered epithelial cells with clus-
ters forming antler-horn projections. Myoepithelial cells
are smaller and darker, and often spindly in appearance.
These cells appear in the background with bipolar and
naked nuclei and are admixed with epithelial cells (Fig.
5-15). Classical-pattern fibroadenomas are easy to diag-
nose; however, when they are associated with prolifera-
tive breast disease, undergo metaplastic change, or
are affected by hormones, they become atypical and
cellular. Loose edematous stroma occasionally displays
myxoid features mimicking mucinous carcinoma (Figs
5-15–5-20).
Cellular fibroadenomas are the most common cause
of false positive diagnosis in breast FNAB. Differential
diagnoses include proliferative breast disease, papillary
lesions, and low-grade carcinomas such as tubular car-
cinoma. In addition, distinction between fibroadenoma
and benign phyllodes tumor is difficult.
High cellularity, presence of a stromal component
that is distinctly separated from the epithelial compo-
nent, naked nuclei in the background, as well as antler-
horn cell clusters are the features that differentiate
between proliferative breast disease and fibroadenomas.
10/26/2006 10:25:49 AM
 FIGURE 5-15
Direct smear of a fibroadenoma characterized by a biphasic pattern,
showing isolated and clusters of epithelial/myoepithelial cells and the
associated stromal components. Note the presence of myoepithelial
cells as naked nuclei in the background.
FIGURE 5-17
Direct smear of a cellular fibroadenoma, showing higher magnification
of the same features as in Fig. 5-14.
FIGURE 5-19
Direct smear of a fibroadenoma with loose myxoid background, simulat-
ing mucoid carcinoma. The presence of myoepithelial cells in the back-
ground substantiates the diagnosis of fibroadenoma.
Ch005-F06731.indd 133
FIGURE 5-16
Direct smear of a cellular fibroadenoma characterized by a cellular
aspirate with isolated and clusters of epithelial/myoepithelial cells with
numerous naked nuclei in the background. The clusters show overriding
of the nuclei commonly seen in proliferative breast disease.
FIGURE 5-18
Direct smear of a cellular fibroadenoma associated with proliferative
breast disease. Another view of the same case as in Fig. 5-16, showing
the presence of a biphasic pattern commonly seen in fibroadenoma.
FIGURE 5-20
Direct smear of the fibroadenoma with myxoid stroma as seen in Fig.
5-17 and the associated antler-horn pattern seen in the same case.
10/26/2006 10:25:49 AM
 134
FIGURE 5-21
Direct smear of a benign phyllodes tumor characterized by a biphasic
pattern of epithelial/myoepithelial cells and the associated cellular
stroma.
Papillary lesions may also resemble a fibroadenoma.
Key features in favor of papillary lesions are high cellu-
larity and three-dimensional architecture of branched
epithelial clusters, the presence of fibrovascular cores,
various numbers of macrophages, apocrine cells, and
columnar epithelial cell clusters. Distinction between
tubular adenoma and fibroadenoma is usually not
possible because of overlapping features. However, this
distinction has no clinical implication.
Fibroadenomas are known to simulate carcinoma.
Extensive search for stromal elements and the presence
of myoepithelial cells are the features favoring a fibro-
adenoma. The myoepithelial origin of spindle cells can
be demonstrated by expression of myoepithelial cell
markers by immunocytochemistry.
The distinction between fibroadenoma and phyllodes
tumor in an aspirate is based on higher cellularity of
stromal elements seen in phyllodes tumors. These cases
should be checked for the presence of abnormal mitosis
and pleomorphism to exclude the possibility of a malig-
nant phyllodes tumor (Figs 5-21 & 5-22). It is important
to note that phyllodes tumors often occur in an older
age than fibroadenomas and present with a larger pal-
pable mass of over 4 cm. A follow-up surgical excision
of fibroadenomas with atypical features is the current
procedure.
PAPILLARY BREAST LESIONS
Papillary lesions of the breast constitute a spectrum of
pathologic entities ranging from intraductal papillomas
to papillary carcinomas. Intraductal papillomas, the
benign forms of papillary lesions, are solitary lesions
of the major ducts, commonly based in the subareolar
region. Papillomas often occur in postmenopausal
Ch005-F06731.indd 134
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 5-22
Direct smear of a benign phyllodes tumor: higher view of case shown
in Fig. 5-21, exhibiting cellular stroma characteristic of a phyllodes
tumor.
PAPILLARY BREAST LESIONS – DISEASE FACT SHEET
Clinical Features
៉ Uncommon tumors of the breast
៉ Occur in postmenopausal women
៉ Presenting symptoms are nipple discharge, nipple retraction, and
association with a palpable mass
៉ Complete removal of the lesion is the recommended procedure
PAPILLARY BREAST LESIONS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Intraductal papilloma: cellular aspirate; proteinaceous or bloody
background; three-dimensional papillary cell clusters; foamy or
hemosiderin-laden macrophages; myoepithelial cells; tall
columnar cells
៉ Papillary carcinoma: cellular aspirate; bloody background;
hemosiderin-laden macrophages; occasional necrotic debris;
papillary clusters of atypical cells enriched by a fibrovascular
core; large atypical nuclei; tall columnar cells; absence of
myoepithelial cells
៉ Intercystic papillary carcinoma: cellular aspirate; hemosiderin-
laden macrophages; monomorphic cell population;
anisonucleosis and pleomorphism; absence of myoepithelial
cells; papillary and/or cribriform pattern
Ancillary Studies
៉ Immunostains for myoepithelial cell markers
women and are frequently seen in the male breast.
Nipple discharge, nipple retraction, and a subareolar
mass are the pre-existing symptoms.
Cytologic diagnosis of intraductal papillomas can be
made by nipple fluid cytology or by the examination of
the breast FNAB. Cytologically, the aspirates are cellu-
10/26/2006 10:25:51 AM
 CHAPTER 5 Breast
FIGURE 5-23
Direct smear of an intraductal papilloma characterized by cellular aspi-
rate showing proliferating epithelial cells with myoepithelial cells in
the background.
FIGURE 5-24
Direct smear of an intraductal papilloma showing proliferating cells
forming various architectural patterns.
lar and contain a proteinaceous background and con-
spicuous numbers of macrophages. Three-dimensional
cell balls, tall columnar cells, apocrine cells, and myo-
epithelial cells are also present (Figs 5-23–5-26).
Distinction between an intraductal papilloma and
well-differentiated papillary carcinoma may be some-
what difficult. These entities share common cytologic
features. However, papillary carcinomas often present
with a monomorphic and uniform-appearing cell
population with no evidence of myoepithelial cell dif-
ferentiation. There are also no apocrine cells (Figs
5-27–5-29).
Papillary carcinomas account for 1% to 2% of breast
cancers and are associated with a good prognosis. Bloody
discharge is the most common presenting symptom, and
in 90% of cases, a mass can be palpated. There is also
Ch005-F06731.indd 135
135
FIGURE 5-25
Direct smear of an intraductal papilloma exhibiting a cell ball or three-
dimensional structure.
FIGURE 5-26
Direct smear of an intraductal papilloma showing clusters of apocrine
cells, columnar cells, and histiocytes in the background.
evidence of skin dimpling and nipple retraction. The
neoplastic cells may display a variety of patterns such
as cribriform and micropapillary. The absence of a myo-
epithelial cell layer is one of the most important charac-
teristics of papillary carcinoma (Fig. 5-30).
Another focus of papillary lesions of the breast is an
intracystic carcinoma. This is a rare breast tumor
accounting for 0.7% of all breast carcinomas. It fre-
quently occurs in black and obese women, with bloody
nipple discharge as the first presenting symptom. Breast
imaging shows a well-circumscribed cystic mass that
persists following FNAB. Cytologically, they mimic the
features seen in papillary carcinoma.
The diagnosis of papillary lesions of the breast by
FNAB requires complete excision of the lesion with a
rim of normal breast tissue. It is advisable to refrain
from attempting to do frozen section because of
10/26/2006 10:25:52 AM
 136
FIGURE 5-27
Direct smear of a papillary carcinoma characterized by highly cellular
aspirate of clusters of epithelial cells forming different architectural
patterns.
FIGURE 5-28
Direct smear of a papillary carcinoma showing isolated and clusters of
a monomorphic population of tumor cells with columnar cell differentia-
tion surrounding a fibrovascular core. No apocrine cells are seen.
experiencing the same difficulty in rendering a definite
diagnosis as in cytology.
FIBROCYSTIC CHANGE
Fibrocystic change represents a spectrum of changes
ranging from normal physiologic alterations to high-
risk proliferative breast disease. Cyst formation, apo-
crine neoplasia, stromal fibrosis, sclerosing adenosis,
and various degrees of epithelial hyperplasia are the
features of fibrocystic change. The association between
these morphologic changes and the subsequent
Ch005-F06731.indd 136
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 5-29
Direct smear of a papillary carcinoma showing a higher magnification
of a monomorphic cell population with columnar cell differentiation.
FIGURE 5-30
Immunostained slide: cell block preparation of a papillary carcinoma
with no evidence of myoepithelial cell differentiation.
FIBROCYSTIC CHANGE – DISEASE FACT SHEET
Clinical Features
៉ The most common breast lesions
៉ Present as a non-palpable breast lesion or as a palpable mass
៉ Asystematic density, mass effect, and calcification are the
common features in breast imaging
៉ The degree of proliferation correlates positively with the
incidence of subsequent development of breast cancer
៉ As a morphologic risk factor, recognition of atypical ductal
hyperplasia helps to stratify patients for risk-reduction modalities
10/26/2006 10:25:53 AM
 CHAPTER 5 Breast 137

Cytologically, a semiquantitative score, the ‘Masood

FIBROCYSTIC CHANGE – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Non-proliferative breast disease: low to moderate cellularity;
fragments of stroma and adipose tissue; monolayered cell
population with honeycomb pattern; histiocytes, apocrine cells,
and myoepithelial cells
៉ Proliferative breast disease without atypia: moderate to high
cellularity; abundant clusters of two-cell population of
epithelial/myoepithelial cells; conspicuous overriding of the
nuclei; occasional nucleoli and focal loss of polarity; apocrine
cells, histiocytes, and occasional calcified particles
៉ Proliferative breast disease with atypia (atypical ductal
hyperplasia): high cellularity; clustering of epithelial/
myoepithelial cells; marked crowding of nuclei forming slit-like
openings and loss of polarity; nuclear enlargement and
macronucleoli; chromatin clumping; occasional apocrine cells
and microcalcified particles
Cytology Index’, has been developed. This cytologic
grading system is based on the comparison of cytomor-
phology of mammographically detected breast fine
needle aspirates and their corresponding needle local-
ization excisional biopsies. Attempts have been made to
incorporate cellular arrangement with the traditional
nucleocytologic features and presence or absence of
myoepithelial cells (Tables 5-1 & 5-2). Controversy
regarding the use of this cytologic grading system in
clinical practice continues. However, this index has
been used as a morphologic risk factor in chemopreven-
tion trials (Fig. 5-31). Recently, an association between
the degree of morphologic abnormality defined by this
index and the frequency of expression of retinoic acid
receptor-β2 promoter methylation has been reported
(Fig. 5-32).

Ancillary Studies
៉ Immunostain for myoepithelial cell markers

Differential Diagnosis and Pitfalls

៉ Papillary lesions: tall columnar cells; hemosiderin-containing
24
macrophages; fibrovascular core
៉ Fibroadenoma: distinct stromal component; naked nuclei in the P<0.0001
background; antler-horn pattern
16
៉ Low nuclear grade ductal carcinoma in situ: monotonous cell
population; lack of myoepithelial cells Total high risk
cohort (N=480)
8
3.9% at 45 months

No FNA atypia (N=378)

0
development of breast cancer is now well established. 0 12 24 36 48 60 72 84 96 108
In addition, the new terminology of non-proliferative
Time from entry on study (months)
breast disease, proliferative breast disease without
atypia and proliferative breast disease with atypia FIGURE 5-31
(atypical hyperplasia), have replaced the commonly The relationship between cellular atypia in fine needle aspiration biopsy
used term fibrocystic disease. and increased risk for breast cancer.

TABLE 5-1
Masood Cytology Index

Cellular Cellular Myoepithelial Anisonucleosis Nucleoli Chromatin Score

arrangement pleomorphism cells clumping

Monolayer Absent Many Absent Absent Absent 1

Nuclear overlapping Mild Moderate Mild Micronucleoli Rare 2
Clustering Moderate Few Moderate Micro- and/or rare Occasional 3
macronucleoli
Loss of cohesion Conspicuous Absent Conspicuous Predominately Frequent 4
macronucleoli

Sum of scores: 6–10 Normal

11–14 Proliferative
15–18 Atypia
≥19 Suspicious for cancer
Modified from Masood S, Frykberg ER, McLellan GL, et al. Prospective evaluation of radiologically directed fine-needle
aspiration biopsy of nonpalpable breast lesions. Cancer 1990;66:1480–1487.

Ch005-F06731.indd 137 10/26/2006 10:25:55 AM

 138 FINE NEEDLE ASPIRATION CYTOLOGY

Methylation present Methylation absent

12
M3 RARbeta P2 methylation
10

Number RPFNA
8 FIGURE 5-32
6 The association between Masood Cytology
Index score and the expression of retinoic acid
4 receptor-β2 promoter methylation in random
periareolar fine needle aspiration.
2

0
10 11 12 13 14 15 >15
Masood cytology index

TABLE 5-2
Concordance Between Cytologic Evaluation and
Histologic Diagnosis in 100 Mammographically Guided
Fine Needle Aspirates

Diagnosis No. of cases Concordance %

Non-proliferative breast 29/34 85

disease
Proliferative breast disease 15/17 88
without atypia
Proliferative breast disease 21/23 91
with atypia
Cancer 17/20 85

Modified from Masood S, Frykberg ER, McLellan GL, et al.

Cytologic differentiation between proliferative and FIGURE 5-33
nonproliferative breast tissue in mammographically guided Direct smear of non-proliferative breast disease characterized by a
fine-needle aspirates. Diagn Cytopathol 1991;7:581–590. monolayered cluster of epithelial/myoepithelial cells, a cluster of
apocrine cells, stromal fragments, and a few histiocytes.

monolayered sheets with a honeycomb pattern. Foam

NON-PROLIFERATIVE BREAST DISEASE
Non-proliferative breast disease may present as a cystic
lesion. This is a common condition which is often the
subject of FNAB. Cysts produce fluids that vary in
appearance from clear to opaque, dark brown, yellow–
green to bloody. Benign cysts are acellular with granu-
lar debris. Occasionally, a few epithelial cells/apocrine
cells may be present. If associated with duct ectasia or
chronic cystic mastitis, the smears are more cellular
and may contain inflammatory cells. Bloody cysts are
also often associated with papillary lesions. Rarely,
medullary carcinomas may become cystic and contain
atypical malignant cells. Since more than 99% of cysts
are benign, there is controversy regarding the need for
cytologic examination of clear cysts. It may be more
cost effective to limit cytologic analysis to the cysts that
are associated with a turbid or bloody appearance.
In non-cystic lesions, aspirates from a non-prolifera-
tive breast disease are characterized by scant or moder-
ate cellularity. The uniform ductal cells are arranged in
cells, apocrine cells, and myoepithelial cells are present
(Figs 5-33 & 5-34).
PROLIFERATIVE BREAST DISEASE
WITHOUT ATYPIA
FNAB of proliferative breast disease without atypia
presents with a higher cell yield and unique cellular
arrangement. The honeycomb monolayered arrange-
ment is changed to clusters of epithelial/myoepithelial
cells that show overriding of the nuclei, occasional loss
of polarity, and some variability in nuclear size. Micro-
nuclei are occasionally seen. Cytologic atypia is incon-
spicuous. Apocrine cells, histiocytes, and occasional
naked nuclei are seen in the background (Figs 5-35 &
5-36).
Differential diagnosis includes fibroadenoma and
papillary lesions. These conditions have overlapping
features. The presence of well-demarcated stroma,

Ch005-F06731.indd 138 10/26/2006 10:25:55 AM

 CHAPTER 5 Breast
FIGURE 5-34
Direct smear of non-proliferative breast disease: a cluster of reactive
apocrine cells with micronucleoli.
FIGURE 5-35
Direct smear of proliferative breast disease without atypia, character-
ized by clusters of proliferating epithelial/myoepithelial cells with
overriding of the nuclei and loss of honeycomb pattern.
various naked nuclei, and an antler-horn pattern
are the features of fibroadenoma. In papillary lesions,
hemosiderin-containing macrophages and polymorphic
populations of tall columnar cells forming papillae are
the differentiating features.
PROLIFERATIVE BREAST DISEASE WITH
ATYPIA (ATYPICAL HYPERPLASIA)
Breast aspirates of lesions with atypical hyperplasia are
characterized by rich cellularity composed of several
clusters of epithelial cells with conspicuous crowding
of the nuclei. The degree of overriding of nuclei forms
different-sized slits and openings with some loss of
Ch005-F06731.indd 139
139
FIGURE 5-36
Direct smear of proliferative breast disease without atypia: higher
magnification of the same case as in Fig. 5-35. Note the conspicuous
crowding of nuclei, with large, oval and pale epithelial cells intermixed
with small, dark and slender myoepithelial cells.
FIGURE 5-37
Direct smear of proliferative breast disease with atypia (atypical ductal
hyperplasia) characterized by a loosely cohesive cluster of proliferating
epithelial/myoepithelial cells with crowding of the nuclei and loss of
polarity forming various-sized slits and openings.
polarity of the contour of ductal elements. Nuclei
display a coarse chromatin pattern and there are some
variations in the cell nuclei. Intermingled with epithe-
lial cells are myoepithelial cells. Rare apocrine cells
and macrophages may also be present (Figs 5-37–
5-40). The differential diagnosis includes a low-grade
ductal carcinoma in situ. A monotonous cell arrange-
ment and the absence of myoepithelial cells are the
key differentiating features. Immunostaining for
myoepithelial cell markers is an important ancillary
study.
10/26/2006 10:25:55 AM
 140
FIGURE 5-38
Direct smear of proliferative breast disease with atypia: higher magni-
fication, highlighting the presence of micronucleoli, nuclear atypia,
intermixed myoepithelial cells, and various-sized cribriform-type
pattern of proliferation.
FIGURE 5-39
Direct smear of proliferative breast disease with atypia: high magnifica-
tion of another view, displaying nuclear features, architectural change,
and hyperchromasia.
DUCTAL CARCINOMA IN SITU
LOW NUCLEAR GRADE DUCTAL CARCINOMA
IN SITU (NON-COMEDO TYPE)
Distinction between atypical ductal hyperplasia and
low nuclear grade ductal carcinoma has remained a
diagnostic challenge in breast pathology. This difficulty
is compounded in interpretation of minimally invasive
specimens such as core needle biopsy and FNAB. It is
generally agreed that the diagnosis of atypical ductal
hyperplasia by any of these minimally invasive proce-
Ch005-F06731.indd 140
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 5-40
Direct smear of proliferative breast disease with atypia, showing an
isolated cluster of atypical epithelial cells. Note the persistence of
accompanying myoepithelial cells.
DUCTAL CARCINOMA IN SITU – DISEASE FACT SHEET
Clinical Features
៉ Increased emphasis in breast cancer screening has resulted in an
increased frequency of detection of in-situ lesions
៉ Microcalcification is the most common mammographic feature of
in-situ lesions
៉ Distinction between an in-situ lesion and an invasive process may
have clinical significance
DUCTAL CARCINOMA IN SITU – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Low nuclear grade: variable cellularity; monomorphic pattern of
cells forming cribriform, solid, and micropapillary patterns;
small to medium-sized cells with uniform nuclei; absence of
myoepithelial cells
៉ High nuclear grade: variable cellularity in a necrotic background;
pleomorphic population of highly anaplastic epithelial cells
with individual cell necrosis and mitosis; absence of
myoepithelial cells
dures requires a follow-up surgical biopsy to exclude
the possibility of a more severe lesion. However, the
diagnosis of atypical ductal hyperplasia by FNAB has
the benefit of identifying high-risk individuals for
breast cancer who may benefit from chemoprevention
and the available risk-reduction modalities. In recent
years, breast cancer awareness and screening programs
have resulted in an increased detection of borderline
breast disease and ductal carcinoma in situ. Clustered
microcalcification is the most frequent feature in breast
imaging.
10/26/2006 10:25:57 AM
 CHAPTER 5 Breast
FIGURE 5-41
Direct smear of low nuclear grade ductal carcinoma in situ demonstrat-
ing clusters of a monomorphic cells forming a cribriform pattern. Myo-
epithelial cells are seen only at the periphery of cell clusters.
FIGURE 5-42
Direct smear of low nuclear grade ductal carcinoma in situ: higher view
of the same case as in Fig. 5-41 with similar features.
Breast aspirates from non-comedo-type ductal carci-
noma in situ is characterized by moderate to high cel-
lularity. Cell population is monomorphic and uniform.
No myoepithelial cells are present. The cell clusters may
form cribriform, solid, and micropapillary patterns.
Microcalcified particles may also be present (Figs 5-41
& 5-42).
HIGH NUCLEAR GRADE DUCTAL
CARCINOMA IN SITU (COMEDO TYPE)
High nuclear grade ductal carcinoma in situ is known
to have a higher rate of local recurrence compared to
Ch005-F06731.indd 141
141
FIGURE 5-43
Direct smear of high nuclear grade ductal carcinoma in situ: pleomor-
phic population of neoplastic cells with necrosis in the background.
FIGURE 5-44
Direct smear of high nuclear grade ductal carcinoma in situ: pleomor-
phic cell population with individualized cell necrosis.
the low nuclear grade ductal carcinoma in situ. It is
associated with a higher rate of microinvasion, expres-
sion of HER-2/neu oncogene, and hormone receptor
negativity. Fine needle aspirates of high nuclear grade
ductal carcinoma in situ are often cellular and display
highly neoplastic epithelial cells with individual cell
necrosis. Extreme pleomorphism with anisonucleosis
occasionally is associated with the microcalcified parti-
cles. Large irregularly shaped nucleoli are also present
(Figs 5-43 & 5-44).
The distinction between high and low nuclear grade
is important since high nuclear grade lesions require
more aggressive therapy and better respond to
chemotherapy. Assessment of the status of invasion
may be critical for treatment planning. Attempts have
been made to cytologically differentiate between an in-
situ versus an invasive breast cancer. However, contro-
versy remains regarding the reliability of cytologic
features to make this distinction. In these circumstances,
10/26/2006 10:25:58 AM
 142
it is best to consider an open biopsy to determine the
presence or absence of an invasive process.
PRIMARY BREAST CARCINOMA
FNAB is one of the most cost-effective procedures for
the initial diagnosis of primary breast carcinoma in
palpable breast lesions. Associated with integration of
clinical presentation and breast imaging, in experi-
enced hands FNAB provides a diagnostic accuracy
similar to that of surgical biopsy. Diagnosis of malig-
nancy in breast cytopathology is based on the combina-
tion of architectural pattern and the nuclear features.
Aside from familiarity with subtle diagnostic pitfalls
associated with various forms of breast carcinoma, rec-
ognition of the limitation of this procedure is the key to
an accurate diagnosis. It is critically important to study
the spectrum of morphologic features of benign and
borderline breast disease that may present with atypia.
To achieve this goal, attempts should be made to refrain
from the casual use of the term atypia. Similarly, recog-
nition of breast malignancies that are associated with
insignificant atypia, such as lobular, tubular, and muci-
nous lesions, is important. Based on the guidelines pro-
posed in the National Cancer Institute (NCI)-sponsored
workshop, rendering the diagnosis of malignancy in a
breast FNAB is sufficient for patient management.
However, typing of breast carcinoma whenever possible
is strongly encouraged.
INFILTRATING DUCT CELL CARCINOMA,
NOT OTHERWISE SPECIFIED (NOS)
Based on data from the Surveillance, Epidemiology,
and End Results (SEER) programs registry of the NCI,
the most common primary carcinoma of the breast is
infi ltrating duct carcinoma, not otherwise specified
(NOS). This form of primary breast cancer accounts
for 68% of all breast carcinomas. Infi ltrating duct cell
carcinoma can present as an image-detected abnormal-
INFILTRATING DUCT CELL CARCINOMA – DISEASE FACT SHEET
Clinical Features
៉ Most common type of primary breast carcinoma
៉ Clinically presents with a palpable mass with or without skin
changes
៉ Mammographically presents as a poorly defined spiculated mass
with or without microcalcifications
៉ Characterized by a hypoechoic mass with irregular borders and an
uneven echo texture by ultrasound
Ch005-F06731.indd 142
FINE NEEDLE ASPIRATION CYTOLOGY
INFILTRATING DUCT CELL CARCINOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellular aspirate
៉ Conspicuous loss of cell cohesion
៉ Variable cell pattern in a clean or necrotic background
៉ Variable nuclear atypia and cellular pleomorphism
៉ Rare multinucleated tumor giant cells
៉ Occasionally, small cells with plasmacytoid appearance
៉ Absence of myoepithelial cells
Histopathologic Findings
៉ Infiltrating duct cell carcinoma NOS varies based on the degree
of differentiation
Ancillary Studies
៉ Immunostain for epithelial versus melanoma specific markers
Differential Diagnosis and Pitfalls
៉ Infl ammatory/reactive/hyperplasia: presence of myoepithelial
cells; preservation of cellular cohesion; polymorphic cell
pattern
៉ Infiltrating lobular carcinoma: more uniformity of the nuclei;
less hyperchromasia; occasional Indian filing; occasional signet-
ring cells; presence of intracytoplasmic mucin vacuoles
៉ Amelanotic melanoma: presence of intranuclear vacuoles;
frequent binucleation; prominent, often cherry red, nucleoli
ity or as a hard mass with or without skin changes. The
more common variety is the stellate lesion, which is
characterized by extensive fibrosis, also known as scir-
rhous carcinoma. Mammographically, the vast majority
of these malignancies present with a poorly defined
spiculated mass with or without microcalcifications.
Sonographically, the most common features of malig-
nancy are those of a hypoechoic mass with irregular
borders and an uneven texture. Histologically, infi ltrat-
ing duct cell carcinoma is characterized by a spectrum
of changes that vary accordingly to atypia and differ-
entiation such as the degree tubule formation, nuclear
pleomorphism, and mitotic activity.
Cytologically, variable patterns reflecting the diverse
histology are seen. Breast aspirates of infiltrating duct
cell carcinoma are cellular and often show conspicuous
loss of cell cohesion. Scattered individual tumor cells
and aggregates of various-sized cells demonstrate three-
dimensional clustering, syncytial groups or, occasion-
ally, gland-like arrangements. Tumor cells are often
large and pleomorphic with prominent nucleoli. The
background may be clear or contain red blood cells and
necrotic debris. Occasionally, multinucleated giant cells
can also be observed. The above-mentioned morpho-
logic features are characteristic of poorly differentiated
infiltrating duct cell carcinoma/grade III tumors. Grade
I and grade II will exhibit sheets of monomorphic cells
with round and bland-appearing nuclei with single
inconspicuous nucleoli (Figs 5-45–5-47).
10/26/2006 10:25:59 AM
 CHAPTER 5 Breast
FIGURE 5-45
Direct smear of an infiltrating duct cell carcinoma yielding a cellular
aspirate with conspicuous loss of cell cohesion.
FIGURE 5-46
Direct smear of an infiltrating duct cell carcinoma, low nuclear grade,
characterized by uniform small nuclei with inconspicuous nucleoli.
Another variant of duct cell carcinoma, which may
be difficult to diagnose cytologically, is the small cell
variant. Breast aspirate of this entity is characterized by
numerous isolated and clusters of small cells with eccen-
tric round nucleoli and a moderate amount of cytoplasm
exhibiting a ‘plasmacytic’ pattern. This entity should be
differentiated from the rare plasmacytomas of the breast
and from a metastatic amelanotic malignant melanoma.
Immunostaining for epithelial markers aids in making
an accurate diagnosis of the small cell variant of infil-
trating duct cell carcinoma, which commonly occurs in
older women. This tumor also shares a similar pattern
with infiltrating lobular carcinoma. Higher cellularity
and increased hyperchromasia of the nuclei are the
features more commonly seen in this variant (Fig.
5-48).
Infiltrating duct cell carcinoma should be differenti-
ated from borderline and atypical benign lesions.
Ch005-F06731.indd 143
143
FIGURE 5-47
Direct smear of an infiltrating duct cell carcinoma, high nuclear grade,
demonstrating various-sized nucleoli with clumped chromatin and con-
spicuous nucleoli.
FIGURE 5-48
Direct smear of an infiltrating duct cell carcinoma, small cell variant,
showing numerous small cells with eccentric nuclei.
Absence of myoepithelial cells is the key to making the
distinction.
TUBULAR CARCINOMA
Tubular carcinoma, a previously rare breast tumor,
now accounts for up to 20% of all carcinomas detected
through mammographic screening. It occurs in a
younger age group than the classic type of infi ltrating
duct cell carcinoma and is associated with a higher
incidence of bilaterality and multiplicity. Because of
their small size and infrequent lymph node involve-
ment, tubular carcinomas are associated with a good
10/26/2006 10:25:59 AM
 144 FINE NEEDLE ASPIRATION CYTOLOGY

TUBULAR CARCINOMA – DISEASE FACT SHEET

Clinical Features
៉ Accounts for up to 20% of mammographically detected
carcinomas
៉ Mammographically, it shares similar features with radial scar
៉ Associated with a low incidence of axillary lymph node metastasis
and a favorable prognosis
៉ Suitable for conservative therapy

TUBULAR CARCINOMA – PATHOLOGIC FEATURES

Cytopathologic Findings FIGURE 5-49

៉ Variable cellularity
Direct smear of tubular carcinoma characterized by isolated and clusters
៉ Presence of epithelial cells forming angulated tubular structures of epithelial cells with tubular structures and cell balls.
៉ Uniform nuclei with occasional nuclear grooving
៉ Cytoplasmic vacuoles

Ancillary Studies
៉ Immunostain for myoepithelial cell markers

Differential Diagnosis and Pitfalls

៉ Radial scar: low to moderate cellularity; admixed myoepithelial
cells with epithelial cells; absence of nuclear grooves and
intracytoplasmic vacuoles
៉ Microglandular adenosis: low cellularity; absence of angulated
tubules; cell balls; myoepithelial cells
៉ Fibroadenoma: complex branching of ductal epithelial cells;
myoepithelial cells within the clusters of epithelial cells and in
the background; absence of nuclear grooving and
intracytoplasmic vacuoles

prognosis and are most suitable for conservative FIGURE 5-50

therapy. Direct smear of tubular carcinoma showing an angulated tubular struc-
Mammographically, tubular carcinomas present as a ture with no myoepithelial cells within the cluster of epithelial cells.
spiculated mass, similar to that of a radical scar, which
may require surgical excision. Grossly, tubular carcino-
mas present as stellate or scirrhous areas of gray–white
discoloration with induration and retroaction. Histo-
logically, the tumor consists of elongated round tubular
structures lined by a single layer of cells, some of which
may exhibit apocrine snouts.
Cytologically, the aspirates are moderately cellular,
containing bland-appearing tumor cells which form
angular branching and three-dimensional tubular struc-
tures. Tumor cells are uniform with a finely granular
chromatin and small nucleoli. Groved nuclei and solitary
intracytoplasmic vacuoles are often features of tubular
carcinomas (Figs 5-49–5-51). The differential diagnosis
includes radial scar, fibroadenoma, and microglandular
adenosis. There are overlapping features between tubular
carcinoma and radial scar. Radial scars, however,
present with lower cellularity and show the presence of
myoepithelial cells within the cell clusters and have FIGURE 5-51
inconspicuous nucleoli. If radial scar is associated with Direct smear of tubular carcinoma showing a uniform population of cells
proliferative breast disease with atypia, the higher with uniform nuclei and no myoepithelial cells.

Ch005-F06731.indd 144 10/26/2006 10:26:00 AM

 CHAPTER 5 Breast 145

cellularity, loss of polarity, and some degree of anisonu-
cleosis may mimic a neoplastic process. Immunostaining
for myoepithelial cell markers is an effective tool in
making the distinction.
Similarly, tubular carcinomas may mimic fibro-
adenomas. However, fibroadenomas often present with
complex branching of ductal epithelial cells admixed
with myoepithelial cells. Tubular carcinomas may occa-
sionally lead to false negative diagnosis, particularly if
the aspirate is not cellular. When in doubt, it is reason-
able to recommend total surgical excision of the
lesion.
MUCINOUS CARCINOMA
are well-circumscribed lesions; on ultrasound, they
are solid and hypoechoic. Histologically, they present
as pure or mixed type, with two prognostically
different behaviors. Pure forms present with a well-
defined gelatinous mass and show small epithelial
islands floating in abundant extracellular mucin. Pure
mucinous carcinomas are associated with a favorable
prognosis.
Cytologically, the aspirates contain thick mucinous
material on smears, and show abundant mucin in the
background. Clusters of relatively small and uniform
epithelial cells with bland-appearing cytologic features
are often seen within the mucinous background. Tumor
cells may appear in three-dimensional clusters, mono-
layered sheets, or as dissociated isolated cells. The epi-
thelial cells are relatively uniform with wispy cytoplasm
and a vesicular chromatin pattern (Figs 5-52 & 5-53).

Mucinous carcinomas represent approximately 2% of

breast cancers. It is also known as colloid, mucoid,
gelatinous, and mucin-producing carcinoma. These
tumors generally occur in older women. Clinically, they
present as a soft mobile mass. Mammographically, they

MUCINOUS CARCINOMA – DISEASE FACT SHEET

Clinical Features
៉ A rare breast tumor that occurs in an older age group
៉ Clinically, it presents as a soft mobile mass
៉ Breast imaging shows a well-defined lesion
៉ Prognosis in pure mucinous carcinomas is favorable
៉ Mixed variety of mucinous carcinoma is associated with the same
prognosis as an infiltrating duct cell carcinoma

FIGURE 5-52
Direct smear of mucinous carcinoma characterized by abundant mucin
in the background and clusters of epithelial cells.

MUCINOUS CARCINOMA – PATHOLOGIC FEATURES

Cytopathologic Findings
៉ Variable cellularity
៉ Mucinous background
៉ Cohesive clustering of small aggregates of epithelial cells with
minimal nuclear atypia
៉ Fragments of stroma and newly formed small vessels

Ancillary Studies
៉ Immunostain for myoepithelial cell markers

Differential Diagnosis and Pitfalls

៉ Mucocele-like tumor: occurs in younger women; associated with
proliferative and premalignant breast disease; contains both
epithelial and myoepithelial cell components
៉ Myxoid fibroadenoma: occurs in younger women; demonstrates
stromal and mixed epithelial components; presence of antler-
horn pattern
៉ Signet-ring cell carcinoma: abundance of signet-ring cells with FIGURE 5-53
intracellular mucin production Direct smear of mucinous carcinoma showing the same features in
higher magnification. The epithelial cells are uniform and there are no
myoepithelial cells.

Ch005-F06731.indd 145 10/26/2006 10:26:01 AM

 146 FINE NEEDLE ASPIRATION CYTOLOGY

The cellularity varies based on the amount of extra-

cellular mucin. In hypocellular aspirates, the bland
appearance of tumor cells may lead to false negative
diagnosis.
The mixed form of mucinous carcinoma is an infil-
trating duct cell carcinoma with mucinous differentia-
tion. The prognosis of this variant is the same as for the
classical form of infiltrative duct cell carcinoma. In the
mixed form, cellular pleomorphism is more conspicuous
with occasional necrosis and a smaller amount of mucin
in the background. Regardless of the cellularity and the
presence of mucinous material, it is best to classify these
lesions as ‘breast carcinoma with a mucinous compo-
nent’ by FNAB.
Mucinous carcinomas must be distinguished from
‘mucocele-like lesions’ and myxoid fibroadenomas.
Mucocele-like tumors of the breast are benign entities
that are associated with a variety of metaplastic and FIGURE 5-54
hyperplastic conditions. They occur in young and in Direct smear of signet-ring cell carcinoma characterized by isolated and
premenopausal women, in contrast to mucinous carci- clusters of neoplastic epithelial cells with a signet-ring pattern.
noma, which is a tumor of old age. Aside from age, the
aspirates from mucoceles display the presence of
both epithelial and myoepithelial cells, which can be
supported by immunostains for myoepithelial cell
markers. SIGNET-RING CELL CARCINOMA – PATHOLOGIC FEATURES
Another entity which should be differentiated from
mucinous carcinoma is fibroadenoma with myxoid Cytopathologic Findings
stroma. Clues to the correct diagnosis are young age of ៉ Moderate to high cellularity
the patient and the presence of stroma and epithelial/ ៉ Abundance of small to medium-sized cells with crescent-shaped
nuclei and intracellular mucin
myoepithelial components. Immunostain for myoepi-
thelial cell markers will provide the supporting evidence.
Ancillary Studies
Signet-ring cell carcinoma of the breast may also mimic
៉ Special stains
mucinous carcinoma. However, in this tumor, the
៉ Electron microscopy
majority of cells show evidence of intracytoplasmic ៉ Panel of immunostains for organ-specific antibodies
mucin.
Differential Diagnosis and Pitfalls
៉ Metastatic adenoma: pertinent clinical history; review of the
original pathology slides; use of ancillary studies
SIGNET-RING CELL CARCINOMA ៉ Infiltrating lobular carcinoma: presence of other forms of
neoplastic epithelial cells; Indian file pattern
៉ Secretory carcinoma: numerous branching sheets of neoplastic
cells with cytoplasmic vacuoles and extracellular lumina; red
Signet-ring cell carcinomas are rare breast tumors that blood cells, cellular debris with tumor diathesis in the
are associated with an unfavorable prognosis. This background; multiple intracytoplasmic vacuoles
lesion occurs in the mid to late fifties. The origin of this ៉ Lipid-rich carcinoma: moderate cellular yield, loose cohesive cell
as a variant of mucinous carcinoma versus an infi ltrat- arrangement; atypical, indented nuclei with nuclear vacuoles;
ing lobular carcinoma remains controversial. Cytologi- abundant intracytoplasmic lipid material, which can be
cally, signet-ring cell carcinomas present with moderate demonstrated on air-dried smears and by the use of oil res
to rich cellularity. The cells are arranged singly or in O staining

SIGNET-RING CELL CARCINOMA – DISEASE FACT SHEET
Clinical Features
៉ A rare breast tumor with an unfavorable prognosis
៉ May mimic other forms of malignancies
៉ Distinction from metastatic tumors is important and requires
clinical information, review of the original tumor, and ancillary
studies
small loose clusters. The cells are small with crescent-
shaped nuclei compressed to the cell periphery by
mucin (Figs 5-54 & 5-55).
The differential diagnosis includes metastatic carci-
noma (especially from gastrointestinal tumors), infil-
trating lobular carcinomas, secretory carcinomas, and
lipid-secreting carcinomas. The clinical history, review
of the original pathology slides, and use of ancillary
studies such as special stains, electron microscopy, and

Ch005-F06731.indd 146 10/26/2006 10:26:02 AM

 CHAPTER 5 Breast
FIGURE 5-55
Direct smear of signet-ring cell carcinoma: higher magnification of the
same case as in Fig. 5-54, showing signet-ring cells with mucin
droplets.
FIGURE 5-56
Direct smear of secretory carcinoma characterized by clusters of
neoplastic epithelial cells with abundant vacuolated cytoplasm.
a panel of immunostains for organ-specific antibodies
are the tools to differentiate between a signet-ring cell
carcinoma and a metastatic tumor.
The distinction between signet-ring cell carcinomas
and other tumors requires special attention to subtle
morphologic differences. Infiltrating lobular carcinomas
often show other characteristics of this tumor, including
the presence of Indian file pattern. Secretory carcino-
mas present with several prominent intracytoplasmic
vacuoles (Figs 5-56 & 5-57). Lipid-rich carcinomas
contain small cytoplasmic vacuoles that present in dif-
ferent forms. The vacuoles are often seen in the peri-
nuclear area, and nuclei are indented. Special stain
demonstrates the presence of fat droplets in the cyto-
plasm of tumor cells.
Ch005-F06731.indd 147
147
FIGURE 5-57
Direct smear of secretory carcinoma: higher magnification of the same
case as in Fig. 5-56, showing multiple vacuoles in the cytoplasm.
MEDULLARY CARCINOMA
Medullary carcinomas of the breast are rare tumors,
accounting for 5% to 7% of all breast cancers, and are
associated with a good prognosis. Medullary carcino-
mas occur in patients aged between 21 and 95 years,
with a mean age of 50 years. In young patients, medul-
lary carcinomas may be associated with genetically
mutated cancer in high-risk individuals. Medullary
carcinomas present as a well-defined lesion, both clini-
cally and mammographically.
On histology, typical medullary carcinomas are
characterized by sharp circumscription and a syncytial
growth pattern of highly pleomorphic epithelial cells
with no glandular pattern and surrounded by a lympho-
cytic infiltration. Tumors that exhibit any or few of
these criteria are called atypical medullary carcinomas.
The behavior and prognosis of these tumors are similar
to those seen in the usual forum of infiltrating duct cell
carcinoma. Therefore, the designation of ‘ductal carci-
noma with medullary features’ is more appropriate for
cytologic diagnosis of medullary carcinoma.
Cytologically, the aspirates from a medullary carci-
noma are hypercellular with a background showing
lymphocytes and plasma cells. The neoplastic epithelial
cells show an extreme degree of pleomorphism,
MEDULLARY CARCINOMA – DISEASE FACT SHEET
Clinical Features
៉ A rare breast tumor that occurs in all age groups
៉ In young patients, may be associated with breast cancer genes
៉ A well-circumscribed lesion, both clinically and mammographically
៉ Associated with a good prognosis
10/26/2006 10:26:02 AM
 148
FIGURE 5-58
Direct smear of medullary carcinoma characterized by clusters of
epithelial cells surrounded by lymphocytes.
MEDULLARY CARCINOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ High cell yield
៉ Pleomorphic cell population forming syncytial growth pattern
៉ Pronounced lymphoplasmacytic infiltration
៉ Necrotic background
Ancillary Studies
៉ Immunophenotyping by immunocytochemistry and/or fl ow
cytometry
Differential Diagnosis and Pitfalls
៉ Malignant lymphoma: monotonous cell population; absence
of epithelial cells; evidence of monoclonality by
immunocytochemistry or flow cytometry
៉ Infiltrating duct cell carcinoma with lymphocytic pattern:
absence of syncytial growth pattern; lesser degree of
anisonucleosis and pleomorphism
anisonucleosis, a high mitotic rate and arrangement in
syncytial sheets (Figs 5-58 & 5-59). Medullary carcino-
mas rarely present as a cystic lesion. They are frequently
hormone receptor-negative and have an abnormal DNA
pattern.
The differential diagnosis includes poorly differenti-
ated infiltrating duct cell carcinoma with lymphocytic
infiltrate and malignant lymphoma. Ductal cell carci-
noma with lymphocytic pattern does not present with
a syncytial growth pattern. Malignant lymphomas are
characterized by a monotonous cell population with no
evidence of epithelial differentiation. Immunopheno-
typing by immunocytochemistry or flow cytometry will
aid in making the differentiation.
Ch005-F06731.indd 148
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 5-59
Direct smear of medullary carcinoma showing syncytial growth
pattern.
APOCRINE CARCINOMA
Apocrine carcinoma, a rare breast tumor, occurs in an
older age group. The apocrine features and biomarker
findings may suggest a difference in steroid metabo-
lism, particularly a higher frequency of androgen recep-
tor positivity compared to the ductal carcinoma not
otherwise specified. It has been suggested that patients
APOCRINE CARCINOMA – DISEASE FACT SHEET
Clinical Features
៉ A rare breast tumor that occurs in an older age group
៉ May have a different pathway of steroid metabolism
APOCRINE CARCINOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellular aspirate
៉ Pleomorphic population of cells with abundant granular
cytoplasm
៉ Marked anisonucleosis with large nuclei and prominent nucleoli
Differential Diagnosis and Pitfalls
៉ Hyperplastic/metaplastic apocrine cells: presence of
accompanying proliferating epithelial cells; lack of significant
anisonucleosis and hyperchromasia
៉ Secretory carcinoma: neoplastic cells with prominent
intracellular spaces; cytoplasmic vacuoles; signet-ring formation
៉ Lipid-rich carcinoma: abundant multivacuolated cells with a
more uniform nuclear appearance; lack of multiple nucleoli
10/26/2006 10:26:03 AM
 CHAPTER 5 Breast
FIGURE 5-60
Direct smear of apocrine carcinoma characterized by a population of
neoplastic epithelial cells with granular cytoplasm and conspicuous
nucleoli.
FIGURE 5-61
Direct smear of apocrine carcinoma showing multinucleation and
prominent nucleoli.
with apocrine carcinoma may experience a longer sur-
vival. Cytologically, the aspirates are often cellular and
show pleomorphic tumor cells with abundant granular
cytoplasm. The nuclei are large, vesicular and are cen-
trally or eccentrically located. The nucleoli are promi-
nent and multinucleation is common (Figs 5-60 &
5-61).
Apocrine carcinomas should be distinguished from
atypical changes seen in proliferative and metaplastic
apocrine cells. The clues are the presence of an accom-
panying polymorphous cell population commonly seen
in proliferative breast disease. Absence of anisonucleo-
sis and significant hyperchromasia are also other fea-
tures seen in atypical apocrine lesions. Other lesions
included in the differential diagnosis are lipid-rich and
secretory carcinomas.
Ch005-F06731.indd 149
149
INFILTRATING LOBULAR CARCINOMA
Infi ltrating lobular carcinoma accounts for approxi-
mately 6.3% of primary breast carcinomas. It occurs in
wide range of age groups, ranging from 26 to 86 years
old. Clinical presentation is similar to that of other
primary breast carcinomas. However, it is not associ-
ated with Paget’s disease and occasionally it may present
as an indurated area without any discrete mass. Infi l-
trating lobular carcinomas have a different pattern of
metastatic presentations and tend to involve skeletal,
visceral, serosal, and meningeal areas. Similarly, ovary,
bone, and uterus are the common sites of metastasis
from this tumor.
Mammographically, it can present as an asymmetric
density with no clearly delineated margin with no or
little architectural distortion. Multifocal infiltrating
lobular carcinoma may present with minimal distor-
tion with no significant mass or increased density or
microcalcification. These subtle mammographic fea-
tures warrant careful examination of the breast and
sampling of any suspicious area. Infiltrating lobular
carcinoma is often bilateral and shows evidence of
multiplicity.
On histology, infiltrating lobular carcinomas are
characterized by diffuse infiltration of mammary stroma
INFILTRATING LOBULAR CARCINOMA – DISEASE FACT SHEET
Clinical Features
៉ Variable clinical and mammographic presentations
៉ Associated with bilaterality and multiplicity
៉ Has a different pattern of metastasis from tumors of ductal origin
INFILTRATING LOBULAR CARCINOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Variable cellularity
៉ Monomorphic cell population of small cells with insignificant
atypia
៉ Eccentrically located nuclei
៉ Cells with intracytoplasmic lumina
៉ Indian file pattern
៉ No myoepithelial cells
Ancillary Studies
៉ Immunostain for myoepithelial cell markers and E-cadherin
Differential Diagnosis and Pitfalls
៉ Fibrocystic change: presence of polymorphic cell pattern;
presence of myoepithelial cells
៉ Low nuclear grade ductal carcinoma: positive immunostain for
E-cadherin
៉ Atypical lobular hyperplasia and lobular carcinoma in situ: less
cellularity; more cohesive cell pattern
10/26/2006 10:26:04 AM
 150
FIGURE 5-62
Direct smear of an infiltrating lobular carcinoma characterized by
isolated and a cluster of epithelial cells with uniform nuclei and
intracytoplasmic lumina.
FIGURE 5-63
Direct smear of an infiltrating lobular cell carcinoma showing clusters
of epithelial cells with no myoepithelial cells.
and ductal structures with neoplastic cells in a pagetoid
growth pattern. An area of carcinoma in situ is com-
monly seen. Infiltrating lobular carcinoma may present
in a variety of patterns with similar prognostic behav-
ior, except for the pleomorphic variant, which is associ-
ated with a more unfavorable outcome.
Cytologically, infiltrating lobular carcinomas present
with variable cellularity. The cells are small and uniform
with small nucleoli, and present as cell balls or with
Indian file appearance. Tumor cells present with eccen-
tric nuclei, occasional intracytoplasmic lumina with
mucin droplets, and rare signet-ring cells (Figs 5-62–
5-64). The pleomorphic variant features more pleomor-
phism and nuclear atypia (Figs 5-65 & 5-66). Infiltrating
lobular carcinomas are one of the main reasons for false
negative diagnosis in breast FNAB. This is often due to
Ch005-F06731.indd 150
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 5-64
Direct smear of an infiltrating lobular cell carcinoma exhibiting an
Indian file pattern.
FIGURE 5-65
Direct smear of an infiltrating lobular carcinoma, pleomorphic variant,
characterized by a cellular aspirate showing an isolated population
of epithelial cells with eccentric nuclei, anisonucleosis. and
hyperchromasia.
insignificant atypia associated with this entity. The
presence of a monomorphic pattern of small cells
arranged in single cells, cords, or clusters with no
recognizable myoepithelial cells is the key feature to
differentiate infiltrating lobular carcinoma from benign
breast lesions.
Differentiation between infiltrating lobular carci-
noma and other entities may be difficult. With a hypo-
cellular specimen, it is best to consider surgical excision
for further characterization of suspicious cells for lobular
carcinoma. There are overlapping features between
atypical lobular hyperplasia, lobular carcinoma in situ,
and an infiltrating lobular carcinoma. These entities are
collectively called lobular neoplasia if the distinction is
not possible. Higher cellularity and a higher proportion
10/26/2006 10:26:04 AM
 CHAPTER 5 Breast 151

FIGURE 5-66
Direct smear of an infiltrating duct cell carcinoma, pleomorphic variant,
showing intracytoplasmic lumina with mucin droplets.
FIGURE 5-68
Direct smear of lobular carcinoma in situ showing acini and clustering
of uniform-appearing epithelial cells.

FIGURE 5-67
Direct smear of lobular carcinoma in situ characterized by clusters of
small uniform-appearing epithelial cells with no myoepithelial cells.

of dissociated cells are commonly seen in an infiltrating

lobular carcinoma (Figs 5-67–5-70). The differential FIGURE 5-69
diagnosis also includes low nuclear grade carcinoma of Direct smear of atypical lobular hyperplasia characterized by prolifera-
ductal origin. Immunostain for E-cadherin can differen- tion of small cells simulating acini.
tiate between these two entities.

METASTASES TO THE BREAST

METASTASES TO THE BREAST – DISEASE FACT SHEET

The breast is not a common site for metastases from
other primary malignancies. The distinction between
a primary breast carcinoma and a metastasis is criti-
cally important because of different therapeutic impli-
cations and the differences in outcome. Clinically, the
presentation of the two entities may be similar; however,
nipple discharge and retraction are not seen in meta-
static tumors. Metastatic tumors have a variety of
mammographic features, ranging from features similar
Clinical Features
៉ Rare
៉ Clinical and mammographic features may be similar to those of
primary breast carcinoma
៉ Cytologic distinction is important for the management and
clinical outcome
៉ Clinical history, review of the original pathology slides, and
ancillary studies are essential to make an accurate diagnosis

Ch005-F06731.indd 151 10/26/2006 10:26:05 AM

 152
FIGURE 5-70
Direct smear of atypical lobular hyperplasia: higher magnification of
the same case as shown in Fig. 5-69.
METASTASES TO THE BREAST – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ High cellularity
៉ Dispersed cell pattern of various types and shapes, dissimilar to
the classic types of breast cancer
៉ Variable cytomorphology similar to the primary site of origin
Ancillary Studies
៉ Special stains
៉ Electron microscopy
៉ Panel of immunostains
៉ Flow cytometry
Differential Diagnosis and Pitfalls
៉ Primary breast carcinoma: clinical history; classic pattern of
cytomorphology for primary breast cancer
to those of proliferative breast disease, cyst, or fibroad-
enoma to those of a malignant lesion such as medullary
carcinoma. Microcalcification is not frequent except in
rare cases of psammoma bodies in metastatic tumors
from the ovary. Patients with metastatic breast lesions
experience a poor outcome and about 80% of them die
within a year.
The differentiation between a primary breast tumor
and a metastasis may not be always possible. The most
important step is the recognition of a cytologic pattern
not commonly seen in a primary breast carcinoma. This
should alert the pathologist to explore the possibility of
a metastasis. Review of the clinical history and the
pathology slides of the primary tumor associated with
special stains and often ancillary studies such as
EM and/or organ-specific immunohistochemical stains
usually resolves the quandary. This process can be com-
pleted by the use of special stains and ancillary studies
such as electron microscopy and of immunostaining for
a panel of specific antibodies.
Ch005-F06731.indd 152
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 5-71
Direct smear of metastatic squamous cell carcinoma showing isolated
and clusters of neoplastic epithelial cells with evidence of
keratinization.
FIGURE 5-72
Direct smear of mucin-producing metastatic adenocarcinoma character-
ized by isolated epithelial cells with centrally located nuclei and
abundant cytoplasm and intracellular mucin.
Cytologically, metastatic tumors present with rich
cellularity. Based on the site of the origin, the aspirates
present with various cell types, sizes, and cellular
arrangements. Malignant melanomas, squamous cell
carcinoma, various adenocarcinomas, Hodgkin disease,
large cell lymphoma, and pleomorphic sarcomas exhibit
pleomorphic large cells. Melanomas, lymphomas, leuke-
mias, and poorly differentiated carcinomas present with
a dispersed cell pattern. Malignant melanoma cells
may contain pigment, intranuclear inclusions and
binucleation (Figs 5-71–5-78).
Neuroendocrine tumors and small cell carcinoma of
the lung often present with small-sized tumor cells.
Spindle cell tumors often represent various types of
sarcomas. The most common metastatic tumors to the
breast are lung and malignant melanoma. Metastasis
from other sites have also been reported. In men,
10/26/2006 10:26:06 AM
 CHAPTER 5 Breast 153

FIGURE 5-73 FIGURE 5-74

Direct smear of non-Hodgkin lymphoma characterized by dispersed cell Direct smear of Hodgkin lymphoma characterized by atypical lymphoid
pattern and various-sized malignant lymphoid cells. elements and classic Reed-Sternberg cell.

FIGURE 5-75 FIGURE 5-76

Direct smear of malignant melanoma: dispersed cell pattern with Immunostained cell block showing expression of HMB-45 (same case as
binucleation and intracytoplasmic vacuoles. Fig. 5-75).

FIGURE 5-77 FIGURE 5-78

Direct smear of metastatic prostate carcinoma characterized by uniform- Metastatic prostate carcinoma: immunostained cell block showing
appearing epithelial cells. expression of prostate-specific antigen.

Ch005-F06731.indd 153 10/26/2006 10:26:07 AM

 154 FINE NEEDLE ASPIRATION CYTOLOGY

prostate cancer is the most common form of metastatic

tumor to the breast. Lymphoma including Hodgkin
disease of the breast is commonly seen as a manifesta-
tion of a known generalized lymphoma and presents no
difficulty in rendering a diagnosis. However, rarely they
may occur as the primary breast carcinoma. Immuno-
phenotyping with immunocytochemistry or flow cyto-
metry can establish the diagnosis.
Sarcomas can also occur as a primary breast carci-
noma or as metastasis from other sites. The aspirate of
sarcomas is cellular with a spindle cell pattern. Electron
microscopy and immunostaining for mesenchymal
markers are helpful in establishing the diagnosis of a
sarcomatous lesion.

MISCELLANEOUS CONDITIONS FIGURE 5-79

Direct smear of granular cell tumor characterized by uniform-appearing
tumor cells with conspicuous granular cytoplasm.

GRANULAR CELL TUMOR

Granular cell tumors are examples of stromal tumors

of the breast, which are rare and present as a palpable
mass. These tumors may resemble breast carcinomas,
both clinically and mammographically, and FNAB is
quite helpful to provide an accurate diagnosis.
Cytologically, the aspirates show moderately cellular
smears with isolated and clusters of cells with granular
and foamy cytoplasm. The nuclei are uniform and the
chromatin is fine. Immunostain for S-100 and electron
microscopy are often used to substantiate the diagnosis
of granular cell tumor (Figs 5-79 & 5-80). Malignant

GRANULAR CELL TUMOR – DISEASE FACT SHEET FIGURE 5-80

Granular cell tumor: immunostained cell block showing expression
Clinical Features of S-100 protein.
៉ Rare form of stromal tumors of the breast
៉ Clinically and mammographically, may mimic primary breast
carcinoma granular cell tumors show extensive pleomorphism
with a high degree of mitotic activity.

GRANULAR CELL TUMOR – PATHOLOGIC FEATURES

GYNECOMASTIA

Cytopathologic Findings
៉ Variable cellularity
៉ Isolated and clusters of cells with uniform nuclei, conspicuous
nucleoli, and fine chromatin pattern
៉ Tumor cells with granular cytoplasm
Differential Diagnosis and Pitfalls
៉ Malignant granular cell tumor: pronounced cellular
pleomorphism; abundant mitosis
Gynecomastia refers to unilateral or bilateral enlarge-
ment of the male breast. This condition may be due
to hormonal changes, testicular or hepatic tumors,
Klinefelter’s syndrome, drug therapy, liver or renal
disease.
Cytologically, gynecomastias present with a cellular
aspirate that shows tightly cohesive groups of epithelial
cells and stromal components, features seen in fibro-
adenomas in the female breast. Apocrine metaplasia,
histiocytes, fragments with cribriform or micropapillary

Ch005-F06731.indd 154 10/26/2006 10:26:09 AM

 CHAPTER 5 Breast
FIGURE 5-81
Direct smear of gynecomastia characterized by uniform-appearing
epithelial/myoepithelial cells with stromal fragments.
GYNECOMASTIA – DISEASE FACT SHEET
Clinical Features
៉ Most frequent breast lesion in men
៉ Commonly caused by hormone-induced conditions
៉ FNAB is most effective in establishment of diagnosis
GYNECOMASTIA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Variable cellularity
៉ Uniform population of small groups of epithelial/myoepithelial
cells
៉ Tall columnar cells
៉ Stromal fragments
Differential Diagnosis and Pitfalls
៉ Primary and metastatic breast cancer: obvious evidence of
morphologic features of malignancy; history of other primary
carcinomas
arrangements, and cystic changes may be associated
with gynecomastia (Figs 5-81 & 5-82). Occasionally, the
cellular patterns, presence of small groups and isolated
cells, and columnar cell differentiation may cause diag-
nostic difficulty. However, a diagnosis of malignancy
should be considered only if the aspirate presents
obvious features of malignancy.
Primary breast cancers in men are similar to those in
women. Intracystic papillary carcinomas are frequent in
men. In addition, there is relatively equal frequency of
primary and metastatic lesions in the male breast, with
Ch005-F06731.indd 155
155
FIGURE 5-82
Direct smear of gynecomastia: a cluster of epithelial/myoepithelial cells
with an architectural pattern similar to a fibroadenoma.
lung cancer, prostrate cancer, and lymphoma being
common metastatic tumors.
SUGGESTED READINGS
Mastitis, Abscess, and Fat Necrosis
Al Nazer MA. Idiopathic granulomatous lobular mastitis. A forgotten clini-
cal diagnosis. Saudi Med J 2003;24:1377–1380.
Asoglu O, Ozmen V, Karanlik H, et al. Feasibility of surgical management
in patients with granulomatous mastitis. Breast J 2005;11:108–114.
Das DK, Sodhani P, Kashyap V, Parkash S, Pant JN, Bhatnagar P. Inflam-
matory lesions of the breast: diagnosis by fine needle aspiration.
Cytopathology 1992;3:281–289.
Galblum LI, Oertel YC. Subareolar abscess of the breast: diagnosis by fine
needle aspiration. Am J Clin Pathol 1983;80:496–499.
Karstrup S, Solvig J, Nolsoe CP, et al. Acute puerperal breast abscesses:
US-guided drainage. Radiology 1993;188:807–809.
Khoda J, Lantsberg L, Yegev Y, Sebbag G. Management of periareolar
abscess and mamillary fistula. Surg Gynecol Obstet 1992;175:306–308.
Macansh S, Greenberg M, Barraclough B, Pacey F. Fine needle aspiration
cytology of granulomatous mastitis. Report of a case and review of the
literature [see comments]. Acta Cytol 1990;34:38–42.
Maier WP, Au FC, Tang CK. Nonlactational breast infection. Am Surg
1994;60:247–250.
Maygarden SJ, Novotny DB, Johnson DE, Frable WJ. Subclassification of
benign breast disease by fine needle aspiration cytology. Comparison
of cytologic and histologic findings in 265 palpable breast masses. Acta
Cytol 1994;38:115–129.
Meguid MM, Oler A, Numann PJ, Khan S. Pathogenesis-based treatment
of recurring subareolar breast abscesses. Surgery 1995;118:775–782.
Tse GM, Poon CS, Ramachandram K, et al. Granulomatous mastitis: a
clinicopathological review of 26 cases. Pathology 2004;36:254–257.
Versluijs-Ossewaarde FN, Roumen RM, Goris RJ. Subareolar breast abscesses:
characteristics and results of surgical treatment. Breast J 2005;11:
179–182.
Weiss RL, Matsen JM. Group B streptococcal breast abscess. Arch Pathol
Lab Med 1987;111:74–75.
Zuka JJ, Crite G Jr, Aryes WW. Fistulas of lactiferous ducts. Am J Surg
1951;81:312–317.
Treatment-Induced Changes
Boyages J, Bilous M, Barraclough B, Langlands AO. Fat necrosis of the
breast following lumpectomy and radiation therapy for early breast
cancer. Radiother Oncol 1988;13:69–74.
10/26/2006 10:26:10 AM
 156
Costa MJ, Stewart G, Perez EA, Goodnight JE. Fine-needle aspiration
cytology in locally advanced breast adenocarcinoma: a case with
complete response to preoperative chemotherapy in association with
granulomatous inflammatory reaction. Diagn Cytopathol 1994;10:357–
361.
Dey P, Karmakar T. Fine needle aspiration cytology in operative
scar nodules in breast carcinoma [letter]. Acta Cytol 1995;39:137–
138.
Filomena CA, Jordan AG, Ehya H. Needle aspiration cytology of the irradi-
ated breast. Diagn Cytopathol 1992;8:327–332.
Ku NN, Mela NJ, Fiorica JV, et al. Role of fine needle aspiration cytology
after lumpectomy. Acta Cytol 1994;39:927–932.
Malberger E, Edoute Y, Toledano O, Sapir D. Fine needle aspiration and
cytologic findings of surgical scar lesions in women with breast cancer.
Cancer 1992;69:148–152.
Maygarden SJ, Novotny DB, Johnson DE, Powers CN, Frable WJ. Fine needle
aspiration cytology of suture granulomas of the breast: a potential
pitfall in the cytologic diagnosis of recurrent breast cancer. Diagn
Cytopathol 1994;19:175–179.
Pedio G, Landolt U, Zobeli L. Irradiated benign cells of the breast: a
potential diagnostic pitfall in fine needle aspiration cytology [letter].
Acta Cytol 1988;32:127–128.
Solin LJ, Fowble BL, Schultz DJ, Rubenstien JR, Goodman RL. The detec-
tion of local recurrence after definitive irradiation for early stage car-
cinoma of the breast. An analysis of the results of breast biopsies
performed in previously irradiated breasts. Cancer 1990;65:2497–
2502.
Hormonal Changes: Secretory, Pregnancy, and Lactational Changes
Bottles K, Taylor RN. Diagnosis of breast masses in pregnant and lactating
women by aspiration cytology. Obstet Gynecol 1985;66(3 Suppl):
76S–78S.
Gupta RK, McHutchinson AGR, Dowle CS, et al. Fine needle aspiration
cytodiagnosis of breast masses in pregnant and lactating women and
its impact on management. Diagn Cytopathol 1993;9:156–159.
Hughes LE. Classification of benign breast disorders. The ANDI classifica-
tion based on physiological processes within the normal breast. Br Med
Bull 1991;47:251–257.
Hughes LE, Mansel RE, Webster DJ. Aberrations of normal development
and involution (ANDI): a new perspective on pathogenesis and nomen-
clature of benign breast disorders. Lancet 1987;2:1316–1319.
Hutson SW, Cowen PN, Bird CC. Morphologic studies of age related changes
in normal human breast and their significance to evolution of mammary
cancer. J Clin Pathol 1985;38:281–287.
Novotny DB, Maygarden SJ, Shermer RW, Frable WJ. Fine needle aspiration
of benign and malignant breast masses associated with pregnancy. Acta
Cytol 1991;35:676–686.
Fibroadenomas
Benoit JL, Kara R, McGregor SE, Duggan MA. Fibroadenoma of the breast:
diagnostic pitfalls of fine needle aspiration. Diagn Cytopathol 1992;
8:643–647.
Bottles K, Chan JS, Holly EA, Chiu SH, Miller TR. Cytologic criteria for
fibroadenoma. A step-wise logistic regression analysis. Am J Clin Pathol
1988;89:707–713.
Dejmek A, Lindholm K. Frequency of cytologic features in fine needle
aspirates from histologically and cytologically diagnosed fibroadeno-
mas. Acta Cytol 1991;35:695–699.
Dusenberry D, Frable WJ. Fine needle aspiration cytology of phyllodes
tumor: potential diagnostic pitfalls. Acta Cytol 1992;36:215–221.
Rogers LA, Lee KR. Breast carcinoma simulating fibroadenoma or fibro-
cystic change by fine needle aspiration. A study of 16 cases. Am J Clin
Pathol 1992;98:155–160.
Simi U, Moretti D, Iacconi P, et al. Fine needle aspiration cytopathology
of phyllodes tumor. Differential diagnosis with fibroadenoma [see com-
ments]. Acta Cytol 1988;32:63–66.
Stanley MW, Tani EM, Rutquist LE, et al. Cystosarcoma phyllodes of the
breast: a cytologic and clinicopathologic study of 23 cases. Diagn
Cytopathol 1989;5:29–34.
Stanley MW, Tani EM, Skoog L. Fine needle aspiration of fibroadenomas
of the breast with atypia: a spectrum including cases that cytologically
mimic carcinoma. Diagn Cytopathol 1990;6:375–382.
Ch005-F06731.indd 156
FINE NEEDLE ASPIRATION CYTOLOGY
Walters TK, Zuckerman J, Nisbet Smith A, Hudson E, Chia Y, Burke M. Fine
needle aspiration biopsy in the diagnosis and management of fibro-
adenoma of the breast. Br J Surg 1990;77:1215–1217.
Papillary Breast Lesions
Al-Kaisi N. The spectrum of the ‘gray zone’ in breast cytology. A review
of 186 cases of atypical and suspicious cytology. Acta Cytol
1994;38:898–908.
Jeffrey PB, Ljung BM. Benign and malignant papillary lesions of the
breast. A cytomorphologic study. Am J Clin Pathol 1994;101:500–
507.
Kline TS. Masquerades of malignancy: a review of 4241 aspirations from
the breast. Acta Cytol 1981;25:263–266.
Koss LG, Woyke S, Olszewski W. Aspiration Biopsy: Cytologic Interpretation
and Histologic Bases. New York: Igaku-Shoin, 1984.
Levine PH, Waisman J, Yang GC. Aspiration cytology of cystic carcinoma
of the breast. Diagn Cytopathol 2003;28:39–44.
Masood S, Loya A, Khalbuss W. Is core needle biopsy superior to fine
needle aspiration breast biopsy in papillary breast lesions? Diagn
Cytopathol 2003;28:329–334.
Saphir O, Parker ML. Intracystic papilloma of the breast. Am J Pathol
1940;16:189–210.
Fibrocystic Change
[Anonymous]. Final version: the uniform approach to breast fine needle
aspiration biopsy. Breast J 1997;3:149–168.
Bibbo M, Scheiber M, Cajulius R, Keebler CM, Wied GL, Dowlatshahi K.
Sterotaxic fine needle aspiration cytology of occult malignant and pre-
malignant breast lesions. Acta Cytol 1988;32:193–201.
Dizura BR, Bonfiglio TA. Needle cytology of the breast. Acta Cytol
1979;23:332–340.
Dupont WD, Page DL. Risk factors for breast cancer in women with prolif-
erative breast disease. N Engl J Med 1985;312:146–151.
Fabian C, Kimler B, Brady D, et al. Phase II chemoprevention trial of
DFMO using the random FNA model. Breast Cancer Res Treat 2000;
64:48.
Fabian CJ, Kimler BF, Brady D, et al. A phase II breast cancer chemo-
prevention trial of oral α-difluoromethylornithine. Clin Cancer Res
2002;8:3105–3117.
Fabian CJ, Kimler BF, Zalles CM, et al. Short term breast cancer prediction
by random periareolar fine needle aspiration cytology and the Gail risk
model. J Natl Cancer Inst 2000;92:1217–1227.
Khan SA, Masood S, Miller L, Numann PJ. Random fine needle aspiration
of the breast of women at increased risk and standard risk controls.
Breast J 1998;4:420–425.
Lim JC, Al-Masri H, Salhadar A, Xie HB, Gabram S, Wojcik EM. The signifi-
cance of the diagnosis of atypia in breast fine-needle aspiration. Diagn
Cytopathol 2004;31:285–288.
Marshall CJ, Schumann GB, Ward JH, Riding JM, Cannon-Albright L,
Skolnik M. Cytologic identification of clinically occult proliferative
breast disease in women with a family history of breast cancer. Am J
Clin Pathol 1991;95:157–165.
Masood S. Cytopathology of the Breast. Chicago: ASCP Press, 1995.
Masood S. Diagnostic terminology in breast fine needle aspiration biopsy:
redefining the term atypia. Cancer (Cancer Cytopathol) 1999;87:1–4.
Masood S. Expanding role of breast cytopathology as a risk predictor. Adv
Anat Pathol 2001;8:255–263.
Masood S, Frykberg ER, McClellan GL, Scalapino MC, Mitchum DG, Bullard
JB. Prospective evaluation of radiologically detected fine needle aspira-
tion biopsy of nonpalpable breast lesions. Cancer 1990;66:1480–
1487.
Masood S, Frykberg ER, McLellan GL, et al. Cytologic differentiation
between proliferative and nonproliferative breast disease in mammo-
graphically guided fine needle aspirates. Diagn Cytopathol 1991;7:581–
590.
Masood S, Hardy NM, Assaf N. The value of muscle specific actin immuno-
staining in differentiation between atypical hyperplasia and carcinoma
in breast fine needle aspirates [abstract]. Acta Cytol 1994;38:
861.
Masood S, Hardy NM, Assof-Munasifi N. Cytologic grading system in diag-
nosis of high-risk and malignant breast lesions: merits and pitfalls.
Acta Cytol 1994;38:797–798.
10/26/2006 10:26:11 AM
 CHAPTER 5 Breast
Masood S, Lu L, Assaf Munasifi N, McCaulley K. Application of immuno-
staining for muscle specific actin for detection of myoepithelial cells in
breast fine needle aspirates. Diagn Cytopathol 1995;13:
71–74.
Masood S, Rasty G. Potential value of cytology in the detection of breast
cancer precursors by fine needle aspiration biopsy: ‘The future Pap
smear for breast cancer.’ Acta Cytol 1999;43:890.
Shiels LA, Mulford D, Dawson AG. Cytomorphology of proliferative breast
disease [abstract]. Acta Cytol 1993;37:768.
Sidawy M, Stoler M, Frable W, et al. Interobserver variability in the
classification of proliferative breast lesions by fine-needle aspiration:
results of the Papanicolaou Society of Cytopathology Study. Diagn
Cytopathol 1998;18:150–165.
Silverman J, Masood S, Ducatman BS, et al. Can FNA biopsy separate
atypical hyperplasia, carcinoma in situ and invasive carcinoma of the
breast? Cytomorphic criteria and limitations in diagnosis. Diagn Cyto-
pathol 1993; 9:713–728.
Sneige N, Staerkel GA. Fine needle aspiration cytology of ductal hyper-
plasia with and without atypia and ductal carcinoma in situ. Hum Pathol
1994;25:485–492.
Stanley MA, Henry-Stanley MJ, Zera R. Prospective study of high-risk
proliferative lesions of breast duct epithelium by fine needle aspiration
[abstract]. Acta Cytol 1991;35:611.
Ductal Carcinoma In Situ
Frable WJ. Fine needle aspiration biopsy: a review. Hum Pathol 1983;14:
9–28.
Frykberg ER, Masood S, Copeland EM, et al. Ductal carcinoma in situ of
the breast. Surg Gynecol Obstet 1993;177:425–440.
Klijanienko J, Katsahian S, Vielh P, Masood S. Stromal infiltration as a
predictor of tumor invasion in breast fine needle aspiration biopsy.
Diagn Ctyopathol 2004;30:182–186.
Lagios MD, Westdahl PR, Margopin FR, et al. Duct carcinoma in situ.
Relationship of extent of noninvasive disease to the frequency of occult
invasion, multiplicity, lymph node metastasis and short-term treatment
failures. Cancer 1982;50:1309–1314.
Lilleng R, Hagmar B. The comedo subtype of intraductal carcinoma. Cyto-
logic characteristics. Acta Cytol 1992;36:345–352.
Malamud YR, Ducatman BS, Wang HH. Comparative features of comedo
and noncomedo ductal carcinoma in situ of the breast on fine needle
aspiration biopsy. Diagn Cytopathol 1991;8:571–576.
Wang HH, Ducatman BS, Eick D. Comparative features of ductal carcinoma
in situ and infiltrating ductal carcinoma of the breast on fine needle
aspiration biopsy. Am J Clin Pathol 1989;92:736–740.
Primary Breast Carcinoma
Abendroth CS, Wang HH, Ducatman BS. Comparative features of carcinoma
in situ and atypical ductal hyperplasia of the breast on fine needle
aspiration biopsy. Am J Clin Pathol 1991;96:654–659.
Ductaman BS, Emery ST, Wang HH. Correlation of histologic grade of
breast carcinoma with cytologic features on fine needle aspiration of
the breast. Mod Pathol 1993;6:539–543.
Patel JJ, Gartel PC, Smallwood JA, et al. Fine needle aspiration cytology
of breast masses: an evaluation of its accuracy and reasons for diag-
nostic failure. Ann R Coll Surg Engl 1987;69:156–159.
Tubular Carcinoma
Bondeson L, Lindholm K. Aspiration cytology of tubular breast carcinoma.
Acta Cytol 1990;34:15–20.
Cleary PMG, Mayze JD. Recognition of tubular breast carcinoma on fine
needle aspiration cytology [abstract]. Acta Cytol 1992;36:773.
de la Torre M, Lindholm K, Lindgren A. Fine needle aspiration cytology
of tubular breast carcinoma and radial scar. Acta Cytol 1994;38:884–
890.
Dei Tos AP, Della-Giustina D, Martin VD, et al. Aspiration biopsy cytology
of tubular carcinoma of the breast. Diagn Cytopathol 1994;11:146–
150.
Evans AT, Hussein KA. A microglandular adenosis-like lesion simulating
tubular adenocarcinoma of the breast. A case report with cytological
and histological appearances. Cytopathology 1990;1:311–316.
Ch005-F06731.indd 157
157
Fisher ER, Gregorio R, Redmond C, Fisher B. Tubulolobular invasive breast
cancer: a variant of lobular invasive cancer. Hum Pathol 1977;8:679–
683.
Frierson JF Jr, Iezzoni J, Covell JL. Stereotaxic fine needle aspiration
cytology of radial scars [abstract]. Acta Cytol 1993;37:814.
Gupta RK, Dowle C. Fine needle aspiration cytology of tubular carcinoma
of the breast in a young woman. Diagn Cytopathol 1991;7:72–74.
Silverman JF. Breast. In: Bibbo M, ed. Comprehensive Cytopathology.
Philadelphia: WB Saunders, 1991:703–770.
Mucinous Carcinoma
Duane GB, Kanter MH, Branigan T, Chang C. A morphologic and morpho-
metric study of cells from colloid carcinoma of the breast obtained by
fine needle aspiration. Distinction from other breast lesions. Acta Cytol
1987;31:742–750.
Fisher CJ, Millis RR. A mucocele-like tumour of the breast associated with
both atypical ductal hyperplasia and mucoid carcinoma. Histopathology
1992;21:69–71.
Ro JY, Sneige N, Sahin AA, Silva EG, Del Junco GW, Ayala AG. Mucocele
like tumor of the breast associated with atypical ductal hyperplasia or
mucinous carcinoma. A clinicopathologic study of seven cases. Arch
Pathol Lab Med 1991;115:137–140.
Stanley MW, Tani EM, Skoog L. Mucinous breast carcinoma and mixed
mucinous-infiltrating ductal carcinoma: a comparative cytologic study.
Diagn Cytopathol 1989;5:134–138.
Weaver MG, Abdul Karim FW, al Kaisi N. Mucinous lesions of the breast.
A pathological continuum. Pathol Res Pract 1993;189(8):873–876.
Signet-Ring Cell Carcinoma
Craig JP. Secretory carcinoma of the breast in an adult. Correlation of
aspiration cytology and histology on the biopsy specimen. Acta Cytol
1985;29:589–592.
Fisher ER, Gregoriao R, Kim WS, et al. Lipid invasive cancer of the breast.
Am J Clin Pathol 1977;68:558–561.
Insabato L, Russo R, Cascone AM, et al. Fine needle aspiration cytology
of lipid-secreting breast carcinoma. A case report. Acta Cytol
1993;37:752–755.
Merino MY, Livolsi VA. Signet ring carcinoma of the female breast. Cancer
1981;48:1830–1837.
Nguyen GK, Neifer R. Aspiration biopsy cytology of secretory carcinoma
of the breast. Diagn Cytopathol 1987;3:234–237.
Ramos CV, Taylor HB. Lipid-rich carcinoma of the breast. A clinicopatho-
logic analysis of 13 examples. Cancer 1974;33:812–819.
Shinagawa T, Tadokoro M, Kitamura H, et al. Secretory carcinoma of the
breast: correlation of aspiration cytology and histology. Acta Cytol
1994;38:909–914.
Shinagawa T, Tadokoro M, Takeuchi E, et al. Aspiration biopsy cytology
of secretory carcinoma of the breast. A case report. Acta Cytol 1992;36:
189–193.
Medullary Carcinoma
Howell LP, Kline TS. Medullary carcinoma of the breast. A rare cytologic
finding in cyst fluid aspirate. Cancer 1990;65:277–282.
Meyer JE, Amin E, Lindfors KK, Lipman JC, Stomper PC, Genest D. Medullary
carcinoma of the breast: mammographic and US appearance. Radiology
1989;179(1 Pt 1):79–82.
Moore OSJ, Foote FWJ. The relatively favourable prognosis of medullary
carcinoma of the breast. Cancer 1949;2:635–642.
Pedersen L, Schiodt T, Holck S, Zedeler K. The prognostic importance of
syncytial growth pattern in medullary carcinoma of the breast. APMIS
1990;98:921–926.
Pedersen L, Zedeler K, Holck S, Schiodt T, Mouridsen HT. Medullary carci-
noma of the breast, proposal for a new simplified histopathological
definition. Based on prognostic observations and observations on inter-
and intraobserver variability of 11 histopathological characteristics in
131 breast carcinomas with medullary features. Br J Cancer 1991;63:
591–595.
Ridolfi RF, Rosen PP, Post A, Kinne T, Mike V. Medullary carcinoma of the
breast. A clinicopathologic study with 10 year follow-up. Cancer 1977;
40:1365–1385.
10/26/2006 10:26:11 AM
 158
Wargotz ES, Silverberg SG. Medullary carcinoma of the breast: a clinico-
pathologic study with appraisal of current diagnostic criteria. Hum
Pathol 1988;19:1340–1346.
Apocrine Carcinoma
Abati AD, Kimmel M, Rosen PP. Apocrine mammary carcinoma. A clinico-
pathologic study of 72 cases. Am J Clin Pathol 1990;94:371–377.
Bryant J. Male breast cancer: a case of apocrine carcinoma with psam-
moma bodies. Hum Pathol 1981;12:751–753.
Frable WJ, Kay S. Carcinoma of the breast. Histologic and clinical features
of apocrine tumors. Cancer 1968;21:756–763.
Gupta RK, McHutchison AG, Simpson JS, Dowle CS. Fine needle aspiration
cytodiagnosis of apocrine carcinoma of the breast. Cytopathology
1992;3:321–326.
Ito F, Avai, Suzuki M, et al. Apocrine carcinoma of the breast with cyto-
logic, histologic and electron microscopic findings: a case report
[abstract]. Acta Cytol 1992;36:792.
Japaze H, Emina J, Diaz C, et al. Pure invasive apocrine carcinoma of the
breast: a new clinicopathological entity? Breast 2005;14:3–10.
Makunura CN, Curling OM, Yeomans P, Perry N, Wells CA. Apocrine adenosis
within a radial scar: a case of false positive breast cytodiagnosis.
Cytopathology 1994;5:123–128.
Page DL, Anderson TJ. Miscellaneous features of carcinoma. In: Diagnostic
Histopathology of the Breast. Edinburgh: Churchill Livingstone, 1987:
294–295.
Simpson JF, Page DL, Dupont WD. Apocrine adenosis – a mimic of
mammary carcinoma. Surg Pathol 1990;3:289–299.
Zajdela A, Ghossein NA, Pilleran JP, et al. The experience of aspiration
cytology in the diagnosis of breast cancer. Experience at the Foundation
Curie. Cancer 1975;35:499–506.
Infiltrating Lobular Carcinoma
Dixon JM, Anderson TJ, Page DL, et al. Infiltrating lobular carcinoma of
the breast: an evaluation of the incidence and consequence of bilateral
disease. Br J Surg 1983;70:513–516.
Ermier WJ, Gaffey TA, Welch JS, et al. Linitis plastica caused by metastatic
lobular carcinoma of the breast. Mayo Clin Proc 1980;55:747–753.
Eusebi V, Maghales F, Azzopardi JG. Pleomorphic lobular carcinoma of the
breast. An aggressive tumor showing apocrine differentiation. Hum
Pathol 1992;23:655–662.
Fechner RE. Histologic variants of infiltrating lobular carcinoma of the
breast. Hum Pathol 1975;6:373–378.
Kline TS. Handbook of Fine Needle Aspiration Biopsy Cytology. St. Louis,
MO: CV Mosby, 1988:199–252.
Kline TS, Joshi LP, Neal HS. Fine needle aspiration of the breast: diag-
nostic pitfalls. Cancer 1979;4:1458–1464.
Koss LG, Woyke J, Olszewski W. Cytologic Interpretation and Histologic
Bases. New York: Igaku-Shoin, 1984.
Rajesh L, Dey P, Joshin K. Fine needle aspiration cytology of lobular breast
carcinoma. Comparison with other breast lesions. Acyta Cytol 2003;47:
177–182.
Salhany KE, Page DL. Fine needle aspiration of mammary lobular carcinoma
in situ and atypical lobular hyperplasia. Am J Clin Pathol 1989;
92:22–26.
Smith DB, Howell A, Harris M, et al. Carcinomatous meningitis associated
with infiltrating lobular carcinoma of the breast. Eur J Surg Oncol
1985;11:33–36.
Metastases to the Breast
Gorczyca W, Olszewski W, Tuziak T, et al. Fine needle aspiration biopsy of
rare malignant tumors of the breast. Acta Cytol 1992;36:918–926.
Gorczyca W, Wlodzimierz O, Tuziak T, Kram A, Woyke S, Ucinski M. Fine
needle aspiration cytology of rare malignant tumors of the breast. Acta
Cytol 1992;36:918–926.
Ch005-F06731.indd 158
FINE NEEDLE ASPIRATION CYTOLOGY
Levine PH, Zamuco R, Yee HT. Role of fine-needle aspiration cytology in
breast lymphoma. Diagn Cytopathol 2004;30:332–340.
Mattia AR, Ferry JA, Harris JA. Breast lymphoma: a B-cell spectrum includ-
ing the low grade B-cell lymphoma of mucosa associated lymphoid
tissue. Am J Surg Pathol 1993;17:574–587.
Miura H, Konaka C, Kamate N, et al. Fine needle aspiration cytology of
metastatic breast tumor originating from leukemia. Diagn Cytopathol
1992;8:605–608.
Nielsen M, Andersen JA, Henriksen FW, et al. Metastases to the breast
from extramammary carcinomas. Acta Pathol Microbiol Scand [A]
1981;89:251–256.
Pettinato G, Manivel JC, Petrella G, De Chiara A. Primary multilobated
T-cell lymphoma of the breast diagnosed by fine needle aspiration
cytology and immunocytochemistry. Acta Cytol 1991;35:294–299.
Silverman JF, Feldman PS, Covell JL, Frable WJ. Fine needle aspiration
cytology of neoplasms metastatic to the breast. Acta Cytol 1987;31:
291–300.
Sneige N, Zachariah S, Fanning TV, Dekmezian RH, Ordonez NG. Fine
needle aspiration cytology of metastatic neoplasms in the breast. Am
J Clin Pathol 1989;92:26–35.
Granular Cell Tumor
Adeniran A, Al-Ahmadie H, Mahone M, Robinson-Smith T. Granular cell
tumor of the breast: a series of 17 cases and review of the literature.
Breast J 2004;19:528–531.
DeMay RM, Kay S. Granular cell tumor of the breast. Pathol Annu
1984;19:121–148.
Geisinger KR, Kawamoto EH, Marshall EB, et al. Aspiration and exfoliative
cytology, including ultrastructure of a malignant granular cell tumor.
Acta Cytol 1985;29:593–597.
Ingram DL, Mossler JA, Snowwhite I, et al. Granular cell tumors of the
breast. Steroid receptor analysis and localization of carcinoembryonic
antigen, myoglobin, and S-100 protein. Arch Pathol Lab Med 1984;108:
897–901.
Lowhagen T, Rubio CA. The cytology of the granular cell myoblastoma of
the breast. Report of a case. Acta Cytol 1977;21:314–315.
Strobel SL, Shah NT, Lucas JG, et al. Granular cell tumor of the breast: a
cytologic immunohistochemical and ultrastructural study of two cases.
Acta Cytol 1985;29:598–601.
Gynecomastia
Gorczyca W, Olszewski W, Tuziak T, et al. Fine needle aspiration biopsy of
rare malignant tumors of the breast. Acta Cytol 1992;36:918–926.
Hajdu SI, Espinosa MH, Robbins GF. Recurrent cystosarcoma phyllodes. A
clinicopathologic study of 32 cases. Cancer 1976;38:1402–1406.
Hoeven KV, Hibbard C, Jones J, et al. Fine needle aspiration diagnosis of
tumors metastatic to the breast. Acta Cytol 1991;35:613.
Koss LG, Woyke S, Olszewski W. Aspiration Biopsy: Cytologic Interpretation
and Histologic Bases. New York: Igaku-Shoin, 1984.
London G, Senige N, Ordonez NG, et al. Carcinoid metastatic to breast
diagnosed by fine needle aspiration biopsy. Diagn Cytopathol 1987;3:
230–233.
Martinez-Onsurbe P, Fuentes-Vaamonde E, Gonzalez-Estecha A,
Hernandez-Ortiz MJ, Ruiz-Villaespesa A. Neurilemmoma of the breast in
a man. A case report. Acta Cytol 1992;36:511–513.
Miura H, Konaka C, Kamate N, et al. Fine needle aspiration cytology of
metastatic breast tumor originating from leukemia. Diagn Cytopathol
1992;8:605–608.
Rao CR, Narasimhamurthy NK, Jaganathan K, Mukherjee G, Hazarika D.
Cystosarcoma phyllodes. Diagnosis by fine needle aspiration cytology.
Acta Cytol 1992;36:203–207.
Simi U, Moretti D, Iacconi P, et al. Fine needle aspiration cytopathology
of phyllodes tumor. Differential diagnosis with fibroadenoma [see com-
ments]. Acta Cytol 1988;32:63–66.
Toker C, Tang CK, Whitely JF, Verkheiser SW, Rachman R. Benign spindle
cell breast tumour. Cancer 1981;48:1615–1622.
10/26/2006 10:26:11 AM
 6 Lung
Ema A Berbescu
Celeste N Powers
INTRODUCTION
Fine needle aspiration (FNA) of the lung has increased
in popularity and frequency over the last two decades.
It is often the preferred method for sampling solid
lesions and can be performed safely and accurately via
transbronchial (during fiberoptic bronchoscopy) or
transthoracic (radiology-guided) methods; however, these
methods are not useful for sampling diffuse pulmonary
infiltrates. Tables 6-1 and 6-2 summarize the indications
for transbronchial and transthoracic lung FNA.
Transbronchial FNA uses a retractable needle (Wang
needle) attached at the tip of a flexible catheter that is
inserted into the flexible bronchoscope. Transthoracic
FNA is performed under radiologic guidance using com-
puted tomography (CT), fluoroscopy, or ultrasonogra-
phy. The needle types more commonly used are Chiba
and Franseen, with needle gauges ranging from 18G to
25G. Selection of the size, gauge, and type of needle is
based on location and predicted consistency of any
given lesion, as well as experience and personal prefer-
ence. Many radiologists tend to select large diameter
needles (18–20G) for these procedures; however, when
these needles are used, this procedure should not be
termed fine needle aspiration biopsy. FNA uses 22G or
smaller-sized needles (23G, 25G) and has much less risk
of complications, such as hemorrhage and/or pneumo-
thorax, which are associated with the use of large-
diameter biopsy needles. Complications of lung FNA are
presented in Table 6-3; contraindications of lung FNA
are summarized in Table 6-4.
NORMAL CONSTITUENTS
Normal cellular constituents that may be encountered
in lung FNA comprise bronchial cells, alveolar macro-
phages, pneumocytes, and mesothelial cells (in trans-
thoracic FNA).
Bronchial cells are usually columnar or cuboidal and
ciliated (Fig. 6-1A). They have basal nuclei with small
nucleoli. Cilia and terminal bars are usually visible at
the apical poles. The presence of cilia in a cell group is
a major clue to its benign nature.
Ch006-F06731.indd 159
• Michael O Idowu •
Alveolar macrophages (Fig. 6-1B) have a similar
morphology to macrophages elsewhere in the body.
They have round, oval, or bean-shaped eccentric nuclei.
They usually have abundant cytoplasm and are typically
laden with dust, carbon, and other particulate matters.
Hemosiderin-laden macrophages usually indicate prior
hemorrhage or infarction; however, this diagnosis can
be overlooked if the pigment is attributed to the normal
‘dust burden’.
Alveolar pneumocytes. Type I pneumocytes are not
usually encountered in aspirate specimens. Type II
pneumocytes are relatively small with finely vacuolated
cytoplasm and centrally placed small nuclei. They may
be difficult to distinguish from macrophages unless the
latter have pigment-laden cytoplasm. Type II pneumo-
cytes can increase in number in reparative states and in
response to chronic injury such as pneumonia, diffuse
alveolar damage, drugs, radiotherapy, etc. In such cases,
they may be in three-dimensional clusters or singly with
a high nuclear to cytoplasmic (N/C) ratio, coarse chro-
matin, and prominent nucleoli – and may resemble
adenocarcinoma, so much so, that the history of pneu-
monia becomes very important.
Mesothelial cells may be seen in the lung FNA, espe-
cially in transthoracic FNA. This is due to the transfer
of the pleural mesothelial lining by the aspiration needle,
often when the FNA target is a peripheral mass. The
morphology of the mesothelial cells in this case is similar
to that of the mesothelial cells covering visceral organs.
Mesothelial cells on FNA present as honeycomb
sheets of evenly spaced, uniform cells with abundant
cytoplasm, narrow gaps or ‘windows’ (due to the inter-
action of the microvilli), and small, discrete nucleoli
(Fig. 6-2).
NON-NEOPLASTIC CONDITIONS
SARCOIDOSIS
CLINICAL FEATURES
Sarcoidosis is a multisystem granulomatous disease of
unknown etiology. It affects predominantly the lungs
(90% of patients), but can also involve extrapulmonary
159
10/26/2006 10:27:24 AM
 160 FINE NEEDLE ASPIRATION CYTOLOGY

A B

FIGURE 6-1
Normal cellular constituents. A, Bronchial cells are columnar cells with small, round–oval, basally located nuclei. Note the presence of cilia and
terminal bars. Identifying cilia in a group of cells indicates their benign nature. Bronchial cells are frequently seen in transbronchial FNA materials.
Papanicolaou stain, medium power. B, Alveolar macrophages have abundant, somewhat vacuolated cytoplasm and a small, round nucleus. Charac-
teristically, macrophages hold on their cytoplasm during slide preparation. Diff-Quik stain, high power.

TABLE 6-1 TABLE 6-3

Indications for Transbronchial FNA Complications of Lung FNA

• Centrally located lesions: 1. Pneumothorax

• beneath the bronchial mucosa • Most common complication (its incidence increases
• intrabronchial polypoid lesions with the number of aspirations)
• Mediastinal adenopathy (sarcoidosis, lymphoma, staging • Most are clinically insignificant
of patients with lung cancer) • 5% of them require chest tube
2. Hemorrhage
3. Air embolism

TABLE 6-2
Indications for Transthoracic FNA

• Peripherally located nodules that cannot be sampled by TABLE 6-4

bronchoscopy
• Evaluation for metastasis in a patient with multiple lung Contraindications of Lung FNA
nodules
• Confirm the diagnosis of lung cancer in an inoperable • Bleeding diathesis and coagulation abnormalities
patient • Pulmonary hypertension (increased risk of bleeding)
• Confirm the diagnosis of small cell carcinoma and avoid • Severe respiratory distress
unnecessary surgery • Severe emphysema with bullae (risk of pneumothorax)

sites such as eye, skin, heart, liver, spleen, salivary
glands, and central nervous system. Between 30% and
50% of patients are asymptomatic and are diagnosed
on routine chest radiographs. One-third of patients
have non-specific symptoms, such as fever, fatigue,
weight loss, malaise, and respiratory symptoms (dry
cough, dyspnea, chest discomfort). Pulmonary sarcoid-
osis has an unpredictable course that may result in
spontaneous remission or lead to progressive loss of
lung function with fibrosis.
The diagnosis of sarcoidosis includes compatible
clinicoradiologic features, pathologic evidence of non-
caseating epithelioid granulomas, and exclusion of
similar diseases. The pathologic proof of epithelioid
granulomas is obtained most commonly by transbron-
chial lung biopsy, but also lymph node or skin biopsy
can be helpful. Bronchoscopy with transbronchial lung
biopsy is non-diagnostic in 30% of patients with sus-
pected sarcoidosis and has a risk of pneumothorax and
hemoptysis. Recently, endoscopic ultrasound-guided

Ch006-F06731.indd 160 10/26/2006 10:27:24 AM

 CHAPTER 6 Lung 161

FIGURE 6-2
Mesothelial cells. They present as
fl at, two-dimensional sheets of
evenly spaced, bland cells. Meso-
thelial cells can be sampled during
transthoracic FNA and usually they
are sparsely present within a given
specimen. It is very important not
to confuse them with the cells
aspirated from a bronchioloalveolar
carcinoma. Clues to the origin of
these cells are sparse cellularity
and lack of single, discohesive cells.
Diff-Quik stain, low power.

particularly methotrexate (Rheumatrex) and azathio-

SARCOIDOSIS – DISEASE FACT SHEET prine (Imuran).

Definition
៉ Granulomatous disease of unknown etiology
R ADIOLOGIC FEATURES
Gender, Race, and Age Distribution
៉ More common in women than in men (incidence of 6.3 cases and Chest X-ray findings are classified in four stages. Stage
5.9 cases per 100,000 person-year, respectively) 0 refers to an apparently normal chest radiograph; stage
៉ Affects all races and ages, but more common in patients younger I consists of bilateral hilar adenopathy without paren-
than 40 years and more prevalent in US Blacks, Swedes, and chymal changes; stage II refers to hilar adenopathy and
Danes
parenchymal involvement; stage III consists of only
parenchymal involvement; and stage IV refers to
Clinical Features
advanced fibrosis with bullae formation.
៉ 30–50% of patients are asymptomatic
៉ One-third of patients have non-specific symptoms

Radiologic Features CYTOPATHOLOGIC FEATURES

៉ Four stages

Prognosis and Treatment The characteristic feature of sarcoidosis is tight, non-

៉ Unpredictable clinical course
៉ Corticotherapy, cytotoxic agents
FNA of enlarged hilar lymph nodes has been performed
in patients with suspected sarcoidosis, with 95% sensi-
tivity and specificity.
Oral corticosteroids are the mainstay therapy for
pulmonary sarcoidosis. Patients who do not respond
to corticosteroids may benefit from cytotoxic agents,
caseating epithelioid granulomas (Fig. 6-3). In general,
in the FNA material from hilar lymph nodes, the
epithelioid granulomas are numerous, in a background
of lymphocytes.
The characteristic cell is the epithelioid histiocyte,
which is a large, polygonal cell with abundant eosino-
philic cytoplasm and indistinct cell borders. The nucleus
is elliptical, slightly curved (‘footprint’) and pale, with
fine chromatin and one or two small nucleoli. Admixed
with the epithelioid histiocytes are multinucleated
giant cells. In general, caseous necrosis is absent, but
occasionally a small focus of necrosis can be seen in
large granulomas.

Ch006-F06731.indd 161 10/26/2006 10:27:25 AM

 162 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 6-3
Sarcoidosis. The characteristic feature of sarcoidosis is the presence of non-caseating epithelioid granulomas. They consist of tight clusters of epi-
thelioid histiocytes admixed with lymphocytes. The inset shows the characteristic features of epithelioid histiocytes: abundant eosinophilic cyto-
plasm with indistinct cell borders and a slightly curved (‘footprint’) nucleus with fine nuclear chromatin. Diff-Quik stain, low power (inset: Diff-Quik
stain, high power).

SARCOIDOSIS – PATHOLOGIC FEATURES

ANCILLARY STUDIES

Cytopathologic Findings
Sarcoidosis is a diagnosis of exclusion. Infectious and
៉ Tight, non-caseating epithelioid granulomas
non-infectious etiologies need to be excluded before
៉ Epithelioid histiocyte is a large cell with abundant eosinophilic
making the diagnosis of sarcoidosis. Special stains for
cytoplasm, indistinct cell borders, and a slightly curved
(‘footprint’) nucleus
microorganisms (Ziehl-Neelsen, Gomori methenamine
៉ Multinucleated giant cells can be present silver [GMS]) need to be performed on the cytology
៉ It is a diagnosis of exclusion material. Cultures can be obtained at the time of FNA.
Foreign material (talc, beryllium, etc.) can be identified
Ancillary Studies by light microscopy using polarized light or by laser
៉ Special stains (Ziehl-Neelsen, GMS) mass spectrometric analysis.
៉ Cultures

Differential Diagnosis and Pitfalls

៉ Mycobacterial infections DIFFERENTIAL DIAGNOSIS AND PITFALLS
៉ Histoplasmosis
៉ Granulomas accompanying malignancy
Non-caseating granulomas are not specific for sarcoid-
osis and they can be seen in a variety of other

Ch006-F06731.indd 162 10/26/2006 10:27:25 AM

 CHAPTER 6 Lung
conditions. The differential diagnosis for epithelioid
granulomas in the hilar lymph nodes includes mycobac-
terial infection (including atypical mycobacteria), histo-
plasmosis, and non-specific granulomas accompanying
malignancy (T-cell lymphomas, Hodgkin lymphoma,
seminomas).
TUBERCULOSIS
CLINICAL FEATURES
Worldwide it is estimated that 1 billion people are
infected with Mycobacterium tuberculosis. In the United
States, the annual tuberculosis case rate is estimated to
be 9.5 per 100,000 persons. Forty percent of tubercu-
losis cases in the United States occur in foreign-born
persons.
Tuberculosis is the result of infection with Mycobac-
terium tuberculosis complex (M. tuberculosis, M. bovis),
transmitted by infected aerosols, by direct person-
to-person contact (M. tuberculosis), or by ingestion of
contaminated food (milk; M. bovis). After the initial
infection (primary tuberculosis), the disease is latent
for a variable period of time and reactivates when the
immune system is weakened (secondary tuberculosis).
Non-tuberculous mycobacterial infections (M. avium-
intracellulare complex) cannot be distinguished on clini-
cal and radiologic grounds from M. tuberculosis complex
infections. This distinction is made only by cultures
with biochemical tests or using polymerase chain reac-
tion (PCR) techniques.
Treatment is characterized by using multiple drugs
for a long period of time to prevent resistance. Major
antituberculous drugs used are isoniazid, rifampin,
pyrazinamide, ethambutol, and streptomycin.
TUBERCULOSIS – DISEASE FACT SHEET
Definition
៉ Infectious disease caused by Mycobacterium tuberculosis
Clinical Features
៉ Pathogenic non-tuberculous mycobacteria species (such as M.
avium-intracellulare complex) produce similar clinical and
radiologic findings; distinction made only by cultures or PCR
៉ In the US, certain populations are at increased risk: foreign-born
individuals, HIV-positive individuals, nursing home residents, and
prison inmates
Radiologic Features
៉ More commonly involves the apical and posterior segments of
upper lobes
៉ Hazy infiltrates that progress to cavitation and fibrosis
Treatment
៉ Multiple antituberculous drugs over a long period of time
Ch006-F06731.indd 163
163
R ADIOLOGIC FEATURES
Typically, tuberculosis involves the apical and poste-
rior segments of upper lobes, but any lung segment can
be affected. The chest X-ray shows hazy infi ltrates that
progress to cavitation and fibrosis.
CYTOPATHOLOGIC FEATURES
The aspirated material shows granulomas, plump his-
tiocytes, and/or necrosis (Figs 6-4 & 6-5). Routine
cytologic stains do not stain the actual bacilli; however,
there may be significant clues that suggest their pres-
ence. Mycobacteria cannot be identified on Papanico-
laou stain. While the Diff-Quik stain does not stain the
individual organisms per se, it does outline them. The
unstained bacilli appear as slender, straight or slightly
curved, colorless rods highlighted against a dirty blue–
grey background. Thus, the terms ‘negative images’ or
‘ghost bacilli’ are used as descriptors. This characteris-
tic ‘negative image’ is presumably the result of hydro-
phobic interactions of the water-based Diff-Quik stain
with the lipid within the cell walls of the bacilli (Fig.
6-6). The identification of these negative images within
histiocytes and in the background is virtually patho-
gnomonic for mycobacteria. Lowering the substage
condenser often increases the refractivity of the bacilli
and enhances their identification when they are scat-
tered in the smear background. In FNA material from
mediastinal lymph nodes, the presence of numerous
organisms both within distended histiocytes and scat-
tered in the background tends to be from atypical myco-
bacterial infections rather than from tuberculosis.
TUBERCULOSIS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Necrotizing granulomatous infl ammation
៉ Routine cytologic stains do not stain the bacilli
៉ ‘Negative images’ or ‘ghost bacilli’ can be seen on Diff-Quik
stain (unstained bacilli as colorless slender rods against a
dirty-blue background)
Ancillary Studies
៉ Acid-fast (Ziehl-Neelsen) or auramine rhodamine stains, or
culture are necessary for confirmation
៉ Material can be obtained for rapid detection of Mycobacterium
tuberculosis by PCR techniques
Differential Diagnosis and Pitfalls
៉ Other conditions associated with granulomatous infl ammation
(sarcoidosis, fungal infections, etc.)
៉ Clofazimine crystals within macrophages can mimic ‘negative
images’
៉ Nocardia species can appear as acid-fast, beaded filamentous
organisms
10/26/2006 10:27:26 AM
 164 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 6-4
Tuberculosis. The FNA yields abundant necrosis and scattered granulomas, characteristic findings in any necrotizing granulomatous process. The
inset shows a Ziehl-Neelsen stain performed on the cell block material that reveals scattered acid-fast bacilli. Diff-Quik stain, low power (inset:
Ziehl-Neelsen stain, high power).

FIGURE 6-5
Tuberculosis. The granulomas in
tuberculosis are loosely formed,
with admixed necrosis and infl am-
matory cells. Contrast this with the
tight granulomas and clean back-
ground seen in sarcoidosis. Papani-
colaou stain, high power.

Ch006-F06731.indd 164 10/26/2006 10:27:26 AM

 CHAPTER 6 Lung
FIGURE 6-6
Atypical mycobacteria. The FNA yields a dirty-grey background in which the unstained bacilli appear as slender, straight or slightly curved colorless
rods (‘negative images’). Ziehl-Neelsen stain performed on an alcohol-fixed slide confirms the presence of numerous acid-fast bacilli (inset). Diff-
Quik stain, low power (inset: Ziehl-Neelsen stain, high power).
Acid-fast stain (Ziehl-Neelsen) can be performed on
smears, cytospins, and cell block sections and should be
used for confirmation. The organisms appear as thin,
slender, red beaded bacilli.
ANCILLARY STUDIES
The diagnosis of tuberculosis is confirmed by identify-
ing acid-fast bacilli in respiratory specimens or cul-
tures. In many instances, when the patient is known
to be immunocompromised or has had prior infections,
the index of suspicion for infection is high and addi-
tional specimens are obtained for culture or fluores-
cence microscopy. PCR can now be used for rapid
detection of M. tuberculosis.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Sarcoidosis, fungal infections, and reaction to an adja-
cent neoplasm (such as Hodgkin lymphoma, seminoma,
T-cell lymphomas) also present with granulomatous
Ch006-F06731.indd 165
165
inflammation with or without necrosis. The presence
of M. tuberculosis or atypical mycobacteria should be
suspected in every case of granulomatous inflamma-
tion, especially when the patient is immunosuppressed,
and confirmed with acid-fast (Ziehl-Neelsen) or aura-
mine rhodamine stains, cultures, or PCR. ‘Negative
images’ are not specific. Patients treated with clofazi-
mine show crystal formation within macrophages that
mimic negative images. Nocardia species can appear
beaded on acid-fast stain; however, they are slender
fi laments, branching at acute angles, and are larger in
diameter than mycobacteria.
FUNGAL INFECTIONS
Pulmonary infections with dimorphic fungi (hyphae at
room temperature and yeasts at body temperature) are
increasing in importance as causes for opportunistic
infections in immunocompromised patients, especially
those with AIDS. The three dimorphic fungi discussed
in this chapter are Histoplasma capsulatum, Blasto-
myces dermatitidis, and Coccidioides immitis. Other
important fungi involved in pulmonary infections in
10/26/2006 10:27:27 AM
 166
immunocompromised individuals that will be dis-
cussed in this chapter are Cryptococcus neoformans,
Aspergillus fumigatus, and fungi belonging to Zygomy-
cetes class (Rhizopus, Absidia, and Mucor species).
HISTOPLASMOSIS
CLINICAL FEATURES
Histoplasmosis is produced by inhalation of microco-
nidia of Histoplasma capsulatum or by reactivation of
latent infection in individuals with past histoplasmosis
who become immunosuppressed. H. capsulatum can
be found throughout the world. In the United States,
H. capsulatum is endemic in the Mississippi and Ohio
river valleys. Bird and bat excrement enhance growth
of the organism in the soil.
In endemic areas, 50–80% of young adults are
infected with H. capsulatum and are asymptomatic.
After low-level exposure, less than 5% of individuals
develop symptomatic disease. After high-level exposure
(work or recreational activities in contaminated sites),
more than 75% of individuals develop symptoms.
There are several clinical manifestations of infection
with H. capsulatum: acute pulmonary histoplasmosis,
chronic pulmonary histoplasmosis, granulomatous
mediastinitis, disseminated histoplasmosis, and fibros-
ing mediastinitis.
HISTOPLASMOSIS – DISEASE FACT SHEET
Definition
៉ Infection resulting from inhalation of Histoplasma capsulatum or
reactivation of latent infection
Incidence and Geographic Distribution
៉ Annual incidence: 5/100,000
៉ Endemic in Mississippi and Ohio river valleys
Clinical Features
៉ 50–80% of infected young adults are asymptomatic
៉ Several clinical manifestations: acute pulmonary histoplasmosis
(mimics flu); chronic histoplasmosis (mimics tuberculosis);
granulomatous mediastinitis (less than 10% of patients);
disseminated histoplasmosis and fibrosing mediastinitis
Radiologic Features
៉ Acute form: hilar and mediastinal adenopathy with pulmonary
infiltrates
៉ Granulomatous mediastinitis: enlarged, cystic mediastinal lymph
nodes
៉ Fibrosing mediastinitis: mediastinal widening
Treatment
៉ Antifungal therapy in symptomatic patients
៉ Antifungal therapy not indicated for self-limited forms of acute
disease or for fibrosing mediastinitis
Ch006-F06731.indd 166
FINE NEEDLE ASPIRATION CYTOLOGY
Acute histoplasmosis is characterized by flu-like
symptoms (fever, chills, myalgia, headache, cough) and
chest X-ray abnormalities. Chronic pulmonary histo-
plasmosis develops in patients with emphysema exposed
to H. capsulatum. They present with cough, dyspnea,
fatigue, fever, and sweats, mimicking tuberculosis.
Granulomatous mediastinitis produces obstruction of
mediastinal structures (airways, superior vena cava,
pulmonary vessels, esophagus). The mediastinal lymph
nodes are enlarged, forming cystic masses with central
necrosis and surrounded by granulomatous inflamma-
tion and encased in a fibrous capsule. Disseminated
histoplasmosis occurs in 1 in 2000 acute infections.
It is rare in immunocompetent individuals and more
common in immunosuppressed individuals (in particu-
lar, AIDS). The infection spreads to extrapulmonary
sites (liver, spleen, bone marrow, skin, gastrointestinal
tract, adrenal glands). Fibrosing mediastinitis is an
excessive fibrotic response to past infection. This is a
rare complication (less than 1 in 5000 infections); 80%
of cases occur in individuals between the ages of 20 and
40 years.
Antifungal therapy (triazole agents and liposomal
formulations of amphotericin B) is indicated in patients
with symptomatic acute pulmonary histoplasmosis,
granulomatous mediastinitis, chronic pulmonary
histoplasmosis, and in disseminated disease. Antifungal
therapy is not indicated in acute, self-limited forms
of pulmonary histoplasmosis or in fibrosing
mediastinitis.
R ADIOLOGIC FEATURES
Chest X-ray in symptomatic acute pulmonary histoplas-
mosis shows enlarged hilar and mediastinal lymph
nodes with focal patchy or nodular pulmonary infi l-
trates. In granulomatous mediastinitis, radiologic
studies show enlarged, often cystic, mediastinal lymph
nodes (measuring up to 10 cm). Chest X-ray in fibrosing
mediastinitis shows subcarinal and mediastinal widen-
ing, but high-resolution chest CT with contrast is
required to delineate the mediastinal abnormalities.
CYTOPATHOLOGIC FEATURES
Material can be obtained by FNA from enlarged medi-
astinal lymph nodes and cavitary lesions. H. capsula-
tum is one of the smallest dimorphic fungi (3 to 5 μm).
It is predominantly intracellular, as foamy or vacuo-
lated oval structures within the cytoplasm of histio-
cytes (Fig. 6-7). Yeast forms of H. capsulatum are easiest
to identify when they are within macrophages; their
engulfment results in a vacuolated or foamy cytoplasm
with small halos surrounding each organism (due to
retraction from the wall creating the appearance of a
pseudocapsule). Macrophages with engulfed organisms
10/26/2006 10:27:28 AM
 CHAPTER 6 Lung
FIGURE 6-7
Histoplasmosis. The yeast forms of Histoplasma capsulatum appear as
foamy or vacuolated oval structures within the cytoplasm of histio-
cytes. The small halos surrounding each organism are the result of wall
retraction. This artifact can mimic the Cryptococcus neoformans capsule.
Diff-Quik stain, high power.
HISTOPLASMOSIS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Histoplasma capsulatum is a small yeast (3 to 5 μm), with
narrow-based budding
៉ Usually intracellular (engulfed by macrophages)
៉ Vacuolated cytoplasm with small halos surrounding the
organism (appearance of pseudocapsule)
៉ On Papanicolaou stain, it is difficult to visualize
៉ On Diff-Quik stain: dark-purple organisms
Ancillary Studies
៉ Confirmatory stain: GMS
៉ PCR performed when morphology is inconclusive
៉ Histoplasma antigen detection and cultures in severe cases,
particularly in disseminated disease
Differential Diagnosis and Pitfalls
៉ Other organisms (Candida species, Cryptococcus neoformans,
Blastomyces dermatitidis, Toxoplasma gondii, Leishmania species,
Pneumocystis carinii)
៉ Staining artifacts
are typically present in a background of granulomatous
inflammation that can also include necrosis, acute
inflammatory cells, and lymphocytes. Yeast forms of
H. capsulatum demonstrate narrow-based (teardrop)
budding. If present in small numbers, H. capsulatum
can be very difficult to visualize on Papanicolaou stain.
The Diff-Quik stain is useful because it stains these
organisms a dark purple that is usually in stark con-
trast to the pale-staining cytoplasm. Confirmatory stain
(GMS) should be performed when this organism is
presumptively identified.
Ch006-F06731.indd 167
167
ANCILLARY STUDIES
PCR studies can be done in cases in which the morphol-
ogy of the yeasts identified in tissue specimens is incon-
clusive. Detection of Histoplasma antigen in body fluids
(blood, urine, bronchoalveolar lavage) allows a rapid
diagnosis (24 to 48 hours) in patients with severe
disease. Cultures are also useful, particularly in the
disseminated form. The highest yield is from blood and
bone marrow specimens.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
GMS stain must be interpreted carefully, as other
organisms (Candida species, Cryptococcus neoformans,
Blastomyces dermatitidis, Toxoplasma gondii, Leishma-
nia species, Pneumocystis carinii) or staining artifacts
can be misinterpreted as H. capsulatum. When the
organism retracts from its wall, it creates a clear space
that mimics the capsule of C. neoformans. If the differ-
ential diagnosis includes leishmaniasis, recognition of
a nucleus and kinetoplast and the absence of budding
will exclude H. capsulatum.
BLASTOMYCOSIS
CLINICAL FEATURES
Blastomycosis is the result of inhalation of spores of
Blastomyces dermatitidis. In the United States, the
BLASTOMYCOSIS – DISEASE FACT SHEET
Definition
៉ Infection caused by inhalation of Blastomyces dermatitidis
Incidence and Geographic Distribution
៉ Annual incidence: 0.5/100,000
៉ Endemic areas in the US are Central, South-central, and
Southeastern
៉ Endemic area overlaps with that of histoplasmosis
Clinical Features
៉ Primary infection in the lung with subsequent dissemination to
skin and bone
Radiologic Features
៉ Variable: round densities, consolidations, mass-like infiltrates,
etc.
Treatment
៉ Itraconazole (in sporadic cases) and amphotericin B (in severely
ill and immunosuppressed patients)
10/26/2006 10:27:28 AM
 168
endemic areas are Central, South-central, and South-
eastern, with the highest incidence along the Missis-
sippi and Ohio river valleys and the western shore of
Lake Michigan. The endemic area overlaps with the
endemic area for histoplasmosis. The annual incidence
is roughly 0.5/100,000.
Clinically, patients can be asymptomatic or can
present with life-threatening pulmonary and dissemi-
nated disease. The majority of patients with sporadic
pulmonary blastomycosis do well with itraconazole
therapy, which is safe, highly effective, and non-toxic.
Severely ill patients require amphotericin B therapy.
Immunosuppressed patients (on prednisone or organ
transplant recipients) require sequential therapy of
amphotericin B until improved clinically, followed by
6–12 months of itraconazole. HIV-infected patients
require a similar sequential therapy, but they are not
permanently cured and lifelong therapy with itracon-
azole is necessary to maintain control.
R ADIOLOGIC FEATURES
Radiologic findings are variable and include single
or multiple round densities scattered throughout,
segmental/lobar consolidation, mass-like perihilar in-
fi ltrates, and diffuse nodular, interstitial, or alveolar
infi ltrates.
CYTOPATHOLOGIC FEATURES
B. dermatitidis produces a granulomatous suppurative
inflammatory reaction. FNA cytology aspirate shows
acute suppurative inflammation, necrotic debris, and
clusters of epithelioid histiocytes, macrophages, and
BLASTOMYCOSIS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Blastomyces dermatitidis is a large yeast (8–15 μm), spherical,
double-contoured with broad-based budding
៉ Has a rigid, refractile cell wall appearing slightly out of plane
of focus
៉ Background shows acute suppurative infl ammation, necrosis,
and macrophages
៉ Yeast forms can be extracellular or engulfed by macrophages
៉ In Papanicolaou stain, appears blue–green
៉ In Diff-Quik stain, appears blue
Ancillary Studies
៉ GMS highlights the yeast forms
៉ Culture takes several weeks
Differential Diagnosis and Pitfalls
៉ Immature spherules of Coccidioides immitis
៉ Can be completely overlooked because is out of plane of focus
Ch006-F06731.indd 168
FINE NEEDLE ASPIRATION CYTOLOGY
multinucleated giant cells. The organisms will be found
in this non-specific background. Only the yeast forms
are identified in vivo. Yeast forms of B. dermatitidis are
large (8–15 μm), spherical, and double-contoured. They
have a rigid, refractile cell wall with a centrally retracted
cytoplasm (Fig. 6-8). The yeast forms are generally
larger than those of Cryptococcus neoformans. Because
of their double-contoured rigid cell wall, they often
appear slightly out of the plane of focus, making detec-
tion difficult on routine screening. Characteristically,
they have a broad-based budding. Broad-based budding
is a useful criterion to differentiate B. dermatitidis
from the other dimorphic fungi. The yeast forms appear
blue–green on Papanicolaou stain and blue on Diff-
Quik stain. Although most often identified extra-
cellularly, these organisms can also be engulfed by
macrophages. Special stain (GMS) can be performed to
highlight the yeast forms. Cytomorphology is usually
sufficient for diagnosis. This is the easiest and fastest
way to make a diagnosis. Culture identification takes
usually several weeks.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
B. dermatitidis yeasts can be confused with the imma-
ture spherules of Coccidioides immitis. The endospores
of C. immitis are not visible in the immature spherules.
This, combined with the thick wall of C. immitis,
results in an erroneous identification as B.
dermatitidis.
Another potential problem is that the pathologist
may overlook these yeast forms. Although larger, yeast
forms of B. dermatitidis are very difficult to identify on
cytologic preparations, chiefly because they are not
numerous and are often out of the plane of focus. The
latter problem is due to their rigid cell walls, which
resist compression by a coverslip.
COCCIDIOIDOMYCOSIS
CLINICAL FEATURES
Coccidioidomycosis is produced by inhalation of arthro-
conidia of Coccidioides immitis. This is a dimorphic
fungus limited to the Western hemisphere, from Cali-
fornia to Argentina. Endemic areas in the United States
are Southwest desert regions (Arizona, California,
Nevada, Utah, New Mexico, and Texas). Patients with
impaired cell-mediated immunity (HIV infection,
prolonged corticotherapy, organ transplant recipients,
patients under chemotherapy, pregnant women) are
most susceptible to C. immitis infection.
Between 60% and 70% of individuals exposed to
C. immitis are completely asymptomatic. The rest of
patients develop signs and symptoms of primary pulmo-
nary coccidioidomycosis. A small group of patients can
10/26/2006 10:27:28 AM
 CHAPTER 6 Lung 169

FIGURE 6-8
Blastomycosis. Yeast forms of Blastomyces dermatitidis are spherical, double-contoured with a rigid, refractile wall. They appear blue on Diff-Quik
stain. The inset shows several yeasts of B. dermatitidis engulfed by a macrophage. Note the broad-based budding. Diff-Quik stain, high power (inset:
GMS stain, high power).

develop disseminated disease, with predilection for skin,

COCCIDIOIDOMYCOSIS – DISEASE FACT SHEET
Definition
៉ Fungal disease caused by inhalation of Coccidioides immitis
Distribution
៉ Endemic in Southwest desert regions
៉ Most susceptible are HIV-positive individuals, organ transplant
recipients, patients under chemotherapy or prolonged
corticotherapy, and pregnant women
Clinical Features
៉ 60–70% of patients are asymptomatic
bones, soft tissues, meninges, and disseminated pulmo-
nary disease. The sequelae of pulmonary disease are
nodules and cavities that are single, asymptomatic, less
than 5 cm, and can persist for a long period of time.
Cavities can be complicated by infection (bacteria from
upper respiratory tract or Aspergillus species), hemo-
ptysis or rupture into the pleural space with pyopneu-
mothorax. The antifungal therapy (with amphotericin
B and azoles) is reserved for immunocompromised
patients with pulmonary or disseminated disease and
for immunocompetent patients whose symptoms have
persisted for more than 6 weeks.

Radiologic Features
៉ Alveolar infiltrates that progress to cavities
R ADIOLOGIC FEATURES

Prognosis and Treatment

In primary pulmonary coccidioidomycosis, the chest
៉ Pulmonary sequelae: cavities that can get infected or rupture
X-ray shows segmental or lobar alveolar infi ltrates with
within pleural space
occasional hilar and mediastinal adenopathy. The cavi-
៉ Antifungal therapy for immunocompromised individuals or
patients with prolonged symptoms
ties are thin-walled, and, when infected, they will
appear with air–fluid level, opacified, and surrounded
by parenchymal infi ltration (Fig. 6-9).

Ch006-F06731.indd 169 10/26/2006 10:27:28 AM

 170
FIGURE 6-9
Cavitary lesion: radiologic findings. An isolated cavitary lesion with
air–fluid level is seen in the left lower lobe. The differential diagnosis
includes infectious process (abscess; tuberculosis; fungal infection,
especially coccidioidomycosis, aspergillosis, and zygomycosis) versus
malignant neoplasm (especially squamous cell carcinoma).
CYTOPATHOLOGIC FEATURES
C. immitis is one of the largest of the dimorphic fungi.
The organism can be identified extracellularly within
a background of acute fibrinopurulent exudate and
granulomatous inflammation or engulfed by macro-
COCCIDIOIDOMYCOSIS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Coccidioides immitis is the largest of the dimorphic fungi
៉ Presents as endospores within thick-walled spherules; the
endospores are expelled and the empty spherule appears folded
and fractured
៉ The spherules are extracellular or engulfed by macrophages
Ancillary Studies
៉ Fungal culture is sensitive (C. immitis in culture grows as a mold
and is highly infectious)
Differential Diagnosis and Pitfalls
៉ Other fungi (Blastomyces dermatitidis, Histoplasma capsulatum)
៉ Pollen grains
៉ Inorganic contaminants
៉ Helpful clue: look for older, folded and fractured spherules
Ch006-F06731.indd 170
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 6-10
Coccidioidomycosis. The thick-walled spherules of Coccidioides immitis
are identified engulfed by macrophages. They appear orangeophilic in
Papanicolaou stain, being easy to identify. Papanicolaou stain, high
power.
phages (Figs 6-10 & 6-11A). This organism presents as
endospores within thick-walled spherules that can vary
tremendously in size. Endospores are not visible in
immature spherules; as the spherules mature, they will
contain numerous small (2–5 μm) endospores. The
endospores are expelled from the spherule, creating an
acute inflammatory reaction. The now-empty spherule
will appear fractured and folded (Fig. 6-11B). This
organism occasionally stains orangeophilic by Papani-
colaou stain, making it easy to detect (Fig. 6-11C). The
spherules stain lightly or not at all with the Diff-Quik
stain, although, with experience, this lack of staining
is a useful clue. Periodic acid–Schiff (PAS) stain after
diastase digestion with a light-green counterstain is a
very useful confirmatory stain, since the spherules
stain a vivid magenta against a pale-green background
(Fig. 6-11D). Rarely, the cavities may be exposed to air,
resulting in the development of mycelial forms with
barrel-shaped arthroconidia (5% of cases).
ANCILLARY STUDIES
Direct examination of respiratory specimens is nega-
tive in approximately 60% of patients with culture-
positive pulmonary coccidioidomycosis. Fungal culture
is a sensitive method of diagnosis. The organism grows
rapidly (3 to 5 days), at 35ºC, on a variety of media. It
should be remembered that in the culture C. immitis
grows as a mold and is highly infectious.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
C. immitis can resemble a variety of other fungi, pollen
grains, and even inorganic contaminants. Endospores
are not visible in immature spherules; combined with
the thick wall of C. immitis, this often results in an
10/26/2006 10:27:29 AM
 CHAPTER 6 Lung 171

A B

C D

FIGURE 6-11
Coccioidomycosis: FNA findings. A, The spherules of Coccidioides immitis are scattered in an acute fibrinopurulent background. They stain very light
with Diff-Quik, and this lack of staining can be a useful clue. Diff-Quik stain, low power. B, After the endospores are expelled, the empty spherule of
C. immitis appears fractured and folded. Diff-Quik stain, high power. C, A mature spherule of C. immitis containing numerous endospores is engulfed
by a macrophage. Note the orangeophilic staining. Papanicolaou stain, high power. D, Three spherules of C. immitis are engulfed by a macrophage.
They appear vivid magenta colored against a pale-green background. PAS stain after diastase digestion with light-green counterstain, high power.

erroneous identification as Blastomyces dermatitidis. CRYPTOCOCCOSIS – DISEASE FACT SHEET

Once the endospores are separated from the spherule,
they may resemble Histoplasma capsulatum and even
Toxoplasma gondii, and a careful search for older, folded
and fractured spherules is necessary. Conversely, when
these older spherules are seen without intact, mature
spherules, they may be overlooked as inorganic
contaminants.
Definition
៉ Infection caused by inhalation of Cryptococcus neoformans
Incidence
៉ Most common fungal infection in immunosuppressed individuals
៉ Isolated pulmonary cryptococcosis is rare

Clinical Features
៉ Affects brain, lung, skin, and bone
CRYPTOCOCCOSIS
Radiologic Features
៉ Pulmonary infiltrates, mimicking neoplasm or other infections
CLINICAL FEATURES
Treatment
៉ Amphotericin B with 5-fluorocytosine
Cryptococcosis is an infection caused by inhalation
from the environment of Cryptococcus neoformans,

Ch006-F06731.indd 171 10/26/2006 10:27:30 AM

 172
which is spread worldwide. The infection affects the
brain, lung, skin, or bone, both in immunocompetent
and in immunosuppressed patients. C. neoformans is
the most common fungal infection complicating HIV
infection. Meningitis is the most common form of
disease. Isolated pulmonary cryptococcosis is very
rare. The majority of patients clear the pulmonary
infection but later develop meningitis, while 90% of
patients with cryptococcal meningitis (excluding
AIDS patients) have a clear chest X-ray and no history
of pneumonia. Treatment of cryptococcal infection in
immunosuppressed patients includes amphotericin B
with 5-fluorocytosine; when clinical improvement is
obtained, then the treatment is switched to fluconazole
for life.
RADIOGRAPHIC FEATURES
The chest radiographic fi lms show pulmonary infi l-
trates, single or multiple, mimicking other pulmonary
infections or neoplasms. Occasionally, patients can
develop large, round masses up to 10 cm in diameter.
FIGURE 6-12
Cryptococcosis. In the FNA material, the organisms are abundant, single or in small clusters. The inset shows the characteristic ‘teardrop’, narrow-
based budding. Diff-Quik stain, low power (inset: GMS stain, high power).
Ch006-F06731.indd 172
FINE NEEDLE ASPIRATION CYTOLOGY
CYTOPATHOLOGIC FEATURES
C. neoformans is a round or oval encapsulated yeast (5
to 10 μm in diameter). The capsule measures from 1 to
30 μm in thickness and is made of polysaccharides. Due
to its large capsule, C. neoformans resists phagocytosis.
T-cell-mediated immunity with granuloma formation
is necessary to stop the infection. In patients with
impaired T-cell-mediated immunity (HIV-positive,
organ transplant recipients), granuloma formation does
not occur and the growth continues, producing large
gelatinous masses of cryptococci with no tissue
reaction.
In FNA material, this organism is usually abundant,
being found individually or as clusters of organisms
with accentuated capsular halos (Fig. 6-12). In Diff-
Quik-stained preparations, the purple yeasts with accen-
tuated clear halos against the deep-purple background
give the smear a punched-out appearance (Fig. 6-13). A
useful feature is the appearance of teardrop, narrow-
based budding. At times, the daughter bud will not
detach and repetition of budding yields small chains
of daughter progeny. Occasionally, the yeast can be
engulfed by histiocytes.
10/26/2006 10:27:31 AM
 CHAPTER 6 Lung 173

based budding is a distinctive, helpful feature to iden-

tify C. neoformans.

ASPERGILLOSIS

CLINICAL FEATURES

Aspergillosis refers to infection, through inhalation,

with molds of the genus Aspergillus. The most common
pathogen encountered in lung infections is A. fumiga-
tus (which is the most pathogenic of all species). Pul-
monary manifestations are numerous and include
FIGURE 6-13 allergic bronchopulmonary aspergillosis, hypersensi-
Cryptococcosis. The yeast forms of Cryptococcus neoformans have a large tivity pneumonitis, asthma, aspergilloma, and invasive
polysaccharide capsule. They appear as purple yeasts with accentuated
clear halos giving the smear a punched-out appearance. Diff-Quik stain,
pulmonary aspergillosis. From all these manifesta-
high power. tions, invasive pulmonary aspergillosis and aspergil-
loma present most commonly as a distinct mass on
radiologic studies and can be sampled by FNA.
Invasive pulmonary aspergillosis is a progressive and
CRYPTOCOCCOSIS – PATHOLOGIC FEATURES usually fatal disease (mortality rate is 80%). Immuno-
suppression predisposes to invasive pulmonary asper-
Cytopathologic Findings
gillosis. Risk factors are prolonged neutropenia,
៉ Cryptococcus neoformans is a round to oval yeast (5 to 10 μm)
corticosteroid therapy, advanced HIV infection, bone
with a polysaccharide capsule
marrow and solid-organ transplant, and chronic granu-
៉ Teardrop, narrow-based budding
៉ In Diff-Quik stain: purple yeasts with accentuated clear halos
lomatous disease. The incidence of invasive aspergillo-
against a deep-purple background sis is 0.7% in renal transplant recipients, 6.4% in bone
marrow transplant recipients, 8.4% in lung transplant
Ancillary Studies recipients, and 5–24% in patients with chemotherapy-
៉ Special stains: GMS (stains the organism), PAS, mucicarmine, induced neutropenia. Clinical manifestations of
Alcian blue (stain the capsule) invasive aspergillosis are fever, non-productive cough,

Differential Diagnosis and Pitfalls

៉ Histoplasma capsulatum
ASPERGILLOSIS – DISEASE FACT SHEET

Diagnosis of C. neoformans still rests primarily on its
cytomorphology, with confirmation, as necessary, by
special stains. Silver stains (GMS) stain the organism
itself, while mucicarmine, PAS, and Alcian blue stain
the mucopolysaccharide capsule.
ANCILLARY STUDIES
The capsule is the target of serologic tests both in serum
and in cerebrospinal fluid (CSF). The best single test
for cryptococcal meningitis is the cryptococcal antigen
assay.
Definition
៉ Infection caused by inhalation of molds of the genus Aspergillus
Clinical Features
៉ Most common in lung infections is Aspergillus fumigatus
៉ Invasive pulmonary aspergillosis and aspergilloma present as
masses
៉ Risk factors for invasive aspergillosis (80% mortality rate):
neutropenia, HIV infection, bone marrow and solid organ
transplant, chronic granulomatous disease, corticosteroid
therapy
៉ Aspergilloma: hyphae of Aspergillus species growing within a
pre-existing cavity
Radiologic Features
៉ Invasive aspergillosis: non-specific lung infiltrate that rapidly
progresses to a cavitary mass or infarct
៉ Aspergilloma: cavitary mass with fungus ball (moves with the
position)

DIFFERENTIAL DIAGNOSIS AND PITFALLS Treatment

៉ Invasive aspergillosis: intravenous amphotericin B
៉ Aspergilloma: surgical excision
When the yeasts are engulfed by histiocytes, they can
be mistaken for Histoplasma capsulatum. Narrow-

Ch006-F06731.indd 173 10/26/2006 10:27:31 AM

 174
dyspnea, and hemoptysis, which can be life-threatening
(due to the ability of A. fumigatus to invade blood
vessels).
An aspergilloma consists of Aspergillus species
hyphae growth within a pre-existing cavity that
communicates with the bronchial tree. The etiology of
such a cavity includes neoplasm, tuberculosis, healed
abscess, cystic fibrosis, congenital cysts, and bullous
emphysema.
The standard therapy in invasive pulmonary asper-
gillosis is intravenous amphotericin. Resection of the
localized consolidated mass has been performed with
good results. Granulocyte–monocyte colony-stimulating
factor may improve the outcome and should be consid-
ered in neutropenic patients.
The treatment of choice for aspergilloma is surgical
excision. In patients with compromised lung function,
in whom surgical excision is not a viable solution, intra-
cavitary instillation of amphotericin can be tried.
R ADIOLOGIC FEATURES
In invasive pulmonary aspergillosis, the initial radio-
logic studies can appear normal or show a non-specific,
FIGURE 6-14
Aspergillosis. The FNA material contains tangled clusters of branched hyphae, acute infl ammation, necrosis, and debris. The inset shows septate
hyphae of Aspergillus species with characteristic progressive, dichotomous, 45-degree branching. Papanicolaou stain, low power (inset: Diff-Quik
stain, high power).
Ch006-F06731.indd 174
FINE NEEDLE ASPIRATION CYTOLOGY
vague lung infi ltrate. This infi ltrate will progress in the
course of days to a classic wedge-shaped infarct or a
consolidated mass with cavitation.
Chest radiography in aspergilloma shows a cavitary
mass, usually in the upper lobes. The fungus ball will
move with the position (when standing and decubitus
films are compared).
CYTOPATHOLOGIC FEATURES
The FNA will show the organisms commonly present
as tangled clusters of branched hyphae that are accom-
panied by acute inflammation, necrosis, and cellular
debris. When a cytologic specimen contains hyphal
structures that are relatively large (3–6 μm in diame-
ter), septate, with regular, progressive dichotomous
branching at 45-degree angles, Aspergillus species
should be immediately suspected (Fig. 6-14). Aspergil-
lus species stain fairly well by Papanicolaou and hema-
toxylin–eosin (H&E) stains, which clearly delineate
the hyphal septations. The organisms also stain with
Diff-Quik; however, many times the staining is extreme,
i.e. either too dark to distinguish internal structure or
too light such that the fungus blends into the dirty
10/26/2006 10:27:32 AM
 CHAPTER 6 Lung
ASPERGILLOSIS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Septate hyphae with regular, progressive, dichotomous
branching at 45-degree angle
៉ Background shows abundant necrosis with reactive atypical
squamous cells
៉ When fungus cavity exposed to air: fruiting bodies with conidia
៉ Rosettes of needle-like calcium oxalate crystals
Differential Diagnosis and Pitfalls
៉ The scattered atypical squamous cells within a necrotic
background can be interpreted as necrotic squamous cell
carcinoma
៉ Clue: low cellularity should preclude a diagnosis of malignancy;
look for septate hyphae
៉ Other fungi (Fusarium species, Pseudoallescheria boydii)
background. Septations are often colorless, creating a
negative image that contrasts with the darkly stained
hyphae. Occasionally, when the fungus cavity is
exposed to air, fruiting bodies with conidia can be
detected in cytologic specimens; their presence helps
confirm the presence of Aspergillus species and can be
used in further classification. Sheaves or rosettes of
needle-like, birefringent crystals, representing calcium
oxalate, may be identified.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Since infection with Aspergillus species can cause a
necrotizing pneumonitis, which presents radiologically
as a cavitary lesion, the immediate concern is the pos-
sibility that this mass may represent a squamous cell
carcinoma with central necrosis. Although malignant
squamous cells do not resemble fungal hyphae, active
infection by Aspergillus species can cause the surround-
ing lung parenchyma to become quite atypical. Severely
reactive squamous cells may mimic carcinoma – this
can result in a false positive diagnosis, with potentially
serious consequences for the patient. Unlike most
FNAs that attempt to sample the center of a mass in
order to maximize recovery of material, FNAs of
cavitary lesions are directed away from the presumed
necrotic center in favor of the peripheral viable lesional
tissue. In aspergillomas, this is precisely where viable
fungus will be located. Recognition of these branched
structures can still be difficult if necrotic debris and
inflammation are also present. Even if close scrutiny
reveals no organisms, in the absence of a positive diag-
nosis of carcinoma, silver stains are recommended to
completely exclude the possibility of an infectious
agent.
A diagnosis of Aspergillus species is sometimes used
as a wastebasket for all morphologically similar fungi,
such as Fusarium species and Pseudoallescheria boydii.
Ch006-F06731.indd 175
175
ZYGOMYCOSES
CLINICAL FEATURES
Zygomycoses are an infrequent, often fatal, group of
infections caused by fungal organisms from the class
of Zygomycetes (Rhizopus, Absidia, and Mucor species).
The most common pathogen is Rhizopus species.
Pulmonary zygomycosis is most common in patients
with hematologic malignancies (leukemia or lymphoma)
with severe neutropenia. The incidence of zygomycosis
in patients with hematologic malignancies is approxi-
mately 1%. Other risk factors are uncontrolled diabetic
ketoacidosis, corticosteroid therapy, neutropenia, burns,
HIV infection, and desferrioxamine therapy.
Patients will present with fever and pulmonary
infiltrates. The organism has a propensity for angio-
invasion, with thrombosis and tissue infarction. This
can lead to massive, life-threatening hemorrhage. The
infection can extend to invade the chest wall, diaphragm,
pericardium, etc. A definite diagnosis is made by
histologic examination and cultures. A negative culture
result does not exclude the possibility of infection, and
the most important is direct histopathologic examina-
tion. Pulmonary zygomycosis in immunosuppressed
patients is a progressive disease, usually fatal within
a few days or weeks. Successful treatment requires
a high index of suspicion, with diagnosis made
early, and aggressive therapy with amphotericin B,
surgical excision of infarcted tissues, and decrease of
immunosuppression.
R ADIOLOGIC FEATURES
Pulmonary zygomycosis presents on CT scan as a seg-
mental or lobar consolidation with central cavitation.
ZYGOMYCOSIS – DISEASE FACT SHEET
Clinical Features
៉ Most common pathogen in lung infections is Rhizopus species
៉ Risk factors: neutropenia, hematologic malignancies, burns, HIV
infection, uncontrolled diabetic ketoacidosis, desferrioxamine
therapy
៉ Propensity for angioinvasion with thrombosis, infarction, and
hemorrhage
Radiologic Features
៉ Segmental/lobar consolidation with cavitation
Prognosis and Treatment
៉ Progressive disease, fatal in a few days in immunosuppressed
patients
៉ Amphotericin B, excision of infarcted tissues, decrease of
immunosuppression
10/26/2006 10:27:32 AM
 176 FINE NEEDLE ASPIRATION CYTOLOGY

CYTOPATHOLOGIC FEATURES ACTINOMYCOSIS

Zygomycetes are characterized by their wide (3–25 μm), CLINICAL FEATURES

waxy, ribbon-like hyphae that branch irregularly and
are pauci-septate. Side branches are short and at 90-
degree angle (Fig. 6-15). Usually associated with promi-
nent acute inflammation and necrosis, these organisms
can be overlooked on Diff-Quik stain and are best seen
on Papanicolaou or H&E stains, while silver stains
(GMS) may be used for confirmation.
Actinomyces species are normal constituents of oral
cavity flora. The most common is A. israelii, but several
other species are seen in humans. There are three dis-
tinctive syndromes associated with A. israelii: cervico-
facial, pulmonary and abdominal actinomycosis.

ZYGOMYCOSIS – PATHOLOGIC FEATURES

ACTINOMYCOSIS – DISEASE FACT SHEET
Cytopathologic Findings
Clinical Features
៉ Zygomycetes class (Rhizopus, Absidia, and Mucor species)
៉ Wide (3–25 μm), waxy, ribbon-like, pauci-septate hyphae with ៉ Risk factors: dental caries and periodontal disease
90-degree branching ៉ Actinomyces species are normal constituents of oral flora
៉ Side branches are short
៉ Background shows marked acute infl ammation and necrosis Radiologic Features
៉ Can be overlooked on Diff-Quik stain ៉ Dense, nodular infiltrates (mimic lung cancer)
៉ Best seen on Papanicolaou stain
Treatment
Ancillary Studies ៉ Penicillin for long period of time
៉ GMS used for confirmation ៉ Surgery to drain the abscess

FIGURE 6-15
Zygomycosis. The Zygomycetes are wide, waxy, ribbon-like hyphae embedded within a prominent acute fibrinopurulent exudate. The inset shows the
pauci-septate hyphae with 90-degree branching. Papanicolaou stain, low power (inset: Papanicolaou stain, high power).

Ch006-F06731.indd 176 10/26/2006 10:27:32 AM

 CHAPTER 6 Lung 177

Pulmonary actinomycosis occurs after aspiration of

infective material. Individuals with dental caries or peri-
odontal disease are predisposed to pulmonary actinomy-
cosis. The incidence is not precisely known; the disease
is uncommon, but not rare. Diagnosis is established by
transbronchial biopsy, open lung biopsy, or radiology-
guided FNA of the nodular cavities. Evaluation of the
upper respiratory specimens or samples obtained by
bronchoscopy is of limited value because they may be
contaminated by upper respiratory flora, which nor-
mally contains Actinomyces species. The treatment of
choice for actinomycosis is penicillin, given for a long
period of time (6 to 12 months). Shorter treatment is
associated with relapses. Surgery is necessary to drain
abscesses. If the disease is recognized early and treated
appropriately, the prognosis is very good.
ACTINOMYCOSIS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Gram-positive bacteria, non-acid-fast, non-motile, strict or
facultative anaerobes
៉ Fragments of slender, delicate, beaded filaments with acute-
angle branching
៉ Background shows suppurative infl ammation
Ancillary Studies
៉ Special stains: Gram, PAS, GMS
៉ Modified acid-fast (Fite’s) stain is negative
Differential Diagnosis and Pitfalls
៉ Nocardia species (but Nocardia is acid-fast with Fite’s stain)

RADIOGRAPHIC FEATURES
Chest radiograph fi lms show a dense, nodular infiltrate
that mimics lung cancer. Half of the patients can have
also nodular cavities.
CYTOPATHOLOGIC FEATURES
Actinomyces species are Gram-positive bacteria, non-
acid-fast, non-motile, strict or facultative anaerobes. In
tissues, they grow in microcolonies that appear as
yellow granules in the drainage from actinomycotic
lesions. They are called sulfur granules because of the
yellow color, but their content in sulfur is actually
low. In cytology specimens, the organisms present as
fragments and tangles of slender, delicate, beaded fi la-
ments with acute-angle branching, usually in a back-
ground of suppurative inflammation (Fig. 6-16). The
equivalent of sulfur granules is accumulations of these
organisms with a very dark granular center with
peripherally radiating fi laments. Splendore-Hoeppli
reaction consists of elongated, club-like structures radi-
ating centrifugally from a dense band at the periphery
of the granules. Necrosis and abscess formation may
also accompany these infections.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
A bacteria morphologically similar to Actinomyces
species is Nocardia species; however, Actinomyces

FIGURE 6-16
Actinomycosis. The FNA shows clus-
ters of delicate, slender filamentous
organisms. Papanicolaou stain, low
power.

Ch006-F06731.indd 177 10/26/2006 10:27:33 AM

 178 FINE NEEDLE ASPIRATION CYTOLOGY

species organisms are slightly larger (1–1.5 μm in

diameter, 20–70 μm in length) than Nocardia species
and branch at acute angles. Most cytologic and histo-
logic stains, including silver stains, can be used to
identify Actinomyces species; however, unlike Nocardia
species, Actinomyces species are not acid-fast when
stained with a modified acid-fast (Fite’s) stain. Other
useful ‘special stains’ include PAS and a modified
Gram stain.

BENIGN NEOPLASMS

HAMARTOMA

CLINICAL FEATURES

Patients are usually asymptomatic and the condition

is discovered incidentally on radiologic images. The
common type is usually in the periphery of the lung.
In the rare endobronchial variant, the patients present
with symptoms of airway obstruction, such as cough
and dyspnea. There is a wide age range, with the peak
age of incidence in the sixth decade. It is relatively rare FIGURE 6-17
in children. Hamartoma: radiologic findings. A well-circumscribed, discrete, ‘coin’
lesion is present in the right upper lobe. This is usually an incidental
finding. This presentation is characteristic for benign pulmonary neo-
plasms such as hamartoma, clear cell (sugar) tumor, granular cell tumor,
R ADIOLOGIC FEATURES and sclerosing hemangioma.

Hamartoma appears as a well-circumscribed, discrete CYTOPATHOLOGIC FEATURES

(‘coin’) lesion (Fig. 6-17). The characteristic ‘popcorn’
calcification can be detected in about 15–30% of cases
on plain radiographs.
PULMONARY HAMARTOMA – DISEASE FACT SHEET
Incidence
៉ Uncommon, benign
៉ Peak age of incidence is the 6th decade
Clinical Features
៉ Usually asymptomatic and discovered incidentally
៉ Rarely presents with symptoms of airway obstruction
Radiologic Features
៉ Well-circumscribed ‘coin’ lesion
៉ May have ‘popcorn’ calcifications
Treatment
៉ Surgical excision
Pulmonary hamartoma is a tumor-like malformation
composed of both an epithelial and a mesenchymal
component. There is usually a mixture of cartilage,
adipose tissue and some cellular fibrous tissue (mesen-
chymal component), and a non-specific epithelial com-
ponent (usually entrapped lung epithelium) (Fig. 6-18).
The cartilage may be predominant with a chondroid
matrix and recognizable chondrocytes. When the epi-
thelial component predominates, a diagnosis of malig-
nancy may be considered (Fig. 6-19). Careful search for
the mesenchymal component resolves the dilemma.
The aspirate smears have variable cellularity, with
metachromatic chondromyxoid stroma on Diff-Quik
stain and fibrillar-myxoid connective tissue with bland,
oval, or spindle nuclei embedded within the stroma,
similar to benign mixed tumors of the salivary gland.
This matrix may be the only indication of a cartilage
component of the tumor. The chondromyxoid matrix is
less characteristic on Papanicolaou stain and may stain
a pale blue, making it difficult to distinguish it from
other extracellular elements (Fig. 6-20). In any case,
the presence of adipose tissue and cartilage in a lung
aspirate should alert one to the possibility of pulmo-
nary hamartoma.

Ch006-F06731.indd 178 10/26/2006 10:27:33 AM

 FIGURE 6-18
Hamartoma. The FNA yields a
mixture of fibrillary metachromatic
chondromyxoid stroma and adipose
tissue. Diff-Quik stain, low power.

FIGURE 6-19
Hamartoma: FNA findings. The epithelial component of a hamartoma
consists usually of fl at, honeycomb groups of cytologically bland cells.
These cells can be confused with mesothelial cells or with a malignant
process, such as bronchioloalveolar carcinoma. Diff-Quik stain, medium
power.

FIGURE 6-20
Hamartoma. The mesenchymal com-
ponent with bland, spindle-shaped
nuclei appears very pale with
Papanicolaou stain and can be over-
looked. Papanicolaou stain, high
power.

Ch006-F06731.indd 179 10/26/2006 10:27:34 AM

 180
PULMONARY HAMARTOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Variable cellularity with epithelial and mesenchymal
components
៉ Metachromatic chondromyxoid stroma with embedded bland,
oval or spindle nuclei (best seen on Diff-Quik stain)
៉ Occasionally adipose tissue
Differential Diagnosis and Pitfalls
៉ Carcinoid tumor, bronchioloalveolar carcinoma, small cell
carcinoma
៉ Predominance of epithelial cells may lead to a diagnosis of
carcinoma; careful search for the mesenchymal component is
necessary
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Evaluation of the accuracy of FNA biopsy of pulmo-
nary hamartoma by the College of American Patholo-
gists (CAP) revealed that FNA has a specificity of 78%
with a false positive rate of 22%. The usual false posi-
tive diagnoses are carcinoid tumor, adenocarcinoma,
and small cell carcinoma. Contributing factors to erro-
neous diagnoses are the fact that the cartilaginous and
the fibromyxoid components may not be easily identi-
fied in Papanicolaou-stained preparations and the fact
that the reactive bronchial cells (the epithelial compo-
nent) may look worrisome with large nuclei, prominent
nucleoli, intranuclear invaginations, and multinucle-
ation. Careful search for the mesenchymal component
helps avoiding diagnostic pitfalls.
CLEAR CELL (SUGAR) TUMOR
CLINICAL FEATURES
This is a rare benign tumor of uncertain nature, which
is usually asymptomatic and found incidentally. There
is an equal occurrence in males and females. There is
a wide age range, from 8 to 73 years, with a mean age
of 49 years. The tumor is usually in the lung periphery,
and circumscribed but not encapsulated. There is
usually no obvious connection with major airways,
blood vessels, or pleura.
R ADIOLOGIC FEATURES
The tumor presents as a circumscribed, ‘coin’
lesion.
Ch006-F06731.indd 180
FINE NEEDLE ASPIRATION CYTOLOGY
CLEAR CELL (SUGAR) TUMOR – DISEASE FACT SHEET
Definition
៉ Benign tumor of uncertain origin
Gender and Age Distribution
៉ Equal incidence in males and females
៉ Wide age range, mean age is 49 years
Clinical Features
៉ Usually asymptomatic, discovered incidentally
Radiologic Features
៉ Well-circumscribed ‘coin’ lesion
Treatment
៉ Surgical excision
CYTOPATHOLOGIC FEATURES
The aspirate is cellular, composed of small irregular
clusters or individual, single, polygonal and spindle-
shaped cells. The neoplastic cells are cytologically
bland. They have abundant clear cytoplasm with
ill-defined borders. The cytoplasm can be occasionally
vacuolated or granular. The tumor cells are easily
stripped of their abundant vacuolated (glycogen-rich)
cytoplasm, resulting in a very granular, foamy back-
ground. The nuclei show minimal pleomorphism, with
fine, evenly distributed chromatin and inconspicuous
nucleoli. The nuclei are round–oval or may be only
slightly indented, resembling histiocytes. Naked
(stripped) nuclei are usually present in the background,
as the cells lose their cytoplasm during smearing
(Fig. 6-21). Mitoses and necrosis are usually absent.
CLEAR CELL (SUGAR) TUMOR – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Variable cellularity with large irregular clusters of polygonal
and spindle-shaped bland cells
៉ Cytoplasm is usually clear with indistinct cell borders; may be
vacuolated or granular
៉ Bland round, oval, or spindle-shaped nuclei
៉ Naked nuclei in the background
Ancillary Studies
៉ Positive for HMB-45 and PAS
Differential Diagnosis and Pitfalls
៉ Metastatic renal cell carcinoma
៉ Carcinoid tumor, clear cell variant
៉ Granular cell tumor
៉ Metastatic clear cell sarcoma
10/26/2006 10:27:35 AM
 CHAPTER 6 Lung 181

FIGURE 6-21
Clear cell (sugar) tumor. The FNA
yields groups of bland-appearing
cells with round–oval nuclei with
finely distributed chromatin. The
cytoplasm is fine, with indistinct
cell borders, and is frequently
detached from the nucleus during
slide preparation. Note naked,
stripped nuclei in the background.
Diff-Quik stain, high power.

ANCILLARY STUDIES squamous cell carcinoma, adenocarcinoma, small cell

Immunohistochemical studies are usually necessary to
confirm the diagnosis. Although the histogenesis of
the ‘sugar’ tumor is still unclear, the tumor cells are
positive for HMB-45 (similar to angiomyolipoma and
lymphangioleiomyomatosis), leading to the speculation
that they may have the same histogenesis. The clear
cells are positive for PAS (due to glycogen content).
Clear cell tumor is negative for epithelial markers.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Differential diagnosis includes metastatic renal cell
carcinoma, clear cell variant of carcinoid tumor, granu-
lar cell tumor, and metastatic clear cell sarcoma. It may
be extremely difficult to differentiate these entities
by cytomorphology alone. Ancillary studies are often
needed to reach the correct diagnosis. Clear (‘sugar’)
cell tumor of lung and metastatic renal cell carcinoma
are both positive for PAS, but renal cell carcinoma is
positive for epithelial markers and negative for HMB-
45, while clear (‘sugar’) cell tumor has the opposite
staining pattern. Granular cell tumor is distinguished
by S-100 protein reactivity and negative results with
PAS. Clear cell variant of carcinoid is negative for
HMB-45 and positive for neuroendocrine markers
(synaptophysin, chromogranin).
PRIMARY MALIGNANT TUMORS
carcinoma, large cell carcinoma, and pleomorphic car-
cinoma. From a practical point of view, based on spe-
cific cytologic criteria, lung carcinoma can be divided
in two main categories: small cell (20% of lung cancer
cases) and non-small cell carcinoma (NSCLC) (80%).
This distinction has clinical and prognostic signifi-
cance. There is no age difference between the patients
with small cell carcinoma and those with NSCLC. The
average age at presentation is 66 years, but there is a
wide age distribution, ranging from younger than 40
years to older than 80 years. Small cell carcinoma is a
rapidly growing and widely metastatic tumor that is
treated primarily with chemotherapy. NSCLC is treated
with surgery, radiotherapy, and chemotherapy, depend-
ing on clinical stage.
SQUAMOUS CELL CARCINOMA
CLINICAL FEATURES
Squamous cell carcinoma is the most common histo-
logic type of lung cancer, with an incidence of 35%. It
is the most common type of lung cancer in smokers.
SQUAMOUS CELL CARCINOMA – DISEASE FACT SHEET
Incidence
៉ Most common histologic type of lung cancer (35% of all cases)
៉ Most common histologic type in smokers
Radiologic Features
៉ Presents commonly as a central, cavitary, submucosal lesion

Lung cancer is the leading type of cancer worldwide Prognosis and Treatment
and is the leading cause of mortality from cancer in
៉ Dependent on stage
both men and women. According to the World Health ៉ Surgery, radiotherapy, and chemotherapy
Organization’s international histologic classification,
there are five major histologic types of lung cancers:

Ch006-F06731.indd 181 10/26/2006 10:27:36 AM

 182
R ADIOLOGIC FEATURES
Squamous cell carcinoma usually presents as a
central, cavitary, submucosal lesion (two-thirds of
cases). Rarely, it can present as a peripheral lesion
(one-third).
CYTOPATHOLOGIC FEATURES
Squamous cell carcinoma is a malignant neoplasm that,
by definition, has features of squamous differentiation.
In cytology, squamous differentiation translates as
keratin pearls, twisted keratin strands (Herxheimer
spirals), partial or complete cytoplasmic rings, and
bizarre-shaped cells with bright orangeophilic cyto-
plasm on Papanicolaou stain. In well-differentiated
neoplasms, all or almost all of these features can be
seen, while in poorly differentiated cases, they can be
completely absent. Such cases can be diagnosed as
poorly differentiated non-small cell carcinomas.
KERATINIZING (WELL- DIFFERENTIATED) SQUAMOUS
CELL C ARCINOMA
FNA of a well-differentiated squamous cell carci-
noma usually yields a cellular aspirate characterized by
cohesive sheets, aggregates, or single malignant cells
with evidence of keratinization (Fig. 6-22). There is
usually little nuclear overlapping. The neoplastic cells
can have bizarre shapes (fiber, strap, tadpole cells) (Fig.
6-23). They have variable amounts of dense, waxy,
‘hard’ cytoplasm with clearly defined cytoplasmic
borders. The N/C ratios range from low to high. The
nuclei are pleomorphic, hyperchromatic, with irregular
Ch006-F06731.indd 182
FINE NEEDLE ASPIRATION CYTOLOGY
KERATINIZING (WELL-DIFFERENTIATED) SQUAMOUS CELL
CARCINOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cohesive sheets and single cells with evidence of keratinization
៉ N/C ratios range from low to high
៉ Dense, waxy, ‘hard’ orangeophilic cytoplasm with clearly defined
borders
៉ Cells with bizarre forms: fiber, strap, tadpole
៉ Nuclei hyperchromatic with inconspicuous nucleoli or pyknotic
(ink dot-like)
៉ Background: necrosis, debris, and ghost cells
Differential Diagnosis and Pitfalls
៉ Pulmonary infarct, pneumonia, mycetoma
៉ Metastatic urothelial carcinoma
៉ Metastatic squamous cell carcinoma from other sites (in
particular, head and neck areas)
nuclear contours, obscured chromatin details, and often
inconspicuous nucleoli. The nuclei can undergo degen-
eration and become pyknotic (ink dot-like). Frequently,
squamous cell carcinoma undergoes central necrosis
and cavitation; hence, the background can show necro-
sis and debris, ghost cells, multinucleated cells, and
inflammation.
NON-KERATINIZING (MODERATELY TO POORLY
DIFFERENTIATED) SQUAMOUS CELL C ARCINOMA
FNA of a non-keratinizing, moderately to poorly dif-
ferentiated squamous cell carcinoma also yields a cellu-
lar specimen with abundant single, discohesive cells or
syncytial groups with no cytologic evidence of keratini-
zation (Fig. 6-24). The neoplastic cells are usually
FIGURE 6-22
Well-differentiated (keratinizing)
squamous cell carcinoma. The FNA
yields a cellular material with
malignant squamous cells with
dark, hyperchromatic, irregular
nuclei and variable amounts of
dense, bright orangeophilic or
cyanophilic cytoplasm. Note the
background containing ghost cells
and pyknotic, degenerating nuclei.
Papanicolaou stain, medium power.
10/26/2006 10:27:36 AM
 CHAPTER 6 Lung
FIGURE 6-23
Well-differentiated (keratinizing)
squamous cell carcinoma. The
malignant squamous cells can have
bizarre shapes (strap cells). Note
the dense eosinophilic cytoplasm.
Papanicolaou stain, high power.
FIGURE 6-24
Poorly differentiated (non-keratinizing) squamous cell carcinoma. The
FNA shows syncytial groups of cells with a moderate amount of cyano-
philic cytoplasm. The nuclei are hyperchromatic and pleomorphic, with
small nucleoli. Papanicolaou stain, high power.
smaller, with high N/C ratios, moderate to scant cyano-
philic cytoplasm, and irregular, pleomorphic nuclei with
irregular, granular chromatin and visible, prominent
nucleoli (Fig. 6-25) (in contrast to a well-differentiated
squamous cell carcinoma, which has dense nuclear
chromatin, inconspicuous nucleoli or pyknotic nuclei).
Since the cytologic features of keratinization are absent
in these cases, it is difficult to distinguish them from
Ch006-F06731.indd 183
183
NON-KERATINIZING (MODERATELY TO POORLY DIFFERENTIATED)
SQUAMOUS CELL CARCINOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Single, discohesive groups of cells with no or very little
evidence of keratinization
៉ High N/C ratio
៉ Hyperchromatic nuclei with visible nucleoli
៉ Scant to moderate, often vacuolated, cytoplasm
Differential Diagnosis and Pitfalls
៉ Adenocarcinoma
៉ Large cell carcinoma
adenocarcinoma. More, squamous cell carcinoma may
have a finely vacuolated cytoplasm. This feature com-
bined with prominent nucleoli may lead to confusion
with adenocarcinoma. From a practical standpoint, this
distinction is not of critical importance because these
cases can be classified as moderately to poorly differenti-
ated non-small cell carcinomas.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Well-differentiated squamous cell carcinoma needs to be
differentiated primarily from: 1) reactive, inflamma-
tory and infectious processes; 2) metastatic low-grade
urothelial carcinoma; and 3) metastatic squamous cell
10/26/2006 10:27:37 AM
 184
carcinoma from other sites, particularly head and neck
primary.
Because of central necrosis and cavitation, a well-
differentiated squamous cell carcinoma can be confused
with reactive, inflammatory and infectious processes
associated with necrosis, such as granulomatous inflam-
mation (fungal [mycetoma], rheumatoid arthritis),
pneumonia, and pulmonary infarct.
Several generalities can be made concerning these
benign conditions: 1) fewer cells are present when com-
pared to carcinoma; 2) the nuclear details are not so
distinct or, if so, they are combined with a relatively
normal N/C ratio; and 3) degeneration is often greater
in these conditions than in carcinomas. Other helpful
features are subtle palisading in granulomatous inflam-
mation and identification of hyphae. A good rule of
thumb is to avoid making a diagnosis of malignancy
in cases with few, degenerated and poorly visualized
cells.
Pulmonary infarct with subsequent repair atypia can
be a source of false positive diagnoses. Pulmonary infarct
may be asymptomatic. It can mimic a lung neoplasm
radiographically. The FNA material shows two-
dimensional sheets of metaplastic squamous cells and
numerous hemosiderin-laden macrophages. The meta-
plastic squamous cells show features of regeneration and
atypia characterized by enlarged nuclei with pale, vesicu-
lar chromatin and a prominent chromocenter or small
nucleolus. The presence of atypical squamous cells on
aspiration smears may result in overdiagnosis, unless the
Ch006-F06731.indd 184
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 6-25
Poorly differentiated (non-
keratinizing) squamous cell carci-
noma. In this aspirate, the cells
have high N/C ratios, with scant,
hard cytoplasm and large, hyper-
chromatic nuclei with prominent
nucleoli. The presence of nucleoli
may suggest the diagnosis of ade-
nocarcinoma. Such cases can be
diagnosed generically as non-small
cell carcinoma. Diff-Quik stain, high
power.
cytologic features are correlated with clinical and radio-
logic findings. Many of these specimens will have limited
numbers of cells to evaluate. However, cellularity and
cell debris may vary greatly, depending upon the age of
the infarction. Recent infarctions may show only hemo-
siderophages and necrotic cellular debris, a potential
source of diagnostic error if confused with a tumor dia-
thesis. A diagnosis of malignancy in a low cellularity
specimen should be made with extreme caution.
Rarely, metastatic urothelial carcinoma may mimic
squamous cell carcinoma, particularly the low-grade
urothelial neoplasms. In FNA specimens, metastatic
urothelial carcinoma tends to occur as flat sheets with
accompanying individual cells that look as if they have
been pulled from these sheets. These single cells and the
cells at the periphery of the fragments have elongated
unipolar cytoplasmic processes with bland hyperchro-
matic nuclei at the apical cytoplasmic pole. These cells
have been termed cercariform cells because of their
resemblance to parasitic cercariform larvae.
Primary lung keratinizing squamous cell carcinoma
is morphologically similar to primary head and neck
squamous cell carcinoma metastatic to the lung. Com-
parison with previous histologic or cytologic material,
clinical presentation, and radiologic findings are neces-
sary in such cases.
Moderately to poorly differentiated squamous cell car-
cinoma may be difficult to distinguish from poorly
differentiated adenocarcinoma and, to a lesser extent,
large cell carcinoma.
10/26/2006 10:27:38 AM
 CHAPTER 6 Lung 185

ADENOCARCINOMA CYTOPATHOLOGIC FEATURES

CLINICAL FEATURES Adenocarcinoma is a malignant neoplasm with glandu-

lar differentiation. In cytology, this translates as cellu-
lar smears with cohesive clusters of cells and acinar
This is the most common type of lung cancer in women
groups. The cell clusters are tridimensional and exhibit
and non-smokers. Most adenocarcinomas arise at the
depth of focus. There is an increased N/C ratio. The
periphery of the lungs. Central adenocarcinomas,
neoplastic cells have round to oval, enlarged nuclei
though uncommon, may be seen. Many peripheral
with irregular nuclear membranes, granular chromatin
tumors reach a substantial size and may actually meta-
(finely or coarsely distributed), and prominent nucleoli
stasize before they cause any symptoms, because major
(which can be multiple). The cytoplasm is scant to
airways are not affected.

R ADIOLOGIC FEATURES
ADENOCARCINOMA – PATHOLOGIC FEATURES

Adenocarcinoma usually presents as a discrete lung mass Cytopathologic Findings

of variable sizes with infiltrative edges (Fig. 6-26).
ADENOCARCINOMA – DISEASE FACT SHEET
Incidence
៉ Most common lung carcinoma in females and non-smokers
Radiologic Features
៉ Discrete lung mass with infiltrative edges
៉ Cohesive sheets or clusters of cells with depth of focus (three-
dimensional)
៉ Columnar, cuboidal, or polygonal cells with scant/moderate
cytoplasm with vacuolization
៉ Enlarged nuclei with prominent nucleoli
៉ Mitoses and necrosis may be present
Ancillary Studies
៉ Positive for CK, EMA, CEA, CD15, CK7, and TTF-1; negative for
CK20

Differential Diagnosis and Pitfalls

Prognosis and Treatment
៉ Metastatic adenocarcinoma (breast, stomach, colon, pancreas,
៉ Prognosis depends on the stage of the tumor
gynecologic tract, etc.)
៉ Resection and/or chemotherapy

FIGURE 6-26
Adenocarcinoma: radiologic findings.
There is an infiltrative mass with
indistinct edges in the right lower
lobe. Surgical follow-up showed this
mass to be an adenocarcinoma.

Ch006-F06731.indd 185 10/26/2006 10:27:38 AM

 186 FINE NEEDLE ASPIRATION CYTOLOGY

A B

FIGURE 6-27
Adenocarcinoma. A, The FNA yields a cellular aspirate with tridimensional clusters of malignant cells with scant cytoplasm and large, hyperchromatic
nuclei with prominent nucleoli. B, Abundant tumor cell necrosis can be seen. Papanicolaou stain, high power.

moderate with coarse to fine vacuolization; occasion-

ally, it may be clear. Mitoses and necrosis may also be
seen (Figs 6-27 & 6-28).

ANCILLARY STUDIES

Immunohistochemical studies are necessary to dis-

tinguish primary lung adenocarcinoma from meta-
static adenocarcinoma. In addition to being positive
for cytokeratin markers, carcinoembryonic antigen
(CEA), epithelial membrane antigen (EMA), and CD15,
primary adenocarcinoma of the lung is usually positive
for cytokeratin 7 (CK7) and thyroid transcription
factor-1 (TTF-1), and negative for cytokeratin 20
(CK20).
FIGURE 6-28
Adenocarcinoma. In this aspirate, note the hyperchromatic nuclei with
irregularly distributed, coarse nuclear chromatin and visible nucleoli.
There is marked nuclear pleomorphism. The cytoplasm is almost absent
and the nuclei are crowded together. Compare with normal bronchial
DIFFERENTIAL DIAGNOSIS AND PITFALLS cells in the upper left. This case can be diagnosed generically as non-
small cell carcinoma. Attention to nuclear details helps in distinguish-
ing non-small cell carcinoma from small cell carcinoma at the time of
Primary lung adenocarcinomas need to be differenti- preliminary interpretation in the radiology suite. Diff-Quik stain,
ated from adenocarcinomas from other sites that medium power.
have metastasized to the lung, i.e. breast, gastro -
intestinal tract (stomach, colon), pancreato-biliary
tract, gynecologic tract, etc. If there is a history of BRONCHIOLOALVEOLAR
a previous neoplasm, comparing the current speci- CARCINOMA (BAC)
men with previous material may help in determin-
ing whether the lung mass is primary or metastatic.
In addition, immunohistochemical stains can be This is an uncommon variant of adenocarcinoma
performed on cell block material or alcohol-fi xed (about 2% of all lung malignancies), which, by defini-
slides. tion, has a pure bronchioloalveolar growth pattern

Ch006-F06731.indd 186 10/26/2006 10:27:39 AM

 CHAPTER 6 Lung
BRONCHIOLOALVEOLAR CARCINOMA – DISEASE FACT SHEET
Incidence
៉ Uncommon; approximately 2% of all lung malignancies
Radiologic Features
៉ Discrete nodule, multiple nodules, or pneumonic infiltrate
Prognosis and Treatment
៉ Better prognosis than bronchogenic adenocarcinoma
៉ Non-mucinous variant has better prognosis that mucinous variant
៉ Treatment: surgical (if discrete nodule), chemotherapy (if multiple
nodules, pneumonic infiltrate)
with no evidence of stromal, vascular, or pleural inva-
sion. BAC presents radiologically as a single nodule,
multiple nodules, or as a diffuse ‘pneumonic’
infi ltrate.
CYTOPATHOLOGIC FEATURES
BAC can have either a mucinous or non-mucinous
appearance. The non-mucinous type is more common
and may be difficult to differentiate from bronchogenic
adenocarcinoma. Aspirate smears are highly cellular
and composed of bland neoplastic cells (cuboidal or
columnar), usually in clusters. No terminal bars or cilia
are identified on these cells. Since BAC’s predominant
pattern of growth is along the alveolar septa, the FNA
FIGURE 6-29
Bronchioloalveolar carcinoma. The
FNA yields a highly cellular aspirate
with fl at groups of cytologically
bland cells. These cells can be con-
fused with alveolar pneumocytes or
mesothelial cells. The high cellular-
ity is a very helpful clue for a malig-
nant diagnosis. Avoid making a
diagnosis of malignancy from speci-
mens with scant cellularity. Papani-
colaou stain, medium power.
Ch006-F06731.indd 187
187
BRONCHIOLOALVEOLAR CARCINOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Non-mucinous and mucinous variants
៉ Highly cellular aspirate with bland cuboidal to columnar
neoplastic cells in papillary clusters or fl at sheets
៉ Nuclear pseudoinclusions and psammoma bodies
៉ Abundant intracellular/extracellular mucin (in the mucinous
variant)
Histopathologic Findings
៉ Tumor cells grow along the alveolar septa, with no stromal,
vascular, or pleural invasion
Differential Diagnosis and Pitfalls
៉ Reactive pneumocytes, mesothelial cells, or bronchial cells
៉ Clues: high cellularity, lack of terminal bars and/or cilia
material will result in flat sheets, acinar arrays, and/or
papillary fragments with depth of focus. The neoplastic
cells may resemble alveolar pneumocytes, mesothelial
cells, or even bronchial cells (Fig. 6-29). The nuclei are
usually enlarged and there is an increase in N/C ratio,
and the nuclear membrane may be slightly irregular
(Fig. 6-30). Nuclear pseudoinclusions and psammoma
bodies may be seen. The mucinous variant of BAC
consists of bland columnar cells with basally oriented
nuclei and abundant apical cytoplasmic mucin (Fig.
6-31). Mucinous BAC is often multicentric and usually
has a worse prognosis than the non-mucinous
variant.
10/26/2006 10:27:40 AM
 188 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 6-30
Bronchioloalveolar carcinoma.
Careful evaluation of the nuclei
identifies slight nuclear variability
and irregular nuclear contours with
occasional nuclear grooves. Note
also slight depth of focus of this
group of malignant cells. Papanico-
laou stain, high power.

FIGURE 6-31
Bronchioloalveolar carcinoma. In
the mucinous variant of bronchio-
loalveolar carcinoma, the neoplas-
tic cells have moderate to abundant,
vacuolated, mucinous cytoplasm.
Extracellular mucin can be present
in the background. The nuclei are
round–oval and uniform. Diff-Quik
stain, high power.

Ch006-F06731.indd 188 10/26/2006 10:27:41 AM

 CHAPTER 6 Lung
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The chief mimics of BAC are reactive pneumocytes,
mesothelial cells, and bronchial cells. Carcinoma should
never be diagnosed in aspirate materials with atypical
cells that have terminal bars and/or cilia. A very impor-
tant clue to the right diagnosis is high cellularity, with
neoplastic cells arranged in flat sheets and/or papillary
fragments. Supportive clinical and radiologic findings
are usually necessary for a definitive diagnosis of
BAC.
SMALL CELL CARCINOMA
CYTOPATHOLOGIC FEATURES
The aspirate smear is very cellular, composed of viable
and degenerating cells dispersed singly or in loose clus-
ters. These tumor cells are very fragile and as such are
often encountered as single cells or stripped hyperchro-
matic nuclei. The cells have an increased N/C ratio
with large, round to oval, hyperchromatic nuclei and
very scant cytoplasm (Fig. 6-32). The nuclear chroma-
tin is hyperchromatic and finely granular, and nucleoli
are inconspicuous. Nuclear molding, crush artifact,
and mitotic figures are commonly seen (Fig. 6-33).
While in effusion specimens the malignant cells are
small, 1–1.5 times the size of a lymphocyte, in FNA
material they may be up to three times the size of a
lymphocyte. This rather dramatic size difference is
attributed to the sampling of viable tumor without
degeneration or necrosis. Nuclear detail, including the
presence of small distinct nucleoli, is easier to visualize
in these larger cells. While tumor cells will be round
with slight nuclear irregularities in the majority of cases,
occasionally the cells will be small and oval or spindle-
shaped, hence the term ‘oat’ cell carcinoma.
SMALL CELL CARCINOMA – DISEASE FACT SHEET
Incidence and Distribution
៉ 20% of lung carcinomas
៉ Adult smokers; median age of 66 years
៉ More common in men
Radiologic Features
៉ Discrete central mass
៉ May have extensive pulmonary and extrapulmonary metastases at
diagnosis
Prognosis and Treatment
៉ Prognosis poor
៉ Chemotherapy and radiotherapy
Ch006-F06731.indd 189
189
SMALL CELL CARCINOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Highly cellular aspirate
៉ High N/C ratio, very little cytoplasm, and large hyperchromatic
nuclei with finely granular chromatin and inconspicuous nucleoli
៉ Spectrum of viability
៉ Nuclear molding, crush artifact
៉ Individual cell necrosis and tumor diathesis
Ancillary Studies
៉ pan-CK, EMA, CK7, TTF-1 (positive in 90% cases);
neuroendocrine markers (positive in 50% of cases); CK20
(negative)
Differential Diagnosis and Pitfalls
៉ Carcinoid tumor
៉ Lymphoma
៉ Poorly-differentiated non-small cell carcinoma
In addition, small cell carcinoma shows a spectrum
of viability that is very characteristic: viable cells with
intact chromatin, smaller more degenerated cells, pyk-
notic nuclei and ghost nuclei (individual cell necrosis).
The process of smearing aspirated material often shears
the scant, delicate cytoplasm from the tumor cells. This,
combined with cell necrosis, creates a very granular
background often with tingible-body macrophages. This
particular background helps to exclude carcinoid from
the differential diagnosis.
FIGURE 6-32
Small cell carcinoma. The FNA yields a very cellular aspirate; the malig-
nant cells have large, round–oval nuclei with very scant cytoplasm.
Note the characteristic nuclear features: hyperchromatic, speckled
chromatin with inconspicuous nucleoli and prominent nuclear molding.
Apoptotic cells are noted in the background (range of viability) as well
as tingible-body macrophages. The cell size is not an important diag-
nostic criterion, as the small cell carcinoma cells reach quite large sizes
in the FNA material. Diff-Quik stain, medium power.
10/26/2006 10:27:42 AM
 190 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 6-33
Small cell carcinoma. The Papanico-
laou stain highlights the character-
istic nuclear features. Note the
crush artifact and the apoptotic
cells. Papanicolaou stain, high
power.

ANCILLARY STUDIES LARGE CELL CARCINOMA AND

Small cell carcinomas of the lung are positive for cyto-
keratins (pan-cytokeratin, low molecular weight cyto-
keratin, EMA, CK7) and TTF-1 (90% of cases). CD56
is positive in more than 90% of cases. Neuroendocrine
markers (chromogranin A, synaptophysin) are positive
in half of cases.
PLEOMORPHIC CARCINOMA
These are rare variants of non-small cell carcinoma.
They share similar cytologic features that help to
separate them from small cell carcinoma, and will be
discussed together.

DIFFERENTIAL DIAGNOSIS AND PITFALLS LARGE CELL CARCINOMA AND PLEOMORPHIC CARCINOMA –
DISEASE FACT SHEET
Small cell carcinoma can be confused with carcinoid
Incidence
tumor, lymphoma, or a poorly differentiated non-small
៉ Large cell carcinoma: 9% of all lung cancers
cell carcinoma. Attention to cytologic features, in
particular identifying the spectrum of viability and
Radiologic Features
the characteristic background with necrosis, debris,
៉ Large cell carcinoma: often found at lung periphery; large necrotic
and mitoses, helps in excluding carcinoid tumor. The
tumors
nuclear chromatin quality (hyperchromatic, finely
៉ Pleomorphic carcinoma: large, peripheral tumors that often invade
granular, small or inconspicuous nucleolus) and the the chest wall
presence of nuclear molding are key features to exclude
a poorly differentiated carcinoma. The absence of lym- Prognosis
phoglandular bodies excludes a lymphoid process. In ៉ Poor
difficult cases, immunohistochemical stains on the cell
block can be performed.

Ch006-F06731.indd 190 10/26/2006 10:27:43 AM

 CHAPTER 6 Lung
LARGE CELL CARCINOMA AND PLEOMORPHIC CARCINOMA –
PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Large cell carcinoma:
៉ Undifferentiated malignant tumor
៉ It is a diagnosis of exclusion
៉ Discohesive, large malignant cells with large nuclei and
moderate amount of cytoplasm
៉ Variant: large cell neuroendocrine carcinoma
៉ Pleomorphic carcinoma:
៉ Poorly differentiated non-small cell carcinoma with giant
cells and/or spindle cells
៉ Giant cells are often multinucleated
៉ Emperipolesis of neutrophils
Histopathologic Findings
៉ Pleomorphic carcinoma: should have at least 10% component of
spindle or giant cells
Large cell carcinoma is an undifferentiated malignant
tumor that lacks the characteristic cytologic features of
squamous cell carcinoma, adenocarcinoma, and small
cell carcinoma. It is a diagnosis of exclusion. The aspi-
rate is cellular, consisting of discohesive large malignant
cells with large nuclei and a moderate amount of cyto-
plasm. The nuclei have irregular contours, unevenly
distributed, coarse chromatin, and prominent nucleoli
(Fig. 6-34). A variant of this tumor is large cell neuro-
endocrine carcinoma, in which neuroendocrine differ-
entiation can be demonstrated by immunochemistry or
electron microscopy. The cell block material may show
FIGURE 6-34
Large cell carcinoma. Large malignant cells with pleomorphic nuclei
with irregular, folded nuclear membranes and irregular chromatin.
Mitotic figures are easily identified. Papanicolaou stain, high power.
Ch006-F06731.indd 191
191
an organoid arrangement. However, cytologically, this
tumor has the features of a non-small cell carcinoma
and is not confused with a small cell carcinoma. Specifi-
cally, this tumor has visible nucleoli, a moderate amount
of cytoplasm, and an abundant necrotic background
with frequent mitoses.
Pleomorphic carcinoma is a poorly differentiated
non-small cell carcinoma that contains giant cells and/
or spindle cells. The giant cells are large, often multi-
nucleated, and discohesive with emperipolesis of
neutrophils (Fig. 6-35).
CARCINOID TUMOR
CLINICAL FEATURES
Carcinoid tumor is a rare lung neoplasm, with an inci-
dence of 0.4–3%. It has now been recognized that even
a typical carcinoid has the ability to metastasize. For
this reason, this tumor is classified as a malignant
neoplasm. The median age at presentation is 47 years,
younger than the median age for lung cancer. There are
no known risk factors associated with the development
of carcinoid tumor. Symptoms at presentation depend
on the location. A centrally located carcinoid tumor
will present with hemoptysis, cough, dyspnea, pain, or
recurrent pneumonia. A peripherally located lesion is
usually asymptomatic, discovered incidentally. This
tumor is treated by surgical excision.
FIGURE 6-35
Pleomorphic carcinoma. Very cellular aspirate with a discohesive popu-
lation of large, multinucleated malignant cells. Some of the cells have
engulfed neutrophils in their cytoplasm, characteristic finding in pleo-
morphic carcinoma. Diff-Quik stain, low power.
10/26/2006 10:27:43 AM
 192
CARCINOID TUMOR – DISEASE FACT SHEET
Incidence
៉ 0.4% to 3%
Clinical Features
៉ Symptomatic if centrally located (cough, dyspnea, hemoptysis,
recurrent pneumonia)
៉ Asymptomatic if peripheral
Radiologic Features
៉ Peripheral mass (25%), central tumor (30%), atelectasis (40%)
៉ Normal chest X-ray (5%)
Treatment
៉ Surgical excision
CYTOPATHOLOGIC FEATURES
The aspirate consists of uniform cells arranged in loose
groups, larger tissue fragments, or dispersed as single
cells. The larger tissue fragments have a distinctive
architecture, reminiscent of the trabecular or festoon-
ing patterns seen histologically. When the cells are
dispersed individually, they tend to form small linear
arrays (similar to the single cell filing seen in lobular
carcinoma of the breast), rosettes, or acini. It is very
characteristic for carcinoid tumor to have uniform,
small cells with very little pleomorphism. These cells
Ch006-F06731.indd 192
FINE NEEDLE ASPIRATION CYTOLOGY
CARCINOID TUMOR – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Uniform population of cells with moderate, finely granular
cytoplasm
៉ Round–oval nuclei, with smooth nuclear contours, stippled
chromatin, and a small, distinct nucleolus
៉ Cells can be spindle-shaped (spindle cell carcinoid)
៉ Background is clean, with occasional naked nuclei (but no
necrosis or mitotic figures)
៉ Atypical carcinoid (difficult diagnosis to make on FNA material)
can be suggested if focal necrosis and rare mitoses are seen
Histopathologic Findings
៉ Atypical carcinoid: 2–10 mitoses/10 HPF or a focus of necrosis
Ancillary Studies
៉ Positive for neuroendocrine markers
៉ Positive for CK7 and TTF-1; negative for CK20
Differential Diagnosis and Pitfalls
៉ Lymphoma
៉ Adenocarcinoma
៉ Other spindle cell lesions
៉ Sclerosing hemangioma
have scant to moderate, finely granular cytoplasm with
poorly defined borders (Fig. 6-36). However, it is not
uncommon that the cytoplasm is stripped from the
nuclei, resulting in single, dispersed bare nuclei. At low
power, these naked, dispersed nuclei can be confused
FIGURE 6-36
Carcinoid tumor. The FNA yields a
cellular aspirate composed of
uniform cells arranged in loose
groups or dispersed as single cells.
They have round nuclei and scant,
fine cytoplasm with indistinct cell
borders. The nuclei have smooth
contours, ‘salt and pepper’ chroma-
tin, and a small nucleolus. Note
the acinar arrangement, which can
be misinterpreted as glandular
differentiation. Papanicolaou stain,
medium power.
10/26/2006 10:27:44 AM
 CHAPTER 6 Lung
FIGURE 6-37
Spindle cell carcinoid tumor. Cellular aspirate consisting of uniform,
discohesive spindle-shaped cells with oval nuclei and small amounts of
cytoplasm. Note the finely granular, ‘salt and pepper’ chromatin. Papa-
nicolaou stain, medium power.
with inflammatory cells. The nuclei are small, round to
oval, with smooth nuclear contours, stippled, ‘salt and
pepper’ chromatin (due to uniform dispersion of the
nuclear chromatin), and a small, distinct nucleolus.
Occasionally, variable numbers of small, spindle tumor
cells can be seen. In some cases, the spindle cells are the
only component (spindle cell carcinoid). The cytoplasm
and nuclear characteristics of spindle cell carcinoid are
similar to those of typical carcinoid tumor (Fig. 6-37).
Smears have a clean background because the cyto-
plasm of these cells, more abundant than in small cell
carcinoma, remains intact during the smearing process
and there is no necrosis, apoptotic bodies, or mitoses.
Atypical carcinoid tumor is defined as a tumor with
a recognizable carcinoid pattern that has 2–10 mitoses/
10 high-power fields or a focus of necrosis. Since these
features may be focal, sampling is critical in correct clas-
sification of this tumor. For this reason, a specific dis-
tinction on FNA between typical and atypical carcinoid
may not be always possible. The morphology of atypical
carcinoid tumor is intermediate between typical car-
cinoid and small cell carcinoma. The tumor cells show
greater cellular pleomorphism, the nuclei can have
modest membrane irregularities, but the nuclear chro-
matin remains finely distributed with small nucleoli. A
diagnosis of atypical carcinoid can be suggested on FNA
material if one sees mitotic activity and necrosis in an
otherwise typical carcinoid tumor.
R ADIOLOGIC FEATURES
Carcinoid tumor can present as a peripheral mass
(25%), as a centrally located tumor (30%), or as atelec-
tasis (40%); in 5% of patients, the chest radiograph is
normal.
Ch006-F06731.indd 193
193
ANCILLARY STUDIES
To confirm the diagnosis, immunohistochemical studies
using neuroendocrine markers (chromogranin A, syn-
aptophysin, neuron-specific enolase) can be performed
on the cell block. In addition, a combination of CK7,
CK20, and TTF-1 helps to differentiate between pul-
monary carcinoid, gastrointestinal carcinoid, and pan-
creatic endocrine tumors. Pulmonary carcinoid tumors
are negative for CK20 and have a variable expression
of CK7 and TTF-1. A profi le of CK7+/CK20−/TTF-1+
has high specificity (100%) and moderate sensitivity
(50%) for pulmonary carcinoid tumors. TTF-1 expres-
sion is highly specific for pulmonary carcinoid but is
negative in one-third of cases. Gastrointestinal tract
carcinoid and pancreatic endocrine tumors are negative
for TTF-1. Sixty-seven percent of gastrointestinal car-
cinoid tumors are CK7−/CK20− and 20% of them are
CK7−/CK20+. Thirty-three percent of pancreatic endo-
crine tumors are CK7+/CK20−, 33% are CK7−/CK20−,
and the rest are equally divided between CK7−/CK20+
and CK7+/CK20+ profi les.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Lymphoma, especially a low-grade type, enters in the
differential diagnosis in cases with abundant stripped,
naked nuclei that at low power are misinterpreted as
lymphocytes. Lack of lymphoglandular bodies, presence
of cohesive groups of epithelial cells with moderate wispy
cytoplasm, and nuclear characteristics favor a carcinoid
tumor. Immunohistochemical stains on the cell block for
leukocyte common antigen (CD45) and neuroendocrine
markers will also help the distinction. In addition, the
rosette formation can be misinterpreted as evidence of
glandular differentiation, resulting in an erroneous diag-
nosis of adenocarcinoma. Spindle cell carcinoid can be
confused with rare spindle cell lesions (leiomyoma, leio-
myosarcoma, neurofibroma) that occur in the lung.
Low cellularity specimens may be underdiagnosed as
‘negative’ when the typical, uniform carcinoid cells are
confused with benign bronchial cells. The lack of termi-
nal bars and cilia should alert the pathologist that these
bland cells are not bronchial cells.
Sclerosing hemangioma shows also bland, monoto-
nous, round to polygonal cells. The cell uniformity and
bland cytology can mimic perfectly a typical carcinoid
tumor. Immunohistochemical studies for neuroendo-
crine markers performed on the cell block will help in
difficult cases.
METASTASES
The lung is a very common site for metastases, because
the entire blood supply must circulate through the
lungs. Pulmonary metastases can be diagnosed using
10/26/2006 10:27:45 AM
 194 FINE NEEDLE ASPIRATION CYTOLOGY

METASTASES – DISEASE FACT SHEET METASTASES – PATHOLOGIC FEATURES

Clinical Features Cytopathologic Findings

៉ Lung is a very common site for metastases
៉ 14–25% of lung FNAs identify metastases
៉ Most common metastases to the lung are adenocarcinomas
(breast, colon, kidney) and malignant melanoma
៉ Although rare, sarcomas can also metastasize to the lung; most
common sarcomas encountered in lung FNA are synovial
sarcoma, chondrosarcoma, osteosarcoma, and alveolar soft part
sarcoma
FNA; indeed, between 14% and 25% of aspirates iden-
tify metastatic disease. The most common metastases
to the lung identified by FNA are adenocarcinomas
(breast, colon, and kidney) and malignant melanoma,
although different series may vary the order of fre-
quency for metastasis.
The cytomorphology of a metastatic adenocarcinoma
overlaps significantly with that of a primary lung adeno-
carcinoma. However, in certain types of tumors, specific
៉ In general, a metastatic adenocarcinoma to the lung has
cytologic features similar to those of primary lung
adenocarcinoma
៉ Clues to a specific diagnosis include the following:
៉ Cells with abundant vacuolated cytoplasm suggest renal cell
carcinoma
៉ Cells with elongated, hyperchromatic, ‘picket-fence’ nuclei
suggest colonic adenocarcinoma
៉ Cercariform cells suggest urothelial carcinoma
៉ Discohesive, epithelioid or spindle cells with prominent
nucleoli, intranuclear inclusions, and pigment suggest
melanoma
cytologic features can help in pinpointing towards a
specific diagnosis (Figs 6-38–6-43). Identification of car-
cinomas as metastatic is often straightforward if clinical
information and/or prior surgical or cytologic speci-
mens are available. In cases in which this correlation is

FIGURE 6-38
Metastatic urothelial carcinoma. The aspirate material is cellular, consisting of discohesive cells with a moderate amount of cytoplasm and centrally
placed, hyperchromatic nuclei. Note in the inset, the cercariform cells, with elongated unipolar cytoplasmic processes and nuclei placed at the
apical pole. Diff-Quik stain, low power (inset: Diff Quik stain, high power).

Ch006-F06731.indd 194 10/26/2006 10:27:46 AM

 CHAPTER 6 Lung 195

FIGURE 6-39
Metastatic urothelial carcinoma. Flat sheet of cells with a moderate amount of cytoplasm and hyperchromatic, round, slightly irregular nuclei. This
appearance can be confused with squamous cell carcinoma. Finding cercariform cells (inset) is a clue to the diagnosis of metastatic urothelial
carcinoma. Papanicolaou stain, low power (inset: Papanicolaou stain, high power).

Ch006-F06731.indd 195 10/26/2006 10:27:46 AM

 196 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 6-40
Metastatic breast carcinoma. The FNA yields a cellular aspirate with discohesive, tridimensional clusters with depth of focus. The cells have the
typical features of an adenocarcinoma, high N/C ratios, hyperchromatic nuclei, and scant to modest amounts of cytoplasm. On cytomorphology
alone, the distinction between primary lung and metastatic breast carcinoma is very difficult. Comparison with previous material (if available) and
immunohistochemical studies on the cell block material are necessary in the majority of cases. Diff-Quik stain, low power.

FIGURE 6-41
Metastatic renal cell carcinoma. The aspirate material is highly cellular, with clusters and discohesive vacuolated cells. Tumor fragments are associ-
ated with small blood vessels and fibrovascular cores. The cells have mildly increased N/C ratios, round regular nuclei with finely granular chromatin,
and abundant finely vacuolated cytoplasm. Most of the cells retain their cytoplasm during smear preparation. Diff-Quik stain, medium power.

Ch006-F06731.indd 196 10/26/2006 10:27:47 AM

 CHAPTER 6 Lung 197

FIGURE 6-42
Metastatic colonic adenocarcinoma. The FNA yields highly cellular smears which show large fragments rather than discohesive cells. Nuclei are fairly
uniform and hyperchromatic, but tend to be elongated and basally oriented, almost in a picket-fence array. The inset shows cell block with a small
fragment of tumor with glandular formation and necrosis, both luminal and in the background. Diff-Quik stain, high power (inset: H&E stain).

FIGURE 6-43
Metastatic malignant melanoma. The aspirated material consists of discohesive, somewhat plasmacytoid, single cells. The cells have enlarged nuclei,
with irregular contours, unevenly distributed chromatin, and prominent nucleoli. Note the intranuclear cytoplasmic inclusion, a non-specific but
common finding in malignant melanoma. The inset shows a binucleated cell with ‘mirror image’ nuclei. Papanicolaou stain, high power (inset:
Papanicolaou stain, high power).

Ch006-F06731.indd 197 10/26/2006 10:27:48 AM

 198
A B
FIGURE 6-44
Metastatic osteosarcoma. Cellular aspirate with discohesive, bizarre-shaped, multinucleated malignant cells. Note the eosinophilic osteoid matrix
material, a useful clue towards the correct diagnosis. Clinical history is critical in such cases. A, Diff-Quik stain, medium power. B, Papanicolaou
stain, medium power.
not possible, immunohistochemical stains need to be
performed on the cell block material or alcohol-fixed
slides.
Primary pulmonary sarcomas are rare tumors; the
most common is leiomyosarcoma, which may arise from
the pulmonary vasculature. Because of the rarity of
primary mesenchymal tumors, metastatic sarcomas
are usually accurately identified (Fig. 6-44). Synovial
sarcoma, chondrosarcoma, alveolar soft part sarcoma,
and osteosarcoma are just some of the types of sarcomas
that can metastasize to the lungs. Both primary and
secondary sarcomas that are composed of spindle cells
will show single, discohesive cells and/or clusters of
cells. The individual cells often have fragile cytoplasm
and granular to coarse chromatin, and there are occa-
sional bizarre multinucleated cells. The sarcomas can
be differentiated from sarcomatoid carcinomas and
melanoma by immunostaining.
SUGGESTED READINGS
Introduction
Bonfiglio TA. Cytopathologic interpretation of transthoracic fine-needle
biopsies. Masson Monographs in Diagnostic Cytopathology. New York:
Masson Publishing USA, 1983.
Mullan CP, Kelly BE, Ellis PK, et al. CT-guided fine-needle aspiration of
lung nodules: effect on outcome of using coaxial technique and imme-
diate cytological evaluation. Ulster Med J 2004;73:32–36.
Stewart CJ, Stewart IS. Immediate assessment of fine needle aspiration
cytology of lung. J Clin Pathol 1996;49:839–843.
Sarcoidosis
Annema JT, Veselic M, Rabe KF. Endoscopic ultrasound-guided fine-needle
aspiration for the diagnosis of sarcoidosis. Eur Respir J 2005;25:
405–409.
Ch006-F06731.indd 198
FINE NEEDLE ASPIRATION CYTOLOGY
Fritscher-Ravens A, Sriram PV, Topalidis T, et al. Diagnosing sarcoidosis
using endosonography-guided fine-needle aspiration. Chest 2000;118:
928–935.
Wildi SM, Judson MA, Fraig M, et al. Is endosonography guided fine needle
aspiration (EUS-FNA) for sarcoidosis as good as we think? Thorax
2004;59:794–799.
Wu JJ, Rashcovsky Schiff K. Sarcoidosis. Am Fam Physician 2004;70:
312–322.
Tuberculosis
Maygarden SJ, Flanders E. Mycobacteria can be seen as ‘negative images’
in cytology smears from patients with acquired immunodeficiency syn-
drome. Mod Pathol 1989;2:239–243.
Niederman MS, Sarosi GA, Glassroth J. Respiratory Infections, 2nd ed.
Philadelphia: Lippincott Williams & Wilkins, 2001.
Palmer PES. The Imaging of Tuberculosis with Epidemiological, Pathologi-
cal, and Clinical Correlation. Berlin: Springer-Verlag, 2002.
Powers CN. Diagnosis of infectious diseases: a cytopathologist’s perspec-
tive. Clin Microb Rev 1998;11:341–365.
Silverman JF, Holter JF, Berns LA, et al. Negative images due to clofazimine
crystals simulating MAI infection in a bronchoalveolar lavage specimen.
Diagn Cytopathol 1993;9:534–540.
Fungal Infections
Chen KTK. Cytodiagnostic pitfalls in pulmonary coccidioidomycosis. Diagn
Cytopathol 1995;12:177–180.
Niederman MS, Sarosi GA, Glassroth J. Respiratory Infections, 2nd ed.
Philadelphia: Lippincott Williams & Wilkins, 2001.
Raab SS, Silverman JF, Zimmerman KG. Fine-needle aspiration biopsy of
pulmonary coccidioidomycosis. Spectrum of cytologic findings in 73
patients. Am J Clin Pathol 1993;99:582–587.
Powers CN. Diagnosis of infectious diseases: a cytopathologist's perspec-
tive. Clin Microbiol Rev 1998;11:341–365.
Sarosi GA, Davies SF. Fungal Diseases of the Lung, 3rd ed. Philadelphia:
Lippincott Williams &Wilkins, 2000.
Wheat LJ, Goldman M, Sarosi G. State-of-the-art review of pulmonary
fungal infections. Semin Respir Infect 2002;17:158–181.
Hamartoma
Hughes JH, Young NA, Wilbur DC, Renshaw AA, Mody DR. Fine-needle
aspiration of pulmonary hamartoma: a common source of false-positive
10/26/2006 10:27:49 AM
 CHAPTER 6 Lung
diagnoses in the College of American Pathologists Interlaboratory Com-
parison Program in Nongynecologic Cytology. Arch Pathol Lab Med
2005;129:19–22.
Clear Cell (Sugar) Tumor
Nguyen GK. Aspiration biopsy cytology of benign clear cell (‘sugar’) tumor
of the lung. Acta Cytol 1989;33:511–515.
Primary Malignant Tumors
Detterbeck FC, Rivera MP, Socinski MA, Rosenman JG. Diagnosis and Treat-
ment of Lung Cancer. An Evidence-Based Guide for the Practicing Clini-
cian. Philadelphia: WB Saunders, 2001.
Linder J. Lung cancer cytology. Something old, something new. Am J Clin
Pathol 2000;114:169–171.
Liu J, Farhood A. Immunostaining for thyroid transcription factor-1 on
fine-needle aspiration specimens of lung tumors: a comparison of direct
smears and cell block preparations. Cancer (Cancer Cytopathol)
2004;102:109–114.
Silverman JF, Weaver MD, Shaw R, Newman WJ. Fine needle aspiration
cytology of pulmonary infarct. Acta Cytol 1985;29:162–166.
Travis WD, Colby TV, Corrin B, et al. World Health Organization Interna-
tional Classification of Tumours. Histological Typing of Lung and Pleural
Tumours, 3rd ed. Berlin: Springer Verlag, 1999.
Travis WD. Pathology of lung cancer. Clin Chest Med 2002;23:65–81.
Ch006-F06731.indd 199
199
Carcinoid Tumor
Anderson C, Ludwig ME, O’Donnell M, Garcia N. Fine needle aspiration
cytology of pulmonary carcinoid tumors. Acta Cytol 1990;34:505–510.
Cai YC, Banner B, Glickman J, Odze RD. Cytokeratin 7 and 20 and thyroid
transcription factor 1 can help distinguish pulmonary from gastrointes-
tinal carcinoid and pancreatic endocrine tumors. Hum Pathol 2001;
32:1087–1093.
Fekete PS, Cohen C, DeRose PB. Pulmonary spindle cell carcinoid. Needle
aspiration biopsy, histologic and immunohistochemical findings. Acta
Cytol 1990;34:50–56.
Gal AA, Nassar VH, Miller JI. Cytopathologic diagnosis of pulmonary
sclerosing hemangioma. Diagn Cytopathol 2002;26:163–166.
Nicholson SA, Ryan MR. A review of cytologic findings in neuroendocrine
carcinomas including carcinoid tumors with histologic correlation.
Cancer (Cancer Cytopathol) 2000;90:148–161.
Metastases
Flint A, Lloyd RV. Colonic carcinoma metastatic to the lung: cytologic
manifestations and distinction from primary pulmonary adenocarci-
noma. Acta Cytol 1992;36:230–235.
Hummel P, Cangiarella JF, Cohen JM, et al. Transthoracic fine-needle
aspiration biopsy of pulmonary spindle cell and mesenchymal lesions.
A study of 61 cases. Cancer (Cancer Cytopathol) 2001;93:187–198.
10/26/2006 10:27:50 AM
 7 Mediastinum
Maureen F Zakowski
INTRODUCTION
Fine needle aspiration (FNA) cytology is commonly
used to investigate space-occupying lesions of the medi-
astinum. As with many other body sites sampled by
FNA, experience on the part of the cytopathologist
is essential in the correct identification of lesions in
this area. Knowledge of the anatomy of the mediasti-
num and familiarity with the normal structures that
it contains is necessary for the correct interpreta-
tion of pathologic conditions. Although a variety of
lesions, reactive and neoplastic, benign and malignant,
occur, some of which are cystic (foregut cysts, bron-
chogenic cysts, neuroenteric cysts, and pericardial
cysts), this discussion will not focus on the predomi-
nantly benign cystic lesions of the mediastinum.
Additionally, tumors originating from the thyroid and
parathyroid which may be encountered in the medias-
tinum are not discussed here, but are the subject of
Chapter 2.
MEDIASTINUM
The mediastinum is the middle compartment between
the right and left thoracic cavities; it extends from the
thoracic inlet cranially to the diaphragm caudally. It
extends from the sternum anteriorly to the spine pos-
teriorly, and between the pleural cavities laterally and
from the diaphragm up to the thoracic inlet (Table 7-1).
The majority of lesions of the mediastinum, both benign
and malignant, present as asymptomatic masses found
on chest radiography. When symptomatic, these lesions
are a result of impingement of vital structures. Pain,
dyspnea, cough, or superior vena cava syndrome may
result from involvement of these structures. Metastases
are more common than primary tumors in the adult
population.
Age plays an important role in the correct diagnosis
of tumors of this area because very different lesions are
expected in childhood as compared to adulthood (Table
7-2). The majority of mediastinal lesions in childhood
are primary malignant tumors. Frequent here are the
neurogenic tumors, specifically neuroblastoma and
Ch007-F06731.indd 201
• Anil V Parwani
ganglioneuroblastoma, lymphoma, germ cell tumors,
and mesenchymal tumors.
In adults, metastatic lesions are the most common
tumors aspirated, most often small cell carcinoma of the
lung, followed by neurogenic tumors, nerve sheath
tumors, paragangliomas, cysts, thymomas, germ cell
tumors, and endocrine tumors such as thyroid, parathy-
roid, and carcinoid. Mesechymal tumors occur infre-
quently in the adult mediastinum and one-half of these
are endothelial in origin.
The FNA method for sampling the mediastinum is
the same as that for the lung, with the same contraindi-
cations to the procedure and a lower complication rate.
The highest rate of complications is found in the middle
mediastinum, probably due to the presence of the great
vessels. Complications include pneumothorax, hemo-
thorax, local hemorrhage, and pain. Mortality is rare.
Sensitivity and specificity are good, but vary with the
series reported. The overall sensitivity and specificity of
FNA versus core biopsy are nearly identical, but some
investigators prefer core biopsy in cases of suspected
mesenchymal lesions because of increased accuracy of
tumor typing and availability of more tissue for ancil-
lary studies.
FNA can distinguish benign from malignant lesions
and most often accurately subtype the malignancy. Par-
ticular diagnostic challenges are seen with spindle cell
lesions, perhaps due to their rarity and lack of experi-
ence on the part of pathologists. Other areas of challenge
include the subclassification of small cell malignancies,
including the misdiagnosis of small cell carcinoma for
lymphoma and the separation of the germ cell tumors
from adenocarcinoma. False positive diagnoses are rare
and false negative rates here, as in other sites, are due
to sampling errors and fibrotic or necrotic conditions.
The unsatisfactory rate as presented in the literature
is approximately 10%. Studies have found that a single
needle pass is sufficient in approximately half the
patients, but that as many as three biopsies may be
needed in the remaining half.
Age is not a factor in performing the FNA of the
mediastinum; so pediatric lesions can be easily aspirated
as well. Most aspirations are done under radiologic
guidance, with computerized tomography (CT) pre-
ferred over fluoroscopy. Ultrasound-guidance is often
employed in the anterior mediastinum. Adults, for
example, have a much lower incidence of neuroblas-
toma, ganglioneuroblastoma, and mesenchymal lesions
than do children. Metastases, while they do occur, are
201
10/26/2006 10:28:49 AM
 202 FINE NEEDLE ASPIRATION CYTOLOGY

TABLE 7-1 TABLE 7-3

The Mediastinum Location of Mediastinal Lesions by
Compartment in Adults
• The middle space between the right and left thoracic
cavities Superior
• Boundaries:
• From thoracic inlet above to diaphragm below Metastases (in all compartments)
• From sternum in front to spine in back Thymoma
• Majority of space-occupying lesions are asymptomatic Thymic cysts
• FNA is an excellent method for sampling the Thyroid lesions
mediastinum Parathyroid neoplasms
Lymphoma

Anterior Middle Posterior

Thymoma Pericardial cysts Neurogenic tumor

TABLE 7-2
Differential Diagnosis of Mediastinal Masses
Pediatric Adults
Neurogenic: Metastases
Neuroblastoma Neurogenic:
Ganglioneuroblastoma Nerve sheath
Lymphoma Paraganglioma
Cysts Cysts
Germ cell Thymoma
Mesenchymal Germ cell
Thymoma (unlikely) Mesenchymal
Carcinoid (unlikely) Endocrine:
Thyroid
Parathyroid
Carcinoid
infrequent in the pediatric population, and almost
always follow a known primary.
Dividing the mediastinum into compartments is
helpful in determining which lesions may be encoun-
tered (Table 7-3). The mediastinum can be considered
to contain several compartments: the superior medias-
tinum, the inferior mediastinum, and the middle medi-
astinum. The inferior mediastinum is further divided
into the anterior and posterior compartments.
The superior mediastinum contains the thymus,
lymph nodes, thyroid, and parathyroid; therefore,
thymoma, carcinoid tumor, lymphoma, goiter, thyroid
and parathyroid adenomas, and various cysts can be
found. The anterior mediastinum is the site for tumors
and cysts of the thymus as well as germ cell tumors.
Lymphoid tissue is present in all compartments and
lymphoma may be encountered in any part of the medi-
astinum. The middle mediastinum is composed mainly
of the heart and great vessels, and atrial myxomas and
associated cardiac lesions may be found here. Neuro-
genic tumors, both benign and malignant, are most com-
monly located in the posterior mediastinum.
Singh et al (1997) examined and reported on 189
cases of mediastinal FNAs. In their series, less than half
of the patients had surgical follow-up. Approximately
Thymic cysts Bronchogenic Schwannoma
Thyroid lesion cysts Neurofibroma
Parathyroid Lymphoma Ganglioneuroma
neoplasm Metastases Ganglioneuroblastoma
Lymphoma Malignant peripheral
Paraganglioma nerve sheath
Angioma tumor
Lipoma Neuroblastoma
Paraganglioma
Gastroenteric cysts
Lymphoma
Metastases
15% of the cases were unsatisfactory and a 6% discor-
dance rate between cytology and histology was found.
This was mostly due to the misclassification of carcino-
mas. They also encountered difficulty in separating
Hodgkin from non-Hodgkin lymphoma.
Geisinger (1995) divided mediastinal tumors into
categories by morphologic pattern. As expected, small
cell patterns were usually seen in lymphomas, carci-
noid, and small cell carcinoma. Polygonal or epithelioid
patterns were seen in thymomas, germinomas, embryo-
nal carcinoma, and metastatic carcinoma. Powers et al
(1996) found that 71% of their 189 cases were neo-
plastic. Interestingly, most of the primary tumors were
thymoma and lymphoma, and the majority of the metas-
tases were small cell carcinoma from the lung. The
remainder of the cases equally divided between un-
satisfactory and non-neoplastic. The sensitivity in this
series was 87%; specificity, 88% for neoplasms and
82% for distinguishing benign from malignant. The
positive predictive value for tumors was 97%. There
were three false positive diagnoses in this group.
As the majority of mediastinal FNAs are done under
radiologic guidance, the benefit of immediate assess-
ment and feedback to the operator by an experienced
cytopathologist or cytotechnologist is obvious. It is also
especially important when considering mediastinal
pathology, because of the frequency of lymphomas
here. On-site assessment can assure material is sent for
flow cytometry or additional molecular studies such as

Ch007-F06731.indd 202 10/26/2006 10:28:50 AM

 CHAPTER 7 Mediastinum
needed for germ cell tumor analysis. Careful teamwork
involving cytology and interventional radiology can
make the difference between a satisfactory specimen
and the need to re-biopsy the patient. Treatment can
be undertaken when the results of the FNA are un-
equivocal, and can eliminate the need for surgery in
cases of inoperable disease. As always, ancillary studies
on cytology material can be done to support diagnoses,
and material such as cell blocks and liquid-based prepa-
rations lend themselves well to immunoperoxidase,
molecular, and genetic analyses.
The cytomorphologic appearances of cysts and
inflammation of the mediastinal compartments are
similar to these conditions at any other site and will not
be further discussed. Chronic sclerosing mediastinitis
can be confused with tumors having a significant scle-
rotic or collagenous component, such as nodular scleros-
ing Hodgkin disease. This condition, however, would
probably not yield much material from an aspirate, and
would likely need surgical biopsy for confirmation.
THYMOMA AND THYMIC LESIONS
THYMOMA
CLINICAL FEATURES
Thymoma – a primary neoplasm of thymic epithelial
cells, with secondary reactive mature T lymphocytes –
is the most common neoplasm of the anterior mediasti-
num in adults, with a median age of 50 years. Thymomas
can also be found in the superior middle mediastinum,
but rarely in the posterior. The various classification
systems depend on the proportion of epithelial cells and
lymphocytes, but it is difficult to apply a classification
system to these tumors using only FNA material. Most
often these masses are asymptomatic, and are discov-
ered on incidental chest films. Some patients may expe-
rience symptoms from mass lesions such as cough,
dyspnea, and chest pain. A subset of patients may come
to medical attention because of associated paraneoplas-
tic syndromes such as myasthenia gravis.
CYTOPATHOLOGIC FEATURES
Since thymoma is a neoplasm with thymic epithelial
cells and secondary reactive mature T lymphocytes, a
correct diagnosis of thymomas is dependent on the
recognition of the two cell types, epithelial and lym-
phocytic. Either component can dominate. Multiple
classification systems have been used to classify thymo-
mas. A common classification used is that of Bernatz
et al., which divides thymoma into four categories: 1)
epithelial predominant, 2) lymphocytic predominant,
Ch007-F06731.indd 203
203
THYMOMA – DISEASE FACT SHEET
Definition
៉ A primary neoplasm of thymic epithelial cells which is associated
with lymphocytes, predominantly immature T cells
Incidence
៉ Most common primary tumor of the anterior mediastinum
៉ Incidence: 0.15 cases per 100,000
៉ 25% of all primary mediastinal tumors
Gender and Age Distribution
៉ Males = females
៉ Most occur in adults, with a mean age of 50 years.
៉ Rare in children
Clinical Features
៉ Most are asymptomatic
៉ Some patients present with chest pain, cough, dyspnea, or
superior vena cava syndrome
៉ Myasthenia gravis is associated with thymoma and is more
common in women
៉ Often large (5–10 cm) at presentation
Prognosis and Treatment
៉ Mixed: associated with aggressive behavior
៉ Spindle: associated with better prognosis
៉ Cytologic appearance does not predict behavior
៉ Prognosis dependent upon capsular invasion
៉ Generally responsive to chemotherapy
THYMOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Usually well encapsulated with fibrous septations
៉ Cystic change common
៉ Some have components that are necrotic and hemorrhagic
៉ Dual population of epithelial and lymphoid components in
variable proportions
៉ Epithelial cells: bland nuclei, smooth contour; nucleoli
prominent but not macro; intranuclear invaginations can occur;
few mitoses; +/− rosettes and Hassall’s corpuscles; spindle and
clear cell variants
៉ Lymphocytes: small and mature-appearing; polymorphic pattern
possible with immature lymphocytes, clefting, chromocenters,
and nucleoli
Ancillary Studies
៉ Pancytokeratin, cytokeratin 5/6
៉ CD5 is usually positive in thymic carcinomas
Differential Diagnosis and Pitfalls
៉ If the lymphocytic component predominates, the lesion may be
mistaken for a lymphoproliferative disorder
៉ If the epithelial component predominates, the lesion may be
mistaken for a metastatic carcinoma
10/26/2006 10:28:50 AM
 204 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 7-1
Thymoma. The classic bimodal pop-
ulation of neoplastic epithelial and
non-neoplastic lymphoid elements.
The cluster of epithelial cells is
cohesive in the background of scat-
tered lymphocytes, with occasional
single cells. The neoplastic cells are
variable in size and shape, with
usually scant to moderate amounts
of cytoplasm. Nuclei are bland with
often-conspicuous nucleoli. Diff-
Quik stain, low magnification.

3) mixed lymphoepithelial, and 4) spindle cell types.

Suster and Moran (1999) have proposed a classification
system with three categories (thymoma, atypical
thymoma, and thymic carcinoma). A well-character-
ized prognostic factor for predicting the behavior of a
thymoma is if it invades into or through the capsule.
More recently, the World Health Organization has pro-
posed that the classification of thymomas and thymic
carcinomas should be as type A thymoma (spindle cell,
medullary), type B thymoma (B1 thymoma [lympho-
cyte-rich, lymphocytic, predominantly cortical, organ-
oid], B2 thymoma [cortical], B3 thymoma [epithelial,
atypical, squamoid, well-differentiated thymic carci-
noma]), type AB thymoma (mixed), and type C
thymoma (thymic carcinoma).
The smears obtained from a thymoma are often cel-
FIGURE 7-2
lular with a characteristic dual (bimodal) population of
Thymoma. Split screen showing cohesive fragments of epithelial cells
cells: the classic neoplastic epithelial cells and the non- on the left with cystic spaces similar to what is seen in histology. Few
neoplastic lymphoid cells (thymocytes) (Fig. 7-1). The lymphocytes are visible among epithelial cells on the right. Papanico-
epithelial cells of thymoma are variable in size and laou stain, low and high magnification.
shape, with usually scant to moderate amounts of
cytoplasm. Nuclei are bland with conspicuous nucleoli.
Mitoses are often not observed (Fig. 7-2). Spindle cell A predominance of lymphocytes or epithelial cells
morphology is common in the epithelial component of may sometimes be obvious. Because malignancy here is
thymomas, and, when plentiful, usually signifies a good dependent on the demonstration of vascular or capsular
prognosis. invasion, cytology is not useful in making the diagnosis
The epithelial cells, even in cases of lymphocyte- of malignant thymoma (Fig. 7-3). Only when the cyto-
predominant thymoma, will demonstrate significant logic atypia is sufficient to categorize a tumor here as
cohesion. Clusters of epithelial cells can be seen with thymic carcinoma, should the word malignant be used
interspersed loosely arranged lymphocytes surrounded in the diagnosis. ‘Suspicious for malignancy’, ‘malig-
by vascular structures (Fig. 7-1). This arrangement of nancy cannot be ruled out’, and ‘satisfactory for evalu-
vessels is similar to that seen in hepatocellular carci- ation consistent with thymoma’ are some of the phrases
noma. The epithelial cells are often arranged in such a that are useful when diagnosing a thymoma using cyto-
way to suggest cystic structures (Fig. 7-2). logic material.

Ch007-F06731.indd 204 10/26/2006 10:28:50 AM

 CHAPTER 7 Mediastinum 205

FIGURE 7-3
Malignant thymoma. Cellular smear
from a patient with a malignant
thymoma. There is a predominance
of epithelial cells. Because malig-
nancy here is dependent on the
demonstration of vascular or capsu-
lar invasion, cytology alone is not
useful in making the diagnosis of
malignant thymoma. Thymoma with
a predominant epithelial component
may be mistaken for a metastatic
carcinoma. Diff-Quik stain, low
magnification.

ANCILLARY STUDIES

The thymoma lymphocytes are mostly small mature T

cells in a polymorphous pattern with some immature
cells and mitotic figures. Immunocytochemical stains for
keratin can demonstrate the epithelial cells when they
are not obvious and thymoma is suspected. Many of the
thymic carcinomas are positive for CD5, while germ cell
tumors and metastatic carcinomas are negative.

DIFFERENTIAL DIAGNOSIS AND PITFALLS

For an accurate diagnosis of thymoma, the characteris- FIGURE 7-4

tic dual population of epithelial and lymphoid elements
must be recognized. If the lymphocytic component is
predominant but, due to sampling the epithelial com-
ponent, is not recognized, the thymic lesion may be
mistaken for a lymphoproliferative disorder. Similarly,
if the epithelial component is predominant, thymoma
may be mistaken for a metastatic non-small cell carci-
noma (Fig. 7-3). Metastatic thymomas are cytologically
similar to the primary tumor. Hassall’s corpuscles
(squamous pearls) can be present, but are rarely seen
and are not necessary for the diagnosis. Care must be
taken not to mistake Hassall’s corpuscles for metastatic
squamous cell carcinoma.
Unlike in Hodgkin disease, eosinophils are not a
feature of this tumor. When the number of lymphocytes
is large, lymphoma must be included in the differential
diagnosis and excluded by ancillary studies.
Thymic carcinoma. Note the presence of large obviously malignant cells
with pleomorphic and hyperchromatic nuclei. Differential diagnosis
here must include metastatic disease. Papanicolaou stain, low
magnification.
THYMIC CARCINOMAS
When necrosis, marked atypia, or epithelial mitosis is
significant, thymic carcinomas must be considered.
Thymic carcinomas are aggressive epithelial malignan-
cies. They are exceedingly rare, and are most frequent
in middle-aged men. Patients often present with cough,
dyspnea, and chest pain and weight loss.
In contrast to thymomas, thymic carcinomas are
cytologically atypical with features of malignancy (Figs
7-4 & 7-5). The most common type of thymic carcinoma

Ch007-F06731.indd 205 10/26/2006 10:28:51 AM

 206
A B
FIGURE 7-5
Well-differentiated thymic carcinoma. Cohesive fragments of neoplastic cells with few lymphocytes in the background. Occasional cells have a
spindled morphology. The nuclei are moderately sized, with predominantly coarse, granular chromatin. A, Diff-Quik stain, low magnification.
B, H&E stain, high magnification.
is squamous cell carcinoma, but almost any subtype of
carcinoma, including small cell, clear cell, carcinosar-
coma, and lymphoepithelioma-like, can be seen. Epithe-
lial markers are useful to confirm the epithelial origin
of the tumors when the differential diagnosis includes
melanoma and lymphoma. The differential diagnosis of
thymic carcinomas includes embryonal carcinoma and
metastatic carcinomas.
Ruling out metastasis must prove primary origin in
the thymus from a distant site. Germ cell tumors can
have a mixture of epithelial cells and lymphocytes, but
the epithelial component here is outright malignant.
Treatment is dependent on tumor stage and grade. Com-
plete surgical resection is the primary treatment.
THYMIC FOLLICULAR HYPERPLASIA
Thymic follicular hyperplasia with an increased
number of follicles is associated with myasthenia gravis
and other autoimmune diseases. True thymic hyper-
plasia is a marked increase in the size of the thymus,
both epithelial and lymphocytic components. This con-
dition usually occurs in children and can be difficult to
separate from normal thymic tissue on cytology.
GERM CELL TUMORS
CLINICAL FEATURES
Only a small percentage of primary germ cell tumors
arise in the mediastinum, but this site accounts for
the majority of all extragonadal germ cell tumors
Ch007-F06731.indd 206
FINE NEEDLE ASPIRATION CYTOLOGY
MEDIASTINAL GERM CELL TUMORS – DISEASE FACT SHEET
Definition
៉ The mediastinum is a common site of extragonadal germ cell
tumors, which are thought to arise from primitive germ cells
that failed to migrate completely during embryonic
development
Incidence
៉ The mediastinum is a common site of extragonadal germ cell
tumors
៉ 25% of all primary mediastinal tumors in children are germ cell
tumors
៉ 15% of all primary mediastinal tumors in adults are germ cell
tumors
៉ Mature cystic teratoma is the most common mediastinal germ cell
tumor
Gender and Age Distribution
៉ Men more than women, except for mature cystic teratoma, which
has equal incidence in men and women
Clinical Features
៉ Rapid growth and invasion of the tumor result in symptoms
៉ Patients may present with chest pain, dyspnea, superior
vena cava syndrome, cough, weight loss, night sweats, and
dysphagia.
៉ Elevated β-HCG (choriocarcinoma, embryonal carcinoma, some
seminomas) and AFP (yolk sac tumors and embryonal carcinoma)
in serum
Prognosis
៉ Non-seminomatous mediastinal germ cell tumors are more
aggressive and metastasize earlier than mediastinal
seminomas
10/26/2006 10:28:52 AM
 CHAPTER 7 Mediastinum
(50% to 70%). They are more common in children
than in adults. The anterior mediastinum is the pre-
ferred site for these tumors and a metastasis to the
mediastinum from the gonads is far more common than
a primary tumor here. Mediastinal germ cell tumors
account for 1–15% of adult anterior mediastinal tumors.
A gonadal primary must always be excluded when
making the diagnosis of primary mediastinal germ cell
tumor. Males are far more likely to have mediastinal
germ cell tumors than are females. The germ cell
tumors that occur in the mediastinum include semi-
noma, endodermal sinus tumor (yolk sac tumors),
embryonal carcinoma, and teratomas. Mature terato-
mas represent the majority of mediastinal germ cell
tumors (60% to 70%). The remaining mediastinal
germ cell tumors are divided between seminomas
(40%) and non-seminomatous germ cell tumors (60%).
Most of the malignant germ cell tumors are symptom-
atic, but only about half of the teratomas produce
symptoms.
CYTOPATHOLOGIC FEATURES
M ATURE CYSTIC TERATOMA
Mature cystic teratoma is the most common medias-
tinal germ cell tumor and is found equally in men
and women, unlike the other germ cell tumors. This
tumor is large, calcified, cystic, and filled with grum-
ous granular material identical to its ovarian counter-
part. FNA can show these components and skin adnexal
structures, gastrointestinal, respiratory, and cartilagi-
nous material (Fig. 7-6). Foreign body granulomas
are common in response to the keratin found in terato-
mas. Hair is not often seen in a cytology specimen, but
short strands can sometimes be observed. Immature
teratomas are more common in men and show the
presence of immature epithelial, mesenchymal, and
neural material. It is an uncommon tumor in the
mediastinum.
SEMINOMA
Germinomas or seminomas occur exclusively in men.
This is the most frequent mediastinal germ cell tumor
in males. The tumor cells here are infiltrated by reactive
lymphocytes, and because of this dual population,
thymoma enters the differential; however, unlike in
thymoma, plasma cells are common. Seminoma is poorly
cohesive and appears malignant at first glance. Hyper-
chromatic enlarged nuclei are seen with very consistent,
prominent nucleoli. Cytoplasm is clear. An often-
reported feature is the striped or ‘tigroid’ pattern in the
background seen in air-dried smears. We find this
feature more often mentioned in the literature than
actually seen on slides. Granulomas and multinucleated
giant cells are common. These giant cells are of the
syncytotrophoblast type, and not the cytotrophoblast
type seen in choriocarcinoma.
Ch007-F06731.indd 207
207
MEDIASTINAL GERM CELL TUMORS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Teratoma:
៉ Tumor is large, calcified, cystic, and filled with grumous
granular material
៉ An FNA smear may show these components and skin
structures, gastrointestinal, respiratory, and cartilaginous
material
៉ Foreign body granulomas are common in response to the
keratin found in teratomas
៉ Hair is not often seen in a cytology specimen, but short
strands can sometimes be noted
៉ Seminoma:
៉ Tumor cells are infiltrated by reactive lymphocytes
៉ Plasma cells are common
៉ Poorly cohesive, and appears malignant at first glance
៉ Hyperchromatic enlarged nuclei are seen with very consistent,
prominent nucleoli; cytoplasm is clear
៉ An often-reported feature is the striped or ‘tigroid’ pattern in
the background seen in air-dried smears
៉ Granulomas and multinucleated giant cells are common
៉ Yolk sac tumor:
៉ Irregular, large, cohesive, 3-D balls and papillae, few single
cells
៉ Large cells with abundant vacuolated cytoplasm
៉ Schiller-Duval bodies: glomeruloid structures formed by the
invagination of malignant cells into an empty space
៉ Hyaline globules: large, round, PAS-positive intracytoplasmic
inclusions containing AFP (also free in background)
៉ Embryonal carcinoma:
៉ Smears show large clusters and papillae of poorly
differentiated cells with vacuolated cytoplasm
៉ Nuclei are large with coarsely granular chromatin and
prominent nucleoli
៉ Close resemblance to poorly differentiated adenocarcinoma
Ancillary Studies
៉ Seminoma: positive for immunostaining with c-kit and PLAP
៉ Embryonal carcinoma: positive for CD30
៉ Yolk sac tumor: positive for AFP
៉ Choriocarcinoma: positive for HCG
៉ The most common karyotype abnormality is i(12p), present in
about 40% of patients
Differential Diagnosis and Pitfalls
៉ Metastatic disease must be excluded
YOLK SAC (ENDODERMAL SINUS) TUMOR
Yolk sac tumor is similar to embryonal carcinoma in
its vacuolated cytoplasm and malignant-appearing cells.
The cytoplasm of these tumor cells contains large red-
staining hyaline globules, which are also found free
in the background. These globules contain alpha-
fetoprotein (AFP), which can be also elevated in the
serum of these patients. The background is bloody with
tumor cell fragments and a ‘dirty’ appearance. An
inflammatory component may be present (Figs 7-7 &
7-8). The presence of glomeruloid or Schiller-Duval
bodies, which are the invagination of cells into a sinus
or small space, signify the yolk sac nature of this tumor
(Fig. 7-9).
10/26/2006 10:28:53 AM
 208 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 7-6
Benign cystic teratoma. This cell
block shows benign epithelial
glandular elements. The corre-
sponding smear consisted of anucle-
ated squames and benign squamous
cells, proteinaceous debris, and
mixed infl ammatory infiltrate. H&E
stain, high magnification.

FIGURE 7-7 FIGURE 7-8

Yolk sac tumor. Papillary-like structure with large cells and prominent Yolk sac tumor. The tumor shows large cells with prominent nucleoli
nucleoli. Infl ammation and mucoid material are present. Diff-Quik stain, and intracytoplasmic hyaline globules. Multiple bizarre cell shapes are
high magnification. present. Papanicolaou stain, high magnification.

EMBRYONAL CARCINOMA ANCILLARY STUDIES

Embryonal carcinoma is seen as large clusters and
papillae of poorly differentiated cells with vacuolated
cytoplasm. The nuclei are large with coarsely granular
chromatin and prominent nucleoli (Fig. 7-10). The
resemblance to poorly differentiated adenocarcinoma is
significant, and tumor and/or serum markers may be
necessary to identify these tumors as germ cell in
origin.
Immunohistochemistry may be helpful in confirming
the diagnosis of germ cell tumors. Seminoma is high-
lighted by immunostain for c-kit and placental-like
alkaline phosphatase (PLAP), while CD30 stains the
embryonal component. AFP stains for yolk sac tumor.
Molecular analysis of i(12p), which is characteristic of

Ch007-F06731.indd 208 10/26/2006 10:28:53 AM

 CHAPTER 7 Mediastinum
FIGURE 7-9
Yolk sac tumor. A cell block of yolk sac tumor showing a Schiller-Duval
body invaginating into a vascular space. Papanicolaou stain, high
magnification.
FIGURE 7-10
Embryonal carcinoma. The smear shows large, undifferentiated epithe-
lial cells with enlarged nuclei and conspicuous nucleoli. Papanicolaou
stain, high magnification.
germ cell tumors, can be done on fresh tissue taken at
the time of the FNA, either as a needle core or as an
additional pass for cytologic material.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
A feature common to germ cell tumors in cytology is
the resemblance to poorly differentiated carcinoma,
such as seen in the lung. Care must be taken to accu-
rately diagnose germ cell tumors, which generally have
a good prognosis with appropriate treatment, from
poorly differentiated/undifferentiated midline carci-
noma, where the prognosis is not favorable.
Germ cell tumor and other midline tumors must be
differentiated from the recently described lethal midline
Ch007-F06731.indd 209
209
or respiratory tract carcinoma with a defining t(15;19).
This tumor occurs in young people and can involve
the area of the thymus. It is a poorly differentiated
carcinoma showing varying degrees of squamous
differentiation.
THYMIC NEUROENDOCRINE
(CARCINOID) TUMORS
CLINICAL FEATURES
Thymic neuroendocrine (carcinoid) tumors are a rare
neoplasm of the anterior mediastinum. These tumors
frequently exhibit a wide spectrum of histology and
appear to follow a more aggressive behavior than their
non-thymic counterparts. Primary neuroendocrine
tumors may occur in the mediastinum and are charac-
terized as atypical or malignant carcinoid tumors.
Rarely, primary small cell carcinomas of the thymus
may also occur. Carcinoid tumors that occur in the
mediastinum, like pulmonary carcinoid, are thought
to be of foregut origin. This disease of adults can
have paraneoplastic symptoms and a minority of these
tumors are associated with multiple endocrine neopla-
sia (MEN) type 1. Thymic carcinoids are more aggres-
sive and have a poorer clinical outcome than do their
THYMIC NEUROENDOCRINE (CARCINOID) TUMORS –
DISEASE FACT SHEET
Definition
៉ A malignant tumor, cytologically similar to carcinoid tumors
found at other sites
Incidence
៉ Highest incidence is in the 4th to 5th decades of life
Gender and Age Distribution
៉ Three out of four patients are men
Clinical Features
៉ Associated with Cushing syndrome and multiple endocrine
neoplasia (MEN) syndromes
៉ Presents as a large and lobulated mass in the anterior
mediastinum
៉ Patients may experience cough, dyspnea, superior vena cava
syndrome, fatigue, fever, and night sweats
Prognosis and Treatment
៉ Metastasis is common (one-third with bone metastases)
៉ Thymic carcinoid associated with MEN syndrome is more
malignant in behavior
៉ Treatment is complete surgical resection
៉ Radiation and chemotherapy may have limited roles
10/26/2006 10:28:55 AM
 210 FINE NEEDLE ASPIRATION CYTOLOGY

pulmonary counterparts, even when morphology is

similar.

CYTOPATHOLOGIC FEATURES

This tumor is composed of a single population of poorly

cohesive, small, round to oval, bland-appearing cells
with a distinctive ‘salt and pepper’ chromatin pattern
(Fig. 7-11). Inconspicuous nucleoli and scant cytoplasm
characterize carcinoid of the mediastinum and of any
site (Figs 7-11 & 7-12). Rosettes and spindle cells may
be present. The mitotic count is the primary tool for
distinguishing typical from atypical carcinoid, but
mitotic figures are often difficult to identify in cytologic
material, even when they are multiple and obvious in FIGURE 7-11
the corresponding tissue. Additionally, it is not practi- Thymic carcinoid tumor. Bland and loosely cohesive fragment of
cal to count mitotic figures per high-power fields in spindled cells, with fine chromatin. Nucleoli are not conspicuous. The
cytology; therefore, we recommend the diagnosis of car- chromatin pattern is distinctively ‘salt and pepper’. A vessel is seen in
cinoid on FNA material without an attempt to classify the mid to upper field. Diff-Quik stain, low magnification.
it into typical or atypical. The differential diagnosis of
thymic or mediastinal carcinoids includes small cell
carcinoma metastatic from, usually, lung. Parathyroid tumors may occur in this location and can
be distinguished by their staining with antibody to
parathormone. Lymphomas will be immunopositive for
leukocyte common antigen, and germ cell tumors will
ANCILLARY STUDIES react with immunostain for PLAP.

Immunohistochemical markers such as chromogranin

and synaptophysin must confirm the neuroendocrine DIFFERENTIAL DIAGNOSIS AND PITFALLS
nature of the cells. These tumors react with antibodies
to cytokeratin and chromogranin A, as well as other
neuroendocrine markers, including synaptophysin. Carcinoid tumors may be distinguished from thymo-
mas by the lack of background lymphocytes, rosette
formation, granularity of cytoplasm, and ‘salt and
pepper’ chromatin (Fig. 7-12).
THYMIC NEUROENDOCRINE (CARCINOID) TUMORS –
PATHOLOGIC FEATURES

Cytopathologic Findings MEDIASTINAL LYMPHOMAS

៉ Composed of single population of poorly cohesive, small, round
to oval, bland-appearing cells with a distinctive ‘salt and
pepper’ chromatin pattern
៉ Inconspicuous nucleoli and scant cytoplasm characterize
CLINICAL FEATURES
carcinoid of the mediastinum and of any site
៉ Rosettes and spindle cells may be present
Malignant lymphoma is the most common primary
middle mediastinal tumor, but occurs more frequently
Ancillary Studies
in the anterior and superior mediastinum overall.
៉ Tumors react with antibodies to cytokeratin and chromogranin
Most mediastinal lymphomas are Hodgkin lymphomas,
A, as well as other neuroendocrine markers, including
synaptophysin
usually the nodular sclerosing subtype.

Differential Diagnosis and Pitfalls

៉ The differential diagnosis of thymic or mediastinal carcinoids
includes small cell carcinoma metastatic from, usually, lung,
CYTOPATHOLOGIC FEATURES
and lymphomas
៉ Lymphomas will be immunopositive for leukocyte common
In Hodgkin lymphoma, the FNA may be scant due to
antigen, and germ cell tumors will react with immunostains for
PLAP
sampling of the collagen and it may be difficult to iden-
tify the necessary Reed-Sternberg (R-S) cells. Nodular
lymphocyte-predominant Hodgkin disease (NLPHD)

Ch007-F06731.indd 210 10/26/2006 10:28:56 AM

 CHAPTER 7 Mediastinum
FIGURE 7-12
Thymic carcinoid tumor. A cellular
smear with cohesive fragments of
monotonous neoplastic cells with
round to ovoid nuclei, and fine
chromatin. Nucleoli are not con-
spicuous. Papanicolaou stain, low
magnification.
THYMIC LYMPHOMAS (HODGKIN AND NON-HODGKIN TYPES) –
DISEASE FACT SHEET
Definition
៉ The three most common types of mediastinal lymphomas include
nodular sclerosing Hodgkin disease, large B-cell lymphoma, and
lymphoblastic lymphoma
៉ Hodgkin disease (HD) is a lymphoma with large abnormal cells
termed Reed-Sternberg (R-S) cells and Hodgkin cells present in a
mixed background of lymphocytes and mixed inflammatory cells
៉ Lymphoblastic lymphoma is the most common lymphoma of
children and most arise in the thymus
Incidence
៉ Malignant lymphoma is the most common primary neoplasm of
the middle mediastinum, but in absolute numbers it is more
common in the anterior and superior mediastinum
៉ HD is the most common mediastinal lymphoma (70%) and nodular
sclerosing is the most common subtype
៉ HD has an incidence of 2–4 per 100,000
Gender and Age Distribution
៉ HD: slightly more common in males; peak age, 15 to 35 years
៉ Non-Hodgkin lymphoma: highest incidence is in white men with a
mean age of 55 years
៉ Lymphoblastic lymphoma: mean age, 28 years
Clinical Features
៉ Subclassification of HD is less important now than earlier (age
and stage most important)
៉ Systemic symptoms (fever, night sweats, weight loss) carry worse
prognosis
Prognosis
៉ HD is curable in >90% with stage I–II disease
៉ Lymphoblastic lymphoma is highly aggressive
Ch007-F06731.indd 211
211
has somewhat pleomorphic, lobated, ‘popcorn-like’ R-S
cell variants (CD30- and CD15-negative), while classi-
cal Hodgkin lymphoma contains the highly pleomor-
phic classic R-S cells (CD30- and CD15-positive).
Smears may show large abnormal lymphoid cells, crush
artifact, and several R-S cells (Fig. 7-13).
The background present in the smears is similar to
that in Hodgkin lymphoma from any other site, with a
heterogeneous population of lymphocytes with plasma
cells and eosinophils (Fig. 7-14). The presence of lym-
phoglandular bodies is often reported in the background
of air-dried smears in lymphoma. These pinched-off bits
of cytoplasm can be found with all stains and indicate
a heavy lymphoid infiltrate. They make no comment on
benign or malignant conditions. We do not find them of
particular help in classifying lymphomas or even in
recognizing lymphoid populations, as cytoplasm frag-
ments from any other cell can mimic lymphoglandular
bodies.
Large cell, B-cell lymphomas also occur, and may be
extranodal or primary in the thymus. All cell types
present are lymphoid, in contrast to the picture of lym-
phoid and epithelial cells in thymoma. Large cell lym-
phoma has large, vesicular nuclei and often-irregular
nuclear membranes (Figs 7-15–7-17). These large lym-
phoid cells may be mixed with smaller reactive cells.
Lymphomas on cytology are rarely of a single popula-
tion of cells and the presence of reactive cells and tingi-
ble-body macrophages should not distract the observer
from the presence of the diagnostic large malignant lym-
phocytes (Figs 7-15 & 7-16).
Lymphoblastic lymphoma is the most common lym-
phoma of children and most arise in the thymus. These
tumors are of pre-T-cell lineage, present with respira-
tory distress, and are often fatal. The diagnostic feature
of these lymphomas is lymphoid blasts, which are
10/26/2006 10:28:56 AM
 212 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 7-13 FIGURE 7-14

Hodgkin lymphoma. Note the large abnormal lymphoid cells, crush Hodgkin lymphoma. This smear shows a classic Reed-Sternberg cell (left
artifact, and several Reed-Sternberg cells. Diff-Quik stain, low of center) and polymorphous background. Diff-Quik stain, low
magnification. magnification.

THYMIC LYMPHOMA (HODGKIN AND NON-HODGKIN TYPES) –

PATHOLOGIC FEATURES

Cytopathologic Findings
៉ Hodgkin disease (HD):
៉ Arises in thymus or lymph nodes, almost never extranodal
៉ Reed-Sternberg (R-S) cells contain bilobed nuclei with
prominent eosinophilic nuclei
៉ R-S cells may be rare; they are necessary but insufficient for
diagnosis
៉ Background important: lymphocytes, plasma cells,
eosinophils, histiocytic
៉ +/− cellular (sparse aspirate from a large node is suspicious
in itself)
៉ Inverse relationship between number of R-S cells and
lymphocytes
៉ Metachromatic material present in smears FIGURE 7-15
៉ Non-Hodgkin lymphoma: Non-Hodgkin lymphoma. Monotonous population of malignant lympho-
៉ Large vesicular nuclei cytes displaying occasional conspicuous nucleoli. Papanicolaou stain,
៉ Nucleoli prominent but not macro low magnification.
៉ Irregular (cleaved) or smooth (non-cleaved) membranes
៉ Large cells may be mixed with smaller cells
៉ Cellularity may be quite limited when sclerotic characterized by a delicate chromatin pattern and
irregular nuclear outlines. Nucleoli are not prominent.
Ancillary Studies Necrosis, mitosis, eosinophils, granulomas, and macro-
៉ Classical HD: R-S cells are positive for CD15 and CD30, and phages may accompany the blasts. Since these lympho-
negative for CD20 mas infiltrate thymic tissue, normal thymic components
៉ Flow cytometry is helpful for the classification of non-Hodgkin
may be present in the aspirates.
lymphoma

Differential Diagnosis and Pitfalls

៉ Differential diagnosis includes thymoma, and germinoma ANCILLARY STUDIES
៉ Cleaved lymphocytes may mimic cells in thymoma but all cell
types here are lymphoid
៉ Sclerotic large cell lymphomas are common in the mediastinum Flow cytometric studies can be done on cytologic mate-
and may mimic HD rial; therefore the importance of on-site cytopathologic
៉ Chronic sclerosing mediastinitis can be confused with tumors
evaluation is critical. Cell blocks may be prepared and
having a significant sclerotic or collagenous component such as
nodular sclerosing HD
appropriate immunostain may be used to further
classify and subtype the lymphomas. These details are
discussed in greater length in Chapter 3.

Ch007-F06731.indd 212 10/26/2006 10:28:57 AM

 CHAPTER 7 Mediastinum
FIGURE 7-16
Non-Hodgkin lymphoma. High-power view of monotonous population of
large malignant lymphocytes with prominent nucleoli. Papanicolaou
stain, high magnification.
FIGURE 7-17
Non-Hodgkin lymphoma. High-power view of malignant lymphoma cells.
Note mitoses and cleaved nuclei. Diff-Quik stain, high magnification.
NEUROGENIC TUMORS
CLINICAL FEATURES
Neurogenic tumors are most frequently located in the
posterior mediastinum and most are malignant sympa-
thetic tumors of childhood. Nerve sheath tumors and
gangliomas are more commonly found in the adult
population. When benign, these neurogenic tumors are
often paucicellular, making FNA diagnosis difficult.
Neuroblastoma appears as atypical small round blue
cell tumor and has the same differential diagnosis and
work-up as elsewhere in the body, remembering that
small cell carcinoma is not expected in children.
Ch007-F06731.indd 213
213
NEUROGENIC TUMORS – DISEASE FACT SHEET
Definition and Incidence
៉ Neurogenic tumors account for the majority of tumors arising in
the posterior mediastinum
៉ Neurogenic tumors include nerve root tumors such as schwannoma
and neurofibroma, and sympathetic ganglion tumors such as
neuroblastoma, ganglioneuroblastoma, and ganglioneuroma
៉ Paragangliomas may rarely present as posterior mediastinal
masses
៉ Schwannoma is the most common neurogenic tumor of the
mediastinum; it is generally solitary and large, with cystic change
or calcification common
Gender and Age Distribution
៉ 20% of all adult mediastinal neoplasms
៉ 40% of all pediatric mediastinal neoplasms
Clinical Features
៉ 95% of these tumors in adults are benign and are usually
asymptomatic
៉ In children, most neurogenic tumors are malignant
Prognosis
៉ 80% of these tumors are benign
Ganglioneuroblastoma occurs in children and is a
neuroblastoma with the presence of ganglion cell dif-
ferentiation; ganglioneuroma is a tumor of adults and is
composed of mature ganglion cells. Ganglia have large
prominent nucleoli and can be bi- or multinucleated. On
a cursory inspection, they can be mistaken for malig-
nant cells.
CYTOPATHOLOGIC FEATURES
Neurofibroma and schwannoma both have bland
spindle cells loosely arranged and may be calcified.
Schwannomas are more common, and when there is
degeneration or atypia present, they can be mistaken
for sarcoma or melanoma. The smears may show an
extensively degenerative background, fragile cytoplasm,
and occasional large atypical cells (Fig. 7-18). Antoni
A and B growth patterns can often be seen in cellular
cytology preparations of schwannomas (Fig. 7-19).
However, malignant schwannoma and malignant
peripheral nerve sheath tumors do occur in the poste-
rior mediastinum and they can be recognized by necro-
sis, mitoses, and nuclear atypia (Figs 7-20–7-22).
Paragangliomas can arise in the superior or anterior
mediastinum and are very vascular tumors of the sym-
pathetic nerve chain. The tumors are composed of cells
grouped into ball-like arrangements, the ‘Zellballen’.
The tumor has large cells with generous, pale, some-
what granular eosinophilic cytoplasm. The nuclei
of these benign cells may show marked atypia and
10/26/2006 10:28:58 AM
 214 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 7-18
Schwannoma. Smear showing degenerative background, spindled cells
with fragile cytoplasm, and occasional large pleomorphic cells. Diff-
Quik stain, high magnification.
FIGURE 7-20
Malignant peripheral nerve sheath tumor. Note the bizarre pleomorphic
cells. This tumor was located in the posterior mediastinum of an adult.
The differential diagnosis includes sarcoma NOS and sarcomatoid carci-
noma. Diff-Quik stain, high magnification.

A B

FIGURE 7-19
Schwannoma. A, Large tissue fragment from an FNA of a schwannoma, showing Antoni A and B areas. B, Higher power of the spindled cells with
uniform oval nuclei. Papanicolaou, low and high magnification.

FIGURE 7-22
FIGURE 7-21 Malignant peripheral nerve sheath tumor. Note the bizarre multinucle-
ate giant cell on the left and sarcomatoid appearance on the right.
Malignant peripheral nerve sheath tumor. Note the spindle and large
Papanicolaou stain, low magnification (left); H&E stain (right).
atypical cells. The appearance is that of a malignant spindle cell neo-
plasm, and clinical history and ancillary studies are vital for an accurate
diagnosis. Papanicolaou stain, low magnification.

Ch007-F06731.indd 214 10/26/2006 10:28:59 AM

 CHAPTER 7 Mediastinum
NEUROGENIC TUMORS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Schwannomas:
៉ Tumor has cellular (Antoni A) and degenerated/myxoid
(Antoni B) areas
៉ Variable cellularity with large thick fragments, smaller
clusters, and single cells
៉ Cells are elongated and spindle-shaped and may palisade
៉ Uniform, round to plump to oval nuclei with fine chromatin
and inconspicuous nucleoli
៉ Regressive or degenerative changes and increased cellularity
possible
៉ Intranuclear cytoplasmic invaginations can be seen
៉ Cytoplasm is fragile and sometimes strips away
៉ Ground substance is fibrillar
៉ No mitoses or necrosis
Ancillary Studies
៉ Immunohistochemistry for S-100 may be helpful when
confirming the neurogenic origin of these tumors
Differential Diagnosis and Pitfalls
៉ Cytologic atypia, mitosis, necrosis – think malignancy
enlargement. Small amounts of focal necrosis can be
present even in benign tumors, and the tumor cells can
resemble the cells of carcinoid, but carcinoids lack the
usual atypia of paragangliomas. Paragangliomas have
been misdiagnosed on cytology material as anaplastic
carcinoma with giant cells and that was thought to be
due to the presence of vascular-rich papillary structures,
acinar-glandular structures, cellular pleomorphism, the
prominent nucleoli, and the ‘squamoid’ appearance of
the cytoplasm.
Mesenchymal tumors are rare in the mediastinum
and resemble their counterparts in other body sites.
METASTATIC LESIONS
FNA is highly reliable for establishing a diagnosis of
metastatic lesions in the mediastinum. The aspirate
and the material collected concurrently, may be helpful
in establishing a new diagnosis or used to confirm that
a secondary lesion is metastatic from a previously
known primary. The material may also be useful for
molecular diagnostic testing, such as the evaluation of
the recently discovered epidermal growth factor recep-
tor (EGFR) mutation, to ascertain therapeutic efficacy
of tyrosine kinase inhibitors
Studies have highlighted that most metastatic lesions
to mediastinal lymph nodes are derived from the lung
and that small cell carcinoma represents one of the most
common metastatic lesions to the mediastinum. Typical
Ch007-F06731.indd 215
215
METASTATIC TUMORS – DISEASE FACT SHEET
Definition
៉ Metastatic lesions are the common cause of a mediastinal mass in
adults
៉ FNA can establish the diagnosis and subtype metastatic lesions to
the mediastinum
៉ This may be a secondary lesion in a patient with a previous
history of cancer or a new presentation
Incidence
៉ Dependent on the tumor type
៉ Small cell carcinoma is the most common type
Gender and Age Distribution
៉ Dependent on the tumor type
Clinical Features
៉ Most common source of mediastinal metastasis is small cell
carcinoma of lung
៉ Associated with multiple endocrine neoplasia type 1
Prognosis and Treatment
៉ Metastatic small cell carcinoma is aggressive with extensive
metastases
៉ Treatment for small cell carcinoma: radiation therapy and
chemotherapy
METASTATIC TUMORS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Variable, but usually overtly malignant features are needed to
document malignancy
Ancillary Studies
៉ Immunohistochemical stains for defining the origin of the lesion,
such as TTF (lung), CK7/CK20 profile, melanoma markers, S-100,
germ cell markers (PLAP, CD30), lymphoma markers
Differential Diagnosis and Pitfalls
៉ FNA can establish the diagnosis and subtype metastatic lesions to
the mediastinum
៉ Other common metastatic lesions include breast, thyroid, head and
neck, kidney, prostate, and testicular tumors, and melanoma
features of small cell carcinoma seen in the primary
lesion are present here, including crush artifact and
nuclear molding (Figs 7-23 & 7-24). Squamous cell car-
cinoma from the head and neck or a lung primary may
present as a metastatic lesion in the mediastinum (Fig.
7-25). Other common metastatic lesions include breast,
thyroid, kidney, prostate, and testicular tumors, and
melanoma.
10/26/2006 10:29:00 AM
 216 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 7-23
Metastatic small cell carcinoma.
Smear depicts cells with prominent
nuclear molding, scant cytoplasm,
mitoses, and nuclear crush artifact.
This is indistinguishable from a
primary mediastinal small cell
carcinoma. Diff-Quik stain, low
magnification.

FIGURE 7-24
Metastatic small cell carcinoma. Characteristic features of small cell carcinoma, with fine nuclear membranes, powdery chromatin, and inconspicuous
nucleoli. Papanicolaou stain, high magnification.

Ch007-F06731.indd 216 10/26/2006 10:29:00 AM

 CHAPTER 7 Mediastinum 217

FIGURE 7-25
Metastatic squamous cell carci-
noma. Smear showing bizarre,
pleomorphic cells with dark nuclear
chromatin, thick opaque cytoplasm,
and conspicuous nucleoli. Papanico-
laou stain, high magnification.

SUGGESTED READINGS Bangerter M, Behnisch W, Griesshammer M. Mediastinal masses diagnosed

as thymus hyperplasia by fine needle aspiration cytology. Acta Cytol
Introduction/Mediastinal Masses 2000;44:743–747.
Chhieng DC, Rose D, Ludwig ME, Zakowski MF. Cytology of thymomas:
Belfiore G, Camera L, Moggio G, Vetrani A, Fraioli G, Salvatore M. Middle
emphasis on morphology and correlation with histologic subtypes.
mediastinum lesions: preliminary experience with CT-guided fine-needle
Cancer 2000;90:24–32.
aspiration biopsy with a suprasternal approach. Radiology 1997;202:
Dadmanesh F, Sekihara T, Rosai J. Histologic typing of thymoma according
870–873.
to the new World Health Organization classification. Chest Surg Clin N
Blegvad S, Lippert H, Simper LB, Dybdahl H. Mediastinal tumours. A report
Am 2001;11:407–420.
of 129 cases. Scand J Thorac Cardiovasc Surg 1990;24:39–42.
Dahlgren S, Sandstedt B, Sundstrom C. Fine needle aspiration cytology of
Duwe BV, Sterman DH, Musani AI. Tumors of the mediastinum. Chest
thymic tumors. Acta Cytol 1983;27:1–6.
2005;128:2893–2909.
Morgenthaler TI, Brown LR, Colby TV, Harper CM Jr, Coles DT. Thymoma.
Geisinger KR. Differential diagnostic considerations and potential pitfalls
Mayo Clin Proc 1993;68:1110–1123.
in fine-needle aspiration biopsies of the mediastinum. Diagn Cytopathol
Okumura M, Ohta M, Miyoshi S, et al. Oncological significance of WHO
1995;13:436–442.
histological thymoma classification. A clinical study based on 286
Panelli F, Erickson RA, Prasad VM. Evaluation of mediastinal masses by
patients. Jpn J Thorac Cardiovasc Surg 2002;50:189–194.
endoscopic ultrasound and endoscopic ultrasound-guided fine needle
Ritter JH, Wick MR. Primary carcinomas of the thymus gland. Semin Diagn
aspiration. Am J Gastroenterol 2001;96:401–408.
Pathol 1999;16:18–31.
Powers CN, Silverman JF, Geisinger KR, Frable WJ. Fine-needle aspiration
Sherman ME, Black-Schaffer S. Diagnosis of thymoma by needle biopsy.
biopsy of the mediastinum. A multi-institutional analysis. Am J Clin
Acta Cytol 1990;34:63–68.
Pathol 1996;105:168–173.
Shin HJ, Katz RL. Thymic neoplasia as represented by fine needle aspira-
Shabb NS, Fahl M, Shabb B, Haswani P, Zaatari G. Fine-needle aspiration
tion biopsy of anterior mediastinal masses. A practical approach to the
of the mediastinum: a clinical, radiologic, cytologic, and histologic
differential diagnosis. Acta Cytol 1998;42:855–864.
study of 42 cases. Diagn Cytopathol 1998;19:428–436.
Suster S, Moran CA. Primary thymic epithelial neoplasms showing com-
Singh HK, Silverman JF, Powers CN, Geisinger KR, Frable WJ. Diagnostic
bined features of thymoma and thymic carcinoma. A clinicopathologic
pitfalls in fine-needle aspiration biopsy of the mediastinum. Diagn
study of 22 cases. Am J Surg Pathol 1996;20:1469–1480.
Cytopathol 1997;17:121–126.
Tao LC, Pearson FG, Cooper JD, Sanders DE, Weisbrod G, Donat EE. Cyto-
Sterrett G, Whitaker D, Shilkin KB, Walters MN. The fine needle aspiration
pathology of thymoma. Acta Cytol 1984;28:165–170.
cytology of mediastinal lesions. Cancer 1983;51:127–135.
Wakely PE Jr. Cytopathology-histopathology of the mediastinum: epithe-
lial, lymphoproliferative, and germ cell neoplasms. Ann Diagn Pathol Germ Cell Tumors
2002;6:30–43.
Wakely PE Jr. Cytopathology-histopathology of the mediastinum II. Chhieng DC, Lin O, Moran CA, et al. Fine-needle aspiration biopsy of
Mesenchymal, neural, and neuroendocrine neoplasms. Ann Diagn Pathol nonteratomatous germ cell tumors of the mediastinum. Am J Clin Pathol
2005;9:24–32. 2002;118:418–424.
Kiffer JD, Sandeman TF. (Primary malignant mediastinal germ cell tumours:
a literature review and a study of 18 cases. Australas Radiol 1999;
Thymic Lesions 43:58–68.
Kwon MS. Aspiration cytology of mediastinal seminoma: report of a case
Ali SZ, Erozan YS. Thymoma. Cytopathologic features and differential with emphasis on the diagnostic role of aspiration cytology, cell block
diagnosis on fine needle aspiration. Acta Cytol 1998;42:845–854. and immunocytochemistry. Acta Cytol 2005;49:669–672.

Ch007-F06731.indd 217 10/26/2006 10:29:01 AM

 218
Moran CA, Suster S, Koss MN. Primary germ cell tumors of the mediasti-
num: III. Yolk sac tumor, embryonal carcinoma, choriocarcinoma, and
combined nonteratomatous germ cell tumors of the mediastinum – a
clinicopathologic and immunohistochemical study of 64 cases. Cancer
1997;80:699–707.
Moran CA, Suster S, Przygodzki RM, Koss MN. Primary germ cell tumors
of the mediastinum: II. Mediastinal seminomas – a clinicopathologic
and immunohistochemical study of 120 cases. Cancer 1997;80:691–
698.
Motoyama T, Yamamoto O, Iwamoto H, Watanabe H. Fine needle aspiration
cytology of primary mediastinal germ cell tumors. Acta Cytol 1995;39:
725–732.
Weidner N. Germ-cell tumors of the mediastinum. Semin Diagn Pathol
1999;16:42–50.
Thymic Neuroendocrine (Carcinoid) Tumors
Caceres W, Baldizon C, Sanchez J. Carcinoid tumor of the thymus: a unique
neoplasm of the mediastinum. Am J Clin Oncol 1998;21:82–83.
Moran CA, Suster S. Spindle-cell neuroendocrine carcinomas of the thymus
(spindle-cell thymic carcinoid): a clinicopathologic and immunohisto-
chemical study of seven cases. Mod Pathol 1999;12:587–591.
Nichols GL Jr, Hopkins MB 3rd, Geisinger KR. Thymic carcinoid. Report of
a case with diagnosis by fine needle aspiration biopsy. Acta Cytol
1997;41:1839–1844.
Slagel DD, Powers CN, Melaragno MJ, Geisinger KR, Frable WJ, Silverman
JF. Spindle-cell lesions of the mediastinum: diagnosis by fine-needle
aspiration biopsy. Diagn Cytopathol 1997;17:167–176.
Wick MR, Scheithauer BW. Thymic carcinoid. A histologic, immunohisto-
chemical, and ultrastructural study of 12 cases. Cancer 1984;53:
475–484.
Mediastinal Lymphomas
Friedman HD, Hutchison RE, Kohman LJ, Powers CN. Thymoma mimicking
lymphoblastic lymphoma: a pitfall in fine-needle aspiration biopsy
interpretation. Diagn Cytopathol 1996;14:165–169; discussion 169–
171.
Sheibani K, Nathwani BN, Winberg CD, et al. Antigenically defined sub-
groups of lymphoblastic lymphoma. Relationship to clinical presenta-
tion and biologic behavior. Cancer 1987;60:183–190.
Silverman JF, Raab SS, Park HK. Fine-needle aspiration cytology of primary
large-cell lymphoma of the mediastinum: cytomorphologic findings with
potential pitfalls in diagnosis. Diagn Cytopathol 1993;9:209–214; dis-
cussion 214–215.
Strickler JG, Kurtin PJ. Mediastinal lymphoma. Semin Diagn Pathol
1991;8:2–13.
Yu GH, Salhany KE, Gokaslan ST, Cajulis RS, De Frias DV. Thymic epithelial
cells as a diagnostic pitfall in the fine-needle aspiration diagnosis
of primary mediastinal lymphoma. Diagn Cytopathol 1997;16:460–
465.
Ch007-F06731.indd 218
FINE NEEDLE ASPIRATION CYTOLOGY
Neurogenic Tumors
de Montpreville VT, Mussot S, Gharbi N, Dartevelle P, Dulmet E. Paragan-
glioma with ganglioneuromatous component located in the posterior
mediastinum. Ann Diagn Pathol 2005;9:110–114.
Geisinger KR. Differential diagnostic considerations and potential pitfalls
in fine-needle aspiration biopsies of the mediastinum. Diagn Cytopathol
1995;13:436–442.
Khanlou H, Khanlou N, Eiger G. Schwannoma of posterior mediastinum: a
case report and concise review. Heart Lung 1998;27:344–347.
Marchevsky AM. Mediastinal tumors of peripheral nervous system origin.
Semin Diagn Pathol 1999;16:65–78.
Slagel DD, Powers CN, Melaragno MJ, Geisinger KR, Frable WJ, Silverman
JF. Spindle-cell lesions of the mediastinum: diagnosis by fine-needle
aspiration biopsy. Diagn Cytopathol 1997;17:167–176.
Strollo DC, Rosado-de-Christenson ML, Jett JR. Primary mediastinal
tumors: part II. Tumors of the middle and posterior mediastinum. Chest
1997;112:1344–1357.
Topcu S, Alper A, Gulhan E, Kocyigit O, Tastepe I, Cetin G. Neurogenic
tumours of the mediastinum: a report of 60 cases. Can Respir J
2000;7:261–265.
Wakely PE Jr. Cytopathology-histopathology of the mediastinum II. Mes-
enchymal, neural, and neuroendocrine neoplasms. Ann Diagn Pathol
2005;9:24–32.
Metastatic Lesions
Al-Haddad M, Wallace MB. Molecular diagnostics of non-small cell lung
cancer using mediastinal lymph nodes sampled by endoscopic ultra-
sound-guided needle aspiration. Cytopathology 2006;17:3–9.
Bavi P, Shet T, Gujral S. Malignant melanoma of mediastinum misdiag-
nosed as a spindle cell thymoma in a fine needle aspirate: a case report.
Acta Cytol 2005;49:424–426.
Blanco N, Kirgan DM, Little AG. Metastatic squamous cell carcinoma of
the mediastinum with unknown primary tumor. Chest 1998;114:938–
940.
Duwe BV, Sterman DH, Musani AI. Tumors of the mediastinum. Chest
2005;128:2893–2909.
Lau CL, Bentley RC, Gockerman JP, Que LG, D’Amico TA. Malignant mela-
noma presenting as a mediastinal mass. Ann Thorac Surg 1999;67:
851–852.
Saad RS, Landreneau RJ, Liu Y, Silverman JF. Utility of immunohisto-
chemistry in separating thymic neoplasms from germ cell tumors and
metastatic lung cancer involving the anterior mediastinum. Appl Immu-
nohistochem Mol Morphol 2003;11:107–112.
Singh HK, Silverman JF, Powers CN, Geisinger KR, Frable WJ. Diagnostic
pitfalls in fine-needle aspiration biopsy of the mediastinum. Diagn
Cytopathol 1997;17:121–126.
Sinner WN. Directed fine needle biopsy of anterior and middle mediastinal
masses. Oncology 1985;42:92–96.
Sterrett G, Whitaker D, Shilkin KB, Walters MN. The fine needle aspiration
cytology of mediastinal lesions. Cancer 1983;51:127–135.
10/26/2006 10:29:02 AM
 8 Liver
Syed Z Ali • Natasha Rekhtman

Along with the pancreas, the liver is one of the most In our experience, benign hepatic entities are often
common visceral organs targeted by fine needle aspira- more taxing to diagnose on FNA, perhaps because they
tion (FNA). The usual clinical scenario is that of an are rarer than malignancies in the liver and also because
asymptomatic patient presenting with a solitary or mul- of a relative lack of characteristic findings on cytopatho-
tiple liver lesions. In a significant number of cases, there logic evaluation (Table 8-5).
is no prior history of malignancy and the liver lesion is
a totally incidental finding, therefore adding to the diag-
nostic challenge when such lesion is aspirated.
Liver is approached through a percutaneous trans- NON-NEOPLASTIC DISEASES OF THE LIVER
abdominal route with radiologic guidance. At Johns
Hopkins, almost all liver lesions are aspirated via ultra-
sound guidance, which is a much faster and safer pro-
cedure than computed tomography (CT) guidance and MACROREGENERATIVE NODULE
offers real-time visualization of the needle positioning
and aspiration. All FNAs are evaluated on-site by a
cytopathologist for adequacy. Material is triaged for CLINICAL FEATURES
ancillary studies (flow cytometry, microbial culture,
etc.) and, if needed and technically feasible, the radio- Macroregenerative nodules (MRNs), also referred to as
logist is asked for tissue core biopsy as well. As in other adenomatous hyperplasia, are, in essence, large regen-
body sites, it is extremely important to be familiar with erative nodules arising in cirrhotic livers. Some authors
the appearances of normal cells comprising a liver FNA have applied the size cut-off of 0.8 cm to distinguish
(Table 8-1; Figs 8-1 & 8-2). these lesions from typical nodules of macronodular cir-
It is imperative to be aware of the exact location of rhosis. MRNs are found in up to 50% of cirrhotic livers.
the lesion in the liver since unusual cell types (repre- MRNs are usually asymptomatic and are discovered
senting needle contaminants; Table 8-2) can be seen in incidentally during the radiographic surveillance of
addition to hepatic tissue; for example, gastric-type epi- patients with cirrhosis. Serum alpha-fetoprotein (AFP)
thelium may be observed in lesions of the left hepatic is not increased.
lobe if the needle traverses the stomach wall, or respira- MRNs are present in the population with cirrhosis:
tory-type epithelium may be seen in lesions located deep incidence increases with advancing age, and men are
in the hepatic dome (Fig. 8-3). Another uncommon cell
type which may add to diagnostic confusion to an inex-
perienced interpreter is mesothelium, often seen as a
flat, monolayered sheet with characteristic spacing in
between individual cells. MACROREGENERATIVE NODULE – DISEASE FACT SHEET
Liver FNA is an extremely safe procedure in experi-
Incidence
enced hands, with rare morbidity (Table 8-3). Mortality
៉ Present in up to 50% of cirrhotic livers
is also extremely rare, having been reported in the
literature as isolated case reports. In our experience,
Gender and Age Distribution
we have seen only two cases of hepatic FNA that led
៉ Reflects the demographic of cirrhosis
to significant intraperitoneal bleeding requiring some
៉ After age 60 in the USA; younger age in Asia and Africa
amount of intensive care. Both cases had occurred in
៉ Men > women (worldwide)
patients with large hepatocellular carcinomas. A recent
review of the literature on this subject revealed a mor- Prognosis
tality rate less than 0.1%.
៉ Premalignant potential is controversial
There are relatively rare contraindications for liver ៉ Up to 25% of lesions regress
FNA in view of an overall excellent safety profile of this
procedure (Table 8-4).
219

Ch008-F06731.indd 219 10/26/2006 10:30:03 AM

 220 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 8-1 FIGURE 8-3

Normal liver. Small fragment of hepatocytes with polygonal cell shapes, Needle contamination. Diaphragmatic skeletal muscle in an FNA of a
granular cytoplasm, and small nucleoli. Focal bile staining is evident. hepatic dome lesion. Diff Quik stain, intermediate power.
Papanicolaou stain, high power.

TABLE 8-2
Normal Non-liver Cell Component
(Needle Contaminants)

• Mesothelium
• Respiratory epithelium
• Gastrointestinal tract epithelium
• Skeletal muscle and skin

TABLE 8-3
Complications of Hepatic FNA (n = number of cases
FIGURE 8-2 reported in the English-language literature)
Normal liver. Biliary epithelium with a more cohesive appearance of the
cells, high N/C ratio, and glandular formations (middle of the field). • Tumor seeding of the needle tract (n = 12):
Numerous hepatocytes are present in the background. Diff Quik stain, • Hepatocellular carcinoma [HCC] (n = 9)
high power. • Metastatic colonic adenocarcinoma (n = 3)
• Bleeding (n = 8):
• HCC (n = 5)
• Hemangioma (n = 2)
• Angiosarcoma (n = 1)
TABLE 8-1 • Bile peritonitis (n = 1)
Liver – Normal Cytologic Constituents • Carcinoid crisis (n = 1)
• Lymphorrhea (n = 1)
• Biliary venous fistula (n = 1)
• Hepatocytes
• Sudden hypoglycemia – clear cell HCC (n = 1)
• Biliary epithelium
• Endothelium
• Kupffer’s cells
• Pigments:
• Bile
• Hemosiderin
• Lipofuscin

Ch008-F06731.indd 220 10/26/2006 10:30:04 AM

 CHAPTER 8 Liver
TABLE 8-4
Contraindications of Hepatic FNA
• Bleeding diathesis
• Difficult anatomic location of the lesion (such as close
proximity to vessels)
• Hydatid disease
TABLE 8-5
Benign Hepatic Diseases on FNA
• Non-neoplastic:
• Granulomatous disease
• Infection:
• Hydatid disease
• Other (amebic, schistosomiasis)
• Congenital cysts
• Focal nodular hyperplasia (FNH)
• Cirrhosis
• Benign neoplasm:
• Hepatic adenoma
• Hemangioma
affected more frequently than women. The premalig-
nant potential of MRNs is a controversial subject. It is
generally believed that MRNs are not associated with
an increased risk of hepatocellular carcinoma (HCC),
and up to 25% of lesions regress on radiographic follow-
up. MRNs may pose a challenge differentiating them
clinically and pathologically from HCC. Patients with
MRNs are followed with more frequent radiographic
studies.
PATHOLOGIC FEATURES
Grossly, MRNs are similar in appearance to the sur-
rounding liver, although more pronounced bile staining
may be present. Lesions are commonly multiple, and
can measure over 5 cm. MRNs are circumscribed by a
rim of fibrous tissue, analogous to the usual smaller
nodules in macronodular cirrhosis.
Histologically, MRNs are indistinguishable from the
surrounding liver: cell plates are of normal thickness
(less than two cells), reticulin network is intact, and
cytologic atypia is absent or minimal. Portal tracts are
present, although they may be decreased in number and
usually show architectural distortion. Cytopathologic
findings are non-specific and may require intact tissue
architecture for a definitive diagnosis. Therefore, in
this setting, a core biopsy accompanying the FNA is
extremely helpful (Figs 8-4 & 8-5).
Ch008-F06731.indd 221
221
FIGURE 8-4
Nodular regenerative hyperplasia. Disorganized fragment of liver tissue.
Cells display prominent nucleoli. However, there is lack of vascular
proliferation and single cells. Papanicolaou stain, low power.
MACROREGENERATIVE NODULE – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Reactive hepatocytes (high N/C ratio, often prominent nucleoli)
៉ Higher than normal amount of biliary epithelium
៉ Varying amount of fibroconnective tissue fragments
៉ Marked focal atypia of hepatocytic or biliary epithelium
៉ Varying amount of lympho-mononuclear cells
៉ Cholestasis
៉ Focal necrosis (rare)
Histopathologic Findings
៉ Gross:
៉ Usually multiple lesions
៉ Can measure over 5 cm
៉ Background cirrhotic liver
៉ Microscopic:
៉ Indistinguishable from surrounding liver
៉ Normal cell plates (<2 cells thick)
៉ Reticulin network intact
៉ Cytologic atypia absent or minimal
៉ Portal tracts present but decreased and distorted
Ancillary Studies
៉ CD34: no endothelial cell wrapping (unlike hepatocellular
carcinoma [HCC])
៉ Reticulin stain: reticulin framework intact (unlike HCC)
Differential Diagnosis and Pitfalls
៉ Well-differentiated HCC: like MRN, arises in cirrhotic liver;
increased cell plate thickness (>2 cells thick); disrupted
reticulin framework; cytologic atypia present, but may be
minimal
៉ Focal nodular hyperplasia (FNH) and hepatocellular adenoma
(HA): distinction impossible based on cytology alone; arise in
non-cirrhotic liver; FNH – central scar, fibrous septae with bile
ducts and infl ammation; HA – history of oral contraceptive use,
absent bile ducts
10/26/2006 10:30:05 AM
 222
FIGURE 8-5
Nodular regenerative hyperplasia. Trabecular arrangement of hepato-
cytes displaying atypia. Although the N/C ratio is low, the cells have
macronucleoli. Papanicolaou stain, high power.
ANCILLARY STUDIES
Immunoperoxidase staining has a limited role. CD34
may be used to help differentiate MRN from HCC:
CD34 highlights endothelial cell wrapping in HCC,
whereas this feature is absent in MRNs. Some studies
(including our own) have demonstrated that expression
of proliferation markers (Ki67 and PCNA) and p53 is
higher in HCC as compared to MRN.
Special stain for reticulin is helpful in distinguishing
MRN from HCC: reticulin stain highlights a disrupted
reticulin network in HCC, whereas reticulin network in
MRN is preserved.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The most important differential diagnosis for MRN is
a well-differentiated hepatocellular carcinoma (WD-
HCC). Both MRN and WD-HCC arise in a cirrhotic
liver and may look identical radiographically. The
distinction is based primarily on an increased cell-
plate thickness and accompanying loss of reticulin
framework in HCC. Cytologic atypia, if present, favors
HCC, but atypical features may be subtle in well-
differentiated cases.
MRN is difficult or impossible to definitively distin-
guish from hepatocellular adenoma (HA) and focal
nodular hyperplasia (FNH) based on cytologic examina-
tion alone. Clinical features may be helpful: in contrast
to MRN, both FNH and HA arise in non-cirrhotic liver.
In addition, FNH frequently displays a central scar,
which may be apparent radiographically. Finally, bile
Ch008-F06731.indd 222
FINE NEEDLE ASPIRATION CYTOLOGY
ducts are absent in HA, whereas they are present in
MRN.
FOCAL NODULAR HYPERPLASIA
CLINICAL FEATURES
An uncommon benign lesion, focal nodular hyperpla-
sia (FNH) is characterized by hyperplastic hepatocytes
and associated stellate scar. The lesion occurs predomi-
nantly in adult women (3rd to 5th decades of life; M : F
= 8 : 1); however, cases have been reported in children.
It has been recently suggested that FNH results from
a vascular malformation which causes a hyperplastic
hepatocellular reaction. A histopathogenetic relation-
ship with oral contraceptives (OCPs) has been sug-
gested. In contrast to hepatocellular adenoma, OCPs
are not directly related to the initial development of
FNH. However, it appears that OCPs cause subsequent
increase in vascularity and enlargement of FNH, which
leads to an increased risk of rupture. Approximately
80% of FNH are solitary, and 80% are clinically asymp-
tomatic. In symptomatic cases, the clinical presentation
includes palpable mass, pain or discomfort, and, rarely,
manifestations of portal hypertension. Unlike hepato-
cellular adenoma, FNH rarely if ever results in hemo-
peritoneum. Liver function tests (including serum
AFP) are within normal limits.
FNH is treated by local or segmental liver resection.
Small lesions or lesions that are deep seated often do not
require surgical intervention. Prognosis is excellent and
risk of complications (rupture or hemorrhage) for unre-
sected lesions is extremely low. Radiologic studies may
show the central scar in 65% of the cases. Enhanced
magnetic resonance imaging (MRI) is considered the
imaging modality of choice for FNH, with a high sensi-
tivity and specificity, often making a tissue diagnosis
unnecessary in these cases.
FOCAL NODULAR HYPERPLASIA – DISEASE FACT SHEET
Incidence
៉ Uncommon
Gender and Age Distribution
៉ Male to female ratio is 8 : 1
៉ Adults (usually 30–50 years old)
Clinical Features
៉ Normal AFP
Prognosis
៉ Benign; no known association with hepatocellular carcinoma
៉ Hemoperitoneum rare (unlike hepatocellular adenoma)
10/26/2006 10:30:05 AM
 CHAPTER 8 Liver 223

PATHOLOGIC FEATURES

Grossly, FNH has a very characteristic appearance:

circumscribed, bulging, lobulated, with a firm to
rubbery consistency and multinodular cut surface due
to multiple stellate scars. Most lesions present as a soli-
tary mass and measure less than 5 cm.
Histologic examination shows thick fibrous bands
dividing hyperplastic but normal-appearing hepatocytes
into nodules. Fibrous septae contain prominent bile
ductule proliferations and inflammatory infiltrate.
Hepatocyte plates are not thickened (one to two cells
thick). No portal tracts or central veins are present
within the hepatocellular nodules.
Cytopathologic evaluation does not show any specific
characteristics. When FNH is suspected on radiologic
and clinical examination, the cytopathologic analysis
can only be supportive of such lesion. In our experience, FIGURE 8-6
Focal nodular hyperplasia. Abundant fibrosis representing sampling of
the central stellate scar and fragments of reactive hepatocytes. Papa-
nicolaou stain, low power.

FOCAL NODULAR HYPERPLASIA – PATHOLOGIC FEATURES

Cytopathologic Findings
៉ Normal-appearing hepatocytes (most often large fragments)
៉ Biliary epithelium (slightly increased in amount)
៉ Fragments of fibrous tissue
៉ Absence of endothelial/vascular proliferation
៉ Lack of atypia (as opposed to cirrhotic liver)
៉ Cell block/tissue core may be extremely helpful

Histopathologic Findings
៉ Gross:
៉ Focal lesion in the background of non-cirrhotic liver
៉ Central stellate scar is often present
៉ Microscopic:
៉ Bands of fibrosis that separate bland hepatocytes into
nodules
៉ Abnormally thick-walled vessels often in the center of the
lesion FIGURE 8-7
៉ Infl ammation and bile ductule proliferation within the fibrous
Focal nodular hyperplasia. Smear shows abundance of biliary epithelium
septae
and unremarkable hepatocytes. The findings are non-specific. Diff Quik
៉ Cell plates are not thickened (1–2 cells)
stain, intermediate power.
៉ No portal tracts or central veins

Ancillary Studies
៉ CD34: no endothelial cell wrapping (unlike hepatocellular
carcinoma [HCC]) rarely if ever is a definitive diagnosis of FNH is made
៉ Reticulin stain: reticulin framework intact (unlike HCC)
on cytology alone. Cytomorphologic changes, therefore,
are non-specific (Figs 8-6 & 8-7).
Differential Diagnosis and Pitfalls
៉ Well-differentiated HCC: arises in cirrhotic liver; increased cell
plate thickness (>2 cells); disrupted reticulin framework;
cytologic atypical present, but may be minimal
ANCILLARY STUDIES
៉ Macroregenerative nodule: arises in cirrhotic liver; cannot be
distinguished from focal nodular hyperplasia based on cytology
alone
As for MRN, CD34 may help differentiate FNH from
៉ Hepatocellular adenoma: like FNH, arises in non-cirrhotic liver;
strong association with oral contraceptive use; cannot be
well-differentiated hepatocellular carcinoma (WD-
distinguished from FNH based on cytology alone HCC). As is the case for MRN, reticulin may be helpful
in differentiating FNH (reticulin framework intact)
from WD-HCC (reticulin framework disrupted).

Ch008-F06731.indd 223 10/26/2006 10:30:06 AM

 224
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Similarly to MRN, the most important differential
diagnosis for FNH is WD-HCC. The distinction is
based predominantly on cytologic atypia in HCC. In
addition, unlike WD-HCC, FNH has an intact reticulin
framework and a normal cell-plate thickness.
Based on cytologic parameters alone, FNH cannot be
distinguished from hepatocellular adenoma (HA) and
MRN in cirrhosis. Clinical features, such as background
cirrhosis (favors MRN), history of OCP use (favors
HA), or presence of stellate scar (favors FNH), may be
helpful in this differential diagnosis.
CYSTIC LESIONS OF THE LIVER
These are distinctly rare compared to more common
solid mass-forming diseases and may include non-
neoplastic diseases, i.e. pseudotumors (e.g. parasitic
cysts) and, rarely, cystic neoplasms (Tables 8-6 & 8-7).
HYDATID DISEASE
CLINICAL FEATURES
Hydatid disease is caused by the flat tapeworm Echi-
nococcus granulosus. It is the most common cause of
hepatic cysts worldwide, particularly in the Middle
East. In the United States, the disease primarily affects
immigrants. Approximately 75% of infected patients
develop hepatic cysts, which may be multiple and pre-
dominantly located in the right hepatic lobe. Hydatid
HYDATID DISEASE – DISEASE FACT SHEET
Incidence
៉ Most common hepatic cysts worldwide
៉ A common disease in the Middle East
៉ Primarily affects immigrant population in the United States
៉ Disease is caused by Echinococcus granulosus
Gender and Age Distribution
៉ No gender predilection
៉ Any age can be affected
Treatment
៉ Surgical removal or percutanous drainage of cyst
៉ Treatment of the cyst with scolicidal agents
៉ Systemic therapy with antihelminthic medication
Ch008-F06731.indd 224
FINE NEEDLE ASPIRATION CYTOLOGY
TABLE 8-6
Cystic Lesions of the Liver
• Congenital/simple cyst
• Ciliated foregut cyst
• Hydatid cyst
• Abscess
• Granulomatous disease
• Cystic neoplasms
TABLE 8-7
Parasitic Cysts of the Liver
• Hydatid cyst (Echinococcus granulosus)
• Schistosoma mansoni
• Entamoeba histolytica
disease can involve all ages and there is no gender
predilection. Cysts are asymptomatic until they enlarge
to the size of at least 10 cm. Clinical manifestations of
hepatic cysts include hepatomegaly, obstructive jaun-
dice, and cholangitis. If untreated, infection can be
fatal. Treatment is surgical removal of cysts or percu-
tanous drainage and treatment of the cyst with scoli-
cidal agents such as hypertonic saline or alcohol.
The treatment is usually in parallel with the use of
antihelminthic medication to prevent recurrence of
disease.
Ultrasonography of the liver lesions demonstrates
cystic membranes, septa, and hydatid sand. CT and MRI
scan show cyst wall calcification and cyst wall defects,
as well as the passage of contents through a defect.
PATHOLOGIC FEATURES
Grossly, the cysts are usually unilocular and solitary.
Circular ‘egg-shell’ calcification of the outer layer of the
cyst is present in 25% of cases.
Histologically, the cyst contains a laminated mem-
brane and is filled with colorless fluid with acellular
debris and occasional protoscolices (future heads of the
adult tapeworm) and loose hooklets. Dense fibroinflam-
matory tissue with prominent eosinophils surrounds
the cyst. Cytopathologic findings on FNA include frag-
ments of scolices or hooklets (Figs 8-8 & 8-9). The
hooklets stain positive for modified acid-fast bacilli
(AFB) stain. Cyst wall may be highlighted by periodic
acid–Schiff (PAS) and Gomori methenamine silver
(GMS).
10/26/2006 10:30:07 AM
 CHAPTER 8 Liver 225

FIGURE 8-8 FIGURE 8-9

Hydatid disease. ‘Shark tooth’ appearance of a loose hooklet in a dirty Hydatid disease. Dense granular debris with an embedded protoscolex.
smear background. Diff Quik stain, high power. Papanicolaou stain, high power.

CILIATED HEPATIC FOREGUT CYST

HYDATID DISEASE – PATHOLOGIC FEATURES

CLINICAL FEATURES
Cytopathologic Findings
៉ Scolices or hooklets Ciliated foregut cysts are extremely rare. Only several
៉ Hooklets stain positive with modified AFB stain dozen case reports were reviewed by the Armed Forces
Institute of Pathology (AFIP). The average age is 48
Histopathologic Findings years, with an equal incidence in males and females.
៉ Gross: Malignant transformation is exceptionally rare. Only
៉ Usually solitary, unilocular
one case of a squamous cell carcinoma arising in a
៉ ’Egg-shell’ calcifications of the cyst wall (25%)
ciliated foregut cyst has been reported.
៉ Microscopic:
៉ Laminated cyst membrane
៉ Cyst fl uid with acellular debris and occasional protoscolices
and loose hooklets
PATHOLOGIC FEATURES
Ancillary Studies
៉ PAS and GMS: highlight cyst wall
Ciliated foregut cyst represents a developmental
៉ AFB: highlights hooklets
anomaly. It is thought to arise from displaced embry-
onic foregut differentiating toward bronchial epithe-
Differential Diagnosis and Pitfalls
lium. Ciliated foregut cyst is usually subcapsular,
៉ Other parasitic diseases: Schistosoma, Clonorchis, Entamoeba
solitary, and unilocular. It is lined by respiratory-type
៉ Non-parasitic solitary cysts: simple unilocular cyst, ciliated
foregut cyst, pseudocyst, neoplastic cysts (bile duct
epithelium consisting of ciliated columnar and mucous
cystadenoma and bile duct cystadenocarcinoma) cells. Cyst fluid is clear or, less commonly, mucinous.

CILIATED HEPATIC FOREGUT CYST – DISEASE FACT SHEET

Incidence
DIFFERENTIAL DIAGNOSIS AND PITFALLS ៉ Extremely rare

Gender and Age Distribution

The differential diagnosis includes other parasitic dis-
៉ Equal gender distribution
eases that present as hepatic mass lesions, including ៉ Average age 48 years
Schistosoma, Clonorchis, and Entamoeba. Non-parasitic
solitary cysts are also considered in the differential Prognosis
diagnosis. These include simple unilocular cyst, ciliated ៉ Malignant transformation is exceedingly rare
foregut cyst, pseudocysts, and neoplastic cysts (bile duct
cystadenoma and bile duct cystadenocarcinoma).

Ch008-F06731.indd 225 10/26/2006 10:30:07 AM

 226 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 8-10
Ciliated foregut cyst. Fragments of glandular epithelium with focal
ciliated cell differentiation (arrow). Possibility of bronchial epithelial
contamination should be considered in such cases before rendering a
definitive diagnosis. Papanicolaou stain, high power.
CILIATED HEPATIC FOREGUT CYST – PATHOLOGIC FEATURES
FIGURE 8-11
Ciliated foregut cyst. Cell block section shows the partially intact cyst
wall with fibrous capsule overlying hepatic tissue. Cells are pseudo-
stratified with ciliated lining. H&E stain, low power.
tamination by bronchial tissue (in subdiaphragmatic
lesions) should also be kept in mind.

Cytopathologic Findings
៉ Clear to viscid material
BENIGN TUMORS OF THE LIVER
៉ Clusters and fragments of tall columnar cells, often with well-
defined ciliated borders
៉ Numerous foamy macrophages HEMANGIOMA (CAVERNOUS HEMANGIOMA)
៉ Mucinous background

Histopathologic Findings CLINICAL FEATURES

៉ Gross:
៉ Subcapsular, solitary, and unilocular
៉ Microscopic: Hemangioma is the most common benign hepatic tumor
៉ Lined by respiratory-type epithelium (ciliated columnar and and the liver is the most common visceral site of
mucous cells) hemangioma. The lesion is usually small and asymp-
៉ Clear, less commonly mucinous, cyst fl uid
tomatic, discovered incidentally during radiographic
evaluation for other diseases. Hemangiomas are found
Differential Diagnosis and Pitfalls
in 1–7% of autopsies. Hemangioma may present at any
៉ Other solitary hepatic cysts: simple unilocular cyst, pseudocyst,
age, with the mean age at diagnosis being 46 years.
bile duct cystadenoma and bile duct cystadenocarcinoma,
parasitic cysts (e.g. echinococcal)
They are more commonly found in women than in

HEMANGIOMA (CAVERNOUS HEMANGIOMA) –

On FNA, the aspirate reveals clear to viscid material. DISEASE FACT SHEET
Clusters of tall columnar cells, often with well-defined
ciliated borders, are noted, as well as numerous foamy Incidence
macrophages, often in a mucinous background (Figs ៉ Most common benign hepatic tumor
8-10 & 8-11).
Gender and Age Distribution
៉ More common in women
៉ Any age (mean age at diagnosis, 46 years)
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Prognosis and Treatment
៉ Usually asymptomatic, discovered incidentally
The differential diagnosis for ciliated foregut cyst
៉ Spontaneous rupture is very uncommon
includes other solitary hepatic cysts: simple unilocular ៉ No resection required for asymptomatic hemangioma
cyst, pseudocyst, bile duct cystadenoma, and bile duct
cystadenocarcinoma. The possibility of needle con-

Ch008-F06731.indd 226 10/26/2006 10:30:08 AM

 CHAPTER 8 Liver 227

men. Spontaneous rupture is a very uncommon com-

plication of hemangiomas, occurring predominantly
with giant hemangiomas (>4 cm in size). Asymptom-
atic hemangiomas do not require surgical resection.

PATHOLOGIC FEATURES

Hemangiomas are typically solitary, less often multiple.

Most commonly they are located in a subcapsular
region. Lesions are grossly dark red with a spongy
consistency.
Histologically, hemangiomas are characterized by
anastomosing dilated thin-walled vessels, which may
have intramural thrombi. Vessels are lined by flat bland-
appearing endothelial cells. Areas of central scarring
and hyalinization are typical. Large ‘feeder vessels’ are FIGURE 8-12
occasionally present at the periphery.
Hemangioma. Cohesive fragment of stromal tissue with uniform fusi-
Cytopathologic features include: extremely bloody form nuclei and background fresh blood. Vascular endothelium is not
smears (fresh blood), scant cellularity (‘unyielding usually evident. Papanicolaou stain, intermediate power.
FNAs’), fragments of acellular fibrous tissue, occasional
small, loosely arranged fragments of vascular endothe-

HEMANGIOMA (CAVERNOUS HEMANGIOMA) –

PATHOLOGIC FEATURES

Cytopathologic Findings
៉ Extremely bloody smears (fresh blood)
៉ Scant cellularity (‘unyielding FNAs’)
៉ Fragments of fibrous stromal tissue
៉ Occasional small fragments of vascular endothelium with
slender to plump, fusiform, often grooved nuclei, loosely
arranged
៉ Well-formed vascular channels rarely observed
៉ Cell blocks usually diagnostic

Histopathologic Findings
៉ Gross: FIGURE 8-13
៉ Usually solitary, but may be multiple
Hemangioma. Single, bland-appearing, spindled nuclei with long taper-
៉ Usually subcapsular ing cytoplasmic processes representing stromal cells of the tumor. Diff
៉ Appear dark red with a spongy consistency Quik stain, high power.
៉ Microscopic:
៉ Anastomosing dilated thin-walled vessels
៉ Bland fl at endothelial cells
៉ Intramural thrombi
lium with slender to plump, fusiform, often grooved
Ancillary Studies
nuclei. Well-formed vascular channels are rarely
observed. Cell blocks are usually diagnostic and depict
៉ Endothelial markers: CD34, CD31, Factor VIII, and Ulex
europaeus
tissue fragments with interconnecting vascular chan-
៉ Electron microscopy: Weibel-Palade bodies nels (Figs 8-12–8-14).

Differential Diagnosis and Pitfalls

៉ Other vascular lesions: angiosarcoma, epithelioid
hemangioendothelioma
ANCILLARY STUDIES
៉ Non-vascular spindle cell lesions: leiomyosarcoma,
granulomatous hepatitis, spindle cell-predominant
angiomyolipoma
The vascular nature of the lesion may be confirmed by
immunohistochemical stains including CD34, CD31,
and Factor VIII.

Ch008-F06731.indd 227 10/26/2006 10:30:09 AM

 228
FIGURE 8-14
Hemangioma. Core biopsy accompanying one of the aspiration samples
clearly displays interconnecting vascular lumina with attenuated endo-
thelial lining supported by a sclerotic stroma. H&E stain, low power.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis includes other spindle cell
lesions of the liver, most common of which are metastatic
leiomyosarcoma, granulomatous hepatitis, and spindle
cell-predominant angiomyolipoma. Other vascular
lesions, such as angiosarcoma and epithelioid heman-
gioendothelioma, are also in the differential diagnosis.
HEPATOCELLULAR ADENOMA
CLINICAL FEATURES
Overall, hepatocellular adenomas (HAs) are rare. The
estimated yearly incidence is 3 to 4 cases per 100,000
women with a history of long-term oral contraceptive
(OCP) use. Over 90% of HAs develop in women of
HEPATOCELLULAR ADENOMA – DISEASE FACT SHEET
Incidence
៉ Rare: per year, 3–4 cases per 100,000 women with a history of
long-term oral contraceptive (OCP) use
Gender and Age Distribution
៉ 90% of cases are women with a history of OCP use
៉ Most patients are under 30 years of age
Prognosis and Treatment
៉ May cause intratumoral and intraperitoneal hemorrhage
៉ 10% association with hepatocellular carcinoma
៉ Resection generally recommended
Ch008-F06731.indd 228
FINE NEEDLE ASPIRATION CYTOLOGY
reproductive age who have a history of OCP use. The
majority of these women are under 30 years of age. In
some cases, OCP use may be remote. Save for OCP use,
hepatic adenomas are seen in only a few other clinical
settings, including patients with androgen use and
patients with glycogen storage diseases (types I and
III).
Unlike focal nodular hyperplasia, HAs are more
often symptomatic. Complication of HA includes intra-
tumoral hemorrhage, which may present with acute
abdominal pain. In addition, HA may rupture through
the liver capsule, causing intraperitoneal hemorrhage
and shock.
Malignant transformation to HCC has traditionally
been considered highly unusual. However, more recent
studies estimate that about 10% of unresected HAs
evolve into HCC. Resection is generally recommended.
PATHOLOGIC FEATURES
HAs arise in non-cirrhotic livers and typically present
as solitary lesions, but occasionally patients may present
with multiple adenomas. Histopathologically, HAs
HEPATOCELLULAR ADENOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Could be entirely non-specific
៉ Abundant normal-appearing hepatocytes
៉ Lack of biliary epithelium, fibrous tissue fragments
៉ Lack of endothelial/vascular proliferation
Histopathologic Findings
៉ Gross:
៉ Solitary, rarely multiple
៉ Background non-cirrhotic liver
៉ Microscopic:
៉ Well-circumscribed, majority encapsulated
៉ Hepatocytes lack normal acinar structure: no portal tracts
៉ Atypia is absent or minimal
៉ Normal cell-plate thickness (<2 cells)
៉ Reticulin framework intact
Ancillary Studies
៉ CD34: no endothelial cell wrapping (unlike hepatocellular
carcinoma [HCC])
៉ Reticulin stain: reticulin framework intact (unlike HCC)
Differential Diagnosis and Pitfalls
៉ Well-differentiated HCC: arises in cirrhotic liver; increased cell
plate thickness (>2 cells); disrupted reticulin framework;
cytologic atypia present, but may be minimal
៉ Focal nodular hyperplasia: cannot be distinguished from
adenoma based on cytology alone; stellate scar; bile ducts
present in fibrous septae
៉ Macroregenerative nodule: arises in cirrhotic liver; cannot be
distinguished from adenoma based on cytology alone
10/26/2006 10:30:09 AM
 CHAPTER 8 Liver
FIGURE 8-15
Hepatic adenoma. Bland-appearing hepatocytes with a slightly disor-
ganized architecture and lacking the second cell component, i.e. biliary
epithelium. Diff Quik stain, low power.
consist entirely of hepatocytes and lack the normal
acinar architecture (bile ducts and central veins are
absent). HAs are well-circumscribed lesions, 75% are
encapsulated. Background liver is always non-cirrhotic.
HAs are composed of bland hepatocytes, indistinguish-
able from normal hepatocytes. Hepatocyte plates are
not thickened (one to two cells thick). Increased steato-
sis is a common feature.
Cytomorphologic features are often entirely non-
specific. Abundant normal-appearing hepatocytes are
seen. There is a total lack of biliary epithelium, fibrous
tissue fragments, and endothelial/vascular proliferation
(Fig. 8-15).
ANCILLARY STUDIES
As described above, CD34 may be useful to distinguish
HA from well-differentiated hepatocellular carcinoma
(WD-HCC): CD34 highlights endothelial cell wrapping
in WD-HCC, whereas this feature is absent in HA.
Preserved reticulin framework is helpful for distinguish-
ing HA from WD-HCC.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The main differential diagnosis for HA is WD-HCC.
The majority of WD-HCCs in the United States arise
in the background of cirrhosis, whereas HAs arise in
non-cirrhotic livers. In addition, cytologic atypia is a
feature of HCC but not HA. As discussed above, dis-
tinction of HA from focal nodular hyperplasia and
Ch008-F06731.indd 229
229
macroregenerative nodule is generally impossible based
on cytologic parameters alone.
BILE DUCT ADENOMA
CLINICAL FEATURES
Bile duct adenoma is found incidentally in approxi-
mately 30% of autopsies. These lesions are also fre-
quently discovered during intra-abdominal surgery for
other disease (70% in one study). Bile duct adenoma
can occur at any age (mean age, 55 years), with a similar
rate in men and women. Bile duct adenoma is always
discovered incidentally. The behavior of this lesion is
benign.
PATHOLOGIC FEATURES
Bile duct adenomas are solitary in the vast majority of
cases. Most of the lesions are subcapsular and measure
less than 0.5 cm, not exceeding 2 cm.
Histologically, bile duct adenomas are well circum-
scribed, but are not encapsulated. They are composed
of numerous angulated tubules with little or no lumen.
They are lined by a single layer of bland biliary epithe-
lium. No atypia or mitotic figures are present. Stroma
is generally fibrotic and hyalinized, often containing
numerous inflammatory cells. Cytomorphology reveals
abundant, normal-appearing biliary epithelium, often
admixed with benign hepatocytes (needle pick-up). Cell
blocks may be helpful.
ANCILLARY STUDIES
These have a limited role in the diagnosis.
BILE DUCT ADENOMA – DISEASE FACT SHEET
Incidence
៉ Very common
៉ Always discovered incidentally
៉ Found incidentally in ~30% of autopsies
Gender and Age Distribution
៉ No gender predilection
៉ Occurs at any age (mean age, 55 years)
Prognosis
៉ Behavior is benign
10/26/2006 10:30:10 AM
 230
BILE DUCT ADENOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Abundant, normal-appearing biliary epithelium
៉ Often admixed with benign hepatocytes (‘needle pick-up’)
៉ Cell blocks may be helpful
Histopathologic Findings
៉ Gross:
៉ Majority are solitary
៉ Usually subcapsular
៉ Usually <0.5 cm; always <2 cm
៉ Microscopic:
៉ Well circumscribed, but unencapsulated
៉ Angulated tubules with little or no lumen
៉ Lined by a single layer of bland biliary epithelium
៉ No atypia or mitotic figures
៉ Stroma fibrotic and hyalinized
៉ Prominent stromal infl ammation
៉ No intraluminal bile
Differential Diagnosis and Pitfalls
៉ Cholangiocarcinoma and metastatic adenocarcinoma: cytologic
atypia present; may be larger than 2 cm
៉ Von Meyenburg complexes: not a solitary lesion (present
diffusely); lumina dilated; contain intraluminal bile
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The main differential diagnoses for bile duct adenoma
are intrahepatic cholangiocarcinoma and metastatic
adenocarcinoma. The distinction is based on the pre-
sence of cytologic atypia in the carcinomas, but not bile
duct adenoma.
Von Meyenburg complexes may look histologically
and cytologically similar to bile duct adenoma. However,
unlike the solitary bile duct adenoma, von Meyenburg
complexes are present diffusely throughout the liver. In
addition, ductal lumina of von Meyenburg complexes
are generally dilated and contain bile plugs, whereas
these features are not present in bile duct adenoma.
HEPATOBILIARY CYSTADENOMA
CLINICAL FEATURES
Hepatobiliary cystadenoma accounts for 5% of solitary
hepatic cysts, with almost 95% developing in women.
Virtually all cases are from adults, with a mean age at
diagnosis of 45 years. Patients usually present with
abdominal pain and, occasionally, jaundice. Develop-
ment of malignancy is a recognized complication of
cystadenoma. Complete surgical resection is the treat-
ment of choice, which is generally curative. Delayed
recurrence has been reported.
Ch008-F06731.indd 230
FINE NEEDLE ASPIRATION CYTOLOGY
HEPATOBILIARY CYSTADENOMA – DISEASE FACT SHEET
Incidence
៉ Accounts for 5% of solitary hepatic cysts
Gender and Age Distribution
៉ 95% develop in women
៉ Adults (mean age, 45 years)
Prognosis and Treatment
៉ May develop into a malignancy
៉ May show delayed recurrence
៉ Complete surgical resection is recommended
PATHOLOGIC FEATURES
Hepatobiliary cystadenomas are generally solitary,
ranging in size from 2.5 to 28 cm. The cysts are
grossly multilocular and generally contain mucinous
secretions.
Benign hepatobiliary cystadenomas are lined by a
single layer of cuboidal or tall columnar mucinous
epithelium, similar to bile duct or gastric foveolar
epithelium. In women, the surrounding stroma shows
distinctive dense spindle cells, resembling ovarian
stroma. These stromal cells are immunoreactive for
estrogen receptors (ER) and progesterone receptors
(PR). These lesions are histologically identical to muci-
nous cystadenomas of other organs.
HEPATOBILIARY CYSTADENOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Single population of benign-appearing ductal epithelium
៉ Monotonous with uniform round nuclei devoid of nucleoli
៉ Mucinous differentiation with goblet cells
៉ Background of extracellular mucin
Histopathologic Findings
៉ Gross:
៉ Solitary
៉ Size range 2.5 to 28 cm
៉ Multilocular
៉ Contain mucinous secretions
៉ Microscopic:
៉ Mucinous epithelial lining (bile duct or gastric foveolar-type)
៉ Ovarian-type spindle cell stroma
៉ Epithelial cells are bland (no dysplasia)
Ancillary Studies
៉ Ovarian-type stroma: ER- and PR-reactive
Differential Diagnosis and Pitfalls
៉ Hepatobiliary cystadenocarcinoma: epithelial dysplasia; stromal
invasion; must be differentiated from metastases (pancreas,
ovary, appendix)
10/26/2006 10:30:10 AM
 CHAPTER 8 Liver
FIGURE 8-16
Hepatobiliary cystadenoma. A tight, three-dimensional fragment of
ductal-type epithelium. Cells have high N/C ratios, some appearing as
naked nuclei. Nuclei are round, uniform, and lack nucleoli. No back-
ground hepatocytes are seen. Papanicolaou stain, high power.
FIGURE 8-17
Hepatobiliary cystadenoma. Cell block section displays well-formed
glandular epithelium with mucinous differentiation. Numerous goblet
cells are seen. H&E stain, intermediate power.
On FNA, the smears show a single population of
benign-appearing ductal-type glandular epithelium.
Cells are monotonous with uniform round nuclei devoid
of nucleoli (Figs 8-16 & 8-17). Mucinous differentiation
is evident in the form of well-developed goblet cells.
Occasionally, the smears show extracellular background
mucin as well. Cellular necrosis is not observed.
ANCILLARY STUDIES
ER and PR are reactive in the ovarian-type stroma.
Ch008-F06731.indd 231
231
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Benign hepatobiliary cystadenoma should be distin-
guished from hepatobiliary cystadenocarcinoma. This
distinction is based on the presence of high-grade dys-
plasia and areas of overt stromal invasion in the carci-
noma. Metastases from other sites, such as pancreas,
ovary, or appendix, should be excluded.
INFLAMMATORY MYOFIBROBLASTIC TUMOR
(INFLAMMATORY PSEUDOTUMOR)
CLINICAL FEATURES
Inflammatory myofibroblastic tumor (IMT) is a lesion
of unclear etiology, currently thought to represent a
neoplastic process in most instances. IMT affects
various organs, most commonly lung. Liver is an
unusual site of involvement by IMT. IMT presents in
adults (mean age, 37 years; range, 10 months to 83
years), with a male to female ratio of 3 : 1. Patients may
present with symptoms of vague abdominal pain,
weight loss, and low-grade fever. Surgical resection is
curative. There are case reports of subsequent recur-
rence as malignant sarcoma.
PATHOLOGIC FEATURES
IMTs are generally solitary and well circumscribed,
varying in size from 1 to 25 cm. The tumor is composed
of plump spindle-shaped myofibroblasts, interspersed
with a prominent inflammatory infi ltrate consisting of
plasma cells, histiocytes, lymphocytes, and granulo-
cytes. Mitotic rate may be brisk, but no atypical mitotic
figures should be present.
On FNA, IMT shows hypercellular smears with an
admixture of various cell types (Figs 8-18 & 8-19),
including inflammatory cells with predominance of
plasma cells, fibroblastic proliferation, granulation tissue
INFLAMMATORY MYOFIBROBLASTIC TUMOR (INFLAMMATORY
PSEUDOTUMOR) – DISEASE FACT SHEET
Incidence
៉ Extremely rare (less than 90 cases reported)
Gender and Age Distribution
៉ Male to female ratio is 3 : 1
៉ Adults (mean age, 37 years; range, 10 months to 83 years)
Prognosis and Treatment
៉ Surgical resection is curative
៉ Case reports of recurrence as malignant sarcoma
10/26/2006 10:30:10 AM
 232 FINE NEEDLE ASPIRATION CYTOLOGY

INFLAMMATORY MYOFIBROBLASTIC TUMOR (INFLAMMATORY

PSEUDOTUMOR) – PATHOLOGIC FEATURES

Cytopathologic Findings
៉ Hypercellular smears with an admixture of various cell types
៉ Infl ammatory cells with predominance of plasma cells
៉ Fibroblastic proliferation, granulation tissue formation
៉ Atypical-appearing histiocytes with enlarged nuclei, occasional
nuclear grooves, and intranuclear inclusions

Histopathologic Findings
៉ Gross:
៉ Solitary
៉ Well circumscribed
៉ Size 1 to 25 cm
៉ Microscopic:
៉ Plump spindle cells
៉ Interspersed infl ammatory infiltrate (plasma cells, histiocytes,
FIGURE 8-18 lymphocytes, granulocytes)
Infl ammatory pseudotumor. Hypercellular smear with predominantly ៉ Mitotic figures allowed
single cells, comprised of a mixture of infl ammatory cells, macrophages, ៉ Should have no atypical mitoses
endothelial cells, and fibroblasts. Diff Quik stain, intermediate power.
Ancillary Studies
៉ ALK-negative (unlike IMT of some other organs, e.g. bladder)
៉ Aberrant cytokeratin reactivity

Differential Diagnosis and Pitfalls

៉ Spindle cell sarcomas (e.g. leiomyosarcoma): frank
pleomorphism; atypical mitotic figures

DIFFERENTIAL DIAGNOSIS AND PITFALLS

Many hepatic masses of various types may be associ-

ated with a brisk inflammatory response and these
lesions should be differentiated from IMT. Particularly,
IMT should be distinguished from spindle-cell sarco-
mas (e.g. leiomyosarcoma). Presence of frank pleomor-
phism and atypical mitotic features favors the latter.
FIGURE 8-19
Infl ammatory pseudotumor. Endothelial cells, macrophages with grooved
nuclei, and infl ammatory cells with predominance of plasma cells.
Papanicolaou stain, high power. MALIGNANT TUMORS OF THE LIVER
formation, and atypical-appearing histiocytes with enlar-
ged nuclei, occasional nuclear grooves, and intranuclear
Primary malignant and metastatic/secondary malig-
inclusions. Fibroblastic proliferation with mitoses may
nant tumors of the liver are listed in Table 8-8 and
mimic mesenchymal neoplasms. Cytomorphology is non-
Table 8-9, respectively.
specific and IMT is usually a diagnosis of exclusion.

PRIMARY MALIGNANT EPITHELIAL TUMORS

ANCILLARY STUDIES
HEPATOCELLULAR CARCINOMA
Anaplastic lymphoma kinase (ALK) expression has
been found in some IMTs, such as IMT involving the CLINICAL FEATURES
bladder. However, expression of ALK has not been found
in the hepatic IMT. Aberrant cytokeratin expression
has been reported in IMT of various sites and should not The most important risk factors for HCC are infection
be misinterpreted as evidence of carcinoma. with hepatitis B virus (HBV) and hepatitis C virus

Ch008-F06731.indd 232 10/26/2006 10:30:11 AM

 CHAPTER 8 Liver 233

common. The estimated annual incidence of HCC in the

TABLE 8-8 United States is 4 cases per 100,000. HCC accounts for
more than 80% of primary liver carcinomas. In addition
Malignant Tumors – Primary to hepatitis viruses and alcohol, a number of chemical
carcinogens have been linked to HCC, including
• Epithelial: aflatoxin B1 (a toxic metabolite of Aspergillus flavus). A
• Hepatocellular carcinoma high risk of HCC is seen in patients with hereditary
• Cholangiocarcinoma hemochromatosis and hereditary tyrosinemia.
• Neuroendocrine neoplasms (extremely rare)
Elevated AFP is present in 50–75% of patients, with
• Non-epithelial:
• Angiosarcoma/other sarcomas values usually over 1000 ng/mL. Levels greater than
• Non-Hodgkin lymphoma/Hodgkin lymphoma 4000 ng/mL are highly suggestive of HCC. Elevated AFP
is, however, not present in all cases of HCC, and AFP
elevation may also be seen with yolk-sac tumors and
several non-neoplastic conditions, including massive
liver necrosis and fetal neural tube defects.
Epidemiology of HCC shows stark geographic vari-
TABLE 8-9 ability. In Asia and Africa, where HBV predominates,
HCC develops at a young age (20–40 years); cirrhosis is
Malignant Tumors – Metastatic/Secondary present in less than 50% of cases. In contrast, in the
United States, where HCV predominates, HCC rarely
• Epithelial: develops before the age of 60 and cirrhosis is present in
• Adenocarcinoma 75–90% of cases. In the United States, the average age
• Squamous cell carcinoma at the time of HCC diagnosis is 61 years. Worldwide,
• Small cell carcinoma HCC is more common in men than in women (M : F
• Other (adenoid cystic carcinoma, renal cell carcinoma,
etc.)
ratio is 2 : 1 to 5 : 1).
• Non-epithelial: The prognosis is extremely poor, with mean survival
• Malignant melanoma of 11 months. The factors that influence survival are
• Granulosa cell tumor age (older patients do worse), gender (men do worse
• Sarcomas than women), tumor stage and grade, and presence of
• Non-Hodgkin lymphoma/Hodgkin lymphoma cirrhosis (worse prognosis if cirrhosis is present).
• Other

HEPATOCELLULAR CARCINOMA – DISEASE FACT SHEET

PATHOLOGIC FEATURES

Incidence
៉ >80% of primary hepatic malignancies
៉ United States: 4 cases per 100,000
៉ Asia, Africa: higher rates (80% of cases arise in Asia)
Gender and Age Distribution
៉ Male to female ratio is between 2 : 1 and 5 : 1
៉ Asia and Africa: 20–40 years (HBV; cirrhosis in <50%)
៉ USA: 61 years (HCV; cirrhosis in 75–90%)
Clinical Features
៉ Elevated AFP (>4000 ng/mL highly suggestive of HCC)
Prognosis
៉ Extremely poor (mean survival, 11 months)
(HCV). The most common cause of HCC worldwide is
HBV, particularly in the areas where HBV infection is
endemic, including Asia and Africa. Nearly 80% of all
HCCs develop in Asian countries.
In the United States, the most important risk factors
for HCC are HCV and chronic alcoholism; HBV is less
Grossly, HCC may be solitary, multinodular, or diffuse.
In cirrhotic liver, HCC tends to present as a solitary
mass with multiple satellite nodules. The tumor ranges
in size from those at the threshold of radiographic
detection to those replacing the entire liver.
Histologically, HCC is characterized by the loss of
normal liver architecture: hepatocyte plates are thick-
ened (greater than two cells thick) and the normal
acinar structure, including portal tracts and central
veins, is absent. The neoplastic cells show crowding and
cytologic atypia, which increases in severity in higher-
grade lesions. Vascular invasion is present in two of
three cases. Presence of cytoplasmic bile pigment and
lipid vacuoles (steatosis) is helpful for differentiating
primary HCC from metastatic tumors.
Multiple architectural patterns may be present,
including trabecular, glandular, and solid. Cytologic
variants include pleomorphic (giant cell), clear cell,
oncocyte-like, and sarcomatoid HCC (Table 8-10).
Cytologic grading of HCC is helpful for a number of
reasons (Table 8-11). A three-tier system of FNA grading
is employed at Johns Hopkins: well-differentiated (Figs
8-20–8-22), moderately differentiated (Figs 8-23 & 8-
24), and poorly differentiated (Figs 8-25–8-28).

Ch008-F06731.indd 233 10/26/2006 10:30:12 AM

 234 FINE NEEDLE ASPIRATION CYTOLOGY

HEPATOCELLULAR CARCINOMA – PATHOLOGIC FEATURES TABLE 8-10

Cytopathologic Findings Hepatocellular Carcinoma – Uncommon Variants
៉ Well-differentiated HCC:
៉ Hypercellularity • Clear cell
៉ Bland-appearing hepatocytes, minimally pleomorphic, mildly • Mixed hepatocellular–cholangiocarcinoma
increased N/C ratio, small nucleoli • Acinar or adenoid cell
៉ Predominantly cohesive fragments, trabecular growth pattern, • Fibrolamellar
often smooth round fragment outline • Giant cell
៉ Prominent bile staining • Sarcomatoid
៉ Vascular proliferation associated with loosely hanging nests • Osteoclastic
of hepatocytes • Sclerotic
៉ Moderately differentiated HCC:
៉ Hypercellular smears, cohesive nests or trabeculae
៉ Fragments with irregular edges, numerous single cells
៉ High N/C ratio, irregular nuclear membrane
៉ Numerous atypical naked nuclei
៉ Prominent nucleoli, intranuclear inclusions
៉ Vascular/endothelial proliferation present (less obvious than
in well-differentiated HCC)
៉ Poorly differentiated HCC:
៉ Extremely hypercellular
៉ Loose nests, occasional 3-D fragments (gland-like)
៉ Marked pleomophism, high N/C ratio, macronucleoli
៉ Endothelial wrap-arounds ‘packeting’
៉ Large naked nuclear population
៉ Tumor giant cells
៉ Vascular/endothelial proliferation rarely seen
៉ Numerous mitoses, necrosis

Histopathologic Findings
៉ Gross:
៉ Solitary, multinodular, or diffuse
៉ Size ranges from small to massive
៉ Microscopic:
៉ Thickened hepatocyte plates (>2 cells thick) FIGURE 8-20
៉ Absence of normal acinar structure (no portal tracts)
Hepatocellular carcinoma. Well-differentiated tumor with irregular
៉ Cellular crowding and cytologic atypia nests of malignant hepatocytes loosely arranged around arborizing
៉ Cytoplasmic bile and lipid vacuoles (steatosis) may be present capillaries. Few single cells are seen as well. Papanicolaou stain, low
power.
Ancillary Studies
៉ HepPar-1, AFP, canalicular polyclonal CEA and CD10
៉ Reticulin highlights the loss of reticulin framework and the
expansion of cell plates
៉ Mucicarmine-negative

Differential Diagnosis and Pitfalls

៉ Well-differentiated HCC:
៉ Normal liver
៉ Hepatocellular adenoma (HA), focal nodular hyperplasia
(FNH), macroregenerative nodule (MRN): hepatocyte plates
not thickened (<2 cells thick); reticulin framework intact;
for HA and FNH, background liver non-cirrhotic
៉ Metastatic tumors: renal cell carcinoma, adrenal cortical
carcinoma
៉ Moderately differentiated HCC:
៉ Metastatic tumors: renal cell carcinoma, melanoma,
adenocarcinoma
៉ Poorly-differentiated HCC:
៉ Cholangiocarcinoma: no bile, no lipid (steatosis); prominent
desmoplasia; mucin; HepPar-1-negative, usually CK7 and CK20
double-positive FIGURE 8-21
៉ Metastatic carcinoma, melanoma, sarcoma, lymphoma: no Hepatocellular carcinoma. Well-differentiated tumor cells show a deli-
bile, no lipid (steatosis); mucin in some adenocarcinomas; cate attachment to fine branching capillaries. The diagnosis is often
melanin pigment in some melanomas made at low magnification, as individual cells may not appear too dif-
ferent from benign hepatocytes. Diff Quik, low power.

Ch008-F06731.indd 234 10/26/2006 10:30:12 AM

 CHAPTER 8 Liver
TABLE 8-11
Cytologic Grading of Hepatocellular Carcinoma:
Why Do We Grade?
• Difference in clinical prognosis and survival
• Treatment options
• Differential diagnosis
FIGURE 8-22
Hepatocellular carcinoma. Well-differentiated neoplasm with large
polygonal hepatocytes anchored to vascular endothelium. Cells have a
low N/C ratio and lack macronucleoli. Papanicolaou stain, high power.
FIGURE 8-23
Hepatocellular carcinoma. Moderately differentiated tumor displays
greater pleomorphism, macronucleoli, and a sprinkling of naked nuclei
in the background. Diff Quik stain, high power.
ANCILLARY STUDIES (Figs 8-29–8-32)
CD34 highlights endothelial cell wrapping in HCC, and
may be helpful for distinguishing HCC from benign
hepatocellular lesions, including focal nodular hyper-
plasia, hepatocellular adenoma, and macroregenerative
Ch008-F06731.indd 235
235
FIGURE 8-24
Hepatocellular carcinoma. Moderately differentiated tumor shows a
diffuse population of naked nuclei with macronucleoli in a very granular
smear background. Papanicolaou stain, intermediate power.
FIGURE 8-25
Hepatocellular carcinoma. Poorly differentiated tumor with a large
syncytial-like fragment of malignant cells. N/C ratio is extremely high,
with all the cells displaying macronucleoli. Morphologic kinship to
hepatocytes is lost and distinction of this lesion from other primary
and metastatic carcinomas may require immunostaining. Papanicolaou
stain, intermediate power.
nodule. In addition, increased p53 expression has
recently been shown to favor HCC.
A number of immunohistochemical stains may be
applied to help distinguish primary HCC from cholan-
giocarcinoma or metastatic carcinomas (Table 8-12).
The markers that favor HCC include HepPar-1 (highly
specific), AFP (non-specific), and a canalicular pattern
of polyclonal carcinoembryonic antigen (pCEA) and
CD10. Also, HCC is unique in its cytokeratin profile:
HCC reacts with low molecular weight cytokeratin anti-
bodies (such as CAM 5.2), but is generally non-reactive
with pancytokeratin antibodies (such as AE1/AE3) or
high molecular weight cytokeratin antibodies (such
as K903). HCC is most commonly CK7 and CK20
double-negative.
10/26/2006 10:30:13 AM
 236
FIGURE 8-26
Hepatocellular carcinoma. Poorly differentiated tumor shows large frag-
ment with tightly packed malignant cells reflecting a markedly expanded
hepatic plate. Cells display macronucleoli and are wrapped around by
endothelium ‘cell packets’. Papanicolaou stain, intermediate power.
FIGURE 8-28
Hepatocellular carcinoma. Poorly differentiated tumor with thick tissue
fragments and abundant necrosis. Necrosis is not a usual feature and
is often noted focally in high-grade HCC. Diff Quik stain, low power.
FIGURE 8-30
Cholangiocarcinoma. In contrast to hepatocellular carcinoma, the
malignant cells display diffuse immunostaining of the cytoplasm with
pCEA. Intermediate power.
Ch008-F06731.indd 236
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 8-27
Hepatocellular carcinoma. Poorly differentiated tumor shows a three-
dimensional gland-like fragment (middle of the field) with numerous
single naked nuclei in the background admixed with non-neoplastic
liver. It is not possible to differentiate this from an adenocarcinoma
without immunostaining. Diff Quik stain, high power.
FIGURE 8-29
Hepatocellular carcinoma. Polyclonal CEA (pCEA) immunostain displays
the characteristic one-sided ‘canalicular’ staining pattern of the cell
surface. Intermediate power.
FIGURE 8-31
Hepatocellular carcinoma. Immunostaining with CD31 shows the
characteristic endothelial reactivity creating ‘packets’ of malignant
hepatocytes. High power.
10/26/2006 10:30:14 AM
 CHAPTER 8 Liver 237

Reticulin stain highlights the loss of reticulin frame-

work and the expansion of cell plates in HCC. Mucin
reactivity is vanishingly rare in HCC; mucin staining
(with mucicarmine or PAS) strongly favors cholangio-
carcinoma or metastatic adenocarcinoma over HCC.
In a recent (as yet unpublished) study, we found that
in a few cases of well-differentiated HCC where the
exclusion of macroregenerative nodule, focal nodular
hyperplasia, or hepatocellular adenoma could be diffi-
cult, p53 immunostaining can play an important role.
However, p53, although quite specific, suffers from rela-
tively low sensitivity (55% for HCC in our experience).
Results are summarized in Table 8-13.

FIGURE 8-32 DIFFERENTIAL DIAGNOSIS AND PITFALLS

Hepatocellular carcinoma. p53 immunostaining shows focal nuclear
positivity in the core biopsy of a difficult case of well-differentiated
tumor where hepatocellular adenoma was difficult to exclude based on
morphology alone. Intermediate power.
The differential diagnosis for well-differentiated HCC
includes other hepatocellular lesions: hepatocellular
adenoma, focal nodular hyperplasia, and macroregen-
erative nodule. The differential diagnosis for poorly
differentiated HCC includes cholangiocarcinoma as
well as metastatic neoplasms, including carcinoma,
melanoma, sarcoma, and lymphoma.

TABLE 8-12
FIBROLAMELLAR HEPATOCELLULAR
Hepatocellular Carcinoma – Immunoperoxidase Staining CARCINOMA
• Conventional markers:
• CAM 5.2 CLINICAL FEATURES
• Polyclonal CEA
• CD34/CD31
• HepPar-1 Fibrolamellar carcinoma (FLC) represents approxi-
• Vimentin mately 5% of all hepatocellular carcinomas. FLC arises
• Alpha-fetoprotein (AFP) in younger patients, with a mean age of 25 years, and
• Alpha-1-antitrypsin (AAT) has a slight female predominance. Traditionally, it has
• More recent markers: been suggested that the prognosis of FLC is better than
• TTF-1 for typical HCC. However, it appears that after correct-
• Glut-1
• MOC-31
ing for age, stage, and other factors, the difference in
• CA 15-3 prognosis may not be significant. FLC has a stronger
propensity for lymph node metastasis than has typical
HCC.

TABLE 8-13
p53 Immunoreactivity in Hepatic FNA

Hepatocellular Carcinoma Focal Nodular Hyperplasia Regenerative Nodule Hepatic Adenoma

p53 6/11 (55%) 0/5 (0%) 0/5 (0%) 0/5 (0%)

Beta-catenin 7/11 (64%) 4/6 (67%) 4/6 (67%) 5/5 (100%)
Ki-67(moderate-high) 4/11 (36%) 0/6 (0%) 0/6 (0%) 0/5 (0%)

Ch008-F06731.indd 237 10/26/2006 10:30:16 AM

 238 FINE NEEDLE ASPIRATION CYTOLOGY

FIBROLAMELLAR HEPATOCELLULAR CARCINOMA –

DISEASE FACT SHEET

Incidence
៉ Represents 5% of all HCC

Gender and Age Distribution

៉ Slight female predominance
៉ Younger patients (mean age, 25 years)

Prognosis
៉ Thought to have a better prognosis than typical HCC

PATHOLOGIC FEATURES FIGURE 8-33

Hepatocellular carcinoma, fibrolamellar variant. Large pleomorphic
hepatocytes loosely arranged around branching capillaries. Distinction
Histopathologically, in contrast to the usual-type from a conventional well-differentiated hepatocellular carcinoma can
be difficult, and clinical information is crucial for accurate subtyping.
HCC, FLC arises in the background of non-cirrhotic Papanicolaou stain, low power.
liver. The tumor is characterized by dense bands of
fibrosis that tend to run in parallel arrays (lamellar
architecture).
On FNA, the smears show predominantly single
discohesive cells; trabeculae are distinctly uncommon.
The neoplastic cells are large and polygonal with
prominent nucleoli, densely granular eosinophilic
‘oncocytic-appearing’ cytoplasm, and prominent intra-
nuclear inclusions. Cytoplasmic hyaline inclusion
bodies as well as occasional cytoplasmic ‘pale bodies’
are characteristically seen. Lymphocytes and frag-
ments of loose fibroconnective tissue may also be seen
(Figs 8-33–8-35).

FIBROLAMELLAR HEPATOCELLULAR CARCINOMA –

PATHOLOGIC FEATURES

Cytopathologic Findings FIGURE 8-34

៉ Discohesive cells, trabeculae distinctly uncommon Hepatocellular carcinoma, fibrolamellar variant. Pleomorphic hepato-
៉ Large polygonal cells, prominent nucleoli, granular eosinophilic cytes, often with bizarre shapes, densely granular ‘oncocytic’ cytoplasm
cytoplasm and macronucleoli. Papanicolaou stain, high power.
៉ Prominent intranuclear inclusions
៉ Cytoplasmic hyaline inclusion bodies, cytoplasmic ‘pale bodies’
ANCILLARY STUDIES
Histopathologic Findings
៉ Background of non-cirrhotic liver
៉ Similar features as HCC, but with dense bands of lamellar The immunohistochemical profi le of FLC is similar to
fibrosis that of HCC, except that FLC is usually CK7-positive,
whereas HCC is generally CK7-negative. In addition,
Ancillary Studies AFP is generally non-reactive.
៉ Immunostaining pattern similar to HCC, except CK7 usually
positive and AFP usually non-reactive

Differential Diagnosis and Pitfalls DIFFERENTIAL DIAGNOSIS AND PITFALLS

៉ Typical HCC: background cirrhotic liver; older patients; absence
of lamellar fibrosis
៉ Cholangiocarcinoma and metastatic malignancies (see HCC)
FLC is distinguished from typical HCC based on the
above morphologic features (lamellar fibrosis) and
demographics (non-cirrhotic liver in young patients).

Ch008-F06731.indd 238 10/26/2006 10:30:17 AM

 CHAPTER 8 Liver
FIGURE 8-35
Hepatocellular carcinoma, fibrolamellar variant. Fragment of sclerotic
tissue, possibly arising from lamellar fibrosis in the tumor, accompany-
ing bizarre malignant hepatocytes. Papanicoalou stain, high power.
INTRAHEPATIC CHOLANGIOCARCINOMA
CLINICAL FEATURES
Cholangiocarcinoma is the second most common
primary hepatic tumor after HCC; however, it is much
less frequent. Cirrhosis is not a risk factor. Risk factors
for cholangiocarcinoma include the diseases that cause
chronic inflammation of the biliary tree: primary scle-
rosing cholangitis, Caroli’s disease, hepatolithiasis, and
parasitic infestation (Clonorchis sinesis or Opisthorchis
viverrini). Other risk factors are exposure to Thorotrast
and anabolic steroids. However, no identifiable risk
factor is present in the majority of cases (80–90%).
Patients typically present with obstructive jaundice.
Serum elevation of CA 19-9 and CEA is typical, and
AFP is not increased.
Most cases of cholangiocarcinoma occur after age 60.
Men and women are affected similarly; however, there
is a strong male predominance in cases arising in the
INTRAHEPATIC CHOLANGIOCARCINOMA – DISEASE FACT SHEET
Incidence
៉ Second most common primary hepatic tumor
៉ Much less frequent than HCC
Gender and Age Distribution
៉ No gender predilection
៉ Majority after age 60
Prognosis and Treatment
៉ Dismal prognosis (survival <1 year)
៉ 80% unresectable at diagnosis
Ch008-F06731.indd 239
239
setting of primary biliary cirrhosis. Patients usually
present with abdominal pain and weight loss. Unlike its
extrahepatic counterpart, intrahepatic cholangiocarci-
noma rarely presents with obstructive jaundice. Patients
with cholangiocarcinoma generally have a dismal prog-
nosis, with most patients succumbing to disease within
1 year of diagnosis. Patients die as a result of extensive
tumor burden, liver failure, gastrointestinal bleeding, or
infection. At autopsy, 75% of patients have metastases.
Treatment options include resection, but 80% of tumors
are deemed unresectable at diagnosis. Transplantation
is no longer performed, since recurrence of carcinoma
is nearly universal.
PATHOLOGIC FEATURES
Cholangiocarcinoma may present either as a solitary
mass or as multiple masses. Tumors are typically
firm and gritty, owing to the exuberant desmoplastic
reaction.
Histologically, the tumor may be well circumscribed
but is never encapsulated. Tumors are usually well to
INTRAHEPATIC CHOLANGIOCARCINOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Usually appears well differentiated
៉ Hypercellular, predominantly crowded fragments
៉ Monolayered or 3-D fragments with acinar formations
៉ High N/C ratio, prominent nucleoli
៉ Occasionally, pleomorphic cells, giant cells
៉ Rarely, mitoses and necrosis
Histopathologic Findings
៉ Gross: solitary mass or multinodular
៉ Microscopic:
៉ Malignant glandular proliferation
៉ Usually well to moderately differentiated
៉ Prominent desmoplastic reaction
៉ No cytoplasmic bile
៉ Cytoplasmic mucin nearly always present
Ancillary Studies
៉ Usually CK7 and CK20 double-positive (unlike HCC, which is CK7
and CK20 double-negative)
៉ High molecular weight cytokeratin and pancytokeratin positive
(unlike HCC)
៉ HepPar-1 and canalicular CEA and CD10 negative (unlike HCC)
Differential Diagnosis and Pitfalls
៉ Hepatocellular carcinoma with a glandular pattern: bile and
steatosis are hints when present; immunostains are helpful
(see above)
៉ Metastatic adenocarcinomas: distinction generally requires
immunostains
៉ Benign and reactive bile duct proliferations (e.g. bile duct
adenoma): no cytologic atypia; no perineural or vascular
invasion
10/26/2006 10:30:17 AM
 240
moderately differentiated and a prominent desmoplastic
response is typical. In contrast to HCC, bile is not pro-
duced. Intracytoplasmic mucin is nearly always present.
FNA shows a usually well-differentiated gland-
forming tumor (Figs 8-36–8-39). Smears are hypercel-
lular and there is a predominance of crowded cellular
fragments with a three-dimensional architecture with
acinar formations. A significant number of cases display
flat monolayered sheets with minimal nuclear enlarge-
ment and mild anisonucleosis; therefore, exclusion of
reactive biliary epithelium with atypia could become a
tricky issue. Few, if any, benign hepatocytes are present
in the background, possibly representing needle sam-
pling outside the main lesion. Poorly differentiated
FIGURE 8-36
Cholangiocarcinoma. Well-differentiated tumor shows a single crowded
fragment of biliary epithelium. Nuclei are small, hyperchromatic, and
tightly packed with a vague three-dimensional architecture. Few back-
ground benign hepatocytes are seen. Diff Quik stain, high power.
FIGURE 8-37
Cholangiocarcinoma. Well-differentiated tumor with a somewhat fl at
monolayered sheet of ductal-type epithelium. Cells show enlarged
nuclei with inconspicuous nucleoli. Differentiation from reactive biliary
epithelium can become a challenge in limited samples. Papanicolaou
stain, high power.
Ch008-F06731.indd 240
FINE NEEDLE ASPIRATION CYTOLOGY
cholangiocarcinomas show high nuclear to cytoplasmic
(N/C) ratio cells, often in smaller fragments or single
cells with prominent nucleoli. Pleomorphic cells, giant
cells, and, rarely, mitoses and necrosis are seen as well.
ANCILLARY STUDIES
There are no markers that are entirely specific for chol-
angiocarcinoma. The pattern of cytokeratin expres-
sion may be used to differentiate cholangiocarcinoma
from poorly differentiated HCC: cholangiocarcinoma is
FIGURE 8-38
Cholangiocarcinoma. Poorly differentiated tumor with large pleomor-
phic nuclei, some naked, with macronucleoli. Focal gland-like architec-
ture is evident. This case needed immunostaining to prove its glandular
origin and distinction from hepatocellular carcinoma. Diff Quik stain,
high power.
FIGURE 8-39
Cholangiocarcinoma. Poorly differentiated tumor with high N/C ratio
cells, macronucleoli, and three-dimensional architecture. Papanicolaou
stain, high power.
10/26/2006 10:30:18 AM
 CHAPTER 8 Liver
typically CK7 and CK20 double-positive, whereas HCC
is usually CK7 and CK20 double-negative. Unlike HCC,
cholangiocarcinoma reacts with pancytokeratins (e.g.
AE1/AE3) and high molecular weight cytokeratins
(e.g. K903). Unlike HCC, cholangiocarcinoma does not
react with HepPar-1 and does not display canalicular
staining with polyclonal CEA and CD10.
Cholangiocarcinoma may be distinguished from meta-
static adenocarcinoma by virtue of negative staining for
various organ-specific markers, such as ER and PR
(breast and ovary), TTF-1 (lung and thyroid), and those
used for colon (CDX-2, CK7-negative, CK20-positive).
Distinction from pancreatic adenocarcinoma may be
aided by the loss of DPC4 expression in 40% of cases.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Cholangiocarcinoma should be differentiated from
HCC with a glandular pattern. Clinically, history of
cirrhosis and elevated AFP strongly favor HCC over
cholangiocarcinoma. Bile and steatosis, when present,
are helpful hints for the diagnosis of HCC over cho-
langiocarcinoma, but frequently immunohistochemical
markers are required to make a definitive diagnosis.
With the exception of colon cancer, cholangiocarci-
noma is difficult or impossible to distinguish from
metastatic adenocarcinoma from other sites based on
morphologic grounds alone. As described above, immu-
nomarkers may be helpful in distinguishing cholangio-
carcinoma from metastases from other organs. In
addition, well-differentiated cholangiocarcinoma should
be differentiated from benign and reactive bile duct
proliferations, including bile duct adenoma and bile
duct hamartoma.
HEPATOBLASTOMA
CLINICAL FEATURES
Hepatoblastoma, although rare as such, represents the
most common primary hepatic tumor in infants and
young children (Table 8-14). Hepatoblastoma accounts
for about 50% of all primary hepatic malignancies in
children and about 0.5% of all pediatric neoplasms.
TABLE 8-14
Pediatric Liver Tumors
• Hepatoblastoma
• Embryonal sarcoma
• Fibrolamellar hepatocellular carcinoma
Ch008-F06731.indd 241
241
HEPATOBLASTOMA – DISEASE FACT SHEET
Incidence
៉ Most common primary hepatic tumor in young children
៉ Rare overall (0.5% of all pediatric neoplasms)
Gender and Age Distribution
៉ Male to female ratio is 2 : 1
៉ Children <5 years of age
Clinical Features
៉ Elevated serum AFP
៉ No association with cirrhosis
Prognosis and Treatment
៉ Surgical resection and chemotherapy
៉ Long-term survival is 60–70% after resection
The majority of hepatoblastomas occur in children
under 5 years of age. Few cases have been diagnosed at
birth and it rarely occurs after age 15. There is a male
predominance (M : F = 2 : 1). Patients usually present
with an abdominal mass. Patients with familial adeno-
matous polyposis have a significantly increased risk of
hepatoblastoma. Serum AFP is elevated with high titers.
There is no association with cirrhosis.
Hepatoblastoma is managed by resection and chemo-
therapy. With current therapy, nearly 90% of tumors
are considered resectable, with 60–70% having long-
term survival.
PATHOLOGIC FEATURES
Hepatoblastoma presents as a solitary mass, more com-
monly involving the right lobe of the liver. It measures
from 3 to 20 cm. Prominent calcifications are often
evident on gross examination.
Histologically, hepatoblastomas are classified as either
epithelial or mixed epithelial–mesenchymal. Epithelial
cells resemble hepatocytes (fetal pattern) or may consist
of more poorly differentiated cells (embryonal pattern).
Osteoid production may be present prominently in the
mixed epithelial–mesenchymal type of hepatoblastoma,
particularly following chemotherapy. Foci of admixed
extramedullary hematopoiesis may be found, which may
help differentiate hepatoblastoma from HCC.
Cytopathologic characteristics (Fig. 8-40) depend on
the subtype of hepatoblastoma.
ANCILLARY STUDIES
Similar to HCC, hepatoblastoma reacts with HepPar-1
and AFP and shows canalicular staining with poly-
clonal CEA and CD10.
10/26/2006 10:30:19 AM
 242 FINE NEEDLE ASPIRATION CYTOLOGY

DIFFERENTIAL DIAGNOSIS AND PITFALLS

In children, hepatoblastoma should be primarily dif-

ferentiated from metastases from other pediatric
malignancies, including neuroblastoma, lymphoblastic
lymphoma, Wilms tumor, and rhabdomyosarcoma.
Primary hepatic neoplasms that enter the differential
diagnosis for hepatoblastoma include undifferentiated
(embryonal) sarcoma and HCC. If an epithelial compo-
nent is present, embryonal sarcoma can be excluded.
HCC is uncommon in children under 5 years of age.
Presence of foci of extramedullary hematopoiesis may
help differentiate hepatoblastoma from HCC.

FIGURE 8-40
PRIMARY MALIGNANT MESENCHYMAL
Hepatoblastoma. Primitive-appearing small round blue cells with a high
N/C ratio, speckled chromatin, and densely pink cytoplasm. No hepato- TUMORS OF THE LIVER
cytic differentiation is evident. Diagnosis is usually straightforward due
to the young age of the patient and a markedly elevated serum AFP.
H&E stain, high power. EPITHELIOID HEMANGIOENDOTHELIOMA

CLINICAL FEATURES
HEPATOBLASTOMA – PATHOLOGIC FEATURES
Epithelioid hemangioendothelioma (EHE) is an uncom-
Cytopathologic Findings mon tumor arising in the liver and various other organs.
៉ Depend on the subtype The risk factors for EHE are not well characterized.
៉ Epithelial (fetal, embryonal): resemble HCC – hypercellular Oral contraceptive use and vinyl chloride exposure
smears with cords, nests, or trabeculae of small crowded have been implicated in isolated cases. EHE most com-
monotonous hepatocytes; cells often oval to spindle-shaped, monly develops in middle-aged women.
high N/C ratio, frequent mitosis Patients generally present with abdominal pain,
៉ Mixed epithelial–mesenchymal: more pleomorphic; also contains
weight loss, and, occasionally, hepatic rupture. In approx-
a neoplastic mesenchymal component (cartilage, bone, or
imately 40% of cases, EHE is found incidentally. Clinical
skeletal muscle)
៉ Anaplastic/small cell undifferentiated: hypercellular smears with
course is unpredictable, although overall survival rates
uniform primitive-appearing small blue cells, high mitotic are better than for angiosarcoma. Survival ranges from
index, karyorrhexis, necrosis several months to 27 years. Treatment of EHE is a con-
troversial subject. Resection is generally the treatment of
Histopathologic Findings choice. Extrahepatic involvement of other organs, such
៉ Gross: as lung, has been found in nearly 50% of cases.
៉ Usually solitary
៉ Prominent calcifications frequent
៉ Microscopic:
៉ Epithelial or epithelial-mesenchymal types
៉ Prominent osteoid production, particularly after EPITHELIOID HEMANGIOENDOTHELIOMA – DISEASE FACT SHEET
chemotherapy
៉ Foci of extramedullary hematopoiesis Incidence
៉ Rare
Ancillary Studies
៉ Similar to HCC: positive for HepPar-1, AFP, canalicular polyclonal Gender and Age Distribution
CEA and CD10
៉ Most common in middle-aged women

Differential Diagnosis and Pitfalls

Prognosis and Treatment
៉ Metastases from other pediatric malignancies: neuroblastoma,
៉ Unpredictable clinical course
lymphoblastic lymphoma, Wilms tumor, rhabdomyosarcoma
៉ Resection generally the treatment of choice
៉ Other primary liver neoplasms:
៉ HCC: rare in children less than age 5 years; no foci of
extramedullary hematopoiesis
៉ Undifferentiated (embryonal) sarcoma: no epithelial
component; cytokeratin-negative

Ch008-F06731.indd 242 10/26/2006 10:30:19 AM

 CHAPTER 8 Liver 243

PATHOLOGIC FEATURES

EHE presents are multiple liver nodules, involving both

lobes of the liver in 80% of cases. Nodule sizes vary
from 1 to 12 cm. The tumor cells form single-fi le cords,
which course through the myxohyaline matrix. A diag-
nostic clue to the vascular nature of this neoplasm is
the presence of ‘blister cells’, characterized by cytoplas-
mic vacuoles representing incipient vascular lumina.
These lumina may contain erythrocytes.
FNA shows a paucicellular aspirate with discohesive,
large polygonal-round epithelioid cells, rarely with
gland-like formations (Fig. 8-41). Cells have large nuclei,
often with vesicular chromatin and prominent nucleoli,
and granular-pale, abundant eosinophilic cytoplasm.
Also observed are intracytoplasmic lumina/vacuoles as
well as intracytoplasmic hemosiderin pigment.
FIGURE 8-41
Epithelioid hemangioendothelioma. Epithelioid cells with round to oval
ANCILLARY STUDIES uniform nuclei resembling a non-small cell carcinoma. An intranuclear
inclusion is also seen. Diagnosis is dependent on immunostaining. Diff
Quik stain, high power.
Electron microscopy may be used to identify Weibel-
Palade bodies, which are the components of endothelial DIFFERENTIAL DIAGNOSIS AND PITFALLS
cells.
EHE reacts with endothelial markers (CD34, CD31,
Factor VIII, Ulex europaeus). Up to 15% of EHE react Vacuoles in blister cells may be mistaken for signet-ring
with cytokeratin stains, which should not be misinter- cells. Unlike signet-ring cells, the blister cells do not
preted as evidence of carcinoma. react with mucicarmine. EHE should also be differenti-
ated from angiosarcoma.

EPITHELIOID HEMANGIOENDOTHELIOMA – ANGIOSARCOMA

PATHOLOGIC FEATURES

Cytopathologic Findings CLINICAL FEATURES

៉ Paucicellular aspirate
៉ Discohesive, large polygonal–round epithelioid cells, rarely
gland-like formations Although rare as such, angiosarcoma is considered the
៉ Large nuclei, often vesicular chromatin, prominent nucleoli most common primary hepatic sarcoma. It represents
៉ Granular–pale, abundant eosinophilic cytoplasm,
intracytoplasmic lumina/vacuoles, hemosiderin

ANGIOSARCOMA – DISEASE FACT SHEET

Histopathologic Findings
៉ Gross:
Incidence
៉ Multiple liver nodules (1 to 12 cm)
៉ Microscopic: ៉ Most common primary hepatic sarcoma
៉ Single-file cords of cells ៉ Overall rare (<1% of primary hepatic neoplasms)
៉ Myxohyaline matrix
៉ ’Blister cells’: cytoplasmic vacuoles with erythrocytes Gender and Age Distribution
(incipient vascular lumina) ៉ Male to female ratio is 3 : 1
៉ Age 60 to 70 years
Ancillary Studies
៉ Endothelial markers: CD34, CD31, Factor VIII, Ulex europaeus Clinical Features
៉ Cytokeratin reactivity in up to 15% of cases ៉ Associated with cirrhosis in 30% of cases
៉ Electron microscopy: Weibel-Palade bodies
Prognosis and Treatment
Differential Diagnosis and Pitfalls ៉ Prognosis extremely poor, most patients dying of disease within 6
៉ Angiosarcoma months of diagnosis
៉ Signet-ring cell carcinoma ៉ Recommended treatment is surgical resection and radiation

Ch008-F06731.indd 243 10/26/2006 10:30:20 AM

 244 FINE NEEDLE ASPIRATION CYTOLOGY

less than 1% of primary hepatic neoplasms. Most

patients are in their sixth or seventh decade of life,
with a male to female ratio of 3 : 1. Similar to HCC,
angiosarcoma is associated with cirrhosis (30%). Other
etiologic factors include exposure to vinyl chloride,
Thorotrast, and arsenic. Most patients present with
hepatomegaly, abdominal pain, ascites, and, uncom-
monly, acute abdomen due to spontaneous rupture of
the tumor. Most cases are treated with surgery and
radiation. Prognosis is extremely poor, with most
patients dying of disease within 6 months.
CT scans show solitary or multiple low-density
masses with lobular or irregular outlines, clear or ill-
defined margins, and curvilinear calcification. Post-
contrast CT scans display progressive and isodense
enhancement.

FIGURE 8-42
Angiosarcoma. Spindled cells with long tapering nuclei densely arranged
PATHOLOGIC FEATURES in a tissue fragment. Diagnosis usually hinges upon immunostaining
with vascular markers. Diff Quik stain, high power.

As in other organs, angiosarcoma is characterized by

formation of anastomosing vascular channels lined by
pleomorphic epithelioid or spindled endothelial cells.
‘Hobnail’ morphology is common. The tumor grows
along the sinusoids.
Cytopathologic characteristics include hypercellular
smears with variably sized fragments and numerous
single cells with prominent pleomorphism (Fig. 8-42).
The malignant cells are predominantly spindly/fusiform
and less often epithelioid in shape. Necrosis is often
observed.
ANCILLARY STUDIES
Electron microscopy may be used to identify Weibel-
Palade bodies. Endothelial markers (CD34, CD31,
Factor VIII, and Ulex europaeus) may be used to confirm
the vascular origin of this neoplasm. Lack of expression
of smooth muscle markers (actin, desmin, calponin)
may be used to rule out a metastatic leiomyosarcoma.

DIFFERENTIAL DIAGNOSIS AND PITFALLS

The differential diagnosis includes epithelioid heman-

ANGIOSARCOMA – PATHOLOGIC FEATURES gioendothelioma and metastatic sarcomas, particularly
leiomyosarcoma.
Cytopathologic Findings
៉ Hypercellular smears, variably sized fragments, numerous single
cells
៉ Pleomorphism, with predominantly spindly cells, less often
PRIMARY HEPATIC LYMPHOMA
epithelioid cells
៉ Necrosis

CLINICAL FEATURES
Histopathologic Findings
៉ Anastomosing vascular channels
៉ Channels lined by pleomorphic ‘hobnail’ epithelioid or spindled Primary hepatic lymphoma is defined as lymphoma
endothelial cells predominantly involving the liver in the absence of
៉ Growth along the sinusoids
nodal or disseminated disease. Primary hepatic lym-
phoma is exceedingly rare, representing less than
Ancillary Studies
0.5% of extranodal lymphomas. Only approximately
៉ Positive for endothelial markers (CD34, CD31, Factor VIII, and
100 cases have been reported in the literature.
Ulex europaeus)
More commonly, the liver is involved by lymphoma-
៉ Electron microscopy: Weibel-Palade bodies
tous infiltrate as part of disseminated lymphoma or
Differential Diagnosis and Pitfalls
hepatosplenic T-cell lymphoma. Liver involvement is
present at diagnosis in up to 10% of patients with
៉ Epithelioid hemangioendothelioma
៉ Metastatic sarcoma (particularly leiomyosarcoma)
Hodgkin lymphoma and up to 40% of patients with
non-Hodgkin lymphoma. There is a wide age spectrum,
ranging from 7 to 87 years, with a median age of 55

Ch008-F06731.indd 244 10/26/2006 10:30:20 AM

 CHAPTER 8 Liver 245

lymphoma, mantle cell lymphoma, lymphoplasmacytic

PRIMARY HEPATIC LYMPHOMA – CLINICAL FEATURES lymphoma, MALT lymphoma, and angiocentric lym-
phoma. Histologic and cytologic features of primary
Incidence tumors correspond to the patterns characteristic of the
៉ Exceedingly rare nodal disease.
៉ Approximately 100 cases reported in the literature FNA shows hypercellular smears with a distinct
population of monotonous-appearing lymphocytes (Figs
Gender and Age Distribution 8-43–8-45). Mitoses and karyorrhexis are often observed,
៉ Male to female ratio is 3 : 1 reflecting the high-grade phenotype of the lymphoma
៉ Wide age spectrum (7 to 87 years; median age, 55 years) process. In cases of Hodgkin lymphoma, the smears are
often not as cellular, and depending on the subtype of
Treatment the disease, Reed-Sternberg cells are observed in varying
៉ Non-surgical numbers. The differential diagnosis involves small
round blue cell tumors (metastatic islet cell tumor in
particular) and, in rare instances, nodular form of extra-
medullary hematopoiesis (Figs 8-46 & 8-47).
years. The male to female ratio is 3 : 1. Therapy is non-
surgical. The chemotherapeutic regimen depends on
lymphoma type.

PATHOLOGIC FEATURES

Primary hepatic lymphoma may present as either a

solitary or multiple liver masses. All described cases
are of a non-Hodgkin lymphoma variety. The vast
majority of primary hepatic lymphomas are of B-cell
origin, with over 75% representing the diffuse large
B-cell lymphoma. Other patterns of primary B-cell lym-
phoma include follicular lymphoma, small lymphocytic

PRIMARY HEPATIC LYMPHOMA – PATHOLOGIC FEATURES FIGURE 8-43

Primary hepatic lymphoma. Monotonous population of small lympho-
Cytopathologic Findings cytes. Immunostaining and flow analysis was consistent with a MALT-
type lymphoma. Papanicolaou stain, high power.
៉ Depends on the type of lymphoma; similar to nodal disease

Histopathologic Findings
៉ Gross:
៉ Solitary or multiple masses
៉ Microscopic:
៉ All cases non-Hodgkin lymphoma
៉ Vast majority B-cell lymphoma
៉ 75% diffuse large B-cell lymphoma

Ancillary Studies
៉ Pan-hematopoietic marker, LCA (CD45), distinguishes lymphoma
from carcinoma, melanoma, or sarcoma
៉ Lymphomas further subtyped with CD3 (T-cell marker), CD20
(B-cell marker) and various other hematopoietic markers
៉ Fresh specimen should be submitted for flow cytometry

Differential Diagnosis and Pitfalls

៉ Poorly differentiated carcinoma, melanoma, and sarcoma
៉ Hepatic involvement by disseminated lymphoma: most common
type of hepatic lymphoma; liver involved in 40% of patients
with non-Hodgkin lymphoma
៉ Hepatic involvement by hepatosplenic T-cell lymphoma
FIGURE 8-44
Primary hepatic lymphoma. High-grade tumor shows medium-sized lym-
phocytes with abundant mitoses and fine cytoplasmic vacuoles consis-
tent with an aggressive Burkitt-type lymphoma. Diff Quik stain, high
power.

Ch008-F06731.indd 245 10/26/2006 10:30:21 AM

 246
FIGURE 8-45
Plasmacytoma. Malignant plasma cells with the characteristic speckled
chromatin and intranuclear inclusions. Papanicolaou stain, high power.
FIGURE 8-46
Extramedullary hematopoiesis. Polymorphous cells with lymphoid and
erythroid elements. Diff Quik stain, high power.
ANCILLARY STUDIES
Leukocyte common antigen, LCA (CD45), is a pan-
hematopoietic marker used to distinguish lymphoma
from carcinoma, melanoma, or sarcoma. Lymphomas
can be further subtyped with CD3 (T-cell marker),
CD20 (B-cell marker), and various other hematopoietic
antigens. If lymphoma is suspected, a fresh specimen
should be submitted for a flow cytometric analysis.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Lymphoma should be differentiated from poorly
differentiated carcinoma, melanoma, and sarcoma.
Immunohistochemical stains and flow cytometry aid in
Ch008-F06731.indd 246
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 8-47
Extramedullary hematopoiesis. Megakaryocyte in a background of mono-
nuclear cells of different lineages. Papanicolaou stain, high power.
this differential diagnosis. Primary hepatic lymphoma
should also be differentiated from hepatic involvement
by disseminated lymphoma and hepatosplenic T-cell
lymphoma.
METASTATIC TUMORS TO THE LIVER
CLINICAL FEATURES (Table 8-15)
Liver, along with the lung, is the organ that is most
frequently involved by metastatic tumors. In the United
States, metastases represent 98% of all hepatic malig-
nancies. However, in patients with cirrhosis, primary
liver malignancies (mainly HCC) are three times more
common than metastases.
In adults, malignancies that most frequently metas-
tasize to the liver include those from the colorectum,
pancreas, breast, lung, stomach, kidney, and skin
METASTATIC TUMORS – DISEASE FACT SHEET
Incidence
៉ Most common type of hepatic malignancy
៉ Metastases represent 98% of hepatic malignancies (in the United
States)
៉ In cirrhotic livers, primary neoplasms are three times more
common than metastases
Gender and Age Distribution
៉ Depends on tumor type
Prognosis and Treatment
៉ Depends on tumor type
10/26/2006 10:30:21 AM
 CHAPTER 8 Liver 247

TABLE 8-15
Metastatic Tumors in the Liver – Common Facts

• Most common cancer in the liver

• Most common indication for hepatic FNA
• Most common – colon, pancreas, breast, lung, kidney,
melanoma
• Source of the primary tumor could be occult
• Cytomorphology alone may not be able to diagnose an
unknown primary (immunoperoxidase stains could be
helpful)

(melanoma). Leiomyosarcoma is the most common soft

tissue tumor to metastasize to the liver. In contrast, it
is unusual for prostate tumors to metastasize to the
liver. In children, neoplasms that commonly metastasize
to the liver include neuroblastoma, Wilms tumor, and
rhabdomyosarcoma.
FIGURE 8-48
Hepatectomy specimen shows a subcapsular nodule of metastatic colonic
adenocarcinoma. This presents the most common scenario for a liver FNA
procedure, which provides an accurate answer within a short time.

PATHOLOGIC FEATURES

Metastatic tumors frequently present as multiple

masses. Histopathology and cytopathology depend on
the tumor of origin (Figs 8-48–8-58). Metastatic
melanoma is a frequently observed secondary tumor in
the liver and may depict significant morphologic overlap
with poorly differentiated HCC. This necessitates a
careful evaluation of subtle morphologic differences
between the two tumor types (Table 8-16).

METASTATIC TUMORS – PATHOLOGIC FEATURES

Cytopathologic Findings FIGURE 8-49

៉ Depends on the type of primary tumor Hepatic metastasis: colonic adenocarcinoma. Columnar-shaped cells in
a background of ‘dirty necrosis’. Papanicolaou stain, high power.
Histopathologic Findings
៉ Gross: usually present as multiple nodules
៉ Microscopic: depends of the tumor of origin

Ancillary Studies
៉ HepPar-1 to distinguish from primary HCC or hepatoblastoma
៉ CK7 and CK20
៉ Organ- and tissue-specific markers: ER/PR (breast, ovary),
TTF-1 (lung, thyroid), PSA (prostate), S-100/Melan A/HMB-45
(melanoma), actin/desmin (leiomyosarcoma)

Differential Diagnosis and Pitfalls

៉ Common metastatic malignancies in adults: colorectum,
pancreas, breast, lung, stomach, kidney, melanoma,
leiomyosarcoma
៉ Common metastatic malignancies in children: neuroblastoma,
Wilms tumor, rhabdomyosarcoma
៉ Primary hepatic neoplasms: hepatocellular carcinoma,
cholangiocarcinoma, and mesenchymal neoplasms are in the FIGURE 8-50
differential diagnosis for metastatic malignancies Hepatic metastasis: adenosquamous carcinoma from a pancreatic
primary. Note admixture of adenocarcinoma with brightly pink keratin-
ized squamous cells. Papanicolaou stain, high power.

Ch008-F06731.indd 247 10/26/2006 10:30:23 AM

 248
FIGURE 8-51
Hepatic metastasis: renal cell carcinoma. Clear cell tumor with large
nuclei and macronucleoli. Renal cell carcinoma shares several morpho-
logic features with hepatocellular carcinoma and usually requires immu-
nostaining for definitive diagnosis. Papanicolaou stain, high power.
FIGURE 8-53
Hepatic metastasis of malignant melanoma. Large pleomorphic and
naked nuclei resembling poorly differentiated hepatocellular carcinoma.
Macronucleoli are visible. Note lack of pigmented cells. Diff Quik stain,
high power.
FIGURE 8-55
Hepatic metastasis: small cell carcinoma from a lung primary. Small,
hyperchromatic nuclei with prominent molding, nuclear ‘streak’ artifact,
and lack of nucleoli. Diff Quik stain, high power.
Ch008-F06731.indd 248
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 8-52
Hepatic metastasis: malignant melanoma from a cutaneous primary.
Discohesive, heavily pigmented malignant cells with an epithelioid
appearance. Note prominent nucleoli and focal resemblance to hepato-
cytes. Papanicolaou stain, high power.
FIGURE 8-54
Hepatic metastasis: squamous cell carcinoma from an esophageal
primary. Extensive cystic necrosis (left side) with densely keratinized
malignant cells (right side). Papanicolaou stain, low to high power.
TABLE 8-16
Hepatocellular Carcinoma (HCC) versus Metastatic
Malignant Melanoma (MM)
• Closest mimic of HCC
• Liver is a very common site for visceral spread of MM
• Cytomorphologic features (MM over HCC):
• More often single cells or sheet-like arrangement
• Plasmacytoid cells (eccentric nuclei)
• More frequent binucleation
• Cytoplasmic tails/prolongations
• Melanin-like pigment
• Necrosis
10/26/2006 10:30:24 AM
 CHAPTER 8 Liver
FIGURE 8-56
Hepatic metastasis: islet cell tumor (pancreatic endocrine neoplasm).
Monotonous population of neoplastic cells with eccentric nuclei (‘plas-
macytoid’ appearance) and speckled chromatin. Uniformity of cells with
a relatively smaller size, lack of prominent nucleoli, and glandular for-
mations differentiate this from an adenocarcinoma. Papanicolaou stain,
intermediate power.
FIGURE 8-57
Hepatic metastasis: hemangiopericytoma from a brain primary. Monoto-
nous, round to oval cells with mostly naked nuclei and scant to no
cytoplasm. Diff Quik stain, intermediate power.
ANCILLARY STUDIES
Various markers may be applied to determine the site
of origin of a metastatic carcinoma. For example: ER
and PR support breast or gynecologic tract primary;
TTF-1, lung or thyroid primary; CDX-2, colorectal
primary; and PSA or PSAP, prostate primary. Meta-
static melanoma reacts with S-100, Melan A, and HMB-
45. Metastatic leiomyosarcoma expresses actin, desmin,
and calponin. In contrast, primary HCC may be distin-
guished from metastatic carcinomas based on expres-
sion of HepPar-1, AFP, and canalicular polyclonal CEA
and CD10.
Ch008-F06731.indd 249
249
FIGURE 8-58
Hepatic metastasis: gastrointestinal stromal tumor from a gastric
primary. Loose fragment of plump fusiform nuclei arranged in a hap-
hazard fashion. Papanicolaou stain, intermediate power.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Metastatic neoplasms must be differentiated from
primary HCC, cholangiocarcinoma, and mesenchymal
neoplasms.
SUGGESTED READINGS
Nodular Regenerative Hyperplasia
Cohen MB, Haber MM, Holly EA, Ahn DK, Bottles K, Stoloff AC. Cytologic
criteria to distinguish hepatocellular carcinoma from nonneoplastic
liver. Am J Clin Pathol 1991;95:125–130.
Yang GC, Yang GY, Tao LC. Distinguishing well-differentiated hepatocel-
lular carcinoma from benign liver by the physical features of fine-needle
aspirates. Mod Pathol 2004;17:798–802.
Focal Nodular Hyperplasia
Kong CS, Appenzeller M, Ferrell LD. Utility of CD34 reactivity in evaluating
focal nodular hepatocellular lesions sampled by fine needle aspiration
biopsy. Acta Cytol 2000;44:218–222.
Ruschenburg I, Droese M. Fine needle aspiration cytology of focal nodular
hyperplasia of the liver. Acta Cytol 1989;33:857–860.
Hydatid Disease
Agarwal PK, Husain N, Singh BN. Cytologic findings in aspirated hydatid
fluid. Acta Cytol 1989;33:652–654.
Parwani AV, Burroughs FH, Ali SZ. Echinococcal cyst of the liver. Diagn
Cytopathol 2004;31:111–112.
Extramedullary Hematopoiesis
Lemos LB, Baliga M, Benghuzzi HA, Cason Z. Nodular hematopoiesis of
the liver diagnosed by fine-needle aspiration cytology. Diagn Cytopa-
thol 1997;16:51–54.
Parwani AV, Ali SZ. Pathologic quiz case: a 52-year-old woman with a liver
mass. Arch Pathol Lab Med 2003;127:631–632.
10/26/2006 10:30:25 AM
 250
Hemangioma
Guy CD, Yuan S, Ballo MS. Spindle-cell lesions of the liver: diagnosis by
fine-needle aspiration biopsy. Diagn Cytopathol 2001;25:94–100.
Layfield LJ, Mooney EE, Dodd LG. Not by blood alone: diagnosis of hem-
angiomas by fine-needle aspiration. Diagn Cytopathol 1998;19:
250–254.
Hepatocellular Adenoma
Pedio G, Landolt U, Zobeli L, Gut D. Fine needle aspiration of the liver.
Significance of hepatocytic naked nuclei in the diagnosis of hepatocel-
lular carcinoma. Acta Cytol 1988;32:437–442.
Suen KC. Diagnosis of primary hepatic neoplasms by fine-needle aspiration
cytology. Diagn Cytopathol 1986;2:99–109.
Ciliated Hepatic Foregut Cyst
Hornstein A, Batts KP, Linz LJ, Chang CD, Galvanek EG, Bardawil RG. Fine
needle aspiration diagnosis of ciliated hepatic foregut cysts: a report
of three cases. Acta Cytol 1996;40:576–580.
Zaman SS, Langer JE, Gupta PK. Ciliated hepatic foregut cyst. Report of
a case with findings on fine needle aspiration. Acta Cytol 1995;39:
781–784.
Bile Duct Adenoma
Bhathal PS, Hughes NR, Goodman ZD. The so-called bile duct adenoma is
a peribiliary gland hamartoma. Am J Surg Pathol 1996;20:858–864.
Shibahara H, Tamada S, Goto M, et al. Pathologic features of mucin-
producing bile duct tumors: two histopathologic categories as counter-
parts of pancreatic intraductal papillary-mucinous neoplasms. Am J
Surg Pathol 2004;28:327–338.
Hepatobiliary Cystadenoma
Devaney K, Goodman ZD, Ishak KG. Hepatobiliary cystadenoma and cyst-
adenocarcinoma. A light microscopic and immunohistochemical study
of 70 patients. Am J Surg Pathol 1994;18:1078–1091.
Logrono R, Rampy BA, Adegboyega PA. Fine needle aspiration cytology
of hepatobiliary cystadenoma with mesenchymal stroma. Cancer 2002;
96:37–42
Infl ammatory Pseudotumor
Hosler GA, Steinberg DM, Sheth S, Hamper UM, Erozan YS, Ali SZ. Inflam-
matory pseudotumor: a diagnostic dilemma in cytopathology. Diagn
Cytopathol 2004;31:267–270.
Malhotra V, Gondal R, Tatke M, Sarin SK. Fine needle aspiration cytologic
appearance of inflammatory pseudotumor of the liver. A case report.
Acta Cytol 1997;41:1325–1328.
Hepatocellular Carcinoma
Kulesza P, Torbenson M, Sheth S, Erozan YS, Ali SZ. Cytopathologic grading
of hepatocellular carcinoma on fine-needle aspiration. Cancer 2004;102:
247–258.
Soyuer I, Ekinci C, Kaya M, Genc Y, Bahar K. Diagnosis of hepatocellular
carcinoma by fine needle aspiration cytology. Cellular features. Acta
Cytol 2003;47:581–589.
Takenaka A, Kaji I, Kasugai H, et al. Usefulness of diagnostic criteria for
aspiration cytology of hepatocellular carcinoma. Acta Cytol 1999;43:
610–616.
Wee A, Nilsson B, Tan LK, Yap I. Fine needle aspiration biopsy of hepa-
tocellular carcinoma. Diagnostic dilemma at the ends of the spectrum.
Acta Cytol 1994;38:347–354.
Ch008-F06731.indd 250
FINE NEEDLE ASPIRATION CYTOLOGY
Fibrolamellar Hepatocellular Carcinoma
Davenport RD. Cytologic diagnosis of fibrolamellar carcinoma of the liver
by fine-needle aspiration. Diagn Cytopathol 1990;6:275–279.
Kunz G Jr, Chung J, Ali SZ. Hepatocellular carcinoma-fibrolamellar variant:
cytopathology of an unusual case. Diagn Cytopathol 2002;26:257–
261.
Intrahepatic Cholangiocarcinoma
Dalton-Clarke HJ, Pearse E, Krause T, McPherson GA, Benjamin IS, Blumgart
LH. Fine needle aspiration cytology and exfoliative biliary cytology in
the diagnosis of hilar cholangiocarcinoma. Eur J Surg Oncol 1986;12:
143–145.
Pitman MB. Fine needle aspiration biopsy of the liver. Principal diagnostic
challenges. Clin Lab Med 1998;18:483–506, vi.
Hepatoblastoma
Wakely PE Jr, Silverman JF, Geisinger KR, Frable WJ. Fine needle aspiration
biopsy cytology of hepatoblastoma. Mod Pathol 1990;3:688–693.
Weir EG, Ali SZ. Hepatoblastoma: cytomorphologic characteristics in
serious cavity fluids. Cancer 2002;96:267–274.
Primary Malignant Mesenchymal Tumors
Smith MB, Silverman JF, Raab SS, Towell BD, Geisinger KR. Fine-needle
aspiration cytology of hepatic leiomyosarcoma. Diagn Cytopathol 1994;
11:321–327.
Wee A, Nilsson B. Fine needle aspiration biopsy of hepatic leiomyosar-
coma. An unusual epithelioid variant posing a potential diagnostic
pitfall in a hepatocellular carcinoma-prevalent population. Acta Cytol
1997;41:737–743.
Epithelioid Hemangioendothelioma
Pettinato G. Fine-needle aspiration cytology of epithelioid hemangio-
endothelioma. Diagn Cytopathol 1990;6:438–439.
Soslow RA, Yin P, Steinberg CR, Yang GC. Cytopathologic features of
hepatic epithelioid hemangioendothelioma. Diagn Cytopathol 1997;17:
50–53.
Angiosarcoma
Boucher LD, Swanson PE, Stanley MW, Silverman JF, Raab SS, Geisinger
KR. Cytology of angiosarcoma. Findings in fourteen fine-needle aspira-
tion biopsy specimens and one pleural fluid specimen. Am J Clin Pathol
2000;114:210–219.
Nguyen GK, Husain M. Fine-needle aspiration biopsy cytology of angio-
sarcoma. Diagn Cytopathol 2000;23:143–145.
Primary Hepatic Lymphomas
Collins KA, Geisinger KR, Raab SS, Silverman JF. Fine needle aspiration
biopsy of hepatic lymphomas: cytomorphology and ancillary studies.
Acta Cytol 1996;40:257–262.
Rappaport KM, DiGiuseppe JA, Busseniers AE. Primary hepatic lymphoma:
report of two cases diagnosed by fine-needle aspiration. Diagn Cytopa-
thol 1995;13:142–145.
Metastatic Tumors
Bizjak-Schwarzbartl M. Fine-needle aspiration biopsy in the diagnosis of
metastases in the liver. Diagn Cytopathol 1987;3:278–283.
Parwani AV, Chan TY, Mathew S, Ali SZ. Metastatic malignant melanoma
in liver aspirate: cytomorphologic distinction from hepatocellular car-
cinoma. Diagn Cytopathol 2004;30:247–250.
10/26/2006 10:30:27 AM
 9 Pancreas
Martha Bishop Pitman
INTRODUCTION
Cytologic specimens are obtained from the pancreas
most commonly by fine needle aspiration biopsy
(FNAB). The aspirated tissue from any lesion can be
prepared in a number of different ways: direct smears,
cytospins (Thermo Shandon Instruments), liquid-
based preparations (ThinPrep® [Cytyc Corporation,
Marlborough, MA] or SurePathTM [TriPath, Inc, Burl-
ington, NC]) and cell blocks. Direct smears are the most
common, particularly for solid masses, but specimens
aspirated as a fluid from a cyst are often processed as
cytospins or liquid-based specimens. Liquid-based
preparations eliminate obscuring blood and inflam-
mation and provide excellent cellular preservation;
however, cellular and extracellular material such as
mucin is attenuated and not as apparent as on direct
smears. Preserving some fluid in the liquid form from
cyst aspirates allows for additional slides dedicated to
special stains for mucin, which may assist in detecting
subtle background or intracellular mucin. Aspirates
rinsed in saline can be used for flow cytometry analysis
in cases suspicious of lymphoma. Cell block prepara-
tions are advantageous given the readily available tissue
for immunocytochemistry.
Percutaneous FNAB with computed tomography
(CT) guidance is most commonly used; however, endo-
scopic ultrasound (EUS)-guided FNAB is becoming
increasingly utilized. It is important to recognize that
EUS-guided biopsies traverse the stomach or duodenal
wall, thereby introducing the potential for epithelial and
mucin contamination.
The interpretation of pancreatic cytology should not
occur in a vacuum, and all clinical, radiologic, and ancil-
lary tests need to be incorporated in order to provide an
accurate diagnosis. The differential diagnosis of pancre-
atic masses is initially established from the radiographic
appearance of the mass, and generally falls into two
categories: solid versus cystic mass lesions. Solid masses
are much more common than cystic masses, and adeno-
carcinoma is by far the most common neoplasm in the
pancreas. Solid mass lesions in the differential diagnosis
include chronic pancreatitis, pancreatic endocrine neo-
plasm, acinar cell carcinoma, pancreatoblastoma, and
metastatic neoplasms. The most common cyst in the
pancreas is a pseudocyst. This non-neoplastic cyst needs
to be distinguished from a neoplastic mucinous cyst,
Ch009-F06731.indd 251
serous cyst, and solid neoplasms with cystic degenera-
tion. Cysts with thick septa and significant internal
debris are suspicious for malignancy, and the presence
of a solid mass in the wall of a cyst in suspicious for an
invasive cystic neoplasm.
NORMAL PANCREAS
A significant pitfall in the interpretation of pancreatic
cytology is the over-interpretation of normal pancreatic
epithelium as neoplastic. The pancreas is composed of
exocrine (acinar cells and ducts) and endocrine (islets
of Langerhans) cells. Eighty-five percent of the pan-
creas is exocrine tissue, predominantly acinar epithe-
lium. In benign processes, except in late chronic
pancreatitis, acinar cells dominate aspiration smears.
Acinar epithelium presents as cohesive, small, grape-
like clusters of cells and scattered polygonal single cells
with occasional stripped nuclei (Fig. 9-1). The round,
regular nuclei are central to eccentric, with uniform
chromatin and often quite prominent nucleoli. The
typically abundant granular cytoplasm stains blue–
green with the Papanicolaou stain and purple with a
Romanowsky stain (Fig. 9-2). The Romanowsky stain
highlights scattered small vacuoles in the cytoplasm.
The cytoplasmic granules may not be very visible. The
architectural arrangement of the cells is key to differ-
entiating benign acinar cells from a neoplastic acinar
cell proliferation, the latter generally forming large
sheets and clusters as apposed to the small, uniform,
grape-like clusters of a benign process (see acinar cell
carcinoma).
Normal pancreatic ducts present as large, flat, cohe-
sive sheets of epithelium with round, uniform, evenly
spaced nuclei, yielding the classic glandular ‘honey-
combed’ appearance (Fig. 9-3). The cytoplasm of normal
ductal cells is not visibly mucinous and can best be seen
when the epithelium is present in strips yielding a
‘picket fence’ arrangement, or in sheets with a luminal
edge (Fig. 9-4). Ductal cells have round to oval nuclei,
even chromatin, and generally small, inconspicuous
nucleoli. Features consistent with a non-neoplastic
process on cytology include cohesion and nuclei with
uniform size, shape, chromatin distribution, and spacing.
Distinguishing benign pancreatic ductal epithelium
251
10/26/2006 10:31:42 AM
 252 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 9-1
Normal pancreatic acinar epithe-
lium. The smear pattern of normal
acinar epithelium is one in which
the majority of acinar epithelial
cells maintain a cohesive small
grape-like clustering. Occasional
stripped nuclei can be identified in
the background. Papanicolaou stain,
low power.

A B

FIGURE 9-2
Benign pancreatic acinar epithelium. Acinar cells are uniform with round, regular, central to slightly eccentric nuclei and often quite prominent
nucleoli. The cytoplasm is granular, staining blue–green with the Papanicolaou stain (A) and purple with the Romanowsky stain, which also high-
lights scattered small cytoplasmic vacuoles (B). A, Papanicolaou stain, high power. B, Romanowsky stain, high power.

Ch009-F06731.indd 252 10/26/2006 10:31:43 AM

 CHAPTER 9 Pancreas 253

FIGURE 9-3
Benign pancreatic ductal epithe-
lium. Benign pancreatic ducts often
present as fl at cohesive sheets
with round, uniform, evenly spaced
nuclei, yielding the classic glandu-
lar honeycombed appearance. Papa-
nicolaou stain, high power.

Cytologically, individual islet cells appear uniform and

polygonal with round nuclei, coarse clumped chroma-
tin, small inconspicuous nucleoli, and pale amphophilic
cytoplasm.

NON-NEOPLASTIC MASS LESIONS

CHRONIC PANCREATITIS

Chronic pancreatitis is a progressive inflammatory

disease of the pancreas that destroys the exocrine com-
ponent – and, in some severe cases, the endocrine com-
ponent – of the gland, leading to irreversible morphologic
changes and function.
FIGURE 9-4
Benign pancreatic ductal epithelium. Occasionally, ductal epithelial
cells can be seen in strips on edge demonstrating basal nuclei and apical
columnar cytoplasm. Note that the cytoplasm is non-mucinous. Papa- CLINICAL FEATURES
nicolaou stain, high power.

In the United States, chronic alcohol abuse accounts for

from gastrointestinal epithelium, especially gastric
epithelium, may be impossible. The misinterpretation
of gastrointestinal epithelium as benign ductal epithe-
lium aspirated from a solid mass can lead to a false
negative biopsy that, in reality, has not sampled the
mass at all.
Benign islet cells are not often appreciated on
aspirate smears of a non-neuroendocrine neoplasm.
roughly 70% of all cases of chronic pancreatitis. Other
causes of chronic pancreatitis include obstruction
(stones, abnormal anatomy, scarring, extrinsic com-
pression), autoimmune disease (lymphoplasmacytic
sclerosing pancreatitis), chronic malnutrition, and
heredity. The condition is more common in men than
in women, and occurs over a wide age range, generally
40–60 years of age.

Ch009-F06731.indd 253 10/26/2006 10:31:44 AM

 254
CHRONIC PANCREATITIS – DISEASE FACT SHEET
Incidence
៉ 70% associated with long-term alcohol abuse
Gender and Age Distribution
៉ M > F
៉ 40–60 years
Radiologic Features
៉ Irregular ductal dilation associated with strictures and
calcifications
៉ Focal areas of expansive fibrosis produce a mass-like lesion
simulating carcinoma
Prognosis and Treatment
៉ A benign disease, but the variable loss of exocrine and endocrine
function is irreversible and the risk of developing carcinoma is
increased
៉ Therapy includes enzyme or hormone supplementation
The morphologic changes of the gland, e.g. loss of
exocrine or endocrine tissue and fibrosis, are irrevers-
ible. The risk of developing carcinoma is increased,
particularly with hereditary chronic pancreatitis. The
therapy for exocrine or endocrine dysfunction is enzyme
or hormone supplementation.
R ADIOLOGIC FEATURES
Most cases of chronic pancreatitis are associated with
non-focal lesions, irregular ductal dilation that is
often associated with stricture formation, obstruction,
and calcifications. Pseudocyst formation may also be
present. Focal involvement of the gland may occur, as
well as dense expanses of fibrosis in more diffuse
disease, both conditions creating mass-like lesions that
mimic pancreatic carcinoma.
CYTOPATHOLOGIC FEATURES
The classic cytologic findings in patients with clinical
and endoscopic evidence of the more common alcohol-
related disease include the presence of fibrotic acinar
tissue, fragments of relatively acellular fibrosis, scant
reactive ductal epithelium, and, occasionally, saponi-
fied fat necrosis and/or chalky to granular calcific
debris (Fig. 9-5). Mixed inflammation and histiocytes
may also be present in the background. Cellular stromal
fragments populated with inflammatory cells (>30 per
60×) (Fig. 9-6) is strongly suggestive of autoimmune
pancreatitis – a condition important to recognize, as
patients can be treated with steroids rather than
surgery. Fat necrosis in contrast to coagulative cellular
Ch009-F06731.indd 254
FINE NEEDLE ASPIRATION CYTOLOGY
CHRONIC PANCREATITIS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Mixed ductal and acinar epithelium
៉ Infl ammation in the background and embedded in stromal
fragments
៉ Cellular stromal fragments with infl ammatory cells >30/60× HPF
is associated with autoimmune etiology
៉ Fat necrosis and calcific debris may be present
៉ Ductal epithelium contains relatively evenly spaced, uniform,
polarized nuclei with even to slightly coarse chromatin and
smooth nuclear membranes; nucleoli may be prominent
៉ Cytoplasm is usually non-mucinous (may see mucinous
metaplasia in pancreatic intraepithelial neoplasia)
Differential Diagnosis and Pitfalls
៉ Ductal adenocarinoma
៉ Gastrointestinal contamination (pitfall)
necrosis supports chronic pancreatitis over adenocarci-
noma (Fig. 9-7). Ductal cells are almost always present,
although they may be quite scant, and can show some
nuclear crowding and coarse chromatin. The benign
‘honeycombed’ pattern of nuclear spacing is generally
maintained and chromatin is evenly distributed in the
nucleus, although it may be somewhat coarse and
display conspicuous nucleoli (Fig. 9-8).
Patients with classic clinical and radiologic evidence
of chronic pancreatitis, however, rarely undergo FNAB
for confirmation of the diagnosis. It is the expansive
sclerosis in chronic pancreatitis, especially in auto-
immune pancreatitis, and focal gland involvement by
chronic pancreatitis that results in a mass lesion often
associated with irregular pancreatic duct contours and
bile duct stricture, radiologic features highly suspicious
for adenocarcinoma. The dominance of ductal cells
without acinar cells or calcific debris is the cytologic
finding that raises the differential diagnosis of
adenocarcinoma.
ANCILLARY STUDIES
Currently there is no reliable ancillary study that dis-
tinguishes between benign and malignant pancreatic
glandular epithelium. In early studies, immunocyto-
chemical staining using B72.3 was shown not to stain
benign pancreatic ductal epithelium, while demonstrat-
ing fine perinuclear punctate staining in gastric and
duodenal epithelium, and strong cytoplasmic staining
in malignant pancreatic ductal epithelium; however,
not all carcinomas label with B72.3, so a negative stain
does not exclude carcinoma. Evaluation of the patient
or pancreatic tissue for mutation of the K-ras gene, a
proto-oncogene on chromosome 12p12, remains contro-
versial. Although most carcinomas tend to harbor a
K-ras gene mutation, some cases of chronic pancreatitis
10/26/2006 10:31:45 AM
 CHAPTER 9 Pancreas 255

FIGURE 9-5
Chronic pancreatitis. A mixture of
fibrotic acinar tissue, acellular frag-
ments of fibrous tissue, scant ductal
epithelium, reactive acinar epithe-
lium, infl ammation, saponified fat
necrosis, and chalky granular cal-
cific debris are characteristic
features of chronic pancreatitis.
Papanicolaou stain, low power.

FIGURE 9-6
Autoimmune pancreatitis (lympho-
plasmacytic sclerosing pancreati-
tis). The presence of cellular stromal
fragments populated with infl am-
matory cells of at least 30 per 60×
high-power field correlates with an
autoimmune etiology. Papanicolaou
stain, medium power.

Ch009-F06731.indd 255 10/26/2006 10:31:45 AM

 256 FINE NEEDLE ASPIRATION CYTOLOGY

A B

FIGURE 9-7
Fat necrosis compared to coagulative cellular necrosis. Fat necrosis is identified by the presence of foamy histiocytes, infl ammatory cells, and
background cellular debris, and is characteristic of chronic pancreatitis (A). Cellular necrosis of carcinoma is distinguished by the presence of ghost
cells, infl ammation, and typically residual atypical epithelial cells in the background (B). A and B, Papanicolaou stain, low power.

FIGURE 9-8
Reactive ductal epithelium of
chronic pancreatitis. The honey-
combed pattern of nuclei with rela-
tively even spacing is maintained
in reactive ductal groups of chronic
pancreatitis. The nuclei may dem-
onstrate slight chromatin clumping
and nucleoli. Papanicolaou stain,
high power.

and pancreatic intraepithelial neoplasia do as well, and
not all carcinomas will demonstrate the mutation, so
the diagnostic utility of the test is limited. Patients
suspected of having autoimmune pancreatitis should
undergo serologic testing for IgG4. Although not ele-
vated in all patients with the condition, an elevated
level is strongly associated with autoimmune pancre-
atitis and supports a cytologic diagnosis.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The primary differential diagnosis of chronic pan-
creatitis is ductal adenocarcinoma. The distinction
between benign and reactive ductal epithelium in
chronic pancreatitis and the malignant ductal epithe-
lium of ductal adenocarcinoma can be challenging. The

Ch009-F06731.indd 256 10/26/2006 10:31:46 AM

 CHAPTER 9 Pancreas 257

A B

FIGURE 9-9
Reactive ductal epithelium compared to adenocarcinoma. The reactive ductal epithelium of pancreatitis maintains relative even nuclear spacing,
uniform nuclear size and nuclear membranes, mild nuclear enlargement, and variation within a single group (A). In contrast and although sometimes
quite subtle, adenocarcinomas demonstrate more variability in nuclear size within a single group, uneven nuclear spacing, a loss of polarity, irregular
nuclear membranes with notches, divots, and grooves, as well as nuclear membrane thickening (B). A and B, Papanicolaou stain, high power.

overall cellularity of smears in chronic pancreatitis
is relatively low compared to adenocarcinoma, and is
often composed of ductal epithelium with acinar epi-
thelium and inflammation, in contrast to a pure ductal
cell population in adenocarcinoma. If biopsies are being
performed by EUS, care must be taken not to include
the contaminating epithelium from the gastrointestinal
tract, which may present in the assessment of overall
cellularity, or to misinterpret the gastrointestinal epi-
thelium as benign ductal epithelium of pancreatitis.
The architecture of cell groups in pancreatitis is gen-
erally organized, with flat, monolayered sheets of ductal
cells that display relatively polarized nuclei with minimal
crowding and overlap compared to the subtle loss of
nuclear polarity and nuclear crowding in adenocarci-
noma. Nuclear size is also more uniform and nuclear
membrane abnormalities minimal in chronic pancreati-
tis, whereas nuclear enlargement and variation of
nuclear size within a single group of cells, and nuclear
membranes with notches, divots, grooves, and thicken-
ing favors adenocarcinoma (Fig. 9-9). The nuclear chro-
matin pattern of benign and reactive cells in chronic
pancreatitis demonstrates evenly distributed granular
chromatin, whereas in adenocarcinoma there is hyper-
chromasia or, in well-differentiated adenocarcinoma,
parachromatin clearing. The cytoplasm of ductal cells in
chronic pancreatitis does not usually contain mucin
visible on routine light microscopy, but may be present
and even abundant in well-differentiated adenocarci-
noma, leading to an exaggerated uneven arrangement of
nuclei, a pattern also referred to as ‘drunken honey-
comb’ (see adenocarcinoma section).
Pitfalls in the cytologic diagnosis include misinter-
preting gastrointestinal epithelial contamination from
endoscopic biopsies as originating from the pancreas,
leading to a false adequacy assessment. In addition, aspi-
rates of chronic pancreatitis with significant amounts
of residual acinar epithelium can present a diagnostic
pitfall. Cellular smears of reactive and injured acinar
cells with a loss of the normal cohesive grape-like clus-
tering, interpreted in the setting of a solid mass lesion,
can be misinterpreted as a neoplasm such as acinar cell
carcinoma, solid-pseudopapillary neoplasm, or pancre-
atic endocrine neoplasm (Fig. 9-10). Ductal cells with
mucinous metaplasia (PanIN), especially with dysplasia
(PanIN-2 or -3), may be aspirated in chronic pancreati-
tis and can cause a false positive interpretation.
PSEUDOCYST
A pancreatic pseudocyst is a localized collection of
pancreatic secretions, necrotic debris, and blood that,
by definition, has no epithelial lining.
CLINICAL FEATURES
Pseudocysts occur as a consequence of damage to the
pancreatic parenchyma that results in hemorrhage,
necrosis, and autodigestion of pancreatic tissue from
the release and activation of pancreatic enzymes. The
incidence of this pancreatic injury is highest in patients
with a well-established history of acute pancreatitis,
the most common etiology of which is alcohol abuse.
Approximately 10% of patients with acute pancreatitis
will develop a pseudocyst.
The age and gender of patients with pseudocysts
parallels that of pancreatitis. Alcohol-related pseudo-
cysts are more common in middle-aged men, while

Ch009-F06731.indd 257 10/26/2006 10:31:47 AM

 258 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 9-10
Disrupted acinar epithelial cells in
autoimmune pancreatitis. A rela-
tively cellular smear composed of
disrupted acinar epithelial cells
with a loss of the grape-like orga-
nized clustering and reactive atypia
can mimic a neoplasm such as
pancreatic endocrine neoplasm,
solid-pseudopapillary neoplasm,
and acinar cell carcinoma. Papani-
colaou stain, low power.

R ADIOLOGIC FEATURES
PSEUDOCYST – DISEASE FACT SHEET

Incidence Pseudocysts are usually solitary, small to very large (up

៉ Occurs in ∼10% of patients with acute pancreatitis; also to 20 cm), well-demarcated, thin-walled, unilocular
associated with chronic pancreatitis and trauma peripancreatic cysts that can occur anywhere in the
pancreas, but are most common in the pancreatic tail.
Gender and Age Distribution
៉ Age and gender are dependent on etiology
៉ Alcohol-related cysts are more common in middle-aged men
៉ Traumatic, biliary, and hereditary causes of pancreatitis lead to CYTOPATHOLOGIC FEATURES
pseudocysts relatively equally in men and women

Radiologic Features The cyst fluid aspirated from an uncomplicated pseu-

៉ Typically, single, unilocular, thin-walled cysts without septations,
occurring anywhere in the pancreas
Prognosis and Treatment
៉ Pseudocysts may resolve spontaneously, but can grow in size
៉ Undrained pseudocysts can rupture, erode into vessels, cause
obstruction, and get infected
៉ Treatment is usually drainage or resection
docyst is generally thin, brown to green, and non-
mucinous. A complicated pseudocyst, however, may
produce thick mucoid-appearing fluid due to the pres-
ence of inflammation. Cytologically, the characteristic
features include degenerative cyst debris with acute
and chronic inflammatory cells, histiocytes, hemosid-
erin, and often bile (Fig. 9-11). By definition, there are
no cyst-lining epithelial cells.

pseudocysts secondary to trauma, biliary disease, and
heredity pancreatitis are relatively equal in men and
women.
Pseudocysts can be complicated by rupture, hemor-
rhage due to erosion into a vessel, obstruction of sur-
rounding structures, and infection. Pseudocysts may be
medically managed, but most are drained or resected.
ANCILLARY STUDIES
To exclude a mucinous cyst, testing the fluid for thin
mucin not appreciated on routine cytology can be done
on cytospin preparations. The typical special stains
for mucin include mucicarmine and Alcian blue
pH 2.5. Chemical analysis of the fluid for amylase and

Ch009-F06731.indd 258 10/26/2006 10:31:48 AM

 CHAPTER 9 Pancreas 259

FIGURE 9-11
Pseudocyst. The characteristic
contents of a pseudocyst include
infl ammatory debris, histiocytes,
and, occasionally, bile pigment.
Papanicolaou stain, high power.

DIFFERENTIAL DIAGNOSIS AND PITFALLS

PSEUDOCYST – PATHOLOGIC FEATURES

Cytopathologic Features The differential diagnosis of pseudocyst includes true

៉ Scant cellularity
៉ Amorphous cyst debris
៉ Infl ammation and bile variable
៉ Histiocytes
៉ No epithelial cells
Ancillary Studies
៉ Histochemical stains: mucicarmine and/or Alcian blue pH 2.5 are
negative
៉ Cyst fluid analysis: amylase high; CEA low
Differential Diagnosis and Pitfalls
៉ Lymphoepithelial cyst
៉ Unilocular or oligolocular variant of serous cystadenoma
៉ Mucinous cystic neoplasm
៉ Intraductal papillary mucinous neoplasm
៉ Solid-pseudopapillary neoplasm
៉ Cystic pancreatic endocrine neoplasm
៉ Gastrointestinal contamination (pitfall)
carcinoembryonic antigen (CEA) is also very helpful.
Amylase is consistently elevated (thousands of U/L) in
pseudocysts, due to the connectivity of the cyst with
the pancreatic ductal system. A cyst fluid with a very
low amylase level is highly unlikely to be a pseudocyst.
Pseudocysts typically have an undetectable or very low
CEA level, whereas mucinous cysts generally have
levels of CEA >200 ng/mL.
cysts of the pancreas and peri-pancreas. True cysts of
the pancreas that can be confused with pseudocyst
include lymphoepithelial cyst, oligocystic and unilocu-
lar variants of serous cystadenoma, mucinous cystic
neoplasm, and intraductal papillary mucinous neo-
plasm. Peripancreatic cysts in the differential diagnosis
include duodenal duplication cysts, cystic gastro-
intestinal stromal tumors, and mesenteric cysts. Solid
neoplasms with cystic degeneration should also be
considered, such as solid-pseudopapillary neoplasm
and pancreatic endocrine neoplasms.
Contamination of the specimen with epithelial or
mesothelial cells from the surrounding pancreatic paren-
chyma, peritoneum, and especially the gastrointestinal
tract from EUS-guided biopsies may produce a potential
diagnostic pitfall. Duodenal epithelium is relatively
characteristic in appearance, presenting as large, folded
sheets of glandular epithelium with uniformly spaced,
round, regular nuclei and studded with goblet cells (see
Fig. 9-49). Gastric epithelium is more difficult to recog-
nize and distinguish from the cyst-lining epithelium of
a mucin-producing cystic neoplasm, as it often presents
in smaller sheets and clusters as well as single cells, and
can display cytoplasmic mucin (see Fig. 9-50). Histio-
cytes can also be mistaken for mucinous epithelial cells,
leading to the incorrect diagnosis of mucin-producing
neoplastic cyst. On the other hand, the absence of cyst-
lining epithelium and detectable mucin in mucinous
cystic neoplasms may lead to the incorrect diagnosis of

Ch009-F06731.indd 259 10/26/2006 10:31:49 AM

 260
pseudocyst. As such, correlation of the cytologic fea-
tures and ancillary studies with the clinical and radio-
logic findings is imperative.
LYMPHOEPITHELIAL CYST
Lymphoepithelial cysts are benign cysts lined by squa-
mous epithelium with subepithelial non-neoplastic
lymphoid tissue.
CLINICAL FEATURES
These cysts are rare, representing approximately 0.05%
of all pancreatic cysts. They are much more common
in men than in women, with a male to female ratio of
4 : 1. It is a cyst of older adults, with a mean age of 56
years.
Lymphoepithelial cysts are benign, with no reported
cases of malignant transformation. Conservative resec-
tion is curative.
R ADIOLOGIC FEATURES
Lymphoepithelial cysts may be unilocular or multi-
locular and generally have thick-appearing walls with
internal debris that corresponds to keratinous debris.
The cysts average almost 5 cm in diameter, with a wide
range of little over 1 cm to 17 cm. They can occur any-
where in the pancreas, and may even appear
extra-pancreatic.
LYMPHOEPITHELIAL CYST – DISEASE FACT SHEET
Incidence
៉ ∼0.05% of all pancreatic cysts
Gender and Age Distribution
៉ Male to female ratio is 4 : 1
៉ Mean age 56 years
Radiologic Features
៉ Unilocular or multilocular cysts averaging ∼5 cm anywhere in the
pancreas or extra-pancreatic area, with thick-appearing walls and
internal debris
Prognosis and Treatment
៉ The cysts are benign and prognosis is excellent
៉ Conservative resection is curative
Ch009-F06731.indd 260
FINE NEEDLE ASPIRATION CYTOLOGY
LYMPHOEPITHELIAL CYST – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Keratinous debris with anucleated and nucleated squamous cells
៉ Background lymphocytes, histiocytes, and cholesterol crystals
៉ May see intact cyst wall with squamous lining cells and
subepithelial lymphoid tissue
Differential Diagnosis and Pitfalls
៉ Pseudocyst
៉ Dermoid cyst
៉ Epidermoid cyst with accessory splenic tissue
CYTOPATHOLOGIC FEATURES
The cytologic appearance is similar to that of an epi-
dermal inclusion cyst, with nucleated and anucleated
squamous cells, keratinous and cholesterol debris. His-
tiocytes and lymphocytes may be noted in the back-
ground. Intact cyst wall with subepithelial lymphoid
tissue may also be seen (Fig. 9-12).
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis is with other squamous-lined
cysts such as a dermoid cyst of the pancreas and splenic
epidermoid cyst, both benign cysts more rare than lym-
phoepithelial cyst. A pseudocyst is also in the differential
diagnosis due to the necrotic appearance of the kerati-
nous debris. The keratinous nature of the cyst contents
is usually apparent on close inspection, however.
SOLID NEOPLASMS
DUCTAL ADENOCARCINOMA
AND ITS VARIANTS
Ductal adenocarcinoma is an invasive malignant neo-
plasm arising from the glandular epithelium of the pan-
creatic ducts which may produce mucin and which can
have variant morphology including signet-ring cells,
squamous cells, pleomorphic giant cells, and osteoclast-
type giant cells.
CLINICAL FEATURES
Ductal adenocarcinoma is the fourth leading cause of
death from cancer in men, women, and overall in the
10/26/2006 10:31:50 AM
 CHAPTER 9 Pancreas 261

FIGURE 9-12
Lymphoepithelial cyst. A back-
ground of anucleated squamous
cells and keratinous debris are
typical of the contents of a lympho-
epithelial cyst. The presence of an
intact cyst wall with squamous cell
lining and subepithelial lymphoid
tissue may occasionally be seen, as
shown here. Papanicolaou stain,
high power.

sis is directly related to resectability, surgical resection

DUCTAL ADENOCARCINOMA – DISEASE FACT SHEET
Incidence
៉ 11 per 100,000
៉ 4th leading cause of cancer death in men and women
Gender and Age Distribution
៉ M > F by 30%
៉ Peak incidence, 7th to 8th decade
Radiologic Features
៉ Hypodense mass with a poorly defined periphery and often a
‘double duct’ sign from dilation of both the pancreatic and bile
ducts
Prognosis and Treatment
៉ 5-year survival rate is 3–4%
៉ Surgical resection is the treatment of choice
United States. It is the eighth leading cause of cancer
death worldwide. This malignancy, including variants,
represents approximately 90% of all pancreatic malig-
nancies. Heredity accounts for approximately 10% of
cases.
Most cases of pancreatic cancer occur between 60
and 80 years of age, and it is more common in men than
in women by about 30%.
The prognosis of pancreatic cancer is universally
poor, with a 5-year survival rate of less than 5%, a rate
that has not significantly improved in decades. Progno-
being the treatment of choice. Patients with unresect-
able tumors typically survive less than 6 months.
R ADIOLOGIC FEATURES
Ductal carcinomas are most commonly staged by high-
resolution helical CT and/or EUS. On CT, tumors
appear as poorly defined, hypodense masses with
central attenuation that deform the normal lobulations
of the pancreas and frequently demonstrate an abrupt
stricture in the main pancreatic duct. When tumors
occur in the pancreatic head, the characteristic ‘double
duct’ sign corresponding to the dually dilated main
pancreatic and bile ducts may be present. On EUS, the
tumors typically appear hypoechoic. A loss of a tissue
interface between the tumor and the large peripancre-
atic vessels (superior mesenteric or celiac axis) indi-
cates invasion and stages the tumor as unresectable.
CYTOPATHOLOGIC FEATURES
CONVENTIONAL TUBULAR-TYPE DUCTAL ADENOCARCINOMA
The morphologic features of ductal adenocarcinoma
vary by tumor grade. High-grade (moderately and poorly
differentiated) tumors typically do not pose a diagnostic
challenge, given the overt malignant features of the

Ch009-F06731.indd 261 10/26/2006 10:31:50 AM

 262
DUCTAL ADENOCARCINOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellularity varies with degree of sclerosis
៉ Relatively pure population of ductal cells
៉ Loss of honeycomb architecture with nuclear crowding,
overlapping, loss of polarity, and uneven spacing (‘drunken
honeycomb’)
៉ Irregular nuclear membranes; may be subtle in well-
differentiated carcinoma
៉ Hyperchromasia generally, but often pale nuclei with
parachromatin clearing in well-differentiated carcinoma
៉ Cytoplasm may be scant to abundant and may show
vacuolization
៉ Variant cytology: adenosquamous; colloid (mucinous non-
cystic); undifferentiated (anaplastic); undifferentiated with
osteoclast-type giant cells; signet-ring cell
Ancillary Studies
៉ Immunocytochemical stains (+): cytokeratins AE1/AE3, CAM 5.2,
CK7, CK8, CK13, CK18, and CK19; CA 19-9, B72.3, CA 125, and
DUPAN-2; MUC1, MUC3, MUC4, and MUC5C
Differential Diagnosis and Pitfalls
៉ Chronic pancreatitis, including autoimmune or
lymphoplasmacytic sclerosing pancreatitis
៉ Intraductal papillary mucinous neoplasm with invasive
carcinoma
៉ Mucinous cystic neoplasm with invasive carcinoma
៉ Metastatic adenocarcinoma
៉ Acinar cell carcinoma
៉ Pancreatic endocrine neoplasm
neoplasm, whereas well-differentiated tumors present
more of a challenge.
In general, aspiration biopsy of carcinoma produces
cellular smears; however, cellularity can vary greatly
and aspirates may be quite paucicellular in tumors with
dense sclerosis. Overall cellularity is also related to the
experience of the interventional radiologist and the
method of biopsy. The technical difficulty of EUS-guided
biopsy relative to percutaneous biopsy can result in a
lower cellular yield. Gastrointestinal contamination can
contribute to what appears to be a highly cellular speci-
men on EUS-guided biopsy and care must be taken to
carefully distinguish epithelium from the stomach and
duodenum from pancreatic ductal epithelium.
The smear background can contain helpful clues to
the diagnosis. Abundant background mucin and coagu-
lative necrosis are features suspicious for, but not inde-
pendently diagnostic of, carcinoma. Coagulative necrosis
is cellular necrosis with ghost tumor cells still visible,
which contrasts with fat necrosis, where saponification
and liquefactive necrosis contain foamy histiocytes with
the inflammation (see Fig. 9-7). If the biopsy is by EUS,
background mucin may be a contaminant, but contami-
nating mucin is typically not abundant, as can be present
in mucin-producing invasive adenocarcinoma.
The composition of the cellular elements on the slide
is important in assessing benign versus malignant.
Ch009-F06731.indd 262
FINE NEEDLE ASPIRATION CYTOLOGY
Smears of carcinoma typically contain only ductal
groups. Smears composed of acinar and ductal groups
should increase the threshold for a malignant diagnosis.
The presence of granulation tissue and fibrous tissue
fragments with inflammation are also features that
are more associated with pancreatitis than with
carcinoma.
The architectural arrangement of epithelial cells in
carcinoma ranges from large crowded sheets to small
three-dimensional clusters and balls to single cells.
Single intact cells are common in high-grade carcinoma
and may be scattered in the smear background or seen
at the edge of more cohesive groups (Fig. 9-13). The
presence of single atypical intact epithelial cells in well-
differentiated carcinoma is significant and supports a
malignant interpretation.
In high-grade carcinoma, the cellular features of
malignancy are overt. The cells have a high nuclear to
cytoplasmic (N/C) ratio and thus increased nuclear
density in cell clusters and sheets relative to benign
ductal groups (Fig. 9-14). Dense nucleation results in
cellular crowding, nuclear overlapping, and loss of
nuclear polarity. The nuclei are enlarged, usually at
least two to three times the size of a normal ductal
cell nucleus, with anisonucleosis of at least three
times within a single sheet, hyperchromasia, irregular
nuclear membranes, and, often, prominent nucleoli
(Fig. 9-15).
In well-differentiated carcinomas, the nuclei are not
as enlarged as in high-grade carcinomas (2.5 times the
size of a red blood cell on air-dried smears) (Fig. 9-16),
and can be subtly crowded or show wide and uneven
spacing. When crowded, the nuclei have a tendency to
overlap at least focally and demonstrate a loss of polarity
and loss of smoothness of the nuclear membranes. With
more abundant, often mucinous cytoplasm, the varia-
tion in cell size and cytoplasmic volume leads to an
irregular and uneven spacing of the nuclei in the sheet
or group, which has been termed ‘drunken honeycomb’,
a feature that contrasts to the generally regular and even
nuclear spacing seen in benign ductal groups (Fig. 9-17).
An extremely benign-appearing, well-differentiated
variant of adenocarcinoma with voluminous mucinous
cytoplasm, termed ‘foamy gland adenocarcinoma’ (Fig.
9-18), has been described. The nuclear chromatin in
well-differentiated carcinomas can be hyperchromatic,
but commonly demonstrates more clearing than clump-
ing (parachromatin clearing) (Fig. 9-19). These subtle
nuclear changes coupled with slight nuclear crowding
and overlapping are the key to a diagnosis of well-
differentiated carcinoma.
CYTOMORPHOLOGY OF ADENOCARCINOMA VARIANTS
Adenosquamous carcinoma is an extremely aggressive
variant of ductal adenocarcinoma in which dual lines
of glandular and squamous differentiation are present.
The cytologic diagnosis is dependent on recognizing
these two malignant cellular components on aspirate
smears. The diagnosis is straightforward when both the
glandular and squamous components are prominent
(Fig. 9-20); however, when either component is scant,
10/26/2006 10:31:51 AM
 CHAPTER 9 Pancreas 263

FIGURE 9-13
Ductal adenocarcinoma. Hyperchro-
matic crowded groups and intact
single malignant cells are architec-
tural features typical of adeno-
carcinoma. Papanicolaou stain, high
power.

FIGURE 9-14
Ductal adenocarcinoma, high grade.
High-grade adenocarcinomas are
relatively easy to recognize due to
the overt features of malignancy,
including dense nucleation, high
N/C ratio, loss of nuclear polarity,
and irregular nuclear membranes.
Papanicolaou stain, high power.

Ch009-F06731.indd 263 10/26/2006 10:31:51 AM

 264 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 9-15
Adenocarcinoma compared to
benign ductal epithelium. The group
of adenocarcinoma on the right
is distinguished from the benign
ductal group on the left by
the nuclear enlargement, uneven
nuclear spacing, and anisonucleosis
of at least three times within a
single sheet. Papanicolaou stain,
low power.

FIGURE 9-16
Adenocarcinoma, well differenti-
ated. The anisonucleosis in well-
differentiated adenocarcinoma is
not as dramatic as with high-grade
carcinomas, demonstrating mild
variability and nuclear enlargement
of approximately 2 1/2 times the size
of a red blood cell (which is noted
to the right of the cell cluster).
Hema III stain, high power.

Ch009-F06731.indd 264 10/26/2006 10:31:52 AM

 CHAPTER 9 Pancreas 265

FIGURE 9-17
Adenocarcinoma, well differenti-
ated. The uneven nuclear spacing
combined with abundant volumi-
nous cytoplasm yields a disarray
often referred to as ‘drunken honey-
comb’. Papanicolaou stain, high
power.

FIGURE 9-18
Foamy gland adenocarcinoma. This
variant of well-differentiated ade-
nocarcinoma is characterized by
voluminous mucinous cytoplasm
and a very bland, almost benign
cytologic appearance. Papanicolaou
stain, high power.

Ch009-F06731.indd 265 10/26/2006 10:31:53 AM

 266 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 9-19
Adenocarcinoma, well differenti-
ated. In contrast to hyperchromasia
typical of most adenocarcinomas
of the pancreas, the presence of
nuclear clearing with peripheral
clumping (also known as para-
chromatin clearing) is a feature
characteristic of well-differentiated
neoplasms. Papanicolaou stain,
medium power.

FIGURE 9-20
Adenosquamous carcinoma. This
variant of ductal adenocarcinoma is
recognized by the presence of both
malignant glandular and squamous
components. Papanicolaou stain,
medium power.

Ch009-F06731.indd 266 10/26/2006 10:31:54 AM

 CHAPTER 9 Pancreas
FIGURE 9-21
Signet-ring cell adenocarcinoma.
This variant of ductal adenocarci-
noma is recognized by the promi-
nence of the signet-ring cell, a
small malignant cell with a cyto-
plasmic vacuole that indents the
nucleus. Papanicolaou stain, high
power.
the diagnosis can be challenging. A careful search for
glandular differentiation is warranted in squamous-
predominant cases, in particular, given the virtual non-
existence of primary squamous cell carcinoma of the
pancreas and thus the potential for a misdiagnosis of a
metastasis.
Colloid (mucinous non-cystic) carcinoma on histology
is similar to colloid carcinomas of the colon and breast,
where the vast majority of the infiltrating tumor cells
(>80% in the pancreas) are present floating in pools of
mucin. These neoplasms are rare and most are found
in association with an intraductal papillary mucinous
neoplasm. Aspiration produces thick viscous mucin that
may or may not contain an identifiable epithelial com-
ponent. Recognition of malignant cells in the thick
mucin, however, is necessary for the diagnosis of a
malignant mucin-producing neoplasm.
The distinction from an in-situ neoplasm that may
also produce only thick viscous mucin is by the fact that
the aspiration is of a solid mass that may or may not be
arising in the wall of a cyst or dilated duct. The issue of
gastrointestinal contamination should not be of concern,
given the abundance of thick mucin.
Signet-ring cell carcinoma is a variant of ductal adeno-
carcinoma in which the predominant infiltrating tumor
cell is a signet-ring cell. Aspirate smears are character-
ized by small collections of cells or individual cells with
a vacuole of intracellular mucin that typically indents
the nucleus, a feature that is helpful in distinguishing
the tumor cells from histiocytes (Fig. 9-21).
Ch009-F06731.indd 267
267
Undifferentiated (anaplastic) carcinoma is a variant
of ductal adenocarcinoma in which there is a loss of
glandular differentiation and tumor cells display large,
polygonal to spindled, often bizarre (anaplastic) and
multinucleated features. The aspirate smears may not
be hypercellular, but the malignant cells present are
unquestionably malignant, with wildly pleomorphic
mononuclear and multinuclear tumor giant cells (Fig.
9-22). These large tumor cells are present in small clus-
ters, and singly may appear spindled and sarcomatoid.
Frequent mitotic activity, cellular cannibalism, and
background necrosis are commonly noted.
Undifferentiated carcinoma with osteoclast-type giant
cells is a rare variant of ductal adenocarcinoma in which
the malignant, usually mononuclear, epithelial cells are
admixed with benign osteoclast-type giant cells. Approx-
imately 40% of these tumors arise in association with
a glandular neoplasm such as conventional adenocarci-
noma and mucinous cystic neoplasms. Aspirate smears
are typically hypercellular with two cell populations, an
obviously malignant mononuclear epithelial prolifera-
tion and benign-appearing osteoclast-like giant cells.
The giant cells vary in number and often contain 10 or
more bland-appearing, centrally clustered and slightly
overlapping nuclei with even chromatin and occasion-
ally prominent nucleoli (Fig. 9-23). The mononuclear
cells appear singly or in small clusters and can range
from medium-sized polygonal epithelioid cells with
clear cytoplasm to large bizarre sarcomatoid cells with
dense and/or spindled cytoplasm.
10/26/2006 10:31:55 AM
 268 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 9-22
Undifferentiated carcinoma. This
variant of ductal adenocarcinoma is
characterized by large, bizarre, ana-
plastic or pleomorphic, mononuclear
to multinucleated giant tumor cells.
Papanicolaou stain, high power.

FIGURE 9-23
Undifferentiated carcinoma with
osteoclast-type giant cells. This
rare variant of ductal adenocarci-
noma is composed of a malignant
mononuclear epithelial cell popu-
lation admixed with benign
osteoclast-type giant cells. Papani-
colaou stain, low power.

Ch009-F06731.indd 268 10/26/2006 10:31:56 AM

 CHAPTER 9 Pancreas
ANCILLARY STUDIES
Special stains for mucin (mucicarmine, Alcian blue
pH 2.5) may demonstrate intracytoplasmic mucin that
helps to classify the neoplasm as an adenocarcinoma.
Immunocytochemical stains can help specify the ade-
nocarcinoma as pancreatic in origin. Most pancreatic
adenocarcinomas are positive for cytokeratins AE1/
AE3, CAM 5.2, CK7, CK8, CK18, and CK19, with about
half expressing CK17 and less than 20% expressing
CK20. CEA, B72.3, CA 125, and DUPAN-2 also stain
tumor cells of pancreatic adenocarcinoma. Mucin
glycoproteins (MUC) are variably expressed, with
most tumors expressing MUC1, MUC3, MUC4, and
MUC5AC, and a minority expressing MUC6 (∼25%)
and MUC2 (<10%). Antibodies against the protein
product dpc4 correlates with the DPC4/MADH4 gene
status, so the loss of dpc4, noted in a little more than
50% of pancreatic adenocarcinomas, helps to distin-
guish malignant from benign, since all benign glandu-
lar epithelium of the pancreas demonstrate dpc4
positivity.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis of pancreatic carcinoma is
dependent on grade. High-grade adenocarcinoma can
be confused with acinar cell carcinoma, pancreatic
endocrine neoplasms, and metastatic malignancies.
The smear pattern of adenocarcinoma tends to be more
FIGURE 9-24
Metastatic renal cell carcinoma.
Metastases should always be con-
sidered in the evaluation of carci-
nomas in the pancreas. One of the
more common carcinomas meta-
static to the pancreas, renal cell
carcinoma is characterized by a
polygonal cell shape, clear to dense
cytoplasm, and a prominent central
nucleolus that may be surrounded
by a clear halo, yielding an ‘owl’s
eye’ appearance. Papanicolaou
stain, high power.
Ch009-F06731.indd 269
269
clustered with scattered single cells, whereas acinar
cell carcinoma and pancreatic endocrine neoplasms
produce a more single cell smear pattern with occa-
sional cell clusters. The cells of high-grade carcinoma
demonstrate much more nuclear atypia than the cells
of the typical acinar cell carcinoma and neuroendo-
crine neoplasm, showing significant nuclear membrane
abnormalities and marked hyperchromasia. This is in
contrast to the rounder, more central and less convo-
luted nuclei of both acinar cell carcinoma and pancre-
atic endocrine neoplasms. Nucleoli may be prominent
in all three of these neoplasms, but are usually more
prominent and irregular in adenocarcinoma. The chro-
matin is also more coarse and clumped (‘salt and
pepper’) in endocrine neoplasms than in adenocarci-
noma. The cytoplasmic differences are also important,
as high-grade adenocarcinomas display either scant,
wispy cytoplasm or abundant, often mucinous cyto-
plasm, whereas acinar cells tend to have granular cyto-
plasm and endocrine neoplasms display eccentric,
dense to finely granular, non-mucinous cytoplasm.
Although extremely rare compared to primary ade-
nocarcinoma, metastatic malignancies should always be
considered in the differential diagnosis of a high-grade
adenocarcinoma. A common carcinoma metastatic to
the pancreas is renal cell carcinoma. Renal cell carci-
noma is recognized by the large polygonal cells which
may be single, in small clusters, or loosely attached to
traversing vessels. The nuclei are usually round and
central with large macronucleoli frequently surrounded
by a clear halo (‘owl’s eye appearance’) (Fig. 9-24). The
cytoplasm is distinguished from that of ductal adenocar-
cinoma by the presence of multiple fine vacuoles (best
10/26/2006 10:31:57 AM
 270
appreciated on air-dried smears), in contrast to the often
large single vacuoles of adenocarcinoma.
Well-differentiated adenocarcinoma can be confused
with benign ductal epithelium in chronic pancreatitis
(discussed more fully in the section on chronic pancre-
atitis), high-grade dysplastic ductal epithelium (pancre-
atic intraepithelial neoplasia, PanIN-2 or -3), and with
reactive glandular epithelium from the stomach or
duodenum contaminating the specimen in EUS-guided
biopsies.
PANCREATIC ENDOCRINE NEOPLASM
Pancreatic endocrine neoplasms (PENs) are mostly
low-grade well-differentiated malignant neoplasms of
the endocrine cells of the pancreas, which are classified
by grade, size, and functional status.
CLINICAL FEATURES
The vast majority of PENs are well-differentiated
tumors, representing about 5% of all pancreatic tumors.
The peak age of incidence is 50–60 years of age, but
PENs can occur in all age groups. Men and women are
equally affected.
The biologic behavior of PENs is difficult, if not
impossible, to predict from cytologic evaluation. The
architectural pattern and cellular pleomorphism, fea-
tures of the neoplasms that can be evaluated on cytol-
ogy, do not correlate with prognosis. Prognosis is highly
dependent on tumor size at detection, a feature that is
often related to the association of the neoplasm with a
syndrome, in addition to ‘favorable’ histologic features
PANCREATIC ENDOCRINE NEOPLASM – DISEASE FACT SHEET
Incidence
៉ ∼2–5% of pancreatic neoplasms
៉ ∼50% are functional and 50% non-functional
Gender and Age Distribution
៉ M = F
៉ Any age, but most between 40 and 60 years
Radiologic Features
៉ Solid, well-circumscribed masses, usually small (<2 cm), but may
be large (>6 cm); can be cystic
Prognosis and Treatment
៉ Prognosis is related to tumor size, mitotic rate, necrosis, extra-
pancreatic invasion, vascular invasion, and nodal or distant
metastases
៉ Small neoplasms without adverse prognostic features are curable
by surgical resection
Ch009-F06731.indd 270
FINE NEEDLE ASPIRATION CYTOLOGY
such as the absence of vascular or perineural invasion,
and less than two mitoses per high-powered field. As
such, it is prudent to confine the cytologic diagnosis to
‘pancreatic endocrine neoplasm’ in most cases.
R ADIOLOGIC FEATURES
By CT scan, most PENs appear as enhancing, solid,
well-circumscribed masses. Cystic degeneration can
occur and calcification is occasionally seen.
CYTOPATHOLOGIC FEATURES
Aspirate smears are generally hypercellular, often with
a bloody background, and are composed of a monoto-
nous population of small to medium-sized polygonal
cells. The tumor cells are mostly single (Fig. 9-25), but
small to medium-sized groups can also be seen. The
nuclei are round, usually bland and uniform, with
coarse, stippled ‘salt and pepper’ chromatin (Fig. 9-26).
Nucleoli may be inconspicuous, but can be quite promi-
nent (Fig. 9-26). Nuclear atypia is variable. Significant
pleomorphism may be present (Fig. 9-27), but this
feature should not lead to a malignant diagnosis. The
relatively scant cytoplasm is usually dense and eccen-
tric, yielding a plasmacytoid appearance. Rare variants
of PEN, such as oncocytic (Fig. 9-28) and clear cell
PANCREATIC ENDOCRINE NEOPLASM – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Dyshesive, single cell smear pattern; few small clusters
៉ Uniform, monotonous population of cells with plasmacytoid
features
៉ Coarse, speckled, ‘salt and pepper’ chromatin pattern
៉ Nucleoli may be prominent
៉ Dense, finely granular cytoplasm; rarely clear or oncocytic
cytoplasm
Ancillary Studies
៉ Histochemical stains: positive for Grimelius stain and PAS
៉ Immunocytochemical stains: cytokeratins CAM 5.2 and AE1/AE3
are usually positive; chromogranin, synaptophysin, Leu-7, and
NSE are typically positive; insulin, glucagon, somatostatin, and
pancreatic polypeptide are variably positive; gastrin, vasoactive
intestinal polypeptide, cholecystokinin, and adrenocorticotropic
hormone may occasionally be positive
៉ Electron microscopy: neurosecretory granules
Differential Diagnosis and Pitfalls
៉ Acinar cell carcinoma
៉ Solid-pseudopapillary neoplasm
៉ Pancreatoblastoma
៉ Plasmacytoma
៉ Normal acinar cell epithelium (pitfall)
10/26/2006 10:31:58 AM
 CHAPTER 9 Pancreas 271

FIGURE 9-25
Pancreatic endocrine neoplasm. The
typical aspirate smears are hyper-
cellular, composed of a predomi-
nantly single cell population of
small to medium-sized, monotonous
polygonal cells that may be associ-
ated with a prominent vascular
component. Papanicolaou stain,
medium power.

FIGURE 9-26
Pancreatic endocrine neoplasm
(PEN) with cystic degeneration.
Cystic PENs are cytologically similar
to solid PENs. The typical coarse
stippled ‘salt and pepper’ chromatin
pattern is similar in both neo-
plasms. Although nucleoli are not
very prominent in most PENs, they
can be quite prominent, as illus-
trated here. Papanicolaou stain,
high power.

Ch009-F06731.indd 271 10/26/2006 10:31:58 AM

 272 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 9-27
Pancreatic endocrine neoplasm. The
presence of nuclear pleomorphism
and mitotic activity cannot be used
as criteria for the diagnosis of
malignancy. Papanicolaou stain,
high power.

FIGURE 9-28
Pancreatic endocrine neoplasm,
oncocytic variant. The presence of
abundant dense, oncocytic cyto-
plasm characterizes this variant.
Papanicolaou stain, medium power.

Ch009-F06731.indd 272 10/26/2006 10:31:59 AM

 CHAPTER 9 Pancreas
FIGURE 9-29
Pancreatic endocrine neoplasm
(PEN), clear cell variant. In contrast
to the typical dense granular cyto-
plasm of most PENs, the cytoplasm
of the clear cell variant demon-
strates cytoplasmic vacuolization
ranging from large vacuoles to small
multiple vacuoles. These neoplasms
can identically mimic renal cell car-
cinomas. Hema III stain, high
power.
(Fig. 9-29), exist. Mitotic figures and necrosis are
uncommon features but may be seen on cytology and
are features that should be noted in the cytology report.
The cytologic features of a cystic PEN are similar to
those of solid neoplasms. High-grade large cell neuro-
endocrine carcinoma and small cell neuroendocrine
carcinoma are neoplasms that appear cytologically
malignant, resembling similar neoplasms in the lung.
ANCILLARY STUDIES
Documenting endocrine differentiation is most com-
monly performed with immunocytochemical staining
for chromogranin and/or synaptophysin, markers posi-
tive in over 95% of tumors. Synaptophysin produces
a consistently strong and diffuse staining pattern,
whereas chromogranin staining can be quite focal.
CD57 (Leu-7) and CD56 (neural cell adhesion mole-
cule) also stain most tumors. Labeling the tumors for
specific peptides demonstrates a wide range of positiv-
ity, the nature of which does not necessarily correlate
with a syndrome. Most PENs also stain with cytokera-
tins CAM 5.2 and AE1/AE3.
Flow cytometry of aspirated tissue may be useful in
distinguishing PEN from non-Hodgkin lymphoma and
plasmacytoma.
Electron microscopy will identify numerous and
randomly distributed neurosecretory granules in PEN.
Ch009-F06731.indd 273
273
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis is dependent on the degree
of cellular atypia. The differential diagnosis of
well-differentiated PEN most commonly includes solid-
pseudopapillary tumor, acinar cell carcinoma, non-
Hodgkin lymphoma, and plasmacytoma. Clear cell and
oncocytic PEN variants can be confused with primary
and metastatic neoplasms with similar cytoplasmic fea-
tures. High-grade PEN demonstrating significant cel-
lular atypia and pleomorphism can be misdiagnosed as
high-grade pancreatic adenocarcinoma and other high-
grade malignancies. Normal acinar cells when aspi-
rated in abundance and with a disrupted architecture
are a pitfall for a false positive diagnosis of PEN (see
Fig. 9-10).
One of the more common neoplasms to be confused
with PEN in women especially is the solid-pseudopapil-
lary tumor. This tumor is distinguished by papillary
groups with vascular cores and myxoid stroma, but this
smear pattern may not be well demonstrated in all cases.
When absent, the bland, oval more than round nuclei,
nuclear grooves, small perinuclear vacuoles, and scant
non-plasmacytoid cytoplasm help to diagnose a solid-
pseudopapillary tumor. Recognizing the stippled chro-
matin of PEN is also helpful.
Acinar cell carcinoma can also closely resemble PEN
on smears. Aspirates of PEN produce mostly single cells
and some cell clusters, in contrast to acinar cell carci-
noma, where cell clusters predominate. Although nucle-
10/26/2006 10:32:00 AM
 274
oli are typically more prominent in acinar cell carcinoma,
PEN can demonstrate very prominent nucleoli, so this
feature is not discriminatory, but the characteristic
stippled ‘salt and pepper’ chromatin pattern of PEN, a
pattern absent in acinar cell carcinoma, is useful.
Granular cytoplasm, when present and visible on smears,
helps to define an acinar cell carcinoma, in contrast
to the dense to finely granular eccentric cytoplasm of
PEN.
Non-Hodgkin lymphoma enters the differential diag-
nosis owing to the single cell smear pattern common
to both neoplasms and the tendency of the delicate
cytoplasm of some PENs to get stripped from the cells,
yielding small round cells mimicking lymphoma. The
differences in the chromatin pattern, cytoplasm of intact
PEN cells, and the absence of lymphoglandular bodies,
stripped globules of cytoplasm from the delicate lym-
phoma cells, help to differentiate PEN from lymphoma.
Extracellular plasmacytoma shares features of eccentric
cytoplasm and stippled chromatin, but the distribution
of the chromatin is more ‘clock-face’ in plasmacytoma
and the eccentric cytoplasm of PEN does not contain a
perinuclear huff (Golgi zone) as may be seen in plasma-
cytoma (Fig. 9-30).
ACINAR CELL CARCINOMA
Acinar cell carcinoma is a malignant proliferation of
the enzyme-producing exocrine (acinar) cells of the
pancreas.
Ch009-F06731.indd 274
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 9-30
Plasmacytoma. Although rare in the
pancreas, plasmacytoma with the
typical single cell smear pattern,
eccentric nucleus, and coarse stip-
pled chromatin mimics a pancreatic
endocrine neoplasm (PEN). Notice,
however, the chromatin clumps in a
clock-face distribution, in contrast
to the even distribution throughout
the nucleus in PEN. Also notice the
pale perinuclear huff (Golgi zone)
in the cell at 11 o’clock. Papanico-
laou stain, high power.
ACINAR CELL CARCINOMA – DISEASE FACT SHEET
Incidence
៉ ∼1–2% of adult pancreatic neoplasms
Gender and Age Distribution
៉ Male to female ratio is 4 : 1
៉ Children << adults; peak incidence, 7th decade
Radiologic Features
៉ Solid masses with well-demarcated borders; rarely cystic
Prognosis and Treatment
៉ Prognosis is directly related to tumor stage and is better than for
ductal adenocarcinoma
៉ Resection is the treatment of choice
CLINICAL FEATURES
Acinar cell carcinoma is a malignant neoplasm of adults
and children, comprising 1–2% of pancreatic neoplasms
in adults and 15% of pancreatic neoplasms in children.
The tumors are most common in adults. Most tumors
occur in the seventh decade and the male to female
ratio is almost 4 : 1. In the pediatric group, the tumors
generally occur between 10 and 20 years of age.
Acinar cell carcinomas generally have a poor progno-
sis, with a median survival of about 11/2 years. The
reported 5-year survival is between 6% and 25%. Chil-
10/26/2006 10:32:01 AM
 CHAPTER 9 Pancreas
FIGURE 9-31
Acinar cell carcinoma. The presence
of stripped naked nuclei with a
granular background from the dis-
persed cytoplasm is a rather char-
acteristic feature of this neoplasm.
Hema III stain, high power.
dren are believed to have a slightly better prognosis,
with reports of long-term survival and cure in this
population.
R ADIOLOGIC FEATURES
Acinar cell carcinomas are typically solid, occasionally
cystic, well-circumscribed, usually large masses
(average size, 10 cm) that may arise in any portion of
the pancreas.
CYTOPATHOLOGIC FEATURES
Aspirate smears of acinar cell carcinoma are usually
moderately cellular and often display a relatively clean
background devoid of necrosis and cyst debris, but the
background may contain cytoplasmic granules from the
stripped cytoplasm of tumor cells. Stripped cells leave
naked tumor nuclei, a rather characteristic feature of
acinar cell carcinoma (Fig. 9-31). These nuclei can
resemble lymphocytes, especially when nucleoli are not
prominent, but when compared to the intact tumor
cells, the similarity is apparent. The clusters of tumor
cells form irregular-shaped groups, sheets, and small
glandular clusters (Fig. 9-32), a pattern that contrasts
to the organoid, grape-like clustering typical of benign
acinar epithelium. Individual tumor cells are frequently
very bland with a polygonal cell shape, low N/C ratio,
and uniform nuclei (Fig. 9-33), resembling to a remark-
Ch009-F06731.indd 275
275
ACINAR CELL CARCINOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Small glandular clusters, single cells
៉ Stripped naked nuclei; +/− loose cytoplasmic granules
៉ May be disarmingly bland, with a polygonal cell shape and low
N/C ratio
៉ Coarse chromatin usually with prominent nucleoli, but not
always
៉ Granular cytoplasm, variably prominent
Ancillary Studies
៉ Histochemical stains: positive for PAS/dPAS
៉ Immunocytochemical stains: trypsin, chymotrypsin, lipase, and
elastase usually positive; amylase is usually negative; positive
for CAM 5.2 and AE1/AE3, but negative for cytokeratins 7, 19,
and 20; EMA is positive in about 50%
Differential Diagnosis and Pitfalls
៉ Pancreatic endocrine neoplasms
៉ Solid-pseudopapillary tumor
៉ Pancreatoblastoma
៉ Normal acinar epithelium (pitfall)
able degree the normal acinar cell. The cells can be
pleomorphic, and may occasionally appear plasmacy-
toid; however, the marked and rather diffuse plasma-
cytoid appearance common in endocrine neoplasms is
not present in acinar cell carcinoma.
The nuclear chromatin in the tumor cells is generally
coarsely clumped, and one, sometimes two, prominent
10/26/2006 10:32:01 AM
 276 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 9-32
Acinar cell carcinoma. In contrast
to the organoid grape-like cluster-
ing of benign acinar epithelial cells,
the cell clusters of acinar cell car-
cinoma are of varying sizes and are
irregular in shape. Papanicolaou
stain, low power.

FIGURE 9-33
Acinar cell carcinoma. The individ-
ual tumor cells are frequently quite
bland with a polygonal cell shape,
low N/C ratio, and uniform nucleus.
Prominent nucleoli may not be
present, and the cells can resemble
normal acinar epithelial cells. Papa-
nicolaou stain, high power.

Ch009-F06731.indd 276 10/26/2006 10:32:02 AM

 CHAPTER 9 Pancreas
FIGURE 9-34
Acinar cell carcinoma. The dense
granularity of the cytoplasm is best
appreciated on H&E-stained smears.
H&E stain, high power.
nucleoli may be seen. This feature and the coarsely
granular cytoplasm are helpful diagnostic findings when
present. The cytoplasmic granularity is not always
readily apparent and is more easily identified on
hematoxylin and eosin (H&E)-stained smears than on
Papanicolaou- or Romanowsky-stained smears (Fig.
9-34). The absence of striking cytoplasmic granularity
and large, prominent nucleoli are not uncommon in
acinar cell carcinoma, adding to the diagnostic diffi-
culty. Identification of mitotic activity supports a neo-
plastic process.
ANCILLARY STUDIES
Documenting the presence of zymogen granules or exo-
crine enzyme production by the tumor cells establishes
the diagnosis of acinar cell carcinoma. When sufficient
in quantity, a periodic acid–Schiff (PAS) stain with
and without diastase digestion will highlight the red-
staining intracytoplasmic granules. Electron micros-
copy can also be used to detect the granules. Although
not widely used, the butyrate esterase stain detects
lipase activity in about 75% of cases, and 75–95% of
cases will label with antibodies to exocrine enzymes
including trypsin, chymotrypsin, lipase, and elastase.
Low and high molecular weight cytokeratins (CAM 5.2
and AE1, respectively) as well as cytokeratins 8 and 18
stain the carcinoma cells, but cytokeratins 7, 19, and
20 are typically negative. Because acinar cell carcino-
mas can contain a small number of endocrine cells (1–
2%), positive immunocytochemical staining with the
Ch009-F06731.indd 277
277
endocrine markers chromogranin and synaptophysin
should not be misinterpreted.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The cytologic differential diagnosis includes PEN,
pancreatoblastoma, solid-pseudopapillary tumor, and
non-neoplastic acinar parenchyma. The most common
neoplasm mistaken cytologically for acinar cell carci-
noma is the PEN. These neoplasms have in common
a uniformity of nuclei, the presence of numerous
individual cells, and a moderate amount of dense non-
vacuolated cytoplasm. Endocrine neoplasms tend to
have a more uniform, dyshesive, single cell smear pattern
with plasmacytoid cells, and less well-developed micro-
glandular (acinar) groups than has acinar cell carci-
noma. Acinar cell carcinoma also lacks the typical
endocrine ‘salt and pepper’ chromatin pattern. However,
given that endocrine tumors can demonstrate prominent
nucleoli and acinar cell carcinomas may not demonstrate
obviously granular cytoplasm, many cases require
immunohistochemical staining for accurate diagnosis.
Features helpful in distinguishing solid-pseudo-
papillary tumor from acinar cell carcinoma include the
formation of pseudopapillary structures with the char-
acteristic myxoid stroma, the fragility of the cytoplasm
(with numerous stripped nuclei), and the presence of
longitudinal nuclear grooves and small perinuclear
vacuoles in solid-pseudopapillary tumors.
Pancreatoblastoma is nearly impossible to distinguish
from acinar cell carcinoma on the basis of cytology,
10/26/2006 10:32:03 AM
 278
since the characteristic squamoid corpuscles of pancre-
atoblastoma are rarely detectable in cytologic smears.
Since both of these neoplasms exhibit acinar differentia-
tion by immunohistochemistry, it may be impossible to
exclude a pancreatoblastoma in a neoplasm otherwise
having cytologic features of acinar cell carcinoma.
The misinterpretation of benign acinar cells as neo-
plastic (acinar cell carcinoma), and vice versa, are diag-
nostic pitfalls. Rarely, aspiration of normal pancreatic
parenchyma may produce a smear with many acini
without the typical organoid grape-like clustering and
uniform acinar formation, raising the possibility of
acinar cell carcinoma. Similarly, a scantily cellular aspi-
rate of a neoplasm may be mistaken for normal acini.
PANCREATOBLASTOMA
Pancreatoblastoma is a malignant neoplasm with mul-
tiple lines of epithelial differentiation, most commonly
acinar differentiation, which also contains squamous
nests and usually a mesenchymal component.
CLINICAL FEATURES
Pancreatoblastoma is an extremely rare neoplasm of
adults and children, with approximately two-thirds
occurring in children and one-third occurring in adults.
It is the most common malignant pancreatic tumor in
children, representing approximately 25% of all pan-
creatic neoplasms in the pediatric population.
There is a bimodal age distribution when pediatric
and adult populations are evaluated separately. In chil-
dren, the peak age is almost 21/2 years, whereas in the
adult, the peak age is 40 years. As a whole, the average
age is about 10 years. Across all ages, the male to female
ratio is equal.
Prognosis appears to be worse in adults than in chil-
dren, and is dependent on tumor resectability and the
PANCREATOBLASTOMA – DISEASE FACT SHEET
Incidence
៉ Rare in adults; 25% of pancreatic tumors in children
Gender and Age Distribution
៉ M = F
៉ Mean age in children is 21/2 years, and in adults, 40 years
Radiologic Features
៉ A well-defined heterogeneous pancreatic or peripancreatic mass
that may contain calcifications
Prognosis and Treatment
៉ Prognosis is generally poor and is worse in adults than in
children
៉ Surgical resection is the treatment of choice
Ch009-F06731.indd 278
FINE NEEDLE ASPIRATION CYTOLOGY
presence of metastases at the time of diagnosis. Patients
typically present with unresectable tumors and over a
third have metastases upon diagnosis.
R ADIOLOGIC FEATURES
CT scans reveal a well-defined, often large (up to 20 cm),
heterogenous and mostly enhancing pancreatic mass,
the minority of which will demonstrate scattered
calcifications.
CYTOPATHOLOGIC FEATURES
Aspirate smears of pancreatoblastoma are cellular,
composed of cell clusters and single cells. The appear-
ance of the epithelial cells will vary depending on the
direction of differentiation. Cells with acinar differen-
tiation have an oval to cuboidal cell shape, round,
central to eccentric nuclei, one or more small nucleoli,
and a moderate amount of granular, amphophilic to
eosinophilic cytoplasm that is impossible to distinguish
from acinar cell carcinoma (Fig. 9-35). Cells with endo-
crine differentiation can resemble acinar cells but
demonstrate a more cuboidal shape, a higher N/C ratio,
denser, less granular cytoplasm, and less conspicuous
nucleoli. Squamoid cells, singly or in clusters, are rec-
PANCREATOBLASTOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellular smears with varying sized cell clusters and single cells
៉ Epithelial cells will vary in appearance depending on their
direction of differentiation: cells with acinar differentiation
dominate and have a polygonal shape, round, central to
eccentric nucleus, one or more small nucleoli, and a moderate
amount of granular cytoplasm
៉ Squamoid nests are recognized in cell block preparations
៉ Stromal fragments with traversing capillaries may be present
Ancillary Studies
៉ Histochemical stains:
៉ Acinar cells: positive for PAS/dPAS
៉ Immunocytochemical stains:
៉ Acinar cells: positive for pancytokeratin, trypsin,
chymotrypsin, and lipase
៉ Endocrine cells: positive for chromogranin, synaptophysin,
and NSE, but usually negative for insulin, glucagon, or
somatostatin
៉ Ductal cells: positive for cytokeratin, CEA, B72.3, and
DUPAN-2
៉ Stroma: positive for vimentin
៉ Squamoid corpuscles are generally not immunoreactive
Differential Diagnosis and Pitfalls
៉ Acinar cell carcinoma
៉ Pancreatic endocrine neoplasm
៉ Solid-pseudopapillary neoplasm
៉ Normal acinar epithelium (pitfall)
10/26/2006 10:32:04 AM
 CHAPTER 9 Pancreas
FIGURE 9-35
Pancreatoblastoma. Acinar differ-
entiation is the most common cell
line of differentiation in this neo-
plasm, which can undergo multiple
lines of epithelial differentiation.
As such, pancreatoblastoma can
identically mimic an acinar cell
carcinoma. Hema III stain, high
power.
ognized in cell block preparations rather than on direct
smears (Fig. 9-36). Stromal fragments may be scant or
prominent, and traversing capillaries may be seen.
ANCILLARY STUDIES
The neoplastic cells will be highlighted by histochemi-
cal and immunohistochemical markers depending on
the line of differentiation of the cells. Most neoplasms
develop an acinar cell phenotype and therefore the
tumor cells will demonstrate zymogen granules that
stain with PAS/dPAS and exocrine antibodies such as
trypsin, chymotrypsin and lipase.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The primary neoplasm in the differential diagnosis is
acinar cell carcinoma, which is discussed in detail on
page 277–278.
CYSTIC NEOPLASMS
SEROUS CYSTADENOMA
Serous cystadenoma is a benign, typically microcystic,
proliferation of small cuboidal epithelial cells rich in
cytoplasmic glycogen which produces serous fluid.
Ch009-F06731.indd 279
279
SEROUS CYSTADENOMA – DISEASE FACT SHEET
Incidence
៉ 2% of all pancreatic neoplasms but ∼10% of resected cysts
Gender and Age Distribution
៉ F >> M
៉ Mean age 65 years
Radiologic Features
៉ Large, mostly microcystic, masses with characteristic ‘soap bubble’
pattern on ultrasound
៉ Central stellate scar frequently with ‘starburst’ pattern of
microcalcifications noted on CT
៉ Oligocystic, macrocystic, and unilocular variants can occur
Prognosis and Treatment
៉ The cysts are benign and prognosis is excellent
៉ Therapy includes resection, or observation for small (<4 cm) cysts
in poor surgical candidates
CLINICAL FEATURES
The incidence of these often asymptomatic neoplasms
is increasing with the common use of CT scanning for
the work-up of patients for other conditions. Of all the
neoplasms arising from the exocrine pancreas, serous
cystadenomas account for roughly 2%, but of resected
cysts of the pancreas, the percentage increases to 10%.
There is an association with von Hippel–Lindau
syndrome.
10/26/2006 10:32:04 AM
 280
Serous cystadenomas are much more common in
women than in men and have greater than a 70-year age
range (18–91 years) with a mean of approximately 65
years.
These neoplasms are benign, with very rare reports
of malignant transformation. Complications of large neo-
plasms such as rupture or erosion into a large vessel can
cause death. Complete surgical resection is curative.
R ADIOLOGIC FEATURES
Microcystic serous cystadenoma often demonstrates
very characteristic radiographic findings precluding the
need for tissue confirmation. Ultrasound demonstrates
a ‘soap bubble’ pattern owing to the numerous micro-
cysts that average less than 2 cm each. CT scan shows
a well-defined mass with multiple, sometimes innumer-
able, small cysts separated by delicate septa. Many
tumors will contain a central stellate scar, and about
30% of these will demonstrate a ‘starburst’ pattern of
microcalcifications within the scar. Oligocystic and
unilocular variants of serous cystadenomas do exist
and produce radiologic features that usually cannot be
distinguished from other cysts in the pancreas. A solid
variant has also been reported.
CYTOPATHOLOGIC FEATURES
The fluid aspirated from serous cystadenomas is clear
and thin and may be bloody, but is not mucoid as in
Ch009-F06731.indd 280
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 9-36
Pancreatoblastoma. This cell block
preparation demonstrates a cluster
of squamoid cells surrounded by
neoplasm with acinar cell differen-
tiation. The cell block is the best
preparation to identify squamoid
cells. This finding helps distinguish
pancreatoblastoma from acinar cell
carcinoma. H&E stain, high power.
SEROUS CYSTADENOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Scantily cellular smears with clean or bloody background
៉ Uniform cuboidal cells with round nuclei, smooth nuclear
membranes, and inconspicuous nucleoli
៉ Scant, pale to finely vacuolated but non-mucinous cytoplasm
Ancillary Studies
៉ Histochemical stains: PAS-positive, dPAS-negative; confirms
cytoplasmic glycogen
៉ Immunocytochemical stains (+): cytokeratins AE1/AE3, CAM 5.2,
CK7, CK8, CK18, and CK19; CEA, MUC2, and MUC5
៉ Cyst fluid analysis: low amylase and CEA
Differential Diagnosis and Pitfalls
៉ Pseudocyst
៉ Mucinous cysts: mucinous cystic neoplasm and side-branch
intraductal papillary mucinous neoplasm
៉ Gastrointestinal contamination (pitfall)
៉ Histiocytes (pitfall)
most mucinous cysts. Smears are frequently very
paucicellular and it is not uncommon for smears to be
acellular. Many cases are considered inadequate for
interpretation due to insufficient cellularity, but iden-
tification of even a couple of small clusters of cells with
bland cuboidal morphology can be very helpful in the
appropriate clinical setting, even if not technically con-
sidered ‘diagnostic’. Tumor cells are uniform cuboidal
cells in small clusters and flat sheets with round, central
10/26/2006 5:58:33 PM
 CHAPTER 9 Pancreas 281

FIGURE 9-37
Serous cystadenoma. The tumor
cells are uniform cuboidal cells with
bland central nuclei, smooth nuclear
membranes, and even chromatin.
The cytoplasm is finely vacuolated
but non-mucinous. The cells may
resemble histiocytes. Papanicolaou
stain, high power.

to slightly eccentric nuclei and scant but visible cyto-

plasm that is homogeneous to finely vacuolated (Fig.
9-37). The nuclei have smooth nuclear membranes,
an even chromatin pattern, and inconspicuous to no
nucleoli, and the cytoplasm is scant and finely vacuo-
lated or dense, but not mucinous (Fig. 9-38).

ANCILLARY STUDIES

PAS stain with and without diastase will confirm the

presence of cytoplasmic glycogen and exclude the pres-
ence of mucin. Tumor cells immunolabel with cyto-
keratins CAM 5.2, AE1/AE3, CK7, CK8, CK18, and
CK19. MUC6 and α-inhibin are positive in most cases,
and MUC1 is positive in about one-third. CEA, MUC2
and MUC5, and all endocrine markers are negative.
Cyst fluid analysis typically shows low levels of amylase
and CEA.

DIFFERENTIAL DIAGNOSIS AND PITFALLS

Bloody specimens that may contain inflammation and

debris and lack epithelial cells can be misinterpreted as
pseudocysts. Cyst fluid analysis helps by showing an FIGURE 9-38
elevated amylase level in pseudocysts. Smears with epi- Serous cystadenoma. This air-dried preparation highlights the non-
thelial cells demonstrating vacuolated cytoplasm may mucinous finely vacuolated cytoplasm. Hema III stain, high power.
indicate the presence of a neoplastic mucinous cyst (see
below).

Ch009-F06731.indd 281 10/26/2006 10:32:05 AM

 282
Gastrointestinal epithelium and mucin contaminat-
ing the smears from EUS-guided biopsies adds to this
diagnostic pitfall. Cyst fluid analysis is helpful if CEA is
elevated above 200 ng/mL.
SOLID-PSEUDOPAPILLARY NEOPLASM
Solid-pseudopapillary neoplasm is a low-grade malig-
nant solid neoplasm with secondary cystic degenera-
tion that produces a proliferation of small bland cells
of uncertain lineage in solid nests and around delicate
blood vessels, creating a pseudopapillary appearance on
histology.
CLINICAL FEATURES
This neoplasm is relatively rare, accounting for less
than 3% of all pancreatic malignancies. It occurs almost
exclusively in women, with an approximate female to
male ratio of 9 : 1. Most women are in their third decade,
but the reported ages range from 7 to 79 years.
Surgical resection is the treatment of choice. The
overall prognosis is excellent, with only about 15% of
patients developing recurrence or metastatic disease,
and this is typically the result of incomplete resection.
Complete resection of node-negative patients is con-
sidered curative. Even with recurrence or metastatic
disease, long-term survival is common.
R ADIOLOGIC FEATURES
Like for serous cystadenomas, solid-pseudopapillary
neoplasms are often diagnosed from the characteristic
clinical and radiologic features. CT and ultrasound
SOLID-PSEUDOPAPILLARY NEOPLASM – DISEASE FACT SHEET
Incidence
៉ ∼1–3% of all pancreatic malignancies, 6% of exocrine tumors,
and ∼24% of all surgically resected cystic lesions in the pancreas
Gender and Age Distribution
៉ ∼90% of patients are female
៉ Most are in their 20s; mean age is 28 years
Radiologic Features
៉ Well-circumscribed mass with solid and cystic components,
commonly in the pancreatic tail
Prognosis
៉ Excellent – only 15% develop recurrence or metastases
Ch009-F06731.indd 282
FINE NEEDLE ASPIRATION CYTOLOGY
demonstrate a typically large, well-demarcated, solid
and cystic heterogeneous neoplasm commonly located
in the tail of the pancreas of a young woman. Calcifica-
tions may also be noted.
CYTOPATHOLOGIC FEATURES
Aspirate smears are hypercellular with a population of
small, uniform cells in cohesive, often branching and
papillary cell clusters, interspersed with many single
cells (Fig. 9-39). The background may be clean or filled
with hemorrhagic cyst debris laden with foamy histio-
cytes and multinucleated giant cells. Delicate fibrovas-
cular cores with myxoid stroma and a zone of cytoplasm
sometimes separating the nuclei of the cells from the
vessel is a diagnostic finding (Fig. 9-40). Individual
tumor cells are uniform with round to oval nuclei,
smooth to slightly indented or grooved nuclear mem-
branes, even and finely granular chromatin, and incon-
spicuous nucleoli (Fig. 9-41). The cytoplasm is scant to
moderate, non-granular to finely granular, and may be
stripped from the nucleus. When intact, a small peri-
nuclear vacuole and, occasionally, intracytoplasmic
hyaline globule may be noted (Fig. 9-42).
SOLID-PSEUDOPAPILLARY NEOPLASM – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Highly cellular smears with branching and papillary cell clusters
interspersed with single cells
៉ Smear background may be clean or filled with hemorrhagic cyst
debris, foamy histiocytes, and multinucleated giant cells
៉ Fibrovascular cores with myxoid stroma is characteristic
៉ Individual tumor cells are homogeneous with little
anisonucleosis and no mitotic activity
៉ Nuclei are round to oval with smooth nuclear membranes except
for frequent nuclear grooves or focal indentations, finely
granular chromatin, and inconspicuous nucleoli
៉ Cytoplasm is scant to moderate and may contain a small
perinuclear vacuole or intracytoplasmic hyaline globule
Ancillary Studies
៉ Histochemical stains: myxoid stroma is positive for PAS/dPAS
៉ Immunocytochemical stains: positive for vimentin, α-1-
antitrypsin, CD10, NSE, CD56, and progesterone receptor;
synaptophysin and cytokeratin (AE1/AE3, CAM 5.2) are variably
positive; CK7 and CK19 are usually negative; β-catenin will
demonstrate abnormal cytoplasmic and nuclear staining in
>90% of tumors; intracytoplasmic hyaline globules stain with
antibodies to α-1-antitrypsin
៉ Molecular analysis: almost all harbor somatic point mutations in
exon 3 of the β-catenin gene
Differential Diagnosis and Pitfalls
៉ Pancreatic endocrine neoplasm
៉ Pseudocysts
៉ Acinar cell carcinoma
៉ Normal acinar epithelium (pitfall)
10/26/2006 10:32:06 AM
 CHAPTER 9 Pancreas 283

FIGURE 9-39
Solid-pseudopapillary neoplasm.
The typical aspirate smears are
hypercellular, composed of a popu-
lation of small uniform cells in
cohesive, often branching and pap-
illary cell clusters interspersed with
many single cells. Papanicolaou
stain, high power.

FIGURE 9-40
Solid-pseudopapillary neoplasm.
The myxoid stroma that separates
the tumor cells from the vessels can
be seen as globules within acinar
structures, as demonstrated here.
Papanicolaou stain, medium power.

Ch009-F06731.indd 283 10/26/2006 10:32:06 AM

 284 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 9-41
Solid-pseudopapillary neoplasm.
The individual tumor cells are bland
with oval to indented nuclei, even
chromatin, nuclear grooves, and no
nucleoli. Note the characteristic
small perinuclear vacuole seen in
some of the cells. Papanicolaou
stain, high power.

FIGURE 9-42
Solid-pseudopapillary neoplasm.
Intracytoplasmic hyaline globules
may also be seen in some tumor
cells, as demonstrated in this neo-
plasm, most prominent in the cell
at 2 o’clock. Note also the occa-
sional perinuclear vacuole. Hema
III stain, high power.

Ch009-F06731.indd 284 10/26/2006 10:32:08 AM

 CHAPTER 9 Pancreas
ANCILLARY STUDIES
Solid-pseudopapillary neoplasms often do not express
cytokeratin (CAM 5.2 or AE1/AE3) and usually do not
express cytokeratins 7 and 19. Most tumors stain with
antibodies to vimentin, CD10 (neprilysin), neuron-
specific enolase (NSE), CD56, β-catenin, cyclin D1,
progesterone receptors, and α-1-antitrypsin, a marker
that also stains the intracytoplasmic hyaline globules.
Cyst fluid analysis demonstrates low amylase and CEA
levels.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The primary solid neoplasm in the differential diagno-
sis is PEN. The uniform, bland-appearing, often dis-
persed epithelial cells of solid-pseudopapillary neoplasm
can greatly resemble those of PEN. Careful attention to
the nuclear details, including the presence of nuclear
grooves, indentations, and the occasional perinuclear
vacuole or intracytoplasmic hyaline droplet seen in
many solid-pseudopapillary neoplasms, will help dis-
tinguish the two when papillary architecture is
absent.
Pseudocyst enters the differential diagnosis when
only the hemorrhagic and necrotic cyst debris is aspi-
rated. Clinical correlation and cyst fluid analysis helps
distinguish these entities. Pseudocysts are more common
in men with a history of pancreatitis. Unlike pseudo-
cysts, solid-pseudopapillary neoplasms have a low
amylase level on cyst fluid analysis.
MUCINOUS CYSTIC NEOPLASM
Mucinous cystic neoplasm (MCN) is a neoplastic mucin-
producing cyst that, in almost all cases, does not com-
municate with the pancreatic ductal system, is lined by
mucinous epithelial cells with varying degrees of atypia,
and contains subepithelial ovarian-type stroma.
CLINICAL FEATURES
Mucinous cystic neoplasms comprise approximately
6% of all primary pancreatic tumors. With rare excep-
tion, patients are female, and the average age is between
40 and 50 years. Mucinous cystic neoplasms with inva-
sive carcinoma often occur in patients in their 60s.
Complete surgical resection is the treatment of choice.
Regardless of the atypia of the lining epithelium, the
prognosis is directly related to the presence or absence
of an invasive carcinoma. As such, cytologic evaluation
cannot predict outcome. Complete and thorough his-
tologic sampling is essential to rule out an invasive
Ch009-F06731.indd 285
285
MUCINOUS CYSTIC NEOPLASM – DISEASE FACT SHEET
Incidence
៉ ∼6% of all primary pancreatic neoplasms and pancreatic cysts
Gender and Age Distribution
៉ Almost all female
៉ 40–50 years
Radiologic Features
៉ Typically, solitary, multiloculated, well-circumscribed masses,
often with peripheral calcifications and a thick capsule; 90% in
the body or tail
៉ Communication with the large pancreatic ducts is absent in
almost all cases
៉ A cyst wall mass suggests an invasive component
Prognosis and Treatment
៉ Prognosis is directly related to the presence or absence of
invasive carcinoma
៉ Surgical resection is the treatment of choice and is curative for
non-invasive neoplasms
component, given that these neoplasms tend to be very
heterogeneous in their lining and that an invasive com-
ponent may not be apparent from gross inspection of
the resected cyst. Complete resection of thoroughly
evaluated, non-invasive neoplasms is considered
curative.
CYTOPATHOLOGIC FEATURES
Aspiration of MCNs produces highly variable amounts
of extracellular mucin and cyst-lining epithelium. In
addition, the degree of epithelial atypia may be variable
and not representative of the highest degree of atypia
of the cyst, owing to the heterogeneity of the cyst lining.
As such, the cytologic diagnosis often underestimates
the ultimate histologic grade of the tumor. In addition,
a specific diagnosis of MCN is less common than a more
general diagnosis of neoplastic mucinous cyst, a generic
term that encompasses both intraductal papillary muci-
nous neoplasm (IPMN) and MCN. This is primarily
due to a lack of architectural specificity of the glandular
epithelium.
The presence of a neoplastic mucinous cyst is often
first suspected at the time of aspiration when thick,
viscous mucus is grossly appreciated by the aspirator.
This mucus is difficult to draw into and express from
the needle. Such thick and viscous cyst fluid is reflected
on the slide as a thick sheet of ‘colloid-like’ mucin that
frequently covers most of the slide (Fig. 9-43). Mucin
contamination from the gastrointestinal tract will not
be ‘colloid-like’. Degenerated inflammatory cells and
histiocytes within the mucin is a feature that also helps
to distinguish contaminating mucin from neoplastic
10/26/2006 10:32:09 AM
 286
MUCINOUS CYSTIC NEOPLASM – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Mucin quality and quantity can vary: thick, ‘colloid-like’ mucin
is consistent with origin from the cyst (rather than
gastrointestinal contamination from EUS biopsy)
៉ Epithelial cells vary in quantity and may be absent in high-
grade neoplasms with only mucin on smears
៉ Epithelial cells range from fl at sheets and single bland columnar
mucinous cells (adenoma) to high-grade dysplastic cells with a
high N/C ratio and irregular nuclei with or without cytoplasmic
mucin
Ancillary Studies
៉ Histochemical stains: mucicarmine and Alcian blue pH 2.5 +/−
៉ Immunocytochemistry (+): cytokeratins AE1/AE3, CAM 5.2, CK7,
CK8, CK18, CK19; CEA, DUPAN-2, CA 19-9, and MUC5AC
៉ Cyst fluid analysis: low amylase and variable CEA (usually
>200 ng/mL)
Differential Diagnosis and Pitfalls
៉ Pseudocyst
៉ Side-branch IPMN
៉ Serous cystadenoma
៉ Gastrointestinal contamination (pitfall)
Ch009-F06731.indd 286
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 9-43
Mucinous cystic neoplasm (MCN).
Colloid-like mucin is typical of a
neoplastic mucinous cyst, including
MCN and intraductal papillary muci-
nous neoplasm. This quality of
mucin is not seen from gastrointes-
tinal contamination. Papanicolaou
stain, medium power.
mucin. However, not all MCNs will have such mucoid
contents. Extracellular mucin can appear as focally
thick clumps, thin wisps, and as focal or diffuse thin
background mucin, not easily visualized on routine
preparations, especially liquid-based preparations where
the mucin can be quite attenuated during processing
(Fig. 9-44). An aliquot of the cyst fluid, if sufficient in
quantity, can be used to prepare cytospin slides for
mucicarmine and/or Alcian blue pH 2.5 to assess for
mucin. Negative special stains, however, do not exclude
the presence of a MCN.
Mucinous cystadenomas are typically scantily cellular,
aspirates producing single cells, small clusters, and flat
sheets of bland glandular epithelial cells that typically
demonstrate cytoplasmic mucin visible on routine light
microscopy (Fig. 9-45). The nuclei are basally located,
round and regular, with even chromatin and inconspicu-
ous to occasionally prominent nucleoli. Occasionally,
muciphages (foamy histiocytes) may be the only cells in
the cyst contents. The epithelial lining of MCNs with
moderate dysplasia and higher-grade neoplasms demon-
strates epithelial cells with nuclear crowding, loss of
polarity, nuclear elongation or rounding, hyperchroma-
sia, and increased N/C ratio (Fig. 9-46). Cells in small
tight bud-like clusters or singly with these same nuclear
features, and cytoplasm with or without mucin is also
consistent with the presence of a MCN with moderate
dysplasia or higher. Crowded groups of cells with open
chromatin, irregular nuclear membranes and nucleoli,
significant background inflammation, and necrosis
support the interpretation of malignancy (Fig. 9-47).
10/26/2006 10:32:09 AM
 CHAPTER 9 Pancreas 287

FIGURE 9-44
Mucinous cystic neoplasm. Mucin
can appear fragmented and quite
attenuated in liquid-based prepara-
tions, making recognition difficult.
ThinPrep®, Papanicolaou stain,
medium power.

FIGURE 9-45
Mucinous cystic neoplasm-adenoma.
Bland adenomatous epithelium
maintains a uniform honeycomb
arrangement and single columnar
cells demonstrate diffuse cytoplas-
mic mucin. ThinPrep®, Papanicolaou
stain, high power.

Ch009-F06731.indd 287 10/26/2006 10:32:09 AM

 288 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 9-46
Mucinous cystic neoplasm with
moderate dysplasia. Increased
nuclear density, nuclear crowding,
loss of polarity, and increased N/C
ratio that may be associated with
a loss of cytoplasmic mucin and
cellular degeneration are features
that correlate with a neoplasm of at
least moderate dysplasia. Papanico-
laou stain, high power.

FIGURE 9-47
Mucinous cystadenocarcinoma.
Crowded three-dimensional groups
containing cells with either hyper-
chromasia or open chromatin, irreg-
ular nuclear membranes, and
nucleoli in a background with sig-
nificant infl ammation and necrosis
support the interpretation of malig-
nancy. Invasion, however, can only
be determined from aspiration of an
associated mural nodule. Papanico-
laou stain, low power.

Ch009-F06731.indd 288 10/26/2006 10:32:10 AM

 CHAPTER 9 Pancreas
FIGURE 9-48
Mucinous cystic neoplasm. Thin
background mucin may not be
appreciated on routine stains.
Special stains for mucin, including
this Alcian blue at pH 2.5, can high-
light extracellular and intracellular
mucin. Alcian blue pH 2.5, medium
power.
Invasion can be determined only by the aspiration of a
mural nodule, as the cytologic features distinguishing
in-situ from invasive carcinoma have not been definitely
established.
ANCILLARY STUDIES
Aspirates producing thin white fluid, not grossly
mucoid, may benefit from special stains for mucin on
cystospin preparations, as mentioned above (Fig. 9-48).
The epithelial cells of MCN stain with antibodies to
cytokeratins (pancytokeratin, CAM 5.2, CK7, CK8,
CK18, and CK19), DUPAN-2, CA 19-9, and MUC5AC.
Almost all MCNs are negative for CK20, MUC1, and
MUC6. MUC2 will stain goblet cells.
Chemical analysis of the cyst fluid can aid in the diag-
nosis and classification of pancreatic cysts. CEA levels
above 200 ng/mL have been found to aid in the distinc-
tion of non-mucinous from mucinous cysts, with very
high levels of CEA correlating with malignancy. Amylase
levels are not high in MCN as in IPMN, due to the
absence of connectivity with the pancreatic duct.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Distinction of mucinous cystadenomas from con-
taminating gastrointestinal epithelium is particularly
challenging, especially gastric epithelium. In con-
trast to duodenal epithelium, which is recognized
Ch009-F06731.indd 289
289
by the presence of large, uniform, flat sheets of
glandular epithelium with a brush-bordered luminal
edge studded with goblet cells containing clear
cytoplasm (Fig. 9-49), gastric epithelium more often
presents as small groups and occasionally as single
columnar glandular epithelial cells that can be con-
fused with the bland epithelium of an adenoma (Fig.
9-50). A cup-like apical pocket of mucinous cytoplasm
seen in the foveolar cells of the gastric epithelium is a
feature that can help differentiate it from the cyst lining
of a MCN adenoma that demonstrates a full columnar
column of mucinous epithelium (see Fig. 9-45).
The differential diagnosis of MCN also includes
IPMN, pseudocyst, oligocystic and unilocular variants
of serous cystadenoma, and cystic PEN. Mucinous cystic
neoplasms devoid of identifiable mucin or epithelial
cells can be mistaken for a pseudocyst. Oligocystic, mac-
rocystic, and unilocular variants of serous cystadenoma
radiologically mimic MCN. The presence of thick,
viscous mucin excludes the diagnosis of a serous cyst
and pseudocyst. Serous cysts produce thin, clear, non-
viscous fluid and scant epithelium. The epithelial cells
are bland cuboidal cells with non-mucinous cytoplasm.
In the absence of background mucin, the small, often
individual cells of a MCN with moderate dysplasia or
carcinoma are similar to the cells of cystic PEN. The
most helpful distinguishing features are those of the
nucleus. In cystic PEN, the nuclei are round with rela-
tively smooth nuclear membranes and have chromatin
that is coarse and stippled in the typical ‘salt and pepper’
neuroendocrine pattern. The presence of even focal
intracytoplasmic vacuoles also supports a diagnosis of
MCN over cystic PEN.
10/26/2006 10:32:11 AM
 290 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 9-49
Duodenal epithelium. During EUS-
guided biopsies of lesions in the
pancreatic head, duodenal epithe-
lium may contaminate the speci-
men. The epithelium is often
recognized by the presence of large
monolayered sheets with a uniform
luminal edge of columnar cells with
a brush border. Goblet cells fre-
quently stud the sheets of epithe-
lium but may not be overtly apparent
in all groups, especially small
groups. Papanicolaou stain, medium
power.

FIGURE 9-50
Gastric epithelium. EUS-guided
biopsies of neoplasms or lesions in
the pancreatic body and tail tra-
verse the gastric wall. Gastric epi-
thelium may demonstrate mucinous
cytoplasm which can be confused
with mucin-producing neoplastic
cysts. The mucinous cytoplasm is
often present in an apical cup-like
compartment. Papanicolaou stain,
high power.

Ch009-F06731.indd 290 10/26/2006 10:32:12 AM

 CHAPTER 9 Pancreas
INTRADUCTAL PAPILLARY MUCINOUS
NEOPLASM
Intraductal papillary mucinous neoplasm (IPMN) is a
mucin-producing neoplastic cyst that arises from and
is directly connected with the pancreatic ductal system,
either the main duct and/or side-branch duct, and is
lined by typically papillary and variably atypical muci-
nous epithelium. These neoplasms are classified by the
WHO as IPMN-adenoma, IPMN with moderate dyspla-
sia (also know as borderline tumor), IPMN with carci-
noma in situ, and IPMN with invasive carcinoma
(either tubular type or colloid type).
CLINICAL FEATURES
It is difficult to establish an accurate incidence of IPMN
owing to its relatively recent distinction as a specific
entity separate from mucinous cystic neoplasms in the
mid 1980s and from serous cysts in the 1970s. In addi-
tion, many small asymptomatic neoplasms are being
incidentally recognized because of the increasing use
of CT scans for other conditions. An estimated inci-
dence from recent reports places IPMN at approxi-
mately 20% of all neoplastic pancreatic cysts and 5%
of all pancreatic neoplasms.
Most IPMNs occur in the elderly population, with a
peak age of close to 65 years. The male to female ratio
INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM –
DISEASE FACT SHEET
Incidence
៉ ∼5% of all pancreatic neoplasms and ∼20% of all neoplastic
pancreatic cysts
Gender and Age Distribution
៉ M > F
៉ Mean age ∼65 years
Radiologic Features
៉ Main duct, side-branch, and combined types exist
៉ Copious ductal mucin produces filling defects
៉ Cysts are single or multiple and connect to the large pancreatic
ducts
៉ 70% occur in the pancreatic head
៉ Cyst wall nodules and markedly dilated main pancreatic duct
suggest malignancy
Prognosis and Treatment
៉ Prognosis is directly related to the presence or absence of
invasive carcinoma
៉ Surgical resection is the treatment of choice and is curative for
non-invasive neoplasms
៉ Invasive side-branch IPMN has a better prognosis than main duct
IPMN
Ch009-F06731.indd 291
291
varies by study and institution, but most studies show
a slight male predominance.
Complete surgical resection is currently the treat-
ment of choice. Prognosis is directly related to the pres-
ence or absence of an invasive carcinoma. Complete and
thorough histologic sampling is essential to rule out an
invasive component, given that these neoplasms tend to
be very heterogenous in their lining and that an invasive
component may not be apparent from gross inspection
of the resected cyst. Non-invasive IPMNs have a greater
than 90% 5-year survival rate. This rate drops to 40%
in IPMN with invasive carcinoma, but this rate is still
significantly better than for conventional ductal adeno-
carcinoma. The prognosis also depends on the type of
IPMN and the type and size of the invasive component.
Side-branch IPMN is reported to behave better than
main duct and combined-type IPMN, and the invasive
IPMN with colloid carcinoma is reported to have a
better prognosis than one with invasive conventional
tubular type carcinoma.
CYTOPATHOLOGIC FEATURES
The gross features of the cyst fluid of IPMNs are identi-
cal to those of MCNs and the same discorrelation is
present between the quality and quantity of mucin and
cells on FNAB with the final grade of the tumor on
histology.
INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM –
PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Mucin quality and quantity can vary: thick, ‘colloid-like’ mucin
is consistent with origin from the cyst (rather than
gastrointestinal contamination from EUS biopsy)
៉ Epithelial cells vary in quantity and may be absent even in
high-grade neoplasms
៉ Epithelial cells range from fl at sheets to papillary clusters and
single cells with bland columnar mucinous cells (adenoma) to
high-grade dysplastic cells singly or in tight epithelial clusters
with a high N/C ratio and irregular nuclei with or without
cytoplasmic mucin; abundant background infl ammation suggests
at least moderate dysplasia, and necrosis at least carcinoma in
situ
Ancillary Studies
៉ Histochemical stains: mucicarmine and Alcian blue pH 2.5 +/−
៉ Immunocytochemical stains (+): cytokeratins AE1/AE3, CAM 5.2,
CK7, CK8, CK18, CK19; CEA, CA 19-9, and MUC5AC
៉ Cyst fluid analysis: high amylase and variable CEA (usually
>200 ng/mL)
Differential Diagnosis and Pitfalls
៉ Pseudocyst
៉ Mucinous cystic neoplasm
៉ Serous cystadenoma
៉ Gastrointestinal contamination (pitfall)
10/26/2006 10:32:13 AM
 292
IPMN-adenoma is lined by bland columnar mucinous
glandular cells arranged in small clusters and flat to
folded sheets with a honeycombed pattern. Single cells
may also be seen. Mucinous papillary epithelial frag-
ments are not often appreciated in adenomas. Columnar
cells with round basal nuclei and abundant columnar
cytoplasm that may or may not appear visibly mucinous
(Fig. 9-51). Dense, oncocytic cytoplasm is consistent
with intraductal oncocytic papillary neoplasm (Fig. 9-
52). Other epithelial types (intestinal, biliary, and gastric
foveolar) are not readily distinguished on cytology.
IPMN-moderate dysplasia and IPMN-carcinoma in situ
are lined by atypical to malignant-appearing glandular
epithelium. The cells display nuclear crowding, loss of
polarity, nuclear elongation, and hyperchromasia.
Hyperchromatic cells with irregular nuclear membranes
and a high N/C ratio may be arranged in papillary clus-
ters, where the length is usually twice the width of
the group (Fig. 9-53), small tight epithelial cells clusters
(Fig. 9-54), or singly (Fig. 9-55). Even if very scant in
amount, the presence of these groups is significant. Open
chromatin, irregular nuclear membranes and nucleoli,
significant background inflammation, and necrosis
support the interpretation of an in-situ or invasive car-
cinoma (Figs 9-56 & 9-57). Only necrosis appears to
correlate with the presence of invasion, but this distinc-
tion cannot be made on aspirates of cyst contents alone.
A mural nodule is indicative of an invasive carcinoma,
and currently, aspiration of this nodule is necessary to
cytologically document an invasive carcinoma.
Ch009-F06731.indd 292
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 9-51
Intraductal papillary mucinous neo-
plasm-adenoma. The bland muci-
nous epithelium is appreciated by
the low N/C ratio, round, regular
nuclei, and abundant columnar
cytoplasm that may or may not
appear visibly mucinous. Papanico-
laou stain, high power.
ANCILLARY STUDIES
Aspirates producing thin white fluid, not grossly
mucoid, may benefit from special stains for mucin on
cystospin preparations, as mentioned above. Negative
mucin stains, however, do not exclude the diagnosis of
IPMN. The epithelial cells of IPMN label with anti-
bodies to cytokeratins (AE1/AE3, CAM 5.2, CK7, CK8,
CK18, and CK19; occasionally with CK20), CEA, and
CA 19-9. Very few IPMNs stain for MUC1 and almost
none stain for MUC7, but most stain for MUC2, MUC3,
MUC4, and MUC5AC. Staining patterns for the MUC
proteins have been correlated with the type of lining
epithelium of the villi and the presence or absence of
an invasive component on histology.
Like in MCN, CEA levels above 200 ng/mL support
a mucinous cyst, with very high levels of CEA correlat-
ing with malignancy. Amylase levels are high in IPMN
but not MCN, due to the connectivity of IPMN with the
pancreatic duct.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis of IPMN is essentially the
same as for MCN and is discussed in the above
section.
10/26/2006 10:32:13 AM
 CHAPTER 9 Pancreas 293

FIGURE 9-52
Intraductal papillary mucinous
neoplasm, oncocytic variant. The
presence of an intraductal lesion
with abundant dense, granular,
oncocytic cytoplasm characterizes
this variant. Hema III stain, high
power.

FIGURE 9-53
Intraductal papillary mucinous
neoplasm (IPMN) with moderate
dysplasia. Papillary clusters of epi-
thelial cells with nuclear crowding,
atypia, and overlap characterizes an
IPMN with at least moderate dyspla-
sia. Papanicolaou stain, medium
power.

Ch009-F06731.indd 293 10/26/2006 10:32:14 AM

 294 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 9-54
Intraductal papillary mucinous
neoplasm with moderate dysplasia.
Small clusters of high N/C ratio
cells with hyperchromatic nuclei
and with or without mucinous cyto-
plasm suggests the presence of a
neoplastic mucinous cyst with at
least moderate dysplasia. This
finding does not separate moderate
dysplasia from carcinoma in situ or
invasive carcinoma. Papanicolaou
stain, high power.

FIGURE 9-55
Intraductal papillary mucinous
neoplasm with carcinoma in situ.
Some neoplasms may demonstrate
only single dysplastic cells that
resemble severe dysplasia of the
cervix. Note the necrosis and
infl ammatory debris surrounding
this dysplastic cell. Papanicolaou
stain, high power.

Ch009-F06731.indd 294 10/26/2006 10:32:15 AM

 CHAPTER 9 Pancreas 295

FIGURE 9-56
Intraductal papillary mucinous neo-
plasm with carcinoma in situ. The
hyperchromatic crowded group con-
tains cells with nuclear overlapping
and distinct parachromatin clear-
ing, features that are consistent
with carcinoma; however, they do
not distinguish in-situ from inva-
sive carcinoma. Papanicolaou stain,
high power.

FIGURE 9-57
Intraductal papillary mucinous
neoplasm with invasive carcinoma.
The presence of coagulative cellular
necrosis is the one feature that
correlates with invasive carcinoma.
Note the thick mucin in the right
of the image. Papanicolaou stain,
medium power.

Ch009-F06731.indd 295 10/26/2006 10:32:16 AM

 296
NON-EPITHELIAL AND METASTATIC
TUMORS
Primary non-epithelial neoplasms account for approxi-
mately 1–2% of all pancreatic neoplasms, and metasta-
ses represent up to 4% of pancreatic tumors.
The clinical behavior and cytologic features of neo-
plasms such as lymphangioma, schwannoma, lipoma,
and (extra-) gastrointestinal stromal tumor are similar
to those outside of the pancreas. Non-Hodgkin lym-
phoma may be primary or secondary. Carcinomas, par-
ticularly from the lung, are the most common malignant
neoplasm metastatic to the pancreas. Other common
metastatic carcinomas include those originating in the
breast, kidney, stomach, and skin (melanoma).
Acknowledgement
I would like to thank my co-authors on the 4th series
AFIP fascicle on Tumors of the Pancreas, Drs Ralph
Hruban and David Klimstra, for providing a rich refer-
ence on which I relied heavily to produce this chapter.
SUGGESTED READINGS
General
Centeno BA, Pitman MB. Fine Needle Aspiration Biopsy of the Pancreas.
Boston: Butterworth-Heinemann, 1999.
DeMay R. Pancreas. In: The Art and Science of Cytopathology. Chicago:
ASCP Press, 1996:1053–1082.
Geisinger KR, Stanley MW, Raab SS, Silverman JF, Abati A. Modern Cyto-
pathology. Philadelphia: Churchill Livingstone, 2004.
Hruban RH, Pitman MB, Klimstra DS. Atlas of Tumor Pathology: Tumors of
the Pancreas, 4th ed. Silver Spring, MD: ARP Press, In press.
Klimstra DS. Pancreas. In: Sternberg SS, ed. Histology for Pathologists.
Philadelphia: Lippincott-Raven, 1997:613–647.
Lack EE. Pathology of the Pancreas, Gallbladder, Extrahepatic Biliary Tract,
and Ampullary Region. New York: Oxford University Press, 2003.
Chronic Pancreatitis
Bentz JS, Kochman ML, Faigel DO, Ginsberg GG, Smith DB, Gupta PK.
Endoscopic ultrasound-guided real-time fine-needle aspiration: clinico-
pathologic features of 60 patients. Diagn Cytopathol 1998;18:98–
109.
Deshpande V, Mino-Kenudson M, Pitman MB, Lauwers GY. Endoscopic
ultrasound guided fine needle aspiration biopsy of autoimmune pan-
creatitis: diagnostic criteria and pitfalls. Am J Surg Pathol 2005;29:
1464–1471.
Fritscher-Ravens A, Brand L, Knofel WT, et al. Comparison of endoscopic
ultrasound-guided fine needle aspiration for focal pancreatic lesions
in patients with normal parenchyma and chronic pancreatitis [see
comment]. Am J Gastroenterol 2002;97:2768–2775.
Hollerbach S, Klamann A, Topalidis T, Schmiegel WH. Endoscopic ultraso-
nography (EUS) and fine-needle aspiration (FNA) cytology for diagnosis
of chronic pancreatitis. Endoscopy 2001;33:824–831.
Stelow EB, Bardales RH, Lai R, et al. The cytological spectrum of chronic
pancreatitis. Diagn Cytopathol 2005;32:65–69.
Voss M, Hammel P, Molas G, et al. Value of endoscopic ultrasound guided
fine needle aspiration biopsy in the diagnosis of solid pancreatic
masses. Gut 2000;46:244–249.
Ylagan LR, Edmundowicz S, Kasal K, Walsh D, Lu DW. Endoscopic ultra-
sound guided fine-needle aspiration cytology of pancreatic carcinoma:
Ch009-F06731.indd 296
FINE NEEDLE ASPIRATION CYTOLOGY
a 3-year experience and review of the literature. Cancer 2002;96:
362–369.
Pseudocyst
Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of
pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst
study. Gastroenterology 2004;126:1330–1336.
Frossard JL, Amouyal P, Amouyal G, et al. Performance of endosonography-
guided fine needle aspiration and biopsy in the diagnosis of pancreatic
cystic lesions. Am J Gastroenterol 2003;98:1516–1524.
Kloppel G. Pseudocysts and other non-neoplastic cysts of the pancreas.
Semin Diagn Pathol 2000;17:7–15.
Kloppel G, Maillet B. Pseudocysts in chronic pancreatitis: a morphological
analysis of 57 resection specimens and 9 autopsy pancreata. Pancreas
1991;6:266–274.
Kosmahl M, Pauser U, Peters K, et al. Cystic neoplasms of the pancreas
and tumor-like lesions with cystic features: a review of 418 cases and
a classification proposal. Virchows Arch 2004;445:168–178.
Lewandrowski K, Lee J, Southern J, Centeno B, Warshaw A. Cyst fluid
analysis in the differential diagnosis of pancreatic cysts: a new approach
to the preoperative assessment of pancreatic cystic lesions. AJR Am J
Roentgenol 1995;164:815–819.
Pinto M, Meriano F. Diagnosis of cystic pancreatic lesions by cytologic
examination and carcinoembryonic antigen and amylase levels of cyst
contents. Acta Cytol 1991;35:456–463.
Lymphoepithelial Cyst
Adsay NV, Hasteh F, Cheng JD, Klimstra DS. Squamous-lined cysts of the
pancreas: lymphoepithelial cysts, dermoid cysts (teratomas), and
accessory-splenic epidermoid cysts. Semin Diagn Pathol 2000;17:56–65.
Adsay NV, Hasteh F, Cheng JD, et al. Lymphoepithelial cysts of the pan-
creas: a report of 12 cases and a review of the literature. Mod Pathol
2002;15:492–501.
Bolis GB, Farabi R, Liberati F, Maccio T. Lymphoepithelial cyst of the
pancreas. Report of a case diagnosed by fine needle aspiration biopsy.
Acta Cytol 1998;42:384–386.
Cappellari JO. Fine-needle aspiration cytology of a pancreatic lymphoepi-
thelial cyst. Diagn Cytopathol 1993;9:77–81.
Centeno BA, Stockwell JW, Lewandrowski KB. Cyst fluid cytology and
chemical features in a case of lymphoepithelial cyst of the pancreas: a
rare and difficult preoperative diagnosis. Diagn Cytopathol 1999;21:
328–330.
Liu J, Shin HJ, Rubenchik I, Lang E, Lahoti S, Staerkel GA. Cytologic
features of lymphoepithelial cyst of the pancreas: two preoperatively
diagnosed cases based on fine-needle aspiration. Diagn Cytopathol
1999;21:346–350.
Mitchell ML. Fine needle aspiration biopsy of peripancreatic lymphoepi-
thelial cysts. Acta Cytol 1990;34:462–463.
Ductal Adenocarcinoma
Al-Kaisi N, Siegler EE. Fine needle aspiration cytology of the pancreas.
Acta Cytol 1989;33:145–152.
Cohen MB, Egerter DP, Holly EA, Ahn DK, Miller TR. Pancreatic adenocar-
cinoma: regression analysis to identify improved cytologic criteria.
Diagn Cytopathol 1991;7:341–345.
Fekete PS, Nunez C, Pitlik DA. Fine-needle aspiration biopsy of the pan-
creas: a study of 61 cases. Diagn Cytopathol 1986;2:301–306.
Henke A, Jensen C, Cohen M. Cytologic diagnosis of adenocarcinoma in
biliary and pancreatic duct brushings. Adv Anat Pathol 2002;9:
301–308.
Lin F, Staerkel GA. Cytologic criteria for well differentiated adenocarci-
noma of the pancreas in fine-needle aspiration biopsy specimens.
Cancer 2003;99:44–50.
Mitchell ML, Carney CN. Cytologic criteria for the diagnosis of pancreatic
carcinoma. Am J Clin Pathol 1985;83:171–176.
Nagle J, Wilbur DC, Pitman MD. Cytomorphology of gastric and duodenal
epithelium and reactivity to B72.3: a baseline for comparison to pan-
creatic neoplasms aspirated by EUS-FNAB. Diagn Cytopathol 2005;33:
381–386.
Robins DB, Katz RL, Evans DB, Atkinson EN, Green L. Fine needle aspira-
tion of the pancreas. In quest of accuracy. Acta Cytol 1995;39:1–10.
10/26/2006 10:32:17 AM
 CHAPTER 9 Pancreas
Van Heek T, Rader A, Offerhaus G. K-ras, p53, and DPC4 (MAD4) alterations
in fine-needle aspirates of the pancreas: a molecular panel correlates
with and supplements cytologic diagnosis. Am J Surg Oncol 2002;117:
755–765.
Ductal Adenocarcinoma Variants
Adsay NV, Pierson C, Sarkar F, et al. Colloid (mucinous noncystic) carci-
noma of the pancreas. Am J Surg Pathol 2001;25:26–42.
Chow LT, Chow WH. Signet-ring mucinous adenocarcinoma of the pan-
creas. Chin Med Sci J 1994;9:176–178.
Gupta RK, Wakefield SJ. Needle aspiration cytology, immunocytochemis-
try, and electron microscopic study of unusual pancreatic carcinoma
with pleomorphic giant cells. Diagn Cytopathol 1992;8:522–527.
Manci EA, Gardner LL, Pollock WJ, Dowling EA. Osteoclastic giant cell
tumor of the pancreas. Aspiration cytology, light microscopy, and
ultrastructure with review of the literature. Diagn Cytopathol 1985;1:
105–110.
Mullick SS, Mody DR. ‘Osteoclastic’ giant cell carcinoma of the pancreas.
Report of a case with aspiration cytology. Acta Cytol 1996;40:975–
979.
Paal E, Thompson LD, Frommelt RA, Przygodzki RM, Heffess CS. A clinico-
pathologic and immunohistochemical study of 35 anaplastic carcinomas
of the pancreas with a review of the literature. Ann Diagn Pathol
2001;5:129–140.
Rahemtullah A, Misdraji J, Pitman MB. Adenosquamous carcinoma of the
pancreas: cytologic features in 14 cases. Cancer 2003;99:372–378.
Silverman JF, Dabbs DJ, Finley JL, Geisinger KR. Fine-needle aspiration
biopsy of pleomorphic (giant cell) carcinoma of the pancreas. Cytologic,
immunocytochemical, and ultrastructural findings. Am J Clin Pathol
1988;89:714–720.
Silverman JF, Finley JL, Berns L, Unverferth M. Significance of giant cells
in fine-needle aspiration biopsies of benign and malignant lesions of
the pancreas. Diagn Cytopathol 1989;5:388–391.
Tracey KJ, O’Brien MJ, Williams LF, et al. Signet ring carcinoma of the
pancreas, a rare variant with very high CEA values. Immunohistologic
comparison with adenocarcinoma. Dig Dis Sci 1984;29:573–576.
Walts AE. Osteoclast-type giant-cell tumor of the pancreas. Acta Cytol
1983;27:500–504.
Pancreatic Endocrine Neoplasm
Al-Kaisi N, Weaver MG, Abdul KFW, Siegler E. Fine needle aspiration cytol-
ogy of neuroendocrine tumors of the pancreas. A cytologic immuno-
cytochemical and electron microscopic study. Acta Cytol 1992;36:
655–660.
Bell DA. Cytologic features of islet-cell tumors. Acta Cytol 1987;31:
485–492.
Collins BT, Cramer HM. Fine-needle aspiration cytology of islet cell tumors.
Diagn Cytopathol 1996;15:37–45.
Dodd LG, Evans DB, Symmans F, Katz RL. Fine-needle aspiration of pan-
creatic extramedullary plasmacytoma: possible confusion with islet cell
tumor. Diagn Cytopathol 1994;10:371–375.
Labate AM, Klimstra DL, Zakowski MF. Comparative cytologic features of
pancreatic acinar cell carcinoma and islet cell tumor. Diagn Cytopathol
1997;16:112–116.
Ligneau B, Lombard-Bohas C, Partensky C. Cystic endocrine tumors of the
pancreas: clinical, radiologic and histopathologic features in 13 cases.
Am J Surg Pathol 2001;25:752–760.
Shaw JA, Vance RP, Geisinger KR, Marshall RB. Islet cell neoplasms. A
fine-needle aspiration cytology study with immunocytochemical corre-
lations. Am J Clin Pathol 1990;94:142–149.
Sneige N, Ordonez NG, Veanattukalathil S, Samaan NA. Fine-needle aspira-
tion cytology in pancreatic endocrine tumors. Diagn Cytopathol
1987;3:35–40. Erratum in: Diagn Cytopathol 1987;3:176.
Sun W, Sneige N, Staerkel G. Comparison of endoscopic ultrasound-guided
and computed tomography-guided fine needle aspiration biopsy in the
diagnosis of islet cell tumor of pancreas. Mod Pathol 2004;17(suppl.
1):82A.
Acinar Cell Carcinoma
Caruso RA, Inferrera A, Tuccari G, Barresi G. Acinar cell carcinoma of the
pancreas. A histologic, immunocytochemical and ultrastructural study.
Histol Histopathol 1994;9:53–58.
Ch009-F06731.indd 297
297
Klimstra DS. Pancreas. In: Sternberg SS, ed. Histology for Pathologists.
Philadelphia: Lippincott-Raven, 1997:613–647.
Klimstra DS, Heffess CS, Oertel JE, Rosai J. Acinar cell carcinoma of the
pancreas. A clinicopathologic study of 28 cases. Am J Surg Pathol
1992;16:815–837.
Labate AM, Klimstra DL, Zakowski MF. Comparative cytologic features of
pancreatic acinar cell carcinoma and islet cell tumor. Diagn Cytopathol
1997;16:112–116.
Samuel LH, Frierson HJ. Fine needle aspiration cytology of acinar cell
carcinoma of the pancreas: a report of two cases. Acta Cytol 1996;
40:585–591.
Villanueva RR, Nguyen-Ho P, Nguyen GK. Needle aspiration cytology of
acinar-cell carcinoma of the pancreas: report of a case with diagnostic
pitfalls and unusual ultrastructural findings. Diagn Cytopathol 1994;10:
362–364.
Pancreatoblastoma
Dhebri A, Connor S, Campbell F, Ghaneh P, Sutton R, Neoptolemos J.
Diagnosis, treatment and outcome of pancreatoblastoma. Pancreatology
2004;4:441–453.
Henke AC, Kelley CM, Jensen CS, Timmerman TG. Fine-needle aspira-
tion cytology of pancreatoblastoma. Diagn Cytopathol 2001;25:118–
121.
Klimstra D, Longnecker D. Pancreatoblastoma. In: Hamilton S, Aaltonen
L, eds. World Health Organization Classification of Tumours. Pathology
and Genetics of Tumours of the Digestive System. Lyon, France: IARC
Press, 2000:244–245.
Klimstra DS, Wenig BM, Adair CF, Heffess CS. Pancreatoblastoma. A clini-
copathologic study and review of the literature. Am J Surg Pathol
1995;19:371–389.
Pitman MB, Faquin WC. The fine-needle aspiration biopsy cytology of
pancreatoblastoma. Diagn Cytopathol 2004;31:402–406.
Silverman JF, Holbrook CT, Pories WJ, Kodroff MB, Joshi VV. Fine needle
aspiration cytology of pancreatoblastoma with immunocytochemical
and ultrastructural studies. Acta Cytol 1990;34:632–640.
Serous Cystadenoma
Hittmair A, Pernthaler H, Totsch M, Schmid KW. Preoperative fine needle
aspiration cytology of a microcystic adenoma of the pancreas. Acta
Cytol 1991;35:546–548.
Lal A, Bourtsos EP, DeFrias DV, Nemcek AA, Nayar R. Microcystic adenoma
of the pancreas: clinical, radiologic, and cytologic features. Cancer
2004;102:288–294.
Lewandrowski K, Lee J, Southern J, Centeno B, Warshaw A. Cyst fluid
analysis in the differential diagnosis of pancreatic cysts: a new approach
to the preoperative assessment of pancreatic cystic lesions. AJR Am J
Roentgenol 1995;164:815–819.
Logrono R, Vyas SH, Molina CP, Waxman I. Microcytic adenoma of the pan-
creas: cytologic appearance on percutaneous and endoscopic ultrasound-
guided fine-needle aspiration. Report of a case. Diagn Cytopathol
1999;20:298–301.
Nguyen GK, Vogelsang PJ. Microcystic adenoma of the pancreas. A report
of two cases with fine needle aspiration cytology and differential
diagnosis. Acta Cytol 1993;37:908–912.
Solid-Pseudopapillary Neoplasm
Abraham SC, Klimstra DS, Wilentz RE, et al. Solid-pseudopapillary tumors
of the pancreas are genetically distinct from pancreatic ductal adeno-
carcinomas and almost always harbor beta-catenin mutations. Am J
Pathol 2002;160:1361–1369.
Brugge WR, Lauwers GY, Sahani D, Fernandez-del Castillo C, Warshaw AL.
Cystic neoplasms of the pancreas. N Engl J Med 2004;351:1218–
1226.
Greenberg ML, Rennie Y, Grierson JM, Quin JW, Boadle RA. Solid and
papillary epithelial tumour of the pancreas: cytological case study with
ultrastructural and flow cytometric evaluation. Diagn Cytopathol
1993;9:541–546.
Pelosi G, Iannucci A, Zamboni G, Bresaola E, Iacono C, Serio G. Solid and
cystic papillary neoplasm of the pancreas: a clinico-cytopathologic and
immunocytochemical study of five new cases diagnosed by fine-needle
aspiration cytology and a review of the literature. Diagn Cytopathol
1995;13:233–246.
10/26/2006 10:32:17 AM
 298
Pettinato G, Di Vizio D, Manivel JC, Pambuccian SE, Somma P, Insabato
L. Solid-pseudopapillary tumor of the pancreas: a neoplasm with dis-
tinct and highly characteristic cytological features. Diagn Cytopathol
2002;27:325–334.
Pettinato G, Manivel JC, Ravetto C, et al. Papillary cystic tumor of
the pancreas. A clinicopathologic study of 20 cases with cytologic,
immunohistochemical, ultrastructural, and flow cytometric observa-
tions, and a review of the literature. Am J Clin Pathol 1992;98:478–
488.
Mucinous Cystic Neoplasms
Brugge WR. Role of endoscopic ultrasound in the diagnosis of cystic
lesions of the pancreas. Pancreatology 2001;1:637–640.
Jhala NC, Jhala D, Eltoum I, et al. Endoscopic ultrasound-guided fine
needle aspiration biopsy: a powerful tool to obtain samples from small
lesions. Cancer (Cancer Cytopathol) 2004;102:239–246.
Klapman JB, Logrono R, Dye CE, Waxman I. Clinical impact of on-site
cytopathology interpretation on endoscopic ultrasound-guided fine
needle aspiration. Am J Gastroenterol 2003;98:1289–1294.
Lau SK, Lewandrowski KB, Brugge WR, Warshaw AL, Centeno BA. Diagnos-
tic significance of mucin in fine needle aspiration samples of pancreatic
cysts. Mod Pathol 2000;13:48A.
Lewandrowski KB, Southern JF, Pins MR, Compton CC, Warshaw AL. Cyst
fluid analysis in the differential diagnosis of pancreatic cysts: a
comparison of pseudocysts, serous cystadenomas, mucinous cystic
neoplasms, and mucinous cystadenocarcinoma. Ann Surg 1993;217:41–
47.
Mallery JS, Centeno BA, Hahn PF, Chang Y, Warshaw AL, Brugge WR.
Pancreatic tissue sampling guided by EUS, CT/US, and surgery: a com-
parison of sensitivity and specificity. Gastrointest Endosc 2002;56:
218–224.
Nagle J, Wilbur DC, Pitman MD. The cytomorphology of gastric and duo-
denal epithelium and reactivity to B72.3: a baseline for comparison to
pancreatic neoplasms aspirated by EUS-FNAB. Diagn Cytopathol 2005;33:
381–386.
Pinto M, Meriano F. Diagnosis of cystic pancreatic lesions by cytologic
examination and carcinoembryonic antigen and amylase levels of cyst
contents. Acta Cytol 1991;35:456–463.
Recine M, Kaw M, Evans DB, Krishnamurthy S. Fine-needle aspiration
cytology of mucinous tumors of the pancreas. Cancer 2004;102:
92–99.
Shin HJ, Lahoti S, Sneige N. Endoscopic ultrasound-guided fine-needle
aspiration in 179 cases: the M. D. Anderson Cancer Center experience.
Cancer 2002;96:174–180.
Intraductal Papillary Mucinous Neoplasm
Faigel DO, Ginsberg GG, Bentz JS, Gupta PK, Smith DB, Kochman ML.
Endoscopic ultrasound-guided real-time fine-needle aspiration biopsy
of the pancreas in cancer patients with pancreatic lesions. J Clin Oncol
1997;15:1439–1443.
Ch009-F06731.indd 298
FINE NEEDLE ASPIRATION CYTOLOGY
Hruban RH, Takaori K, Klimstra DS, et al. An illustrated consensus on the
classification of pancreatic intraepithelial neoplasia and intraductal
papillary mucinous neoplasms. Am J Surg Pathol 2004;28:977–987.
Jhala NC, Jhala D, Eltoum I, et al. Endoscopic ultrasound-guided fine
needle aspiration biopsy: a powerful tool to obtain samples from small
lesions. Cancer (Cancer Cytopathol) 2004;102:239–246.
Klapman JB, Logrono R, Dye CE, Waxman I. Clinical impact of on-site
cytopathology interpretation on endoscopic ultrasound-guided fine
needle aspiration. Am J Gastroenterol 2003;98:1289–1294.
Layfield LJ, Cramer H. Fine-needle aspiration cytology of intraductal
papillary-mucinous tumors: a retrospective analysis. Diagn Cytopathol
2005;32:16–20.
Maire F, Couvelard A, Hammel P, et al. Intraductal papillary mucinous
tumors of the pancreas: the preoperative value of cytologic and histo-
pathologic diagnosis. Gastrointest Endosc 2003;58:701–706.
Michaels PJ, Brachtel EF, Bounds BC, Brugge WR, Pitman MB. Intraductal
papillary mucinous neoplasm of the pancreas: cytologic features predict
histologic grade. Cancer (Cancer Cytopathology) 2006;108:163–173.
Recine M, Kaw M, Evans DB, Krishnamurthy S. Fine-needle aspiration
cytology of mucinous tumors of the pancreas. Cancer 2004;102:
92–99.
Shin HJ, Lahoti S, Sneige N. Endoscopic ultrasound-guided fine-needle
aspiration in 179 cases: the M. D. Anderson Cancer Center experience.
Cancer 2002;96:174–180.
Stelow EB, Stanley MW, Bardales RH, et al. Intraductal papillary-mucinous
neoplasm of the pancreas. The findings and limitations of cytologic
samples obtained by endoscopic ultrasound-guided fine needle aspira-
tion. Am J Clin Pathol 2003;120:398–404.
Non-Epithelial and Secondary Neoplasms
Adsay NV, Andea A, Basturk O, Kilinc N, Nassar H, Cheng JD. Secondary
tumors of the pancreas: an analysis of a surgical and autopsy database
and review of the literature. Virchows Arch 2004;444:527–535.
Caffert L, Katz R, Ordonez N, Carrasco C, Cabanillas F. Fine needle aspira-
tion diagnosis of intra-abdominal and retroperitoneal lymphomas by a
morphologic and immunocytochemical approach. Cancer 1990;65:72–
77.
Dong HY, Harris NL, Preffer FI, Pitman MB. Fine-needle aspiration biopsy
in the diagnosis and classification of primary and recurrent lymphoma:
a retrospective analysis of the utility of cytomorphology and flow
cytometry. Mod Pathol 2001;14:472–481.
Ferrozzi F, Zuccoli G, Bova D, Calculli L. Mesenchymal tumors of the pan-
creas: CT findings. J Comput Assist Tomogr 2000;24:622–627.
Paal E, Thompson LD, Heffess CS. A clinicopathologic and immunohisto-
chemical study of ten pancreatic lymphangiomas and a review of the
literature. Cancer 1998;82:2150–2158.
Wieczorek TJ, Faquin WC, Rubin BP, Cibas ES. Cytologic diagnosis of gastro-
intestinal stromal tumor with emphasis on the differential diagnosis
with leiomyosarcoma. Cancer (Cancer Cytopathol) 2001;93:276–287.
Young NA, Al-Saleem TI, Ehya H, Smith MR. Utilization of fine-needle
aspiration cytology and flow cytometry in the diagnosis and subclassi-
fication of primary and recurrent lymphoma. Cancer 1998;84:252–
261.
10/26/2006 10:32:18 AM
 10 Kidney and Adrenal Gland
Yener S Erozan
KIDNEY
Fine needle aspiration (FNA), performed under ultra-
sound (US) or computed tomography (CT) guidance, is
a safe and accurate technique for the diagnosis of mass
lesions of the kidney (Table 10-1). It has been used in
the diagnosis of single and multiple masses, as well as
selected cystic lesions of kidney. The majority of single
masses in the kidney are primary renal neoplasms,
with renal cell carcinomas being the most common.
Other single masses include urothelial carcinoma
arising from kidney pelvis, benign neoplasms such as
angiomyolipoma and oncocytoma, and tumor-like
lesions such as xanthogranulomatous pyelonephritis
and abscess.
Childhood tumors of kidney are rarely sampled by
FNA. Exceptions are nephroblastoma (Wilms tumor)
and rhabdoid tumor, which can be diagnosed by FNA
and will be presented in this chapter.
Cystic lesions in kidney are common, and most are
benign, simple cysts (Table 10-2). Only those for which
imaging studies suggest a neoplasm, such as complex
multilocular cysts, are aspirated.
As in other FNAs, on-site evaluation of the speci-
mens for adequacy improves the diagnosis. Based on the
results, core biopsies can be performed or additional
samples can be obtained for ancillary studies.
RENAL CELL CARCINOMA (RCC)
CLINICAL FEATURES
Renal cell carcinomas comprise about 3% of adult
malignancies and occur in older age groups (median
age, 55 years). They are more common in men than in
women (approximately 1.5 : 1), and in the United States
the incidence is higher in blacks than in whites. Heavy
smoking and obesity increase the risk for RCC.
Most RCCs are confined to the kidney for a long
period of time, stay asymptomatic, and are detected inci-
dentally during imaging studies. When they become
symptomatic (i.e. hematuria, flank pain, or flank mass),
they are usually in an advanced stage. Radiologic tech-
niques (CT and US) are very effective for detecting
Ch010-F06731.indd 299
RENAL CELL CARCINOMA (RCC) – DISEASE FACT SHEET
Incidence
៉ About 3% of adult malignancies
៉ In USA, higher in black population
Gender and Age Distribution
៉ M : F = 1.5 : 1
៉ Median age, 55 years
Clinical Features
៉ Most confined to kidney for a long time and stay asymptomatic
៉ Many detected incidentally (on CT or US)
៉ Hematuria, flank pain, or flank mass occurs in advanced stages
Genetic Abnormalities
៉ Multiple chromosomal abnormalities (specifically chromosome #3)
៉ Up to 55% of patients with von Hippel–Lindau syndrome develop
RCC
៉ Increased risk in patients with tuberculous sclerosis and acquired
cystic kidney disease
Prognosis
៉ Determined by stage, nuclear grading, and tumor type
renal neoplasms, as well as for obtaining FNA samples
and core biopsies from the lesions.
Most RCCs have multiple chromosomal abnormalities,
specifically involving chromosome 3. Up to 55% of
patients with von Hippel–Lindau (VHL) syndrome
develop RCC. There is an increased risk of RCC in
patients with tuberous sclerosis and acquired cystic
kidney disease, and an association between genetic alter-
ations and specific types of RCC has been documented.
Prognosis for RCC is determined by stage, nuclear
grading, and type of the tumor.
CLASSIFICATION
The current classification of RCC is shown in Table
10-3. The most common type of RCC is clear cell (about
70%), followed by papillary (10–15%) and chromo-
phobe cell (approximately 5%). Collecting duct and
medullary types of RCCs are very rare.
299
10/26/2006 10:33:34 AM
 300 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 10-1
Low-grade renal cell carcinoma
(grade 1). Uniform, small, round
nuclei with dense chromatin. No
visible nucleoli. Papanicolaou stain,
low power.

TABLE 10-1 TABLE 10-3

Mass Lesions of Kidney Classification of Renal Cell Carcinoma

• Neoplasms:
• Renal cell carcinoma
• Oncocytoma
• Nephroblastoma (Wilms tumor)
• Rhabdoid tumor
• Urothelial carcinoma
• Angiomyolipoma
• Lymphoma
• Metastatic neoplasms
• Non-neoplastic masses:
• Xanthogranulomatous pyelonephritis From Murphy WM, Grignon DJ, Perlman EJ. Tumors of the
• Abscess Kidney, Bladder, and Related Urinary Structures. Atlas of
Tumor Pathology, 4th Series, Fascicle 1. Washington, D.C:
Armed Forces Institute of Pathology, 2004.

TABLE 10-2
Cystic Lesions of Kidney
• Benign cysts
• Malignant cystic lesions:
• Multilocular cystic clear cell carcinoma
• Other renal cell carcinomas with cystic degeneration
NUCLEAR GRADING
Nuclear grading (Fuhrman’s nuclear grading system) of
RCC has been shown to be a significant prognostic tool,
and similar criteria are applicable to both histologic and
cytologic specimens. Grade 1 RCCs have small, round
nuclei with dense chromatin and inconspicuous nucle-
oli (Fig. 10-1). Grade 2 RCCs have somewhat larger,
round nuclei with finely granular chromatin and small
nucleoli which are not visible under low power (10×)
(Fig. 10-2). Grade 3 RCCs have larger, round or oval
nuclei with a coarse granular chromatin pattern and
prominent nucleoli (Fig. 10-3). Grade 4 RCCs have
large pleomorphic nuclei with irregular nuclear borders
and prominent nucleoli (Fig. 10-4). Correlation between
cytopathologic and histopathologic grading is moderate.
Accuracy increases when a two-grade system, ‘low
grade’ (combined grades 1 and 2) and ‘high grade’ (com-
bined grades 3 and 4), is used. When adequate cellular
samples are obtained, discrepancies between cytopa-

Ch010-F06731.indd 300 10/26/2006 10:33:35 AM

 CHAPTER 10 Kidney and Adrenal Gland 301

FIGURE 10-2
Low-grade renal cell carcinoma
(grade 2). Uniform, somewhat larger
nuclei. No visible nucleoli. Diff-Quik
stain, low power.

FIGURE 10-3
High-grade renal cell carcinoma
(grade 3). Large, round to oval
nuclei, some with irregular borders.
Prominent nucleoli. Papanicolaou
stain, medium power.

thologic (FNA specimens) and histopathologic (resected CYTOPATHOLOGIC FEATURES

tumor) specimens are usually caused by sampling error
due to tumor heterogeneity. In our experience, inter-
observer concordance in FNA samples is higher
than that of cytopathologic and histopathologic correla-
tion, supporting sampling error as the major reason for
disconcordance.
The cytopathologic features of RCC presented in most
textbooks are based on those of clear cell carcinoma,
which is the most common type. There is also adequate
information about papillary RCC in the literature;

Ch010-F06731.indd 301 10/26/2006 10:33:35 AM

 302 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 10-4
High-grade renal cell carcinoma
(grade 4). Large pleomorphic nuclei
with macronucleoli. Papanicolaou
stain, medium power.

specimens for cell blocks and/or needle core biopsies,

RENAL CELL CARCINOMA (RCC) – PATHOLOGIC FEATURES when needed, increases the specificity of the diagnosis.

Classification
៉ Histologic subtypes of RCC:
៉ Clear cell (conventional) (~70%) CLEAR CELL (CONVENTIONAL-TYPE)
៉ Papillary (10–15%) RENAL CELL CARCINOMA
៉ Chromophobe cell (~5%)
៉ Collecting duct (very rare)
៉ Medullary (very rare) CLINICAL FEATURES
Nuclear Grading (Fuhrman’s Grading System)
៉ Significant prognostic tool Clear cell is the most common subtype, comprising
៉ Similar criteria applicable to histologic and cytologic specimens about 70% of RCCs. Granular cell RCCs, which were
៉ Moderate correlation between histopathologic and considered a separate category previously, are now
cytopathologic grading included in this group. Both sporadic and familial forms
៉ Accuracy increases when a two-grade system is used: (VHL) have genetic abnormalities involving chromo-
៉ ‘Low grade’ (grades 1 and 2)
some 3. The VHL gene is located in 3p25, which is
៉ ‘High grade’ (grades 3 and 4)
mutated or lost in clear cell papillary RCCs. Additional
Cytopathologic Findings
suppressor genes are found in chromosome 3, most
commonly in the region of 3p14. Continuous deletion
៉ Vary according to type and nuclear grading (discussed in detail
under specific subtype)

Differential Diagnosis and Pitfalls

៉ Well-differentiated RCC vs other clear cell neoplasms CLEAR CELL (CONVENTIONAL-TYPE) RENAL CELL CARCINOMA –
៉ Poorly differentiated RCC vs metastatic neoplasm or urothelial DISEASE FACT SHEET
carcinoma
Incidence
៉ Most common type of RCC (70%)

Genetic Abnormalities
however, FNA findings of chromophobe, collecting duct,
៉ Both sporadic and familial forms (genetic abnormalities involving
and medullary RCCs are limited. Subtypes of RCC, as
chromosome #3)
well as Fuhrman nuclear grading, can be determined ៉ Continuous deletion from 3p24.2 to 3p25 in 96% of clear cell
fairly accurately in FNA specimens. Errors usually RCCs
occur due to lack of adequate sampling or to the poor
differentiation of the tumor. Obtaining adequate

Ch010-F06731.indd 302 10/26/2006 10:33:36 AM

 CHAPTER 10 Kidney and Adrenal Gland 303

FIGURE 10-5
Renal cell carcinoma, clear cell (con-
ventional) type. Many large tissue
fragments of tumor with scattered
single cells or small groups. Diff-
Quik stain, low power.

FIGURE 10-6
Renal cell carcinoma, clear cell
(conventional) type. A large frag-
ment of tumor. Note the thin-walled
blood vessels traversing the tumor.
Diff-Quik stain, medium power.

from 3p24.2 to 3p25 is found in up to 96% of clear cell
carcinomas.
CYTOPATHOLOGIC FEATURES
Most FNAs yield abundant material comprised pre-
dominantly of tissue fragments of tumor (Fig. 10-5).
Some, however, are predominantly blood and require
multiple attempts to obtain adequate cellular material.
Thin-walled blood vessels crossing the fragments is a
characteristic feature (Fig. 10-6). Branching blood
vessels surrounded by several layers of tumor cells
form a papillary-like architecture (Fig. 10-7). Tumor
cells have clear or finely vacuolated cytoplasm (Fig.
10-8) which contains lipids, cholesterol, and glycogen.
Other cells may have acidophilic granular cytoplasm

Ch010-F06731.indd 303 10/26/2006 10:33:37 AM

 304
(Fig. 10-9). Intracytoplasmic hyaline globules may be
present; the nuclei of the tumor cells are usually round
with finely granular chromatin. Nucleoli may be absent,
small, or prominent, depending on the grade of the
neoplasm.
ANCILLARY STUDIES
Clear cell RCCs react to RCC and CD10 antibodies.
They also react to antibodies to low molecular weight
cytokeratins, epithelial membrane antigen (EMA), and
vimentin.
Ch010-F06731.indd 304
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 10-7
Renal cell carcinoma, clear cell
(conventional) type. A large frag-
ment of tumor with papillary-like
formations. Diff-Quik stain, low
power.
FIGURE 10-8
Renal cell carcinoma, clear cell
(conventional) type. Tumor cells
with intracytoplasmic, small,
uniform vacuoles which are best
seen in air-dried Romanowsky-
stained specimens. These vacuoles
contain lipids and glycogen, which
could be shown by staining with
Oil-Red O and PAS stains. Diff-Quik
stain, high power.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Clear cell RCCs have distinct cytologic features, and the
diagnosis is not difficult when the specimen is obtained
by FNA of a mass in the kidney. The only challenging
differential diagnosis might be for oncocytoma when
the tumor contains a large number of tumor cells with
granular eosinophilic cytoplasm rather than clear cells.
Oncocytomas lack large nucleoli and mitoses. Unlike
clear cell RCC, oncocytoma does not react to antibodies
for vimentin and RCC.
10/26/2006 10:33:38 AM
 CHAPTER 10 Kidney and Adrenal Gland 305

FIGURE 10-9
Renal cell carcinoma, clear cell
(conventional) type. A fragment of
high-grade RCC. Moderately pleo-
morphic nuclei with prominent
nucleoli. Most of the cells have
dense cytoplasm; a few have clear
cell features. Papanicolaou stain,
medium power.

CLEAR CELL (CONVENTIONAL-TYPE) RENAL CELL CARCINOMA – PAPILLARY RENAL CELL CARCINOMA – DISEASE FACT SHEET
PATHOLOGIC FEATURES
Incidence
Cytopathologic Findings ៉ 10–15% of RCCs
៉ Abundant material, predominantly tissue fragments in FNAs ៉ Multiple tumors more common than in clear cell RCC
៉ Thin-walled blood vessels traversing tissue fragments
៉ Branching blood vessels surrounded by tumor cells form
papillary-like architecture
៉ Finely vacuolated cytoplasm (lipids and glycogen)
៉ Other cells may have acidophilic granular cytoplasm
៉ Intracytoplasmic hyaline globules may be present
CYTOPATHOLOGIC FEATURES
៉ Nuclei usually round with finely granular chromatin
៉ Nucleoli absent, small or prominent, depending on grade
In type 1 papillary RCC, which comprises more than
two-thirds of papillary RCCs, fine needle aspirates
Ancillary Studies
usually show abundant papillary structures with vas-
៉ Reacts antibodies to RCC, CD10, low molecular weight
cular cores (Fig. 10-10). Single or lobulated globular
cytokeratins, EMA, and vimentin
forms with sharp outlines may also be present (Fig.
Differential Diagnosis and Pitfalls
10-11). Psammoma bodies (Fig. 10-12), lipid-laden
histiocytes, and intracytoplasmic hemosiderin pigment
៉ Could be confused with oncocytoma
៉ Oncocytomas lack large nucleoli and mitoses and do not react
in both histiocytes and tumor cells are characteristic
to antibodies for vimentin and RCC features of this tumor, although they are not always
present (Figs 10-13 & 10-14). Evidence of necrosis and
hemorrhage, which commonly occur in the tumor, may
also be seen in FNA specimens. In type 2 papillary
RCC, the cells have large acidophilic cytoplasm and a
higher nuclear grade (Grade 3) with prominent
PAPILLARY RENAL CELL CARCINOMA nuclei.

CLINICAL FEATURES
Approximately 10–15% of RCCs are papillary type, and
multiple tumors occur more commonly than in clear
cell renal carcinoma.
ANCILLARY STUDIES
Most papillary RCCs react to RCC markers, pancyto-
keratins, low molecular weight cytokeratins, and CD9

Ch010-F06731.indd 305 10/26/2006 10:33:40 AM

 306 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 10-10
Renal cell carcinoma, papillary type.
Papillary structure with vascular
core. Diff-Quik stain, low power.

FIGURE 10-11
Renal cell carcinoma, papillary type.
Lobulated, globular formations in
a background of loosely attached
tumor cells with ill-defined cyto-
plasm. One rosette-like structure
with an early forming psammoma
body in the center. Papanicolaou
stain, medium power.

Ch010-F06731.indd 306 10/26/2006 10:33:41 AM

 CHAPTER 10 Kidney and Adrenal Gland 307

FIGURE 10-12
Renal cell carcinoma, papillary type.
Small tissue fragments and loose
aggregates of tumor cells mixed
with macrophages. Several psam-
moma bodies surrounded with tumor
cells. Papanicolaou stain, medium
power.

FIGURE 10-13
Renal cell carcinoma, papillary type.
A tissue fragment of tumor. Tumor
appears to be high grade. Hemo-
siderin-laden macrophages and
several tumor cells next to a larger
tissue fragment. Papanicolaou stain,
medium power.

Ch010-F06731.indd 307 10/26/2006 10:33:42 AM

 308 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 10-14
Renal cell carcinoma, papillary type.
Slightly enlarged, round or oval
nuclei consistent with a low-grade
(grade 2) tumor. Note the intra-
cytoplasmic hemosiderin pigment
in the tumor cells.

and tumor cells, and psammoma bodies differentiates

PAPILLARY RENAL CELL CARCINOMA – PATHOLOGIC FEATURES these tumors from other types of RCC.

Cytopathologic Findings
៉ Tumor tends to have hemorrhage, necrosis, and cystic
formations CHROMOPHOBE RENAL CELL CARCINOMA
៉ Type 1 papillary RCC: abundant papillary structures with vascular
cores; single or lobulated globular forms; psammoma bodies,
lipid-laden histiocytes, intracytoplasmic hemosiderin in CLINICAL FEATURES
histiocytes and tumor cells
៉ Type 2 papillary RCC: large acidophilic cytoplasm; higher nuclear
grade, prominent nucleoli The chromophobe cell type comprises about 5% of
RCCs. It occurs predominantly in middle-aged patients
Ancillary Studies and in both sexes equally.
៉ React to RCC markers, pancytokeratins, low molecular weight
cytokeratins, CD9 and CD10

Differential Diagnosis and Pitfalls CYTOPATHOLOGIC FEATURES

៉ Differentiating characteristics: papillary structures, lipid-laden
histiocytes, intracytoplasmic hemosiderin in histiocytes and
tumor cells, and psammoma bodies In FNA specimens, chromophobe cell RCCs occur as
single cells and in tight groups (Fig. 10-16). Tumor cells

and CD10 (Fig. 10-15). Reaction to high molecular

weight cytokeratins is rare and focal. Reactivity to CHROMOPHOBE RENAL CELL CARCINOMA – DISEASE FACT SHEET
vimentin is inconsistent.
Incidence
៉ About 5% of RCCs

DIFFERENTIAL DIAGNOSIS AND PITFALLS Gender and Age Distribution

៉ No gender predilection
៉ Predominantly middle-aged patients
The presence of papillary structures, lipid-laden histio-
cytes, intracytoplasmic hemosiderin in both histiocytes

Ch010-F06731.indd 308 10/26/2006 10:33:43 AM

 CHAPTER 10 Kidney and Adrenal Gland 309

A B

FIGURE 10-15
Renal cell carcinoma, papillary type. A, Strong positive reaction to RCC
antibody. Cell block immunostain for RCC, medium power. B, Papillary RCC
with psammoma bodies. Strong reactivity for AE1/AE3. Cell block, medium
power. C, Membranous staining with CD10. Cell block, medium power.

FIGURE 10-16
Renal cell carcinoma, chromophobe
cell type. Single cells and tight
groups of tumor cells. Nuclei vary in
size and are eccentrically located.
Diff-Quik stain, low power.

Ch010-F06731.indd 309 10/26/2006 10:33:44 AM

 310
CHROMOPHOBE RENAL CELL CARCINOMA –
PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Single cells and tight groups
៉ Tumor cells vary in size with usually abundant cytoplasm
៉ Two types of cells:
៉ Classic: pale cytoplasm with distinct borders
៉ Eosinophilic: dense, granular cytoplasm
៉ Perinuclear halos rarely seen
៉ Hyperchromatic nuclei with mildly irregular borders
៉ Binucleation is common
៉ Small nucleoli may be present
Ancillary Studies
៉ Reacts to antibodies to cytokeratins and EMA
៉ About half are positive for RCC marker
៉ Do not react for vimentin
៉ Diffuse cytoplasmic staining with Hale’s colloidal iron stain
Differential Diagnosis and Pitfalls
៉ Most likely to be confused with oncocytoma
៉ Nuclear border irregularities and perinuclear halos are not
present in oncocytoma, binucleation is rare
៉ Hale’s colloidal iron stain is negative
vary in size with usually abundant cytoplasm, which
could be pale with distinct borders or dense granular,
corresponding to the ‘classic’ and ‘eosinophilic’ type
cells in histologic preparations. Others have vacuolated
or flocculent cytoplasm. Perinuclear halos may be seen;
but, unlike in histologic preparations, they are rare and
Ch010-F06731.indd 310
FINE NEEDLE ASPIRATION CYTOLOGY
not always clearly defined. Nuclei are hyperchromatic
with mildly irregular borders and vary in size. Binucle-
ation is common (Fig. 10-17). Occasional intranuclear
pseudoinclusions may be seen (Fig. 10-18). Small nucle-
oli may be present.
ANCILLARY STUDIES
Chromophobe cell RCCs react with antibodies to cyto-
keratins (i.e. 7, 14, and pancytokeratin) and EMA.
Approximately half of the chromophobe cell RCCs are
positive for the RCC marker. They do not react for
vimentin. In cell blocks, chromophobe RCCs show
diffuse cytoplasmic staining with Hale’s colloidal iron
stain.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The main differential diagnosis of chromophobe cell
RCC is from oncocytoma. The former shows frequent
binucleation, pleomorphism (mostly variation in the
size of nuclei), nuclear border irregularities, and peri-
nuclear halos, in contrast to the round to oval uniform
nuclei of oncocytomas. Binucleation is rare, and nuclear
border irregularities and perinuclear halos are not
present in oncocytomas. Hale’s colloidal iron stain,
which is positive in chromophobe cell RCC and nega-
tive in oncocytomas, is also helpful in the differential
diagnosis.
FIGURE 10-17
Renal cell carcinoma, chromophobe
cell type. Tumor cells have abun-
dant cytoplasm with well-defined
borders. Note the cells with clear,
pale and dense cytoplasm. Thin
perinuclear clearing is noticeable
in some cells. Binucleation is
frequent. There is moderate aniso-
cytosis and some nuclear border
irregularity. Diff-Quik stain, medium
power.
10/26/2006 10:33:45 AM
 CHAPTER 10 Kidney and Adrenal Gland
FIGURE 10-18
Renal cell carcinoma, chromophobe
cell type. Intranuclear pseudoinclu-
sions. Occasional large nuclei with
irregular borders. Tumor cells with
pale and dense cytoplasm. Diff-Quik
stain, high power.
COLLECTING DUCT RENAL CELL
CARCINOMA
CLINICAL FEATURES
This type accounts for less than 1% of RCCs and occurs
in a younger age group (34–43 years) with a male to
female ratio of 2 : 1. It is an aggressive tumor with a
poor prognosis and is located in the medulla. Cytoge-
netic abnormalities found in this tumor (loss of arms
6p, 8p, 13q, and 21q, and monosomies 1, 6, 14, 15, and
22) are different from those in conventional and
COLLECTING DUCT RENAL CELL CARCINOMA –
DISEASE FACT SHEET
Incidence
៉ Less than 1% of RCCs
Gender and Age Distribution
៉ Male to female ratio is 2 : 1
៉ Occurs in younger age group (34–43 years of age)
Clinical Features
៉ Aggressive tumor with poor prognosis
៉ Located in the medulla
៉ Cytogenetic abnormalities are different from those in
conventional and papillary RCCs
៉ Multicystic formations are frequent
Ch010-F06731.indd 311
311
papillary RCCs. Multicystic formations, due to dilated
ducts, are frequent.
CYTOPATHOLOGIC FEATURES
Fine needle aspirates reveal small tissue fragments and
single cells with apparent malignant features (Figs
10-19 & 10-20). The former could be monolayer sheets
COLLECTING DUCT RENAL CELL CARCINOMA –
PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Small tissue fragments and single cells with apparent malignant
features
៉ Sheets and tubular, rarely papillary, forms
៉ Eccentrically located, enlarged pleomorphic nuclei, irregular
nuclear borders, vesicular or coarse chromatin
៉ Single or multiple, prominent nucleoli
៉ Small to moderate amounts of cytoplasm
៉ Fine or larger vacuoles containing mucin may be present
Ancillary Studies
៉ Reacts to pankeratin, low and high molecular weight
cytokeratins, EMA, and peanut agglutinin
៉ RCC marker is negative
Differential Diagnosis and Pitfalls
៉ Differs from chromophobe RCC, which has low-grade nuclei
៉ Positive staining with high molecular weight cytokeratins and
intracytoplasmic mucin differentiate it from conventional RCC
10/26/2006 10:33:46 AM
 312 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 10-19
Renal cell carcinoma, collecting
duct cell type. A tissue fragment of
tumor. Many malignant features are
present, including marked nuclear
pleomorphism and marked variation
in N/C ratio. Diff-Quik stain, medium
power.

FIGURE 10-20
Renal cell carcinoma, collecting
duct cell type. Markedly atypical
single tumor cells. Diff-Quik stain,
high power.

Ch010-F06731.indd 312 10/26/2006 10:33:47 AM

 CHAPTER 10 Kidney and Adrenal Gland 313

FIGURE 10-21
Renal cell carcinoma, collecting
duct cell type. Tumor cells with
large nuclei, macronucleoli, and
intracytoplasmic vacuoles. Papani-
colaou stain, high power.

and tubular or, rarely, papillary forms. Desmoplastic
stromal tissue fragments may be present. The tumor
cells have eccentrically located, enlarged, pleomorphic
nuclei with irregular borders, vesicular or coarse chro-
matin, single or multiple prominent nucleoli, and small
or moderate amounts of cytoplasm, which may contain
fine or larger vacuoles (Fig. 10-21). Mucin may be
present.
Differential diagnosis from medullary type RCC and
metastatic neoplasms is difficult on cytomorphologic
bases. Correlation with the clinical findings is neces-
sary in most cases.
MEDULLARY-TYPE RENAL CELL
CARCINOMA

ANCILLARY STUDIES CLINICAL FEATURES

The tumor cells react to pankeratin (AE1/AE3), low This is a very aggressive, rare type of RCC which occurs
and high molecular weight cytokeratins, EMA, cyto- in young African-American men with sickle cell disease
keratins 7, 8, and 18, and peanut agglutinin. RCC or sickle cell trait. It is usually diagnosed in the advanced
marker is reported to be negative. stage.

DIFFERENTIAL DIAGNOSIS AND PITFALLS

The collecting duct RCC has a distinctly different MEDULLARY-TYPE RENAL CELL CARCINOMA –
cytomorphology from those of conventional-type and DISEASE FACT SHEET
chromophobe RCCs. The latter usually have low-grade
Clinical Features
nuclei, in contrast to the high-grade nuclei of collecting
៉ Very aggressive, rare type of RCC
duct RCC. Positive staining with antibodies to high
៉ Occurs in young African-American men with sickle cell disease or
molecular weight cytokeratins, and the presence of
sickle cell trait
intracytoplasmic mucin (mucicarmine and periodic ៉ Usually diagnosed in advanced stage
acid–Shiff [PAS] with diastase digest), help to differen-
tiate collecting duct RCC from conventional type.

Ch010-F06731.indd 313 10/26/2006 10:33:48 AM

 314 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 10-22
Medullary-type renal cell carcinoma.
A tissue fragment. Poorly differen-
tiated carcinoma with large nuclei,
prominent nucleoli, and occasional
intracytoplasmic vacuoles. H&E
stain, low power. Courtesy of Srini-
vas R Mandavilli, MD.

CYTOPATHOLOGIC FEATURES ANCILLARY STUDIES

There are limited data on the cytopathologic features The tumor cells react to cytokeratins. Reaction to EMA
of this tumor. Cytomorphology is similar to that of and carcinoembryonic antigen (CEA) is variable. Mucin
other high-grade carcinomas. Tumor cells appear pre- stains are positive in the majority of the tumors.
dominantly in loosely cohesive groups. The nuclei are
large and pleomorphic with prominent nucleoli. Cyto-
plasm may be dense or vacuolated (Fig. 10-22).
DIFFERENTIAL DIAGNOSIS AND PITFALLS

Cytopathologic features of this tumor overlap with

those of collecting duct RCC and other poorly differen-
tiated primary or metastatic carcinomas. Clinical cor-
MEDULLARY-TYPE RENAL CELL CARCINOMA –
PATHOLOGIC FEATURES
relation is usually necessary to establish a definitive
diagnosis, since it occurs exclusively in patients with
Cytopathologic Findings sickle cell disease or sickle cell trait.
៉ Cytomorphology similar to other high-grade carcinomas
៉ Tumor cells appear predominantly in loosely cohesive groups
៉ Large pleomorphic nuclei with prominent nucleoli
៉ Cytoplasm may be dense or vacuolated SARCOMATOID RENAL CELL CARCINOMA

Ancillary Studies
៉ Reacts to antibodies to cytokeratins
CLINICAL FEATURES
៉ Variable reaction for EMA and CEA
៉ Mucin is positive in the majority of the tumors
Sarcomatoid changes are present in 1% to 6.5% of
RCCs, and many occur in large portions of the tumor.
Differential Diagnosis and Pitfalls
They may be found in all types of RCC and are not
៉ Difficult to differentiate from collecting duct RCC, and other
considered a separate type. Sarcomatoid changes indi-
poorly differentiated primary or metastatic carcinomas; clinical
correlation is necessary
cate a poor prognosis. In spite of the sarcomatous
morphology, tumor cells have the ultrastructural and
histochemical features of epithelial differentiation.

Ch010-F06731.indd 314 10/26/2006 10:33:49 AM

 CHAPTER 10 Kidney and Adrenal Gland 315

SARCOMATOID RENAL CELL CARCINOMA – DISEASE FACT SHEET SARCOMATOID RENAL CELL CARCINOMA – PATHOLOGIC FEATURES

Incidence Cytopathologic Findings

៉ Present in 1% to 6.5% of RCCs ៉ Spindle cells with varying degrees of atypia, multinucleated
៉ May occur in all types of RCC (not considered a separate type) giant cells, and significant pleomorphism may be present
៉ Associated with other types of RCC
Clinical Features
៉ Indicates a poor prognosis Ancillary Studies
៉ Reaction to antibodies to cytokeratins and EMA varies
៉ RCC markers usually negative in sarcomatous cells

Differential Diagnosis and Pitfalls

៉ Rare metastatic sarcomas can be ruled out by reaction for
cytokeratins and the presence of other types of RCC
CYTOPATHOLOGIC FEATURES

In fine needle aspirates, in addition to the cellular com-

ponent presenting features of one of the specific types
of RCC, there are spindle cells with varying degrees
of atypia (Fig. 10-23). Multinucleated giant cells and reaction for cytokeratins. RCC marker is usually nega-
significant nuclear pleomorphism may be present. tive in sarcomatous cells of the tumor.

ANCILLARY STUDIES DIFFERENTIAL DIAGNOSIS AND PITFALLS

Immunohistochemical reaction with antibodies to With adequate sampling, identification of other types
cytokeratins and EMA varies. Both sarcomatous and of RCC and positive reaction to antibodies to cytokera-
epithelial components in some tumors have a positive tins helps to differentiate it from metastatic sarcomas.

FIGURE 10-23
Sarcomatoid renal cell carcinoma.
Poorly differentiated atypical cells
with sarcomatoid features. Papani-
colaou stain, high power.

Ch010-F06731.indd 315 10/26/2006 10:33:49 AM

 316
ONCOCYTOMA
CLINICAL FEATURES
Oncocytomas are benign neoplasms comprising 3.5%
of renal tumors in adults. The majority of these tumors
occur in persons over the age of 50 years and are more
common in men than in women (2.3 : 1). About two-
thirds of oncocytomas are incidentally detected by
radiologic examinations performed for other reasons.
The most common cytogenetic abnormalities are
losses of chromosomes 1 and 7, deletion of chromosome
14, and rearrangements involving chromosome 11q13.
CYTOPATHOLOGIC FEATURES
FNA usually provides a moderately cellular specimen
with a combination of single, loose aggregates, and
tissue fragments of oncocytic cells (Figs 10-24 & 10-
25). The cells have uniform, round nuclei with small,
ONCOCYTOMA – DISEASE FACT SHEET
Incidence, and Age and Gender Distribution
៉ Benign neoplasms comprising 3.5% of RCCs in adults over the age
of 50
៉ Male to female ratio is 2.3 : 1
៉ About two-thirds are incidentally detected by imaging studies
Genetic Abnormalities
៉ Cytogenetic abnormalities include loss of chromosomes 1 and 7,
deletion of 14, and rearrangement of 11q13
Ch010-F06731.indd 316
FINE NEEDLE ASPIRATION CYTOLOGY
ONCOCYTOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Combination of single, loose aggregates and tissue fragments of
oncocytic cells
៉ Uniform, round nuclei with small, bright red nucleoli
៉ Finely granular, acidophilic cytoplasm with well-defined borders
Ancillary Studies
៉ Reacts to antibodies to EMA, low molecular weight cytokeratins,
and most pancytokeratin cocktails
៉ CK7 strongly positive in scattered cells
៉ Reaction to CK20 varies
៉ Most oncocytomas are non-reactive to antibodies to vimentin
៉ RCC marker is negative
Differential Diagnosis and Pitfalls
៉ Differential diagnoses include RCCs with oncocytic component
៉ With adequate sampling, other cell types can be ruled out
៉ Necrosis, mitoses, and macronucleoli rule out oncocytoma
៉ Eosinophilic-type chromophobe RCC vs oncocytoma can be
difficult
៉ Chromophobe RCCs’ irregular nuclear borders with perinuclear
halos contrast with the uniform nuclear borders of oncocytic
cells
៉ Hale’s colloidal iron stain is negative in oncocytoma
bright red nucleoli and abundant, finely granular,
acidophilic cytoplasm with well-defined borders.
Mitoses and background necrosis are absent.
ANCILLARY STUDIES
Oncocytomas react to EMA, low molecular weight
cytokeratins, and most pancytokeratin cocktails. CK7
FIGURE 10-24
Oncocytoma. Round, uniform nuclei
with prominent nucleoli and abun-
dant cytoplasm. Diff-Quik stain,
high power.
10/26/2006 10:33:50 AM
 CHAPTER 10 Kidney and Adrenal Gland
FIGURE 10-25
Oncocytoma. These tumor cells
show characteristic features of
oncocytoma: single cells with
large, centrally located nuclei and
prominent nucleoli. Cytoplasm is
granular. Papanicolaou stain, high
power.
is strongly positive in scattered cells, and reaction to
CK20 varies. Most oncocytomas are non-reactive to
vimentin. The RCC marker is negative.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Many RCCs have oncocytic cells; however, entirely
oncocytic cell populations occur only in oncocytomas.
Extensive samplings of the tumor, along with clinical
and radiologic correlations, are necessary for a defini-
tive diagnosis. The presence of necrosis, mitoses, and
macronucleoli rules out a diagnosis of oncocytoma. The
differential diagnosis between oncocytoma and the
eosinophilic type of chromophobe RCC can be difficult.
Chromophobe RCCs have irregular nuclear borders
(‘raisinoid’ nuclei) with perinuclear halos, in contrast
to the uniform, smooth nuclear borders of oncocytic
cells of oncocytomas. Eosinophilic-type chromophobe
RCC shows diffuse cytoplasmic staining with Hale’s
colloidal iron, which is negative in oncocytoma. Lack
of intracytoplasmic glycogen and mucin, and non-
reactivity to RCC marker, can be helpful in distinguish-
ing oncocytomas from RCCs.
NEPHROBLASTOMA (WILMS TUMOR)
CLINICAL FEATURES
Nephroblastoma is a malignant embryonal neoplasm of
childhood. It is the most common genitourinary malig-
nant neoplasm in children, and comprises approxi-
mately 90% of pediatric renal malignancies. Ninety-eight
percent of the nephroblastomas occur in children under
Ch010-F06731.indd 317
317
NEPHROBLASTOMA (WILMS TUMOR) – DISEASE FACT SHEET
Incidence
៉ Most common genitourinary neoplasm in children
៉ Comprises ~90% of pediatric renal malignancies
Gender and Age Distribution
៉ 98% of nephroblastomas occur in children under 10 years of age
៉ Mean age is 36 months for males and 42 months for females
Clinical Features
៉ Association with genetic syndromes involving WT1 and WT2 genes
has been shown
៉ The majority of tumors are single, but multiple synchronous
unilateral or bilateral tumors may occur
10 years of age, the mean age being 36 months for males
and 42 months for females. Association with certain
genetic syndromes involving WT1 and WT2 genes
among others has been shown. The majority of nephro-
blastomas are single tumors; however, multiple syn-
chronous unilateral or bilateral tumors may occur.
CYTOPATHOLOGIC FEATURES
Cytopathologic diagnosis of nephroblastoma requires
adequate sampling of the tumor. Blastemal cells occur
in sheets, groups, or single forms. Some molding is
present. The cells are small with very scant, fragile
cytoplasm (Fig. 10-26). Nuclei show fine, evenly dis-
tributed chromatin and inconspicuous nucleoli. Epithe-
lial cells form glandular structures of primitive cells.
Stromal cells are seen in cellular tissue fragments com-
posed of tightly arranged spindle cells and capillaries.
10/26/2006 10:33:51 AM
 318
NEPHROBLASTOMA (WILMS TUMOR) – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Blastemal cells occur in sheets, groups, or singly
៉ Small cells with scant, very fragile cytoplasm
៉ Fine, evenly dispersed chromatin, inconspicuous nucleoli
៉ Glandular structures of primitive epithelial cells
៉ Cellular tissue fragments of spindle cells and capillaries
៉ Admixture of blastemal epithelial and stromal cells
៉ Anaplasia characterized by hyperchromatic nuclei and multipolar
mitotic figures
Ancillary Studies
៉ Blastemal cells positive for vimentin, may be positive with NSE,
and are positive with WT1 in early differential stages
៉ Also positive with desmin, but negative for primitive muscle
markers
Differential Diagnosis and Pitfalls
៉ Include other primary pediatric tumors of kidney
៉ These tumors are rare and, with a few exceptions, specific
diagnosis can only be made on tissue samples representative of
the tumor
Areas of an admixture of two or all three components
are present. Anaplasia can be diagnosed using the same
criteria as those for histopathologic specimens. The
presence of very large, hyperchromatic nuclei and
multipolar mitotic figures confirms the diagnosis.
ANCILLARY STUDIES
Immunohistochemical reactions vary according to the
differentiation. Blastemal cells are usually positive for
Ch010-F06731.indd 318
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 10-26
Wilms tumor. A fragment of undif-
ferentiated carcinoma. Tumor cells
have somewhat pleomorphic nuclei
and high N/C ratio. On morphology
alone, this tumor cannot be differ-
entiated from other small cell
tumors of childhood. Papanicolaou
stain, high power.
vimentin and may express neuron-specific enolase
(NSE). Nuclear staining for WT1 is positive in blaste-
mal cells and in epithelial cells in early differential
stages. Blastemal cells are also positive for desmin,
but they are usually negative for primitive muscle
markers.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis of nephroblastoma includes
other primary pediatric tumors of kidney, such as rhab-
doid tumor, clear cell carcinoma, congenital mesoblas-
tic nephroma, and so-called small blue cell tumors. Blue
cell tumors in childhood include neuroblastoma, primi-
tive neuroectodermal tumor (PNET), rhabdomyo-
sarcoma, and lymphoma. These tumors are rare and
together comprise about 15% of pediatric renal neo-
plasms. With a few exceptions, a specific diagnosis of
these tumors can be made only by examining tissue
samples representative of the tumor. In the appropriate
clinical setting, the presence of three characteristic
patterns of nephroblastoma with positive WT1 stain-
ing differentiates this tumor from others with similar
morphology.
RHABDOID TUMOR
CLINICAL FEATURES
Rhabdoid tumor is a highly malignant, rare renal neo-
plasm (2.5% of pediatric renal tumors), 95% of which
occur in children under 3 years of age. Genetic
10/26/2006 10:33:51 AM
 CHAPTER 10 Kidney and Adrenal Gland
RHABDOID TUMOR – DISEASE FACT SHEET
Incidence and Age Distribution
៉ Rare, highly malignant neoplasm
៉ Comprises ~2.5% of pediatric renal tumors
៉ 95% in children under 3 years of age
Genetic Abnormalities
៉ Genetic abnormalities involving hSNF5/IN11 gene located at
chromosome 22q11
abnormalities involving the hSNF5/INI1 gene located
at chromosome 22q11 are present in both renal and
extrarenal rhabdoid tumors of infancy.
CYTOPATHOLOGIC FEATURES
FNA specimens are usually very cellular and composed
of monotonous, atypical tumor cells with abundant
eosinophilic cytoplasm and eccentric large nuclei with
centrally located prominent nucleoli (Fig. 10-27).
Necrosis and frequent mitotic figures are present.
ANCILLARY STUDIES
Intense reactivity for vimentin and the presence of
strong immunoreactivity for cytokeratins and EMA in
a background of non-reactive tumor cells are character-
istic of these tumors.
Electron microscopy shows intracytoplasmic whorls
of thick intermediate filaments, which are characteristic
of this tumor (Fig. 10-28).
FIGURE 10-27
Rhabdoid tumor. Large cells with
eccentric nuclei and macronucleoli.
High power. Courtesy of Paul E
Wakely, Jr, MD.
Ch010-F06731.indd 319
319
RHABDOID TUMOR – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Hypercellular aspirates
៉ Monotonous atypical tumor cells with abundant eosinophilic
cytoplasm, eccentric large nuclei, centrally located prominent
nucleoli
៉ Necrosis and frequent mitotic figures
Ancillary Studies
៉ Immunohistochemistry:
៉ Intense reactivity for vimentin
៉ Scattered cells showing strong immunoreactivity for
cytokeratins and EMA in a background of non-reactive tumor
cells
៉ Electron microscopy: intracytoplasmic whorls of thick
intermediate filaments
Differential Diagnosis and Pitfalls
៉ Neuroblastoma, nephroblastoma, congenital mesoblastic
nephroma, and clear cell sarcoma may have foci similar to
rhabdoid tumor
៉ Differential diagnosis may be difficult, if not impossible, in
limited samples
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Neuroblastoma, nephroblastoma, congenital meso-
blastic nephroma, and clear cell sarcoma of kidney
may have foci similar to rhabdoid tumor, making the
differential diagnosis difficult in limited samples.
Examination of the entire tumor with ample sampl-
ing may be required to find areas characteristic of
other types of tumors to differentiate them from
rhabdoid.
10/26/2006 10:33:52 AM
 320
ANGIOMYOLIPOMA
CLINICAL FEATURES
Angiomyolipoma is a benign mesenchymal neoplasm
composed of a mixture of adipose tissue, smooth muscle
cells, and thick-walled blood vessels. The tumor has a
strong association with tuberous sclerosis, which is a
genetic disorder caused by mutation of either the TSC1
or TSC2 gene. While about 80% of patients with tuber-
ous sclerosis develop angiomyolipomas, less than half
of patients with angiomyolipomas have tuberous scle-
rosis. Other hereditary disorders associated with angio-
myolipoma include von Hippel–Lindau syndrome, von
Recklinghausen disease, and autosomal dominant poly-
cystic kidney disease. Angiomyolipomas comprise up
to 2% of renal tumors, and the female to male ratio is
2 : 1. These tumors can be distinguished radiologically
from other renal neoplasms.
ANGIOMYOLIPOMA – DISEASE FACT SHEET
Incidence
៉ Up to 2% of renal tumors
Gender Distribution
៉ Female to male ratio is 2 : 1
Clinical Features
៉ Strong association with tuberous sclerosis
៉ About 80% of tuberous sclerosis patients develop angiomyolipoma
៉ Other hereditary disorders associated with angiomyolipoma are
von Hippel–Lindau syndrome, von Recklinghausen disease, and
autosomal dominant polycystic kidney disease
Ch010-F06731.indd 320
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 10-28
Rhabdoid tumor. Electron micro-
graph showing whorled intermedi-
ate filaments. They can also be
found in other diseases. Courtesy of
Paul E Wakely, Jr, MD.
CYTOPATHOLOGIC FEATURES
FNA usually provides the diagnosis by allowing iden-
tification of adipose tissue and smooth muscle cells
(Fig. 10-29). Thick-walled blood vessels are seen both
in cell blocks and in core biopsies. Smooth muscle cells
show varying degrees of nuclear atypia. In some cases,
significant nuclear atypia may suggest a malignant neo-
plasm; but the presence of fat tissue and more differen-
tiated elements of smooth muscle help to establish the
correct diagnosis.
ANCILLARY STUDIES
Muscle markers (desmin, smooth muscle actin, muscle-
specific actin) and vimentin are consistently positive.
ANGIOMYOLIPOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Varying proportion of adipose tissue and smooth muscle cells
៉ Thick-walled blood vessels seen in cell blocks and core biopsies
៉ Varying degrees of nuclear atypia in smooth muscle cells
Ancillary Studies
៉ Muscle markers and vimentin consistently positive
៉ HMB-45 is usually expressed
៉ c-kit (CD117) is positive in all cases
Differential Diagnosis and Pitfalls
៉ Rarely, atypical smooth muscle cells may be confused with
cancer
៉ Presence of adipose tissue and thick-walled blood vessels
confirms the diagnosis
10/26/2006 10:33:52 AM
 CHAPTER 10 Kidney and Adrenal Gland 321

B
A

C D

FIGURE 10-29
Angiomyolipoma. Mixture of adipose tissue and large cells with atypical smooth muscle cells with large nuclei, one (D) with intranuclear pseudo-
inclusion. A, Diff-Quik stain, low power; B, Diff-Quik stain, high power; C,D, Papanicolaou stain, high power.

Melanocytic markers, specifically HMB-45, are usually

expressed; and c-kit (CD117) is positive in all cases. CYSTIC LESIONS OF KIDNEY – DISEASE FACT SHEET

Clinical Features
៉ Common in kidney
DIFFERENTIAL DIAGNOSIS AND PITFALLS ៉ Most are benign, simple cysts
៉ FNA is indicated in multilocular complex cysts
៉ Multiloculated complex cysts are considered atypical
In general, the cytopathologic findings are sufficient to
establish a definitive diagnosis of this tumor. The pres-
ence of adipose tissue and characteristic blood vessels
helps to differentiate it from benign and malignant
smooth muscle tumors and sarcomatous RCC. Some (Figs 10-30 & 10-31). In addition to the renal neoplasms
angiomyolipomas with epithelioid features can be dif- with cystic growth patterns, up to 15% of RCCs have
ferentiated from melanoma with the help of immuno- degenerative cystic changes.
histochemistry, with positive staining for smooth
muscle markers.

CYSTIC LESIONS OF KIDNEY
Cystic lesions of kidney are common. Most are benign,
simple cysts; however, multiloculated complex cysts are
considered atypical, and FNA is indicated to rule out
malignancy. In the aspirates of cystic fluid, exfoliated
cells of benign epithelium may show significant atypia
BENIGN CYSTS
CYTOPATHOLOGIC FEATURES
The predominant cell component of benign cysts is
macrophages. In aspirates, they appear as single cells
or loose aggregates. They have eccentric or centrally
located nuclei with bland chromatin patterns and

Ch010-F06731.indd 321 10/26/2006 10:33:53 AM

 322 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 10-30
Cystic lesions. Rounded tissue frag-
ment of atypical epithelial cells.
This patient had a benign cyst with
atypical epithelial lining. Papanico-
laou stain, high power.

FIGURE 10-31
Cystic lesions. Two groups of
atypical, but markedly degenerated
cells, which may be of epithelial or
histiocytic origin. Note that these
are not true tissue fragments, but
rather aggregates of cells with
degenerative changes. Papanico-
laou stain, high power.

moderate amounts of cytoplasm, which may contain

BENIGN CYSTS – PATHOLOGIC FEATURES engulfed particles, usually hemosiderin. Nucleoli, when
present, are usually small, but prominent nucleoli
Cytopathologic Findings may be seen. Ring-shaped structures with double walls
៉ Macrophages are the predominant cell population in aspirates (Liesegang rings) may be found in the cyst fluid (Fig.
៉ Appear singly or in loose aggregates 10-32) Epithelial elements include fragments of renal
៉ Eccentric or centrally located nuclei, bland chromatin pattern tubular epithelium and cyst-lining epithelium.
៉ Cytoplasm containing engulfed particles, usually hemosiderin
៉ Prominent nucleoli may be present
៉ Epithelial cells may represent renal tubular epithelium or
cyst-lining epithelium
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Differential Diagnosis and Pitfalls
៉ Should be differentiated from malignant neoplasms
៉ Liesegang rings may be confused with cysts of ova of parasites
Distinction from malignant cystic neoplasms can
be difficult in FNA specimens, especially in aspirates
with scant cellularity. The differential diagnosis

Ch010-F06731.indd 322 10/26/2006 10:33:55 AM

 CHAPTER 10 Kidney and Adrenal Gland
A B
FIGURE 10-32
Cystic lesions. Double-walled, round structures (Liesegang rings) in an infl ammatory background. A, Papanicolaou stain, low power; B, cell block,
medium power.
will be discussed in detail under malignant cystic
lesions.
MALIGNANT CYSTIC LESIONS
The majority of malignant cystic lesions in kidney are
cystic degeneration of various types of RCCs. Papillary
RCCs usually present as a cystic lesion with a thick
capsule. Multilocular cystic RCC is primarily a cystic
malignant renal neoplasm considered to be a subtype
of clear cell RCC.
CYTOPATHOLOGIC FEATURES
Tumor cells are present singly or in small aggregates or
tissue fragments. Cell morphology varies according to
the tumor type and nuclear grade. In RCCs with degen-
erative changes, necrotic debris and hemosiderin-laden
macrophages can be present.
MALIGNANT CYSTIC LESIONS – DISEASE FACT SHEET
Clinical Features
៉ Majority of malignant cystic lesions are cystic degeneration of
RCCs
៉ Papillary RCCs present as a cystic lesion with a thick capsule
៉ Multilocular cystic RCC is a subtype of clear cell RCC
Ch010-F06731.indd 323
323
MALIGNANT CYSTIC LESIONS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Tumor cells present singly, as small aggregates, or tissue
fragments
៉ Necrotic debris and hemosiderin-laden macrophages may be
present
Differential Diagnosis and Pitfalls
៉ Differential diagnosis between benign cyst and RCC with cystic
degeneration can be difficult
៉ Tissue fragments with cytologic atypia, when present, are
indicative of malignancy
៉ Immunohistochemistry is of limited value in differential
diagnosis
៉ Macrophage and epithelial markers would help in differential
diagnosis of macrophages from RCC
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis between clear cell RCC and
multilocular cystic RCC cannot be made in fine needle
aspirates. The differential diagnosis between benign
cysts and RCCs with cystic degeneration can also be
difficult in cytologic samples. In benign cysts, macro-
phages and epithelial lining cells are present. Both may
have vacuolated cytoplasm and prominent nucleoli.
Intracytoplasmic hemosiderin pigment may occur in
both macrophages and the papillary variant of RCC.
Tissue fragments, when present, are a reliable feature
for differentiating neoplastic cells from macrophages,
which usually occur as single cells or loose aggre-
gates. Although prominent nucleoli may be seen in
macrophages and benign epithelial cells, the single
10/26/2006 10:33:56 AM
 324 FINE NEEDLE ASPIRATION CYTOLOGY

macronucleoli, which are frequently present in RCCs, CYTOPATHOLOGIC FEATURES

are not usually present in benign cyst-lining epithelium
or in macrophages. In the absence of well-preserved
tumor cells with macronucleoli or tissue fragments
composed of atypical cells, the diagnosis of RCC should
be made with great caution.
Immunohistochemistry has limited use in the differ-
ential diagnosis. Macrophage markers (e.g. CD68 and
HAM 56) and AE1/AE3 would help in the differential
diagnosis of macrophages from RCC.
The majority of urothelial tumors of kidney pelvis are
high grade. FNA specimens are usually cellular, com-
prised predominantly of loose aggregates, single cells,
and some tissue fragments. Tumor cells have pleomor-
phic nuclei and a moderate to high nuclear to cytoplas-
mic (N/C) ratio. Tumor nuclei show uneven chromatin
clumping, irregular nuclear borders, and prominent
nucleoli (Fig. 10-33).

UROTHELIAL CARCINOMA OF RENAL PELVIS

CLINICAL FEATURES
UROTHELIAL CARCINOMA OF RENAL PELVIS –
PATHOLOGIC FEATURES
Urothelial carcinomas of renal pelvis are rare. They
occur in older populations (mean age, 67 years) and Cytopathologic Findings
are more common in men. Approximately half of the ៉ Majority of these tumors are high grade
patients also have lower urinary tract neoplasms. ៉ Cellular specimen, predominantly loose aggregates, single cells,
and some tissue fragments
៉ Moderate to high N/C ratio
៉ Uneven chromatin clumping, irregular nuclear borders, and
UROTHELIAL CARCINOMA OF RENAL PELVIS – prominent nucleoli
DISEASE FACT SHEET
Ancillary Studies
Incidence
៉ Immunostains are positive for CK7 and CK20, thrombomodulin,
៉ Rare CK903, and CEA
៉ Uroplakin III is more specific, but not sensitive
Gender and Age Distribution
៉ Occurs in older population, mostly in men Differential Diagnosis and Pitfalls
៉ Majority of RCCs have characteristic cytologic features
Clinical Features differentiating them from urothelial carcinoma
៉ Approximately half of patients also have lower urinary tract ៉ Poorly differentiated RCCs, however, may not be differentiated
neoplasms from high-grade carcinomas

FIGURE 10-33
Urothelial carcinoma of renal pelvis.
Poorly differentiated carcinoma
with pleomorphic nuclei. Although
these cytopathologic features are
unusual for RCC, the primary site
cannot be determined on morpho-
logic basis alone. Papanicolaou
stain, high power.

Ch010-F06731.indd 324 10/26/2006 10:33:57 AM

 CHAPTER 10 Kidney and Adrenal Gland
ANCILLARY STUDIES
Tumor cells react to antibodies for CK7 and CK20,
thrombomodulin, high molecular weight cytokeratin
(CK903), and CEA; however, these antibodies are not
specific. Uroplakin III is more specific, but not
sensitive.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The majority of RCCs have characteristic cytologic fea-
tures which differentiate them from urothelial carcino-
mas without difficulty. In limited samples, however,
poorly differentiated, high-grade RCCs may not be dif-
ferentiated from high-grade urothelial carcinomas.
LYMPHOMA
Kidneys are commonly involved in the late stages of
lymphomas. Primary lymphomas of kidney are rare
and comprise less than 1% of primary extranodal lym-
phomas. Both kidneys are involved in more than 40%
of the cases. FNA usually provides the diagnosis by
cytopathologic examination and flow cytometry
analysis.
CYTOPATHOLOGIC FEATURES
Primary renal cell lymphomas are usually diffuse, large
B-cell type, but other subtypes may occur. FNAs reveal
a uniform, round, single cell population (Fig. 10-34).
Lymphomas should be considered in any cytologic
sample composed of uniform, single cells, with high
N/C ratio. Cytomorphology differs according to the cell
type, ranging from normal-appearing lymphocytes (e.g.
MALT) to undifferentiated malignant tumor cells (e.g.
anaplastic lymphomas). Ancillary techniques (i.e. flow
cytometry or immunohistochemistry), in addition to
cytopathologic examination, are necessary to deter-
mine the lymphoid nature and clonality of the tumor
cells to establish a definitive diagnosis.
LYMPHOMA – DISEASE FACT SHEET
Clinical Features
៉ Lymphomas in late stages commonly involve kidneys
៉ Primary lymphomas are rare (less than 1% of primary extranodal
lymphomas)
៉ Both kidneys are involved in more than 40% of cases
Ch010-F06731.indd 325
325
LYMPHOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Primary lymphomas are usually diffuse, large B-cell type
៉ FNA specimens contain uniform, round, single cells
៉ Morphology differs according to cell type
៉ In addition to cytopathologic examination, ancillary techniques
are necessary to establish a diagnosis
Ancillary Studies
៉ Flow cytometry from rinses of FNA samples, or
immunohistochemistry performed on cell blocks, core biopsies,
or rinses is necessary for specific diagnosis
Differential Diagnosis and Pitfalls
៉ In adult patients, small cell carcinoma of lung is the main
tumor in differential diagnosis
៉ Presence of tissue fragments with nuclear molding
differentiates small cell carcinoma from lymphoma, which has
single cells
៉ Immunohistochemistry with neuroendocrine and lymphocytic
markers usually establishes the diagnosis in equivocal cases
៉ In children, differential diagnoses include small blue cell
tumors, which can also be differentiated using lymphocytic
markers
ANCILLARY STUDIES
A specific diagnosis of lymphoma requires phenotyping
studies by flow cytometry from rinses of FNA samples
or immunohistochemistry performed on cell blocks,
core biopsies, or rinses. Detailed discussion of lympho-
mas is covered in Chapter 3.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
In adult patients, the main differential diagnosis is
from metastatic small cell carcinoma of lung. The pres-
ence of tissue fragments with nuclear molding in small
cell carcinoma versus single cells in lymphoma is a reli-
able differential diagnostic feature for both low- and
high-grade lymphomas. It should be kept in mind that
in air-dried, Diff-Quik-stained specimens, and in some
alcohol-fi xed smears, tight cellular aggregates of lym-
phoma may give the impression of molding. Although
the evenly dispersed, granular chromatin pattern (‘salt
and pepper’) characteristic for neuroendocrine neo-
plasms is helpful in the differential diagnosis, it is not
always present; and, depending on cell preservation,
nuclei of small cell carcinomas can have irregular chro-
matin clumping or diffuse hyperchromasia. Immuno-
histochemistry with neuroendocrine and lymphocytic
markers usually establishes the diagnosis in morpho-
logically equivocal cases. Among primary small round
10/26/2006 10:33:57 AM
 326 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 10-34
Large B-cell lymphoma. Single round
cells with prominent nucleoli.

cell tumors of kidney, immunohistochemical staining CYTOPATHOLOGIC FEATURES

characteristics separate primitive neuroectodermal
tumor (PNET) and nephroblastoma from lymphomas.
PNET/Ewing sarcomas are characterized by MIC2/ Cytopathologic findings vary according to the tumor.
CD99 expression. Immunostains show membranous
staining.

ANCILLARY STUDIES
METASTATIC NEOPLASMS TO KIDNEY
Cytokeratins help to determine the epithelial nature of
poorly differentiated malignant neoplasms. Organ- or
In late stages, malignant neoplasms from other sites tumor-specific antibodies, such as those for thyro-
may metastasize to the kidneys. Carcinomas of lung, globulin, prostate-specific antigen (PSA), thyroid
breast, and gastrointestinal tract, malignant melanoma,
as well as RCC of the contralateral kidney are among
the most common metastatic neoplasms to kidney.
Metastases into the RCC may also occur. In most cases,
the primary tumor is clinically known. METASTATIC NEOPLASMS TO KIDNEY – PATHOLOGIC FEATURES

Cytopathologic Findings
៉ Vary according to the tumor

Ancillary Studies
៉ Cytokeratins help to identify the epithelial origin of poorly
differentiated neoplasms
៉ Organ- or tumor-specific antibodies, along with morphology,
METASTATIC NEOPLASMS TO KIDNEY – DISEASE FACT SHEET determine the primary site

Clinical Features Differential Diagnosis and Pitfalls

៉ Most common metastatic tumors are carcinomas of lung, breast, ៉ Majority of RCCs can be differentiated from metastatic tumors
and gastrointestinal tract, and malignant melanoma by their distinct morphology

Ch010-F06731.indd 326 10/26/2006 10:33:58 AM

 CHAPTER 10 Kidney and Adrenal Gland
transcription factor-1 (TTF-1), and HepPar 1, are
helpful in determining the primary site of neoplasms
of unknown primary site or in the differential diagno-
sis of tumors with similar morphology.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Differential diagnosis is usually not difficult. The
majority of RCCs have distinct morphology which dif-
ferentiates them from metastatic tumors. In addition to
morphology, immunohistochemistry can be helpful for
determining or confirming the specific type of the neo-
plasm. Poorly differentiated RCCs, including collecting
duct type and medullary type, can be difficult to dif-
ferentiate from metastatic poorly differentiated neo-
plasms on morphologic bases alone. In these cases,
immunohistochemistry has limited value because of
overlapping results. Core biopsies, as well as clinical
and radiologic correlations, are helpful in establishing
the diagnosis.
ADRENAL GLAND
Fine needle aspirations of adrenal glands are performed
on nodular lesions or diffusely enlarged glands to deter-
mine the nature of a lesion which is clinically and
radiologically unclear. Nodular lesions may be symp-
tomatic or asymptomatic and benign or malignant. The
adrenal cortex secretes corticosteroids, aldosterone,
cortisol, and sex steroids, and the medulla secretes cat-
echolamines, epinephrine, and norepinephrine. Hyper-
secretory neoplasms or hyperplastic lesions have
clinical symptoms caused by hypersecretion of one of
these products. An increasing number of clinically
occult neoplasms or hyperplastic nodules are inciden-
tally detected by abdominal imaging studies (i.e. CT,
MRI, or US) performed for other reasons. These lesions
are called ‘incidentaloma’ in the literature. Clinically
symptomatic, functional adrenal masses are usually
removed without prior FNA. The majority of inciden-
talomas are benign, non-functioning adenomas; malig-
nancy rates vary from 4% to 35% in published series.
Larger masses (over 4 cm) have a higher incidence of
malignancy, and they are usually operated on without
prior FNA. Malignant neoplasms, however, have been
reported in up to about 18% of nodules measuring less
than 2 cm. Correlation of FNA and MRI is recom-
mended as a cost-effective approach to the diagnosis of
these tumors.
In general, FNA has a high sensitivity (about 85%)
and specificity (100%) in the diagnosis of mass lesions
of the adrenal glands. Higher inadequacy rates (28–
33.3%) have been reported in some series of CT- or
US-guided FNAs. In recent years, endoscopic ultra-
sound (EUS) has been used successfully for sampling
Ch010-F06731.indd 327
327
left adrenal masses. The adequacy rate is 100% in most
series, with a very high accuracy in diagnosis. Complica-
tions of FNA of the adrenal gland are rare. Pneumotho-
rax, hemorrhage, abscess, and tumor implant in needle
tract have been reported.
ADRENAL CYSTS
CLINICAL FEATURES
Cystic lesions of adrenal glands are rare. They are clas-
sified as pseudocysts, endothelial cysts (angiomatous
and lymphangiomatous), epithelial cysts, and parasitic
cysts. Pseudocysts are the most common type (56%)
followed by endothelial cysts (24%). True epithelial
cysts are very rare, comprising about 6% of the cystic
lesions. Parasitic cysts, which are usually caused by
Echinococcus, occur in areas endemic for this parasite.
The majority of the cysts range between 5 and 10 cm
(mean size, 9.6 cm), but very large cysts, over 20 cm,
may occur (the largest reported was 50 cm). The female
to male ratio is 2 : 1. The age distribution has two peaks:
one at <1 month; the other in the fourth and fifth
decades. Adrenal cysts may be either symptomatic
or discovered incidentally (34%). Association with
adrenal cortical neoplasms and pheochromocytomas
has been reported. Metastatic carcinomas from various
sites may form cystic lesions on rare occasions. Aspira-
tion of the cysts is recommended for both diagnostic
and therapeutic purposes. If the cyst fluid is bloody,
ADRENAL CYSTS – DISEASE FACT SHEET
Incidence
៉ Cystic lesions of adrenal glands are rare
៉ Classified as pseudocysts, endothelial, epithelial, and parasitic
cysts
៉ Pseudocysts are the most common (56%), followed by endothelial
cysts (24%)
៉ True epithelial cysts are very rare (6%)
៉ Parasitic cysts, usually caused by Echinococcus, occur only in
areas where this parasite is endemic
Gender and Age Distribution
៉ Male to female ratio is 2 : 1
៉ Age distribution has two peaks: <1 month, and 4th and 5th
decades
Clinical Features
៉ Majority of the cysts range between 5 and 10 cm, but cysts more
20 cm may occur
៉ About one-third are discovered incidentally
៉ FNA recommended for both diagnostic and therapeutic purposes
៉ Surgery is indicated if fluid is bloody, cystogram is irregular, or
pheochromocytoma or malignancy is suspected
10/26/2006 10:33:58 AM
 328
ADRENAL CYSTS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Specimen is usually hypocellular
៉ Bloody specimens may be seen in malignancy
៉ Hemosiderin- or lipid-laden macrophages may be present
Differential Diagnosis and Pitfalls
៉ Bloody fl uids should be examined carefully to rule out
malignancy
៉ Cortical adenomas can be difficult to differentiate from lipid-
laden macrophages in hypocellular specimens
cystogram is irregular, or pheochromocytoma or malig-
nancy is suspected, surgery is indicated.
CYTOPATHOLOGIC FEATURES
Cyst fluid could be clear, turbid, or bloody. The latter
may be seen in malignancy, but it also occurs in pseu-
docysts. The specimen is usually hypocellular. Eryth-
rocytes, leukocytes, and hemosiderin- or lipid-laden
macrophages may be present.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
In bloody cyst fluids, the specimen should be examined
carefully to rule out malignancy. Benign neoplasms,
such as cortical adenomas, can be difficult to differenti-
ate from lipid-laden macrophages in hypocellular
specimens.
MYELOLIPOMA
CLINICAL FEATURES
Myelolipoma is a rare, benign neoplasm of adrenal
gland. It is generally asymptomatic and diagnosed inci-
dentally by imaging studies or at autopsy. With the
advancement of imaging techniques, an increasing
number of myelolipomas are detected. The tumor is
roughly equally distributed between males and females,
the average age being around 50 years. Myelolipoma
usually occurs unilaterally; bilateral occurrence is very
rare. Tumor size varies greatly, ranging from less than
1 cm to more than 30 cm. Rare ‘giant myelolipomas’,
over 4000 g (the largest, 6000 g), have been reported.
These tumors may be associated with endocrine dis-
orders. Because most of these tumors have typical
Ch010-F06731.indd 328
FINE NEEDLE ASPIRATION CYTOLOGY
MYELOLIPOMA – DISEASE FACT SHEET
Incidence
៉ Rare benign neoplasm of adrenal gland
Gender and Age Distribution
៉ Roughly equally distributed between males and females
៉ Average age is around 50 years
Clinical Features
៉ Generally asymptomatic and incidentally found by imaging studies
or at autopsy
៉ Usually occurs unilaterally
៉ Tumor size varies greatly, ranging from <1 cm to >30 cm
៉ Because of their typical radiologic features (on CT and MRI), FNA
is rarely performed for diagnosis
radiologic features, specifically on CT and MRI, FNA
is rarely performed for diagnosis.
CYTOPATHOLOGIC FEATURES
These are usually cellular specimens composed of a
mixture of adipose tissue and hematopoietic cells in
varying proportions (Fig. 10-35). Hematopoietic cells
include myeloid, lymphoid, and erythroid elements in
various stages of maturation, and megakaryocytes.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Combined with the radiologic findings, FNA diagnosis
of myelolipoma is definitive. In cases with predomi-
nantly hematopoietic cells and minimal adipose tissue,
extramedullary hematopiesis may be considered in the
differential diagnosis. The latter usually involves mul-
tiple organs, in contrast to adrenal myelolipoma.
MYELOLIPOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cellular specimens composed of a mixture of adipose tissue and
hematopoietic cells in varying proportions
៉ Hematopoietic cells include myeloid, lymphoid, and erythroid
elements, and megakaryocytes
Differential Diagnosis and Pitfalls
៉ Combined with radiological findings, FNA diagnosis of
myelolipoma is definitive
៉ Cases with predominantly hematopoietic cells may be mistaken
for extramedullary hematopoiesis; the latter usually involves
multiple organs
10/26/2006 10:33:58 AM
 CHAPTER 10 Kidney and Adrenal Gland 329

FIGURE 10-35
Myelolipoma. Low power: mixture of
adipose tissue and myeloid and lym-
phoid elements. High power: mega-
karyocytes. Papanicolaou stain.

NODULAR CORTICAL HYPERPLASIA AND abdominal CT scanning, 1.3–3.4% of patients may be

CORTICAL ADENOMA found to have clinically occult adrenal masses more
than 1 cm in size. Adrenal cortical hyperplasia and
adenoma may be hyperfunctional and accompanied by
CLINICAL FEATURES clinical syndromes such as Cushing (excess cortisol
secretion), Conn (hyperaldosteronism), and viriliza-
tion or feminization (excess testosterone or estradiol).
Cortical nodules in adrenal glands are not uncommon.
They are found incidentally in 2–9% of autopsies. With

NODULAR CORTICAL HYPERPLASIA AND CORTICAL ADENOMA –
DISEASE FACT SHEET
Incidence
៉ Cortical nodules in adrenal gland are not uncommon
៉ Found incidentally in 2–9% of autopsies
៉ With abdominal CT scanning, 1.3% to 3.4% of patients may be
found to have occult adrenal masses larger than 1 cm
Clinical Features
៉ Hyperfunctional nodules accompanied by clinical syndromes (e.g.,
Cushing’s, Conn’s, virilization of feminization)
CYTOPATHOLOGIC FEATURES
Cortical hyperplastic nodules and adenomas have
similar cytomorphology and cannot be distinguished in
FNA specimens. Functional hyperactivity also cannot
be determined by morphology. FNA usually yields
cellular material. The cells are arranged mostly singly,
and have round, uniform nuclei and vacuolated cyto-
plasm which is best seen in Romanowsky-based stains
(e.g. Diff-Quik). Anisonucleosis and intranuclear pseu-
doinclusions may be present. Because of the delicate
cytoplasm, some cells are stripped of their cytoplasm,
leaving bare nuclei in a ‘bubbly’ background (Fig.
10-36).

Ch010-F06731.indd 329 10/26/2006 10:33:58 AM

 330
NODULAR CORTICAL HYPERPLASIA AND CORTICAL ADENOMA –
PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Cortical hyperplastic nodules and adenomas have similar
cytomorphology
៉ FNA usually yields cellular material
៉ Mostly single cells with round, uniform nuclei and vacuolated
cytoplasm
៉ Anisonucleosis and intranuclear pseudoinclusions may be
present
៉ Some cells, striped of their cytoplasm, appear as bare nuclei in
a ‘bubbly’ background
Ancillary Studies
៉ Neoplastic or non-neoplastic adrenal cortical cells react to anti-
A103 (Melan A) and anti-α-inhibin
Differential Diagnosis and Pitfalls
៉ Differential diagnosis of adrenal cortical adenoma (ACA)
includes adrenal cortical carcinoma (ACC), renal cell carcinoma
(RCC), and, rarely, hepatocellular carcinoma
៉ Very rarely, small clusters of bare nuclei of cortical cells may
mimic small cell carcinoma
៉ Differential diagnosis between ACA and well-differentiated ACC
cannot be made on FNA
៉ Immunohistochemical stains in cell blocks are helpful to
differentiate ACA from HCC and RCC
ANCILLARY STUDIES
Diagnosis in FNA specimens is usually made on routine
preparations stained by Papanicolaou and Diff-Quik
stains. Immunohistochemistry can be helpful in the
Ch010-F06731.indd 330
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 10-36
Nodular cortical hyperplasia and
cortical adenoma. Benign adrenal
tissue. Cortical hyperplasia and
cortical adenoma have the same
morphology, mostly bare nuclei in
a ‘bubbly’ background. Diff-Quik
stain, medium power.
distinction from metastatic carcinomas with clear
cell features. Adrenal cortical cells, neoplastic or
non-neoplastic, react to anti-A103 (Melan A) and
anti-α-inhibin.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The differential diagnosis of adrenal cortical adenoma
(ACA) usually involves adrenal cortical carcinoma
(ACC) and metastatic tumors with clear cell features,
such as renal cell carcinoma (RCC) and, rarely, hepato-
cellular carcinoma (HCC). In rare instances, small clus-
ters of bare nuclei of cortical cells may mimic metastatic
small cell carcinoma of lung.
Distinguishing between ACA and well-differentiated
ACC can be very difficult without examining the entire
tumor. Tumor size, invasion, and number of mitotic
figures have been used as criteria for malignancy. Some
cortical adenomas, however, can be very large; and inva-
sion and mitotic count cannot be assessed in FNA speci-
mens. Certain cytopathologic features, such as larger
nuclei with scattered bizarre forms, may raise the
suspicion of ACC. Immunohistochemical stains in cell
blocks are helpful in the distinction from RCC and HCC.
Immunostains for Melan A and inhibin are positive in
ACA, but negative in RCC and HCC. Furthermore,
CD10, which is positive in RCC, is negative in ACA.
Characteristic canalicular-type staining with antibodies
to polyclonal CEA and CD10 differentiates the HCC
from ACA. Bare nuclei mimicking small cell carcinoma
rarely causes a problem. The nuclei of ACA are round
with small nucleoli, and they do not mold. Small cell
carcinomas show molding and often irregular nuclear
borders, and they lack nucleoli. The neuroendocrine
10/26/2006 10:34:00 AM
 CHAPTER 10 Kidney and Adrenal Gland
chromatin pattern in small cell carcinoma, if present, is
helpful, but due to degenerative changes, diffuse hyper-
chromasia or irregular chromatin distribution may also
be seen in small cell carcinoma.
ADRENOCORTICAL CARCINOMA (ACC)
CLINICAL FEATURES
Adrenocortical carcinoma is a rare tumor. In the litera-
ture, an incidence of 1–4 per million is cited. It occurs
predominantly in the fourth and fi fth decades of life
with another smaller peak in the first decade, and it is
slightly more common (58.6%) in women. Approxi-
mately 60% of ACCs are functional hypercortisolism
(e.g. Cushing syndrome) or Cushing syndrome with
virilization. Hyperaldosteronism is very rare. The
tumors are usually very large: an average weight ranging
from 510 to 1200 g and an average size from 12.0 to
16.6 cm have been reported. Although the size of the
tumor is considered one of the indications of malig-
nancy, especially those larger than 6 cm, very large
adenomas and small carcinomas may occur. The prog-
nosis of ACC is poor. The mortality rate in adults is
50–90%, with the majority of deaths occurring within
2 years of diagnosis. Under 20 years of age, the worst
survival rates occur in adolescents compared with
children under 5 years old. Metastases usually develop
within 10 years, the most common sites being liver,
lungs, and intra-abdominal or intrathoracic lymph
nodes.
ADRENOCORTICAL CARCINOMA (ACC) – DISEASE FACT SHEET
Incidence
៉ ACC is a rare tumor (incidence of 1 to 4 per million)
Gender and Age Distribution
៉ Slightly more common (58.6%) in women
៉ Occurs predominantly in the 4th and 5th decades of life, with
another smaller peak in the 1st decade
Clinical Features
៉ Approximately 60% of ACCs are functional hypercortisolism or
Cushing syndrome with virilization
៉ Usually very large tumors: average weight, 510–1200 g; average
size, 12–16.6 cm
៉ Although the larger size is one of the indications of malignancy,
very large adenomas and small carcinomas may occur
៉ Prognosis is poor; mortality in adults is 50–90%
៉ Metastases usually develop within 10 years
៉ Most common sites of metastases are liver, lungs, and intra-
abdominal or intrathoracic lymph nodes
Ch010-F06731.indd 331
331
CYTOPATHOLOGIC FEATURES
Fine needle aspirates of ACC are very cellular with
predominantly single cells and loose cellular groups;
capillary vasculature traversing the groups has been
described. Tumor cells have uniform to markedly pleo-
morphic nuclei with coarse chromatin, depending upon
the differentiation of tumor (Figs 10-37 & 10-38).
Nucleoli are usually prominent. Multinucleation and
bizarre nuclear forms are common in poorly differenti-
ated ACCs (Fig. 10-39). Cytoplasm is usually dense
granular. Intranuclear pseudoinclusions may be present.
Finely vacuolated (lipid-rich) cytoplasm may be present
in some tumors, but is rarely observed in FNA speci-
mens. Frequent mitotic figures, including atypical ones,
and necrosis are commonly seen in poorly differenti-
ated tumors; but they are less frequently observed in
fine needle aspirates. Another feature, intracytoplas-
mic hyaline inclusions described in some of the ACCs,
is not seen in fine needle aspirates.
ANCILLARY STUDIES
ACCs react to antibodies for inhibin, Melan A, and
calretinin. Immunostains for synaptophysin and CD56
are positive, but stain for chromogranin is negative.
ADRENOCORTICAL CARCINOMA (ACC) – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Very cellular specimens, predominantly single cells and loose
cellular groups
៉ Uniform to markedly pleomorphic nuclei with coarse chromatin,
usually prominent nucleoli; multinucleated bizarre nuclei are
common in poorly differentiated ACC
៉ Intranuclear pseudoinclusions may be present
៉ Dense granular cytoplasm
៉ Frequent mitotic figures, including atypical ones
Ancillary Studies
៉ ACC reacts to antibodies to inhibin, Melan A, and calretinin
៉ Immunostains for synaptophysin and CD56 are positive, but
stain for chromogranin is negative
Differential Diagnosis and Pitfalls
៉ Differential diagnosis between ACC and ACA cannot be made in
FNA specimens alone
៉ Pheochromocytoma vs ACC morphologically can be similar
៉ Immunostains for inhibin, Melan A, calretinin, synaptophysin,
chromogranin, and S-100 are helpful (see Table 10-4)
៉ Among metastatic neoplasms, renal cell carcinoma (RCC) and
hepatocellular carcinoma (HCC) should be considered in the
differential diagnosis
៉ Immunohistochemistry again is helpful in morphologically
similar cases (see Tables 10-5 and 10-6)
10/26/2006 10:34:00 AM
 332
DIFFERENTIAL DIAGNOSIS AND PITFALLS
The distinction between ACC and ACA cannot be made
with certainty in FNA specimens alone. Some ACAs
may have significant cellular atypia, and some well-
differentiated ACCs could have the same cytomorphol-
ogy as ACAs. The exact nature of some of the cortical
neoplasms may not even be determined after examina-
tion of the resected tumor. The presence of metastasis
and venous and/or capsular invasion is considered
definitive evidence of malignancy. The number of
mitoses, presence of atypical mitosis, and necrosis are
stated as evidence of ACC in the literature. None of
Ch010-F06731.indd 332
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 10-37
Adrenocortical carcinoma. Large,
relatively uniform nuclei. Better
differentiated part of ACC. Papani-
colaou stain, medium power.
FIGURE 10-38
Adrenocortical carcinoma. Pleomor-
phic tumor cells with multinucle-
ated forms. Although there is
significant atypia, this still could
be a benign adenoma. Papanicolaou
stain, medium power.
these features, perhaps with the exception of very
poorly differentiated ACCs, can be accurately assessed
in cytopathologic specimens.
Among other primary adrenal neoplasms, pheochro-
mocytoma should be considered. Nuclear pleomorphism
and intranuclear inclusions may be seen in pheochro-
mocytomas. Immunohistochemistry in cell blocks is
helpful in the differential diagnosis (Table 10-4). Immu-
nostains for inhibin, Melan A (A103), and calretinin
are positive in ACC but negative in pheochromocyto-
mas. Synaptophysin and CD56 are positive in both ACC
and pheochromocytoma, but chromogranin is positive
in pheochromocytoma and negative in ACC. p53 also
is positive in pheochromocytoma but negative in ACC.
10/26/2006 10:34:00 AM
 CHAPTER 10 Kidney and Adrenal Gland 333

FIGURE 10-39
Adrenocortical carcinoma. Bizarre
nucleus in adrenocortical carci-
noma. Diff-Quik stain, high power.

TABLE 10-4
Immunohistochemistry of ACN and Pheochromocytoma

Inhibin A Melan A (A103) Calretinin Ad4BP Chromogranin P53 S-100

ACN + + + + − − −
PHEO. − − − − + + +*

ACN, adrenocortical neoplasms; PHEO., pheochromocytoma.

*Stains sustentacular cells.

TABLE 10-5
Immunohistochemistry of ACN and RCC

CD10 Melan A (A103) Inhibin A Calretinin Ad4BP EMA AE1/AE3 RCCa

ACN − + + + + − − −
RCC + − − − − + + +

ACN, adrenocortical neoplasms; RCC, renal cell carcinoma; RCCa, antibody for renal cell carcinoma.

S-100 stains sustentacular cells in pheochromocytomas,
but it is negative in ACC. Among metastatic neoplasms,
renal cell carcinoma, hepatocellular carcinoma, and,
rarely, other carcinomas may be considered in the
differential diagnosis of ACC. The cytomorphology of
renal cell carcinomas (e.g. grade 3 RCCs) may resemble
ACC. The latter, however, rarely have clear cell features
and frequently have focal marked atypia. Immunohisto-
chemistry is helpful in the differential diagnosis. RCC
reacts to antibodies for CD10, RCC marker, AE1/AE3,
and EMA, and does not react to Melan A (A103),
inhibin, calretinin, and Ad4BP. Reactions to those anti-
bodies are reverse in ACC (Table 10-5).
Hepatocellular carcinoma may have similar cellular
morphology to ACC with acidophilic, granular or finely
vacuolated, lipid-rich cytoplasm and intranuclear
inclusions. When present, well-defined tissue fragments
of atypical hepatocytes surrounded with sinusoidal
endothelial cells, are characteristic for HCC, differen-
tiating it from ACC. Most HCCs, usually moderately

Ch010-F06731.indd 333 10/26/2006 10:34:01 AM

 334
Immunohistochemistry of ACN and HCC
Melan A (A103) Ad4BP Calretinin
ACN + +
HCC − −
ACN, adrenocortical neoplasms; HCC, hepatocellular carcinoma.
*Staining in canalicular pattern.
differentiated ones, tend to show uniform atypicality
with large round nuclei and single macronucleoli,
without markedly atypical single cells or groups of cells
as seen focally in ACC. Immunohistochemistry is also
helpful (Table 10-6). Immunostains for Melan A,
Ad4BP, calretinin, and inhibin are positive for ACC but
negative for HCC. Immunostains for polyclonal CEA
and CD10 stain HCCs in a canalicular pattern, and
CD34 stains the sinusoidal endothelial cells surround-
ing tissue fragments (thick, abnormal trabeculae of the
tumor).
METASTATIC NEOPLASMS
CLINICAL FEATURES
The majority of the malignant neoplasms of adrenal
gland are metastatic tumors. The adrenal is the fourth
most common site of metastases after lung, liver, and
bone. About one-third of FNAs of adrenal gland are
metastatic carcinomas. Lung and breast are reported to
be the most common primary sites. Data published in
recent years indicate that lung carcinoma is the leading
type (up to 67.9%) of metastatic cancer diagnosed by
FNAs, and non-small cell carcinomas, specifically
adenocarcinoma, are the most common type. Other
primary sites include kidney, gastrointestinal tract,
pancreas, liver, and ovary. Bilateral involvement is
common (30% to 49% in recently reported series). In
most cases, patients have known cancers of the other
sites; in rare instances, however, the metastatic tumor
METASTATIC NEOPLASMS – DISEASE FACT SHEET
Clinical Features
៉ Majority of malignant neoplasms of adrenal gland are metastatic
tumors
៉ Lung and breast are the most common primary sites
៉ Bilateral involvement is common
Ch010-F06731.indd 334
FINE NEEDLE ASPIRATION CYTOLOGY
TABLE 10-6
Inhibin CAM 5.2 HepPar-1 pCEA CD10
+ + − − ± −
− − + + +* +*
is incidentally discovered by imaging studies performed
on patients without any clinical evidence of cancer
(incidentalomas).
CYTOPATHOLOGIC FEATURES
Most of the metastatic carcinomas are adenocarcino-
mas with varying degree of differentiation (Fig. 10-40).
Squamous cell carcinoma (Fig. 10-41), adenocarcinoma,
and small cell carcinoma (Fig. 10-42) usually have the
characteristic features seen in the primary site. Lym-
phomas secondarily involve adrenal glands (Fig. 10-
43). They are found in 18% to 25% of patients with
disseminated lymphomas at autopsy. The specific diag-
nosis of most of the metastatic tumors can be made by
correlating clinical and microscopic findings, in certain
cases, with the help of ancillary techniques.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
One of the major diagnostic challenges is distinguish-
ing metastatic clear cell carcinomas from primary
adrenal cortical hyperplasia or neoplasms. Renal cell
carcinomas are the most common type of clear cell
METASTATIC NEOPLASMS – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Most metastatic carcinomas are adenocarcinomas
៉ Metastatic tumors present varying cytomorphology depending
on the type of the tumor
Differential Diagnosis and Pitfalls
៉ Most of the metastatic tumors can be differentiated from
primary adrenal neoplasms without difficulty
៉ In morphologically similar cases of primary neoplasms of
adrenal glands, immunohistochemistry helps in the differential
diagnosis (see Tables 10-4–10-6)
10/26/2006 10:34:02 AM
 CHAPTER 10 Kidney and Adrenal Gland 335

FIGURE 10-40
Metastatic neoplasms: adenocarci-
noma from lung. Fragment of tumor
with large nuclei, macronucleoli,
and cytoplasmic vacuoles charac-
teristic of adenocarcinoma. Papani-
colaou stain, medium power.

FIGURE 10-41
Metastatic neoplasms: squamous
cell carcinoma from esophagus.
Atypical keratinized squamous cells
with hyperchromatic nuclei. One
cell shows sharp angulation of the
nucleus, which is characteristic of
malignancy. Papanicolaou stain,
medium power.

carcinoma. Well-differentiated RCCs (grades 1 and 2)
are morphologically indistinguishable from adrenal
cortical hyperplasia or cortical adenomas. Well-
differentiated ACCs have uniform cell populations
with eccentric nuclei and scattered bizarre cells, with
large pleomorphic, single or multiple nucleoli. Clear cell
RCC has a uniform cell population with usually cen-
trally located nuclei and finely vacuolated cytoplasm.
Immunohistochemistry is helpful in differentiating
adrenal cortical neoplasms from RCC (Table 10-5).
Adrenal cortical neoplasms react to monoclonal
antibody A103 (Melan A) and anti-α-inhibin, but do not
react to CD10. Clear cell RCCs react to antibodies for
CD10, EMA, and AE1/AE3, but do not react to Melan
A, inhibin A, and Ad4BP. Metastatic hepatocellular
carcinomas to adrenal gland have the typical canalicular
pattern with pCEA and CD10. Metastatic adenocarcino-
mas are usually identifiable by their characteristic cyto-
morphology. Unlike adrenal cortical neoplasms, they
react to antibodies for cytokeratin and EMA. In cases
of unknown primary sites, CK7, CK20, and TTF-1 are
helpful in suggesting the primary sites, specifically lung
or gastrointestinal tract, the carcinomas of which are
likely to metastasize to the adrenal gland.
Melanomas may mimic adrenal cortical carcinomas
and both react to Melan A. Other melanoma markers,
HMB-45 and S-100, however, are negative in adrenal
cortical carcinomas (Figs 10-44 & 10-45).

Ch010-F06731.indd 335 10/26/2006 10:34:02 AM

 336
PHEOCHROMOCYTOMA
CLINICAL FEATURES
Pheochromocytoma is a rare tumor with an estimated
incidence in the United States of 8 per 1 million person-
years. Studies in other countries have shown an inci-
dence of about 2 per million. It occurs roughly equally
Ch010-F06731.indd 336
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 10-42
Metastatic neoplasms: small cell
carcinoma from lung. Undifferenti-
ated malignant tumor cells with
very high N/C ratio and nuclear
molding. Some nuclei show a stip-
pled chromatin pattern, which is
typical of neuroendocrine differen-
tiation. Papanicolaou stain, high
power.
FIGURE 10-43
Metastatic neoplasms: large B cell
lymphoma. Large, round, single
cells. This was confirmed by pheno-
typing studies. Diff-Quik stain,
medium power.
in both sexes. The peak age is at the fi fth decade, but
it may occur at any age. More than 90% of the pheo-
chromocytomas are sporadic. Between 5% and 10% of
these tumors occur at extramedullary sites. About 5%
of sporadic pheochromocytomas and 50% of familial
pheochromocytomas are bilateral. In the pediatric age
group, an increased number of cases occur bilaterally
and at extramedullary sites. Approximately 5–10% of
pheochromocytomas are familial. They are usually a
part of one of the multiple endocrine neoplasia (MEN)
10/26/2006 10:34:03 AM
 CHAPTER 10 Kidney and Adrenal Gland 337

FIGURE 10-44
Metastatic neoplasms: melanoma.
This is the characteristic appear-
ance of melanoma. Predominantly
single cells, some with eccentrically
located nuclei. Other cells have
cytoplasmic extensions. Diff-Quik
stain, medium power.

FIGURE 10-45
Metastatic neoplasms: melanoma.
Positive immunostaining with
HMB-45. High power.

syndromes, MEN IIA or MEN IIB. MEN IIA (Sipple
syndrome) includes varying combinations of pheochro-
mocytoma, medullary carcinoma of thyroid, and para-
thyroid hyperplasia. Pheochromocytomas occur in
50% of the cases with this syndrome. MEN IIB includes
pheochromocytoma, medullary thyroid carcinoma,
mucosal neuromas involving lips, tongue, and other
mucosal surfaces, and ganglioneuromatosis of the gas-
trointestinal tract. More than one-third of pheochro-
mocytomas are clinically unsuspected. In the great
majority of cases, there is an increased level of vanil-
lylmandelic acid (VMA) and catecholamines can be
detected in urine and plasma. The majority of pheo-
chromocytomas can be diagnosed based on combined
clinical, radiologic, and biochemical studies. FNA is not
performed in cases of clinically diagnosed or suspected
pheochromocytomas, because of potentially serious
complications.
Clinically malignant pheochromocytomas are rare.
The incidence of malignancy varies from 2.4% to 14%
in published series. The 5-year survival rate in two
series was reported as 44% and 53%. Hematogenous
and lymphatic metastasis may occur. Liver, lymph
nodes, and bone are the common sites for metastasis.

Ch010-F06731.indd 337 10/26/2006 10:34:04 AM

 338
PHEOCHROMOCYTOMA – DISEASE FACT SHEET
Incidence
៉ Pheochromocytoma is a rare tumor
៉ Estimated incidence in the United States is 8 per 1 million
person-years
Gender and Age Distribution
៉ Occurs roughly equally in both sexes
៉ Peak age is at the 5th decade, but may occur at any age
Clinical Features
៉ More than 90% are sporadic
៉ 5–10% occur at extramedullary sites
៉ About 5% of sporadic pheochromocytomas and 50% of familial
pheochromocytomas are bilateral
៉ Approximately 5–10% are familial and usually a part of the
multiple endocrine neoplasia syndromes (MEN IIA or MEN IIB)
៉ More than one-third of pheochromocytomas are clinically
unsuspected
៉ Clinically malignant pheochromocytomas are rare; incidence of
malignancy varies from 2.4% to 14%
៉ Common metastatic sites are liver, lymph nodes, and bone
CYTOPATHOLOGIC FEATURES
FNA specimens are hypercellular with loose groups or
single cells (Fig. 10-46). Tumor cells show a broad spec-
trum of changes ranging from large cells with multiple
nucleoli to smaller, more monotonous cellular compo-
nent. The cells vary in size and shape, and usually have
large polygonal or ill-defined cytoplasm. Binucleated
or multinucleated cells are present. Smaller and more
uniform tumor cells and rare intranuclear pseudoinclu-
sions may also be seen. Intracytoplasmic hyalin inclu-
sions found in histologic specimens are not usually
observed in FNA specimens. Spindle cell forms can be
seen. Some tumor cells have a bland chromatin pattern
with prominent nucleoli. Rare pigmented (lipofuscin or
melanin) forms have been reported. The spectrum of
the cytomorphology of pheochromocytoma can be seen
in Figures 10-47 to 10-49.
ANCILLARY STUDIES
Immunohistochemical stains for synaptophysin, chro-
mogranin (Fig. 10-50), and NSE are positive. S-100
stains the sustentacular cells.
With electron microscopy, numerous electron-dense,
neurosecretory-type granules are seen.
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Differential diagnosis includes ACC, sarcomatoid RCC,
and, rarely, retroperitoneal sarcomas. Pheochromo-
Ch010-F06731.indd 338
FINE NEEDLE ASPIRATION CYTOLOGY
PHEOCHROMOCYTOMA – PATHOLOGIC FEATURES
Cytopathologic Findings
៉ Hypercellular specimens with loose groups or single cells
៉ Tumor cells vary in size and shape, usually have large, ill-
defined cytoplasm
៉ Binucleated and multinucleated cells are present
៉ Smaller and more uniform tumor cells and rare intranuclear
pseudoinclusions may be seen
Ancillary Studies
៉ Immunohistochemistry:
៉ Synaptophysin, chromogranin, and NSE are positive
៉ S-100 stains the sustentacular cells
៉ Electron microscopy: numerous electron-dense neurosecretory-
type granules present
Differential Diagnosis and Pitfalls
៉ Differential diagnosis includes adrenocortical carcinoma (ACC),
sarcomatoid renal cell carcinoma, and, rarely, retroperitoneal
sarcomas
៉ Pheochromocytoma and ACC have some common
cytomorphologic features
៉ Immunohistochemistry is helpful in the differential diagnosis
(see Table 10-4)
cytoma and ACC have some common cytopathologic
features, such as nuclear pleomorphism and intra-
nuclear pseudoinclusions, and differential diagnosis
can be difficult based on morphology alone. Immuno-
histochemistry is helpful in these cases (Table 10-6).
Although both ACC and pheochromocytoma react to
antibodies to synaptophysin, immunostain for chromo-
granin is positive only in pheochromocytomas. Fur-
thermore, stains for inhibin and Melan A are positive
in ACC and negative in pheochromocytes. Positive
staining for neuroendocrine markers differentiates
pheochromocytoma from sarcomatoid RCC and retro-
peritoneal sarcomas.
NEUROBLASTOMA AND
GANGLIONEUROBLASTOMA
CLINICAL FEATURES
Neuroblastoma is the fourth most common malignant
neoplasm of the pediatric age group, following leuke-
mias, lymphomas, and brain tumors. The estimated
incidence of neuroblastoma is 8.7 per 1 million; and for
ganglioneuroblastoma, it is 6.8 per 1 million. Most neu-
roblastomas occur in children under the age of 5 years.
Occurrence in adulthood is rare. Adrenal is the most
common site for neuroblastoma, followed by abdomen
and thoracic cavity. The tumor is almost always soli-
tary. Age and stage are the most significant prognostic
factors. However, some histologic grading systems
10/26/2006 10:34:05 AM
 CHAPTER 10 Kidney and Adrenal Gland 339

FIGURE 10-46
Pheochromocytoma. Tumor cells
occur singly or in loose groups.
Scattered multinucleated cells are
also present. Diff-Quik stain, low
power.

FIGURE 10-47
Pheochromocytoma. Large cells with
single or multiple nuclei. Cytomor-
phology characteristic of pheochro-
mocytoma. Diff-Quik stain, medium
power.

Ch010-F06731.indd 339 10/26/2006 10:34:05 AM

 340 FINE NEEDLE ASPIRATION CYTOLOGY

FIGURE 10-48
Pheochromocytoma. Larger cells
with single or double nuclei and
prominent nucleoli represent gan-
glion cell differentiation. The fusi-
form nuclei in the background are
probably sustentacular cells. Papa-
nicolaou stain, high power.

FIGURE 10-49
Pheochromocytoma. Smaller cells
with eccentric nuclei and scattered
larger cells. There is a similarity
between this cytomorphology and
that of melanoma. Papanicolaou
stain, medium power.

Ch010-F06731.indd 340 10/26/2006 10:34:07 AM

 CHAPTER 10 Kidney and Adrenal Gland 341

FIGURE 10-50
Pheochromocytoma. Immunohis-
tochemical stains of cell block –
positive for chromogranin. Medium
power.

distributed. Nucleoli are inconspicuous or absent.

NEUROBLASTOMA AND GANGLIONEUROBLASTOMA –
DISEASE FACT SHEET
Incidence
៉ Neuroblastoma is the fourth most common malignant neoplasm of
the pediatric age group
៉ Estimated incidence of neuroblastoma is 8.7 per 1 million, and
for ganglioneuroblastoma is 6.8 per 1 million
Clinical Features
៉ Most tumors occur in children under the age of 5 years
៉ Adrenal is the most common site, followed by abdomen and
thoracic cavity
៉ Tumor is almost always solitary
៉ Age and stage are the most significant prognostic factors; some
histologic grading systems linked to age have been used
Occasional cells may show unipolar extension of cyto-
plasm (Fig. 10-51B). A fibrillar background resembling
neutrophils, present in histologic preparations, can
also be seen in both Diff-Quik- and Papanicolaou-
stained cytologic preparations. In some cases, neoplas-
tic cells form Homer Wright rosettes surrounding
round areas of fibrillary material. The fibrillary back-
ground is characteristic for neuroblastomas and helpful
in the differential diagnosis. Ganglion cell differentia-
tion is characterized by larger and denser cytoplasm
and large nuclei with prominent nucleoli. Ganglioneu-
roblastomas are composed of predominantly neoplastic
ganglion cells with large, dense cytoplasm and multiple
nuclei with prominent nucleoli.

ANCILLARY STUDIES
linked to age have been shown to be effective in predict-
ing the prognosis. Immunostain for NSE is consistently positive (Fig.
10-52). Neuroblastomas and ganglioneuroblastomas
also react to stains for neurofi lament proteins and
microtubule-associated proteins (MAP1 and MAP2),
CYTOPATHOLOGIC FEATURES and α and β tubulin.

FNA specimens usually are hypercellular and com-

posed of small cells with high N/C ratio. Tumor cells
appear singly or in groups. Areas of nuclear molding
may be seen. The nuclei vary slightly in size and are
round, oval, or slightly irregular in shape (Fig. 10-51A).
Nuclear chromatin is finely granular and evenly
DIFFERENTIAL DIAGNOSIS AND PITFALLS
Distinguishing neuroblastoma from other small round
cell tumors of the pediatric age group – specifically,

Ch010-F06731.indd 341 10/26/2006 10:34:08 AM

 342 FINE NEEDLE ASPIRATION CYTOLOGY

A B

FIGURE 10-51
Neuroblastoma. Hypercellular specimen with predominantly single small cells and high N/C ratio. Occasional cells with unipolar cytoplasmic exten-
sions are present. A, Diff-Quik stain, low power; B, Papanicolaou stain, high power.

NEUROBLASTOMA AND GANGLIONEUROBLASTOMA –

PATHOLOGIC FEATURES

Cytopathologic Findings
៉ FNA samples show small cells with high N/C ratio, appearing
singly or in groups
៉ Areas of nuclear molding are present
៉ Nuclei are round, oval, or slightly irregular in shape and vary in
size
៉ Nuclear chromatin is finely granular and evenly distributed
៉ Nucleoli are inconspicuous or absent
៉ Occasional cells may show unipolar cytoplasmic extensions
៉ A fibrillar background resembling neutrophils can be seen
៉ Homer Wright rosettes may be present
៉ Ganglion cell differentiation characterized by larger and denser
cytoplasm and large nuclei with prominent nucleoli may be
present in varying proportions
៉ Ganglioneuroblastomas are composed predominantly of
neoplastic ganglion cells FIGURE 10-52
Neuroblastoma. Immunostain of cell block – positive for NSE. High
Ancillary Studies power.
៉ Immunostains for NSE consistently positive

Differential Diagnosis and Pitfalls

៉ Differential diagnoses include other small round cell tumors of
the pediatric age group
៉ Additional aspirations for flow cytometry and cell blocks, as
well as a core biopsy are usually needed
៉ In some cases, material for electron microscopy and cytogenetic
studies is also required for diagnosis
៉ NSE differentiates neuroblastoma from other tumors except for
PNET, which may react to stain for CD99, which is negative in
neuroblastoma
៉ Lymphomas and rhabdomyosarcoma can be identified with
lymphoma and muscle markers
nephroblastoma, lymphomas, PNET/Ewing sarcoma,
and rhabdomyosarcoma – often requires the use of
ancillary techniques. Additional aspirations for flow
cytometry and cell blocks, as well as a core biopsy, are
usually needed. In some cases, material for electron
microscopy and cytogenetic studies is also required.
Positive staining for NSE differentiates neuroblastoma
from others except for PNET. The latter may react to
stain for CD99, which is negative in neuroblastoma.
Lymphomas and rhabdomyosarcoma can be identified
with lymphoma and muscle markers.

Ch010-F06731.indd 342 10/26/2006 10:34:09 AM

 CHAPTER 10 Kidney and Adrenal Gland 343

FIGURE 10-53
Ganglioneuroma. Schwann cells.
Papanicolaou stain, medium power.

GANGLIONEUROMA CYTOPATHOLOGIC FEATURES

CLINICAL FEATURES Mature ganglion cells and an abundant spindle cell

(Schwann cells) background are seen (Figs 10-53 &
10-54). The proportion of ganglion cells varies. Some
Ganglioneuroma is a benign tumor, usually occurring tumors have predominantly spindle cells.
in the posterior mediastinum, less frequently in adrenal
glands. The age range is 6 to 20 years, and it occurs
more commonly in females.
DIFFERENTIAL DIAGNOSIS AND PITFALLS

Because of the paucity of ganglion cells in some tumors,

FNA samples contain only Schwann cells and can be
misdiagnosed as neurofibroma.

GANGLIONEUROMA – DISEASE FACT SHEET

GANGLIONEUROMA – PATHOLOGIC FEATURES
Incidence
៉ A benign tumor, usually in the posterior mediastinum, less Cytopathologic Findings
frequently in adrenal glands ៉ Ganglion cells in an abundant Schwann cell background
៉ Proportion of ganglion cells and Schwann cells varies
Gender and Age Distribution
៉ More common in females Differential Diagnosis and Pitfalls
៉ Age range is 6 to 20 years ៉ Due to sampling error, may be misdiagnosed as neurofibroma

Ch010-F06731.indd 343 10/26/2006 10:34:09 AM

 344
SUGGESTED READINGS
Kidney
General
Brierly RD, Thomas PJ, Harrison NW, Fletcher MS, Nawrocki JD, Ashton-Key
M. Evaluation of fine-needle aspiration cytology for renal masses. BJU
Int 2000;85:14–18.
Eble JN, Sauter G, Epstein JI, Sesterhenn IA, eds. World Health Organiza-
tion Classification of Tumors: Pathology and Genetics of Tumors of the
Urinary System and Male Genital Organs. Lyon, France: IARC Press,
2004.
Geisinger KR, Stanley MW, Raab SS, Silverman JF, Abati A. Kidney. In:
Modern Cytopathology. New York: Churchill Livingstone, 2004:529–
618.
Murphy WM, Grignon DJ, Perlman EJ. Tumors of the Kidney, Bladder
and Related Urinary Structures. Atlas of Tumor Pathology, 4th series,
Fascicle 1. Washington, DC: Armed Forces Institute of Pathology,
2004.
Truong LD, Todd TD, Dhurandhar B, Ramzy I. Fine-needle aspiration of
renal masses in adults: analysis of results and diagnostic problems in
108 cases. Diagn Cytopathol 1999;20:339–349.
Renal Cell Carcinoma, Clear Cell (Conventional) Type
Al Nazer M, Mourad WA. Successful grading of renal-cell carcinoma in
fine-needle aspirates. Diagn Cytopathol 2000;22:223–226.
Cheville JC, Lohse CM, Zincke H, Weaver AL, Blute ML. Comparisons of
outcome and prognostic features among histologic subtypes of renal
cell carcinoma. Am J Surg Pathol 2003;27:612–624.
Ficarra V, Martignoni G, Maffei N, et al. Original and reviewed nuclear
grading according to the Fuhrman system: a multivariate analysis of
388 patients with conventional renal cell carcinoma. Cancer 2005;103:
68–75.
McGregor DK, Khurana KK, Cao C, et al. Diagnosing primary and metastatic
renal cell carcinoma. The use of monoclonal antibody ‘renal cell carci-
noma marker.’ Am J Surg Pathol 2001;25:1485–1492.
Nayar R, Bourtsos E, DeFrias EV. Hyaline globules in renal cell carcinoma
and hepatocellular carcinoma. A clue or a diagnostic pitfall on fine-
needle aspiration? Am J Clin Pathol 2000;114:576–582.
Ch010-F06731.indd 344
FINE NEEDLE ASPIRATION CYTOLOGY
FIGURE 10-54
Ganglioneuroma. Ganglion cells.
Diff-Quik stain, high power.
Renshaw AA, Lee KR, Madge R, Granter SR. Accuracy of fine needle aspira-
tion in distinguishing subtypes of renal cell carcinoma. Acta Cytol
1997;41:987–994.
Simsir A, Chhieng D, Wei XJ, Yee H, Waisman J, Cangiarella J. Utility of
CD10 and RCCma in the diagnosis of metastatic conventional renal-cell
adenocarcinoma by fine needle aspiration biopsy. Diagn Cytopathol
2005;33:3–7.
Renal Cell Carcinoma, Papillary Type
Dekmezian R, Sneige N, Shabb N. Papillary renal-cell carcinoma: fine-
needle aspiration of 15 cases. Diagn Cytopathol 1991;7:198–203.
Wang S, Filipowicz EA, Schnadig VJ. Abundant intracytoplasmic hemosid-
erin in both histiocytes and neoplastic cells: a diagnostic pitfall in
fine-needle aspiration of papillary renal-cell carcinoma. Diagn Cytopa-
thol 2001;24:82–85.
Renal Cell Carcinoma, Medullary Type
Assad L, Resetkova E, Oliveira VL, et al. Cytologic features of renal medul-
lary carcinoma. Cancer (Cancer Cytopathol) 2005;105:28–34.
Larson DM, Gilstad CW, Manson GW, Henry MR. Renal medullary carcinoma:
report of a case with positive urine cytology. Diagn Cytopathol 1998;18:
276–279.
Qi J, Shen PU, Rezuki WN, Currier AA, Westfall PK, Mandavilli SR. Fine
needle aspiration cytology diagnosis of renal medullary carcinoma: a
case report. Acta Cytol 2001;45:735–739.
Renal Cell Carcinoma, Chromophobe Cell Type
Grunter SR, Renshaw AA. Fine-needle aspiration of chromophobe renal cell
carcinoma. Analysis of six cases. Cancer 1997;81:122–128.
Peyromaure M, Misrai V, Thiounn N, et al. Chromophobe renal cell carci-
noma: analysis of 61 cases. Cancer 2004;100:1406–1410.
Wang HY, Mills SE. KIT and RCC are useful in distinguishing chromophobe
renal cell carcinoma from the granular variant of clear renal cell carci-
noma. Am J Surg Pathol 2005;29:540–546.
Wiatrowska BA, Zakowski MF. Fine-needle aspiration biopsy of chromo-
phobe renal cell carcinoma and oncocytoma: comparison of cytomor-
phologic features. Cancer 1999;87:161–167.
10/26/2006 10:34:10 AM
 CHAPTER 10 Kidney and Adrenal Gland
Renal Cell Carcinoma, Collecting Duct Type
Caraway NP, Wojcik EM, Katz RL, Ro RY, Ordonez NG. Cytologic findings
of collecting duct carcinoma of kidney. Diagn Cytopathol 1995;13:
304–309.
Layfield LJ. Fine-needle aspiration biopsy of renal collecting duct carci-
noma. Diagn Cytopathol 1994;48:843–848.
Ono K, Nishino E, Nakamine H. Renal collecting duct carcinoma. Report
of a case with cytologic findings on fine needle aspiration. Acta Cytol
2000;44:380–384.
Sarode VR, Islam S, Wooten D, Watamull LM, Molberg K, Ashfaq R. Fine
needle aspiration of collecting duct carcinoma of kidney: report of a
case with distinctive features and differential diagnosis. Acta Cytol
2004;48:843–848.
Sarcomatous Renal Cell Carcinoma
Auger M, Katz RL, Sella A, Ordonez RE, Thung SN, Szporn A. Fine needle
aspiration cytology of sarcomatoid renal cell carcinoma: a morphologic
and immunocytochemical study of 15 cases. Diagn Cytopathol 1993;9:
46–51.
Cheville JC, Lohse CM, Zincke H, et al. Sarcomatoid renal cell carcinoma:
an examination of underlying histologic subtype and an analysis of
associations with patient outcome. Am J Surg Pathol 2004;28:435–
441.
Wadih GE, Raab SS, Silverman JF. Fine needle aspiration cytology of renal
and retroperitoneal angiomyolipoma. Report of two cases with cytologic
findings and clinico-pathologic pitfalls in diagnosis. Acta Cytol
1995;39:945–950.
Wang J, Weiss LM, Hu B, et al. Usefulness of immunohistochemistry in
delineating renal spindle cell tumours. A retrospective study of 31
cases. Histopathology 2004;44:462–471.
Oncocytoma
Caputo V, Repetti ML, Bordoni U, Radice F. Preoperative diagnosis of renal
oncocytoma by fine needle aspiration (FNA). Cytopathology 1996;7:
366–371.
Huo L, Sugimura J, Tretiakova MS, et al. C-kit expression in renal onco-
cytoma and chromophobe renal cell carcinomas. Hum Pathol 2005;
36:262–268.
Liu J, Fanning CV. Can renal oncocytoma be distinguished from renal cell
carcinoma on fine-needle aspiration specimens? A study of conventional
smears in conjunction with ancillary studies. Cancer (Cancer Cytopa-
thol) 2001;93:390–397.
Nephroblastoma (Wilms Tumor)
Serrano R, Rodriguez-Peralto JL, DeOrbe GG, Melero C, de Agustin P.
Intrarenal neuroblastoma diagnosis by fine-needle aspirations: a report
of two cases. Diagn Cytopathol 2002;27:294–297.
Sharifah NA. Fine needle aspiration cytology characteristics of renal
tumors in children. Pathology 1994;26:359–364.
Rhabdoid Tumor
Barroca HM, Costa MJ, Carvalho JL. Cytologic profile of rhabdoid tumor
of kidney. A report of 3 cases. Acta Cytol 2003;47:1055–1058.
Wakely PE Jr, Giacomantonio M. Fine needle aspiration cytology of meta-
static rhabdoid tumor. Acta Cytol 1986;30:533–537.
Angiomyolipoma
Glento JA, Partoft S. Ultrasound-guided percutaneous aspiration of renal
angiomyolipoma: report of two cases diagnosed by cytology. Acta Cytol
1984;28:265–268.
Kulkarni B, Desai SB, Dave B, Tongaonkar HB, Kulkarni JN, Chinoy RF.
Renal angiomyolipomas: a study of 18 cases. Indian J Pathol Microbiol
2005;48:459–463.
Mai KT, Yazdi HM, Perkins DG, Thijssen A. Fine needle aspiration biopsy
of epithelioid angiomyolipoma. A case report. Acta Cytol 2001;45:
233–236.
Ch010-F06731.indd 345
345
Wadih GE, Raab SS, Silverman JF. Fine needle aspiration cytology of renal
and retroperitoneal angiomyolipoma. Report of two cases with cytologic
findings and clinicopathologic pitfalls in diagnosis. Acta Cytol
1995;39:945–950.
Cystic Lesions
Horwitz CA, Manivel JC, Inampudi S, Kaye K. Diagnostic difficulties in the
interpretation of needle aspiration material from large renal cysts.
Diagn Cytopathol 1994;11:380–383.
Katz LB, Ehya H. Liesegang rings in renal cyst fluid. Diagn Cytopathol
1990;6:197–200.
Raso DS, Greene WB, Finley JL, Silverman JF. Morphology and pathogen-
esis of Liesegang rings in cyst aspirates: report of two cases with
ancillary studies. Diagn Cytopathol 1998;19:116–119.
Todd TD, Dhurandhar B, Mody D, Ramzy I, Truong LD. Fine needle aspira-
tions of the cystic lesions of the kidney. Morphologic spectrum and
diagnostic problems in 41 cases. Am J Clin Pathol 1999;111:317–328.
Urothelial Carcinoma of Kidney Pelvis
Olgac S, Mazumdar M, Dalbagni G, Reuter VE. Urothelial carcinoma of the
renal pelvis: a clinicocytopathologic study of 130 cases. Am J Surg
Pathol 2004;28:1545–1552.
Lymphoma
Truong LD, Caraway N, Ngo T, Laucirica R, Katz R, Ramzy I. Renal lym-
phoma. The diagnostic and therapeutic roles of fine-needle aspiration.
Am J Clin Pathol 2001;115:18–31.
Metastatic Neoplasms
Gattuso P, Ramzy I, Truong LD, et al. Utilization of fine-needle aspiration
in the diagnosis of metastatic tumors to kidney. Diagn Cytopathol
1999;21:35–38.
Adrenal Gland
General
deAugustin P, Lopez-Rios F, Alberti N, Perez-Barrios A. Fine-needle aspira-
tion biopsy of the adrenal glands: a ten-year experience. Diagn Cyto-
pathol 1999;21:92–97.
Geisinger KR, Stanley MW, Raab SS, Silverman JF, Aboti A. Adrenal gland.
In: Modern Cytopathology. New York: Churchill Livingstone, 2004:
619–624.
Harisinghani MG, Maher MM, Gervais DA, et al. Incidence of malignancy
in complex cystic renal masses (Bosniak category III): should imaging-
guided biopsy precede surgery? AJR Am J Roentgenol 2003;181:
1425–1426.
Lack EE. The adrenal gland. In Silverberg SC, ed. Principles and Practice
of Surgical Pathology and Cytopathology. New York: Churchill Livings-
ton, 1997:2751–2799.
Zaman MB. The adrenals. In Koss LG, ed. Koss’ Diagnostic Cytopathology
and Its Histopathologic Bases, 5th ed. Philadelphia: Lippincott Williams
and Wilkins, 2005:1482–1494.
Incidentalomas
Kasperlik-Zeluska AA, Roslonowska E, Slowinska-Srzeclnicka J, et al. Inci-
dentally discovered adrenal mass (incidentaloma): investigation and
management of 208 patients. Clin Endocrinol (Oxf) 1997;46:29–37.
Lumachi F, Borsato S, Tregnaghi A, et al. CT-scan, MRI and image-guided
FNA cytology of incidental adrenal masses. EJSO 2003;29:689–692.
Complications of FNA
Mody MK, Kazerooni EA, Korobkin M. Percutaneous CT-guided biopsy of
adrenal masses: immediate and delayed complications. J Comput Assist
Tomogr 1995;19:434–439.
10/26/2006 10:34:11 AM
 346
EUS-Guided FNA
Eloubeidi MA, Seewald S, Tamhane A, et al. EUS-guided FNA of the left
adrenal gland in patients with thoracic or GI malignancies. Gastrointest
Endosc 2004;59:627–633.
Jhala NC, Jhala D, Eloubedi MA, et al. Endoscopic ultrasound-guided fine-
needle aspiration biopsy of the adrenal glands: analysis of 24 patients.
Cancer 2004;102:308–314.
Stelow EB, Debol SM, Stanley MW, Mallery S, Lai R, Bardales RH. Sampling
of the adrenal glands by endoscopic ultrasound-guided fine-needle
aspiration. Diagn Cytopathol 2005;33:26–30.
Varadarajulu S, Fraig M, Schmulewitz N, et al. Comparison of EUS-guided
19-gauge Trucut needle biopsy with EUS-guided fine-needle aspiration.
Endoscopy 2004;36:397–401.
Adrenal Cysts
Akcay MN, Akcay G, Balik AA, Boyuk A. Hydatid cysts of adrenal gland:
review of nine patients. World J Surg 2004;28:97–99.
deBree E, Schoretsanitis G, Melissas J, Christodoulakis M, Tsiftsis D. Cysts
of the adrenal gland: diagnosis and management. Int Urol Nephrol
1998;30:369–376.
Ericksen LA, Lloyd RV, Harman R, Thompson G. Cystic adrenal neoplasms.
Cancer 2004;101:1537–1544.
Tung GA, Pfister RC, Papanicolaou N, Yoder JC. Adrenal cysts: imaging and
percutaneous aspirations. Radiology 1989;173:107–110.
Myelolipoma
Meyer A, Behrend M. Presentation and therapy of myelolipoma. Int J Urol
2005;12:239–243.
Settakorn J, Sirivanichai C, Rangdaeng S, Chaivun B. Fine-needle aspira-
tion cytology of adrenal myelolipoma: case report and review of litera-
ture. Diagn Cytopathol 1999;21:4009–4012.
Primary Neoplasms
Handa U, Khullar U, Mohan H. Pigmented pheochromocytoma: report of
a case with diagnosis by fine needle aspiration. Acta Cytol 2005;49:
421–423.
Lumachi F, Borsato S, Brandes AA, et al. Fine-needle aspiration cytology
of adrenal masses in noncancer patients: clinicoradiologic and histo-
logic correlations in functioning and nonfunctioning tumors. Cancer
2001;93:323–329.
Porcaro AB, Novella G, Ficarra V, D’Amico A, Antoniolli SZ, Curti P. Inci-
dental adrenal pheochromocytoma. Report on 5 operated patients and
update of literature. Arch Ital Urol Androl 2003;75:217–225.
Ch010-F06731.indd 346
FINE NEEDLE ASPIRATION CYTOLOGY
Saboorian MH, Katz RL, Charsangavec C. Fine needle aspiration cytology
of primary and metastatic lesions of the adrenal gland. A series of 188
biopsies with radiologic correlation. Acta Cytol 1995;39:843–851.
Sharma S, Singh R, Verma K. Cytomorphology of adrenocortical carcinoma
and comparison with renal cell carcinoma. Acta Cytol 1997;41:
385–392.
Suen KC, McNeely TB. Adrenal cortical cells mimicking small cell anaplastic
carcinoma in a fine needle aspirate. Mod Pathol 1991;4:594–595.
Wadih GE, Nance KV, Silverman JF. Fine-needle aspiration cytology of the
adrenal gland. Fifty biopsies in 48 patients. Arch Pathol Lab Med
1992;116:841–846.
Walther MM, Keiser HR, Linehan WM. Pheochromocytoma: evaluation,
diagnosis, and treatment. World J Urol 1999;17:35–39.
Metastatic Neoplasms
Candel AG, Gattuso P, Reyes CV, Prinz RA, Castelli MJ. Fine-needle aspira-
tion biopsy of adrenal masses in patients with extraadrenal malignan-
cies. Surgery 1993;114:1132–1136.
Kocijancic K, Kocijancic I, Guna F. Role of sonographically guided fine-
needle aspiration biopsy of adrenal masses in patients with lung cancer.
J Clin Ultrasound 2004;32:12–16.
Lack EE. Tumors metastatic to adrenal glands. In: Tumors of the Adrenal
Gland and Extra-adrenal Paraganglia. Atlas of Tumor Pathology. Wash-
ington, DC: Armed Forces Institute of Pathology; 1997:199–212.
Lam KY, Lo CY. Metastatic tumors of the adrenal glands: a 30-year
experience in a teaching hospital. Clin Endocrinol (Oxf) 2002;56:95–
101.
Immunohistochemistry
Fetsch PA, Powers CN, Zakowski MF, Abati A. Anti-alpha inhibin: marker
of choice for the consistent distinction between adrenocortical carci-
noma and renal cell carcinoma in fine-needle aspiration. Cancer (Cancer
Cytopathol) 1999;87:168–172.
Jorda M, De MB, Nadji M. Calretinin and inhibin are useful in separating
adrenocortical neoplasms from pheochromocytoma. Appl Immunohisto-
chem Mol Morphol 2002;10:67–70.
Sasano H, Shizawa S, Suzuki T, et al. Transcription factor adrenal 4 binding
protein as a marker of adrenocortical malignancy. Hum Pathol
1995;26:1154–1156.
Shin SJ, Hoda RS, Ying L, DeLellis RA. Diagnostic utility of the monoclonal
antibody A103 in fine-needle aspiration biopsies of the adrenal. Am J
Clin Pathol 2000;113;295–302.
Yang B, Ali SZ, Rosenthal DL. CD10 facilitates the diagnosis of metastatic
renal cell carcinoma from primary adrenal cortical neoplasm in adrenal
fine-needle aspiration. Diagn Cytopathol 2002;27:149–152.
10/26/2006 10:34:11 AM
 Index

Abscess, breast, 127–8, 127f, 127t, 128f clinical features, 113–14t

Acinar cell carcinoma, 274–8 differential diagnosis and pitfalls, 115
ancillary studies, 277 pathologic features, 114–15, 114f, 114t
clinical features, 274–5, 274t Apocrine carcinoma, 148–9, 148t, 149f
cytopathology, 275–7, 275f, 275t, 276f, 277f Aspergillosis, 173–5
differential diagnosis and pitfalls, 277–8 clinical features, 173–4, 173t
radiologic features, 275 cytopathologic features, 174–5, 174f, 175t
Acinic cell carcinoma, 25–7 differential diagnosis and pitfalls, 175
clinical features, 25–6, 26t radiologic features, 174
cytopathologic features, 26–7, 26f, 26t, 27f Autoimmune pancreatitis, 255f, 258f
differential diagnosis and pitfalls, 27 Autoimmune sialadenitis, 4
Actinomycosis, 176–8
clinical features, 176–7, 176t Basal call adenocarcinoma, 18
cytopathologic features, 177f, 177t Basal cell adenoma, 17–18
differential diagnosis and pitfalls, 177–8 clinical features, 17t
radiographic features, 177 cytopathologic features, 17–18, 17f, 18f, 18t, 19f
Adenocarcinoma Benign cystic teratoma, 207, 208f
basal cell, 4 Benign mixed tumor of salivary glands, 7–10
ductal, 160–70 Bile duct adenoma, 229–30, 229t, 230t
foamy gland, 262, 265f Blastomycosis, 167–8
lung, 185–6 clinical features, 167–8, 167t
ancillary studies, 186 cytopathologic features, 168t, 169f
clinical features, 185t differential diagnosis and pitfalls, 168
cytopathologic features, 185–6, 185t, 186f radiologic features, 168
differential diagnosis, 186 Breast, 127–58
radiological features, 185f apocrine carcinoma, 148–9, 148t, 149f
polymorphous low-grade, 21–3, 21t, 22f ductal carcinoma in situ, 140–2, 140t, 141f
signet-ring cell, 267f fi broadenoma, 132–4, 132t, 133f
Adenocortical carcinoma, 331–4 fi brocytic change, 136–40, 136t, 137f, 137t, 138f, 138t
ancillary studies, 331 non-proliferative breast disease, 138, 138f, 139f
clinical features, 331t proliferative breast disease with atypia, 139, 140f
cytopathologic features, 331t, 332f proliferative breast disease without atypia, 138–9, 139f
differential diagnosis and pitfalls, 332–4, 333f, 333t, 334t granular cell tumor, 154f, 154t
Adenoid cystic carcinoma, 19–21 gynecomastia, 154–5, 155f, 155t
clinical features, 19t infi ltrating lobular carcinoma, 149–51, 149t, 150f, 151f
cytopathologic features, 19–21, 19t, 20f, 21f mastitis, abscess and fat necrosis, 127–8, 127f, 127t, 128f
Adenoma medullary carcinoma, 147–8, 147t, 148f, 148t
basal cell, 17–18 metastases, 151–4, 151t, 152f, 152t, 153f
bile duct, 229–30, 229t, 230t mucinous carcinoma, 145–6, 145f, 145t
cortical, 329–31 papillary lesions, 134–6, 134t, 135f, 136f
hepatocellular, 228–9, 228t, 229f primary breast carcinoma, 142–3, 142t, 143f
Adipose tissue tumors, 93–7 secretory, pregnancy and lactational changes, 130–2, 130t, 131f,
lipoma, 93–4 131t, 132f
liposarcoma, 94–7 signet-ring cell carcinoma, 146–7, 146t, 147f
Adrenal gland, 327–44 treatment-induced changes, 128–30, 128t, 129f, 129t, 130f
adenocortical carcinoma, 331–4 tubular carcinoma, 143–5, 144f, 144t
cysts, 327–8 Bronchial cells, 159, 160f
ganglioneuroma, 343–4 Bronchioalveolar carcinoma, 186–9, 186t
metastatic neoplasms, 334–6 cytopathologic features, 187–8, 187f, 187t, 188f
myelolipoma, 328–9 Burkitt lymphoma, 91f
neuroblastoma, 338, 341–2
nodular cortical hyperplasia and cortical adenoma, 329–31 Carcinoid tumor
pheochromocytoma, 336–8 lung, 191–3
Alveolar pneumocytes, 159 ancillary studies, 193
Alveolar soft part sarcoma, 120–1, 120f, 120t, 121t clinical features, 191–2, 192t
Anaplastic carcinoma, 64–7 cytopathologic features, 192–3, 192f, 192t, 193f
ancillary studies, 66 differential diagnosis and pitfalls, 193
clinical features, 64–5, 65t radiologic features, 193
cytopathologic features, 65–6, 65t, 66f, 67f thymic neuroendocrine, 209–10, 211t
differential diagnosis and pitfalls, 67f Carcinosarcoma of salivary glands, 12f
Angiomyolipoma, 320–1, 320t, 321f Cat-scratch disease, 76f
Angiosarcoma Cavernous hemangioma see Hemangioma
liver, 243–4 Cholesterol crystals, 45f
ancillary studies, 244 Chromophobe renal cell carcinoma, 308–11
clinical features, 243–4, 243t ancillary studies, 310
differential diagnosis and pitfalls, 244 clinical features, 308t
pathologic features, 244f, 244t cytopathologic features, 209f, 308–10, 310t, 311f
soft tissue, 113–15, 243–4 differential diagnosis and pitfalls, 310
ancillary studies, 115 Chronic lymphocytic thyroiditis see Hashimoto’s thyroiditis
347

INDEX-F06731.indd 347 10/26/2006 10:35:03 AM

 348 INDEX

Chronic pancreatitis, 253–7 Fibrolamellar hepatocellular carcinoma, 237–9

ancillary studies, 254, 256 ancillary studies, 238
clinical features, 253–4, 254t clinical features, 237, 238t
cytopathologic features, 254t, 255f, 256f differential diagnosis and pitfalls, 238
differential diagnosis and pitfalls, 256–7, 257f, 258f pathologic features, 238, 238f, 238t, 239f
radiologic features, 254 Fibromatosis, 98–100
Ciliated hepatic foregut cyst, 225–6, 225t, 226f, 226t ancillary studies, 99
Clear cell renal carcinoma, 302–5 clinical features, 98–9, 98t
ancillary studies, 304 differential diagnosis pitfalls, 100
clinical features, 302–3, 302t pathologic features, 99f, 99t
cytopathologic features, 303–4, 303f, 304f, 405f Fibrosarcoma, 101–2
differential diagnosis and pitfalls, 304 ancillary studies, 101
Clear cell (sugar) tumor, 180–1, 180t, 181f clinical studies, 101t
Coccidioidomycosis, 168–71 differential diagnosis, 101–2
ancillary studies, 170 pathologic features, 101f, 101t
clinical features, 160t, 168–9 Foamy gland adenocarcinoma, 262, 265f
cytopathologic features, 170f, 170t, 171f Focal nodular hyperplasia, 222–4
differential diagnosis and pitfalls, 170–1 ancillary features, 223
radiologic features, 169, 170f clinical features, 222t
Collecting duct renal cell carcinoma, 311–13 differential diagnosis and pitfalls, 224
ancillary studies, 313 pathologic features, 223f, 223t
clinical features, 311t Follicular lymphoma, 83, 84f
cytopathologic features, 311–13, 311t, 312f, 313f Fungal infections
differential diagnosis and pitfalls, 313 lung, 165–76
Cryptococcosis, 171–3 aspergillosis, 173–5
ancillary studies, 173 blastomycosis, 167–8
clinical features, 171–2, 171t coccidioidomycosis, 168–71
cytopathologic features, 172–3, 172f, 173f, 173t cryptococcosis, 171–3
differential diagnosis and pitfalls, 173 histoplasmosis, 166–7
radiographic features, 172 zygomycoses, 175–6
Cystic lesions of kidney, 321–4, 322f, 322t, 323f, 323t
Cystic papillary carcinoma, 46 Ganglioneuroblastoma see Neuroblastoma
Cysts Ganglioneuroma, 344f
adrenal gland, 327–8, 327t, 328t Gastrointestinal stromal tumor, 115–17
ciliated hepatic foregut, 225–6 ancillary studies, 116–17
lymphoepithelial, 260 clinical features, 115t
retention, 4–5, 6f differential diagnosis and pitfalls, 117
salivary glands, 4–5, 6f pathologic features, 115–16, 115t, 116f
Germ cell tumors
Dedifferentiated liposarcoma, 96f mediastinum, 206–9
Dermatofi brosarcoma protuberans, 100–1 ancillary studies, 208–9
ancillary studies, 101 clinical features, 206–7, 206t
clinical features, 100t cytopathologic features, 207–8, 207t, 208f,
differential diagnosis, 101 209f
pathologic features, 100f, 100t differential diagnosis and pitfalls, 209
Ductal adenocarcinoma, 260–70 Glial fi brillary acidic protein, 13
ancillary studies, 269 Goitre see Nodular goitre
clinical features, 260–1, 261t Granular cell tumor, 106–7, 154f, 154t
cytopathologic features, 261–8, 262t, 263f, 264f, 265f, 266f, breast, 154f, 154t
267f, 268f soft tissue
differential diagnosis and pitfalls, 269–70, 269f ancillary studies, 107
radiologic features, 261 clinical features, 106t
Ductal carcinoma in situ, 140–2, 140t, 141f differential diagnosis and pitfalls, 107
pathologic features, 106–7, 106t, 107f
Embryonal carcinoma, 208, 209f Granulomatous lymphadenopathy, 74–7
Entamoeba histolytica, 224t ancillary studies, 76f
Epithelioid hemangioendothelioma, 242–3 clinical features, 74–5, 75t
ancillary studies, 243 cytopathologic features, 75–6, 75t, 76f
clinical features, 242t differential diagnosis and pitfalls, 76–7
differential diagnosis, 243 Granulomatous sialadenitis, 5f
pathologic features, 243f, 243t Gynecomastia, 154–5, 155f, 155t
Epithelioid sarcoma, 118–20
ancillary studies, 119 Hamartoma, 178–80
clinical features, 118–19, 118t clinical features, 178t
differential diagnosis and pitfalls, 120 cytopathologic features, 178–80, 179f, 180t
pathologic features, 119f, 119t differential diagnosis and pitfalls, 180
Epstein-Barr virus, 77 radiologic features, 178f
Hashimoto’s thyroiditis, 37–41
Fat necrosis of breast, 127–8, 127f, 127t, 128f ancillary studies, 39
Fibroadenoma, 132–4, 132t, 133f clinical features, 37–8, 38t
Fibroblastic/fi brohistiocytic tumors, 97–103 cytopathologic features, 39f, 39t, 40f, 41f
dermatofi brosarcoma protuberans, 100–1 differential diagnosis and pitfalls, 39–40
fi bromatosis, 98–100 Hassall’s corpuscles, 205
fi brosarcoma, 101–2 Hemangioma, 226–8
malignant fi brous histiocytoma, 102–3 ancillary studies, 227
nodular fasciitis, 97–8 clinical features, 226–7, 226t

INDEX-F06731.indd 348 10/26/2006 10:35:03 AM

 INDEX 349

differential diagnosis and pitfalls, 228 Lactation, breast changes, 130–2, 130t, 131f, 131t, 132f
pathologic features, 227, 227f, 227t, 228f Large cell carcinoma, 190–1, 190t, 191f
Hepatobiliary cystadenoma, 230–1, 230t, 231f Leiomyosarcoma, 112–13
Hepatoblastoma, 241–2, 241t, 242f, 242t ancillary studies, 112–13
Hepatocellular adenoma, 228–9, 228t, 229f clinical features, 112t
Hepatocellular carcinoma, 232–7 differential diagnosis and pitfalls, 113
clinical features, 232–3, 233t pathologic features, 112, 112f, 113f
see also Fibrolamellar hepatocellular carcinoma Lipoma, 93–4
Histiocytoid cells, 57 ancillary studies, 94
ancillary studies, 235, 236f, 237f, 237t clinical features, 93t
differential diagnosis, 237 differential diagnosis and pitfalls, 94
pathologic features, 233–5, 234f, 234t, 235f, 236f pathologic features, 94f, 94t
Histoplasmosis, 166–7 Liposarcoma, 94–7
ancillary studies, 167 ancillary features, 96
clinical features, 166t clinical features, 94–5, 95t
cytopathologic features, 166–7, 167f, 167t dedifferentiated, 96f
differential diagnosis and pitfalls, 167 differential diagnosis and pitfalls, 96
radiologic features, 166 myxoid, 96f
Hodgkin lymphoma, 78–81, 212f pathologic factors, 95–6, 95t, 96f, 97f
ancillary features, 79–80, 80t pleomorphic, 97f
clinical features, 78–9t Liver, 219–50, 220f
cytopathologic features, 79t, 80f, 81f benign tumors, 226–32
differential diagnosis and pitfalls, 80–1 bile duct adenoma, 229–30
Hürthle cell neoplasms, 49–51 hemangioma, 226–8
ancillary studies, 51 hepatobiliary cystadenoma, 230–1
clinical features, 49–50, 49t hepatocellular adenoma, 228–9
cytopathologic features, 50–1, 50f, 50t, 51f inflammatory myofi broblastic tumor, 231–2
differential diagnosis and pitfalls, 51 contraindications to fine needle aspiration, 221t
Hyaline cell myoepithelioma, 13 cystic lesions, 224–6
Hyalinizing trabecular adenoma, 59f ciliated hepatic foregut cyst, 225–6
Hydatid disease, 224–5 hydatid disease, 224–5
clinical features, 224t metastatic tumors, 246–9, 246t, 247f, 247t, 248f, 248t,
differential diagnosis and pitfalls, 225 249f
pathologic features, 224–5, 225f, 225t needle contamination, 220f, 220t
non-neoplastic diseases, 219–24
Infectious mononucleosis, 77–8 focal nodular hyperplasia, 222–4
ancillary studies, 77–8 macroregenerative nodule, 219–22
clinical features, 77t normal cytology, 220t
cytopathologic features, 77t, 78f parasitic cysts, 224t
differential diagnosis and pitfalls, 78 primary malignant epithelial tumors, 232–42
Inflammatory myofi broblastic tumor, 231–2, 231t, 232f, 232t fi brolamellar hepatocellular carcinoma, 237–9
Insular carcinoma, 63–4 hepatoblastoma, 241–2
ancillary studies, 64 hepatocellular carcinoma, 232–7
clinical features, 63t intrahepatic cholangiocarcinoma, 239–41
cytopathologic features, 63–4, 64f, 64t, 65f primary malignant mesenchymal tumors, 242–6
differential diagnosis and pitfalls, 64 angiosarcoma, 243–4
Intraductal papillary mucinous neoplasm, 291–6 epithelioid hemangioendothelioma, 242–3
ancillary studies, 292 primary hepatic lymphoma, 244–6
clinical features, 291t Lung, 159–99
cytopathologic features, 291–2, 291t, 292f, 293f, 294f, 295f benign neoplasms, 178–81
differential diagnosis and pitfalls, 292 clear cell (sugar) tumor, 180–1
Intrahepatic cholangiocarcinoma, 239–41 hamartoma, 178–80
ancillary studies, 240–1 carcinoid tumor, 191–3
clinical features, 239t metastases, 193–8, 194f, 194t, 195f, 196f, 197f, 198f
differential diagnosis and pitfalls, 241 non-neoplastic conditions, 159–78
pathologic features, 239–40, 239t, 240f actinomycosis, 176–8
fungal infections, 165–76
Kidney, 299–327 sarcoidosis, 159–63
angiomyolipoma, 320–1 tuberculosis, 163–5
cystic lesions, 321–4, 322f, 322t, 323f, 323t normal constituents, 159
benign, 321–3 primary malignant tumors, 181–91
malignant, 323–4 adenocarcinoma, 185–6
lymphoma, 325–6 bronchioloalveolar carcinoma, 186–9
metastatic neoplasms, 326–7 large cell carcinoma, 190–1
nephroblastoma (Wilms tumor), 317–18 pleomorphic carcinoma, 190–1
oncocytoma, 316–17 small cell carcinoma, 189–90
renal cell carcinoma, 299–315 squamous cell carcinoma, 181–4
chromophobe type, 308–11 Lymph nodes, 71–92
clear cell type, 302–5 granulomatous lymphadenopathy, 74–7
collecting duct type, 311–13 ancillary studies, 76f
medullary type, 313–14 clinical features, 74–5, 75t
papillary type, 305–6 cytopathologic features, 75–6, 75t, 76f
sarcomatoid type, 314–15 differential diagnosis and pitfalls, 76–7
rhabdoid tumor, 318–20 Hodgkin lymphoma, 78–81
urothelial carcinoma of renal pelvis, 324–5 ancillary features, 79–80, 80t
Kuttner tumor, 2 clinical features, 78–9t

INDEX-F06731.indd 349 10/26/2006 10:35:03 AM

 350 INDEX

cytopathologic features, 79t, 80f, 81f Medullary renal cell carcinoma, 313–14
differential diagnosis and pitfalls, 80–1 ancillary studies, 314
infectious mononucleosis, 77–8 clinical features, 313t
ancillary studies, 77–8 cytopathologic features, 314f, 314t
clinical features, 77t differential diagnosis and pitfalls, 314
cytopathologic features, 77t, 78f Mesothelial cells, 159
differential diagnosis and pitfalls, 78 Metastases
non-Hodgkin lymphoma adrenal gland, 334–6, 334t, 335f, 336f, 337f
large-cell, 86–9 breast, 151–4, 151t, 152f, 152t, 153f
pediatric, 89–91 kidney, 326–7
small-cell, 81–6 liver, 246–9, 246t, 247f, 247t, 248f, 248t, 249f
reactive lymphoid hyperplasia, 71–4 lung, 193–8, 194f, 194t, 195f, 196f, 197f, 198f
ancillary studies, 73–4 mediastinum, 215–17
clinical features, 71t Mucinous carcinoma, 145–6, 145f, 145t
cytopathologic features, 71–3, 71t, 72f, 73f Mucinous cystic neoplasm, 285–90
differential diagnosis and pitfalls, 74 ancillary studies, 289
Lymphoepithelial cysts, 260t, 261f clinical features, 285t
Lymphoepithelial sialadenitis, 4 cytopathologic features, 285–9, 286f, 286t, 287f, 288f,
Lymphoma 289f
follicular, 83, 84f differential diagnosis, 289, 290f
hepatic, 244–6 Mucocele, 4–5, 6f
ancillary studies, 246 Mucoepidermoid carcinoma, 9, 23–5
clinical features, 244–5, 245t clinical features, 23–4, 23t
differential diagnosis and pitfalls, 246 cytopathologic features, 24f, 24t, 25f
pathologic features, 245–6, 245f, 245t, 246f differential diagnosis and pitfalls, 24–5
Hodgkin see Hodgkin lymphoma Mycobacterial lymphadenitis, 76f
kidney, 325–6, 325t, 326f Myelolipoma, 328–9, 328t, 329f
mantle, 83, 84f Myoepithelioma, 12–13, 13f, 14f
mediastinal, 210–13 Myxoid liposarcoma, 96f
ancillary studies, 212 Myxoma, 117–18, 117t, 118f
clinical features, 210, 211t
cytopathologic features, 210–12, 212f, 212t, 213f Nasopharyngeal carcinoma, 89f
non-Hodgkin see Non-Hodgkin lymphoma Necrotizing sialometaplasia, 4
salivary glands, 30–1 Nephroblastoma (Wilms tumor), 317–18
clinical features, 30t ancillary studies, 318
cytopathologic features, 30–1, 30f, 31f, 31t clinical features, 317t
differential diagnosis and pitfalls, 31 cytopathologic features, 317–18, 318t
small lymphocytic, 83–4, 84f differential diagnosis and pitfalls, 318
thyroid gland, 68–9, 68t, 69f Neural tumors, 104–9
granular cell tumor, 106–7
Macroregenerative nodule, 219–22 malignant peripheral nerve sheath tumors, 108–9
ancillary studies, 222 neurofi broma and schwannoma, 104–6
clinical features, 219–21, 219t Neuroblastoma, 338, 341–2
differential diagnosis and pitfalls, 222 ancillary studies, 341
pathologic features, 221–2, 221f, 221t, 222f clinical features, 338, 341t
Malignant fi brous histiocytoma, 102–3 cytopathologic features, 341, 342f, 342t
ancillary studies, 103 differential diagnosis and pitfalls, 341–2
clinical features, 102t Neurofi broma, 104–6
differential diagnosis and pitfalls, 103 ancillary studies, 106
pathologic features, 102–3, 103f, 103t clinical features, 104t
Malignant melanoma, 90f differential diagnosis and pitfalls, 106
Malignant mixed tumor of salivary glands, 10–12, 11f pathologic features, 104–6, 104t, 105f
Malignant peripheral nerve sheath tumors, 108–9, 108t, 109f Neurogenic tumors, 213–15
Mantle lymphoma, 83, 84f clinical features, 213t
Marginal zone lymphoma, 84–5, 85f cytologic features, 213–15, 214f, 215t
Masood Cytology Index, 137t, 138f Nodular cortical hyperplasia and cortical adenoma, 329–31
Mastitis, 127–8, 127f, 127t, 128f ancillary studies, 330
Mediastinal lymphomas, 210–13 clinical features, 329t
Mediastinum, 201–18, 202t cytopathologic features, 329–30, 330f, 330t
differential diagnosis, 202t differential diagnosis and pitfalls, 330–1
germ cell tumors, 206–9 Nodular fasciitis, 97–8
location of mediastinal lesions, 202t ancillary studies, 98
mediastinal lymphomas, 210–13 clinical features, 97t
metastatic lesions, 215–17 differential diagnosis and pitfalls, 98
neurogenic tumors, 213–15 pathologic features, 97–8, 97t, 98f
thymic carcinomas, 205–6 Nodular goitre, 41–6
thymic follicular hyperplasia, 206 ancillary studies, 46
thymic neuroendocrine (carcinoid) tumors, 209–10 clinical features, 41t
thymoma, 203–5 cytopathologic features, 41–2, 42f, 42t, 43f, 44f, 45f, 46f
Medullary carcinoma, 60–3, 147–8, 147t, 148f, 148t differential diagnosis and pitfalls, 46
breast, 147–8, 147t, 148f, 148t Non-Hodgkin lymphoma, 212f, 213f
thyroid gland large-cell, 86–9
ancillary studies, 61–2 ancillary studies, 88
clinical features, 60t clinical features, 86–7, 86t, 87t
cytopathologic features, 60–1, 60t, 61f, 62f, 63f cytopathologic features, 87–8, 87t, 88f
differential diagnosis and pitfalls, 62–3 differential diagnosis, 86–7, 87f, 88f, 89f, 90f

INDEX-F06731.indd 350 10/26/2006 10:35:04 AM

 INDEX 351

pediatric, 89–91 clinical features, 71t

ancillar studies, 91 cytopathologic features, 71–3, 71t, 72f, 73f
clinical features, 89–90, 90t differential diagnosis and pitfalls, 74
cytopathologic features, 90–1, 91f Reed-Sternberg cells, 80f, 81f, 82f
differential diagnosis and pitfalls, 91 Renal cell carcinoma, 299–315, 300f
small-cell, 81–6 chromophobe type, 308–11
ancillary studies, 85 classification, 299, 300t
clinical features, 81–3, 82t clear cell type, 302–5
cytopathologic features, 83–5, 83t, 84f, 85f, 85t clinical features, 299t
differential diagnosis and pitfalls, 85–6, 86f collecting duct type, 311–13
cytopathologic features, 301–2, 302t
Oncocytic carcinoma, 16 medullary type, 313–14
Oncocytoma, 16, 316–17 nuclear grading, 300–1, 301f, 302f
ancillary studies, 316–17 papillary type, 305–6
clinical features, 316t sarcomatoid type, 314–15
cytopathologic features, 316f, 316t, 317f Retention cyst, 4–5, 6f
differential diagnosis and pitfalls, 317 Rhabdoid tumor, 318–20
Owl’s eye appearance, 269f ancillary studies, 319, 320f
Pancreas, 251–98 clinical features, 318–19, 319t
cystic neoplasms, 279–96 cytopathologic features, 319f, 319t
intraductal papillary mucinous neoplasm, 291–6 differential diagnosis and pitfalls, 319
mucinous cystic neoplasm, 285–90 Rhabdomyosarcoma, 109–11
serous cystadenoma, 279–82 ancillary studies, 111
solid-pseudopapillary neoplasm, 282–5 clinical features, 109–10, 109t
non-epithelial and metastatic tumors, 296 differential diagnosis and pitfalls, 111
non-neoplastic mass lesions, 253–60 pathologic features, 110–11, 110f, 110t, 111f
chronic pancreatitis, 253–7
lymphoepithelial cysts, 260 Salivary duct carcinoma, 28–9
pancreatic pseudocyst, 257–60 clinical features, 28, 28t
normal, 251–3, 252f, 253f cytopathologic features, 28–9, 28t, 29f
solid neoplasms, 260–79 differential diagnosis and pitfalls, 29
acinar cell carcinoma, 274–8 Salivary glands, 1–36, 2f
ductal adenocarcinoma, 260–70 acinic cell carcinoma, 25–7
pancreatic endocrine neoplasm, 270–4 clinical features, 25–6, 26t
pancreatoblastoma, 278–9 cytopathologic features, 26–7, 26f, 26t, 27f
differential diagnosis and pitfalls, 27
Pancreatic endocrine neoplasm, 270–4 adenocarcinoma, 32
ancillary studies, 273 basaloid neoplasms, 17–23
clinical features, 270t adenoid cystic carcinoma, 19–21
cytopathologic features, 270–3, 270f, 271f, 272f, basal cell adenocarcinoma, 18
273f basal cell adenoma, 17–18
differential diagnosis and pitfalls, 273–4, 274f polymorphous low-grade adenocarcinoma, 21–3
Pancreatic pseudocyst, 257–60 benign mixed tumor, 7–10
ancillary features, 258–9 clinical features, 7–8, 7t
clinical features, 257–8, 258t cytopathological features, 7–8, 8f, 9f
cytopathologic features, 258, 259f, 259t differential diagnosis and pitfalls, 8–10, 10f, 11f
differential diagnosis and pitfalls, 259–60 carcinosarcoma, 12f
radiologic features, 258 clear cell carcinoma, 32
Pancreatoblastoma, 278–9, 278t, 279f, 280f lymphoepithelial carcinoma, 32, 33t
Papillary carcinoma, 51–9 malignant lymphoma, 30–1
ancillary studies, 58 malignant mixed tumor, 10–12, 11f
clinical features, 51–2, 51t mucoepidermoid carcinoma, 23–5
cytopathologic features, 52–8, 53f, 54f, 55f, 56f, 57f, 58f clinical features, 23–4, 23t
differential diagnosis and pitfalls, 58–9, 59f cytopathologic features, 24f, 24t, 25f
Papillary renal cell carcinoma, 305–6 differential diagnosis and pitfalls, 24–5
ancillary studies, 305, 308, 309f myoepithelial neoplasms, 12–13, 13f, 14f
clinical features, 305t non-neoplastic cystic lesions, 4–7
cytopatologic features, 305, 306f, 307f, 308t cytopathologic features, 5–6, 6f
differential diagnosis and pitfalls, 308 differential diagnosis and pitfalls, 6–7
Parathyroid cyst, 46 non-neoplastic lesions, 1–7
Pheochromocytoma, 336–8 sialadenitis, 1–4, 2t, 3f, 4f
ancillary studies, 338, 341f sialadenosis, 1
clinical features, 336–8, 338t oncocytic neoplasms, 13–16
cytopathologic features, 338t, 339f, 340f oncocytoma and oncocytic carcinoma, 16
differential diagnosis and pitfalls, 338 Warthin tumor, 13–16
Plasmacytoma, 274f primary small cell carcinoma, 31–2, 32f
Pleomorphic carcinoma, 190–1, 190t, 191f salivary duct carcinoma, 28–9
Pleomorphic liposarcoma, 97f sarcoma, 32
Polymorphous low-grade adenocarcinoma, 21–3, 21t, secondary tumors, 32–4, 34f
22f squamous cell carcinoma, 32, 33t
differential diagnosis and pitfalls, 22–3 ‘Salt and pepper’ chromatin, 211f, 270, 271f
pathologic features, 23t Sarcoidosis, 76f, 159–63
Pregnancy, breast changes, 130–2, 130t, 131f, 131t, 132f ancillary studies, 162
clinical features, 159–61, 160f, 160t, 161f, 161t
Reactive lymphoid hyperplasia, 71–4 cytopathologic features, 161–2, 162f, 162t
ancillary studies, 73–4 differential diagnosis and pitfalls, 162–3

INDEX-F06731.indd 351 10/26/2006 10:35:04 AM

 352 INDEX

lung, 159–63 Thymic carcinoma, 205–6, 205f, 206f

radiologic features, 161 Thymic follicular hyperplasia, 206
Sarcoma Thymic neuroendocrine (carcinoid) tumors, 209–10
alveolar soft part, 120–1, 120f, 120t, 121t ancillary features, 210
epithelioid, 118–20 clinical features, 209–10, 209t
salivary gland, 32 cytopathologic features, 210f, 210t, 211f
synovial, 121–3 differential diagnosis and pitfalls, 210, 211f
Sarcomatoid renal cell carcinoma, 314–15, 315f, 315t Thymoma, 203–5
Schistosoma mansoni, 224t ancillary studies, 205
Schwannoma, 104–6, 213f clinical features, 203t
ancillary studies, 106 cytopathologic features, 203–5, 203t, 204f
clinical features, 104t differential diagnosis, 205, 205f
differential diagnosis and pitfalls, 106 Thyroid gland, 37–70, 38f
pathologic features, 104–6, 104t, 105f anaplastic carcinoma, 64–7
Seminoma, 89f, 207 ancillary studies, 66
Serous cystadenoma, 279–82 clinical features, 64–5, 65t
ancillary studies, 281 cytopathologic features, 65–6, 65t, 66f, 67f
clinical features, 279–80, 279t differential diagnosis and pitfalls, 67f
cytopathologic features, 280–1, 280t, 281f follicular neoplasms, 47–9
differential diagnosis and pitfalls, 281–2 ancillary studies, 48–9
radiologic features, 280 clinical features, 47t
Sialadenitis, 1–4 cytopathologic features, 47–8, 47t, 48f, 49f
clinical features, 1–2t differential diagnosis and pitfalls, 49
cytopathologic features, 2–4, 2t, 3f, 4f, 5f Hashimoto’s thyroiditis, 37–41
differential diagnosis and pitfalls, 4 ancillary studies, 39
Sialadenosis, 1 clinical features, 37–8, 38t
Sialolithiasis, 2 cytopathologic features, 39f, 39t, 40f, 41f
Signet-ring cell adenocarcinoma, 267f differential diagnosis and pitfalls, 39–40
Signet-ring cell carcinoma, 146–7, 146t, 147f Hürthle cell neoplasms, 49–51
Sjögren syndrome, 4 ancillary studies, 51
Skeletal muscle tumors, 109–11 clinical features, 49–50, 49t
Small cell carcinoma, 189–90, 189f, 189t, 190f cytopathologic features, 50–1, 50f, 50t, 51f
Small lymphocytic lymphoma, 83–4, 84f differential diagnosis and pitfalls, 51
Smooth muscle tumors, 112–13 insular carcinoma, 63–4
Soft tissue, 93–126 ancillary studies, 64
adipose tissue tumors, 93–7 clinical features, 63t
lipoma, 93–4 cytopathologic features, t, 63–4, 64f, 64t, 65f
liposarcoma, 94–7 differential diagnosis and pitfalls, 64
alveolar soft part sarcoma, 120–1 lymphoma, 68–9, 68t, 69f
epithelioid sarcoma, 118–20 medullary carcinoma, 60–3
fi broblastic/fi brohistiocytic tumors, 97–103 ancillary studies, 61–2
dermatofi brosarcoma protuberans, 100–1 clinical features, 60t
fi bromatosis, 98–100 cytopathologic features, 60–1, 60t, 61f, 62f, 63f
fi brosarcoma, 101–2 differential diagnosis and pitfalls, 62–3
malignant fi brous histiocytoma, 102–3 nodular goitre, 41–6
nodular fasciitis, 97–8 ancillary studies, 46
gastrointestinal stromal tumor, 115–17 clinical features, 41t
myxoma, 117–18 cytopathologic features, 41–2, 42f, 42t, 43f, 44f, 45f, 46f
neural tumors, 104–9 differential diagnosis and pitfalls, 46
granular cell tumor, 106–7 papillary carcinoma, 51–9
malignant peripheral nerve sheath tumors, 108–9 ancillary studies, 58
neurofi broma and schwannoma, 104–6 clinical features, 51–2, 51t
skeletal muscle tumors, 109–11 cytopathologic features, 52–8, 53f, 54f, 55f, 56f, 57f, 58f
smooth muscle tumors, 112–13 differential diagnosis and pitfalls, 58–9, 59f
synovial sarcoma, 121–3 Tuberculosis, 163–5
vascular tumors, 113–15 ancillary studies, 165
Solid-pseudopapillary neoplasm, 282–5 clinical features, 163t
ancillary studies, 285 cytopathologic features, 163–5, 163t, 164f, 165f
clinical features, 282t differential diagnosis and pitfalls, 165
cytopathologic features, 282–4, 282t, 283f, 284f radiologic features, 163
differential diagnosis and pitfalls, 285 Tubular carcinoma, 143–5, 144f, 144t
radiologic features, 282
Squamous cell carcinoma Urothelial carcinoma of renal pelvis, 324–5, 324f, 324t
lung, 181–4
clinical features, 181t Vascular tumors, 113–15
cytopathologic features, 182–3, 182f, 182t, 183f, 183t, Warthin tumor, 4, 13–16
184f clinical features, 13, 14t
differential diagnosis and pitfalls, 183–4 cytopathological features, 14–15, 15f, 16f
radiologic features, 182 differential diagnosis and pitfalls, 15–16
salivary glands, 32, 33t
Squamous pearls, 205 Yolk sac tumor, 207, 208f, 209f
Synovial sarcoma, 121–3
ancillary studies, 122 Zygomycoses, 175–6
clinical features, 121t clinical features, 175t
differential diagnosis and pitfalls, 123 cytopathologic features, 176f, 176t
pathologic features, 121–2, 122f, 122t, 123f radiologic features, 175

INDEX-F06731.indd 352 10/26/2006 10:35:04 AM