Cytopathology of Neuroendocrine Neoplasia - Color Atlas and Text

CYTOPATHOLOGY
OFNEUROENDOCRINE
NEOPLASIA
COLOR ATLAS AND TEXT
(c) 2015 Wolters Kluwer. All Rights Reserved.

CYTOPATHOLOGY
OFNEUROENDOCRINE
NEOPLASIA
COLOR ATLAS AND TEXT
Sudha R. Kini, MD
Division of Cytopathology
Department of Pathology
Henry Ford Hospital
Detroit, Michigan

Aquisitions Editor: Ryan Shaw
Product Manager: Amy G. Dinkel
Production Project Manager: Priscilla Crater
Vendor Manager: Alicia Jackson
Senior Manufacturing Manager: Benjamin Rivera
Senior Marketing Manager: Caroline Foote
Designer: Holly McLaughlin
Production Service: SPi Global
2013 by LIPPINCOTT WILLIAMS & WILKINS, a WOLTERS KLUWER business

Two Commerce Square
2001 Market Street
Philadelphia, PA 19103 USA
LWW.com
Previous edition copyright info here.
All rights reserved. This book is protected by copyright. No part of this book may be
reproduced in any form by any means, including photocopying, or utilized by any information
storage and retrieval system without written permission from the copyright owner, except for
brief quotations embodied in critical articles and reviews. Materials appearing in this book
prepared by individuals as part of their official duties as U.S. government employees are not
covered by the above-mentioned copyright.
Printed in China
Library of Congress Cataloging-in-Publication Data

Kini, Sudha R.
Cytopathology of neuroendocrine neoplasia : color atlas and text / Sudha R. Kini.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-4511-7633-9
I. Title.
[DNLM: 1. Neuroendocrine TumorspathologyAtlases. 2. Cytodiagnosismethods
Atlases. 3. Neuroendocrine TumorsclassificationAtlases. 4. Neuroendocrine Tumors
diagnosisAtlases. WK 17]
616.99'407582dc23
2012030610
Care has been taken to confirm the accuracy of the information presented and to describe
generally accepted practices. However, the authors, editors, and publisher are not responsible
for errors or omissions or for any consequences from application of the information in this
book and make no warranty, expressed or implied, with respect to the currency, completeness,
or accuracy of the contents of the publication. Application of the information in a particular
situation remains the professional responsibility of the practitioner.
The authors, editors, and publisher have exerted every effort to ensure that drug selection
and dosage set forth in this text are in accordance with current recommendations and practice
at the time of publication. However, in view of ongoing research, changes in government
regulations, and the constant flow of information relating to drug therapy and drug reactions,
the reader is urged to check the package insert for each drug for any change in indications
and dosage and for added warnings and precautions. This is particularly important when the
recommended agent is a new or infrequently employed drug.
Some drugs and medical devices presented in the publication have Food and Drug
Administration (FDA) clearance for limited use in restricted research settings. It is the
responsibility of the health care provider to ascertain the FDA status of each drug or device
planned for use in their clinical practice.
To purchase additional copies of this book, call our customer service department at (800) 638-
3030 or fax orders to (301) 223-2320. International customers should call (301) 223-2300.
Visit Lippincott Williams & Wilkins on the Internet at LWW.com. Lippincott Williams &
Wilkins customer service representatives are available from 8:30 am to 6 pm, EST.
10 9 8 7 6 5 4 3 2 1

Dedication
To all the patients who were a continuous source of learning and knowledge
To all my teachers, professional colleagues, residents, fellows, and technical staffpast and
present
To my daughters Sarita and Sunita for their continued support and encouragement and to
the loving memories of my late husband and my late parents

Contributors
Preface
Mithra R. Baliga, MD Shilpa Rungta, MD

Professor and Chief, Division of Cytopathology Clinical Lecturer, Department of Pathology
University of Mississippi Medical Center University of Michigan Hospitals and Health Centers
Jackson, Mississippi Staff Pathologist
Chapters 12 and 13 VA Ann Arbor Health System
Ann Arbor, Michigan
Min W. Lee, MD Chapter 4
Senior Staff Pathologist
Henry Ford Hospital
Detroit, Michigan
Chapter 1
vi

Preface
My decision to compile an atlas and text of cytopathology diagnoses is critical, especially when the morphology does
of neuroendocrine neoplasia stemmed from the difficul- not fit in a particular box. In general, the exposure to
ties I had personally endured in my cytopathology prac- cytomorphology of neuroendocrine tumors is limited
tice, especially in earlier years, and the embarrassment for cytotechnologists and pathologists/cytopathologists.
for having missed the diagnosis on several occasions. I The lack of a reference book with generous illustrations
was not very well conversant with the diffuse neuroen- became an impetus to undertake this task.
docrine system. Its complexity, the wide distribution of I have tried to cover neuroendocrine neoplasms at
the neuroendocrine cells and the ubiquitous nature of several sites. However, it has been difficult to illustrate
their neoplasms in the body, was overwhelming. Equally neuroendocrine neoplasm from each and every site in
perplexing was the morphologic broad spectrum of the the body, for which I offer my apologies. I felt details on
neoplasms, different terminologies, their immunocytohis- molecular testing and cytogenetics were beyond the scope
tochemical properties, ultrastructural findings, secretory of this atlas as my intentions were to focus on the cytopa-
products, and their association with many hereditary syn- thology of neuroendocrine tumors and to offer guidelines
dromes. A difficult case would often prompt an exten- in the initial evaluation of the specimens; make a tentative
sive literature search, and retrieval of several case reports diagnosis of neuroendocrine neoplasms, to be confirmed
on cytopathologic findings, most of which were sparsely subsequently by immunostains and/or surgery.
illustrated. Differential diagnoses were neither discussed We at Henry Ford Hospital prefer and continue to
in detail nor well illustrated. It also became very clear to use spray fixation and Papanicolaou stain rather than
me that large comprehensive text books on cytopathol- Romanowsky stain, and we prefer conventional meth-
ogy lacked detailed information on cytomorphology of ods of cytopreparation to liquid-based preparation. The
neuroendocrine neoplasia whereas in surgical pathology images in this atlas, depicting excellent cytomorphology
the literature is voluminous. Currently there is no single of neuroendocrine neoplasms, can attest to this time-
publication dedicated solely to cytopathology of neuroen- tested method of cytopreparation and staining.
docrine neoplasia. The classification of the neuroendocrine neoplasms
The frustration caused by the limited information continues to be debated, modified, and revised. A num-
in cytopathology literature had steered me to explore ber of schemes have been proposed and recommended by
the diffuse neuroendocrine system in much more detail. various scientific groups and individuals over the years.
Historical data shed considerable light on how the neu- Classifications recommended and utilized for few years
roendocrine system evolved over the years and helped me are changed again. It had been quite difficult to keep the
understand the complex system. nomenclature simple and consistent in this atlas. I have
The neuroendocrine system is fascinating, intriguing, included the current classifications for each system as an
and complex and has sustained the interest of scientists appendix in the respective chapter. I have resorted to the
for over centuries. Although uncommon, neuroendocrine four-tier system of carcinoid, atypical carcinoid, small
tumors arise anywhere in the body, from head to toe. cell carcinoma, and large cell neuroendocrine carcinoma
They are encountered when least expected, and they pres- for the sake of convenience and also provided the recom-
ent a broad range of cytohistologic patterns that overlap mended terminologies in parenthesis.
not only with other neuroendocrine neoplasms but also I could not have completed the manuscript with-
with several types of nonneuroendocrine neoplasms. This out the help of my professional colleagues and friends.
overlap widens the differential diagnostic possibilities Dr. Min Lee with his strong interest in the neuroendocrine
that can be very site specific. Thus, keeping in mind the system did an excellent job in presenting an overview
possibility of a neuroendocrine neoplasm in differential including the historical aspects. I cannot thank enough
vii

viii Preface
Dr. Mithra Baliga of University of Mississippi at Jackson, decades of my cytopathology practice. I am proud of the
Mississippi, for Chapters 12 and 13. Dr. Shilpa Rungta, quality of the images, the credit for which mainly goes
my cytopathology fellow during 2010 to 2011, was gra- to Ms. M. Jane Purslow, exlaboratory supervisor of the
cious enough to write Chapter 4 on Neuroendocrine Cytopathology Laboratory at Henry Ford Hospital. Last
Tumors of the Gastrointestinal Tract for which I extend but not least, I want to acknowledge Lippincott Williams
my heartfelt thanks. At this time I must acknowledge the & Wilkins for allowing me the generous use of images.
extensive publications by Dr. Ronald DeLellis, which had Finally, I do hope this atlas will provide the assistance
provided me with much needed information and explana- to those practicing cytopathology in the diagnosis of neu-
tory notes. roendocrine tumors when needed.
I have made ample use of images of neuroendocrine
neoplasms personally encountered over the last few Sudha R. Kini, MD

Acknowledgments
Preface
My sincere thanks to the following professional col- Health Centers, 4241 Medical Science I, Ann Arbor,
leagues from within the United States and internationally Michigan for Figure 4.5.
for graciously providing the images at my request:
Dr. Ajay Shah, Fine Needle Aspiration Clinic, Toledo,
Ms. Karen Atkinson, MPA, CT(ASCP), CMIAC, Direc- Ohio, for Figures 8.47AE and 15.8AE.
tor of Education and Training, BD Diagnostics
A. Vodovnik, MD, Calderdale Royal Hospital, HX3 OPW
Womens Health and Cancer, and Mr. Tim Collins, BS,
Halifax, England, for Figure 8.46A and B.
CT(ASCP), Senior Scientist, Research and Develop-
ment, BD DiagnosticsWomens Health and Cancer, Ami J. Walloch, MD, and Rashead Hammadeh, MD,
Burlington, for Figure 12.4 Christ Hospital, Oaklawn, Illinois, for Figure 8.45A
and B.
Mithra Baliga, MD, University of Mississippi, Jackson,
Mississippi, for Figures 5. 8A and B, 5.11AE, 5.16AF,
I want to express my gratitude to several of my past resi-
5.23AF, 8.20AC, 8.38A and B, 12.5 and 12.6, 13.1AD,
dents and fellows for digital photography, particularly
13.3AD, 13.8AD, 13.11EH, 14.8AE, and 15.13AD.
Drs. Songling Liang, Osama Alasi, Kedar Inamdar,
Dr. Jenine Benoit, Saskatoon City Hospital, Saskatoon, Dongping Shi, Ziyang Zhang, Oslin Seglam, Leo Newman,
Canada, for Figure 14.13AC. Aditya Raghavan, Gaurav Sharma, and Robert Stapp.
Dr. Irving Dardick of Pathology Images Inc, Ottawa, Can-
I am indebted to Ms. Linda Brandt and Ms. Laure Gratopp
ada, for a major complement of images for Chapter 7
for their secretarial assistance. I am also extremely grate-
on Neuroendocrine Tumors of the Salivary Glands.
ful to Media Services at Henry Ford Hospital for provid-
Dr. Mariza de Peralta-Venturina, Cedar-Sinai Hospital, ing an excellent service for the image files, editing, and
Los Angeles, California, for Figures 8.26AE, 12.20, color balance. Special thanks are due to Ms. Reva Sayegh-
and 12.21. McCullen for her expertise and patience.
Dr. Michael Glant, Director, Diagnostic Cytology Clinic,
Indianapolis, Indiana, for Figure 9.9AC. ACKNOWLEDGMENTS ARE DUE FOR THE
FOLLOWING COPYRIGHTED MATERIAL:
Dr. John F. Goellner, previously of Department of Pathol-
ogy, Mayo Clinic Rochester, Minnesota, for Figure 8.22. To Lippincott Williams &Wilkins for
Dr. Barbara McKenna, Godfrey D. Stobbe Professor of Reproduction of several images from Color Atlas of Dif-
Pathology, Director of Division of Education Pro- ferential Diagnosis in Exfoliative and Aspiration Cyto-
grams, University of Michigan, Ann Arbor, Michigan pathology, 2nd ed., 2011.
for Figure 4.4.
Figure 1.2; DeLellis RA, Dayal Y. The neuroendocrine
Dr. Robert Osamura, Professor and Director, Diagnostic system, Chapter 47. In: Mills SE, ed. Histology for
Pathology Center, International University of Health Pathologists. 3rd ed. Philadelphia, PA: Lippincott Wil-
and Welfare, INHW Mita Hospital, Tokyo, Japan, for liams & Wilkins; 2007:1190, Fig. 47.1.
Figure 5.15A and B.
Figure 12.19; Koss LG. Diagnostic Cytology of the Urinary
Dr. Shilpa Rungata, Clinical Lecturer, Department of Tract with Histopathologic and Clinical Correlations.
Pathology, University of Michigan Hospitals and Philadelphia, PA: Lippincott-Raven; 1995:color plate 5-2.
ix

x Acknowledgments
To Armed Forces Institute of Pathology for To Elsevier Ltd., The Boulevard, Langford Lane,
Kidlington, Oxford, OXS 1GB UK for
Figure 1.1; Lloyd RV, Douglas BR, Young WF. Diffuse
neuroendocrine system. In: King DW, Sobin LH, Tables 6.1 and 6.2; Moran CA. Primary neuroendocrine
Stocker JT, et al., eds. Endocrine Diseases. Atlas of carcinomas of the mediastinum: review of current cri-
Nontumor Pathology. Washington, DC: AFIP; 2002. teria for histopathologic diagnosis and classification.
Semin Diagn Pathol. 2005;22:223229. Reproduced
Figures 15.1A and B; Lack EE. Tumors of the adrenal
with permission from Elsevier Inc. Philadelphia, PA.
glands and extra-adrenal paraganglia. AFIP Atlas of
Tumor Pathology, Series 4, Fascicle 8, Washington,
DC: American Registry of Pathology; 2007:283,
Fig. 11.1; 323, Fig. 12.1.

Contents
Preface
Contributors vi
Preface vii
Acknowledgments ix
1. Dispersed Neuroendocrine System: An Overview 1

Min W. Lee and Sudha R. Kini
2. Types of Cytologic Specimens and Cytopreparations 17
SECTION I: EPITHELIAL TYPE NEUROENDOCRINE TUMORS
3. Pulmonary Neuroendocrine Tumors 29
4. Neuroendocrine Tumors of the Gastrointestinal Tract, Appendix, Gallbladder

and Extrahepatic Biliary Tract 85
Shilpa Rungta and Sudha R. Kini
5. Neuroendocrine Tumors of the Pancreas 103
6. Neuroendocrine Tumors in the Mediastinum 133
7. Neuroendocrine Tumors of the Salivary Glands 147
8. Neuroendocrine Tumors of the Thyroid Gland 163
9. Neoplasms of the Parathyroid Glands 209
10. Neoplasms of the Pituitary Gland 225
11. Neuroendocrine Tumors of the Skin (Merkel Cell Carcinoma) 239
12. Neuroendocrine Tumors of the Genitourinary Tracts 249

Mithra R. Baliga and Sudha R. Kini
13. Miscellaneous Neuroendocrine Tumors of the Epithelial Type: Breast, Liver,

Sinonasal Tract 271
Mithra R. Baliga and Sudha R. Kini
xi

xii Contents
SECTION II: NEURAL TYPE NEUROENDOCRINE TUMORS
14. Adrenal Pheochromocytoma 295
15. Extra-Adrenal Paragangliomas 315
16. Neuroendocrine Neoplasms in the Pediatric Age Group and Adolescents 351
17. Miscellaneous Neuroendocrine Tumors of the Neural Type: Olfactory Neuroblastoma

and Central Neurocytoma 373
Glossary 389
Index 391

1 DISPERSED NEUROENDOCRINE
SYSTEM: AN OVERVIEW
Min W. Lee Sudha R. Kini
cells. These cells were named enterochromaffin cells by

INTRODUCTION Caccio (1906). The term carcinoid (Karzinoid Tumoren,
carcinoma-like) was coined by Oberndorfer (1907) to
Neuroendocrine neoplasia is an enigmatic family of
describe an ileal tumor of characteristic morphology and
tumors sharing a phenotype characterized by the simulta-
biologic behavior. Although much earlier Merling (1838)
neous expression of multiple genes, which encode a wide
and Langhans (1867) may have published a description of
variety of neuronal and endocrine traits (Rosai, 2011).
what is considered a carcinoid, Lubarsch (1888) got the
Neuroendocrine-programmed cells are distributed
credit for first describing in detail the tumor that was later
widely in the body regardless of their embryologic deri-
named carcinoid tumor. Huebschmann (1910) was said
vation (Fig. 1.1). Certain organs are entirely composed
to be the first one who speculated carcinoid tumor was
of neuroendocrine cells such as the pituitary gland and
possibly arising from enterochromaffin cells.
parathyroid glands. In other nonneuroendocrine organs,
Gosset and Masson (1914) in a study of appendiceal
neuroendocrine cells are aggregated to form structures
tumors titled Endocrine Tumors of Appendix demon-
that can be identified microscopically with routine stains
strated these cells as being positive for argentaffin reac-
(H&E). Examples are adrenal medulla and pancreatic
tion. Hamperl (1938) demonstrated positive argyrophilic
islets of Langerhans. Neuroendocrine cells are also dif-
reactions in larger population of cells than the argentaffin
fusely dispersed in the epithelium mostly of endodermal-
ones in the GI tract and suggested a possible endocrine
derived organs such as the salivary glands, lungs, thyroid
role for these cells as well. Later on, he also recognized a
(C cells), bile ducts, and gastrointestinal (GI) tract as well
bronchial counterpart of intestinal carcinoid.
as the ectodermal-derived structures: neuronal structures,
Feyrter (1938) found similar cells with clear cytoplasm
Merkel cells of skin, and mesodermal-derived structures,
(helle zellen) that were dispersed in the mucosa through-
such as kidney and reproductive organs (urogenital ridge).
out the GI tract, introducing a concept diffuse endocrine
system.
Around the same time, Ernst and Berta Scharrer were
able to demonstrate secretory granules in neuronal cells
HISTORICAL PERSPECTIVE in the supraoptic nucleus of fish brain suggesting that the
hormone might be produced by such neurons. They called
Neuroendocrine tumors (NETs) have captured and sustained these cells neurosecretory neurons. Subsequently, the term
the attention of scientists for decades. Extensive research neuroendocrine secretion became popular.
done in this field has greatly expanded the understanding In 1969, Pearse indicated that these specialized cells
and knowledge of this complex system. A brief history of were capable of uptaking and decarboxylating amine
evolution of the system is provided in the following section. precursors, introducing the concept of Amine Precursors
More than a century ago, Heidenham (1870) was the Uptaking and Decarboxylation (APUD) system. He also
first to describe scattered chromaffin-positive cells using postulated that APUD cells originated from the neural
potassium dichromate in the GI tract. Shortly thereaf- crest on the basis of the similarities between neuron and
ter, Kultschitsky (1897) identified the presence of cells neuroendocrine cells. However, this concept was soon
exhibiting different polarity from the mucus-secreting refuted by Fontaine and LeDouarins (1977) embryonic
cells with basal position in the mucosa. His discovery and study employing chickquail chimera system with inter-
study were credited by naming these cells Kultschitsky ruption of neural crest migration. The study supported

2 Chapter 1: Dispersed Neuroendocrine System: An Overview
Fig. 1.2: Secretory Activities of Neuroendocrine Cells and Neu-

rons. A: Neuroendocrine cells may secrete their products through
the basement membrane into adjacent capillaries for interaction
with target tissues at distant sites (endocrine function). B: Neuro-
endocrine cells may secrete their products locally to influence the
Fig. 1.1: Schematic review of the diffuse neuroendocrine system, activities of adjacent epithelial cells (paracrine function). C: Neu-
which is composed of classic endocrine organs as well as scat- roendocrine cells may secrete their products within a glandular
tered neuroendocrine cells in various organs and tissues. The cells lumen (luminal secretion). D: Neurons may secrete their products
are characterized by specific peptides such as chromogranin and into the circulation for interaction with target tissues at distant sites
synaptophysin and ultrastructural evidence of secretory granules. (neurosecretory activity). E: Neurons may also secrete products that
(From Lloyd RV, Douglas BR, Young WF. Diffuse neuroendocrine serve as neurotransmitters or neuromodulators. (From DeLellis RA,
system. In: King DW, Sobin LH, Stocker JT, et al. eds. Endocrine Dayal Y. The neuroendocrine system, Chapter 47. In: Mills SE, ed.
Diseases. Atlas of Non-Tumor Pathology. Washington, DC: AFIP; Histology for Pathologists. 3rd ed. Philadelphia, PA: Lippincott
2002:259308. Reproduced with permission from American Reg- Williams & Wilkins; 2007, with permission.)
istry of Pathology.)
the concept that the neuroendocrine neoplasms derived recommended that all neuroendocrine neoplasms be
from stem cells. first grouped into two main phenotypical categories: the
Neuroendocrine-programmed cells are now known to neural phenotype (positive immunoreactivity for neuro-
have more complex modes of secretion with paracrine, filaments but negative for cytokeratins) and epithelial
autocrine, and even exocrine secretion of cell products, in phenotypes (positive for cytokeratins but generally nega-
addition to endocrine secretion (Fig. 1.2). Furthermore, tive for neurofilaments).
some cells are capable of secreting different cytoplasmic Secondly it was recommended that all epithelial type
products through both exocrine and endocrine secretory neuroendocrine neoplasms be addressed as neuroendo-
mode, referred to as amphicrine. Typical example is illus- crine carcinomas and subclassified into three categories
trated in a goblet cell carcinoid tumor of the appendix with assigned grades: I, II, and III (Wick, 2000). Several
(Fig. 1.3) other schemes were subsequently recommended, based on
(1) site of origin, for example, pulmonary neuroendocrine
neoplasms, thymic neuroendocrine neoplasms, pancreatic
endocrine neoplasms, GI neuroendocrine neoplasms; (2)
TAXONOMY OF NEUROENDOCRINE tumor grade: well, moderately, and poorly differentiated
TUMORS or low grade, intermediate grade, and high grade; (3) inva-
sive characteristics (especially in GI tract and pancreas); (4)
The classification and nomenclature of neoplasms with secretory products and functional behavior: gastrinoma,
neuroendocrine differentiation have generated consid- somatostatinoma, glucagonoma, etc. The new schemes
erable debate and controversy over the years. The term were two-tiered (NET and neuroendocrine carcinoma for
carcinoid connoted a benign behavior to some, even GI tract and pancreas or well-differentiated and poorly
though these tumors had the potential to metastasize and differentiated for thymus), three-tiered, or the traditional
behave in a malignant fashion. Neoplasms with similar four-tiered classifications. There remained no consistency.
morphology were designated different terms, none of Even with different classification schemes, the term carci-
which reflected the mode of behavior. It was suggested and noid is entrenched in the medical literature. It is still being

Chapter 1: Dispersed Neuroendocrine System: An Overview 3
Fig. 1.3: Amphicrine Cell in Adenocarcinoid of Appendix:

A: Histologic section of a goblet cell carcinoid (H&E). B: Electron
micrograph illustrating large apical mucosomes (arrows) and basal
C neurosecretory granules (arrowheads in C). C: Higher magnification.
widely used as judged from the most current literature. For (PNET)/Ewing sarcoma for soft tissues, and neuroblas-
this reason, and to simplify the terminologies, the author toma/medulloblastoma are also retained
has decided to retain the term carcinoid and also fol- The neural phenotype includes neuroblastomas and
low the time-honored, four-tiered terminology, especially related tumors, PNET/Ewing sarcoma, and neoplasms
for pulmonary NETs in this atlas, along with correspond- of the paraganglia (adrenal medulla and extra-adrenal),
ing newer terminologies recommended for any particular while epithelial phenotype includes the majority of neuro-
site or system. However, for the epithelial phenotypes, the endocrine cells and their tumors occurring in the viscera.
terms such as pituitary adenoma/carcinoma, parathyroid There are often overlapping features between neural and
adenoma/carcinoma, thyroid medullary carcinoma, and epithelial phenotypes. Examples are the tumors particu-
Merkel cell carcinoma of the skin are retained. The terminol- larly of foregut-derived organs such as those seen in the
ogies for the neural phenotypes, for example, pheochromo- larynx, lung, thymus, and thyroid, which exhibit spindle
cytoma of adrenal medulla, extra-adrenal paragangliomas, cell morphology in some and frequent association with
retinoblastoma of eye, Primitive neuroectodermal tumors Schwann-like cells (sustentacular cells).

programmed cells is the presence of small secretory

MIXED ADENONEUROENDOCRINE granules, often referred to as neurosecretory granules,
CARCINOMA crowding the basal or peripheral portion of the cyto-
plasm. These cells are readily recognized by ultrastructural
These neoplasms consist of both exocrine and neuroendo-
identification of neurosecretory granules or immunohisto-
crine components. At least 30% of tumor volume must be
chemical expression of neuroendocrine markers.
composed of either adenocarcinoma or neuroendocrine
neoplasm. Adenocarcinoma with scattered neuroendo-
crine cells is not considered to be mixed adenoneuroen-
TUMOR GROWTH PATTERN
docrine carcinoma (MANEC).
Various growth patterns are observed in neuroendocrine
neoplasms (Figs. 1.4 to 1.6). Well-differentiated NET of
GENERAL FEATURES OF epithelial phenotype has so-called organoid architecture
NEUROENDOCRINE TUMORS AND either in solid nests (insular pattern or classic type), trabec-
SHARED CHARACTERISTICS ular, gyriform, or combinations there of. Typical carcinoid
tumors, particularly of endodermal-derived organs, display
Neuroendocrine-programmed cells present various his- rather unique pattern for each segment of different embry-
tomorphologic and cytomorphologic appearances (Figs. 1.4 ologic derivation: trabecular in foregut, nesting in midgut
to 1.9). The common denominator for neuroendocrine- carcinoid, and mixed in hind gut carcinoid (see Table 4.2).
A
B
C D
Fig. 1.4: Histologic Spectrum of Growth Patterns in Well-differentiated Neuroendocrine Neoplasms (Typical and
Atypical Carcinoid Tumors). A: Large islands and insulae of uniform cells separated by fibrous stroma (H&E).
B: Anastomosing trabeculae and cords of neoplastic cells (H&E). C: Alveolar or nesting pattern (H&E). D: Large
islands with a glandular pattern (H&E).

E F
G H
Fig. 1.4: (continued) E: Uniform, round to cuboidal cells forming a large island (H&E). F: Higher magnification de-
picting appreciable cytoplasm and uniform nuclear pattern (H&E). G: NET with both round and spindle cell pattern
(H&E). H: NET composed entirely of spindle cells (H&E).
Tumors with primitive neural phenotype such as seen of neural phenotype are typically associated with Schwann-
in neuroblastomas or primitive neuroectodermal tumors like cells, designated as sustentacular cells. Schwann-like
exhibit undifferentiated small cells arranged in sheets (see cells are also frequently seen in some NETs of epithelial
Figs. 16.1 and 17.1). Cells in paraganglioma often form phenotype, not only in tissues of foregut derivation but also
nests, commonly referred to as Zellballen (Fig. 1.6). NETs in tumors with classical neuroendocrine growth pattern.
A B
Fig. 1.5: Histologic Spectrum of Poorly Differentiated Neuroendocrine Carcinomas. A: Medium power view showing
a neoplasm with a solid growth pattern and large area of necrosis (H&E). B: Small cell carcinoma forming large masses
of undifferentiated small cells with peripheral palisading (H&E).

C D
E F
Fig. 1.5: (continued) C: Small cell carcinoma with diffuse popula-

tion of small undifferentiated cells without any architectural pat-
terns (H&E). D: Higher magnification of a small cell carcinoma
with diffuse growth pattern, formed by small round undifferenti-
ated cells (H&E). E: An admixture of round and short spindle cells
with scant indistinct cytoplasm, coarsely granular hyperchromatic
nuclei (H&E). F: Large cell neuroendocrine carcinoma with large
areas of necrosis (H&E). G: Higher magnification of (F) showing
larger cells, larger nuclei with scant cytoplasm, high N/C ratios, and
G prominent nucleoli (H&E).
CYTOLOGIC CHARACTERISTICS neuroendocrine carcinomas (Fig. 1.8B). In general, nuclei

have none or small inconspicuous nucleoli in the well-
Despite the well-known common nuclear characteris- differentiated NETs. However, prominent nucleoli are fre-
tics of neuroendocrine neoplasms, chromatin patterns quently observed in pulmonary large cell neuroendocrine
vary from so-called saltpepper-like coarsely granular carcinoma.
pattern (Fig. 1.7A) typically observed in better-differ- The cell size varies from small, medium, to large with
entiated neuroendocrine neoplasms to hyperchromatic occasional giant forms. The tumors can be monomor-
homogeneous, compact pattern as seen in small cell phic and uniform or very pleomorphic with variations

A B
Fig. 1.6: Histologic Patterns of NETs of Neural Type (Pheochromocytoma, Paraganglioma). A: Characteristic alveolar
or nesting pattern referred to as Zellballen. B: Another characteristic pattern with a trabeculae formed by elongated
cells containing nuclei with saltpepper chromatin.
in cell size and shape. The neoplastic cells range from pheochromocytoma, pale in gastric enterochromaffin-
round, oval, cuboidal, low columnar, polygonal, to spin- like-cell neoplasms, and more abundant in polygonal
dle cells with occasionally bizarre forms. Spindle cell cells present in extra-adrenal paragangliomas. These
morphology is typically seen in both neural phenotype cytoplasmic variations occur as a result of different char-
(such as paraganglioma; Fig. 1.9) and epithelial pheno- acteristics of neurosecretory granules, mitochondria, and
type of foregut-derived organs (such as lungs, thymus, cytoplasmic lipid content.
and thyroid). Most neuroendocrine cells possess common and/or
Cytoplasm of the NET cells varies in amount and specific secretory products, their precursors, and share
staining characteristics. It is scant to indistinct in small histochemical characteristics.
cell carcinomas while in better-differentiated neuroen- It is interesting to note that there are morphologic
docrine neoplasms, it is variable from small to moder- overlaps between NETs of neural phenotype and foregut
ate amounts and occasionally abundant. It can be clear, epithelial phenotype. Amphicrine nature of cytoplasmic
pale to dense, eosinophilic, and granular. The cyto- expression is well known, particularly in appendiceal car-
plasm can be abundant, oncocytic type, amphophilic in cinoid, namely, adenocarcinoid (Fig. 1.3).
A B
Fig. 1.7: Cytologic Features of Well-differentiated Neuroendocrine Carcinomas. A: Typical saltpepper nuclear chro-
matin pattern. Note eccentric nuclei and rudimentary to short cytoplasmic processes and inconspicuous or absent
nucleoli. B: Syncytial tissue fragment of small, round cells with poorly defined cell borders, high N/C ratios, and striking
uniformity with no nuclear molding, favoring low-grade malignancy.

C
D
Fig. 1.7: (continued) C: Another pattern of neuroendocrine malig-

nancy, depicting very small but uniform cells, discrete, in groups,
and in syncytial tissue fragments as seen in carcinoid tumors. Note
coarsely granular chromatin and scant cytoplasm. D: These cells are
in syncytial tissue fragments, with coarsely granular, hyperchromat-
ic nuclei with some pleomorphism. Such an atypical pattern falls
between a low-grade neoplasm (carcinoid) and poorly differenti-
ated neuroendocrine carcinoma. E: Another example of cells from
a neuroendocrine carcinoma (atypical carcinoid) with cellular pleo-
E morphism and demonstrating typical saltpepper chromatin.
SECRETORY PRODUCTS Gastrin, ACTH, cholecystokinin, somatostatin, moti-

lin, vasoactive intestinal peptide
More than 17 different types of neuroendocrine cells pancreatic polypeptide (GI tract)
depending on their secretory products are known to exist Calcitonin, somatostatin, gastrin-releasing peptide
in the GI tract and pancreas. Some of these cells secrete (thyroid C cell)
more than one hormone. Somatostatin, leu- and metencephalin, calcitonin
(adrenal medulla)
Amine and Amine Precursors

Catecholamines (epinephrine and norepinephrine) HISTOCHEMISTRY
Serotonin (GI tract, mostly in midgut, accounting for
90% of body serotonin store) The use for traditional histochemical stains has decreased
over the years as a result of introduction of newer technol-
ogies. Development of antibodies for immunohistochemi-
Peptides
cal techniques and newer probes in molecular studies are
Prolactin growth hormone, ACTH, FSH, LH, TSH, favored over conventional histochemistry in diagnostic
MSH (adenohypophysis) cytopathology/surgical pathology practices.
Somatostatin, calcitonin (thymus)
Gastrin-releasing peptide (bombesin, calcitonin, soma-
Chromaffin Reaction
tostatin, leuenkephalin [lung])
Insulin, glucagon, pancreatic polypeptide, somatosta- When fresh tissue containing amine or amine precur-
tin (pancreas) sor is exposed to chromate (chromium salt, commonly a

A B
Fig. 1.8: Cytopathologic Features of Poorly Differentiated Neuro-

endocrine Carcinoma. A: Small cell carcinoma in bronchial brush-
ings with round, oval to short spindle cells, poorly defined cell bor-
ders, scant to indistinct cytoplasm, high N/C ratios, molded nuclear
borders, and karyorrhexis. B: The malignant cells are small, intense-
ly hyperchromatic with nuclear molding. C: Large cell neuroendo-
crine carcinoma with larger cells, high N/C ratios, scant to indistinct
cytoplasm, coarsely granular deep-staining chromatin with nucleoli.
These cells exhibit considerable pleomorphism, nuclear molding,
and stretch artifacts. Karyorrhexis and necrosis are often seen in
C the background.
A B
Fig. 1.9: Cytopathologic Features of Pheochromocytoma/Paraganglioma. A: FNA of a paraganglioma showing a pleo-
morphic cell pattern consisting of small, medium, and large-sized cells with round, oval, plasmacytoid to triangular, and
spindle shapes. Note eccentric nuclei and cytoplasmic processes. The nuclear chromatin is coarsely granular to compact.
B: This cytologic pattern presents predominantly plasmacytoid shapes with short cytoplasmic processes. The nuclear
chromatin is coarsely granular. Presence of nucleoli is not generally a feature of neuroendocrine neoplasms.

Fig. 1.11: A: Diazo reaction producing pigment when nitrous acid

reacts with amines. B: Argentaffin reaction with Fontana-Masson
technique. C: Argyrophilic reaction with Grimelius technique.
copper to silver salt in order to have silver ion impregna-

tion on the tissue. Certainly, all argentaffin-positive cells
Fig. 1.10: Chromaffin Reaction of a Carcinoid Tumor. Comparison
of chromaffin reactions with various chromate solutions. are also positive for argyrophilic stain but not all argyro-
philic cells are positive for argentaffin reaction. Most of
peptide-containing neuroendocrine cells are positive for
mixture of dichromate and chromate), one time used as a argyrophilic stain but often negative for argentaffin reac-
fixative (Henle, 1865), the tissue becomes yellow-brown tion. Many modified versions of argyrophilic reaction
in color (chromaffin reaction), presumably due to precipi- including Bodian, Sevier-Munger, Pascual, Grimelius,
tate of chromium dioxide. Fixatives containing potassium Churukian-Schenk stains are used to detect neuroendo-
dichromate such as Zenkers solution and Hellys fluid crine cells (Fig. 1.11).
have been tried with similar results (Fig. 1.10). Positive
chromaffin reaction was noted in adrenal medulla but was
Ferric Ferricyanide Reduction and
expanded to tissue containing polyphenols, aminophenols,
Azo Coupling Reaction
and polyamines. Mucosal tissues of the GI tract also gave
positive chromaffin reaction due to cells containing sero- These techniques have been infrequently used to demon-
tonin; hence, the term enterochromaffin cells was born. strate enterochromaffin cells, more likely argentaffin posi-
tive ones. However, argyrophilic-positive neuroendocrine
cells often fail to react with these stains (Fig. 1.11).
Silver Salt Reaction
Argentaffin Reaction. Masson (1914) first described
Formaldehyde-induced Autofluorescence
an affinity for silver salt in enterochromaffin cells in
appendiceal carcinoid. This argentaffin reaction on tis- Neuroendocrine cells containing biogenic monoamines
sues is often referred to as Fontana-Masson or Masson- such as catecholamine and serotonin (5-HT) using
Hamperl stain. Secretory products in enterochromaffin formaldehyde fixative or vapor are fluorescent when
cells were known to serve as a strong electron donor, viewed under the fluorescent microscopy as formalde-
reducing silver salt resulting in precipitates of free sil- hyde converts them into highly fluorescent compounds.
ver particles, mostly localized in the secretory granules Formaldehyde induced autofluorescence in normal and
in the cytoplasm of cells. On tissue sections, positive neoplastic neuroendocrine cells containing immunoreac-
result appears as black cytoplasmic granules. The positive serotonin (Fig. 1.12).
tive argentaffin reaction is mostly observed in carcinoid
tumors of small intestine and appendix, midgut-derived
bowel, presumably due to the serotonin content in this IMMUNOCHEMISTRY
carcinoid tumor (Fig. 1.11).
Neuroendocrine neoplasms of epithelial phenotype
Argyrophilic Reaction. Cellular product (neurosecretory exhibit different immunophenotypic expressions from
content) acts as a weak electron donor, requiring an addi- those of the neural phenotype with positive reactiv-
tional reducing agent such as hydroquinone, formalin, or ity for cytokeratins but generally negative reactivity for

processing of regulatory peptides. Other secretogranins

III, IV, V, and VI possibly in the granin family are also
identified.
Granule-associated enzymes and cytochrome b561
(chromomembrin B) are also localized in neuroendocrine
cells but are not used as a routine diagnostic tool in surgi-
cal pathology practice.
Synaptic Vesicle and Docking Proteins
Fig. 1.12: A: Formalin-induced autofluorescence in normal Kultsch- Synaptophysin, a calcium-binding protein in neuronal
itsky cells in GI mucosa. B: Formalin-induced autofluorescence in synaptic vesicles that is encoded by SYP gene, is widely
serotonin-producing carcinoid. distributed in the cytoplasm of neuroendocrine cells and
their corresponding tumors as well as synapses in neuro-
neurofilaments as contrasted to positive immunoreac- nal cells. Adrenal cortical cells also express synaptophysin.
tivity for neurofilaments but negative reactivity to cyto- Synaptic vesicle protein 2 (SV2) and vesicular mono-
keratins in neural phenotype, although there are some amine transporter 1 and 2 (VMAT 1 and 2) are also
overlapping features. found in neuroendocrine cells. Hindgut carcinoid is often
Immunohistochemical reactions for neuroendocrine not immunoreactive for chromogranin A but can be deco-
cells and their neoplasms target (1) their specific secretory rated with SV2. SV2 also expressed in GI tumors.
hormonal products, (2) cytoplasmic enzymes involved in
secretory production, (3) secretory granules, (4) synaptic
Other Markers
vesicles and docking protein, and (5) intermediate fila-
ments, receptor protein, and transcription factors. Intermediate filaments such as cytokeratin of certain
molecular weight and neurofilament, may be useful in
differentiation of morphologically similar tumors such as
Cellular Products
cytokeratin 20 in favor of Merkel cell carcinoma of the
Peptide hormones and amines. (Refer above to secretory skin over the metastatic pulmonary small cell undifferen-
products, page 8.) tiated carcinoma.
Neural cell adhesion molecule (CD56) plays a key
role in cell binding, migration, differentiation, and pro-
Cytoplasmic Enzymes
liferation and has a wide distribution in neuroendocrine
Aromatic L-aminoacid decarboxylase is distributed in cells.
most of neuroendocrine cells and their tumors. Other Somatostatin receptors are often overexpressed in
specific enzymes involved in tyrosine metabolism can be NETs. Radionuclide conjugates of synthetic analogs
localized in certain neuroendocrine neoplasms. have been used successfully for imaging and treatment of
Neuron-specific enolase (NSE) is present widely in tumors.
neuroendocrine cells and their neoplasm although its Thyroid transcription factor-1 (TTF-1) is a tissue-spe-
specificity is low. cific transcription factor that is expressed almost exclu-
Protein Gene Product 9.5 (PGP 9.5, ubiquitin carboxy- sively by normal thyroid and lung cells and by tumors
terminal hydrolase) involving degradation, denatured derived from these organs. These markers may be useful
protein, is expressed in many neuroendocrine cells and in determining specific sites of neuroendocrine neoplasms.
tumors. Caution should be exercised, since TTF-1 is not pres-
ent in squamous cell carcinoma or majority of mucinous
adenocarcinomas of the lung but can be seen in extrapul-
Dense Core Granules/Vesicles
monary small cell neuroendocrine carcinomas
Granin (chromogranin/secretogranin) is a major constitu- CDX2 transcription factor is expressed both in neu-
ent of neurosecretory granules and is a family of differ- roendocrine and nonneuroendocrine tumors of the
ent proteins including chromogranin A, chromogranin B GI tract.
(secretogranin I), and chromogranin C (secretogranin II), Frequently used markers in the diagnosis of neuroen-
whose role may be involved in packaging and/or docrine neoplasms are listed in Appendix.

ULTRASTRUCTURE
HEREDITARY NEUROENDOCRINE
TUMORS AND SYNDROMES:
The most important ultrastructural characteristic of
MOLECULAR STUDIES AND
neuroendocrine cells and their neoplasms is the pres-
CYTOGENETICS
ence of small electron dense core granules and synaptic
vesicles. These granules represent secretory products of
Several types of NETs are inherited as autosomal domi-
specific neuroendocrine cells, packaged in the cytoplasm
nant and are components of many syndromes. Some
to be discharged. Because of the endocrine property of
syndromes are more frequent than others and are summa-
cells in their mode of secretion, they tend to crowd the
rized in Table 1.1. This section highlights the molecular
basal (peripheral) portion of the cytoplasm (Fig. 1.2).
studies and cytogenetics involved. A detailed discussion is
Granules are discharged through displaced exocytosis.
beyond the scope of this atlas.
These granules vary in size ranging from 50 to 450 nm
and in shape in different tumor cells at different loca-
tions, presumably reflecting the different types of secre-
tory products. PHENOTYPIC EXPRESSION OF
Certain morphologic characteristics of neurosecre- NEUROENDOCRINE CELLS
tory granules are helpful in identifying the types in
organs such as pancreas, pituitary gland, and adrenal The genetic role governing neuroendocrine phenotypic
medulla. Some examples are pleomorphic granules expression is not clearly understood but appears to be
for serotonin, crystalloid inclusions for insulin, and involved in multiple complex pathways.
owl-eye appearance for norepinephrine and glucagon In the GI tract, a transcription factor involving early
(Fig.1. 13AC). development and differentiation of intestinal epithelium
A B
Fig. 1.13: Ultrastructural appearances of some neurosecretory

granules. A: Large numbers of pleomorphic neurosecretory granules
in serotonin-producing intestinal carcinoid. B: Typical neurosecre-
tory granules of insulin-producing cells showing crystalline cores
(arrows) with a wide halo beneath the limiting membrane (arrow-
heads). C: Adrenal medulla showing large clear granules with ec-
centrically placed dense core (arrows), a characteristic feature of
norepinephrine storage. D: Small slightly irregular granules of epi-
nephrine in pheochromocytoma.

TABLE 1.1. NEUROENDOCRINE NEOPLASMS IN HEREDITARY SYNDROMES
Organs/Sites for Neoplasms Associated Location of the Gene

Syndrome Inheritance with Syndrome (Gene Product)
MEN type 1 Autosomal dominant Pancreas, usually multiple, microadenomas, Mutation MEN1 gene in
mostly nonfunctional; functional tumors chromosome 11q13
may be gastrin or insulin-producing; anterior
pituitary (pituitary adenoma); parathyroid
glands (hyperplasia and adenoma); GI tract
NET (stomach and duodenum); gastrinomas
associated with Zollinger-Ellison syndrome;
thymic and bronchopulmonary carcinoids;
adrenal cortex hyperplasia
MEN type 2A Autosomal dominant Thyroid C-cell hyperplasia/medullary Germline mutation

carcinoma; adrenal pheochromocytoma; RET proto-oncogene on
parathyroid hyperplasia/adenoma chromosome 10q11.2
MEN type 2B Autosomal dominant Thyroid C-cell hyperplasia/medullary Germline mutation

carcinoma; adrenal pheochromocytoma; RET protooncogene on
parathyroid hyperplasia/adenoma; chromosome 10q11.2
ocular, oral, and GI neuromatosis and
ganglioneuromatosis; marfanoid habitus/
skeletal abnormalities.
Familial type medullary Autosomal dominant Thyroid C-cell hyperplasia/medullary Germline mutation
thyroid carcinoma carcinoma; RET protooncogene on
chromosome 10q11.2
von Hippel-Landau Autosomal dominant Pancreatic NET always nonfunctional; Germline mutation in von
disease renal cell carcinoma; central nervous Hippel-Lindau (VHL)
system (CNS)hemangioblastoma; tumor suppressor gene in
pheochromocytoma 3p25
von Recklinghousen Autosomal dominant Neurofibromas; duodenal somatostatinomas; Mutation NF1 GENE ON
disease pheochromocytoma 17q11.2
Familial paraganglioma- Autosomal dominant; 50% bilateral carotid body paragangliomas; SDHB, SDHC and SDHD
pheochromocytoma paternal transmission pheochromocytoma germline mutations
of the gene
SDHB, succinyl dehydrogenase B; SDHC, succinyl dehydrogenase C; SDHD, succinyl dehydrogenase D.
is CDX2. Differentiation into secretory stem cells is for bHLH-leading neuroendocrine differentiation, while
directed by Math1. Further differentiation into endocrine Hes1 serves as repressor for bHLH to differentiate cells
cells requires transcription factors, neurogenin 3 (ngn3) to Clara cells.
and neuroD/BETA2. Notch signaling leading pathway to
differentiate into enterocytes is known to rather repress
endocrine differentiation. TUMORIGENESIS
In the development of pancreatic endocrine cell, pan-
creas duodenum homeodomain protein 1 is required with Loss of chromosome arm 18q is a constant finding in
additional activation of ngn3 and neuroD/BETA2. the GI endocrine tumor, particularly in midgut carcinoid
In pulmonary neuroendocrine cells, proneuronal basic where as allelic loss on chromosome arm 11q is more fre-
helixloophelix (bHLH) network and notch signaling quently associated with foregut carcinoid. Other genetic
pathway appear to play an important role in neuroen- anomalies possibly associated with tumor progression
docrine differentiation. Mash 1/hASH1 is an activator have been described. Multiple endocrine neoplasia (MEN)

characterized by multifocal endocrine tumors affecting in addition to renal cell carcinoma and CNS heman-
parathyroid, endocrine pancreas, and anterior pituitary gioblastoma is due to germline mutation of VHL tumor
gland is due to mutation of the tumor suppressor gene suppressor gene.
MENIN on chromosome 11q13. Neurofibromatosis 1, which includes pheochromocy-
MEN type 2, manifested by multiple endocrine tumors toma and carcinoid tumors of upper GI tract in addition
involving thyroid (medullary thyroid carcinoma), adrenal to neurofibromatosis, is caused by mutation of NF1 gene
medulla, and parathyroid gland, is caused by germline in 17q11.2.
mutations of the RET protooncogene.
von Hippel-Lindau (VHL) syndrome characterized by
pheochromocytoma and pancreatic endocrine tumors
SUGGESTED READING
Bosman FT, Carneiro F, Hruben RH, et al. WHO Classification of Lloyd RV. Practical markers used in the diagnosis of neuroendocrine
Tumours of the Digestive System. 4th ed. Lyon, France: IARC tumors. Endocrine Pathol. 2003;14:293302.
Press; 2010. Lloyd RV, Douglas BR, Young WF. Diffuse neuroendocrine system.
DeLellis RA. The neuroendocrine system and its tumors: an In: King DW, Sobin LH, Stocker JT, et al., eds. Endocrine
overview. Am J Clin Pathol. 2001;115(suppl):S5S16. Diseases. Atlas of Non-Tumor Pathology. Washington, DC:
DeLellis RA, Dayal Y. The neuroendocrine system, Chapter 47. In: AFIP; 2002:259308.
Mills SE, ed. Histology for Pathologists. 3rd ed. Philadelphia, Moran CA, Suster S, Coppola D, et al. Neuroendocrine
PA: Lippincott Williams & Wilkins; 2007. carcinomas of the lung. A critical analysis. Am J Clin Pathol.
DeLellis RA, Lloyd RV, Heitz PU, et al. Pathology and Genetics 2009;132:206221.
of Tumors of Endocrine Organs. Lyons, France: IARC Press; Rosai J. The origin of neuroendocrine tumors and the neural crest
2004. saga. Mod Pathol. 2011;24:S53S57.
DeLellis RA, Tischler AS. The dispersed neuroendocrine cell Travis WD, Brambilla E, Muller-Hermelink HK, et al. Pathology
system. In: Kovacs K, Asa SL, eds. Functional Endocrine and Genetics of Tumours of the Lung, Pleura, Thymus and
Pathology. 2nd ed. Malden, MA: Blackwell Science; 1998: Heart. World Health Organization Classification of Tumours.
529549. Lyon, France: IARC Press; 2004.
Kloppel G, et al. The gastroenteropancreatic neuroendocrine cell Wick MR. Neuroendocrine neoplasia. Current concepts. Am J Clin
system and its tumors. The WHO Classification. Ann NY Acad Pathol. 2000;113:331338.
Sci. 2004;1014:1327.

APPENDIX
FREQUENTLY USED IMMUNOCHEMICAL
MARKERS FOR THE DIAGNOSIS OF
NEUROENDOCRINE NEOPLASMS
1. Neuroendocrine differentiation 3. Site specific
Chromogranin CDX2
Synaptophysin Thyroid transcription factor-1 (TTF-1)
Neuron specific enolase (NSE) 4. Adjunctive markers useful in differential diagnosis of

neuroendocrine differentiation
CD56
Intermediate filaments
CD57 (Leu7)
Cytokeratins (AE-1/AE-3, CAM 5.2, CK7, CK20)
2. Secretory products
Neurofilament proteins
Calcitonin
CD99
Serotonin
Somatostain
Parathyroid hormone
S100 protein
Pituitary hormones

2 TYPES OF CYTOLOGIC SPECIMENS
AND CYTOPREPARATIONS
Cytopathologic diagnosis of neuroendocrine neopla- such as balanced salt solution, or fixed in various grades
sia can be made by examining a variety of specimens of alcohols, or in commercial liquid fixatives such as
obtained from several body sites that represent both exfo- Saccomanno or Cytolyte and Cytorich.
liative and aspiration cytopathology. Frequently received The specimens may also be submitted as prepared
specimens include fine needle aspiration (FNA) biopsies smears, either from the fine needle aspirates prepared at
and the specimens from the respiratory tract, especially the site of procedure or the direct smears prepared from
for the diagnosis of pulmonary small cell neuroendocrine the endoscopic brushings or from scrapings of the lesions.
carcinomas. Table 2.1 lists various types of nongyneco- The smears (cell spreads) are also prepared from the sedi-
logic specimens with possible diagnostic entities pertain- ments of centrifuged liquid specimens such as bronchial
ing to neuroendocrine neoplasia. Table 2.2 lists common brush rinsings, bronchial washings, bronchoalveolar
sites for aspiration biopsy specimens. lavage, body cavity fluids, cyst aspirates, or needle rinses
Regardless of the specimen type, proper handling, following fine needle biopsy procedures.
optimal cytopreparatory techniques, and staining are Monolayered thin cell spreads are ideal for cytopatho-
absolutely essential and critical for rendering a mean- logic evaluation. Thick, bloody, uneven smears are unsat-
ingful diagnosis in the best interest of the patient. isfactory. Several techniques are described for preparing
Cytopreparation is the crux of cytopathology. Its impor- the smears; personal preference dictates the technique
tance cannot be overemphasized. Expertise of the cyto- used, quality of which is extremely variable.
pathologists or the skills of cytotechnologists are of no Liquid specimens such as body cavity fluids may be
use if they have to evaluate poorly prepared and poorly processed by conventional methods or with liquid-based
stained preparations. It leads to sheer frustration, espe- technology. Specimens collected in alcohol-based fixatives
cially when the cellular material is more than adequate are difficult to smear. Specimens collected in Saccomanno
but definite diagnosis cannot be offered as a result of fixative have produced good results in terms of cell block
suboptimal preparation. Poor cytopreparations may also preparations. Smears are difficult to make, as the fixed
lead to misinterpretations resulting in both false-positive cellular material cannot be spread evenly if at all. The
and false-negative diagnosis. exception is sputum collected in Saccomanno fixative,
Unlike surgical pathology, where the histologic prepa- which is processed by an entirely different technique.
ration (fixation, processing, and staining) is standard- The prepared smears are subsequently fixed either
ized, cytopathology laboratories utilize several different by air-drying or fixed in alcohols of various strengths
modalities for cytopreparatory techniques. There are con- or by using commercial spray fixatives depending on
siderable variations involving each and every step of cyto- the choice of stains. Prompt wet fixation is required for
preparatory technique, from specimen submission to the Papanicolaou stain to bring about the nuclear details,
final product (stained smear). for example, the saltpepper chromatin of neuroendo-
Specimens for cytologic evaluation include fine needle crine tumor cell nuclei (Fig. 2.1A). In the authors expe-
aspirates, body cavity fluids, specimens obtained by vari- rience, this nuclear pattern is best demonstrated with
ous endoscopic procedures such as bronchoscopy (smears spray-fixed, Papanicolaou-stained preparations. Slightest
from brushings, washings, or bronchoalveolar lavage), delay in fixing the smears for Papanicolaou staining will
cervical smears, urines, urinary bladder washings, etc. result in pale, swollen nuclei making the cytologic inter-
The specimens may be submitted, fresh and unfixed, pretation difficult (see Fig. 3.59). Compact dark-staining
fresh but collected in nonalcohol-based fluid medium nuclear chromatin, karyorrhexis, and nuclear molding are
17

18 Chapter 2: Types of Cytologic Specimens and Cytopreparations
TABLE 2.1. TYPES OF CYTOLOGIC SPECIMENS FOR THE DIAGNOSIS OF NEUROENDOCRINE TUMORS:
EXFOLIATIVE CYTOPATHOLOGY
Types of Specimens Possible Diagnostic Entities See Figure(s) and Chapter

Cerebrospinal fluid Medulloblastomas Figure 2.2
Neuroblastomas
Metastatic neuroendocrine carcinomas (small cell carcinomas)
Effusion fluids Metastatic neuroendocrine carcinomas Figures 2.32.8

Peritoneal/pelvic Carcinoid tumors (typical/atypical)
washings Islet cell tumors
Ovarian carcinoid tumors
Carcinoid tumors of the appendix
Small cell carcinomas (lung, GI tract)
Metastatic neuroblastomas
Metastatic peripheral neuroectodermal tumors (PNET)
Urine Neuroendocrine carcinomas (small cell carcinomas) Figures 12.1912.21
Sputum Neuroendocrine carcinomas (small cell carcinomas/large cell Figures 2.12, 3.46A3.48F
neuroendocrine carcinomas)
Bronchial brushings/ Neuroendocrine carcinomas Chapter 3

washings Carcinoid tumors (typical and atypical), small cell carcinomas
Bronchoalveolar lavage Large cell neuroendocrine carcinomas
Metastatic neuroendocrine tumors
Esophageal/gastric Neuroendocrine carcinomas

brushings Carcinoid tumors
Small cell carcinomas
Pancreatic and bile duct Neuroendocrine carcinomas Figures 2.10 and 2.11
brushings via ERCP Islet cell tumors
Small cell carcinomas
Cervical/vaginal smears Neuroendocrine carcinomas (small cell carcinomas) Figure 2.9
Scrapings of cutaneous Merkel cell carcinomas

lesions
Eye chambers washings Retinoblastoma
also best visualized in spray-fixed Papanicolaou-stained sections for immunostains, especially when neuroendo-
preparations (Fig. 2.1B). crine neoplasia is suspected.
The cell blocks are usually prepared, specimen permit- Several techniques exist for processing the cell blocks
ting. The term cell block refers to the examination of the including the commercial cell block processor. Most
sediment, blood clots, or grossly visible flecks of tissue neuroendocrine neoplasms require confirmation of
from cytologic specimens that are processed by paraffin the diagnosis via immunostains. Cell blocks are best
embedding and staining by hematoxylin and eosin. Small suited for the purpose. In the absence of the cell blocks,
tissue flecks must be wrapped in tissue paper and then Papanicolaou-stained smears can certainly be processed
placed in the cassette. Cell blocks are complementary to for immunostains.
the smears and allow extra slides to be cut for ancillary The staining methods used in cytopathology labora-
tests when special stains are anticipated. When submit- tories are varied as well. In general, Papanicolaou stain
ting a cell block for processing, it is prudent to place a is utilized for exfoliative cytopathology, for example,
note in the cassette for the histotechnologist to cut extra nongynecologic specimens. However, Papanicolaou,

Chapter 2: Types of Cytologic Specimens and Cytopreparations 19
TABLE 2.2. TYPES OF CYTOLOGIC SPECIMENS FOR THE DIAGNOSIS OF NEUROENDOCRINE

TUMORS: FNA BIOPSY
Types of Specimens Possible Diagnostic Entities See Figure(s) and Chapter(s)

Superficial Palpable Lesions
Cutaneous nodules Neuroendocrine carcinomas Chapter 11
Lymph nodes Metastatic neuroendocrine carcinomas Chapters 7, 8, 9, and 13

Thyroid Medullary carcinomas, paragangliomas
Parathyroid Parathyroid adenomas
Salivary gland lesions Small cell carcinomas, primary or metastatic
Breast Paragangliomas Chapter 15
Neck soft tissues
Deep-seated Lesions
Under Radiologic Guidance: Ultrasound;

Computerized Tomography
Lung Neuroendocrine carcinomas metastatic Chapter 3
neuroendocrine carcinomas from other
body sites
Mediastinum Thymic neuroendocrine carcinomas Chapter 6
Metastatic neuroendocrine carcinomas
from other body sites, primitive
Neuroectodermal tumors
Neuroblastomas, paragangliomas
Liver Metastatic neuroendocrine carcinomas
from other body sites Chapter 13
Retroperitoneum Paragangliomas
Adrenal glands Pheochromocytomas Chapters 14, 15
Bones Ewing sarcoma; metastatic neuroendocrine
carcinomas from other body sites Chapter 16; 3.28A and 3.28B
Under Endoscopic Ultrasound Guidance

Pancreas, peripancreatic lesions Pancreatic neuroendocrine tumors Chapter 5
Under Endoscopic Bronchial Ultrasound
Guidance
Hilar, mediastinal lesions, thymus Mediastinal lymph nodes for metastatic Chapters 3, 6
neuroendocrine carcinomas, thymic
carcinoids, neuroblastomas, PNET
Pituitary adenomas
Stereotactic biopsies of Intracranial PNET, neurocytomas, paragangliomas Figures 2.17A and 2.17B;
lesions and crush preparations Sinonasal tumors Chapters 10, 16, 17
Pituitary tumors
CNS tumors
hematoxylin and eosin, and Romanowsky stains are all The cytomorphology of the cellular components of
used for fine needle aspirates. The choice of stain depends any specimen tends to vary with fixation, different cyto-
on personal preference. Several variations of Romanowsky preparatory techniques, and type of stain used. Criteria
stains are available. The most commonly used one is com- based on one type of preparation may not be applicable
mercially available Diff-Quik. Papanicolaou stain is rela- to preparations that involve different methods of fixation
tively standardized. However, its quality control must be and different staining methods or different processing
carried out on a daily basis. technology (e.g., liquid-based technology).

A B
Fig. 2.1: A: Bronchial brushings of a carcinoid tumor. This is an excellent example of well-fixed and well-stained
cytologic preparation depicting classic saltpepper chromatin. B: Bronchial brushings, direct smears, from a small cell
carcinoma showing intensely hyperchromatic nuclei, and karyorrhectic debris.
The authors laboratory utilizes a commercial spray medulloblastoma, or poorly differentiated neuroendo-
fixative and Papanicolaou stain for all specimens includ- crine (small cell carcinomas) carcinomas with meningeal
ing rapid Papanicolaou stain at the site of fine needle involvement.
biopsy procedure. The spray fixation does not lyse the red
blood cells in the background. The intact red cells pres-
ent in the background serve as a guide for assessing the
nuclear as well as cell size. This important parameter is SEROUS EFFUSION FLUIDS, PERITONEAL/
lost when the specimen is fixed in 95% ethyl alcohol or PELVIC WASHINGS
any alcohol-based carrying fluid for liquid-based technol-
ogy since the red blood cells will lyse. The liquid-based Serous effusion fluids can harbor neuroendocrine carci-
technology is used routinely for cervical smears and noma cells originating from any body site (Figs. 2.3 to2.8).
urines. Conventional methods are used for most of the Some are more frequent, such as pulmonary small cell
nongynecologic specimens. However, many cytopathol- carcinomas (Fig. 2.6AC), than the others. Pancreatic
ogy laboratories have resorted to the use of liquid-based endocrine carcinomas as well as pulmonary well and mod-
technology for all types of specimens. The majority of the erately differentiated neuroendocrine carcinomas (typical/
illustrated images in this atlas represent spray-fixed and atypical carcinoid tumors) can also involve the serous cav-
Papanicolaou-stained material. ities (Figs. 2.3 to 2.5 and 2.7). The typical morphology of
Following sections describe application of each type of
specimen in the diagnosis of neuroendocrine tumors. The
reader can refer to the literature for detailed information
on the various cytopreparatory techniques and staining
methods.
CEREBROSPINAL FLUID
The specimen should be freshly submitted. Because of the

small amount and scant cellularity, cerebrospinal fluid
is best processed immediately upon the receipt, using
a cytocentrifuge. The diagnostic cells can be identified
(Fig. 2.2) in cases of meningeal involvement by malig- Fig. 2.2: Cerebrospinal Fluid. Exfoliated malignant cells from a
nancy. Examples are exfoliated cells from neuroblastoma, metastatic small cell carcinoma of the lung.

A
Fig. 2.3: AC: Peritoneal fluid containing cells of neuroendocrine tumor of the pancreas.
well to moderately differentiated neuroendocrine tumors neoplasia (Fig. 2.8AC; see Figs. 3.75 and 11.15). Their
is often altered in a liquid medium. The characteristic dis- cytomorphology in well-prepared cytologic preparations
persed cell pattern is usually not appreciated. Single small is diagnostic.
neoplastic cells often are obscured by mesothelial cells. In
addition, neuroendocrine carcinoma cells from atypical
carcinoids with considerable nuclear atypia may cluster
and mimic adenocarcinoma cells. Without a prior his- SPECIMENS FROM THE FEMALE
tory, these cells may be interpreted as adenocarcinoma. GENITAL TRACT
However, the characteristic cytomorphology when pres-
ent may lead to surprises. Two such cases are described Cervical/vaginal (Pap) smears are currently processed by
in Figure 12.13AG and Figure13.1AD. Exfoliation of liquid-based technology. Conventional methods offer best
poorly differentiated (small cell) neuroendocrine carcino- cytomorphology for small cell neuroendocrine carcino-
mas originating in lung, pancreas, or skin can demonstrate mas (Fig. 2.9A) as compared to the liquid-based prepara-
characteristic morphologic features of neuroendocrine tions (Fig. 2.9B).
A B
Fig. 2.4: A: Peritoneal fluid containing metastatic neuroendocrine tumor, grade II of the pancreas. The neoplastic cells
are pleomorphic and are suggestive of an adenocarcinoma. B: Pleural fluid showing metastatic pulmonary carcinoid
tumor. The neoplastic cells are in a thick and tight cluster with intensely hyperchromatic nuclei and do not appear to
present a neuroendocrine morphology. Without a history of previous endocrine neoplasm, the diagnosis may be difficult
and even with the history the diagnosis must be confirmed by immunostains.

Fig. 2.7: Peritoneal Fluidcontaining Cells of Goblet Cell Carcinoid

Tumor of the Appendix. These malignant cells (arrows) appear typi-
cally of glandular origin. Immunostains on the surgically excised
lesion confirmed both glandular and neuroendocrine features (see
Fig. 4.9).
Fig. 2.5: Peritoneal Washings Containing Cells of Neuroendocrine
Carcinoma of the Ovary. Note that the cytomorphology of these
cells is so characteristic that the cytologic diagnosis of neuroendo-
crine tumor was followed by reexamination of a surgically excised, and FNA biopsies of the gastric and esophageal mass
very large loculated cystic teratoma of the ovary and subsequent lesions or pancreatic/biliary mass lesions. Although the
detection of an ovarian carcinoid tumor. direct brushings of the gastric neuroendocrine tumors
may offer diagnostic results, the procedure is not widely
utilized in clinical practice. However, pancreatic and bile
SPECIMENS FROM THE duct brushings performed under endoscopic retrograde
GASTROINTESTINAL AND cholangiopancreatography (ERCP) can be very reward-
PANCREATOBILIARY TRACTS ing (Figs. 2.10 and 2.11). Fine needle biopsies of the solid
lesions are also performed successfully under endoscopic
Specimens from the gastrointestinal (GI) and pancreatobi- ultrasound guidance (EUS). The cytologic presentation
liary tracts include gastric, esophageal, or colonic brush- of the neuroendocrine tumor is quite characteristic and
ings of the lesions; pancreatic and bile duct brushings; offers a high diagnostic accuracy (see Chapter 5).
C
Fig. 2.6: Pleural Fluid Containing Metastatic Small Cell Carcinoma of the Lung. A: Syncytial tissue fragment of small
cell carcinoma cells. B: An onion-skin pattern is one of the characteristic presentations of pulmonary small cell carci-
noma cells in the serous fluids. C: These exfoliated small cell carcinoma cells demonstrate nuclear molding (arrows).
The chromatin, however, is finely granular.

Fig. 2.8: AD: Metastatic neuroblastoma cells in pleural fluid from

a 7-year-old child who presented with severe respiratory distress
and was found to have massive pleural effusion. The small undiffer- Fig. 2.9: Small Cell Carcinoma of the Uterine Cervix. A: Conven-
entiated malignant cells were subsequently proven to be metastatic tional. Cervical smear showing small cell carcinoma cells dem-
from a neuroblastoma. onstrating classic cytomorphology with saltpepper chromatin.
B: Cervical smear processed by liquid-based technology, showing
small cell carcinoma cells. Note that the cytomorphology of small
cell carcinoma is not as clear as that seen in a conventional smear.
SPECIMENS FROM THE RESPIRATORY
TRACT majority of carcinoid tumors are submucosal in location.
However, sputum can contain diagnostic cells originating
The respiratory tract offers several types of specimens from centrally located small cell carcinomas (Fig. 2.12).
for cytologic evaluation and diagnosis. They are: sputum,
bronchial brushings, bronchial washings, bronchoalveo-
lar lavage, and fine needle biopsies of pulmonary mass
lesions as well as mediastinal lesions. SPECIMENS OBTAINED VIA
Sputum is best submitted either fresh, unfixed or in BRONCHOSCOPY
Saccomanno fixative. Direct smears are prepared from the
fresh specimen while the specimen in Saccomanno fixative Following a bronchoscopic procedure, specimens are sub-
is processed by a special technique. Sputum samples are mitted in several ways. They include direct smears prepared
not useful in the diagnosis of bronchial carcinoid tumors, by brushing the bronchoscopically visible lesion, brush
as the latter are less likely to exfoliate in the airways, since rinsings, bronchial washings, and bronchoalveolar lavage,
A B
Fig. 2.10: A,B: Pancreatic duct brushings via ERCP showing characteristic cytomorphology of a neuroendocrine neo-
plasm with small to medium-sized cells, poorly defined cell borders, scant to indistinct cytoplasm, and high N/C ratios.
The chromatin is granular, sometimes saltpepper type. Note some nuclei contain nucleoli.

Fig. 2.13: Carcinoid tumor cells in direct smears of the bronchial

brushings, confirmed as an atypical carcinoid tumor following sur-
Fig. 2.11: Bile Duct Brushings via ERCP Showing Neuroendocrine gical excision.
Tumor of the Pancreas. Note the characteristic cytomorphology
characterized by round cells, with uniform nuclei, scant indistinct
cytoplasm, and granular chromatin.
SPECIMENS FROM THE URINARY TRACT
as well as specimens obtained via transbronchial parenchy-
mal or hilar/mediastinal lymph nodes (Figs. 2.13 to 2.15) Specimens from the urinary tracts are mostly voided
When properly prepared and stained, the direct smears urine samples, bladder washings, and brushings/washings
of the bronchial brushings offer the best results. The of the renal pelvis and ureters. The specimens should be
brush, as soon as it is withdrawn, should be immediately fresh and can be processed by using cytocentrifuge and
smeared on the slide in a circular motion over a smaller cytospin preparations or by liquid-based technology.
area such as the size of a nickel or a quarter and fixed Urine or bladder washings may yield small cell carcinoma
immediately. Dragging the brush from one end of the cells, on very rare occasions. Neuroendocrine tumors of
glass slide to the other will result in air-drying of the cel- the urinary tract are extremely rare.
lular material. Bronchial washings and bronchoalveolar
lavage should be processed like body cavity fluids.
Transbronchial mediastinal or parenchymal FNA
biopsies are processed as any FNA biopsy procedure (see SCRAPINGS AND FINE NEEDLE
below the section on FNA). ASPIRATION BIOPSIES OF THE
CUTANEOUS LESIONS
The possible settings for the diagnosis of neuroendocrine

tumors involving the skin and subcutis include Merkel
cell carcinoma and cutaneous metastases from known
neuroendocrine carcinomas (see Figs. 5.36 and 8.45). The
scrapings should be placed on the glass slide, and spread
using another slide, and immediately fixed and stained.
FINE NEEDLE ASPIRATION

BIOPSY SPECIMENS
The aspiration biopsy specimens are processed in several

different ways:
Fig. 2.12: Sputum often serves as the initial diagnostic method for
pulmonary malignancies, especially the centrally located lesions.
Small cell carcinoma cells usually exfoliate and present in streaks. Direct smears performed at the site of the proce-
These cells are variably preserved and are often diagnostic. dure, fixed by air-drying for Romanowsky staining

A B
Fig. 2.14: A: Small cell carcinoma with a well-preserved cytomorphology in direct smears of the bronchial brushings.
B: Bronchial washings showing cells of small cell carcinoma. Compare the cytomorphology of cells in direct smears to
those seen in a processed specimen.
method or wet-fixed for Papanicolaou stain. A rapid become a routine procedure in the diagnosis of mass
Papanicolaou staining method is suitable for on-site lesions. Advancement in radiologic techniques and neu-
evaluation. rosurgical procedures has made access possible to prac-
Rinsings of the needles following the aspiration biopsy tically every region of the CNS. Lesions in areas such
procedure(s); for cytopreparation in the laboratory, as suprasellar, intraventricular, brain stem, or pineal
where cell spreads and/or cytospin preparations, and regions, once thought to be inaccessible, are now eas-
the cell block(s) are prepared. ily biopsied. A proper smearing technique, thin smears,
The entire aspirate may be collected in a carrying fluid prompt fixation, and good staining are critical for micro-
and submitted to the laboratory for processing. scopic evaluation. The common techniques include
(i) crush preparation, (ii) smear preparation, and (iii)
touch imprints. The smears are routinely stained by
hematoxylin and eosin technique (Fig. 2.16). Other stains
CNS: INTRAOPERATIVE CONSULTATION: such as Papanicolaou may also be used.
CRUSH PREPARATIONS
Aspiration biopsy of the central nervous system (CNS)

lesions performed under stereotactic CT guidance has
SPECIMENS FOR ANCILLARY TESTING
For ancillary techniques such as histochemical and immu-

nochemical stains, the preferred cytopreparation is the cell
block. Immunostains can be performed on Papanicolaou-
stained smears if the cell blocks are not available. Bloody
smears should be avoided, as the red cells in the back-
ground will result in diffuse staining. Immunostains may
also be performed on specimens processed by liquid-
based technology such as Thin-Prep. The author has no
personal experience.
For molecular studies, a cell block is ideal. However,
diagnostic cells can be lifted off the smears when the cell
block is not available. Ultrastructural examination is
performed on tissues fixed in glutaraldehyde. When this
Fig. 2.15: FNA of a lymph node depicting metastatic pulmonary examination is anticipated prior to the processing, an ali-
small cell carcinoma. quot should be placed in a proper fixative.

A B
Fig. 2.16: A, B: Crush preparations of CNS lesions often present a diagnostic cellular pattern. A: Pituitary adenoma
(H&E). B: Central neurocytoma (H&E).
MICROSCOPIC EVALUATION OF determined by their cytoplasmic characteristics. The eval-

CYTOLOGIC SPECIMENS uation process should be methodical, taking into consid-
eration cellularity, evaluation of architectural patterns of
Microscopic evaluation of the cytologic specimens the tissue fragments, cellular features of the cells, nuclear
entails assessment of specimen adequacy and analysis of and cytoplasmic characteristics, and the background
cellular features as presented by the architecture of tis- features (Kini, 2011). To render a cytologic diagnosis,
sue fragments, their component cells, as well as discrete one requires familiarity with the basic concepts in cyto-
and groups of cells. Malignant criteria are appreciated pathology. Readers are requested to review the classic
in the nucleus, while the differentiation of the cells is monogram by Frost.
SUGGESTED READING
Dabbs D. Diagnostic Immunohistochemistry. 2nd ed. Philadelphia, methods, specimen submission, cytopreparation and staining.
PA: Churchill Livingstone; 2006. In: Kini SR. Color Atlas of Pulmonary Cytopathology.
Elsheikh TM, Kirkpatrick JL, et al. Comparison of thin Prep and New York, NY: Springer; 2002.
cytospin preparations in the evaluation of exfoliative cytology Gupta PK, Baloch ZW. Cytohistology: essentials and basic
specimens. Cancer. 2006;108:144149. concepts. In: Geisinger KR, Pitman MB, eds. Cytopathology of
Frost JK. The cell in health and disease. In: Ward GL, ed. Small Samples. New York, NY: Cambridge University Press;
Monographs in Clinical Cytology. 2nd ed. New York, NY: 2011.
SKarger; 1986. Kini SR. Differential Diagnosis in Exfoliative and Aspiration
Greenstreet P, Purslow MJ, Kini SR. Respiratory specimen types Cytopathology: Atlas and Text. 2nd ed. Philadelphia, PA:
for cytologic diagnosis. Specimen procurement, collection Lippincott Williams & Wilkins; 2011.

SECTION I
EPITHELIAL
TYPE
NEUROENDOCRINE
TUMORS

3 PULMONARY NEUROENDOCRINE
TUMORS
The spectrum of pulmonary neuroendocrine tumors morphologic features of neuroendocrine and negative
encompasses several types of neoplasms, some encoun- staining for neuroendocrine markers.
tered more frequently than the others. Their classification
is quite complex, as is the terminology (see Chapter 1, The traditional four-tier classification of pulmonary
Taxonomy). Not all neuroendocrine tumors are identified neuroendocrine neoplasms included (1) typical carci-
in cytologic specimens, especially the preneoplastic neu- noid tumor, (2) atypical carcinoid tumor, (3) LCNEC,
roendocrine lesions that are included in the most recent and (4) small (Appendix) cell carcinoma. This classifica-
World Health Organization/International Association for tion is retained by WHO (2004) and is followed in this
the Study of Lung Cancer (WHO/IASLC) (2004) classifi- chapter. The corresponding new terminology is given in
cation of the lung tumors. parenthesis.
The pulmonary NECs comprise up to 20% of all pulmo-
nary malignancies. They present a spectrum of morpho-
logic features ranging from benign-appearing, uniform
CLASSIFICATION OF PULMONARY cellular patterns to highly anaplastic ones. Their biologic
NEUROENDOCRINE TUMORS behavior likewise ranges from that of a protracted course
in typical carcinoid tumors to an aggressive one with a
The classification of pulmonary neuroendocrine tumors fatal outcome as seen in large cell neuroendocrine and
as a whole has generated considerable debate over the small cell carcinomas. Despite the differences in their bio-
years. A recent publication (Moran et al., 2009) consoli- logic behavior, pulmonary neuroendocrine tumors share
dated several recommended classifications and proposed several properties, such as morphologic features, growth
a three-tier one that is considered practical. patterns, presence of cytoplasmic secretory granules,
For typical carcinoid tumor, the recommended ter- expression of broad-spectrum neuroendocrine markers,
minology would be grade I neuroendocrine carcinoma and expression of specific peptide hormones and amines.
(NEC) or well-differentiated NEC or low-grade NEC See Table 3.10 for the summary of their clinicopathologic
with fewer than 3 mitotic figures per 10 high-power field and cytopathologic features.
(HPF) and only punctate necrosis.
For atypical carcinoid tumor, the recommended termi-
nology would be grade II NEC or moderately differen-
tiated NEC or intermediate grade NEC with more than PULMONARY CARCINOID TUMORS
3mitotic figures per 10 HPF and necrosis, usually com- (NEC, GRADE I, WELL-DIFFERENTIATED
edo-like necrosis. NEC, LOW-GRADE NEC)
Grade III NEC or poorly differentiated NEC or high-
grade NEC to include Typical carcinoid tumors are neoplasms with low
malignant potential, accounting for 1% to 2% of all
Small cell carcinoma (tumor with or without posi- primary lung cancers. The carcinoid tumors are derived
tive neuroendocrine markers and with more than 10 from neuroendocrine cells (Kulchitsky cells) known to
mitotic figures per 10 HPF and necrosis) exist in normal airways. Pulmonary carcinoid tumors
Large cell neuroendocrine carcinoma (LCNEC): tumor occur more frequently in women, at any age, with a
with positive neuroendocrine markers and tumor with mean of 55 years. There is no association with smoking.
29

30 Section I: Epithelial Type Neuroendocrine Tumors
The majority of patients harboring carcinoid tumors Spindle cell carcinoid tumors are unusual occurrences,
are asymptomatic. Those with centrally located tumors comprising 5% of all pulmonary carcinoid tumors. They
may present with hemoptysis, dyspnea, and postob- tend to be peripheral and are not anatomically related to
structive pneumonia. Roughly 2% to 7% of patients the airways. Spindle cell carcinoids are well circumscribed
with carcinoid tumors develop carcinoid syndrome and nonencapsulated. Tumor nodules may infiltrate into
resulting from increased production of serotonin. The the surrounding parenchyma. Microscopically, spindle cell
majority of the patients with carcinoid syndrome have carcinoids are composed of swirling bundles of short to
hepatic metastasis. Some patients with carcinoid tumors long spindle cells with round to oblong nuclei contain-
develop Cushing syndrome due to ectopic production ing saltpepper type chromatin, a characteristic feature of
of ACTH. Hilar lymph nodes are involved in roughly neuroendocrine tumors (see Fig. 3.15). Nucleoli are incon-
20% of the cases and 5-year disease-free survival is spicuous. The cells of spindle cell carcinoids have indistinct
reported to be 100%. In general, carcinoid tumors fol- cell borders and possess a modest amount of pale eosino-
low an indolent course. However, they do metastasize philic cytoplasm. Spindle cell carcinoid tumors may con-
to the distant sites, such as liver, bones, serous cavities, tain areas with morphology of a typical carcinoid tumor.
and skin.
CYTOPATHOLOGIC FEATURES
GROSS AND HISTOLOGIC FEATURES
The cytologic specimens for the diagnosis of carcinoid
Carcinoid tumors are equally located centrally, in the mid tumors include those obtained via bronchoscopy such as
portion of the lung, and peripherally. Central carcinoid bronchial brushings, washings, bronchoalveolar lavage,
tumors frequently present as a large endobronchial exo- and transbronchial fine needle aspiration (FNA) biopsies
phytic fleshy polypoid mass with a smooth surface pro- of the lung or mediastinal lymph nodes. Transthoracic
truding into the bronchial lumen (Fig. 3.1). The tumor fine needle biopsy procedure under computed tomog-
infiltrates the underlying tissues beyond the cartilage raphy (CT) guidance is sometimes utilized. Fine needle
plates into the surrounding parenchyma. The cut surface biopsies are also utilized for metastatic lesions from the
may appear tan-yellow to red. Gross necrosis and hemor- carcinoid tumors beyond the thoracic cavity. Spread to
rhage are not the features of a typical carcinoid tumor. the serous membranes may be diagnosed by examination
Peripheral carcinoid tumors are situated in the subpleural of the serous effusion fluids.
parenchyma and anatomically are not related to a bron- Carcinoid tumors rarely, if ever, shed cells spontane-
chus or a bronchiole. They are circumscribed, nonencap- ously in airways since they are mostly in submucosal
sulated, may be multiple, and tend to be smaller in size location. Sputum samples therefore are usually nondiag-
than the central carcinoids. nostic. Bronchial brushings, washings, bronchoalveolar
Histologically, the typical carcinoid tumor consists lavage, and aspiration biopsies are useful in establishing
of uniform small, round to cuboidal cells with varied the diagnosis. Bronchial carcinoid tumors in subepithelial
growth patterns that are characteristic of neuroendocrine locations cannot be sampled by brushing if the overlying
tumors (neuroendocrine growth pattern) (Fig. 3.2). The mucosa is intact. Bronchial brushings in such instances
neoplastic cells are compactly arranged in well-defined are often nondiagnostic.
alveoli, nests, islands, trabeculae, and ribbons separated The cells of typical carcinoid tumors present a distinc-
by delicate vascular stroma. Other morphologic patterns tive pattern (Table 3.1; Figs. 3.3 to 3.14). They occur
include pseudoglandular, rosettes, and sometimes palisad- as loosely cohesive cells in a dispersed fashion or form
ing arrangement at the periphery of the islands of tumor syncytial tissue fragments with various architectural
cells. Papillary pattern may rarely be encountered. The patterns such as nests, trabeculae, and occasionally
nuclei of the carcinoid tumor cells are round to oval with apseudoacinar or a pseudopapillary pattern. Strikingly
coarsely granular, stippled, saltpepper chromatin with uniform, small, round to cuboidal, sometimes plasma-
inconspicuous nucleoli. The cell borders are well-defined. cytoid cells with typical saltpepper chromatin granules
The cytoplasm is variable, scant to moderate, pale to are a hallmark of carcinoid tumors (Fig. 3.3B,C). The
eosinophilic, and at times clear. Several morphologic vari- nuclear membranes are smooth and regular. Nucleoli are
ants have been described, namely, oncocytic, clear cell, inconspicuous, and nuclear molding, stretch artifacts,
spindle cell, and melanotic. karyorrhexis, or mitotic figures are not present. The cells

Pulmonary Typical Carcinoid Tumors (Neuroendocrine Carcinoma, Grade I, Well-differentiated NEC,
Low-grade NEC)
Fig. 3.1: Gross photograph of an endobronchial tumor, partially ob-

structing the lumen, histologically confirmed as a typical carcinoid
tumor.
Spectrum of Histologic Features of Typical Carcinoid Tumors
A B
C D
Fig. 3.2: A: A medium-power view of a carcinoid tumor exhibiting a trabecular pattern, formed by uniform cuboidal
cells. Note that the tumor is richly vascular, with trabeculae separated by sinusoids (H&E). B: Another example show-
ing broad islands of uniform cells, separated by delicate stroma. There is a pseudoglandular pattern (H&E). C: Uniform
cuboidal cells, arranged around the capillaries with a pseudoacinar pattern (H&E). D: Branching trabeculae formed by
uniform cells with nuclei containing granular chromatin (H&E).

E F
Fig. 3.2: (continued) E: Higher magnification showing nests of car-

cinoid tumor cells (H&E). F: Histologic section of a typical car-
cinoid tumor with very small loosely cohesive cells with a diffuse
pattern (H&E). G: Histologic section of a carcinoid tumor showing
G large islands of neoplastic cells with a glandular pattern (H&E).
TABLE 3.1. CYTOPATHOLOGIC FEATURES OF CARCINOID TUMORS
Cellularity Variable, generally very cellular
Presentation Cells dispersed, isolated, in loosely cohesive groups or in syncytial tissue fragments as cords,
nests, or anastomosing ribbons with occasional acinar pattern; dispersed pattern more frequent
in brushings and washings; perivascular location with cells lining capillaries in FNA specimens
Cells Small, round to cuboidal; cell borders well to poorly defined; uniform, monotonous pattern with
occasional large pleomorphic forms; short to long spindle cells in some peripheral carcinoids
Nucleus Round to oval in typical carcinoids; oblong in spindle cell carcinoids; smooth nuclear borders;
N/C ratios generally high; chromatin coarsely granular, saltpepper type; nucleolus +/; no
nuclear molding; no karyorrhexis; mitoses absent; no stretch artifacts
Cytoplasm Scant to moderate; pale occasionally foamy (mistaken for adenocarcinoma), rarely oncocytic
Background Clean
Histochemistry Argyrophilic
Immunoprofile Reactive to neuroendocrine markers and (CAM5, 2 and CK7), TTF-1, CD56
Ultrastructure Membrane bound neurosecretory granules
Modified from Kini SR. Color Atlas of Pulmonary Cytopathology. New York: Springer-Verlag Inc.; 2002.

Chapter 3: Pulmonary Neuroendocrine Tumors 33
Spectrum of Cytopathologic Features of Typical Carcinoid Tumors (Figs. 3.3 to 3.14)
A B
Fig. 3.3: Bronchial Brushings, Direct Smear. A: Low-power view,

showing a cellular smear, with streaks of small uniform cells. B:
Higher magnification showing well-preserved cells with a strikingly
uniform size. These cells are round, with poorly defined cell borders
and indiscernible cytoplasm. The nuclei have granular (saltpep-
per) chromatin and nucleoli are conspicuous. Note that there is no
nuclear molding. C: Different field from the same case with cells
presenting similar cytomorphology. Note the typical saltpepper
C chromatin.
A B
Fig. 3.4: Typical Carcinoid Tumor. A: Direct smear of bronchial brushings showing a characteristic pattern of typical
carcinoid tumor with uniform, small cuboidal to round cells. Their nuclei are likewise uniform with granular chromatin
and inconspicuous nucleoli. The cytoplasm is indistinct. B: Another example of a typical carcinoid tumor identified in
bronchial brushings. The neoplastic cells are small round, resembling lymphoid cells with high N/C ratios. Note the
densely stained chromatin. Note the perivascular location of the neoplastic cells.

A B
Fig. 3.5: Typical Carcinoid Tumor. A, B: Direct smears of the bronchial brushings. The neoplastic cells are small to
medium-sized forming broad trabeculae. Their nuclei exhibit saltpepper chromatin, very typical of neuroendocrine
neoplasms.
A B
Fig. 3.6: Typical Carcinoid Tumor. Direct smears of the bronchial

brushings. A, B: The smears demonstrate tissue fragments of medi-
um-sized malignant cells with nuclei containing fine granular chro-
matin and prominent nucleoli. These cells possess appreciable pale
to foamy cytoplasm, suggesting adenocarcinoma. C: Staining for
chromogranin is strongly positive, confirming the neuroendocrine
C nature.

A B
Fig. 3.7: Typical Carcinoid Tumor. Direct smears of the bronchial

brushings. A, B: The smears demonstrate loosely cohesive, very
pleomorphic neoplastic cells ranging from medium to large, round
to polygonal containing abundant dense cytoplasm. Their nuclei
are eccentric with coarse chromatin. Some cells are binucleated.
Note the cytomorphology strongly resembles that of a medullary
thyroid carcinoma. No history of thyroid carcinoma was available.
C: Strong positive reactivity to chromogranin. Bronchial biopsy and
C the excision confirmed a carcinoid tumor.
A B
Fig. 3.8: Typical Carcinoid Tumor. Bronchial washings. A: This smear shows a large number of deeply stained cells
with poorly defined cell borders, indistinct cytoplasm with high N/C ratios. These cells resemble lymphoid cells. There
is no nuclear molding. A diagnosis of carcinoid tumor, however, was made earlier on the smears of the direct brushings.
B: Different field from the same preparations. The carcinoid tumor cells are small, few in numbers but well-preserved,
dispersed, obscured by bronchial epithelial cells, and can be easily overlooked (arrows). Note the classic morphology
seen in direct smears is not seen in washings or lavage.

A B
Fig. 3.9: Typical Carcinoid Tumor. FNA of a lung mass. A: Me-

dium-power view of a very cellular aspirate consisting of loosely
cohesive small cells. B: Higher magnification shows neoplastic cells
that are isolated in loosely cohesive groups and syncytial tissue frag-
ments. The cells are medium-sized with well to poorly defined cell
borders and scant to moderate cytoplasm. The nuclear chromatin is
granular to dense. Note the capillary traversing as seen by the elon-
gated endothelial cell (arrows). C: This field shows carcinoid tumor
C cells attached to the blood vessels (arrow).
Fig. 3.10: Typical Carcinoid Tumor. FNA of a lung mass show- Fig. 3.11: Typical Carcinoid Tumor. FNA of a lung mass. This syn-
ing a syncytial tissue fragment of uniform cuboidal to round cells cytial tissue fragment of neoplastic cells consists of cells with varied
with scant cytoplasm and typical nuclear pattern with saltpepper nuclear morphology. Some nuclei contain fine granular chromatin
chromatin. with occasional nucleoli suggest a possibility of an adenocarcinoma.

A B
Fig. 3.12: Typical Carcinoid Tumor. FNA of a lung mass. A, B: The aspirate is very cellular consisting of medium-sized
round cells with high N/C ratios. The nuclear chromatin is granular and the cytoplasm is scant. The excised tumor
confirmed the diagnosis of a typical carcinoid tumor.
Fig. 3.13: Typical Carcinoid Tumor. FNA of lung nodule showing

a syncytial tissue fragment of carcinoid tumor cells. The neoplastic
cells are small to medium-sized, with poorly defined cell borders.
The nuclei are uniform with granular chromatin. No nucleoli are
present. Note the pseudoacinar pattern (arrows), which may be mis-
interpreted as an adenocarcinoma (see Fig. 3.24D).
A B
Fig. 3.14: Typical Carcinoid Tumor. A, B: FNA of a lung mass. These well-defined syncytial tissue fragments of neo-
plastic cells that are cuboidal with uniform nuclei containing granular chromatin strongly suggest a carcinoid tumor,
but must be differentiated from an adenocarcinoma.

of typical carcinoid tumors in cytologic preparations ULTRASTRUCTURE

generally exhibit poorly defined cell borders and insig-
nificant or scant pale cytoplasm in contrast to histologic Ultrastructurally, the carcinoid tumor cells demonstrate
sections. Occasionally, the cells may exhibit pale some- dense core neurosecretory granules.
what bubbly cytoplasm resembling well-differentiated
adenocarcinoma cells (Fig. 3.8A,B) and are distinguished
by positive reactivity to neuroendocrine markers (Fig.
3.8C). Abundant granular cytoplasm in the oncocytic DIAGNOSTIC ACCURACY OF
variant of a carcinoid tumor has been misinterpreted PULMONARY CARCINOID TUMORS
as a granular cell tumor. On rare occasions, carcinoid
tumor cells may demonstrate a very pleomorphic cell Adequacy of the specimen and optimal cytoprepara-
pattern with an admixture of plasmacytoid and short tion are essential for an accurate cytologic diagnosis
spindle cells with cytoplasmic processes, reminiscent of (Figs. 3.21 to 3.23). Scant specimen with dispersed cells may
medullary thyroid carcinoma or a paraganglioma (Fig. result in a false-negative diagnosis (Figs. 3.22 and 3.23).
3.7A,B). The background is clean, and necrosis is absent. The carcinoid tumors are often submucosal in location
A perithelial pattern with carcinoid cells attached to the and do not yield to brushings. In bronchial washings, the
capillaries is quite characteristic in fine needle aspirates carcinoid tumor cells tend to shrink and are not easily
(Fig. 3.9C). recognized (Fig. 3.8). The bronchial epithelium overlying
The cytologic diagnosis of spindle cell carcinoid is a submucosal lesion may undergo squamous metaplasia.
offered from specimens obtained via fine needle biop- With varying degrees of cellular and nuclear atypia, the
sies, as these tumors are usually peripheral and may brushings of this metaplastic squamous epithelium may
not be accessible to brushings. As seen in histologic be interpreted as squamous carcinoma, resulting in a
sections (Fig. 3.15), cytologically, spindle cell carcinoid false-positive diagnosis (Fig. 3.21AC).
tumors demonstrate short to long spindle cells, discrete,
in groups, or in fascicles with cytoplasmic processes
(Figs. 3.16 to 3.18). Their nuclei are round to oblong
with smooth nuclear membranes containing typical
DIFFERENTIAL DIAGNOSES OF
saltpepper type chromatin and inconspicuous nucleoli.
PULMONARY CARCINOID TUMORS
The cytoplasm is pale and variable. Spindle cell carci-
The differential diagnostic possibilities of pulmonary car-
noid tumors may be associated with cells presenting the
cinoid tumors include all the lesions both nonneoplastic
cytomorphology of a typical carcinoid (Fig. 3.17D). In
and neoplastic that are composed of small cells as well as
aspiration biopsy specimens, the spindle cell carcinoid
other neuroendocrine tumors (Table 3.3).
tumors must be differentiated from neoplasms that
The benign entities, such as reserve cell hyperplasia,
are composed of spindle cells, for example, soft tissue
bronchial epithelial cell (columnar cell) hyperplasia, lym-
tumors, squamous carcinoma with spindle cell pattern,
phocytes, and alveolar lining cells (in washings and lavage
metastatic medullary thyroid carcinoma, malignant
specimens), may mimic the cells of carcinoid tumor (see
melanoma with a spindle cell pattern, and malignant
Figs. 3.61 and 3.63 to 3.65). Among the malignant neo-
mesothelioma with sarcomatous pattern (Table 3.2;
plasms with a small cell pattern, the diagnostic consider-
Figs. 3.19 and 3.20).
ations are other neuroendocrine tumors, namely atypical
carcinoid, small cell carcinoma, LCNEC, malignant lym-
phoma, adenoid cystic carcinoma, poorly differentiated
HISTOCHEMISTRY squamous carcinoma and its basaloid variant, primary
and metastatic adenocarcinomas, and malignant mela-
The cells of pulmonary carcinoid tumors are argyrophilic. noma (see Figs. 3.60 to 3.70). Pulmonary adenocarcino-
mas with asmall cell pattern may be extremely difficult
to differentiate from cells of carcinoid tumors (Fig. 3.24).
IMMUNOPROFILE In addition to the above diagnostic entities, neuroen-
docrine tumors involving the mediastinal structures such
The carcinoid tumor cells are reactive to neuroendocrine as thymus, lymph nodes, or soft tissues must be consid-
markers, cytokeratin and TTF-1, and CD56. ered in specimens obtained by transbronchial fine needle

Spindle Cell Carcinoid Tumor (Figs. 3.15 to 3.18)
A B
Fig. 3.15: A, B: Histologic sections of a spindle cell carcinoid tumor, showing a solid growth pattern with closely
packed spindle cells. Note the typical saltpepper chromatin (H&E).
Fig. 3.16: FNA of a Peripheral Lung Mass Diagnosed as a Spindle

Cell Type Carcinoid Tumor. Note the closely packed oblong to short
spindle cells with deeply staining granular chromatin. The N/C ra-
tios are high and the cytoplasm is insignificant.
A B
Fig. 3.17: FNA of a Lung Mass. A: Low-power view of a very cellular aspirate showing several tissue fragments.
Spindle cell pattern can be appreciated even at this power. B: Higher magnification showing delicate spindle cells with
elongated slender nuclei containing typical saltpepper chromatin.

C D
Fig. 3.17: (continued) C: This field depicts spindle cells containing saltpepper chromatin and a very uniform pattern.
Note a tissue fragment of benign mesothelial cells (arrow) that was a contaminant in this transthoracic fine needle
biopsy procedure. D: A different field from the same aspirate. Spindle cell carcinoid tumors may contain areas with
morphology of a typical carcinoid tumor as depicted in this image.
Fig. 3.18: Transthoracic FNA of a Peripheral Spindle Cell Carci-

noid Tumor. Note the tissue fragments of spindle cells with uniform
nuclei containing typical saltpepper chromatin.
biopsy. These include thymic carcinoids, thymomas and

thymic carcinomas, metastatic malignant melanoma, and
METASTATIC CARCINOID TUMORS TO
in younger patients, primitive neuroectodermal tumors
OTHER BODY SITES
(PNETs).
Pulmonary carcinoid tumors or NECs grade I metastasize
Since the various neuroendocrine tumors of the lung
to other body sites infrequently as compared to higher
share several of the morphologic features, their dif-
grade NECs. Common sites for metastases are hilar/
ferential diagnostic possibilities are similar with some
mediastinal lymph nodes, liver, bones, skin, and subcuta-
exceptions. In order to avoid repetition, the differential
neous tissues (Figs. 3.25 to 3.28). The cytomorphology of
diagnoses of carcinoid tumors are discussed in the section
the metastatic carcinoid tumors is usually characteristic
on Small Cell Carcinoma (Table 3.3 and see Table 3.9).
enough for their correct identification.

TABLE 3.2. CYTOPATHOLOGIC FEATURES OF CARCINOID TUMOR, SPINDLE CELL TYPE
Cellularity Variable, generally very cellular
Presentation Loosely cohesive cells and in tissue fragments with fascicular pattern or swirls
Cells Round to spindle shaped, well to poorly defined cell borders
Nucleus Round to oval; oblong; smooth nuclear borders; N/C ratios generally high; chromatin
coarsely granular, saltpepper type; nucleolus +/; no nuclear molding; no karyorrhexis;
mitoses absent; no stretch artifacts
Cytoplasm Scant to moderate; rarely oncocytic
Background Clean
Immunoprofile Reactive to neuroendocrine markers and (CAM5, 2 and CK7), TTF-1, CD56
Ultrastructure Membrane-bound neurosecretory granules
Differential Diagnoses Medullary thyroid carcinoma

Spindle cell thymoma
Malignant melanoma
Soft tissue tumors
Squamous carcinoma with spindle cell pattern
Differential Diagnoses of Spindle Cell Carcinoid Tumor (Figs. 3.19 and 3.20)
A B
Fig. 3.19: A, B: FNA of a pulmonary nodule from a patient with a history of medullary thyroid carcinoma. Without
the history, this neoplasm may be interpreted as a spindle cell carcinoid tumor.

A B
Fig. 3.20: A, B: FNA of malignant melanoma with a spindle cell pattern. Note the similarity to spindle cell carcinoid
tumor seen in Figure 3.17.
Typical Carcinoid Tumor; Diagnostic Problems (Figs. 3.21 to 3.23)
A B
Fig. 3.21: A: Histologic section of a bronchial biopsy with a sub-

mucosal tumor proven to be a carcinoid tumor (low power, H&E).
B: Higher magnification shows the overlying epithelium with squa-
mous metaplasia with significant atypia (arrows) (medium power,
H&E). C: Bronchial brushings showing a tissue fragment of atypi-
cal squamous epithelium. No neoplastic cells indicative of a carci-
noid tumor were identified. The carcinoid tumor being submucosal
with an intact overlying mucosa does not yield to the brush, result-
C ing in a false-negative diagnosis.

Fig. 3.22: FNA of a Lung Mass. The aspirate was poorly cellular. Fig. 3.23: A, B: Another example of a poorly cellular sample, re-
A: This field shows a small number of dispersed cells, which were sulting in a false-negative diagnosis. The neoplastic cells are few,
misinterpreted as lymphocytes. B: Another field revealed a tissue discrete, resembling lymphoid cells, and interpreted as such. Surgi-
fragment of uniform cells that closely resembles a mesothelium. The cal excision confirmed a carcinoid tumor.
surgically excised tumor was proven to be a typical carcinoid tumor.
PULMONARY ATYPICAL CARCINOID

TABLE 3.3 DIFFERENTIAL DIAGNOSES OF
TYPICAL CARCINOID TUMOR TUMOR (NEC, GRADE II, MODERATELY
DIFFERENTIATED NEC, INTERMEDIATE-
1. Lymphocytes from nonneoplastic lymphoproliferative GRADE NEC)
disorders
Atypical carcinoid tumors are uncommon neoplasms,
2. Reactive/hyperplastic bronchial epithelial cells behave more aggressively than the typical carcinoid
tumors, and comprise 11% to 24% of all pulmonary
3. Reserve cell hyperplasia
carcinoids. They are more frequent in males, occurring
4. Alveolar lining cells at an older age than typical carcinoid tumors. Roughly
20% of the cases demonstrate metastasis at the time of
5. Small cell carcinoma presentation, with regional lymph node involvement in
40% to 48% of the cases. Five-year survival is reported
6. Atypical carcinoid tumor to be 69%.
7. Large cell neuroendocrine carcinoma
8. Poorly differentiated squamous carcinoma and basaloid

variant
Grossly, atypical carcinoid tumors tend to be larger than
9. Poorly differentiated adenocarcinoma; primary or the typical carcinoids and may reveal areas of hemor-
metastatic rhage and necrosis.
Microscopically, atypical carcinoids show a spectrum of
10. Adenoid cystic carcinoma
findings that range from patterns resembling a typical carci-
11. Malignant lymphoma
noid to one that appears very similar to small cell carcinoma.
Histologic diagnosis of atypical carcinoid is based on
12. Thymoma the presence of one or more of the following four crite-
ria: (1) increased number of mitotic figures; (2) pleomor-
13. Thymic carcinoma phism or irregularity of the nuclei, prominent nucleoli,
hyperchromasia, and increased N/C ratios; (3) areas of
14. Thymic carcinoid
increased cellularity with disorganization of the architec-
ture; and (4) necrosis either punctate, focal, or large areas
15. Malignant melanoma
(Fig. 3.29). Except for cytologic atypia, features such as

Differential Diagnoses of Typical Carcinoid Tumor
A B
C D
Fig. 3.24: A, B: Carcinoid tumor cells in bronchial brushings. Note coarsely granular nuclear chromatin. C: Pulmonary
adenocarcinoma in a respiratory specimen. D: Pulmonary adenocarcinoma in FNA. Note the similarity between carci-
noid tumor cells (see Fig. 3.13) and adenocarcinoma cells, when the latter are of small size.
Metastatic Carcinoid Tumor to Other Body Sites (Figs. 3.25 to 3.28)
Fig. 3.25: AD: Metastatic Carcinoid Tumor. FNA of a subcutane-

ous mass over the shoulder in a patient with a history of pulmonary
carcinoid tumor.

A B
Fig. 3.26: Metastatic Pulmonary Carcinoid Tumor in Liver. A: FNA of a liver mass in a patient with a history of pul-
monary carcinoid tumor (same case as Fig. 3.4). B: Another example of a metastatic pulmonary carcinoid to the liver.
FNA of one of the multiple liver nodules with typical cytomorphology of carcinoid tumor.
Fig. 3.27: Metastatic Pulmonary Carcinoid Tumor in Serous Effu-

sion Fluid. This syncytial tissue fragment of neoplastic cells shows
morphology that is suggestive of an adenocarcinoma. The patient
had a history of carcinoid tumor of the lung with resection.
A B
Fig. 3.28: A, B: Metastatic Carcinoid Tumor in Bone. FNA of a lytic lesion of the bone in a patient with a history of
pulmonary carcinoid tumor. The aspirate was very cellular, consisting of several syncytial tissue fragments, consisting of
uniform round cells with high N/C ratios, and scant to indistinct cytoplasm. There is no nuclear molding, karyorrhexis
or necrosis. Immunostains on the cell block confirmed neuroendocrine nature.

Pulmonary Atypical Carcinoid Tumor (Neuroendocrine Carcinoma, Grade II, Moderately Differentiated NEC,
Intermediate-grade NEC)
A B
C D
Fig. 3.29: Histologic Features of Atypical Carcinoid Tumor. A: This carcinoid tumor composed of a mixed spindle and
round cell pattern shows punctate necrosis (arrowheads) (H&E). B: Higher magnification of (A). Also note occasional
mitosis (arrows) (H&E). C: This atypical carcinoid tumor shows large areas of necrosis (arrows) (H&E). D: Higher
magnification of (C) highlighting the necrotic foci (H&E).
punctate necrosis, mitotic rate, and invasive characteris- the cytologic pattern resembles either a small cell car-
tics cannot be appreciated in cytologic preparations. cinoma or an LCNEC (Figs. 3.31 to 3.34). There is
not a single cytologic feature that is characteristic of
an atypical carcinoid tumor. The immunoprofile and
CYTOPATHOLOGIC FEATURES OF the ultrastructural findings are similar to that of typical
PULMONARY ATYPICAL CARCINOID carcinoid tumors.
TUMORS
The exact cytologic typing of an atypical carcinoid is DIAGNOSTIC ACCURACY AND

not possible. Its cytologic interpretation ranges from a DIFFERENTIAL DIAGNOSES OF
typical carcinoid to a small cell carcinoma (Table 3.4, PULMONARY ATYPICAL CARCINOID
Figs. 3.30 to 3.34). When tumor cell necrosis is mini- TUMORS
mal, mitotic figures are sparse, and the overall archi-
tecture is maintained, the cytologic pattern strongly As noted earlier, atypical carcinoid is a histologic diag-
resembles that of a typical carcinoid tumor (Fig. 3.30). nosis. It cannot be specifically typed accurately from
With prominent nuclear atypia, mitosis, and necrosis, cytologic samples. However, the general diagnosis of

TABLE 3.4. CYTOPATHOLOGIC FEATURES OF

ATYPICAL CARCINOID LARGE CELL NEUROENDOCRINE
CARCINOMA (LCNEC), (NEC, GRADE III,
Cellularity Variable, generally very cellular POORLY DIFFERENTIATED NEC, HIGH-
GRADE NEC)
Presentation Cells dispersed, isolated, in loosely
cohesive groups, or in syncytial tissue LCNECs have been fairly recently recognized as a subtype of
fragments as cords, nests, or anastomosing
pulmonary neuroendocrine tumors, characterized by their
ribbons, occasional acinar pattern or
rosettes; perivascular arrangement of cells distinctive morphology such as neuroendocrine growth
in fine needle aspirates patterns, large cells with coarse nuclear chromatin, promi-
nent nucleoli, variable amounts of cytoplasm, high mitotic
Cells Small, round to cuboidal; well to rate, infarct-like necrosis, and neuroendocrine differentia-
poorly defined cell borders; high N/C tion both immunohistochemically and ultrastructurally.
ratios; uniform to varying degrees of
LCNECs are uncommon, with a reported incidence of
pleomorphism
<2% of all lung carcinomas. They occur in an age range
Nucleus Round to oval with smooth nuclear of 35 to 75 years with a median age of 64 years and are
membrane; saltpepper chromatin more common in males with a M:F ratio of 6:1. A strong
pattern and inconspicuous nucleoli to association with heavy cigarette smoking is well docu-
hyperchromatic nuclei with nuclear mented. LCNECs are aggressive neoplasms and metasta-
molding and nucleoli; mitoses +/;
size widely with 1-year survival of 58.5%.
karyorrhexis +/
Cytoplasm Variable, scant insignificant to moderate

amount GROSS AND HISTOLOGIC FEATURES
Background Clean to necrosis LCNECs may be centrally located but more frequently
are peripheral. Grossly, they range from small to large
bulky tumors, extensively replacing the lung parenchyma,
Immunoprofile Reactive to neuroendocrine markers and often with large areas of necrosis. Peripherally located
cytokeratin (CAM5, 2 and CK7), TTF-1, tumors often lack lymph node metastasis and do not
CD56 show evidence of systemic spread. The tumor is well cir-
cumscribed, nonencapsulated and may be multinodular.
Ultrastructure Membrane-bound neurosecretory granules The cut surface is yellow-white to tan.
Modified from Kini SR. Color Atlas of Pulmonary Cytopathology. New Histologically, LCNECs present typical neuroendo-
York: Springer-Verlag Inc.; 2002. crine growth patterns with large nests or well-defined
islands of neoplastic cells demonstrating peripheral
palisading or trabeculae and rosettes (Fig. 3.35). Large
areas of necrosis are frequent. The neoplastic cells are
a neuroendocrine tumor can be easily made, but the pleomorphic in size, round, spindle-shaped to polygonal
diagnostic specificity is low. The differential diagnoses cells with interspersed, very large forms. Their N/C ratios
of atypical carcinoid tumors are the same as for other are variable. The nuclear chromatin is coarsely granu-
pulmonary neuroendocrine tumors (see Tables 3.3, 3.8 lar. Macronucleoli may be a prominent feature. A very
to 3.10). high mitotic rate is characteristic of LCNECs (22 to 38
mitotic figures per 10 HPF), so also the large geographic,
infarct-like areas of necrosis. Azzopardi effect (DNA
staining and hematoxylin encrustation of the vessel wall)
METASTATIC ATYPICAL CARCINOID is uncommon.
TUMORS TO OTHER BODY SITES
Atypical carcinoid tumors metastasize more frequently CYTOPATHOLOGIC FEATURES

than typical carcinoid tumors do. The common sites are
hilar/mediastinal lymph nodes, liver, bones, serous mem- The cytologic specimens for the diagnosis of LCNEC
branes skin, and subcutaneous tissues. include those obtained via bronchoscopy and FNA biopsies.

Cytopathologic Features of Atypical Carcinoid Tumor (Figs. 3.30 to 3.34)
A B
Fig. 3.30: Atypical Carcinoid. A: Bronchial brushings of a histo-

logically proven atypical carcinoid showing a cytologic presentation
of typical carcinoid tumor. B, C: A different example of histologi-
cally confirmed atypical carcinoid tumor. These bronchial brush-
ing smears show small neoplastic cells with a pattern suggestive of
a small cell carcinoma. Note the coarsely granular chromatin and
suggestion of nuclear molding. The excised neoplasm was interpret-
ed as an atypical carcinoid tumor.
Note: It must be noted that the diagnosis of atypical carcinoid
is made only on histologic examination based on specific features
present in histologic sections and which cannot be evaluated on
cytologic specimens. The neoplasm may present a pattern of typical
carcinoid tumor but on histology may reveal focal necrosis. The
neoplasm may show considerable nuclear atypia, often suggesting
a small cell carcinoma but is confirmed as atypical carcinoid on
C histology.
A B
Fig. 3.31: A, B: Atypical Carcinoid. These two images depict a malignant cell population with pleomorphic round to
oblong nuclei, containing coarse, deep-staining chromatin suggesting the diagnosis of small cell carcinoma. Note scat-
tered necrotic cells (arrows). This tumor was confirmed histologically as an atypical carcinoid.

Fig. 3.32: Atypical Carcinoid. Bronchial brushings showing a syncy-

tial tissue fragment of small to medium-sized round cells with poorly
defined cell borders, indistinct cytoplasm, and large nuclei with high
N/C ratios. The nuclear chromatin is compact as seen in small cell
carcinomas. There is no nuclear molding or necrosis. The cytologic
differential diagnoses included carcinoid tumor and small cell carci-
noma. Surgical resection confirmed atypical carcinoid tumor.
Fig. 3.33: Atypical Carcinoid. Bronchial brushings showing small

to medium-sized round cells with poorly defined cell borders and
scant, indistinct cytoplasm. Their N/C ratios are high. The nuclear
chromatin is either coarsely granular or compact. Single cells with
similar morphology are seen in the background. The differential
diagnosis was carcinoid tumor and small cell carcinoma. Surgical
excision revealed an atypical carcinoid tumor.
A B
Fig. 3.34: A, B: Atypical Carcinoid. FNA of a lung mass. These syncytial tissue fragments are composed of closely
packed round cells with poorly defined cell borders, indistinct cytoplasm, and large nuclei with high N/C ratios. Note
an occasional rosette formation. The nuclear chromatin is compact as seen in small cell carcinomas. There is no nuclear
molding or necrosis. The cytologic differential diagnoses included carcinoid tumor and small cell carcinoma. Surgical
resection confirmed atypical carcinoid tumor.

Large Cell Neuroendocrine Carcinoma (LCNEC), (NEC, Grade III, Poorly Differentiated
NEC, High-grade NEC)
A B
Fig. 3.35: Histologic Sections. A: The neoplasm shows large islands of short spindle-shaped malignant cells with large
foci of central necrosis. The cells at the periphery of the islands demonstrate palisading of nuclei (H&E). B: Higher
magnification showing spindle and round malignant cells. Note prominent nucleoli (H&E).
TABLE 3.5. CYTOPATHOLOGIC FEATURES OF Cytologically, LCNEC presents (Table 3.5) a wide
LARGE CELL NEUROENDOCRINE CARCINOMA spectrum of cytomorphologic features ranging from one
that closely resembles a small cell carcinoma to large cell
Cellularity Variable, generally cellular undifferentiated carcinoma (LCUC).
The aspirates are generally very cellular (Figs. 3.36 to
Presentation Malignant cells discrete, in loosely
cohesive groups or in syncytial tissue
3.40). The malignant cells are isolated, in loosely cohesive
fragments without any architectural groups or aggregates and in syncytial-type tissue frag-
pattern or forming trabeculae and ments with trabeculae that often anastomose. An occa-
occasionally rosette formation; stretch sional rosette formation may be appreciated. Stretch
artifacts +/, peripheral palisading of artifacts involving individual cells are characteristic both
nuclei in tissue fragments +/
under low and high power (Figs. 3.39B and 3.41B). The
Cells Small- to medium-sized; pleomorphic malignant cells are less uniform than in small cell carci-
with frequent giant forms; round, oval noma and often display a pleomorphic pattern with cells
to polygonal, occasionally fusiform; N/C varying in size and shape ranging from round, oval to
ratios high; cell borders poorly defined polygonal forms. Fusiform cells are less frequent. Often
interspersed are large giant forms either with abundant
Nucleus Large, round, oval, occasionally fusiform;
cytoplasm (Figs. 3.36 and 3.39) or as naked nuclei, simi-
nuclear membranes sharp; chromatin
stippled, coarsely granular; nucleoli lar to those seen in other neuroendocrine tumors, such as
usually prominent; mitoses karyorrhexis pheochromocytomas or medullary thyroid carcinomas.
+; naked nuclei +; nuclear molding +/ The cell borders of LCNEC cells are poorly defined with
variable scant to appreciable amount of pale cytoplasm.
Cytoplasm Scant, indiscernible to moderate, pale The N/C ratios vary from high to low. The nuclei are
round, oval, and sometimes spindle shaped with regu-
Background Necrosis
lar nuclear membranes. The chromatin is dark staining,
Immunoprofile Neuroendocrine markers ; cytokeratin coarsely granular, and at times thready. Macronucleoli
(CAM5, 2 and CK7) +; TTF-1 +; CK20 are frequently present in contrast to small cell carcinoma.
; CD56 + Nuclear molding is often present, aiding in its differentia-
tion from LCUC, but this feature is less conspicuous than
Ultrastructure Membrane-bound neurosecretory in small cell carcinomas. Mitotic activity is brisk and con-
granules
spicuous. Karyorrhexis is common with fragmented nuclei

Cytopathologic Features of Large Cell Neuroendocrine Tumor (LCNEC) (Figs. 3.36 to 3.40)
A B
Fig. 3.36: FNA of a Lung Nodule. A: The malignant cells are very pleomorphic with an occasional giant form. The
cytoplasm of the cells is variable and many cells exhibit eccentric nuclei with coarsely granular chromatin. Nucleoli
are not appreciated. B: The malignant cells are large to giant sized and extremely pleomorphic with spindle forms. The
nuclear chromatin is coarsely granular. Nucleoli are occasionally seen. Note nuclear molding (arrows).
Fig. 3.37: FNA of a Histologically Confirmed LCNEC. These ma-

lignant cells are large, very pleomorphic with spindle and round
forms. The nuclear chromatin is deep staining, granular to compact
with occasional nucleoli.
A B
Fig. 3.38: A, B: FNA of an LCNEC of the Lung. The malignant cells are discrete, loosely cohesive, and pleomorphic
ranging from small to large. Note nuclear molding and stretch artifacts.

A B
C D
Fig. 3.39: FNA of an LCNEC of the Lung. AC: The malignant cells are mostly discrete and loosely cohesive, small to
large with high N/C ratios, and scant to indistinct cytoplasm. Note nuclear molding and stretch artifacts. Note necrotic
debris (arrow). D: Bronchial biopsy showing a malignant tumor (H&E). LCNEC confirmed on surgical excision.
A B
Fig. 3.40: FNA of an LCNEC of the Lung. A, B: These malignant cells are large, round to oval with high N/C ratios,
scant indiscernible cytoplasm, and appear undifferentiated. The nuclear chromatin is coarsely granular, saltpepper
type, and macronucleoli are very prominent. Occasional oblong and spindle-shaped nuclei with compact chromatin are
present. Neuroendocrine markers were positive.

C Fig. 3.40: (continued) C: Malignant cells stained with Romanowsky.
present within the tissue fragments. Foci of acellular debris

METASTATIC LARGE CELL
(Fig. 3.36B, 3.38A), when present, suggest tumor necrosis,
NEUROENDOCRINE CARCINOMAS TO
a characteristic feature of LCNEC.
OTHER BODY SITES
Common sites for metastatic LCNEC are hilar/mediasti-

IMMUNOPROFILE nal lymph nodes, liver, bones, adrenals, brain, skin, and
subcutaneous tissues.
LCNECs react positively to most of the neuroendocrine
markers and cytokeratin.
SMALL CELL CARCINOMA (NEC, GRADE

DIFFERENTIAL DIAGNOSES OF LARGE III, POORLY DIFFERENTIATED NEC,
CELL NEUROENDOCRINE CARCINOMA HIGH-GRADE NEC)
The differential diagnoses of LCNEC (Table 3.6) include Small cell carcinomas comprising up to 20% of all lung
small cell carcinoma, carcinoid tumors (both typical cancers are highly malignant neoplasms with a very
and atypical), LCUC, poorly differentiated adeno or aggressive clinical course and a high mortality rate. Most
squamous carcinomas, and several types of soft tis- patients have distant metastasis at the time of diagnosis. It
sue sarcomas that present an epithelioid cell pattern presents an age range of 32 to 79 years with a median age
(Figs. 3.41 to 3.43). of 60 years. There is a male preponderance and a strong
The cytologic differentiation between small cell association with smoking.
carcinoma and LCNEC can be extremely difficult and The majority of the patients are symptomatic with
to a large extent depends on sampling of the lesion. cough, dyspnea, wheezing, hemoptysis, chest pain, or
Both carcinomas share many morphologic features. postobstructive pneumonia. Mediastinal involvement is
Pleomorphism of the cells with frequent large forms common; small cell carcinoma may manifest as superior
and infrequent nuclear molding, prominent nucleoli venacaval syndrome or with recurrent laryngeal nerve
and, variable and sometimes abundant cytoplasm paralysis. Symptoms may be related to ectopic hormone
favors LCNECs. Most often, the final diagnosis is production by the tumor cells and also due to metastatic
made on histologic examination. Also the differentia- involvement of sites such as the central nervous system,
tion of LCNEC from LCUC can be extremely difficult bones, and liver. Chest radiographic findings are vari-
on Papanicolaou staining and without immunostains able and often show a perihilar mass or mediastinal
(Table 3.6). widening.

TABLE 3.6. CYTOPATHOLOGIC FEATURES DIFFERENTIATING LCUC AND LCNEC
Large Cell Neuroendocrine Carcinoma Large Cell Undifferentiated Carcinoma

Cellularity Variable, generally cellular Variable, generally cellular
Presentation Malignant cells discrete, in loosely cohesive groups Malignant cells discrete, in loosely cohesive groups
or in syncytial tissue fragments without any or in syncytial tissue fragments without any
architectural pattern or forming trabeculae and architectural pattern; stretch artifacts
occasionally rosette formation; stretch artifacts +
Cells Medium-sized; pleomorphic with frequent giant Medium to large; uniform to pleomorphic, giant
forms; round, oval to polygonal, occasionally forms +/; round to polygonal, spindle cells +/;
fusiform; N/C ratios high; cell borders poorly defined N/C ratios high; cell borders well to poorly defined
Nucleus Large, round, oval, occasionally fusiform; nuclear Large, round to oval; nuclear membrane sharp,
membrane sharp; chromatin stippled, coarsely smooth to irregular; chromatin fine to coarsely
granular; prominent nucleoli +/; mitoses +; granular with parachromatin clearing; nucleoli
karyorrhexis +; naked nuclei +/; nuclear +; micronucleoli/macronucleoli ; mitoses +;
molding + karyorrhexis ; naked nuclei ; nuclear molding
Cytoplasm Scant, indiscernible to moderate, pale; Scant to moderate, pale, lacy to dense;
emperipolesis emperipolesis +/
Background Necrosis can be extensive Necrosis with large bulky tumors; may be cystic
Histochemistry Alcian blue ; PAS with and without digestion Alcian blue +/; PAS with and without digestion +/
Immunochemistry Positive reactivity to neuroendocrine markers Negative reactivity except in cases with
neuroendocrine neuroendocrine differentiation
markers
Ultrastructure Neurosecretory granules present; no squamous or Neurosecretory granules generally absent; may be
glandular differentiation present in a small population; features of squamous
or glandular differentiation may be present
Modified from Kini SR. Color Atlas of Pulmonary Cytopathology. New York: Springer-Verlag Inc.; 2002.
Differential Diagnoses of Large Cell Neuroendocrine Carcinoma (Figs 3.41 to 3.43)
A B
Fig. 3.41: A: FNA of a LCUC of the Lung. Compare this with (B) showing cells of LCNEC. Except for stretch artifacts
in LCNEC, the cytomorphology in both cases appear similar.

A B
Fig. 3.42: A, B: Two Different Examples of LCUCs. Note that cytologic presentation can be identical to LCNEC.
A B
Fig. 3.43: A, B: FNA of a lung mass from a patient with a history of malignant melanoma containing discrete and loose-
ly cohesive, large round, malignant cells with high N/C ratios. Note prominent macronuclei. Their cytoplasm is scant.
These malignant cells from a metastatic malignant melanoma share morphologic features with both LCUC and LCNEC.
GROSS AND HISTOLOGIC FEATURES Necrosis may be minimal and some tumors may show
desmoplastic reaction. Azzopardi effect is often noted
Roughly 70% of cases of small cell carcinomas present (Fig. 3.45F). The malignant cells are small, round to fusi-
as a perihilar mass with extensive lymph node metastasis. form containing scant cytoplasm, finely granular nuclear
The tumor is white-tan, soft, and friable, frequently with chromatin, and absent or inconspicuous nucleoli. Nuclear
extensive necrosis. Small cell carcinoma is typically situ- molding is difficult to visualize in histologic sections. A
ated in a peribronchial location. Submucosal and circum- very high mitotic rate, sometimes exceeding 10 per HPF
ferential infiltrates may occur along bronchi. Bronchial is characteristic.
lumen may be obstructed (Fig. 3.44). A small number
of small cell carcinomas (5%) present as solitary (coin)
lesions. CYTOPATHOLOGIC FEATURES
Small cell carcinomas are characterized by extensive
necrosis. Their growth patterns consist of nests, streams, The specimens for cytologic diagnosis include sputum and
and ribbons with palisading of cells at the periphery of those obtained by bronchoscopy as well as by FNA biop-
the nests, occasionally rosettes may be formed (Fig. 3.45). sies of pulmonary lesions and mediastinal lymph nodes.

Small Cell Carcinoma (Neuroendocrine Carcinoma, Grade III, Poorly Differentiated NEC, High-grade NEC)
A B
Fig. 3.44: A: Gross photography at autopsy of a formalin-fixed lung showing an endobronchial tumor, almost complet-
ing occluding the lumen. B: Cut section shows a very large tumor with a fleshy lobulated surface. Histologic examina-
tion showed a small cell carcinoma.
Spectrum of Histologic Features of Small Cell Carcinoma
A B
C D
Fig. 3.45: A: Diffuse growth pattern showing sheets and lobules of small undifferentiated cells (H&E). B: Higher mag-
nification of small cell carcinoma comprised of small round, monomorphic, round to cuboidal cells. Their cell borders
are poorly defined. Nuclei are large and hyperchromatic (H&E). C: Large interconnecting islands composed of small
undifferentiated cells with peripheral palisading of nuclei (H&E). D: Small cell carcinoma with round and short spindle
cells. The nuclear chromatin is coarsely granular. Nucleoli are not apparent (H&E).

E F
Fig. 3.45: (continued) E: Small cell carcinoma consisting of a dif-

fuse, small, round cell population (H&E). F: Small cell carcinoma
exhibiting Azzopardi effect (arrows) (H&E). G: Small cell carcino-
G ma with a spindle cell pattern (H&E).
TABLE 3.7. CYTOPATHOLOGIC FEATURES OF SMALL CELL CARCINOMA
Cellularity Variable, scant (e.g., sputum) to overwhelmingly cellular in direct brushings smears or FNA
Presentation Malignant cells discrete, in aggregates or in syncytial tissue fragments usually without any architectural
patterns; crush artifacts may be extensive in direct smears of brushings or FNA; in sputum samples, often
present as single cells or in groups of two or three cells in a mucus streak
Cells Small, round, 3 to 3.5 times the size of a resting lymphocyte to slightly larger; oval to short spindle
shaped; cell borders poorly defined, often flush with the nucleus
Nucleus Round to oval; multinucleation not observed; N/C ratios very high; nuclear membranes smooth; nuclear
chromatin very coarsely granular to compact and deep-staining; nucleoli inconspicuous; nuclear molding
+; mitoses +; karyorrhexis +; stretch artifacts +
Cytoplasm Indiscernible to very scant; paranuclear vacuoles in Romanowsky-stained preparations
Background Dirty; necrosis; fragmented forms
Immunoprofile Neuroendocrine markers +; cytokeratin (CAM5, 2 and CK7) +; TTF-1 +; CK20 ; CD56 +

Spectrum of Cytopathologic Features of Small Cell Carcinoma (Figs. 3.46 to 3.58)
A B
C D
E F
Fig. 3.46: Small Cell Carcinoma Cells in the Sputum. A: The malignant cells are small with poorly defined cell borders
and inconspicuous cytoplasm. Their nuclei are ovoid with molded borders. The nuclear chromatin is dense. B: The malig-
nant cells present in a streak as isolated cells. Some are poorly preserved. They have poorly defined cytoplasm and deep-
staining chromatin. Nuclear molding is not conspicuous. C: Small cell carcinoma cells in the sputum. These malignant
cells are isolated (arrows), small and difficult to identify in the background of large numbers of squamous cells. Nuclear
molding can still be appreciated. D: Another example of small cell carcinoma cells in the sputum showing a small num-
ber of cells with hyperchromatic India Ink nuclei with molding. Note karyorrhexis and necrosis around the malignant
cells. E: Small cell carcinoma cells in the sputum, present in a streak with characteristic morphology. F: Remarkably well
preserved small cell carcinoma cells in the sputum arranged in a tissue fragment with characteristic cytomorphology.

A B
Fig. 3.47: Small Cell Carcinoma Cells in Bronchial Brushings. A: The cytomorphology of the carcinoma cells is well
preserved. The cells are loosely cohesive, medium-sized with poorly defined cell borders, scant indistinct cytoplasm, and
high N/C ratios. The chromatin is coarsely granular. Note nuclear molding. B: The brushings show a large syncytial
tissue fragment consisting of undifferentiated small cells. The morphology is best appreciated at the periphery where
the cells are better visualized.
A B
Fig. 3.48: Small Cell Carcinoma Cells in Bronchial Brushings. A: The malignant cells have molded deeply stained nu-
clei. Note bronchial epithelial cells in the background (arrow). B: A different field showing carcinoma cells and normal
respiratory epithelial cells (arrows). Compare the nuclear pattern of bronchial epithelial cells and small cell carcinoma
cells.
A B
Fig. 3.49: A, B: Small Cell Carcinoma Cells in Bronchial Brushings. These malignant cells are well preserved and show
molded nuclei. The chromatin is lighter. Karyorrhexis can be seen in the background.

A B
Fig. 3.50: Small Cell Carcinoma in Bronchial Brushings. A: Low-power view of a direct smear of bronchial brushings
showing marked cellularity. B: Higher magnification. Note the malignant cells are small, round, isolated, and in small
syncytial tissue fragments. Some have molded nuclei. The nuclear chromatin is granular with occasional micronucleoli,
while some have dense chromatin pattern. Extensive karyorrhexis can be seen in the background.
Fig. 3.52: Small Cell Carcinoma Cells in Bronchial Brushings.

Fig. 3.51: Bronchial Brushings. Small cell carcinoma cells with nor- These malignant cells are pleomorphic, larger, and may raise the
mal respiratory epithelial cells in the background. possibility of an LCNEC.
A B
Fig. 3.53: Small Cell Carcinoma. AE: The malignant cells collected in a liquid medium such as bronchial washings
tend to ball up and also undergo shrinkage. Compared to direct brushings, the malignant cells are less well preserved.

C D
E F
Fig. 3.53: (continued) F: Same case. Note excellent morphology seen in direct smears of bronchial brushings.
A B
Fig. 3.54: FNA, Lung Mass, Small Cell Carcinoma. A: Low-power view of an overwhelmingly cellular aspirate with a
large numbers of syncytial tissue fragments. Stretch artifacts can be appreciated even at this magnification. B: Higher
magnification showing small round cells with nuclear molding and coarsely granular chromatin.

A B
Fig. 3.55: A, B: FNA of a hilar mass depicting typical cytologic pattern of small cell carcinoma.
A B
Fig. 3.56: FNA of a Lung Mass. A: Medium-power view of a very

cellular aspirate consisting of interdigitating tissue fragments. The
spindle cell nature of the component cells is evident at this power.
Note the stretch artifacts. B: Higher magnification showing spindle
cells in fascicles. Their cell borders are poorly defined with scant cy-
toplasm. The N/C ratios are high. The nuclear chromatin is coarsely
granular and typical saltpepper type. C: A different field showing
round malignant cells with coarse chromatin, molding, and stretch
C artifacts.

A B
C D
E F
Fig. 3.57: Combined Small Cell and Squamous Carcinoma. A, B: Bronchial brushings showing malignant squamous
cells. C, D: Different fields showing malignant cells with typical cytomorphology of small cell carcinoma. E: Bronchial
biopsy confirmed squamous carcinoma (H&E). F: Also present were areas of small cell carcinoma (H&E).

A B
C D
Fig. 3.58: Combined Small Cell and Adenocarcinoma. A: Bronchial brushings depicting tissue fragment of small cell
carcinoma cells exhibiting typical cytomorphology. B: Lobectomy confirming small cell carcinoma (H&E). C: A dif-
ferent field from the bronchial brushings containing malignant cells with glandular differentiation, consistent with
adenocarcinoma. D: The lobectomy also revealed areas of adenocarcinoma (H&E).
The cytologic features of small cell carcinomas are very frequent, so are karyorrhexis and necrotic debris in the
characteristic (Table 3.7; Figs. 3.46 to 3.56). The cyto- background.
morphology is best appreciated in the direct smears of The cells of small cell carcinoma with scant cyto-
bronchial brushings when they are well fixed and stained plasm tend to air dry quickly, losing cellular details,
by Papanicolaou method. In sputum samples, the small often making cytologic interpretation very difficult. The
cell carcinoma cells often occur in streaks. They appear neoplastic cells are also very fragile and exhibit stretch
deeply stained and display nuclear molding. Degenerative artifacts that result from the smearing process (Figs.
changes are frequent (Fig. 3.46). 3.54 and 3.55B). The stretch or crush artifact seen in
The small cell carcinoma cells are small, 3 to 3.5 small cell carcinoma is described by some as a distinc-
times the resting lymphocyte, and present as discrete tive feature, generally involving single cells manifested
cells, in groups, or in varying sized syncytial tissue frag- by long streaks or fine strands of chromatic material
ments without any architectural patterns. The malig- extending from the nuclear membrane of otherwise
nant cells are round, oval to fusiform with molded intact carcinoma cells. It is also seen as elongated nuclei
nuclear borders. The nuclear chromatin is very coarsely with finely pointed ends. In contrast to small cell carci-
granular, staining with varying intensity, even appear- noma cells, the crush artifacts involving lymphoid cells
ing compact. Nucleoli are absent to inconspicuous. The both benign and malignant involve aggregates and not
small cell carcinoma cells contain scant to insignifi- individual cells, appearing as thick ropy strands of chro-
cant cytoplasm with almost invisible cell borders, giv- matic material that does not extend from the nuclei of
ing an appearance of naked nuclei. Mitotic figures are intact cells.

ULTRASTRUCTURE The cytologic diagnosis of combined small cell car-

cinomas depends on the sampling of the respective
Ultrastructurally, small cell carcinoma shows neurose- component(s).
cretory granules, approximately 100 nm in diameter, in
majority of the cases.
DIAGNOSTIC DIFFICULTIES AND
ACCURACY
IMMUNOPROFILE The diagnostic accuracy depends on adequacy of the
specimen, the type of specimen, and cytoprepara-
The immunoprofile of small cell carcinoma includes position including adequate fixation. The direct smears of
tive reactivity to neuroendocrine markers, cytokeratin, the bronchial brushings are generally cellular and best
and TTF-1. preserved. However, the technique of bronchoscopy,
brushings, and smearing the brush on glass slides are
operator-dependent and can result in poor fixation and
scant specimen (Fig. 3.59). The cells in bronchial wash-
COMBINED SMALL CELL CARCINOMA ings often ball up in three-dimensional structures and
tend to lose the characteristic morphologic features
Combined small cell carcinomas consist of a variable (Fig. 3.53AE).
component of squamous carcinoma or an adenocarci-
noma, generally comprising <5% of the carcinomas. The
combined small cell carcinomas are rare, with a reported DIFFERENTIAL DIAGNOSES OF
incidence of 1% to 3% of all squamous carcinomas. The PULMONARY SMALL CELL CARCINOMA
clinical characteristics are the same as for pure small cell
carcinomas. Histologically, these tumors exhibit small The typical cytomorphologic pattern of small cell car-
cell carcinoma with either adenocarcinoma or squamous cinomas offers high diagnostic accuracy provided the
carcinoma (Figs. 3.57 and 3.58). cytologic sample is adequately cellular and properly
Diagnostic Difficulties
Fig. 3.59: Diagnostic Difficulties Due to Scant and Air-dried Samples.

A: Bronchial brushings. These cells have poorly preserved nuclei.
They could represent either bronchial columnar cells or small cell
carcinoma. B: These cells from a poorly cellular bronchial brush-
ings smear are totally air-dried, precluding definite cytologic inter-
pretation.

TABLE 3.8. DIFFERENTIAL DIAGNOSES OF hyperplastic respiratory epithelial cells may be a prob-
SMALL CELL CARCINOMA lem (Fig. 3.63). Presence of tissue fragments of reserve
cell hyperplasia also constitutes a diagnostic pitfall
I. Nonneoplastic (Fig. 3.64A,B).
A. Lymphocytes
In bronchial washings and bronchoalveolar lavage,
Follicular bronchitis and bronchiolitis
Diffuse lymphoid hyperplasia the cells of small cell carcinoma tend to ball up and stain
Pseudolymphoma deeply. Their characteristic morphology is often com-
Reactive lymphadenitis promised. Karyorrhexis, stretch artifacts, and nuclear
B. Reactive bronchial epithelial cells molding are not always visualized (Fig. 3.53AE). They
C. Reserve cell hyperplasia resemble lymphoid cells or reserve cell hyperplasia.
D. Alveolar lining cells
II. Neoplastic
In transbronchial aspirates of the hilar or mediasti-
A. Neuroendocrine tumors nal masses, the differential diagnostic entities are sev-
Carcinoid tumors eral. Since most small cell carcinomas involve the hilar
Atypical carcinoid tumor lymph nodes, malignancies affecting the lymph nodes
Large cell neuroendocrine carcinoma in this area must be considered in the differential diag-
B. Poorly differentiated squamous carcinoma and
noses, for example, non-Hodgkin lymphoma (Figs. 3.71
basaloid variant
C. Poorly differentiated adenocarcinoma (primary or and 3.72), thymic carcinoid (Fig. 3.69A), thymoma
metastatic) (Fig. 3.69B) and thymic carcinoma (see Fig. 6.7), poorly
D. Adenoid cystic carcinoma differentiated adenocarcinoma (Figs. 3.67 and 3.68B) or
E. Malignant lymphoma (non-Hodgkin type) poorly differentiated squamous carcinoma and its basa-
F. Malignant melanoma loid squamous variant (Fig. 3.66), metastatic Merkel
G. Thymoma
H. Thymic carcinoma
cell carcinoma (see Fig. 11.14), LCNEC, and malignant
I. Thymic carcinoid melanoma.
J. Metastatic Merkel cell carcinoma In transthoracic aspirates, differential diagnoses include
K. PNET carcinoid tumors, atypical carcinoids, large cell neuroen-
Modified from Kini SR. Color Atlas of Pulmonary Cytopathology. New
docrine tumors, malignant lymphoma, pseudolymphoma,
York: Springer; 2002:87. poorly differentiated carcinomas, and, infrequently, adenoid
cystic carcinomas (Fig. 3.70) with a solid pattern either pri-
mary bronchial or metastatic, originating from the salivary
preserved. The differential diagnostic possibilities are glands. LCNECs, although of infrequent occurrence are
several and are also dependent on the type of specimens often difficult to differentiate from small cell carcinomas.
(Table 3.8). Their differentiating features are described in The same is true with carcinoid tumors (both typical and
Table 3.9 and illustrated in Figures 3.60 to 3.70. atypical).
In sputum, small cell carcinomas may be mistaken A diagnostic challenge that is often faced in the prac-
for lymphocytes and vice versa (Figs. 3.61 and 3.62). tice of cytopathology is differentiation between malignant
The degenerated discrete malignant cells may not exhibit lymphoma and small cell carcinoma especially in fine nee-
nuclear molding and must also be differentiated from dle aspirates (Figs. 3.71 and 3.72). Immunocytochemical
pyknotic nuclei of the respiratory epithelial cells (Fig. studies and flow cytometry are essential. Currently, molec-
3.63E). However, there are not too many malignant neo- ular studies can be of diagnostic value. In transbronchial
plasms whose exfoliated cells in sputum pose differen- aspirates, reactive or hyperplastic epithelium or reserve
tiating problems from small cell carcinoma. Diagnostic cell hyperplasia may cause diagnostic difficulties. Reactive
difficulties may be experienced with malignant lymphoma lymphadenitis involving the mediastinal lymph nodes or
(Fig. 3.62) and with cells of poorly differentiated squa- follicular bronchitis are also diagnostic challenges.
mous carcinomas with a small cell pattern (Fig. 3.66A).
In bronchial brushings, small cell carcinomas must be
differentiated from other neoplasms that are composed
of small cells such as typical and atypical carcinoid METASTATIC SMALL CELL CARCINOMA
tumors, LCNEC (Fig. 3.60), and poorly differentiated TO OTHER BODY SITES
squamous carcinomas, including the basaloid variant
(Fig. 3.68), adenocarcinomas (Figs. 3.67 and 3.68), and Small cell carcinomas tend to be widely metastatic,
rarely adenoid cystic carcinoma (Fig. 3.70). Reactive and involving regional and distant lymph nodes, pleura and

TABLE 3.9. DIFFERENTIAL DIAGNOSES OF SMALL CELL CARCINOMA, CYTOPATHOLOGIC FEATURES
Diagnostic Entity Cytopathologic Features See Figure(s)

Small cell carcinoma Neoplastic cells present isolated, in loosely cohesive groups and in syncytial Figures 3.46
tissue fragments without any architectural patterns; malignant cells often 3.57
present in mucus streaks in sputum; size small, 2 to 2.5 times the lymphocytes;
high N/C ratios; nucleus round, oval to fusiform; coarsely granular, deep-
staining chromatin; nucleoli inconspicuous to absent; nuclear molding
characteristic; stretch or crush artifacts of nuclei; karyorrhexis +; mitoses
+; indiscernible cytoplasm; necrosis in the background +/; immunoprofile:
cytokeratin +; neuroendocrine markers +; TTF-1 +; p63 ; LCA
Benign
Follicular bronchitis, Mature lymphocytes in sputum in mucus streaks; polymorphic lymphoid Figure 3.61
pulmonary lymphoid cell population with follicular center cells, tingible body histiocytes, and
hyperplasia; pseudolymphoma; plasma cells in other types of respiratory specimens; no nuclear molding;
hilar/mediastinal reactive no stretch artifacts; no karyorrhexis or necrosis; immunoprofile: LCA +,
lymphadenopathy (FNA) polyclonal
Reactive/hyperplastic Cells predominantly in tissue fragments; round to cuboidal when viewed Figure 3.63
bronchial epithelial (columnar) enface and columnar on profile; variable cytoplasm; N/C ratios high;
cells round to oval nuclei with smooth nuclear membranes; finely granular
chromatin; micronucleoli/macronucleoli; no nuclear molding; no stretch
artifacts; mitoses rare; no karyorrhexis
Reserve cell hyperplasia Only in tissue fragments; single cells are difficult to identify; often attached
to the strips of columnar cells in basal location; compactly arranged;
poorly defined cell borders; indiscernible cytoplasm with high N/C ratios;
minimal nuclear molding; dense staining, compact nuclear chromatin;
nucleoli ; no mitosis; no karyorrhexis; no stretch artifacts
Alveolar lining cells In tissue fragments; usually recognized easily because of uniformity;
small cell size; scant cytoplasm; no nuclear molding; coarsely granular
chromatin; nucleoli ; no mitosis; no karyorrhexis; no stretch artifacts
Malignant
Pulmonary carcinoid tumor Carcinoid tumor cells generally do not exfoliate in sputum; neoplastic cells Figure 3.60A
(typical) discrete or in groups with a dispersed pattern or in syncytial tissue fragments,
forming cords, nests, trabeculae, ribbons or acinar pattern; cells strikingly
uniform, small, round to cuboidal; occasional binucleation; nuclei round
to oval, with smooth nuclear membranes; stippled, coarsely granular, salt
pepper type chromatin; nucleoli +/; no nuclear molding; no stretch artifacts;
no mitosis; cytoplasm scant and variable; may be moderate; no necrosis; no
karyorrhexis; immunoprofileneuroendocrine markers +; cytokeratin +
Atypical carcinoid Cytomorphology ranges from that of a typical carcinoid tumor to Figure 3.60B
that of a small cell carcinoma; diagnosis made on histologic criteria;
immunoprofileneuroendocrine markers +; cytokeratin +
Large cell neuroendocrine Most often encountered in FNA specimens; cells isolated, in loosely Figure 3.60C
carcinoma cohesive groups and in syncytial tissue fragments with no architectural
patterns; peripheral palisading of nuclei +/; cells variable in size, generally
larger than those of small cell carcinomas; considerable pleomorphism
with giant forms; cytoplasm variable; high N/C ratios; nuclei pleomorphic,
round, oval or fusiform; coarsely granular chromatin; nucleoli very
prominent; nuclear molding+; mitosis frequent; stretch artifacts +; necrosis
+; immunoprofileneuroendocrine markers +; cytokeratin +

TABLE 3.9. DIFFERENTIAL DIAGNOSES OF SMALL CELL CARCINOMA, CYTOPATHOLOGIC FEATURES

(continued)

Poorly differential squamous Cells isolated, in loosely cohesive groups or in syncytial tissue fragments, Figure 3.66A,C
carcinoma and basaloid no architectural patterns; cells round, small in size, similar to or slightly
squamous variant larger than small cell undifferentiated carcinoma; mild pleomorphism;
scant cytoplasm; high N/C ratios; smooth to irregular nuclear membranes;
coarsely granular chromatin; nucleoli often conspicuous; no molding;
no stretch artifacts; mitoses frequent; necrosis +/; immunoprofile:
neuroendocrine markers ; TTF-1 ; cytokeratin +; p63 +
Poorly differentiated Cells isolated, in loosely cohesive groups, or in syncytial tissue fragments;, Figures 3.67 and
adenocarcinoma primary or no architectural patterns; cells round, small in size, similar to or slightly 3.68
metastatic larger than small cell undifferentiated carcinoma; mild pleomorphism;
scant cytoplasm; high N/C ratios; smooth to irregular nuclear membranes;
coarsely granular chromatin; nucleoli often conspicuous; mitoses
frequent; necrosis +/; immunoprofile: CEA +; CK7 +; TTF-1 +; p63 ;
neuroendocrine markers
Adenoid cystic carcinoma Cells mostly in tissue fragments with three-dimensional pattern with Figure 3.70
or without enclosed spaces presenting a sieve-like pattern; spaces
contain acellular material, bright magenta in Romanowsky-stained
preparation; cells very small, tightly packed; poorly defined cell boarders;
scant, indiscernible cytoplasm; high N/C ratios; nuclei round to oval;
monomorphic; no nuclear molding; smooth nuclear membranes; granular
chromatin; nucleoli +/; background clean, may contain acellular material;
immunoprofile: CEA ; cytokeratin ; S100 protein; +; neuroendocrine
markers
Malignant lymphoma Discrete, immature lymphoid cells; no follicular center cells or tingible Figures 3.62A,C
body histiocytes; finely granular chromatin with micronucleoli/
macronucleoli; no nuclear molding; karyorrhexis +; mitoses +; necrosis
+/; immunoprofile: LCA +; CEA ; B or T cell markers +; neuroendocrine
markers
Thymoma Differential diagnosis to be considered only for transbronchial FNA 3.69B

of mediastinal lesions; large population of mature lymphoid cells
obscuring neoplastic epithelial cells occurring singly, in groups, or
tissue fragments; poorly defined cell borders; pale cytoplasm and bland
nuclei; ultrastructural findings of perinuclear garland of tonofilaments;
immunoprofile: cytokeratin +; neuroendocrine markers
Thymic carcinoid Differential diagnosis to be considered only for transbronchial FNA Figure 3.69A
of mediastinal lesions; cytopathologic features similar to pulmonary
carcinoid tumors
Thymic carcinoma Malignant cells, isolated, in groups or in syncytial tissue fragments; Figure 6.7
cytoplasm scant; no differentiating features; high N/C ratios; granular
chromatin; prominent nucleoli; neuroendocrine markers
PNET Dispersed cell population; syncytial tissue fragments; Homer-Wright Figures 13.28,
rosettes frequent; small to slightly larger; poorly defined cell borders; 17.5AC,
high N/C ratios; unipolar cytoplasmic tags or processes +/; spindle 16.2216.24
forms in 10%20% of the cases; round to oval; smooth to irregular
nuclear membranes; chromatin fine to coarsely granular, saltpepper type;
micronucleoli +; mitoses +/; molding +/; scant, cytoplasmic; CD99 +;
neuroendocrine markers +; reciprocal translocation between the long arms
of chromosomes 11 and 22 [t(11:22)q24:q12]

TABLE 3.9 DIFFERENTIAL DIAGNOSES OF SMALL CELL CARCINOMA, CYTOPATHOLOGIC FEATURES

(continued)

Merkel cell carcinoma Cells isolated, in loosely cohesive groups or in syncytial tissue fragments Figures 6.11 and
(metastatic) without any architectural patterns; cells small, round to oval; high N/C 11.14
ratios; cell borders poorly defined; nucleus round to oval; irregular nuclear
membranes; molding +; coarsely granular chromatin; inconspicuous
nucleoli; mitoses +; karyorrhexis+; stretch artifacts +; indiscernible
cytoplasm; immunoprofile: neuroendocrine markers +; cytokeratin +; TTF-
1 ; CK20 +
Malignant melanoma Cells discrete, small size with or without tailing of the cytoplasm; fine
brownish dusting of the cytoplasm +/; scant cytoplasm; high N/C ratios;
granular chromatin; nucleolus prominent; no nuclear molding; mitoses
+/; necrosis +/; immunoprofile: neuroendocrine markers ; CEA ;
cytokeratin ; S100 protein +; HMB 45 +; Melan A +
Modified from Kini SR. Color Atlas of Pulmonary Cytopathology. New York: Springer; 2002:87.
Differential Diagnoses of Small Cell Carcinoma (Figs. 3.60 to 3.70)
A B
C D
Fig. 3.60: Neuroendocrine Carcinomas. The four subtypes of NECs present overlapping features and are not always
accurately typed from cytologic samples. A: Carcinoid tumor. B: Atypical carcinoid. C: Large cell neuroendocrine car-
cinoma. D: Small cell carcinoma.

A B
Fig. 3.61: Lymphoid Proliferations versus Small Cell Carcinoma. A: Sputum sample showing discrete well-preserved
lymphocytes. B: Bronchial washings containing a large number of lymphoid cells proven to be follicular bronchitis.
A B
C D
Fig. 3.62: Lymphoid proliferations versus small cell carcinoma. A: Chronic lymphocytic leukemia in FNA specimen.
B: Small cell carcinoma cells. C: FNA of lung showing discrete malignant lymphoma cells without nuclear molding or
stretch artifacts. D: Small cell carcinoma cells for comparison.

A B
E
Fig. 3.63: Small Cell Carcinoma versus Reactive Respiratory Epithelial Cells. A: Bronchial brushings showing respira-
tory epithelial cells with uniform round nuclei, high N/C ratios. Their chromatin is granular. These cells may be misin-
terpreted as either a carcinoid tumor or small cell carcinoma. B: Bronchial brushings showing small cell carcinoma cells.
These cells are pleomorphic with nuclear molding (arrows). Note the similarity to A. C: Bronchial brushings showing
small cell carcinoma cells with poorly defined cell borders, insignificant cytoplasm, and molded nuclei. Their chromatin,
however, is finely granular and mimics respiratory epithelial cells. D: Bronchial brushings with benign reactive respira-
tory epithelial cells. Note their uniformity. The crowding and overlap may lead to misinterpretation. E: Degenerating
respiratory columnar epithelial cells with elongated naked nuclei (arrows) may lead to misinterpretation.
C
Fig. 3.64: Small Cell Carcinoma versus Reserve Cell Hyperplasia. A, B: Bronchial washings showing tissue fragments
of reserve cells mimicking small cell carcinoma. C: Bronchial brushings showing a tissue fragment of crowded, over-
lapped small, uniform cells with compact chromatin, poorly defined cell borders and indistinct cytoplasm, and repre-
sent reserve cells.

Fig. 3.65: Small Cell Carcinoma versus Reactive Type II Pneumo-

cytes. A, B: Sputum smears with tissue fragments of reactive/hyper-
plastic alveolar type II pneumocytes. The lack of nuclear molding,
scant cytoplasm, and knobby external contour of the tissue fragment
do not support the diagnosis of small cell carcinoma.
A B
Fig. 3.66: Small Cell Carcinoma versus Poorly Differentiated Squa-

mous Carcinoma. A: The sputum smear shows syncytial tissue frag-
ments and discrete small cells with morphology consistent with that
of small cell carcinoma cells. There is karyorrhexis in the back-
ground. A bronchial biopsy and subsequent lobectomy revealed
a poorly differentiated squamous carcinoma, small cell variant.
B: Bronchial brushings with small cell carcinoma showing necro-
sis and karyorrhexis for comparison. C: FNA smear of a basaloid
squamous carcinoma, showing morphologic similarities to small
C cell carcinoma.

Fig. 3.67: Small Cell Carcinoma versus Adenocarcinoma with

a Single Cell Pattern. This fine needle biopsy specimen revealed
discrete, mildly pleomorphic malignant cells. Their cell borders are
poorly defined with indistinct cytoplasm. Nuclear molding was not
conspicuous. The differential diagnoses included small cell carcino-
ma, malignant lymphoma, and poorly differentiated adenocarcino-
ma. The latter diagnosis was supported by negative neuroendocrine
markers and positive TTF-1.
A B
Fig. 3.68: AC: Small Cell Carcinoma versus Adenocarcinoma.

These three separate examples of adenocarcinomas consist of small
round cells with scant cytoplasm and high N/C ratios mimic small
cell carcinoma. Since TTF-1 would be positive in both, neuroendo-
C crine markers should be done to differentiate from NECs.

A B
Fig. 3.69: Small Cell Carcinoma versus Thymic Neoplasms. A: FNA of a mediastinal mass. The cytomorphology of
these discrete small cells with hyperchromatic nuclei offer a differential diagnosis of carcinoid tumor, small cell carci-
noma, and malignant lymphoma. Immunostains are required to exclude malignant lymphoma. Surgical resection con-
firmed a thymic carcinoid tumor. B: FNA of a mediastinal mass showing a syncytial tissue fragment of thymic epithelial
cells from a thymoma with scant cytoplasm, high N/C ratios mimicking small cell carcinoma.
Fig. 3.70: A to D: Small Cell Carcinoma versus Adenoid Cystic

Carcinoma. FNA lung mass in a patient with a history of adenoid
cystic carcinoma. These are syncytial tissue fragments of small hy-
perchromatic compact nuclei with three-dimensional pattern mim-
icking small cell carcinoma or a carcinoid tumor.
pericardium, causing pleural/pericardial effusion, organs (Fig. 3.75A,F) and is characterized by tissue fragments with
such as brain, bones, adrenals, liver and thyroid, salivary onion-skin pattern or Indian file arrangement. The malig-
glands, and skin and subcutis. The characteristic cytomor- nant cells do show nuclear molding. If a history of primary
phology of small cell carcinomas in various types of spec- pulmonary neoplasm is available, the cytologic diagnosis
imens allow an accurate diagnosis (Figs. 3.71 to 3.77). is usually an accurate one. In sites such as salivary glands,
Not uncommonly, small cell carcinomas of the lung pres- metastatic pulmonary small cell carcinoma must be differ-
ent initially at the metastatic sites. entiated from a primary small cell carcinoma of the sali-
The cytopathologic features of metastatic small cell car- vary glands (refer Chapter 7). Some of the problems in the
cinomas are as characteristic as the primary tumor. Their diagnosis of metastatic pulmonary small cell carcinomas
presentation in the effusion fluids, however, is quite varied include differentiating normal adrenocortical cells from

metastatic small cell carcinoma (Fig. 3.76), differentiating

metastatic small cell carcinoma to the lymph nodes from
PULMONARY PARAGANGLIOMAS
malignant lymphoma, and differentiating other neuroen-
Primary pulmonary paragangliomas are very uncommon
docrine tumors with a small cell pattern.
and only a few cases have been reported in the literature.
The clinicopathologic and cytopathologic features
However, lungs may be involved secondarily (see Chapter
of pulmonary endocrine carcinomas are summarized in
14; Fig. 14.14AC).
Table 3.10.
Metastatic Small Cell Carcinoma to Different Body Sites (Figs. 3.71 to 3.77)
A B
Fig. 3.71: Metastatic Small Cell Carcinoma to the Lymph Nodes.

A: FNA of a mediastinal lymph node showing a malignant neo-
plasm consisting of small cells. The differential diagnoses included
small cell carcinoma and malignant lymphoma. B: The presence of
syncytial tissue fragments of malignant cells favored a small cell
carcinoma. C: Positive reactivity to cytokeratin supported the diag-
C nosis of small cell carcinoma.

A B
Fig. 3.72: Metastatic Small Cell Carcinoma versus Malignant Lymphoma. A: FNA of an enlarged cervical lymph node
showing discrete small malignant cells with a differential diagnosis of malignant lymphoma and metastatic small cell
carcinoma. B: Positive cytokeratin stain confirmed a small cell carcinoma.
A B
Fig. 3.73: Metastatic Small Cell Carcinomas to the Liver. AC:

These three images represent different cases of metastatic small
cell carcinoma. Their cytomorphology is characteristic allowing
C an accurate diagnosis.

Fig. 3.74: Metastatic Small Cell Carcinoma to the Parotid Gland.

FNA of a parotid gland mass showing typical cytomorphology of
a small cell carcinoma. This cytologic pattern is same as that of a
primary salivary gland small cell carcinoma or a metastatic Merkel
cell carcinoma. Both are TTF-1 negative and CK20 positive.
A B
C D
Fig. 3.75: Metastatic Small Cell Carcinomas in the Body Cavity Fluids Present Several Different Morphologic Presen-
tations. A: Syncytial tissue fragments of small cells with indistinct cytoplasm, high N/C ratios, deep-staining compact
chromatin, and nuclear molding. BD: Onion-skin pattern with concentric arrangement of small malignant cells with
indistinct cytoplasm, high N/C ratios, deep-staining compact chromatin, and nuclear molding.

E F
Fig. 3.75: (continued) E: Dispersed cells pattern with Indian file pattern (arrows). F: Dispersed cells with nuclear molding.
A B
Fig. 3.76: Metastatic Small Cell Carcinoma to the Thyroid. A, B: These two images represent two different examples
of metastatic small cell carcinoma to the thyroid. Rarely, thyroid metastasis can be the initial presentation of the lung
primary.
Fig. 3.77: Metastatic Small Cell Carcinoma to the Adrenal Gland.

Small cell carcinomas frequently metastasize to the adrenal glands.
Although the cytomorphology of normal adrenocortical cells is
characteristic their stripped, naked nuclei strongly mimic metastatic
small cell carcinoma and may be erroneously diagnosed as such.
However, adrenal cortical cell nuclei do not demonstrate nuclear
molding as seen in small cell carcinomas (arrows).

TABLE 3.10. PULMONARY NEUROENDOCRINE NEOPLASMS: CLINICAL HISTOLOGIC AND

CYTOLOGIC FEATURES
Large Cell
Atypical Carcinoid Neuroendocrine
(NEC, Grade Carcinoma (LCNEC)
II; Moderately (Neuroendocrine Small Cell NEC
Carcinoid Tumors Differentiated Carcinoma, Grade III; (NEC, Grade III;
(NEC, Grade I, Well- Intermediate-grade; High-grade; Poorly High-grade; Poorly
differentiated; Low-grade) Poorly Differentiated) Differentiated) Differentiated)
Incidence 1%2% of all primary lung 11%24% of all 2% of all primary lung Up to 20% of all lung
cancers pulmonary carcinoids cancers cancers
Age: range 2370 y 2167 y 3575 y 4564 y
Average 46 y Slightly older than seen 64 y 52 y

for typical carcinoid
Sex M:F 2:3 2:1 4:1 2:1
Smoking history +/ +/ 100% 100%
Presenting Dependent on location Often detected as an Dependent on tumor Obstructive symptoms;

symptoms and centrally located cause incidental finding, location; ectopic hemoptysis; superior
signs hemoptysis, dyspnea, usually asymptomatic hormone production venacaval syndrome;
postobstructive pneumonia; not observed in pleural effusion +/;
often asymptomatic; may be reported cases symptoms may be
related to ectopic hormone related to ectopic
production or associated with hormone production
MEN 1 or Cushing syndrome
Radiographic Solitary nodule Solitary nodule Chest mass, variable Hilar/mediastinal mass
findings in size
Location 30% central; 30% mid 50% central; 50 Central or peripheral; Predominantly central;
zone; 30% peripheral peripheral may replace the lung 5% peripheral
Biologic behavior Indolent; regional node More aggressive than Very aggressive; fatal Very aggressive; fatal
metastasis; up to 15%; typical carcinoid;
metastasis at the time of regional node
presentation; none; 2%7% involvement 40%45%;
demonstrate carcinoid metastasis at the time
syndrome with 86% liver of presentation: 20%;
metastasis; 5-y disease free 5-y disease free survival
survival 100%; 10-y disease 69%; 10-y disease free
free survival 87% survival 52%
Metastasis at Hilar lymph nodes 20% Hilar lymph nodes Hilar/mediastinal Local and distant
the time of 40%; liver metastasis lymph nodes metastases
presentation 20%
Gross Features
Tumor size 0.73.5 cm; average 1.512 cm; average 2.44 cm; average Data not available
1.5 cm; smooth surface; no 4.5 cm; necrosis and 3.2 cm; necrosis and (surgical resections are
hemorrhage or necrosis hemorrhage on cut hemorrhage infrequent); necrosis
surface +/ and hemorrhage


CYTOLOGIC FEATURES (continued)
Large Cell
Histomorphology Neuroendocrine growth Neuroendocrine Neuroendocrine Large masses of
pattern; nests, trabeculae growth pattern; growth pattern; large compactly arranged
with or without disruption of the nests and islands with cells
anastomosing pattern; architecture +/; peripheral palisading
rosettes, acinar, papillary peripheral palisading of
very uniform nuclei in large islands
Cell size and Small round to uniform Small to medium-sized; Large round, oval Small round, oval,
shape monomorphic; well-defined round to oval; uniform to fusiform; very to fusiform; poorly
cell borders; lower N/C to pleomorphic; well pleomorphic; well to defined cell borders;
ratios to poorly defined cell poorly defined cell high N/C ratios; less
borders; low to high borders; lower N/C pleomorphic
N/C ratios ratios
Nucleus Nuclei round to oval; Nuclei round to Nuclei round to oval Nuclei round, oval
smooth nuclear membrane; oval; smooth nuclear fusiform; smooth to fusiform; intense
stippled coarsely granular membrane; chromatin nuclear membrane; hyperchromasia;
saltpepper chromatin coarsely granular typical stippled salt nucleoli absent; mitotic
pattern; nucleoli stippled to dense; pepper chromatin rate high; nuclear
inconspicuous; mitoses nucleoli may be pattern; nucleoli molding always;
none; karyorrhexis none; prominent; mitoses prominent frequent karyorrhexis always;
nuclear molding none; up to 10/10 HPF; giant forms; very high stretch artifacts always
stretch artifacts none nuclear molding +/; mitotic rate; >22/HPF;
karyorrhexis +/; nuclear molding +/;
stretch artifacts +/ karyorrhexis frequent;
stretch artifacts +
Cytoplasm Scant to modest; Variable, scant to Modest Insignificant

eosinophilic; granular modest
Azzopardi effect None Very rare Not common Very common
Necrosis None Punctate, small foci to Large infarct-like areas Large infarct-like areas
large areas of necrosis of necrosis
Cytologic Features
Cellularity Variable, generally very Variable, generally very Variable, generally Variable, scant
cellular cellular cellular (e.g., sputum) to
overwhelmingly
cellular in direct
brushings, smears or
FNA


Large Cell
Presentation Cells dispersed, isolated, Cells dispersed, Malignant cells Malignant cells
in loosely cohesive groups isolated, in loosely discrete, in loosely discrete, in aggregates,
or in syncytial tissue cohesive groups or cohesive groups or or in syncytial
fragments as cords, nests in syncytial tissue in syncytial tissue tissue fragments
or anastomosing ribbons fragments as cords, fragments, without any usually without any
with occasional acinar nests, or anastomosing architectural pattern or architectural patterns;
pattern; dispersed pattern ribbons, occasional forming trabeculae and crush artifacts may
more frequent in brushings acinar pattern or occasionally rosette be extensive in direct
and washings; perivascular rosettes; perivascular formation; stretch smears of brushings or
location with cells lining arrangement of cells in artifacts +, peripheral FNA; often present as
capillaries in FNA fine needle aspirates palisading of nuclei in single cells or in groups
specimens tissue fragments +/ of two and three cells
in a mucus streak
Cells Small, round to cuboidal; Small, round to Small to medium- Small, round, 3 to
cell borders well to cuboidal; well to sized; pleomorphic 3.5 times the size of
poorly defined; uniform, poorly defined cell with frequent giant a resting lymphocyte
monotonous pattern borders; high N/C forms; round, oval to to slightly larger to
with occasional large ratios; uniform to polygonal, occasionally oval to short spindle-
pleomorphic forms; short varying degrees of fusiform; N/C ratios shaped 3.5 to 4 times
to long spindle cells in some pleomorphism high; cell borders the lymphocyte; cell
spindle cell carcinoids poorly defined borders poorly defined,
often flush with the
nucleus
Nucleus Round to oval in typical Round to oval with Large, round, oval, Round to oval;
carcinoids; oblong in smooth nuclear occasionally fusiform; multinucleation not
spindle cell carcinoids; membrane; salt- nuclear membranes observed; N/C ratios
smooth nuclear borders; pepper chromatin sharp; chromatin very high; nuclear
N/C ratios generally pattern and in stippled, coarsely membranes smooth;
high; chromatin coarsely conspicuous nucleoli to granular; nucleoli +/; nuclear chromatin
granular, saltpepper type; hyperchromatic nuclei mitoses +; karyorrhexis very coarsely granular
nucleolus +/; no nuclear with nuclear molding +; naked nuclei +/; to compact and deep-
molding; no karyorrhexis; and nucleoli; mitoses nuclear molding +; staining; nucleoli
mitoses absent; no stretch +/; karyorrhexis +/; stretch artifacts +/ inconspicuous; nuclear
artifacts no specific cytologic molding +;
criteria mitoses +; karyorrhexis
+; stretch artifacts +
Cytoplasm Scant to moderate; Variable, scant Scant, indiscernible to Indiscernible to very

pale occasionally insignificant to moderate, pale scant; paranuclear
foamy (mimicking moderate amount vacuoles in
adenocarcinoma), rarely Romanowsky stained
oncocytic preparations
Background Clean Clean to necrosis Necrosis Dirty; necrosis;

fragmented forms


Large Cell
Immunoprofile Neuroendocrine markers +; Neuroendocrine Neuroendocrine Neuroendocrine
cytokeratin (CAM5, 2 and markers +; cytokeratin markers +; cytokeratin markers +; cytokeratin
CK7) +; TTF-1 +; CK20 ; (CAM5, 2 and CK7) (CAM5, 2 and CK7) (CAM5, 2 and CK7)
CD56 + +; TTF-1 +; CK20 ; +; TTF-1 +; CK20 ; +; TTF-1 +; CK20 ;
CD56 + CD56 + CD56 +
Ultrastructure Membrane-bound Membrane-bound Membrane-bound Membrane-bound

neurosecretory granules neurosecretory neurosecretory neurosecretory granules
granules granules present; no
squamous or glandular
differentiation
SUGGESTED READING
Anderson C, Ludwig ME, ODonnell M. Fine needle aspiration Renshaw AA, Jaja JC, Lozano RL, et al. Distinguishing carcinoid
cytology of pulmonary carcinoid tumors. Acta Cytol. tumor from small cell carcinoma of the lung: correlating
1990;34:505510. cytologic features and performance in the Collage of American
Bertino E, Confer P, Colonna J, et al. Pulmonary neuroendocrine/ Pathologists Non-Gynecologic Cytology Program. Arch Pathol
carcinoid tumors. Cancer. 2009;115:44344441. Lab Med. 2005;129:614618.
Carter D. The neuroendocrine tumors of the lung, 1926 Shin H, Ju C, Caraway NP. Fine needle aspiration biopsy of
1998: some historical observations. Semin Diagn Pathol. metastatic small cell carcinoma from extrapulmonary sites.
2008;25:154165. Diagn Cytopathol. 1998;19:177181.
Chhieng DC, Ko EC, Yee HT, et al. Malignant pleural Sica G, Vasquez MF, Altorki N, et al. PAX-5 expression in
effusions due to small-cell lung carcinoma: a cytologic and pulmonary neuroendocrine neoplasms: its usefulness in surgical
immunocytochemical study. Diagn Cytopathol. 2001;25:356360. and fine needle aspiration biopsy specimens. Am J Clin Pathol.
Gustafsson BI, Kidd M, Chan A, et al. Bronchopulmonary 2008;129:556562.
neuroendocrine tumors. Cancer. 2008;113:521. Siddiqui MT. Pulmonary neuroendocrine neoplasms: a review of
Kini SR. Color Atlas and Text of Pulmonary Cytopathology. New clinicopathologic and cytologic features. Diagn Cytopathol.
York, NY: Springer; 2002. 2010;38:607617.
Kini SR. Color Atlas of Differential Diagnosis in Exfoliative and Stoll LM, Johnson MW, Burroughs F, et al. Cytologic diagnosis
Aspiration Cytopathology. 2nd ed. Philadelphia, PA: Lippincott and differential diagnosis of lung carcinoid tumors.
Williams & Wilkins; 2011. A retrospective study of 63 cases with histologic correlation.
Marmor S, Koran R, Halpern M, et al. Transthoracic needle biopsy Cancer Cytopathol. 2010;118:457467.
in the diagnosis of large-cell neuroendocrine carcinoma of the Travis WP, Brumbilla E, Muller-Hermelink HK, et al. World
lung. Diagn Cytopathol. 2005;33:238243. Health Organization Classification of Pathology and Genetics
Moran CA, Suster S, Coppola D, et al. Neuroendocrine of Tumors of the Lung, Pleura, Thymus and Heart. Lyon,
carcinomas of the lung. A critical analysis. Am J Clin Pathol. France: IARC Press; 2004.
2009;132:206221. Travis WD, Linnoila RH, Tsokos MG, et al. Neuroendocrine
Morandi U, Casali C, Rossi G. Bronchial typical carcinoid tumors. tumors of the lung with proposed criteria for large-
Semin Thorac Cardiovasc Surg. 2006;18:191198. cell neuroendocrine carcinoma. An ultrastructural,
Nicholson SA, Beasley MB, Brambilla E, et al. Small cell lung immunohistochemical and flow cytometric study of 35 cases.
carcinoma (SCLC): a clinicopathologic study of 100 cases Am J Surg Pathol. 1991;15:529553.
with surgical specimens. Am J Surg Pathol. 2003;26: Yang YJ, Steele CT, Ou XL, et al. Diagnosis of high-grade
11841197. pulmonary neuroendocrine carcinoma by fine needle aspiration
Pelosi G, Rodriguez J, Viale G, et al. Typical and atypical pulmonary biopsy: non-small-cell or small-cell type? Diagn Cytopathol.
carcinoid tumor overdiagnosed as small cell carcinoma on 2001;25(5):292300.
biopsy specimens: a major pitfall in the management of lung
cancer patients. Am J Surg Pathol. 2005;29:179187.

APPENDIX
WHO HISTOLOGIC CLASSIFICATION OF
TUMORS OF THE LUNG
Malignant Epithelial Tumors Large Cell Neuroendocrine Carcinoma
Squamous cell carcinoma Combined Large Cell
Papillary Neuroendocrine Carcinoma
Clear cell Basaloid carcinoma
Small cell Lymphoepithelioma-like carcinoma
Basaloid Clear cell carcinoma
Small Cell Carcinoma Large cell carcinoma w/rhabdoid phenotype
Combined Small Cell Carcinoma Adenosquamous carcinoma
Adenocarcinoma Sarcomatoid carcinoma
Adenocarcinoma, mixed subtype Pleomorphic carcinoma
Acinar adenocarcinoma Spindle cell carcinoma
Papillary adenocarcinoma Giant cell carcinoma
Bronchioloalveolar carcinoma Carcinosarcoma
Nonmucinous Carcinoid Tumor
Mucinous Typical Carcinoid
Mixed nonmucinous and mucinous or indeterminate Atypical Carcinoid
Solid adenocarcinoma with mucin production Salivary gland tumors
Fetal adenocarcinoma Mucoepidermoid carcinoma
Mucinous (colloid) carcinoma Adenoid cystic carcinoma
Mucinous cystadenocarcinoma Epithelial-myoepithelial carcinoma
Signet ring adenocarcinoma Preinvasive lesions
Clear cell carcinoma Squamous carcinoma in situ
Large cell carcinoma Atypical adenomatous hyperplasia
(Continued)

APPENDIX
TUMORS OF THE LUNG
Diffuse idiopathic pulmonary neuroendocrine cell Alveolar adenoma
hyperplasia
Papillary adenoma
Mesenchymal tumors
Adenomas of the salivary gland type
Epithelioid hemangioendothelioma
Mucous gland adenoma
Angiosarcoma
Pleomorphic adenoma
Pleuropulmonary blastoma
Others
Chondroma
Mucinous cystadenoma
Congenial peribronchial myofibroblastic tumor
Lymphoproliferative tumors
Diffuse pulmonary lymphangiomatosis
Marginal zone B-cell lymphoma of the mucosa-
Inflammatory myofibroblastic tumor associated lymphoid tissue (MALT) type
Lymphangioleiomyomatosis Diffuse large B-cell lymphoma
Synovial sarcoma Lymphomatoid granulomatosis
Monophasic Langerhans cell histiocytosis
Biphasic Miscellaneous tumors
Pulmonary artery sarcoma Hamartoma
Pulmonary vein sarcoma Sclerosing hemangioma
Benign epithelial tumors Clear cell tumor
Papillomas Germ cell tumors
Squamous cell papilloma Teratoma, mature
Exophytic Immature
Inverted Other germ cell tumors
Glandular papilloma Intrapulmonary thymoma
Mixed squamous cell and glandular papilloma Melanoma
Adenomas Metastatic tumors
From Travis WP, Brumbilla E, Muller-Hermelink HK, et al. World Health Organization Classification of Pathology and Genetics of Tumors of the Lung,
Pleura, Thymus and Heart. Lyon, France: IARC Press; 2004.

4 NEUROENDOCRINE TUMORS OF
THE GASTROINTESTINAL TRACT,
APPENDIX, GALLBLADDER, AND
EXTRAHEPATIC BILIARY TRACT
Shilpa Rungta Sudha R. Kini
This chapter covers the neuroendocrine neoplasms aris- index. The classification is basically a two-tier system that
ing in the gastrointestinal (GI) tract, the appendix, the includes two groups: neuroendocrine tumors and neuro-
gallbladder, and extrahepatic biliary ducts. endocrine carcinomas. Grading is combined with a site-
specific staging system to improve prognostic strength
(see Appendixes I and II).
Neuroendocrine neoplasms are exceedingly rare in
NEUROENDOCRINE NEOPLASMS OF esophagus (0.8% to 3.1% of esophageal malignancies)
THE GASTROINTESTINAL TRACT and the anus. Most reported neuroendocrine carcinomas
of the esophagus are all poorly differentiated or small cell
Neuroendocrine neoplasms of the GI tract are uncom- carcinomas. Their cytologic documentation is rare and is
mon. Their annual incidence is stated to be 2.0/100,000 based on endoscopic esophageal washings, a procedure
for men and 2.4/100,000 for women in the United States. that is currently not utilized.
GI neuroendocrine neoplasms present a spectrum of
lesions from low-grade carcinomas (carcinoids) to high-
grade carcinomas (small cell carcinoma), the former
accounting for the majority. They arise anywhere in the NEUROENDOCRINE TUMORS
GI tract from esophagus to anus. (CARCINOID) OF THE
The classification of GI neuroendocrine neoplasms has GASTROINTESTINAL TRACT
undergone several modifications over the years. World
Health Organization (WHO) in 2010 revisited the nomen-
clature and classification of neuroendocrine neoplasms of INTRODUCTION
the digestive system, taking into account the following
concepts as proposed by the European Neuroendocrine Neuroendocrine tumors or carcinoid tumors arise in dif-
Tumor Society (ENTS): (1) tumor heterogeneity, that is, ferent parts of the GI tract with varying frequency. They
tumors differ according to the site of origin; (2) tumor dif- also present different demographics, arise from different
ferentiation, that is, tumors differ according to tumor cell embryonic segments, secrete different hormones, and pres-
differentiation status; and (3) malignancy, that is, long- ent different morphologic patterns and biologic behavior.
term follow-up indicates that neuroendocrine tumors Small nonfunctioning tumors are usually clinically silent
as a category are malignant. The proposed grading was and may be discovered only at autopsy or following resec-
based on proliferation and offered three tiers (G1, G2, tion for other indications. Symptoms are attributable to
G3) with the following definitions of mitotic count and local tumor effects caused by local adhesions or fibrosis
Ki 67 index: G1mitotic count < 2 per 10 high power giving rise to abdominal pain or small bowel obstruction
fields (HPFs) and/or 2% Ki 67 index; G2mitotic count or to secretion of bioactive substances such as serotonin,
2 to 20 per 10 HPFs and/or 3% to 20% Ki 67 index; and histamine, or gastrin. The carcinoid syndrome (cutaneous
G3mitotic count > 20 per 10 HPFs and/or >20% Ki 67 flushing of upper chest, neck, and face; gut hypermotility
85

TABLE 4.1 GASTROINTESTINAL NEUROENDOCRINE TUMORS (CARCINOID) OF THE

GASTROINTESTINAL TRACT
Foreguta Midgut Hindgut

Stomach, Duodenum, Distal Jejunum and Ileum
and Proximal Jejunum and Appendix Colon and Rectum
Histology Trabecular Classic(solid nest) Mixed
Silver Reaction Argyrophilic Argentaffin Nonreactive
Hormones 5 HTP (serotonin) Serotonin None

5 HIAA
Carcinoid Syndrome Occasional Common Extremely rare
Syndrome Pattern Prolonged flush Brief multiple flushes
Secretory Granules Small, round Pleomorphic Small, round

150250 nm 75500 nm 165230 nm
a
Foregut carcinoids also include carcinoid tumors of lung and thymus.
5 HTP, 5 hydroxytryptamine (serotonin); 5 HIAA, 5-hydroxy indol acetic acid.
Modified after Williams ED, Sandler M. The classification of carcinoid tumors. Lancet. 1963;1:238239.
with diarrhea) occurs in <10% of patients. Diagnostic upper colon; and hindgut for distal colon and rectum. Each
strategies for patients suspected of having GI neuroendo- of these has specific characteristics that are site specific
crine neoplasms include biochemical testing for urinary (Table 4.1) as classified by Williams and Sandler (1963).
5-hydroxyindoleacetic acid or serum testing for increased It is extremely important to appreciate the fact that
chromogranin A levels, followed by localization of the tumor unlike neuroendocrine tumors occurring at most other
by OctreoScan scintigraphy, positron emission tomography body sites, a primary cytologic diagnosis of most GI neu-
(PET), or other radiographic imaging techniques. roendocrine neoplasms is rarely made. Reasons are several.
Grossly, these tumors are usually submucosal or can Gastric lesions are usually biopsied for histologic diagno-
present as thickened muscularis propria in the area of the sis. Brushings as a diagnostic procedure for cytologic inter-
tumor as a result of secretion of trophic factors by the pretation is generally not favored by the clinicians except
tumor cells. They may also present as annular strictures as for duodenal lesions that can be approached via endo-
a result of dense fibrosis associated with the tumor. Rarely, scopic ultrasound (EUS) guidance for aspiration biopsies
ischemic injury secondary to vascular sclerosis can be asso- or via endoscopic retrograde cholangiopancreatography
ciated with small bowel tumors. Multicentricity is common (ERCP) for brushings. The lesions of the jejunum, ileum,
and is site related; gastric and jejunoileal tumors (33%) are and appendix are usually diagnosed incidentally because
more commonly multiple, whereas multiplicity is rare with of their metastases to lymph nodes, liver, or peritoneal
colonic or appendiceal neuroendocrine tumors. cavities. Same holds true for colonic and rectal neoplasms.
Microscopically, most GI neuroendocrine tumors are
well-differentiated or low-grade carcinomas (carcinoid
tumors), composed of uniform cells with round to oval
nuclei with finely granular saltpepper chromatin and NEUROENDOCRINE TUMORS
inconspicuous nucleoli. Their growth pattern varies from (CARCINOID) OF THE STOMACH
solid sheets, insular or nests, or trabecular. (FOREGUT)
In general, GI neuroendocrine neoplasms are divided
into three categories based on their embryologic deriva- Majority of the gastric neuroendocrine tumors of the
tions: foregut for stomach, duodenum, and proximal stomach are well-differentiated or low-grade carcinomas
jejunum; midgut for distal jejunum, ileum, appendix, and (carcinoid tumors). They are rare lesions, accounting for

Chapter 4: Neuroendocrine Tumors of the Gastrointestinal Tract, Appendix, Gallbladder, and Extrahepatic Biliary Tract 87
<2% of all carcinoids and 9% to 11% of all GI carcinoid GROSS AND HISTOLOGIC FEATURES
tumors. Three types of gastric neuroendocrine tumors are
recognized. Grossly, Type I and Type II gastric neuroendocrine tumors
Type I is the most frequent type, comprising 70% tend to be well circumscribed, multiple, small, <1 cm, and
to 80% of all the cases, and is associated with chronic located in submucosa of the fundus and body. The spo-
atrophic (autoimmune) gastritis, hypergastrinemia radic Type III gastric neuroendocrine neoplasms tend to
with multiple small fundic tumors, limited to mucosa be solitary (Fig. 4.1A), larger with high risk for lymph
and submucosa and enterochromaffin-like (ECL)-cell node and liver metastasis.
hyperplasia. Histologically, gastric carcinoids present a trabecular
Type II represents 6% of the gastric carcinoid tumors growth pattern characteristic for foregut-derived GI seg-
and occurs in association with multiple endocrine neopla- ment. The neoplastic cells are uniform, small, and cuboi-
sia type 1 (MEN 1) with Zollinger-Ellison syndrome and dal with high N/C ratios. Their nuclei present typical
hypergastrinemia. saltpepper chromatin. These tumors may exhibit marked
Type III represents 13% of gastric carcinoids and pleomorphism with prominent nucleoli. The tumor may
usually affects males, mean age being 55 years. These infiltrate the underlying muscularis.
are sporadic and have no association with chronic
atrophic (autoimmune) gastritis, MEN, or Zollinger-
Ellison syndrome. These tumors are usually larger and CYTOPATHOLOGIC FEATURES
may be infiltrative and metastasize to the lymph nodes
and liver. Cytologic diagnosis is not generally made since endo-
The prognosis is generally good for Type I and Type scopic gastric brushings as a diagnostic procedure are
II. The sporadic Type III presents an aggressive behavior. not generally recommended or performed. The cytologic
A B
Fig. 4.1: A: Gross photograph of an autopsy specimen of the stom-

ach showing a tumor (arrow) that was proven to be a carcinoid
which metastasized widely. B, C: Fine needle aspiration (FNA) of
the liver metastases, during life, showing loosely cohesive medium-
sized cells with scant cytoplasm, poorly defined cell borders, and
high N/C ratios. The nuclear chromatin is coarse and saltpepper
type. Nucleoli are prominent. There is considerable nuclear pleo-
C morphism.

diagnosis is made on metastatic lesions involving liver of gastrinomas are associated with MEN 1 (G-cell hyper-
or lymph nodes by fine needle aspiration biopsies. The plasia), the remainder 75% occurring sporadically (usu-
neoplastic cells exhibit a wide range of morphology, from ally solitary). These tumors are associated with increased
uniform, small, to medium-sized cells with variable N/C gastrin levels and two-thirds of the patients present with
ratios and nuclei with coarsely granular chromatin and Zollinger-Ellison syndrome. Sixty to seventy percent of
with or without multiple nucleoli (Fig. 4.1B,C). these tumors occur in the first portion of the duodenum.
The important prognostic factor to be considered is that
even though small in size, these duodenal tumors have
HISTOCHEMISTRY an aggressive behavior with early lymph node metastasis
and therefore are considered malignant regardless of other
The cells of gastric neuroendocrine tumors (carcinoids) features.
are argyrophilic. Somatostatinomas comprise 15% to 20% of the
duodenal neuroendocrine tumors and are predominantly
located in the periampullary region. Around one-third of
IMMUNOPROFILE the cases are associated with Type 1 neurofibromatosis
(von Recklinghausen disease) and some with MEN 1.
The cells of gastric neuroendocrine tumors (carcinoids) are Patients with duodenal somatostatinomas rarely present
reactive to pan neuroendocrine markers and cytokeratin. with the somatostatin syndrome (diabetes, achlorhydria,
cholelithiasis, and diarrhea), which is clinically observed
in patients with pancreatic somatostatinomas. The duo-
ULTRASTRUCTURE denal/periampullary tumors are unrelated to the pancre-
atic ones.
Ultrastructural findings include the presence of neurose- Gangliocytic paraganglioma is an unusual tumor pre-
cretory granules. senting features of paraganglioma, carcinoid tumor, and
ganglioneuroma. It almost always occurs in the second
part of the duodenum. These tumors are often large up
DIFFERENTIAL DIAGNOSES to 7 cm. Histologically, the neoplasm consists of epithe-
lioid areas similar to those seen in paraganglioma, with
The cytologic differential diagnoses of gastric carcinoids ribbon-like, and trabecular pattern of carcinoid tumors
include gastric adenocarcinomas with a small cell pattern that are surrounded by delicate network of Schwann cells
(Fig. 4.2) and malignant lymphoma (Fig. 4.3). Malignant and nerve axons. Scattered, variably differentiated gan-
melanoma with a small cell pattern needs to be consid- glion cells are present within Schwannian stroma. These
ered as well. tumors are uncommon and there is no documentation of
cytologic features.
NEUROENDOCRINE TUMORS CYTOPATHOLOGIC FEATURES

(CARCINOIDS) OF THE DUODENUM AND
PROXIMAL JEJUNUM (FOREGUT) Neuroendocrine neoplasms of the duodenum are more
accessible to the endoscopic procedures. Cytologic diag-
The incidence of duodenal and upper jejunal neuroendo- nosis via EUS-guided fine needle biopsy or by brush-
crine tumors in relation to all GI neuroendocrine tumors ings via ERCP can be rendered (Figs. 4.4 and 4.5). The
ranges from 3% to 22% with a slight male predominance cytologic preparations demonstrate high cellularity
with the male:female ratio being 1.5:1. Usually, patients with malignant cell population represented by uniform
in fifth and sixth decades are affected. Four distinct his- small round to cuboidal cells, occurring singly with a
tologic types are recognized that include (1) gastrinomas, dispersed pattern or in loosely cohesive groups and in
(2) somatostatinomas, (3) nonfunctioning serotonin- and syncytial tissue fragments. The tissue fragments may
calcitonin-producing tumors, and (4) gangliocytic para- present a trabecular pattern with or without branch-
gangliomas. Clinical history and laboratory data are of ing. The neoplastic cells have poorly defined cell borders
considerable help in the diagnosis as approximately 25% and scant cytoplasm with high N/C ratios. Their nuclei

Differential Diagnosis of Gastric Neuroendocrine Tumors (Carcinoids) (Figs. 4.2 and 4.3)
A B
Fig. 4.2: A: Gastric brushings showing adenocarcinoma cells that are small in size and have scant cytoplasm. These
cells can be misinterpreted as neuroendocrine tumor. B: Another case of gastric adenocarcinoma depicting single cells
in brushings. These may be mistaken for a neuroendocrine tumor.
A B
Fig. 4.3: A, B: Malignant Lymphoma of the Stomach. These two different cases yielded small malignant cells on gastric
brushings. The dispersed pattern and coarse chromatin may result in mistyping these as neuroendocrine tumors.
contain coarsely granular, saltpepper chromatin, and terminal ileum and adjacent cecum. These patients often
inconspicuous nucleoli. present with small bowel stenosis associated with fibrosis
of the peritumoral tissues, peritoneal cavity, and retroper-
itoneum, therefore presenting more in the surgical units
rather than being worked up for a mass lesion.
NEUROENDOCRINE TUMORS The clinical course of jejunoileal neuroendocrine tumors
(CARCINOID) OF DISTAL JEJUNUM AND tends to be aggressive with frequent metastasis to regional
ILEUM (MIDGUT) lymph nodes and liver. It has also been noted that since
serotonin is metabolized in the liver, these patients are at
This is the single most common site (especially termi- a greater risk of developing serotonin syndrome (flushing,
nal ileum) for neuroendocrine tumors in the GI tract diarrhea, bronchospasm, and endocardial fibrosis).
(~ 25%) with peak incidence in the sixth decade and Grossly, ileal carcinoid tumors vary in size, from a few
equal male:female distribution. They commonly occur in millimeters to larger than 2 cm, invade the underlying

Neuroendocrine Tumor of the Duodenum (Figs. 4.4 and 4.5)
A B
Fig. 4.4: Duodenal Carcinoid Tumor. EUS-guided FNA of a peri-

ampullary mass of the duodenum. A: Syncytial tissue fragments of
small round cells with poorly defined cell borders, scant, indistinct
cytoplasm with high N/C ratios. The cells are uniform with coarsely
granular chromatin. Nucleoli are not evident. There is no nuclear
molding or necrosis. B: Low-power view of the cell block of the
aspirate showing a large population of small cells (H&E). C: High-
er magnification. The excised neoplasm confirmed as gastrinoma
(H&E). (Courtesy of Dr. Barbara J. McKenna, Godfrey D. Stobbe
Professor of Pathology, Director of Division of Education Programs,
C University of Michigan, Ann Arbor, Michigan.)
Fig. 4.5: EUS-guided FNA of a periampullary mass of the duo-

denum, showing marked cellularity, comprising uniform small
cells presenting a dispersed pattern. The neoplastic cells are small,
round to cuboidal, with poorly defined cell borders and scant
cytoplasm. The N/C ratios are high. The chromatin is deep-staining.
The cytologic pattern is consistent with a neuroendocrine tumor.
This neoplasm was proven to be a gastrinoma, with metastases to
periportal lymph nodes. (Courtesy of Shilpa Rungta, M.D., Clini-
cal Assistant Professor of Pathology, University of Michigan, Ann
Arbor, Michigan.)

tissues, and involve the lymph nodes. They can be mul-

tiple (Fig. 4.6A,B) in 25% to 30% of the cases. These car-
NEUROENDOCRINE TUMORS
cinoid tumors may induce fibrosis and cause kinks in the
(CARCINOID) OF THE APPENDIX
intestine (Fig. 4.6C). Approximately 20% of the patients
(MIDGUT)
with ileal carcinoids have liver metastases and develop
Neuroendocrine tumors or carcinoids are one of the most
carcinoid syndrome.
common tumors constituting 19% of all GI carcinoid
Histologically, ileal carcinoids present a classic,
tumors. The neuroendocrine tumors account for most
solid nesting pattern (see Fig. 1.4A) and are argentaffin
appendiceal neoplasms and more often discovered inci-
positive.
dentally in approximately 0.5% of all surgically resected
A primary cytologic diagnosis of neuroendocrine tumor
specimens.
of the jejunum and ileum is not possible or rendered, obvi-
Clinically, carcinoid tumors of the appendix can pres-
ously due to their location. Most are detected incidentally
ent as appendicitis with recurrent abdominal pain. They
or at the metastatic sites (Fig. 4.7) by fine needle aspiration
usually occur in fourth and fifth decades of life and are
biopsies of the liver or lymph nodes (see Fig. 13.9).
more common in females. Appendiceal neuroendo-
The differential diagnoses of metastatic carcinoid
crine neoplasms are believed to be enterochromaffin cell
tumors to the liver are discussed in Chapter 13.
Neuroendocrine Tumor of the Small Intestine (Figs. 4.6 to 4.8)
A B
Fig. 4.6: A: Gross photograph of small intestine showing multiple

carcinoid tumors (arrows). B: Another example of multiple, very
small nodules (arrows) proven to be carcinoid tumors. C: Gross
photograph of small intestinal carcinoid tumor arising at the muco-
salsubmucosal junction. The intestine has become kinked and the
C tumor itself is visible at the highest portion of the specimen.

A B
Fig. 4.7: FNA Biopsy of Liver Metastasis from the Case depicted in
Figure 4.6B. A, B: Low-power view of the cellular aspirate consist-
ing of several large branching, large tissue fragments of neoplastic
cells. C: Higher magnification showing uniform, round, to cuboidal
cells with scant cytoplasm, high N/C ratios, and granular chromatin
with inconspicuous nucleoli. The cytopathologic features are consis-
C tent with a metastatic carcinoid tumor.
Fig. 4.8: Gross photograph of an appendix showing an infiltrating

tumor proven to be neuroendocrine tumor, located at the tip.

neoplasms. Most are small, <1 cm in diameter, and aris- Majority of the tumors are discovered as inciden-
ing in the distal portion. Grossly, they are grayish-white, tal findings. Carcinoid syndrome is unusual, even with
well circumscribed, and firm in consistency. Larger lesions hepatic metastases.
may be infiltrative (Fig. 4.8) invading the underlying mus- Neuroendocrine tumors can occur anywhere in the
cularis and into the adjacent adipose tissue. Regional large bowel, but are common in rectum followed by the
lymph node metastases are not common with smaller cecum, sigmoid, rectosigmoid, and ascending colon.
sized lesions. Grossly, they present as submucosal mass with nor-
The cytohistomorphology is similar to that seen in mal overlying mucosa, ranging from 2 to 5 cm or larger.
carcinoids of midgut origin and is argentafinic. One of Colonic carcinoids tend to be larger, averaging 4.9 to 6 cm.
the morphologic variants of appendiceal carcinoids is The tumor may be ulcerative and invade the perico-
adenocarcinoid or goblet cell carcinoid, which presents lonic fat. Histologically, the tumors present features simi-
features of glandular as well as neuroendocrine differ- lar to those seen in carcinoid tumors elsewhere. Larger
entiation (see Fig. 1.3). Cytohistologic features of meta- tumor size and mitotically active tumors are high-risk fea-
static goblet cell carcinoid are illustrated in Figure 4.9. tures. Cytologic diagnosis is possible if the rectal lesions
The tubular variant of appendiceal carcinoid strongly are subjected to brushings.
resembles an adenocarcinoma and is often misinter- The clinicopathologic features of well-differentiated
preted as such. Histologically, it shows discrete tubules GI neuroendocrine tumors (carcinoid tumors) are sum-
with mucin in their lumens. Short trabecular structures marized in Table 4.2.
may be seen but the nesting architecture is not seen. The
neoplastic cells are chromogranin, glucagon, and sero-
tonin positive.
Appendiceal carcinoids are immunoreactive to pan NEUROENDOCRINE CARCINOMAS
neuroendocrine markers. These tumors run a protracted (SMALL CELL CARCINOMAS)
course. Larger lesions, however, may spread locally and OF GASTROINTESTINAL TRACT
metastasize. Peritoneal involvement may result in excess
accumulation of mucin. Small cell carcinomas (poorly differentiated or grade III)
neuroendocrine carcinomas involving the GI tract are
very uncommon. Very few cases are reported in the lit-
erature. Their cytologic documentation is equally sparse.
NEUROENDOCRINE TUMORS Small cell carcinomas of stomach have been reported
(CARCINOID) OF THE COLON AND but none is documented for small intestines. They do occur
RECTUM (HINDGUT) in colon and rectum (Fig. 4.10) and involve the perito-
neum diffusely. The malignant cells can be identified from
Carcinoid tumors of the colon and rectum represent 10% peritoneal fluids. Small cell carcinomas show strong syn-
to 20% of all GI carcinoid tumors. The overall incidence aptophysin positivity and weak reaction to chromogranin
is 8 per 100,000 populations. They are more common in A. Diagnostic confusion can occur between prostatic ade-
females with slight predominance in African American nocarcinomas and rectal neuroendocrine carcinomas as the
population. The average age of the diagnosis is between latter are sometime prostatic acid phosphatase positive and
sixth and seventh decades of life. The patients are usually chromogranin A negative. These tumors are very aggressive
asymptomatic. Large bulky tumors may cause obstructive and metastasize locally in the peritoneum and lymph nodes
symptoms. as well as to liver and distant organs. The prognosis is poor.

Neuroendocrine Tumor of the Appendix (Figs. 4.9 and 4.10)
A B
C D
Fig. 4.9: An Example of Goblet Cell Variant of Carcinoid Tumor of

the Appendix. A, B: Peritoneal fluid showing medium to large ma-
lignant cells, some containing cytoplasmic vacuoles. C: Low-power
view of the appendix involved by a neoplasm in the submucosa
(arrows) (H&E). D: Medium-power view showing adenocarcinoma
with varying sized neoplastic glandular structures (arrows) with an
infiltrative pattern (H&E). E: Higher magnification showing car-
cinoma cells streaming through muscularis. The mucin stain and
E neuroendocrine markers were positive (H&E).

A B
C D
Fig. 4.10: Poorly Differentiated Neuroendocrine (Small Cell) Car-

cinoma of the Colon. A: Low-power view of the malignant tumor
exhibiting solid growth pattern with large areas of necrosis (H&E).
B: Islands of malignant cells within the necrotic areas (H&E).
C: Higher magnification of the neoplasm consisting of closely
packed small cells with scant cytoplasm (H&E). D, E: Intraoper-
ative FNA of the peritoneal mass, showing a large population of
small undifferentiated cells consistent with poorly differentiated
E neuroendocrine carcinoma.

TABLE 4.2 CLINICOPATHOLOGIC FEATURES OF GASTROINTESTINAL NEUROENDOCRINE

TUMORS (CARCINOID)
Incidence Mean Age

% of All GI Gender Associated Lesions/ Biologic
Site Carcinoids Preference Syndromes Pathologic Features Behavior
Gastric 9%11%
Type I 60% of 63 y; Chronic atrophic Multiple small, well- Risk for

gastric NET common (autoimmune) gastritis, circumscribed, submucosal metastases
in females pernicious anemia; nodules in body and fundus; low; 5% with
M:F, 1:2.5 hypergastrinemia gastrin levels <12 cm; uniform small round lymph node
elevated cells, coarsely granular salt metastases 5-y
pepper chromatin; mitotic survival rate of
activity very low; <2/HPF; 93%
solid, ribbon-like, trabecular or
nesting pattern; argyrophilic.
Immunoprofile: neuroendocrine
markers +; pan-cytokeratin +;
ECL-cell hyperplasia +/
Type II 15% of 50 y; no Associated with MEN Multiple small foci; located in Risk for
gastric NET gender 1 syndrome; Zollinger- body and fundus; Uniform small metastases
predilection Ellison (ZE) syndrome, round cells, coarsely granular up to 30%;
M:F, 1:1 hypergastrinemia gastrin levels saltpepper chromatin; mitotic prognosis
elevated activity very low; <2/HPF; intermediate
solid, ribbon-like, trabecular or between Type I
nesting pattern; argyrophilic. and Type III
Immunoprofile: neuroendocrine
markers +; pan-cytokeratin +
Type III 20% of 55 y; Sporadic; no predisposing Solitary, located in prepyloric Risk for
gastric NET common in factors gastrin levels normal area; can be large; small round metastases
males M:F, cells, to moderately pleomorphic; 50%100%;
2.8:1 coarsely granular saltpepper 5-y survival
chromatin; mitotic activity rate of 50%;
variable; solid, ribbon-like, often develop
trabecular or nesting pattern; lymph node
argyrophilic. Immunoprofile: and liver
neuroendocrine markers +; metastases
pancytokeratin +
Small intestine
Duodenum 22% 59 y Two-thirds are gastrinomas; Nonfunctioning gastrinomas Run a

and 1% M:F, 1.5:1 some are functional located in the duodenal bulb, protracted
proximal (G-cell tumors) causing functioning ones are equally course; risk for
jejunum ZE syndrome and one- located in all parts of duodenum; metastases low
third are somatostatinomas somatostatinomas have
(D-cell tumors); 30% of predilection for periampullary
somatostatinomas associated region; small polypoid
with neurofibromatosis; lesions, <2 cm; submucosal;
gangliocytic paraganglioma histomorphology psammoma
may occur; enterochromaffin bodies and calcification.
(EC) cell, serotonin-producing Immunoprofile: neuroendocrine
tumors; clinically, may present markers +; pan-cytokeratin +
with obstructive jaundice

TABLE 4.2 CLINICOPATHOLOGIC FEATURES OF GASTROINTESTINAL NEUROENDOCRINE
TUMORS (CARCINOID) (continued)
Incidence Mean Age

% of All GI Gender Associated Lesions/ Biologic
Site Carcinoids Preference Syndromes Pathologic Features Behavior
Distal 23%28% 62 y; no EC cell, serotonin-producing Most arise at the mucosal 5 y survival
jejunum gender tumors account for 95%; submucosal junction; multifocal, rate 72%;
and ileum predilection 5%7% present with small nodules in up to 30% of mortality
carcinoid symptoms; up cases; typically yellow; slow rate 20%;
to 16% associated with growing, extending into deeper higher risk
adenocarcinoma layers; deeply invasive tumors for metastases
with considerable fibrosis; with larger
characteristic rounded nests of tumors
closely packed tumor cells, often
with peripheral palisading; or solid
nests associated with rosette-like
or glandular pattern; argentaffin
positive. Immunoprofile: positive
reactivity to neuroendocrine
markers, cytokeratin, CDX2, CEA
and occasionally to prostatic acid
phosphatase
Appendix 19% 3243 y None; most often detected Usually small, <1 cm, arise at Favorable
50%85% More incidentally; may cause the distal end; firm, grayish- outcome
of all common in appendicitis due to obstruction yellow, well-circumscribed but
appendiceal females lack capsule; mixed endocrine
tumors exocrine carcinoma and goblet
cell carcinoids arise anywhere
in the appendix; whitish with
mucinous appearance; argentaffin
positive; Immunoprofile: positive
markers and cytokeratin;
morphologic variantgoblet
cell carcinoid characterized by a
predominant submucosal growth,
invading through the wall, in
a concentric manner; does not
produce a well-defined tumor;
mucosa is characteristically
spared; consists of signet ring-like
cells; intensely positive for mucin.
Colon and 10%20% More Usually none; mostly detected Submucosal mass, 25 cm Generally
rectum common as incidental findings; large or larger; may be ulcerated; favorable;
in females, bulky tumors may cause microscopic pattern similar surgical
and in obstruction; more common in to low-grade neuroendocrine resection for
African rectum carcinomas or carcinoid tumors smaller lesions
American elsewhere in the GI tract; larger very effective;
population; size, cellular and nuclear atypia 5-y survival for
sixth and with increased mitoses are colonic NETs
seventh unfavorable characteristics; is 42% and for
decades of may infiltrate the underlying rectal tumors
life tissues and also metastasize is 72%.
locally. Immunoprofile: positive
markers and cytokeratin;
variably positive to CEA; 80% of
rectal carcinoids are PSA positive
NET, neuroendocrine tumors; CEA, carcinoembryonic antigen; PSA, prostatic specific antigen.

for gallbladder and bile ducts, respectively. Small cell

NEUROENDOCRINE TUMORS OF THE carcinomas occur more frequently than the carcinoid
GALLBLADDER AND EXTRAHEPATIC tumors. Histologic patterns for both carcinoids and small
BILE DUCTS cell carcinomas parallel those of similar neoplasms at
other sites. Their cytologic documentation is rare and is
Neuroendocrine tumors of the gallbladder and extrahe-
not discussed further.
patic bile ducts are extremely rare. The reported incidence
for carcinoid tumors is 0.2% and 0.01% of all carcinoids
SUGGESTED READING
Borch K, Ahren B, Ahlman H, et al. Gastric carcinoids: biologic Nets of the Stomach
behavior and prognosis after differentiated treatment in
relation to type. Ann Surg. 2005;242:6473. Borch K, Ahren B, Ahlman H, et al. Gastric carcinoids: biologic
Bosman FT, Carneiro F, Hruben RH, et al. WHO Classification of behavior and prognosis after differential treatment in relation
Tumours of the Digestive System, 4th ed. Lyon, France: IARC to type. Ann Surg. 2005;242:6473.
Press; 2010. Kloppel G, Anlauf M. Epidemiology, tumor biology and
Fenoglio-Preiser CM. Gastrointestinal neuroendocrine/ histopathologic classification of neuroendocrine tumors of
neuroectodermal tumors. Am J Clin Pathol. 2001;115:S79S83. the gastrointestinal tract. Best Pract Res Clin Gastroentrol.
Iacobuzio-Donahue C, Montgomery EA. Gastrointestinal and liver 2005;19:507517.
pathology. In: Goldblum JR, ed. Foundations in Diagnostic
Pathology. Philadelphia, PA: Churchill Livingstone; 2005.
Nets of the Duodenum and Upper Jejunum
Kloppel G, et al. The gastroenteropancreatic neuroendocrine cell
system and its tumors. The WHO Classification. Ann NY Acad (Foregut and Midgut)
Sci. 2004;1014:1327 Cunningham JD, Aleali R, Aleali M, et al. Malignant small bowel
Kloppel G, Anlauf M. Epidemiology, tumour biology and neoplasms: histopathologic determinants of recurrence and
histopathologic classification of neuroendocrine tumours of survival. Ann Surg. 1997;242:6573.
the gastrointestinal tract. Best Pract Res Clin Gastroentrol. Garbrecht N, Anlauf M, Schmitt A, et al. Somatostatin-producing
2005;19:507517. neuroendocrine tumors of the duodenum and pancreas:
Pape UF, Jann H, Muller-Nordhorn J, et al. Prognostic incidence, types, biological behavior, association with inherited
relevance of a novel TNM classification system for upper syndromes, and functional activity. Endocr Relat Cancer.
gastroenteropancreatic neuroendocrine tumors. Cancer. 2008;15:229241.
2008;113:256265. Nesi G, Marcucci T, Rubio CA, et al. Somatostatinoma: clinico-
Rindi G, Kloppel G, Alhman H, et al. TNM staging of foregut pathological features of three cases and literature reviewed.
(neuro)endocrine tumors: a consensus proposal including a JGastroenterol Hepatol. 2008;23:521526.
grading system. Virchows Archiv. 2006;449:395401. Pipeleers-Marichal M, Donow C, Heitz PU, et al. Pathologic
Williams ED, Sandler M. The classification of carcinoid tumors. aspects of gastrinomas in patients with Zollinger-Ellison
Lancet. 1963;1:238239. syndrome with and without multiple endocrine neoplasia type
Yao JC, Hassan M, Phan A, et al. One hundred years after I. World J Surg. 1993;17:481488.
carcinoid: epidemiology of and prognostic factors for
neuroendocrine tumors in 35,825 cases in the United States.
JClinl Oncol. 2008;26:30633072. Net of Jejunum and Ileum
Burke AP, Thomas RM, Elsayed AM, et al. Carcinoids of the
Nets of the Esophagus jejunum and ileum: an immunohistochemical study of 167
cases. Cancer. 1997;79:10861093.
Gollard R, Ellis C, VanderHarten C. Small cell neuroendocrine Kidd M, Modlin IM, Shapiro MD, et al. CTGF, intestinal stellate
carcinoma of the esophagus: presentation of two cases and cells and carcinoid fibrogenesis. World J Gastroenterol.
review of literature. Tumori. 2010;96:780786. 2007;13:52085216.
Hoda SA, Hajdu SI. Small cell carcinoma of the esophagus, Modlin IM, Shapiro MD, Kidd M, et al. Carcinoid tumors
cytology and immunology in four cases. Acta Cytol. and fibrosis: an association with no explanation. Am J
1992;36:113120. Gastroenterol. 2004;99:24662478.
Kuo C-H, Hsieh C-C, Chan M-L, et al. Small cell carcinoma of the
esophagus: a report of 15 cases from a single institution and
literature review. Ann Thorac Surg. 2011;91:373379.

Net of Appendix Saclarides TJ, Szeluga D, Staren ED. Neuroendocrine cancers of the
colon and rectum. Dis Colon Rectum. 1994;37:635642.
Bak M, Asschenfeldt P, Bak M, et al. Adenocarcinoid of the Silverman JF, Baird DB, Teot LA, et al. Fine needle aspiration
vermiform appendix. A clinicopathologic study of 20 cases. Dis cytology of metastatic small cell carcinoma of the colon: a
Colon Rectum. 1988;31:605612. report of three cases. Diagn Cytopathol. 1996;15:5459.
Burke AP, Sobin LH, Federspiel BH, et al. Appendiceal carcinoids: Soga J. Carcinoma of the rectum: an evaluation of 1271 reported
correlation of histology and immunohistochemistry. Mod cases. Surg Today. 1997;27:112119.
Pathol. 1989;2:630637.
Burke AP, Sobin LH, Federspiel BH, et al. Goblet cell carcinoids
and related tumors of the vermiform appendix. Am J Clin Neuroendocrine Neoplasms of the Gall
Pathol. 1990;94:2735. Bladder and Extrahepatic Bile Ducts
Glasser CM, Bhagavan BS, Glasser CM, et al. Carcinoid tumors of
the appendix. Arch Pathol Lab Med. 1980;104:272275. Fuji H, Aotake T, Horiiuchi T, et al. Small cell carcinoma of
Syracuse DC, Perzin KH, Price JB, et al. Carcinoid tumors of the the gall bladder: a case report and review of 53 cases in the
appendix. Mesoappendiceal extension and nodal metastases. literature. Hepatogastroenterology. 2001;48:15881593.
Ann Surg. 1979;190:5863. Iype S, Mirza TA, Propper DJ, et al. Neuroendocrine tumors of the
Tang LH, Shia J, Soslow RA, et al. Pathologic classification and gall bladder: three cases and a review of the literature. Postgrad
clinical behavior of the spectrum of goblet cell carcinoid tumors Med J. 2009;85:213218.
of the appendix. Am J Surg Pathol. 2008;32:14291443. Maitra A, Tascila M, Hruban R, et al. Small cell carcinoma of the
gall bladder: a clinicopathologic, immunohistochemical and
molecular study of 12 cases. Am J Surg Pathol. 2001;25:
Neuroendocrine Neoplasms of the Colon and Rectum 595601.
Okamura Y, Maeda A, Matsunaga K, et al. Small cell carcinoma
Federspiel BH, Burker AP, Sobin LH, et al. Rectal and colonic
in the common bile duct treated with multidisciplinary
carcinoids: a clinicopathologic study of 84 cases. Cancer.
management. J Hepatobiliary Pancreat Surg. 2009;16:575578.
1990;65:135140.
Thomas NE, Burroughs FH, Ali SZ. Small cell carcinoma of the
Kimura N, Sasano M. Prostate-specific acid phosphatase in
extrahepatic bile duct and concurrent clonorchiasis. Diagn
carcinoid tumors. Virchows Archiv A, Pathol Anat Histol.
Cytopathol. 2005;32(2):9293.
1986;410:247251.

APPENDIX I
WHO CLASSIFICATION OF
GASTROINTESTINAL NEUROENDOCRINE
NEOPLASMS
Stomach Ampullary Region Small Intestine Appendix Colon and Rectum
Neuroendocrine Neuroendocrine tumors Neuroendocrine tumors Neuroendocrine tumors Neuroendocrine tumors

tumors (NET) (NET) (NET) (NET) (NET)
G1 (carcinoid) G1 (carcinoid) G1 (carcinoid) G1 (carcinoid) G1 (carcinoid)
G2 G2 G2 G2 G2
Neuroendocrine Neuroendocrine Neuroendocrine Neuroendocrine Neuroendocrine

carcinoma (NEC) carcinoma (NEC) carcinoma (NEC) carcinoma (NEC) carcinoma (NEC)
Large cell NEC Large cell NEC Large cell NEC Large cell NEC Large cell NEC
Small cell NEC Small cell NEC Small cell NEC Small cell NEC Small cell NEC
Mixed Mixed Mixed Mixed Mixed

adenoneuroendocrine adenoneuroendocrine adenoneuroendocrine adenoneuroendocrine adenoneuroendocrine
carcinoma (MANEC) carcinoma (MANEC) carcinoma (MANEC) carcinoma (MANEC) carcinoma (MANEC)
EC-cell serotonin- EC-cell serotonin- EC-cell serotonin- EC-cell serotonin- EC-cell serotonin-
producing NET producing NET producing NET producing NET producing NET
Gastrinoma Gangliocytic Gangliocytic Goblet cell carcinoid L-cell glucagon-like

paraganglioma paraganglioma L-cell glucagon-Like peptide and PP/PYY-
Somatostatin-producing Somatostatin-producing peptide and PP/PYY- producing NET
NET NET producing NET
Gastrinoma
L-cell glucagon-like
peptide and PP/PYY-
producing NET
From Bosman FT, Carneiro F, Hruben RH, et al. WHO Classification of Tumours of the Digestive System, 4th ed. Lyon, France: IARC Press; 2010.

APPENDIX II
WHO GRADING SYSTEM FOR
GASTROINTESTINAL NEUROENDOCRINE
TUMORS
Grade 1 Mitotic count <2 per 10 HPFs and/or 2% Ki67 index
Grade 2 Mitotic count 220 per 10 HPFs and/or 3%20% Ki67 index
Grade 3 Mitotic count >20 per 10 HPFs and/or > 20% Ki67 index
From Bosman FT, Carneiro F, Hruben RH, et al. WHO Classification of Tumours of the Digestive System, 4th ed. Lyon, France: IARC Press; 2010.

5 NEUROENDOCRINE TUMORS
OFTHE PANCREAS
Pancreatic neuroendocrine neoplasms, previously referred and parasympathetic nerve fibers, closely associated with
to as pancreatic endocrine tumors (PETs), are uncommon, the blood vessels.
constituting 1% to 2% of all pancreatic neoplasms. In Each islet of Langerhans is composed of approxi-
the United States, their incidence is estimated at <1 per mately 1,000 endocrine cells, filled with characteristic
100,000 people. Pancreatic neuroendocrine neoplasms neurosecretory granules. Four major cell types are rec-
were previously referred to as islet cell tumor/islet cell ognized in the islets, namely, alpha secreting glucagons,
carcinoma, because of the assumption that they arise beta secreting insulin, delta secreting somatostatin, and
from the islets of Langerhans. Pancreatic endocrine neo- PP cells secreting PP. Each islet cell produces a single
plasms are now considered to be arising from the multi- peptide. Ultrastructurally, secretory granules of each
potential epithelial cells in pancreatic ductules. type have distinctive appearance: (1) Alpha-cell granules
measure 180 to 300 nm. They are round and contain an
eccentric electron-dense core within a less dense periph-
eral region. There is a thin halo beneath the limiting
ENDOCRINE PANCREAS membrane. These constitute 15% to 20% of total endo-
crine cells. (2) Beta-cell granules measure 225 to 375 nm
constituting 60% to 70% of total endocrine cells. They
HISTOLOGY AND CYTOLOGY are polymorphous and contain crystalline cores with a
wide halo beneath the limiting membrane. (3) Delta-
Majority of the pancreas (85%) consists of exocrine cell granules constitute 2% to 10% of total endocrine
component that includes acinar tissue and ductal system cells. The granules measure 170 to 220 nm and are
(Fig. 5.1) and the remaining represents the endocrine round with a moderately dense core surrounded by
tissue. Ninety percent of all pancreatic endocrine cells a very thin halo. (4) The granules of PP cells consti-
in the adult pancreas reside in the islets of Langerhans tute 15% to 20% of total endocrine cells and measure
(Fig. 5.1A). Fewer than 10% are distributed singly or in 138 to 208 nm. The granules are smaller and have
clusters among the ductal cells or paraductular acinar homogeneous hypodense cores.
cells. The islets consist of aggregates of lightly staining
endocrine cells, well demarcated from the surrounding
exocrine tissue. They are embedded in reticulin and col-
lagen fibers and lack a true capsule. Two types of islets are PANCREATIC NEUROENDOCRINE
recognized based on their architecture and location: ordi- NEOPLASMS
nary or regular islets and pancreatic polypeptide (PP)-rich
irregular islets. The regular islets are evenly distributed in Pancreatic neuroendocrine neoplasms or tumors (NETs)
the anterior part of the head, body, and tail of the pan- were classified by the World Health Organization (WHO)
creas. They are round to ovoid, arranged into ribbons or in 2010 (see Appendix) on the bases of criteria similar
lobules. The diameter of the ordinary islets ranges from to those for neuroendocrine neoplasms of the gastroin-
75 to 225 mm. The PP-rich irregular islets are large, 400 to testinal tract (see Chapter 4; Appendixes I and II). This
500 mm, and have trabecular architecture. The islets are classification also introduces a grading system determined
penetrated by a rich network of anastomosing sinusoids. by proliferative rate replacing the grade- and stage-based
The innervation of the islets are derived from sympathetic system as recommended in 2004 WHO classification.
103

A B
C D
Fig. 5.1: Normal Histology and Cytology of the Pancreas (Exocrine and Endocrine). A: Histologic section of the
pancreas showing acinar tissue formed by large triangular cells containing abundant eosinophilic granular cytoplasm,
basally located round nuclei. An islet of Langerhans is seen in the center of the field (arrow). The component cells
(neuroendocrine) of the islet are smaller, with scant, pale eosinophilic cytoplasm, uniform round nuclei, and high N/C
ratios (H&E). B: Fine needle aspiration (FNA) biopsy specimen showing normal pancreatic acinar tissue (low power).
C, D: Higher magnification depicting the cytomorphology of the acinar cells. Normal islet cells usually not seen in the
aspirated samples.
PETs occur either sporadically or as a part of heredi-

PANCREATIC NEUROENDOCRINE tary syndromes. The sporadic tumors are solitary, whereas
TUMORS pancreatic tumors in hereditary settings such as multiple
neuroendocrine neoplasia Type I and von Hippel-Lindau
Majority of the pancreatic neuroendocrine neoplasms fall
disease are frequently multiple (Table 5.1).
in the category of pancreatic NET Grade I and Grade II,
previously classified (WHO, 2004) as well-differenti-
ated endocrine tumors, well-differentiated endocrine CLINICAL FEATURES
tumor with unknown potential, and well-differentiated
carcinoma. Cytologically, these three types cannot be The mean reported age at presentation for pancreatic
differentiated and are described together. NET is 58 years, with a range of 12 to 78 years. The
PETs can be nonfunctioning (30% to 40%) or function- patients with hereditary syndromes are usually younger
ing with elaboration of a number of different hormones. with a mean age of 35 years. There is no gender pre-
The relative frequency of PETs is estimated to be 30% for dilection. The presenting symptoms in nonfunction-
insulinoma, 16% to 30% for gastrinoma, 10% for vasoac- ing tumors are related to the size of the tumor, which
tive intestinal polypeptide-secreting tumor, 5% to 6% for remains silent for a long period of time. The presenting
glucagonoma, and 25% to 36% for nonfunctioning tumors. symptoms include abdominal pain, cachexia, weight loss,

Chapter 5: Neuroendocrine Tumors ofthe Pancreas 105
TABLE 5.1. PANCREATIC NEUROENDOCRINE TUMORS (NETS) IN HEREDITARY SYNDROMES
Frequency of Location of the Gene Sites for Associated

Syndrome Inheritance Pancreatic Tumors and (Gene Product) Tumors
MEN type 1 Autosomal dominant More than 60%; 11q13(610amino acid Anterior pituitary
usually nonfunctional; protein, MENIN) (pituitary adenoma)
multiple Parathyroid glands
microadenomas; (hyperplasia and adenoma)
functioning tumors GI Tract NET (stomach
gastrinomas and and duodenum),
20% insulin producing gastrinomas associated
with Zollinger-Ellison
syndrome
Adrenal cortex
von Hippel-Lindau Autosomal dominant 2%12%; always 3p25.5 (213amino acid Renal cell carcinoma
disease nonfunctioning protein) Hemangioblastoma
Pheochromocytoma
von Recklinghausen Autosomal dominant 6% somatostatinoma 17q11.2 (2485 Neurofibromas

disease amino acid protein,
neurofibromin)
and jaundice. In case of functioning tumors, the present- The cut surface may be soft, red to yellow-tan, hemor-
ing signs depend on the effects of hormone secreted by rhagic, or grey and firm with fibrosis, or may show exten-
the tumor. sive cystic change. Larger tumors may show lobulations.
Most of the pancreatic NETs follow an indolent course; Cystic change is frequent.
they may metastasize to distant organs several years after Microscopically, several architectural patterns are
the initial diagnosis have been made. The organs most fre- recognized (Fig. 5.3): (1) trabecular (gyriform), (2) aci-
quently involved are liver, lymph nodes, and lungs. More nar, and (3) solid or diffuse. The sheets or nests of cells
than 90% of insulinomas are benign and cured by com- may be separated by strands of fibrous tissue or closely
plete surgical removal. packed with a thin vascular stroma. Frequently cells are
arranged around the blood vessels or spaces with eosino-
philic material. The growth pattern in these tumors varies
RADIOGRAPHIC FINDINGS
Radiographically, pancreatic neuroendocrine can be

detected as localized mass lesions. Magnetic resonance
imaging can also detect peripancreatic lymph node and
liver involvement.
GROSS AND MICROSCOPIC FEATURES
Regardless of the functioning status of the tumor and the

type of hormone elaborated by the tumor, the gross find-
ings and the cytohistomorphology remain similar in all
PETs. Grossly, PETs (Fig. 5.2) are well demarcated and
well circumscribed, may or may not be encapsulated, and
can occur anywhere in the pancreas but commonly involve
body and the tail. Their size is variable. The functioning Fig. 5.2: Gross Photograph of Pancreatic Neuroendocrine Tumor.
tumors are usually smaller than the nonfunctioning ones. Well-defined, large tumor with a bulging cut surface.

A B
C D
E F
Fig. 5.3: Spectrum of Histologic Features of Pancreatic NETs. A: Histologic section showing a solid growth pattern
(low power, H&E). B: Medium-sized cells with modest eosinophilic cytoplasm, central to eccentric uniform nuclei
(H&E). C: A closer view of a PET showing round to cuboidal cells with moderate amounts of eosinophilic cytoplasm.
The nuclear chromatin is granular (H&E). D: Broad trabeculae separated by abundant stroma (H&E). E: Higher
magnification of D showing uniform cells with insignificant cytoplasm (H&E). F: Neuroendocrine tumor with broad
trabeculae and insulae consisting of moderately pleomorphic nuclei. The cells are larger with appreciable eosinophilic
cytoplasm.

G H
I J
K L
Fig. 5.3: (continued) G: Neuroendocrine carcinoma depicting an insular pattern consisting of small uniform cells
(H&E). H: Neuroendocrine tumor presenting an acinar and a pseudopapillary pattern (H&E). I: This neuroendocrine
tumor consists of delicate cords with an anastomosing pattern (H&E). J: Fibrous tissue strands separating islands of
neoplastic cells (H&E). K: Higher magnification showing smaller neoplastic cells with hyperchromatic nuclei (H&E). L:
This pancreatic neuroendocrine tumor shows cords and nests of uniform tumor cells diffusely infiltrating the extensive
fibrous stroma (H&E).

considerably within the same tumor. Although the archi- an internal core structure, with only an indistinct halo
tectural pattern suggests the endocrine nature, there is no and no crystalline configurations. This corresponds to
reliable relationship between architectural patterns and glucagon granules.
the cell type, hormone production, or biologic behavior.
The tumor cells are generally uniform in size and shape.
They may be round, polygonal, or elongated. The cell CYTOPATHOLOGIC FEATURES
borders are usually well-defined. The cytoplasm is eosino-
philic or clear. The nuclei are uniform, and the nucleoli The specimens for cytopathologic diagnosis include
range from inconspicuous to prominent. The saltpepper mostly fine needle aspiration (FNA) biopsies of the pan-
chromatin is characteristic but not universally present. creatic mass lesions via endoscopic ultrasound (EUS)
Pleomorphic large cells may be scattered throughout the guidance. Brushings of the biliary ducts and pancreatic
tumor. Mitoses are generally rare. The cytoplasm is usu- ducts obtained via endoscopic retrograde cholangiopan-
ally scant but can be appreciable and eosinophilic in onco- creatography (ERCP) are also utilized. Metastatic tumors
cytic variants. PETs are richly vascular with a prominent can be identified by fine needle biopsies. The deep-seated
capillary network. Hyalinization of the tumor stroma is organs are sampled mostly under radiologic guidance.
common and may be extensive. Amyloid is sometimes Body cavity fluids are also evaluated for the metastatic
present, especially in insulinomas. spread to the serous membranes (Table 5.2).
The cytologic presentation of the pancreatic NETs
is characteristic (Table 5.3; Figs. 5.4 to 5.17). The
HISTOCHEMISTRY aspirates are generally very cellular. The neoplastic
cells are small to medium-sized and are either uni-
The pancreatic neuroendocrine tumor cells are both form and monomorphic or may demonstrate pleo-
argentophilic and argyrophilic and stain positively with morphism. They present themselves as isolated and in
Fontana-Masson and Grimelius, respectively. Periodic loosely cohesive groups forming a dispersed cell pattern
acid-Schiff (PAS) and mucin stains are negative. (Fig. 5.11D) or in syncytial tissue fragments. The lat-
ter may present trabecular pattern, insulae, rosettes or
may form no architectural configuration. The neoplas-
tic cells are small to medium-sized, either round, cuboi-
IMMUNOPROFILE dal to plasmacytoid, and very rarely spindle shaped
(Fig. 5.15) with central or eccentric nuclei. Spindle and
PETs react positively to cytokeratin and pan-neuroen-
large giant forms are occasionally present. A given case
docrine markers such as chromogranin, synaptophysin,
of pancreatic NETs may show a monomorphic pattern
neuron-specific enolase, PGP 9.5, CD56, or CD57. In
addition, peptide hormones can be detected by using spe-
cific antibodies. Immunohistochemical assessment of spe-
cific hormone production is valuable and correlates with TABLE 5.2. TYPES OF SPECIMENS FOR
CYTOPATHOLOGIC DIAGNOSIS OF PANCREATIC
the clinical symptoms and the blood profile.
ENDOCRINE TUMORS
Endoscopic brushings/rinsings of pancreatic duct under

ULTRASTRUCTURE (1) Endoscopic retrograde cholangiopancreatography
(ERCP)
(2) Endoscopic ultrasound guidance (EUS)
Ultrastructurally, the pancreatic NETs demonstrate
dense core neurosecretory granules, ranging from 80 EUS-guided FNA biopsy of the pancreatic or
to 300 nm in diameter and with a tendency to cluster peri-pancreatic lesions (lymph nodes)
around Golgi complexes. Two subtypes of neurosecre-
tory granules present a characteristic ultrastructural Intraoperative FNA
pattern that relates to the product synthesized. The first
FNA of the metastatic lesions
displays a crystalline core and an irregular submem-
branous halo and correspond to insulin granules (see Peritoneal/pleural fluids
Chapter 1; Fig. 7.1B). The second shows dual density of

TABLE 5.3. CYTOPATHOLOGIC FEATURES OF PANCREATIC NEUROENDOCRINE TUMORS
Cellularity Usually very cellular
Presentation Cells discrete, in loosely cohesive groups or in syncytial tissue fragments; dispersed cell pattern
frequent; tissue fragments may be trabecular, form well-defined nests (insulae) or acinar pattern;
solid cell groups may be traversed by branching blood vessels; cells attached to the blood vessels
Cells Small to medium-sized with occasional large forms; round to cuboidal to plasmacytoid, sometimes
polygonal and rarely triangular or spindle shaped; usually a monomorphic pattern; cell borders
poorly defined with high N/C ratios
Nucleus Central to eccentric; round to oval; smooth nuclear membranes; saltpepper chromatin;
micronucleoli +/; molding, mitotic activity and karyorrhexis are not the features of well-
differentiated neoplasms
Cytoplasm Variable; insignificant to scant; pale to granular; abundant and eosinophilic in oncocytic variant
Background Usually clean; necrotic in high-grade lesions or with cystic change; hemorrhagic +/
Histochemistry Positive reactivity with silver stains; argentophilic and argyrophilic
Immunoprofile Positive reactivity with panneuroendocrine markers and cytokeratin; specific peptide markers
depending on tumor type
Differential diagnoses Well-differentiated duct adenocarcinoma with small cell pattern

Acinar cell carcinoma
Solid pseudopapillary tumor
Pancreatoblastoma (rare)
Other NETs
Malignant lymphoma
Serous microcystic adenoma (rare) with cystic NETs
Normal acinar tissue
A B
Fig. 5.4: AC: FNA of a Pancreatic Neuroendocrine Tumor. The cellular aspirate consists of small to medium-sized cells
in loosely cohesive groups and syncytial tissue fragments. The cells have poorly defined cell borders, scant cytoplasm,
and pleomorphic nuclei containing coarsely granular chromatin. Some contain nucleoli.

C Fig. 5.4: (continued)
A B
Fig. 5.5: FNA of Pancreatic Neuroendocrine Tumor. A: This aspirate consists of discrete cells that are uniform, small
with poorly defined cell borders, high N/C ratios. The nuclear chromatin is typical saltpepper type. B: This field shows
an area of necrosis (arrow).
A B
Fig. 5.6: A, B: FNA of a Pancreatic Neuroendocrine Tumor. The aspirate reveals dissociated cell pattern. The neoplastic
cells are pleomorphic in size and shape. The nuclear chromatin is saltpepper type.

A B
Fig. 5.7: AC: FNA of a Pancreatic Neuroendocrine Tumor. The

cellular aspirate shows syncytial tissue fragments of uniform small
C cells with bland chromatin pattern.
A B
Fig. 5.8: FNA of a Pancreatic Neuroendocrine Tumor. A: This image shows a dispersed pattern of plasmacytoid cells
with occasional giant forms. B: Same case stained by H&E. (Courtesy of Dr. Mithra Baliga, University of Mississippi,
Jackson, Mississippi.)

A B
Fig. 5.9: A, B: FNA of a pancreatic mass showing a cellular aspirate, consisting of uniform, small round cells, discrete,
in groups, and in syncytial tissue fragments. Their cell borders are poorly defined with high N/C ratios. The cytoplasm
is variable. The nuclear chromatin is granular. The cytologic diagnosis of neuroendocrine neoplasm was confirmed at
surgical exploration.
A B
Fig. 5.10: A: Direct brushings of the pancreatic duct showing typical cytomorphology of neuroendocrine tumor.
B: Chromogranin stain demonstrating positive reactivity.
A B
Fig. 5.11: FNA of a Pancreatic Neuroendocrine Tumor. AC: The H&E-stained aspirate shows small to medium-sized
cells in syncytial tissue fragments and singly. The cells are cuboidal with well-defined cell borders and scant eosinophilic
cytoplasm. The nuclei are uniform.

C D
E F
Fig. 5.11: (continued) D: Same case with Papanicolaou stain exhibiting a hypercellular aspirate with tissue fragments
as well as loosely cohesive cells in the background (low power). E: Higher magnification uniform small plasmacytoid
cells with typical saltpepper chromatin. Nucleoli can be seen in some of the cells. F: Same aspirate stained by Ro-
manowsky method. (Courtesy of Dr. Mithra Baliga, University of Mississippi, Jackson, Mississippi.)
A B
Fig. 5.12: A, B: FNA of a pancreatic neuroendocrine tumor depicting uniform round cells, scant cytoplasm with high
N/C ratios, and typical saltpepper chromatin.

A B
Fig. 5.13: A, B: FNA of a Pancreatic Neuroendocrine Tumor. The neoplastic cells are forming syncytial tissue garments
and are associated with fibrous stroma. Typical nuclear pattern of an endocrine tumor is not present due to poor cel-
lular fixation and preservation.
A B
Fig.5.14: FNA of a Pancreatic Neuroendocrine Tumor. A: The

neoplastic cells are in syncytial tissue fragment with a cribriform
pattern. The cells are small, uniform, and cuboidal to round with
granular chromatin. B: Different field with uniform small cells
mostly discrete and in small tissue fragments. C: Different smear
from the same case showing loosely cohesive neoplastic cells with
variation in size. Their cell borders are well to poorly defined with
scant cytoplasm. The nuclear chromatin is coarsely granular. Nucle-
C oli are not apparent. Note occasional large nuclei.

A B
Fig. 5.15: A: FNA of a pancreatic neuroendocrine tumor. An unusual pattern with loosely cohesive and discrete spin-
dle-shaped cells with delicate cytoplasmic processes. Their nuclei are round and display typical saltpepper chromatin.
B: Surgical excision of the neoplasm located in the tail of the pancreas confirmed a neuroendocrine tumor with a
spindle cell pattern. Immunostain with somatostatin was positive. The preoperative levels of serum somatostatin were
elevated. (Courtesy of Robert Osamura, M.D., Professor and Director, Diagnostic Pathology Center, International Uni-
versity of Health and Welfare, INHW Mita Hospital Tokyo, Japan.)
A B
Fig. 5.16: A: Histologic section of a cystic neuroendocrine tumor.

Note the lining of the cysts formed by thin neoplastic tissue (H&E).
B: Higher magnification showing typical endocrine histomorphol-
ogy (H&E). C: Loose tissue fragments of the neoplasm floating in
C the cystic cavity (H&E).

D E
Fig. 5.16: (continued) D: FNA of the same cystic pancreatic

neuroendocrine tumor. The cellular aspirate shows syncytial tissue
fragment with uniform component cells containing nuclei with char-
acteristic nuclear morphology (H&E).E: The same aspirate stained
by Papanicolaou. F: Aspirate stained by Romanowsky. (Courtesy of
F Dr. Mithra Baliga, University of Mississippi, Jackson, Mississippi.)
A B
Fig. 5.17: AC: FNA of a Pancreatic Neuroendocrine Tumor. The neoplastic cells are small and present isolated, in
loosely cohesive groups and in syncytial tissue fragments. The cell borders are poorly defined; the cytoplasm is indis-
tinct. The nuclei are uniform and round.


DIFFERENTIAL DIAGNOSES
With an adequate aspirate, the cytologic diagnosis from

a cell population composed of small, uniform cells with
a typical saltpepper type nuclear chromatin is clearly
apparent. However, diagnostic difficulties may be encoun-
tered with inadequate specimens containing fewer small
cells or with necrosis and cystic change. The differential
diagnostic entities include lesions composed of small cells
(Tables 5.3 and 5.4; Figs. 5.18 to 5.26). A PET with exten-
sive cystic degeneration must be differentiated from other
C cystic lesions of the pancreas (see Tables 5.5 and 5.6).
Fig. 5.17: (continued)
(Figs. 5.7, 5.9 to 5.12, and 5.14) or a pleomorphic pat-

tern (Figs. 5.4 to 5.6, 5.8, 5.9, and 5.13). The nuclei are PANCREATIC NEUROENDOCRINE
round to oval; nuclear membranes are smooth and crisp. TUMOR VERSUS NORMAL ACINAR
The chromatin is characteristic of the neuroendocrine TISSUE
family of tumors, being uniformly and coarsely granu-
lar presenting a saltpepper pattern. Nucleoli are not Thick tissue fragments of pancreatic acinar tissue occasion-
consistently present. The nuclei tend to be uniform but ally may be mistyped as a neuroendocrine tumor (Fig. 5.18).
may be variable in size. The cytoplasm ranges from
scant to moderate, pale to dense, and is eosinophilic
in oncocytic variant. Capillary network may be promi-
nent in the background and neoplastic cells may be seen PANCREATIC NEUROENDOCRINE
in perivascular location. Mitotic activity or necrosis is TUMOR VERSUS DUCT
usually not present but can be seen in widely invasive ADENOCARCINOMA
NETs (Fig. 5.5). The cell block preparations can be
extremely useful in the diagnostic evaluation since they Pancreatic duct adenocarcinomas, composed of smaller
allow ancillary testings. malignant cells may be mistyped as NETs (Fig. 5.19).
The presence of invasion or potential for it cannot be Smaller size of the cells and lack of nuclear pleomorphism
determined on cytomorphology. in adenocarcinomas may lead to diagnostic difficulties.
TABLE 5.4. DIFFERENTIAL DIAGNOSES OF PANCREATIC NEUROENDOCRINE TUMORS
Diagnostic Entity Cytopathologic Features Ancillary Tests See Figure(s)

Pancreatic Cellular aspirate, uniform, small to medium- Neuroendocrine markers Figures 5.4
neuroendocrine tumors sized, round, cuboidal, plasmacytoid or +; specific hormonal 5.17
spindle cells,; dispersed pattern common; marker for a given tumor;
cells isolated, in groups and in syncytial tissue US neurosecretory
fragments; rarely pseudopapillary or acinar granules
patterns; perithelial location of neoplastic
cells; well to poorly defined cell borders; high
N/C ratios; scant cytoplasm; saltpepper
chromatin; inconspicuous nucleoli
Normal acinar Lobules of acinar tissue, uniform cells with Neuroendocrine markers Figure 5.18
tissue small nuclei; low N/C ratios negative

TABLE 5.4. DIFFERENTIAL DIAGNOSES OF PANCREATIC NEUROENDOCRINE TUMORS (Continued)

Well-differentiated Variable cellularity; cells loosely cohesive and Epithelial markers +; Figures
pancreatic in syncytial tissue fragments with and without neuroendocrine markers 5.19A, B
adenocarcinoma acinar pattern; cells small with scant cytoplasm
with a small cell and poorly defined cell borders; nuclei crowded
pattern and overlapped; minimally pleomorphic;
nuclear membrane irregularities +/; finely
granular chromatin; parachromatin clearing;
micronucleoli +; mitoses +/
Acinar cell Cellular aspirate; cells, discrete, in groups PAS diastase resistant +; Figures 5.20
carcinoma and in syncytia with acinar pattern; strong diffusely positive for and 5.21
resemblance to the normal counterpart; cells keratin; lipases + (trypsin,
triangular with abundant granular cytoplasm; alpha-antitrypsin,
nuclei round with smooth nuclear membrane, amylase);
finely granular chromatin with prominent US zymogene granules
nucleoli; no mitotic activity; variable, clear to
granular cytoplasm
Solid Aspirates usually cellular; tissue fragments Positive reactivity to; Figures 5.21
pseudopapillary of small to medium-sized round cells with vimentin, NSE, alpha- and 5.22
tumor (SPT) syncytial and papillary architecture, uniform, antitrypsin, alpha-
bland nuclei with evenly dispersed chromatin, antichemotrypsin;
micronucleoli; grooves +/; no molding; no CAM5.2; focally +;
necrosis; scant cytoplasm; intra- or extracellular variable positivity to
hyaline globules +/; background debris +/, chromogranin and
hemorrhage, cystic change +/; histiocytes synaptophysin
Malignant non- Usually cellular aspirate with a dispersed Cytokeratin ; Figure 5.25
Hodgkin lymphoma pattern; cells discrete with rare tissue fragment; neuroendocrine markers ;
small to medium-sized; poorly defined cell LCA +; CD20, CD45,
borders; high N/C ratios, nuclei round; nuclear CD38 +; monoclonal light
membrane irregularities +/; parachromatin chain restriction
clearing; nucleoli a large single one to
multiple small ones; mitoses +; no nuclear
molding; karyorrhexis; stretch artifacts +/
Paraganglioma Cellular aspirate; monomorphic to S100 protein +; Figure 5.24

pleomorphic cell pattern; cells small, round, neuroendocrine markers +
oval, plasmacytoid to medium to large with
occasional giant forms; polygonal to spindle
shapes; nuclei round, oval, oblong to spindle-
shaped, salt-pepper chromatin; variable
cytoplasm with or without unipolar processes
Pancreatoblastoma Cellular aspirate, cells small with variable reactivity

neuroendocrine features with or without to immunostains,
acinar cell component; squamous morulae; dependent on the lines of
mesenchymal component; usually seen in differentiation
pediatric age group
Serous microcystic Uniform, medium-sized cells, round to Glycogen; PAS +; diastase Figure 5.26
adenoma cuboidal, scant pale cytoplasm, loosely sensitive
cohesive groups; characteristic radiologic
presentation

Differential Diagnoses of Pancreatic Well-differentiated Neuroendocrine Tumors (Figs. 5.18 to 5.26)
Fig. 5.18: Lobules of normal acini with infolding of the tissue frag-
ments may appear syncytial. This well-preserved pattern with uni-
form nuclei may be misinterpreted not only as acinar cell carcinoma
but also as well-differentiated adenocarcinoma and a neuroendo-
crine tumor.
Fig. 5.19: Pancreatic Well-differentiated Neuroendocrine Tumor versus Well-differentiated Adenocarcinoma.

A, B: These adenocarcinoma cells are small with high N/C ratios. Nucleoli are prominent. The chromatin is finely
granular. C, D: A different example of well-differentiated pancreatic adenocarcinoma consisting of small cells, misinter-
preted as neuroendocrine tumor. Surgical exploration confirmed an adenocarcinoma.
A B
Fig. 5.20: A, B: Pancreatic Neuroendocrine Tumors versus Acinar Cell Carcinoma. The cellular aspirate from an acinar
cell carcinoma consists of syncytial tissue fragments of medium-sized cells with uniform nuclei and high N/C ratios.
The cytoplasm is variable and granular. There is morphologic similarity to NETs.

A B
Fig. 5.21: A, B: Pancreatic Well-differentiated Neuroendocrine Tumors versus Acinar Cell Carcinoma. The aspirate
consists of round to cuboidal, small to medium-sized cells in syncytial tissue fragments with no architectural pattern.
The cytoplasm is moderate and eosinophilic. The nuclei are uniform. A differential diagnosis of neuroendocrine tumor
and acinar cell carcinoma were given. The latter was confirmed following the excision.
A B
Fig. 5.22: Pancreatic Neuroendocrine Tumors versus Solid Cystic Pseudopapillary Tumor. FNA of a pancreatic mass.
A: The aspirate demonstrates a dispersed cell pattern of mildly pleomorphic, plasmacytoid cells, uniform nuclei, and
cytoplasmic tailing strongly resembling a neuroendocrine tumor. B: Different field showing discrete and loosely cohe-
sive plasmacytoid cells. Note a large capillary traversing through these cells. The neoplasm was confirmed as solid cystic
pseudopapillary tumor on surgical excision.

A B
C D
E F
Fig. 5.23: Pancreatic Neuroendocrine Tumors versus Solid Cystic Pseudopapillary Tumor. A: This FNA of a pancreatic
mass is overwhelmingly cellular. This presentation formed by monolayered, branching, and anastomosing trabeculae of
varying thickness with rich vascular network suggests a neuroendocrine tumor (medium power). B: Higher magnifica-
tion of a tissue fragment reveals uniform cells with poorly defined cell borders with scant cytoplasm. C: A different field
showing discrete, uniform, round neoplastic cells, isolated and in loosely cohesive groups. Note that these small cells are
difficult to differentiate from cells of a neuroendocrine tumor. D: A different smear from the same aspirate stained with
H&E. The differential diagnoses included neuroendocrine tumor and SPT. E, F: The cell block supported the diagnosis
of solid cystic pseudopapillary tumor (H&E). Neuroendocrine markers were negative. Surgical excision confirmed SPT.

A B
C D
Fig. 5.24: Pancreatic Well-differentiated Neuroendocrine Tumors

versus Paraganglioma. FNA of a periduodenal/peripancreatic mass.
A: The cellular aspirate shows isolated and loosely cohesive round
cells with scant cytoplasm. Note the single racket-shaped large cell
with eccentric nucleus. B: This field shows a syncytial tissue frag-
ment of uniform cells. A minor proportion of the cells are larger,
containing abundant granular cytoplasm. CE: Same case showing
mild to moderately pleomorphic cells with some containing granu-
lar cytoplasm. The general pattern of this aspirate indicated neuro-
endocrine origin. The pleomorphic cells suggested paraganglioma,
confirmed by positive S100 stain for sustentacular cells and by sur-
E gical excision.

Fig. 5.25: Pancreatic Well-differentiated Neuroendocrine Tumors ver-

sus Malignant Lymphoma. FNA of a peripancreatic/pancreatic mass
showing discrete round cells with high N/C ratios and scant cytoplasm.
The nuclear borders are smooth to irregular. The differential diagnoses
included poorly differentiated adenocarcinoma, neuroendocrine tumor,
and malignant lymphoma. The latter was confirmed by flow cytometry.
A B
Fig. 5.26: Cystic Pancreatic Well-differentiated Neuroendocrine

Tumor versus Pancreatic Serous Cystadenoma. A, B: The pancre-
atic cyst aspirate is cellular, consisting of small uniform cells that
are loosely cohesive and in monolayered tissue fragments. The cell
borders are poorly defined and the cells contain scant pale to clear
cytoplasm. The nuclei are uniform. The aspirate interpreted as pos-
sible neuroendocrine tumor. C: The surgical excision confirmed a
C serous cystadenoma.

Positive epithelial markers and negative neuroendocrine

markers will support epithelial malignancy.
PANCREATIC NEUROENDOCRINE
TUMOR VERSUS PARAGANGLIOMA
Generally there is a morphologic overlap between differ-

ent types of neuroendocrine neoplasms. Paragangliomas
PANCREATIC NEUROENDOCRINE in retroperitoneum especially in the peripancreatic region
TUMOR VERSUS ACINAR CELL may be mistaken for a pancreatic neuroendocrine tumor.
CARCINOMA Their aspirates with small to medium-sized cells exhib-
iting neuroendocrine features cannot be differentiated
The aspirates of acinar cell carcinomas demonstrate from pancreatic NETs. Occasional pleomorphic cell with
medium-sized cells that are often loosely cohesive and cytoplasmic process may be a clue. Positive S100 protein
dispersed. Their cytoplasm may be scant and cell borders will favor paraganglioma (Fig. 5.24).
poorly defined. Their nuclei may be eccentric. In this set-
ting, the aspirates may be mistyped as neuroendocrine
tumor (Figs. 5.20 and 5.21).
CYSTIC NEUROENDOCRINE TUMORS
Neuroendocrine carcinomas (NECs) occasionally undergo

PANCREATIC NEUROENDOCRINE cystic change and must be differentiated from other cystic
TUMOR VERSUS SOLID lesions of the pancreas (Table 5.5; Fig. 5.26). Their dif-
PSEUDOPAPILLARY TUMOR ferentiating features are listed in Table 5.6. Pseudocysts
There is considerable overlap between the cells of NETs TABLE 5.5. CYSTIC LESIONS OF THE PANCREAS
and that of solid pseudopapillary tumor (SPT). The dis-
persed and loosely cohesive cells of SPT are plasmacytoid Non-Neoplastic
(Figs. 5.22 and 5.23) and strongly resemble the neuroen-
docrine cells. The tissue fragments with pseudopapillary Pseudocyst
pattern if present will favor SPT.
Congenital cysts
Retention cysts
PANCREATIC NEUROENDOCRINE Lymphoepithelial cysts

TUMOR VERSUS PANCREATOBLASTOMA
Infectious cysts
Pancreatoblastoma is a rare malignant neoplasm, which
Neoplastic
shows multiple lines of differentiation. Both the acinar
and neuroendocrine components resemble each other. The Mucinous neoplasms
presence of squamous morulae favors pancreatoblastoma.
Mucinous cystic neoplasms
Intraductal papillary mucinous neoplasm
PANCREATIC NEUROENDOCRINE Serous microcystic adenoma

TUMOR VERSUS MALIGNANT NON-
HODGKIN LYMPHOMA Solid pseudopapillary neoplasm
The small to medium-sized malignant lymphoma cells Acinar cell carcinoma

with a dispersed pattern strongly resemble the dispersed
Duct adenocarcinoma with cystic degeneration
pattern of small neuroendocrine tumor cells (Fig. 5.25).
They can be distinguished and correctly typed with Neuroendocrine tumor with cystic degeneration
immunostains.

TABLE 5.6. DIFFERENTIAL DIAGNOSES OF CYSTIC NEOPLASMS OF THE PANCREAS
Diagnostic Entities Clinicopathologic Features Ancillary Studies

Cystic neuroendocrine tumor 1% of cystic pancreatic neoplasms; M:F, Neuroendocrine markers +; serum CEA
1;1; fifth to sixth decade; asymptomatic or levels low
symptomatic with functioning tumor; mass
lesion; circumscribed; functioning tumors with
cystic degeneration more frequent in head or
tail; nonfunctioning ones in the body; aspirated
fluid clear to turbid or hemorrhagic; cellularity
often low; cells isolated, in loosely cohesive
groups or in syncytial tissue fragments;
cells small, uniform, round to cuboidal;
poorly defined cell borders; high N/C ratios;
occasional large forms; round to oval nuclei;
smooth nuclear membranes, salt-pepper; type
chromatin; nucleoli prominent; no molding;
mitoses uncommon; scant cytoplasm; necrosis;
karyorrhexis in high-grade tumors
Ductal adenocarcinoma with 4% of cystic pancreatic neoplasms; M>F; sixth Neuroendocrine markers serum CEA
cystic degeneration to eighth decade; abdominal pain, jaundice, levels elevated
wt loss; Mass lesion; infiltrating; common
bile duct or pancreatic duct obstruction;
located anywhere; more common in the
head; aspirated fluid turbid to hemorrhagic;
cellularity variable; malignant cells, isolated, in
loosely cohesive groups and in syncytial tissue
fragments with or without acinar pattern; cells
pleomorphic in size, small to large, round,
cuboidal to polygonal; poorly defined cell
borders; high N/C ratios; nuclei pleomorphic
in size; round to oval, smooth to irregular
nuclear membranes; fine to coarsely granular
chromatin with parachromatin clearing;
micro/macronucleoli; mitoses +/; nuclear
hypochromasia +/; cytoplasm variable, pale,
vacuolated to dense; background cellular and
inflammatory debris, macrophages; mucin +/
Solid Pseudo-Papillary 20% of cystic pancreatic neoplasms; M:F NSE +; beta catenin +;
Tumor (SPT) 1; 9.5; fourth decade; rarely macrocystic; CD56+; CD10+; vimentin +;
cysts with solid component; located in body antichemotrypsin +
and tail; usually large, round, 820 cm;
lobulated with areas of necrosis; aspirated
fluid grossly hemorrhagic; cellularity usually
high; dispersed cell pattern, loose aggregates
or syncytial tissue fragments with papillary
pattern with or without branching; cells
monomorphic, small to medium-sized;
poorly defined cell borders; round, high N/C
ratios; nuclei uniform, round to oval; central
to eccentric; smooth nuclear membranes;
longitudinal grooves; finely granular, evenly
dispersed chromatin; micronucleoli +;
cytoplasm scant; eosinophilic; hyaline globules +;
background with necrosis hemorrhage;
psammoma bodies +/; histiocytic giant cells +/;
calcific debris +/; intra or extracellular
hyaline globules of varying size

TABLE 5.6. DIFFERENTIAL DIAGNOSES OF CYSTIC NEOPLASMS OF THE PANCREAS (Continued)
Diagnostic Entities Clinicopathologic Features Ancillary Studies

Serous cystadenoma 38.5% of pancreatic cystic neoplasms; M:F CEA ; PAS diastase sensitive +;
(Microcystic) 1:2; fifth decade; may be asymptomatic or neuroendocrine markers ; serum CEA
nonspecific symptoms; often an incidental levels low
finding; imaging characteristics-microcystic
with a honeycomb pattern; intramural
calcifications; central stellate scar; lobulated
outline; location-body, tail; aspirated fluid
clear; acellular or low cellularity; monolayered
sheets with honeycomb arrangement;
small aggregates or nests; cells uniform,
cuboidal; well-defined cell borders; low
N/C ratios; nuclei small round, smooth
nuclear membranes; finely granular, evenly
dispersed chromatin; nucleoli inconspicuous;
cytoplasm pale to clear; modest amounts; clean
background; no mucin
Intraductal papillary 30% of cystic pancreatic neoplasms; M:F CEA +; neuroendocrine markers ;
mucinous neoplasm 1.5:1; sixth to seventh decade; often detected serum CEA levels high
incidentally; macrocystic; communication with
the main pancreatic duct and large branches;
located anywhere in the pancreas; more
common in head; aspirated fluid thick, viscous,
and mucoid; cells isolated, in groups and in
tissue fragments; often embedded in the mucin;
honeycomb pattern to syncytial arrangements
with or without papillary architecture; small
to medium-sized; round to columnar cells;
well to poorly defined cell borders; N/C ratios
variable; goblet cells +/; nuclei uniform to
pleomorphic in size; bland, benign-appearing
to atypical; nuclei +/; micronucleoli +/;
cytoplasm modest, vacuolated; background
mucinous
Mucinous Cystic Neoplasms 10% of cystic pancreatic neoplasms; CEA +; neuroendocrine markers ;
exclusively in perimenopausal women; serum CEA levels high
fifth decade; often detected incidentally;
unilocular; macrocystic; no communication
with the ductal system; common location
being the tail; uni- to multilocular aspirated
fluid thick mucoid; cells small to medium-
sized, round to columnar; well to poorly
defined cell borders; N/C ratios variable;
goblet cells +; nuclei pleomorphism in
size +/; round to oval, basally located
or eccentric, nuclear membrane smooth
to irregular; finely granular chromatin;
micronucleoli; cytoplasm variable, large
cytoplasmic vacuoles; background mucinous;
definite diagnosis only made on histologic
examination, based on the presence of ovarian
stroma

are the most common nonneoplastic cystic lesions of the frequent. The cytomorphology parallels that of small cell
pancreas. Absence of epithelial cells in the aspirated cyst NECs at other sites.
contents along with inflammatory debris and high serum
amylase levels in a typical clinical background suggests
the diagnosis.
METASTATIC PANCREATIC
NEUROENDOCRINE CARCINOMAS TO
OTHER BODY SITES
PANCREATIC NEUROENDOCRINE
CARCINOMAS Pancreatic NECs usually metastasize to the regional
lymph nodes and the liver. Other typical sites include
Pancreatic NECs were previously referred to as poorly lung, bones, subcutaneous tissues, and peritoneal cavity.
differentiated NECs and included large cell and small The specimens for cytologic diagnosis include fine needle
cell NECs of the pancreas. They are very uncommon biopsies as well as body cavity fluids (Figs. 5.32 to 5.36).
and constitute 2% to 3% of all pancreatic neuroendo-
crine neoplasms. Poorly differentiated carcinomas occur
in adults with a male predominance. Some patients may
present with paraneoplastic syndromes. Most present PANCREATOBLASTOMA
with symptoms similar to those of ductal adenocarci-
nomas, including back pain, cachexia, and jaundice. In Pancreatoblastoma is a malignant neoplasm showing mul-
contrast to NETs, these neoplasms (carcinomas) run tiple lines of differentiation including acinar differentiation
an aggressive course, and metastasize widely with fatal and squamoid nests. Neuroendocrine and ductal differenti-
outcome. ation as well as a distinct mesenchymal component can also
be present. Majority occur in children. Pancreatoblastomas
are usually solitary and can attain a large size. They are
GROSS AND MICROSCOPIC FEATURES gray-white to tan-yellow, soft, and lobulated with areas
of necrosis and cyst formations. Histologically, the tumor
Grossly, the pancreatic NECs are solid, white to tan, with demonstrates a nesting or an organoid growth pattern. The
variable consistence, and with poorly defined borders and lobules are composed of highly cellular islands of uniform,
areas of necrosis. polygonal cells with distinct cell borders, pale basophilic
Histologically, small cell carcinomas present a pattern cytoplasm, and central nuclei and merge into an acinar
similar to that seen in pulmonary small cell carcinomas. component. Squamoid nests are present at the periphery.
The neoplasm is composed of large islands of small cells In addition, pancreatoblastomas also contain an endocrine
with extensive areas of necrosis. The mitotic activity is component in two-thirds of cases. Some cases show mesen-
very brisk. The tumor is widely infiltrative. chymal as well as a primitive cell component. The immu-
The large cell neuroendocrine carcinoma exhibits a noprofile is variable, depending on cell differentiation.
more pronounced nesting pattern, increased rate of mito-
sis, and larger cell size with abundant cytoplasm.
The cytologic features are documented sparsely. The

CYTOPATHOLOGIC FEATURES aspirate material tends to be cellular. The cytomorphol-
ogy depends on the cell differentiation. Cells with acinar
The aspirates of NECs tend to be cellular showing small differentiation appear polygonal with round, central to
malignant cells with scant cytoplasm and high N/C ratios eccentric nuclei containing micronucleoli and moderate
(Figs. 5.27 to 5.31). The nuclei contain deep-staining, amounts of granular cytoplasm. Cells with endocrine
coarsely granular chromatin. Nucleoli are not appreci- differentiation are smaller, cuboidal, with less cytoplasm
ated. Nuclear molding, karyorrhexis, and necrosis are and nuclei with coarsely granular chromatin.

Poorly Differentiated Neuroendocrine (Small Cell) Carcinoma (Figs. 5.27 to 5.31)
Fig. 5.27: FNA of a Histologically Confirmed Poorly Differentiated Fig. 5.28: FNA of a Histologically Confirmed Poorly Differentiated
Neuroendocrine Carcinoma. These malignant cells strongly resem- Neuroendocrine Carcinoma. These malignant cells strongly resem-
ble an adenocarcinoma. ble an adenocarcinoma.
Fig. 5.29: FNA of a Small Cell Carcinoma of the Pancreas. Note

the small cell size, scant cytoplasm with poorly defined cell borders,
high N/C ratios, and nuclear molding. There is karyorrhexis in the Fig. 5.30: Another example of a primary small cell carcinoma
background. (poorly differentiated neuroendocrine carcinoma) of the pancreas.
C
Fig. 5.31: AC: FNA of a Small Cell Carcinoma (Poorly Differentiated Neuroendocrine Carcinoma). The
neoplastic cells are small, with poorly defined cell borders, indistinct cytoplasm, and high N/C ratios. The
nuclear chromatin is deep-staining, coarsely granular to compact.

Metastatic Pancreatic Neuroendocrine Neoplasms (Figs. 5.32 to 5.36)
Fig. 5.32: A, B: FNA of Metastatic Lesions in Liver. The patient had

a history of neuroendocrine carcinoma of the pancreas. Note the
cytomorphology is that of a neuroendocrine tumor.
A B
Fig. 5.33: A, B: FNA of one of the several liver nodules with no history of primary lesion in a 21-year-old woman. The
aspirate is very cellular consisting of a round cell population with poorly defined cell borders, scant to indistinct cyto-
plasm. The nuclei are slightly pleomorphic in size. Many nuclei show typical saltpepper chromatin pattern. Positive
reactivity to neuroendocrine markers supported the cytologic diagnosis of neuroendocrine carcinoma. Further studies
identified a pancreatic mass that was excised and confirmed as neuroendocrine tumor

Fig. 5.35: A, B: Peritoneal fluid exhibiting metastatic neuroendo-

Fig. 5.34: Metastatic pancreatic neuroendocrine tumor in perito-
crine carcinoma of the pancreas.
neal fluid.
A B
Fig. 5.36: A, B: FNA biopsy of a mass involving the subcutaneous tissues of the thigh in a patient with
well-differentiated neuroendocrine carcinoma of the pancreas.
exocrine growth pattern with an endocrine component.

MIXED EXOCRINEENDOCRINE Endocrine population forms at least one-third of the
TUMORS OF THE PANCREAS tumor cell population. These are rare tumors.
Mixed exocrineendocrine tumor of the pancreas is

defined as an epithelial tumor with a predominant
SUGGESTED READING
Asa SL. Pancreatic endocrine tumors. Mod Pathol. 2011;24:S66S77. Collins BT. Fine needle aspiration biopsy of pancreatic endocrine
Bosman FT, Carneiro F, Hruben RH, Theise ND. WHO neoplasms by endoscopic ultrasound guidance. Acta Cytol.
Classification of Tumours of the Digestive System. 4th ed. Lyon, 2001;45:905907.
France: IARC Press; 2010. Deshpande V, Lawrence GV. Cystic pancreatic endocrine tumor:
Collins BT, Cramer HM. Fine needle aspiration cytology of islet a variant commonly confused with cystic adenocarcinoma.
cell tumors. Diagn Cytopathol. 1996;15:3745. Cancer Cytopathology. 2007;111:4753.

Frenkel WL. Update on pancreatic neuroendocrine tumor. Arch Jhala D, Eloubeidi M, Chhieng DC, et al. Fine needle aspiration
Path Lab Med. 2006;130:963966. biopsy of the islet cell tumors of the pancreas: a comparison
Gu M, Ghafari S, Lin F, et al. Cytological diagnosis of endocrine between computerized axial tomography and endoscopic
tumors of the pancreas by endoscopic ultrasound-guided fine ultrasound-guided fine needle aspiration biopsy. Ann Diagn
needle aspiration biopsy. Diagn Cytopathol. 2005;32:204210. Pathol. 2002;6:106112.
Heitz PU, Komminoth P, Perren A, et al. Pancreatic endocrine Jimenez-Heffermanan JA, Vicendi B, Lopez-Ferrer P, et al. Fine
tumours: introduction. In: DeLellis RA, Lioyd RV, Heitz PU, needle aspiration cytology of endocrine neoplasms of the
Eng C, eds. World Health Organization Classification of pancreas. Acta Cytol. 2004;48:295301.
Tumours Pathology and Genetics Tumors of Endocrine Organs. Labate AM, Klimstra DL, Zakowsk MF. Comparative cytologic
Lyon, France: IARC Press; 2004. features of pancreatic acinar cell carcinoma and islet cell tumor.
Hida S, Friedel DM, Hazar M. Multiple cystic pancreatic Diagn Cytopathol. 1997;16:112116.
neuroendocrine neoplasms in a patient diagnosed via Ligneau B, Lombard-Bohas C, Partensky C, et al. Cystic endocrine
endoscopic ultrasound-fine needle aspiration. Clin tumors of the pancreas: clinical, radiologic and histopathologic
Gastroenterol Hepatol. 2006;5:6. features in 13 cases. Am J Surg Pathol. 2001;25:752760.
Hruban RH, Bishop Pittman M, Klimstra DS. Tumors of the Wenig BM, Heffess CS, Adair CF. Atlas of Endocrine Pathology.
Pancreas. 4th series, fascicle. Washington, DC: Armed Forces 2nd ed. Philadelphia, PA: W.B. Saunders; 2008.
Institute of Pathology; 2007. Wick MR, Graeme-Cook FM. Pancreatic neuroendocrine
Jensen RT. Pancreatic neuroendocrine tumors: overview of recent neoplasms: a current summary of diagnostic, prognostic
advances and diagnosis. J Gastrointest Surg. 2006;10: and differential diagnostic information. Am J Clin Pathol.
324326. 2001;115(Suppl 1):S28S45.

APPENDIX
WHO HISTOLOGIC CLASSIFICATION
OF PANCREATIC NEUROENDOCRINE
NEOPLASMS
Neuroendocrine Tumors (NETs)
Grade 1 Mitotic count <2 per 10 high power fields (HPF) and/or 2% Ki67 index.
Grade 2 Mitotic count 220 per 10 HPF and/or 3%20% Ki 67 index.
Nonfunctional pancreatic NET G1, G2
Neuroendocrine Carcinoma (NEC)
Large cell NEC
Small cell NEC
From Klimstra DS, Arnold R, et al. Neuroendocrine neoplasms of the pancreas. In: Bosman FT, Carneiro F, Hruben RH, Theise ND. WHO Classification of
Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press; 2010.

INTHE MEDIASTINUM
Anatomically, the mediastinum is defined as a space high-grade poorly differentiated NEC small cell carci-
between the two pleural cavities, with its boundaries nomas, and large cell NECs (Table 6.1). World Health
formed superiorly by the thoracic inlet, inferiorly by the Organization (WHO) classification for thymic neuro-
diaphragm, anteriorly by the sternum, and posteriorly by endocrine tumors (Appendix) includes two categories,
the spinal column. The mediastinum is subdivided arbi- namely, well differentiated for carcinoid tumors (typi-
trarily into superior and inferior compartments by an cal and atypical) and poorly differentiated for small cell
imaginary line extending from the manubrium sterni to carcinoma and large cell NECs. Both terminologies are
the fourth thoracic vertebrae. The inferior mediastinum used in this chapter.
again is subdivided into anterior, middle, and posterior Majority of the thymic NEC are either well differenti-
compartments. Besides the major anatomic structures ated (typical carcinoid tumor) or moderately differenti-
such as pericardial cavity containing the heart, major ated (atypical carcinoid). The poorly differentiated NEC
blood vessels, trachea, major bronchi, and esophagus, the of thymus are very uncommon.
mediastinum contains thymus, lymph nodes, soft tissues,
nerve trunks, and paraganglia.
Neuroendocrine tumors of the mediastinum include
those derived from neuroendocrine cells within the thy- ASSOCIATION WITH HEREDITARY
mus (anterior mediastinum), from paraganglionic rests, SYNDROMES
or from misplaced embryonal structures within the medi-
astinum such as parathyroid tissue. Also encountered Thymic NECs may be associated with multiple neuroen-
are primitive neuroectodermal tumors and neuroblasto- docrine neoplasia syndrome type I (MEN I).
mas. This chapter covers mainly thymic neuroendocrine
tumors since they are the most common neuroendocrine
neoplasms in the mediastinum.
WELL AND MODERATELY
DIFFERENTIATED NEUROENDOCRINE
CARCINOMAS (TYPICAL AND ATYPICAL
PRIMARY NEUROENDOCRINE CARCINOID TUMORS) OF THE THYMUS
CARCINOMAS OF THE THYMUS
Thymic carcinoid tumors constitute 2% to 5% of thy-
Primary neuroendocrine carcinomas (NECs) of the thymic epithelial tumors. In contrast to pulmonary carcinoid
mus are uncommon tumors accounting for 2% to 4% tumors (well-differentiated NEC), majority of the thymic
of all anterior mediastinal neoplasms. They include carcinoid tumors are represented by atypical carcinoid
carcinoid tumors, atypical carcinoids, small cell carci- tumors (NEC, moderately differentiated, or intermediate-
noma, and large cell NEC. Suster and Moran recom- grade) and are noted to follow a more aggressive behav-
mended a three-tier classification for thymic endocrine ior than its counterparts in other locations such as lungs.
tumors, namely, low-grade or well-differentiated NEC According to published reports, 80% of thymic carcinoid
(typical carcinoid tumors), intermediate-grade or mod- tumors exhibited malignant behavior as compared to
erately differentiated NEC (atypical carcinoid tumors), 26% of bronchial carcinoid tumors.
133

TABLE 6.1. CLASSIFICATION AND NOMENCLATURE OF THYMIC NEUROENDOCRINE CARCINOMAS
Traditional WHO Morana

Carcinoid (typical) Well-differentiated NEC Well-differentiated NEC (low-grade)
Atypical carcinoid Well-differentiated NEC Moderately differentiated NEC (intermediate-grade)
Large cell NEC Poorly differentiated NEC Poorly differentiated NEC (high-grade)
Small cell carcinoma Poorly differentiated NEC Poorly differentiated NEC (high-grade)
a
Moran CA. Primary neuroendocrine carcinomas of the mediastinum: review of current criteria for histopathologic diagnosis and classification. Semin Diagn
Pathol. 2005;22:223229.Reproduced with permission from Elsevier Inc., Philadelphia, Pennsylvania.
NEC, Neuroendocrine carcinoma.
CLINICAL FEATURES small foci of necrosis. Majority exhibit pronounced cyto-

logic atypia, increased mitotic activity (3 to 10 mitotic
The thymic NECs occur in all age groups, but show predi- figures per 10 HPF), extensive areas of necrosis, and foci
lection for adults between 40 and 60 years of age, with a of vascular invasion. Majority of the NECs of the thymus
male:female ratio of 3:1. About 50% of well-differentiated show histologic patterns consistent with atypical carci-
NECs exhibit local symptoms such as chest pain, cough, noid tumor (Table 6.2).
and dyspnea. Acute symptoms such as superior vena-
caval syndrome are uncommon. Carcinoid syndrome is
TABLE 6.2. CRITERIA FOR HISTOLOGIC
extremely rare. However, up to 30% of adults and over CLASSIFICATION OF NEUROENDOCRINE
50% of children with thymic carcinoid tumors are associ- CARCINOMAS OF THE THYMUS
ated with Cushing syndrome due to ectopic adrenocor-
ticotropic hormone production. About 25% of thymic 1. Typical carcinoid/well-differentiated NEC (low-grade)
carcinoids have a positive family history of MEN 1 syn- Well-differentiated neuroendocrine growth pattern
drome (see Chapter 1, Table 1.1). Thymic NECs follow Mild cellular atypia
Fewer than 3 mitotic figures per 10 HPF
an aggressive course. Fifty percent show local metasta-
Small foci of necrosis
sis, invasion into adjacent organs, and pleural or pericar-
dial cavity. Lymph node metastases include mediastinal, 2. Atypical carcinoid/moderately differentiated NEC
cervical, and supracervical lymph nodes. Hematogenous (intermediate-grade)
spread to distant organs has been reported. Focal preservation of neuroendocrine growth
pattern
Moderate cellular atypia
49 mitotic figures per 10 HPF
GROSS AND HISTOLOGIC FEATURES More extensive foci of necrosis
Thymic carcinoid tumors are unencapsulated. Grossly, 3. Large cell undifferentiated NEC/poorly differentiated
they are either well defined or invasive. Their size ranges NEC (high-grade)
from 2 to 20 cm with a mean of 8 to 10 cm. Their cut Complete loss of neuroendocrine growth pattern
Marked cellular atypia
surface is gray-white and gritty. The consistence is firm.
More than 10 mitotic figures per 10 HPF
They usually lack the lobulated pattern of thymomas. Extensive areas of necrosis
Oncocytic variant may show tan or brown discoloration.
Foci of hemorrhage and necrosis are present in 70% of 4. Small cell NEC/poorly differentiated NEC (high-grade)
the cases. Calcifications are frequent. Complete loss of neuroendocrine growth pattern
Histologically, thymic carcinoids exhibit a wide spec- Marked cellular atypia
More than 10 mitotic figures per 10 HPF
trum of patterns that depends on the degree of differ-
Extensive areas of necrosis
entiation and biologic behavior. Some demonstrate the
histologic pattern of a pulmonary typical carcinoid tumor From Moran CA. Primary neuroendocrine carcinomas of the mediastinum:
review of current criteria for histopathologic diagnosis and classification.
(see Fig. 3.2AG), with mild cytologic atypia, scattered Semin Diagn Pathol. 2005;22:223229. Reproduced with permission from:
mitotic figures (<3 per 10 high power field [HPF]), and Elsevier Inc., Philadelphia, Pennsylvania.

Chapter 6: Neuroendocrine Tumors inthe Mediastinum 135
Several morphologic variants of thymic endo- present as discrete or loosely cohesive cells and some-
crine carcinomas have been described. These include times in syncytial tissue fragments. Their cell borders
spindle cell type, oncocytic type, mucinous type, pig- are well to poorly defined. The cytoplasm is usually
mented type, angiomatoid type, and with amyloid-like scant. The nuclei are round with high N/C ratios and
stroma. contain typical saltpepper chromatin (Fig. 6.1). The
aspirates of atypical carcinoid tumors (moderately dif-
ferentiated NEC) are cellular with considerable cellular
CYTOPATHOLOGIC FEATURES and nuclear pleomorphism (Fig. 6.3). Foci of necrosis
are frequent (Fig. 6.2). However, nuclear molding and
The specimens for cytopathologic diagnosis represent stretch artifacts are not present.
fine needle aspiration (FNA) biopsies performed either
via percutaneous transthoracic route or transbronchial
route via endoscopic ultrasound guidance. In general, fine HISTOCHEMISTRY
needle biopsy of thymic lesions is not a very popular diag-
nostic technique and is not widely practiced. The cyto- The cells of thymic NECs are argyrophilic, and stain with
logic documentation of thymic neuroendocrine tumors Grimelius.
therefore is sparse.
The cytologic features of NECs parallel those of pul-
monary carcinoid tumors (See Chapter 3; Tables 3.1 IMMUNOPROFILE
and 3.4) (Figs. 6.1 to 6.4). The cellularity of the aspirate
is usually variable depending on the amount of stroma Thymic carcinoid tumor cells react positively to all neu-
and extent of necrosis. In low-grade tumors (typical car- roendocrine markers, cytokeratins (CAM 5.2, AE1/AE3),
cinoid), the neoplastic cells are small, round to oval, and and CD56 and CD57.
Fig. 6.1: Well and Moderately Differentiated NECs (Carcinoid

Tumors). AC: FNA of a mediastinal mass showing a poorly cel-
lular aspirate depicting aggregates of small round cells with well to
poorly defined cell borders and scant cytoplasm with high N/C ra-
tios. The nuclei are uniform but their chromatin pattern not well vi-
sualized due to partial air-drying. A cytologic diagnosis of carcinoid
can only be suggested. D, E: Surgical exploration revealed a thymic
E neoplasm, histologically confirmed as carcinoid tumor (H&E).

A B
C D
Fig. 6.2: Well and Moderately Differentiated NECs (Carcinoid Tumors). AD: FNA of a mediastinal mass showing
small round cells with scant cytoplasm and high N/C ratios. Note there is considerable necrosis (arrows) of the tumor
cells with several ghost forms (arrowheads). There is mild nuclear atypia. Surgical exploration confirmed thymic car-
cinoid.
A B
Fig. 6.3: Well and Moderately Differentiated NECs (Carcinoid Tumors). A, B: FNA of a mediastinal mass. This cellu-
lar aspirate consists of discrete and loosely cohesive cells with poorly defined cell borders and indistinct cytoplasm. The
N/C ratios are high. The nuclei are moderately pleomorphic in size and shape with some short spindle forms. Surgical
exploration with excision of the thymic neoplasm confirmed moderately differentiated neuroendocrine tumor or an
atypical carcinoid.

Fig. 6.4: Well and Moderately Differentiated NECs (Carcinoid Tumors). AD: FNA of a mediastinal mass. This
aspirate consists of several syncytial tissue fragments of small cells with high N/C ratios, indistinct cytoplasm, and
mild pleomorphism in the nuclear size. There is no nuclear molding. The cytologic interpretation was carcinoid tumor,
confirmed histologically.
ULTRASTRUCTURE
POORLY DIFFERENTIATED
NEUROENDOCRINE CARCINOMAS OF
Ultrastructurally, the thymic NEC cells demonstrate neu-
THE THYMUS
rosecretory granules.
Poorly differentiated NECs include large cell NEC and
DIAGNOSTIC DIFFICULTIES AND small cell carcinoma.
DIFFERENTIAL DIAGNOSES Large cell NECs present morphology similar to that
seen in lungs (see Chapter 3). These neoplasms are large
Thymic carcinoid tumors (NECs) being uncommon neo- with extensive necrosis and brisk mitotic activity with
plasms are seldom encountered in routine cytopathol- more than 10 mitotic figures per 10 HPF (Table 6.2).
ogy practice. Differentiation of typical carcinoid tumors There is more pleomorphism and frequent giant forms as
from an atypical carcinoid is not possible from aspira- compared to atypical carcinoid tumors.
tion biopsy specimens, as necrosis and mitotic activity Small cell carcinomas or poorly differentiated NECs
may not be reflected in the cytologic specimen. Likewise, of the thymus exhibit morphology of a conventional
presence or absence of invasion cannot be assessed from small cell carcinoma seen in lung (Table 6.2). It is nec-
cytologic specimens. essary to first eliminate the possibility of lung primary
The differential diagnoses of thymic carcinoids before designating the neoplasm as primary thymic small
(NECs) include neoplasms with a small cell pattern cell carcinoma, as the former is more frequent and often
(Table 6.3; Figs. 6.5 to 6.14), such as thymomas, metastasizes to the mediastinal lymph nodes. Metastatic
thymic carcinomas, reactive lymph nodes, malignant Merkel cell carcinoma should also be considered in the
lymphoma, primary thymic and metastatic small cell differential diagnosis.
carcinomas (NEC, high-grade), metastatic Merkel cell
carcinoma, metastatic adenocarcinoma with a small
cell pattern, metastatic poorly differentiated squa-
mous carcinoma, and malignant melanoma small cell MEDIASTINAL PARAGANGLIOMA
type. In pediatric age group and adolescents, neu-
roblastoma and primitive neuroectodermal tumors Paragangliomas in the mediastinum associated with the
(PNETs) must also be considered in the differential pulmonary arteries and the aortic arch originate from the
diagnosis. aorticopulmonary paraganglia present in the superior and

TABLE 6.3. DIFFERENTIAL DIAGNOSES OF THYMIC NEUROENDOCRINE CARCINOMAS

Thymic carcinoids Neoplastic cells isolated, in loosely cohesive groups and in syncytial Figures 6.16.4
(Well and moderately tissue fragments; cells small, round; N/C ratio 1:1; cell borders poorly
differentiated NEC) defined; no molding; saltpepper type chromatin; nucleoli inconspicuous;
mitoses infrequent; scant, pale cytoplasm; necrosis in the background +/;
immunoprofile: NSE +;chromogranin +; synaptophysin +; cytokeratin +
Malignant lymphoma, Discrete, monomorphic cells; small, round; with high N/C ratios; cell borders Figures 6.11A,B
non-Hodgkin type well-defined; nucleus round with clefts, grooves, convolutions; coarsely
granular to stippled chromatin; micronucleoli; mitoses frequent; cytoplasm
pale and scant; lymphoglandular bodies +; immunoprofile: LCA+; specific
lymphoma markers +
Small cell carcinoma Cells isolated, in loosely cohesive groups or in syncytial tissue fragments Figures 6.9A,B
(poorly differentiated without any architectural patterns; cells small, round to oval; high N/C
NEC) primary or ratios; cell borders poorly defined; nucleus round to oval; irregular nuclear
metastatic membrane; molding +; coarsely granular chromatin; inconspicuous nucleoli;
mitoses +; karyorrhexis+; stretch artifacts +; indiscernible cytoplasm; nuclear
molding +; stretch artifacts +; necrosis; nuclear debris in the background;
immunoprofile: NSE +; chromogranin +; synaptophysin +; cytokeratin +;
CK20-; TTF-1 +
Primary thymic Malignant cells isolated, in groups or in syncytial tissue fragments; cytoplasm Figure 6.7
carcinoma scant; no differentiating features; high N/C ratios; granular chromatin;
prominent nucleoli; neuroendocrine markers-; cytokeratin +
Poorly differentiated Cells isolated, in loosely cohesive groups or in syncytial tissue fragments Figures 6.8A,B
carcinomas squamous or with marked crowding and overlapping; no architectural pattern; cells
adenocarcinoma small, round to cuboidal; high N/C ratio; cell borders well to poorly defined;
nucleus round, central; nuclear membrane smooth to irregular; chromatin
fine to coarsely granular; no molding; nucleoli present; mitoses +; scant, pale
to dense cytoplasm; background clean to necrotic; immunoprofile: CEA +;
cytokeratin +; neuroendocrine markers
Merkel cell carcinoma Cells isolated, in loosely cohesive groups or in syncytial tissue fragments Figures 6.10AC
(metastatic) without any architectural patterns; cells small, round to oval; high N/C 11.14
ratios; cell borders poorly defined; nucleus round to oval; irregular nuclear
membrane; molding +; coarsely granular chromatin; inconspicuous nucleoli;
mitoses +; karyorrhexis+; stretch artifacts +; indiscernible cytoplasm; strings
of nuclear material; immunoprofile: NSE +; chromogranin +; synaptophysin
+; cytokeratin +; CK20 +; TTF-1 -
Malignant melanoma Cells mostly isolated, in cohesive groups or tissue fragments very rare; cells Figure 6.11C
round, well-defined cell borders; nucleus round, eccentric; smooth nuclear
membrane; fine to coarsely granular chromatin; prominent macronucleoli;
cytoplasm scant, brownish discoloration; rudimentary cytoplasmic tailing;
background clean; S100 protein +; HMB 45 +; Melan-A/MART-1 +
Thymoma, lymphocyte Large population of mature lymphoid cells, obscuring neoplastic epithelial Figures 6.5 and 6.6
predominant cells, occurring singly, in groups, or in tissue fragments; poorly defined cell
borders; pale cytoplasm and bland nuclei; epithelial cells highlighted by
positive reactivity to cytokeratin

Differential Diagnoses of NECs of the Thymus (Figs. 6.5 to 6.14)
A B
Fig. 6.5: Well and Moderately Differentiated NECs (Carcinoid

Tumors) of the Thymus versus Thymoma. A, B: FNA of a medias-
tinal mass proven to be a thymoma, lymphocyte predominant. This
pattern may be misinterpreted as NEC. The epithelial cells are not
readily identified. C: FNA of a spindle cell type thymoma and must
C be differentiated from a spindle cell NEC (carcinoid).
A B
Fig. 6.6: Well and Moderately Differentiated NECs (Carcinoid Tumors) of the Thymus versus Thymoma. A, B: FNA
of a mediastinal mass proven to be a thymoma showing a cellular aspirate with predominant lymphoid cells. Epithelial
cells are difficult to identify without immunostains. A uniform small cell pattern is also seen in a typical carcinoid tumor.

Fig. 6.7: NECs of the Thymus versus Primary Thymic Carcinoma.

A: FNA of a mediastinal mass showing poorly differentiated malig-
nant pleomorphic cells with no cytoplasmic differentiation. Surgical
exploration confirmed a thymic carcinoma.
A B
Fig. 6.8: Poorly Differentiated NECs of the Thymus versus Metastatic Poorly Differentiated Adeno/Squamous Carci-
noma. A: FNA of this metastatic poorly differential carcinoma to the mediastinum is cellular, consisting of very pleo-
morphic round to plump spindle-shaped nuclei with hyperchromatic nuclei. Note the molded borders. The differential
diagnoses include poorly differentiated NEC, thymic carcinoma, and metastatic squamous carcinoma. Surgical explo-
ration, confirmed metastatic carcinoma. B: This metastatic poorly differentiated adenocarcinoma resembles poorly
differentiated NEC (large cell NEC).
A B
Fig. 6.9: Poorly Differentiated NECs of the Thymus versus Metastatic Pulmonary Small Cell Carcinoma. A, B: These
two images represent two different examples of metastatic small cell carcinoma. A diagnosis of primary thymic small
cell carcinoma can only be made after the exclusion of a pulmonary small cell carcinoma. Morphologically they cannot
be discriminated.

A B
Fig. 6.10: A, B: Poorly Differentiated NECs of the Thymus versus

Metastatic Merkel Cell Carcinoma. FNA of mediastinal mass prob-
ably a lymph node in a patient with a history of Merkel cell carcino-
ma. Note the morphology is similar to poorly differentiated NEC.
The confirmatory test is immunostaining for CK20 which would be
C positive. C: FNA of a thymic NEC (carcinoid) for comparison
A B
Fig. 6.11: A, B: NECs of the Thymus versus Malignant Lymphoma, Non-Hodgkin Type. These two examples of
mediastinal malignant non-Hodgkin lymphoma show discrete small round cells with high N/C ratios. Note the lack of
saltpepper chromatin.

Fig. 6.11: (continued) C: FNA of a malignant melanoma consisting

of small malignant cells with no melanin pigment must be differen-
C tiated from a NEC.
A B
Fig. 6.12: A, B: FNA of a mediastinal mass in a child proven to be neuroblastoma. These undifferentiated small cells
present cytomorphology, typical of a NEC. The diagnostic clues would be the presence of Homer Wright rosettes and
neuropil. The young age of the patient is in favor of neuroblastoma.
A B
Fig. 6.13: FNA of a Mediastinal PNET. A: This cellular aspirate shows a malignant pleomorphic cell population with
prominent vascular stroma. B: Same case stained by Romanowsky method. The diagnosis was confirmed by positive
CD99 stain.

A B
Fig. 6.14: A, B: Germinoma. This FNA of a mediastinal germinoma shows only rare lymphocytes. Without a dual cell
population, germinoma with small- to medium-sized round malignant cells resemble a poorly differentiated NEC (large
cell NEC).
middle mediastinum. Those in the posterior mediastinum

originate from aorticosympathetic (paravertebral) para-
NEUROECTODERMAL TUMORS
ganglia. Mediastinal paragangliomas occur in younger
Neuroectodermal tumors of the mediastinum are
age groups. Symptoms are related to the catecholamine
predominantly seen in pediatric age groups and adoles-
secretion. They tend to run an aggressive clinical course.
cents, and include neuroblastomas, ganglioneuroblasto-
Mediastinal paragangliomas are extremely uncom-
mas, ganglioneuromas, and primitive neuroectodermal
mon, and the documentation of cytopathologic findings
tumors (PNETs) (Figs. 6.12 and 6.13). These are dis-
is still more uncommon. There are only a few reviews on
cussed in Chapter 16.
cytopathologic findings of mediastinal aspirates; however,
none documented paragangliomas.
SUGGESTED READING
Chetty R, Batitang S, Guvender D. Large cell neuroendocrine Moran CA, Suster S. Spindle cell neuroendocrine carcinomas of
carcinoma of the thymus. Histopathology. 1997;31:274276. the thymus (spindle cell thymic carcinoid): a clinicopathologic
Dusenbury D. Spindle cell thymic carcinoid occurring in multiple and immunohistochemical study of seven cases. Mod Pathol.
endocrine neoplasia I: fine needle aspiration findings in a case. 1999;12:587591.
Diagn Cytopathol. 1996;15:435441. Moran CA, Suster S, Fishback N, et al. Mediastinal
Gherardi G, Marveggio C, Placidi A. Neuroendocrine carcinoma paragangliomas: a clinicopathologic and immunohistochemical
of the thymus: aspiration biopsy, immunocytochemistry, and study of 16 cases. Cancer. 1993;72:23582364.
clinicopathologic correlates. Diagn Cytopathol. 1995;12:158164. Nichols GI, Hopkins MB, Geisinger KR. Thymic carcinoid: report
Klemm KM, Moran CA. Primary neuroendocrine carcinomas of of a case with diagnosis by fine needle aspiration biopsy. Acta
the thymus. Semin Diagn Pathol. 1999;16:3241. Cytol. 1997;41:18391844.
Lack EE. Tumors of Adrenal and Extra-Adrenal Paraganglion Shimosato Y, Mukai K, Matsumo Y. Tumors of the Mediastinum.
System. Atlas of Tumor Pathology. 4th series. Fascicle, Atlas of Tumor Pathology. 4th series. Fascicle 11, Washington,
Washington, DC: Armed Forces Institute of Pathology; 2008. DC: Armed Forces Institute of Pathology; 2010.
Marx A, Shimosato Y, Kuo TT, et al. Thymic neuroendocrine Suster S, Moran CA. Neuroendocrine neoplasms of the
tumours. In: Travis WD, Brambilla E, Mller-Hermelink HK, mediastinum. Am J Clin Pathol. 2001;115:S17S27.
et al., eds. World Health Organization Classification of Tumors Wakely PE Jr. Cytopathology-histopathology of the mediastinum
Pathology & Genetics Tumours of the Lung, Pleura, Thymus II: mesenchymal, neural and neuroendocrine neoplasms. Ann
and Heart. Lyon, France: IARC Press; 2004. Diagn Pathol. 2005;9:2432.
Moran CA. Primary neuroendocrine carcinomas of the mediastinum: Wang DY, Kuo SH, Chang DB, et al. Fine needle aspiration cytology
review of current criteria for histopathologic diagnosis and of thymic carcinoid tumor. Acta Cytol. 1995;39:423427.
classification. Semin Diagn Pathol. 2005;22:223229. Wick MR. The mediastinum. In: Mills SF, ed. Sternbergs
Moran CA, Suster S. Thymic neuroendocrine carcinomas with Diagnostic Pathology, 4th ed. New York, NY: Lippincott
combined features ranging from well-differentiated (carcinoid) Williams & Wilkins; 2004;12531321.
to small cell carcinoma. Am J Clin Pathol. 2000;113:345350. Wick MR, Rosai J. Neuroendocrine neoplasms of the
Moran CA, Suster S. Neuroendocrine carcinomas (carcinoid tumor mediastinum. Semin Diagn Pathol. 1991;8:3551.
of the thymus): a clinicopathologic analysis of 80 cases. Am
J Clin Pathol. 2000;114:100118.

APPENDIX
TUMORS OF THE THYMUS
Epithelial Tumors Atypical carcinoid
Thymoma Poorly differentiated NEC
Type A (spindle cell; medullary) Large cell NEC
Type AB (mixed) Small cell carcinoma, neuroendocrine type
Type B1 (lymphocyte-rich; lymphocytic; predominantly Undifferentiated carcinoma

cortical; organoid)
Combined thymic epithelial tumors, including NEC
Type B2 (cortical)
Germ Cell Tumors (GCT) of the Mediastinum
Type B3 (epithelial; atypical; squamoid; well-
differentiated thymic carcinoma) GCTs of one histologic type (pure GCTs)
Micronodular thymoma Seminoma
Metaplastic thymoma Embryonal carcinoma
Microscopic thymoma Yolk sac tumour
Sclerosing thymoma Choriocarcinoma
Lipofibroadenoma Teratoma, mature
Thymic-carcinoma (including neuroendocrine epithelial Teratoma, immature

tumors of the thymus)
GCTs of more than one histologic type (mixed GCT)
Squamous cell carcinoma
Variant: Polyembryoma
Basaloid carcinoma
GCTs with somatic-type malignancy
Lymphoepithelioma-like carcinoma
GCTs with associated hematologic malignancy
Sarcomatoid carcinoma (carcinosarcoma)
Mediastinal Lymphomas and Hematopoietic Neoplasms
Clear cell carcinoma
B-cell lymphoma
Adenocarcinoma
Primary mediastinal large B-cell lymphoma
Papillary adenocarcinoma
Thymic extranodal marginal zone B-cell lymphoma of
Carcinoma with t(15;10) translocation mucosa-associated lymphoid tissue
Well-differentiated NEC (carcinoid tumors) T-cell lymphoma
Typical carcinoid Precursor T-lymphoblastic lymphoma

Precursor T-lymphoblastic leukemia Mesenchymal Tumors of the Thymus and Mediastinum
(Precursor T-cell acute lymphoblastic lymphoma [LEBL]) Thymolipoma
Anaplastic large cell lymphoma and other rare mature T Lipoma of the mediastinum
and NK-cell lymphomas of the mediastinum
Liposarcoma of the mediastinum
Hodgkin lymphoma of the mediastinum
Solitary fibrous tumor
Grey Zone between Hodgkin and non-Hodgkin
lymphoma Synovial sarcoma
Histiocytic and dendritic cell tumors Vascular neoplasms
Langerhans cell histiocytosis Rhabdomyosarcoma
Langerhans cell sarcoma Leiomyomatous tumors
Histiocytic sarcoma Tumors of peripheral nerves
Malignant histiocytosis Rare Tumors of the Mediastinum
Follicular dendritic cell tumor Ectopic tumors of the thymus
Follicular dendritic cell sarcoma Ectopic thyroid tumors
Interdigitating dendritic cell tumor Ectopic parathyroid tumors
Interdigitating dendritic cell sarcoma Metastasis to Thymus and Anterior Mediastinum
Myeloid sarcoma and extramedullary acute myeloid

leukemia
From Travis WP, Brumbilla E, Muller-Hermelink HK, et al. World Health Organization Classification of Pathology and Genetics of Tumors of the Lung,
Pleura, Thymus and Heart. Lyon, France: IARC Press; 2004.

OFTHE SALIVARY GLANDS
Neuroendocrine tumors of the salivary glands include and hemorrhage. The tumor may be infiltrating into the
mostly small cell neuroendocrine or poorly differentiated adjacent tissues.
neuroendocrine carcinomas. Other types of neuroen- Microscopically, small cell carcinomas show a diffuse
docrine tumors such as carcinoid tumors and paragan- growth pattern or nests, large islands, and trabeculae
gliomas of salivary glands are not documented in the of small cells with areas of necrosis, which can be very
literature. Rare examples of large cell neuroendocrine extensive (Fig. 7.1A,B). The malignant cells are round,
carcinoma have been reported. Salivary glands are more oval to short, and spindle shaped with scant, indiscern-
often the sites for metastatic neuroendocrine carcinomas. ible cytoplasm and high N/C ratios (Figs. 7.1C and 7.2).
Neuroendocrine cells have been identified in intercalated The nuclei have deep-staining, compact chromatin lack-
ducts and mucoserous acini of the salivary glands. ing nucleoli. Mitosis, karyorrhexis, and nuclear molding
are typically seen. Many carcinomas show focal ductal or
squamous differentiation (see Fig. 7.7F).
SMALL CELL CARCINOMA
(NEUROENDOCRINE CARCINOMA,
HIGH-GRADE) CYTOPATHOLOGIC FEATURES
The cytologic specimen is usually a fine needle aspi-

Small cell carcinomas (neuroendocrine carcinomas, grade
rate of the salivary gland mass. The cytologic features
III, or poorly differentiated) are rare primary malignant
(Table 7.1; Figs. 7.3 to 7.7) are similar to those seen
neoplasms of the salivary glands, accounting for <1% of
in pulmonary small cell carcinomas. The aspirates of
all salivary gland tumors. Small cell carcinomas constitute
small cell carcinomas present variable cellularity but
2.8% to 1.8% of all malignant tumors of the major and
are usually very cellular with the malignant cells occur-
minor salivary gland tumors, respectively. Small cell carci-
ring singly, in groups, or in small to large syncytial tissue
nomas demonstrate cytologic, histologic, ultrastructural,
fragments without any architectural patterns. Rosettes
and immunochemical features similar to that of pulmo-
are seen only occasionally. The malignant cells are small,
nary small cell carcinomas. Over 80% of these tumors
round, and oval to fusiform with molded nuclear bor-
occur in the parotid gland.
ders. Their nuclei have very coarsely granular chromatin
Small cell carcinomas typically present as painless rap-
of varying intensity, often appearing compact. Nucleoli
idly growing mass of short duration. Most patients are in
are absent to inconspicuous. The small cell carcinoma
their fifth to sixth decades of life. Small cell carcinoma is
cells contain scant to insignificant cytoplasm with
slightly more common in males. Cervical lymphadenopa-
almost invisible cell borders giving an appearance of
thy is common. Primary small cell carcinoma of the sali-
naked nuclei to the malignant cells. Mitotic figures are
vary glands is an aggressive tumor and can metastasize
easily found. Karyorrhectic and necrotic debris is often
widely with a fatal outcome.
present in the background.
The small cell carcinomas may exhibit focal squa-
GROSS AND HISTOLOGIC FEATURES mous differentiation (Fig. 7.7C,F). Small tissue frag-
ments of squamous cells may be present amidst the
Grossly, small cell carcinoma occurs as a lobulated, malignant cells. The cells of small cell carcinoma with
poorly defined mass, white to grayish-white with necrosis scant cytoplasm tend to air-dry quickly, losing cellular
147

A B
Fig. 7.1: A: Histologic section of a primary small cell carcinoma of

the parotid gland showing large areas of tumor necrosis (medium
power, H&E). B: Another field showing islands of small malignant
cells with scant cytoplasm and high N/C ratios (medium power,
H&E). C: Higher magnification with a solid growth pattern and
C focal necrosis (high power, H&E).
details, often making cytologic interpretation very diffi- IMMUNOPROFILE

cult. The neoplastic cells are also very fragile and exhibit
stretch artifacts that result from the smearing process. In The small cell carcinoma cells of the salivary glands react
Romanowsky-stained preparations, the cells of small cell positively to pan-neuroendocrine markers, pancytokera-
carcinoma often demonstrate paranuclear vacuoles. tin (AE1/AE3, CAM5.2), and CK20. They do not react to
TTF-1, S100-protein, and CK7. With cytokeratin, typical
punctate pattern of staining is noted.
ULTRASTRUCTURE
Ultrastructurally, the small cell carcinoma cells contain

neurosecretory granules.
The cytomorphology of primary small cell carcino-

mas (neuroendocrine carcinoma, grade III) of the sali-
vary glands is identical to that of small cell carcinomas
Fig. 7.2: A: Another example of a primary small cell carcinoma of occurring at other body sites especially the lung. From
the parotid gland, showing islands of small cells with peripheral
palisading (medium power, H&E). B: Higher magnification of (A) morphology alone, these tumors cannot be distin-
(H&E). guished from each other. Positive immunoreactivity to

Chapter 7: Neuroendocrine Tumors ofthe Salivary Glands 149
TABLE 7.1 CYTOPATHOLOGIC FEATURES OF SMALL CELL CARCINOMA (NEUROENDOCRINE

CARCINOMA) OF THE SALIVARY GLANDS
Cellularity Scant to very cellular

Presentation Malignant cells discrete, in aggregates or in syncytial tissue fragments usually without any architectural
patterns; rosettes infrequent; crush artifacts may be extensive resulting in poor cytopreparation
Cells Small, round, 2.53 times the size of a resting lymphocyte to slightly larger, oval to short spindle shaped, cell
borders poorly defined, and often flush with the nucleus
Nucleus Round, oval to oblong; multinucleation not observed; N/C ratios very high; nuclear membranes smooth;
nuclear chromatin very coarsely granular to compact and deep-staining; nucleoli inconspicuous; nuclear
molding +; mitoses +; karyorrhexis +; stretch artifacts +
Cytoplasm Indiscernible to very scant; paranuclear vacuoles in Romanowsky stained preparations; squamous
differentiation present occasionally
Background Dirty; necrosis; fragmented forms
Immunoprofile Neuroendocrine markers +; pancytokeratin (AE1/AE3) +; CD56+; CD57+; TTF-1 ; CK20 +; S100 protein
Differential Metastatic small cell carcinoma

diagnoses Merkel cell carcinoma
Metastatic poorly differentiated carcinomas
Basaloid squamous carcinoma
Basal cell adenoma/basal cell adenocarcinoma
Cutaneous basal cell carcinoma (from skin overlying parotid gland)
Pleomorphic adenoma with a predominant basaloid cell pattern
Reactive intraparotid lymph node
Malignant non-Hodgkin lymphoma
From Kini SR, Dardick I. Salivary Gland Tumor. Cytopathology. CD ROM, Ottawa, Pathology Images Inc. 2006.
A B
Fig. 7.3: A, B: Fine needle aspiration (FNA) biopsy of a parotid mass showing syncytial tissue fragments and loosely
cohesive small cells with round to oval nuclei, compact chromatin, high N/C ratios, and nuclear molding (arrows),
consistent with a diagnosis of small cell carcinoma.

A B
Fig. 7.4: A, B: FNA biopsy of a parotid mass showing typical cytomorphology of a small cell carcinoma. Note round,
oval to oblong nuclei, poorly defined cell borders, indistinct cytoplasm, and deep-staining coarsely granular to compact
chromatin. Nuclear molding is easily appreciated.
A B
Fig. 7.5: A, B: The malignant cells from this case of small cell carcinoma demonstrate intense staining of the nuclear
chromatin. Note nuclear molding.
A B
Fig. 7.6: A, B: These malignant cells from another case of primary small cell carcinoma of the parotid are slightly larger
but show dark-staining chromatin and nuclear molding.

A B
C D
E F
Fig. 7.7: A, B: The aspiration biopsy specimen from a parotid gland mass shows syncytial tissue fragments of small
cells with marked crowding and overlapping. Nuclear molding is evident. Note that the single malignant cells in the
background are rounded and strongly resemble the lymphocytes. C: The tissue fragment of small cell carcinoma cells
shows squamous differentiation. Note the squamous pearl (arrow). Excision of the parotid mass confirmed a small
cell carcinoma. D: A medium power view showing a neoplasm with broad areas of necrosis (medium power, H&E).
E: Higher magnification showing carcinoma with peripheral palisading (H&E). F: Areas within the carcinoma also
demonstrated marked squamous metaplasia (high power, H&E).

cytokeratin 20 has been used to differentiate primary gland are extremely rare (<1% of salivary malignancies)
salivary gland small cell carcinoma and/or metastatic and primary small cell carcinomas of the lung are more
Merkel cell carcinoma from pulmonary small cell common, it is prudent to rule out a metastatic process
carcinoma. in the salivary glands before diagnosing the aspirate as a
The cytologic diagnosis of small cell carcinoma is primary lesion. The differential diagnostic considerations
easily made because of the characteristic cytomorphol- include all the lesions that are composed of small cells as
ogy. Since primary small cell carcinomas of the salivary listed in Table 7.2.
TABLE 7.2 DIFFERENTIAL DIAGNOSES OF SALIVARY GLAND TUMORS WITH A SMALL CELL PATTERN
Diagnostic Entities Cytopathology Features See Figure(s)

Small cell carcinoma; Neoplastic cells discrete, in loosely cohesive groups or in syncytial tissue fragments Figure 7.8
metastatic, from lung with no architectural patterns; cells small, round to oval, occasionally oblong to
(NEC) spindle shaped; nuclear membranes smooth to irregular; chromatin deep-staining and
coarsely granular; nucleoli inconspicuous to absent; nuclear molding +; stretch artifacts
+; mitoses +; karyorrhexis +; cytoplasm scant to indiscernible; cellular necrosis +;
Immunoprofile: CK (AE1/AE3) +; CK 20; neuroendocrine markers +; S100 protein ;
LCA ; TTF-1 +
Merkel cell Neoplastic cells discrete, in loosely cohesive groups with no architectural pattern; Figure 7.9
carcinoma cells small, round to oval; nuclear membranes smooth to irregular; chromatin deep-
staining, coarsely granular; nucleoli inconspicuous to absent; nuclear molding +;
stretch artifacts +; mitoses +; karyorrhexis +; cytoplasm scant to indiscernible; necrosis
+; Immunoprofile: CK20 +; neuroendocrine markers +; TTF-1 ; history of Merkel cell
carcinoma helpful
Poorly differentiated Malignant cells isolated, in loosely cohesive groups or in syncytial tissue fragments with Figure 7.10
carcinomas no architectural patterns; cells small, round, oval to cuboidal; occasionally oblong to
spindle shaped; nuclear membranes smooth to irregular; chromatin deep-staining and
coarsely granular; parachromatin clearing; nucleoli usually conspicuous; no nuclear
molding; mitoses +; karyorrhexis +/; cytoplasm variable, scant to indiscernible;
cellular necrosis +; Immunoprofile: CK +; neuroendocrine markers ; S100 protein ;
LCA
Basaloid squamous Malignant cells isolated, in loosely cohesive groups or in syncytial tissue fragments with Figure 7.11
cell carcinoma no architectural patterns; cells small, round, oval to cuboidal; occasionally oblong to
spindle shaped; nuclear membranes smooth to irregular; chromatin deep-staining and
molding; mitoses ; karyorrhexis +/; cytoplasm variable, scant to indiscernible;
cellular necrosis ; Immunoprofile: CK +; neuroendocrine markers ; S100 protein ;
LCA ; p53 +
Adenoid cystic Neoplastic cells mostly in syncytial tissue fragments with intense crowding and Figure 7.15
Carcinoma overlapping, forming three-dimensional cell balls or in tight aggregates; cribriform
pattern +/; cylindrical cores of acellular, homogeneous hyaline material within the
tissue fragments or in extracellular locations, staining intensely magenta pink with
Romanowsky stain and pale green with Papanicolaou stain; neoplastic cells small with
high N/C ratios; cell borders poorly defined; nuclei round to oval with smooth nuclear
membranes; finely granular to compact chromatin; no nuclear molding; nucleoli
inconspicuous to absent; no mitoses; no necrosis; background clean; bare nuclei +/;
Immunoprofile: CK +; S100 protein +; antibasement membrane antibody +; calponin
+; p63 +

TABLE 7.2 DIFFERENTIAL DIAGNOSES OF SALIVARY GLAND TUMORS WITH A SMALL

CELL PATTERN (continued)
Diagnostic Entities Cytopathology Features See Figure(s)

Basal cell Aspirate usually cellular; neoplastic cells discrete, in aggregates and in syncytial tissue Figure 7.13
adenocarcinoma fragments with or without branching and with crowding and overlapping of nuclei;
peripheral palisading of nuclei may be present within the tissue fragments; cells small,
uniform to slightly pleomorphic and enlarged; lymphocyte-like; high N/C ratios;
scant to indiscernible cytoplasm; cell borders poorly defined; nuclei round to oval
with smooth nuclear membranes; finely granular to compact chromatin; no nuclear
molding; nucleoli inconspicuous to absent; no mitoses; no necrosis; background clean;
bare nuclei +/; Immunoprofile: CK +; S100 protein +
Basal cell adenoma Aspirate usually cellular; neoplastic cells discrete, in aggregates and in syncytial tissue Figure 7.12
fragments with crowding and overlapping of nuclei; cells small, uniform, lymphocyte-
like; high N/C ratios; scant to indiscernible cytoplasm; cell borders poorly defined;
nuclei round to oval with smooth nuclear membranes; finely granular to compact
chromatin; no nuclear molding; nucleoli inconspicuous to absent; no mitoses; no
necrosis; background clean; Immunoprofile: CK +; S100 protein +
Pleomorphic Small basaloid cells, mostly in syncytial tissue fragments or in tight aggregates, acinar Figure 7.16
adenoma with a pattern with hyaline globules +/; cells small with high N/C ratios; poorly defined
predominant basaloid cell borders; round to oval nuclei with smooth nuclear membranes; coarsely granular
cell pattern to compact chromatin; nucleoli inconspicuous; scant cytoplasm; clean background;
fibrillar stroma with aggregates of neoplastic cells in a diagnostic clue; Immunoprofile:
CK +; S100 protein +; calponin +; p63 +;
Cutaneous Basal Aspirate usually cellular; neoplastic cells discrete, in aggregates and in syncytial tissue Figure 7.14
Cell Carcinoma fragments with or without branching and with crowding and overlapping of nuclei;
(from skin overlying peripheral palisading of nuclei may be present within the tissue fragments; cells small,
salivary gland) uniform to slightly pleomorphic and enlarged; lymphocyte-like; high N/C ratios; scant to
indiscernible cytoplasm; cell borders poorly defined; nuclei round to oval with smooth
nuclear membranes; finely granular to compact chromatin; no nuclear molding; nucleoli
inconspicuous to absent; no mitoses; no necrosis; background clean; bare nuclei +/
Reactive intraparotid Polymorphic lymphoid cell population with germinal center cells; tingible body Figure 7.17
lymph node histiocytes
Malignant non- Dissociated cell pattern; lymphoma cells discrete and in aggregates; small, Figure 7.18
Hodgkin lymphoma monomorphic pattern with well to poorly defined cell borders; high N/C ratios; nuclei
round to oval with smooth to irregular nuclear membrane; finely granular chromatin
with parachromatin clearing; prominent nucleoli; cytoplasm variable but scant; no
nuclear molding; mitoses +; karyorrhexis +; Immunoprofile: CK ; LCA +; B/T-cell
markers +; neuroendocrine markers ; S100 protein
PRIMARY SMALL CELL CARCINOMA PRIMARY SMALL CELL CARCINOMA OF

OF THE SALIVARY GLANDS VERSUS THE SALIVARY GLANDS VERSUS MERKEL
METASTATIC PULMONARY SMALL CELL CELL CARCINOMA
CARCINOMA
Other neuroendocrine carcinomas such as Merkel cell
The cytomorphology of small cell carcinomas regardless carcinoma that frequently arise in the head and neck
of their site of origin is same and does not allow identifi- region may involve the salivary gland (Fig. 7.9). The cyto-
cation of the source (Fig. 7.8). It is very necessary to first morphology of the Merkel cell carcinoma cells is very
rule out clinically a primary lung cancer since it is the most similar to that of small cell carcinomas (see Chapter11)
common site of origin. Positive reactivity to TTF-1 and and does not allow their differentiation from cytology
negative reactivity to CK20 will favor pulmonary origin. alone. Both demonstrate positive immunoreactivity to

pancytokeratin and neuroendocrine markers. However,

studies have shown that the cells of primary small cell
PRIMARY SMALL CELL CARCINOMA OF
carcinoma of the salivary glands and Merkel cell car-
THE SALIVARY GLANDS VERSUS BASAL
cinoma are immunoreactive to cytokeratin 20. Clinical
CELL ADENOCARCINOMA
history of primary Merkel cell carcinoma is of utmost
The cells of basal cell adenocarcinoma share morphologic
importance. Ultrastructurally, Merkel cell carcinoma
similarities with that of small cell carcinoma. The tissue frag-
cells demonstrate paranuclear whorls of intermediate
ments of small basaloid cells with or without nucleoli, periph-
filaments (see Chapter 11, Fig. 11.7D), a pattern not
eral palisading of the nuclei, lack of nuclear molding, and
observed in pulmonary or salivary gland small cell
necrosis should favor basal cell adenocarcinoma (Fig. 7.13).
carcinomas.
Ancillary tests with neuroendocrine markers are necessary.
PRIMARY SMALL CELL CARCINOMA PRIMARY SMALL CELL CARCINOMA

OF THE SALIVARY GLANDS VERSUS OF THE SALIVARY GLANDS VERSUS
POORLY DIFFERENTIATED METASTATIC CUTANEOUS BASAL CELL CARCINOMA
CARCINOMAS OVERLYING THE SALIVARY GLAND
Metastatic poorly differentiated adeno or squamous car- A basal cell carcinoma occurring in the skin overlying the
cinomas are sometimes extremely difficult to differentiate parotid gland may mimic the small cell carcinoma. The
from primary small cell carcinomas (Fig. 7.10). Ancillary aspirates of cutaneous basal cell carcinoma show elon-
studies are necessary to confirm the diagnosis. gated deeply stained nuclei with high N/C ratios, strongly
resembling small cell carcinoma (Fig. 7.14).
PRIMARY SMALL CELL CARCINOMA

PRIMARY SMALL CELL CARCINOMA
OF THE SALIVARY GLANDS VERSUS
OF THE SALIVARY GLANDS VERSUS
BASALOID SQUAMOUS CELL
ADENOID CYSTIC CARCINOMA
CARCINOMA
The cells of an adenoid cystic carcinoma with a solid
The basaloid squamous cell carcinoma presents a simi-
pattern demonstrate morphologic similarity to the cells
lar morphologic pattern along with extensive necrosis.
of small cell carcinomas (Fig. 7.15). The latter, however,
However, nuclear molding is not a prominent feature in
shows characteristic nuclear molding, stretch artifacts,
basaloid squamous carcinoma (Fig. 7.11).
frequent mitosis, and karyorrhexis.
PRIMARY SMALL CELL CARCINOMA OF PRIMARY SMALL CELL CARCINOMA

THE SALIVARY GLANDS VERSUS BASAL OF THE SALIVARY GLANDS VERSUS
CELL ADENOMA PLEOMORPHIC ADENOMA WITH
A PREDOMINANT BASALOID CELL
The small cell pattern of basal cell adenoma of the sali- PATTERN
vary glands always enters the differential diagnosis of
small cell carcinoma. The cells of basal cell adenoma are The pleomorphic adenomas present a wide morphologic
small with uniform nuclei, unlike deep-staining pleomor- spectrum. Any pattern consisting of basaloid cells that
phic nuclei of small cell carcinoma (Fig. 7.12). However, constitute a predominant cell type in an aspirate may
lack of nuclear molding, mitosis, and necrosis will favor a present features that resemble a small cell carcinoma
basal cell adenoma. Neuroendocrine markers are negative (Fig.7.16). Examination of several fields may reveal fea-
in basal cell adenoma. tures suggestive of pleomorphic adenoma.

PRIMARY SMALL CELL CARCINOMA PRIMARY SMALL CELL CARCINOMA

OF THE SALIVARY GLANDS VERSUS OF THE SALIVARY GLANDS VERSUS
REACTIVE INTRAPAROTID MALIGNANT NON-HODGKIN
LYMPH NODE LYMPHOMA
The aspirate of an enlarged reactive intraparotid lymph Malignant lymphoma is always considered in the differ-
node may be misinterpreted as a small cell carcinoma ential diagnosis of small cell carcinoma often causing a
(Fig.7.17). Presence of transforming lymphocytes and diagnostic problem (Fig. 7.18). Immunostains with cyto-
tingible body histiocytes will favor a reactive lymph keratin and leukocyte common antigen (LCA) are often
node. necessary for correct diagnosis.
Differential Diagnoses of Small Cell Carcinoma of the Salivary Glands (Figs. 7.8 to 7.18)
B
A
Fig. 7.8: Primary Small Cell Carcinoma versus Metastatic Pulmo-

nary Small Cell Carcinoma to the Parotid Gland. A: FNA of the
parotid mass showing typical cytomorphology of a small cell carci-
noma. B: Bronchial brushings from the same patient showing small
cell carcinoma cells, indicating the parotid lesion to be metastatic
one. C: An example of primary small cell carcinoma of the parotid
C gland indistinguishable from the pulmonary carcinoma.

Fig. 7.9: Primary Small Cell Carcinoma versus Metastatic Merkel

Cell Carcinoma. FNA of a parotid mass in a patient with a history
of Merkel cell carcinoma of the face. The cytomorphology of a pri-
mary small cell carcinoma and the metastatic Merkel-cell carcinoma
is similar. Their immunoprofile is similar as well. Without a clinical
history, the differentiation between the two is not possible.
A B
C D
Fig. 7.10: Primary Small Cell Carcinoma versus Metastatic Poorly Differentiated Carcinomas. AC: FNA of a parotid
mass. This aspirate from a parotid mass was interpreted as small cell carcinoma because of the small cells, high N/C
ratios, deep-staining compact chromatin, and indistinct cytoplasm. The neuroendocrine markers were negative. This
patient had an excision of squamous cell carcinoma of the ipsilateral pinna and this lesion may represent the meta-
static from primary squamous carcinoma of the ear lobe. DG: FNA of a parotid mass from a patient with widespread
metastasis and unknown primary. The malignant cells are in syncytial tissue fragments with scant cytoplasm that do not
exhibit any differentiating features. The malignant cells strongly resemble small cell carcinoma cells. However, there is
no nuclear molding, or stretch artifacts. Some malignant cells in other fields showed granular chromatin and nucleoli
suggesting the diagnosis of poorly differentiated carcinoma. Immunostains for neuroendocrine markers were negative.

G
Fig. 7.11: Primary Small Cell Carcinoma versus Basaloid Squa-

mous Cell Carcinoma in the Neck. AC: FNA of a basaloid squa-
mous carcinoma. The syncytial tissue fragments of small malignant
cells with deep-staining chromatin bear a strong resemblance to
small cell carcinoma. Note, however, that nuclear molding is absent
and some nuclei show micronucleoli. D: FNA of a primary salivary
D gland small cell carcinoma for comparison.

A B
Fig. 7.12: Primary Small Cell Carcinoma versus Basal Cell Adenoma. A, B: FNA of a parotid mass. The small cell pat-
tern of basal cell adenoma always enters the differential diagnosis of a small cell carcinoma. However, lack of nuclear
molding and karyorrhexis favor basal cell adenoma. Also neuroendocrine markers should be negative in basal cell
adenoma.
A B
Fig. 7.13: Primary Small Cell Carcinoma versus Basal Cell Adenocarcinoma. A, B: This aspirate from a basal cell ad-
enocarcinoma shows morphologic overlap with cells of small cell carcinoma. Tissue fragments of malignant cells with
peripheral palisading and lack of nuclear molding will rule out a small cell carcinoma.
A B
Fig. 7.14: Primary Small Cell Carcinoma versus Cutaneous Basal Cell Carcinoma. A, B: A FNA biopsy of a cutaneous
nodule overlying the parotid gland showed a basal cell carcinoma of the skin. Note morphologic similarity to small
cell carcinoma.

A B
Fig. 7.15: Primary Small Cell Carcinoma versus Adenoid Cystic Carcinoma. A, B: These three images are from an ad-
enoid cystic carcinoma with a solid pattern demonstrating morphologic similarity to small cell carcinoma cells. Nuclear
molding and karyorrhexis are lacking.
A B
Fig. 7.16: Primary Small Cell Carcinoma versus Pleomorphic

Adenoma. AC: These three images are from three different cases of
pleomorphic adenoma of the parotid gland showing predominantly
C small basaloid cells and raise the possibility of small cell carcinoma.

Fig. 7.17: Primary small cell carcinoma versus FNA of a reactive

intraparotid lymph node depicting polymorphous lymphoid cells.
A B
Fig. 7.18: A: FNAMalignant lymphoma of the parotid.

C B, C: FNA of small cell carcinoma for comparison.

SUGGESTED READING
Banks ER, Frierson HF, Mills SE, et al. Basaloid squamous cell Klijanienko J, Lagace R, Servois V, et al. Fine-needle sampling
carcinoma of the head and neck: A clinicopathologic and of primary neuroendocrine carcinomas of salivary glands:
immunohistochemical study of 40 cases. Am J Surg Pathol. Cytohistological correlations and clinical analysis. Diagnos
1992;16:939946. Cytopathol. 2001;24:163166.
Cameron WR, Johansson L, Tennvall J. Small cell carcinoma of the Larson LG, Donner LR. Large cell neuroendocrine carcinoma
parotid. Fine needle aspiration and immunochemical findings in of the parotid gland: Fine needle aspiration, and light
a case. Acta Cytologica. 1990;34:837841. microscopic and ultrastructural study. Acta Cytologica.
Chan JKC, Suster S, Wenig BM, et al. Cytokeratin 20 1999;43:534536.
immunoreactivity distinguishes Merkel Cell (primary cutaneous Mair S, Phillips JI, Cohen R. Small cell undifferentiated
neuroendocrine) carcinomas and salivary gland small cell carcinoma of the parotid gland. Cytologic, histologic,
carcinomas from small cell carcinomas of various sites. Am J immunohistochemical and ultrastructural features of a
Surg Pathol. 1997;21:226234. neuroendocrine variant. Acta Cytologica. 1989;33:164168.
Currens HS, Sajjad SM, Lukeman JM. Aspiration cytology of oat- Nagao T, Sugano I, Ishida Y, et al. Primary large cell
cell carcinoma metastatic to the parotid gland (letter). Acta neuroendocrine carcinoma of the parotid gland:
Cytologica. 1982;26:566567. Immunohistochemical and molecular analysis of two cases.
Ellis GI, Auclair PL. Tumors of the Salivary Glands, AFIP Atlas of the Mod Pathol. 2000;13:554561.
Tumor Pathology, series 4. Fascicle 9. Maryland: ARP Press, 2008. Rollins CE, Yost BA, Costa MJ, et al. Squamous differentiation in
Henke AC, Cooley ML, Hughes JH, et al. Fine-needle aspiration small cell carcinoma of the parotid gland. Archiv Pathol Lab
cytology of small cell carcinoma of the parotid. Diagnos Med. 1995;119:183185.
Cytopathol. 2001;25:126129. Shin HJ, Caraway NP. Fine needle aspiration biopsy of metastatic
Huber GF, Khalil M, Falck V, et al. Merkel cell carcinoma with small-cell carcinoma from extrapulmonary sites. Diagnos
solitary parotid metastasis: diagnostic dilemma in the absence Cytopathol. 1998;19:177181.
of a primary site. J Otolaryngol. 2007;36:E70E72. Wenig BM. Atlas of Head and Neck. 2nd ed. Philadelphia, PA: W B
Jorcano S, Casado A, Berenguer J, et al. Primary neuroendocrine Saunders, 2008.
small cell undifferentiated carcinoma of the parotid gland. Yasuo H, Tatemoto K. Bilateral parotid gland metastases as the
Clinic Translat Oncol. 2008;10:303306. initial manifestation of a small cell carcinoma of the lung. Am J
Kini SR, Dardick I. Salivary Gland Tumor. Cytopathology. CD Otolaryngol. 1998;19:140143.
ROM, Ottawa, Pathology Images Inc. 2006.

OFTHE THYROID GLAND
Neuroendocrine tumors of the thyroid include medul-

lary carcinoma, paraganglioma, and small cell carcinoma,
MEDULLARY CARCINOMA OF THE
majority being medullary carcinomas.
THYROID
The neuroendocrine cells of the thyroid are referred
Medullary carcinoma of the thyroid arises from the
to as C cells or calcitonin-producing cells, also known
calcitonin-producing C cells comprising 3% to 10% of
as parafollicular cells or clear cells. The C cells are
all thyroid malignancies. It occurs in two forms; roughly
located individually or in small groups within thyroid fol-
20% are familial and the remaining as sporadic forms.
licles. They are found at the periphery of the follicular
The hereditary form of medullary carcinomas transmit-
wall within the basement membrane and without contact
ted as an autosomal dominant trait includes three types:
with the follicular lumen. They are in an intrafollicular
multiple endocrine neoplasia (MEN) syndromesMEN
rather than interfollicular position as confirmed by ultra-
2A, MEN 2B, and non-MEN familial type (Table 8.1).
structural examination. The C cells are separated from
The MEN 1 syndrome is associated with tumors of the
the thyroid interstitium by the basal lamina. They are
other endocrine organs (see Table 1.1).
restricted to the midupper and upper thirds of the lat-
eral lobes of the thyroid; hence, medullary carcinomas are
found only in these locations (see Fig. 8.2C) and not in CLINICAL FEATURES
the isthmus or the extreme upper or lower third of the
lateral lobes. The sporadic form of medullary carcinoma occurs more
The C cells are derived embryologically from the rem- commonly in women, primarily in the older individuals
nants of the ultimobranchial body. By light microscopy, in fifth to sixth decades of life. They clinically present
the C cells cannot be visualized in routine hematoxylin as a unilateral, palpable thyroid nodule and have a high
and eosin (H&E)-stained sections, but can be highlighted incidence (up to 50%) of cervical lymph node metasta-
by special stains. Most C cells are round to polygonal. ses. Distant metastases via hematogenous spread to liver,
Special stains show that they are argyrophilic (Grimelius lungs, bone, and occasionally to brain occur in roughly
stain). They exhibit marked metachromasia with tolu- 15% of the cases. Occult medullary carcinomas with
idine blue. Ultrastructurally, C cells contain the hallmark local metastatic disease involving the cervical lymph
of polypeptide-producing cells, that is, membrane-bound nodes have been described.
neurosecretory granules. The latter are of two types: The familial forms are common in males and occur at
larger 250 to 280 nm and the smaller 130 nm. The C cells a younger age. The non-MEN familial medullary carci-
are rich with mitochondria and also contain abundant noma is slightly more common in women.
endoplasmic reticulin with lamellar stacking. Occasional Majority of the patients present with a painless thyroid
C cells have prominent cytoplasmic processes that extend nodule that is cold on scan. Up to 50% of the patients will
beyond the adjacent follicular cell. They stain intensely have nodal metastases and up to 15% may have distant
with calcitonin and calcitonin gene-related peptide as metastases. Virtually all medullary carcinomas produce calci-
well as other neuroendocrine markers such as chromo- tonin. Elevated serum levels are diagnostic of the malignancy.
granin, synaptophysin, neuron-specific enolase, and carci- Medullary thyroid carcinomas in general project good
noembryonic antigen (CEA). clinical outcome, especially in sporadic forms. Aggressive
C-cell hyperplasia is considered a precursor lesion for clinical behavior with fatal outcome is described in some
medullary carcinomas (Fig. 8.1AC). hereditary forms.
163

Medullary Carcinoma (Figs. 8.1 and 8.2)
A
B
Fig. 8.1: A: Histologic section of a thyroid demonstrating C-cell

hyperplasia. Note well-defined nests of cuboidal to polygonal cells
in between the thyroid follicles. There was no grossly visible tumor.
The patient had several members of the family with hereditary
type medullary carcinoma. B: Higher magnification. These cells
have abundant eosinophilic cytoplasm. C: Imprint of the surgi-
cally resected specimen showing discrete C cells with plasmacytoid
C appearance.
A B
Fig. 8.2: A: A gross photograph of a nonfamilial (sporadic) form of medullary thyroid carcinoma located in the middle
third of the left lobe and lymph node metastases (arrow). B: This nonfamilial medullary carcinoma is large replacing
the entire right lobe. The tumor presents a flat cut surface.

Chapter 8: Neuroendocrine Tumors ofthe Thyroid Gland 165
Fig. 8.2: (continued) C: An example of hereditary medullary

carcinoma. Note the tumor is located in the middle third of the lobe
C and bilateral.
RADIOLOGIC FINDINGS variable in size, ranging from <1 cm to several centime-

ters, and may replace the entire lobe (Fig. 8.2A,B). Its cut
Medullary carcinomas present as hypofunctioning cold nod- surface is tan-white to gray or pink, usually flat. The con-
ules. The plain x-rays of the neck may show dense calcifica- sistence is soft to firm, at times gritty, without areas of
tion. Ultrasound reveals a hypoechoic mass. Imaging with hemorrhage and necrosis. Calcification may be present.
ultrasonography using 131I metaiodobenzylguanidine dem- The hereditary forms are usually multifocal and bilateral
onstrates a positive uptake and is a useful diagnostic tool. (Fig. 8.2C). Their gross appearance is similar to the spo-
radic medullary carcinomas.
Like many neuroendocrine tumors, the medullary thy-
GROSS AND HISTOLOGIC FEATURES roid carcinomas present an extremely wide spectrum of
morphologic patterns that varies from tumor to tumor
The sporadic form of medullary carcinoma occurs as a and within the same tumor. They also share morphologic
unilateral, well-defined, nonencapsulated solitary nodule similarities with other neuroendocrine tumors such as
paragangliomas, carcinoid tumors, and small cell carcino-
mas. In addition, medullary carcinomas mimic not only
TABLE 8.1. HEREDITARY FORMS OF MEDULLARY
several types of thyroid follicular cell derived tumors, such
THYROID CARCINOMA
as follicular adenomas including hyalinizing trabecular
MEN 2A adenoma, follicular carcinoma, papillary, insular, Hrthle
Medullary thyroid carcinoma cell, or anaplastic carcinomas, but also a wide array of
Adrenal pheochromocytoma nonthyroid neoplasms as well as nonneoplastic entities as
Parathyroid hyperplasia described in differential diagnoses (see Table 8.4) The his-
Associated precursor lesions tologic patterns of medullary carcinomas (Fig. 8.3AO)
C-cell hyperplasia
Adrenal medullary hyperplasia
are similar in both the familial type and the sporadic type
showing multiple growth patterns such as lobular, insu-
MEN 2B lar, trabecular, solid, rarely follicular or papillary, and
Medullary thyroid carcinoma fascicular, the latter formed by the spindle cells simulat-
Adrenal pheochromocytoma ing a sarcomatous pattern. The nests of tumor cells vary
Mucosal neuromas
in size, separated by variable stromal tissue, imparting
Gastrointestinal ganglioneuromas
Musculoskeletal abnormalities an organoid pattern. The medullary carcinoma cell types
Melanosis vary in size and shapes, ranging from small, medium, to
Associated precursor lesions large with occasional giant forms. Their shapes vary from
C-cell hyperplasia round to oval, carcinoid-like cells, cuboidal, plasmacy-
Adrenal medullary hyperplasia toid, polygonal or epithelioid, to spindle shape, triangu-
lar, and caudate to racket shaped. Their cell borders are
Non-MEN familial type
well to poorly defined, and the cytoplasm varies from
MEN, multiple endocrine neoplasia. scant to abundant, clear, pale, to dense. Some may contain

Spectrum of Histopathologic Patterns of Medullary Carcinoma
A B
C D
Fig. 8.3: A: Medullary carcinoma showing a lobular growth pattern and is composed of small round cells (H&E).
B: Medullary thyroid carcinoma showing lobules of pleomorphic cells of varying size consisting of small to large po-
lygonal and short spindle cells separated by amyloid containing stroma (H&E). C: Medullary thyroid carcinoma. The
left half of the field shows tumor composed of large polygonal cells with abundant eosinophilic cytoplasm, while the
rest consists of smaller round to cuboidal cells (H&E). D:Medullary carcinoma is composed predominantly of large
polygonal cells with abundant eosinophilic cytoplasm bearing a morphologic resemblance to oncocytes (H&E).

E F
G H
I J
Fig. 8.3: (continued) E: Histologic section of a medullary carcinoma showing a lobular pattern. The lobules vary in size
separated by bands of fibrous tissue septae. Also note clear change in the cytoplasm (H&E). F: Medullary carcinoma
exhibiting a lobular and a trabecular growth pattern. The trabeculae vary in thickness from slender to broad and are
interdigitating (medium power, H&E). G: Higher magnification of (F) showing broad trabeculae consisting of very
pleomorphic, round to short spindle-shaped cells (H&E). H: Medullary carcinoma exhibiting nests of small cuboidal
cells separated by amyloid (H&E). I: This medullary carcinoma is composed of uniform cuboidal cells forming small
nests with a pseudofollicular growth pattern (H&E). J: A solid growth pattern of medullary carcinoma. The cells con-
tain scant to indiscernible cytoplasm (H&E).

K L
M N
O P
Fig. 8.3: (continued) K: Medullary carcinoma cells are short spindle shaped and separated by stroma (H&E).
L: Medullary carcinoma with a spindle cell pattern. The spindle cells are forming large nests separated by fibrous tissue
septae (H&E). M: Histologic pattern of this medullary carcinoma with nests of elongated spindle cells resembling a
paraganglioma (H&E). N: Medullary carcinoma with abundant amyloid in the stroma. Fine needle aspirates from such
areas may be poorly cellular (H&E). O: Medullary carcinoma with stromal fibrosis and calcification (H&E). P: His-
tologic section of medullary carcinoma showing apple green birefringence of amyloid stained with Congo red (H&E).

Q R
Fig. 8.3: (continued) Q: Bright green fluorescence of amyloid when

stained with thioflavin T and viewed under ultraviolet light (H&E).
R: Medullary carcinoma demonstrating a strong positive reactivity
with calcitonin stain. S: Electron micrograph of medullary carci-
noma showing membrane-bound, spherical neurosecretory granules
with an electron-dense core (arrow). Uranyl acetate and lead citrate
S preparation (42,000).
mucin. Their nuclei can be monomorphic to pleomor- The medullary carcinoma may also contain a signifi-
phic, round, oval, oblong to spindle shape with stippled cant amount of collagenous stroma, with (Fig. 8.3O) or
to coarsely granular chromatin popularly referred to as without calcification. Several morphologic variants of
saltpepper chromatin. Intranuclear cytoplasmic inclu- medullary carcinoma have been described. These include
sions are almost always present. Hemorrhage, necrosis, follicular or tubular, papillary, small cell, giant cell, clear
and mitotic activity are infrequent findings in medullary cell, melanotic (pigmented), oncocytic, squamous, amphi-
carcinomas. Agiven tumor may be monomorphic show- crine (composite calcitonin and mucin-producing), and
ing a predominant cell type or pleomorphic with mixed paraganglioma-like.
patterns containing several cell types. The latter is more
frequent.
Medullary carcinoma is characterized by the pres- HISTOCHEMISTRY
ence of amyloid deposits in the stroma in up to 80% of
the cases (Fig. 8.3H,N). The amyloid shows green bire- Argyrophilia as demonstrated by silver stain (Grimelius)
fringence under crossed polarized light when stained is present in 90% of medullary carcinomas. The stroma
by Congo red (Fig. 8.3P) and green fluorescence under shows periodic acid-Schiff stain and Alcian blue posi-
ultraviolet light when stained by thioflavin T (Fig. 8.3Q). tivity. Both, intra and extracellular mucin are demon-
Medullary carcinoma cells react strongly to calcitonin strated by mucicarmine stain in a high proportion of
antibody (Fig. 8.3R). cases.

IMMUNOPROFILE OF MEDULLARY CYTOPATHOLOGIC FEATURES

CARCINOMA
The specimens for cytopathologic diagnosis mostly
Positive reactivity to calcitonin is very specific for med- represent fine needle aspiration (FNA) biopsies of thy-
ullary carcinomas, although rare negative reactivity has roid nodules or neck masses such as enlarged lymph
been reported. The stain works well on alcohol-fixed nodes involved by metastatic medullary carcinoma.
cytologic preparations. The carcinoma cells react posi- Aspiration biopsies of organs such as lung, liver, bone,
tively to a host of antibodies such as chromogranin and and subcutaneous masses are also examined to rule
synaptophysin, aimed at neuroendocrine differentiation out a metastatic disease. Occasionally, specimens are
(Table8.2). Medullary carcinoma cells show positive reac- obtained via bronchoscopy in cases of pulmonary
tivity to CEA and low molecular weight cytokeratin but involvement.
very rarely to high molecular weight keratin. Reactivity to Cytopathologic features of medullary carcinoma
vimentin is variable. encompass a broad spectrum (Table 8.3; Figs. 8.4 to 8.20),
Depending on the histomorphology of a given medullary
carcinoma, the cytologic presentation will be either mono-
ULTRASTRUCTURE morphic, that is, if only one pattern is evident, or pleomor-
phic with a combination of different morphologic patterns.
Ultrastructurally, medullary carcinoma cells demon- The pleomorphic pattern is more frequently observed.
strate characteristic membrane-bound secretory granules The aspirates of medullary carcinomas are usually
(Fig. 8.3S). adequate to hypercellular; scant cellularity is encountered
with carcinomas containing extensive amyloid deposits
and calcification.
The direct smears of the aspirate show malignant cells
TABLE 8.2. IMMUNOPROFILE OF MEDULLARY either isolated, presenting a dispersed cell pattern, or in loosely
CARCINOMA cohesive groups (Figs. 8.4A, 8.5, and 8.12B). Syncytial-type
tissue fragments are also encountered although infrequently
Antibodies Reactivity (Fig. 8.4B). A true papillary or follicular pattern is not identi-
Calcitonin Positive fied. However, a pseudofollicular pattern may rarely be seen
(see Fig. 8.29A). The spindle cells may be present in fascicles,
Low molecular weight cytokeratin Positive dispersed, or aggregates with intertwining cytoplasmic pro-
cesses (Figs. 8.9A,B; 8.13B; 8.14A; and 8.18A,B).
High molecular weight cytokeratin Rarely expressed Medullary carcinoma cells are very pleomorphic; any
size or shape may be present (Figs. 8.4C,D; 8.5; 8.12A;
Vimentin Variable
8.13A; and 8.15A). The carcinoma cells can be small,
Neuron-specific enolase Positive round to cuboidal, reminiscent of carcinoid tumor cells
(Fig.8.6 and 8.7B), or oval to plasmacytoid (Fig. 8.12B).
Synaptophysin Positive They may be triangular, polyhedral, racket shaped, cau-
date, or spindle-shaped (Fig. 8.18AC). Their size also var-
Chromogranin Positive ies: the small, round cells are slightly larger than the thyroid
follicular cells, and the larger cells are several microns in
CEA Positive
their largest dimension (Fig. 8.15A). A cellular aspirate
Thyroglobulin Negative with a dispersed cell pattern formed by pleomorphic cells
is virtually pathognomonic of medullary carcinoma (Fig.
TTF-1 Positive 8.5), whereas a monomorphic pattern comprising only one
type of cell is not frequently observed (Figs. 8.28A, 8.30A,
Somatostatin Positive 8.32B, and 8.33B). The latter does cause typing difficulties.
The nuclei of medullary carcinoma cells are always
CD56 Positive
eccentric, regardless of the cell shape, cell size, or num-
TTF-1 Positive
ber of nuclei. Extreme marginal location of the nucleus is
characteristic of the plasmacytoid cell type, and bi- and

TABLE 8.3. CYTOPATHOLOGIC FEATURES OF MEDULLARY CARCINOMA
Cellularity Variable, depends on the stromal/amyloid content; usually very cellular
Presentation Cells mostly isolated, in aggregates and infrequently in syncytial tissue fragments forming
nests and trabeculae; follicular or papillary architecture not usually present; pseudofollicular
pattern rarely present; dispersed cell pattern very characteristic; aggregates of spindle cells
may present a fish-school pattern or occur in fascicles
Cells Uniform to markedly pleomorphic; size ranging from small, medium-sized to large with
frequent giant forms; varied shapes: round, cuboidal, plasmacytoid, polygonal, caudate,
racket shaped, triangular, short to elongated spindle shaped; unipolar cells; admixture of
various types is characteristic; cell borders well to poorly defined; variable N/C ratios
Nucleus
Location Always eccentric with extreme marginal location
Numbers Bi-multinucleation frequent
Shape Round, oval, oblong to spindle-shaped; smooth nuclear membranes
Chromatin Deep-staining, coarsely granular (saltpepper) to chunky
Parachromatin clearing Not common
Nucleoli +/
Nuclear grooves Not observed
Intranuclear inclusions Almost always present
Mitotic activity Generally absent
Cytoplasm Variable; scant, indiscernible to abundant; clear, pale, granular to dense; drawn into
cytoplasmic processes; rudimentary tailing to delicate intertwining processes; azurophilic
cytoplasmic granules in Romanowsky-stained preparations
Psammoma bodies Extremely rare
Background Usually clean; amorphous, fluffy to hyaline, acellular material staining positive for amyloid
(Congo red or thioflavin T); strongly resembles colloid with Papanicolaou stain; necrosis
generally absent
Histochemistry Argyrophilic granules in the cytoplasm
Immunoprofile Positive reactivity to calcitonin, low molecular weight keratin, CEA, neuroendocrine markers
(chromogranin A, synaptophysin, somatostatin, neuron-specific enolase), and TTF-1; negative
reactivity to thyroglobulin
Ultrastructure Electron dense, membrane-bound neurosecretory granules

Spectrum of Cytopathologic Patterns of Medullary Thyroid Carcinoma (Figs. 8.4 to 8.20)
A B
C D
Fig. 8.4: FNA of a Medullary Thyroid Carcinoma. A: Low pow-

er showing the characteristic dispersed cell pattern. B: Medium
power. Note the syncytial tissue fragments such as seen here are less
frequently present. C: Higher magnification showing the discrete,
medium-sized to large, pleomorphic, and plasmacytoid neoplas-
tic cells. Binucleation is frequent. Note the intranuclear inclusions
(arrow). D: The medullary carcinoma cells are large to giant form
with multinucleation. The nuclei have coarse chromatin and exhibit
extreme eccentric location. E: Same case, different field, showing a
pleomorphic cell pattern with small round cells containing scant
E cytoplasm, while some cells have cytoplasmic processes.

Fig. 8.5: FNA of a Medullary Carcinoma. A pleomorphic cell

pattern such as seen here is the hallmark of medullary carcinoma.
Fig. 8.6: FNA of a Medullary Carcinoma. The cells are very uni-
form, medium-sized, and plasmacytoid with moderate amount of
cytoplasm. These cells strongly resemble either follicular cells or
Hrthle cells and may be interpreted as follicular or Hrthle cell
neoplasm.
A B
Fig. 8.7: FNA of a Medullary Carcinoma. A: Loosely cohesive medium-sized to large cells consisting of short spindle
and cuboidal cells with high N/C ratios and dense nuclear chromatin. B: Another field from the same case showing
predominantly small cells with poorly defined cell borders and high N/C ratios.

A B
Fig. 8.8: FNA of a Medullary Carcinoma. A: The aspirate shows

a pleomorphic cell pattern with coarsely granular nuclear chroma-
tin pattern (saltpepper) characteristic of a neuroendocrine tumor.
Note nucleoli are not appreciated. The cells possess delicate cyto-
plasmic processes. B: Smear stained for calcitonin showing positive
reactivity. C: Different example of medullary carcinoma. Reactivity
to calcitonin is usually very strong as demonstrated by these medul-
C lary carcinoma cells.
A B
Fig. 8.9: A, B: FNA of a Medullary Carcinoma. A predominant spindle cell pattern with delicate, long, unipolar cyto-
plasmic processes and eccentric nuclei. Note the characteristic saltpepper chromatin.

A B
Fig. 8.10: FNA of a Medullary Carcinoma Stained with Romanowsky

Stain. A: The cells are loosely cohesive. B, C: These medullary car-
cinoma cells contain the characteristic azurophilic granules in their
C cytoplasm (arrows).
Fig. 8.11: FNA of a Medullary Carcinoma. These medullary carci-

noma cells are dispersed, monomorphic, small, round with mostly
poorly defined cell borders and scant cytoplasm that is indiscernible
to a thin rim of dense cyanophilic (arrows). An occasional cell is
large with appreciable cytoplasm. The nuclei are round with coarse-
ly granular chromatin. There is no nuclear molding. With a mono-
morphic pattern of small round cells, malignant lymphoma must be
considered in the differential diagnosis.

A B
Fig. 8.12: FNA of a Medullary Carcinoma. A: The pleomorphic neoplastic cells are present singly, with many
spindle forms possessing cytoplasmic processes. The background contains fluffy acellular material which may
represent amyloid. B: Another field from the same case demonstrating plasmacytoid cells with minimal varia-
tion in size.
A B
Fig. 8.13: FNA of a Medullary Carcinoma. A: The aspirate is characterized by a pleomorphic cell pattern with pre-
dominant spindle cells. Note long cytoplasmic processes, eccentric nuclei, and coarsely granular chromatin. B: Different
example of medullary carcinoma with a spindle cell pattern.

A B
Fig. 8.14: FNA of a Medullary Carcinoma. A: The medullary car-

cinoma cells are spindle shaped and in fascicles with an admixture
of round cells. Note the acellular cyanophilic material in close
association with carcinoma cells and probably representing amyloid
(arrows). B: A different field showing pleomorphic malignant cells.
Note multinucleation and intranuclear inclusions (arrowheads). The
background shows abundant dense acellular material that probably
represents amyloid (AM). In Papanicolaou-stained smears, amy-
loid resembles colloid. C: The cell block of the aspirate showing a
very pleomorphic, diagnostic cell pattern of medullary carcinoma
C (H&E).
A B
Fig. 8.15: FNA of Medullary Carcinoma. A: The neoplastic cells are very pleomorphic and were misinterpreted as an
anaplastic carcinoma. B: Different field depicting loosely cohesive, round, and spindle-shaped cells with eccentric nuclei.

Fig. 8.16: FNA of a Medullary Carcinoma. These medullary carci-

noma cells are small with hyperchromatic nuclei and indiscernible
cytoplasm, some showing rudimentary cytoplasmic processes. This
pattern may be mistaken for a follicular neoplasm.
A B
Fig. 8.17: FNA of a Medullary Carcinoma. A, B: Large syncytial

tissue fragments such as depicted here are an unusual presenta-
tion of medullary thyroid carcinoma. C: Note the strong positive
C reaction to calcitonin.

A B
Fig. 8.18: FNA of Medullary Carcinoma. A: The medullary carci-

noma cells are pleomorphic in size and shape. The small round cells
have scant indiscernible cytoplasm with rudimentary cytoplasmic
processes while the larger cells that are spindle and triangular
shaped have long cytoplasmic processes. B: Larger cells with cyto-
plasmic processes. C: Small round cells with poorly defined cell bor-
ders and larger triangular cells with eccentric nuclei and cytoplasmic
C processes.
A B
Fig. 8.19: A, B: FNA of a medullary thyroid carcinoma with an exclusive spindle cell pattern raising the possibility of
a soft tissue tumor. Calcitonin stain was positive. Medullary carcinoma was confirmed on thyroidectomy.

A B
Fig. 8.20: FNA of a Medullary Carcinoma. A, B: This aspirate

stained with Romanowsky stain shows a pleomorphic cell pattern
with some cells containing azurophilic granules in their cytoplasm
(arrows). C: Same aspirate with Papanicolaou stain. (Courtesy of
C Mithra Baliga, M.D., University of Mississippi, Jackson, Mississippi.)
multinucleation occur very frequently (Fig. 8.4D). The unipolar with eccentric nuclei. A group of spindle cells with
nuclei are round, sometimes oval, and occasionally oblong delicate intertwined cytoplasmic processes is a characteristic
or elongated as in spindle-shaped cells. Their chromatin finding in smears from medullary carcinoma (Fig. 8.9A,B).
is coarsely granular, stippled with saltpepper pattern, Another feature of diagnostic importance is the pres-
characteristic of neuroendocrine tumors (Figs. 8.8 and ence of azurophilic granules in the cytoplasm of medullary
8.9). The presence of nucleoli is not a consistent finding. carcinoma cells that are seen only in air-dried prepara-
Bizarre nuclei, such as those seen in anaplastic carcino- tions stained by the Romanowsky method (Fig. 8.10B,C)
mas, are rare but do occur. A remarkable and consistent and not visualized in Papanicolaou-stained preparations.
feature is the presence of intranuclear cytoplasmic inclu- These granules are present in about 5% to 10% of the
sions (Figs. 8.4C and 8.14B). neoplastic cell population.
The cytoplasm of medullary carcinoma cells is variable. One of the characteristic features of medullary carci-
In small round cells, it is very scant and hardly discernible noma is the presence of stromal amyloid. The latter can be
(Fig. 8.11), whereas in plasmacytoid or large polyhedral seen in cytologic preparations as fluffy, finely granular, or
cells, it is moderate to abundant (Figs. 8.15A and 8.17A). dense acellular material in the background (Fig.8.14A,B).
It generally stains pale and has a fibrillar quality. The cyto- The amyloid has the same staining characteristics as the
plasm is often drawn out in a delicate process or may be colloid in Papanicolaou-stained preparations and cannot
rudimentary in cuboidal cells (Fig. 8.8A). The spindle cells be differentiated from it without special stains such as
of medullary carcinoma are usually and characteristically Congo red (Fig. 8.3P) or thioflavin T (Fig.8.3Q). Although

the presence of intracellular cytoplasmic amyloid has been spindle-shaped cells, is infrequent and may be mistaken
described, it is not appreciated in Papanicolaou-stained for other types of thyroid neoplasms, and vice versa
preparations. The use of special stains to identify amyloid (Table 8.4). Neoplasms such as Hrthle cell carcinomas
in cytologic preparations is time consuming and not rec- are often confused with medullary carcinoma because
ommended. It is best performed on cell block preparations. of the plasmacytoid cells. A case of plasmacytoma
mistyped as medullary carcinoma has been reported.
Follicular neoplasms, for example, hyalinizing trabecu-
DIAGNOSTIC ACCURACY lar adenoma, follicular adenomas, and carcinomas, have
been misinterpreted as medullary carcinomas. Extreme
The cytologic typing of medullary carcinoma can be pleomorphism with bizarre nuclei or a spindle cell pat-
achieved with a high degree of accuracy. However, tern may be mistaken for anaplastic carcinoma. Aspin-
because of the morphologic overlap, medullary carcino- dle cell pattern can also be confused with soft tissue
mas can be mistyped as various different types of thyroid
cancers, both histologically and cytologically. Medullary TABLE 8.4. DIFFERENTIAL DIAGNOSES OF
thyroid carcinomas can also be misinterpreted as benign MEDULLARY CARCINOMA
nonneoplastic entities, other neuroendocrine neoplasms,
and as nonthyroid neoplasms. Nodular goiter
Typing errors are generally due to inexperience and
unfamiliarity with the varied cytopathologic features of Follicular cell hyperplasia
medullary carcinoma.
Spindle-shaped stromal cells
False-negative diagnosis is rendered due to inadequate
specimens or occasionally when the carcinoma cells are mis- Amyloidosis or amyloid goiter
interpreted as benign follicular cells. A diligent search is nec-
essary in poorly cellular specimens with abundant stromal Follicular neoplasms
substance (amyloid) to identify medullary carcinoma cells.
A cytologic diagnosis of medullary carcinoma must be Hyalinizing trabecular adenoma
confirmed by other means, such as
Cellular follicular adenoma
1. Immunostain for calcitonin Follicular carcinoma

2. Serum calcitonin levels
Hrthle cell carcinoma
DIFFERENTIAL DIAGNOSES Papillary carcinoma
Poorly differentiated insular carcinoma

Medullary carcinomas may be overdiagnosed in the
presence of benign spindle cells of stromal origin in Anaplastic (undifferentiated) carcinoma
cases of nodular goiters when they are present in large
numbers. Proliferating fibroblasts from granulation tis- Other neuroendocrine tumors
sues and fascicles of smooth muscle fibers from blood
vessels mimic the cytologic pattern of spindle cell pat- Carcinoid tumor
tern of medullary carcinomas. Hyperplastic nodular
Paraganglioma
goiters have been also interpreted as medullary carci-
noma. The rare cases of amyloid goiter in patients with Calcitonin-free small cell carcinoma
systemic amyloidosis are another example of diagnostic
pitfall, where a diagnosis of medullar carcinoma may (Neuroendocrine carcinoma)
be rendered.
The pleomorphic cell pattern is characteristic and Soft tissue tumors (primary or metastatic)
diagnostic of medullary carcinoma. It is more frequently
Malignant lymphoma
encountered allowing an accurate cytologic diagnosis.
A monomorphic cell pattern, comprising only one cell Malignant melanoma
type such as small round cells, plasmacytoid cells, or

tumors. Medullary carcinomas demonstrate morpho- fibroblasts are bipolar with central nuclei, while medul-
logic overlap with other neuroendocrine tumors such lary carcinoma cells are unipolar with eccentric nuclei.
as carcinoid tumors, paragangliomas, or the rare oat Negative stain for calcitonin (Table 8.5) will favor the
cell carcinoma of the thyroid. The small cell pattern benign diagnosis.
may also be mistyped as poorly differentiated insular
thyroid carcinoma, metastatic small cell carcinoma, or a
Medullary Carcinoma versus Hyperplastic
malignant lymphoma.
Nodular Goiter
The differentiating features between medullary car-
cinoma and several other diagnostic entities are listed in Follicular hyperplasia in a nodular goiter has been misin-
Tables 8.5 to 8.11 and illustrated in Figures 8.21 to8.42. terpreted as medullary thyroid carcinoma as reported in the
literature. The hypercellular specimens composed of round
to cuboidal follicular cells may be responsible for mistyping.
Medullary Carcinoma versus Stromal Cells in
Nodular Goiter
Medullary Carcinoma versus Amyloid
Occasionally, in a nodular goiter, the fibroblasts from the
Goiter
supporting stroma or the granulation tissue from an orga-
nizing hematoma may appear very similar to the spindle Systemic amyloidosis involving the thyroid gland rarely
cells of medullary carcinoma (Fig. 8.21AH). Features presents as a goiter (Fig. 8.22). Extensive amyloid depos-
of nodular goiter, if present in other areas of the smears, its in a cytologic sample may be misinterpreted as medul-
should aid in correct interpretation. Also, the stromal lary carcinoma.
TABLE 8.5. DIFFERENTIATING FEATURES BETWEEN BENIGN AND MALIGNANT SPINDLE CELLS OF
STROMAL ORIGIN AND MEDULLARY CARCINOMA WITH A SPINDLE CELL PATTERN
Medullary Carcinoma with a

Spindle Cell Pattern Benign Spindle Cells of Stromal Origin
Presentation In tissue fragments, loosely In tissue fragments or loosely cohesive groups; isolated cells
cohesive groups or isolated cells; infrequent
may be in fascicles
Arrangement May be in fascicles or loosely In fascicles with palisading of nuclei, directional flow to the
cohesive groups cytoplasm; swirling arrangement; cells may be separated by collagen
Cells Pleomorphic in size Large, mildly pleomorphic
Cytoplasm Variable; cytoplasmic processes Abundant, pale, bipolar cytoplasmic processes

thin, delicate, and unipolar, often
intertwining
Nuclei Round, oval, oblong to spindle Round, oval, oblong, spindle to cigar shaped, uniform to mildly
shape; pleomorphic in size; pleomorphic, smooth nuclear membranes, notch on the membrane
intranuclear inclusions +; nuclear +/, compact to evenly dispersed, finely granular chromatin;
chromatin with saltpepper multiple micro/macronucleoli +/; intranuclear inclusions +/;
pattern mitosis regular +/
Background Clean Clean to inflammatory; features of nodular goiter or Hashimoto

thyroiditis +/
Immunochemistry Calcitonin and neuroendocrine Calcitonin and neuroendocrine markers negative

markers positive

TABLE 8.6. DIFFERENTIATING FEATURES BETWEEN MEDULLARY CARCINOMA AND HYALINIZING
TRABECULAR ADENOMA
Medullary Carcinoma Hyalinizing Trabecular Adenoma

Cellularity Variable, usually cellular Variable
Presentation Cells mostly isolated or in loosely cohesive groups with a dispersed Cells isolated, in loosely cohesive groups and
pattern; syncytial tissue fragments not common; no architectural in syncytial tissue fragments, some with central
configurations acellular hyaline material with cells springing
from it; trabecular with branching +/
Cells Monomorphic to markedly pleomorphic; round, plasmacytoid, Round, oval, elongated, spindle shape with
spindle shaped with unipolar cytoplasmic processes; well to poorly bipolar cytoplasmic processes; well to poorly
defined cell borders; N/C ratios variable defined cell borders; N/C ratios low
Nucleus Eccentric with extreme marginal location; bi and multinucleation Central to eccentric; round to oval, smooth
frequent; giant forms +/pleomorphic, round, oval, oblong to nuclear membranes; bi-multinucleation not
spindle shaped, smooth nuclear membranes; saltpepper type seen; finely granular chromatin; micronucleoli
granular chromatin, sometimes chunky; nucleoli usually not seen; +/; perinucleolar halo +; intranuclear
intranuclear inclusions always present; grooves not appreciated inclusions always present; nuclear grooves +
Cytoplasm Variable; scant to abundant; pale, granular to dense; Abundant, pale

intracytoplasmic azurophilic granules with Romanowsky stain
Background Clean; amorphous, acellular, hyaline material confirmed as Clean; amorphous, acellular, hyaline material;
amyloid with Congo red stain or thioflavin T negative staining for amyloid; hyaline material
of basement membrane origin
Immunoprofile Positive reactivity to calcitonin; negative reactivity to Negative reactivity to calcitonin; positive
thyroglobulin reactivity to thyroglobulin
TABLE 8.7. DIFFERENTIATING FEATURES BETWEEN MEDULLARY CARCINOMA WITH ROUND CELL
PATTERN AND FOLLICULAR ADENOMA/FOLLICULAR CARCINOMA
Medullary Carcinoma Follicular Adenoma/Carcinoma

Cellularity Usually cellular Variable
Presentation Cells mostly isolated, or in loosely cohesive groups Cells arranged in syncytial tissue fragments with and
with a dispersed pattern; syncytial tissue fragments without follicular pattern; isolated and loosely cohesive
not common; no architectural configurations; groups less frequent
pseudofollicular pattern +/
Cells Small, round to cuboidal; ill to well-defined cell Small, round to cuboidal; ill-defined cell borders; high
borders; high N/C ratios N/C ratios
Nucleus Eccentric; round, oval; smooth nuclear membranes; Central location; round with smooth nuclear
saltpepper type granular chromatin, sometimes membranes; coarsely granular chromatin; micronucleoli
chunky; nucleoli usually not seen; intranuclear +/; intranuclear inclusions absent
inclusions always present
Cytoplasm Scant, pale to dense; cytoplasmic tailing (rudimentary Scant indiscernible cytoplasm; no cytoplasmic processes
process) +/
Amyloid +/ Absent
Colloid Absent May be present in the background or within the

follicular lumens
Immunoprofile Positive reactivity to calcitonin; negative reactivity to Negative reactivity to calcitonin; positive reactivity to
thyroglobulin thyroglobulin

TABLE 8.8. DIFFERENTIATING FEATURES BETWEEN MEDULLARY CARCINOMA WITH MONOMORPHIC

ROUND, OVAL TO PLASMACYTOID CELLS AND HRTHLE CELL CARCINOMA
Medullary Carcinoma Hrthle Cell Carcinoma

Cellularity Highly cellular Highly cellular
Pattern Cells mostly discrete, in groups rarely in syncytial tissue Cells discrete, in groups or in syncytial tissue
fragments without any architectural patterns, dispersed fragments, a dispersed pattern is frequent
pattern frequent and characteristic
Cells Medium-sized, round, oval, plasmacytoid, mildly Medium-sized, round, oval to plasmacytoid,
pleomorphic; cell borders well to poorly defined; N/C uniform in a given case; cell borders well defined
ratios variable in discrete cells; N/C ratios very high
Nucleus Almost always eccentric, binucleation frequent; round, Central to eccentric; binucleation frequent;
variably sized; smooth nuclear membranes, coarsely round, mostly uniform with little variation in
granular chromatin to saltpepper type chromatin; size; smooth nuclear membranes, finely granular
nucleoli not conspicuous; intranuclear inclusions chromatin; macro nucleoli conspicuous;
frequent intranuclear inclusions +/
Cytoplasm Variable; pale, lacy to dense; azurophilic granules in Variable, usually scant; granular to dense;
Romanowsky-stained preparations azurophilic granules in Romanowsky-stained
preparations not present
Background Colloid absent; amyloid present; clean with no necrosis Colloid +/; amyloid absent; necrosis+/
Immunoprofile Calcitonin +; thyroglobulin Calcitonin ; thyroglobulin +
Ultrastructure Neurosecretory granules Abundant mitochondria
TABLE 8.9. DIFFERENTIATING FEATURES BETWEEN MEDULLARY CARCINOMA AND PAPILLARY

CARCINOMA WITH A SINGLE CELL PATTERN
Medullary Carcinoma Papillary Carcinoma

Pattern Cells mostly discrete, in groups rarely in syncytial tissue Cells mostly discrete, in groups rarely in
fragments without any architectural patterns, dispersed syncytial tissue fragments without any
pattern frequent and characteristic architectural patterns, dispersed pattern
Cells Small, round to cuboidal; ill to well-defined cell borders; Small, round to cuboidal; to short columnar, ill
high N/C ratios to well-defined cell borders; high N/C variable
Nucleus Eccentric; round, oval; smooth nuclear membranes; Eccentric to central; round, oval; smooth
saltpepper type granular chromatin, sometimes nuclear membranes; saltpepper type
chunky; nucleoli usually not seen; binucleation frequent; granular chromatin; nucleoli usually not
intranuclear inclusions always present seen; binucleation not a feature; intranuclear
inclusions always present
Cytoplasm Scant, pale to dense; cytoplasmic tailing (rudimentary Variable, pale, clear, or vacuolated; azurophilic
process) +/; azurophilic granules in Romanowsky- granules in Romanowsky-stained preparations
stained preparations not present
Background Colloid absent; amyloid present Colloid +/; amyloid absent
Immunoprofile Calcitonin +; thyroglobulin Calcitonin ; thyroglobulin +

TABLE 8.10. DIFFERENTIAL DIAGNOSES OF MEDULLARY CARCINOMA WITH SMALL,

ROUND CELL PATTERN
Malignant Lymphoma
Medullary Carcinoma (Non-Hodgkin Type/ Metastatic Small Cell
(Small Cell Type) Insular Carcinoma Plasmacytoma) Carcinoma
Presentation Neoplastic cells discrete, Dispersed cell pattern or Cells mostly isolated Neoplastic cells
in loosely cohesive cells in syncytial tissue with dispersed pattern; isolated, in loosely
groups, infrequently in fragments forming nests, rare syncytial tissue cohesive groups and
syncytial tissue fragments; insulae or trabeculae; fragment in syncytial tissue
pseudofollicular pattern microfollicular pattern fragments without any
+/ +/; intense crowding architectural patterns
and overlapping of nuclei
Cells Small monomorphic; Small in size, Small, monomorphic Small pleomorphic in

poorly defined cell monomorphic, round, poorly defined cell size, poorly defined
borders; high N/C ratios poorly defined cell borders; high N/C ratios cell borders; high N/C
borders; high N/C ratios ratios
Nucleus Round; smooth nuclear Approximately 10 mm in Round; smooth to Round, oval, oblong to
membrane; coarsely diameter; round; smooth irregular nuclear short spindle shaped;
granular chromatin; nuclear membrane, finely membrane; finely smooth nuclear
nucleoli +/ granular chromatin granular chromatin with membrane; compact
with parachromatin parachromatin clearing; chromatin; nucleoli
clearing; micronucleoli microncleoli +; no not appreciated;
+; no nuclear molding; nuclear molding; mitosis nuclear molding
no stretch artifacts; +; stretch artifacts +; characteristics; mitosis
mitosis +/; intranuclear intranuclear inclusions +; stretch artifacts +;
inclusions +/; nuclear ; nuclear grooves ; intranuclear inclusions
grooves +/; karyorrhexis karyorrhexis + ; nuclear molding +;
not observed karyorrhexis +
Cytoplasm Scant, insignificant; Scant, insignificant; may Scant, indiscernible Scant, indiscernible
rudimentary cytoplasmic contain small vacuoles
tailing
Colloid Absent /+ Absent Absent
Amyloid Present Absent Absent Absent
Background Clean Clean or necrosis Clean or necrotic debris Necrosis +/
Immunoprofile
Calcitonin +
TTF-1 + + +
Cytokeratin + + +
Thyroglobulin +
Neuroendocrine + +
markers
Leukocyte +
common
antigen

TABLE 8.11. DIFFERENTIATING FEATURES BETWEEN MEDULLARY CARCINOMA AND

ANAPLASTIC CARCINOMA
Medullary Carcinoma Anaplastic Carcinoma

Cellularity Generally high Generally high, can be low with markedly desmoplastic
cancer
Pattern Cells mostly discrete, in groups presenting a Isolated, loosely cohesive; in syncytial tissue fragments
fish-school pattern; rarely in fascicles
Cells Variably sized, spindle shaped; delicate, slender; Variably sized, slender to plump spindle shaped, well-
well-defined cell borders; N/C ratios variable defined cell borders; N/C ratios variable; giant forms
frequent
Nucleus Eccentric, round to oval, short spindle Central to eccentric; very pleomorphic; multinucleation
shaped; pleomorphism may be pronounced; +; coarsely granular chromatin with excessively cleared
smooth nuclear membranes; coarsely granular parachromatin; smooth to irregular nuclear membranes;
chromatin; nucleoli not conspicuous; bizarre forms frequent; multiple micro/macronucleoli
intranuclear inclusions present; mitosis with irregular forms; intranuclear inclusions +; mitotic
activity + with normal and abnormal mitoses
Cytoplasm Variable; pale lacy to dense; unipolar with Variable, can be abundant and dense; cytoplasmic
delicate cytoplasmic processes often intertwining processes rare
Background Clean; amyloid +; necrosis absent; stromal tissue Amyloid ; necrosis frequent; stromal tissue fragments
fragments not present +/
Immunoprofile Calcitonin +; thyroglobulin Calcitonin ; thyroglobulin usually negative
Ultrastructure Electron dense, membrane-bound; No neurosecretory granules

neurosecretory granules
Medullary Thyroid Carcinoma versus Follicular adenomas were referred to as paraganglioma-like fol-
Neoplasms licular adenoma. The distinction between the two may be
very difficult without the aid of immunochemical stains
The aspirates of medullary carcinomas may be misinter-
for calcitonin and thyroglobulin. Table 8.6 lists the differ-
preted as follicular neoplasms and vice versa. A morpho-
entiating cytologic features of both medullary carcinoma
logic variant of follicular adenoma namely hyalinizing
and hyalinizing trabecular adenoma.
trabecular adenoma presents a cytologic pattern that is
very difficult to differentiate from medullary carcinoma
(see below). Cellular follicular adenomas such as microfol- Medullary Carcinoma versus Follicular Adenoma/
licular or trabecular types and well-differentiated follicu- Carcinoma
lar carcinomas may be mistyped as medullary carcinoma.
The common cytologic presentations of medullary carci-
When in doubt, immunostains must be performed either
nomas include isolated or loosely cohesive pleomorphic
on smears or the cell block, if available
cells. However, the infrequently encountered cytologic
presentation with syncytial-type tissue fragments form-
ing a pseudofollicular pattern and small, round to
Medullary Carcinoma versus Hyalinizing
cuboidal cells with nuclei containing coarse chromatin
Trabecular Adenoma
may be mistyped as follicular adenoma or carcinoma.
Hyalinizing trabecular adenoma is an infrequent sub- The presence of intranuclear cytoplasmic inclusions
type of follicular adenoma that strongly resembles favors a diagnosis of medullary carcinoma or a fol-
medullary carcinoma both cytologically and histologi- licular variant of papillary carcinoma. Recognition of
cally (Figs. 8.23 to 8.26). In fact, hyalinizing trabecular medullary carcinoma may be extremely difficult unless

Differential Diagnoses of Medullary Carcinoma (Figs. 8.21 and 8.22)
A B
C D
E F
Fig. 8.21: Medullary Carcinoma versus Benign Spindle Cells of Stromal Origin. A: Medullary carcinoma versus nodular
goiter. An example of pleomorphic stromal cells from an aspirate of nodular goiter. Note that the stromal cells have bi-
polar cytoplasmic processes with central nuclei, unlike medullary carcinoma cells that are usually unipolar with eccentric
nuclei. B: Spindle-shaped stromal cells from nodular goiter may be mistaken for medullary carcinoma. The delicate slender
spindle cells bear a strong resemblance to medullary carcinoma cells. The stromal cells are, however, few in numbers and
occur in the background of nodular goiter. C: A different case of nodular goiter depicting aggregates of uniform spindle
cells containing regular nuclei. These cells represent a proliferating granulation tissue originating from an organizing he-
matoma. D: FNA of a medullary carcinoma showing unipolar spindle-shaped cells for comparison. E: FNA of a mass clini-
cally considered to be of thyroidal origin. Spindle-shaped actively proliferating fibroblasts with delicate cytoplasmic pro-
cesses. The nuclei are uniform with finely granular chromatin suggesting the diagnosis of medullary carcinoma. Excision
revealed granulation tissue and an organizing hematoma. F: Medullary carcinoma cells for comparison with fibroblasts.

G H
Fig. 8.21: (continued) G, H: FNA of a nodular goiter showing longitudinally sectioned blood vessel with palisading, uni-
form cigar-shaped nuclei consistent with leiomyocytes. These fascicles of spindle cells may be misinterpreted as medullary
carcinoma.
Fig. 8.22: Medullary Carcinoma versus Amyloid Goiter. FNA of an

amyloid goiter. The aspirate is poorly cellular consisting of predomi-
nantly acellular material that is proven histochemically as amyloid.
This case may be typed as medullary thyroid carcinoma. (Courtesy
of John F. Goellner, M.D., Previously of Department of Pathology,
Mayo Clinic Rochester, Minnesota.)
Medullary Carcinoma versus Follicular Neoplasms (Figs. 8.23 to 8.30)
A B
Fig. 8.23: Medullary Carcinoma versus Hyalinizing Trabecular Adenoma. A: Histologic section showing trabeculae
formed by elongated follicular cells (H&E). B, C: Histologic sections of a different case of hyalinizing trabecular ad-
enoma. B: This field shows large follicular cells forming trabeculae and nests. Note focal area in the center, where nuclei
appear very clear similar to that seen in papillary carcinoma. Also, note stromal hyalinization (arrows) (H&E).

Fig. 8.23: (continued) C: Another field showing dense hyalinizing

stroma (arrows) separating the islands and trabeculae of neoplastic
C follicular cells (H&E).
A B
Fig. 8.24: FNA of a Surgically Confirmed Hyalinizing Trabecular Adenoma. A: The follicular cells are in syncytial
tissue fragments forming trabeculae. Note the abundant granular cytoplasm. Their nuclei have powdery chromatin,
grooves, and inclusions (arrows). B: The cells are discrete and loosely cohesive. They are large, elongated, some showing
delicate filamentous cytoplasmic processes. Note intranuclear inclusions (arrows). This case was originally interpreted
as either a papillary carcinoma or a medullary carcinoma.
A B
Fig. 8.25: FNA of Hyalinizing Trabecular Adenoma. A, B: These two images show syncytial fragments of follicular
cells with a trabecular pattern. Their nuclei are enlarged with pale granular chromatin. Note the intranuclear inclusions
(arrows) and nuclear grooves.

Fig. 8.25: (continued) C: This field shows stromal hyaline material

C (arrow) surrounded by neoplastic follicular cells.
A B
C D
Fig. 8.26: FNA of Hyalinizing Trabecular Adenoma. A: The cells are elongated, spindle shaped, and have bland nuclei.
The pattern has a strong resemblance to medullary thyroid carcinoma cells and is interpreted as such. B: Syncytial tissue
fragments of follicular cells without any architectural configurations. The nuclei have finely granular chromatin, grooves,
occasional micronucleoli, and frequent inclusions (arrows). C: This field shows intercellular hyaline material (arrows). The
nuclei have powdery chromatin and inclusions. D: Note a pseudofollicular pattern. The collagen seen in the center may be
mistaken for amyloid.

Fig. 8.26: (continued) E: Histologic section of the hyalinizing

trabecular adenoma. Note that the aspirate can easily be misinter-
preted as a medullary carcinoma. (Courtesy of Marizza de Peralta-
E Venturina, M.D., Cedar Sinai Hospital, Los Angeles, California.)
A B
Fig. 8.27: A, B: Medullary Carcinoma versus Follicular Adenoma/Carcinoma. An example of medullary carcinoma
cytologically interpreted as cellular follicular adenoma. The syncytial arrangement of cuboidal cells favored the
diagnosis of follicular neoplasm. The short spindle cells, rudimentary cytoplasmic processes, and intranuclear inclusions
were not appreciated at the time of examination. Thyroidectomy revealed a medullary carcinoma.
A B
Fig. 8.28: Medullary Carcinoma versus Follicular Adenoma. AC: Syncytial tissue fragments of neoplastic cells with-
out a follicular pattern. Their nuclei are uniform. Along the periphery, note that the cells are plasmacytoid. This case
was interpreted as a follicular adenoma. Medullary carcinoma was confirmed on surgical excision.

A B
Fig. 8.29: Medullary Carcinoma versus Follicular Adenoma/Car-

cinoma. A: This cellular aspirate showed a monomorphic popu-
lation of small- to medium-sized cells, discrete, and in small tis-
sue fragments with a pseudofollicular pattern (arrows) (medium
power). B: Higher magnification demonstrated eccentric nuclei and
minimal pleomorphism. Note the pseudofollicular pattern (arrows).
The aspirate was interpreted as a cellular follicular adenoma. C:
Thyroidectomy revealed a medullary carcinoma, confirmed by posi-
C tive calcitonin stain (H&E).

A B
Fig. 8.30: Medullary Carcinoma versus Follicular Carcinoma. A, B: This cellular aspirate consisted of syncytial tissue
fragments of round to cuboidal cells with scant cytoplasm. The nuclear chromatin was uniform and bland, lacking the
coarse granularity of medullary carcinoma cell nuclei. Absence of pleomorphism and saltpepper chromatin leads to
the diagnosis of a follicular neoplasm. Thyroidectomy revealed a medullary carcinoma.
cytoplasmic processes are identified (Table 8.7) (Figs. Medullary Carcinoma versus Insular
8.28 to 8.30). Appropriate immunostains will confirm the Carcinoma
diagnosis.
The small cell variant of medullary carcinoma shows
morphologic overlap with other small cell malignancies
Medullary Carcinoma versus Hrthle Cell
such as poorly differentiated or insular carcinoma of the
Carcinoma
thyroid as well as malignant lymphoma and metastatic
Cells aspirated from some Hrthle cell carcinomas exhibit small cell neuroendocrine carcinoma. The aspirate of
a strong morphologic resemblance to plasmacytoid cells medullary carcinoma consisting of small uniform cells is
of medullary carcinoma. A prominent cherry-red macro- very difficult to distinguish from insular carcinoma of the
nucleolus favors the diagnosis of Hrthle cell carcinoma. thyroid without the help of immunostains (Fig. 8.36A).
Whenever an aspirate shows a monomorphic pattern of Insular carcinomas (Fig. 8.36B) often show necrosis and
oval to plasmacytoid cells with no other cytologic fea- increased proliferative activity, a feature generally not
tures of medullary carcinoma or Hrthle cell carcinoma, observed with medullary carcinomas. Calcitonin will be
it is prudent to recommend tests to rule out medullary strongly positive with medullary carcinoma cells. Arare
carcinoma (Table 8.8; Figs. 8.31 to 8.34). primary neuroendocrine tumor referred to as calcito-
nin-free, oat cell carcinoma will be extremely difficult
to differentiate from either a medullary carcinoma or a
Medullary Carcinoma versus Papillary Carcinoma
metastatic small cell carcinoma (see Fig. 8.48). The dif-
Most papillary carcinomas of thyroid are easily recog- ferential diagnosis of thyroid aspirates with small cells is
nized by the varied architectural patterns of the tissue listed in Table 8.10 and illustrated in Figure 8.41AC.
fragments and the characteristic nuclear morphology.
Very infrequently, aspirates from papillary carcinomas
Medullary Carcinoma versus Anaplastic
present a single cell pattern with a large population of
Carcinoma
cuboidal, short, columnar, or spindle-shaped cells similar
to those seen in medullary carcinomas. Other diagnostic The monomorphic spindle cell pattern of medullary carci-
features of papillary carcinoma may not be present in the noma may be mistyped as anaplastic carcinoma, particu-
aspirated sample. Intranuclear cytoplasmic inclusions are larly when occasional nuclei appear bizarre (Figs. 8.37
seen in both carcinomas and are not helpful in differenti- to 8.40). On the other hand, in the absence of the usual
ating the two. Powdery nuclear chromatin, micronucleoli, cytopathologic features, such as pleomorphic and bizarre
and a chromatin ridge or the groove, if present, suggest nuclei and tumor diathesis, the aspirate of anaplastic
papillary carcinoma (Table8.9) (Fig.8.35AC). carcinoma may be mistyped as medullary carcinoma.

Medullary Carcinoma versus Hrthle Cell Neoplasms (Figs. 8.31 to 8.34)
A B
Fig. 8.31: Medullary Carcinoma versus Hrthle Cell Carcinoma. A, B: FNA of a Hrthle cell carcinoma with medium-
sized round cells, excentric nuclei, and appreciable cytoplasm. Prominent nucleoli seen in some cells (arrows) should
exclude the possibility of medullary carcinoma.
A B
Fig. 8.32: Medullary Carcinoma versus Hrthle Cell Carcinoma. A: FNA of a Hrthle cell carcinoma. The cells are
monomorphic with eccentric nuclei. A differential diagnosis of Hrthle cell carcinoma and medullary carcinoma
was considered. Immunostain for thyroglobulin was positive and negative for calcitonin. Thyroidectomy confirmed
a Hrthle cell carcinoma. B: FNA of a medullary carcinoma demonstrating cytomorphology similar to Hrthle cell
neoplasm.
A B
Fig. 8.33: Medullary Carcinoma versus Hrthle Cell Carcinoma. A: FNA of a Hrthle cell carcinoma showing plasma-
cytoid cells resembling the cells of medullary carcinoma. Macronucleoli in some cells suggested the diagnosis of Hrthle
cell neoplasm. A calcitonin stain was nondiagnostic. Thyroidectomy revealed a Hrthle cell carcinoma. B: FNA of a
medullary carcinoma showing cells with morphology similar to Hrthle cell carcinoma.

A B
C D
Fig. 8.34: Medullary Carcinoma versus Hrthle Cell Carcinoma.

FNA of a Hrthle cell carcinoma. A: The aspirate is very cellular
consisting of discrete, pleomorphic cells (low power). B: Higher
magnification showing plasmacytoid shapes with eccentric nuclei.
The chromatin is coarsely granular, and macronucleoli are not ap-
preciated. C: A different field showing a syncytial tissue fragment of
similar cells with abundant dense cytoplasm; some cells are short
and spindle shaped. A differential diagnosis of Hrthle cell neo-
plasm and medullary carcinoma was considered. A calcitonin stain
was negative, while the cells were reactive to thyroglobulin. D: Thy-
roidectomy confirmed a Hrthle cell carcinoma (H&E). E: Medul-
E lar carcinoma cells showing morphologic similarity for comparison.
Intranuclear cytoplasmic inclusions are seen in both types Medullary Carcinoma versus Malignant
of cancer cells. The presence of other features of medul- Lymphoma
lary carcinoma as described earlier is helpful in making
Medullary carcinomas may consist predominantly of small
a correct diagnosis. Intertwining cytoplasmic processes
cells that present a dissociated pattern (Fig. 8.41A,B).
are not a feature of anaplastic carcinoma (Table 8.11).
With uniform, small, round cells, scant cytoplasm,
Immunostains for calcitonin are necessary to confirm the
and high N/C ratios, a malignant lymphoma must be
diagnosis of medullary carcinoma.

Medullary Carcinoma versus Papillary Carcinoma
A B
Fig. 8.35: Medullary Carcinoma versus Papillary Carcinoma.

A, B: FNA of two different cases of papillary carcinoma exhibiting a
dispersed cell pattern with round to short spindle cells, some show-
ing intranuclear inclusions may be typed as medullary carcinoma.
C: These medium to large cells with nuclei containing coarse thready
chromatin favored medullary carcinoma. Other smears from the
same aspirate showed features suggestive of papillary carcinoma
C and confirmed on thyroidectomy.
considered in the differential diagnosis (Table 8.10). diagnosis must be rendered and appropriate ancillary
Cytoplasmic tailing, lack of nucleoli, and coarsely granu- tests need to be performed for accurate typing.
lar chromatin are the features that help differentiate med-
ullary carcinomas from malignant lymphomas. The latter Medullary Carcinoma versus Malignant
exhibits malignant cells with nucleoli, high proliferative Melanoma
activity, karyorrhexis, and necrosis (Fig. 8.41C). Ancillary
diagnostic tests are required for accurate diagnosis. Malignant melanoma is a great mimicker and must always
be considered in any differential diagnosis. With a broad
spectrum of morphologic patterns, it is conceivable that a
Medullary Carcinoma versus Plasmacytoma
melanoma may be diagnosed as medullary carcinoma in
The medullary carcinoma cells may be predominantly thyroid aspirates. On the other hand, medullary carcinoma
plasmacytoid in shape and resemble a plasmacytoma. will be typed as melanoma if such a past history is available.
Medullary Carcinoma versus Soft Tissue Tumors Medullar Carcinoma versus Other Nonthyroid
Neoplasms with Spindle Cells
An exclusive spindle cell pattern is unusual for medullary
carcinoma and when present may be mistyped as soft tis- A fine needle biopsy of a palpable and movable nodule
sue tumor (Fig. 8.40AD). The medullary carcinoma cells over the thyroid isthmus was interpreted as medullary
tend to be discohesive and unipolar. Spindle cells running carcinoma on account of spindle cells. Calcitonin stain
in fascicles like the ones seen in leiomyoma or fibrous was negative. The excision confirmed a mixed tumor of
histiocytomas are very unusual. Again, a differential the dermal adnexa (Fig. 8.42AC).

Medullary Carcinoma versus Insular Carcinoma of Thyroid
A B
Fig. 8.36: A: FNA of a thyroid mass composed of small malignant cells with insignificant cytoplasm and high N/C
ratios. Such a pattern with small cells may be mistaken for an insular carcinoma. Thyroidectomy confirmed medullary
carcinoma. B: FNA of an insular carcinoma for comparison.
Medullary Carcinoma versus Anaplastic Carcinoma (Figs. 8.37 to 8.39)
A B
Fig. 8.37: Medullary Carcinoma versus Anaplastic Carcinoma. AC: FNA of a medullary carcinoma showing syncytial
tissue fragments of markedly pleomorphic cells interpreted as possibly anaplastic carcinoma with a differential diag-
nosis of medullary carcinoma.

C D
E F
Fig. 8.37: (continued) D: The cells reacted strongly to calcitonin. Thyroidectomy confirmed the medullary carcinoma.
E: Histologic section of the medullary carcinoma. F: FNA of an anaplastic carcinoma for comparison.
A B
Fig. 8.38: A: FNA of an anaplastic carcinoma showing pleomorphic cells containing large nuclei. Medullary carcinoma
must be considered in the differential diagnosis. B, C: FNA of medullary carcinoma. Note the morphologic similarity.

A B
Fig. 8.39: A: FNA of a spindle cell anaplastic carcinoma consisting of tissue fragment of malignant cells. B: Same
aspirate depicting pleomorphic malignant cells with numerous spindle and giant forms (Diff-Quik). (Courtesy of
Mithra Baliga, M.D., University of Mississippi, Jackson, Mississippi.)

Medullary Carcinoma with a Spindle Cell Pattern versus Soft Tissue Tumors
A B
C D
Fig. 8.40: Medullary Carcinoma versus Soft Tissue Tumors. A, B: FNA of a medullary carcinoma. An exclusive spindle
cell pattern as seen here is unusual in FNA of a medullary carcinoma. C: FNA of a thyroid nodule with metastatic
leiomyosarcoma. D: FNA of a metastatic chondrosarcoma.
Medullar Carcinoma versus Other Neuroendocrine of metastases from extra thyroidal carcinoid tumor to
Carcinomas the thyroid gland that may be confused with medullary
carcinomas.
Medullary Carcinoma versus Paraganglioma. Medullary
carcinomas with histologic pattern similar to that of a
paragangliomas (see Chapter 15) may be interpreted as
the cells of primary paraganglioma of the thyroid (see MEDULLARY CARCINOMA METASTATIC
Figs. 8.46 and 8.47). TO OTHER BODY SITES
Medullary Carcinoma versus Carcinoid Tumor. The Medullary thyroid carcinoma tends to metastasize early,
small cell pattern of medullary thyroid carcinoma with particularly to cervical lymph nodes. Distant hematog-
saltpepper nuclear chromatin morphologically resem- enous spread occurs to liver, lungs, bones, occasion-
bles a carcinoid tumor. Fine needle aspirates of carci- ally to the brain, and soft tissues outside the neck.
noid tumor metastatic to the thyroid may be interpreted Figures 8.43 to 8.48 illustrate the cytomorphology of
as medullary carcinoma. There are isolated case reports metastatic medullary carcinoma. It must be noted that

Medullary Carcinoma versus Malignant Lymphoma
A B
Fig. 8.41: A, B: FNA of a thyroid nodule showing a large popula-

tion of small loosely cohesive cells with scant to indistinct cyto-
plasm and high N/C ratios. A malignant lymphoma was suspected.
Lymphoid markers were negative. Because of some pleomorphic
cells in other fields, a calcitonin stain was performed. A positive
reaction with calcitonin and thyroidectomy confirmed medullary
carcinoma. C: FNA of a malignant lymphoma of the thyroid for
C comparison.
medullary carcinoma may present initially as cervical The composite tumors of the thyroid show two dis-
lymphadenopathy. Depending on the location of the tinct cell populations, thyroglobulin reactive papillary
metastatic tumor, differential diagnostic entities differ, carcinoma and calcitonin reactive medullary carcinoma.
requiring immunostains for establishing an accurate Composite tumors differ from mixed tumors in that the
diagnosis. parafollicular and follicular cell origin can be demon-
strated in two distinct cell populations rather than within
the same tumor of mixed type. Their cytopathologic fea-
MIXED MEDULLARY, FOLLICULAR, AND tures are sparsely documented.
COMPOSITE CARCINOMAS
These tumors show both parafollicular and follicular cell OTHER NEUROENDOCRINE TUMORS OF
differentiation in the same tumor. Two types are described, THE THYROID
mixed carcinoma and composite carcinoma.
Mixed tumors demonstrate both medullary (C-cell)
Paraganglioma
and follicular cell differentiation, the latter with a follicu-
lar or papillary growth pattern. The tumor cells express Intrathyroidal paragangliomas are rare tumors; very few
reactivity to both calcitonin and thyroglobulin. cases are reported. Documentation of cytologic features

Medullary Carcinoma versus Nonthyroidal Lesion
A B
Fig. 8.42: FNA of a movable and palpable nodule over the thyroid
isthmus, thought to be of thyroidal origin. A,B: These medium-sized
round and short spindle cells were considered as originating from
medullary carcinoma. Calcitonin stain on the smears was negative.
The surgical excision revealed a mixed tumor of the skin overlying
the thyroid. C: Retrospective review of the aspirate revealed myo-
C epithelial cells and the myxoid matrix.
is still rare. All reported cases occurred in females with a while the sustentacular cells are highlighted with S100
mean age of 48 years. protein. Negative calcitonin stain will support the diag-
Most patients present with an asymptomatic neck nosis of paraganglioma.
mass. Grossly, paragangliomas are circumscribed, encap- The differential diagnoses of intrathyroidal para-
sulated tumors with a gray-tan to brown cut surface. ganglioma include medullary thyroid carcinoma and
The size can range from 1.5 to 10 cm, the average being follicular neoplasms such as hyalinizing trabecular ade-
3 cm. These are usually benign tumors offering a good noma and conventional follicular adenoma/carcinoma
prognosis. (Table8.12).
Histologically, paragangliomas of the thyroid present a
pattern similar to that seen in paragangliomas at other loca-
tion with a typical alveolar or a nesting (zellballen) pattern. SMALL CELL NEUROENDOCRINE
Cytologically, the aspirates present a pleomorphic pat- CARCINOMA
tern with round to spindle cells and polygonal epithelioid
cells similar to that seen in paragangliomas in other loca- Small cell carcinoma of the thyroid is reported rarely.
tions (see Chapter 15). The immunochemical stains with One case in authors experience is illustrated in Figures
neuroendocrine markers stain the chief cells positively, 8.48AE.

Metastatic Medullary Carcinoma to Different Body Sites
A B
C D
Fig. 8.43: This patient had a palpable thyroid nodule and cervi-
cal lymphadenopathy. FNA biopsy of the thyroid was unsatisfac-
tory. A, B: Aspiration biopsy of the cervical lymph node showing
cells with cytomorphology consistent with medullary carcinoma.
C: Histologic section of the thyroidectomy showing medullary car-
cinoma. Metastases were present in the lymph nodes. D: Another
example of a metastatic medullary carcinoma to the cervical lymph
node. Note the high cellularity and a dispersed cell pattern (low
power). E: Higher magnification showing a pleomorphic cell pat-
tern with cytoplasmic cell processes and typical saltpepper nuclear
E chromatin.

B
A
Fig. 8.44: A, B: FNA of a metastatic medullary thyroid carcinoma

to the lung. Note the intranuclear cytoplasmic inclusions (arrows).
C: FNA of a spindle cell carcinoid tumor of the lung demonstrating
morphologic similarity to the medullary carcinoma cells. Note the
C saltpepper chromatin pattern.
A B
Fig. 8.45: A, B: FNA of metastatic medullary thyroid carcinoma to the thigh in a patient with a history of medullary
thyroid carcinoma. The neoplastic cells are pleomorphic (Diff-Quik). (Courtesy of Ami J. Walloch, M.D. and Rashead
Hammadeh, M.D., Christ Hospital, Oaklawn, Illinois.)

Other Neuroendocrine Neoplasms of the Thyroid

Paraganglioma
A B
Fig. 8.46: FNA of a Histologically Confirmed Primary Paraganglioma of the Thyroid. A, B: The marginally cellular
aspirate demonstrates medium-sized to large cells with poorly defined cell borders. The nuclei are moderately pleomor-
phic, large, round to oval with evenly dispersed chromatin. Nucleoli are only occasionally present. These cells have
insignificant to scant, pale, and bluish cytoplasm. A cytologic diagnosis of paraganglioma is not possible from this mor-
phology alone, as they also bear similarities to medullary carcinoma cells (Romanowsky). (Courtesy of A. Vodovnik,
M.D. Calderdale Royal Hospital, HX3 OPW Halifax, England.)
A B
Fig. 8.47: FNA of a Histologically Confirmed Primary Paraganglioma of the Thyroid. A: The aspirate is bloody consist-
ing of pleomorphic round and spindle cells containing deep-staining nuclei with compact chromatin. B, C: Different
fields revealed a pleomorphic, loosely cohesive, and round to spindle cells.

C D
Fig. 8.47: (continued) D: These cells from the same aspirate showed
a pseudofollicular pattern reminiscent of a follicular neoplasm.
E: Histologic section showing a typical nesting pattern of paragan-
glioma (H&E) (Courtesy of Dr. Ajay Shah, Fine Needle Aspiration
E Clinic, Toledo, Ohio.)
Neuroendocrine Carcinoma Grade III
A B
Fig. 8.48: Neuroendocrine Carcinoma Grade III. A: FNA of a thyroid mass. The aspirate is markedly cellular consisting
of several syncytial tissue fragments as well as loosely cohesive cells (low power). B,C: Higher magnification showing
the syncytial tissue fragment of the malignant cells without any architectural pattern. The malignant cells have scant
undifferentiated cytoplasm. Their nuclei are slightly larger than the usual insular carcinoma cells and bear a strong
resemblance to neuroendocrine carcinoma cells.

D
C
Fig. 8.48: (continued) D: The cell block of the aspirate showing sev-
eral tissue fragments forming insulae. There is marked necrosis in the
background (medium power). E: Higher magnification demonstrat-
ing an insular pattern. The tumor cells did not express thyroglobulin,
TTF-1, calcitonin, or any neuroendocrine markers. Only cytokeratin
was positive. The neoplasm strongly resembles a small cell neoplasm
but the exact morphologic type remains undetermined. This may
represent an endocrine carcinoma (clinically serum calcitonin levels
E were not elevated).
TABLE 8.12. DIFFERENTIAL DIAGNOSES OF PARAGANGLIOMA OF THE THYROID:

DIFFERENTIATING FEATURES

Paraganglioma of Monomorphic to pleomorphic cell pattern; cells discrete, in Thyroglobulin Figures 8.46A,B;
the thyroid loosely cohesive groups or in syncytial tissue fragments without ; calcitonin ; 8.47AE; and
any architectural pattern. Neoplastic cells variable in size from neuroendocrine 15.8AE
small to large with occasional giant forms; round, plasmacytoid, markers +; S100 +
polygonal to spindle shaped; uniform, round, eccentric nuclei;
granular chromatin with saltpepper appearance; sometimes
compact; cytoplasm variable; may be drawn into delicate
process; eosinophilic cytoplasmic granules with Romanowsky
stain; mitoses ; necrosis
Follicular Cells mostly in loose aggregates or syncytial tissue fragments Thyroglobulin Figure 8.47D
neoplasms with or without a follicular pattern; cells round; lack +; calcitonin ;
pleomorphic shapes; spindle cells not seen; fine to coarse neuroendocrine
granular chromatin; no intranuclear inclusions; colloid in the markers ; S100
follicular lumina or in the background

TABLE 8.12. DIFFERENTIAL DIAGNOSES OF PARAGANGLIOMA OF THE THYROID:

DIFFERENTIATING FEATURES (continued)

Medullary thyroid Monomorphic to pleomorphic cell pattern; cells discrete, in Thyroglobulin Figure 15.25AC
carcinoma loosely cohesive groups or in syncytial tissue fragments without ; calcitonin +;
any architectural pattern; neoplastic cells variable in size from neuroendocrine
small to large with occasional giant forms; round, plasmacytoid, markers +; S100
polygonal to spindle shaped; uniform, round, eccentric nuclei;
granular chromatin with saltpepper appearance; sometimes
compact; cytoplasm variable; may be drawn into delicate
process; eosinophilic cytoplasmic granules with Romanowsky
stain; mitoses ; necrosis ; amyloid +/
Hyalinizing Cellular aspirate; cells dispersed, in loosely cohesive aggregates Thyroglobulin +; Figures 8.248.26
trabecular or in syncytial tissue fragments; may present a trabecular pattern; calcitonin
adenoma anastomosing trabeculae with hyaline stroma; medium to large,
round to spindle cells with well to poorly defined cell borders;
neoplastic follicular cells may surround acellular, hyaline
material; eccentric nuclei with granular chromatin, micronucleoli
and intranuclear inclusions and grooves; variable cytoplasm,
sometimes granular; some cells show cytoplasmic processes
SUGGESTED READING
Baloch ZW, LiVolsi VA. Pathology of the thyroid gland. Eds: Kini SR. Thyroid Cytopathology. An Atlas and Text. Philadelphia,
LiVolsi VA, Asa SA In: Endocrine Pathology. Philadelphia, PA: PA: Lippincott Williams & Wilkins; 2008.
Churchill Livingston; 2002. Kini SR, Miller JM, Hamburger JI, et al. Cytopathology of
Bockhorn M, Sheu SY, Frilling A, et al. Paraganglioma-like medullary medullary carcinoma of the thyroid. Arch Pathol Lab Med.
thyroid carcinoma: a rare entity. Thyroid. 2005;15:13631367. 1984;108:156159.
Bourtsos E, Bedrossian CWM, De Frias DVS, et al. Thyroid LaGuette J, Matias-Guiu X, Rosai J. Thyroid Paraganglioma: a
plasmacytoma mimicking medullary carcinoma. A potential pitfall clinicopathologic and immunohistochemical study of 3 cases.
in aspiration cytology. Diagn Cytopathol. 2000;23:354358. Am J Surg Pathol. 1997;21:748753.
Casey MB, Sebo TJ, Carney JA. Hyalinizing trabecular adenoma Luboshitzky R, Dharan M. Mixed follicular-medullary thyroid
of the thyroid gland. Cytologic features in 29 cases. Am J Surg carcinoma: a case report. Diagn Cytopathol. 2004;30:122124.
Pathol. 2004;28:850867. Maly A, Meir K, Maly B. Isolated carcinoid tumor metastatic to
Chang T-C, Wu S-L, Hsiao Y-L. Medullary thyroid carcinoma. the thyroid gland. Report of a case initially diagnosed by fine
Pitfalls in diagnosis by fine needle aspiration cytology and needle aspiration cytology. Acta Cytologica. 2006;50:8487.
relationship of cytomorphology to RET Proto-oncogene Matias-Guiu X, DeLellis RA, Moley JF, et al. Medullary thyroid
mutations. Acta Cytologica. 2005;49:477482. carcinoma. In: DeLellis RA, Lloyd RV, Heitz PU, et al, eds.
Duskova J, Janotova D, Svobodova E, et al. Fine needle aspiration Pathology and Genetics of Tumors of Endocrine Organs. World
biopsy of mixed medullary follicular thyroid carcinoma. A Health Organization Classification of Tumors. Lyon, France:
report of two cases. Acta Cytologica. 2003;47:7177. IARC Press; 2004;8691.
Eusebi V, Damiani S, Riva C, et al. Calcitonin free oat-cell Matias-Guiu X, LlaGuette J, Puras-Gil AM, et al. Metastatic
carcinoma of the thyroid gland. Virchows Arch (A). neuroendocrine tumors to the thyroid gland mimicking
1990;417:262271. medullary carcinoma: A pathologic and immunohistochemical
Ferri E, Manconi R, Armato E, et al. Primary paraganglioma of study of six cases. Am J Surg Pathol. 1997;21:754762.
thyroid gland: A clinicopathologic and immunohistochemical Papotti M, Bussolati G, Komminoth P, et al. Mixed medullary
study with review of literature. Acta Otorhinolaryngol Ital. and follicular cell carcinoma. In: DeLellis RA, Lloyd RV, Heitz
2009;29:97102. PU, et al, eds. Pathology and Genetics of Tumors of Endocrine
Forrest CH, Frost FA, Bastiaan de Boer D, et al. Medullary Organs. World Health Organization Classification of Tumors.
carcinoma of the thyroid. Accuracy of diagnosis by fine needle Lyon: IARC Press, 2004;9293.
aspiration cytology. Cancer (Cancer Cytology). 1998;84:295302. Rosai J, Carcangiu ML, DeLellis RA. Tumors of the Thyroid
Goellner JR, Carney JA. Cytologic features of fine needle aspirates Gland. Fascicle Five, Third Series, Atlas of Tumor Pathology.
of hyalinizing trabecular adenoma of the thyroid. Am J Clin Washington, DC, Armed Forces Institute of Pathology, 1993.
Pathol. 1989;91:115119. Vodovnik A. Fine needle aspiration cytology of primary thyroid
Green I, Ali SZ, Allen EA, et al. A spectrum of morphologic variations paraganglioma. Report of a case with cytologic, histologic
in medullary thyroid carcinoma. Cancer. 1997;81:4044. and immunohistochemical features and differential diagnostic
Huss LJ, Mendelsohn G. Medullary carcinoma of the thyroid considerations. Acta Cytologica. 2002;46:11331137.
gland: An encapsulated variant resembling the hyalinizing Zeppa P, Vetrani A, Marino M, et al. Fine needle aspiration
trabecular (paraganglioma-like) adenoma of the thyroid. Mod cytology of medullary thyroid carcinoma: A review of 18 cases.
Pathol. 1990;3:581585. Cytopathol. 1990;1:3544.

9 NEOPLASMS OF THE
PARATHYROID GLANDS
The dispersed neuroendocrine system includes two periodic acidSchiff (PAS)-positive material resembling
organs that are predominantly or exclusively composed colloid. The stroma contains mature fat cells, blood ves-
of neuroendocrine cells; parathyroid glands are one sels, and varying amounts of connective tissue, the pro-
and anterior pituitary is the other organ, discussed in portion of which changes with age. The immunoprofile
Chapter 10. of parathyroid parenchymal cells includes positive reac-
tivity to parathyroid hormone and chromogranin.
The parathyroid cells secrete parathyroid hormone,
which, along with the other two hormones, calcitriol
ANATOMY AND HISTOLOGY OF (produced in the kidney) and calcitonin (produced in the
NORMAL PARATHYROID GLANDS thyroid), regulates calcium and phosphorus levels.
Neoplasms of the parathyroid mostly include ade-
The parathyroid glands, derived from branchial pouches nomas and carcinomas. The latter are extremely rare.
III and IV, are small, red-brown, flattened, ovoid struc- Parathyroid adenomas may also arise in ectopic locations
tures, generally measuring 4 to 6 mm in length, 2 to 4 mm such as thyroid or mediastinum.
in width, and 1 to 2 mm in thickness, with an average
combined weight of 120 mg. Most normal adults have
four parathyroid glands, the superior pair located about
1 cm above the intersection of the recurrent laryngeal PARATHYROID ADENOMA
nerve and the inferior thyroid artery. The inferior para-
thyroids are typically found inferior, posterior, or lateral Parathyroid adenomas are benign neoplasms of the
to the lower pole of the thyroid and sometimes high up parathyroid glands. They are functional and cause pri-
on the anterior aspect of the thyroid lobe. The parathy- mary hyperparathyroidism due to increased secretions
roid glands are highly vascularized and thinly encap- of parathyroid hormone resulting in increased levels of
sulated. Histologically, the parathyroid gland shows a serum calcium. Roughly 80% to 85% of the cases of
mixture of parenchyma and adipose tissue (Fig. 9.1A). primary hyperparathyroidism are caused by adenomas.
The parenchyma consists of chief cells, varying num- Parathyroid adenomas are more common in women with
bers of oncocytic cells, and transitional oncocytic cells a male:female ratio of 1:34. They occur over a broad
(Fig. 9.1B). The parenchymal cells are often arranged age range, the average being 55 years. More than 50%
in a lobular pattern. The chief cells are polyhedral, 8 to of patients may be asymptomatic and diagnosed inciden-
10 mm in diameter, with round central nuclei contain- tally because of high serum levels of calcium. When symp-
ing sharp nuclear membrane with coarse chromatin. tomatic, patients with hyperparathyroidism complain of
Their cytoplasm is eosinophilic to amphophilic and weakness, fatigue, and muscle weakness. Late effects of
often appears clear or vacuolated in formalin-fixed tis- hypocalcemia such as nephrolithiasis and osteitis fibrosa
sues. The cells are rich in glycogen and contain variable cystica are very infrequently encountered. Hypercalcemia
amounts of neutral lipid. The chief cells may form solid may result in calcium deposition in various tissues and
sheets; branching anastomosing cords; and sometimes organs. With advances in biochemical techniques, serum
small, acinar structures, which may contain eosinophilic abnormalities are detected sooner.
209

A B
Fig. 9.1: A: Histologic section of the normal parathyroid gland with a mixture of parenchyma and adipose tissues (low
power, H&E). B: Higher magnification showing islands of chief cells with intervening adipose tissue (H&E).
ASSOCIATION WITH HEREDITARY Histologically, adenomas are encapsulated neoplasms

SYNDROMES with compressed normal parenchyma outside the capsule.
The growth pattern consists of closely packed chief cells
Parathyroid adenomas may be associated with multiple arranged in anastomosing cords, nests, glandular forma-
neuroendocrine neoplasia (MEN 1 and MEN 2A) syn- tions, and sheets separated by a delicate network of sinu-
dromes (refer Chapter 1, Table 1.1). soids (Fig. 9.3). The dominant cell type is chief cells, often
larger than their normal counterpart. The cell outlines are
indistinct. Their cytoplasm ranges from faintly eosino-
RADIOLOGIC FINDINGS philic to clear and contains abundant glycogen deposits.
The nuclei are round and central with dense chromatin
Several imaging modalities are used to localize parathyroid and occasional nucleoli. A few cells may contain large,
gland lesions. These include ultrasonography, CT scan- hyperchromatic nuclei.
ning, MRI, thallium substation scanning, and the recent The adenomas frequently contain cystic structures,
technetium-99m sestamibi imaging. Ultrasonography is the which may be empty or filled with PAS-positive, eosin-
most frequently used modality for primary hyperparathy- ophilic, homogeneous material that strongly resembles
roidism. A normal parathyroid gland is typically not seen colloid. The cells contain glycogen and fat. Argyrophilic
with ultrasound. A parathyroid adenoma or a carcinoma granules in the cytoplasm of adenoma cells have been
is seen as a round, elliptical, or oblong hypoechoic mass. described.
These may contain cysts and calcifications. Hyperplastic
glands are usually much smaller than adenomas. Ultrasound
cannot localize ectopic parathyroids. Thyroid nodules or
lymph nodes may be mislabeled as parathyroids.
GROSS AND MICROSCOPIC FEATURES
Parathyroid adenoma involves a single gland. A typical

parathyroid adenoma is a thinly encapsulated, tan to
reddish-brown neoplasm, homogeneous in consistence
with a smooth external surface. Adenomas vary consider-
ably in size and shape. They may be round, ellipsoid, bean
or kidney shaped, or flattened and elongated (Fig. 9.2).
Larger adenomas may undergo cystic change and may
yield fluid contents at fine needle aspiration (FNA) biopsy. Fig. 9.2: Gross Photograph of a Large Parathyroid Adenoma.

Chapter 9: Neoplasms of the Parathyroid Glands 211
A B
C D
Fig. 9.3: Histologic Sections Demonstrating Various Cell Types

and Growth Patterns of Parathyroid Adenomas. A: Parathyroid
adenoma showing nests and insulae of cells (H&E). B: Trabecular
growth pattern of chief cells. Note the rich sinusoidal network
(H&E). C: Follicular growth pattern (H&E). D: Clear cell pattern
E (H&E). E: Oncocytic cell pattern.

F G
Fig. 9.3: (continued) F: Note marked nuclear atypia that is sometimes present in parathyroid adenomas (H&E).
G:Higher magnification of an adenoma composed of chief cells depicting a follicular pattern, small cuboidal cells with
uniform nuclei (H&E).
IMMUNOPROFILE various architectural configurations (Figs. 9.4 to 9.8).

They may be monolayered (two-dimensional, Fig. 9.6E),
The cells of parathyroid adenoma exhibit positive reac- trabecular (Figs. 9.6B and 9.7C), with branching and inter-
tivity to parathyroid hormone, chromogranin A, and low digitating to enclose spaces (Figs. 9.5B,D and 9.6B), or fol-
molecular weight cytokeratin and negative reactivity to licular (Figs. 9.4C and 9.6C) or may appear papillary-like
calcitonin, thyroglobulin, and vimentin. with complex branching and frayed edges (Fig. 9.7D).
Frequently, the extreme crowding and overlapping of
nuclei within a tissue fragment result in a three-dimensional
CYTOPATHOLOGIC FEATURES pattern (Figs. 9.4A and 9.7C). Another characteristic fea-
ture of parathyroid adenomas is the branching network
Specimens for the cytologic diagnosis mostly represent of capillaries. The neoplastic cells are often seen along the
fine needle biopsies of the suspected, enlarged parathy- capillaries (Fig. 9.7C; see Fig. 9.12C). The parathyroid
roid glands. Not uncommonly, the aspirates are submitted adenoma cells are round to cuboidal, slightly smaller than
as thyroid FNA biopsies. The aspirate is variably cellular normal thyroid follicular cells, measuring 6 to 7 mm in
consisting of a large population of small round to cuboidal diameter. Their nuclei are round and uniform, contain-
epithelial cells displayed singly, in loosely cohesive groups, ing coarsely granular chromatin (salt-pepper type) and
or in thick syncytial type tissue fragments with or without micronucleoli. Nuclear pleomorphism is occasionally
A B
Fig. 9.4: Scrape Smears of a Parathyroid Adenoma. A: The syncytial tissue fragment consists of small cells with extreme
crowding and overlapping of uniform, round nuclei with granular chromatin. The N/C ratios are very high. The cell
borders are indistinct and the cytoplasm is pale, scant but variable. B: The syncytial tissue fragments of small cells pres-
ent a trabecular pattern.

C D
E F
Fig. 9.4: (continued) C: Syncytial tissue fragments with a follicular pattern. D: Positive reactivity to parathyroid hor-
mone antibody. E: Histologic section of the resected specimen showing a variegated growth pattern such as insular,
trabecular, and follicular (medium power). F: Higher magnification showing chief cells.
A B
Fig. 9.5: A,B: FNA of a parathyroid gland adenoma. The specimen submitted as that from a thyroid nodule and inter-
preted as a cellular follicular adenoma. The parathyroid cells are in syncytial tissue fragments forming anastomosing
chords and trabeculae, enclosing spaces. The component cells demonstrate extreme crowding and overlapping of small
uniform nuclei with finely granular chromatin. The background is clean.

C D
E F
Fig. 9.5: (continued) C,D: Some of the neoplastic cells contain scant, pale cytoplasm. Their nuclei are uniform with
granular chromatin. E: Histologic sections of the parathyroid adenoma composed of chief cells presenting a follicular
growth pattern (low power, H&E). F: Higher magnification (H&E).
A B
Fig. 9.6: A: Low-power view of a cellular aspirate from parathyroid adenoma, showing a dispersed cell pattern. Note
the branching blood vessels. B: Low-power view of a different field showing loosely cohesive and discrete epithelial
cells with poorly defined cell borders. The nuclei are mildly pleomorphic, and many appear to be stripped off their
cytoplasm.

C D
Fig. 9.6: (continued) C: Higher magnification showing loosely co-

hesive and discrete epithelial cells with poorly defined cell borders.
Their nuclei are mildly pleomorphic and appear stripped. D: Differ-
ent field showing broad capillaries in the background. E: The para-
E thyroid adenoma cells are uniform and stripped off their cytoplasm.
A B
Fig. 9.7: Fine Needle Biopsy of a Parathyroid Adenoma Submitted as Thyroid Nodule. A: The aspirate is very cellular
consisting of large, branching tissue fragments of epithelial cells and fibrovascular stroma (low power). B: Medium
power. Another field showing very large tissue fragments of epithelial cells. Note the perivascular location of the epithe-
lial cells and vascularized stromal tissue fragment (arrows).

C D
E F
G H
Fig. 9.7: (continued) C: Low-power view depicting a branching net-

work of crisscrossing delicate vascular stroma. D,E: Higher magnifi-
cation. The syncytial tissue fragments of epithelial cells demonstrate
no architectural configurations. The nuclei are round, with granular
chromatin, and contain nucleoli. The cell borders are poorly defined,
and the cytoplasm is scant. F,G: The neoplastic cells show character-
istic perivascular location. H: Histologic section of the encapsulated
parathyroid adenoma (low power) demonstrating a thick capsule
(C) (H&E). I: Higher magnification showing a solid growth pattern
I composed of uniform cells. Note the tumor is richly vascular (H&E).

present. Nuclear molding has been described as a hith- vacuoles are noted within the cytoplasm. The oncocytic
erto unreported diagnostic feature but has not been cells contain appreciable amounts of granular cytoplasm
documented by others. The parathyroid chief cells have and morphologically resemble Hrthle cells of the thy-
scanty, pale cytoplasm with ill-defined cell borders and roid but for their smaller size. Although a monomorphic
are frequently displayed as stripped nuclei, presenting a cellular pattern is commonly seen in adenomas, pleomor-
lymphocyte-like pattern (Fig. 9.6B). Occasionally single phic size and shapes may occasionally be encountered.
A B
C D E
Fig. 9.8: An Example of Intrathyroidal Parathyroid Adenoma. A,B:

This aspirate, submitted as that from a thyroid nodule, was mar-
ginally cellular, consisting of syncytial tissue fragments of small cells
with uniform nuclei containing finely granular chromatin. The cell
borders are vaguely appreciated. The cytoplasm is scant and appears
pale to foamy. C,D: These cells are slightly larger and possess granu-
lar cytoplasm and probably represent an oncocytic component. The
aspirate was interpreted as nondiagnostic/unsatisfactory due to poor
cellularity. E: Total thyroidectomy revealed a 2 cm encapsulated nod-
ule with compressed normal parathyroid parenchyma external to the
capsule (H&E). F: The neoplasm is predominantly composed of chief
F cells and showed areas with clear cells and oncocytic cells (H&E).

G H
Fig. 9.8: (continued) G: The neoplasm showed positive reactivity to parathyroid hormone antibody (PHA). H: The
neoplastic cells exhibited negative reactivity to thyroglobulin (TG), which highlighted the normal thyroid parenchyma
outside the tumor capsule (H&E).
Mitoses or karyorrhexis is not present. The background (see Fig. 9.10A). The presence of fat globules favors hyper-
contains delicate, branching, vascularized stromal tissue plasia. The background may contain proteinaceous fluid
fragments (see Fig. 9.12C). Histiocytes are rarely pres- or colloid-like material. The cytologic features of parathy-
ent in the background, and fat globules are not identified roid adenoma are summarized in Table 9.1.
TABLE 9.1. CYTOPATHOLOGIC FEATURES OF PARATHYROID ADENOMA
Cellularity Generally hypercellular
Presentation Cells isolated or discrete, in loosely cohesive groups or in tissue fragments; dispersed cell pattern frequent;
network of branching capillaries with tissue fragments of epithelial cells in perivascular location; lymphocyte-
like pattern due to naked nuclei of chief cells
Architecture Syncytial tissue fragments, without any architectural patterns with extreme crowding and overlapping
of the tissue of nuclei, often appearing three-dimensional; trabecular arrangement with branching and interdigitating,
fragments enclosing varying-sized spaces, mimicking acinar pattern; monolayered small-to-large tissue fragments;
microfollicular pattern; papillary-like architecture
Cells Small, round to cuboidal; poorly defined, indistinct cell borders; 79 mm in diameter
Nucleus Usually round, with high N/C ratios; smooth nuclear membranes; coarsely granular to compact, deep-staining
chromatin; micronucleoli +/; usually uniform but occasionally pleomorphic; size slightly larger than the
normal counterpart; intranuclear inclusions extremely rare
Cytoplasm Insignificant to moderate; clear, pale to granular; cytoplasmic vacuole +/
Background Usually clean; naked nuclei; colloid-like material +/; fat globules absent, lymphocytes rare; macrophages with
or without hemosiderin +/; branching network of delicate excessively vascularized stroma
Histochemistry Argyrophilic granules in the cytoplasm
Immunoprofile Positive reactivity to parathyroid hormone and chromogranin A and low molecular weight cytokeratin;
negative to thyroglobulin
Ultrastructure Neurosecretory granules

DIAGNOSTIC ACCURACY AND C. Differentiation of parathyroid adenoma from thyroid

DIFFERENTIAL DIAGNOSES lesions, namely nodular goiter, chronic lymphocytic
thyroiditis, follicular neoplasms, Hrthle cell tumors,
Recognition of parathyroid lesions from the cytologic and papillary carcinoma
samples has historically presented difficulties. FNA
biopsy is not routinely performed in evaluation of the The diagnostic accuracy of parathyroid lesions from cyto-
parathyroid gland lesions. Consequently, information on logic specimens, in general, is low but can be maximized,
their cytopathologic findings is lean, limiting their expo- if the parathyroid location is known or suspected in
sure and familiarity with cytopathologic patterns. which case, the ancillary tests will offer conclusive results.
Due to their intimate anatomic location in thyroid area,
lesions of the parathyroid glands may masquerade as thyroi-
dal lesions. The parathyroid glands either in their usual or
in ectopic locations may be clinically and/or radiologically PARATHYROID CYSTS VERSUS
appear to be of thyroidal origin. Thus, specimens submitted PARATHYROID ADENOMA
as thyroidal lesions may indeed be parathyroidal in origin.
Furthermore, the specimens from these parathyroid lesions Parathyroid cysts are rare. They may be derived from
are difficult to recognize accurately because of the morpho- the embryologic remnants or coalescence of microcysts.
logic overlap between thyroid and parathyroid lesions. Parathyroid cysts can occur as a result of degeneration
The diagnostic problems include the following: within an adenoma. The aspirated cyst fluid can measure
up to several milliliters and is characteristically clear and
A. Differentiation of a non-neoplastic parathyroid cyst watery. The fluid is often acellular or poorly cellular, con-
from a cystic parathyroid adenoma sisting of rare tissue fragments of small cuboidal cells with
B. Differentiation of parathyroid hyperplasia from round nuclei containing granular to compact chromatin
parathyroid adenoma (Fig. 9.9). The cells are arranged in regular microfollicles
A B
Fig. 9.9: Parathyroid Cyst versus Parathyroid Adenoma. A: Cyto-

preparation of an aspirated parathyroid cyst fluid depicting monolay-
ered tissue fragments of small cuboidal cells in a honeycomb arrange-
ment. The nuclei are small and uniform, with compact chromatin. Note
their strong resemblance to thyroid follicular cells. B: The same speci-
men stained by Romanowsky method (Heme-3 stain). C: A tissue frag-
ment of tightly packed small parathyroid cells with scant cytoplasm
and high N/C ratios (Heme-3 stain). (Courtesy of Michael Glant, M.D.,
C Director, Diagnostic Cytology Clinic, Indianapolis, Indiana.)

or honeycomb sheets. Oncocytic cells and histiocytes are be distinguished from parathyroid hyperplasia since both
rarely seen. The background shows proteinaceous debris. present similar cytologic features.
The parathyroid hormone levels in cyst fluids are always
elevated; however, needle rinses of parathyroid adenomas
also demonstrate high levels of parathyroid hormone.
Based on cytology alone, parathyroid cyst cannot be dif- PARATHYROID ADENOMA VERSUS
ferentiated from cystic parathyroid adenoma. THYROID LESIONS
Aspirates from parathyroid lesions are frequently inter-

preted as thyroid lesions, both non-neoplastic and neoplas-
PARATHYROID ADENOMA VERSUS tic. There is considerable cytomorphologic overlap between
PARATHYROID HYPERPLASIA thyroid follicular cells and parathyroid cells. Furthermore,
many parathyroid adenomas arise in intrathyroid location,
Primary parathyroid hyperplasia accounts for up to 15% and the specimens are submitted as thyroidal. There are no
of primary hyperparathyroidism. It can also be associated definite cytologic criteria that help accurately identify the
with the dominantly inherited multiple endocrine neopla- parathyroid lesions without the help of ancillary diagnos-
sia (MEN 1 or MEN 2A) syndromes. Parathyroid hyper- tic techniques, coupled with clinical and radiologic data.
plasia is often nodular and involves all four parathyroid Parathyroid adenomas may also on occasion be diffi-
glands but not uniformly. Histologically, the hyperplasia cult to differentiate from oncocytic or clear cell neoplasms
involves chief cells as well as oncocytic cells (Fig. 9.10A). of the thyroid and also share morphologic similarities
It can be diffuse or nodular and sometimes can form glan- with metastatic renal cell carcinoma.
dular patterns. The stromal adipose tissue is reduced or
absent.
The smears of parathyroid hyperplasia are variably
cellular, showing tissue fragments of small parathy- PARATHYROID ADENOMA VERSUS
roid cells containing round, uniform nuclei, with finely NODULAR GOITER
granular chromatin. The cytoplasm of the chief cells is
scant and pale or may be finely vacuolated. The onco- The parathyroid adenoma cells morphologically resemble
cytic cells are slightly larger and contain appreciable follicular cells in nodular goiter (Fig. 9.11). However, they
slightly denser cytoplasm. The stromal fat if identified are usually much smaller. Without a clinical suspicion,
in the aspirate will favor the diagnosis of hyperplasia and ancillary tests, parathyroid adenoma cells cannot be
(Fig. 9.10B). Cytologically, a parathyroid adenoma cannot differentiated from nodular goiters.
A B
Fig. 9.10: Parathyroid Hyperplasia versus Parathyroid adenoma. A: Scrape preparation of a hyperplastic parathyroid
gland. The parathyroid cells are small with poorly defined cell borders and scant cytoplasm and contain round nuclei.
The chromatin is compact. The cells are in aggregates or small tissue fragments and are separated by fat cells. B: Histo-
logic section of the excised hyperplastic parathyroid gland revealing hyperplasia of both chief and oncocytic cells (H&E).

Parathyroid Adenoma versus Thyroid Lesions (Figs. 9.11 to 9.13)
A B
Fig. 9.11: A: FNA of a nodular goiter. Tissue fragment of benign follicular cells, with a honeycomb pattern, lacking
extreme crowding and overlapping of nuclei. The nuclear size is slightly larger than the parathyroid cells. Note the
morphologic overlap between thyroid follicular cells and parathyroid cells (see Fig. 9.9). B: FNA of a cystic nodular
goiter showing macrophages and benign follicular cells. The cytologic pattern is indistinguishable from that of a para-
thyroid cyst.
A B
Fig. 9.12: Parathyroid Adenoma versus Follicular Neoplasm. A: FNA of a cellular follicular adenoma. Note the hy-
percellularity of the aspirate with large tissue fragments of follicular cells. B: Higher magnification showing syncytial
architecture, with and without a follicular pattern. The cells are slightly larger than those seen in parathyroid adenoma.
The chromatin is granular. This cytologic presentation is very similar to that of parathyroid adenoma (compare with
Figs. 9.7D,E).

A B
C D
Fig. 9.13: Parathyroid Adenoma versus Papillary Carcinoma. A: FNA of a PTC depicting large monolayered tissue
fragments. B: Higher magnification showing a syncytial arrangement with enlarged nuclei, powdery chromatin, micro-
nucleoli, nuclear grooves, and intranuclear inclusions. C: FNA of a parathyroid adenoma depicting large monolayered
tissue fragments. D: Higher magnification showing the syncytial arrangement of uniform nuclei, lacking minimal crite-
ria for papillary carcinoma.
carcinoma). However, the thyroid follicular cell nuclei in

PARATHYROID ADENOMA VERSUS adenoma/carcinoma are considerably enlarged. Colloid is
CHRONIC LYMPHOCYTIC THYROIDITIS usually scant or absent in cellular follicular neoplasms.
The differentiation between the parathyroid adenoma
Rarely, the presence of oncocytic cells and bare nuclei of
and thyroid follicular neoplasms are extremely difficult.
the parathyroid cells have been misinterpreted as lym-
Immunostains with either thyroglobulin or parathyroid
phocytes and resulted in the misdiagnosis of lymphocytic
hormone will be diagnostic. Increased levels of the serum
thyroiditis.
parathyroid hormone levels from the needle rinse fol-
lowing a fine needle biopsy will support the diagnosis of
parathyroid adenomas.
PARATHYROID ADENOMA VERSUS

FOLLICULAR ADENOMA/CARCINOMA
PARATHYROID ADENOMA VERSUS
In cytologic samples, follicular neoplasms share morpho- PAPILLARY THYROID CARCINOMA
logic similarities with parathyroid adenomas (Table9.2;
Fig. 9.12). Syncytial type tissue fragments and coarse Aspirates of parathyroid adenomas have been misinter-
nuclear chromatin are characteristic of both parathyroid preted as papillary thyroid carcinoma (PTC) (Table 9.2).
hyperplasia/adenoma and follicular neoplasms (adenoma/ The latter presents a wide spectrum of cytologic features

TABLE 9.2. CYTOPATHOLOGIC FEATURES OF PARATHYROID ADENOMA, PAPILLARY THYROID

CARCINOMA AND FOLLICULAR NEOPLASMS
Thyroid Cellular Follicular

Papillary Thyroid Adenoma/Follicular
Parathyroid Adenoma Carcinoma Carcinoma
Cellularity Generally hypercellular Generally hypercellular Generally hypercellular
Pattern Cells isolated, in loose aggregates, Cells isolated, in loosely Cells in syncytial tissue
or in syncytial tissue fragments; bare cohesive groups and in fragments; bare nuclei is not
nuclei frequent syncytial tissue fragments a feature
with various different
architectural patterns, bare
nuclei is not a feature
Architecture of the Small-to-large tissue fragments with Architectural patterns include Syncytial with or without
tissue fragments or without branching; trabecular papillary with or without follicular patterns; slim-
pattern frequent; follicular pattern branching, papillary-like, to-broad trabeculae, with or
+/; extreme crowding and with or without follicular without branching; crowding
overlapping of nuclei; perivascular pattern, monolayered, three- and overlapping of nuclei,
arrangement of neoplastic cells; dimensional clusters; swirls intense in carcinomas
branching network of delicate
capillaries characteristic
Cells Small, round to cuboidal, poorly Variable size; pleomorphic; Larger than parathyroid
defined cell borders; 69 mm in larger than parathyroid cells; cells; variable in size; poorly
diameter well- to poorly defined cell defined cell borders
borders
Nucleus Round; smooth nuclear membranes; Enlarged; demonstrate Variably enlarged, smooth
coarsely granular chromatin; nuclear criteria of papillary nuclear membranes; fine to
micronucleoli; high N/C ratios carcinoma (powdery to pale coarsely granular chromatin;
granular chromatin; micro/ nucleoli +/ in adenomas but
macronucleoli; nuclear grooves present in carcinomas
and intranuclear inclusions)
Cytoplasm Scant, indiscernible to modest; clear, Variable Scant

granular, occasionally oxyphilic
Psammoma bodies Absent May be present Absent
Background Clean to proteinaceous material; fat No proteinaceous material or No proteinaceous material or

globules in hyperplasia fat globules; macrophages +/ fat globules
Colloid Absent Colloid +/; dense blobs to Colloid +/; may be present
stringy in follicular lumens
Needle rinse Levels of parathyroid hormone Levels of parathyroid Levels of parathyroid

following FNA biopsy elevated hormone not elevated hormone not elevated
Immunoprofile
Parathyroid +
hormone
Thyroglobulin + +
Chromogranin +

with several characteristics that are not seen in parathy-

roid adenomas. Branching tissue fragments of epithelial
PARATHYROID CARCINOMA
cells with papillary-like pattern alone, which are seen in
The cytopathologic features of parathyroid carcinoma are
cytologic specimens of parathyroid adenomas, must not
sparsely documented as individual case reports. The cyto-
be considered a diagnostic feature of PTC unless accom-
logic features described are extremely variable, ranging
panied by nuclear features, for example, enlargement,
from uniform small cells with regular nuclei to pleomorphic
powdery chromatin, micronucleoli, nuclear grooves, and
cell pattern; evenly dispersed chromatin to coarsely granu-
intranuclear inclusions (Fig. 9.13). Positive immunostains
lar; single to multiple macronucleoli; and dispersed pattern
for parathyroid hormone will confirm the parathyroid
to syncytial tissue fragments. Parathyroid hyperplasia/ade-
origin.
noma and carcinoma are difficult to separate cytologically.
SUGGESTED READING
Absher K, Truong LD, Khurana K, et al. Parathyroid cytology: Layfield LJ. Fine needle aspiration cytology of cystic parathyroid
avoiding diagnostic pitfalls. Head Neck. 2002;24:187164. lesions. A cytomorphologic overlap with cystic lesions of the
Auger M, Charbonneau M, Huttner J. Unsuspected intrathyroidal thyroid. Acta Cytol. 1991;35:447450.
parathyroid adenoma: mimic of lymphocytic thyroiditis in fine Lerud KS, Tabbara SO, DelVecchio DM, et al. Cytomorphology
needle aspiration specimensa case report. Diagn Cytopathol. of cystic parathyroid lesions: report of four cases evaluated
1999;21:276279. preoperatively by fine needle aspiration. Diagn Cytopathol.
Bondeson L, Bondeson A-G, Nissbong A, et al. Cytopathological 1996;15:306311.
variables in parathyroid lesions: a study based on 1,600 cases Liu F, Gnepp DR, Pisharodi LR. Fine needle aspiration of
of hyperparathyroidism. Diagn Cytopathol. 1997;16:476482. parathyroid lesions. Acta Cytol. 2004;48:133136.
Crescenzo DG, Shabahang M, Garvin D, et al. Intrathyroidal Pitsilos SA, Webster R, Baloch ZW, et al. Ectopic parathyroid
parathyroid cancer presenting as a left neck mass. Thyroid. adenoma initially suspected to be a thyroid lesion. Arch Pathol
1998;2:652657. Lab Med. 2002;126:15411542.
DeLellis RA. Parathyroid tumors and related disorders. Mod Rossi ED, Mule A, Zannoni GF, et al. Asymptomatic intrathyroidal
Pathol. 2011;24:S78S93. parathyroid adenoma. Report of a case with a cytologic
Giorgadza T, Stratton B, Baloch ZW, et al. Oncocytic parathyroid differential diagnosis including thyroid neoplasms. Acta Cytol.
adenoma: problem in cytological diagnosis. Diagn Cytopathol. 2004;48:437440.
2004;31:276280. Tseng TU, Hsiao YL, Chang TC. Ultrasound guided fine needle
Halbauer M, Crepinko I, Brzae HT, et al. Fine needle aspiration aspiration cytology of parathyroid lesions. A review of 72
cytology in the preoperative diagnosis of ultrasonically enlarged cases. Acta Cytol. 2002;46:10291036.
parathyroid tumors. Acta Cytol. 1991;35:728735.
Hara H, Oyama T, Kimura M, et al. Cytologic characteristics
of parathyroid carcinoma: a case report. Diagn Cytopathol.
1998;18:193198.

10 NEOPLASMS OF THE PITUITARY
GLAND
The anterior part of the pituitary gland, also referred to

as adenohypophysis, is one of the two organs in the dis-
PITUITARY ADENOMAS
persed neuroendocrine system that are entirely composed
Pituitary adenomas, derived from parenchymal cells of
of neuroendocrine cells. Pituitary neoplasms, especially
the adenohypophysis, are one of the most common benign
adenomas, are one of the frequently occurring central
neoplasms of the CNS.
nervous system (CNS) tumors, with a reported incidence
of 6% to 10% of all intracranial tumors. Intraoperative
consultation is often sought for, and crush preparations CLASSIFICATION OF PITUITARY
are utilized for the diagnostic purposes. ADENOMAS
There are several classification systems for pituitary ade-

ANATOMY AND HISTOLOGY OF nomas such as functional, anatomic or radiologic, his-
NORMAL PITUITARY GLAND tologic, immunohistochemical, and ultrastructural (Asa,
2011). The World Health Organization (WHO) classifi-
The adult human pituitary gland is housed in sella tur- cation of pituitary adenomas (2004) separates them into
cica, under the base of the brain. It is a bean-shaped organ, typical and atypical types and utilizes immunochemistry
divided into two parts, anterior pituitary or adenohypoph- and ultrastructural examination, correlating them with
ysis and posterior pituitary or neurohypophysis. The ante- clinical findings and specific hormone production.
rior pituitary is derived from Rathkes pouch. The anterior The purpose of an intraoperative consultation is to
pituitary constitutes the larger part of the gland, roughly identify the lesion as a pituitary neoplasm and not to sub-
75% to 80%, and is formed by three components, namely type it. The specific histologic type requires ancillary stud-
the pars distalis, pars intermedia, and the pars tuberalis. ies. Therefore, this chapter is limited only to presenting
The posterior pituitary is derived from the nervous system. the general cytopathologic features and the differential
The pituitary gland measures approximately 13 9 diagnosis.
6 mm and weighs about 0.6 g. It is surrounded by many
important anatomic structures, relevant in differential
diagnostic process. CLINICAL FEATURES
Histologically, the anterior pituitary consists of acini,
composed of eosinophilic, basophilic, and chromophobe Pituitary adenomas may be functional and symptomatic or
cells in varying proportions. These represent specific cell nonfunctional. Approximately 25% of patients with pitu-
types, each type associated with specific hormone produc- itary adenomas lack a characteristic clinical syndrome or
tion and function. The acini are surrounded by capillary- serum hormonal marker. Those without endocrine func-
rich reticulin network. tions tend to present in a slightly older age group, usually
Individual cell types can be correctly identified by after fifth decade, whereas adenomas with secretory activ-
immunohistochemical localization of the hormone prod- ity arise between 30 and 50 years of age. They are uncom-
ucts and ultrastructural morphology. mon in children under 12 years of age. Majority of the
The neurohypophysis consists almost entirely of axo- childhood pituitary adenomas are small and functional.
nal terminations and accompanying glial cells (pituicytes) The nonfunctional pituitary adenomas may be an inciden-
in a capillary-rich stroma. tal finding or cause symptoms due to the increased size.
225

The presenting symptoms caused by hormonal over- Microscopically, pituitary adenomas show a diffuse
production include amenorrhea, infertility, Cushing syn- growth pattern consisting of sheets of uniform cells
drome, and acromegaly. Those caused by compression of interrupted by delicate capillary network (Fig. 10.1).
the surrounding tissues or organs include impaired eye Perivascular location of neoplastic cells may result in the
movements, visual disturbances, nerve palsies, and com- formation of pseudorosettes and pseudopapillary forma-
pression of the optic chiasma. tion. The cells are small to medium sized and round. Their
An overwhelming majority of pituitary adenomas arise nuclei are typically uniform, round to oval, exhibiting a
in the anterior hypophysis and are initially intrasellar. saltpepper chromatin pattern. There is mild anisonucle-
These tumors have a marked tendency to grow beyond osis, and distinct micronucleoli can usually be observed.
the confines of pituitary fossa and occupy suprasellar or The cell borders are well to poorly defined. The neoplas-
parasellar areas. tic cells demonstrate uniform tinctorial quality. Lack of
stroma is characteristic. The cytoplasm can be eosino-
philic or basophilic or amphophilic.
ASSOCIATION WITH HEREDITARY
SYNDROMES
Up to 3% of the operated pituitary adenomas are associ- CYTOPATHOLOGIC FEATURES

ated with multiple neuroendocrine neoplasia syndrome,
The specimens represent tissue samples submitted for
type 1 (MEN 1). See Chapter 1, Table 1.1.
intraoperative consultation and processed by crush prep-
arations. Due to lack of stroma, the tissue samples from
RADIOGRAPHIC FINDINGS pituitary adenomas easily produce a thin monolayered
smear across the slide. The cytologic presentation is quite
Neuroimaging (CT or MRI) shows uniformly enhancing characteristic (Table 10.1; Figs. 10.2 to 10.7). The smears
mass involving the pituitary gland. are usually quite cellular and composed of closely packed
small- to medium-sized tumor cells, with high N/C ratios
presenting a dispersed cell pattern. Pseudofollicular pat-
GROSS AND MICROSCOPIC FEATURES tern is frequent. The adenoma cell nuclei are centrally
placed, containing granular chromatin imparting a
Grossly, most of the pituitary adenomas are solid and saltpepper chromatin pattern, and small nucleoli. The
soft in consistency. Cystic change with hemorrhage is cellular shapes may be round, oval, or polyhedral, and
uncommon. the cytoplasm in most instances is acidophilic or faintly
A B
Fig. 10.1: Histologic Sections of Pituitary Adenoma. A: Low-power view of a pituitary adenoma with a diffuse growth
pattern (H&E). B: Higher magnification depicting a monotonous, small, round cell pattern. The cellular borders are
poorly defined; the cytoplasm is eosinophilic and scant. The nuclei are round, containing finely granular chromatin, and
micronucleoli are frequently present (H&E).

Chapter 10: Neoplasms of the Pituitary Gland 227
TABLE 10.1. CYTOPATHOLOGIC FEATURES OF The cytoplasmic granulation varies among the different
PITUITARY ADENOMA subtypes, but uniform in a given tumor. Occasionally, the
neoplastic cells are seen in small aggregates or balls (Figs.
Cytopathologic Features
10.3A and 10.4D). Scattered large nuclei may be seen
Cellularity Highly cellular; no resistance to making (Fig. 10.6D,E).
smears
Presentation Monomorphic, dispersed cell pattern;

short chains IMMUNOPROFILE
Cells Medium sized, cell borders well to poorly The cells of pituitary adenomas are immunoreactive for
defined synaptophysin and chromogranin and, apart from a few
null cell adenomas, also express one or more of the pitu-
Nucleus Uniform, round, smooth nuclear itary hormones.
membranes; granular chromatin (salt
pepper type); micronucleoli; mildly
pleomorphic; occasional giant forms
ULTRASTRUCTURE
Cytoplasm Scant, granular; eosinophilic, basophilic to
amphophilic Ultrastructurally, pituitary adenoma cells demonstrate
secretory granules (sparsely granulated or densely granu-
Background Granular due to spilled cytoplasmic
lated), which vary in terms of numbers, size, and shapes
contents; no necrosis
and electron density depending on the type of adenohy-
Immunoprofile Neuroendocrine markers +; specific pophysial cell. The secretory granules may be spherical,
hormones flattened, dented, heart shaped, teardrop shaped, or elon-
gated. They vary from 150 to 700 nm in diameter, average
Ultrastructure Pleomorphic secretory granules, variable being 150 to 400 nm. In some cells, the secretory granules
in size, shape, numbers, and electron demonstrate misplaced exocytosis (release of secretory
density
material in intercellular space). Some demonstrate cyto-
Differential Normal pituitary parenchyma plasmic processes (thyrotroph adenomas).
diagnoses Metastatic poorly differentiated carcinoma
Plasmacytoma
Malignant lymphoma DIFFERENTIAL DIAGNOSES
Meningioma, small cell type
Paraganglioma
Hemangiopericytoma Several neoplasms in the CNS are composed of small uni-
Glioblastoma, small cell type form cells and enter the differential diagnosis. The loca-
Oligodendroglioma tion of the lesions as well as clinical and radiologic data
Central neurocytoma are critical.
Medulloblastoma The smears of the pituitary adenomas must be differ-
Peripheral neuroectodermal tumor (PNET)
entiated from normal pituitary parenchyma. The latter,
Pineocytoma
Clear cell ependymoma because of its stromal content is extremely difficult to
smear, resulting in thick tissue fragments that are difficult
to visualize and interpret. This is in contrast to the sam-
basophilic. The tumors display abundant capillary sinu- ples from adenomas, which offer no resistance, allowing
soids, and mitosis, necrosis, cellular pleomorphism, or cell a smooth cell spread. If great pressure is used in smear-
processes are very seldom found. ing technique, the neoplastic cells may be crushed, deeply
Nuclear monotony and minimal matrix are the rule. stained, and mistaken for metastatic small cell carcinoma.
Tumors with trabecular architecture present short chains The differential diagnoses of pituitary adenoma include
or circles of cells (Fig. 10.4A). The background may show neoplasms with small round cells that occur in the sel-
diffuse granularity due to disruption of the cell borders lar or parasellar area. They are listed in Table 10.2 and
and spillage of the cytoplasmic contents (Fig. 10.3D). illustrated in Figures 10.8 to 10.18. All the listed entities,
Occasionally, the neoplastic cells may contain dense aci- although conceptually apply because of the round cell
dophilic cytoplasm (Fig. 10.4D), resembling oncocytes. pattern, may not be applicable anatomically.

A B
Fig. 10.2: Crush Preparation of Pituitary Adenoma. A: Note the

dispersed cell pattern formed by small- to medium-sized cells with
poorly defined cell borders and scant eosinophilic cytoplasm. The
nuclei are round, mildly pleomorphic in size with coarsely granular
chromatin. B: This field demonstrates moderately pleomorphic cells
with an occasional large nucleus. C: A predominantly dispersed cell
C pattern. Note pseudofollicles (arrows).
A B
Fig. 10.3: Crush Preparations of Pituitary Adenoma. AC: These three images highlight the monomorphic pattern with
small round cells, forming a follicular pattern (arrows).
All crush preparations are stained with hematoxylin and eosin unless otherwise stated.

C D
Fig. 10.3: (continued) D: This field shows a diffuse granular background, the granularity being caused by spilled cyto-
plasmic contents. The nuclear chromatin is coarsely granular with a saltpepper pattern.
A B
C D
Fig. 10.4: Crush Preparations of Pituitary Adenoma. A: Medium-power view depicting uniform, loosely cohesive cells
and a prominent capillary network. Note the cells forming short chains (arrowheads) and follicles (arrows). B,C: High-
er magnification showing medium-sized cells with well-defined cell borders, appreciable eosinophilic cytoplasm, central
to eccentric nuclei, and containing saltpepper chromatin. D: The same case. The cells and their nuclei are moderately
pleomorphic. Note abundant eosinophilic cytoplasm.

A B
Fig. 10.5: Crush Preparations of Pituitary Adenoma. A: The smear is thick, showing syncytial tissue fragments of uni-
form, small round cells, better visualized at the periphery. The cytoplasm of the neoplastic cells is granular. B: The same
case stained with Papanicolaou. Note that the cytoplasmic granularity is not very apparent.
A B
C D
Fig. 10.6: A: Histologic section of a pituitary adenoma showing a prominent vascular stroma. Crush preparations of
pituitary adenoma. B: Dispersed cell pattern with poorly defined cell borders and variable granular cytoplasm. The
background shows a granular material. C: Higher magnification showing typical cell morphology with saltpepper
chromatin. Note deeply eosinophilic granular cytoplasm. D,E: Papanicolaou-stained smears showing a dispersed cell
pattern. Also note occasional large pleomorphic cells.

E Fig. 10.6: (continued)
A B
Fig. 10.7: Crush Preparations of Pituitary Adenoma Stained by Ro-

C manowsky Method. A: Medium power. B,C: Higher magnification.

TABLE 10.2. DIFFERENTIAL DIAGNOSES OF PITUITARY ADENOMA
Diagnostic Clues/
Pituitary adenoma Highly cellular; cells small round to polygonal cells; cell Location; synaptophysin; Figures 10.210.7
borders well to poorly defined; nuclei round, uniform pituitary hormones +/
with smooth nuclear membrane; coarsely granular
chromatin; nucleoli +/; mitoses absent; cytoplasm
variable, scant to abundant; no cell processes; no
necrosis; may form cords, ribbons or papillary
structures, richly vascularized; granular background
Normal pituitary Poorly cellular; difficult to smear, thick smears; cells

parenchyma not well visualized
Paraganglioma Monomorphic cell pattern; cells discrete or in loosely S100 protein + Figure 10.16
cohesive groups; neoplastic cells small to medium
with occasional giant forms; round to plasmacytoid,
uniform, round, eccentric nuclei; granular chromatin
with saltpepper appearance; sometimes compact;
intranuclear inclusions +/; cytoplasm variable; may be
drawn into delicate process; eosinophilic cytoplasmic
granules with Romanowsky stain; mitoses
Primary CNS Highly cellular; cells isolated; 2 to 3 times the LCA +; B/T-cell markers Figure 10.10A,B
Lymphoma size of normal lymphocytes; round nucleus; nuclear +; location; B/T-cell gene
membrane irregularity +/; granular chromatin; rearrangement + for
nucleoli prominent; mitoses +; cytoplasm scant; no dominant clones
cell processes; necrosis +; background may contain
reactive astrocytes
Plasmacytoma Diffuse population of plasma cells with eccentric oval Monoclonal cytoplasmic Figure 10.11
nuclei; different stages of maturity; no matrix or stroma immunoglobulins +
Meningioma Highly cellular; cohesive, small cells with poorly Location; EMA +; Figure 10.15A,B
(small cell type) defined cell borders; whorling pattern helpful, oval vimentin +; GFAP
nuclei with finely granular chromatin; inconspicuous
micronucleoli, intranuclear inclusions; mitoses absent
Clear cell Compact cellularity forming a solid neoplasm; GFAP +; perivascular

ependymoma uniform, small, round-to-oval nuclei with single, zones; EMA +; luminal
distinct micronucleoli; perivascular nuclear-free zones surfaces
and true ependymal rosettes
Glioblastoma, Highly cellular; no true cell cohesion but smears may GFAP +; neuroendocrine Figure 10.14
small cell type be crowded with pseudosyncytial pattern; nuclei markers
pleomorphic but no coarse chromatin or nucleoli;
scant cytoplasm but cell processes should be visible in
at least some cells; mitoses, necrosis and pronounced
endothelial proliferation

TABLE 10.2. DIFFERENTIAL DIAGNOSES OF PITUITARY ADENOMA (Continued)
Diagnostic Clues/
Medulloblastoma Highly cellular; cells isolated, in cohesive groups, Age; location; glial/ Figure 10.17
or in syncytial tissue fragments; rosette formation neuronal markers may
+/; cells small, round with round or oval to be positive in fibrillary
carrot-shaped nuclei; smooth nuclear membrane, zones
coarsely granular deep-staining chromatin; nucleoli
inconspicuous; mitoses +; cytoplasm scant to
indiscernible; no cell processes; necrosis +
Pineocytoma Highly cellular, uniform small round cells; poorly Age; location; Figure 10.18
defined cell boarders; appear as bare nuclei; nuclei neuroendocrine
round, finely granular chromatin; small nucleoli; markers +; neurofilament;
cytoplasm, cell processes; pineocytic rosettes with protein +
central cell processes, surrounded by neoplastic cell
nuclei; no mitoses
Hemangiopericytoma Cellular smears; sheets and fascicles with randomly CD 34 +; Figure 15.30
oriented, oval-to-elongated nuclei; poorly defined cell neuroendocrine
borders, indistinct cytoplasm; characteristic network markers
of staghorn blood vessels surrounded by neoplastic
cells
Central/ Moderately cellular; individually dispersed small Age; location; Figures 10.9A,B;
extraventricular monomorphic round cells; nuclei round with smooth neuroendocrine 17.1417.18
neurocytoma nuclear membrane, characteristic delicate stippled markers +;
chromatin; small nucleoli; mitoses absent; fine synaptophysin +; NSE +;
cellular processes; perinuclear halo; no necrosis; chromogranin +; GFAP
calcification
Oligodendroglioma Moderate-to-high cellularity; monotonous population GFAP +/; Leu 7 +/; Figure 10.8A,B
of single, small, round cells with ill-defined cell concurrent loss of
borders; perinuclear clearing; fried egg pattern; 1p/19q chromosomal
increased N/C ratios; smooth nuclear membrane; arms; neuroendocrine
finely granular, evenly distributed chromatin; markers
inconspicuous nucleoli; calcification frequent;
may contain astrocytes and thin-walled blood
vessels
Peripheral Uniform small round cells with scant cytoplasm, Positive neuroendocrine Figure 10.13AC
neuroectodermal high N/C ratios; coarsely granular saltpepper markers; CD 99 +
tumor (PNET) chromatin, Homer-Wright rosettes +;
neuropil +
Metastatic poorly Uniform small round cells with scant cytoplasm, high Positive neuroendocrine Figure 10.12A,B
differentiated N/C ratios; coarsely granular saltpepper chromatin; markers; TTF-1 +
neuroendocrine nuclear molding +/; necrosis +/; karyorrhexis +
carcinoma

Differential Diagnoses of Pituitary Adenoma (Figs. 10.8 to 10.18)
A B
Fig. 10.8: Pituitary Adenoma versus Oligodendroglioma. A: This crush preparation of an oligodendroglioma presents
a cytomorphology similar to that of a pituitary adenoma. The anatomic location of sellar region however will favor a
pituitary adenoma. B: The same case stained by Papanicolaou.
A B
Fig. 10.9: Pituitary Adenoma versus Central Neurocytoma. A: This

crush preparation of a central neurocytoma shows a uniform, small
round cell population with fibrillar stroma (neuropil; NP), which is
a distinguishing feature. B: This field shows minimal neuropil and
resembles a smear of pituitary adenoma. C: Different example of a
central neurocytoma with a dispersed cell pattern that mimics pitu-
C itary adenoma.

A B
Fig. 10.10: Pituitary Adenoma versus Malignant Lymphoma. A: Malignant lymphoma presents small- to medium-
sized cells with a dissociated pattern like pituitary adenoma. Malignant lymphoma, however, shows karyorrhexis and
prominent mitotic activity. The cytoplasm is indistinct and lacks the granularity of pituitary adenoma cells. B: The same
tumor stained by Papanicolaou.
A B
Fig. 10.11: Pituitary Adenoma versus Multiple Myeloma. A: Crushed preparation of multiple myeloma, showing
varying-sized myeloma cells with eccentric nuclei and lacking granularity in the cytoplasm. Clinical history is very
helpful. B: Papanicolaou-stained preparation of the same case.

A B
Fig. 10.12: Pituitary Adenoma versus Metastatic Neuroendocrine Carcinoma. A: Medium-power view of a crush prep-
aration showing a large population of small cells, discrete, in loosely cohesive groups and in syncytial tissue fragments.
Their cell borders are poorly defined and the cytoplasm is indistinct. The nuclear chromatin is intensely deep staining.
Note nuclear molding and stretch artifacts. B: Higher magnification depicting round-to-oval nuclei and stretch artifacts.
A B
Fig. 10.13: Pituitary Adenoma versus PNET. AC: All three images
of crush preparations of a PNET show cytomorphology similar to a
C pituitary adenoma, except for a fibrillar background.

Fig. 10.14: Pituitary Adenoma versus Small Cell Glioblastoma.

Crush preparation of a glioblastoma multiforme with a small cell
pattern showing a morphologic resemblance to pituitary adenoma.
A B
Fig. 10.15: Pituitary Adenoma versus Meningioma, Small Cell Type. Crush preparation of a meningioma. A: The neo-
plastic cells are small and dispersed. Note the cytoplasmic processes. B: Higher magnification.
Fig. 10.16: Pituitary Adenoma versus Paraganglioma. Crush prepa- Fig. 10.17: Pituitary Adenoma versus Medulloblastoma. Crush
ration of a paraganglioma showing a uniform cell pattern formed preparation of a medulloblastoma. This primitive neuroectodermal
by small- to medium-sized, round to plasmacytoid cells with moder- tumor shows diffuse population of uniform round, small cells, oc-
ate amounts of eosinophilic cytoplasm. casionally presenting a pseudorosette.

A B
Fig. 10.18: Pituitary Adenoma versus Pineocytoma. A: Low-power view showing a very cellular preparation. B: Higher
magnification showing uniform, small cells with poorly defined cell borders and scant cytoplasm. Note pineocytic ro-
sette (arrows).
SUGGESTED READING
Asa SL. Tumors of the Pituitary Gland. AFIP Atlas of Tumor Pathology. Pathology and Genetics. Tumors of Endocrine Organs. World
4th series, Fascicle 15. Silver Spring, MD: ARP Press; 2011. Health Organization Classification of Tumours. Lyon, France:
Burger PC, Scheithauer BW, Vogel FS. Surgical Pathology of the IARC Press; 2004.
Nervous System and Its Coverings. 4th ed. New York, NY: Luk ISC, Chan JKC, Leung S. Pituitary adenoma presenting
Churchill Livingston; 2002. as sinonasal tumors: pitfalls in diagnosis. Hum Pathol.
Ironside JW, Moss TH, Louis DN, et al. Neuronal and mixed neuronal- 1996;27:605609.
glial tumors. In: Diagnostic Pathology of Nervous System Tumours. Ng H-K. Smears in the diagnosis of pituitary adenomas. Acta
New York, NY: Churchill Livingstone; 2002:240242. Cytol. 1998;42:514618.
Joseph JT. Diagnostic Neuropathology Smears. Philadelphia, PA: Nguyen GK, Johnson ES, Mielke JW. Comparative
Lippincott Williams & Wilkins; 2007. cytomorphology of pituitary adenomas and oligodendroglioma
Kontogeorgos G, Bassiouka I, Giannou P, et al. Diagnosis in intraoperative crush preparations. Acta Cytol. 1992;36:
of pituitary adenomas on touch preparations assisted by 661667.
immunocytochemistry. Acta Cytol. 1995;39:143152. Pegolo G, Buclwalter JG, Weiss MH, et al. Pituitary adenomas.
Lloyd RV, Trouillas J, Kovacs K, et al. Pituitary tumors: Correlation of the cytologic with biologic behavior. Acta Cytol.
introduction. In: DeLellies RA, Lloyd RA, Heitz PU, et al., eds. 1995;39:887892.

OF THE SKIN (MERKEL CELL
CARCINOMA)
Merkel cell carcinoma is a rare and aggressive primary with an average of 2 to 3 cm. They appear as gray-white
cutaneous neuroendocrine (small cell) carcinoma of masses.
the skin arising from the basal epidermis. Toker first Histologically, Merkel cell carcinomas present two
described it in 1972 as trabecular carcinoma of the basic growth patterns namely trabecular (Figs. 11.1AC)
skin. The tumor is derived from Merkel cells, which are and a diffuse, sheet-like growth pattern (Fig. 11.1D),
specialized epithelial cells with neuroendocrine features, which more closely resembles a malignant lymphoma.
more commonly found in the skin with high hair den- The trabecular pattern consists of cords of tumor
sity, in glabrous epithelium of the digits and lips, and in cells, two to three cells thick, but the cords can be much
the region of the oral cavity. Fredrich Merkel first identi- wider. The neoplastic cells are round and small with
fied Merkel cells in 1875 as specific touch-sensitive cells scant rim of amphophilic cytoplasm. The nuclei are
in the skin. Normally, without special stains, Merkel round and hyperchromatic with finely granular chro-
cells cannot be distinguished from the surrounding cells. matin and inconspicuous nucleoli. Their N/C ratios
Ultrastructurally, the Merkel cells demonstrate electron- are very high. Mitotic activity is usually very brisk.
dense, membrane-bound secretory granules and interme- Spindling of the tumor cells can be seen. The Merkel
diate filament buttons. cell carcinoma is usually separated from the epidermis
Primary neuroendocrine carcinoma of the skin occurs by a zone of dermal collagen (Fig. 11.1A). The tumor
usually in elderly white patients, primarily involving is usually restricted to the dermis, but the involvement
the sun-exposed areas. The incidence is reported to be of subcutaneous fat, fascia, and muscles can be seen.
0.34/100,000 in men as compared to 0.17/100,000 in Lymphoplasmacytic infiltrate is often seen surrounding
women. The majority of the patients are older than 65 the tumor and within the tumor. Pagetoid growth of the
years. Nearly half the cases (46%) occur in head and carcinoma cells has been described. The stroma of the
neck, including lip and eyelid, followed by upper extremi- tumor is richly vascularized. Areas of coagulative necro-
ties 21%, lower extremities 14%, and trunk 7%, with the sis may produce geographic patterns, and crush artifacts
remaining 7% involving miscellaneous sites. are seen in approximately 50% of the cases. Invasions
Clinically, Merkel cell carcinoma presents as a rapidly of the dermal lymphatics and vessels, as well as encrus-
growing, solitary, purple, dome-shaped papule or plaque tation of the blood vessels with DNA (Azzopardi
on sun-exposed skin, frequently localized in the head and phenomenon/effect), are other features seen in these
neck region. Merkel cell carcinomas are aggressive tumors tumors. Amyloid deposits have been described. Merkel
with a propensity for local recurrences and metastases to cell carcinomas may be associated with squamous and
the regional lymph nodes as well as distant sites. basal cell carcinomas.
GROSS AND HISTOLOGIC FEATURES CYTOPATHOLOGIC FEATURES
Grossly, Merkel cell carcinomas are confined to the dermis The specimens for the cytologic diagnosis of Merkel
and subcutis and vary in size, ranging from 0.3 to 6 cm cell carcinoma usually represent fine needle biopsies of
239

A B
C D
Fig. 11.1: A: A low-power view of an excised cutaneous nodule showing a dermal neoplasm. Note the band of
collagen separating the epidermis and the dermis (H&E). B: At medium power, the neoplasm appears to be very
cellular, composed of nests and trabeculae of small neoplastic cells with scant stroma (H&E). C: Higher magnifica-
tion showing the small, uniform neoplastic cells with high N/C ratios (H&E). D: Histologic section of a different
example of Merkel cell carcinoma presenting a solid growth pattern. Note the uniform cells with a brisk mitotic
activity (H&E).
cutaneous nodules or masses and those of metastatic sites defined, and the cytoplasm is indiscernible to scant. The
such as cervical or mediastinal lymph nodes, salivary nuclei are round to oval with high N/C ratios. Their chro-
glands, skin nodules, and visceral organs. Serous effusion matin is granular; nuclear molding and stretch artifacts
fluid is also utilized to detect metastases. may be noted. The nuclear membranes are smooth to
The aspirates of Merkel cell carcinomas are usually irregular and occasionally highly convoluted. Mitoses
very cellular, consisting of a large population of mono- are frequent as is individual cell necrosis. Merkel cell
morphic small, round to cuboidal cells. The neoplastic carcinoma cells have scant cytoplasm, but occasionally it
cells are present as discrete, in loosely cohesive groups appears pale-pink, homogeneous with well-circumscribed
or in syncytial tissue fragments without any architec- round-to-oval buttons of dense cytoplasm in perinuclear
tural patterns, closely resembling high-grade neuroen- locations. These buttons are described as either attached
docrine carcinomas (small cell carcinomas) (Table 11.1; to the nucleus, lying in the indentation of the nucleus, or
Figs. 11.2 to 11.6). Occasionally, pseudorosettes may detached, lying free outside the nucleus. Ultrastructurally,
be present. The neoplastic cells are also seen clustering these correspond to the distinct whorls of intermediate
around the blood vessels. Their cell borders are poorly filaments (Fig. 11.7D).

Chapter 11: Neuroendocrine Tumors of the Skin (Merkel Cell Carcinoma) 241
TABLE 11.1. CYTOLOGIC FEATURES OF MERKEL CK20 and the negative reactivity to TTF-1 are important
CELL (CUTANEOUS NEUROENDOCRINE) features that differentiate pulmonary small cell carcino-
CARCINOMA mas from Merkel cell carcinoma.
Cellularity Highly cellular
Presentation Dissociated pattern common, cells mostly

isolated; also in groups and in syncytial ULTRASTRUCTURE
tissue fragments
Ultrastructurally, Merkel cell carcinoma cells invari-
Cells Monomorphic, small, round, 1016 mm ably demonstrate membrane-bound, dense-core secre-
in largest dimension; poorly defined cell tory granules, 80 to 300 nm in diameter. In many cases,
borders; high N/C ratios
the granules demonstrate a clear zone surrounding the
Nucleus Round to oval; smooth nuclear dense-core granules. Another important feature is the
membrane; convoluted shapes have presence of perinuclear or juxtanuclear whorls of inter-
been described; saltpepper chromatin; mediate filaments, an important feature that differentiates
nucleolus +/; mitoses frequent; nuclear Merkel cell carcinoma from other neuroendocrine tumors
molding +/; karyorrhexis +/; stretch
(Fig. 11.7D).
artifacts +/
Cytoplasm Indiscernible to scant
Background Necrosis +/; stripped nuclei DIAGNOSTIC ACCURACY AND

Immunoprofile Positive reactivity to neuroendocrine
markers; neurofilament protein; low
The cytomorphology of Merkel cell carcinoma is char-
molecular weight cytokeratin and CK20;
negative reactivity to CK7; TTF-1; S100 acteristic enough to suggest the diagnosis when the pri-
protein, high molecular weight keratin, mary site is head and neck or sun-exposed area and is
and leukocyte common antigen (LCA) supported by immunostains. However, the diagnostic
problems are encountered with Merkel cell carcinomas at
Ultrastructure Electron-dense, membrane-bound the metastatic sites.
secretory granules; paranuclear whorls or
The cytological differential diagnoses of Merkel cell
buttons of intermediate filaments
carcinoma include neoplasms that are composed of small
Differential Other neuroendocrine carcinomas cells and are site specific. Primary Merkel cell carcinoma
diagnoses Small cell carcinomas presents an overlapping pattern with cutaneous lesions
Metastatic carcinoid tumors such as poorly differentiated squamous carcinoma, basa-
Reactive lymph node loid squamous carcinoma, metastatic neuroendocrine
Malignant lymphoma/leukemia
carcinomas to the skin, for example, small cell carcino-
Malignant melanoma
Metastatic poorly differentiated mas and metastatic carcinoid tumors, and malignant
squamous/adenocarcinomas non-Hodgkin lymphoma/leukemia. Merkel cell carci-
Basaloid squamous carcinoma noma often metastasizes to the salivary glands, particu-
larly the parotid gland, and must be differentiated from
neoplasms composed of small cells such as primary or
metastatic small cell neuroendocrine carcinoma, adenoid
IMMUNOPROFILE cystic carcinoma, malignant lymphoma/leukemia, meta-
static poorly differentiated squamous and adenocarci-
Merkel cell carcinoma cells react positively to several nomas, and malignant melanoma. The same holds true
neuroendocrine markers such as chromogranin, synapto- with aspirates of metastatic Merkel cell carcinoma at
physin, and neuron-specific enolase. The cells are reactive various body sites. History of Merkel cell carcinoma is
to low molecular weight keratin, cytokeratin 20 (CK20), critical. The differentiating features of diagnostic entities
and neurofilament protein. Merkel cell carcinoma cells are are listed in Table 11.2 and illustrated in Figures 11.8 to
nonreactive to high molecular weight keratin and thyroid 11.13. Ancillary tests are required for accurate typing of
transcription factor-1 (TTF-1). The positive reactivity to the neoplasm.

A B
Fig. 11.2: A: Fine needle aspirate of a Merkel cell carcinoma depicting high cellularity, composed of small round cells
with scant indiscernible cytoplasm and high N/C ratios. The chromatin is coarsely granular and deep staining. Some
nuclei demonstrate molding. B: The same aspirate stained with Diff-Quik stain.
A B
Fig. 11.3: A: Fine needle aspirate of a different case of Merkel cell carcinoma exhibiting marked cellularity with small
cells in syncytial tissue fragments and in loosely cohesive groups. The nuclei are mildly pleomorphic, round to short,
and spindle shaped. B: Cell block of the same aspirate (H&E).
A B
Fig. 11.4: Fine needle aspirate of an enlarged submandibular lymph node from a patient with the history of Merkel cell
carcinoma of the face. A: A low-power view showing marked cellularity with a dispersed cell pattern. Note the stretch
artifacts. B: Higher magnification showing mildly pleomorphic small malignant cells with indiscernible cytoplasm, nu-
clear molding, and stretch artifacts.

A B
Fig. 11.5: A, B: Fine needle aspirate of a large gluteal mass in an elderly man showing typical cytomorphology of
a small cell neuroendocrine carcinoma, confirmed as Merkel cell carcinoma by immunohistochemistry on excised
specimen.
A B
Fig. 11.6: A: Fine needle aspirate of Merkel cell carcinoma showing a predominant short spindle cell pattern. B: The
same aspirate stained by Diff-Quik.
A C D
Fig. 11.7: A: Histologic section of a Merkel cell carcinoma demonstrating positive reactivity with CK20. B: Electron
micrograph of Merkel cell carcinoma showing electrodense secretory granules. C: Higher magnification highlighting
the secretory granules (arrowheads). D: Electron micrograph of Merkel cell carcinoma showing cytoplasmic whorls of
intermediate filaments (arrows).

TABLE 11.2. DIFFERENTIAL DIAGNOSES OF MERKEL CELL CARCINOMA

Merkel cell Neoplastic cells discrete, in loosely cohesive groups with no architectural pattern; cells Figures
carcinoma small, round to oval; nuclear membranes smooth to irregular; chromatin deep staining, 11.211.7
coarsely granular; nucleoli inconspicuous to absent; nuclear molding +; stretch artifacts
+; mitoses +; karyorrhexis +; cytoplasm scant to indiscernible; necrosis +; Immunoprofile:
CK20 +; neuroendocrine markers +; TTF-1 ; history of Merkel cell carcinoma helpful
Small cell Neoplastic cells discrete, in loosely cohesive groups or in syncytial tissue fragments with Figure 11.8
carcinoma, primary no architectural patterns; cells small, round to oval; occasionally oblong to spindle shaped;
or secondary nuclear membranes smooth to irregular; chromatin deep staining and coarsely granular;
(neuroendocrine nucleoli inconspicuous to absent; nuclear molding +; stretch artifacts +; mitoses +;
carcinoma) karyorrhexis +; cytoplasm scant to indiscernible; cellular necrosis +; Immunoprofile: CK +;
neuroendocrine markers +/; TTF-1 + if secondary from lung; S100 protein ; LCA ; CK20
Metastatic Neoplastic cells discrete, in loosely cohesive groups or in syncytial tissue fragments with Figure 3.25
carcinoid tumor nests and cords; cells small, round to oval, very uniform; occasionally oblong to spindle
shaped; nuclear membranes smooth; chromatin coarsely granular with saltpepper
appearance; nucleoli +/; nuclear molding absent; stretch artifacts absent; mitoses rare +;
karyorrhexis ; cytoplasm scant to indiscernible; cellular necrosis ; Immunoprofile: CK
+; neuroendocrine markers +; S100 protein ; LCA ; CK20
Basaloid squamous Malignant cells isolated, in loosely cohesive groups or in syncytial tissue fragments with Figure 11.9B
cell carcinoma no architectural patterns; cells small, round, oval to cuboidal; occasionally oblong to
spindle shaped; nuclear membranes smooth to irregular; chromatin deep staining and
molding; mitoses +; karyorrhexis +/; cytoplasm variable, scant to indiscernible; cellular
necrosis +; Immunoprofile: CK +; neuroendocrine markers ; S100 protein ; LCA
Poorly Malignant cells isolated, in loosely cohesive groups or in syncytial tissue fragments with Figures 11.9A
differentiated no architectural patterns; cells small, round, oval to cuboidal; occasionally oblong to and 11.10
squamous/ spindle shaped; nuclear membranes smooth to irregular; chromatin deep staining and
adenocarcinoma coarsely granular; parachromatin clearing; nucleoli usually conspicuous; no nuclear
molding; mitoses +; karyorrhexis +/; cytoplasm variable, scant to indiscernible; cellular
necrosis +; Immunoprofile: CK +; neuroendocrine markers ; S100 protein ; LCA
Adenoid cystic Neoplastic cells mostly in syncytial tissue fragments with intense crowding and Figure 3.70
carcinoma overlapping, forming three-dimensional cell balls or in tight aggregates; cribriform
pattern +/; cylindrical cores of acellular, homogeneous hyaline material within the
tissue fragments or in extracellular locations, staining intensely magenta pink with
Romanowsky stain and pale green with Papanicolaou stain; neoplastic cells small
with high N/C ratios; cell borders poorly defined; nuclei round to oval with smooth
nuclear membranes; finely granular to compact chromatin; no nuclear molding; nucleoli
inconspicuous to absent; no mitoses; no necrosis; background clean; bare nuclei +/;
Immunoprofile: S100 protein +; calponin +; CK
Reactive lymph Polymorphic lymphoid population, tingible body histiocytes; polyclonal cell population Figure 7.17
node
Malignant Dissociated cell pattern; lymphoma cells discrete and in aggregates; small, monomorphic Figure 11.11
lymphoma/ pattern with well- to poorly defined cell borders; high N/C ratios; nuclei round to
leukemia oval with smooth-to-irregular nuclear membranes; finely granular chromatin with
parachromatin clearing; prominent nucleoli; cytoplasm variable but scant; no nuclear
molding; mitoses +; karyorrhexis +; Immunoprofile: CK ; LCA +; monoclonal cell
population; neuroendocrine markers ; S100 protein
Malignant Monomorphic small cell population with scant cytoplasm and high N/C ratios; Melan-A Figure 11.12
melanoma +; HMB 45 +; S100 protein +

Differential Diagnoses of Merkel Cell Carcinoma (Figs. 11.8 to 11.13)
A B
Fig. 11.8: A: Merkel Cell Carcinoma versus Small Cell Neuroendocrine Carcinoma. FNA of a primary small cell
carcinoma of the salivary gland, metastatic to the cervical lymph node. B: Aspirate of a Merkel cell carcinoma, which
exhibits an identical morphologic pattern seen in A.
Fig. 11.9: Merkel Cell Carcinoma versus Poorly Differentiated

Metastatic Squamous Carcinoma. FNA of a poorly differentiated Fig. 11.10: Merkel Cell Carcinoma versus Metastatic Basaloid
squamous carcinoma of the ear lobe showing a syncytial tissue frag- Squamous Carcinoma. FNA of a parotid mass showing a syncytial
ment of small cells with high N/C ratios and scant cytoplasm. Neu- tissue fragment of small malignant cells proven to be metastatic
roendocrine markers and CK20 showed negative reactivity. Note basaloid squamous carcinoma. Cytologic differentiation from neu-
the strong morphologic resemblance to Merkel cell carcinoma. roendocrine neoplasm is not possible without ancillary tests.
Fig. 11.11: Merkel Cell Carcinoma versus Metastatic Poorly Dif-

ferentiated Epithelial Malignancy. These small malignant cells with
deep-staining nuclei and scant to indistinct cytoplasm can be easily
misinterpreted as a neuroendocrine carcinoma.

Fig. 11.12: Merkel Cell Carcinoma versus Malignant Non-Hodgkin Fig. 11.13: Merkel Cell Carcinoma versus Malignant Melanoma.
Lymphoma. Single small malignant cells from a malignant lym- This aspirate shows an amelanotic melanoma, composed of small
phoma such as seen here are always in the differential diagnosis uniform cells with scant indistinct cytoplasm and high N/C ratios
of a neuroendocrine carcinoma. Immunostains for neuroendocrine and resembles Merkel cell carcinoma.
markers and CK20 are required to confirm Merkel cell carcinoma.
Positive lymphoid markers will support malignant lymphoma.
Metastatic Merkel Cell Carcinoma (Figs. 11.14 and 11.15)
A B
Fig. 11.14: FNA of an enlarged mediastinal lymph node in a

79-year-old woman with a history of abdominal skin nodule his-
tologically diagnosed as Merkel cell carcinoma. AC: The aspirate
consists of malignant cells, loosely cohesive and in syncytial frag-
ments. They are small to medium sized and mildly pleomorphic,
with scant to indiscernible cytoplasm. Nuclear molding can be
C appreciated.

A B
Fig. 11.15: Peritoneal fluid from a 68-year-old man with a history

of Merkel cell carcinoma of the arm, presented with widespread
metastatic disease and ascites. A, B: The smear preparation shows
large population of small malignant cells, present isolated, in loose-
ly cohesive groups and small syncytial tissue fragments. They have
scant cytoplasm with high N/C ratios. Note nuclear molding. The
cytomorphology is consistent with metastatic Merkel cell carcino-
ma. C: Cell block of the peritoneal fluid showing metastatic Merkel
C cell carcinoma cells.
METASTATIC MERKEL CELL CARCINOMA involvement and cytologic diagnosis by fine needle aspi-
TO OTHER BODY SITES ration (FNA) biopsy has been reported. Cytopathologic
features of mediastinal lymph node metastasis and involve-
Merkel cell carcinoma metastasizes to regional and dis- ment of abdominal organs resulting in peritoneal effusion
tant lymph nodes and to various sites in body. Pancreatic are illustrated in Figures 11.14 and 11.15.
SUGGESTED READING
Bickle K, Glass LF, Messina JL, et al. Merkel cell carcinoma: a Dim CD, Nugent SL, Darwin P, et al. Metastatic Merkel cell
clinical, histopathologic and immunohistochemical review. carcinoma of the pancreas mimicking primary pancreatic
Semin Cutan Med Surg. 2004;23:4653. endocrine tumor diagnosed by endoscopic ultrasound-guided
Cheuk W, Kwan MY, Suster S, et al. Immunostaining for thyroid fine needle aspiration biopsy: a case report. Acta Cytol.
transcription factor 1 and cytokeratin 20 aids the distinction 2009;53:223228.
of small cell carcinoma from Merkel cell carcinoma, but not Gherardi G, Marveggio C, Stiglich F. Parotid metastasis of
pulmonary from extrapulmonary small cell carcinoma. Arch Merkel cell carcinoma in a young patient with ectodermal
Pathol Lab Med. 2001;125:228231. dysplasia: diagnosis by fine needle aspiration cytology and
Collins BL, Elmberger PG, Tani EM, et al. Fine needle aspiration immunochemistry. Acta Cytol. 1995;34:831836.
of Merkel cell carcinoma of the skin with cytomorphology Gupta RK, Teague CA. Aspiration cytodiagnosis of metastatic
and immunocytochemical correlation. Diagn Cytopathol. Merkel cell carcinoma. Diagn Cytopathol. 1995;2:
1998;18:251257. 259262.

Hallman JR, Shaw JA, Geisinger KR, et al. Cytomorphologic Placidi A. Observation of intermediate filament buttons in
features of Merkel cell carcinoma in fine needle aspiration fine needle aspirates of Merkel cell carcinoma. Acta Cytol.
biopsies: a study of two cases. Acta Cytol. 2000;44: 1996;40:613615.
185193. Plaza JA, Suster S. The Toker tumor: spectrum of morphologic
Kabukcuoglu F, Sungun A, Polat N, et al. Fine needle aspiration features in primary neuroendocrine carcinomas of the skin
cytology of Merkel cell carcinoma. Acta Cytol. 2003;47:311313. (Merkel cell carcinoma). Ann Diagn Pathol. 2006;10:
Melbolom L, Akerman M, Carlen B. Aspiration cytology of 376385.
neuroendocrine (Merkel cell) carcinoma of the skin: report Pulitzer MP, Amin BD, Busam KJ. Merkel cell carcinoma: review.
of a case. Acta Cytol. 1984;28:297300. Adv Anat Pathol. 2009;16:135144.
Pettinato G, De Chiare A, Insabato L. Diagnostic significance Toker C. Trabecular carcinoma of skin. Arch Dermatol.
of intermediate filament buttons in fine needle aspirates of 1972;105:107110.
neuroendocrine (Merkel cell) carcinoma of the skin. Acta Wu H, Elenitsas R, Zhang P, et al. Merkel cell carcinoma. In:
Cytolo. 1989;338:420421. LiVolsi VA, Asa SL, eds. Endocrine Pathology. New York, NY:
Pettinato G, De Chiare A, Insabato L, et al. Neuroendocrine Churchill Livingstone; 2002:297311.
(Merkel cell) tumor of the skin: fine needle aspiration cytology,
histology, electron microscopy and immunochemistry of 12
cases. Appl Pathol. 1988;6:1727.

OFTHE GENITOURINARY TRACTS
Mithra R. Baliga Sudha R. Kini
This chapter covers neuroendocrine neoplasms of the

genitourinary tracts, which occur only infrequently.
NEUROENDOCRINE TUMORS OF THE
Neuroendocrine neoplasms are more common in geni-
FEMALE GENITAL TRACT
tal tracts and more common in the female than in the
Neuroendocrine tumors of the female genital tract,
male genital tract as compared to the urinary tract. In
although very rare, have been described in various sites
females, the uterine cervix is the frequent site, followed
such as endometrium, cervix, fallopian tubes, vagina,
by ovaries. Neuroendocrine tumors of the endome-
vulva, and ovaries. Of these, small cell carcinoma (poorly
trium, vagina, and vulva also have been reported in the
differentiated neuroendocrine carcinoma) of the uterine
literature.
cervix and carcinoid tumors of the ovaries are more fre-
Male genital tract neuroendocrine tumors are of
quent and will be described in detail.
unusual occurrence. However, they involve prostate more
frequently than the rest of the organs. Other neuroendo-
crine tumors include testicular carcinoids and small cell
neuroendocrine carcinomas that occur rarely in the scro- POORLY DIFFERENTIATED
tum, penis, and penile urethra. Urinary tract neuroendo- NEUROENDOCRINE (SMALL CELL)
crine neoplasms are very uncommon. CARCINOMA OF THE UTERINE CERVIX
The cytologic diagnosis of neuroendocrine tumors
of the genitourinary tract is provided only from cervi- Small cell neuroendocrine carcinoma is a highly aggres-
cal smears in cases of poorly differentiated neuroen- sive malignant neoplasm of the uterine cervix, accounting
docrine carcinomas of the uterine cervix. Rarely small for 3% to 5% of all cervical cancers. The incidence is
cell carcinomas of the urinary bladder may exfoliate 0.5/100,000 in the United States. There is no racial pre-
in the urine and identified via cytologic examination. dilection. Patients average age is 36 to 42 years, and the
Except for these two sites, a primary cytologic diagno- patients are typically younger than those with squamous
sis of genitourinary tract neuroendocrine tumors is not carcinomas. Up to 80% of small cell carcinomas are asso-
generally made. Most of these neoplasms are identi- ciated with human papilloma virus (HPV), type 18. HPV
fied by either surgical biopsies or excision. Metastatic type 16 has been detected in a minority of patients with
sites such as lymph nodes, liver, or lungs are occa- small cell carcinomas.
sionally subjected to fine needle biopsy procedures The patients may be asymptomatic or clinically pres-
for the cytologic diagnosis. Body cavity fluids may ent with vaginal bleeding. Less frequently, they may
also be examined for the cytologic diagnosis. Overall, present with paraneoplastic syndromes such as Cushing
the documentation of cytologic features, therefore, is syndrome, carcinoid syndrome, and hypoglycemia. Small
very lean. cell carcinomas are very aggressive tumors and metastasize
This chapter covers neuroendocrine neoplasms of the widely. Greater than 75% of the patients are dead from the
female genital tract, followed by male genital tract, pros- disease within 1 year. The tumors are detected less often on
tate, and urinary tract. screening cervical smears than squamous cell carcinomas.
249

GROSS AND HISTOLOGIC FEATURES biopsies of the metastatic sites or body cavity fluids.
The cytopathologic features are similar to those seen
The smaller lesions are inconspicuous on gross examina- in pulmonary small cell carcinomas (ref. Chapter 3;
tion of the cervix. Larger lesions may present as ulcerated Table3.7). The conventional cervical smears (Figs. 12.2
masses, often invading the deeper structures. Microscopic and 12.3) present excellent cytomorphology as com-
examination reveals a pattern similar to its pulmonary pared to the liquid-based preparations (Figs. 12.4 to
counterpart, characterized by large islands and masses of 12.6). The conventional smears show varying numbers
small, round, oval-to-short spindle cells with scant indis- of malignant cells, isolated, in loosely cohesive groups
cernible cytoplasm and large nuclei and very high N/C and in syncytial tissue fragments without any architec-
ratios (Fig. 12.1; see Fig. 12.6). Palisading of the neoplas- tural patterns. The neoplastic cells are small with high
tic cells at the periphery of the tumor islands is charac- N/C ratios. Their nuclei are round to oval, occasion-
teristic. The carcinoma also presents a trabecular pattern ally oblong to short spindle shaped, containing coarsely
or a solid growth pattern. The nuclei demonstrate mold- granular chromatin with either a saltpepper appear-
ing and are intensely hyperchromatic with a brisk mitotic ance (Figs. 12.2 and 12.3) or deep-staining compact
activity. Karyorrhexis and large areas of tumor necrosis pattern. Nucleoli are not conspicuous, and nuclear
are frequent. molding is often noted. In the liquid-based prepara-
tions, the small cell carcinoma cells tend to aggregate
in three-dimensional balls or present in a dispersed
CYTOPATHOLOGIC FEATURES fashion (Figs. 12.4 to 12.6). These dispersed single
cells can easily be overlooked or mistaken for endo-
The specimens for cytologic diagnosis mostly represent metrial cells. Within these three-dimensional balls, the
cervical/vaginal smears and occasionally aspiration nuclei of the small cell carcinoma cells in liquid-based
A B
Fig. 12.1: Histologic Sections of Poorly Differentiated Neuroendo-

crine (Small Cell) Carcinoma of the Uterine Cervix. A, B: Medium-
power view showing a solid and trabecular growth pattern (H&E).
C: Higher magnification showing peripheral palisading of nuclei.
C The cells are short spindle shaped with high N/C ratios (H&E).

Chapter 12: Neuroendocrine Tumors ofthe Genitourinary Tracts 251
A B
Fig. 12.2: Conventional Cervical Smear from the Same Case as Figure 12.1. A: Medium-power view,
showing a large population of malignant cells in varying-sized syncytial tissue fragments. B: Higher
magnification demonstrating the large population of small malignant cells, with mildly pleomorphic
nuclei containing compact chromatin. Nucleoli are not seen. Nuclear molding can be appreciated.
The cell borders are poorly defined, and the cytoplasm is indistinct with high N/C ratios.
A B
Fig. 12.3: AC: Another example of histologically proven small

cell neuroendocrine carcinoma of the uterine cervix. The malig-
nant cells are discrete and loosely cohesive, small with poorly
defined cell borders, scant, indiscernible cytoplasm, and high N/C
ratios. Note single cells are difficult to type as malignant. Note the
C classic saltpepper chromatin in B (conventional smear).

Fig. 12.4: Liquid-Based Preparation of a Cervical Smear, Depicting

Small Cell Carcinoma Cells. Note the number of malignant cells is
very small and they are present isolated or in small groups. They
resemble lymphoid cells as no features suggestive of small cell car-
cinoma are readily appreciated. (Courtesy of Ms. Karen Atkinson,
MPA, CT (ASCP), CMIAC, Director of Education and Training, and
Mr. Tim Collins, BS, CT (ASCP), Senior Scientist, Research and De-
velopment, BD Diagnostics-Womens Health and Cancer, Burling-
ton, North Carolina.)
preparations are extremely crowded and overlapped DIAGNOSTIC DIFFICULTIES AND

and their morphology may not be well visualized. DIFFERENTIAL DIAGNOSES
Recognition of malignant cells originating from small

IMMUNOPROFILE cell neuroendocrine carcinoma may be compromised
because of small number of cells, poor cytologic details,
The small cell carcinoma cells are immunoreactive to neu- or misinterpretation. The differential diagnoses of
roendocrine markers such as chromogranin, synaptophy- small cell carcinomas of the cervix include diagnostic
sin, neuron-specific enolase, TTF-1, CD56, and cytokeratin. entities that are composed of cells with a small size,
namely endometrial cells, endometrial adenocarcinoma,
high-grade squamous intraepithelial lesion, and poorly
ULTRASTRUCTURE differentiated squamous carcinoma, florid follicular cer-
vicitis, and malignant lymphoma. The differential diag-
Ultrastructurally, cells of small cell carcinomas demon- nostic features are listed in Table 12.1 and illustrated in
strate dense-core neurosecretory granules. Figures12.7 to 12.13.
A
Fig. 12.5: AC: Liquid-based preparation of a cervical smear, depicting small cell carcinoma cells from a case of his-
tologically confirmed small cell neuroendocrine carcinoma. Note that these cells are in tight three-dimensional groups
and their cytomorphology is not readily apparent. Cervical biopsy revealed a small cell neuroendocrine carcinoma.

A B
C D
E F
Fig. 12.6: A 38-year-old woman with a history of multiple abnormal pap smears complained of right lower quadrant
pain. Pelvic examination revealed a large cervical mass. A pap smear was obtained and multiple cervical biopsies
were done. AD: Liquid-based preparation of a cervical smear showing syncytial tissue fragments of small cells with
poorly defined cell borders, very high N/C ratios, and indistinct cytoplasm. The nuclear chromatin is compact and
deep staining. A few discrete cells are present in the background. The smear was interpreted as high-grade squamous
intraepithelial lesion. The cervical biopsies revealed a widely invasive small cell carcinoma. E: This low-power view of
the cervical biopsy shows a small cell carcinoma in subepithelial location and diffusely infiltrating the cervical stroma
(H&E). F:Higher magnification highlighting the small cell carcinoma. (Courtesy of Dr. Mithra Baliga, University of
Mississippi, Jackson, Mississippi.)

TABLE 12.1. DIFFERENTIAL DIAGNOSES OF SMALL CELL CARCINOMA OF THE UTERINE CERVIX

Small cell carcinoma of Neoplastic cells present isolated, in loosely cohesive groups Figures 12.212.6
the uterine cervix and in syncytial tissue fragments without any architectural
patterns; malignant cells often present in mucus streaks;
size small, 22.5 times the lymphocytes; high N/C ratios;
nucleus round, oval to fusiform; coarsely granular to
compact, deep-staining chromatin; nucleoli inconspicuous
to absent; nuclear molding characteristic; stretch or crush
artifacts of nuclei; karyorrhexis; mitoses +; indiscernible
cytoplasm; necrosis in the background +/; surface
markers; Immunoprofile: cytokeratin +; neuroendocrine
markers +; LCA
Normal endometrial Cells, isolated, in aggregates or in tissue fragments; cells, Figure 12.8AC
cells small, the size of an entire neutrophil; cytoplasm scant to
indistinct; poorly defined cell borders; nuclear chromatin
coarsely granular to compact and deep staining; no
nuclear molding; no stretch artifacts; no necrosis in the
background
Endometrial Cells, isolated, in aggregates or in tissue fragments; round Figure 12.8D

adenocarcinoma, well to cuboidal; size same as normal or slightly larger; tightly
differentiated packed nuclei; coarsely granular chromatin; nucleolus
+/; no nuclear molding; no stretch artifacts; occasional
cytoplasmic vacuole
Lymphofollicular Lymphocytes well preserved and easily recognizable Figure 12.7A,B

cervicitis in conventional smears; cluster together in liquid-based
preparations appearing darkly stained; germinal center
cells present in conventional smear but not in LBP;
Immunoprofile: cytokeratin ; neuroendocrine markers ;
LCA +
Malignant lymphoma Extremely rare; discrete cell population; no nuclear

molding; no stretch artifacts; monomorphic cell
population; LCA +
Poorly differentiated Large numbers of exfoliated cells; isolated, in aggregates Figures 12.912.12
squamous carcinoma and in syncytial tissue fragments with no architectural
patterns; malignant cells small, round with well- to poorly
defined cell borders; scant to indiscernible cytoplasm;
high N/C ratios; smooth to irregular nuclear membranes;
coarsely granular chromatin; parachromatin clearing;
nucleoli +; occasional cell with rigid cell border and
keratinization can be a clue for squamous carcinoma;
no nuclear molding; no stretch artifacts; necrosis +/;
inflammation +/

Differential Diagnoses of Cervical Poorly Differentiated Neuroendocrine (Small Cell) Carcinoma (Figs. 12.7 to 12.12)
A B
Fig. 12.7: A: Conventional cervical smear showing a polymorphic lymphoid cell population consistent with lymphofol-
licular cervicitis. B: Liquid-based preparation showing a tight aggregate of lymphoid cells that can be mistaken for a
small cell carcinoma.
A B
C D
Fig. 12.8: Endometrial Cells and Endometrial Adenocarcinoma. A, B: These two different conventional smears contain
well-preserved endometrial cells, which morphologically resemble small cell carcinoma cells. C: Liquid-based prepa-
ration showing endometrial cells. D: Conventional cervical smear showing cells of well-differentiated endometrial
adenocarcinoma.

Fig. 12.8: (continued) E: Small cell carcinoma cells in a conven-

E tional Pap smear for comparison.
Fig. 12.9: Conventional Cervical Smear Showing a Syncytial

Tissue Fragment of in High-Grade Intraepithelial Squamous Lesion
(In Situ Squamous Carcinoma). Note the morphologic similarity
with small cell carcinoma.
A B
Fig. 12.10: AC: These three images depict loosely cohesive small round malignant cells with scant cytoplasm and high
N/C ratios (conventional smear). Biopsy confirmed an invasive poorly differentiated squamous carcinoma.

A B
Fig. 12.11: AC: These three images depict loosely cohesive small
round malignant cells with scant cytoplasm and high N/C ratios.
Note nuclear molding (conventional smear). Biopsy confirmed an
C invasive poorly differentiated squamous carcinoma.

Fig. 12.12: Invasive poorly differentiated squamous carcinoma

showing small malignant cells with poorly defined cell borders and
scant cytoplasm with high N/C ratios. Note the morphologic simi-
larity to small cell neuroendocrine carcinoma cells.
tumors have been reported in the contralateral ovary.

OTHER NEUROENDOCRINE TUMORS Ovarian carcinoid tumors are sometimes seen grossly as
OF THE UTERINE CERVIX a solid nodule of tan or yellowish tissue adjacent to or
protruding into a cyst or as a mural thickening of the cyst
Other neuroendocrine tumors of the uterine cervix
wall of the cystic teratoma. Primary carcinoid tumors of
include large cell neuroendocrine carcinoma and carci-
the ovary have been divided into four major histologic
noid tumor.
subtypes: (i) insular (midgut derivation), which is the
Large cell neuroendocrine carcinomas have been
most common type and frequently a component of cys-
reported with cytologic documentation. Anecdotal cases
tic teratoma; (ii) trabecular (foregut or hindgut derived,
of carcinoid tumors of the uterine cervix have also been
the uncommon type); (iii) strumal carcinoid (mixed car-
described.
cinoid tumor and struma ovarii); and (iv) mucinous car-
cinoid (carcinoid tumor with goblet cell differentiation).
Carcinoid syndrome is found only in association with
insular type carcinoid.
NEUROENDOCRINE TUMORS Histologically, the carcinoid tumor presents typical
OF THE OVARIES neuroendocrine growth patterns. The insular carcinoids
show nests and islands of tumor cells, separated by deli-
Ovarian neuroendocrine neoplasms include carcinoid cate vascular stroma. The cells are small, round, uniform
type tumors, small cell carcinomas (poorly differentiated with larger nuclei containing typical saltpepper chro-
neuroendocrine carcinoma pulmonary type and hypercal- matin. The cytoplasm is scant and variable. The trabec-
cemic type), and large cell neuroendocrine carcinoma. ular pattern is uncommon, with only a few cases being
reported in the literature. They are not associated with
signs and symptoms of carcinoid syndrome. The trabecu-
lar type carcinoid may be associated with a dermoid cyst
WELL-DIFFERENTIATED or in a pure form. The size is variable, ranging from 4 to
NEUROENDOCRINE CARCINOMA 25 cm in reported cases. Histologically, the tumor is com-
(CARCINOID TUMORS) posed of long, wavy, ramifying, and anastomosing cords;
ribbons; or trabeculae of uniform round to cuboidal cells
Primary ovarian carcinoids are rare, accounting for <1% separated by loose, edematous to fibrotic stroma (see
of all carcinoid tumors. They can occur at any age. The Fig. 12.13E). The nuclei present typical neuroendocrine
most common clinical manifestation is the pelvic mass. pattern.
Ovarian carcinoid tumors are invariably unilateral; the Strumal carcinoids are infrequent and found as a pre-
majority occur in association with mature cystic terato- dominant component of a dermoid cyst. The strumal
mas but can also occur in pure forms. However, in 15% component may represent normal thyroid parenchyma or
of cases, cystic teratomas, Brenner tumors, and mucinous a follicular adenoma.

Neuroendocrine Carcinoma of the Ovary
A B
C D
Fig. 12.13: Peritoneal/pelvic washings from a woman who had

myomectomy and left oophorectomy for a cystic teratoma or a der-
moid cyst, which weighed 200 g. The initial gross and histologic
examination was consistent with a benign dermoid cyst. AD: These
four images show tissue fragments of uniform cuboidal cells with
scant cytoplasm and high N/C ratios. Their nuclear chromatin is
coarsely granular and is highly suggestive of a neuroendocrine tu-
mor. Note that these cells present entirely different cytomorphology
than mesothelial cells or cells of endosalpingiosis. Following the cy-
tologic findings of neuroendocrine tumor in the washings, the ovar-
ian tumor was re-examined. A small yellow-tan friable neoplasm on
the wall of one of the loculate was noted, which had infiltrated the
wall, extending to the outer (peritoneal) surface. Histologic sections
confirmed a low-grade or well-differentiated neuroendocrine carci-
noma (carcinoid). E: Histologic section of the ovarian tumor con-
E firming the diagnosis of an endocrine tumor (medium power, H&E).

The goblet cell variant of the carcinoid tumor presents CYTOPATHOLOGIC FEATURES
morphology similar to that seen in appendiceal goblet cell
carcinoid tumor (see Chapter 4). The cytologic presentation of ovarian carcinoid is not doc-
umented in the literature. A primary diagnosis of an ovar-
ian neuroendocrine carcinoma is rarely if ever made from
HISTOCHEMISTRY cytologic specimens. A case of ovarian carcinoid tumor
in association with a dermoid cyst that was identified in
The tumor cells stain with Grimelius and Fontana- peritoneal/pelvic washings is illustrated (Fig. 12.13). The
Masson. Stains for mucin such as periodic acidSchiff presence of carcinoid tumor cells was an unsuspected
(PAS) diastase resistant and mucicarmine are positive in finding. Possibility of such tumors must always be kept
the goblet cell variant. in mind. The carcinoid tumor cells must be differenti-
ated from several diagnostic entities in peritoneal/pelvic
washings such as strips of mesothelium, endosalpingio-
IMMUNOPROFILE sis, endometriosis, well-differentiated adenocarcinomas,
either from ovary or from endometrium, and granulosa
Immunochemical stains with pan-neuroendocrine mark- cell tumor. Their differentiating features are listed in
ers and cytokeratin are positive. Table12.2 and illustrated in Figures 12.14 to 12.18.
TABLE 12.2. DIFFERENTIAL DIAGNOSES OF SMALL CELL POPULATION IN PERITONEAL FLUID

(EFFUSION AND WASHINGS)
Diagnostic Clues
Disease Entity Clinicopathologic Features Cytopathologic Features Ancillary Test
Mesothelial tissue Mechanical stripping during Two-dimensional sheets, with well-defined cell Folded sheets may
fragments peritoneal/pelvic washings borders, uniform round to kidney-shaped nuclei; appear syncytial;
crisp nuclear membranes; evenly dispersed, finely focus up and down
granular chromatin; macronucleoli +/; pale
cytoplasm; low N/C ratios; collagen balls +/
Endometriosis Frequent occurrence, but Tissue fragments of endometrial cells with closely Glandular and
not usually encountered in packed, overlapped nuclei; ill-defined cell borders; stromal cells;
washings compact chromatin; inconspicuous micronucleoli; hemosiderin-
high N/C ratios; aggregates of endometrial stromal containing
cells; hemosiderin containing macrophages macrophages
Endosalpingiosis Frequent occurrence, often in Syncytial tissue fragments of epithelial cells without Cilia and psammoma
(mllerian the presence of malignancy any architectural configurations or with a papillary bodies
inclusions) pattern; cells small with scant cytoplasm, poorly
defined cell borders, high N/C ratios; nuclei round
to oval, containing coarsely granular chromatin;
inconspicuous micronucleoli; cilia+/;psammoma
bodies frequent, either naked or incorporated in
the tissue fragments
Implants of SBT accounts for 10%20% Malignant cells forming syncytial tissue fragments Operative findings
ovarian serous of all ovarian epithelial with or without acinar or a papillary pattern; supporting the
borderline (SBT) neoplasms; occur in slightly cells generally small- to medium-sized containing presence of ovarian
tumors younger women; usually scant cytoplasm; high N/C ratios; nuclei round tumor; no cilia
staged when diagnosed; to oval; chromatin fine to coarsely granular with
length of survival longer parachromatin clearing; nuclear membrane smooth
as compared to invasive to irregular; conspicuous nucleoli; cytoplasmic
carcinomas; recurrence may vacuoles not common; isolated malignant cells
be as late as 20 y or more infrequent and difficult to recognize; mitoses not
after diagnosis common; psammoma bodies +/

TABLE 12.2. DIFFERENTIAL DIAGNOSES OF SMALL CELL POPULATION IN PERITONEAL FLUID

(EFFUSION AND WASHINGS) (Continued)
Diagnostic Clues
Disease Entity Clinicopathologic Features Cytopathologic Features Ancillary Test
Granulosa cell Very uncommon; peritoneal Neoplastic cells small occurring in syncytial Presence of Call-
tumor washings positive with tissue fragments; cell borders poorly defined with Exner bodies;
disseminated tumor to the scant to insignificant cytoplasm; high N/C ratios; negative reactivity
peritoneum nuclei round to oval with coarsely granular, to keratin, CEA, and
evenly dispersed chromatin, and nuclear grooves; vimentin
micronucleoli +/; Call-Exner bodies +/
Neuroendocrine Low-grade tumors or The cytologic presentation of typical carcinoid Positive reactivity to
tumors carcinoid tumors rarely tumor (low-grade neuroendocrine) carcinoma pan-neuroendocrine
metastasize to the present a characteristic pattern with uniform, markers and keratin
peritoneum; high-grade small, round to cuboidal cells with syncytial
neuroendocrine carcinomas arrangement and trabecular pattern; high N/C
may involve the peritoneum/ ratios; scant cytoplasm; round nuclei with salt
pelvis; ovarian carcinoid pepper chromatin; micronucleoli +/
tumors are extremely rare
and may be associated with
cystic teratomas or struma
ovarii
Differential Diagnoses of Neuroendocrine Carcinoma of Ovary in Peritoneal Fluid and Pelvic Washings
(Figs. 12.14 to 12.18)
A B
Fig. 12.14: Endosalpingiosis in Peritoneal Washings. A: Low-power view, demonstrating enormous, branching tissue
fragments. B: Higher magnification showing the tissue fragments to be composed of tightly packed smaller cells with
poorly defined cell borders, scant cytoplasm, and high N/C ratios. Note the psammoma bodies (arrows). The nuclear
chromatin is dense and malignant features are not present.

A B
Fig. 12.15: A, B: Malignant cells originating from ovarian adenocarcinoma. Compare these with cells of endosalpin-
giosis, where the component cells are smaller and more uniform.
Fig. 12.16: Malignant Cells Originating from Endometrial Adeno-

carcinoma.
Fig. 12.17: Endometriosis in Peritoneal/Pelvic Washings. Note the

tubular tissue fragment of endometrial cells.

A B
Fig. 12.18: Granulosa Cell Tumor in Peritoneal Fluid. A: The neoplastic granulose cells are small, uniform with high
N/C ratios and scant indiscernible cytoplasm. They are forming a pseudoacinar pattern around acellular material and
are referred to as Call-Exner body. B: Syncytial tissue fragment of uniform small cells with poorly defined cell borders
and high N/C ratios.
women. The histologic pattern is similar to its pulmonary

POORLY DIFFERENTIATED
counterpart.
NEUROENDOCRINE CARCINOMAS
The large cell neuroendocrine carcinomas have been
(SMALL CELL NEUROENDOCRINE
reported in women between 22 and 77 years of age. All
CARCINOMA AND LARGE CELL
tumors were unilateral and large, ranging in size from
NEUROENDOCRINE CARCINOMA) OF
9to 30 cm. Each tumor had a surface epithelial compo-
THE OVARIES
nent as well as a solid neuroendocrine component. The
neuroendocrine component had large cells with highly
Poorly differentiated (small- cell) neuroendocrine carci-
atypical nuclei, ample cytoplasm, extensive necrosis,
nomas of the ovaries are extremely rare. Two types are
and abundant mitosis. The neuroendocrine markers
describedhypercalcemic type and pulmonary type.
were demonstrated more readily in these tumors than
The hypercalcemic type small cell carcinoma is rare.
in small cell undifferentiated carcinoma of the ovary,
It generally occurs in young women with a mean age
pulmonary type.
of 24 years. It is almost always unilateral. The patients
present with abdominal swelling and pain, majority have
hypercalcemia, and over 50% have extraovarian involve-
ment at the time of diagnosis. Grossly, hypercalcemic type NEUROENDOCRINE TUMORS OF THE
small cell carcinoma is large, ranging from 6 to 26 cm, MALE GENITAL TRACT
solid, lobulated, and pale-white to gray. Histologically, the
tumor shows a diffuse growth pattern or solid nests, tra- Neuroendocrine tumors of the male genital tract include
beculae, and cords. Follicle-like spaces containing eosin- rare examples of testicular carcinoids and small cell carci-
ophilic fluid are present in over 80% of the cases. The nomas of the penis. These are not discussed further.
tumor cells are small, round to short spindle shaped, uni-
form with high N/C ratios, scant cytoplasm, and hyper-
chromatic nuclei with small nucleoli. Mitotic activity is
brisk with areas of necrosis. The scant stroma is edem- NEUROENDOCRINE TUMORS OF THE
atous and fibrotic. There is often a component of large PROSTATE
cells with epithelioid or rhabdoid features. Up to 10%
are associated with mucinous epithelium. Immunoprofile Primary neuroendocrine tumors of the prostate are very
includes positive reactivity to epithelial markers and vari- rare and include carcinoid tumors, small cell carcinomas,
able reactivity to neuroendocrine markers. and large cell neuroendocrine carcinomas. The carcinoid
The pulmonary type small cell ovarian carcinoma is tumors are exceedingly rare and not likely to be encoun-
extremely rare and occurs in peri- or postmenopausal tered in cytologic practice.

Poorly differentiated small cell neuroendocrine car- Carcinoid tumors are slow growing and may remain
cinomas of the prostate account for 1% of all prostate asymptomatic for several years. The clinical presentation
malignancies. Small cell carcinoma of the prostate may is similar to other renal neoplasms. They may present
occur by itself or simultaneously with an adenocarci- with flank or abdominal pain, hematuria, weight loss, or
noma, or it may manifest later in the progression of pros- an abdominal mass. Carcinoid tumors have a potential to
tate adenocarcinoma. The majority of patients do not secrete hormonal substances and may induce carcinoid or
have an elevated prostate-specific antigen or prostatic Cushing syndrome.
acid phosphatase but do have elevated serum levels of Carcinoid tumors are usually unilateral, solitary, typi-
carcinoembryonic antigen (CEA). Rare cases of ectopic cally well circumscribed, yellow or tan-brown on cut
hormonal secretion have been reported. surface with some foci of calcification, hemorrhage, or
Histologically, small cell carcinomas present a pattern necrosis.
similar to its pulmonary counterpart. Focal neuroendo- Histologically, renal carcinoid tumors have a trabecu-
crine differentiation may be seen in adenocarcinomas. lar or ribbon-like growth pattern along with peripheral
A primary diagnosis of prostatic small cell carcinoma palisading, leading to the typical rosette-like arrangement.
is generally not made from cytologic specimens, since the Necrosis, hemorrhage, and calcification are often identified.
fine needle aspiration biopsy of the prostate as a diag- Large cell neuroendocrine carcinomas have a typical
nostic procedure has long been replaced by core-needle neuroendocrine growth pattern (organoid, nesting, pali-
biopsy. However, metastatic lesions involving lymph sading, rosette, or trabeculae). Mitotic rate is very high
nodes and liver are diagnosed from fine needle biopsies and large zones of necrosis are observed.
or from body cavity fluids. The cytologic features of small Small cell neuroendocrine carcinoma cells are small and
cell carcinoma of the prostate are indistinguishable from possess scant cytoplasm, high N/C ratios, saltpepper chro-
that of small cell carcinomas from other body sites. matin pattern or deep-staining compact chromatin, incon-
Large cell neuroendocrine carcinomas of the prostate spicuous nucleoli, high mitotic rate, and large-zone necrosis.
have been reported. Their number is extremely small.

NEUROENDOCRINE TUMORS OF THE URINARY BLADDER
URINARY TRACT
Neuroendocrine tumors involving the urinary bladder are
Neuroendocrine tumors of kidney, its pelvicalyceal sys- very rare and include small cell carcinomas and paragan-
tem, and urinary bladder are rare and include carcinoid gliomas (extraadrenal pheochromocytoma). Anecdotal
tumors, small cell carcinomas, and paragangliomas. These examples of carcinoid tumors and large cell neuroendo-
neoplasms are more common in the renal pelvis, as com- crine carcinomas have been reported. Neuroendocrine
pared to renal parenchyma, ureters, and urinary bladder. tumors in the bladder can coexist with urothelial carci-
Like genital tract endocrine neoplasms, primary cytologic nomas or adenocarcinomas. The most common neuro-
diagnosis is rarely rendered, if ever. endocrine tumor of the urinary bladder is the small cell
(poorly differentiated neuroendocrine) carcinoma, with
more than 100 cases having been described.

KIDNEY
POORLY DIFFERENTIATED (SMALL CELL)
The neuroendocrine tumors of the kidney include carci- NEUROENDOCRINE CARCINOMA OF
noid tumors and small cell and large cell neuroendocrine THE URINARY BLADDER
carcinomas.
Carcinoid tumors of the kidney are unusual and are Small cell neuroendocrine carcinoma of the urinary blad-
frequently associated with horseshoe kidney and terato- der is extremely rare, comprising <0.5% of all bladder
mas. The peak age for neuroendocrine tumors is between neoplasms. The patients are usually in their seventh
fifth and sixth decades. Although no gender predilection decade of life. Males are more often affected. Patients may
is noted, carcinoid tumors in horseshoe kidneys are more present with gross or microscopic hematuria or with non-
frequently reported in men. specific symptoms. Although paraneoplastic syndromes

occur, they are less common than with small cell carci- numerous. Necrosis is frequent. Small cell carcinomas
nomas of the lung. Majority of the patients have large, may associate with high-grade urothelial carcinomas or
deeply invasive tumors at the time of diagnosis, and up to adenocarcinomas and squamous carcinomas.
65% either have or will soon develop metastases.
Cystoscopically, small cell carcinomas tend to be pol-
ypoid or nodular, often presenting as ulcerated masses CYTOPATHOLOGIC FEATURES
that cannot be distinguished from high-grade urothelial
cancers. They may occur at various locations and are not Cytologic samples such as voided urine and/or instru-
predominantly localized at the base. mented samples (catheterized urine, bladder washings)
contain variable numbers of malignant cells, occurring in
loose aggregates or as discrete cells (Figs. 12.19 to 12.21)
GROSS AND HISTOLOGIC FEATURES and also in syncytial tissue fragments. These cells are small
with poorly defined cell borders, scant, indistinct cyto-
Gross examination reveals a solid tumor mass that origi- plasm, and high N/C ratios. The chromatin is deep stain-
nates from the mucosa and often penetrates deeply into ing, coarsely granular to compact. Nuclear molding may
the bladder wall. Microscopically, small cell carcinomas be appreciated. Because of the processing technique (cyto-
are indistinguishable from small cell carcinomas else- centrifugation or liquid-based preparation), the small cell
where in the body. They are composed of loosely cohe- carcinoma cells tend to be dispersed and are difficult to
sive sheets of small cells with scant cytoplasm. Necrosis identify (Figs. 12.20 and 12.21). Nuclear molding is dif-
is common. Nuclei are usually round, polygonal but may ficult to appreciate in single small, exfoliated malignant
be short spindle shaped. Nuclear molding can be seen. cell. The background often contains inflammatory and
The nuclear chromatin is coarsely granular and evenly necrotic debris, obscuring the discrete small malignant
distributed. Nucleoli are inconspicuous. Mitoses may be cells and can easily be overlooked.
Poorly Differentiated Neuroendocrine (Small Cell Carcinoma) of the Urinary Bladder (Figs. 12.19 to 12.21)
Fig. 12.19: Poorly Differentiated Neuroendocrine (Small Cell

Carcinoma) Cells in Voided Urine. This image demonstrates small-
to medium-sized mildly pleomorphic, discrete malignant cells Fig. 12.20: AD: Voided urine from a patient with a history of
with poorly defined cell borders, scant cytoplasm, and high N/C small cell carcinoma of the urinary bladder. (Courtesy of Mariza
ratios. (From Koss LG. Diagnostic Cytology of the Urinary Tract dePeralta Venturina, Cedar Sinai Hospital, Los Angeles, California.)
with Histopathologic and Clinical Correlations. Philadelphia, PA:
Lippincott-Raven, 1995, color plate 5-2. Reproduced with permis-
sion from Lippincott Williams & Wilkins.)

Fig. 12.21: A, B: Small cell carcinoma cells in voided urine.

(Courtesy of Mariza dePeralta Venturina, Cedar Sinai Hospital, Los
Angeles, California.)
IMMUNOPROFILE small, discrete, and escape the attention. Degenerative

changes in the milieu of the urine are another reason for
The small cell carcinoma cells show positive reactivity to poor recognition. The small size of the malignant cells
neuroendocrine markers, CD56, cytokeratin (CAM5.2), and their morphologic resemblance to lymphocytes,
and epithelial membrane antigen. especially in the background of necrotic and inflam-
matory debris, makes the identification difficult. If the
associated component of high-grade urothelial carci-
DIAGNOSTIC DIFFICULTIES AND noma or nonsmall cell carcinoma is present in large
DIFFERENTIAL DIAGNOSES numbers, small cell carcinoma cells may be difficult to
recognize.
Cytologic recognition of small cell carcinoma cells in The differential diagnoses of small cell carcinoma
urinary tract specimens is not always possible for sev- cells (Table 12.3) in cytologic preparations of urine
eral reasons. The number of exfoliated cells may be too include high-grade urothelial carcinoma, (Fig. 12.22),
and metastatic small cell neuroendocrine carcinomas
especially from the lung, uterine cervix in females and
TABLE 12.3. DIFFERENTIAL DIAGNOSES OF
SMALL CELL (NEUROENDOCRINE) CARCINOMA prostate in males, or other extrapulmonary sites and
IN URINE malignant lymphomas. Clinical history is very helpful.
Malignant lymphomas of the bladder are rare and have
Metastatic small cell (neuroendocrine) carcinoma a good prognosis with good response to chemotherapy.
The cytomorphologic features of bladder lymphomas
Pulmonary include single cells with round-to-oval nuclei, increased
nuclear/cytoplasmic ratio, and centrally located nuclei
Extrapulmonary sites; e.g. uterine cervix, prostate,
often with prominent nucleoli. The cytomorphologic
GI tract, pancreas
features of metastatic pulmonary small cell carcinoma
Poorly differentiated urothelial carcinoma are indistinguishable from primary small cell carcinoma
of the bladder. However, if they coexist with a minor
Poorly differentiated squamous/adenocarcinoma high-grade urothelial carcinoma component, a primary
bladder lesion is most likely. A benign condition to cause
Malignant lymphoma differentiating problem is possibly polyoma virus infec-
tion (Fig. 12.23). Immunostain with Mab/BK T.1 will
Polyoma virus infection
confirm the viral infection.

Differential Diagnoses of Poorly Differentiated Neuroendocrine (Small Cell) Carcinoma of the Urinary Bladder
(Figs 12.22 and 12.23)
A B
Fig. 12.22: A, B: Voided urine showing malignant cells originated from high-grade urothelial carcinoma. These
malignant cells are small with hyperchromatic, compact nuclei and can easily be misinterpreted as neuroendocrine
carcinoma.
Fig. 12.23: Voided urine, showing discrete small- to medium-sized

round cells with large nuclei, containing compact chromatin. Note
poorly defined cell borders and high N/C ratios. However, there is
no nuclear molding. Immunostain for polyoma virus was positive.
symptom complex is the micturition attack, consisting

EXTRAADRENAL of bursting headache, anxiety, tremulousness, pounding
PHEOCHROMOCYTOMA/ sensation, blurred vision, sweating, and even syncope.
PARAGANGLIOMA OF THE URINARY Hypertension is observed in most patients. Catecholamines
BLADDER or their metabolites are elevated in the serum or urine in at
least 50% of the individuals tested.
Extraadrenal pheochromocytomas or paragangliomas
are infrequently occurring tumors, comprising <0.1% of
all bladder neoplasms. GROSS AND HISTOLOGIC FEATURES
Patients are 10 to 78 years old, with the mean age being
42 years. Young women are more commonly affected. Grossly, the paragangliomas vary in size. Microscopically,
Hematuria is a common complaint. Over 50% of the these tumors present typical Zellballen pattern (see
patients experience symptoms directly related to the release Chapters 14 and 15).
of catecholamines from the tumors. Discomfort is associ- These tumors do not exfoliate cells; hence the cytologic
ated with a full bladder or voiding. The most characteristic findings are not documented.

SUGGESTED READING
Neuroendocrine Carcinomas of the Uterine Cervix Neuroendocrine Carcinomas of the Ovaries

Albores-Saavedra J, Garsell D, Gilks CB. Terminology of endocrine Crowder S, Tuller E. Small cell carcinoma of the female genital
tumors of the uterine cervix: results of a workshop sponsored tract. Semin Oncol. 2007;34:5763.
by the College of American Pathologists and the National Davis KP, Hartmann LK, Keeney GL, et al. Primary ovarian
Cancer Institute. Arch Pathol Lab Med. 1887;121:3439. carcinoid tumors. Gynecol Oncol. 1996;61:259265.
Albores-Saavedra J, Martinez-Benitez B, Luevano E. Small cell Eichhorn JH, Young RH. Neuroendocrine tumors of the female
carcinomas and large cell neuroendocrine carcinomas of the genital tract. Am J Clin Pathol. 2001;115:S94S112.
endometrium and cervix: polypoid tumors and those arising in Eichhorn JH, Young RH, Scully RE. Primary ovarian small
polyps may have a favorable prognosis. Int J Gynecol Pathol. cell carcinoma of pulmonary type: a clinicopathologic,
2008;27:333339. immunohistologic and flow cytometric analysis of 11 cases. Am
Ciesla MC, Guidos BJ, Selvaggi SM. Cytomorphology of small J Surg Pathol. 1992;16:926938.
cell (neuroendocrine) carcinoma on Thin-Prep cytology Fukunaga M, Endo Y, Miyazawa Y, et al. Small cell
as compared to conventional smears. Diagn Cytopathol. neuroendocrine carcinoma of the ovary. Virchows Arch.
2001;24:4652. 1997;430(4):343348.
Conner MG, Richter H, Moran CA, et al. Small cell carcinoma of Kini SR. Color Atlas of Differential Diagnosis in Exfoliative
the cervix: a clinicopathologic and immunocytochemical study and Aspiration Cytopathology. Philadelphia, PA: Lippincott
of 23 cases. Ann Diagn Pathol. 2002;6:345348. Williams & Wilkins; 1998:119131.
Gilks CB, Young RB, Clement PB. Large cell neuroendocrine Mungen E, Ertekin A, Yergok YZ, et al. Primary mixed trabecular
carcinoma of the uterine cervix: a clinicopathologic study of and insular carcinoid tumor of the ovary: a case report. Acta
17cases. Am J Surg Pathol. 1997;21:905914. Obstet Gynecol Scand. 1997;76(3):279281.
Hoeri HD, Schink J, Hartenback E, et al. Exfoliative cytology Soga J, Osaka M, Yakuwa Y. Carcinoids of the ovary: an analysis
of primary poorly-differentiated (small cell) neuroendocrine of 329 reported cases. J Exp Clin Cancer Res. 2000;19:271
carcinoma of the uterine cervix in Thin-Prep material: a case 280.
report. Diagn Cytopathol. 2000;23:1418.
Khunamornpong S, Siriaunkgul S, Supraseri P. Cytology of small
cell carcinoma of the uterine cervix in serous effusion: a report Male Genital Tract
of two cases. Diagn Cytopathol. 2001;24:253255. Mazzucchelli R, Morichetti D, Lopez-Beltran A, et al.
Kim Y, Ha H-J, Kim J-S, et al. Significance of cytologic smears in Neuroendocrine tumours of the urinary system and male
the diagnosis of small cell carcinoma of the uterine cervix. Acta genital organs: clinical significance. BJU Int. 2009;103:
Cytol. 2002;46:637644. 14641470.
Kim MJ, Kim NR, Cho Y, et al. Differential diagnostic features of Murali R, Kneale K, Lalak N, et al. Carcinoid tumors of
small cell carcinoma in the uterine cervix. Diagn Cytopathol. the urinary tract and prostate. Arch Pathol Lab Med.
2008;36:618623. 2006;130:16931706.
Lee WY. Exfoliative cytology of large cell neuroendocrine
carcinoma of the uterine cervix. Acta Cytol. 2002;46:
11761179. Neuroendocrine Tumors of the Prostate
Ng W-K, Cheung LKN, Li ASM, et al. Thin-layer cytology findings Caraway NP, Fanning CV, Shin HJC, et al. Metastatic small cell
of small cell carcinoma of the lower female genital tract: review carcinoma of the prostate diagnosed by fine needle aspiration
of three cases with molecular analysis. Acta Cytol. 2003;47: biopsy. Diagn Cytopathol. 1998;19:1216.
5664. Hanazawa K, Higashi N, Kawachi Y, et al. Small cell carcinoma of
Niwa K, Nonka-Shibata M, Satoh E, et al. Cervical large cell the prostate with hypercalcemia. Int J Urol. 2005;2:108110.
neuroendocrine carcinoma with cytologic presentation. Acta Haukaas SA, et al. Cushings syndrome in prostate cancer:
Cytol. 2010;54:977980. an aggressive course of prostatic malignancy. Urol Int.
Nucci MR. Gynecologic pathology. In: Goldblum JR, ed. 1999;63:126129.
Foundations in Diagnostic Pathology. Philadelphia, PA: Helpap B. Morphology and therapeutic strategies for
Churchill Livingstone; 2009. neuroendocrine tumors of the genitourinary tract. Cancer.
Reich O, Pickel H, Purstner P. Exfoliative cytology of invasive 2002;95:14151420.
neuroendocrine small cell carcinoma in a cervical cytologic Helpap B, Kloppel G. Neuroendocrine carcinomas of the prostate
smear. Acta Cytol. 1996;40:980984. and urinary bladder: a diagnostic and therapeutic challenge.
Sato Y, Shimamoto T, Amada S, et al. Large cell neuroendocrine Virchows Arch. 2002;440:241248. (Epub)
carcinoma of the uterine cervix: a clinicopathologic study of six Miyoshi Y, Uemura H, Kitami K, et al. Neuroendocrine
cases. Int J Gynecol Pathol. 2003;22:226230. differentiated small cell carcinoma presenting as recurrent
Tsunoda S, Jobo T, Arai M, et al. Small cell carcinoma of the prostate cancer after androgen deprivation therapy. BJU Int.
uterine cervix: a clinicopathologic study of 11 cases. Int J 2001;88:982983.
Gynecol Cancer. 2005;15:295300. Reyes A, Moran CA. Low-grade neuroendocrine carcinoma
Zhou C, Hayes MM, Clement PB, et al. Small cell carcinoma (carcinoid tumor) of the prostate. Arch Pathol Lab Med.
of the uterine cervix: cytologic findings in 13 cases. Cancer. 2004;128:e166e168.
1998;84:281288.

True L. Why we must better understand neuroendocrine Neuroendocrine Tumors of the Urinary Bladder
differentiation in prostate cancer. J Urol. 2004;171:443
444. Abrahmas NA, Moran C, Reyes AO, et al. Small cell carcinoma of
Yashi M, Ishikawa S, Ochi M, et al. Small cell/neuroendocrine the urinary bladder: a contemporary clinicopathologic study of
carcinoma may be a more common phenotype in advanced 51 cases. Histopathology. 2005;46:5763.
prostate cancer. Urol Int. 2001;69:166168. Ali SZ, Reuter VE, Zakowski MF. Small cell neuroendocrine
carcinoma of the urinary bladder: a clinico-pathological study
with emphasis on cytologic features. Cancer. 1997;79:356361.
Alijo S F, Sanchez-Mora N, Angel AJ, et al. Large cell and small
Neuroendocrine Tumors of the Urinary Tract cell neuroendocrine bladder carcinoma: immunohistochemical
and outcome study in a single institution. Am J Clin Pathol.
Acs G, Gupta PK, Baloch ZW. Cytomorphology of high-grade 2007;128:733739.
neuroendocrine carcinomas of the urinary tract. Diagn Bertaccini A, Marchiori D, Cricca A, et al. Neuroendocrine
Cytopathol. 2000;23:9296. carcinoma of the urinary bladder: case report and review of the
Fine SW. Neuroendocrine lesions of the genitourinary tract. Adv literature. Anticancer Res. 2008;28:13691372.
Anat Pathol. 2007;14:286296. Cheng L, Pan CX, Yang VJ. Small cell carcinoma of the urinary
Murphy WM, Grignon DJ, Perlman EJ. AFIP Atlas of Tumor bladder: a clinicopathologic analysis of 64 patients. Cancer.
Pathology, Series 4. Tumors of the Kidney, Bladder, and Related 2004;101:957962.
Urinary Structures. Washington, DC: ARP; 2004. Choong NW, Quevedo JF, Kaur JS. Small cell carcinoma of
the urinary bladder: the Mayo Clinic experience. Cancer.
2006;103:11721178.
Neuroendocrine Tumors of the Kidney Koss LG. Diagnostic Cytology of the Urinary Tract with
Histopathologic and Clinical Correlations. Philadelphia, PA:
Guillon L. Neuroendocrine carcinoma of the kidney. In: Eble JN, Lippincott-Raven; 1995.
Sauter G, Epstein JI, et al., eds. Pathology and Genetics of Mukesh M, Cook N, Hollingdale AE, et al. Small cell carcinoma
Tumors of the Urinary System and Male Genital Organs. World of the urinary bladder: a 15-year retrospective review of
Health Organization Classification of Tumours. Lyon, France: treatment and survival in the Anglian Cancer Network. BJU
IARC; 2004:82. Int. 2008;103:747752
La Rosa S, Bernasconi B, Micello D, et al. Primary small cell Nguyen-Ho P, Nguyen GK, Villanueva RR. Small cell anaplastic
neuroendocrine carcinoma of the kidney: morphological, carcinoma of the prostate: report of a case with positive urine
immunohistochemical, ultrastructural, and cytogenetic study of cytology. Diagn Cytopathol. 1994;10:159161.
a case and review of the literature. Endocr Pathol. 2009;20: Rollins S, Schumann GB. Primary urinary cytodiagnosis of a bladder
2024. small cell carcinoma. Diagn Cytopathol. 1991;7:779782.
Romero FR, Rais-Bahrami S, Permpongkosol S, et al. Primary Van Hoeven KH, Artymyshyn RL. Cytology of small cell
carcinoid tumors of the kidney. J Urol. 2006;176:2359 carcinoma of the urinary bladder. Diagn Cytopathol.
2366. 1996;14:292297.

13 MISCELLANEOUS
NEUROENDOCRINE TUMORS OF
THE EPITHELIAL TYPE: BREAST,
LIVER, SINONASAL TRACT
Mithra R. Baliga Sudha R. Kini
This chapter focuses on some infrequently occurring The clinical and imaging features of neuroendocrine
neuroendocrine neoplasms of epithelial type, namely neoplasms of the breast mimic those of other tumor types
neuroendocrine tumors of the breast, neuroendocrine with no notable or other specific differences in presen-
neoplasms of the liver, and sinonasal neuroendocrine car- tation. Patients often present with a palpable nodule,
cinomas (SNNECs). which usually appears as a circumscribed mass on mam-
mographic and ultrasound examination. Poorly differen-
tiated NECs usually present at an advanced stage, with
more than 50% having lymph node metastases.
NEUROENDOCRINE NEOPLASMS OF
THE BREAST
Primary neuroendocrine carcinomas (NECs) of the breast
are defined as a group of tumors that exhibit morpho- Histologically, well-differentiated NECs (carcinoid
logic features similar to those of neuroendocrine tumors tumors or solid-type NECs) consist of densely cellular,
of both gastrointestinal tract and lungs. These include solid sheets or nests (alveoli) and trabeculae of cells
well-differentiated NECs (carcinoid tumors) and poorly that vary from round, plasmacytoid, spindle-shaped,
differentiated carcinomas (small cell/oat cell carcinoma and large clear cells separated by delicate fibrovascular
and large cell undifferentiated NEC). The World Health stroma. These tumor cells form rosette-like structures
Organization (WHO) classification (2003) of breast and display peripheral palisading. The adjacent breast
tumors addresses carcinoid tumors as solid-type NEC. tissue may show cribriform type of ductal carcinoma in
While focal neuroendocrine differentiation may be situ (DCIS).
noted in many ductal and lobular breast carcinomas, the Poorly differentiated NECs or small cell carcinomas
term neuroendocrine carcinomas is to be applied when histologically are composed of densely packed hyperchro-
more than 50% of the tumor shows differentiation by matic small cells, with scant cytoplasm displaying an infil-
expression of neuroendocrine markers. Breast can also trative pattern, resembling its pulmonary counterpart. An
be involved secondarily from neuroendocrine neoplasms in situ small cell carcinoma component may be present
from extramammary sites. involving the ducts. Areas of tumor necrosis containing
pyknotic hyperchromatic nuclei may be observed along
with crush artifacts and nuclear streaming.
CLINICAL AND IMAGING FEATURES OF Large cell NECs demonstrate a solid growth pattern
NEUROENDOCRINE NEOPLASMS OF formed by large polygonal cells, low nucleus:cytoplasm
BREAST (N/C) ratios, finely granular eosinophilic cytoplasm,
occasionally prominent nucleoli, peripheral palisading,
Primary NECs of the breast are extremely rare tumors increased mitotic activity, and necrosis. Mitotic figures
constituting 2% to 5% of all breast carcinomas. can range from 18 to 35 per 10 high-power field. These
271

tumors exhibit neuroendocrine differentiation similar to on routine histopathologic study. A high index of suspi-
those encountered in the lung. cion may help one to consider this possibility and apply
appropriate immunohistochemistry for identification.
The differential diagnoses of mammary NECs include
CYTOPATHOLOGIC FEATURES OF metastatic carcinoid tumors or small cell carcinomas
NEUROENDOCRINE NEOPLASMS OF THE from extramammary sites as well as lobular carcinomas
BREAST and duct carcinomas of the breast with neuroendocrine
differentiation. Immunohistochemistry may be helpful
Cytopathologic features of primary neuroendocrine in distinguishing between metastatic and primary breast
tumors of the breast have been reported as individual small cell carcinomas. Mammary small cell carcinomas
case reports. They present features similar to those seen are CK7 positive and CK20 negative while pulmonary
in their pulmonary counterparts (see Chapter 3) and will small cell carcinomas are negative for both. The pres-
not be discussed here. ence of DCIS with similar cytologic features is supportive
of breast origin. Also the expression of ER and PR, and
GCDFP-15, is supportive of primary breast carcinoma.
HISTOCHEMISTRY The negative immunoreactivity for E-cadherin in lob-
ular carcinomas, in contrast to a positive reactivity in
Neuroendocrine neoplasms of the breast are argyrophilic. 100% of small cell carcinomas, is useful in the differential
diagnosis.
Differential diagnoses should also include direct inva-
IMMUNOPROFILE sion of the breast by Merkel cell carcinoma, malignant lym-
phoma, either primary or as a manifestation of systemic
Most cases are positive for chromogranin, synaptophysin, disease, and malignant melanoma. Immunohistochemistry
thyroid transcription factor-1, and cytokeratin-7 (CK7). such as leukocyte common antigen (LCA) (CD45), neuro-
Neuron-specific enolase (NSE) is expressed in major- endocrine markers, CK 20, S100 protein, and HMB 45
ity (100%) of small cell carcinomas of the breast. Gross are helpful in differentiating these lesions.
cystic disease fluid protein (GCDFP-15) frequently shows
strong positivity. Steroid receptors are frequently positive
(estrogen receptor [ER] 80%, progesteron receptor [PR]
35%, and androgen receptors 45%). NEUROENDOCRINE NEOPLASMS
IN THE LIVER
DIAGNOSTIC DIFFICULTIES AND Neuroendocrine tumors are of uncommon occurrence in

DIFFERENTIAL DIAGNOSES the liver, estimated to be in the range of 1% to 5% of all
liver neoplasms. Primary hepatic well-differentiated NECs
Since the incidence of primary NECs of the breast as well (carcinoid) as well as poorly differentiated NECs (small
as its secondary involvement by NECs of extramammary cell carcinomas) are exceedingly rare as very few cases are
site is extremely low, they are encountered very rarely in documented. Primary hepatic carcinoid tumors, encoun-
a routine cytologic practice resulting in lack of familiar- tered more frequently than the other neuroendocrine
ity. Another reason for the limited exposure is that the tumors, are more common in females with a mean age of
diagnostic fine needle aspiration biopsies of breast lesions 49 years. The presenting sign is usually an abdominal mass
have been replaced by core-needle biopsies. Because of with or without associated abdominal pain. Less than 30%
their rarity, these lesions may be easily overlooked by both of cases have signs and symptoms due to excess hormone
surgical pathologists and cytopathologists. An example of production, carcinoid syndrome being the most common.
a case of primary large cell NEC of the breast that was A variety of other secretory products have been described.
overlooked by the pathologist, which was subsequently Primary poorly differentiated NECs (small cell carci-
diagnosed correctly by cytologic examination of pleural noma) of the liver are very rare and have been described.
fluid several years later, is illustrated (Fig. 13.1). One case of small cell carcinoma in authors experience is
This case highlights the need to closely observe cytologic illustrated in Figure 13.2. A secondary lesion in the liver
details to identify this tumor that may otherwise appear must be first ruled out before confirming the neoplasm as
to be invasive duct carcinoma not otherwise specified a primary neuroendocrine tumor of the liver.

Neuroendocrine Tumors of Breast (Figs. 13.1 and 13.2)
A B
C D
Fig. 13.1: Pleural effusion in a 61-year-old woman with a history of mastectomy for an invasive, moderately differentiat-
ed duct carcinoma of the breast. A: Smear of the pleural fluid showing large malignant cells in a syncytial tissue fragment
(Diff-Quik stain). B: The same specimen, stained with Papanicolaou method showing malignant cells with hyperchromat-
ic nuclei and scant cytoplasm. A suspicion of possible neuroendocrine tumor necessitated special stains, which confirmed
a large cell NEC. Retrospective review of the mastectomy and the ancillary tests confirmed the NEC. C, D: Histologic
sections of the large cell NEC (H&E). (Courtesy of Dr. Mithra Baliga, University of Mississippi, Jackson, Mississippi.)
Fig. 13.2: Fine Needle Aspiration (FNA) Biopsy of a Large Hepat-

ic Mass Showing Cytomorphology of a Poorly Differentiated NEC
(Small Cell Carcinoma). No primary site was identified. This neo-
plasm could represent a primary SNEC of the liver.

However, the liver is a common site for metastases The histologic features of metastatic NECs are similar
from well-differentiated NECs that originate in the to those already described for primary lesions in several
gastrointestinal tract, pancreas, lungs, and biliary tract organ sites (see Chapters 3 to 5).
(Figs. 13.3 to 13.10). Poorly differentiated NECs aris-
ing from the lungs, uterine cervix, salivary glands, or
skin (Merkel cell carcinoma) are also known to metas- CYTOPATHOLOGIC FEATURES
tasize to the liver (Figs. 13.11 and 13.12). In pediatric
age group, neuroblastomas frequently metastasize to the The specimens for the cytologic diagnosis of neuroen-
liver. Neuroendocrine tumors such as pheochromocyto- docrine neoplasms involving the liver represent the fine
mas, paragangliomas, and medullary thyroid carcinomas needle biopsies performed under radiologic guidance.
metastasize to the liver infrequently. The cytopathologic features of both well-differentiated
and poorly differentiated NECs have already been
described in detail and will not be repeated. Several
CLINICAL FEATURES examples of metastatic well-differentiated and poorly
differentiated NECs are illustrated in Figures 13.3 to
Hepatic metastases of NECs may be associated with excess
13.12. A history of primary neoplasm is extremely help-
hormone secretions. The presenting signs and symptoms
ful in establishing a diagnosis. It is prudent to review
depend upon the type of hormone produced and the syn-
the cytohistologic material of the primary neoplasm for
drome. In cases of nonfunctional NECs, the presenting
comparison.
symptoms are related to the extent of liver involvement.
Owing to the slow growth, several years may lapse, from
the time of resection of the primary neuroendocrine neo-
plasm to the occurrence of metastatic lesions. DIFFERENTIAL DIAGNOSES
The spectrum of cytologic differential diagnoses of neu-

RADIOLOGIC FINDINGS roendocrine tumors in the liver is wide because of the
morphologic overlap with several non-neuroendocrine
Ultrasound, computed tomography (CT), magnetic res- neoplasms (Table 13.1; Figs. 13.13 to 13.17). They
onance imaging (MRI), and angiography findings are include cholangiocarcinoma, metastatic adenocarcino-
sometimes useful in distinguishing carcinoids from other mas with a small cell pattern, metastatic poorly differ-
tumors. CT with intravenous contrast and MRI with entiated squamous carcinoma, malignant non-Hodgkin
gadolinium often show enhancement, highlighting tumor lymphoma, plasmacytoma, metastatic malignant mela-
hypervascularity. Angiographic findings of an intense noma with small cell features, and well-differentiated
rapid homogeneous vascular tumor blush can be helpful hepatocellular carcinoma. Some of the gynecologic malig-
in further verification. Octreotide receptor scintigraphy nancies, especially cases of ovarian malignant tumors
may be useful in identifying an extrahepatic site of dis- with small cell features, particularly granulose cell tumors
ease in patients with suspected hepatic carcinoid tumors. metastatic to the liver, should also be considered in the
differential diagnosis.
Metastatic neuroblastoma must be differentiated
GROSS AND MICROSCOPIC FEATURES from hepatoblastoma in pediatric patients (Figs. 13.16
and 13.17).
Liver metastases from NECs are usually multiple and of For diagnostic confirmation of neuroendocrine
varying sizes. In most cases, both liver lobes are affected, but neoplasia, immunostains with neuroendocrine markers
miliary seedings throughout the liver are occasionally seen. and CK are necessary.

Chapter 13: Miscellaneous Neuroendocrine Tumors of the Epithelial Type: Breast, Liver, Sinonasal Tract 275
Neuroendocrine Tumors involving the Liver (Figs. 13.3 to 13.12)
A B
C D
Fig. 13.3: Pancreatic Neuroendocrine Tumor Metastatic to Liver. A 57-year-old man with the complaint of severe
epigastric pain radiating to back and weight loss was found to have a large pancreatic mass (7 cm) encasing and nearly
occluding the mesenteric, and splenic veins and celiac axis. Multiple masses involving the liver were noted, compatible
with the metastatic disease. A CT-guided core biopsy of the liver nodule was performed and the core biopsy imprints
were made. A: Imprint stained by Diff-Quik showing uniform small cells. B: This imprint presents a typical dispersed
pattern of plasmacytoid, medium-sized cells with eccentric uniform nuclei consistent with a neuroendocrine tumor
(H&E). C: Imprint from the same specimen stained by Papanicolaou method exhibiting a cytologic presentation con-
sistent with a neuroendocrine tumor. D: Histologic section of the concurrent core biopsy demonstrating a pattern con-
sistent with NEC (H&E). (Courtesy of Dr. Mithra Baliga, University of Mississippi, Jackson, Mississippi.)

Fig. 13.4: Metastasis to Liver from a Pancreatic Endocrine Carci-
noma. FNA of the liver nodule depicting syncytial tissue fragments
of uniform small, round cells with ill-defined cell borders, contain-
ing large nuclei with high N/C ratios. The nuclear chromatin is
coarsely granular presenting a salt-pepper pattern. The cytologic
interpretation of neuroendocrine neoplasm was confirmed at surgi-
cal exploration.
C
Fig. 13.5: Metastasis to Liver from a Pancreatic Endocrine Carcinoma. A, B: FNA of the liver nodule demonstrating
poor cellularity. The neoplastic cells are small, round occurring in small groups and syncytial tissue fragments. Their
N/C ratios are high and the cytoplasm is scant. C: The resection of the liver lobe revealed cystic change within a large
metastatic NEC of the pancreas (H&E).
A B
Fig. 13.6: Small-Bowel Carcinoid Tumor Metastatic to Liver in a Patient with a Prior History of Breast Carcinoma.
A 56-year-old woman with a history of mammary duct carcinoma in the recent past was found to have liver nodules on
follow-up examination. CT-guided core biopsy and imprints were performed. A: Low-power view showing a cellular
smear with several tissue fragments and discrete cells (Diff-Quik). B: Higher magnification showing uniform, small- to
medium-sized cells, in loosely cohesive groups. The cells are round to plasmacytoid with uniform nuclei and contain
variable cytoplasm (Diff-Quik).

C D
Fig. 13.6: (continued) C: This imprint shows small- to medium-sized neoplastic cells in syncytial tissue fragments as
well as discrete and in loosely cohesive groups. The cells are uniform and round to plasmacytoid (H&E). A diagnosis of
metastatic duct carcinoma of the breast was rendered. D: Histologic section of the liver biopsy was also interpreted as
metastatic breast carcinoma (H&E). Retrospective review (conducted for Quality Assurance purposes) of the case was
followed by neuroendocrine markers on the liver biopsy that confirmed neuroendocrine nature. The neuroendocrine
markers on mastectomy specimen were negative. A detailed workup subsequently revealed multiple tumor nodules in
the small bowel. (Courtesy of Dr. Mithra Baliga, University of Mississippi, Jackson, Mississippi.)
A B
Fig. 13.7: FNA Biopsy of a Liver Nodule from a Patient with a History of Bronchial Carcinoid Tumor Resected in the
Recent Past. A: The direct smear of the aspirate showing a syncytial tissue fragment, consisting of uniform small round
cells with poorly defined cell borders, scant cytoplasm, and high N/C ratios. There is no nuclear molding, stretch arti-
facts, or necrosis. B: The cell block of the aspirate confirmed metastatic carcinoid tumor (H&E).

A B
Fig. 13.8: FNA Biopsy of a Liver Nodule from a Patient with a History of Bronchial Carcinoid Tumor. A: The direct
smear of the aspirate showing large syncytial tissue fragments, consisting of uniform small round cells with poorly
defined cell borders, scant cytoplasm, and high N/C ratios. There is no nuclear molding, stretch artifacts, or necrosis.
B: The cell block of the aspirate (H&E).
A B
Fig. 13.9: FNA Biopsy of a Liver Nodule from a Patient with a History of Bronchial Carcinoid Tumor. A, B: The direct
smear of the aspirate showing syncytial tissue fragments, consisting of small round cells with poorly defined cell bor-
ders, scant cytoplasm, and high N/C ratios. Note mild nuclear pleomorphism and coarsely granular chromatin. There
is no nuclear molding, stretch artifacts, or necrosis.
A B
Fig. 13.10: Liver Metastases from Small Intestinal Neuroendocrine Neoplasm. The patient had small-intestine resec-
tion 10 years prior (same case as depicted in Fig. 4.6B) for multiple carcinoid tumors. A: FNA biopsy of the liver nodule
showing a cellular aspirate consisting of large tissue fragments of neoplastic cells (low power). B, C: Higher magnifi-
cation showing uniform cells, small to medium sized, with scant but variable cytoplasm. The cell borders are well to
poorly defined and N/C ratios are high. Nuclear chromatin is granular.

A B
C D
Fig. 13.11: Metastatic Small Cell Neuroendocrine Carcinoma to the Liver. AD: These four images represent four
different examples of liver metastases from pulmonary SNECs. All four cases demonstrate typical cytomorphology of
poorly differentiated NEC.

E F
G H
Fig. 13.11: (continued) EH: Different case of metastatic small cell carcinoma. A 73-year-old male with a history of
a small cell carcinoma of the lung with a widespread metastatic disease including the liver. A fine needle biopsy of the
liver mass was performed. EG: Smears exhibiting tissue fragments consisting of small malignant cells with high N/C
ratios and indistinct cytoplasm. Note the nuclear molding and stretch artifacts (Romanowsky stain). H: Histologic
section of the liver biopsy showing metastatic small cell carcinoma. (EH: Courtesy of Dr. Mithra Baliga, University of
Mississippi, Jackson, Mississippi.)
A B
Fig. 13.12: Small Cell Carcinoma of the Uterine Cervix Metastatic to the Liver. FNA biopsy of a liver nodule in a pa-
tient with a history of SNEC of the uterine cervix. A: The aspirate is very cellular, showing a large population of small,
round discrete cells with indistinct cytoplasm. History of primary cervical small cell carcinoma was not provided at the
time of biopsy. A cytologic diagnosis of malignant lymphoma was rendered. B: Immunostain for CK was positive and
that for LCA was negative, confirming small cell carcinoma.

TABLE 13.1. DIFFERENTIAL DIAGNOSES OF Presenting signs and symptoms include nasal obstruc-
NEOPLASMS WITH SMALL CELLS IN LIVER tion, epistaxis, and pain. Local invasion may lead to
exophthalmos. Small cell carcinomas run a very aggres-
Primary neuroendocrine tumors sive clinical course with a median survival of 14.5 months.
Carcinoid tumor
Local recurrence and distant metastases to cervical
Small cell carcinoma
Metastatic neuroendocrine tumors lymph nodes, lung, liver, and bones occur frequently with
Carcinoid/atypical carcinoid (from gastrointestinal reported rates of 45% to 35%, respectively.
tract, lungs, and pancreas)
Small cell carcinoma, pulmonary and
extrapulmonary sites GROSS AND MICROSCOPIC FEATURES
Merkel cell carcinoma
Well-differentiated cholangiocarcinoma
Metastatic well-differentiated adenocarcinoma Histologically, SNECs are very cellular, presenting sev-
Mammary duct/lobular carcinoma eral growth patterns such as solid, cords and ribbons,
Prostate adenocarcinoma and large islands with extensive areas of necrosis. The
Pancreatic adenocarcinoma with small cell pattern cells are small with scant cytoplasm and high N/C ratios.
Hepatocellular carcinoma
Their nuclei are round, oval to short spindle shaped, and
Malignant melanoma intensely hyperchromatic. Mitotic activity is brisk and
In pediatric and adolescent age groups individual cell necrosis is noted. Squamous cell foci may
Hepatoblastoma be occasionally observed.
The specimen for cytologic diagnosis mostly includes fine

NEUROENDOCRINE CARCINOMAS OF needle biopsies. The malignant cells present characteris-
THE SINONASAL TRACT tic features of small cell carcinoma (Fig. 13.18) seen in
SNECs at other sites such as the lungs (see Chapter 3;
The sinonasal tract includes the nasal cavity and the para- Table 3.7; Figs. 3.46 to 3.56).
nasal sinuses. Neuroendocrine neoplasms at these sites
occur on extremely rare occasions. Of these, the most
commonly encountered subtype of neuroendocrine neo-
Histochemistry
plasms in this region is small cell carcinoma (NEC high The neoplastic cells are argyrophilic.
grade) followed by atypical and typical carcinoid tumors,
the latter being the least common.
Immunoprofile
The cells of sinonasal SNEC react positively to all neu-
roendocrine markers, pancytokeratin, S100 protein and
SINONASAL SMALL CELL negatively to CK20.
NEUROENDOCRINE CARCINOMA
Poorly differentiated NECs or small cell neuroendocrine

Ultrastructure
carcinomas (SNECs) comprise <3% of the malignant Ultrastructurally, the SNEC cells show neurosecretory
neoplasms of the sinonasal tract. They occur equally in granules.
men and women and over a wide age range, from third to
eighth decades of life with a mean of 49 years.
Small cell carcinomas most commonly involve the
Differential Diagnoses
superior or posterior nasal cavity, often with the exten- The differential diagnoses of sinonasal SNEC include high-
sion into adjacent paranasal sinuses such as ethmoid and grade neoplasms both, primary and metastatic, seen in
maxillary sinuses. Small cell carcinoma can also arise these anatomic locations. They are sinonasal undifferenti-
primarily in the paranasal sinuses. ated carcinoma (SNUC), olfactory neuroblastoma (ONB),

Differential Diagnoses of Neuroendocrine Tumors in Liver (Figs 13.13 to 13.17)
A B
C D
Fig. 13.13: Adenocarcinoma versus Neuroendocrine Carcinoma. A: Primary cholangiocarcinoma of the liver consist-
ing of small cells with no cytoplasmic secretions, and scant cytoplasm mimic carcinoid tumors. B: Metastatic adenocar-
cinoma of the breast morphologically can mimic an NEC. C: Metastatic prostatic adenocarcinoma can present a similar
morphology. D: Metastatic NEC for comparison. Immunostains will help to categorize the neoplasms.
Fig. 13.14: Poorly Differentiated Squamous Carcinoma versus

Neuroendocrine Carcinoma. Metastatic poorly differentiated squa-
mous carcinoma, morphologically resembling an SNEC.

A B
Fig. 13.15: Hepatocellular Carcinoma versus Neuroendocrine Car-

cinoma. Hepatocellular carcinoma on occasion shows a dispersed
pattern with bare nuclei, stripped off their cytoplasm and mimic a
dispersed pattern of neuroendocrine neoplasm. A: Low-power view
of an aspirate of hepatocellular carcinoma showing diffuse presence
of bare nuclei and an occasional tissue fragment. B: Higher magni-
fication reveals these nuclei to contain targetoid macronucleoli, a
feature not seen in neuroendocrine neoplasms. Immunostains are
necessary to identify the primary. C: NEC for comparison. Note the
C absence of targetoid macronucleoli.
Fig. 13.16: Metastatic Neuroblastoma versus Hepatoblastoma.

FNA of hepatic mass showing metastatic neuroblastoma. In the
pediatric age group, a metastatic neuroblastoma must be differenti-
ated from hepatoblastoma since both represent small blue round
cell tumors.

A B
Fig. 13.17: Adenocarcinoma versus Neuroendocrine Carcinoma. A: FNA of a large hepatic mass in an infant showing
a cellular aspirate consisting of large anastomosing trabeculae of miniature liver cells (low power). B: Higher magnifica-
tion showing round cells with no differentiating features. Surgical exploration confirmed a hepatoblastoma. Immunos-
tains such as neuroendocrine markers or HepPar-1 will be useful in establishing a correct diagnosis.
Sinonasal Neuroendocrine Carcinoma (Small cell Carcinoma)(SNEC)
A B
Fig. 13.18: AC: FNA of a nasal mass, showing a cellular aspirate

consisting of discrete aggregates and syncytial tissue fragments of
small undifferentiated cells, with scant cytoplasm, high N/C ratios,
C nuclear molding, and deep-staining compact chromatin.

metastatic poorly differentiated squamous carcinoma and TABLE 13.2. DIFFERENTIAL DIAGNOSES OF
its basaloid variant, nasopharyngeal undifferentiated SINONASAL NEUROENDOCRINE CARCINOMA
carcinoma (lymphoepithelial carcinoma/lymphoepitheli- (SMALL CELL CARCINOMA)
oma), mucosal malignant melanoma, nasal type NK/T cell
Olfactory neuroblastoma
malignant lymphoma, rhabdomyosarcoma, peripheral
Sinonasal undifferentiated carcinoma
neuroectodermal tumor (PNET)/Ewing sarcoma (EWS), Nasopharyngeal undifferentiated carcinoma
and adenoid cystic carcinoma (Table 13.2, Figs. 13.19 to (lymphoepithelial carcinoma)
13.26). Most of the differential diagnostic entities listed Poorly-differentiated metastatic adenocarcinoma
in Table 13.2 also enter the differential diagnoses of ONB Basaloid squamous carcinoma
and are also described in Chapter 17 (see Table 17.2, Figs. Adenoid cystic carcinoma, metastatic
Malignant melanoma
17.4 to 17.13). There is considerable morphologic over-
lap between these diagnostic entities. Immunostains are Rhabdomyosarcoma
an essential ancillary test (Table 13.3). EWS/PNET
Differential Diagnoses of Sinonasal Neuroendocrine Carcinoma (SNEC) (Figs 13.19 to 13.26)
A B
C D
Fig. 13.19: Sinonasal Undifferentiated Carcinoma versus Sinonasal Neuroendocrine Carcinoma. A: Histologic section
of an SNUC, showing a solid growth pattern with large sheets and islands of undifferentiated cells, separated by scant
stroma (H&E). B, C: Crush preparation for intraoperative consultation showing loosely cohesive small cells with scant
cytoplasm, and displaying no differentiating features (H&E). D, E: The same case stained by Papanicolaou, highlighting
the malignant nuclei with prominent nucleoli. The cytoplasm is scant. These tumors will be nonreactive to neuroendo-
crine markers unlike sinonasal NECs.

E F
G H
Fig. 13.19: (continued) FH: Different case of sinonasal undifferentiated carcinoma. FNA of a nasal mass. F: Diff-
Quik-stained sample. Low-power view showing a cellular smear with a dispersed cell pattern. G: Higher magnification
showing round, medium-sized cells with poorly defined cell borders and larger nuclei (Diff-Quik). H: Papanicolaou-
stained preparation showing undifferentiated cells with high N/C ratios and prominent nucleoli.
A B
Fig. 13.20: Olfactory Neuroblastoma versus Sinonasal Neuroendocrine Carcinoma. A, B: FNA of an ONB of high
grade, showing small- to medium-sized round cells with scant cytoplasm. Note a carrot-shaped nucleus (arrow),
described as one of the characteristic feature.

Fig. 13.20: (continued) C: Intraoperative crush preparation of a dif-

C ferent case of ONB, depicting discrete small undifferentiated cells.
Fig. 13.22: Adenoid Cystic Carcinoma versus Sinonasal Neuroen-

docrine Carcinoma. FNA of a paranasal sinus mass in a patient with
Fig. 13.21: Malignant Melanoma versus Sinonasal Neuroendocrine a history of an adenoid cystic carcinoma of the salivary gland shows
Carcinoma. Malignant melanoma consisting of a small cell pattern, a syncytial tissue fragment composed of tightly packed small cells
and without melanin pigment, will offer diagnostic difficulties in with scant cytoplasm and deep-staining compact nuclear chromatin.
differentiating it from SNEC. Without clinical history, such cells will offer diagnostic problems.
Fig. 13.23: Basaloid Squamous Carcinoma versus Sinonasal Neu-

roendocrine Carcinoma. This syncytial tissue fragment consists of
closely packed small round cells with poorly defined cell borders,
scant cytoplasm, high N/C ratios, and coarsely granular chromatin.
Note the morphologic similarity to SNEC.

A B
Fig. 13.24: Metastatic Poorly Differentiated Neuroendocrine Carcinomas versus Sinonasal Small Cell Neuroendocrine
Carcinoma. A, B: Intraoperative crush preparations. The cytomorphology of SNECs is same regardless of the site of
origin. A primary site elsewhere, such as the lung, must be first ruled out before establishing a diagnosis of primary
sinonasal NEC.
Fig. 13.25: Rhabdomyosarcoma versus Sinonasal Neuroendocrine

Carcinoma. FNA of an embryonal rhabdomyosarcoma with small
round cells, scant cytoplasm, and high N/C ratios may present cyto-
morphology similar to sinonasal SNEC.
Fig. 13.26: PNET versus Sinonasal Neuroendocrine Carcinoma.

PNET presents a cytomorphologic pattern very similar to SNEC.
Without a proper history and immunostains, differentiation may
be difficult.

TABLE 13.3. IMMUNOCYTOHISTOCHEMICAL TESTS IN DIFFERENTIAL DIAGNOSES OF SINONASAL

SMALL CELL NEUROENDOCRINE CARCINOMA
CK S100a LCA NSE Chromogranin Synaptophysin NFP Desmin CD99 EMA EBV
SNNEC + + + +
SNUC + +
ONB /+ +/ + + + + +
NPC + +
EWS/PNET + + +
RMS +
MM +
ML + +
BSQ +
ACC +
a
Note: S100 protein is not effective on alcohol-fixed specimens especially for cytopathology.
SNNEC, sinonasal neuroendocrine carcinoma; SNUC, sinonasal undifferentiated carcinoma; ONB, olfactory neuroblastoma; NPC, nasopharyngeal
carcinoma; EWS/PNET: Ewing sarcoma/peripheral neuroectodermal tumor; RMS, rhabdomyosarcoma; MM, malignant melanoma; ML, malignant
lymphoma; BSQ, basaloid squamous variant of squamous carcinoma; ACC, adenoid cystic carcinoma; CK, cytokeratin; LCA, leukocyte common antigen;
NSE, neuron-specific antigen; NFP, neurofilament protein; EMA, epithelial membrane antigen; EBV, Epstein-Barr virus.
consisting of medium-sized cells with well- to poorly

SINONASAL SMALL CELL defined cell borders, large nuclei with high N/C ratios,
NEUROENDOCRINE CARCINOMA and scant cytoplasm. The nuclear chromatin is granu-
(SNEC) VERSUS SINONASAL lar, often with parachromatin clearing and prominent
UNDIFFERENTIATED CARCINOMA macronucleoli (Fig. 13.19). The immunoprofile includes
(SNUC) positive reactivity to epithelial membrane antigen (EMA),
CK, NSE, and p53. Reactivity to chromogranin, synapto-
SNUC is an uncommon, highly aggressive tumor involv-
physin, S100 protein, or Leu-7 is usually negative.
ing the sinonasal tract. The age range is broad, from third
to ninth decades, the median being sixth decade.
Clinically, it presents as a rapidly growing mass
in the sinonasal tract and may involve nasopharynx.
The symptoms are of short duration and may include SINONASAL SMALL CELL
nasal obstruction, visual disturbances, facial pain, and NEUROENDOCRINE CARCINOMA (SNEC)
symptoms resulting from cranial nerve involvement. VERSUS OLFACTORY NEUROBLASTOMA
Histologically, the carcinoma is an undifferentiated neo- (ONB)
plasm, cellular with varied growth patterns including
solid, trabecular, lobular, and organoid. The surface epi- ONB arises from the olfactory membrane of the sino-
thelium may show dysplasia or carcinoma in situ. The nasal tract. The high-grade ONB (Fig. 13.20) that lacks
cells are small to medium sized with scant undifferenti- the neurofibrillary matrix and Homer-Wright rosettes
ated cytoplasm and large round nuclei with prominent are least differentiated, consisting of cells with pleo-
nucleoli. There is increased mitotic activity and large morphic nuclei, prominent nucleoli, and scant cyto-
areas of tumor necrosis. Squamous differentiation is not plasm and strongly resemble SNUC (see Chapter 17;
present. Cytologically, the aspirates tend to be cellular, Figs.17. 1 to 17.3).

SINONASAL SMALL CELL SINONASAL SMALL CELL

NEUROENDOCRINE CARCINOMA NEUROENDOCRINE CARCINOMA
VERSUS UNDIFFERENTIATED VERSUS RHABDOMYOSARCOMA
NASOPHARYNGEAL
(LYMPHOEPITHELIAL) CARCINOMA OF Primary sarcomas of the sinonasal tract are rare. Most
THE SINONASAL TRACT are botryoid type, arising as polyps in the nasal cavity
or within the sinuses. The gross appearance is typical.
Nasopharyngeal carcinoma (syn-lymphoepithelial carci- The embryonal and alveolar types may either arise pri-
noma, lymphoepithelioma) of the sinonasal tract is a squa- marily or metastasize to these locations from other body
mous carcinoma arising from the nasopharyngeal mucosa sites. Cytologically, the aspirates exhibit a small cell pat-
and represents the undifferentiated type. It is the common tern with scant cytoplasm and no differentiating features.
type of nasopharyngeal carcinoma, more frequent in males Immunostains for muscle-specific actin, desmin, myoglo-
with the age range of fourth to sixth decades of life. This bin, and MyoD1 will be positive (Fig. 13.25).
carcinoma is strongly associated with Epstein-Barr virus
(EBV). This tumor is very aggressive with 65% 5-year
survival.
Histologically, nasopharyngeal carcinoma shows a SINONASAL SMALL CELL
solid growth pattern with medium to large cells, scant NEUROENDOCRINE CARCINOMA VERSUS
cytoplasm, and large nuclei containing prominent mac- BASALOID SQUAMOUS CARCINOMA
ronucleoli. Some demonstrate non-neoplastic lymphoid
cell infiltrate (hence the term, lymphoepithelioma). Basaloid squamous carcinoma is a morphologic variant
Cytologically, the cells of nasopharyngeal undifferentiated of squamous carcinoma. It is an aggressive tumor com-
(lymphoepithelial) carcinoma are oval to spindle shaped posed of lobules of basaloid cells with peripheral pali-
with enlarged nuclei, containing finely granular chroma- sading and brisk mitosis. The cells are small with scant
tin, prominent nucleoli. Their cytoplasm is eosinophilic cytoplasm (Fig. 13.23).
and scant and the cell borders are indistinct (see Fig.
17.10). Immunoprofile includes negative reactivity to neu-
roendocrine markers and positive reactivity to pancyto-
keratin and EMA. Since nasopharyngeal undifferentiated SINONASAL SMALL CELL
carcinomas (lymphoepitheliomas) have a strong associa- NEUROENDOCRINE CARCINOMA VERSUS
tion with EBV, EBV-encoded RNA is strongly expressed METASTATIC SMALL CELL CARCINOMA
by the tumor.
Morphologically, SNCEs regardless of the site of origin
present the same pattern. It is the clinical history that is
very critical. Immunostains such as CK20 and TTF-1 are
SINONASAL SMALL used to differentiate pulmonary from salivary gland small
CELLNEUROENDOCRINE cell carcinomas and Merkel cell carcinomas (Fig. 13.24).
CARCINOMAVERSUS MALIGNANT
MELANOMA
Malignant melanomas may arise from the mucus mem- SINONASAL SMALL CELL
branes of the sinonasal tract and account for 3.5% of NEUROENDOCRINE CARCINOMA
all tumors involving the sinonasal tract. The cells of VERSUS ADENOID CYSTIC CARCINOMA
malignant melanoma are known to be a great mim-
icker and must always be considered in the differential Adenoid cystic carcinomas of the salivary glands can
diagnosis. Positive immunoreactivity to S100 protein, metastasize to the paranasal sinuses. Syncytial tissue frag-
HMB 45, and Melan-A will be positive and diagnostic ments of closely packed small cells with scant cytoplasm
(Fig.13.21). will mimic sinonasal small cell carcinoma (Fig. 13.22).

SINONASAL SMALL CELL SINONASAL SMALL CELL

NEUROENDOCRINE CARCINOMA NEUROENDOCRINE CARCINOMA
VERSUSMALIGNANT LYMPHOMA/ VERSUS EWS/PNET
LEUKEMIA
Morphologically, the cells of SNEC and EWS/PNET both
Differentiation from neuroendocrine small cell carcino- appear undifferentiated, being small with scant cytoplasm
mas from malignant non-Hodgkin lymphomas including and high N/C ratios. Small cell carcinoma cells present
nasal type NK/T cell malignant lymphoma is a common nuclear molding and karyorrhexis. The cells of EWS/PNET
diagnostic problem because of morphologic overlap. do not exhibit nuclear molding. Neuropil is not seen in small
Positive neuroendocrine markers and negative lymphoid cell carcinoma but present in PNET. Both are reactive to neu-
markers will support the SNEC. roendocrine markers. However, EWS/PNET cells are reac-
tive to CD99 and exhibit genetic anomalies (see Chapter 16).
SUGGESTED READING
Neuroendocrine Tumors of the Breast Neuroendocrine Tumors in Liver

Arzu Y, CAnan K, Metin A, et al. Primary neuroendocrine carcinoma Ali SZ. Metastatic granulosa cell tumor in the liver: cytopathologic
of the breast: a case report. Tumori. 2007;93:496498. findings and staining with inhibin. Diagn Cytopathol.
Hussein KA, Sanders DS, Preece PE, et al. Argyrophil 1998;19(4):293297.
carcinoma ofthe breast: a cytologic, histochemical and Fenoglio LM, Severini S, Ferrigno D, et al. Primary hepatic
ultrastructuralstudy of a case. Diagn Cytopathol. 1989;5: carcinoid: a case report and literature review. World J
217220. Gastroenterol. 2009;15:24182422.
Kadir A, Iyengar K, Suat Cheng P, et al. Fine needle aspiration Gupta RK, Kenwright DN, Naran S, et al. Cytodiagnosis of small cell
cytology of neuroendocrine carcinoma of the breast a malignancies found in fine needle aspirate (FNA) of the liver: an
case report and review of literature. Malaysian J Pathol. immunocytochemical study. Cytopathology. 2000;11:262267.
2008;30(1):5761. Hertz G, Reddy VB, Green L. Fine needle aspiration biopsy of the
Loo CK, Burchett U. Fine needle aspiration biopsy of liver: a multicenter study of 602 radiologically guided FNA.
neuroendocrine breast carcinoma metastatic to thyroid. A case Diagn Cytopathol. 2000;23:326328.
report. Acta Cytol. 2003;47:8387. Khalbuss WE, Grigorian S, Nul MM, et al. Small-cell tumors of
Naeem L, Marilin R, Laila S, et al. An unusual case of primary the liver: a cytologic study of 91 cases and a review of the
small cell neuroendocrine carcinoma of the breast. Breast J. literature. Diagn Cytopathol. 2005;33:814.
2010;16:647651. Pishrodi LR, Bedrossian C. Diagnosis and differential diagnosis of
Rivero JQ, Garcia JL, Rodriguez JJC, et al. Extrapulmonary small cell lesions of the liver. Diagn Cytopathol. 1998;19:2932.
small cell carcinoma in breast and prostate. Clin Trans Oncol. Prosser JM, Dusenberry D. Histocytologic diagnosis of neuroendocrine
2009;11:698700. tumors in the liver. Diagn Cytopathol. 1997;16:383391.
Samli AB, Celik S, Evrensel T, et al. Primary neuroendocrine Shawn BJ, James W. Fine needle aspiration cytology of metastatic
small cell carcinoma of the breast. Arch Pathol Lab Med. carcinoid tumor: report of a case and review of the literature.
2000;124(2):296298. Diagnostic Cytopathol. 2002;28(1):4953.
Sapino, Papotti M, Pietribiasi F, et al. Diagnostic cytological Shin HJC, Caraway NP. Fine needle aspiration biopsy of metastatic
features of neuroendocrine differentiated carcinoma of the small cell carcinoma from extrapulmonary sites. Diagn
breast. Virchows Arch. 1998;433:217222. Cytopathol. 1998;19:171181.
Saqi A, Qster MW, Vasquez MF. Metastatic mammary carcinomas Soga J. Statistical evaluation of 2001 carcinoid cases with
with endocrine features: potential diagnostic pitfalls. Diagn metastases, collected from the literature: a comparative study
Cytopathol. 2005;33:4953. between ordinary carcinoids and atypical varieties. J Exp Clin
Tavassoli FA, Devilee P. Pathology and Genetics, Tumors of Cancer Res. 1998;17:312.
theBreast and Female Genital Organs. WHO Classification Touzios JG, Kiely JM, Pitt SC, et al. Neuroendocrine hepatic
ofTumor Series. Lyon, France: IARC Press; 2003:3234. metastases. Ann Surg. 2005;241:776785.
Tse GM, Ma TK. Fine needle aspiration cytology of breast Wee A, Nilsson B, Yap I. Fine needle aspiration biopsy of small/
carcinoma with endocrine differentiation. Cancer. intermediate cell tumors in the liver. Consideration in Southeast
2000;90:286291. Asian population. Acta Cytol. 1996;40:937947.
Yin H, Schinella R. Cytologic characteristics of endocrine Ylagan LR, Middleton WD, Dehner LP. Fine needle aspiration
ductalcarcinoma in situ of the breast. Acta Cytol. cytology of recurrent granulosa cell tumor: case report with
2002;46:873876. differential diagnosis and immunocytochemistry. Diagn
Cytopathol. 2002;27:3841.

Sinonasal Small Cell Neuroendocrine Carcinoma Jeozzoni JC, Mills SE. Undifferentiated small round cell tumors
of the sinonasal tract: differential diagnosis update. Am J Clin
Asim E, Wenig BM. Sinonasal undifferentiated carcinoma: clinical Pathol. 2005;124 (suppl):S110S121.
and pathologic features and a discussion on classification, Ordonez NG, Mackay B. Neuroendocrine tumors of the nasal
cellular differentiation, and differential diagnosis. Adv Anat cavity. Pathol Ann. 1993;28:77111.
Pathol. 2005;12:134143. Perez-Ordonez B, Caruana SM, Huvos A, et al. Small cell
Bardales RH, Baker S, Mukunyadzi P. Fine needle aspiration neuroendocrine carcinoma of the nasal cavity and paranasal
cytology, findings in 214 cases of non-parotid lesions of the sinuses. Hum Pathol. 1998;29:825838.
head and neck. Diag Cytopathol. 2000;22:569577. Rosenthal DI, Barker JL, EL-Naggar AK, et al. Sinonasal
Bellizzi AM, Bourne TD, Mills SE, et al. The cytologic features malignancies with neuroendocrine differentiation. Patterns
of sinonasal undifferentiated carcinoma and olfactory of failure according to histologic phenotype. Cancer.
neuroblastoma. Am J Clin Pathol. 2008;129:367376. 2004;101:25672573.
Helsel JC, Bardales RH, Mukunyadzi P. Fine needle aspiration Wenig B M. Atlas of Head and Neck. 2nd ed. Philadelphia, PA: W
biopsy cytology of malignant neoplasms of the sinonasal tract. B Saunders, 2008.
A review of 22 primary and metastatic tumors. Cancer (Cancer
Cytopathology). 2003;99:105112.

SECTION II
NEURAL TYPE
NEUROENDOCRINE TUMORS

14 ADRENAL PHEOCHROMOCYTOMA
The paired adrenal glands are a composite of two medulla are rare neoplasms. Their incidence is esti-
endocrine organs: one steroid producing, the other cat- mated to be 8 cases/million persons/year in the United
echolamine producing. They are located in the retroperi- States.
toneum, superomedial to the kidneys. The two organs Pheochromocytomas occur over a broad age
have different embryonic origin, histology, and functions. range from infancy to old age, with a peak in the fifth
This chapter describes the neuroendocrine part, which are decade. There is no gender predilection. Roughly 10%
the adrenal medulla and the tumors arising from it. occur in children. Common presenting symptoms are
mostly related to the abnormal secretion of epineph-
rine and norepinephrine and include headache, palpita-
tions, diaphoresis, flushing of the skin, anxiety, nausea,
STRUCTURE OF NORMAL ADRENAL and constipation. The less common symptoms include
MEDULLA dyspnea, chest pain, visual disturbances, abdominal
pain, fatigue, and paresthesias. The triad of headaches,
The adrenal medulla is of neuroectodermal origin and made palpitations, and sweating are particularly predictive of
up of chromaffin cells arranged in nests and anastomosing a diagnosis of pheochromocytoma. Hypertension with or
cords. The cells have basophilic to amphophilic granular without tachycardia is the key physical finding. Roughly
cytoplasm and indistinct cell borders. Some chromaffin 10% to 15% of patients harboring pheochromocytoma
cells contain cytoplasmic hyaline globules and are thought have a palpable abdominal mass. Laboratory studies
to represent dense-core secretory granules. They may be show increased levels of catecholamines in 24-hour urine
present in up to 80% of the cases. Medulla contains two as well as their plasma levels. Most pheochromocytomas
other types of cells namely, ganglion cells and sustentacular present a benign course. A small number do metastasize
cells. Ganglion cells are found singly or in association with with fatal outcome.
myelinated nerve bundles. Sustentacular cells are present at
the periphery of the medullary cords, are spindle shaped,
and can be highlighted with S100 protein.
Ultrastructurally, the chromaffin cells demonstrate FAMILIAL PHEOCHROMOCYTOMA
dense-core secretory granules that are quite pleomorphic
and range in size from 150 to 300 nm in diameter. There Approximately 10% of pheochromocytomas are
is moderate amount of rough endoplasmic reticulum. reported to be familial. However, a recent study has
Neuroendocrine neoplasms of the adrenal medulla indicated 20% to be occurring in a familial setting.
include pheochromocytoma, neuroblastoma, and periph- The familial cases are most notable in patients with
eral neuroectodermal tumors (PNETs). multiple neuroendocrine neoplasia (MEN 2A or MEN
2B). They can also occur in von Recklinghausen disease
or von Hippel-Lindau disease. Pheochromocytomas
develop in 30% to 50% of patients with MEN type 2.
PHEOCHROMOCYTOMA The tumors are bilateral or multifocal in 70% of the
cases (see Chapter 1, Table 1.1). For more information,
Pheochromocytomas, also known as adrenal paragan- the reader is referred to the extensive literature on the
glioma, arising from the chromaffin cells of the adrenal subject.
295

296 Section II: Neural Type Neuroendocrine Tumors
RADIOLOGIC FINDINGS the deep mahogany color after exposure to air. Following
immersion in a dichromate solution, the tumor turns deep
On CT scans, pheochromocytomas appear as well- brown as a result of oxidation of the catecholamines.
demarcated and circumscribed nonhomogeneous tumors. Histologically, most are encapsulated. Pheochro-
The lack of homogeneity is due to hemorrhage, necro- mocytomas demonstrate various growth patterns such as
sis, and cystic degeneration. The 131I-MIBG scan using a trabecular with anastomosing cell cords, alveolar or nest-
radioactive material that is taken up by neuroendocrine ing (Zellballen), and diffuse (Fig. 14.2AJ). Pseudoacinar,
tumors is diagnostically useful. pseudopapillary, or perivascular arrangement may occur.
Spindle cell patterns are occasionally observed (see Fig.
14.9D). The tumors are very vascular, with a promi-
GROSS AND HISTOLOGIC FEATURES nent network of delicate capillaries surrounding groups
of neoplastic cells. The predominant cell type is large
Sporadic pheochromocytomas are usually single, uni- polygonal with moderate-to-abundant granular cyto-
lateral tumors, 2 to 10 cm in diameter but can attain a plasm that is eosinophilic to amphophilic (Fig. 14.2F).
large size. Multiple and bilateral tumors are common in a The cytoplasm may be vacuolated or clear and con-
hereditary setting. The cut surface is gray to pink-tan or tain melanin pigment. Some cells mimic ganglion cells.
red with areas of recent hemorrhage. Areas of old hemor- Intracytoplasmic eosinophilic hyaline globules have been
rhage, fibrosis, and cystic degeneration and necrosis are detected in 47% of the cases. Intranuclear inclusions are
frequent in large neoplasms (Fig. 14.1). The tumor takes commonly seen. Pheochromocytomas also demonstrate
A B
Fig. 14.1: A: Histologic section of a normal adrenal gland showing

external cortex and interior medulla (arrow). B: Gross photograph
of a pheochromocytoma. The tumor is well defined, ovoid, and has
a smooth cut surface. Note small cystic areas. C: Gross photograph
of a different pheochromocytoma with multiple varying-sized cysts,
C some with hemorrhage.

Chapter 14: Adrenal Pheochromocytoma 297
Spectrum of Histologic Patterns of Pheochromocytoma
A B
C D
E F
Fig. 14.2: A: Typical alveolar or nesting pattern (Zellballen) formed by large cells, outlined by delicate, vascular stroma. The
cells have well-defined borders and appreciable eosinophilic cytoplasm. The nuclei are very uniform with coarsely granular,
evenly dispersed chromatin, imparting a salt-pepper appearance. Nucleoli are conspicuous (H&E). B: Another example of
an alveolar or nesting pattern. The cells and their nuclei are uniform. There is abundant pale eosinophilic cytoplasm (H&E).
C: This pheochromocytoma demonstrates a trabecular pattern with broad trabeculae of uniform medium-sized cells with
eosinophilic cytoplasm and high N/C ratios (H&E). D: Pheochromocytoma with a diffuse growth pattern, formed by small
round to cuboidal cells with high N/C ratios (H&E). E: Degenerative and cystic changes have resulted in a pseudopapillary
pattern (H&E). F: Higher magnification of a histologic section of pheochromocytoma, showing nests of large polygonal cells
containing abundant, deep-staining, granular eosinophilic cytoplasm. The nuclei are uniform. The N/C ratios are low (H&E).

G H
I J
Fig. 14.2: (continued) G: Histologic section of a pheochromocytoma with neoplastic cells containing pale to clear
abundant cytoplasm. Note the alveolar pattern (H&E). H: Histologic section of a pheochromocytoma with smaller
cells and high N/C ratios (H&E). I: Histologic section of a pheochromocytoma showing a solid growth pattern with
small round and spindle cells (H&E). J: Histologic section of a pheochromocytoma, stained with S100 protein, to high-
light positively stained sustentacular cells seen at the periphery of the neoplastic cell nests (H&E).
giant multinucleated bizarre cells. Stromal amyloid has pattern, cell composition, as well as the cell characteristics
been reported in 70% of the cases. (Table 14.1; Figs. 14.3 to 14.13). The aspirates tend to be
bloody. The cellularity of the aspirate is variable and often
compromised due to excessive blood. The neoplastic cells
CYTOPATHOLOGIC FEATURES appear isolated, in loosely cohesive groups and in syncytial
tissue fragments, without any architectural patterns. The
The specimens for cytologic diagnosis almost always rep- neoplastic cells vary in size and range from small to large
resent fine needle aspiration (FNA) biopsies. The fine nee- with frequent giant forms. The cells in a given case can
dle biopsy procedure is usually not recommended when be monomorphic or pleomorphic. They can be round,
pheochromocytoma is clinically suspected due to possible cuboidal, plasmacytoid, polygonal, racquet shaped, cau-
complications during the procedure. The documentation date, or spindle shaped. The characteristic large polygonal
of cytologic features in literature is rather lean. The cyto- cells with deep eosinophilic cytoplasm, seen in histologic
logic findings presented in this chapter represent both, the preparations, are only rarely appreciated in cytologic
scrape preparations of the surgically excised neoplasms smears. The cell borders are well to poorly defined. Their
and FNA biopsies. nuclei are central to eccentric, round to ovoid with stip-
The cytologic features of pheochromocytomas vary pled chromatin (salt-pepper) and small nucleoli. The
widely from case to case and are dependent on the growth nuclear pleomorphism may be striking with the presence

TABLE 14.1. CYTOPATHOLOGIC FEATURES OF PHEOCHROMOCYTOMA

(ADRENAL PARAGANGLIOMA)
Cellularity Variable; scant to cellular, bloody
Presentation Cells discrete with a dispersed pattern, in loosely cohesive

groups and in syncytial tissue fragments as nests, trabeculae, and
occasionally rosettes
Cells Size and shapes variable; monomorphic to extremely

pleomorphic; small-to-giant forms; round, oval, plasmacytoid,
polygonal to spindle shapes, strap cells; some resemble ganglion
cells; cell borders poorly defined; N/C ratios variable
Nucleus Variable in size; central to eccentric; bi- to multinucleation;

round to oblong; smooth nuclear membranes; occasionally
convoluted; granular chromatin; nucleoli prominent in
aggressive tumors; intranuclear inclusions +/; mitoses /+
Cytoplasm Variable, scant indiscernible to abundant; pale, dense to granular

to vacuolated; cytoplasmic processes, generally unipolar;
melanin pigment +/
Background Bare nuclei frequent; bloody
Immunoprofile Positive reactivity to neuroendocrine markers; S100 positivity

for sustentacular cells
Differential diagnoses Adrenal cortical carcinoma

Renal cell carcinoma
Hepatocellular carcinoma
Malignant melanoma
Malignant lymphoma, anaplastic large cell type
Metastatic poorly differentiated adeno/squamous carcinoma
Adrenal myelolipoma
of giant forms with pyknosis (Figs. 14.6B,C and 14.8C). HISTOCHEMISTRY

Intranuclear inclusions may also be present. Their cyto-
plasm of pheochromocytoma cells is variable. The nuclear/ The cells of pheochromocytoma possess argyrophilic
cytoplasmic ratios likewise vary. Some cells appear large granules that can be demonstrated by Grimelius and
and ganglion-like (Fig. 14.8C), while some exhibit wispy Churukian-Schenk stains.
cytoplasmic processes (Fig. 14.8B). It is not unusual to
encounter disruption of the lipid-rich cytoplasm resulting
in a large population of uniform naked nuclei (Figs. 14.12 IMMUNOCHEMISTRY
and 14.13A). The cytoplasm of the pheochromocytoma
cells may contain eosinophilic, periodic acidSchiff (PAS)- The most useful antibody is chromogranin, which stains
positive globules. Red cytoplasmic granules are seen in neuroendocrine cells. Several other neuroendocrine mark-
Romanowsky-stained preparations. Old and new hemor- ers demonstrate positive reactivity. S100 protein antibody
rhage and degenerative changes are frequent. stains the supporting sustentacular cells (Fig. 14.2J).

Spectrum of Cytopathologic Features of Pheochromocytoma (Figs. 14.3 to 14.14)
A B
Fig. 14.3: AC: Scrape preparations of a surgically excised

pheochromocytoma. Note the pleomorphic pattern formed by
medium to large cells with variable pale cytoplasm and well- to poorly
defined cell borders. The nuclei vary in size, eccentric in location, and
range from round, oval to oblong, containing coarsely granular chro-
C matin. Note the delicate cytoplasmic processes (arrows).
A B
Fig. 14.4: Scrape Preparations of a Surgically Excised Pheochromocytoma. A: This field shows a syncytial tissue
fragment of large polygonal and round neoplastic cells with well- to poorly defined cell borders. The cells contain
abundant granular, eosinophilic cytoplasm. The nuclei are slightly pleomorphic. The nuclear chromatin is coarsely
granular and nucleoli are occasionally seen. B, C: The cellular borders are disrupted, resulting into spillage of the
granular cytoplasm in the background with dispersed, pleomorphic naked nuclei. The chromatin is coarsely granular.
Nucleoli are also present.

A B
Fig. 14.5: A, B: FNA of a pheochromocytoma. This Romanowsky-stained preparation shows dispersed and aggregates
of large cells with poorly defined cell borders. The nuclei are large and pleomorphic. Their cytoplasm is not visualized.
A B
Fig. 14.6: AC: Scrape preparations of a surgically excised pheochromocytoma, showing considerable nuclear
pleomorphism. Note the giant cells with giant nuclei, some with multilobulation. The chromatin is compact and deeply
staining. The background cells demonstrate poorly defined cell borders and variable granular cytoplasm.

A B
Fig. 14.7: Scrape Preparations of a Surgically Excised Pheochromocytoma. A: This field shows crowded and over-
lapped nuclei with indistinct cell borders. The cytoplasm is not readily visualized. The nuclei are pleomorphic and
contain granular chromatin. B: Note spindle-shaped cells with delicate cytoplasmic processes.
A B
Fig. 14.8: FNA of a Pheochromocytoma. A: The neoplastic cells are pleomorphic in size with poorly defined cell
borders. Note finely granular nuclear chromatin. Their cytoplasm is variable and stained eosinophilic (H&E). B: Note
spindle-shaped cells with unipolar, delicate cytoplasmic processes and eccentric uniform nuclei (H&E).

C D
Fig. 14.8: (continued) C: This field shows enormously large cells

resembling the ganglion cells (H&E). D: Papanicolaou-stained
preparation. Note morphologic similarity to medullary thyroid
carcinoma. E: The same aspirate, Romanowsky stain. (Courtesy
of Dr. Mithra Baliga, University of Mississippi Medical Center,
E Jackson, Mississippi.)
A B
Fig. 14.9: FNA of a Pheochromocytoma. A: Low-power view showing a dispersed cell pattern. Cellular and nuclear
pleomorphism can be appreciated even at this magnification. B, C: Note a very pleomorphic cell pattern consisting of
small to large, round, plasmacytoid to triangular and spindle forms with cytoplasmic processes, a pattern very similar
to medullary thyroid carcinoma.

C D
Fig. 14.9: (continued) D: Histologic section showing a spindle cell pattern.
A B
Fig. 14.10: FNA of a Pheochromocytoma. A: Medium-power view

demonstrating anastomosing trabeculae consisting of pleomorphic
cells (H&E). B: Higher magnification showing an admixture of
round and spindle cells (H&E). C: Another field exhibiting pleo-
C morphic spindle cells (H&E).

A B
Fig. 14.11: A, B: Scrape preparation of a pheochromocytoma demonstrating a pleomorphic pattern with predominant
spindle cells. Note unipolar cytoplasmic processes.
A B
Fig. 14.12: A, B: Scrape preparation of a pheochromocytoma demonstrating dispersed small naked nuclei in a granular
background. The nuclei are mostly uniform, stripped off their cytoplasm. Note an occasional large nucleus.
A B
Fig. 14.13: FNA of a Pheochromocytoma. A: Low-power view showing stripped pleomorphic nuclei. B: Higher magni-
fication of another field showing a syncytial tissue fragment with poorly defined cell borders.

Fig. 14.13: (continued) C: Histologic section showing a typical

morphology of pheochromocytoma with a nesting pattern and large
polygonal cells with abundant deep eosinophilic cytoplasm (H&E).
(Courtesy of Dr. Jenine Benoit, Saskatoon City Hospital, Saskatoon,
C Canada.)
A B
Fig. 14.14: AC: Bronchial washings from a patient with multiple

pulmonary nodules and a history of pheochromocytoma removed in
remote past. The patient also had lytic vertebral lesions confirmed as
metastatic pheochromocytoma. Note the syncytial tissue fragments
of malignant cells with a cytologic pattern resembling adenocarci-
noma. The diagnosis was confirmed by positive immunostains for
C neuroendocrine markers.

ULTRASTRUCTURE be considered in the differential diagnosis. These include

adrenal cortical carcinoma, renal cell carcinoma, hepa-
The diagnostic feature is the presence of membrane-bound tocellular carcinoma, metastatic poorly differentiated
neurosecretory granules ranging from 150 to 250 nm. carcinomas, malignant melanoma, and malignant lym-
phomas, large cell type (Table 14.2; Figs. 14.15 to 14.20).
Appropriate immunostains are required for correct iden-
tification of the neoplasm. Paraganglioma involving the
MALIGNANCY IN retroperitoneum may mimic the radiologic pattern of an
PHEOCHROMOCYTOMAS adrenal neoplasm. Its cytomorphology is indistinguish-
able from that of pheochromocytoma. On rare occasions,
Malignancy in pheochromocytomas is diagnosed only adrenal myelolipoma with megakaryoblasts and mega-
with wide invasion and in the presence of metastases. The karyocytes may mimic a pheochromocytoma (Fig. 14.21).
reported incidence is 14% to 50%. Several features are
associated with malignancy; however, there is no single
criterion. Large size, coarsely nodular or multinodular,
confluent necrosis, mitosis, extensive local invasion, large COMPOSITE PHEOCHROMOCYTOMA
Zellballen with central degeneration, lack of hyaline glob-
ules, dopamine secretion, small cells with high N/C ratios, Composite pheochromocytoma is referred to a neoplasm
monotony of cytologic pattern, and spindle cell pattern that is composed in part of typical pheochromocytoma
are all associated with malignancy. The tumor may show and has a component resembling neuroblastoma, ganglio-
extensive local spread or metastasize to the distant organs. neuroblastoma, or ganglioneuroma.
Such a case is illustrated in Figure 14.14. The patient died
of widespread metastasis.
OTHER NEUROENDOCRINE TUMORS OF

THE ADRENAL MEDULLA
DIFFERENTIAL DIAGNOSES Other neuroendocrine neoplasms of the adrenal medulla
include those derived from neuroectoderm namely neuro-
Given the location of the lesion and an adequate aspi- blastomas and PNETs.
rate, the cytologic features of pheochromocytomas usu- Neuroblastomas, arising from the primitive neuroec-
ally lend themselves to correct identification of the tumor. toderm, are neoplasms of childhood. They are described
Being a very vascular neoplasm, the aspirates may be separately in Chapter 16.
bloody, obscuring the cellular details, and may result PNETs are more frequent in pediatric age group but
in unsatisfactory samples and false-negative diagnosis. may be encountered in older age group (Fig. 14.22A,B).
Because of the morphologic overlap, several neoplasms The small cell pattern may be difficult to differenti-
involving the adrenal gland as well as those in the vicin- ate from metastatic small cell carcinoma (Fig. 14.22C).
ity of the adrenal gland, that is, retroperitoneum, must PNETs are described in more detail in Chapter 16.

TABLE 14.2. DIFFERENTIAL DIAGNOSES OF PHEOCHROMOCYTOMA 308
Metastatic Poorly
Pheochromocytoma/ Adrenal Cortical Differentiated Carcinoma Metastatic Renal Metastatic Malignant Hepatocellular
Paraganglioma Carcinoma Adeno/Squamous Cell Carcinoma Melanoma Carcinoma
Cellularity Variable Cellular Cellular Cellular Cellular Usually cellular
Presentation Cells isolated, in loose Cells mostly Cells isolated, in loosely Cells isolated, in Cells mostly isolated or in Cell discrete, in loosely
aggregates or in syncytial isolated, in loosely cohesive groups or in syncytial loosely cohesive loosely cohesive groups; cohesive groups and
tissue fragments without cohesive groups or tissue fragments with or groups or in syncytial tissue fragments unlikely in syncytial tissue
any architectural in syncytial tissue without acinar pattern tissue fragments; fragments, predominantly
patterns fragments with monolayered, papillary, a trabecular pattern
no architectural or without any with smooth contours,
patterns architectural pattern pseudoacinar pattern;
cell nests and trabeculae
with endothelial envelop;
capillaries transgress
through the tissue
fragments
Section II: Neural Type Neuroendocrine Tumors
Cells Monomorphic to Uniform to Variable in size, round to Variable in size, round Variable in size and shape, Variable in size, but
pleomorphic cell markedly polygonal; well- to poorly to polygonal; poorly round to polygonal to usually large, polygonal
population; small, large pleomorphic, round, defined cell borders; high N/C defined cell borders; giant forms; well-defined with well- to poorly
to giant forms, oval, plasmacytoid, ratio N/C ratio mildly cell borders; high N/C defined cell borders; N/C
polyhedral, myoid, cuboidal to increased ratio ratios variable
spindle shapes; cell polygonal; N/C
borders well defined; ratios mildly
N/C ratios variable increased in well-
differentiated
tumors, markedly
increased in poorly
differentiated types

Nucleus Uniform round to Variable size, Round, central to eccentric, Round, central Round, central to Central; binucleation
oblong, egg-shaped; round, oval pleomorphic in size; location, smooth eccentric, bi- to frequent; size variable,
eccentric bi- to to elongated; smooth to irregular nuclear nuclear membranes; multinucleation frequent; round with smooth
multinucleation; salt- ultinucleation+/; membranes; fine to coarsely finely granular nuclear membrane to irregular nuclear
pepper chromatin; central or eccentric granular chromatin, chromatin; micro smooth, to irregular; membranes; chromatin
micro/macronucleoli; smooth to parachromatin clearing; to prominent fine to coarsely granular granular with excessive
intranuclear inclusions irregular nuclear micro/macronucleoli macronucleoli chromatin; multiple parachromatin clearing;
+/; giant nuclei with membranes; micro/macronucleoli; single; large targetoid
clumped chromatin +/ very coarsely intranuclear cytoplasmic macronucleus to
granular to inclusions frequent multiple micronucleoli;
chunky chromatin; pseudoinclusions +/;
prominent multinucleated tumor
macronucleoli; giant cells on rare
intranuclear occasions
cytoplasmic
inclusions +/
Cytoplasm Variable, scant to Variable, moderate Variable, scant to Variable, moderate Variable, scant to Variable usually dense,
abundant, pale to abundant, clean, abundant, pale to dense, to abundant, pale to abundant, pale, granular granular bile +/
granular to dense; vacuolated, granular secretory vacuoles +/; granular; glycogen to dense; cytoplasmic inclusions bare
cytoplasmic processes to dense; glycogen glycogen +; mucin +/; no +; no cytoplasmic tailing +/ nuclei +/
absent; cytoplasmic cytoplasmic processes processes
processes rare
Background Bloody, bare nuclei Bloody; necrosis Necrosis +/ Bloody; necrosis +/; Clean Usually clean;
bare nuclei in clear bloody +/
cell type
Immunoprofile Vimentin ; epithelial Vimentin +; epithelial Vimentin ; epithelial Vimentin +; epithelial S100 protein +; HMB 45 Hep Par 1 +; alpha
markers ; markers ; Lewis blood markers + markers ; Lewis +; Melan-A + fetoprotein +; polyclonal
Lewis blood group antigen ; blood group antigen CEA +
group antigen ; calretinin +; inhibin + +; keratin +; CD10 +;
neuroendocrine RCC Ma +
markers +; S100
protein +; cytokeratins
+
Ultrastructure Electron-dense, Whorls of smooth Adenocarcinomasurface Microvilli, copious Melanosomes Bile canaliculi
membrane-bound endoplasmic microvilli; intracytoplasmic cytoplasmic glycogen;
secretory granules reticulum; lipid lumina; secretory granules; lipid vacuoles
vacuoles intercellular findings;
irregularly distributed
intermediate filaments
squamoustonofilaments
and desmosome
Adjunct Elevated plasma Elevated levels of 17 NA NA NA Elevated serum alpha

laboratory and urinary levels of ketosteroids in urine/ fetoprotein +/

studies catecholamines and serum
vanillylmandelic acid
Chapter 14: Adrenal Pheochromocytoma
309
Differential Diagnoses of Pheochromocytoma (Figs. 14.15 to 14.21)
A B
C D
Fig. 14.15: Pheochromocytoma versus Adrenal Cortical Carcinoma. AC: FNA of an adrenal cortical mass. Cellular
aspirate showing round to polygonal cells exhibiting considerable pleomorphism in size and shape. Their N/C ratios are
high. The nuclear chromatin is very coarse. Note prominent macronucleoli. Intranuclear cytoplasmic inclusions can be
seen. The cell borders are well defined. The variable cytoplasm is dense. D: Another example of FNA of an adrenocorti-
cal carcinoma. Note the morphologic similarity to pheochromocytoma.
A B
Fig. 14.16: Pheochromocytoma versus Renal Cell Carcinoma. A: FNA of a renal mass showing large pleomorphic
malignant cells with abundant variable, dense to granular cytoplasm, and large nuclei. The nuclear chromatin is coarse.
Nucleoli are prominent. B: FNA of renal mass showing a chromophobe type renal cell carcinoma. Note that large
round-to-polygonal cells bear a strong resemblance to the cells of pheochromocytoma.

A B
Fig. 14.17: Pheochromocytoma versus Hepatocellular Carcinoma.

AC: FNA of a poorly differentiated hepatocellular carcinoma. The
morphologic overlap with pheochromocytoma/paraganglioma is
C clearly apparent.
A B
Fig. 14.18: Pheochromocytoma versus Malignant Melanoma. A, B: Malignant melanoma cells are known to mimic a
wide range of neoplasms. These plasmacytoid and polygonal cells strongly resemble a neuroendocrine tumor.

A B
Fig. 14.19: Pheochromocytoma versus Metastatic Poorly Differentiated Carcinoma. A, B: These large pleomorphic
malignant cells originating from a poorly differentiated esophageal adenocarcinoma may be misinterpreted as a pheo-
chromocytoma.
Fig. 14.20: Pheochromocytoma versus Metastatic Hrthle Cell

Carcinoma. Hrthle cell carcinomas of the thyroid occasionally present
a very pleomorphic pattern. With large pleomorphic cells and abundant
cytoplasm, they enter the differential diagnosis of pheochromocytoma.
A B
Fig. 14.21: Pheochromocytoma versus Adrenal Myelolipoma. A, B: The aspirate of an adrenal mass contained numerous
megakaryoblasts and megakaryocytes, which may be misinterpreted as pleomorphic cells of a pheochromocytoma.
The precursors of erythroid and myeloid cells should be a clue for the diagnosis of myeloblastoma.

A B
Fig. 14.22: A, B: FNA of an adrenal mass in an elderly male, show-

ing a large population of small undifferentiated cells. There is no
nuclear molding. The surgical excision confirmed a primitive neu-
roectodermal tumor. The tumor later metastasized to the cervical
lymph node. C: Metastatic pulmonary small cell carcinoma. In older
age group, PNET must be differentiated from metastatic pulmonary
C small cell carcinoma as depicted here.
SUGGESTED READING
Deodhar S, Chalvardjian A, Lata A, et al. Adrenal Lack EE. Tumors of the Adrenal Glands and Extra-Adrenal
pheochromocytoma mimicking small cell carcinoma on fine Paraganglia. Washington, DC: AFIP; 2007.
needle aspiration biopsy. Acta Cytol. 1996;40:10031006. Ren R, Guo M, Sneige N, et al. Fine needle aspiration of adrenal
Ellison DA, Parham DM. Tumors of the autonomic nervous cortical carcinoma. Cytologic spectrum and diagnostic
system. Am J Clin Pathol. 2001;115(Suppl 1):S45S55. challenges. Am J Clin Pathol. 2006;126:389398.
Jimenez-Heffernan JA, Vicandi B, Lopez-Ferrer P, et al. Shidham VB, Galindo LM. Pheochromocytoma: cytologic findings
Cytologic features of pheochromocytoma and retroperitoneal on intraoperative scrape smears in five cases. Acta Cytol.
paraganglioma. A morphologic and immunohistochemical 1999;43:207213.
study of 13 cases. Acta Cytol. 2006;50:372378.

15 EXTRA-ADRENAL
PARAGANGLIOMAS
Paraganglia, derived from the neural crest, are widely into sympathetic and parasympathetic types. A new term
dispersed in the body and are composed of morphologi- chemodectoma was introduced for the neoplasms
cally and cytochemically similar neuroendocrine cells. derived from these organs. Another term for the parasym-
Paraganglia have varied anatomic distributions. Their pathetic paraganglia is glomus, and the tumors arising
characteristic cells perform different functions. For from these organs are referred to as glomus jugulare, not
physiologic and pathophysiologic purposes, they may be to be confused with thermoregulatory vascular structures
broadly divided into two groups, existing in close prox- in the skin called as glomus tumor or glomangioma. It was
imity to branches of either the sympathetic or parasym- also noted that these paraganglia did not develop reaction
pathetic nervous systems. The prototype for sympathetic with chromate salts, hence the term nonchromaffin.
paraganglia is adrenal medulla, while that of parasympa- All paraganglionic cells appear to be derived from the
thetic paraganglia is carotid body. Both are functionally neural crest. The term paraganglia connotes a constella-
different. Sympathetic paraganglia are distributed along tion of morphologic and functional characteristics associ-
the pre- and paravertebral sympathetic chains and follow ated with these cells and are not dependent on a single
the sympathetic innervation of the pelvic and retroperito- histochemical reaction. Morphologically the neoplasms
neal organs. Parasympathetic paraganglia are distributed arising from both types of paraganglia resemble each
along the cervical and thoracic branches of the vagus and other and are often indistinguishable. They also exhibit
glossopharyngeal nerves. widely overlapping secretory products and other neuro-
The sympathetic paraganglia are referred to as chro- endocrine markers reflecting the similarities of their nor-
maffin cells because of the brown discoloration with mal counterparts.
addition of chromates, while those of parasympathetic
paraganglia, which do not react with chromate salts, are
referred to as nonchromaffin. This reaction is now con-
sidered to be due to oxidation of stored catecholamines DISTRIBUTION OF NORMAL
rather than the affinity for chromates. PARAGANGLIA
Paraganglia are grouped into four categories, based on

location and innervation: branchiometric, intravagal, aor-
HISTORY ticosympathetic, and visceral autonomic (Fig. 15.1).
Sympathetic paraganglia are found associated with
Kohn at the beginning of the 20th century coined the term all parts of the peripheral sympathetic nervous system
paraganglia because they formed ganglion-like bodies, along the sympathetic trunks and in connective tissue in
were composed of chromaffin cells, and were connected or near the walls of the pelvic organs. They are small,
to the sympathetic nervous system. However, they still not grossly visible, except for organs of Zuckerkandl.
were not genuine ganglion cells as they lacked axons and Parasympathetic paraganglia are associated with distribu-
dendrites; hence Kohn referred them as paraganglia. tion of cranial and thoracic branches of the glossopharyn-
Subsequently, the finding of innervation of carotid body geal nerve. Those associated with vagus nerves are located
by glossopharyngeal nerve and the discovery of chemo- along jugular, superior and inferior laryngeal, subclavial
receptor functions of the carotid and other similar bod- and aortopulmonary, and cardiothoracic branches near
ies associated with vagus nerve divided the paraganglia the base of the great vessels.
315

A B
Fig. 15.1: A: Anatomic distribution of sympathoadrenal paraganglia. B: Anatomic distribution of paraganglia in head
and neck. (From Lack EE. Tumors of the Adrenal Glands and Extra-Adrenal Paraganglia. AFIP Atlas of Tumor Pathol-
ogy Series 4, Fascicle 8, Washington, DC: American Registry of Pathology; 2007, pp. 283, Fig. 11.1; pp. 323, Fig. 12.1.
Reproduced with permission from American Registry of Pathology.)
The cells of paraganglia are polygonal, have abundant

STRUCTURE OF PARAGANGLIA cytoplasm, small, round to ovoid, pale-staining nucleus.
The cells can be identified by silver stains, autofluores-
With the exception of the organs of Zuckerkandl and
cence, ultrastructure, or neuroendocrine markers. These
carotid bodies, paraganglia are <1 mm in size and not
cells are completely surrounded by glial cells, which
visible to the naked eye. They contain two types of cells
contain less cytoplasm and flattened more deep-staining
namely neuroendocrine cells and Schwann celllike glial
nuclei containing coarse chromatin, and stain positively
cells. The former is referred to as chromaffin cells or
with S100 protein.
granule-containing cells when associated with sympa-
thetic paraganglia. Those associated with parasympa-
thetic ganglia are termed as glomus cells, type I cells, or HISTOCHEMISTRY
chief cells. The Schwann celllike glial cells are referred
to as sustentacular cells, type II cells, satellite cells, or The chief cells of the paraganglia are argyrophilic and
supporting cells. stain positively with Grimelius.

Chapter 15: Extra-Adrenal Paragangliomas 317
ULTRASTRUCTURE TABLE 15.1. PRIMARY SITES OF EXTRA-ADRENAL

PARAGANGLIOMASa
Ultrastructurally, paraganglia cells demonstrate neurose-
cretory granules. Carotid body paraganglioma Base of the heart,
aorticopulmonary sulcus
Jugulotympanic region Larynx

IMMUNOPROFILE
External ear Trachea
The chief cells react positively to neuroendocrine markers
(neuron-specific enolase, synaptophysin, chromogranin, Superior vagal nerve Lungs
and CD56) and do not react to cytokeratin. The susten-
Sella turcica Mediastinum
tacular cells in areas, peripheral to the cell nests, react
positively to S100 protein. Orbit Paraaortic region
(retroperitoneum)
Nose and paranasal sinuses Aortic bifurcation

NEOPLASMS OF THE PARAGANGLIA
Nasopharynx Cauda equine
Neoplasms of the paraganglia are referred to as paragan-
Parapharyngeal space Gallbladder
gliomas. Those arising in adrenal medulla are referred to
as pheochromocytoma or adrenal paraganglioma. The Thyroid Urinary bladder
rest are referred to as extra-adrenal paragangliomas. The
a
cytohistologic features, histochemical properties, ultra- This is not an exclusive list of sites for paragangliomas.
structure, and the immunoprofile of adrenal pheochro-

mocytoma and extraadrenal paragangliomas, whether vicinity of organs of Zuckerkandl. The anatomic distri-
sympathetic or parasympathetic, are similar. However, bution of sympathetic paragangliomas is intra-abdominal
pheochromocytomas occurring in adrenal medulla have (85%), urinary bladder (10%), intrathoracic (12%), and
different clinical presentations than a wide variety of para- cervical (3%).
gangliomas at extraadrenal sites. Pheochromocytomas are The superior paraaortic paragangliomas (45%)
frequently associated with multiple endocrine neoplasia include those located adjacent to the adrenal glands, in
syndromes. They are described separately in Chapter 14. and around the hilum of the kidney and the renal pedicle.
Inferior paraaortic (30%) paragangliomas arise below
the inferior pole of the kidneys and extend down to the
iliac vessels. Paragangliomas in latter location arise from
EXTRA-ADRENAL PARAGANGLIOMA the remnants of organs of Zuckerkandl.
Intra-abdominal paragangliomas occur at any age, but
Extra-adrenal paragangliomas occur at any site in the most occur in third to fifth decades of life. Signs and symp-
body. The locations described in Table 15.1 cover a long toms may be due to excess catecholamine secretions. The
topographic list but by no means an exclusive one. They symptoms may also be related to the anatomic location.
can also be seen in locations where paraganglia are not Approximately 25% to 27% of the paragangliomas associ-
usually identified. ated with sympathetic nerves are functional. Nonfunctional
tumors may present with symptoms resulting from the
effects of a mass lesion or as incidental findings. Extra-
adrenal sympathetic paragangliomas are more likely to be
EXTRA-ADRENAL SYMPATHETIC malignant as compared to their intra-adrenal counterparts
PARAGANGLIOMA (pheochromocytoma), with a likelihood of multicentricity
and potential for metastasis. Approximately 30% to 40%
Extra-adrenal paragangliomas associated with the sym- of retroperitoneal paragangliomas are reported to metas-
pathetic nervous system can occur anywhere from the tasize. Despite their general similarities, extra-adrenal
upper neck to the pelvic floor. More than 90% occur in paragangliomas in different locations vary somewhat in
the retroperitoneum, and 30% to 50% of these are in the terms of age distribution and gender predilection.

Urinary bladder paragangliomas have been reported in are carotid body paragangliomas, jugulotympanic para-
patients between 11 and 78 years of age with no gender gangliomas, intraabdominal (retroperitoneal) paragan-
preference. The majority of the patients exhibit a clini- gliomas, and spinal paragangliomas involving the cauda
cal triad consisting of paroxysmal hypertension, gross equina. Table 15.2 lists their clinicopathologic features.
intermittent hematuria, and micturitional attacks of Those involving rare sites will not be further discussed
headache, pallor, sweating, anxiety, and other catechol- as they share the same histologic features as the rest of
amine-related symptoms. Urinary bladder paraganglio- paragangliomas. Cytologic documentation of the para-
mas may be nonfunctional and present as incidental gangliomas at the rare sites is very sparse and reported as
findings. Visceral paragangliomas also include those asso- anecdotal cases. Readers are requested to refer to the lit-
ciated with the gallbladder. erature for more information on the extremely rare cases.
Intrathoracic paravertebral paragangliomas are usu-
ally located in the midthoracic region and may present
with catecholamine-related symptoms. GROSS AND MICROSCOPIC FEATURES
Spinal paragangliomas are more frequently found in
the region of the cauda equina and filum terminale. Less The paragangliomas are usually solitary but may be mul-
common sites include cervical and thoracic regions. They tiple. The gross appearance (Fig. 15.2A) is similar to that
present as extradural or intradural mass without infiltra- of pheochromocytomas. They are well-defined tumors
tion of the spinal cord, soft tissues, or bone. They may ranging from 2 to 10 cm and can attain a large size.
also invade the cranial cavity as local extension from the Paragangliomas are vascular tumors and may show hem-
skull base. orrhage, degeneration, and cystic changes.
Paragangliomas of the cauda equina are very uncommon Histologically, paragangliomas present features iden-
and are usually located in the filum terminale. The tumors tical to that of pheochromocytomas (Fig. 15.2BG).
are mostly intradural, occur slightly more frequently in The characteristic alveolar or nesting pattern, popularly
males, and may be associated with low back pain, neu- referred to as Zellballen, consists of rounded masses of
rologic deficiencies, and incontinence. Paragangliomas of neoplastic cells that can be delineated by reticulin stain.
the cauda equina region are generally egg shaped or sau- The other frequent pattern is a trabecular one with slen-
sage shaped, encapsulated, dark-red tumors, attached to der to broad anastomosing trabeculae. The third pattern
the filum terminale or a nerve root. The size varies from is solid or diffuse growth pattern. Sinusoidal vessels are
2to 4 cm and can be easily shelled out. often noted separating the tumor cells. A given paragan-
glioma may be monomorphic or present combination of
patterns. The paraganglioma cells vary in size and shape.
They can be large polygonal or small round to cuboidal
EXTRA-ADRENAL PARASYMPATHETIC and plasmacytoid. Spindle, racket-shaped, and strap cells
PARAGANGLIOMAS are seen in pleomorphic paragangliomas. The cell bor-
ders are well to poorly defined. Their cytoplasm is vari-
Jugular and tympanic paraganglia are the most com- able, and cytoplasmic processes are frequently noted. The
mon sites of origin of parasympathetic paragangliomas nuclei are round, oval to oblong with typical saltpepper
in most published series (57% to 81% of tumors), fol- chromatin. Intranuclear inclusions are often seen. Large,
lowed by carotid body (8% to 36%), vagal (4% to 13%), pyknotic, deep-staining nuclei with and without mul-
and aortic (4% to 10%). In contrast to adrenal and tilobulation are occasionally encountered. Mitoses are
extra-adrenal sympathetic paragangliomas, which cause unusual. Areas of degeneration, hemorrhage, and necrosis
catecholamine-related symptoms in majority of the cases, may be present. Excessive, sclerotic stroma is sometimes
only about 1% of parasympathetic paragangliomas are seen in paragangliomas, especially the jugulotympanic
clinically functional. paragangliomas, resulting in lack of typical nesting or
Irrespective of the site, origin, or location, cytohis- alveolar pattern (see Figs.15.7G and 15.8E).
tologic features of all paragangliomas are the same.
However, their incidence, variations in clinical presenta-
tion, radiologic findings, and differential diagnosis may CYTOPATHOLOGIC FEATURES
differ, which are site specific. Although paragangliomas
as a whole are relatively uncommon tumors, some are The specimens for cytologic diagnosis are predominantly
more frequently encountered than the others are. These fine needle aspiration (FNA) biopsies. In cases originating

TABLE 15.2. CLINICOPATHOLOGIC FEATURES OF EXTRA-ADRENAL PARAGANGLIOMAS
Retroperitoneal Cauda Equina/Filum

Carotid Body Tumor Jugulotympanic Intra-abdominal Terminale
Synonyms Chemodectoma, Glomus tumor, glomus Extra-adrenal
nonchromaffin jugulare, glomus paraganglioma
paraganglioma tympanicum
Location Neck, at the bifurcation Middle ear, external Along the sympathetic Intradural, or
of the carotid artery; meatus 85%, trunk; commonly in extradural; attached
localized deep to the parapharyngeal retroperitoneum; can to filum terminale or a
anterior border of space, base of the skull; arise from organs of nerve root
sternocleidomastoid intracranial extension Zuckerkandl visceral
muscle, just below the possible involving urinary
angle of mandible; bladder, gall bladder
may be attached to
the arteries or even
encasethem
Incidence 85% of head and neck Most common tumor of 90% associated with Very uncommon
paragangliomas the middle ear sympathetic nervous
system
Average age Wide age range but Fifth decade Third to fifth decade Third to fifth decade
common in fifth decade
Gender None; but common Common in females; None Slight increase in males
predilection in females at higher M:F, 1:5
altitude
Radiologic Homogeneous Soft tissue mass; bone Mass on CT scan Mass on CT scan,
findings hypervascular, well- erosion MRI, blockage on
delineated mass lesion myelogram
at the carotid artery
bifurcation by carotid
arteriogram
Association May be associated May be associated None None

with other with jugulotympanic with carotid body
paragangliomas paragangliomas, a paraganglioma; can
and syndromes part of Carney triad be part of familial
(GIST, pulmonary multifocal head and neck
chondroma, and paragangliomas as an
carotid body tumor); autosomal dominant trait
may be associated with
pheochromocytoma, or
MEN syndrome
Presenting Painless, slowly Tinnitus; aural pulsations; Back pain; palpable Lower back pain,
symptoms enlarging neck mass, conduction-type hearing mass; symptoms radicular pain or
located below the angle loss; ear fullness; pain; due to secretion of sciatica is common;
of the mandible; deep otorrhea; vertigo; dizziness; norepinephrine sensorymotor deficits
to the anterior border facial palsy; bulging of include paraplegia and
of sternocleidomastoid tympanic membrane; sphincter disturbances
muscle; vertically tumor may fill the middle-
fixed but movable ear cavity and extend into
horizontally; may be external auditory canal or
pulsatile extend into cranial cavity
(continued)

TABLE 15.2. CLINICOPATHOLOGIC FEATURES OF EXTRA-ADRENAL PARAGANGLIOMAS (Continued)
Retroperitoneal Cauda Equina/Filum

Carotid Body Tumor Jugulotympanic Intra-abdominal Terminale
Gross Encapsulated, well Polypoid, red fragile 320 cm; well-defined Generally egg shaped
pathology circumscribed; ovoid, mass; bleed profusely mass, solid cut surface; or sausage shaped;
rubbery to firm; red- to touch hemorrhage and cystic encapsulated; dark
pink to tan-gray change frequent; usually red, attached to filum
solitary terminale or a nerve root;
size 24 cm
Histology Typical alveolar Typical nesting pattern; Typical alveolar Typical alveolar or
or nesting pattern may show marked or nesting pattern nesting pattern or
(Zellballen); can be stromal fibrosis, lacking (Zellballen); can be solid growth pattern;
trabecular, or solid the typical pattern trabecular, or solid ganglionic differentiation
with diffuse growth with diffuse growth frequent; may express
pattern; monomorphic pattern; monomorphic cytokeratin
to pleomorphic; scant to pleomorphic; scant
stroma stroma; prominent
vascularity; no attached
remnants of adrenal
tissue
Differential Medullary thyroid Hemangiopericytoma Adrenocortical Hemangiopericytoma

diagnoses carcinoma Pituitary adenoma carcinoma Ependymoma
Malignant melanoma Meningioma, small cell Renal cell carcinoma Chondrosarcoma
Alveolar soft-part type Hepatocellular Malignant lymphoma
sarcoma Malignant lymphoma carcinoma Plasmacytoma
Malignant lymphoma Plasmacytoma Metastatic poorly Meningioma
Metastatic carcinoma Olfactory differentiated
neuroblastoma carcinoma
Middle ear adenoma Malignant melanoma
Malignant lymphoma
Soft tissue tumors
in central nervous system, the specimens are small for- caudate, racket, and spindle shaped. Their cell borders
ceps biopsies for intraoperative consultation and are are well to poorly defined, and their cytoplasm is vari-
processed by crush preparations. Exfoliative cytology able in amount, appearing pale to dense. Sometimes, the
is used on extreme occasions. With lung involvement, cytoplasm is vacuolated, and prone to disintegrate, result-
bronchoscopically obtained specimens may be processed ing in naked nuclei (Fig. 15.9B). The cytoplasm is often
(see Fig. 14.14). drawn into delicate cytoplasmic processes intertwining
The cytopathologic features of paragangliomas with neighboring cells. Red granules are noted in the cyto-
(Table 15.3; Figs. 15.3 to 15.16) are similar to that of plasm with Romanowsky stain. Their nuclei are eccentric,
pheochromocytomas (see Figs. 14.3 to 14.13). The cellu- round, oval, elliptical to elongated, spindle shaped, with
larity of the aspirated specimens is variable, from poor to coarsely granular chromatin (saltpepper), and with or
overwhelmingly cellular. The presentation can be mono- without nucleoli. Intranuclear inclusions are often seen.
morphic to pleomorphic. The latter is more frequent. In Mitoses are rare.
Papanicolaou-stained material, the neoplastic cells are
predominantly discrete, loosely cohesive, and occasion-
ally in tissue fragments. They are small, medium to large HISTOCHEMISTRY
with occasional giant forms. In fact, the presence of an
occasional giant cell in the background is quite common Paragangliomas associated with sympathetic nervous sys-
(Figs. 15.3C,D; 15.8B,C; 15.9B; 15.14D). The pleomor- tem are argentaffin positive while those associated with
phic cells can be round, oval to plasmacytoid, polygonal, parasympathetic nerves are argyrophilic.

Gross and Histologic Patterns of Paragangliomas
A B
C D
E F
Fig. 15.2: A: Gross photograph of a carotid body paraganglioma. Note the fleshy surface and areas of hemorrhage and
cystic changes. B: Typical alveolar or nesting pattern, also known as Zellballen, consisting of large round to polygonal cells
arranged in alveoli or nests, separated by a delicate stromal network that can be highlighted with reticulin stain. Note the cells
are large with uniform nuclei and moderate amount of cytoplasm (H&E). C: Trabecular pattern formed by elongated cells,
aligned perpendicular to the sinusoids. The nuclei are uniform and the cytoplasm is moderate in amount (H&E). D: Diffuse
pattern formed by round to cuboidal cells with scant cytoplasm and uniform nuclei (H&E). E: Pleomorphic cell pattern. Note
the cells with giant forms (arrows) (H&E). F: The Zellballen pattern is formed by spindle-shaped neoplastic cells (H&E).

Fig. 15.2: (continued) G: This paraganglioma of the middle ear

shows a dispersed pattern formed by small cuboidal cells, separated
G by an appreciable stroma (H&E).
IMMUNOPROFILE ULTRASTRUCTURE
The paraganglioma cells react to all neuroendocrine Ultrastructurally, the paraganglioma cells demonstrate
markers: chromogranin, synaptophysin, neuron-specific neurosecretory granules.
enolase, and CD56. They do not react to cytokeratin. The
sustentacular cells react positively to S100 protein.
TABLE 15.3. CYTOPATHOLOGIC FEATURES OF EXTRA-ADRENAL PARAGANGLIOMASa
Cellularity Variable; scant to cellular
Presentation Cells discrete with a dispersed pattern and/or in loosely cohesive groups and in syncytial tissue fragments
as nests, trabeculae, occasionally rosettes; naked nuclei +/
Cells Size and shapes variable; monomorphic to extremely pleomorphic; small to giant forms; round, oval,
plasmacytoid, polygonal to spindle shapes, strap cells; cell borders poorly defined; N/C ratios variable
Nucleus Variable in size; central to eccentric; bi- to multinucleation; round to oblong; smooth nuclear membranes;
occasionally convoluted; granular chromatin; nucleoli prominent in aggressive tumors; intranuclear
inclusions +/; mitoses +/; large bare nuclei +/
Cytoplasm Variable, scant indiscernible to abundant; pale, dense to granular to vacuolated; cytoplasmic processes,
generally unipolar, may intertwine with neighboring cells; melanin pigment +/, lipid +/
Background Bare nuclei frequent; bloody; necrosis
Chromaffin reaction + with paragangliomas associated with sympathetic nervous system; negative with those associated with
parasympathetic nervous system
Immunoprofile Positive reactivity to neuroendocrine markers; S100 positivity for sustentacular cells; TTF-1 negative;
cytokeratin negative

a
Note: The cytomorphology of extra-adrenal paragangliomas is identical to that of adrenal paraganglioma or pheochromocytoma.

Spectrum of Cytopathologic Features of Paragangliomas (Figs. 15.3 to 15.16)
A B
C D
Figs. 15.3: AD: FNA of a carotid body paraganglioma. The aspirate is very cellular, consisting of a large population
of small- to medium-sized round to cuboidal cells with poorly defined cell borders. The nuclei are uniform with bland
chromatin pattern. Also, note frequent giant forms (arrows).
A B
Fig. 15.4: FNA of a carotid body paraganglioma. A, B: This cellular aspirate shows very pleomorphic cells ranging from
small round to spindle cells with cytoplasmic processes. The nuclei are round, with coarsely granular to compact chro-
matin. Note the eccentric location of the nuclei. Their cytoplasm is variable and the cell borders are poorly defined. This
pattern can be mistaken for medullary thyroid carcinoma.

Fig. 15.4: (continued) C, D: FNA of a different case of carotid body

paraganglioma. C: The neoplastic cells are small, arranged in a syn-
cytial tissue fragment with no architectural pattern. The cytoplasm
is scant with high N/C ratios. D: This field shows loosely cohesive
spindle cells with delicate cytoplasmic processes. The differential di-
agnoses should include medullary thyroid carcinoma, paraganglio-
ma, and possibly a soft tissue tumor. Immunostains are necessary for
correct diagnosis.
A B
E
Fig. 15.5: FNA of carotid body paraganglioma. AD: The cellularity is poor consisting of rare groups of small, round
lymphocyte-like cells. The aspirate was interpreted as nondiagnostic. E: Surgical excision confirmed paraganglioma
(H&E).

A B
C D
Fig. 15.6: AC: Jugulotympanic paraganglioma. Intraoperative consultation. Crush preparation of a soft tissue mass
involving the left middle ear and infratemporal fossa mass. The cellular component represented by small- to medium-
sized round to cuboidal cells, in tissue fragments, loosely cohesive groups. The cell borders are poorly defined with
scant cytoplasm. The nuclei are very uniform (H&E). D: The surgical excision confirmed a paraganglioma, composed
of small, round cells forming a trabecular pattern (H&E).
Fig. 15.7: FNA of a mass in the parapharyngeal space. AE: The

aspirate is poorly cellular and partially air dried and consists of rare
groups of small lymphoid-like cells and was interpreted as nondiag-
nostic. Surgical exploration revealed a soft tissue mass at the base of
the skull, confirmed as paraganglioma.

Fig. 15.7: (continued) F: Low power of the tumor. Note extensive

stromal tissue separating small nests of neoplastic cells. G: Higher
magnification to highlight the dense stroma and lack of typical nest-
ing pattern of the paragangliomas. Note streaks of small round cells
G within the stroma.
A B
Fig. 15.8: Paraganglioma of the thyroid. FNA of an incidentally detected thyroid nodule. A: This image shows cells
with poorly defined cell borders containing spindle-shaped nuclei attempting to form a fascicle. The nuclei are variable
in size. Note the bloody background.B: This field demonstrates very pleomorphic cells with frequent giant nuclei. The
cell borders are poorly defined.

C D
Fig. 15.8: (continued) C: A pleomorphic cell pattern with predomi-

nant round cells. Note the large triangular cell. The cytologic fea-
tures suggest the possibility of a medullary carcinoma. D: Histologic
section of the excised tumor showing the typical alveolar or nest-
ing (Zellballen) pattern (H&E). E: Different field showing marked
sclerosis of the stroma. Immunostains on this histologic material
confirmed the diagnosis of paraganglioma (H&E). (Courtesy of Dr.
E Ajay Shah, Fine Needle Aspiration Clinic, Toledo, Ohio.)
A B
Fig. 15.9: FNA of a retroperitoneal paraganglioma. A, B: Note the pleomorphic cell pattern composed of loosely cohesive
and discrete neoplastic cells. These cells are round, cuboidal to spindle shaped with wispy cytoplasmic processes. The nuclei
are variable in size, round, elliptical, egg shaped, and eccentric. Also, note multinucleation and intranuclear inclusion (arrow).

A B
Fig. 15.10: FNA of a retroperitoneal paraganglioma. A, B: This

cellular aspirate consists predominantly of small- to medium-sized
round cells with an admixture of some plasmacytoid and large cells.
C: Histologic section of the surgically excised paraganglioma de-
C picting a typical alveolar pattern (H&E).
A B
Fig. 15.11: A, B: FNA of a retroperitoneal paraganglioma. The aspirate is cellular showing a pleomorphic cell popula-
tion, highly suggestive of paraganglioma. Surgical excision confirmed paraganglioma (H&E). CF: FNA of a different
case of retroperitoneal paraganglioma.

Fig. 15.11: (continued) C, D: These tissue fragments consist of large

polygonal cells with abundant cytoplasm. The nuclei are large with
dense chromatin. E: The neoplastic cells are better visualized. They
are mildly pleomorphic, round to polygonal with nuclei containing
dense chromatin. F: A core biopsy of the retroperitoneal mass con-
F firmed paraganglioma (H&E).
A B
Fig. 15.12: FNA of a retroperitoneal (peripancreatic) paraganglioma. The aspiration biopsy performed via endoscop-
ic ultrasound for clinically and radiologically suspected pancreatic carcinoma. A: The medium-sized neoplastic cells
are discrete, loosely cohesive, and in syncytial tissue fragments. Some cells have appreciable eosinophilic cytoplasm.
Their nuclei have typical saltpepper chromatin. B: This field shows monomorphic small round cells with saltpepper
chromatin, suggesting the diagnosis of a pancreatic neuroendocrine neoplasm.

C D
E F
G H
Fig. 15.12: (continued) C, D: These two fields contain cells with appreciable, wispy cytoplasm, a feature more com-
monly seen with paragangliomas. E: Another field contains large polygonal cells with abundant granular cytoplasm. F:
Surgical excision confirmed the diagnosis of paraganglioma. G: Positive reactivity to chromogranin. H: Focal positivity
noted with S100 protein confirming the presence of sustentacular cells.

A B
C D
E F
Fig. 15.13: FNA of a retroperitoneal mass. A: Pleomorphic cells varying in size and shapes, occurring in loosely cohe-
sive groups. Note large nuclei and spindle-cell pattern with cytoplasmic processes (H&E). B: The neoplastic cells are in
tissue fragments. They are large, polygonal with abundant eosinophilic cytoplasm and contain uniform nuclei (H&E).
C: The same aspirate showing smaller cells, bland nuclei (Papanicolaou). Their cytoplasm is not visible. D: Pleomorphic
cells with plasmacytoid and triangular forms (Papanicolaou). E: Histological section of the excised paraganglioma,
low power (H&E). F: Higher magnification, of (E) (H&E). (Courtesy of Dr. Mithra Baliga, University of Mississippi,
Jackson, Mississippi.)

A B
C D
Fig. 15.14: Paraganglioma at cauda equina. Intraoperative consulta-

tion. Crush preparation of a biopsy of a mass at cauda equina. AC: The
cell population is represented by discrete and loosely cohesive small-
to medium-sized plasmacytoid cells with eccentric nuclei containing
coarsely granular chromatin. Nucleoli are not seen. Their cytoplasm
is variable, with some having processes (H&E). D: Crush prepara-
tion stained by Papanicolaou. Note the typical pleomorphic pattern.
E E: Histologic confirmation of paraganglioma (H&E).

A B
C D
Fig. 15.15: Intraoperative consultation. Crush preparation of a soft tissue mass biopsy involving the cauda equina.
A: Low-power view showing a dispersed population of plasmacytoid cells (H&E). B: Higher magnification showing
uniform nuclei, deep eosinophilic cytoplasm, occasionally drawn into rudimentary processes (H&E). C, D: Histological
examination confirmed a paraganglioma (H&E).
Fig. 15.16: AD: Intraoperative consultation. Crush preparation of

a paraspinal mass biopsy with a lytic vertebral lesion showing a
pleomorphic cell population. Note small round to cuboidal cells,
plasmacytoid cells, triangular forms, and polygonal cells. Their cell
borders are well to poorly defined with variable cytoplasm. Also,
A note the cytoplasmic processes (H&E).

B C
Fig. 15.16: (continued) D: Histologic section of the paraspinal mass

showing features of paraganglioma. Explanatory note: At the time
of surgery, no past history was available. A history of pheochromo-
cytoma that was excised several years earlier was subsequently made
known. This patient had multiple pulmonary metastases, which
D were identified in bronchial washings (see Chapter 14; Figs. 14.14).
with malignancy. The tumor may show extensive local

MALIGNANCY IN PARAGANGLIOMAS
spread or metastasize to the distant organs.
Malignancies in paragangliomas cannot be determined
simply based on histocytopathologic features alone. It
is diagnosed only with wide invasion and in the pres- ASSOCIATION WITH MULTIPLE
ence of metastases. The reported incidence is varied. ENDOCRINE TUMORS
Retroperitoneal paragangliomas have a higher inci-
dence of malignancy. Several features are associated Unlike pheochromocytomas, paragangliomas are less
with malignancy; however, there is no single criterion. likely to be associated with multiple endocrine tumors.
Large size, coarsely nodular or multinodular, conflu- They are associated with familial pheochrocytoma and
ent necrosis, mitoses, extensive local invasion, large paraganglioma syndromes (see Chapter 1; Table 1.1).
Zellballen with central degeneration, small cells with Their association has also been described in Carney triad,
high nucleus:cytoplasm (N/C) ratios, monotony of cyto- which consists of gastrointestinal stromal tumors (GISTs),
logic pattern, and spindle-cell pattern are all associated pulmonary chondromas, and paragangliomas. The latter

are usually located in the head and neck and tend to be melanomas, they share morphology with a wide range of
multiple and more common in women. neoplasms. Awareness of the possibility of paraganglioma
is a key factor that might aid in accurate interpretation.
DIAGNOSTIC ACCURACY
Paragangliomas although uncommon are ubiquitous and DIFFERENTIAL DIAGNOSES OF EXTRA-

can occur at any site in the body. Their cytologic findings ADRENAL PARAGANGLIOMAS
are sparsely documented in the literature and are mostly in
the form of case reports. Unlike surgical pathology, their The differential diagnostic entities for extra-adrenal
reviews are limited to only fewer cases. Lack of detailed paragangliomas are innumerable. They are not only site
information on cytopathologic features, relatively infre- specific but also depend on cytologic presentation, cell
quent use of fine needle biopsy procedures by the clinicians, shapes, size, and whether monomorphic or pleomor-
inexperience, and lack of familiarity on the part of patholo- phic. Paragangliomas present overlapping patterns, not
gist/cytopathologist are the factors responsible for poor rec- only with other neuroendocrine neoplasms but also with
ognition leading to diagnostic difficulties. Over 50% of the a wide variety of epithelial and mesenchymal tumors.
reported cases of paragangliomas have been cytologically Table 15.4 lists differential diagnostic possibilities based
misinterpreted. The reported diagnostic accuracy is disap- on their location and the cell morphology.
pointingly low. Paragangliomas do make their appearance The discussion on differentiating features of paragangli-
when least expected, and especially when paraganglioma is omas from other diagnostic entities is limited to sites more
not considered in the differential diagnosis. Like malignant frequently encountered and listed in Tables 15.5 to 15.8.
TABLE 15.4. DIFFERENTIAL DIAGNOSES OF PARAGANGLIOMAS
Large Polygonal Cell Pleomorphic Cell

Round-Cell Pattern Pattern Pattern Spindle Cell Pattern
Retroperitoneum Pancreatic neuroendocrine Adrenal cortical Soft tissue tumors Soft tissue tumors
tumor carcinoma Metastatic adeno/ Malignant melanoma
Pancreatic adenocarcinoma Hepatocellular squamous
Pancreatic solid cystic carcinoma carcinoma
papillary tumor Renal cell carcinoma Malignant melanoma
Malignant lymphoma Malignant melanoma Dendritic cell sarcoma
PNET Poorly differentiated
Neuroblastoma carcinoma (metastatic)
Neck Medullary thyroid carcinoma Medullary thyroid Medullary thyroid Medullary thyroid
Follicular neoplasms of carcinoma carcinoma carcinoma
thyroid Malignant melanoma Malignant melanoma Malignant melanoma
Small cell carcinoma Alveolar soft-part Soft tissue tumors Soft tissue tumors
Malignant lymphoma sarcoma Metastatic carcinomas
Malignant melanoma Metastatic carcinomas
Middle ear, Pituitary adenoma Malignant melanoma

parapharyngeal Hemangiopericytoma
space, base of the Meningioma
skull Malignant lymphoma
Plasmacytic malignancy
Olfactory neuroblastoma
Sinonwasal undifferentiated
carcinoma
Cauda equina Ependymoma Schwannoma

Chondrosarcoma
Meningioma
Hemangiopericytoma

TABLE 15.5. DIFFERENTIAL DIAGNOSES OF RETROPERITONEAL PARAGANGLIOMA: DIFFERENTIATING

FEATURES
Diagnostic
Entity Cytopathologic Features Ancillary Tests See Figure(s)
Paraganglioma Monomorphic to pleomorphic cell pattern; cells discrete, Neuroendocrine markers Figures 15.9
in loosely cohesive groups or in syncytial tissue fragments +; S100 +; thyroglobulin to 15.13
without any architectural pattern; neoplastic cells variable ; calcitonin
in size from small to large with occasional giant forms;
round, plasmacytoid, polygonal to spindle shaped; uniform,
round, eccentric nuclei; granular chromatin with saltpepper
appearance; sometimes compact; intranuclear inclusions
+/; cytoplasm variable; may be drawn into delicate process;
eosinophilic cytoplasmic granules with Romanowsky stain;
mitoses ; necrosis
Adrenal cortical Cellular aspirate; cells isolated, in loosely cohesive groups or Vimentin +; epithelial Figure 15.17AD
carcinoma in syncytial tissue fragments with no architectural patterns; and neuroendocrine
cells uniform to markedly pleomorphic; round, cuboidal, markers ; calretinin +;
plasmacytoid, to polygonal; medium sized to large, with inhibin +
or without giant forms; nuclei variable in size; round, oval
to elongated; N/C ratios variable; multinucleation and
multilobulation +/; coarsely granular to chunky chromatin;
nucleoli prominent; intranuclear inclusions +/; cytoplasm
variable; clear, pale, dense to vacuolated; glycogen absent
Renal cell Aspirates usually cellular; cells predominantly in aggregates Vimentin +; epithelial Figure 15.18AC
carcinoma or in syncytial tissue fragments; dispersed cell pattern more and neuroendocrine
frequent with chromophobe type; common; tissue fragments markers ; CD10 +;
in monolayered configuration or papillary pattern; neoplastic RCC Ma +; Lewis blood
cells medium to large; round to polygonal; well- to poorly group antigen +
defined cell borders; abundant, pale, granular, or dens
cytoplasm; nuclei uniform in low-grade neoplasms but
pleomorphic in high grade; nuclei round, finely granular
chromatin, parachromatin clearing; micro/macronucleoli;
bloody; necrosis+/
Malignant Variable cellularity; cells dispersed, in aggregates; spindle- S100 protein +; Figure 14.18A,B
melanoma shaped cells of various sizes; cytoplasmic processes; unipolar Melan-A +; HMB 45 +;
and bipolar; well-defined cell borders; nuclei eccentric to neuroendocrine markers
central; smooth to irregular cell borders; fine to coarsely
granular chromatin; parachromatin clearing; prominent
micro/macronucleoli; intranuclear cytoplasmic inclusions;
cytoplasm variable; melanin pigment +/; background;
necrosis +/
Hepatocellular Cellular aspirates; neoplastic cells, isolated, in loosely Hep Par 1 +; alpha Figure 14.17AC
carcinoma cohesive groups and in syncytial tissue fragments with a fetoprotein +/;
trabecular pattern with branching; tissue fragments with polyclonal CEA +;
endothelial envelope; capillaries traversing through the neuroendocrine markers
tissue fragments; neoplastic cells variable in size, usually
large, round to polygonal; cell borders usually well defined;
nuclei variable in size; central; bi- to multinucleation +/;
granular chromatin with targetoid macronucleolus frequent;
multiple micronucleoli may be present; intranuclear
inclusions frequent; cytoplasm variable; pale, granular, dense,
vacuolated; presence of bile diagnostic; hyaline inclusions in
the cytoplasm; bare nuclei +/

TABLE 15.5. DIFFERENTIAL DIAGNOSES OF RETROPERITONEAL PARAGANGLIOMA: DIFFERENTIATING

FEATURES (Continued)
Diagnostic
Entity Cytopathologic Features Ancillary Tests See Figure(s)
Anaplastic large Pleomorphic malignant cell population with large Neuroendocrine markers Figure 15.21
cell lymphoma multinucleated cells with wreath-like nuclear arrangement or ; CD2 +; CD3 +; CD43
Reed-Sternberglike malignant cells +; ALK +; CD20 ;
PAX5 ; CD30 +
Metastatic Pleomorphic giant tumor cells; mononucleate or Vimentin ; epithelial Figure 15.23AC
poorly multinucleated; malignant nuclear features; mitoses frequent; markers +; cytokeratin;
differentiated background shows necrosis neuroendocrine markers
carcinoma
Soft tissue Tumors:
Pleomorphic Pleomorphic cell population; mononucleate or multinucleated Vimentin +; epithelial Figure 15.20A,B;
sarcoma (MFH) tumor giant cells with malignant features; mitoses frequent; markers 20B15.20CE
background shows necrosis +/; very cellular; cells isolated Neuroendocrine markers Figure 15.20CE
in aggregates and in tissue fragments; spindle-shaped
cells; bland to pleomorphic nuclei with coarsely granular
chromatin; micro/macronucleoli; mitoses +/; necrosis +/;
backgroundfibrillar
Gastrointestinal Short to elongated spindle cells, round, cuboidal, plasmacytoid CD117/c-kit+; Figure 15.19A,B
stromal tumor to polygonal; variable in size; cell borders well to poorly defined; neuroendocrine markers
dispersed, in aggregates, or in syncytial tissue fragments; small
nests, fascicles, or whorls; traversing capillaries through tissue
fragments +/; round, oval to spindle-shaped nuclei with smooth
to irregular membranes; binucleation +/; eccentric nuclei; fine
to coarsely granular chromatin; micronucleoli; intranuclear
inclusions +/; nuclear grooves +/; nuclear pleomorphism
mild in benign types to marked in malignant ones; mitoses in
malignant variety; delicate long wispy cytoplasmic processes
Dendritic cell Spindle-cell proliferation, admixed with numerous Neuroendocrine markers Figure 15.22
sarcoma lymphocytes; cells large with pleomorphic round to oval ; CD35 +; CD21 +;
nuclei, evenly dispersed chromatin, inconspicuous nucleoli; CD23 +; S100 protein ;
variable eosinophilic cytoplasm CD1a
DIFFERENTIAL DIAGNOSES OF DIFFERENTIAL DIAGNOSES OF

RETROPERITONEAL PARAGANGLIOMAS CAROTIDBODY
PARAGANGLIOMA
Retroperitoneal paragangliomas are more common than
paragangliomas at other locations. Their cytologic pat- The aspirates of carotid body paraganglioma (Figs. 15.2
terns present a wide spectrum, so are the differential to 15.5) present an overlapping pattern with those of
diagnostic possibilities. These include adrenal cortical car- other neuroendocrine tumors in the neck such as medul-
cinoma, renal cell carcinoma, hepatocellular carcinoma, lary carcinoma. They also present diagnostic difficulties
metastatic poorly differentiated carcinomas, malignant in their differentiation from thyroid follicular neoplasms,
melanoma, and malignant lymphomas, large cell type especially hyalinizing trabecular adenoma and soft tis-
(Table 15.5; Figs. 15.17 to 15.24). sue neoplasms (Figs. 15.25 to 15.29). Morphologically

TABLE 15.6. DIFFERENTIAL DIAGNOSES OF CAROTID BODY PARAGANGLIOMA: DIFFERENTIATING

FEATURES

Carotid body Monomorphic to pleomorphic cell pattern; cells discrete, Neuroendocrine Figures 15.2
paraganglioma in loosely cohesive groups or in syncytial tissue fragments markers +; S100 to 15.7
without any architectural pattern; neoplastic cells variable +; thyroglobulin ;
in size from small to large with occasional giant forms; calcitonin
round, plasmacytoid, polygonal to spindle-shaped; uniform,
round, eccentric nuclei; granular chromatin with saltpepper
appearance; sometimes compact; cytoplasm variable; may
be drawn into delicate process; eosinophilic cytoplasmic
granules with Romanowsky stain; mitoses ; necrosis
Medullary thyroid Monomorphic to pleomorphic cell pattern; cells discrete, Thyroglobulin Figure 15.25
carcinoma in loosely cohesive groups or in syncytial tissue fragments ; calcitonin +; AC
without any architectural pattern; neoplastic cells variable neuroendocrine
in size from small to large with occasional giant forms; markers +; S100
round, plasmacytoid, polygonal to spindle shaped;
uniform, round, eccentric nuclei; granular chromatin with
saltpepper appearance; sometimes compact; cytoplasm
variable; may be drawn into delicate process; eosinophilic
cytoplasmic granules with Romanowsky stain; mitoses ;
necrosis ; amyloid +/
Soft-tissue tumors Very cellular; pleomorphic cell population; mono-, bi-, or Vimentin +; Figures 15.19
multinucleated marked variable in size and shape; round, neuroendocrine and 15.20
oval, spindle to polygonal; abundant foamy or vacuolated markers
cytoplasm some with ingested debris
Metastatic Dispersed cells; round to polygonal; variable in size; Epithelial markers Figure 15.29
adenocarcinoma cell borders well to poorly defined; cytoplasm scant to +; neuroendocrine
poorly differentiated abundant, pale to dense; nuclei round with smooth to markers
irregular border; chromatin granular with parachromatin
clearing; nucleoli prominent; mitoses +/
Anaplastic large-cell Pleomorphic malignant cell population with large Neuroendocrine Figure 15.21
lymphoma multinucleated cells with wreath-like nuclear arrangement markers; CD2 +;
or Reed-Sternberglike malignant cells CD3 +; CD43 +; ALK
+; CD20 -; PAX5 ;
CD30 +
Hemangioperi- Very cellular; large tissue fragments, enclosing arcade CD34 +; Figure 15.30
cytoma/solitary spaces; closed packed, short, delicate, spindle-shaped cells; neuroendocrine AC
fibrous tumor round to ovoid nuclei; short cytoplasmic processes; tumor markers
cells attached to the capillaries; mast cells; background clean
Malignant Highly cellular; dispersed cell pattern, markedly S100 protein +; Figures 15.27
melanoma pleomorphic malignant cells with frequent giant forms; Melan-A +; HMB 45 and 15.28
irregular nuclei with coarsely granular, clumped chromatin +; neuroendocrine
with parachromatin clearing; single/multiple prominent markers
nucleoli; intranuclear cytoplasmic inclusions; mitoses +;
necrosis +/; variable cytoplasm
Malignant Very cellular; pleomorphic, round to spindle cells; large Monoclonal cell Figure 15.33A
lymphoma, non- nuclei; high N/C ratio; coarsely granular chromatin; population; leukocyte
Hodgkin type, large micronucleoli common antigen (LCA)
B-cell type +; neuroendocrine
markers ; CD20 +;
PAX5 ; CD3 ; CD5 +

TABLE 15.7. DIFFERENTIAL DIAGNOSES OF JUGULOTYMPANIC PARAGANGLIOMA: DIFFERENTIATING

FEATURES

Paraganglioma Monomorphic to pleomorphic cell pattern; cells Neuroendocrine Figures 15.6 and 15.7
discrete, in loosely cohesive groups or in syncytial markers +; S100
tissue fragments without any architectural pattern; +; thyroglobulin ;
neoplastic cells variable in size from small to large calcitonin
with occasional giant forms; round, plasmacytoid,
polygonal to spindle shaped; uniform, round,
eccentric nuclei; granular chromatin with salt
pepper appearance; sometimes compact; cytoplasm
variable; may be drawn into delicate process;
eosinophilic cytoplasmic granules with Romanowsky
stain; mitoses ; necrosis ; poor cellularity often
due to excessive fibrous stroma
Pituitary adenoma Highly cellular; small round to polygonal; cell Neuroendocrine Figures 10.1 to 10.7
borders well to poorly defined; nuclei round, markers +
uniform with smooth nuclear membrane; coarsely
granular chromatin; nucleoli ; mitoses absent;
cytoplasm variable, scant to abundant; no cell
processes; no necrosis; may form cords, ribbons, or
papillary structures, richly vascularized
Hemangiopericytoma Cellular smears; sheets and fascicles with randomly CD34 +; Figure 15.30AC
oriented, oval to elongated nuclei; poorly defined neuroendocrine
cell borders, indistinct cytoplasm; characteristic markers
network of staghorn blood vessels surrounded by
neoplastic cells
Small-cell Neoplastic cells present isolated, in loosely cohesive Neuroendocrine Figure 13.25
neuroendocrine groups and in syncytial tissue fragments without any markers +; TTF-1 +;
carcinoma architectural patterns; malignant cells often present cytokeratin +;
(poorly differentiated in mucus streaks in sputum; size small, 3 to 3 times neurofilament
neuroendocrine the lymphocytes; high N/C ratios; nucleus round,
carcinoma) oval to fusiform; coarsely granular deep-staining
chromatin; nucleoli inconspicuous to absent; nuclear
molding characteristic; stretch or crush artifacts
of nuclei; karyorrhexis; mitoses +; indiscernible
cytoplasm; necrosis in the background +/
Olfactory Cellular aspirate consisting of small round cells Neuroendocrine Figures 17.1 to 17.3
neuroblastoma with indistinct cytoplasm; cells dispersed, in small markers +; S100
aggregates or syncytial tissue fragments; nuclei protein +; neurofilament
deeply hyperchromatic; nucleoli +/; high N/C + Cytokeratin
ratios; Homer-Wright rosettes +/, neuropile; no
nuclear molding
Meningioma Highly cellular; cohesive, small cells with poorly EMA+; neuroendocrine Figure 15.34
(small-cell type) defined cell borders; whorling pattern helpful, oval markers
nuclei with finely granular chromatin; inconspicuous
micronucleoli; intranuclear inclusions +; mitoses absent
Middle ear adenoma Remarkably uniform cuboidal or cylindrical Neuroendocrine

cells, anastomosing cords, or trabeculae, not very markers ; EMA +;
vascular; may have an neuroendocrine component; cytokeratin +
not vascular

TABLE 15.8. DIFFERENTIAL DIAGNOSES OF PARAGANGLIOMA AT CAUDA EQUINA: DIFFERENTIATING

FEATURES

Paraganglioma Monomorphic to pleomorphic cell pattern; cells Neuroendocrine markers Figures 15.14
discrete, in loosely cohesive groups or in syncytial tissue +; S100 +; thyroglobulin to 15.16
fragments without any architectural pattern; neoplastic ; calcitonin
cells variable in size from small to large with occasional
giant forms; round, plasmacytoid, polygonal to spindle-
shaped; uniform, round, eccentric nuclei; granular
chromatin with saltpepper appearance; sometimes
compact; cytoplasm variable; may be drawn into
delicate process; eosinophilic cytoplasmic granules with
Romanowsky stain; mitoses ; necrosis
Hemangiopericytoma Cellular smears; sheets and fascicles with randomly CD34 +; vimentin +; S100 Figure 15.30
oriented, oval to elongated nuclei; poorly defined cell +; actin +;
borders, indistinct cytoplasm; characteristic network of neuroendocrine markers ;
staghorn blood vessels surrounded by neoplastic cells
Ependymoma Compact cellularity; uniform, small round to oval nuclei S100 +; vimentin +; GFAP Figure 15.32
with single distinct micronucleoli; perivascular nuclear- +; EMA +; neuroendocrine
free zones and true ependymal rosettes markers
Chondrosarcoma Large round cells with clear cytoplasm; small central S100 +; vimentin ; GFAP Figure 15.31
nuclei; low N/C ratio; finely granular chromatin with ; EMA ;
micro/macronucleoli; clean background neuroendocrine markers ;
Malignant lymphoma, Very cellular; pleomorphic, round to spindle cells; large nuclei; LCA +; B/T-cell markers +; Figure 15.33A
non-Hodgkin type high N/C ratio; coarsely granular chromatin; micronucleoli neuroendocrine markers
Plasmacytoma/ Diffuse population of plasma cells with eccentric oval Cytoplasmic Figure 15.33B
multiple myeloma nuclei; different stages of maturity; no matrix or stroma immunoglobulins;
neuroendocrine markers
Differential Diagnoses of Retroperitoneal Paragangliomas (Figs. 15.17 to 15.24)
A B
Fig. 15.17: Extra-adrenal retroperitoneal paraganglioma versus adrenal cortical carcinoma. FNA of an adrenal cortical
carcinoma. AD: The malignant cells are large with frequent giant forms. They are loosely cohesive, round, plasmacy-
toid, and occasionally spindle shaped. The cell borders are well defined. The variable cytoplasm is dense. The nuclear
chromatin is very coarse. The cytomorphology closely resembles that of a pheochromocytoma/paraganglioma.

C D
A B
Fig. 15.18: Extra-adrenal retroperitoneal paraganglioma versus re-

nal cell carcinoma. A: FNA of a renal cell carcinoma, showing anas-
tomosing trabeculae of medium-sized neoplastic cells with uniform
nuclei. B: This renal cell carcinoma is comprised of large polygonal
cells with foamy pale cytoplasm. C: FNA of a chromophobe-type
renal cell carcinoma showing discrete and loosely cohesive large
round to polygonal, varied-sized cells with abundant, dense cyto-
plasm. Note that cytomorphology of all three cases overlap with
C that of paraganglioma.

A B
Fig. 15.19: Extra-adrenal paraganglioma versus soft tissue tumors. FNA of a retroperitoneal mass. A: The neoplastic
cells are loosely cohesive, large polygonal with abundant cytoplasm, and have well-defined cell borders. Their nuclei
are uniform with bland chromatin. B: A different field showing small- to medium-sized cells with uniform nuclei. Their
cytoplasm is variable, with some suggestion of cytoplasmic processes. The immunostain with CD117 (c kit) was posi-
tive, confirming the diagnosis of GIST.
A B
Fig. 15.20: Extra-adrenal paraganglioma versus soft tissue tumors.

A, B: FNA of a retroperitoneal mass consisting of loosely cohesive
neoplastic cells with frequent spindle cells, some with cytoplasmic
processes. The nuclei present malignant features. The cytologic in-
terpretation was malignant fibrous histiocytoma and was confirmed
on surgical excision. Note that paraganglioma may present a very
similar cytologic pattern. C: FNA of a retroperitoneal mass showing
C a hypercellular aspirate (low power).

D E
Fig. 15.20: (continued) D, E: Higher magnification demonstrating pleomorphic malignant cells. Paraganglioma was
considered in the differential diagnosis along with soft tissue tumors. Neuroendocrine markers were negative. The le-
sion was proven to be a soft tissue sarcoma.
Fig. 15.21: Paraganglioma versus anaplastic large-cell malignant

lymphoma. FNA of a retroperitoneal mass consisting of large, round,
dispersed malignant cells with very high N/C ratios and scant, indis-
tinct cytoplasm. Although location wise, paraganglioma is a consid-
eration, blatantly malignant cells, brisk mitotic activity, and stretch
artifacts are features in favor of a malignant lymphoma.
Fig. 15.22: Paraganglioma versus dendritic cell sarcoma. FNA of a

retroperitoneal mass showing very pleomorphic discrete malignant
cells in the background of lymphocytes. These malignant cells were
nonreactive virtually to all epithelial cell markers, neuroendocrine
markers, melanoma markers, or malignant lymphoma. Final diagno-
sis was made on surgically excised tumor.

A B
Fig. 15.23: Paraganglioma versus adenocarcinoma. A, B: Poorly

differentiated metastatic adenocarcinomas in the retroperitoneum,
with a pleomorphic pattern, may be mistyped as paraganglioma.
Both these images represent poorly differentiated adenocarcinoma
of the pancreas. C, D: FNA of an adrenal metastasis of poorly dif-
ferentiated esophageal carcinoma.
Fig. 15.24: Paraganglioma versus pancreatic neuroendocrine tu-

mor. This fine needle aspirate of a pancreatic mass consists of syn-
cytial tissue fragments of small- to medium-sized round to cuboidal
cells, containing nuclei with saltpepper chromatin. Although this
morphologic pattern is consistent with a pancreatic neuroendocrine
tumor, a paraganglioma must be ruled out if the tumor is located in
the retroperitoneum.

they may be indistinguishable. Clinical history of a slow- Immunostains with neuroendocrine markers, thyro-
growing mass, sometimes pulsatile, bruit over the mass, globulin, calcitonin, and S100 protein will identify the
the location suggesting close approximation with carotid lesion accurately. Soft tissue tumors with spindle-cell pat-
arteries, and radiologic findings will suggest the pos- tern, malignant lymphomas, and malignant melanomas
sibility of a carotid body tumor. Other neuroendocrine must also be considered in the differential diagnosis. With
tumors that may resemble carotid body tumors are meta- large polygonal cells, alveolar soft-part sarcoma remains
static small cell carcinomas. a differential diagnostic possibility.
Differential Diagnoses of Paragangliomas in the Neck (Figs. 15.25 to 15.29)
A B
Fig. 15.25: Carotid body paraganglioma versus medullary thyroid

carcinoma. A: This FNA of a medullary thyroid carcinoma depicts
a classic, pleomorphic pattern diagnostic of this tumor. Note the
similarity to carotid body tumor seen in Figure 15.3B. Calcitonin
and S100 protein stains are necessary to differentiate. B: Another
example of medullary thyroid carcinoma with a spindle-cell pattern.
Compare this morphology with cells seen in Figure 15.4B. C: The
FNA of this surgically confirmed medullary thyroid carcinoma is
composed of small round to cuboidal cells, very similar to that of a
C carotid body paraganglioma depicted in Figure 15.10A.

Fig. 15.26: Paraganglioma versus soft tissue tumors. FNA of a soft

tissue mass in the neck. The cellular aspirate consisted of small- to
medium-sized round cells with scant cytoplasm and high N/C ra-
tios. The differential diagnoses included neuroendocrine tumor and
metastatic carcinoma. The past history included a soft tissue sarco-
ma of the gastrointestinal tract which was classified as leiomyoblas-
toma. Subsequently immunostain with CD117/ckit was performed.
A strong positive reaction classified this tumor as gastrointestinal
stromal smear. Note that the uniform round-cell pattern is certainly
compatible with a carotid body paraganglioma.
A B
Fig. 15.27: Paraganglioma versus malignant melanoma. A, B: FNA of a soft tissue mass in the neck. This cellular aspi-
rate revealed neoplastic cells with a dispersed pattern. The cells are pleomorphic in size from small to medium, round
with occasional large form. Their cytoplasm is variable and nondescript. The nuclei contain deep-staining chromatin
without apparent nucleoli. The differential diagnoses included malignant melanoma, malignant lymphoma, and neuro-
endocrine neoplasms. The neuroendocrine markers and LCA were negative while HMB 45 and Melan-A were strongly
positive, confirming the diagnosis of malignant melanoma.
Fig. 15.28: FNA of a cervical lymph node showing metastatic

malignant melanoma. Without a history, this pattern may be mis-
taken for either medullary carcinoma or a paraganglioma.

Fig. 15.29: Paraganglioma versus poorly differentiated metastatic

adenocarcinoma. FNA of soft tissue neck mass with no previous
history of malignancy. The aspirate is very cellular, consisting of
large, round, discrete malignant cells with scant cytoplasm that
presented no functional differentiation. The nuclei contain granular
chromatin and micronucleoli. The differential diagnoses included
malignant melanoma, neuroendocrine tumor, malignant lymphoma,
and metastatic carcinoma. Immunostains for all these entities were
nondiagnostic. Ultrastructural studies revealed glandular differen-
tiation.
including hyalinizing trabecular adenoma, a variant of

DIFFERENTIAL DIAGNOSES OF
follicular adenoma, which presents morphologic similari-
JUGULOTYMPANIC PARAGANGLIOMAS
ties with paragangliomas (Fig. 15.8). In fact, they were
referred to as paraganglioma-like follicular adenoma.
These neoplasms may involve the middle ear, external
(see Chapter 8 on Neuroendocrine Neoplasms of the
auditory meatus, base of the skull, and parapharyngeal
Thyroid.)
space. The differential diagnostic possibilities based
on the location include middle-ear adenoma, pituitary
adenoma, malignant lymphoma, plasmacytoma, heman-
giopericytoma, olfactory neuroblastoma, and small cell
neuroendocrine carcinoma. Jugulotympanic paraganglio-
OF PRIMARY SPINAL
mas often have extensive fibrous stroma and may lack
PARAGANGLIOMAS
the typical nesting pattern. The aspirates may be poorly
cellular resulting in nondiagnostic aspirates.
The primary spinal paragangliomas can be intra- or extra-
dural. They are more commonly seen at cauda equina and
filum terminale. Their diagnostic accuracy is reported to
be very low even in surgical pathology literature. Of 48
DIFFERENTIAL DIAGNOSES OF cases reviewed in a study, 52% were misinterpreted: 20
PARAGANGLIOMAS OF THE THYROID as ependymoma; 2 as hemangioblastoma; 2 as metastatic
carcinoma; 1 as meningioma. The differential diagnostic
Literature lists reports where paragangliomas have been entities are listed in Table 15.8 and illustrated in Figures
misinterpreted as follicular neoplasms of the thyroid, 15.30 to 15.34.

Differential Diagnoses of Paragangliomas at Cauda Equina (Figs. 15.30 to 15.34)
A B
Fig. 15.30: Paraganglioma versus hemangiopericytoma. Intraoper-

ative consultation. Crush preparation of a biopsy of a mass at cauda
equina. A: The smear shows crowded round medium-sized cells with
large very nuclei and scant cytoplasm. This uniform, round, discrete
cell pattern is very similar to paraganglioma (see Figs. 15.14A and
15.16C) (H&E). B: Medium-power view of branching tissue frag-
ments with small round cells springing from the vascular stroma.
C: Higher magnification highlights the morphology and the capil-
laries in the stroma (Papanicolaou). The surgical excision confirmed
C the diagnosis of hemangiopericytoma.
A B
Fig. 15.31: Paraganglioma versus chondrosarcoma. FNA of a large soft tissue mass in sacrococcygeal area. A, B: The
aspirate is very cellular consisting of discrete and loosely cohesive round cells with scant indistinct cytoplasm. Their
nuclei are mildly pleomorphic in size with granular chromatin.

Fig. 15.31: (continued). C: Myxoid stroma and some spindle cells

raised the possibility of a soft tissue sarcoma, proven to be chon-
C drosarcoma.
A B
Fig. 15.32: Paraganglioma versus ependymoma. Ependymomas can occur at filum terminale. A: This crush prepara-
tion of an ependymoma shows no cell processes. The nuclei are round and pleomorphic (H&E). B: The same specimen
stained with Papanicolaou technique. Histological examination revealed ependymoma.
A B
Fig. 15.33: A: Malignant lymphoma with small round-cell pattern at cauda equina may raise the possibility of a
paraganglioma with a round-cell pattern. B: Paraganglioma versus plasmacytoma. Multiple myeloma/plasmacytoma
presents a cytologic pattern that can be mimicked by a paraganglioma with a plasmacytoid pattern (see Fig. 15.15B).

Fig. 15.34: Paraganglioma versus meningioma. Crush preparation

of a dural mass confirmed as meningioma, showing small- to medi-
um-sized cells with well-defined cell borders and variable cytoplasm
with occasional processes. Their nuclei are round and slightly pleo-
morphic in size containing granular chromatin.
SUGGESTED READING
Ashkenzi E, Onseti ST, Kader A, et al. Paraganglioma of the filum Linnolla RI, Keiser HR, Steinberg SM, et al. Histopathology of
terminale: case report and literature review. J Spinal Disord. benign versus malignant sympathoadrenal paragangliomas:
1998;11:540547. clinicopathologic study of 120 cases including unusual
Cozzolino I, Bianco R, Vigliar E, et al. Fine needle aspiration histologic features. Hum Pathol. 1990;21:11681180.
cytology of a cutaneous metastasis from an extra-adrenal Monabati A, Hodjati H, Kumar PV. Cytologic findings in carotid
paraganglioma. Acta Cytologica. 2010;54:885888. body tumors. Acta Cytologica. 2002;46:11011104.
Ellison DA, Parham DM. Tumors of the autonomic nervous Moran CA, Rush CW, Mena H. Primary spinal paraganglioma:
system. Am J Clin Pathol. 2001;115:(suppl 1)S45S55. a clinicopathological and immunohistochemical study of 30
Flemming MV, Oertel YC, Rodriguez ER, et al. Fine needle aspiration cases. Histopathology. 1997;31:167173.
of six carotid body paragangliomas. Diagn Cytopathol. 1993; Naniwadeker MR, Jagdtap SV, Kshirsagar AY, et al. Fine needle
9:510515. aspiration diagnosis of carotid body tumor in a case of
Gong Y, DeFRIAS DVS, Nayar R. Pitfalls in fine needle aspiration multipleparagangliomas presenting with facial palsy. A case
cytology of extraadrenal paraganglioma. A report of 2 cases. report. Acta Cytologica. 2010;54:635639.
Acta Cytologica. 2003;47:10821086. Rana RS, Dey P, Das A. Fine needle aspiration (FNA) cytology of
Gupta RK, Cheung YK, Wakefield L, et al. Fine needle aspiration extra-adrenal paragangliomas. Cytopathology. 1997;8:
cytology of malignant retroperitoneal paraganglioma. Diagn 108113.
Cytopathol. 1998;18:287290. Sonneland PR, Scheithauer BW, LeChago J, et al. Paraganglioma
Ironside JW, Moss TH, Louis DN, et al. Neuronal and mixed of the cauda equina region. Clinicopathologic study of 31 cases
neuronal-glial tumors. In: Diagnostic Pathology of Nervous with special reference to immunocytology and ultrastructure.
System Tumors. New York, Churchill Livingstone; 2002:240242. Cancer. 1986;58:17201735.
Jayaram G, Kaliperumal S, Kumar G. Bilateral carotid body tumor Tischler AS. Pheochromocytoma and extra-adrenal paraganglioma:
diagnosed on cytology. Acta Cytologica. 2005;49:690692. update. Arch Pathol Lab Med. 2008;132:12721284.
Jimenez-Heffernan JA, Vicandi B, Lopez-Ferrer P, et al. Verma K, Jain S, Mandal S. Cytomorphologic spectrum in
Cytologic features of pheochromocytoma and retroperitoneal paraganglioma. Acta Cytologica. 2008;52:549556.
paraganglioma. A morphologic and immunohistochemical Wenig B M. Atlas of Head and Neck. 2nd ed. Philadelphia, PA:
study of 13 cases. Acta Cytologica. 2006;50:372378. W B Saunders; 2008.
Lack E. Tumors of the Adrenal Gland and Extra-Adrenal Zaharopoulos P. Diagnostic challenges in the fine needle aspiration
Paraganglioma. Washington, DC: Armed Forces Institute of diagnosis of carotid body paragangliomas: report of two cases.
Pathology, 1997. Diagn Cytopathol. 2000;23:202207.
Lack EE, Cubilla AL, Woodruff JM, et al. Paraganglioma of the
head and neck region: a clinical study of 69 patients. Cancer.
1977;39:397409.

16 NEUROENDOCRINE NEOPLASMS
INTHE PEDIATRIC AGE GROUP
ANDADOLESCENTS
Neuroendocrine tumors (NETs) in childhood and ado- Neuroblastoma/ganglioneuroblastoma is one of the

lescents are uncommon. According to the Surveillance, common solid tumors of infancy and childhood and the
Epidemiology, and End Results database, every type fourth most common malignancy in this age group, after
of NET that occurs in adults also occurs in childhood, leukemia, brain tumors, and malignant lymphomas. They
although infrequently. In these data, the most common represent 10% to 20% of all malignant pediatric tumors.
NETs in pediatric and adolescents groups represented One-fourth of the cases are congenital. The annual inci-
neoplasms of neural crest origin such as neuroblastomas. dence in the United States is reported to be 9.2 per mil-
NETs in this age group may be associated with certain lion children. The incidence is higher in Japan, reported as
hereditary syndromes (Chapter 1; Table 1.1). Several of 19 per million children as a result of prenatal screening.
these neuroendocrine neoplasms such as thyroid medul-
lary carcinomas, pheochromocytomas, pituitary adeno-
mas, and gastrointestinal and pancreatic NETs have CLINICAL FEATURES
already been described in previous chapters and are not
repeated. This chapter describes frequently encountered Neuroblastomas occur in various paraspinal locations
NETs in childhood and adolescents, which represent and in parenchymal organs, the most frequent sites being
neuroblastic tumors such as neuroblastoma, ganglioneu- adrenal medulla, extra-adrenal retroperitoneal areas,
roblastoma and ganglioneuroma, and Ewing sarcoma/ mediastinum, cervical ganglia, and head and neck region.
peripheral neuroectodermal tumors. Olfactory neuroblas- The majority is diagnosed in children <5 years of age.
toma can occur rarely in the pediatric age group and is There is no gender predilection. The presenting symptoms
discussed in Chapter 17. depend on location of the tumor and presence or absence
The application of diagnostic procedures such as fine of associated syndromes. Children with neuroblastomas
needle aspiration (FNA) biopsy is generally underuti- often appear systemically sick, wasted, and with nonspe-
lized in large Pediatric Centers. Overall, the exposure to cific symptoms, or the symptoms may be related to the
cytopathology of pediatric tumors for most pathologists/ metastatic disease. Patients may have bluered cutaneous
cytopathologists is rather modest. The author has made metastatic lesions, present with Horner syndrome, or
serious efforts to cover the subject in fair detail. have opsoclonusmyoclonus syndrome (rapid alternat-
ing eye movements followed by myoclonic movements of
extremities). Paraneoplastic syndromes such as vasoac-
tive intestinal polypeptide syndrome with chronic watery
NEUROBLASTOMA diarrhea, abdominal distension, and hypertension are not
rare. A palpable abdominal mass is noted in a significant
Neuroblastomas, ganglioneuroblastomas, and ganglio- number of patients.
neuromas arise from primitive cells of neural crest ori- Laboratory studies include high urinary levels of cat-
gin and represent maturational stages of a common echolamines and their metabolites that are characteristic
neoplasm. The first two being malignant are considered findings. Neuroblastomas can metastasize widely, to liver
together, while ganglioneuroma, the differentiated neuro- and bones, including orbit, maxillofacial bones, and para-
blastic neoplasm, is described separately. nasal sinuses.
351

The biologic behavior of neuroblastomas varies from type shows grossly visible nodules of neuroblastic tissue
excellent to fatal outcome. It is dependent on the age separated by schwannomatous stroma containing spin-
at detection, histologic grade, extent of the metastatic dle-shaped Schwann cells. The intermixed type shows dif-
spread, and the stage of the disease. Two-year survival fuse population of neuroblastic cells and ganglionic cells
rates vary from 100% to 18%. in varying stages of maturation.
The ganglion cells are identified by their large size,
round-to-polygonal shape, and abundant granular cyto-
RADIOLOGIC FINDINGS plasm. They may be mononucleated, binucleated, or
multinucleated with coarsely granular chromatin and a
A mass lesion along the sympathetic trunk or in the adre- prominent macronucleolus. Neuroblastomas often show
nal medulla is the most common finding on CT or MRI, fibrillar or bubbly intercellular matrix representing neural
with the adrenal gland being the most common site. The processes, referred to as neuropil.
mass often shows calcifications. Metastatic lesions in
bones are osteolytic and have a predilection for the skull,
femur, and humerus. IMMUNOPROFILE
The neuroblastoma cells react positively to all neuroendo-

GROSS AND MICROSCOPIC FEATURES crine markersneuron-specific enolase, chromogranin,
and synaptophysin. They also react positively to protein
Grossly, neuroblastomas vary in size and consistency. gene product PCP 9.5, CD56, CD57 (Leu 7), and NB-84.
They are often well-circumscribed with a lobulated con- Neuroblastomas do not react to GFAP, myelin basic pro-
tour. They may be reddish purple to grayish homogenous tein, and CD99.
with microcalcifications.
Histomorphology of neuroblastomas presents a wide
spectrum dependent on the maturation of the neuroblas- ULTRASTRUCTURE
tic cells (Fig. 16.1AE). The classic pattern consists of uni-
form, small round cells, with large hyperchromatic nuclei, The neuroblastoma cells present neural differentiation in the
arranged in nests, separated by fibrovascular septae. The form of dendritic processes that contain parallel arrays of
cells may demonstrate rosettes (Homer-Wright type). microtubules and dense core secretory granules (Fig. 16.1F).
Mitoses are not frequent. Ganglioneuroblastomas consist The dense core granules are found in small aggregates in the
of variable proportion of ganglion cells and neuroblastic elongated cell processes as well as in the cell body. The neural
cells (see Fig. 16.1CE). Two types of ganglioneuroblasto- processes form interweaving matted medusa-like aggregates,
mas are describednodular and intermixed. The nodular particularly in the central portions of the rosettes.
A B
Fig. 16.1: Spectrum of Histologic Features of Neuroblastoma. A: Medium-power view showing a solid growth pattern
formed by small undifferentiated cells (H&E). B: This image of a neuroblastoma shows a diffuse population of neuro-
blastoma cells with intervening neuropil (H&E).

Chapter 16: Neuroendocrine Neoplasms inthe Pediatric Age Group and Adolescents 353
C D
E F
Fig. 16.1: (continued) C: Neuroblastoma showing ganglionic differentiation. The darker areas represent undifferenti-
ated neuroblastoma cells (arrowheads). The lighter areas consist of an admixture of undifferentiated neuroblastoma
cells and cells showing ganglionic differentiation (arrows) (H&E). D: Higher magnification highlighting undifferenti-
ated neuroblastoma cells and cells showing ganglionic differentiation (H&E). E: Different field showing neuroblastoma
cells in different stages of development (H&E). F: Ultrastructure demonstrating neurosecretory granules (arrows).
MOLECULAR/CYTOGENETIC FINDINGS undifferentiated cells to the cells with various stages of

maturation toward ganglion cells. The aspirates are usu-
Neuroblastomas show amplification of MYCN and con- ally highly cellular consisting of a large population of
sistent loss of heterozygosity of 1p and 11q. small round cells with poorly defined cell borders and
scant cytoplasm with high N/C ratios (Figs. 16.2 to16.7).
The nuclei are round to oval with deep-staining chro-
CYTOPATHOLOGIC FEATURES matin, often presenting the typical salt-pepper pattern.
Nucleoli are inconspicuous. Nuclear molding may be
The specimens for cytologic diagnosis mostly represent present. The cells form syncytial tissue fragments with
FNA biopsies at either the primary or metastatic sites. or without rosette formations (Homer-Wright type). The
Crush preparations of the tissues submitted for intraop- rosettes consist of central matrix or neuropil surrounded
erative consultation and body cavity fluids have also been by neuroblastoma cells. The latter may possess unipolar
useful in cytologic diagnosis. cytoplasmic process or tailing. The presence of ganglion
The cytologic features of neuroblastomas (Table16.1) cells indicates a maturation process. The background may
depend on the differentiation of the tumor, ranging from contain neurofibrillar matrix or neuropil.

TABLE 16.1. CYTOPATHOLOGIC FEATURES OF NEUROBLASTOMA
Cellularity Generally high
Presentation Mostly isolated and in loosely cohesive groups with or without rosette formations (Homer-Wright type)
Cells Generally uniform small, round (slightly larger than lymphocytes); variation in size may be present; cell
borders indistinct
Nucleus Round to oval; very high N/C ratios; nuclear membrane smooth to slight irregularity; coarsely granular
chromatin, evenly dispersed; nucleoli inconspicuous; molding +/; mitoses infrequent; larger cells with or
without binucleation, prominent nucleoli, and granular cytoplasm suggest ganglionic differentiation
Cytoplasm Very scant, pale; unipolar cytoplasmic tails
Background Fibrillar to granular matrix (neuropil)
Immunoprofile Neuroendocrine markers: synaptophysin, chromogranin, neuron specific enolase +, CD56 and CD57 +; CD99
Ultrastructure Microtubules and neurosecretory granules
Cytogenetics and Loss of heterozygosity of 1p(1p36) and 11q(11q23)

molecular studies MYCN amplification
Differential Small blue round-cell tumors

diagnoses
DIFFERENTIAL DIAGNOSES differentiating primitive cells. Immunostains for CD45 is

helpful in identifying the lymphoid cells.
The differential diagnoses of neuroblastoma include small
round-cell tumors of childhood (Table 16.2; Figs 16.8 to
METASTATIC NEUROBLASTOMA TO
16.16). The presence of rosettes, neuropil, and ganglion
OTHER BODY SITES
cells offers support to the diagnosis of neuroblastoma.
The difficulties arise when these features are not present
Neuroblastomas metastasize widely, the frequent sites
and the cells are totally undifferentiated.
being liver, bones including orbit, maxillofacial bones,
Neuroblastic tumors frequently contain lymphoid
paranasal sinuses, bone marrow (Fig. 16.7), lungs, and
cell aggregates that may result in diagnostic problems in
pleural cavities (Fig. 16.17).
A B
Fig. 16.2: FNA of a Neuroblastoma. A: Low-power view of a cellular aspirate of a mediastinal mass in a youngster
consisting of several tissue fragments of small cells along with dispersed cells in the background. B: Low-power view,
showing a large tissue fragment of closely packed small cells.

C D
Fig. 16.2: (continued) C: Higher magnification exhibiting small undifferentiated cells with poorly defined cell borders,
indistinct cytoplasm, and deeply-stained nuclei. D: Another field showing loosely cohesive undifferentiated cells with
deep-staining nuclei, presenting coarsely granular chromatin.
Fig. 16.3: FNA of a Neuroblastoma. The syncytial tissue fragment

consists of small primitive cells. Note the suggestion of rosettes.
A B
Fig. 16.4: FNA of a Neuroblastoma. A, B: The aspirate shows discohesive small malignant cells in a background of
abundant neuropil (NP).

A B
C D
Fig. 16.5: FNA of a Neuroblastoma Presenting as a Large Liver

Mass. A, B: Loosely cohesive, uniform, small undifferentiated
cells with poorly defined cell borders, high N/C ratios, and granu-
lar chromatin. C: This field shows attempt at rosette formations
(arrow). D: Different field showing undifferentiated cells. An
occasional giant nucleus is present (arrow). E: Cell block prepara-
E tion (H&E).

A B
Fig. 16.6: A, B: FNA of a ganglioneuroblastoma depicting an admixture of neuroblastoma cells with varying stages of
differentiation. Note the large ganglion cells.
A B
Fig. 16.7: Metastatic Neuroblastoma to the Bone Marrow. A:

Medium-power view showing closely packed small undifferenti-
ated cells in a bone marrow aspirate, in a patient with a history
of neuroblastoma (Romanowsky stain). B: The malignant cells are
small with poorly defined cell borders and scant indiscernible cyto-
plasm. Some exhibit nuclear molding. Note the rosette formations
(Romanowsky stain). C: Different examples of metastatic neuro-
C blastoma in bone marrow (Romanowsky stain).

TABLE 16.2. CYTOPATHOLOGIC FEATURES OF EWING SARCOMA/PNET
Ewing Sarcoma PNET

Presentation Dispersed cell population; rare syncytial tissue Dispersed cell population; syncytial tissue fragments;
fragments; rosettes extremely rare; perivascular Homer-Wright rosettes frequent
aggregates; no rosettes
Cells Small, round, monomorphic; poorly defined cell Small to slightly larger; poorly defined cell borders; high
borders; high N/C ratios, no spindle cells N/C ratios; unipolar cytoplasmic tags or processes +/;
spindle forms in 10%20% of the cases
Nucleus Round; smooth, crisp nuclear membranes; Round to oval; smooth to irregular nuclear membranes;
finely granular evenly dispersed chromatin; chromatin fine to coarsely granular, salt-pepper type;
micronucleoli micronucleoli +; mitoses +/; molding +/
Cytoplasm Scant, pale; vacuolated +/glycogen, PAS Scant, cytoplasmic vacuoles +/

positive; diastase sensitive
Background Clean; necrosis +/; no neuropil Clean to necrotic; bloody; neuropil +/; no ganglion cells;
no lymphoglandular bodies in Diff-Quik preparations
Immunoprofile CD99 +; neuroendocrine markers +/ CD99 +; neuroendocrine markers +; pgp 9.5 +
Ultrastructure Scarce organelles; absent dense core granules; Neurosecretory granules; glycogen; neural differentiation
absent neurotubules; neuritic processes absent; seen with dendritic processes and arrays of microtubules
abundant glycogen; poorly developed Golgi
apparatus; few mitochondria
Cytogenetic Reciprocal translocation between the long arms Reciprocal translocation between the long arms of
analysis of chromosomes 11 and 22 [t(11:22)q24:q12] chromosomes 11 and 22 [t(11:22)q24:q12]
Note: Ewing sarcoma and PNETs represent two ends of the morphologic expressions of same biologic entity.
Differential Diagnoses of Small Blue Round-Cell Tumors (Figs. 16.8 to 16.16)
A B
Fig. 16.8: Neuroblastoma. A: FNA showing tissue fragments of small round cells with rosette formation. Note neuro-
pil (NP). B: Another field from the same case depicting small round cells with high N/C ratios and coarsely, granular,
deep-staining chromatin.

Fig. 16.8: (continued) C: The neuroblastoma cells are dispersed and

C mimic malignant lymphoma.
A B
Fig. 16.9: A: Malignant non-Hodgkin B-cell lymphoma in a 16-year-old teenager. FNA of an anterior mediastinal
mass showing a large population of discrete, monomorphic round cells with poorly defined cell borders and uniform,
round, nuclei with granular chromatin and micronucleoli. B: Malignant non-Hodgkin T-cell lymphoblastic lymphoma
in a child.
Fig. 16.10: Ewing sarcoma showing discrete and loosely cohesive

small round cells with round nuclei, containing finely granular chro-
matin, some with micronucleoli. Their cytoplasm is scant to moder-
ate and pale.

A B
Fig. 16.11: PNET. A, B: Syncytial tissue fragments of undifferentiated, uniform, small round cells with poorly defined
cell borders, scant to indistinct cytoplasm, and high N/C ratios, confirmed as PNET.
A
Fig. 16.12: A: FNA of a desmoplastic round-cell tumor, showing a large syncytial tissue fragment of undifferentiated,
small round cells with scant cytoplasm and high N/C ratios (H&E). Surgical excision confirmed desmoplastic round-
cell tumor. B, C: Different case. This adolescent presented with massive ascites and a large bulky mass involving the
peritoneum. The effusion fluid showing syncytial tissue fragments of malignant cells without any architectural pattern.
The cells are small with poorly defined cell borders, scant to modest, pale to vacuolated cytoplasm, and high N/C ratios.
The diagnosis of desmoplastic round-cell tumor was histologically confirmed.
A B
Fig. 16.13: A: FNA of a lung mass with a history of embryonal rhabdomyosarcoma. B, C: FNA of an alveolar rhabdo-
myosarcoma, arising in the soft tissues of the hand, presented with an enlarged epitrochlear lymph node. A: Medium-
power view showing a very cellular aspirate consisting of several syncytial tissue fragments, loosely cohesive cell groups,
and discrete cells. B: Higher magnification showing slightly pleomorphic, round cells with insignificant cytoplasm and
high N/C ratios. The nuclei contain granular chromatin.

C D
Fig. 16.13: (continued) D, E: FNA of an embryonal rhabdomyosar-

coma, showing syncytial tissue fragments of small round cells with
E indiscernible cytoplasm and no differentiating features.
A B
Fig. 16.14: A, B: FNA of a lytic lesion of the shoulder in an 18-year-old man with a history of medulloblastoma. The
aspirate consists of scattered small round cells with scant cytoplasm, high N/C ratios, and insignificant cytoplasm,
consistent with medulloblastoma.

A B
Fig. 16.15: A, B: FNA. Two separate examples of Wilms tumor showing small, round, undifferentiated cells.
A B
Fig. 16.16: FNA Hepatoblastoma. A: FNA of a large hepatic mass in

an infant showing a cellular aspirate consisting of large, anastomos-
ing trabeculae of miniature liver cells (low power). B: Higher magni-
fication showing round cells with no differentiating features. C: This
field demonstrates the neoplastic cells, small but with strong resem-
blance to mature hepatocytes. These miniature hepatocytes support
the diagnosis of hepatoblastoma. Surgical exploration confirmed a
hepatoblastoma. Immunostains such as neuroendocrine markers or
C HepPar-1 will be useful in establishing a correct diagnosis.

Fig. 16.17: AD: Metastatic neuroblastoma cells in pleural fluid

from a 7-year-old child who presented with severe respiratory dis-
tress and was found to have massive pleural effusion. The small
undifferentiated malignant cells were subsequently proven to be
metastatic from neuroblastoma.
GANGLIONEUROMAS and undifferentiated cells resembling germinal or matrix

cells of the embryonic neural tube and arising in the
Ganglioneuromas, the differentiated neuroblastic tumors, central nervous systems (CNSs) of children and young
are of two subtypes. One is completely differentiated tumor adults. The term central PNET (cPNET) has been used
with spindle-cell matrix of Schwann cells interspersed to describe such tumors that arise in the brain or spinal
with aggregates of mature ganglion cells (Fig.16.18). The cord, with the cerebellar medulloblastoma being the most
maturing subtype shows scattered collections of differen- common and the best characterized cPNET. The PNET
tiating neuroblasts or ganglion cells in varying stages of concept has also been applied to non-CNS tumors of the
maturation, in the background of Schwannian stroma. soft tissues, bone, and nerve with morphologic features
Ganglioneuromas, unlike neuroblastomas, occur in chil- of the germinal neuroepithelium. These small round-cell
dren older than 10 years. Their location differs from neu- neoplasms have been referred to as peripheral PNETs.
roblastomas as well. They are more common in posterior In the last decade or two, the common genetic abnor-
mediastinum, followed by retroperitoneum. There is no mality shared by neoplasms such as Ewing sarcoma,
gender predilection. Patients harboring ganglioneuromas PNETs, and Askin tumor has resulted in including all
tend to have normal levels of catecholamines. Radiologic three tumors into one group referred to as Ewing sar-
findings include a large mass with intralesional calcification. coma/PNET family of tumors. These three types of neo-
Grossly, ganglioneuromas are well circumscribed with plasms represent different morphologic expressions of the
fibrous capsule, with gray to yellow cut surface. Histologically, same biologic entity.
the tumor consists of bundles of longitudinally and horizon-
tally oriented Schwann cells, crisscrossing each other in irreg-
ular fashion. Scattered throughout the spindle-cell mass are CLINICAL FEATURES
relatively mature ganglion cells, either dispersed or in small
aggregates. No satellite cells are present. The ganglion cells Ewing sarcoma/PNETs most commonly develop in the
are large with abundant eosinophilic cytoplasm and contain second decade of life and show a slight male preponder-
one or more nuclei. There is mild-to-moderate atypia. ance. They may also be seen in children and older indi-
Cytopathologic features of ganglioneuroma consist of viduals. There is male predominance. These tumors are
ganglion cells, either dispersed or in clusters and tissue least common in non-Caucasians. Ewings sarcoma rep-
fragments of stroma containing spindle-shaped Schwann resents the second most common bone neoplasms in this
cells (Fig. 16.18A,B). age group, and also occurs in the soft tissues. Typical pre-
senting signs and symptoms include a mass and/or pain
at the primary site. Ewing sarcomas or the bone PNETs
most often arise in the long bones of the extremities as
EWING SARCOMA AND PRIMITIVE metaphyseal or diaphyseal lesions. Soft tissue PNETs may
NEUROECTODERMAL TUMORS arise virtually at any site in the body but usually in chest
wall and paravertebral, extradural locations as well as
The term primitive neuroectodermal tumor (PNET) was extremities, retroperitoneum, and sometimes in associa-
first used to describe tumors composed of small, round, tion with large nerves.

A B
C D
Fig. 16.18: A, B: FNA of a Ganglioneuroma. A: Pleomorphic cell population consisting of scattered large ganglion
cells in the background of small discrete cells with scant cytoplasm and dark-stained nuclei. C, D: Histologic section
showing fragments of stroma, containing spindle cells, which stain positively with S100 protein, indicating Schwannian
origin (H&E).
They present as a rapidly growing deep-seated mass. is characterized by a solid growth pattern consisting of
When attached to the nerve, the patients may experience sheets of monotonous small cells with poorly defined cell
sensory and motor deficits. Chest wall lesions may be borders and scant cytoplasm that often contains glycogen.
associated with pleural effusion. Ewing sarcoma/PNET The nuclei are round with smooth nuclear membranes,
is not associated with elevated levels of catecholamines. finely granular chromatin, and micronucleoli. The N/C
These tumors are highly aggressive and progress rapidly ratios are high. Sometimes there are light and dark areas,
with metastases to the lungs, bones, and bone marrow. the latter formed by hyperchromatic compact nuclei.
Mitotic activity may be brisk. Spindle cells or rosettes are
rare. The stroma is very scant to absent. The cytoplasm
RADIOLOGIC FINDINGS contains glycogen. The cells do not have neural processes.
No neuropile is present. The atypical variant of Ewing
Both CT and MRI are useful modalities and will demon- sarcoma contains larger cells with more cytoplasm with
strate soft tissue lesions as well as involvement of the bones. smaller amounts of glycogen, large nuclei with coarser
chromatin, and prominent nucleoli compared to typical
Ewing sarcoma cells.
GROSS AND MICROSCOPIC FINDINGS The PNETs histologically resemble neuroblastomas
(Fig. 16.19). They are composed of sheets and lobules
Although Ewing sarcoma and PNETs are the members of small round cells containing deep-staining, round-
of the same family of tumors, there is variation in their to-oval nuclei. Nucleoli may be prominent. Their cyto-
morphologic patterns. Histologically, Ewing sarcoma plasm is indistinct except in areas where the cells are more

Fig. 16.19: Histologic Features of PNETs. A: Low-power view

depicting a solid growth pattern formed by uniform small cells.
Neuropil is focally seen (arrow) (H&E). B, C: Higher magnifica-
tion highlighting the uniform pattern of the neoplastic cells (H&E).
D: Different field showing neoplastic cells separated by neuropil
(arrows) (H&E). E: This image depicts neuropil with surround-
ing neoplastic cells with the formation of Homer-Wright rosettes
E (arrows) (H&E).

mature, and the elongated hair-like cytoplasmic exten- cytopathologic features are dissimilar and are sparsely
sions coalesce to form rosettes. Most rosettes are similar documented in the literature. Ewing sarcoma/PNET are
to those seen in neuroblastomas referred to as Homer- very uncommon and are not routinely subjected to fine
Wright rosettes, containing a central solid core of neuro- needle biopsy procedures. In general, the aspirates of
fibrillary material or neuropil. Some tumors demonstrate Ewing sarcoma (Figs. 16.20 and 16.21) tend to be very
cords and trabeculae bearing a resemblance to carcinoid cellular, consisting of a large population of small, very
tumors or small cell carcinomas. Between 10% and 20% uniform, monomorphic, round cells, presenting as dis-
of PNETs display a spindle-cell component. Large areas crete, in small loosely cohesive groups, and in syncytial
of necrosis are frequent. tissue fragments. A dispersed cell pattern is more com-
mon. The malignant cells are round with poorly defined
cell borders and scant cytoplasm with high N/C ratios.
CYTOPATHOLOGIC FEATURES Their nuclei are round with smooth nuclear membranes,
containing finely granular chromatin and few micronu-
The specimens for cytologic diagnosis mostly represent cleoli. The cytoplasm is scant, pale, and vacuolated due
FNA biopsies either at the primary or at the metastatic to glycogen. A second population of dark cells with com-
sites. Crush preparations of the tissues submitted for pact chromatin may be identified. The background may
intraoperative consultation and body cavity fluids have show necrosis.
also been useful in cytologic diagnosis. The aspirates of PNET are cellular consisting of
Although Ewing sarcoma and PNETs belong to the small cell population seen as discrete dispersed cells, in
same family by virtue of common genetic alterations, their loosely cohesive groups or in syncytial tissue fragments
B
A
Fig. 16.20: FNA Ewing Sarcoma. AC: These cells from a histo-
logically proven Ewing sarcoma show syncytial tissue fragments of
monomorphic cells with poorly defined cell borders and indistinct
cytoplasm. Their nuclei are round, containing pale, finely granular
C chromatin, and nucleoli.

A B
Fig. 16.21: FNA Ewing Sarcoma. A: Low-power view showing a cellular aspirate with a large population of small neo-
plastic cells with a dispersed pattern. B: Higher magnification showing monomorphic round cells with scant cytoplasm
and large nuclei containing pale, finely granular chromatin with micronucleoli.
(Figs.16.22 to 16.24). Homer-Wrighttype rosettes may ULTRASTRUCTURE

be present in varying numbers. The neoplastic cells are
often seen lined up against the capillaries and produce Ewing sarcoma cells ultrastructurally demonstrate poorly
pseudorosettes. The malignant cells are round with formed cell junctions and few organelles and show abun-
poorly defined cell borders and scant cytoplasm with dant glycogen. Neurosecretory granules found only rarely.
high N/C ratios. Cellular and nuclear pleomorphism PNET cells show variable numbers of neurosecretory gran-
may be present in a small number of tumors and include ules, cytoplasmic glycogen, and intermediate filaments.
spindle forms. Some cells demonstrate unipolar cytoplas-
mic processes. The nuclear membranes are smooth and
the chromatin is fine to coarsely granular, evenly distrib- CYTOGENETIC ANALYSIS
uted, and deep staining. Nucleoli are variably present.
Intranuclear inclusions are frequently noted. Nuclear A finding common to Ewing sarcoma, Askin tumor, and
molding and mitoses are infrequent. No ganglion cells PNET leads to the conclusion that these tumors belong to
are present. the same family and is represented by a reciprocal trans-
location between the long arms of chromosomes 11 and
22 [t(11:22)q24:q12].
IMMUNOPROFILE
The Ewing sarcoma/PNET cells react positively to neu- DIFFERENTIAL DIAGNOSES

roendocrine markers and CD99 (O13, MIC 2). Variable
reactivity is demonstrated with cytokeratin, S100 protein The differential diagnosis of Ewing sarcoma/PNET
and negative reactivity to desmin and CD45 (leukocyte include all childhood tumors referred to as small blue
common antigen). round-cell tumors (Table 16.3; Figs 16.10 to 16.16).

A B
C D
Fig. 16.22: FNA of PNET. A, B: The undifferentiated small malignant cells are in syncytial tissue fragments. Note scant,
indistinct cytoplasm, high N/C ratios, and hyperchromatic nuclei. Note occasional intranuclear inclusion (arrows).
C: Different field showing a pleomorphic pattern with spindle cells. D: The same specimen stained with Romanowsky
stain.
A B
Fig. 16.23: FNA of PNET. A, B: This cellular aspirate consists of a large population of uniform, small round cells with
poorly defined cell borders and scant insignificant cytoplasm. Rosette formations (arrows) are evident.

C D
Fig. 16.23: (continued) C: Another field demonstrating intranuclear cytoplasmic inclusions (arrows). D: Cell block of
the aspirate.
A B
C D
Fig. 16.24: FNA of PNET. A: Low-power view of the aspirate of a chest mass in a 15-year-old teenager. The aspirate
is cellular, consisting of several aggregates of dark-staining small cells in a hemorrhagic background. B: Higher power
depicting small slightly pleomorphic cells with poorly defined cell borders and high N/C ratios. Note some short spindle
forms. C, D: Syncytial tissue fragments of undifferentiated small cells.

TABLE 16.3 DIFFERENTIAL DIAGNOSES OF SMALL ROUND-CELL TUMORS OF CHILDHOOD: CYTOPATHOLOGIC FEATURES 370
Malignant Desmoplastic Rhabdomyosarcoma
Lymphoma Non- Ewing Sarcoma / Nephroblastoma (Wilms Small Cell (Embryonal and
Hodgkin Type Neuroblastoma PNET Tumor) Tumor Alveolar)
Cellularity Highly cellular Highly cellular Variable, usually very Highly cellular Variable Highly cellular
cellular
Presentation Cells discrete Cell discrete, in loosely Cells discrete and Cells in loosely cohesive Cells discrete Cells discrete and
cohesive groups and in loosely cohesive groups and in tissue and in syncytial in loosely cohesive
in syncytial tissue groups; branching fragments generally mixed tissue fragments, groups
fragments; Homer- blood vessels with population (triphasic); no architectural
Wright rosettes + attached cells, Homer- blastermal, stromal, and patterns
Wright rosettes +/ epithelial
Cells Round, Small, round to oval, Uniform, small, Blastemal cellssmall, Small, round; Uniform, small, round
monomorphic; high mild variation in size; round; cell borders round, isolated, loosely mildly cells, minimal degree
N/C ratios; size high N/C ratios; cell indistinct, spindle cells cohesive or in tissue pleomorphic, of pleomorphism; few
variable, dependent borders indistinct; large, +/ fragments; Epithelial well to poorly spindled or polygonal
Section II: Neural Type Neuroendocrine Tumors
on morphologic round-to-polygonal cellssmall to slightly defined cell cells; cell borders

type, 3 to 3.5 times ganglion cells +/ larger than blastemal, in borders indistinct
the size of resting tissue fragments with or
lymphocyte; cell without tubular pattern;
borders indistinct Mesenchymal cellsround,
polygonal to spindle-shaped
to fiber forms
Nucleus Round to oval; Round to oval, smooth Round to oval, Blastemal cellssmall, Round, evenly Round to oval,
lobulated or to irregular nuclear uniform; nuclear round to oval with distributed, smooth to irregular
cleaved; smooth to membranes; fine to molding +; nuclear granular chromatin and finely granular nuclear membranes;

irregular nuclear coarsely granular membranes smooth micronucleoli; Epithelial chromatin; chromatin finely
membranes; fine to chromatin; nucleoli to slightly irregular; cellsround, central micronucleoli; granular; nucleoli
coarsely granular inconspicuous; nuclear nucleoli inconspicuous to eccentric, smooth mitosis +/; inconspicuous;
chromatin; nucleoli molding +/; ganglion to irregular nuclear nuclear molding intranuclear
inconspicuous cells have prominent membranes; granular inclusions +/; bi- to
to prominent nucleoli chromatin with nucleoli, multinucleated cells
(morphology parachromatin clearing;
dependent on type Mesenchymal cells
of lymphoma) pleomorphic, round
to elongated, smooth
to irregular nuclear
membranes; fine to coarsely
granular chromatin;
multiple micro/macro
nucleoli
Cytoplasm Insignificant to scant Variable, scant, Scant, vacuoles, +/; Variable, dependent on the Scant; vacuoles Scant, differentiated
pale with unipolar unipolar cytoplasmic cell type +/ rhabdomyoblast have
cytoplasmic tags; glycogen in ES moderate eosinophilic
tails; granular in PAS + cytoplasm
differentiated cells
Background Karyorrhexis +/; Neuropil-fibrillar Neuropil in PNET +/ Necrosis +/ Clean to bloody; Myxoid matrix
lymphoglandular to granular matrix no background +/; bare nuclei;
bodies consisting of tangled material lymphoglandular-
(Romanowsky stain) neuritic processes like bodies; tigroid
background in
Romanowsky stained
preparation
Immunoprofile Neuroendocrine Neuroendocrine Neuroendocrine Neuroendocrine markers -; Neuroendocrine Neuroendocrine

markers ; LCA +; markers +; S100 protein markers +; CD99 + vimentin +/; desmin +/; markers ; markers ; vimentin
T or B phenotype; +; CK ; LCA ; CD56 CK +/ vimentin +; CK +; myoglobin +;
CK +; CD57 +; CD99 +; desmin + desmin +; CK
Ultrastructure No cytoplasmic Microtubules; cell Rare dense cores; Well-formed intercellular Scant cell Myosin filaments;
organelles; lack of processes with dense granules; glycogen junctions; microvilli; junctions; Z-bands
cell junctions core granules; primitive +/; no microtubules phagolysosomes paranuclear
cell junctions aggregates of
intermediate
filaments
Other tests Catecholamine No catecholamine

secretions secretions

Cytogenetics 8:14 translocation in Loss of heterozygosity Reciprocal - Translocation Specific translocation
Burkitt lymphoma of 1p(1,p36) and translocation between t(11:22) t(2;13(q35;q14)
11Q(11Q23) MYCN the long arms of (p12:q12)
amplification chromosomes 11 and
22 [t(11:22)q24q12]
Chapter 16: Neuroendocrine Neoplasms inthe Pediatric Age Group and Adolescents
371
SUGGESTED READING
Caraway NP, Fanning CV, Amato RJ, et al. Fine needle aspiration Parham DM, Ellison DA. Rhabdomyosarcomas in adults and
of intra-abdominal desmoplastic small cell tumor. Diagn children. An update. Arch Pathol Lab Med. 2006;130:
Cytopathol. 1993;9:465470. 14541464.
Crapanzano JP, Cardillo M, Lin O, et al. Cytopathology of Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis,
desmoplastic small round cell tumor: a series including findings and treatment Hematol Oncol Clin N Am. 2010;24:6586.
in ThinPrep. Cancer Cytopathol. 2002;96:2131. Sarvida M-E, ODorisio MS. Neuroendocrine tumors in children and
Dabbs D. Diagnostic Immunohistochemistry. 2nd ed. Philadelphia, young adults: rare or not so rare. Endocrinol Metab Clin N Am.
PA: Churchill Livingstone; 2006. 2010;40:6589.
Lack EE. Tumors of the Adrenal Glands and Extraadrenal Stocker JT, Dehner LP. Pediatric Pathology. 2nd ed. Philadelphia,
Paraganglia. AFIP Atlas of Tumor Pathology, Series 4, Fascicle PA: Lippincott Williams & Wilkins; 2002.
8, Washington, DC: ARP; 2007. Weiss SW, Goldblum JR. Soft Tissue Tumors. 4th ed. Philadelphia,
Parham DM. Neuroectodermal and neuroendocrine tumors PA: Mosby Elsevier; 2008.
principally seen in children. Am J Clin Pathol. 2001;115(suppl 1):
S113S128.

17 MISCELLANEOUS
NEUROENDOCRINE TUMORS OF
THE NEURAL TYPE: OLFACTORY
NEUROBLASTOMA AND CENTRAL
NEUROCYTOMA
This chapter covers two of the neuroendocrine neoplasms disturbances. The most common sites of occurrence are
of neural type that occur very rarely and includes olfac- upper nasal cavity, in the area of cribriform plate and eth-
tory neuroblastoma and central neurocytoma. They are moid sinus. Olfactory neuroblastomas can also occur in
encountered occasionally in the practice of cytopathol- paranasal sinuses. The tumor presents as a rapidly grow-
ogy. Their documentation in cytopathology literature ing mass and has a tendency to invade the central nervous
amounts to rare case reports only. system (CNS).
The biologic behavior of olfactory neuroblastoma par-
allels the histologic grade of the tumor. Metastases occur
in 30% of the cases, most often involving the cervical
OLFACTORY NEUROBLASTOMA lymph nodes and also the brain, lungs, bones, and viscera.
Olfactory neuroblastomas, also known as esthesioneu-

roblastomas, are malignant neuroectodermal tumors RADIOLOGIC FINDINGS
thought to arise from the olfactory neuroepithelium of the
sinonasal tract in the upper one-third to one-half of the CT or MRI demonstrates a sinonasal mass causing opaci-
nasal septum, the cribriform plate, and the superomedial fication with or without bone destruction. MRI shows the
surface of the superior turbinate. With aging, the olfac- presence of a vascular lesion.
tory epithelium degenerates and is replaced by respira-
tory epithelium. The olfactory epithelium is composed of
bipolar sensory neurons, supporting cells, and the reserve GROSS AND MICROSCOPIC FEATURES
or basal cells. The basal cells are mitotically active and
are the presumed progenitor of olfactory neuroblastoma. Grossly, olfactory neuroblastoma presents as a soft, pol-
ypoid mass, covered by glistening mucosa, varying from 1
cm to a mass filling the nasal cavity with possible exten-
CLINICAL FEATURES sion into paranasal sinuses and nasopharynx.
Histologically, olfactory neuroblastomas are classified
Olfactory neuroblastomas are uncommon, representing into four grades, based on differentiation.
2% to 3% of malignant sinonasal tract tumors. There is Grade I is the most differentiated tumor type, pre-
no gender predilection. It occurs over a wide age range, senting a lobular architecture with communicating lob-
from 3years to the ninth decade, with a bimodal peak in ules consisting of uniform, small cells. Their nuclei are
the second and sixth decades of life. The presenting symp- round with coarsely granular chromatin and inconspicu-
toms include unilateral nasal obstruction, epistaxis, anos- ous nucleoli. The cell borders are indistinct. The stromal
mia, headache, pain, excessive lacrimation, and visual matrix demonstrates neurofibrillary material (neuropil)
373

(Figs. 17.1 and 17.2C). Homer-Wright rosettes are often IMMUNOPROFILE

present. The tumor appears monomorphic with no mitotic
activity or necrosis. The interlobular stroma is fibrous or Olfactory neuroblastomas are reactive to neuroendo-
can be very vascular. Calcification may be present. crine markers such as neuron-specific enolase synapto-
Grade II olfactory neuroblastomas present the same physin and variably reactive to chromogranin, CD56,
histologic pattern as that of grade I, except for lesser neu- and CD57. Variable reactivity is also seen with glial
rofibrillar stroma. The neoplastic cells are more pleomor- fibrillary acidic protein, neurofilament protein, S100
phic with some mitotic activity. protein, and epithelial membrane antigen (EMA). Some
Grade III olfactory neuroblastomas retain the lobu- demonstrate positive reactivity to cytokeratin. Olfactory
lar architecture and are more cellular with numerous neuroblastomas are nonreactive to CD99, a differenti-
mitosis and necrosis. The neurofibrillar component is ating feature from primitive neuroectodermal tumor
less and focally present. These less differentiated olfac- (PNET).
tory neuroblastomas may contain true rosettes (Flexner-
Wintersteiner rosettes). Calcification is absent.
Grade IV olfactory neuroblastomas present a diffuse ULTRASTRUCTURE
growth pattern. The lobular architecture may be main-
tained. The neoplasm is undifferentiated and anaplastic, Ultrastructure reveals secretory granules, neurofilaments,
with pleomorphic nuclei, prominent nucleoli, and indis- neurotubules, and Schwann-like cells.
tinct cytoplasm. Mitotic activity is brisk and necrosis is
very common. The neurofibrillary matrix is absent. True
rosettes may be present. DIFFERENTIAL DIAGNOSES
The differential diagnoses of olfactory neuroblastomas

CYTOPATHOLOGIC FEATURES include several high-grade lesions consisting of small-
sized cells that either arise primarily in sinonasal area
The specimens for cytologic diagnosis represent either fine or metastasize to sinonasal region. The differential diag-
needle aspiration biopsies of the nasal cavity mass or crush nostic considerations differ in different age groups. In
preparations of biopsy specimens performed during intra- pediatric and adolescent age groups, metastatic neuro-
operative consultation. Scrapings of the mass lesion have blastoma, PNET/Ewing sarcoma, malignant lymphoma,
been described. The cytologic presentation depends on the rhabdomyosarcoma, and pituitary adenoma must be
grade of the tumor (Table 17.1; Figs. 17.2 and 17.3). In included in the differential diagnoses. In adults, sino-
low-grade neoplasms, the smears are usually cellular con- nasal undifferentiated carcinoma, small cell neuroen-
sisting of monomorphic population of small round cells, docrine carcinoma, metastatic poorly differentiated
dispersed or in loosely cohesive groups. The cells have adenocarcinoma/squamous carcinomas, nasopharyn-
poorly defined cell borders, indistinct cytoplasm, and high geal carcinoma, PNET/Ewing sarcoma, malignant lym-
N/C ratios. Their nuclei are round with granular chroma- phoma, solitary plasmacytoma, pituitary adenomas,
tin and nucleoli are not prominent. Rarely carrot-shaped metastatic Merkel cell carcinoma, and small cell type
elongated nuclei are present. There may be slight nuclear malignant melanoma enter the differential diagnoses.
molding. Homer-Wright rosettes and fibrillary matrix can Many of these diagnostic entities have been discussed
be appreciated in low-grade tumors. In high-grade olfac- in Chapter 13 in the section Sinonasal Small Cell
tory neuroblastomas, the cells are more pleomorphic and Neuroendocrine Carcinoma and will not be repeated.
contain prominent nucleoli. Their cytoplasm is scant. The However, they are summarized in Table17.2 and illus-
fibrillar matrix is inconspicuous (Fig. 17.3). trated in Figures 17.4 to 17.13.

Chapter 17: Miscellaneous Neuroendocrine Tumors of the Neural Type: Olfactory Neuroblastoma 375
Olfactory Neuroblastoma (Figs 17.1 to 17.3)
A B
Fig. 17.1: Histologic sections of an olfactory neuroblastoma in a

51-year-old woman with a large mass at the base of the skull and
also involving the sphenoid sinus and cavernous sinuses. A: Low-
power view showing lobular masses of loosely cohesive small cells
(H&E). B: Higher magnification showing neurofibrillar stroma sep-
arating neoplastic cells (H&E). C: Different case of olfactory neu-
roblastoma, depicting tumor arising from the olfactory epithelium
and involving the subepithelial area. The neoplasm shows a diffuse
growth pattern and is composed of small round cells with high N/C
ratios. The nuclear chromatin is granular with micronucleoli. Neu-
rofibrillar stroma is seen in focal areas. Note the olfactory mucosa
C (arrow) (H&E).
A B
Fig. 17.2: Intraoperative Consultation. Crush preparation of an olfactory neuroblastoma. A, B: These smears depict
loosely cohesive small round cells with poorly defined cell borders, scant stroma, and high N/C ratios. Neurofibrillary
stroma is not conspicuous (H&E).

Fig. 17.2: (continued) C: Histologic section of this tumor showing

a solid growth pattern formed by uniform small cells. Note occa-
C sional rosettes and focal neurofibrillary stroma (H&E).
A B
Fig. 17.3: FNA of an Intranasal Mass. AF: These six images repre-
sent a marginally cellular specimen showing small- to medium-sized
cells with ill-defined cell borders, pleomorphic nuclei, and promi-
nent nucleoli. The chromatin is coarsely granular. Their cytoplasm
is pale and variable. The tumor histologically confirmed as olfactory
C D
neuroblastoma.

E F
TABLE 17.1. CYTOPATHOLOGIC FEATURES OF OLFACTORY NEUROBLASTOMA
Cellularity Variable, can be marked
Presentation Dispersed pattern frequent, cells in loosely cohesive groups with pseudorosettes, fibrillar stroma
Cells Small, round, monomorphic in low-grade tumors, mild-to-marked pleomorphism in higher grades;
high N/C ratios
Nucleus Round to oval; chromatin coarsely granular with typical saltpepper appearance in low grade; coarsely
granular chromatin with parachromatin clearing, occasional carrot-shaped nuclei; nucleoli prominent
in high-grade tumors
Cytoplasm Scant to indistinct
Background Neurofibrillar stroma; necrosis +/; mitoses +/
Immunoprofile Positive reactivity to neuroendocrine markers; S100 protein, neurofilament proteins; occasionally
reactive to cytokeratin
Ultrastructure Neurosecretory granules, neurofilaments, neurotubules, and Schwann-like cells
Differential diagnoses In pediatric and adolescent age groups:

Metastatic neuroblastoma
Ewing sarcoma/PNET
Rhabdomyosarcoma
Malignant lymphoma
Pituitary adenoma
In adults:
Sinonasal neuroendocrine carcinoma
Sinonasal undifferentiated carcinoma
Nasopharyngeal carcinoma
Malignant lymphoma
Malignant melanoma
Pituitary adenoma
Ewing sarcoma/PNET
Basaloid squamous carcinoma
Rhabdomyosarcoma

TABLE 17.2. DIFFERENTIAL DIAGNOSES OF OLFACTORY NEUROBLASTOMA

Olfactory Monomorphic, small, round cells; dispersed cell pattern; pseudorosettes; Figures 13.20A,B;
neuroblastoma uniform nuclei with saltpepper chromatin pattern; nucleoli seen in high-grade 17.117.3
tumors; carrot-shaped nuclei +/; neurofibrillar stroma; immunoreactive to
neuroendocrine markers, S100 protein (Schwann cells in stroma); neurofilament
protein, protein gene product (pgp) 9.5 and occasionally to cytokeratin; CD99
Neuroblastoma Monomorphic, small, round cells; dispersed cell pattern; Homer-Wright rosettes Figures 13.16;
+; uniform nuclei with saltpepper chromatin pattern; nucleoli seen in high- 16.316.6; 17.4A, B
grade tumors; ganglionic differentiation +/; neurofibrillar stroma (neuropil)
+; immunoreactive to neuroendocrine markers, S100 protein (Schwann cells in
stroma), pgp 9.5; negative to cytokeratin and CD99
Ewing sarcoma/ Dispersed cell population; syncytial tissue fragments; Homer-Wright rosettes Figures 13.28;
PNET frequent; small to slightly larger cells; poorly defined cell borders; high N/C 17.5AC;
ratios; unipolar cytoplasmic tags or processes +/; spindle forms in 10%20% 16.2216.24
of the cases; round to oval; smooth to irregular nuclear membranes; chromatin
fine to coarsely granular, saltpepper type; micronucleoli +; mitoses +/; molding
+/; scant, cytoplasm; CD99 +; neuroendocrine markers +; pgp 9.5 +; reciprocal
translocation between the long arms of chromosomes 11 and 22 (t[11:22]q24:q12)
Rhabdomyosarcoma Cellular smears; small- to medium-sized uniform cells with poorly defined Figures 13.27;
cell borders; scant cytoplasm with high N/C ratios; granular chromatin with 16.13; 17.6A,B
nucleoli; no nuclear molding; strap cells +/; Desmin and muscle-specific actin +;
neuroendocrine markers ; CD99 ; specific translocation: t(2;13)(q35; q14) for
alveolar type
Pituitary adenoma Highly cellular; small round to polygonal cells; cell borders well to poorly Figures 10.210.7
defined; nuclei round, uniform with smooth nuclear membranes; coarsely
granular chromatin; nucleoli ; mitoses absent; cytoplasm variable, scant to
abundant; no cell processes; no necrosis; may form cords, ribbons or papillary
structures, richly vascularized; granular background; neuroendocrine markers +
In adult population:
Sinonasal Small cells, with scant indistinct cytoplasm, occur singly and in syncytial Figures 13.18AC;
neuroendocrine tissue fragments without any architectural patterns; nuclear molding +; deep- 17.9A,B
carcinoma staining compact chromatin; nucleoli not appreciated; mitoses +; necrosis +;
neuroendocrine markers +; thyroid transcription factor (TTF-1) +; cytokeratin +;
Sinonasal Highly cellular, small- to medium-sized cells, discrete, in loosely cohesive groups Figures 13.19AE;
undifferentiated and in syncytial tissue fragments; poorly defined cell borders; scant cytoplasm 17.8A,B
carcinoma with high N/C ratios; granular chromatin with parachromatin clearing; nucleoli
distinct; no nuclear molding; neuroendocrine markers ; cytokeratin +; EMA +
Nasopharyngeal Malignant cells isolated, in groups and in syncytial tissue fragments without Figure 17.10A,B
carcinoma any architectural patterns; the neoplastic cells are medium sized with
granular chromatin, parachromatin clearing and nucleoli; non-neoplastic
lymphoplasmacytic infiltrate +/; Immunoprofile: CK +; neuroendocrine markers
; Epstein-Barr virus (EBV) +
Basaloid squamous Small basaloid cells either loosely cohesive or in syncytial tissue fragments with Figure 17.11AC
carcinoma closely packed small cells, poorly defined cell borders, scant stroma and high
N/C ratios; deep-stained nuclear chromatin; no nuclear molding; neuroendocrine
markers ; cytokeratin +; p53 +
(continued)

TABLE 17.2. DIFFERENTIAL DIAGNOSES OF OLFACTORY NEUROBLASTOMA (Continued)

Malignant non- Depends on the type; Figure 10.10
Hodgkin lymphoma 1) B-cell or T-cell types; highly cellular; cells isolated; 2 to 3 times the size of
1) B-cell type normal lymphocytes; round nucleus; nuclear membrane irregularity +/; granular
2) peripheral T-cell chromatin; nucleoli prominent; mitoses +; cytoplasm scant; no cell processes;
type necrosis +; background may contain reactive astrocytes; lymphoid markers +;
3) extranodal monoclonal population; cytokeratin and neuroendocrine markers
NK/T-cell type Extranodal natural killer (NK)/T-cell type; shows a polymorphous cell population
composed of normal-appearing small lymphocytes, plasma cells, immunoblasts
and atypical lymphocytes, mitoses +; Immunoprofile: CD56 +; EBV +; CD3+
Malignant Primary mucosal malignant melanoma, may present an undifferentiated small Figures 17.12 and
melanoma cell pattern; also present a pleomorphic cell pattern with spindle, plasmacytoid, 6.11C
epithelioid type cells+/; melanin pigment +/; Immunoprofile: strong reactivity with
HMB 45, S100 protein and Melan-A; negative reactivity to neuroendocrine markers
Paraganglioma Monomorphic cell pattern; cells discrete, or in loosely cohesive groups; neoplastic Figures 15.6; 15.7;
cells small to medium with occasional giant forms; round to plasmacytoid, 17.13A, B
uniform, round, eccentric nuclei; granular chromatin with saltpepper
appearance; sometimes compact; intranuclear inclusions +/; cytoplasm variable;
may be drawn into delicate process; eosinophilic cytoplasmic granules with
Romanowsky stain; mitoses absent; neuroendocrine markers +; S100 protein +
Differential Diagnoses of Olfactory Neuroblastoma (Figs. 17.4 to 17.13)
A B
Fig. 17.4: A, B: Neuroblastoma. These two images depict a fine

needle aspiration of a neuroblastoma. C: Olfactory neuroblastoma.
Note that the cytomorphology of both tumors is very similar. Neu-
roblastomas can rarely arise in the head and neck area or metasta-
C size to the sinonasal region.

A B
Fig. 17.5: A: An intraoperative consultation. Crush preparation

of a PNET showing dispersed small round cells in a neurofibril-
lar stroma (H&E). B: Different example of a PNET showing small
uniform cells in syncytial tissue fragments and loosely cohesive
groups. These cells do not give any clues as to their differentiation.
C: Different field showing loosely cohesive cells with poorly defined
cell borders and high N/C ratios. Immunostains are necessary for
C further classification.
Fig. 17.6: FNA of Ewing Sarcoma. Note the similarity to cells of

olfactory neuroblastoma (see Fig. 17.3).

A B
Fig. 17.7: A, B: FNA of a rhabdomyosarcoma showing small undifferentiated cells with no differentiating features.
Diagnosis established only following positive immunostains with Desmin and muscle-specific actin or myoglobin.
A B
C D
Fig. 17.8: Intraoperative Consultation. Crush preparation of a nasal mass proven to be a sinonasal
undifferentiated carcinoma. A: Papanicolaou-stained smear showing uniform small- to medium-sized
round cells with indistinct cytoplasm. The nuclear chromatin is finely granular with prominent nucleoli.
BD: H&E-stained preparations showing undifferentiated round cells. Neuroendocrine markers were
negative. Cytokeratin was positive.

A B
Fig. 17.9: Sinonasal Neuroendocrine Carcinoma. A: FNA depicting a primary small cell carcinoma of the sinonasal
tract, consisting of small round cells with high N/C ratios and hyperchromatic nuclei with nuclear molding. B: Metastatic
small cell carcinoma to the sinonasal region. Note the cytomorphology of a typical small cell neuroendocrine carcinoma.
A B
Fig. 17.10: A: FNA of a Nasopharyngeal Carcinoma. The malignant cells are in syncytial tissue fragment with no
architectural pattern and are undifferentiated. B: FNA of a Nasopharyngeal Carcinoma. The malignant cells are large
and discrete in a background of nonneoplastic lymphoid infiltrate (lymphoepithelioma).
A B
Fig. 17.11: A: Histologic section of a basaloid squamous carcinoma, showing a lobular growth pattern with palisading of
nuclei at the periphery. The tumor is mitotically very active. B: FNA of basaloid squamous carcinoma depicting a syncytial
tissue fragment consisting of closely packed small round cells with poorly defined cell borders, scant cytoplasm, high N/C
ratios, and coarsely granular chromatin. Note the morphologic similarity to small cell neuroendocrine carcinoma.

Fig. 17.11: (continued) C: FNA from a different case of basaloid

squamous carcinoma, showing a dispersed pattern of undifferenti-
ated cells with round, oval to short spindled nuclei. Note poorly
C defined cell borders and lack of cytoplasm. There is no molding.
Fig. 17.12: Malignant melanoma consisting of a small cell pattern,

and without melanin pigment, will offer diagnostic difficulties in
differentiating it from small cell neuroendocrine carcinoma.
A B
Fig. 17.13: A: Intraoperative Consultation. Crush preparation of a paraganglioma. The neoplastic cells are small to
medium sized, with well- to poorly defined cell borders. Many cells have appreciable and pale cytoplasm. The nuclei are
uniform and eccentric. Note short cytoplasmic processes (H&E). B: Different example of a paraganglioma consisting
of small- to medium-sized round cells with high N/C ratios. Their cell borders are well to poorly defined and the cyto-
plasm is variable, often with unipolar short processes. Note eccentric nuclei. The nuclear chromatin is coarsely granular.

inconspicuous nucleoli. A small proportion of cases con-

CENTRAL NEUROCYTOMA tain isolated cells with a more ganglionic nuclear appear-
ance with prominent nucleoli. There may be a hint of
Central neurocytoma is defined as a discrete intraven-
basophilic Nissl substance. Perivascular pseudorosettes
tricular tumor composed of cytologically uniform small,
may be present. The intratumoral blood vessels are thin
mature neurons. They may occur outside their original
walled, straight, and of capillary size. Mitosis or nuclear
central location in the midline of the central ventricular
pleomorphism is absent.
system. Central neurocytomas constitute <1% of intra-
cranial tumors. There is no gender predilection and can
occur at any age with a peak in the third decade of life. IMMUNOPROFILE
Majority of the tumors described are located in a mid-
line site straddling the lateral and the third ventricles, The cells of central neurocytoma show strong positive
often in relation to foramen of Monro. However, cases reactivity to synaptophysin, class III beta tubulin, and
with no ventricular connection have been described and neurofilament protein.
referred to as simply neurocytoma.
Most patients present with symptoms due to increased
intracranial pressure with blockage of cerebrospinal fluid ULTRASTRUCTURE
and acute hemorrhage. Central neurocytomas offer a
good prognosis. Ultrastructurally, the cells of central neurocytoma dem-
onstrate microtubules and dense-core neurosecretory
granules.
RADIOLOGIC FINDINGS
CT scan shows isodense or mildly hyperdense lesions CYTOPATHOLOGIC FEATURES

with strong, generally uniform contrast enhancement.
Cystic change may or may not be present. There may be Neurocytomas smear easily. A monotonous, population
calcification. of small, discohesive cells forming a sheet-like pattern
is characteristic of neurocytomas (Figs. 17.14 to 17.18).
The neoplastic cells have round, uniform nuclei. The cell
GROSS AND HISTOLOGIC FEATURES borders are poorly defined and the cytoplasm is not vis-
ible. The nuclear chromatin is stippled with small incon-
Grossly, the tumor is gray, resembling the gray matter, spicuous nucleoli. Background neuropil is characteristic
firm, and gritty due to focal mineralization. as are thin-walled long blood vessels.
Microscopically, the central neurocytoma consists
of uniform, medium-sized cells with round nuclei and
scant cytoplasm and appears virtually identical to oli- DIFFERENTIAL DIAGNOSES
godendrogliomas, including artificial cytoplasmic vacu-
olization, leading to perinuclear halo or fried egg First, cytohistologically, central neurocytomas strongly
appearance. resemble oligodendrogliomas. However, the latter are
The tumor displays a solid growth pattern with closely unlikely to occur in central location. Second, oligoden-
packed cells, with filamentous stroma containing delicate drogliomas are not discrete, and not located within the
neuropil-like quality (see Fig. 17.15E). Also present are ventricular system, and may show areas of trapped CNS
ill-defined rosettes and fibrillary nuclear-free zones. The parenchyma. Oligodendrogliomas demonstrate negative
nuclei are round, with finely stippled chromatin and small reactivity to neuroendocrine markers.

Central Neurocytoma (Figs 17.14 to 17.18)
A B
Fig. 17.14: Intraoperative Consultation. Crush preparation of

a central neurocytoma. A: Low-power view showing a dispersed
cell pattern (H&E). B, C: Higher magnification showing uniform
round cells with ill-defined cell borders, indistinct cytoplasm, and
round nuclei with high N/C ratios. The nuclei are very uniform with
C granular chromatin. The background shows fibrillar stroma (H&E).
A B
Fig. 17.15: Intraoperative Crush Preparation of a Central Neurocytoma. A, B: Characteristic dispersed pattern formed
by uniform, small, round cells with high N/C ratios. Note Homer-Wright rosettes (arrows) (H&E).

C D
Fig. 17.15: (continued) C, D: The same specimen stained by Papa-

nicolaou technique. E: Histologic section of central neurocytoma
depicting multiple Homer-Wright rosettes and fibrillar stroma (neu-
E ropil) (H&E).
A B
Fig. 17.16: Intraoperative Consultation. Crush preparation of a central neurocytoma. A: This field shows broad bands
of neurofibrillary matrix. The neoplastic cells are strikingly uniform (H&E). B: Another field showing delicate and
sparse stroma separated by uniform round cells (H&E).

A B
Fig. 17.17: Intraoperative Consultation. Crush preparation of a

central neurocytoma. A: This crush preparation shows discrete cells
as well as clustered cells. Note rosette formations (H&E). B: The
neurocytoma cells are pleomorphic, some rather large containing
nucleoli and may be differentiating toward ganglionic cells (arrows)
(H&E). C: The neurocytoma cells are in tight cluster. The cell
borders are visible with pale appreciable cytoplasm. The nuclei are
C uniform (H&E).
Fig. 17.18: Intraoperative Consultation. Crush preparation of an

oligodendroglioma. Note the striking resemblance between oligo-
dendroglioma and central neurocytoma in Figure 17.16B. Location
is the clue for the correct diagnosis, since oligodendroglioma is in-
traparenchymal while neurocytoma is in close relation with ven-
tricles.

SUGGESTED READING
Olfactory Neuroblastoma Logrno R, Fultoran RM, Hartig G, et al. Olfactory neuroblastoma

(esthesioneuroblastoma): appearance on fine needle aspiration:
Bellizzi AM, Boume TD, Mills SE, et al. The cytologic features report of a case. Diagn Cytopathol. 1997;17:205208.
of sinonasal undifferentiated carcinoma and olfactory Lund VJ, Howard D, Wei W, et al. Olfactory neuroblastoma: past,
neuroblastoma. Am J Clin Pathol. 2008;129:367376. present and future? Laryngoscope. 2003;113:502507.
Broich L, Pagilari A, Ottaviani F. Esthesioneuroblastoma: a general Mahooti S, Wakely PE Jr. Cytopathologic features of olfactory
review of the cases published since the discovery of the tumor neuroblastoma. Cancer. 2006;108:8692.
in 1924. Anticancer Res. 1997;17:26832706. Unal A, Ozlugedik S, Tezer MS, et al. An atypical
Chung J, Park ST, Jang J. Fine needle aspiration cytology of esthesioneuroblastoma of the anterior nasal cavity and
metastatic olfactory neuroblastoma: a case report. Acta Cytol. maxillary sinus: report of a case. Tumori. 2006;92:440443.
2002;46:4045. Weiss SW, Goldblum JR. Soft Tissue Tumors. 4th ed. Philadelphia,
Ejaz A, Wenig BM. Sinonasal undifferentiated carcinoma: clinical PA: Mosby Elsevier; 2008.
and pathologic features and a discussion on classification, Wenig BM. Atlas of Head and Neck Pathology. 2nd ed.
cellular differentiation, and differential diagnosis. Adv Anat Philadelphia, PA: W B Saunders; 2008.
Pathol. 2005;12:134143.
Fagan MF, Rone R. Esthesioneuroblastoma: cytologic features
with differential diagnostic considerations. Diagn Cytopathol. Central Neurocytoma
1985;1:322326. Ashkan K, Casey AT, DArrigo C, et al. Benign central neurocytoma.
Ferris CA, Schnadig VJ, Quinn FB, et al. Olfactory neuroblastoma: Cancer. 2000;89:11111120.
cytodiagnostic features in a case with ultrastructural and Bannykh S, Stuger J, Ocal I, et al. Central neurocytoma. J Neurooncol.
immunohistochemical correlation. Acta Cytol. 1988;32:381385. 2005;71:31.
Frierson HF Jr, Ross JW, Mills SE, et al. Olfactory neuroblastoma: Caccamo DV, Kini SR. Cytologic patterns of recently
additional immunohistochemical characteristics. Am J Clin recognized central nervous system tumors. Am J Clin Pathol.
Pathol. 1990;94:547553. 1995;103:506.
Hirose T, Scheithauer BW, Lopes BS, et al. Olfactory Johnson ES, Nguyen-Ho P, Nguyen G-K. Cytology of central
neuroblastoma: an immunohistochemical, ultrastructural and neurocytomas in intraoperative crush preparations: a case
flow cytometric study. Cancer. 1995;78:419. report. Acta Cytol. 1994;38:764766.
Iezzoni JC, Mills SE. Undifferentiated small round cell tumors Kobayashi TK, Bamba M, Ueda M, et al. Cytologic diagnosis of
of the sinonasal tract. differential diagnosis update. Am J Clin central neurocytoma in intraoperative squash preparations.
Pathol. 2005;124(Suppl):S110S121. Acta Cytol. 2010;54:209212.
Jelen M, Wozniak Z, Rak J. Cytologic appearance of Ng HK. Cytologic features of central neurocytoma of the brain.
esthesioneuroblastoma in a fine needle aspirate. Acta Cytol. Acta Cytol. 1999;43:252256.
1988;32:377380. Scmidt MH, Gotfried ON, von Koch CS, et al. Central
Jobst SB, Ljung BM, Gilroy FN, et al. Cytologic diagnosis of neurocytoma: a review. J Neurooncol. 2004;66:377384.
olfactory neuroblastoma. Acta Cytol. 1983;27:299305. Sugita Y, Tokunaga O, Morimatsu M, et al. Cytodiagnosis of
Lack EE. Tumors of the Adrenal Glands and Extraadrenal central neurocytoma in intraoperative preparations. Acta Cytol.
Paraganglia. AFIP Atlas of Tumor Pathology, Series 4, Fascicle 8, 2004;48:194198.
Washington, DC: ARP; 2007.

Glossary
Glossary of Terms Associated with the Diffuse Neuroendocrine System.
Amphicrine. Modes of secretion in both exocrine and Cytosol. The liquid medium of the cytoplasm, that is,
endocrine function, by the same cells as exemplified by cytoplasm minus organelles and nonmembranous
cells containing cytoplasmic mucin in apical portion insoluble components
and neurosecretory granules in basal portion
Endocrine. Secretion of products through the basement
APUD. Amine precursor uptake and decarboxylation membranes into adjacent capillaries for interaction
with target tissues at distant sites
APUDOMA. A term applied to tumors of the (neuro-
endocrine) cells that are capable of amine precursor Exocrine. Secretion of products externally through the
uptake and decarboxylation surface of the cells facing lumen of the duct or the
gland
Argentaffin. Ability of cells to reduce silver salt resulting
in silver precipitate in cells Enterochromaffin. Neuroendocrine cells in the small
intestinal mucosa
Argyrophil. Capacity to reduce silver salts, with the aid of
reducing agent to precipitate the silver that stains black EC-L cell. Enterochromaffin-like cell. Type of neuroendo-
Autocrine. Secretory product acting on receptors of its crine cells secreting histamine, found in gastric mucosa
own cells Flexner-Wintersteiner rosette. Nuclei around a central
Autofluorescence. Emission of light when excited by tubule; cilia seen ultrastructurally
ultraviolet ray of suitable wave length. Protein- Ganglion. A collection of neurons outside the central
containing tryptophan, tyrosine, and phenylalanine are nervous system; occasionally the term applied to col-
autofluorescent. lection of neurons in the brain or spinal cord; for
Azzopardi effect. Basophilic DNA encrustation of the example, basal ganglia
blood vessels in necrotic areas, in small cell neuroen- Homer Wright rosette. Tumor cells arranged around a
docrine carcinomas central core of neurofibrillary material or neuropil
Carotid body. Paraganglionic (neuroendocrine) tissue, Kulchitsky cells. Enterochromaffin cells of the gastroin-
located at the bifurcation of carotid artery testinal tract, named after the Russian scientist
Chromaffin. Affinity for chromate salts. The tissues
MEN. Multiple endocrine neoplasia
develop brown discoloration upon the addition of
chromic salts, also referred to as chromaffin reaction. Neuroendocrine cell. The cell secreting its products into
the bloodstream upon receiving neural signals
C cells. Neuroendocrine cells in the thyroid. Also referred
to as calcitonin-producing cells or clear cells. Nonchromaffin. Cells that do not demonstrate chromaf-
fin reaction
Chemoreceptors. Receptors adapted for excitation by
chemical substances, for example, olfactory or gusta- Neural crest. It is formed by cells from the neural plate in
tory receptors or a sense organ, as carotid body or aor- early embryonic life, before the fusion of the plate to
tic body which is sensitive to chemical changes in the form the neural tube. The neural plate is an ectodermal
blood stream, especially reduced oxygen content, and derivative.
reflexly increases both respiration and blood pressure. The neural crest is the source of neurons and satellite
Chemoreception is the function of paraganglia. cells in the autonomic and sensory ganglia.
389

390 Glossary
Neuroectoderm. The portion of the ectoderm in the early Pheochromocytoma. Neuroendocrine tumor of the adre-
embryo that gives rise to central nervous system nal medulla or extraadrenal chromaffin tissue secreting
catecholamines
NET. Neuroendocrine tumors
PNET. Primitive neuroendocrine tumor
Neuropil. Tangle of axon terminals, dendrites, and glial
cell processes, where synaptic connections are formed PPNET. Primitive peripheral neuroectodermal tumor
Neurosecretory granules. Membrane-bound dense core PEN. Pancreatic neuroendocrine neoplasms
granules representing packaged cytoplasmic secretory
PET. Pancreatic endocrine tumors
products ready to be released/secreted
Rathke pouch. Diverticulum from the embryonic buccal
Organs of Zuckerkandl. Paraganglia in the lower abdo-
cavity, from which the anterior lobe of the pituitary
men at the bifurcation of the aorta or at the origin
gland is developed
of inferior mesenteric artery. It can be a source of
extraadrenal pheochromocytoma. Schwann cells. Derived from neural crest. Principal glial
cell of the peripheral nervous system, wrap themselves
Paracrine. Secretion of products locally to influence the
around nerve axons and form myelin sheath around
activities of adjacent epithelial cells
the nerves.
Paraganglia. A collection of cells (neuroendocrine) derived
Sustentacular cells. Synonymssupporting cells, type II
from neural ectoderm, occurring outside the adrenal
cells, satellite cells; are Schwann-like cells, glial in nature.
medulla
Present in paraganglia. Immunoreactive to S100 protein
Paraganglioma. Tumors of paraganglia
Zellballen. Nest-like cluster of cells (forming cell ball),
Pheochromocyte. Cells of the adrenal medulla characteristic of paraganglioma

Index
Note: Page numbers in italics denote figures; those followed by a t denote tables.
A Amyloid, in medullary thyroid carcinoma, Breast

Acinar cell carcinoma vs. pancreatic 168, 169, 169, 180181 clinical and imaging features, 271
endocrine tumors, 118t, 119, Anaplastic carcinoma vs. medullary cytopathologic features, 272
120, 124 thyroid carcinoma, 186t, 193, diagnostic difficulties and differential
Acinar tissue, 117, 117t, 119 195, 197200 diagnoses, 272, 273
Adenocarcinoma, 282, 284 Anaplastic large-cell lymphoma vs. gross and histologic features, 271272
gastric, 89 paraganglioma, 338t, 343 histochemistry, 272
vs. pancreatic endocrine tumors, Ancillary tests (see specific tumor type) immunoprofile, 272
118t,119 Appendiceal carcinoids, 86t, 91, 92, 93, Bronchial brushings, 24, 6365
vs. paraganglioma, 338t, 344, 347 94, 97t atypical carcinoid tumors, 48, 49
pulmonary, 44 Appendix carcinoid tumor cells, 20, 24
and small cell carcinoma, 64, 73 amphicrine cell in adenocarcinoid of, 3 large cell neuroendocrine
Adenohypophysis, 225 goblet cell carcinoid tumor of, 22 carcinoma,52
Adenoid cystic carcinoma, 68t, 244t Argentaffin, 389 parotid gland, primary small cell
vs. other salivary gland tumors, 152t, reaction, 10, 10 carcinoma, 155
154,159 Argyrophil, 389 small cell carcinoma, 9, 20, 25, 5961,
vs. sinonasal neuroendocrine reaction, 10, 10 66, 71, 72
carcinoma, 287, 290 Askin tumor, 363, 367 typical carcinoid tumors, 3335, 44
Adenoma Autocrine, 389 Bronchial washings, 25, 35, 66, 70,
basal cell, of salivary gland, 153t, Autofluorescence, 389 71,306
154,158 Azo coupling reaction, 10, 10 Bronchoscopy, specimens, 2324, 24, 25
follicular thyroid, 183t, 186, 191, 192 Azzopardi effect, 389
hyalinizing trabecular, 183t, 188190, C
208t B Calcitonin-producing cells (C cells), 163,
middle ear, 339t Basal cell adenocarcinoma vs. other 164,389
parathyroid, 209224 (see also salivary gland tumors, 153t, Carcinoid tumor, 1, 2, 244t
Parathyroid adenomas) 154, 158 bronchial brushings, 20, 24
pituitary, 26 (see also Pituitary Basal cell adenoma vs. other salivary gland chromaffin reaction, 10
adenoma) tumors, 153t, 154, 158 gastrointestinal (GI) tract (see
pleomorphic, 154, 159 Basaloid squamous carcinoma, 72, 378t, Gastrointestinal (GI) tract,
serous microcystic, 118t 382383 carcinoid tumors)
Adeno/squamous carcinoma vs. thymic vs. Merkel cell carcinoma, 244t, 245 of kidney, 264
neuroendocrine carcinomas, vs. salivary gland tumors, 152t, 154, vs. medullary thyroid carcinoma, 200
138t, 140 157 ovaries, 258, 259, 260261t, 261263
Adolescents vs. sinonasal neuroendocrine pulmonary (see also Pulmonary
Ewing sarcoma and primitive neuroec- carcinoma, 287, 290 neuroendocrine tumors)
todermal tumors, 363369 Bile duct brushings, ERCP, 22, 24 atypical, 43, 46, 4647, 47t, 4849
ganglioneuromas, 363, 364 Body cavity fluids (see also Serous effusion clinical histologic and cytologic
neuroblastomas, 351363 fluids) features, 7982t
Adrenal cortical carcinoma metastatic carcinoid tumors, 45 typical, 2930, 3137, 32t, 38,
vs. pheochromocytoma, 308309t, 310 metastatic carcinoid tumors of 3945, 40, 41t
vs. retroperitoneal paraganglioma, appendix, 22, 94 Carotid body, 389
336t, 340341 metastatic islet cell/pancreatic neuroen- Carotid body paraganglioma, 319320t,
Adrenal gland, metastatic small cell docrine tumors, 130 321
carcinoma,78 metastatic neuroblastoma, 23, 363 ancillary tests, 338t
Adrenal medulla, structure of, 295 metastatic neuroendocrine carcinomas, differential diagnoses, 337, 338t, 345,
Adrenal myelolipoma vs. pheochromocy- 130 345347
toma, 312 metastatic ovarian carcinoid tumors, FNA of, 323324
Adrenal paraganglioma (see 22, 261263 vs. medullary thyroid carcinoma, 345
Pheochromocytoma) metastatic small cell Cauda equina, paragangliomas, 318,
Amphicrine, 389 carcinoma, 7778 319320t, 332, 333
Amphicrine cell, in adenocarcinoid of Bone marrow, metastatic neuroblastoma, ancillary tests, 340t
appendix, 3 357 differential diagnoses, 340t, 347,
Amyloid goiter vs. medullary thyroid Bone, metastatic pulmonary carcinoid 348350
carcinoma, 182, 188 tumor, 45 Cell blocks, 242
391

392 Index
Central nervous system (CNS) lymphoma, Cytologic specimens cytoplasmic enzymes, 11

232t ancillary testing, 25 dense core granules/vesicles, 11
Central neurocytoma, 26, 233t bronchial brushings, 20 markers, 11
cytopathologic features, 384 bronchoscopy, 2324, 24, 25 synaptic vesicle and docking
delicate and sparse stroma, 386 cell blocks, 18, 25 proteins, 11
dispersed cell pattern, 385 cerebrospinal fluid, 20, 20 mixed adenoneuroendocrine
Homer-Wright rosettes, 385, 386 CNS, crush preparations, 25, 26 carcinoma, 4
intraoperative consultation, crush cytopreparations, 17 secretory activities of neuroendocrine
preparation, 385387 exfoliative cytopathology, 18t cells and neurons, 2
neurofibrillary matrix, 386 female genital tract, 21, 23 secretory products
Papanicolaou stain, 386 fine needle aspiration biopsy, 19t, amine and amine precursors, 8
definition, 384 2425 peptides, 8
differential diagnoses, 384, 387 gastrointestinal and pancreatobiliary taxonomy of neuroendocrine tumors,
gross and histologic features, tracts, 22, 23, 24 23
384, 385 liquid-based technology, 17, 20, 23 tumor growth pattern
immunoprofile, 384 microscopic evaluation, 26 neural type, histologic spectrum,
vs. pituitary adenoma, 234 Papanicolaou stain, 17, 20 5, 7
radiologic findings, 384 respiratory tract, 23, 24 poorly differentiated neuroendo-
ultrastructure, 384 serous effusion fluids, peritoneal/pelvic crine carcinomas, histologic
Cerebrospinal fluid, 18t, 20, 20 washings, 2021, 2123 spectrum, 56
Cervical lymphadenopathy and palpable spray fixation, 20 well-differentiated neuroendocrine
thyroid nodule, 203 staining methods, 1819 neoplasms, histologic spectrum,
Cervical smear, 23, 251253, 255, 256 urinary tract, 24 45
Chemoreceptors, 389 Cytoplasm, 38 ultrastructure, 12, 12
Chief cells, 209, 210, 211, 213 characteristics of neuroendocrine cells, 7 Distal jejunum and ileum (midgut), car-
Chondrosarcoma vs. paraganglioma, 340t, pulmonary neuroendocrine neoplasms, cinoid tumors, 86t, 89, 91, 91,
348349 80t,81t 92, 97t
Chromaffin, 389 Cytoplasmic enzymes, Docking proteins, immunochemistry, 11
reaction, 8, 10, 10 immunochemistry, 11 Duct adenocarcinomas, of pancreas, 117,
Chromaffin cells, 295 Cytosol, 389 124,125t
Chronic lymphocytic leukemia in FNA Duct carcinoma of breast, 272, 273
specimen, 70 D Duodenum and proximal jejunum
Clear cell ependymoma, 232t Dendritic cell sarcoma vs. paraganglioma, (foregut), carcinoid tumors,
Colon 337t,343 86t, 96t
and rectum (hindgut), carcinoid Dense core granules/vesicles, 11 cytopathologic features, 8889
tumors, 86t, 93, 97t Dermoid cyst, peritoneal/pelvic washings, EUS-guided FNA of periampullary
small cell carcinoma, 95 259 mass, 90
Columnar cells, 38, 65, 67t Diazo reaction, 10 types, 88
Columnar epithelial cells, 71 Differential diagnoses (see under specific
Combined small cell carcinomas, 6365, tumor) E
6566, 6667t, 6976 Diff-Quik stain, 242, 243 Electron micrograph of Merkel cell
Composite carcinomas, 201 Dispersed neuroendocrine system carcinoma, 243
Crush preparation, 234237, 285, 287, amphicrine cell, in adenocarcinoid of Embryonal rhabdomyosarcoma,
288, 325, 332, 333, 348350 appendix, 3 FNAof,361
of central neurocytoma, 385387 cytologic characteristics, 6 Endocrine, 389
of CNS lesions, 26 cytoplasm, 7 Endocrine pancreas, normal histology and
of nasal mass, 381 pheochromocytoma/ cytology, 103, 104
of olfactory neuroblastoma, 375 paraganglioma, 9 Endometrial adenocarcinoma, 262
of paraganglioma, 383 poorly differentiated neuroendo- vs. small cell carcinoma of cervix, 254t,
of pituitary adenomas, 228231 crine carcinoma, 9 255256
of PNET, 380 well-differentiated neuroendocrine Endometrial cells vs. small cell carcinoma
Cutaneous basal cell carcinoma vs. carcinomas, 78 of cervix, 254t, 255256
salivary gland tumors, 153t, diffuse neuroendocrine system, Endometriosis vs. ovarian carcinoid, in
154,158 schematic of, 2 peritoneal/pelvic washings,
Cutaneous lesions, 24, 241 hereditary syndromes 260t,262
Cutaneous neuroendocrine (small cell) neuroendocrine neoplasms in, 13t Endosalpingiosis vs. ovarian carcinoid, in
carcinoma (see Merkel cell phenotypic expression, 1213 peritoneal washings, 260t, 261
carcinoma) tumorigenesis, 1314 Endoscopic retrograde cholangiopancrea-
Cystic lesions of pancreas, 124t histochemistry tography (ERCP), 22
Cystic neoplasms of pancreas, 125126t chromaffin reaction, 8, 10, 10 bile duct brushings, 22, 24
Cystic neuroendocrine tumors, 123, ferric ferricyanide reduction and azo pancreatic duct brushings, 22, 23
124126t, 127 coupling reaction, 10, 10 Endoscopic ultrasound (EUS)-guided FNA
Cystic nodular goiter, 221 formaldehyde-induced of periampullary mass, 90
Cystic teratoma/dermoid cyst, peritoneal/ autofluorescence, 10, 11 Enterochromaffin, 389
pelvic washings, 259 silver salt reaction, 10, 10 Ependymoma
Cytokeratin, small cell carcinoma, history of, 12 clear cell, 232t
75, 76 immunochemistry vs. paraganglioma, 340t, 349

Index 393
ERCP (see Endoscopic retrograde cholan- Female genital tract, neuroendocrine of retroperitoneal paraganglioma,
giopancreatography (ERCP)) tumors,249 327330
Esophageal adenocarcinoma, 312 cytologic specimens, 21, 23 of rhabdomyosarcoma, 381
Esthesioneuroblastomas (see Olfactory Ferric ferricyanide reduction and azo of small cell carcinoma, 61, 62, 128
neuroblastoma) coupling reaction, 10, 10 of soft tissue mass, 346
European Neuroendocrine Tumor Society Fibrous histiocytoma, 342 of typical carcinoid tumors, 36, 37, 39,
(ENTS), 85 Fibrous tissue septae, 167, 168 4043
Ewing sarcoma Fibrous tissue strands, 107 Fixatives, 10, 17, 20, 23
clinical features, 363364 Fine needle aspiration (FNA) biopsy Flexner-Wintersteiner rosette, 389
cytogenetic analysis, 367 of adrenal mass, 310, 313 FNA (see Fine needle aspiration (FNA)
cytopathologic features, 358t, 366, of alveolar rhabdomyosarcoma, 360 biopsy)
366, 367 atypical carcinoid tumors, 49 Follicular adenoma/carcinoma
differential diagnosis, 359, 367 of basaloid squamous carcinoma, 157, vs. medullary thyroid carcinoma, 183t,
gross and microscopic findings, 364 382 186, 191193, 193
immunoprofile, 367 of carotid body paraganglioma, vs. parathyroid adenomas, 221, 222,
vs. olfactory neuroblastomas, 378t, 380 323324 223t
radiologic findings, 364 of cervical lymph node, 346 Follicular neoplasms, of thyroid, 186,
vs. sinonasal neuroendocrine carci- cytologic specimens, 19t, 2425 188193, 206, 207t, 221, 223t
noma, 291 of desmoplastic round-cell Fontana-Masson/Masson-Hamperl stain,
ultrastructure, 367 tumor, 360 10
Exfoliative cytopathology, of neuroendocrine of embryonal rhabdomyosarcoma, 361 Formaldehyde-induced autofluorescence,
tumors, cytologic specimens, 18t of enlarged mediastinal lymph node, 10, 11
Exocrine, 389 246
Exocrine pancreas, normal histology and of Ewing sarcoma, 366, 367, 380 G
cytology, 104 of follicular adenoma, 221 Gallbladder and extrahepatic bile ducts,
Extra-adrenal paragangliomas, 267 of hepatic mass, 273 neuroendocrine tumors of, 98
clinicopathologic features, 319320t of hepatoblastoma, 362 Gangliocytic paraganglioma, 88
cytopathologic features, 318, 320, 322t of hepatocellular carcinoma, 311 Ganglion, 389
carotid body, FNA of, 323324 of intranasal mass, 376377 Ganglioneuroblastoma, 352, 357
cauda equina, 332, 333 of large cell neuroendocrine carcinoma, Ganglioneuromas, 363, 364
intraoperative consultation, 325, 5155 Gastric adenocarcinoma, 88, 89
332, 333 of liver metastasis, 92 Gastrinomas, 88
jugulotympanic paraganglioma, 325 of liver nodule, 277, 278 Gastrointestinal stromal tumor, 337t
parapharyngeal space, FNA of mass, of lymph node, 25 Gastrointestinal (GI) tract
325326 of mass in parapharyngeal space, carcinoid tumors, 8586, 86t
paraspinal mass biopsy, crush prep- 325326 appendix (midgut), 86t, 91, 92, 93,
aration of, 333334 of mediastinal mass, 74, 135137, 94,97t
retroperitoneal mass, FNA of, 331 139142 clinicopathologic features of,
retroperitoneal paraganglioma, of medullary carcinoma, 172180 9697t
FNA of, 327330 of anaplastic carcinoma, 198, 199 colon and rectum (hindgut), 86t,
thyroid, 326327 of Hrthle cell carcinoma, 93, 97t
differential diagnoses 194, 195 distal jejunum and ileum (midgut),
carotid body, 337, 338t, 345, of insular carcinoma, 197 86t, 89, 91, 91, 92, 97t
345347 of malignant lymphoma, 201 duodenum and proximal jejunum
cauda equina, 340t, 347, 348350 metastatic, 204 (foregut), 86t, 8889, 90, 96t
jugulotympanic, 339t, 347 of soft tissue tumors, 200 stomach (foregut), 8688, 87, 89
location and cell morphology, 335t of thyroid mass, 206 neuroendocrine neoplasms, classifica-
primary spinal paragangliomas, 347 of thyroid nodule, 200, 201 tion, 85
retroperitoneal, 336337t, 337, of medullary thyroid carcinoma, 345 small cell carcinomas, 93, 95
340344 of Merkel cell carcinoma, 242243 specimens from, 22
thyroid, 347 of nasal mass, 284 WHO classification
gross and microscopic features, 318 of nasopharyngeal carcinoma, 382 neuroendocrine neoplasms,
carotid body paraganglioma, 321 of neuroblastomas, 354357 85, 100
diffuse pattern, 321 of nodular goiter, 221 neuroendocrine tumors, 101
dispersed pattern, 322 of olfactory neuroblastoma, 286 Genitourinary tracts, neuroendocrine
pleomorphic cell pattern, 321 of pancreatic endocrine tumors, tumors
trabecular pattern, 321 109117 cytologic diagnosis, 249
Zellballen pattern, 321 of pancreatic mass, 120, 121 female genital tract, 249
parasympathetic, 318 of paraganglioma, 9 kidney, 264
primary sites, 317t of parathyroid adenomas, 213, 222 male genital tract, 263
sympathetic, 317318 of parotid mass, 149, 150, 155, 156, ovaries
Extra-adrenal pheochromocytomas, 267 158 poorly differentiated (small cell and
of periduodenal/peripancreatic mass, large cell carcinoma), 263
F 122,123 well-differentiated (carcinoid
Familial pheochromocytoma, 13t, 295 of pheochromocytoma, 301306 tumors), 258, 259, 260261t,
Familial type medullary thyroid of renal mass, 310 261263
carcinoma, 13t of retroperitoneal mass, 331 prostate, 263264

394 Index
Genitourinary tracts, neuroendocrine I small-bowel carcinoid tumor,

tumors (Continued) Ileum (midgut), carcinoid tumors, 86t, 89, 276277
urinary bladder, 264 91, 91, 92, 97t metastatic lesions, FNA of, 129
extraadrenal pheochromocytomas/ Immunochemistry, 1011 primary hepatic carcinoid tumors, 272
paragangliomas, 267 Insular thyroid carcinoma vs. medul- radiologic findings, 274
poorly differentiated (small cell) lary thyroid carcinoma, 185t, Lobular carcinoma, of breast, 272
carcinoma, 264266, 265267, 193,197 Lung (see also see Pulmonary neuroendo-
266t Intermediate filaments, 11 crine tumors; Pulmonary small
urinary tract, 264 Intraductal papillary mucinous neoplasm, cell carcinoma)
uterine cervix, small cell carcinoma of 126t metastatic medullary thyroid
cytopathologic features, 250, Intrathyroidal parathyroid adenoma, carcinoma, 204
251253, 252 217218 metastatic small cell carcinoma of, 22
diagnostic difficulties and dif- Islet of Langerhans, 103 Lymph nodes, metastatic small cell
ferential diagnoses, 252, 254t, carcinoma, 75
255258 J Lymphadenopathy
gross and histologic features, Jugulotympanic paraganglioma, 319320t, cervical, 203
250,250 325 mediastinal, 67t
immunoprofile, 252 ancillary tests, 339t Lymphofollicular cervicitis, 254t, 255
ultrastructure, 252 differential diagnoses, 339t, 347 Lymphoid proliferations vs. small cell
Germ cell tumors, 144 carcinoma, 70
Germinoma, 143 K
Glial fibrillary acidic protein (GFAP), 232t, Kidney, neuroendocrine tumors, 264 M
233t,340t Kulchitsky cells, 389 Malignant fibrous histiocytoma, 342
Glioblastoma vs. pituitary adenoma, Malignant lymphoma, 68t, 185t, 244t
232t,237 L vs. medullary thyroid carcinoma, 185t,
Glomus jugulare, 315 Large cell lymphoma, 337t, 338t 195196, 201
Goblet cell carcinoid tumor of Large cell neuroendocrine carcinoma vs. metastatic small cell carcinoma, 76
appendix,22 (LCNEC), 9 vs. neuroendocrine carcinoma, 123,
Goblet cell variant of appendiceal carci- clinical histologic and cytologic fea- 141, 291
noids, 93, 94 tures, 7982t vs. paraganglioma, 340t, 349
Granin (chromogranin/secretogranin), 11 cytopathologic features, 47, 50, vs. pituitary adenoma, 235
Granulosa cell tumor, 261t 50t, 53 vs. sinonasal neuroendocrine carci-
in peritoneal fluid, 263 differential diagnoses, 53, 54, 54t, 55 noma, 291
Grimelius technique, argyrophilic FNA, 5155 vs. small cell carcinoma of salivary
reaction, 10 gross and histologic features, 47, 50 gland, 153t, 155, 160
Growth patterns, of neuroendocrine immunoprofile, 53 of stomach, 89
neoplasms, 45, 46 metastatic, 53 Malignant melanoma, 69t
ovarian, 263 vs. medullary thyroid carcinoma, 196
H Large cell undifferentiated carci- vs. Merkel cell carcinoma, 244t, 246
Head and neck, paraganglia distribution, noma (LCUC) vs. large cell vs. olfactory neuroblastomas,
316 neuroendocrine carcinoma, 54t 379t, 383
Hemangiopericytoma, 233t, 338t Leiomyosarcoma, 200 vs. paraganglioma, 336t, 338t, 346
vs. paraganglioma, 339t, 340t, 348 Liquid-based preparation, 17, 20, 23 vs. pheochromocytoma, 308309t, 311
Hepatoblastoma cervical smear, 252, 253 vs. sinonasal neuroendocrine carci-
FNA of, 362 endometrial cells, 255 noma, 287, 290
vs. metastatic neuroblastoma, 283 lymphoid cells, 255 Mediastinum
Hepatocellular carcinoma, 283, 336t Liver, neuroendocrine tumors of hereditary syndromes, 133
vs. pheochromocytoma, 308309t, 311 clinical features, 274 neuroectodermal tumors, 142, 143
Hepatocytes, 362 cytopathologic features, 274 paragangliomas, 137, 143
High-grade squamous intraepithelial differential diagnoses, 274, 281t thymus
lesion, 253 vs. adenocarcinoma, 282, 284 poorly differentiated NECs, 137
Histiocytoma, 342 vs. hepatoblastoma, 283 primary carcinomas of, 133, 134t
Histochemistry, 8, 10, 10, 11 vs. hepatocellular carcinoma, 283 typical and atypical carcinoid tu-
Homer Wright rosettes, 142, 365, 385, vs. poorly differentiated squamous mors, 133137
386, 389 carcinoma, 282 Medullary thyroid carcinoma
Hrthle cell carcinoma FNA biopsy, poorly differentiated clinical features, 163
vs. medullary thyroid carcinoma, 184t, NEC, 273 cytopathologic features
193, 194, 195 gross and microscopic features, 274 amyloid, 180181
vs. pheochromocytoma, 312 metastatic azurophilic granules, 180
Hyalinizing trabecular adenoma, 208t bronchial carcinoid tumor, FNA calcitonin, 174, 178
vs. medullary thyroid carcinoma, 183t, biopsy, 277, 278 cytoplasm, 180
186, 188191 pancreatic, 275, 276 dispersed cell pattern, 172
Hypercalcemic type small cell ovarian car- small cell carcinoma, 76, 279280, FNA, 172180
cinoma, 263 280 nuclei, 170, 180
Hyperplastic nodular goiter vs. medullary small intestinal neuroendocrine Papanicolaou stain, 180
thyroid carcinoma, 182 neoplasm, 278279 plasmacytoid cells, 176

Index 395
pleomorphic, 170, 172174, 176, Melanoma (see Malignant melanoma) Mixed adenoneuroendocrine carcinoma, 4
177, 179, 180 Meningioma Mucinous cystic neoplasms, 126t
Romanowsky stain, 175, 180 vs. paraganglioma, 339t, 350 Mllerian inclusions, 260t
salt-pepper chromatin, 174 vs. pituitary adenoma, 237 Multiple endocrine neoplasia (MEN) syn-
spindle and cuboidal cells, 173 Merkel cell carcinoma, 69t drome, 13t, 14, 105t, 163, 165t
spindle cell pattern, 174, 176, 179 cytopathologic features, 239240, 241t Multiple myeloma
syncytial tissue fragments, 172, 178 cell block, 242 vs. paraganglioma, 340t, 349
diagnostic accuracy, 181 CK20, positive reactivity, 243 vs. pituitary adenoma, 235
differential diagnoses, 181, 181t Diff-Quik stain, 242, 243 Myxoid stroma, 349
vs. amyloid goiter, 182, 188 electron micrograph, 243
vs. anaplastic carcinoma, 186t, 193, enlarged submandibular lymph N
195, 197200 node, 242 Nasopharyngeal carcinoma, 378t, 382
vs. carcinoid tumor, 200 FNA, 242243 vs. sinonasal neuroendocrine
vs. cells of stromal origin, benign gluteal mass, 243 carcinoma, 290
and malignant spindle cells, spindle cell pattern, 243 Neck, paraganglia, 316, 335t, 345
182t, 187 syncytial tissue fragments, 242 Nephroblastoma (Wilms tumor), 370t
vs. follicular adenoma/carcinoma, differential diagnoses, 241, 244t Neural cell adhesion molecule, 11
183t, 186, 191193, 193 and diagnostic accuracy, 241 Neural crest, 389
vs. Hrthle cell carcinoma, 184t, vs. malignant melanoma, 246 Neuroblastoma, 142
193, 194, 195 vs. metastatic basaloid squamous clinical features, 351352
vs. hyalinizing trabecular adenoma, carcinoma, 245 cytopathologic features, 353, 354t
183t, 186, 188191 vs. metastatic poorly differentiated discohesive small malignant cells in
vs. hyperplastic nodular goiter, 182 epithelial malignancy, 245 abundant neuropil, 355
vs. insular carcinoma, 185t, vs. poorly differentiated metastatic FNA of, 354357
193,197 squamous carcinoma, 245 ganglioneuroblastoma, 357
vs. malignant lymphoma, 185t, vs. small cell neuroendocrine carci- as large liver mass, 356
195196, 201 noma, 245 metastatic to bone marrow, 357
vs. malignant melanoma, 196 gross and histologic features, 239, 240 rosette formations, 353, 356, 357
vs. neoplasms with small, round cell immunoprofile, 241 syncytial tissue fragment, 355
pattern, 185t incidence, 239 tissue fragments, low-power
vs. neoplasms with spindle cell pat- metastatic, 246, 247, 247 view,354
tern, 200 vs. salivary glands, primary small cell undifferentiated cells, 355357
vs. nonthyroid neoplasms with carcinoma of, 153154, 156 differential diagnoses, 354
spindle cells, 196, 202 vs. thymic neuroendocrine carcinomas, alveolar rhabdomyosarcoma, FNA
vs. papillary carcinoma, 184t, 138t,141 of, 360
193,196 ultrastructure, 241, 243 desmoplastic round-cell tumor,
vs. paraganglioma, 200, 205, 206 Mesothelial tissue fragments, 260t FNA of, 360
vs. plasmacytoma, 185t, 196 Metastatic chondrosarcoma, FNA of, 200 embryonal rhabdomyosarcoma,
vs. soft tissue tumors, 196, 200 Metastatic leiomyosarcoma, FNA of, 200 FNA of, 361
vs. stromal cells in nodular goiter, Metastatic medullary thyroid carcinoma, Ewing sarcoma, 359
182, 187188 200202, 203207 FNA of lung mass, embryonal
syncytial tissue fragments of, Metastatic neuroblastoma vs. rhabdomyosarcoma, 360
189191, 193, 195, 197 hepatoblastoma, 283 FNA of lytic lesion of shoulder,
gross and histologic features, 165, Metastatic neuroendocrine carcinoma vs. medulloblastoma, 361
166169, 169 pituitary adenoma, 236 hepatoblastoma, 362
hereditary forms, 163, 165, 165t Metastatic pulmonary carcinoid tumor malignant non-Hodgkin B-cell
histochemistry, 169 in bone, 45 lymphoma, 359
immunoprofile, 170, 170t FNA of subcutaneous mass, 44 malignant non-Hodgkin T-cell
metastatic, 200 in liver, 45 lymphoblastic lymphoma, 359
grade III neuroendocrine carcinoma, in serous effusion fluid, 45 massive ascites and bulky mass,
206207 Metastatic small cell carcinoma, 66, peritoneum, 360
lung, 204 7475, 185t PNET, 360
mixed medullary, follicular, and to adrenal gland, 78 small blue round-cell tumors,
composite carcinomas, 201 in body cavity fluids, morphologic 358359
palpable thyroid nodule and cervi- presentations, 7778 syncytial tissue fragment, 360
cal lymphadenopathy, 203 to liver, 76, 279280 Wilms tumor, 362
paraganglioma, 201202, 205206, of lung, 22 gross and microscopic features, 352,
207208t to lymph nodes, 75 352353
small cell carcinoma, 202, 206207 vs. malignant lymphoma, 76 immunoprofile, 352
thigh, 204 to parotid gland, 77 metastatic, 354, 357, 363
vs. paraganglioma, 338t, 345 pulmonary, 313 molecular/cytogenetic findings, 353
radiologic findings, 165 to thyroid, 78 olfactory, 339t
sporadic form, 163, 164 Metastatic squamous carcinoma, 245 olfactory neuroblastomas, 378t, 379
ultrastructure, 170 Microscopic evaluation, of cytologic radiologic findings, 352
Medulloblastoma vs. pituitary adenoma, specimens, 26 ultrastructure, 352, 353
233t,237 Middle ear adenoma, 339t Neuroectoderm, 390

396 Index
Neuroectodermal tumors, 142, 143 P ultrastructure, 108

Neuroendocrine cell, 1, 2, 10, Pancreas, metastatic neuroendocrine carci- WHO classification, 103, 132
1213, 389 noma cells in peritoneal fluid, 21 Pancreatic neuroendocrine tumor
Neuron specific enolase (NSE), 11 Pancreatic duct adenocarcinomas, 117, metastatic to liver, 275
Neuropil, 390 124, 125t vs. paraganglioma, 344
Neurosecretory granules, 12, 12, 390 Pancreatic duct brushings, ERCP, 22, 23 Pancreatic polypeptide (PP) cells, 103
Nodular goiter Pancreatic endocrine tumors (PETs) Pancreatobiliary tracts, specimens
vs. parathyroid adenomas, 220, 221 carcinomas from, 22
stromal cells in, 182, 187188 cytopathologic features, 127, 128 Pancreatoblastoma vs. pancreatic
Non-Hodgkin lymphoma, 359, 379t gross and microscopic features, 127 endocrine tumors, 118t,
vs. Merkel cell carcinoma, 246 clinical features, 104105 124, 127
vs. pancreatic endocrine tumors, 118t, cystic, 123, 124126t, 127 Pap smear, 256
123, 124 cytopathologic features, 108, 109t, 117 Papillary carcinoma
vs. thymic neuroendocrine carcinomas, chromogranin stain, positive vs. medullary thyroid carcinoma, 184t,
138t, 141142 reactivity, 112 193,196
NSE (see Neuron specific enolase (NSE)) cystic neuroendocrine tumor, vs. parathyroid adenomas, 222, 222,
115116 223t,224
O direct brushings of pancreatic duct, Paracrine, 390
Olfactory neuroblastoma, 339t 112 Paraganglia, 390
clinical features, 373 discrete cells, 110 history, 315
cytopathologic features, 374, 377t dispersed pattern of plasmacytoid neoplasms of, 317
FNA of intranasal mass, 376377 cells, 111 normal, distribution of, 315, 316
intraoperative consultation, crush dissociated cell pattern, 110 parasympathetic, 315
preparation, 375376 FNA, 109117 structure of
differential diagnoses, 374, 378379t loosely cohesive groups, 109, cells, 316
basaloid squamous carcinoma, 113116 histochemistry, 316
382383 necrosis, 110 immunoprofile, 317
Ewing sarcoma, 380 Papanicolaou stain, 113, 116 ultrastructure, 317
malignant melanoma, 383 Romanowsky stain, 113, 116 sympathetic, 315
nasopharyngeal carcinoma, 382 saltpepper type chromatin, 110, Paraganglioma, 137, 143, 308309t,
neuroblastoma, 379 113, 115 390 (see also Extra-adrenal
paraganglioma, 383 spindle cell pattern, 115 paragangliomas)
PNET, 380 syncytial tissue fragments, 109, 111, cytopathologic features, 9
rhabdomyosarcoma, 381 112, 114, 116 diagnostic accuracy, 335
sinonasal neuroendocrine carci- types of specimens, 108t malignancy in, 334
noma, 382 typical endocrine histomorphology, vs. medullary thyroid carcinoma, 200,
sinonasal undifferentiated 115 205,206
carcinoma, 381 differential diagnoses, 117118t metastatic, 201202, 205206,
grades of, 373374 vs. acinar cell carcinoma, 119, 120, 207208t
gross and microscopic features, 124 and multiple endocrine tumors,
373374, 375, 376 cystic well-differentiated tumor vs. 334335
immunoprofile, 374 serous cystadenoma, 123 vs. olfactory neuroblastomas,
radiologic findings, 373 and diagnostic difficulties, 117 379t, 383
vs. sinonasal neuroendocrine carci- lobules of normal acini, 119 vs. pancreatic endocrine tumors, 118t,
noma, 286287, 289 vs. malignant lymphoma, 123, 124 122,124
ultrastructure, 374 vs. paraganglioma, 122, 124 vs. pituitary adenoma, 232t, 237
Oligodendroglioma, 384, 387 vs. solid pseudopapillary tumor, pulmonary, 75
vs. pituitary adenoma, 233t, 234 120, 121, 124 Paranasal sinuses, 281, 287
Oral cavity, 239 vs. well-differentiated adenocarci- Paraspinal mass biopsy, crush preparation
Organs of Zuckerkandl, 390 noma, 119 of, 333334
Ovarian adenocarcinoma, 262 vs. duct adenocarcinomas, 117, 124 Parasympathetic (extra-adrenal)
Ovaries gross and microscopic features, 105, paragangliomas, 318
peritoneal washings, 22 105107, 108 Parathyroid adenomas
poorly differentiated (small cell and hereditary syndromes, 104, 105t vs. chronic lymphocytic thyroiditis, 222
large cell carcinoma), 263 histochemistry, 108 vs. cysts, 219220
well-differentiated (carcinoid immunoprofile, 108 cytopathologic features, 212, 217218,
tumors) metastatic carcinomas, 127 218t, 223t
cytopathologic features, 260 FNA biopsy of subcutaneous branching tissue fragments, 215
differential diagnoses, 260261t, tissues, 130 broad capillaries, 215
261263 in liver, 129 dispersed cell pattern, 214
histochemistry, 260 in peritoneal fluid, 130 FNA, 213
histology, 258, 259 mixed exocrine-endocrine tumor of the follicular growth pattern, 213, 214
immunoprofile, 260 pancreas, 130 intrathyroidal, 217218
peritoneal/pelvic washings, cystic vs. normal acinar tissue, 117, 117t, 119 loosely cohesive and discrete
teratoma/dermoid cyst, 259 vs. pancreatoblastoma, 124, 127 epithelial cells, 214, 215
subtypes, 258 radiographic findings, 105 low-power view, 214, 216

Index 397
parathyroid hormone antibody, small cell population of ovary, dif- saltpepper chromatin, 229, 230
positive reactivity, 213, 218 ferential diagnoses, 260261t, syncytial tissue fragments, 230
presenting as thyroid nodule, 261263 differential diagnoses, 227, 232233t
215216 Peritoneal/pelvic washings, 18t, 2021, vs. central neurocytoma, 234
scrape smears, 212213 261263 vs. malignant lymphoma, 235
syncytial tissue fragment, 212, 213 cystic teratoma/dermoid cyst, 259 vs. medulloblastoma, 237
diagnostic accuracy and differential Pheochromocyte, 390 vs. meningioma, small cell type, 237
diagnoses, 219 Pheochromocytoma, 13t, 267, 295, 317, vs. metastatic neuroendocrine
vs. follicular adenoma/carcinoma, 221, 318,390 carcinoma, 233t, 236
222,223t bronchial washings, 306 vs. multiple myeloma, 235
gross and microscopic features, 210, composite, 307 vs. oligodendroglioma, 234
210212 cytopathologic features, 9, 298299, vs. paraganglioma, 237
hereditary syndromes, 210 299t vs. pineocytoma, 238
hyperparathyroidism, 209 dispersed cell pattern, 303 vs. PNET, 236
vs. hyperplasia, 220, 220 FNA of, 301306 vs. small cell glioblastoma, 237
immunoprofile, 212 granular nuclear chromatin, 302 gross and microscopic features,
vs. nodular goiter, 220, 221 nesting pattern and large polygonal 226,226
vs. papillary carcinoma, 222, 222, cells, 306 hereditary syndromes, 226
223t, 224 Papanicolaou stain, 303 immunoprofile, 227
radiologic findings, 210 pleomorphic cell pattern, 300, radiographic findings, 226
vs. thyroid lesions, 220, 221 303,305 ultrastructure, 227
Parathyroid carcinoma, 224 Romanowsky stain, 301, 303 Pituitary gland, anatomy and histology,
Parathyroid glands, normal, anatomy and scrape preparations, 300302, 305 225
histology of, 209, 210 spindle-shaped cells, 302, 304 Plasmacytoma, 185t, 232t
Parotid gland syncytial tissue fragment, 300, 305 vs. medullary thyroid carcinoma,
metastatic small cell carcinoma, 77 differential diagnoses, 308309t 185t,196
primary small cell carcinoma, 148, 155 vs. adrenal cortical carcinoma, 310 vs. paraganglioma, 340t, 349
Pediatric and adolescents vs. adrenal myelolipoma, 312 Pleomorphic adenomas vs. salivary gland
Ewing sarcoma and primitive neuroec- diagnostic difficulties, 307 tumors, 153t, 154, 159
todermal tumors, 363369 vs. hepatocellular carcinoma, 311 Pleomorphic sarcoma, 337t
ganglioneuromas, 363, 364 vs. malignant melanoma, 311 Pleural fluid
neuroblastomas, 351363 vs. metastatic Hrthle cell carci- metastatic neuroblastoma cells, 23, 363
Pelvic washings, 18t, 2021, 259, noma, 312 metastatic small cell carcinoma
261263 vs. metastatic poorly differentiated oflung,22
Peptides, 8 carcinoma, 312 PNET (see Peripheral neuroectodermal
Peripancreatic paraganglioma, 329330 vs. renal cell carcinoma, 310 tumors (PNET))
Peripheral neuroectodermal tumors gross and histologic features, 296, Primary spinal paragangliomas, differen-
(PNET), 68t, 307, 313 296,298 tial diagnoses, 347
central and peripheral, 363 alveolar/nesting pattern (Zellballen), Prostate, neuroendocrine tumors of,
clinical features, 363364 297 263264
cytogenetic analysis, 367 diffuse growth pattern, 297 Proximal jejunum (foregut), carcinoid
cytopathologic features, 358t, 366367, pseudopapillary pattern, 297 tumors, 86t, 8889, 90, 96t
368, 369 solid growth pattern, 298 Psammoma bodies, 261
differential diagnosis, 360, 367 stained with S100 protein, 298 Pulmonary adenocarcinoma, 44
gross and microscopic findings, 364, trabecular pattern, 297 Pulmonary neuroendocrine tumors
365,366 histochemistry, 299 atypical carcinoid tumors
immunoprofile, 367 immunochemistry, 299 bronchial brushings, 48, 49
mediastinal, 142 malignancy in, 306, 307 cytopathologic features, 46, 47t,
vs. olfactory neuroblastomas, 378t, 380 radiologic findings, 296 48, 49
vs. pituitary adenoma, 233t, 236 symptoms, 295 diagnostic accuracy and differential
radiologic findings, 364 ultrastructure, 307 diagnoses, 4647
rosette formations, 366, 368 Pineocytoma vs. pituitary adenoma, FNA of lung mass, 49
vs. sinonasal neuroendocrine carci- 233t,238 gross and histologic features, 43,
noma, 288, 291 Pituitary adenoma, 26, 339t, 378t 46, 46
ultrastructure, 367 classification, 225 metastatic, 47
Peritoneal fluid, 18t clinical features, 225226 classification, 29
cells of neuroendocrine carcinoma of cytopathologic features, 226227, 227t clinical histologic and cytologic fea-
ovary,22 crush preparation, 228231 tures, 7982t
goblet cell carcinoid tumor of dispersed cell pattern, 228, 230 combined small cell carcinomas
appendix, 22 eosinophilic cytoplasm, 229, 230 and adenocarcinoma, 64, 73
Merkel cell carcinoma, 247 follicular pattern, 228 and squamous carcinoma, 63, 72
metastatic neuroendocrine carcinoma granular cytoplasm, 229, 230 large cell neuroendocrine carcinoma,
of pancreas, 130 Papanicolaou stain, 230231 47, 50, 5055, 50t, 53, 54t
metastatic pulmonary carcinoid pleomorphic cells, 228 metastatic small cell carcinoma, 66,
tumor,21 prominent vascular stroma, 230 7475
pancreas, 21 Romanowsky method, 231 to adrenal gland, 78

398 Index
Pulmonary neuroendocrine tumors vs. thymic neuroendocrine carcinomas, vs. metastatic pulmonary small cell
(Continued) 140 carcinoma, 153, 155
in body cavity fluids, morphologic transbronchial aspirates of hilar/ vs. pleomorphic adenomas, 154,
presentations, 7778 mediastinal masses, 66 159
to liver, 76 transthoracic aspirates, 66 vs. poorly differentiated metastatic
to lymph nodes, 75 carcinomas, 154, 156157
vs. malignant lymphoma, 76 R vs. reactive intraparotid lymph
to parotid gland, 77 Rathke pouch, 390 node, 155, 160
to thyroid, 78 Reactive intraparotid lymph node vs. sali- ultrastructure, 148
paragangliomas, 75 vary gland tumors, 153t, 155, 160 Saltpepper chromatin, 7, 110, 113, 115,
small cell carcinoma, 53, 55, 5662, Reactive respiratory epithelial cells vs. 169, 174, 229, 230, 251, 329
57t, 6465 small cell carcinoma, 71 SBT (see Serous borderline tumors)
typical carcinoid tumors Rectum (hindgut), carcinoid tumors, 86t, Schwann cells, 390
bronchial brushings, 3335, 44 93, 97t ganglioneuromas, 363, 364
bronchial washings, 35 Renal cell carcinoma Scrapings, 24
chromogranin staining, 34, 35 vs. pheochromocytoma, 308309t, 310 Serous borderline (SBT) tumors, 260t
cytopathologic features, 30, 32t, vs. retroperitoneal paraganglioma, Serous cystadenoma vs. pancreatic endo-
3337, 38, 3942 336t, 341 crine tumors, 118t, 123, 126t
diagnostic accuracy, 38, 42, 43 Reserve cell hyperplasia vs. small cell car- Serous effusion fluids, 2021, 2123
differential diagnoses, 38, 40, cinoma, 67t, 71 metastatic neuroblastoma, 23
43t,44 Respiratory tract, specimens from, 23, 24 metastatic ovarian carcinoid tumor, 22
FNA of lung mass, 36, 37, 39, Retroperitoneal mass, FNA of, 331, metastatic pancreatic endocrine
40,43 342,343 tumors, 21
gross and histologic features, 30, Retroperitoneal paraganglioma, 335t metastatic pulmonary carcinoid
31, 32 ancillary tests, 336337t tumor, 45
histochemistry, 38 clinicopathologic features, 319320t metastatic pulmonary small cell
immunoprofile, 38 differential diagnoses, 336337t, 337, carcinoma,22
loosely cohesive cells, 35, 36 340344 Silver salt reaction, 10, 10
metastatic, 40, 44, 45 FNA of, 327330 Sinonasal neuroendocrine carcinoma
pattern of tumor cells, 30, 38 Rhabdomyosarcoma (SNEC), 378t, 382
saltpepper chromatin, 33, 34, 40 vs. olfactory neuroblastomas, 378t, 381 cytopathologic features, 281, 284
spindle cell, 30, 38, 39, 4042, 41t vs. sinonasal neuroendocrine carci- differential diagnoses, 281, 285, 285t
syncytial tissue fragment, 36, 37 noma, 288, 290 vs. adenoid cystic carcinoma, 287,
ultrastructure, 38 Romanowsky stain, 113, 116, 142, 175, 290
WHO histologic classification, 8384 180, 219, 231, 301, 303, 357, 368 vs. basaloid squamous carcinoma,
Pulmonary small cell carcinoma Rosette formations, 353, 356358, 368, 387 287,290
vs. adenoid cystic carcinoma, 74 immunocytohistochemical tests,
bronchial brushings, 65, 66, 70, 71 S 289t
bronchial washings and bronchoalveo- S100 protein, 68t, 69t, 118t, 149t, 152t, vs. malignant melanoma, 287, 290
lar lavage, 66 153t, 207t, 289t, 340t vs. metastatic poorly differentiated
diagnostic accuracy, 65 Salivary glands, small cell carcinoma neuroendocrine carcinomas,
diagnostic challenge, 66 cytopathologic features, 147148, 149t 288,290
diagnostic difficulties, scant and air- FNA biopsy of parotid mass, 149, vs. olfactory neuroblastoma,
dried samples, 65 150 286287, 289
differential diagnoses, 6566, necrosis, 151 vs. PNET, 288, 291
6669t,69 nuclear molding, 150, 151 vs. rhabdomyosarcoma, 288, 290
gross and histologic features, 55, 56, 57 peripheral palisading, 151 vs. sinonasal undifferentiated carci-
immunoprofile, 65 squamous differentiation, 151 noma (SNUC), 285286, 289
vs. lymphoid proliferations, 70 squamous metaplasia, 151 vs. EWS, 291
metastatic syncytial tissue fragments, 149, 151 gross and microscopic features, 281
FNA of lymph node, 25 differential diagnoses, 148, 152153t histochemistry, 281
vs. peripheral neuroectodermal gross and histologic features, 147, 148 immunoprofile, 281
tumors, 313 immunoprofile, 148 vs. malignant lymphoma/leukemia, 291
vs. primary small cell carcinoma of primary, 148 ultrastructure, 281
salivary glands, 153, 155 vs. adenoid cystic carcinoma, vs. undifferentiated nasopharyngeal
vs. Merkel cell carcinoma, 244t, 245 154,159 (lymphoepithelial) carcinoma, 290
onion-skin pattern, 22 vs. basal cell adenocarcinoma, Sinonasal tract, 281
vs. poorly differentiated squamous 154,158 Sinonasal undifferentiated carcinoma
carcinoma, 72 vs. basal cell adenoma, 154, 158 (SNUC), 285286, 289, 378t, 381
vs. reactive respiratory epithelial vs. basaloid squamous cell carci- Skin (see Merkel cell carcinoma)
cells,71 noma, 154, 157 Small cell carcinoma, 53, 7982t
vs. reactive type II pneumocytes, 72 vs. cutaneous basal cell carcinoma, metastatic (see Metastatic small cell
vs. reserve cell hyperplasia, 71 154, 158 carcinoma)
sputum, 66, 70, 72 vs. malignant lymphoma, 155, 160 neuroendocrine, 339t
and squamous carcinoma, 63 vs. Merkel cell carcinoma, 153154, of ovaries, 263
vs. thymic neoplasms, 74 156 of pancreas, 128

Index 399
of prostate, 264 Thymic neoplasms vs. small cell Transthoracic aspirates, 66

of thyroid, 202, 206207 carcinoma, 74 Tumor growth pattern
ultrastructure, 65 Thymoma, 68t, 139 neural type, histologic spectrum, 5, 7
urinary bladder, 264266, 265267, Thymus poorly differentiated neuroendocrine
266t classification, 134t, 144145 carcinomas, histologic spectrum,
of uterine cervix, 23, 249258 (see poorly differentiated NECs, 137, 140 56
also Uterine cervix, small cell primary carcinomas of, 133 well-differentiated neuroendocrine neo-
carcinoma of) typical and atypical carcinoid tumors plasms, histologic spectrum, 45
Small intestinal neuroendocrine neoplasm, clinical features, 134 Tumorigenesis, 1314
liver metastases from, 278279 cytopathologic features, 135
Small round-cell tumors diagnostic difficulties and differen- U
of childhood, cytopathologic features, tial diagnoses, 137, 138t Urinary bladder
370371t FNA of mediastinal mass, 135137, extraadrenal pheochromocytomas/
differential diagnoses, 358362 139142 paragangliomas, 267
Small-bowel carcinoid tumor metastatic to gross and histologic features, paragangliomas, 318
liver, 276277 134135, 135t poorly differentiated neuroendocrine
SNEC (see Sinonasal neuroendocrine histochemistry, 135 (small cell) carcinoma, 264
carcinoma (SNEC)) immunoprofile, 135 cytopathologic features, 265, 265,
Soft tissue tumors vs. malignant lymphoma, non- 266
vs. medullary thyroid carcinoma, Hodgkin type, 141142 diagnostic difficulties, 266
196,200 vs. metastatic Merkel cell carci- differential diagnoses, 266,
vs. paraganglioma, 337t, 338t, noma, 141 266t,267
342343, 346 vs. metastatic poorly differentiated gross and histologic features, 265
Solid pseudopapillary tumor (SPT) vs. adeno/squamous carcinoma, 140 immunoprofile, 266
pancreatic endocrine tumors, vs. metastatic pulmonary small cell Urinary tract, 264
118t, 120, 121, 124, 125t carcinoma, 140 specimens from, 24
Solitary fibrous tumor, 338t vs. primary thymic carcinoma, 140 Urine, small cell carcinoma in, 265266,
Somatostatin, 11 vs. thymoma, 139 266t
Somatostatinomas, 88 ultrastructure, 137 Urothelial carcinoma, 267
Specimens (see Cytologic specimens) well and moderately differentiated Uterine cervix, small cell carcinoma of
Spindle cells NECs, 135137, 139 cytopathologic features
anaplastic carcinoma, 199 Thyroid gland cervical biopsy, low-power view of,
carcinoid tumors, 30, 38, 39, 41 calcitonin-producing cells (C cells), 253
medullary thyroid carcinoma, 163, 164 cervical smear, 251253
nonthyroid neoplasms with, lesions vs. parathyroid adenomas, 220, saltpepper chromatin, 251
196, 202 221 syncytial tissue fragments, 251, 253
of stromal origin, medullary thyroid medullary carcinoma differential diagnoses, 254t
carcinoma, 182t, 187 clinical features, 163 cervical smear, polymorphic
Sputum, 18t, 23, 24, 58 cytopathologic features, 170, lymphoid cell population, 255
small cell carcinoma cells in, 58, 66, 170180, 171t, 180181 and diagnostic difficulties, 252
70, 72 diagnostic accuracy, 181 endometrial cells and endometrial
Squamous carcinoma, 245, 254t, 256258, differential diagnoses, 181182, adenocarcinoma, 255256
282 181186t, 187200, 193, high-grade intraepithelial squamous
and small cell carcinoma, 63 195196, 200 lesion, 256
Stomach (foregut), carcinoid tumors, 86t gross and histologic features, 165, liquid-based preparation, lymphoid
cytopathologic features, 8788 166169, 169 cells,255
differential diagnoses, 88 hereditary forms, 163, 165, 165t squamous carcinoma, 256258
gastric brushings, adenocarcinoma, histochemistry, 169
89 immunoprofile, 170, 170t V
malignant lymphoma, 89 metastatic, 200202, 203207, Von Hippel-Lindau disease, 13t, 14, 105t
gross and histologic features, 87, 87 207208t Von Recklinghausen disease, 13t, 105t
histochemistry, 88 radiologic findings, 165
immunoprofile, 88 ultrastructure, 170 W
types of, 87 metastatic small cell carcinoma, 78 Wilms tumor, FNA of, 362
ultrastructure, 88 paraganglioma, 201202, 207208t World Health Organization (WHO)
Sustentacular cells, 390 alveolar/nesting (Zellballen) classification
Sympathoadrenal paraganglia, anatomic pattern,327 gastrointestinal (GI) tract
distribution, 316 differential diagnoses, 347 neuroendocrine neoplasms, 85, 100
Synaptic vesicle protein 2 (SV2), 11 pleomorphic cells, 326, 327 neuroendocrine tumors, 101
Synaptophysin, 11 spindle-shaped nuclei, 326 pancreatic endocrine tumors, 103, 132
stroma, sclerosis of, 327 pulmonary neuroendocrine tumors,
T small cell carcinoma, 202, 206207 8384
Thigh Thyroid nodule, parathyroid adenomas, of tumors of thymus, 144145
FNA biopsy of mass, 130 215216
metastatic medullary thyroid Thyroid transcription factor-1 (TTF-1), 11 Z
carcinoma, 204 Transbronchial aspirates, 66 Zell Ballen, 390

Cytopathology of Neuroendocrine Neoplasia - Color Atlas and Text

Încărcat de

Informații document

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

Cytopathology of Neuroendocrine Neoplasia - Color Atlas and Text

Încărcat de

Drepturi de autor:

Formate disponibile

CYTOPATHOLOGY

(c) 2015 Wolters Kluwer. All Rights Reserved.

(c) 2015 Wolters Kluwer. All Rights Reserved.

2013 by LIPPINCOTT WILLIAMS & WILKINS, a WOLTERS KLUWER business

Previous edition copyright info here.

Library of Congress Cataloging-in-Publication Data

(c) 2015 Wolters Kluwer. All Rights Reserved.

(c) 2015 Wolters Kluwer. All Rights Reserved.

Mithra R. Baliga, MD Shilpa Rungta, MD

(c) 2015 Wolters Kluwer. All Rights Reserved.

(c) 2015 Wolters Kluwer. All Rights Reserved.

(c) 2015 Wolters Kluwer. All Rights Reserved.

(c) 2015 Wolters Kluwer. All Rights Reserved.

(c) 2015 Wolters Kluwer. All Rights Reserved.

1. Dispersed Neuroendocrine System: An Overview 1

2. Types of Cytologic Specimens and Cytopreparations 17

SECTION I: EPITHELIAL TYPE NEUROENDOCRINE TUMORS

3. Pulmonary Neuroendocrine Tumors 29

4. Neuroendocrine Tumors of the Gastrointestinal Tract, Appendix, Gallbladder

5. Neuroendocrine Tumors of the Pancreas 103

6. Neuroendocrine Tumors in the Mediastinum 133

7. Neuroendocrine Tumors of the Salivary Glands 147

8. Neuroendocrine Tumors of the Thyroid Gland 163

9. Neoplasms of the Parathyroid Glands 209

10. Neoplasms of the Pituitary Gland 225

11. Neuroendocrine Tumors of the Skin (Merkel Cell Carcinoma) 239

12. Neuroendocrine Tumors of the Genitourinary Tracts 249

13. Miscellaneous Neuroendocrine Tumors of the Epithelial Type: Breast, Liver,

(c) 2015 Wolters Kluwer. All Rights Reserved.

SECTION II: NEURAL TYPE NEUROENDOCRINE TUMORS

14. Adrenal Pheochromocytoma 295

15. Extra-Adrenal Paragangliomas 315

17. Miscellaneous Neuroendocrine Tumors of the Neural Type: Olfactory Neuroblastoma

(c) 2015 Wolters Kluwer. All Rights Reserved.

cells. These cells were named enterochromaffin cells by

(c) 2015 Wolters Kluwer. All Rights Reserved.

Fig. 1.2: Secretory Activities of Neuroendocrine Cells and Neu-

(c) 2015 Wolters Kluwer. All Rights Reserved.

Fig. 1.3: Amphicrine Cell in Adenocarcinoid of Appendix:

(c) 2015 Wolters Kluwer. All Rights Reserved.

programmed cells is the presence of small secretory

(c) 2015 Wolters Kluwer. All Rights Reserved.

(c) 2015 Wolters Kluwer. All Rights Reserved.

Fig. 1.5: (continued) C: Small cell carcinoma with diffuse popula-

CYTOLOGIC CHARACTERISTICS neuroendocrine carcinomas (Fig. 1.8B). In general, nuclei

(c) 2015 Wolters Kluwer. All Rights Reserved.

(c) 2015 Wolters Kluwer. All Rights Reserved.

Fig. 1.7: (continued) C: Another pattern of neuroendocrine malig-

SECRETORY PRODUCTS Gastrin, ACTH, cholecystokinin, somatostatin, moti-

Amine and Amine Precursors

(c) 2015 Wolters Kluwer. All Rights Reserved.

Fig. 1.8: Cytopathologic Features of Poorly Differentiated Neuro-

(c) 2015 Wolters Kluwer. All Rights Reserved.

Fig. 1.11: A: Diazo reaction producing pigment when nitrous acid

copper to silver salt in order to have silver ion impregna-

(c) 2015 Wolters Kluwer. All Rights Reserved.

processing of regulatory peptides. Other secretogranins

Synaptic Vesicle and Docking Proteins

(c) 2015 Wolters Kluwer. All Rights Reserved.

Fig. 1.13: Ultrastructural appearances of some neurosecretory

(c) 2015 Wolters Kluwer. All Rights Reserved.

TABLE 1.1. NEUROENDOCRINE NEOPLASMS IN HEREDITARY SYNDROMES

Organs/Sites for Neoplasms Associated Location of the Gene

MEN type 2A Autosomal dominant Thyroid C-cell hyperplasia/medullary Germline mutation