Transabdominal Fine-Needle Aspiration Biopsy: A Color Atlas and Monograph, 2nd edition

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Transabdominal Fine-Needle Aspiration Biopsy A Colour Atlas and Monograph Second Edition

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Transabdominal Fine-Needle

Aspiration Biopsy

(Second Edition)

A Colour Atlas and Monograph (with CD-ROM)

Grace Chia-yu Hsu Yang, MD, FIAC Professor, New York University Medical Center, New York

Liahng-Che Tao, MD, FRCPC Professor Emeritus, Indiana University Medical Center, Indianapolis, USA

World Scientific NEW JERSEY . LONDON . SINGAPORE . BEIJING . SHANGHAI . HONGKONG . TAIPEI . CHENNAI

Published by World Scientific Publishing Co. Pte. Ltd. 5 Toh Tuck Link, Singapore 596224 USA office: 27 Warren Street, Suite 401-402, Hackensack, NJ 07601 UK office: 57 Shelton Street, Covent Garden, London WC2H 9HE

Library of Congress Cataloging-in-Publication Data Yang, Grace C. H. Transabdominal fine-needle aspiration biopsy : a color atlas and monograph (with CD-ROM) / Grace C.H. Yang, Liang-Che Tao. 2nd ed. p. cm. Rev. ed. of: Transabdominal fine-needle aspiration biopsy / Liang-Che Tao. c1990. Includes bibliographical references and index. ISBN-13 978-981-256-882-3 -- ISBN-10 981-256-882-4 1. Abdomen--Cancer--Cytodiagnosis. 2. Abdomen--Needle biopsy. 3. Abdominal Neoplasms--diagnosis. 4. Biopsy, Needle--methods. I. Tao, Liang-Che. RC280.A2 T36 2007 616.99'495--dc22 2006053047

British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library.

Copyright © 2007 by World Scientific Publishing Co. Pte. Ltd. All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system now known or to be invented, without written permission from the Publisher.

For photocopying of material in this volume, please pay a copying fee through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA. In this case permission to photocopy is not required from the publisher.

Typeset by Stallion Press Email: [email protected]

Printed in Singapore.

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Dedication

This book is dedicated to the first author’s mother, Wan-yun Lee, a homemaker who gave unconditional love and support to her five children and three grandchildren, and who died of small cell lung cancer at age 68.

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Foreword to the Second Edition

I am pleased and honored to write this foreword to the second edition of Dr. Liang-Che Tao’s monograph on Transabdominal Fine-Needle Aspiration Biopsy. This monograph has been extensively revised and extended by Dr. Grace Yang. It carries on as a significant reference text to an ever expanding and complex area of fine-needle aspiration biopsy. New observations in tumor pathology, classification of tumors, radiologic imaging methods and the specialized techniques of immunohistochemistry and molecular pathology have significantly expanded during the 16 years since the first edition of this monograph was published. The refinements in imaging equipment have greatly increased the interventional radiologist’s reach such that not only are aspirations samples being taken from a growing number of asymptomatic masses within the abdomen but staging of cancer is also being performed. This is a considerable challenge to the cytopathologist, calling upon not only a substantial experience in the interpretation of cytologic and small biopsy specimens but also a broad knowledge of surgical pathology and the application of the special techniques of immunohistochemistry and molecular biology. The continuing evolution of the classification of lymphomas requires not only that good morphologic samples be obtained by aspiration but sufficient specimen be available for flow cytometry and molecular genetics. All of this requires a close working relationship between the cytopathologist and interventional radiologist to maximize information for the benefit of the patient. That relationship has been well described in the current edition. It is equally important to assess the risk and benefits of transabdominal aspiration biopsy when considering assessment of the asymptomatic lesion, the vii

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viii Transabdominal Fine-Needle Aspiration Biopsy

so-called “incidentaloma.” It is easy to employ new procedures but we must constantly be aware of the balance between good and harm to the patient by any new testing modality. The readers will find in the second edition of Transabdominal Fine-Needle Aspiration Biopsy a well-illustrated and comprehensive guide to the interpretation of both common and uncommon lesions that may be encountered within the abdomen. The use of the Ultrafast Papanicolaou stain, devised by Dr. Yang, provides excellent cellular details as an aid in reaching the correct interpretation. The improvement in cell block preparation provides fineneedle core biopsies. Thus the pathologist can combine both cytopathology and traditional tissue pathology to arrive at the correct diagnosis and has available a more suitable sample in many cases for special methods, particularly immunohistochemistry. The emerging area where aspiration biopsy will become even more important is obtaining the sample for not only an interpretation but for a tumor profile using microarrays and the potential of developing tailored therapy. Dr. Tao remains as a pioneer cytopathologist in image-guided aspiration biopsy interpretation with both specimens from the thoracic and abdominal cavity. His lifelong devotion to cytopathology is carried on in the second edition of Transabdominal Fine-Needle Aspiration Biopsy.

William J. Frable, MD, FIAC Principal Editor Cancer (Cancer Cytopathology) Professor of Pathology Virginia Commonwealth University Medical Center Richmond, Virginia May 25, 2006

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Preface to Second Edition

Transabdominal fine-needle aspiration biopsy was introduced in 1975 by Dr. Liang-Che Tao and radiologist colleagues at the Toronto General Hospital, Canada. Dr. Tao summarized his experience in the first edition before he moved to Indiana University Medical Center. There have been several significant developments in tumor pathology during the 16 years that have elapsed since the first edition of this book was published in 1990. New cancers discovered during this time period include gastrointestinal stromal tumors and intraabdominal desmoplastic small round cell tumors, to name a few. New understanding of tumor biology led to the new classifications of lymphoma, kidney and pancreas, among others. A new chapter in gynecologic tumors has been added to the original ovarian tumors. New preparation methods to increase the sensitivity and specificity of samples obtained by fine-needle aspiration biopsy have been developed, including Ultrafast Papanicolaou stain and compact cell block. During this time, immunohistochemistry has become the standard in cytopathology, with ever increasing new markers. The most useful immunomarkers in the first author’s experience are included in the last chapter. An attempt has been made to incorporate this new information into the framework of the first edition with all new color illustrations that the first author encountered mainly at the New York University Medical Center. However, there is no change in the tried-and-true cytologic approach for transabdominal fine-needle aspiration biopsy advocated in the first edition. Emphasis on the cytohistological correlation is made by using composite images from either the cell block or resected tumor whenever possible. Except for the size of the sample, for every histopathology entity there should be a counterpart in cytopathology, since both are derived from the same tumor ix

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Transabdominal Fine-Needle Aspiration Biopsy

undergoing the same pathological process. The difference is in the different artifacts; thus, an attempt has been made to explain the artifact of cytology, so that surgical pathologists can understand the cytologic approach. In addition, the ultrastructural basis of cytological features is emphasized since I was an electron microscopist for 16 years before entering medical school and signed out electron microscopy of all tumor cases when I worked at the Cornell University Medical College, prior to moving to NYU Medical Center in 1996. Both cytology and electron microscopy classify tumors based on small sample by analyzing the cytoplasmic features and the type of cell junctions. All of the micrographs including the electron micrographs, except a case of acinar cell carcinoma of the pancreas, were photographed and arranged by me personally. This edition is a tribute to the pioneer of transabdominal fine-needle aspiration, Dr. Liang-Che Tao, who retired in 1999 from the Indiana University School of Medicine. Hopefully, the new edition will introduce Dr. Tao’s cytologic approach to new generations of pathologists. I wish to thank my husband, Shu Shu Yang, for constant support for my medical career late in life, and George and Jean for being understanding of a mom who was not always there during their growing up. The fellows and residents over the past 14 years are my inspiration to learn more, and I value the friendship from my seven cytopathologists colleagues, 10 cytotechologists, and three preparation technicians at NYU Medical Center. I am deeply grateful to Dr. William J. Frable who read the manuscript during his month long vacation in Florida and made numerous detailed and valuable suggestions. Finally, I wish to thank Dr. Doreen Liebeskind and Dr. Albert V. Messina for inviting me in November, 1994 to Park Avenue Radiologists, PC, to provide immediate diagnosis to their patients using Ultrafast Papanicolaou stain. All of the CT scan images illustrated in this edition were provided by them.

Grace C. H. Yang, MD, FIAC Professor of Pathology New York University Medical Center New York, New York, USA May, 2006

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Preface to First Edition

The development of transabdominal fine-needle aspiration biopsy is considered to be a logical extension of the practice of sophisticated imaging techniques. These imaging techniques can reliably detect and localize an intraabdominal lesion but cannot determine the pathologic nature of the lesion. These techniques, however, combined with the use of fine-needles to obtain cytologic specimens, are able to establish the pathologic diagnosis without the need for surgical intervention. This combination has become such a powerful tool that it has completely revolutionized the approach to the clinical diagnosis of space-occupying lesions in the abdomen. What were previously major diagnostic problems requiring exploratory laparotomy can now be easily solved by a simple, safe outpatient procedure. In about 70% of the 3803 cases in which transabdominal fine-needle aspiration biopsy was performed in our series, surgical intervention was deemed unnecessary. In the last few years the field of radiology has experienced great technological advances. A number of improved imaging techniques, such as ultrasonography and computed tomography, which use powerful computers and can display sectional images, have been developed. They can avoid the superimposition of structures that was inherent in the older radiologic techniques, and thus can reliably detect small lesions throughout the body, particularly in the abdomen. These newer imaging techniques also allow the planning of a safe access route, thereby reducing the risk of complications. The position of the needle tip in relation to the lesion can be readily verified prior to aspiration, ensuring the acquisition of a representative cytologic sample. Because of this development, transabdominal fine-needle aspiration biopsy has been increasingly recognized as an excellent diagnostic method. At the Toronto xi

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General Hospital, it has become an essential part of clinical management, resulting in a substantial change in the pattern of clinical practice. At the Toronto General Hospital, transabdominal fine-needle aspiration biopsy was first performed in 1975, and currently we have approximately 600 cases a year. The rapid increase in the demand for transabdominal aspiration biopsy attests to the wide acceptance of this technique as a useful diagnostic modality. In 1986, at the invitation of Tilde S. Kline, MD, I summarized our 20-year experience in the field of transthoracic fine-needle aspiration biopsy in my book, Guides to Clinical Aspiration Biopsy: Lung, Pleura and Mediastinum (New York, Igaku-Shoin, 1988). After its publication in 1988, I have been asked and encouraged by both readers and peers to summarize our vast experience in the field of transabdominal fine-needle aspiration biopsy. The increasing utilization of transabdominal fine-needle aspiration biopsy prompts a comprehensive description of the diagnostic cytology of samples aspirated from intraabdominal lesions. In order to share my experiences in the interpretation of transabdominal aspiration biopsy specimens, I have prepared this book in a way that gives emphasis to the pitfalls in the interpretation and problems in the differential diagnosis, in the hope that newcomers to the field can avoid making such mistakes. This book contains my personal experience accumulated from many years of practice in this field. This experience could hardly have been gained without sharing and interacting with many past and present colleagues. I am particularly grateful to Bernard Langer, MD, Chairman of the Department of Surgery, University of Toronto; Chia-Sing Ho, MD, radiologist-in-chief; Stephanie Wilson, MD, head of the Division of Ultrasound; and Michael J. McLoughlin, MD, senior staff radiologist at the Toronto General Hospital, for stimulating my interest and supporting my practice in transabdominal aspiration biopsy cytology in the early years, a time when many clinicians and pathologists were doubtful that reliable pathologic diagnosis could be made with such tiny samples. Without their efforts in obtaining excellent specimens and representative cytologic samples in the majority of cases, we could not have gained the kind of accurate results we have in obtaining a pathologic diagnosis. My special thanks to the cytotechnologists on Cytology Service at the Toronto General Hospital for their care in the preparation and screening of the challenging specimens we receive on a daily basis. Finally, I wish to

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thank my wife, Pauline, for her supportive role in my work and for her understanding and patience while I was spending long hours virtually every weekend and during vacation in my computer room over a long period.

Liang-Che Tao, MD

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Contents

Foreword to the Second Edition

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Preface to Second Edition

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INTRODUCTION History . . . . . . . . . . . . . . . . . . . . . . . . . . . . Indications and contraindications . . . . . . . . . . . . . . Advantages . . . . . . . . . . . . . . . . . . . . . . . . . . Complications . . . . . . . . . . . . . . . . . . . . . . . . Reliability . . . . . . . . . . . . . . . . . . . . . . . . . . . Accuracy of needling to obtain a representative sample Accuracy of cytomorphologic interpretation . . . . . . Endoscopic ultrasound-guided fine needle aspiration biopsy . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . .

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PROCEDURES AND TECHNIQUES Localization methods . . . . . . . . . . . . . . . Aspiration biopsy instruments and material . . . Techniques of transabdominal aspiration biopsy Processing of the aspirated material . . . . . . . Procedure of direct smear preparation . . . . . . xv

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Ultrafast Papanicolaou stain . . . . . . . . . . . . . . . . . . . . Cell block preparation . . . . . . . . . . . . . . . . . . . . . . . False-negative results . . . . . . . . . . . . . . . . . . . . . . . . 3. APPROACHES TO THE INTERPRETATION OF TRANSABDOMINAL FINE-NEEDLE ASPIRATION BIOPSY . . . . . . . . .

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THE LIVER Normal cellular components . . Hepatocytes . . . . . . . . Bile duct epithelial cells . . Sinusoidal endothelial cells Kupffer cells . . . . . . . . Nonneoplastic mass lesions . . Nonparasitic cyst . . . . . Hydatid cyst . . . . . . . . Pyogenic abscess . . . . . Granulomas . . . . . . . . Benign mesenchymal tumors . Cavernous hemangioma . Angiomyolipoma . . . . . Nodular hepatocellular lesions . Fatty metamorphosis . . . Focal nodular hyperplasia . Liver cell adenoma . . . .

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Team approach to diagnosis . . . . . . . . . . . . . . . . . Cytologic criteria for the interpretation of aspiration biopsy Cohesion factor (Intercellular cohesion) . . . . . . . . Average nuclear size in tumor cells . . . . . . . . . . . General nuclear shape of tumor cells . . . . . . . . . . Arrangement of tumor cells . . . . . . . . . . . . . . . A unique cytologic feature or special structure . . . . . Other cytologic criteria . . . . . . . . . . . . . . . . . Pitfalls and limitations . . . . . . . . . . . . . . . . . . . . 4.

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Macroregenerative nodule . . . . . . . . . . . . . . Borderline nodule . . . . . . . . . . . . . . . . . . . Hepatocellular carcinoma . . . . . . . . . . . . . . . Well-differentiated cell type . . . . . . . . . . . Classic . . . . . . . . . . . . . . . . . . Microtrabecular variant . . . . . . . . . Microacinar variant . . . . . . . . . . . Clear cell variant . . . . . . . . . . . . . Moderately-differentiated cell type . . . . . . . Poorly differentiated cell type . . . . . . . . . . Pleomorphic large cell type . . . . . . . . . . . Fibrolamellar cell type . . . . . . . . . . Hepatoblastoma . . . . . . . . . . . . . . . . . . . . Pure fetal epithelial type . . . . . . . . . Embryonal and fetal type . . . . . . . . Mixed epithelial and mesenchymal type Tumors of intrahepatic bile duct . . . . . . . . . . . . . . Bile duct adenoma . . . . . . . . . . . . . . . . . . Cholangiocarcinoma . . . . . . . . . . . . . . . . . Angiosarcoma . . . . . . . . . . . . . . . . . . . . . . . Epitheloid hemangioendothelioma . . . . . . . . . . . . Embryonal (undifferentiation) sarcoma . . . . . . . . . . Metastatic tumors . . . . . . . . . . . . . . . . . . . . . Carcinomas metastatic from the respiratory system . Carcinomas metastatic from the prostate . . . . . . . Carcinomas metastatic from the breasts . . . . . . . Malignant melanoma metastatic to the liver . . . . . 5.

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THE PANCREAS Normal cellular components . . . . Acinar cells . . . . . . . . . . Islet cells . . . . . . . . . . . . Pancreatic duct epithelial cells Other cells . . . . . . . . . . . Pancreatitis . . . . . . . . . . . . .

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Acute pancreatitis . . Chronic pancreatitis Pseudocyst . . . . . . Tumors of the pancreas . . Caroli’s disease . . . Ciliated foregut cyst . Serous cystadenoma .

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Solid-Pseudopapillary neoplasm . . . . . Mucinous cystic neoplasm . . . . . . . . Intraductal papillary mucinous neoplasm Colloid carcinoma . . . . . . . . . . . .

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Ductal adenocarcinoma . . . . . . . . . Well-differentiated cell type . . . . Moderately differentiated cell type . Mucinous cell type . . . . . . . . . Poorly differentiated cell type . . . Undifferentiated small cell carcinoma . Anaplastic carcinoma . . . . . . . . . . Pleomorphic giant cell carcinoma . Adenosquamous carcinoma . . . . . . Ampullary carcinoma . . . . . . . . . . Pancreatic endocrine neoplasms . . . . Islet cell tumor . . . . . . . . . . . Islet cell hyperplasia . . . . . . . . Islet cell carcinoma . . . . . . . . . Acinar cell carcinoma . . . . . . . . . . Pancreatoblastoma . . . . . . . . . . .

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MASS LESIONS OF THE KIDNEY Normal cellular components Tubular cells . . . . . . Glomeruli . . . . . . . Nonneoplastic mass lesions Renal cysts . . . . . . .

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Contents

Tuberculosis . . . . . . . . . . . . . . . . . Abscess . . . . . . . . . . . . . . . . . . . Infarct . . . . . . . . . . . . . . . . . . . . Benign mesenchymal tumors . . . . . . . . . . Perirenal lipoma . . . . . . . . . . . . . . . Angiomyolipoma . . . . . . . . . . . . . . Classification of renal epithelial tumors based on cytogenetics . . . . . . . . . . . . Metanephric adenoma . . . . . . . . . . . Mixed epithelial and stromal tumor . . . . Cystic nephroma . . . . . . . . . . . . . . Oncocytoma . . . . . . . . . . . . . . . . . Malignant tumors . . . . . . . . . . . . . . . . Renal cell carcinoma . . . . . . . . . . . . Conventional renal cell carcinoma . . . Papillary renal cell carcinoma . . . . . Chromophobe renal cell carcinoma . . Collecting duct carcinoma of renal medulla Sarcomatoid renal cell carcinoma . . . . . . Carcinomas of the renal pelvis . . . . . . . Sarcomas . . . . . . . . . . . . . . . . . . Wilms’ tumor . . . . . . . . . . . . . . . . 7.

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PRIMARY LESIONS OF THE ADRENAL GLAND Normal cellular components . . . . . . Cortical cells . . . . . . . . . . . . Medullary cells . . . . . . . . . . Nonneoplastic lesions . . . . . . . . . Tuberculosis and fungal infections Adrenocortical nodules . . . . . . . . . Adrenocortical hyperplasia . . . . Cortical nodules . . . . . . . . . . Tumors of the adrenal cortex . . . . . . Adrenocortical adenoma . . . . . Adrenocortical carcinoma . . . .

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Problems in cytologic diagnosis of adrenal cortical nodules . . . . . . . . . . Tumors of the adrenal medulla . . . . . . . . . . . . Pheochromocytoma . . . . . . . . . . . . . . Neuroblastic tumors . . . . . . . . . . . . . . Neuroblastoma . . . . . . . . . . . . . . . Ganglioneuroblastoma . . . . . . . . . . . Ganglioneuroma . . . . . . . . . . . . . . Adrenal myelolipoma . . . . . . . . . . . . . . 8.

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PRIMARY RETROPERITONEAL MASS LESIONS Nonneoplastic mass lesions . . . . . . . . . . . . . . . . Tuberculosis and other mycobacterial infections . . . Abscess . . . . . . . . . . . . . . . . . . . . . . . . Idiopathic retroperitoneal fibrosis . . . . . . . . . . . . . Sarcomas . . . . . . . . . . . . . . . . . . . . . . . . . . Fibromatosis . . . . . . . . . . . . . . . . . . . . . Fibrosarcoma . . . . . . . . . . . . . . . . . . . . . Leiomyosarcoma . . . . . . . . . . . . . . . . . . . Liposarcoma . . . . . . . . . . . . . . . . . . . . . . Rhabdomyosarcoma . . . . . . . . . . . . . . . . . Angiosarcoma . . . . . . . . . . . . . . . . . . . . . Malignant fibrous histiocytoma . . . . . . . . . . . Hemangiopericytoma . . . . . . . . . . . . . . . . . Ewing’s sarcoma . . . . . . . . . . . . . . . . . . . . Neurogenic tumors . . . . . . . . . . . . . . . . . . . . . Neurofibroma . . . . . . . . . . . . . . . . . . . . . Schwannoma . . . . . . . . . . . . . . . . . . . . . Malignant peripheral nerve sheath tumor (MPNST) Paraganglioma . . . . . . . . . . . . . . . . . . . . Germ cell tumors . . . . . . . . . . . . . . . . . . . . . . Seminoma . . . . . . . . . . . . . . . . . . . . . . . Embryonal carcinoma . . . . . . . . . . . . . . . . Yolk sac tumor . . . . . . . . . . . . . . . . . . . . Malignant lymphomas . . . . . . . . . . . . . . . . . . .

212 214 215 215 217 218 219 220 234

. . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . .

235 236 236 237 237 238 238 239 240 241 243 243 244 245 246 246 247 247 248 249 249 250 250 251

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Contents

Other tumors . . . . . . . . . . Chordoma . . . . . . . . . Alveolar soft part sarcoma Synovial sarcoma . . . . . 9.

. . . .

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GYNECOLOGIC TUMORS Endometriosis . . . . . . . . . . . . . . . . . . . . . . . . . . Uterine tumors . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrioid adenocarcinoma . . . . . . . . . . . . . . . Mucinous carcinoma . . . . . . . . . . . . . . . . . . . . Uterine papillary serous carcinoma . . . . . . . . . . . . . Clear cell carcinoma . . . . . . . . . . . . . . . . . . . . Carcinosarcoma (malignant mixed mullerian tumor) . . . Endometrial stromal sarcoma . . . . . . . . . . . . . . . Myometrial tumors . . . . . . . . . . . . . . . . . . . . . . . . Leiomyoma . . . . . . . . . . . . . . . . . . . . . . . . . Leiomyosarcoma . . . . . . . . . . . . . . . . . . . . . . Cervix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mucinous adenocarcinoma . . . . . . . . . . . . . . . . . Squamous cell carcinoma . . . . . . . . . . . . . . . . . . Fallopian tube cancers . . . . . . . . . . . . . . . . . . . . . . Ovarian cancers . . . . . . . . . . . . . . . . . . . . . . . . . . Surface epithelial tumors . . . . . . . . . . . . . . . . . . Serous neoplasms . . . . . . . . . . . . . . . . . . . Endometrioid carcinoma . . . . . . . . . . . . . . . Mucinous neoplasm . . . . . . . . . . . . . . . . . . Borderline mucinous cystic neoplasm . . . . . . . . . Mucinous adenocarcinoma . . . . . . . . . . . . . . Carcinosarcoma (malignant mixed mullerian tumor) Sex cord-stromal tumors . . . . . . . . . . . . . . . . . . Granulosa cell tumor . . . . . . . . . . . . . . . . . . Fibrothecoma . . . . . . . . . . . . . . . . . . . . . Germ cell tumors . . . . . . . . . . . . . . . . . . . . . . Broad ligament tumors . . . . . . . . . . . . . . . . . . . . . .

xxi

251 252 252 253 286

. . . . . . . . . . . . . . . . . . . . . . . . . . . .

287 288 288 289 289 290 290 291 292 292 292 294 294 295 296 296 296 296 297 298 298 299 299 300 300 301 301 302

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Perivascular epithelioid cell tumor (PEComa) . . . . . . . . 302 Ependymoma . . . . . . . . . . . . . . . . . . . . . . . . . 303 Potential for aspiration biopsy of ovarian masses . . . . . . . . . 303 10.

INTRAPERITONEAL MASSES Intraabdominal desmoplastic small round cell tumors Peritoneal papillary serous carcinoma . . . . . . . . . Peritoneal serous borderline tumors . . . . . . . . . Pseudomyxoma peritonei . . . . . . . . . . . . . . . Malignant epithelial mesothelioma . . . . . . . . . . Cohesive cell type . . . . . . . . . . . . . . . . . Noncohesive cell type . . . . . . . . . . . . . . . Papillary cell type . . . . . . . . . . . . . . . . . Reactive mesothelial hyperplasia . . . . . . . . . . . Tumors of the gastrointestinal tract . . . . . . . . . . . . Adenocarcinoma of the stomach . . . . . . . . . . . Mucinous cystic tumors of the appendix . . . . . . . Carcinoid tumors . . . . . . . . . . . . . . . . . . . Adenocarcinoma of the colon . . . . . . . . . . . . . Gastrointestinal stromal tumors . . . . . . . . . . . .

11.

327 . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . .

. . . . . . . . . . . . . . .

MALIGNANT LYMPHOMAS Classification of non-Hodgkin lymphomas . . . . . . . . . Current concept and development of lymphomas . . . . . . General cytologic criteria for the diagnosis of non-Hodgkin lymphomas . . . . . . . . . . . . . . . . . . . . . . . . . Cytologic presentations of non-Hodgkin lymphomas . . . . B-Cell Neoplasms . . . . . . . . . . . . . . . . . . . . . . . Disseminated (Bone marrow) clinical presentation . . . Small lymphocytic lymphoma/chronic lymphocytic leukemia . . . . . . . . . . . . Lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia . . . . . . . . . . . . . Plasma cell myeloma . . . . . . . . . . . . . . . .

328 329 329 329 330 331 331 332 332 333 334 335 336 337 338 360

. . 361 . . 364 . . . .

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366 367 367 367

. . 367 . . 370 . . 370

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Extranodal clinical presentation . . . . . . . . . . . . . . . Marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma . . . . . . Nodal clinical presentation . . . . . . . . . . . . . . . . . Mantle cell lymphoma . . . . . . . . . . . . . . . . . Follicular lymphoma . . . . . . . . . . . . . . . . . . Nodal or Extranodal clinical presentation . . . . . . . . . . Diffuse large B-cell lymphoma . . . . . . . . . . . . . Centroblastic . . . . . . . . . . . . . . . . . . . Immunoblastic . . . . . . . . . . . . . . . . . T-cell/histiocyte rich . . . . . . . . . . . . . . . Anaplastic . . . . . . . . . . . . . . . . . . . . Mediastinal (thymic) large B-cell lymphoma . . . . . Primary effusion lymphoma . . . . . . . . . . . . . . Burkitt lymphoma . . . . . . . . . . . . . . . . . . . Burkitt-like lymphoma . . . . . . . . . . . . . . . . . T-Cell Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . Precursor T-lymphoblastic lymphoma/leukemia . . . . . . Mature T-cell and NK-cell neoplasms . . . . . . . . . . . . Leukemic or disseminated lymphoma . . . . . . . . . . . . . . Adult T-cell leukemia/lymphoma . . . . . . . . . . . . . . Extranodal T/NK cell lymphomas . . . . . . . . . . . . . . . . Mature extranodal T/NK-cell lymphomas . . . . . . . . . Mycosis fungoides/Sézary syndrome . . . . . . . . . . . . Nodal T/NK cell lymphomas . . . . . . . . . . . . . . . . . . . Anaplastic large cell lymphoma . . . . . . . . . . . . . . . Angioimmunoblastic T-cell lymphoma . . . . . . . . . . . Peripheral T-cell lymphoma, unspecified . . . . . . . . . . Hodgkin lymphoma . . . . . . . . . . . . . . . . . . . . . . . . Nodular lymphocyte predominant Hodgkin lymphoma . . Classic Hodgkin lymphoma . . . . . . . . . . . . . . . . . Histiocytic and dendritic neoplasms . . . . . . . . . . . . . . . Langerhans cell histiocytosis . . . . . . . . . . . . . . . . . Follicular dendritic cell sarcoma . . . . . . . . . . . . . . .

fm

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371 371 372 372 372 374 374 374 375 375 376 376 376 377 377 378 378 378 379 379 380 380 380 381 381 382 382 382 383 383 386 387 387

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12.

IMMUNOMARKERS FOR TRANSABDOMINAL ASPIRATION BIOPSY Immunohistochemical staining for aspiration biopsy . . Avidin-Biotin-Immunoperoxidase staining procedure for aspiration preparations . . . . . . . . . . . . . . . . . Technical problems in immunohistochemical staining for aspiration preparations . . . . . . . . . . . . . . . . . Useful tumor markers for the interpretation of transabdominal aspiration biopsy specimens . . . . . Frequently ordered immunomarkers . . . . . . . . . . . Commercially available antibodies . . . . . . . . . . . .

Index

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416 . . . . 417 . . . . 418 . . . . 420 . . . . 421 . . . . 423 . . . . 426

449

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CHAPTER 1

Introduction

In diagnosing an intraabdominal mass lesion discovered either by clinical examination or by an imaging technique, the clinician must choose from a variety of methods, ranging from exfoliative cytology and different forms of biopsy, e.g. percutaneous fine-needle aspiration biopsy and large-bore needle biopsy, endoscopic ultrasound-guided fine needle aspiration, to exploratory surgical procedures. The risk and discomfort of any method chosen must be balanced against its potential diagnostic yield. In general, simple and safe techniques with high accuracy are the first choice. Exfoliative cytology is a simple and safe method, but it is ineffective if the intraabdominal tumors do not exfoliate cells or the exfoliated cells do not reach body cavities, excretory ducts, or tracts. To determine the pathologic nature of such lesions, transabdominal fine-needle aspiration biopsy is one of the diagnostic methods that have been used preferentially in many hospitals in the past two decades. Transabdominal fine-needle aspiration biopsy is a cytologic technique for diagnosis, requiring a sample smaller than that needed for histologic examination. It is a method of cell investigation that is based on removal of a cell sample by use of a fine needle (22- to 25-gauge; outside diameter, 0.5 to 0.7 mm). The aspirated cell sample is a suspension of various types of cells in a minute amount of blood or tissue fluid, which is smeared on glass slides for cytomorphologic study. Some clinicians have mistakenly regarded fine-needle aspiration biopsy as a simple, less accurate version of tissue needle biopsy. It should be stressed that fine-needle aspiration biopsy is different from tissue needle biopsy, which is performed with a large-bore needle (e.g. a Jamshidi, Menghini, Vim Silverman, or other needle; 12- to 18-gauge; outside diameter, 1.3 to 2.7 mm). The latter consists of tissue cores that are embedded 1

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Transabdominal Fine-Needle Aspiration Biopsy Table 1.1 Transabdominal Fine Needle Aspiration Biopsy (Toronto General Hospital, 1975–1988) Anatomic Sites Pancreas Liver Kidney Adrenal Retroperitoneal mass Intraperitoneal mass Total

Number of Cases 584 1383 276 167 494 508 3803

in paraffin and sectioned for histopathologic examination and which involves pattern diagnosis. Virtually any part of the body can be investigated by percutaneous fine-needle aspiration biopsy. This is not the case with tissue needle biopsy, which is potentially dangerous because of the possibility of puncture trauma to the bowel, blood vessels, and excretory ducts. Since the introduction of percutaneous fine-needle aspiration biopsy of intraabdominal lesions under the guidance of an imaging technique, the scope of cytology has been greatly expanded. This capability makes modern cytology sophisticated and challenging. Transabdominal fine-needle aspiration biopsy may provide information otherwise obtainable only by laparotomy. Transabdominal fine-needle aspiration biopsy started in Toronto General Hospital in Canada in 1975, and within 14 years, 3803 cytology specimens (Table 1.1) have been processed and interpreted in the Cytopathology Division. This contributes to a substantial change in the pattern of clinical practice in that hospital. Starting with 48 cases a year in 1975, it reached 598 cases in 1989. The rapid increase in the clinical demand for transabdominal fine-needle aspiration biopsy attests to the wide acceptance of this technique as a useful diagnostic modality.

HISTORY For many years there was a marked fluctuation in the clinical applications of needle biopsy, which was performed intermittently in the latter half of the 18th century and the early years of the 19th century.18,25 Most early

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Introduction 3

biopsies were done with a large-bore needle (12- to 18-gauge). In 1883, Leyden obtained, by transthoracic needle biopsy, tissue samples that contained microorganisms from a patient with pneumonia. In 1884 Krönig was the first person to diagnose lung cancer by means of aspiration biopsy.29 Two years later, Ménétrier also diagnosed lung cancer by using this technique.37 In 1904, Greig and Gray identified trypanosomes in aspirates from lymph nodes of patients with sleeping sickness.15 In 1912, Hirschfeld identified a lymphoma of the skin on the basis of an aspiration smear19 and later extended his work to other tumors.20 In 1921, Guthrie published his work on the diagnosis of lymph node aspirates.16 Aspiration biopsy was first popularized at the Memorial Hospital for Cancer and Allied Diseases, New York, in the 1930s.34,46 In 1930, Martin and Ellis published their initial observations34 and in 1934 they published again their work based on experience with 1405 diagnoses of cancer.35 At that time, aspiration biopsy was done with 18-gauge needles, which, in addition to providing material for cytologic study, might yield tissue fragments for histopathologic examination. In 1947, Ochsner and DeBakey condemned this procedure because of the occurrence of tumor implants along the needle tracts.41 Similarly, others strongly denounced needle biopsy because of the fear of tumor implants.2,6,9 This resulted in a sharp decline in the use of needle biopsy in the United States. In Germany, Mannheim reported his findings in 43 aspirated tumors in 1931.33 During the late 1940s and the early 1950s, European physicians developed the technique of aspiration biopsy performed with a fine needle (21- to 23-gauge).5,11 Cardozo and Söderström were the pioneers of the technique.45 The initial attempts were performed mainly on palpable superficial lesion, particularly enlarged lymph nodes and breast lumps. Because the initiators of the techniques were versed in hematology, air-dried smears and May-Gr˝unwald-Giemsa stain were applied in the study of aspirates. The development of image intensification and television made possible the performance of transthoracic fine-needle aspiration biopsy under fluoroscopic control.7,31 Nordenst˝om and Franzen and Zajicek popularized the use of small-bore needle (20 or smaller gauge) technique, which avoided the greater risk of needle biopsy done with a large-bore needle.12,38–40 With the development of an ever-increasing number of available imaging techniques, transabdominal fine-needle aspiration biopsy has created great

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interest.14,17,24,28,32,56 In the past decade, the field of radiology has experienced great technological advances. A number of improved imaging techniques, such as computed tomography (CT scan) and ultrasonography that use powerful computers and produce sectional images, have been developed. They can reliably detect small lesions in the abdomen. These new imaging techniques also permit the planning of a safe access route, thereby reducing the risk of complications. The position of the needle tip in relation to the lesion can be readily verified prior to aspiration, ensuring the acquisition of a representative cytologic sample. Because of this development, transabdominal fine-needle aspiration biopsy has been increasingly recognized as an excellent diagnostic method.51–53 It soon became indispensable in some centers, where it was introduced and produced highly accurate results. By 1989 when the senior author left the Toronto General Hospital for Indiana University Medical Center, transabdominal fine-needle aspiration biopsy had already become an essential part of the clinical management of the patients.21–23,36,47–51

INDICATIONS AND CONTRAINDICATIONS Transabdominal fine-needle aspiration biopsy is considered most useful in patients with suspected malignant diseases. Virtually any accessible mass in the abdomen, retroperitoneum, or pelvis can be investigated by percutaneous fine-needle aspiration biopsy, except under circumstances that are considered contraindications to needle biopsy, such as the existence of bleeding disorders, suspected hydatid disease, ileus or bowel distention, uncontrolled coughing, and poor patient cooperation. The indications for the procedure vary from center to center. This diagnostic procedure is certainly the method of choice in the following settings: 1. Medical contraindications to laparotomy, or a patient’s refusal of surgery, or the presence of a metastatic disease. 2. Inoperable cancer in which a pathologic diagnosis is required before radiotherapy and/or chemotherapy. 3. For the confirmation of a suspected cancer in a patient who is a marginal surgical risk to indicate the need for operation. 4. For the confirmation of a suspected localized benign lesion, especially in poor risk patients, thereby obviating laparotomy.

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Introduction 5

5. For the confirmation of a suspected recurrent or metastatic malignant tumor. 6. In cases in which there is a clinical suspicion of more than one type of malignant lesion, including malignant lymphoma. 7. For the identification of offending organisms in cases of infection, e.g. an intraabdominal abscess. 8. For the staging work-up of a malignant tumor in a patient who has adrenal or liver lesions and/or enlarged pelvic or retroperitoneal lymph nodes suspected of harboring metastases. By late 1980s, clinicians started to give preference to the fine-needle aspiration method over other diagnostic procedures because it provides a rapid diagnosis, thus streamlining the investigation. At the Toronto General Hospital, reports on cytology specimens obtained by fine-needle aspiration biopsy were sent out the day the specimens were received. On special requests (e.g. intraoperative aspiration biopsy), the results were ready in less than 15 minutes. Therefore, additional laboratory investigation and hospital days are saved, not to mention that laparotomy is frequently canceled because of the results of the procedure.

ADVANTAGES This diagnostic procedure has been used preferentially in many hospitals over the past two decades. The reason is not difficult to understand. The method is easy and safe, and the diagnosis is quick. In experienced hands, the procedure is highly accurate in obtaining a pathologic diagnosis, and the clinician can opt to perform the technique without hesitation. Clinicians will come to realize that many major diagnostic procedures can be avoided if the cytomorphologic features of obscure lesions can be identified at once by direct aspiration biopsy. For many patients, hospitalization and costly operations may be averted. In one series of 106 patients with abdominal lesions, percutaneous fine-needle aspiration biopsy was instrumental in avoiding 61 planned invasive investigations and 11 surgical explorations.4 In about 70% of the 3803 cases in which transabdominal fine-needle aspiration biopsy was performed in the Toronto General Hospital series, surgical intervention was deemed unnecessary. Because the procedure can be done on an outpatient

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basis, the economic advantage is also obvious. This is certainly a great savings in healthcare resources. The morbidity and mortality associated with this technique are far less than those associated with large-bore needle biopsy or exploratory laparotomy. The savings in morbidity, mortality, and healthcare resources are considered the major advantage of this diagnostic method. In patients in whom surgical intervention is indicated, a diagnostic biopsy specimen may allow the surgeon to plan the operation with knowledge of the type of lesion he or she is dealing with and eliminate frozen section, thereby saving operation time. Because of the minor nature of transabdominal fine-needle aspiration biopsy, the procedure can be performed on an outpatient basis, be readily repeated, be used for multiple lesions, and be done in debilitated patients.

COMPLICATIONS The many complications of tissue needle biopsies with large-bore needles are apparently due to puncture trauma that is related to the outside diameter of the needles. The use of fine needles greatly reduces this hazard. The crosssectional area of a 22-gauge needle is approximately five times less than that of a Menghini needle and 12 times less than that of a Vim Silverman needle.36 Although bowel or stomach is traversed by the needle in almost every biopsy of deep-seated organs or retroperitoneal masses, this does not appear to be a matter of concern, since the needle is smaller in size than surgical sutures used in these organs. We have not noticed any instance of perforation of the bowel or stomach or of infection. In the Toronto General Hospital series, cases showing evidence of hemorrhage following aspiration biopsy by one of the imaging techniques were rarely encountered, and no treatment was required. One patient who developed pancreatitis following aspiration biopsy of a slightly enlarged but normal pancreas was recorded. However, we observed no complications when mass lesions of the pancreas were aspirated. Occasional patients experienced mild vasovagal reactions and usually responded promptly to intravenous fluid. In general, the morbidity from transabdominal fine-needle aspiration biopsy is minimal and is far outweighed by the clinical value of the procedure. In experimental animals subjected to laparotomy following needle biopsy, the puncture sites usually cannot be seen. Goldstein et al. conducted

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Introduction 7

a study on dogs which were anesthetized and on which several percutaneous needle biopsies directed into solid and hollow viscera were performed. Laparotomy at varying time intervals after the biopsies revealed no significant findings, and in most instances the needle biopsy site could not be found. In the early 1970s the senior author and radiologist colleagues used this technique on the bodies of patients who died of carcinoma of the pancreas to obtain cytologic specimens from the tumors under fluoroscopic control. We found no leakage of gastric fluid after withdrawal of needles and no abnormality during autopsy, in spite of the fact that in some cases the needles had to traverse the stomach to reach the tumor masses (Fig. 1.1). In most patients undergoing laparotomy after transabdominal fine-needle aspiration biopsy, no hemorrhagic complications was observed, even when major arteries were punctured. Similarly, Lalli had needled the pulmonary artery and vein, the aorta, and aortic aneurysm many times with no resulting complication.30 The possibility of tumor spread along the needle tract following needle biopsy, especially cutting needle biopsy, has been mentioned in the literature. Although a number of such cases following transperineal biopsy of the prostate, transabdominal biopsy of the liver, and transthoracic biopsy of the lung with a large-bore needle have been reported,1,8,42,43,55 the risk of tumor spreading considered is negligible when the fine-needle technique is used. Another concern is the possibility of hematogenous or lymphagitic spread of the cancer by fine-needle aspiration biopsy with resultant distant dissemination of tumor cells and lower survival rates. However, studies of cancer of the breast,3,13,44,54 kidney,54 and lung26,44 have failed to show evidence of shortened survival among patients undergoing percutaneous fine-needle aspiration biopsy as compared with the survival of matched control subjects. Experimental studies by Engzell et al. also failed to substantiate dissemination of tumor cells following fine-needle aspiration biopsy.10

RELIABILITY If this method is to be advocated for most patients and to be relied upon in disease management, it must be highly reliable, must have a reasonably high diagnostic yield (i.e. few false-negative results), and must be safe. In turn, the reliability of this method depends upon two factors. These are now discussed.

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Accuracy of Needling to Obtain a Representative Sample An operator capable of obtaining an adequate amount of the target tissue is essential for a successful biopsy. This does not seem to be a problem in experienced hands. In recent years, as a result of improved imaging techniques which can display sectional images, the position of the needle tip in relation to the lesion can be readily verified prior to aspiration, ensuring the acquisition of the target tissue. In the majority of aspiration biopsies of intraabdominal masses done by experienced radiologists in the Toronto General Hospital at the time, representative cytology samples were obtained on the first pass. The smallest, intraabdominal lesion successfully aspirated in the series was 7 mm in its greatest dimension. In approximately 5% of cases, no representative material from the lesion was received, even when the radiologists were certain that the tip of the needle was in the lesion. This problem is a sampling error. The settings in which sampling errors may occur include a carcinoma in a large area of fibrous tissue; a large reactive zone surrounding a small tumor; the presence of a large amount of inflammatory exudates in the proximity of the tumor; and an infiltrating but nonsolid cancerous growth. In addition, if a lesion is distant from the site of entry and smaller than 2 cm in diameter, and when the position of the needle cannot be documented before aspiration, the needle tip may miss the target lesion. According to the results with aspiration biopsy of intraabdominal lesions at the Toronto General Hospital at that time, the chance that a single pass would yield a representative sample was 72.3%. However, for three passes with slight modification in the angle of approach, the chance increased to 95% in experienced hands. Because transabdominal fine-needle aspiration biopsy is performed under the guidance of imaging techniques and the accuracy of needling to obtain a representative sample can be improved by multiple passes, fineneedle aspiration biopsy is far superior to tissue needle biopsy in the diagnosis of hepatic malignancy. In 1975 when fine-needle aspiration biopsy of the liver was first performed at the Toronto General Hospital, in order to compare the results of large-bore needle biopsy with those of fine-needle aspiration biopsy, concurrent Jamshidi needles to obtain a tissue core and 22-gauge fine-needles to obtain a cytology sample were used for every case. Among the first 20 cases of proven hepatic malignancy, the diagnostic rate

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Introduction 9

by fine-needle aspiration biopsy was 90% (18 cases), whereas by Jamshidi needle biopsy, it was 25% (5 cases). It appears that fine-needle aspiration biopsy enhances the potential for the diagnosis of malignant lesions.

Accuracy of Cytomorphologic Interpretation Although fine-needle aspiration biopsy is considered easy to perform, difficulty arises in the interpretation of aspirate preparations. A disadvantage of fine-needle aspiration biopsy is that it provided a small amount of material for examination. Another disadvantage is that the histologic patterns of lesions seen in tissue section are absent, thus necessitating considerable expertise on the part of cytopathologists. Therefore, the crucial part of this method appears to lean heavily on a cytopathologist’s interpretation of aspirate preparations. From the experience with transthoracic and transabdominal aspiration biopsies, the senior author realized that the so-called cytologic criteria for malignancy described in pathology and cytology books are not applicable to the interpretation of many cases, because malignant cells from some tumors appear benign in aspirate preparations and vice versa. These are the pitfalls in cytomorphologic interpretation of aspirate preparations and are expected to continuously cause misinterpretations. Thus, special training is required to become familiar with the cytologic features of different types of tumors in aspiration preparations, which have markedly different morphologic appearances from those seen in tissue sections. It is our belief that the pitfalls in the cytomorphologic interpretation of transabdominal aspiration biopsy specimens, which often account for unsuccessful attempts, can be readily avoided with experience. With experience, it is also possible to type tumors and to determine primary tumor sites on the basis of cytomorphologic features in many cases of well-differentiated cancers and even in some cases of poorly differentiated lesions.47–49,51 With ever increasing number of antibodies against cellular antigens, immunohistochemistry provides a useful adjunct in the interpretation of transabdominal fine-needle aspiration biopsy specimens and may help resolve some difficult diagnostic problems. Having examined more than 13,000 cytology specimens obtained by transabdominal and transthoracic fine-needle aspiration biopsy, we are convinced that this technique, when practiced by well-trained

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and experienced cytopathologists, is an excellent diagnostic method that has a high degree of accuracy in obtaining a pathologic diagnosis.

Endoscopic Ultrasound-Guided Fine Needle Aspiration Biopsy In the late 1990s, cytopathology laboratories began to receive fine needle aspiration samples of abdominal lesions obtained via endoscopic ultrasound guidance from gastroenterologists. Under sedation, the instrument enters via the oropharynx of the patient into the gastrointestinal tract. The procedure is technically demanding, thus the diagnostic yield is highly operator-dependent. The samples are frequently contaminated by the normal glandular epithelium and intraluminal mucin present along the needle path of the gastrointestinal tract, and are therefore difficult to be distinguished from well-differentiated adenocarcinoma. Although the diagnostic yield can be increased by on-site assessment by pathologists,27 in an editorial comment, Schwartz asked “Why is there not rapid assessment of adequacy at all institutions?” The reason is “time and money.” The time spent is considerable and the reimbursement low. However, the most important issue is the patients, who endured 1–2 hours of endoscopic ultrasound-guided biopsy under general anesthesia but ended up with non-diagnostic reports.

CONCLUSIONS Our experience and published material in the past 30 years indicate that transabdominal fine-needle aspiration biopsy is inexpensive, safe, and highly accurate (in experienced hands) in obtaining a pathologic diagnosis. It may provide information otherwise obtainable only by laparotomy, and it can enhance the potential for the diagnosis of malignant lesions, especially small, early cancers. For many patients, major diagnostic procedures, costly operations, and hospitalization may be averted. It is evident that this technique can bring great savings in healthcare. In light of these factors, this diagnostic procedure deserves widespread clinical application. Because the accuracy of cytomorphologic interpretation plays a major role in the success of the technique, adequate training in transabdominal aspiration biopsy cytology, as well as a full awareness of the pitfalls in the interpretation, is essential.

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Introduction 11

Adequate sampling, experience in interpretation, and close working relationships among the clinician, the radiologist, and the cytopathologist are factors essential to the success of transabdominal fine-needle aspiration biopsy. Transabdominal fine-needle aspiration biopsy, which has become an indispensable procedure in clinical management in the medical centers, does not constitute a challenge to histopathology. Instead, cytologic and histologic methods complement each other, and close cooperation between cytopathologists and histopathologists will make clinical diagnosis and healthcare more efficient, more accurate, and less traumatic to patients.

REFERENCES 1. Addonizio JC, Kapoor SN. (1976) Perineal seeding of prostatic carcinoma after needle biopsy. Urology 8:513–515. 2. Allbritten FF Jr, Nealon T, Gibbon JH Jr. (1952) The diagnosis of lung cancers. Surg Clin North Am 32:1657. 3. Berg JW, Robbins G. (1962) A late look at the safety of aspiration biopsy. Cancer 15:826–827. 4. Bret PM, Fone A, Casola G. (1986) Abdominal lesions: A prospective study of clinical efficacy of percutaneous fine-needle biopsy. Radiology 159:345–346. 5. Cardozo PL. (1954) Clinical Cytology. Leiden, Netherlands, Straflen. 6. Crile G Jr, Vickery AL. (1952) Special uses of the Silverman biopsy needle in office and at operation. Am J Surg 83:83–85. 7. Dahlgren SE, Nordenstrom B. (1966) Transthoracic Needle Biopsy. Chicago, Year Book. 8. Desai SG, Woodruff LM. (1974) Carcinoma of the prostate: Local extension following perineal needle biopsy. Urology 3:87–88. 9. Dutra R, Geraci C. (1954) Needle biopsy of the lung. JAMA 155:21–24. 10. Engzell U, Esposti PL, Rubio C. (1971) Investigation on tumor spread in connection with aspiration biopsy. Acta Radiol 10:385–398. 11. Franseen CC. (1941) Aspiration biopsy with a description of a new type of needle. N Eng J Med 224:1054–1058. 12. Franzen S, Giertz G, Zajicek J. (1960) Cytological diagnosis of prostatic tumor by transrectal aspiration biopsy: A preliminary report. Br J Urol 32:193. 13. Franzen S, Zajicek J. (1968) Aspiration biopsy in diagnosis of palpable lesions of the breast. Critical review of 3479 consecutive biopsies. Acta Radiol 7:241–262.

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14. Goldstein HM, Zornoza J, Wallace S, et al. (1977) Percutaneous fine-needle aspiration biopsy of pancreas and other abdominal masses. Radiology 123: 319–322. 15. Greig EDW, Gray ACH. (1904) Note on the lymphatic glands in sleeping sickness. Br Med J 1:1252. 16. Guthrie CG. (1921) Gland puncture as a diagnostic measure. Bull Johns Hopkins Hosp 32:266–269. 17. Hancke S, Holm HH, Koch F. (1975) Ultrasonically guided percutaneous fine needle biopsy of the pancreas. Surg Gynecol Obstet 140:361–364. 18. Hellendal H. (1899) Fin beitrag zur diagnostik der lungengeschwullste. Z Klin Med 37:435. 19. Hirschfeld H. (1912) Leber isolierte aleukaemische Lymphadenose der Haut. Z Krebsforsch 11:397–407. 20. Hirschfeld H. (1919) Bericht ueber einige histologischmikroskopische and experimentelle Arbeiten bet den boesartigen Geschwuelsten. Z Krebsforsch 16:33–39. 21. Ho CS, McLoughlin MJ, McHattie JD, et al. (1977) Percutaneous fine-needle aspiration biopsy of the pancreas following endoscopic retrograde cholangiopancreatography. Radiology 125:351–353. 22. Ho CS, McLoughlin MJ, Tao LC, et al. (1981) Guided percutaneous fine needle aspiration biopsy of the liver. Cancer 47:1781–1785. 23. Ho CS, Tao LC, McLoughlin MJ. (1978) Percutaneous fine-needle aspiration biopsy of intra-abdominal masses. Can Med Assoc J 119:1311–1314. 24. Holm HH, Pederson JG, Kristensen K, et al. (1975) Ultrasonically guided percutaneous puncture. Radiol Clin North Am 13:493–503. 25. Horder TJ. (1909) Lung puncture: A new application of clinical pathology. Lancet 2:1539–1540. 26. Jackson R, Coffin L, DeMeules J. (1980) Percutaneous needle biopsy of pulmonary lesions. Am J Surg 139:586–590. 27. Jhala NC, Jhala D, Eltoum I, et al. (2004) Endoscopic ultrasound-guided fineneedle aspiration biopsy: A powerful tool to obtain samples from small lesions. Cancer Cytopathol 102:239–246. 28. Kaminsky DB. (1984) Aspiration biopsy in the context of the new Medicare fiscal policy. Acta Cytol (Baltimore) 28:333–336. 29. Kristensen JK, Holm HH, Rasmussen SN, et al. (1972) Ultrasonically guided percutaneous puncture of renal masses. Scand J Urol Nephrol (Suppl) 6:49–56. 30. Kronig G. (1887) Diagnostischer Beitrag Zur Herz-and Lungen pathologic. Bert Klin Wochenschr 24:961–967.

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Introduction 13

31. Lalli AF. (1973) Roentgen-guided aspiration biopsies of thoracic, renal and skeletal lesions. In: Meaney TF, Lath AF, Altidi RJ (eds.), Complications and Legal Implications of Radiologic Special Procedures. St. Louis, CV Mosby, pp. 83–91. 32. Lath AF, Naylor B, Whitehouse WM. (1967) Aspiration biopsy of thoracic lesions. Thorax 22:404–407. 33. Lunderquist A. (1971) Fine-needle aspiration biopsy of the liver: Applications in clinical diagnosis and investigation. Acta Med Scand (Suppl) 520:1–28. 34. Mannheim EP. (1931) Die Bedeutung der Tumorpunktion fur Tumordiagnose. Z Krebsforsch 34:574–593. 35. Martin HE, Ellis EB. (1930) Biopsy by needle puncture and aspiration. Ann Surg 62:169–181. 36. Martin HE, Ellis EB. (1934) Aspiration biopsy. Surg Gynecol Obstet 59:578–589. 37. McLoughlin MJ, Ho CS, Langer B, et al. (1978) Fine-needle aspiration biopsy of malignant lesions in and around the pancreas. Cancer 41:2413–2419. 38. Menetrier P. (1886) Cancer primitif du Poumon. Bull Soc Anat 11:643. 39. Nordenstrom B. (1965) A new technique for transthoracic biopsy of lung changes. Br J Radiol 38:550–553. 40. Nordenstrom B. (1967) Transthoracic needle biopsy. N Engl J Med 276: 1081–1082. 41. Nordenstrom B. (1975) New instruments for biopsy. Radiology 117:474–475. 42. Ochsner A, DeBakey M, Dixon JL. (1947) Primary cancer of the lung. JAMA 135:321–327. 43. Sakurai M, Seki K, Okamura J. (1983) Needle implantation of hepatocellular carcinoma after percutaneous liver biopsy. Am J Surg Pathol 7:191–195. 44. Schachter EN, Basta W. (1973) Subcutaneous metastasis of an adenocarcinoma following a percutaneous pleural biopsy. Am Rev Respir Dis 107:283–285. 45. Schwartz MR. (2004) Endoscopic ultrasound-guided fine needle aspiration: Time, diagnostic changes, and clinical impact. Cancer (Cancer Cytopathol) 102: 203–206. 46. Sinner WN. (1976) Complications of percutaneous transthoracic needle aspiration biopsy. Acta Radiol (Diagn) 17:813–828. 47. Soderstrom N. (1966) Fine-Needle Aspiration Biopsy. Stockholm, Almqvist & Wiksells. 48. Stewart FW. (1933) The diagnosis of tumors by aspiration. Am J Pathol 9:901. 49. Tao LC, Donat EE, Ho CS, et al. (1979) Percutaneous fine needle aspiration biopsy of the liver: Cytodiagnosis of hepatic cancer. Acta Cytol 23:287–291.

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50. Tao LC, Ho CS, McLoughlin ML, et al. (1978) Percutaneous fine-needle aspiration biopsy of the pancreas: Cytodiagnosis of pancreatic carcinoma. Acta Cytol 22:215–220. 51. Tao LC, Ho CS, McLoughlin MJ, et al. (1984) Cytologic diagnosis of hepatocellular carcinoma by fine-needle aspiration biopsy. Cancer 53:547–552. 52. Tao LC, Negin ML, Donat EE. (1984) Primary retroperitoneal seminoma diagnosed by fine needle aspiration biopsy. Acta Cytol 28:598–600. 53. Tao LC, Pearson FG, Delarue NC, et al. (1980) Percutaneous fine-needle aspiration biopsy: 1. Its value to clinical practice. Cancer 45:1480–1485. 54. Tao LC, Sanders D, McLoughlin ML, et al. (1980) Current concepts in fine-needle aspiration biopsy cytology. Hum Pathol 11:93–94. 55. Tao LC, Sanders DE,Weisbrod GL, et al. (1986) Value and limitations of transthoracic and transabdominal fine-needle aspiration cytology in clinical practice. Diagn Cytopathol 2:271–276. 56. Von Schreeb T, Arner O, Skousted G. (1967) Renal adenocarcinoma. Is there a risk of spreading tumor cells in diagnostic puncture? Scared J Urol Nephrol 1:270–276. 57. Wolinsky H, Lisehner MW. (1969) Needle track implantation of tumor after percutaneous lung biopsy. Ann Intern Med 71:359–362. 58. Zornoza J, Jonsson K, Wallace S, et al. (1977) Fine needle aspiration biopsy of retroperitoneal nodes and abdominal masses: An updated report. Diagn Radiol 125:87–88.

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Introduction 15

Fig. 1.1 Minimal invasiveness of percutaneous fine-needle aspiration biopsy of the pancreas demonstrated in an autopsy case. (A) A needle was directed to the tumor in the head of the pancreas under the fluoroscopic control; (B) The needle entered the anterior wall of the stomach in the pylorus region (arrow); (C) The needle exited the posterior wall of the stomach and then entered the tumor in the head of the pancreas; (D) The stomach remained distended without leakage of gastric fluid after withdrawal of the needle. Note that the puncture site (arrow) was unremarkable.

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CHAPTER 2

Procedures and Techniques

In the past decades, the field of radiology has experienced great technological advances. A number of improved imaging techniques, such as ultrasonography and CT-scan that use powerful computers and produce sectional images, have been developed. By avoiding the superimposition of structures that was inherent in older radiologic techniques, small lesions throughout the body, particularly in the abdomen, can be reliably detected. These imaging techniques combined with the use of fine needles to obtain cytology specimens have completely revolutionized the approach to the clinical diagnosis of space-occupying lesions in the abdomen. These imaging techniques also permit the planning of a safe access route, thereby reducing the risk of complications. Transabdominal aspiration biopsy often renders exploratory surgery unnecessary. Because of the minor nature of transabdominal fineneedle aspiration biopsy, this procedure can be performed on an outpatient basis. For many patients, hospitalization can be averted. What were previously major diagnostic problems requiring exploratory laparotomy can now be solved by a simple, safe outpatient procedure.

LOCALIZATION METHODS Historically, a number of imaging modalities, including angiography,31,32 radioisotopic scan,16 endoscopic retrograde cholangiopancretography,15 percutaneous transhepatic cholangiography,29 lymphangiography,10,47 have been used for localizing intraabdominal mass lesions. On rare occasions, an abdominal mass can be localized by palpation.38 The choice of the imaging 16

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modality depends on the anatomic location and size of the lesion, availability of equipment, and training and skill of the person performing the aspiration biopsy.17,39 Angiography may reveal an encasement of a blood vessel by a tumor growth or an abnormal configuration of blood vessels and of blood supply.31,32 Endoscopic retrograde cholangiopancreatography permits the visualization of the pancreatic duct. It may reveal small carcinomas of the pancreas, because obstruction of the pancreatic duct is often an early change of cancerous growths arising from the ductal epithelium. Cholangiopancreatography was used as a guide to aspiration of the pancreas in the 1970s.15 However, it is not a good localizing method, due to the fact that the site of obstruction is sometimes a result of focal edema, fibrosis, or inflammation that may coexist with a malignant tumor. Material aspirated from the site of obstruction may not contain tumor cells. Percutaneous transhepatic cholangiography also provides information on the distribution of the biliary duct system that may be disturbed by a tumor. At present, ultrasonography4,9,12,18,21,33,34,36 and CT scan4–6,8,11,37 CT scan have largely replaced all other techniques in the assessment of intraperitoneal and retroperitoneal lesions because of their sensitivity in detecting small lesions. Lesions in the liver as small as 0.5 cm can be reliably detected and accurately aspirated under the guidance of these two imaging techniques. Ultrasonography can display two-dimensional anatomic cross-sections of the abdomen. Superficial biopsy transducers designed for use with percutaneous aspiration biopsy is available. It also has the advantage of real-time imaging, greater scanning flexibility, speed, and the absence of radiation exposure. CT scan offers cross-sectional images of the human body. It may automatically calculate the optimal distance to the lesion and the angle of needle entry and then display them on the monitor. The position of the needle tip in relation to the lesion can be readily verified prior to aspiration. CT scan is particularly useful as a guide to aspiration of small, deeply seated lesions and lesions close to the pelvic bones, as it provides an excellent definition of the skeleton and adjacent soft tissues. A major advance in imaging in the past decade is the development of the spiral CT-scanner. Original CT-scanners (1974–1987) would photograph a cross-sectional image, then rotate in the opposite direction to photograph the next slice. Between each slice, the machine would stop and reverse directions while the patient table was advanced an increment equivalent to a

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slice. In the mid-1980s, an innovation called the “power slip ring” allowed scanners to rotate continuously, e.g. “spiral” or “helical” scanning.22,23 Spiral CT-scanners can take 100 continuous photographs of the abdomen in approximately 15 seconds, and provide high resolution, three-dimensional images of the entire abdominal organs and vessels.46 At this speed, the radiation exposure to the patients is reduced to a minimum; consequently, spiral CT has become the primary imaging technique for the abdomen, in addition to lungs, chests and bones. Spiral CT-scanning combined with fine needle aspiration biopsy has been used successfully as a screening tool to detect lung cancers at curable stage in the Early Lung Cancer Action Project.13,14 Another advance is the positron emission tomography (PET) scan, which can detect cancerous growth via the increased metabolic activity. Combining CT with PET scanning provides a more complete picture of a tumor’s location and spread than either test alone.1

ASPIRATION BIOPSY INSTRUMENTS AND MATERIAL The basic tools for transabdominal aspiration biopsy are the fine needle and the syringe. Several types of needles have been used for transabdominal fineneedle aspiration biopsy. They include: 1. Sharply beveled spinal needle of Chiba (20- to 22-gauge, Cook, Blomington, IN).3,19 These needles are routinely used for transthoracic and transabdominal fine-needle aspiration biopsy at many medical centers, and they provide adequate material for cytologic examination. The drawback of this needle is its tendency to bend, making needle placement into a firm lesion difficult. 2. Turner cutting needles (20- to 22-gauge, Cook, Blomington, IN). These thin-walled needles have a circumferentially sharpened, 45◦ cutting edge. The cutting edge produces tissue cores of a lesion. 3. Greene needles (20- to 22-gauge, Cook, Blomington, IN).20,41 These needles have a cutting bevel tip used for acquiring tissue cores. 4. Slotted needle of Wescott (20- to 22-gauge, SH-2902, Becton Dickenson, Ruthford, NJ).40 These needles have a slotted opening approximately 3 mm from the needle tip. The slot adds a second cutting edge to the cutting edge of the needle tip.

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5. Other types of needles, such as the trephine needle of Franseen (20- to 22-gauge),7 Rotex screw needle (19- to 22-gauge, Nordenströtrom),27,28 and the pencil-point needle (20- to 23-gauge, Cook, Blomington, IN)24 have also been used and reported in the literature. Individual preference determines selection of the needle used for aspiration biopsy. At the Indiana University Medical Center and New York University (NYU) Medical Center, 22-gauge, sharply beveled spinal needles are routinely used for transabdominal aspiration biopsy. At Park Avenue Radiology, 25-gauge, 3-1/2 inch spinal needle is used for all CT-guided fineneedle aspiration biopsies. The 20-gauge needles are used infrequently when a firm lesion is experienced, and the gastrointestinal tract, biliary ducts and portal vein are not expected along the needle tract. The needles are available in four lengths: 3, 5, 7 and 10 inches. The length of the needle selected is based on the depth of the lesion, and the shortest needle that will permit penetration of a lesion should be chosen. A 10-ml syringe and well-fitting needles are prerequisites for obtaining a good specimen from an intraabdominal lesion. The use of a single grip syringe is not recommended for transabdominal aspiration biopsy because the operator is free to use both hands in handling the needle and syringe assembly. At the NYU Medical Center, clear glass slides are used for the preparation of smears. The syringe and needle are rinsed and the residual tissue fragments placed directly in CytoRich Red solution (TriPath Imaging, Burlington, North Carolina) for cell block.

TECHNIQUES OF TRANSABDOMINAL ASPIRATION BIOPSY Premedication is not required for transabdominal fine-needle aspiration biopsy unless the patient is anxious or may create a problem, such as coughing, during the procedure. The location of the lesion is determined by one or more of the imaging techniques. CT scan and ultrasonography, which display two-dimensional anatomic cross-sections of the human body, are used as a guide to fine needle aspiration of the lesion. The distance to the lesion and the angle of needle entry may be automatically calculated and displayed on the monitor. Verification of the position of the needle tip in relation to the lesion can be readily done prior to aspiration.

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After the localization of the target lesion and the selection of the entry site, the skin is marked for local anesthesia. Local anesthetic is then infiltrated into the skin and body wall down to the peritoneum. Some radiologists would make a small nick with the tip of a scalpel to facilitate entry of the needle. Others would insert the needle directly. The needle, together with a stylet, is guided to the lesion during suspended respiration. Once the needle tip is situated within the lesion, the stylet is withdrawn partially, and the needle is moved back and forth in the lesion with short, jerky movements three to five times. The stylet is then removed and suction is applied a few times with the use of a 10-ml syringe attached to the needle and by rotating the needle during suction. The syringe and needle are quickly withdrawn the rest of the way, so as to avoid needle tract seeding. This is different from the technique used for the aspiration biopsy of a superficial palpable lesion with a short needle, which needs release of suction before withdrawal of the needle, so as to keep the small amount of aspirated material within the needle. A cytologist is on-site to prepare the smears and check for adequacy on Diff-Quik stained smears. This procedure is usually repeated until adequate, usually 2–3 times, through the same skin incision, using a different needle and with slight modification of the angle of approach, so that samples from several areas of the lesion are obtained.

PROCESSING OF THE ASPIRATED MATERIAL Proper handling and preparation of aspirated material are crucial to the success of this procedure. There are several types of aspirate preparations used for cytologic examination, including direct smears, millipore filter, liquid-based preparations, and cell block. No one method is considered standard, and every cytology laboratory must decide which processing method best satisfies its needs. At the NYU Medical Center, direct smears with on-site assessment by a cytologist is the standard. In addition to the direct smears, a cell block is made from the needle rinses for histology and immunohistochemistry. During the past 35 years, the protocol of processing aspirated material has been modified several times to improve the quality of aspirate preparations.

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The goals are listed below: 1. To increase cellular recovery so that we can examine every bit of material aspirated from the lesions and thus minimize the number of false-negative results caused by inadequacy of the specimen. 2. To achieve the highest possible resolution of nuclear and cytoplasmic details for cytomorphologic interpretation, especially in the typing of tumors. 3. To shorten the time required for specimen processing without sacrificing the quality of aspirate preparations, rendering this procedure suitable for the intraoperative diagnosis of intraabdominal lesions. In the late 1960s to early 1990s, wet smears on glass slides were fixed directly in 95% ethyl alcohol. However, the aspirated blood in Papanicolaou (Pap) stain interferes with optimal evaluation. Diff-Quik (DQ), a rapid Romanowsky stain, is excellent for hematopoietic disorders and adenocarcinomas, and more sensitive than the wet-fixed Pap-stained cells for cancer detection.42 However, it is limited by its opacity to subtype other types of tumor. In 1995, Ultrafast Papanicolaou stain43 (UFP) was developed to solve the problems of Pap stain with blood and to be complementary to the DQ by providing transparency and polychromasia. In addition to reducing the time from 20 minutes to 90 seconds, UFP increased the resolution of cellular details via flattened, larger transparent cells and clean background. The smears are air-dried and then hemolysed and rehydrated by normal saline,2 followed by rapid fixation by alcoholic formalin, and stained with HematoxylinII, which uses 40 times the mordant to deliver the dye to the nuclei within 10–15 seconds and Cytostain which combines EA and Orange G (Personal communication, Jerry Fredenburgh, Richard-Allan Scientific, Inc). A comparison of Pap and UFP-processed aspiration smears from a case of renal cell carcinoma is shown in Fig. 2.1. In addition to rapid cytologic evaluation, excellent immunostaining can be obtained on UFP-stained smears48 due to the alcoholic formalin fixation.35 The residual sample in the needle hub was collected by flushing the syringe and needle with 5–10 ml of CytoRich Red (TriPath Imaging, Burlington, North Carolina). There are several radiologists who performed the aspiration biopsy at the NYU Medical Center; the radiologist with the

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highest diagnostic yield routinely made a dedicated pass for cell block preparation to assure adequate sample for immunohistochemistry for various diagnostic and prognostic markers. The technical details of the preparation of aspiration samples are described below.

PROCEDURE OF DIRECT SMEAR PREPARATION Direct smear preparations is the only cytology method that can provide immediate cytologic diagnosis. Smears should be made as quickly as possible to avoid clotting artifacts, which would ruin the sample. The step-by-step sequence of events in the preparation of direct smears is as follows. 1. As soon as the sample appears in the transparent needle hub, the radiologist should stop the aspiration and immediately hands over the syringe with the needle to the on-site cytologist. 2. The needle is disconnected from the syringe, which is filled with air when the plunger is retracted. 3. The needle is reconnected to the syringe, and with the beveled edge down, the sample is expelled from the needle hub onto the clear glass slides. The needle hub is tapped to expel the residual material adhering to the hub onto another slide or rinsed in CytoRich Red for cell block.

Diagram 2.1

Swedish method of smear preparation.

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4. As illustrated in Diagram 2.1, the direct smears are made using the Swedish method as taught by the late Torsten Löwhagen of Karolinska Institute. The aspirate was deposited near the frosted end of the slide. Holding the frosted end with the left thumb and index finger and the rest of the slide supported by the remaining three fingers, the slide is kept horizontal and motionless. Another slide is held by the right thumb and index finger at a right angle to the bottom slide, the top slide being placed on the bottom slide at a 45◦ angle, at a distance so that when the top slide is lowered to 0◦ angle; the major part, but not all, of the sample will be touched and oval smears with “head, body and tail” are made. At the midline of the smear, tissue fragments are located, and at the periphery of the smear, single cells are localized. Prior to on-site smear preparation, the cytologist had been trained by using a creamy hand lotion to perfect the technique. Diagram 2.2 illustrates the different cytologic preparations used at the NYU Medical Center.

Diagram 2.2 Cytologic preparations (diagram inspired by the egg analogy first used by Orell et al.30 ). Wet-fixed Pap stain is analogous to a pouched egg, DQ is analogous to a sunny-side up egg, UFP is analogous to a transparent sunny-side up egg, and the cell block is analogous to section of a hard-boiled egg.

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We routinely make several smears for each pass, so that the cells can be processed for Diff-Quik (DQ) stain, and UFP stain. DQ is opaque and is best for demonstrating the secretory product in the background of the smear, i.e. mucin, myxoid substance, serous fluid, colloid and glycogen and to highlight the metachromatic matrix (Fig. 2.2). It is also used to detect negative images such as intracytoplasmic lipid droplets, glycogen, crystals or microorganisms (Fig. 2.3), and essential for hematologic malignancies so that hematologic criteria can be applied. UFP is a polychromatic stain rendering RNA (nucleoli) red, DNA (chromatin) blue, keratin red/orange/ blue, and its transparency will not mask the intrinsic colors of brown melanin, green bile, golden hemosiderin, yellow-red α-fetoprotein hyaline globules (Fig. 2.4) and brown skeletal muscle (Fig. 2.5). DQ and UFP offer complementary cytologic clues for diagnosis. The advantage of using both DQ and UFP for each case is illustrated in a case of plasma cell myeloma (Fig. 2.6).

ULTRAFAST PAPANICOLAOU STAIN43 In the traditional Papanicolaou stain, wet smears are immediately plunged in a Coplin jar containing 95% ethanol or sprayed by spray fixative. It is ideal for cervicovaginal smears, because the exfoliated squamous cells are flat and the background is clean when the test is done at the midcycle of the menstrual period. However, fine-needle aspiration biopsy inevitably aspirated blood and the cells are tridimensional. The aspirated blood can be eliminated by Millipore filter or fixative containing glacial acetic acid. However, the aspirated cells are still spherical. In 1988, Chan and Kung2 reported that air-dried cells can be restored to transparency by normal saline. Ultrafast Papanicolaou stain43 incorporated Chan’s method as the first step, because this method not only hemolyzed the aspirated blood with easily available odorless saline, but it also created flattened, therefore enlarged, and transparent cells, maximizing the resolution of nuclear and cytoplasmic details and increasing the sensitivity of cancer detection.42 Allow the smears to air-dry thoroughly and processed within 4 hours for optimal cytomorphology and processed as shown in Table 2.1.

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Procedures and Techniques Table 2.1

1. Normal saline 2. 95% Ethanol 3. Alcoholic formalin# 4. Water 5. Hematoxylin II∗

6. Water 7. 8. 9. 10.

95% Ethanol Cytostain∗ 95% Ethanol 100% Ethanol

11. Xylene 12. Mount & coverslip Total time

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Ultrafast Papanicolaou Stain On-site or Intra-Op Routine Cases 30 sec 30 sec to restore transparency & hemolysis 1 dip 1 min in CytoRich Red to assure no residual hemoglobin particles 10 sec 10 sec 6 slow dips 6 slow dips 2 slow dips 10 sec (newly opened) to 15 sec (2 weeks old). Overstain at this step will prevent red nucleoli. 6 slow dips Take the rack to a container with running water to squeaky clean. 6 slow dips 1 min 4 slow dips 90 sec to 2 min (for red nucleoli) 6 slow dips 3 changes, 1 min each to squeaky clean 6 slow dips 2 changes, 1 min each, then (100% Ethanol + Xylene) 10 slow dips 2 changes, 1 min each 90 sec

∗ Richard-Allan

Scientific, Inc., Kalamazoo, Michigan, USA. #Alcoholic formalin (3 liters) (4% formaldehyde in 65% ethyl alcohol) 300 ml 38–40% formaldehyde, 2053 ml 95% ethyl alcohol, 647 ml distilled water.

CELL BLOCK PREPARATION Cell block is important for histology and immunohistochemistry for tumor typing and prognostic markers. At the NYU Medical Center, we have been using “compact” cell block since it was developed in 1997.44 The purpose of the compact cell block is to obtain an ideal cell block wherein maximal number of cells are displayed within the smallest area at the block surface. The compact cell block is about 1/5 to 1/10 the size of a conventional cell block, yet more cells are on display, thus reducing screening time and eliminating the need for deeper cuts. The rationale for the compact cell block is illustrated in Diagram 2.3. 1. Rinse the remaining sample in the needle hub into 5–10 ml CytoRich Red solution each time after the direct smears are made. In addition, a dedicated pass is made for the cell block.

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Diagram 2.3

The rationale of the compact cell block technique.

2. CytoRich Red can simultaneously fix the nucleated cells, hemolyse the red blood cells and solubilize the extracellular proteins. According to Maksem, 1 ml of CytoRich Red can hemolyse 25 µl of gross blood.25,26 In the laboratory, the test tube is vortexed and centrifuged at 3000 rpm for 8 minutes and the supernatant discarded. Add 4 drops of plasma (outdated fresh frozen plasma available from the hospital Blood Bank) and 3 drops of topical Thrombin (5000 units/10 ml, hospital pharmacy). It is important to gently agitate the mixture to let fibrin strands catch the cells scattered in the CytoRich Red solution. Initially, flakes are formed which coalesce to form a slippery, gelatinous fibrin clot containing trapped cells. When the clot stops growing, most of the cells have been extracted from the CytoRich Red-based mixture. This process usually takes less than 2 minutes. A wood applicator is then used to slide the clot onto a lens paper which has been placed on top of paper towels. The lens paper is folded once over the clot, which is then molded into a flat, smooth and compact aggregate. As illustrated in Diagram 2.3, the lens tissue/paper towel combination is analogous to a diaper: the lens tissue keeps the cells in place, while the paper towels absorb the fluid. The fibrin strands collapse under the pressure of molding, and the fibrin monomers dissolve into CytoRich Redbased solution and are then absorbed by the paper towels. The flattened compact cell aggregate is painted orange-red with Mercurochrome (drug store), and then tightly wrapped by the lens tissue, before being placed into formaldehyde. In the histology laboratory, special care is taken to

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prevent the separation of packed cells during embedding in melted paraffin. Without the block surface being shaved, a ribbon of paraffin sections is immediately mounted on a microscopic slide for histological evaluation or onto positively charged blank slides for immunohistochemistry.

FALSE-NEGATIVE RESULTS An operator capable of obtaining an adequate amount of the target tissue is essential for a successful transabdominal aspiration biopsy. In recent years, with the development of improved imaging techniques, this does not seem to be a problem in experienced hands. The causes of false-negative results in transabdominal aspiration biopsy are as follows: 1. The needle tip missing the target lesion. This error could result from inexperience or technical difficulty during aspiration biopsy. It appears that smaller and deeply seated lesions are more often missed by the needle tip. In general, this occurs when a lesion is distant from the site of entry and smaller than 2 cm in diameter, and when the position of the needle tip cannot be documented before aspiration. In such cases, practical experience is the only guide. Occasionally, in cases of firm lesions such as scirrhous carcinoma of the pancreas, the needle tip may buckle rather than pierce the lesion. 2. Sampling errors. A technically adequate aspiration may not always be of diagnostic value. It appears that sampling errors occur more often with large lesions than with small lesions. The settings in which sampling errors may occur include: the presence of a large amount of necrosis or inflammatory exudate in the proximity of the tumor; a carcinoma in a large area of fibrous tissue; a large reactive zone surrounding a small tumor; and an infiltrating but nonsolid tumor growth. To some extent sampling errors can be avoided by multiple needle aspiration attempts with slight variation in the angle approach. 3. Unsatisfactory specimens. Poorly fixed specimens and poorly prepared smears (too thick or poorly stained) are examples of unsatisfactory specimens. The number of diagnostic cells in aspirate preparations is also affected by the processing method used. Unlike tissue sections of a lesion, cytology specimens also contain variable amounts of nondiagnostic

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cellular components. Cell block method cannot recover and use all the material aspirated from a lesion for examination, and thus may lose the diagnostic cellular components of the lesion during processing, increasing the number of false negative results. 4. Diagnostic cells missed during screening. This error usually occurs when a relatively inadequate specimen contains a large number of reactive cells but few malignant cells. It also constitutes a sampling error. 5. Misinterpretation. This problem is most common among inexperienced examiners and occurs when neoplastic cells have a relatively innocent appearance (e.g. some renal cell carcinomas and metastatic bronchioloalveolar carcinoma). Misinterpretation can be avoided with increased experience. When the cytopathologist and radiologist are both experienced, falsenegative results are due mainly to sampling errors, which account for about 5% of all cases. Sampling errors are a limitation of transabdominal fineneedle aspiration biopsy. Multiple aspirations and repeat aspiration biopsies may reduce the incidence of sampling errors but will not eliminate them. Therefore, a negative aspiration biopsy report does not necessarily rule out a malignant condition. If clinical suspicion persists, an appropriate tissue biopsy is indicated.

REFERENCES 1. Bar-Shalom R, Yefremov N, Guralnik L, et al. (2003) Clinical performance of PET/CT in evaluation of cancer: Additional value for diagnostic imaging and patient management. J Nuclear Med 44:1200–1209. 2. Chan JKC, Kung ITM. (1988) Rehydration of air-dried smears with normal saline: Application in fine needle aspiration cytologic examination. Am J Clin Pathol 89:30–34. 3. Chin WS, Yee IS. (1978) Percutaneous aspiration biopsy of malignant lung lesions using the Chiba needle: An initial experience. Clin Radiol 29:617–619. 4. Cooperberg PL, Hutchinson D, Li D, et al. (1981) Percutaneous fine needle aspiration biopsy under ultrasound and computed tomographic control. Br Columbia Med J 23:537–541. 5. Ferrucci JT, Wittenberg J. (1978) CT biopsy of abdominal tumors: Aids for lesion localization. Radiology 129:739–744.

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6. Ferrucci JT, Wittenberg J, Mueller PR, et al. (1980) Diagnosis of abdominal malignancy by radiological fine needle aspiration biopsy. AIR 134:323–330. 7. Franseen CC. (1941) Aspiration biopsy with a description of a new type of needle. N Engl J Med 224:1054–1058. 8. Gatenby RA, Mulhern CB, Strawtz V. (1983) CT-guided percutaneous biopsies, head and neck masses. Radiology 146:717–719. 9. Goldberg BB, Pallack HM, Kellerman E. (1975) Ultrasonic localization for renal biopsy. Radiology 115:167–170. 10. Gothlin JH. (1976) Post-lymphangiographic percutaneous fine needle biopsy of lymph nodes guided by fluoroscopy. Radiology 120:205–207. 11. Haaga Jr, Alfidi RJ. (1976) Precise biopsy localization by CT scan. Radiology 118:603–607. 12. Haneke S, Holm HH, Koch F. (1975) Ultrasonically guided percutaneous fine needle biopsy of the pancreas. Surg Gynecol Obstet 140:361–364. 13. Henschke CI, McCauley DI, Yankelevitz DF, et al. (1999) Early Lung Cancer Action Project: Overall design and findings from baseline screening. Lancet 354:99–105. 14. Henschke CI, Yankelevitz DF, Libby D, Kimmel M. (2002) CT screening for lung cancer: The first ten years. Cancer J 1(8):S47–854. 15. Ho CS, McLoughlin ML, McHattie JD, et al. (1977) Percutaneous fine needle aspiration biopsy of the pancreas following endoscopic retrograde cholangiopancreatography. Radiology 125:351–353. 16. Ho CS, McLoughlin MJ, Tao LC, et al. (1981) Guided percutaneous fine needle aspiration biopsy of the liver. Cancer 47:1781–1785. 17. Ho CS, Tao LC, McLoughlin MJ. (1978) Percutaneous fine-needle aspiration biopsy of intra-abdominal masses. Can Med Assoc J 119:1311–1314. 18. Holm HH, Pedersen JF, Kritensen JK, et al. (1975) Ultrasonically guided percutaneous puncture. Radiol Clin North Am 13:493–503. 19. Hutton L. (1979) Percutaneous pulmonary aspiration biopsy using the Chiba needle. J Can Assoc Radiol 132:563–567. 20. Isler RJ, Ferrucci IT, Wittenberg J. (1981) Tissue core biopsy of abdominal tumors with a 22-gauge cutting needle. AJR 136:725–728. 21. Juul N, Torp-Pedersen S, Gronvall S, et al. (1985) Ultrasonically guided fine needle aspiration biopsy of renal masses. J Urol 133:579–581. 22. Kalender WA, Polacin A. (1991) Physical performance-characteristics of spiral CT scanning. Med Phys 18:910–915. 23. Kalender WA, Seissler W, Klotz E, Vock P. (1990) Spiral volumetric CT with single-breath-hold technique, continuous transport, and continuous scanner rotation. Radiology 176:181–183.

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24. Koss LG, Melamed MR. (2005) Koss’ Diagnostic Cytology and Its Histologic Bases, 5th ed. Lippincott William & Wilkins. 25. Maksem JA. (1999) Endervical cell collection using cytobrush, liquid fixation and cytocentrifuge: A feasibility study using 455 hysterectomy specimens. Diagn Cytopathol 21:419–426. 26. Maksem JA. (1996) The CytoRich Fixation System. Burlington, North Carolina, TriPath Imaging, Inc. 27. Nordenstrom B. (1967) Transthoracic needle biopsy. N Engl J Med 276: 1081–1082. 28. Nordenstrom B. (1975) New instruments for biopsy. Radiology 117:474–475. 29. Oduka K, Tanikawa K, Emura T. (1974) Non-surgical, percutaneous transhepatic cholangiography-diagnostic significance in medical conditions of the liver. Am J Dig Dis 19:21–26. 30. Orell SR, Sterrett GF, Whitaker D. (2005) Fine-Needle Aspiration Cytology, 4th ed., Philadelphia, Elsevier. 31. Oscarson J, Stormby N, Sundgren R. (1972) Selective angiography in fine needle aspiration cytodiagnosis of gastric and pancreatic tumors. Acta Radiol (Diagn) (Stockh) 12:739–748. 32. Pereiras RV, Meiers A, Kunhardt B, et al. (1978) Fluoroscopically guided thin needle aspiration biopsy of the abdomen and retroperitoneum. AJR 131: 197–202. 33. Rasmussen SN, Holm HI, Kristenssen JF, et al. (1972) Ultrasonically guided liver biopsy. Br Med J 2:500–502. 34. Rosenblatt R, Kutcher R, Moussouris HF, et al. (1982) Sonographically guided fine needle aspiration of liver lesions. JAMA 248:1639–1641. 35. Shidham VB, Chang CC, Rao RN, et al. (2003) Immunostaining of cytology smears: A comparative study to identify the most suitable method of smear preparation and fixation with reference to commonly used immunomarkers. Diagn Cytopathol 29:217–221. 36. Smith EH, Bartrum RJ Jr, Chang YC, et al. (1975) Percutaneous aspiration biopsy of the pancreas under ultrasonic guidance. N Engl J Med 292:825–828. 37. Sundram M, Wolverson MK, Heiberg E, et al. (1982) Utility of CT-guided abdominal aspiration procedures. AJR 139:1111–1115. 38. Swaroop VS, Gupta SK, Dilwari JB. (1982) Fine needle aspiration cytology in the diagnosis of abdominal lumps. Indian J Med Res 76:265–271. 39. Tao LC. (1988) Guides to Clinical Aspiration Biopsy: Lung, Pleura and Mediastinum. New York, Igaku-Shoin. 40. Westcott JL. (1980) Direct percutaneous needle aspiration of localized pulmonary lesions: Results in 422 patients. Radiology 137:31–35.

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41. Wittenberg J, Mueller PR, Ferrucci JT Jr, et al. (1982) Percutaneous core biopsy of abdominal tumors, using 22-gauge needle. Further observations. AJR 139: 75–80. 42. Yang GCH. (1994) The mathematical basis for the increased sensitivity in cancer detection on air-dried cytopreparation. Modern Pathol 7:681–684. 43. Yang GCH, Alvarez II. (1995) Ultrafast Papanicolaou stain: An alternative preparation for fine-needle aspiration cytology. Acta Cytol 39:55–60. 44. Yang GCH, Wan LS, Papellas J, Waisman J. (1998) Compact cell blocks: Use for body fluids, fine needle aspirations, and endometrial brush biopsies. Acta Cytol 42:703–706. 45. Yang GCH, Yee HT, Waisman J. (2003) Metaplastic carcinoma of the breast with rhabdomyosarcomatous element: Aspiration cytology with histological, immunohistochemical and ultrastructural correlations. Diagn Cytopathol 28:153–158. 46. Zeman RK, Fox SH, Silverman PM, et al. (1993) Helical (spiral) CT of the abdomen. Am J Roentgenol 160(4):719–725. 47. Zornoza J, Jonsson K, Wallace S, et al. (1977) Fine-needle aspiration biopsy of retroperitoneal lymph nodes and abdominal masses: An updated report. Radiology 125:87–88. 48. Zu Y, Gangi MD, Yang GCH. (2002) Ultrafast Papanicolaou stain and celltransfer technique enhance cytologic diagnosis of Hodgkin lymphoma. Diagn Cytopathol 27:308–311.

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Fig. 2.1 Comparison of Papanicolaou stain and Ultrafast Papanicolaou stain. Renal cell carcinoma aspirated from a 64-year-old male, 400×. (A) Fragments of tumor epithelial cells obscurred by the aspirated red blood cells. Tumor cells are small and are at different focal planes. Papanicolaou stain, 400×; (B) Large and flat tumor cells displayed in a clean background. UFP stain, 400×.

Fig. 2.2 Diff-Quik stain is used to demonstrate background substance associated with the tumor. (A) Mucin in adenocarcinoma; (B) Myxoid substance in myxoid liposarcoma; (C) Serous fluid in microcystic adenoma of pancreas; (D) Colloid, a product of thyroid gland. (E) Metachromatic matrix, a clue for sarcoma; (F) Tigroid background substance, a clue for glycogen-rich tumor.

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Fig. 2.3 Negative images can only been seen in Diff-Quik stain. (A) Lipid droplets in lipid-rich follicular thyroid carcinoma. DQ 400×; (B) Glycogen in seminoma. DQ 1000×; (C) Crystals in alveolar soft part sarcoma. DQ 1000×; (D) Mycobacterium avian intracellulare within macrophages. DQ 1000×.

Fig. 2.4 UFP provides polychromatic clues for tumor type. (A) Red/orange/blue keratin, clue for squamous cell carcinoma; (B) Intrinsic green bile (arrow), clue for hepatocellular carcinoma; (C) Intrinsic brown melanin, clue for melanoma; (D) Yellow/pink intracytoplasmic α-fetoprotein hyaline globules, clue for yolk sac tumor.

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Fig. 2.5 Intrinsic brown inclusions correlate to sacromeres ultrastructurally.45 (A) Brown skeletal muscle aspirated from sternocleidomastoid. UFP, 100×; (B) A few tumor cells with brown inclusions. UFP, 400×; (C) A tumor cell with brown inclusion. UFP, 1000×; (D) Electron microscopy of the tumor cells revealed sacromeres. 15,000×.

Fig. 2.6 Complementary clues from DQ and UFP maximize information for cytologic diagnosis. (A) Plasma cells with perinuclear hof (golgi), blue cytoplasm from ribosomes, but we are not sure whether these plasma cells are malignant. DQ, 1000×; (B) Clearly malignant nuclei with irregular nuclear membrane (arrowhead), but it is difficult to recognize these cells as plasma cells. UFP, 1000×.

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CHAPTER 3

Approaches to the Interpretation of Transabdominal Fine-Needle Aspiration Biopsy

The interpretation of fine-needle aspiration biopsy specimens is very different from that of tissue sections. In aspirate preparations, the histologic pattern and cellular arrangements of various lesions seen in tissue sections cannot be visualized. The relationship between the cellular components of a lesion and the normal structures of an organ is also distorted. Another disadvantage of fine-needle aspiration biopsy is that it provides a small amount of material for examination. Moreover, there are numerous look-alikes and pitfalls involved in the cytomorphologic interpretation. Any pathologist who simply applies histopathologic approach to cytopathology and who is unfamiliar with the cytologic features and unaware of the pitfalls in the cytologic interpretation will be expected to make frequent mistakes or end up with many “suspicious” reports. This provides no help to clinical management. As transabdominal fine-needle aspiration biopsy has not been widely practiced in North America until the 1980s, pathologists should prepare themselves in this field and have adequate training before attempting to make cytologic diagnoses.

TEAM APPROACH TO DIAGNOSIS The use of transabdominal fine-needle aspiration biopsy has made the diagnosis of malignancies much easier for clinicians and much easier on patients 35

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but often poses a serious challenge to pathologists. In the hospital setting, most patients with an intraabdominal mass or masses who undergo transabdominal aspiration biopsy have no known diagnosis. In many such patients, few clinical investigations have been done at the time of aspiration biopsy. In fact, many aspiration biopsies are not scheduled in advance but are performed on an outpatient basis. This usually happens when a lesion is found at ultrasonography, and the referring clinician is contacted. It is most efficacious for clinical management and beneficial for the patient to have the biopsy done at the same visit and to receive the report on cytology specimens after a short time interval.11,16 Under such conditions, a close working relationship among the clinician, the radiologist, and the pathologist is essential for the accurate interpretation of transabdominal fine-needle aspiration biopsy specimens, particularly in problem cases.11 Some avoidable mistakes have been made because of insufficient radiographic information or a lack of clinical information. To minimize these mistakes, the radiologist and clinician must communicate with the pathologist.12 The clinician should take final responsibility for correlating the clinical, laboratory, radiologic and cytopathologic data to make a final diagnosis and recommend treatment. If a positive cytology report is totally unexpected or distinctly at odds with the clinical or radiologic data, the matter should be discussed with the cytopathologist to ensure an error has not occurred. In some cases, radiographic information about an intraabdominal lesion provides important diagnostic clues and is, therefore, helpful in differential diagnosis. Useful information obtainable from a radiologist who performs an aspiration biopsy should include: 1. Anatomic location and size of the lesion under investigation, as well as the duration of the disease. 2. Radiographic appearance of the lesion, for instance, cavitary, cystic, partially cystic, solid or multilocular. 3. Consistency of the lesion, for example, a firm, soft, or empty sensation felt during aspiration biopsy. 4. Gross appearance of the aspirate, for example, mucous, purulent, cheesy or clear fluid. In other cases, clinical information, including signs and symptoms, laboratory data, and a history of malignant diseases, as well as clinical

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impressions, are useful for the cytologic differential diagnosis. In our institutions, most patients with an intraabdominal lesion or lesions who undergo transabdominal aspiration biopsy have no diagnosis. In many such patients, few clinical investigations have been done at the time of aspiration biopsy. It is not uncommon for the clinical information and radiographic impressions provided on the requisition forms to be incorrect and thus misleading, putting the examiner on the wrong track. Therefore, one should always examine aspirate smears before reading the clinical and radiographic information so as to avoid being bias in interpretation. The only information a cytopathologist needs to make an initial examination of an aspirate preparation is the patient’s age and sex, the exact site of the aspiration biopsy, and a gross description of the aspirated material. Although clinical data and impressions are sometimes helpful in establishing the cytologic diagnosis, especially for the differential diagnosis, one should use this information only to ascertain whether it agrees with the cytologic diagnosis.12 If the information does not correlate with the diagnosis, a careful reexamination of the aspirate preparations may reveal the cause of discrepancy. If the cytomorphologic findings are definitive and the cytologic diagnosis is conclusive, one should not go along with a clinical impression. If the preliminary cytologic diagnosis is based on inadequate evidence and is not conclusive, a conservative approach is recommended. One should not try to make a cytologic diagnosis on the basis of unsatisfactory specimens. There should be no guessing in the interpretation of aspiration biopsy specimens. To establish a cytologic diagnosis with high accuracy, the examiner should have full knowledge of the anatomy, histology, and cytologic characteristics of the cellular components of the organ to be investigated, as well as pathologic features of various conditions of that organ. Although a thorough understanding of the histopathology of the organ under study is important for the correct interpretation of a cytology specimen, it is also crucial that the examiner be familiar with the cytologic features of different lesions seen in that organ and the cytologic criteria for the interpretation of aspiration biopsy specimens. Because the cytologic appearances of various lesions in aspirate preparations are different from the morphologic appearances as seen in tissue sections, the criteria used for the cytologic diagnosis are also different from those for the histologic diagnosis.15

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CYTOLOGIC CRITERIA FOR THE INTERPRETATION OF ASPIRATION BIOPSY In our practical work, the so-called “cytologic criteria for malignancy” as generally described in pathology and cytology books are not applicable to the interpretation of transabdominal aspiration biopsy specimens in many instances because malignant cells from some tumors (e.g. some renal cell carcinomas and well-differentiated ductal adenocarcinoma of the pancreas have a benign appearance (Fig. 3.1), and irritated epithelial cells (e.g. injury, or chemotherapy and irradiation effects) and reactive macrophages may meet the cytologic criteria for malignancy12 (Fig. 3.2). Thus, there are cytologic criteria only for various types or subtypes of tumors. Neoplasms seen in transabdominal fine-needle aspiration biopsy are highly heterogeneous and include tumors derived from various epithelial, neuroepithelial, mesenchymal and mesothelial cells. Oversimplification of cytologic criteria for the interpretation of aspiration biopsy specimens only misleads the examiner. The cytomorphologic interpretation of transabdominal aspiration biopsy specimens is very different from the interpretation of tissue biopsy samples. Interpretation of a tissue biopsy sample involves pattern diagnosis. What appears on the slides are cross-sections of the tissue sample. All of the histologic structures and cellular arrangements in histologic sections are in the same plane, not in three dimensions. In aspirate preparations, histologic patterns are not visualized. All of the histologic features and cellular arrangements seen in tissue sections do not exist in aspirate preparations. Therefore, the criteria used to arrive at a histologic diagnosis are not applicable to the establishment of a cytologic diagnosis.8,14 On the basis of our experience in dealing with thousands of intraabdominal and intrathoracic lesions12 and published material,1–4,6–11 the cytologic criteria for the interpretation of aspiration biopsy specimens can be summarized in the following sections.

Cohesion Factor (Intercellular Cohesion) This cytologic feature is related to cohesion between tumor cells. If tumor cells are scattered all over the slides, occur singly, or are present in loose groupings, there is poor cohesion between the cells. This poor cohesion is typical of malignant lymphomas and most sarcomas. In general, most carcinomas

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Approaches to the Interpretation of Transabdominal Fine-Needle Aspiration Biopsy Table 3.1

39

Cohesion between Tumor Cells

Cohesion Factors

Solitary Cells

Loose Groupings or Noncohesive Clusters of Cells

0 1 2 3 4 5

+ + ++ +++ +++ ++ + −

− ++ ++ +++ +++ +

Cohesive Clusters or Cell Fragments − − + ++ +++ + + ++

have good intercellular cohesion, forming tightly packed cell clusters. Exceptions include squamous cell carcinoma of the keratinizing large cell type; small cell anaplastic carcinoma; giant cell carcinoma and well-differentiated neuroendocrine carcinoma (carcinoid, islet cell tumors, medullary thyroid carcinoma); adrenocortical carcinoma; lobular carcinoma of the breast, signet ring cell gastric carcinoma of the linitis plastica type; and fibrolamellar hepatocellular carcinoma. This cytologic feature cannot be appreciated or assessed by studying histologic sections. In general, the intercellular cohesion for any type or subtype of tumor is relatively constant and consistent in different aspirate preparations from the same tumor. Also, for any type or subtype of tumor, the degree of intercellular cohesion is fairly consistent among tumors from different patients and even from tumor metastases of the same type or subtype.12 Thus, this cytologic feature is useful in the interpretation of aspirate preparations, especially for the differential diagnosis. In this book, the authors will use the term“cohesion factor,” which is graded from 0 to 5 to designate the degree of intercellular cohesion for any type or subtype of tumor,12 as illustrated in Table 3.1.

Average Nuclear Size in Tumor Cells The average nuclear size of any type or subtype of tumor cell tends to be relatively constant. The nuclear sizes of tumor cells are readily obtainable by comparison with those of red blood cells (7 µm in diameter) that are present on virtually every slide in Diff-Quik stained smears. In general, primary and metastatic cancers seen in transabdominal aspiration biopsy specimens can be divided into three groups on the basis of nuclear size (Fig. 3.3).

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1. Tumor cells that have small nuclei (< 20 µm in diameter), including those of abdominal desmoplastic small round cell tumor, Wilms’ tumor, neuroblastoma, Ewing’s sarcoma, carcinoid, metastatic small cell anaplastic carcinoma of the lung and malignant lymphomas of the small lymphocytic type. 2. Tumor cells that have medium-sized nuclei (20 to 30 µm in diameter), including those of well-differentiated adenocarcinoma of the pancreas, prostate, and endometrium; borderline serous tumor of the ovary; cholangiocarcinoma; large cell lymphomas; metastatic bronchioloalveolar carcinoma; and metastatic ductal carcinoma of the breast. 3. Tumor cells that have large nuclei (> 30 µm in diameter), including those of most poorly differentiated adenocarcinomas of various origins, most squamous cell carcinomas, and most sarcomas. The nuclei of tumor cells in this group tend to be more variable in size.

General Nuclear Shape of Tumor Cells For most types or subtypes of tumor cells, there are certain tendencies regarding nuclear shape. Tumors of various origins can be divided into five groups on the basis of nuclear shape (Fig. 3.4): 1. Tumor cells that have round nuclei. The tumor cells of most adenocarcinomas frequently have round nuclei, especially those of well-differentiated renal cell carcinoma, and adenocarcinoma of the prostate. The tumor cells of well-differentiated hepatocellular carcinoma also have round nuclei. 2. Tumor cells that have mixed ovoid and round nuclei, including those of most well-differentiated adenocarcinomas of various origins, epithelial malignant mesothelioma, and metastatic bronchioloalveolar carcinoma. 3. Tumor cells that have elongated and spindle-shaped nuclei, including those of sarcomatoid carcinoma; and spindle cell variants of carcinoid; gastrointestinal stromal tumor; spindle cell sarcoma (e.g. fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, and hemangiopericytoma); fibrous malignant mesothelioma; peripheral nerve sheath tumors; and desmoplastic malignant melanoma. 4. Tumor cells that have irregular nuclei, including those of most poorly differentiated carcinomas and high-grade sarcomas and lymphomas.

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5. Tumor cells that have multinucleated nuclei, including those of osteogenic sarcoma; rhabdomyosarcoma of the pleomorphic type; malignant fibrous histiocytoma; and giant cell carcinoma of the lung, pancreas and thyroid.

Arrangement of Tumor Cells This cytologic feature is also helpful in typing some tumors in aspirate preparations, i.e. tumors which cannot be appreciated or assessed by examining histologic sections (Fig. 3.5): 1. Tumor cells in a monolayer arrangement (sheet arrangement). Primary or metastatic bronchioloalveolar carcinoma of the nonsecretory type is often composed of many groups of tumor cells in a monolayer arrangement in aspirate preparations. Well-differentiated ductal carcinoma of the pancreas may also show many groups of tumor cells in a monolayer arrangement. 2. Tumor cells in a multilayer arrangement (three-dimensional), including those of most adenocarcinomas of various origins and squamous cell carcinoma of the nonkeratinizing large cell-type. 3. Tumor cells forming papillary structures, including those of solidpseudopapillary neoplasm of the pancreas; papillary serous carcinoma of the ovary; papillary renal cell carcinoma; and malignant mesothelioma of the papillary type. However, not all papillary carcinomas identified in tissue sections are found to have papillary structures in aspirate preparations. Papillary transitional cell carcinoma is one such neoplasm. In such tumor cells, cohesion is low between the tumor cells, as cohesion of the tumor cells around the fibrovascular cores is disrupted by the force of smearing.

A Unique Cytologic Feature or Special Structure Any tumor that has a unique cytologic feature, special structure, or secretory product can be readily identified, and its origin can often be determined. Examples include keratinization in squamous cell carcinoma; an endothelial lining wrapping around a group of tumor cells in well-differentiated hepatocellular carcinoma and psammoma bodies in papillary serous carcinoma of the ovary, and mesothelioma of the papillary type (Fig. 3.6).

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Other Cytologic Criteria Some minor cytologic criteria are also helpful in the interpretation of aspirate preparations in some cases. These include: 1. The location of nuclei in tumor cells. In tumor cells from some tumors, especially those with moderate or large amounts of cytoplasm, the usual locations of nuclei are characteristic. For instance, the nuclei in tumor cells from adrenocortical carcinomas are usually eccentrically placed (Fig. 3.7D), whereas those in tumor cells from hepatocellular carcinoma of the well-differentiated type are centrally located (Fig. 3.6C). 2. The amount of cytoplasm in tumor cells. Tumor cells from some tumors have an abundance of cytoplasm, e.g. hepatocellular carcinomas of the pleomorphic large cell type (Fig. 4.33), whereas tumor cells from other cancers have no recognizable cytoplasm, e.g. small cell carcinoma (Fig. 4.51) and some sarcomas (Fig. 8.32; Fig. 10.3). 3. The texture of cytoplasm of tumor cells. This cytologic feature also helps in identifying various tumor cells. For instance, the cytoplasm of mucinsecreting tumor cells appears multivacuolated, and tumor cells from epithelial mesotheliomas of the noncohesive epithelial cell type have abundant dense cytoplasm. Ultrastructurally, multivacuolated (Fig. 3.7A,B) correlates to mucin droplets; fibrillary (Fig. 3.7C) correlates to long cytoplasmic extensions in peripheral nerve sheath tumors; dense (Fig. 3.7E) correlates to tonofilaments in mesothelioma; ground glass (Fig. 3.7D) correlates to lipid droplets; and mitochondria in adrenal cortical carcinoma, brown cytoplasmic inclusion (Fig. 2.5) correlates to sacromeres,17 and granular correlates to mitochrondria-filled cytoplasm in oncocytic tumors (Fig. 3.7F). 4. The size and number of nucleoli in tumor cells. Tumor cells from different cancers may have a single prominent nucleolus or several conspicuous nucleoli, or have no recognizable nucleoli. For instance, lymphoma cells of the immunoblastic type have a single prominent nucleolus (Fig. 11.16), and those of the large noncleaved cell type have several conspicuous nucleoli (Fig. 11.14). Tumor cells from islet cell tumors (Fig. 5.36) or carcinoid tumors (Fig. 10.21C) have no recognizable nucleoli. When examining aspirate preparations, one should always observe the gross characteristic prior to mounting the best smear of the case on the

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microscope and always scan the smears at the lowest available magnification to have a general impression. The examiner can often narrow down the differential diagnosis to a few tumors and then study the tumor cells in greater detail at a higher magnification to make a final interpretation. The whole range of objectives should be used, including 100× oil immersion lens for difficult cases. The final diagnosis should always be made on the basis of the overall findings. One should not give too much consideration to a few abnormal-looking cells, which can confuse the diagnosis and be alert for floaters from an earlier case with large tumor load. A few abnormal cells or groupings of abnormal cells could be reactive or irritated epithelial cells, or they could simply be an artifact of the sampling technique employed.

PITFALLS AND LIMITATIONS The technique of transabdominal fine-needle aspiration biopsy is considered easy. It must not be forgotten, however, that the method ceases to be so easy at the microscope. An aspirate smear is a much more difficult specimen to assess than a histologic section. Often the cytologic diagnosis is not straightforward and is missed or misinterpreted by inexperienced examiners. The difficulties in the cytomorphologic interpretation of transabdominal fine-needle aspiration biopsy specimens14,15 arise because: 1. Neoplastic cells aspirated from different malignant tumors have variable cytomorphologic appearances, ranging from benign to bizarre-looking, in aspirate preparations. In our daily work, bizarre-looking cells (e.g. atypical hepatocytes in the cirrhotic liver) are not necessarily malignant and, on the contrary, malignant cells from some tumors (e.g. well-differentiated renal cell carcinoma) often look benign. 2. Different types of tumors may have similar cytomorphologic appearances. There are many look-alikes in transabdominal aspiration biopsy cytology. For instance, clear tumor cells from renal cell carcinoma and adrenal cortical adenoma may look alike in aspirate preparations. Other examples, such as an islet cell tumor, as opposed to well-differentiated adenocarcinoma of the pancreas; carcinoid to well-differentiated adenocarcinoma; and serous cystadenoma to serous cystadenocarcinoma, may also present the same diagnostic problem.

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3. Tumors of the same origin may have different cytomorphologic appearances. Most tumors have several cytomorphologic patterns. For instance, on the basis of cytomorphologic features, the neoplastic cells of renal cell carcinoma can have a clear or granular cytoplasm, arranged in loosely cohesive groupings or cohesive papillary fragments, and can have a sarcomatoid appearance. Therefore, a large number of cytomorphologic patterns may be seen in transabdominal aspiration biopsy cytology. 4. Samples from a tumor obtained by different cytologic methods may have variable cytomorphologic appearances. For instance, cell balls are a prominent finding in metastatic ductal carcinoma of the breast in effusions (Fig. 3.8); however, no cell balls are seen if a specimen is directly aspirated from the breast nodule. 5. A specimen prepared by different cytologic techniques shows variable cytomorphologic appearances. Aspirated material can be made into different preparations for cytomorphologic study, for example, direct smears, liquid based preparations, and cell blocks. In general, the cohesion factor is best demonstrated in direct smears rather than liquid-based preparations, where the aspirated samples are immediately fixed in the transport medium. Histology features are best appreciated in cell blocks. 6. Irritated epithelial cells and reactive cells may meet the so-called “cytologic criteria for malignancy (Fig. 3.2).” Atypical pancreatic ductal cells (e.g. in pancreatitis); atypical type 2 pneumocytes (e.g. in alveolar hemorrhage, pneumonia, or infection); reactive macrophages (e.g. in tuberculosis lesion); and atypical mesothelial cells (e.g. irradiation effects) may have highly abnormal appearances in aspirate preparations. From our combined experience in dealing with more than 30,000 transabdominal and transthoracic fine-needle aspiration biopsy, these pitfalls in the cytomorphologic interpretation of transabdominal aspiration biopsy specimens, which often account for unsuccessful attempts, can be readily avoided with experience.13 It is also well-recognized that there are some limitations in aspiration biopsy cytology, as in any other method dealing with morphology.5,15 The limitations in aspiration biopsy cytology are different in different sites and also in different types of tumors. For instance, no conclusive diagnosis can be made on purely cytomorphologic grounds for follicular neoplasms of the thyroid because the cytomorphologic features of

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endocrine tumors are not a reliable indicator of malignancy. It is not possible to assess capsular and vascular invasion on cytology. In the cytomorphologic interpretation of transabdominal aspiration biopsy specimens, the differentZiation between reactive lymphoid hyperplasia and low grade small cell lymphomas of various types can be difficult without immunophenotyping by flow cytometry. Any cytopathologist who is fully aware of the limitations in aspiration biopsy cytology can avoid erroneous interpretations by triaging such cases for further studies, e.g. flow cytometry, immunocytochemistry, or tissue assessment.

REFERENCES 1. Atkinson BF. (2003) Atlas of Diagnostic Cytopathology, 2nd ed. Philadelphia, W.B. Saunders. 2. DeMay RM. (1996) The Art and Science of Cytopathology. Chicago: ASCP Press. 3. Gesinger KR, Stanley MW, Raab SS, et al. (2004) A Modern Cytopathology. Philadelphia, Churchill Livingstone. 4. Frable WJ. (1983) Thin Needle Aspiration Biopsy. Philadelphia, WB Saunders. 5. Hajdu SI, Melamed MR. (1984) Limitations of aspiration cytology in the diagnosis of primary neoplasms. Acta Cytol 28:337–345. 6. Kaminsky DB. (1981) Aspiration Biopsy for the Community Hospital. New York, Masson. 7. Kline TS. (1988) Handbook of Fine Needle Aspiration Biopsy Cytology, 2nd ed. New York, Churchill Livingstone. 8. Koss LG, Melamed MR. (2005) Koss’ Diagonstic Cytology and its Histologic Bases, 5th ed. Baltimore, Lippincott, Williams & Wilkins. 9. Linsk JA, Franzen S. (1983) Clinical Aspiration Cytology. Philadelphia, JB Lippincott. 10. Orell SR, Sterrett GF, Whitaker D. (2005) Fine Needle Aspiration Cytology, 4th ed. Philadelphia, Churchill Livingstone. 11. Suen KC. (1987) Retroperitoneum and intestine. In: Kline TS (ed.), Guides to Clinical Aspiration Biopsy. New York, Igaku-Shoin. 12. Tao LC. (1988) Guides to Clinical Aspiration Biopsy: Lung, Pleura and Mediastinum. New York, Igaku-Shoin. 13. Tao LC, Pearson FG, Delarue NC, et al. (1980) Percutaneous fine-needle aspiration biopsy. I. Its value to clinical practice. Cancer 45:1480–1485. 14. Tao LC, Sanders D, McLoughlin MJ, et al. (1980) Current concepts in fine-needle biopsy cytology. Hum Pathol 1:93–94.

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15. Tao LC, Sanders DE, Weisbrod GL, et al. (1986) Value and limitations of transthoracic and transabdominal fine-needle aspiration cytology in clinical practice. Diagn Cytopathol 12:271–276. 16. Yang GCH, Liebeskind D, Messina A. (1996) On-site immediate diagnosis for fine needle aspiration biopsies: Experience at an outpatient radiology clinic. Acta Cytol 40:1099 (Abstract). 17. Yang GCH, Yee HT, Waisman J. (2003) Metaplastic carcinoma of the breast with rhabdomyosarcomatous element: Aspiration cytology with histological, immunohistochemical and ultrastructural correlations. Diagn Cytopathol 28:153–158.

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Fig. 3.1 Malignant cells that have a benign nuclear features. (A) Many cohesive epithelium with uniform, small bland nuclei. UFP, 1000×; (B) Nephrectomy shows renal cell carcinoma with vascular invasion. H&E, 40×; (C) Sheets of ductal epithelium with equal-sized bland nuclei. UFP, 1000×; (D) Surgery shows pancreatic ductal carcinoma. H&E, 400×.

Fig. 3.2 Irritated benign cell that have a malignant nuclear features. Scanty marked atypical glandular cells with coarse chromatin and prominent irregular nuclei, reported as “suspicious for adenocarcinoma.” (A–C) UFP, 1000×; (D) Wedge resection showed alveolar hemorrhage lined by irritated hyperplastic type 2 pneumocytes. H&E, 40×.

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Fig. 3.3 Average nuclear size in tumor cells. (A) Small (< 20 µm); (B) Medium (20– 30 µm); (C) Large (> 30 µm). Top row: Nuclear size is best measured in DQ due to background RBCs (= 7 µm). Bottom row: Nuclear and nucleolar features are best seen in UFP, 400×.

Fig. 3.4 General nuclear shape in tumor cells. (A) Round; (B) Mixed ovoid and round; (C) Elongated and spindle-shaped; (D) Irregular; (E) Multinucleated. UFP, 400×.

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Fig. 3.5 Arrangement of tumor cells. (A) Monolayer; (B) Multilayer; (C) Papillary. UFP, 400×.

Fig. 3.6 Unique features of tumor cells. (A) Keratinization in squamous cell carcinoma. UFP, 400×; (B) Parallel cigar-shaped nuclei in colonic adenocarcinoma. UFP, 400×; (C) Endothelial wrapping in hepatocellular carcinoma. UFP, 400×; (D) Psammoma bodies of papillary serous carcinoma of the ovary. UFP, 400×.

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Fig. 3.7 Cytoplasmic texture of tumor cells. UPF, 400×. (A & B) Multivacuolated in adenocarcinoma. UFP, 400×; (C) Fibrillary in peripheral nerve sheath tumor. (D) Ground glass in adrenal cortical carcinoma. (E) Dense in mesothelial cells; (F) Granular.inonococytic cells.

Fig. 3.8 Ductal carcinoma of the breast in different environment. (A) Loosely cohesive cells aspirated from the breast nodule. UFP, 100×; (B) Cell balls in a pericardial effusion due to surface tension. UFP, 40×; (C) High power shows closely packed tumor cells. UFP, 100×; (D) Estrogen receptor positivity confirms breast origin. Cell block, 100×.

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CHAPTER 4

The Liver

The liver is the most frequent site of blood-borne metastases from cancers of various origins, and cancer growth in the liver is a frequent finding at laparotomy or autopsy. Because positive findings for hepatic malignancy imply a grave prognosis and may alter clinical management, biopsy confirmation is often required. Confirmation of hepatic metastases may obviate the need for extensive diagnostic procedures or surgery, although it does not alter the usual dismal prognosis. In general, for the purpose of establishing the pathologic diagnosis, percutaneous needle biopsy is the method of choice. There are two types of percutaneous needle biopsy of the liver, namely, tissue needle core biopsy via large-bore needles (e.g. the Jamshidi, Menghini or Vim-Silverman techniques) and fine-needle aspiration biopsy. In general, large-bore needle is the method of choice for the diffuse medical liver diseases such as hepatitis, cirrhosis, etc., whereas fine-needle aspiration biopsy has provided excellent results for liver mass lesions.2,19,27,28,43,48,50,59,62,63,74 One of the major advantages of image-guided fine-needle aspiration biopsy is that it can sample anywhere in the liver, e.g. in the left lobe or in the area of porta hepatis, where the use of large-bore needle may be very risky. Another advantage is that multiple samples can be obtained based on imaging findings, and thus the chance of obtaining a representative sample by fine-needle aspiration is greatly increased. From the senior author’s experience in dealing with image guided fine-needle aspiration biopsy of the liver, the diagnostic rate of hepatic malignancy increases from 72.3% with one pass to 95% with three passes.62 Therefore, for any mass or masses in the liver suspicious for malignancy, we believe that image guided fine-needle aspiration biopsy is the method of choice.4,12,25,28,43,44,52,53,57,60,62,67 51

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For patients with a solitary or localized hepatocellular carcinoma without evidence of lymph node or distant spread, the definitive treatment is surgical excision, when it is technically possible. For small hepatocellular carcinoma, localized or unresectable tumors, chemoembolization via hepatic artery,10,66 radiofrequency ablation,14 cryosurgery, or percutaneous ethanol injection39,66 may be used. Liver transplantation26 has been increasing used for tumor localized to the liver. There is a tendency for hepatocellular carcinoma to remain localized without distance metastases. Anthony reported that 42% of hepatocellular carcinomas in a series of 126 cases were confined to the liver at the time of autopsy1 and Craig et al. reported that the fibrolamellar variant of hepatocellular carcinoma had a better prognosis with surgical resection.13 Therefore, the differentiation of primary liver cancer from metastatic tumors and the early recognition of hepatocellular carcinoma are of special importance in our clinical practice. This is crucial to the welfare of the patient. With the introduction of an ever-increasing number of sophisticated imaging techniques, the early detection of liver cancer is now possible. In the Toronto General Hospital series, the smallest hepatocellular lesion diagnosed by guided fine-needle aspiration biopsy was a 7 mm nodule. In addition, the antibodies available nowadays for immunocytochemistry further enhance the diagnostic accuracy of the typing of hepatic cancers.

NORMAL CELLULAR COMPONENTS Normal liver is made up of lobules of hepatic parenchyma. Each lobule contains a center efferent vein, the centrilobular vein, and peripheral portal triads. Each portal triad consists of connective tissue, in which are embedded a branch of portal vein, arterioles, and interlobular bile duct, in addition to lymphatics and nerves. Portal triads may contain a small number of lymphoid cells. Interlobular bile ducts drain into large ones as septal or trabecular ducts. The hepatic parenchyma consists of hepatocytes that form interconnecting plates separated from each other by sinusoids. The sinusoids drain into centrilobular veins and are lined by an incomplete layer of flattened endothelial cells, together with Kupffer cells, which are more numerous near the portal triads. Between the liver cells are the bile canaliculi, which empty into bile ducts. Aspirates from the normal liver contain hepatocytes, bile duct epithelial cells, sinusoidal

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endothelial cells, and Kupffer cells, as well as a few mononuclear cells and fibroblasts.

Hepatocytes (Fig. 4.1) In aspirate preparations, the polygonal hepatocytes occur as monolayered sheets, in cohesive groupings, and as solitary cells. They have abundant, granular, well-defined cytoplasm and one or two, centrally located nuclei with frequent conspicuous or prominent nucleoli. In sheets of hepatocytes, narrow gaps that correspond to intercellular bile canaliculi may be seen between cells. Multinucleated hepatocytes are unusual in normal liver. There are considerable variations in the nuclear size among different individuals. In old persons, the nuclei of hepatocytes tend to increase in size with age and there is variation in nuclear size in hepatocytes. Intracytoplasmic lipofuscin pigment (Fig. 4.1B) also becomes more abundant in the old persons. Hepatocytes may contain bile plugs (Fig. 4.1C) and have glycogenated nuclei (Fig. 4.1D). The latter is associated with diabetes mellitus.

Bile Duct Epithelial Cells (Fig. 4.2) Bile ducts in the smallest portal triads are referred to as interlobular ducts, larger ones as septal or trabecular ducts. Interlobular bile ducts are lined by cuboidal or low columnar epithelium. Septal bile ducts are lined by tall columnar cells with basal nuclei. In aspirate preparations, epithelial cells of the interlobular bile ducts are often in sheet arrangements. They have relatively scanty, poorly defined cytoplasm oval nuclei and indistinct nucleoli. Tall columnar epithelial cells of the larger bile ducts are usually in cohesive groupings or in palisading arrangements. They have moderate amounts of well-defined cytoplasm and ovoid nuclei.

Sinusoidal Endothelial Cells (Fig. 4.3A) Hepatocytes are arranged in interconnecting plates that are normally one cell thick and are separated from each other by the sinusoids. In tissue sections, the sinusoids are lined by an incomplete layer of flattened endothelial cells, together with Kupffer cells. In aspirate preparations, the sinusoidal

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endothelial cells are usually seen at the edge of cohesive groupings of hepatocytes and appear as lining cells with spindle-shaped nuclei in a lengthwise arrangement. They have relatively scanty cytoplasm. Interestingly, sinusoidal endothelial cells are sometimes seen as lining cells of neoplastic cell fragments of the hepatocellular origin. This finding is helpful in distinguishing hepatocellular carcinoma from other carcinomas.63

Kupffer Cells (Fig. 4.3B) Kupffer cells are the principal hepatic phagocytes. In tissue sections, they are more numerous near the portal triads and can be distinguished from endothelial cells by their positive staining with periodic acid-Schiff (PAS) after amylase digestion. In aspirate preparations, Kupffer cells have ovoid, elongated, or spindle-shaped nuclei and scanty but well-defined cytoplasm. They are in close proximity to hepatocytes and are often attached to hepatocytes, but not as lining cells. They may lie singly and can be distinguished from fibroblasts by their well-defined cytoplasm. When the cytoplasm of Kupffer cells contains phagocytosed material, they have a rounded appearance, and their nuclei are in an eccentric position. On direct smears, the Vimentin-positive spider-shaped Kupffer cells is the clue for hepatocellular carcinoma at metastatic sites.78

NONNEOPLASTIC MASS LESIONS In the 1970s, most of the senior author’s cases of aspiration biopsy of the liver were carried out under the guidance of an isotopic liver scan, which cannot differentiate solid mass lesions from cystic ones. We have encountered many cases of cystic lesions, including five cases of hydatid cyst. Among these five cases of hydatid cyst, only one patient showed signs of focal peritoneal irritation after aspiration biopsy, but no hypersensitivity reaction and no evidence of dissemination were noted. Fine-needle aspiration biopsy thus appears to be safer than large-bore needle biopsy in the diagnosis of hydatid disease. With the increasing popularity and use of fine-needle aspiration biopsy of the liver, pathologists are being introduced to a variety of nonneoplastic mass lesions that previously have not been routinely diagnosed by cytologic means. Moreover, with the increasing use of modern imaging techniques

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in our clinical practice, many benign asymptomatic nodules or masses that previously could not be detected are now frequently biopsied for diagnosis. In many cases of benign lesions of the liver, there are often serious diagnostic problems if no previous radiographs are available for comparison. Most such lesions are presumed to be malignant until proven otherwise.

Nonparasitic Cyst Nonparasitic cysts of the liver commonly affect women between 40 and 60 years of age. They may be solitary or multiple. Their cavities contain clear or bile-tinged fluid and have a columnar or cuboidal epithelial lining. The wall is composed of compact fibrous tissue with an outer, well-vascularized layer. The cysts probably develop as a result of local obstruction of hepatic ducts. Aspirate preparations of the fluid contain numerous columnar ductal epithelial cells in noncohesive or cohesive groupings. Cuboidal ductal epithelial cells in a sheet arrangement may be present. Hepatocytes are not seen. Although the presence of ductal epithelial cells in aspirate preparations is a nonspecific finding, the diagnosis of nonparasitic cyst can be established through a combined use of ultrasonographic presentation, the gross appearance of the aspirate, and the cytologic findings.

Hydatid Cyst (Figs. 4.4–4.5) In North America, hydatid disease is caused by the ova of the tapeworm, Echinococcus granulosus, a parasite of dogs and wolves. The ova are passed free in a dog’s or wolf ’s feces and develop into six-hooked embryos in the duodenum when swallowed by a human host. The embryos enter the venules and are filtered by the liver, developing into hydatid cysts that bear numerous scolices provided with hooklets. Scolices represent the future heads of adult tapeworms. The fluid aspirated from a young hydatid cyst is usually clear and contains debris, a few inflammatory cells, and numerous scolices. In old cysts, the aspirate yield large fragments of a laminated layer54 of the cyst wall in a dirty background with debris containing detached hocklets and calcareous corpuscles. The scolices may be difficult to find, but the hooklets in a ring-like

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arrangement often remain. The finding of scolices or a laminated layer of the cyst wall is diagnostic of hydatid disease.

Pyogenic Abscess Most abscesses of the liver are of bacterial pyogenic origin. The symptoms may be rather subtle. The occurrence of liver abscesses may constitute a severe clinical disorder, often with a delay in diagnosis and treatment and a high mortality. Pyogenic abscesses are caused by bacterial infections through ascension of the biliary tract (in cases of acute cholangitis), through the portal vein (in cases of subphrenic abscess), or following trauma. They may be single or multiple. Suppurative abdominal disease with or without pylephlebitis may result in septic emboli, giving rise to liver abscesses. These most often occur in the right lobe when the suppurative disorder is drained by the right superior mesenteric vein, whereas disease in the left side of the abdomen may cause suppuration in one or both lobes. Occasionally, abscesses of the liver are caused by Actinomyces israelii. Aspirate preparations from a pyogenic abscess contain a heavy neutrophilic inflammatory exudate and nuclear debris. Necrotic hepatocytes are usually not seen. The aspirate is pus-looking and foul-smelling. Material aspirated from an actinomycotic abscess contains numerous neutrophils and phagocytic macrophages. Reactive fibroblasts are abundant. The organisms in the lesions occur as colonies (granules), which are composed of delicate, branching, intertwined, Gram-positive filaments with granular basophilic centers.

Granulomas (Fig. 4.6) The causes of granulomas of the liver include infectious diseases (e.g. tuberculosis, schistosomiasis, brucellosis, histoplasmosis and coccidioidomycosis); drug sensitivity; foreign body reaction (e.g. silicosis and intravenous talc granulomatosis); and sarcoidosis.35 Tuberculosis and sarcoid granulomas are the most frequently seen. Aspirates from the tuberculous lesions often contain caseous necrosis, epithelioid cells, lymphocytes, other mononuclear cells, and Langhan’s giant cells. The lesions of sarcoidosis contain epithelioid cells, a few lymphocytes and occasional multinucleated giant cells. No necrosis is seen. Granulomas following drug use are noncaseous and are characterized

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by epithelioid cell reaction with giant cells and eosinophils. Infectious granulomas are often associated with systemic granulomatosis. The cytologic diagnosis is based on finding organisms or ova.

BENIGN MESENCHYMAL TUMORS Cavernous Hemangioma (Figs. 4.7–4.8) Cavernous hemangiomas are common incidental findings at autopsy or operation and are often seen in multiparous women, possibly as a result of an increase of circulating estrogenic hormones during pregnancy. They appear as circumscribed, dark red nodules measuring from a few millimeters to several centimeters in diameter. The patients are usually asymptomatic. The lesions are composed of endothelium-lined channels supported by a fibrous stroma. Fine-needle aspiration cytology has been reported.34 At the NYU Medical Center, we encountered nine cases of cavernous hemangioma aspirated by fine needle, most frequently in the setting of metastatic work-up. The aspirates from such lesions are invariably very bloody. They contain scattered noncohesive groupings of stromal cells with spindly nuclei and poorly defined cytoplasm (Fig. 4.8A). As in the diagnosis of liver cell adenoma, only if the aspirator makes certain that the needle tip is in the lesion and has been checked by an imaging technique, can the abovementioned cytologic findings, coupled with radiographic and clinical presentations, be considered to be consistent with cavernous hemangioma. However, if the aspirator uses fine needle in a rotational motion to cut the lesion, large tissue fragments can be obtained (Fig. 4.8B–D). The tissue fragments closely correlated to the histologic findings and are diagnostic for cavernous hemangioma.

Angiomyolipoma On CT-scan, hepatic angiomyolipoma is a circumscribed, round mass up to 20 cm with areas of low attenuation consistent with fat. The histology and aspirate preparation see similar to renal angiomyolipoma (Figs. 6.3–6.4). The mean age is the 50 years with female predominance (80%). A member of the PEComa family, the neoplastic cells contain prelanosomes ultrastructurally and immunoreactive to HMB45.

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NODULAR HEPATOCELLULAR LESIONS Recent advances in liver imaging, surgery and transplantation have drawn attention to a variety of lesions that are found in chronically diseased, usually cirrhotic, livers. A multinational panel of five liver pathologists reviewed23 such nodules and were able to reach a consensus on the diagnostic criteria and to devise a standard nomenclature to describe these lesions. They proposed that benign nodules showing little histologic difference from cirrhotic nodules be classified as “macroregenerative” nodules, and nodules with atypical features not diagnostic of carcinoma be classified as “borderline.” In addition, the absence or marked decrease in reticulin is considered an important criterion for malignancy.23 The proposed nomenclature was endorsed by an international working party.73 Clinically, the presence or absence of cirrhosis is most important. In the setting of cirrhosis, hepatocellular carcinoma is a more likely finding. Macroregenerative and borderline nodules that occur in cirrhosis may have the characteristic of hepatocellular carcinoma on imaging studies. In this setting, the size of the nodule is important. A hepatocellular nodule > 2 cm occurring in cirrhotic liver is highly suspicious of hepatocellular carcinoma unless proven otherwise. Smaller nodules may be borderline or macroregenerative in nature. In a liver without cirrhosis, liver cell adenoma and focal nodular hyperplasia are more likely. In addition, almost all fibrolamellar variant of hepatocellular carcinoma and 15–20% of the usual hepatocellular carcinomas occur in non-cirrhotic liver.22

Fatty Metamorphosis The accumulation of neutral triglycerides in hepatocytes is one of the most common pathologic changes in the liver. Major causes of fatty metamorphosis of the liver include excess alcohol intake, malnutrition, obesity, diabetes mellitus and debilitating systemic diseases, e.g. leukemias. Excess alcohol intake is by far the most common cause of fatty liver in North America. Fatty change in alcoholics ranges from vacuolation of a few liver cells to severe involvement of the whole liver. Fatty metamorphosis can present as infiltrative mass lesion of the liver, leading to biopsy.

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In aspirate preparations, the cytoplasm of hepatocytes contains a single, large, clear vacuole or, less frequently, multiple, small vacuoles of variable sizes. The large vacuoles displace the nuclei to the periphery of the cells and also distend the cells. In the cases of advanced fatty metamorphosis, groupings of liver cells with fatty changes may appear as small fragments of adipose tissue in aspirate preparations. The presence of occasional large, round nuclei in some cells clearly distinguishes liver cell fragments from adipose tissue. It is not possible to tell whether the fatty metamorphosis is due to alcoholism or to some other causes on purely cytomorphologic grounds.

Focal Nodular Hyperplasia (Figs. 4.9–4.10) Cases of focal nodular hyperplasia of the liver are not rare, but they are often undetected because the lesions in most cases are asymptomatic. The lesions are usually solitary but may be multiple. They are well-circumscribed but not encapsulated. They measure 1 to 8 cm in diameter and grow slowly and do not become malignant. The nodules are composed of liver parenchyma intersected by fibrous septa that often radiate from a central scar (Fig. 4.9). The normal-appearing liver cells are arranged in small pseudolobules. Bile ducts are present. Focal nodular hyperplasia can occur in any age group; most cases, however, are seen during the 3rd to 5th decades of life. Eightyfive percent of the patients with focal nodular hyperplasia are females. A possible relationship to oral contraceptives has been postulated.36 Aspirate preparations show normal hepatocytes that are intermingled with numerous fibroblasts or embedded in fragments of fibrous tissue, mimicking cirrhosis (Image 4.10). However, in the cases of focal nodular hyperplasia, there is no pleomorphism of hepatocytes, no mitotic figures, and no necrotic hepatocytes, as seen in aspirates from a cirrhotic liver. Fatty changes in hepatocytes may be seen. In some instances, the fibrous element is underrepresented in aspirate preparations, and the diagnosis of focal nodular hyperplasia in such cases is difficult on purely cytomorphologic grounds. However, parallel rows of fibrocytes that traverse large fragments of liver parenchyma can usually be found after a careful search, and this finding is helpful in establishing the diagnosis.

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Liver Cell Adenoma (Figs. 4.11–4.12) Liver cell adenomas were relatively rare until the use of oral contraceptives.36 They almost exclusively occur in women over 30 years of age who have been taking oral contraceptives for longer than five years. Estrogen is believed to be responsible. They are usually solitary, circumscribed, and encapsulated, but 10% of cases are multiple. Some adenomas have regressed after withdrawal of the oral contraceptives, but the tumor develops again in 25% of women who resume oral contraceptive use after resection of an adenoma.17 Malignant transformation has been reported in rare instances.16 The tumors are composed of liver parenchyma without portal triads or bile ducts. There are abundant small arteries within the tumor, and areas of hemorrhage and necrosis are often present. The gross appearance of the aspirates is rigid cores of tissue difficult to smear.79 On histology, the reticulin network is normal or slightly reduced.22 Aspirate preparations contain numerous closely packed, three-dimensional groupings of hepatocytes and fragments of liver parenchyma. No bile duct epithelial cells or fibroblasts are present. The hepatocytes are normal-looking. Mitoses are not seen. Necrotic hepatocytes may be noted. The cytologic findings are not diagnostic of liver cell adenoma on purely cytomorphologic grounds. However, if the aspirator makes certain that the needle tip is in the lesion and its position has been checked by an imaging technique, the abovementioned cytologic findings, coupled with clinical history, are in keeping with a liver cell adenoma.

Macroregenerative Nodule (Fig. 4.13) This term, according to the new nomenclature, refers to benign nodules showing little histologic difference from cirrhotic nodules. It is also called low grade (large cell) dysplasia, large cell change22,73 and adenomatous hyperplasia. Macroregenerative nodules have abundant cytoplasm and relatively normal nuclear/cytoplasmic ratio and normal reticulin network with maintenance of normal liver plate architecture.22,79 Aspirate preparations show a combination of regenerative changes, fibrosis, degenerative changes, and fatty metamorphosis. Regenerative changes are represented by pleomorphism of hepatocytes, an increase in the number of mitotic figures, and an increase in

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the number of binucleate hepatocytes. The nuclei of hepatocytes often show variation in size and have prominent nucleoli.

Borderline Nodule (Figs. 4.14–4.15) Borderline nodule,22,73 also termed high grade dysplasia, small cell dysplasia, small cell change,22,73 atypical adenomatous hyperplasia. This term, according to the new nomenclature,23 refers to atypical hepatic nodules that are not fully diagnostic of carcinoma. Borderline nodules are present in 5–15% of cirrhotic livers. This lesion is a precursor to hepatocellular carcinoma. Borderline nodules are frequently multiple. The size of the nodule is usually < 2 cm. It is characteristized by increased N/C ratio from reduced cytoplasm. Reticulin fibers are decreased or absent. In aspirate preparation, the smear pattern is indistinguishable from well-differentiated hepatocellular carcinoma, except that the size is < 2 cm. The case illustrated in Fig. 4.15 was aspirated from a 1.5 cm solid, hypervascular nodule in a patient with cirrhosis and prior to liver transplant. The histological follow-up in the liver explant three months later was high grade (small cell) dysplasia.80 The smears were finely granular grossly, and show numerous microtrabeculae with monotonous small hepatocytes with prominent nucleoli. Reticulin fibers were markedly decreased. However, the size of the nodule regressed to 0.9 cm in the liver explant and had no infiltrative border.

Hepatocellular Carcinoma Hepatocellular carcinoma used to have a relatively low incidence in Western Europe and North America, accounting for 1.2 to 2.5% of all malignancy. However, in recent years, the incidence is rising,20 largely due to chronic hepatitis C virus infection from transfusion of blood and blood products unscreened for hepatitis C virus in the recent past. The incidence of hepatitis B virus and hepatitis C surface antigenemia in patients with hepatocellular carcinoma is > 90% both in North America and other countries.9 In a prospective study of 795 patients from Japan,29 the development of hepatocellular carcinoma over a 15-year period was 27% in hepatitis B virus and 75% in hepatitis C virus. In the Orient and

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Africa, hepatocellular carcinoma has always been one of the most common malignant tumors. In Taiwan, 20% of the deaths from malignancy are from hepatocellular carcinoma. Hepatocellular carcinoma also has a high incidence in all African countries south of the Sahara. In these countries hepatitis B viral infection has been identified as a major risk factor. Reports from Taiwan show that 80% of patients with hepatocellular carcinoma have a chronic form of hepatitis B,69 and the tumor develops in HBsAg carriers.3 The incorporation of hepatitis B51 and hepatitis C65,70 viral DNA into the DNA of neoplastic cells of hepatocellular carcinoma has been detected. Hepatocellular carcinoma is less likely to develop in patients with alcoholic cirrhosis of the liver. In the United States, only about 4% of patients with alcoholic cirrhosis develop hepatocellular carcinoma. Since alcoholic cirrhosis is much more common in the Western world than in the Orient, it plays an important role in the etiology of hepatocellular carcinoma in North America. In some African countries, the ingestion of aflatoxins, metabolic products of the growth of Aspergillus flavus, may be involved in the etiology of hepatocellular carcinoma.47 Studies show that aflatoxin B1, the most toxic of the aflatoxins, is highly carcinogenic for some animal species. In Mozambique, the incidence of hepatocellular carcinoma is the highest in the world, and the per capita intake of aflatoxins is also the highest.71 The possible role of oral contraceptives or anabolic steroid use in liver carcinogenesis has been a matter of concern for some years, although its relationship remains speculative. Circumstantial evidence of a possible etiologic relationship between the long-term administration of sex steroids and primary liver tumors has been collected during the recent years.58 In a study by Tao,64 one such association has been identified. A 38-year-old woman developed hepatocellular carcinoma after a 10-year use of oral contraceptive steroids. Grossly, hepatocellular carcinoma may present as a solitary mass (Fig. 4.16), as multiple nodules, or as diffuse liver involvement. Hepatocellular carcinoma may permeate the liver through the portal venous system. The growth of carcinoma in the branches of the portal vein may lead to tumor thrombi of the portal trunk and sudden increase of portal hypertension. Metastases to regional lymph nodes and distant spread may also

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occur. However, there is a tendency for hepatocellular carcinomas to remain localized in the liver without metastases. Hepatocellular carcinoma typically appear solid and hypervascular on imaging studies. The combination of the improved imaging techniques and the fine-needle aspiration biopsy used, provides the opportunity to establish the diagnosis before it is too late for surgical excision. Morphologic differences among different cases of hepatocellular carcinoma are well recognized in histologic sections. As can be expected, aspirate preparations of the tumors from different patients exhibit various cytomorphologic appearances. Many histologic patterns of hepatocellular carcinoma have been described. They often cannot be distinguished from one another in aspirate preparations. The increasing utilization of transabdominal fineneedle aspiration biopsy prompts the description of such cytomorphologic features and cytologic diagnostic criteria of different cytologic types of hepatocellular carcinoma, which are helpful in accurately diagnosing this tumor and differentiating them from secondary cancers. On the basis of cytomorphologic features of hepatocellular carcinoma observed in aspirate preparations in correlation with histopathology, the tumors can be classified into four types: well-differentiated, moderately differentiated, poorly differentiated, and pleomorphic large cell type.63 Since 1996, 234 cases of hepatocellular carcinoma, including 71 of the well-differentiated cell type (2 cases of clear cell variant); 41 of the moderately differentiated cell type; 21 of the poorly differentiated cell type; and 7 of the pleomorphic large cell type (four cases of fibrolamellar variant), have been diagnosed by fine-needle aspiration biopsy at the New York University Medical Center. The cytomorphologic features of these four types of hepatocellular carcinoma are summarized as follows. Prior to microscopic examination, the physical characteristics of the liver aspirates (Fig. 4.17) provide the first clue in distinguishing benign from malignant hepatic lesions.79 Benign liver aspirates, including cirrhosis, macroregenerative nodule, liver cell adenoma, focal nodular hyperplasia, typically present as cores of tissue that are difficult to smear, in contrast to the finely granular smears in malignant or pre-malignant liver aspirates, i.e. borderline hepatocellular nodules (high grade small cell dysplastic) nodules. The histologic basis of this phenomenon is that the benign hepatic aspirates

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are supported by a reticulin network along a single hepatocyte plate architecture, which protects the tissue during aspiration and smearing. The malignant transformation of hepatocytes leads to the marked decrease or absence of the reticulin, permitting the breakdown of the tissue by the force of aspiration and smearing. There are exceptions to the rule; in our study of 67 welldifferentiated hepatocellular carcinoma, six cases (9%) presented as rigid cores (Fig. 4.18). Microscopic examination shows tightly packed hepatocytes with clearly malignant nuclei. Reticulin stain demonstrates decreased reticulin fibers. Trichrome stain does not demonstrate increased fibrosis. However, E-Cadherin holds the malignant hepatocytes together during smearing.

Well-Differentiated Cell Type (Figs. 4.19–4.21) The aspirate preparations are usually highly cellular and contain many fragments of neoplastic tissue and tightly packed, cohesive cell clusters. The neoplastic cells (cohesion factor, 4 to 5) are often arranged in a trabecular fashion, thick cords, papillae, or cell balls. They are relatively small cells and have regular, uniform, centrally located round nuclei, with a finely granular chromatin pattern. The cytoplasm is less abundant than that of benign hepatocytes seen in the same specimen, and nucleoli are usually small. In some neoplastic cells, intracytoplasmic bile may be found. It stains green with Ultrafast Papanicolaou stain and appears coarsely granular. The neoplastic hepatocytes of well-differentiated cell type have minimal nuclear atypia and possess intact cell membranes that can survive the force of smearing. The microtrabecular and microacinar variants80 of this type are the major source of false negative diagnosis as atypical or reactive hepatocytes. Reticulin stain on cell block is most helpful for confirming the malignant nature of the bland hepatocytes by demonstrating the absence or marked decrease of reticulin fibers and the loss of single cell plate architecture.22,23,80

Classic (Fig. 4.19) The aspirates present as numerous trabeculae (cohesion factor, 4 to 5) with the narrowest regions ≥ 3-cells in thickness, wrapped by peripheral endothelium. The trabeculae are composed of monotonous small hepatocytes with small nucleoli. The histology on cell block shows a trabecular

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(Fig. 4.19D) arrangement. This tumor can be recognized at low power examination by cytomorphology alone.

Microtrabecular variant80 (Figs. 4.20–4.21) The aspirates present as numerous thin trabeculae with the narrowest region of only 1–2 cells in thickness with or without peripheral endothelium. The microtrabeculae are composed of monotonous small hepatocytes with small nucleoli. The histology on cell block shows a compact (Fig. 4.20D) or microtrabecular arrangement (Fig. 4.21D).

Microacinar variant80 (Figs. 4.22–4.23) The aspirates present as numerous dyscohesive rosette-like microacini, composed of as few as 5–6 cells. The microacini have a central canaliculus and peripheral nuclei. Histology on cell block shows compact (Fig. 4.22D) or microacinar (Fig. 4.23D) arrangements.

Clear cell variant (Fig. 4.24) In the NYU series of four cases of clear cell variant, the neoplastic hepatocytes have extensive steatosis as well as glycogen accumulation. As shown in Fig. 4.24, the majority of the cells are distended by a single fat globule. Occasional cells show smaller fat globules. PAS stain with and without diastase demonstrates that the cytoplasmic space between fat droplets is filled by glycogen (Fig. 4.24D). There is another clear cell variant, where the clear cell change of the neoplastic hepatocytes is due to the abundant of glycogen.30

Moderately-Differentiated Cell Type (Figs. 4.25–4.28) This type is characterized by the fragility of the cell membrane of neoplastic hepatocytes which would burst during smearing, resulting in numerous naked nuclei in the smear (Fig. 4.25). The naked nuclei are round with prominent nucleolus and are identical to the atypical nuclei of neoplastic hepatocytes that survive the smearing. Histology on cell block may show trabecular (Fig. 4.26D) or pseudoglandular arrangement (Fig. 4.27D). In some

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cases, the nuclear pseudoinclusions are conspicuous (Fig. 4.27C). In other cases, ring-form nuclei are present (Fig. 4.28C). The diagnosis of moderately differentiated cell type is straightforward. The atypical naked nuclei is evidence for malignancy, and the intact tumor cells that survive the smearing look like hepatocytes. No special stains are needed.

Poorly Differentiated Cell Type (Figs. 4.29–4.31) This type of tumor is too poorly differentiated to be recognized as hepatocellular carcinoma based on cytomorphology alone. Aspirate preparations contain a few cohesive cell clusters but many solitary cells and loose groupings of neoplastic cells (cohesion factor, 2 to 3). The tumor cells appear bizarre and contain large, round or ovoid nuclei with prominent nucleoli. The nuclei are either centrally located or eccentric in position. Binucleation may be seen, but multinucleation is uncommon (Figs. 4.29 and 4.30). The cytoplasm is relatively scanty and, thus, the N/C ratio appears high. Bile production is rare in this type. Sometimes, the tumor cells are so poorly differentiated that there is no resemblance to hepatocytes (Fig. 4.31). The nuclei are irregular in shape and without prominent nucleoli. In addition, the cell border is indistinct and the cytoplasm is vacuolated. In this case the cytoplasm is negative for Hepar-1, but positive for α-fetoprotein immunostain (Fig. 4.31D). Histologically, hepatocellular carcinoma of the poorly differentiated type shows masses of bizarre-appearing neoplastic cells without a definite cellular arrangement (Fig. 4.31D left). Poorly differentiated cell type is easily recognized as malignant, but the hepatic origin may need immunohistochemical confirmation. This includes canalicular expression of polyclonal CEA or CD10,45 cytoplasmic expression of Hepar-111 or α-fetoprotein, and coordinated CK7/CK20 profile to rule out non-hepatic carcinomas.72 Of note, the Hepar-1 expression is related to nuclear grade. Most poorly differentiated hepatocellular carcinoma may not express Hepar-1.11

Pleomorphic Large Cell Type (Figs. 4.32–4.34) Aspirate preparation shows that neoplastic cells (cohesion factor, 0 to 1) are present either in small loose groupings, or lie singly. They are variable in size

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and shape but are often large, some of them being giant-sized. The cytoplasm is abundant and well-defined. The nuclei also have variations in size and shape and tend to be eccentric in position. The nucleoli are prominent in many cells. Multinucleated neoplastic cells are a common finding and may contain more than 10 nuclei (Figs. 4.32D and 4.33C). Bile production by the tumor cells, either mononuclear or multinucleated, is a frequent finding. Sinusoidal endothelial lining cells, as seen in the well-differentiated cell type, are not present. In rare cases of this type, mucin-secreting activity may be seen in some neoplastic cells of which the cytoplasm appears vacuolated and shows a positive reaction with mucicarmine stain.63 The fibrolamellar variant (Figs. 4.33–4.34) has distinct clinical features, i.e. young age at presentation, equal gender presentation, absence of cirrhosis, a better resectability rate and survival rate than the usual hepatocellular carcinoma.30 The CT-scan image is similar to focal nodular hyperplasia in terms of a central scar. Histologically, tumor nests are separated by fibrous lamellae of varied thickness (Fig. 4.34C). However, in aspirates the fibrous stroma is usually underrepresented due to its resistance to aspiration. Frequently, no fibrocytes are present in the aspirate, thus the general feature of the sample is similar that of the pleomorphic large cell type of the usual hepatocellular carcinoma. However, the nuclear and cytoplasmic features of the two look-alike entities have subtle differences. The cytoplasm of the fibrolamellar variant is oncocytic and contains numerous mitochondia (Fig. 4.34D). Their nuclei, though large, possess smooth nuclear membrane with vesicular chromatin and a single prominent nucleolus, unlike the hyperchromatic nuclei with their irregular nuclear membrane and the multiple nucleli of the usual pleomorphic large type of hepatocellular carcinoma (Fig. 4.32). A diagnosis of fibrolamellar hepatocellular carcinoma on fine-needle aspiration should only be made in the clinical setting of a noncirrhotic patient.22 The cytomorphologic features of hepatocellular carcinomas of these four types are distinctly different and are summarized and compared in Table 4.1. Their cytomorphologic characteristics appear quite different from those of most metastatic cancers. Immunostainings for α-fetoprotein and Hepar-1 are also helpful in establishing the definitive diagnoses in some problem cases.

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Table 4.1 Comparison of Cytomorphologic Features of Different Types of Hepatocellular Carcinoma

Cellular Arrangement 1. General cytologic pattern

2. Sinusoidal endothelial lining Cells 1. Average size 2. Nucleus/ Cytoplasmic ratio 3. Cohesion between cells Nuclei 1. Shape 2. Location 3. Size 4. Prominent nucleoli 5. Multinucleation Cytoplasm 1. Abundance 2. Bile production 3. Hyaline globules

Well Differentiated Cell Type

Moderately Differentiated Cell Type

Poorly Differentiated Cell Type

Many tissue fragments and cohesive groupings

Numerous naked nuclei and some cohesive tissue fragments

Common findings

Occasionally seen

Cohesive groupings, loose groupings and solitary cells Occasionally seen

Relatively small Intermediate

Intermediate

Good

Round (mostly) or Central

Central

Small Unusual

Pleomorphic Large Cell Type

Loose groupings and solitary cells

Absent

Relatively large High

Large Low

Good in the intact cells

Rather poor

Poor

Round

Variable ovoid

Intermediate Frequent

Round or ovoid Central or peripheral Large Frequent

Unusual

Unusual

Unusual

Variable Relatively common Frequent

Less abundant Common Uncommon

Intermediate Fragile Uncommon Uncommon

Scanty

Abundant

Rare Occasional

Frequent Rare

Peripheral

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Hepatoblastoma (Figs. 4.35–4.38) Hepatoblastoma, the most common pediatric liver cancer, can also occur in young adults. It mimics the developing embryonal and fetal liver, including extramedullary hematopoiesis.30 Patients frequently have very high levels of α-fetoprotein in the serum. The physical characteristics of hepatoblastoma aspirates is similar to hepatocellular carcinoma and easily smeared into finely granular smears.

Pure Fetal Epithelial Type (Figs. 4.35–4.36) The aspirates consist of cohesive fragments of small immature hepatocytes and many naked nuclei. The neoplastic cells resemble fetal hepatocytes with small round nuclei, small nucleoli and reduced cytoplasm. The cell membrane is fragile, resulting in naked nuclei in the smear. Extramedullary hematopoisis with scattered megakaryocytes are frequently present. Histologically, the fetal hepatocytes are arranged in thin microtrabeculae of 1–3 cells in thickness or in macrotrabecular pattern. Fat and glycogen are present in some neoplastic cells.

Embryonal and Fetal Type (Fig. 4.37) The aspirates consist of cohesive fragments of embryonal hepatocytes with hyperchromatic nuclei and scanty cytoplasm, intermixed with fetal hepatocytes with a moderate amount of cytoplasm. High molecular weight cytokeratin AE1/AE3 and CK7 are expressed by the embryonal hepatocytes, but not the fetal hepatocytes. Extramedullary hematopoisis may be present.

Mixed Epithelial and Mesenchymal Type (Fig. 4.38) The aspirates consist of mesenchymal tissue intermixed with embryonal and fetal hepatocytes. The mesenchymal tissue may be primitive as in the illustrated case or can have foci of divergent differentiation toward cartilage or osteoid.

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TUMORS OF INTRAHEPATIC BILE DUCT Bile Duct Adenoma (Fig. 4.39) Bile duct adenomas are small, firm nodules, rarely over 1 cm in diameter and usually located beneath Glisson’s capsule. They are composed of small, well formed bile ducts embedded in a mature fibrous stroma. They are usually solitary but, when in multiple form, may mimic metastatic carcinoma. The aspirate preparations contain many cohesive clusters of bile duct epithelial cells, ranging from cuboidal to columnar in typed. The ductal cells do not show atypia. No cholestasis is noted. Hepatocytes are not seen. Fibroblasts and/or fragments of fibrous tissue may be seen in variable numbers but are usually underrepresented in aspirate preparations, as compared to the fibrous element seen in tissue sections, because they are difficult to aspirate.

Cholangiocarcinoma (Figs. 4.40–4.45) Cholangiocarcinomas may arise anywhere between the papilla of Vater and the small branches of the bile ducts within the liver but originates most often from the large hilar bile ducts at the bifurcation of the common hepatic duct or from the extrahepatic bile ducts. Intrahepatic cholangiocarcinoma is much less common than hepatocellular carcinoma and represents 10 to 18% of primary liver cancers in different countries. Cholangiocarcinoma is known to follow Clonorchis sinensis infestation, hemochromatosis, and Thorotrast77 injection and, occasionally, the tumor arises in patients with chronic ulcerative colitis. Histologically, cholangiocarcinoma is an adenocarcinoma of the cuboidal- or columnar-cell type. There is much more fibrous stroma than in hepatocellular carcinoma, and the tumor is much less vascular. Mucin is usually demonstrable but is rarely abundant. Cholangiocarcinomas that exhibit prominent secretory activity are only occasionally encountered in our daily work. The aspirate preparations show that neoplastic cells (cohesion factor, 4 to 5) occur in cohesive groupings without a definite cellular arrangement and, only occasionally, in sheet arrangements. They are relatively small and have ovoid nuclei and small amounts of cytoplasm, resembling atypical bile duct epithelial cells (Figs. 4.40 to 4.41). Variation in nuclear size and prominent nucleoli are noted in some cells. Most cholangiocarcinomas were

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nonsecretory or minimally secretory (Figs. 4.41 to 4.43). Only occasional tumors show prominent secretory activity (Fig. 4.44). Cytomorphologically, some cases of cholangiocarcinomas are indistinguishable from adenocarcinomas of the pancreas arising from the pancreatic duct. Findings of imaging techniques, particularly percutaneous transhepatic cholangiography, are helpful in the determination of the tumor origin. One rarely reports cholangiocarcinoma without correlating with clinical findings and doing the coordinating cytokeratins immunostaining on cell block material. Cholangiocarcinomas are typically CK7+/CK20+,72 similar to ductal adenocarcinoma of the pancreas; thus, the fine-needle aspiration biopsy report is usually “adenocarcinoma of bile duct or pancreatic ductal primary,” unless the pancreatic primary has already been excluded by radiologic study. Rare variants of cholangiocarcinoma include mucinous, adenosquamous, squamous, mucoepidermoid, clear cell and spindle cell variants.30 We have encountered a case of adenosquamous variant which is illustrated in Fig. 4.45.

Angiosarcoma (Fig. 4.46) Angiosarcomas of the liver are uncommon, highly malignant tumors. They form multiple or, less often, solitary hemorrhagic masses. They have been associated with injection of Thorotrast,77 industrial exposure to vinyl chloride,68 or previous arsenic treatment.38 A relationship to copper sulphate in vineyard sprayers,49 to anabolic steroid,20 and to phenelzine15 has also been suggested. Eighty-five percent of patients are in their 6th and 7th decades of life. About one-third of cases are associated with cirrhosis.42 Both open and percutaneous large-bore needle biopsies for histologic diagnosis are associated with significant intraabdominal bleeding in 16% of the cases and death in 5%.41 Fine-needle aspiration biopsy of the tumor is expected to greatly reduce this hazard. Histologically, the tumor may show cavernous or solid growth patterns. Irregular vascular spaces lined with neoplastic cells with round, ovoid or elongated nuclei are noted. Thrombosis and infarction are common. The aspirate preparations show that neoplastic cells (cohesion factor, 0 to 1) either occur in loose groupings or lie singly. Some of them have

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round or ovoid nuclei and no recognizable cytoplasm. Other cells are spindleshaped and have elongated nuclei. Occasionally, large bizarre-appearing neoplastic cells with intracytoplasmic hemosiderin pigment may be seen. These could represent malignant Kupffer cells.46 The smears are typically bloody, and necrotic cellular debris may be present in the background. Factor VIII, CD31 and CD34 are detected in the cytoplasm of some neoplastic cells by immunohistochemistry on cell block sections, indicative of an endothelial origin.

Epitheloid Hemangioendothelioma (Fig. 4.47) Epitheloid hemangioendothelioma is a malignant vascular tumor of intermediate aggressiveness.31 The typical presentation is from relatively healthy young men, with increased enzymes in routine liver function test. A CT scan of the abdomen shows multiple liver masses with no known primary.56 The epitheloid endothelial cells are invariably associated with a stroma that varies from loose and myxoid to dense and fibrous. The neoplastic endothelial cells have abundant cytoplasm, forming intracytoplasmic lumens that express CD31, CD34 and factor VIII. The aspirate preparations56 are paucicellular due to the fibrotic stroma and contain scattered single cells and occasional small tissue fragments. There is an admixture of small bland cells with scanty cytoplasm, spindled cells, and large pleomorphic cells with abundant cytoplasm. Scattered cells contain prominent nucleoli, while others demonstrate hyperchromasia. Rare multinucleated tumor cells are present. It is almost impossible to diagnose hepatic epitheloid hemangioendothelioma based on cytology alone. It is crucial during on-site assessment to request for a cell block sample for histology and immunohistochemistry. It is an important diagnosis, since long-term disease-free survival in possible, especially in the setting of an orthotopic liver transplantation.37

Embryonal (Undifferentiated) Sarcoma (Fig. 4.48) Embryonal sarcoma is a pediatric primitive mesenchymal tumor, but rarely occurs in adults.30 The majority are located in the right lobe of the liver. The tumor cells are stellate- or spindle-shaped with ill-defined outlines. They

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may be compactly or loosely arranged with mucopolysaccharide matrix, and marked anisonucleosis nisonucleosis with hyperchromatic and rare bizarre giant cells. The tumor cells express vimentin, but may show focal differentiation to rhabomyoblastic and leiomyoblastic cell types. The aspirate preparations show cohesive fragments of irregular shaped hyperchromatic tumor cells with invisible cytoplasm held together by fibrillary matrix. The shape of the nuclei ranges from spindly to oblong to ovoid with marked variation of nuclear size.

METASTATIC TUMORS Of the abdominal organs, the liver is the most frequent site of blood-borne metastases from cancers of various origins. The cancer cells may reach the liver through the portal vein, hepatic artery, or hilar lymphatics, or by direct extension. Practically, all malignant cells grow well in liver parenchyma, and metastatic carcinomas usually grow rapidly in the liver, with patients rarely living more than a year after the establishment of the diagnosis.33 Primary malignant tumors of the gallbladder, extrahepatic bile ducts, pancreas and stomach frequently involve the liver by direct extension. Distant metastases from carcinomas of the large bowel, kidney, pancreas, stomach, lung and breast appear with great frequency. Sarcomas may also metastasize to the liver. Metastasis to the liver occurs in 38% of all cancers, 41% of lung cancers, 56% of colon cancers, 70% of pancreatic cancers, 53% of breast cancers and 44% of gastric cancers.18 Once implanted in the liver, the cancer cells may form small or large nodules or grow diffusely throughout the liver. In about 10% of cases, metastatic nodules are solitary. Many benign lesions and primary liver tumors may have a gross appearance and roentgenographic pictures indistinguishable from metastatic cancers. Therefore, it is imperative that a microscopic confirmation be obtained in every patient in whom a liver mass or masses are detected by means of imaging techniques. The presence of liver metastases virtually precludes the possibility of curative surgery at the site of the primary cancer. Transabdominal fine-needle aspiration biopsy is of great value in patients who are scheduled to undergo operative resection of a primary cancer if ultrasonography or computed tomography demonstrates a lesion or lesions in the liver.

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COMMON METASTATIC TUMORS The common metastatic tumors encountered include: 1. Carcinomas metastatic from the digestive system A. B. C. D. E. F.

Adenocarcinoma of the colon (Fig. 10.25) Adenocarcinoma of the stomach (Figs. 10.15–10.18) Carcinoid (Fig. 10.22) Ductal adenocarcinoma of the pancreas (Figs. 5.17–5.29) Giant cell carcinoma of the pancreas (Figs. 5.31–5.32) Pancreatic neuroendocrine neoplasm (Figs. 5.35–5.36)

2. Carcinomas metastatic from the respiratory system A. B. C. D. E. F. G.

Squamous cell carcinoma (Figs. 4.49–4.50) Small cell anaplastic carcinoma (Figs. 4.51–4.52) Adenocarcinoma (Figs. 4.51–4.53) Bronchioloalveolar carcinoma (Figs. 4.54–4.56) Undifferentiated large cell carcinoma (Fig. 4.57) Giant cell carcinoma (Fig. 4.58) Spindle cell carcinoma (Figs. 4.59–4.60)

3. Carcinomas metastatic from the genitourinary system A. B. C. D. E. F. G.

Renal cell carcinoma (Figs. 6.11–6.32) Urothelial carcinoma (Figs. 6.34–6.37) Adenocarcinoma of the prostate (Figs. 4.61–4.62) Serous carcinoma of the ovary (Figs. 9.25–9.27) Mucinous carcinoma of the ovary (Fig. 9.30) Adenocarcinoma of the endometrium (Figs. 9.3–9.10) Granulosa cell tumor of the ovary (Figs. 9.31–9.33)

4. Carcinomas metastatic from the breasts A. Lobular carcinoma (Fig. 4.63) B. Ductal carcinoma (Figs. 4.64–4.67) 5. Cancers metastatic from the adrenals A. Adrenocortical carcinoma (Figs. 7.10–7.15) B. Malignant pheochromocytoma (Figs. 7.16–7.17) C. Neuroblastoma (Fig. 7.18)

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6. Sarcomas metastatic to the liver A. B. C. D. E. F. G. H.

Fibrosarcoma (Figs. 8.7–8.8) Leiomyosarcoma (Figs. 8.9–8.13 and Figs. 9.16–9.18) Liposarcoma (Figs. 8.15–8.18) Rhabdomyosarcoma (Figs. 8.19–8.20) Angiosarcoma (Figs. 8.23–8.25) Malignant fibrous histiocytoma (Figs. 8.26–8.28) Malignant peripheral sheath tumor (Figs. 8.37–8.38) Malignant hemangiopericytoma (Fig. 8.29)

7. Malignant lymphomas A. Non-Hodgkin lymphoma B. Hodgkin lymphoma 8. Other cancers metastatic to the liver A. Malignant melanoma (Figs. 4.68–4.70) The cytomorphologic features of malignant tumors metastatic to the liver seen in aspirate preparations are essentially the same as those of the primary tumors from other organs. The aspiration biopsy cytology of tumors metastatic to the liver has been discussed and illustrated in other chapters; carcinomas metastatic from the respiratory system, from the prostate, from the breasts, and metastatic melanoma, are described and illustrated in the sections that follow.

Carcinomas Metastatic from the Respiratory System A. Squamous cell carcinoma in liver aspirate preparations a. Keratinizing large cell type (Fig. 4.49) 1. Large tumor cells (cohesion factor, 1 to 2), variable in size and shape, in loose groupings, and as solitary cells 2. Nuclei that tend to be pyknotic, also variable in size and shape 3. The cytoplasm of keratinized tumor cells has an orange coloration with Papanicolaou stain and appears dense, nontransparent, and sharply demarcated and variable in amount 4. Occasional epithelial pearls that are composed of keratinized tumor cells with pyknotic nuclei in a whorl arrangement

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5. Necrotic tumor cells and ghost cells often intermingled with numerous neutrophils b. Nonkeratinizing large cell type (Fig. 4.50) 1. Tumor cells (cohesion factor, 4 to 5) in cohesive clusters and, occasionally, loose groupings 2. Medium-sized or large, round, ovoid, or irregularly shaped nuclei with coarsely granular chromatin 3. Cohesive clusters of tumor cells with nuclei in polar arrangements 4. Small nucleoli and rare prominent nucleoli B. Small cell anaplastic carcinoma a. Oat cell type (Fig. 4.51) 1. Small tumor cells (cohesion factor, 1 to 2) in loose groupings and as solitary cells 2. Tumor cells that have little recognizable cytoplasm 3. Round, ovoid, irregular, or spindle-shaped nuclei with dark, clumped chromatin 4. Nuclear molding and tumor necrosis 5. Paranuclear apoptotic nuclei b. Intermediate cell type (Fig. 4.52) 1. Tumor cells (cohesion factor, 2 to 3) in loose groupings, as solitary cells and, occasionally, in cohesive groupings 2. Medium-sized, pleomorphic nuclei with dark, clumped chromatin 3. Tumor cells that have little recognizable cytoplasm 4. Nuclear molding and tumor necrosis 5. Paranuclear aopoptotic nuclei C. Adenocarcinoma a. Well-differentiated cell type (Fig. 4.53) 1. Tumor cells (cohesion factor, 4 to 5) in cohesive clusters and in loose groupings 2. Medium-sized or large, round, or ovoid nuclei 3. Prominent nucleoli seen in many tumor cells 4. Tumor cells that have moderate amounts of foamy or vacuolated cytoplasm

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b. Poorly differentiated cell types (Fig. 4.54) 1. Tumor cells (cohesion factor, 3 to 4) in loose groupings, as solitary cells and, occasionally, in cohesive groupings 2. Large nuclei variable in size 3. Prominent nucleoli seen in many cells 4. Frequent mitotic figures 5. A few multinucleated tumor cells D. Bronchioloalveolar carcinoma a. Nonsecretory cell type (Fig. 4.55) 1. Tumor cells (cohesion factor, 4 to 5) in sheets, in cohesive sheets, and in papillary arrangements 2. Medium-sized, round, or ovoid, uniform and regular nuclei, often centrally located 3. Small nucleoli and a fine chromatin pattern 4. Relatively scanty, poorly defined cytoplasm 5. Occasional psammoma bodies b. Secretory cell type (Fig. 4.56) 1. Tumor cells (cohesion factor, 4 to 5) in cohesive clusters and loose groupings 2. Medium-sized, uniform and regular, centrally located, round or ovoid nuclei with a finely granular chromatin pattern 3. Prominent nucleoli seen in many tumor cells 4. Abundant, foamy or clear cytoplasm E. Undifferentiated large cell carcinoma (Fig. 4.57) 1. Tumor cells (cohesion factor, 2 to 3) in loose groupings and as solitary cells 2. Large, pleomorphic nuclei with a coarsely granular chromatin pattern 3. Frequent multinucleation and mitotic figures 4. Prominent nucleoli seen in many cells F. Giant cell carcinoma (Fig. 4.58) 1. Tumor cells (cohesion factor, 0) as solitary cells 2. Giant tumor cells with irregular nuclear membrane and prominent nucleoli

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3. Occasional multinucleation 4. Background and intracytoplasmic neutrophils. G. Spindle cell carcinoma (Figs. 4.59–4.60) 1. Tumor cells (cohesion factor, 0) as solitary cells 2. Spindle cells with oval nuclei and tapered cytoplasm 3. Occasional multinucleation (Figs. 4.58C, 4.59C) or binucleation (Fig. 4.60D) 4. Nucleoli are present, but not prominent.

Carcinomas Metastatic from the Prostate A. Adenocarcinoma a. Well-differentiated cell type (Fig. 4.61) 1. 2. 3. 4. 5.

Tumor cells (cohesion factor, 2 to 3) in loose and cohesive groupings Medium-sized, relatively uniform, round nuclei Prominent nuclei in some tumor cells A relatively small amount of poorly defined cytoplasm Prostate-specific protein and prostatic acid phosphatase detected in the cytoplasm of some tumor cells by immune stains.

b. Poorly differentiated cell type (Fig. 4.62) 1. Tumor cells (cohesion factor, 2 to 3) in cohesive clusters and loose groupings 2. Medium-sized or large, round nuclei 3. Prominent nucleoli in many tumor cells 4. A moderate amount of cytoplasm, often poorly defined

Carcinomas Metastatic from the Breasts A. Lobular carcinoma (Fig. 4.63) 1. Signet ring-like tumor cells (cohesion factor, 1 to 2) in loose groupings and as solitary cells 2. Medium-sized, round or ovoid nuclei, many located eccentrically 3. Inconspicuous nucleoli 4. A moderate amount of well-defined cytoplasm containing mucin

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B. Ductal carcinoma a. Small cell type (Fig. 4.64) 1. Small tumor cells (cohesion factor, 2 to 3) in cohesive clusters and loose groupings, a few in a “cell in cell” arrangement 2. Small, round or ovoid nuclei with evenly distributed chromatin 3. Inconspicuous nucleoli 4. A small amount of poorly defined cytoplasm b. Intermediate cell type (Fig. 4.65) 1. Medium-sized tumor cells (cohesion factor, 3 to 4), many in cohesive clusters 2. Medium-sized, round or ovoid nuclei that have no recognizable nucleoli 3. A moderate amount of well-defined cytoplasm 4. A few acinar structures c. Large cell type (Fig. 4.66) 1. Large tumor cells (cohesion factor, 3 to 4) in cohesive clusters and loose groupings 2. Large, round or ovoid nuclei with variation in size 3. Prominent nucleoli in many tumor cells 4. A moderate amount of cytoplasm, often poorly defined

Malignant Melanoma Metastatic to the Liver a. Round cell type (Fig. 4.67) 1. Tumor cells (cohesion factor, 0 to 1) in loose groupings and as solitary cells 2. Small to large, round nuclei 3. A single prominent nucleolus or two or more conspicuous, irregularly shaped nucleoli in many tumor cells 4. A small or moderate amount of cytoplasm, often poorly defined 5. Pigmentation of some tumor cells 6. S-100 protein and HMB-45 detected in the cytoplasm of some tumor cells by means of immunoperoxidase staining

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b. Spindle cell type (Fig. 4.68) 1. Tumor cells (cohesion factor, 0 to 1) in loose groupings and as solitary cells 2. Small spindle-shaped nuclei and a small amount of poorly defined cytoplasm in some tumors 3. Large spindle-shaped nuclei and a single prominent nucleolus or two or more conspicuous nucleoli in other tumors 4. Pigmentation of a few tumor cells c. Pleomorphic large cell type (Fig. 4.69) 1. Tumor cells (cohesion factor, 0 to 1) in loose groupings and as solitary cells 2. Large nuclei with variations in size and shape and poorly defined cytoplasm 3. Two or more conspicuous nucleoli or a single prominent nucleolus in many tumor cells 4. Two or more nuclei in many tumor cells 5. Pigmentation of a few tumor cells d. Small cell type (Fig. 4.70) 1. Tumor cells (cohesion factor, 0 to 1) in loose groupings and as solitary cells 2. Small, round, ovoid or irregularly shaped nuclei 3. Rare tumor cells with multinucleation and a few that have inconspicuous nucleoli 4. A small amount of well-defined cytoplasm 5. Pigmentation of a few tumor cells

REFERENCES 1. Anthony PP. (2001) Hepatocellular carcinoma: An overview. Histopathol 39: 109–118. 2. Bagnel C, Rougier P, Leclerc J, et al. (1988) Fine needle aspiration of the liver and pancreas with ultrasound guidance. Acta Cytol 32:22–26. 3. Beasley RP, Hwang LY, Lin CC, et al. (1981) Hepatocellular carcinoma and hepatitis B virus. Lancet 2:1129–1133.

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19. Ekelund P, Wasastjerna C. (1971) Cytological identification of primary hepatic carcinoma cells. Acta Med Scand 189:373–375. 20. El-Serag HB, Mason AC. (1999) Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 340:745–750. 21. Falk H, Thomas LB, Popper H, et al. (1979) Hepatic angiosarcoma associated with androgenic-anabolic steroids. Lancet 2:1120–1123. 22. Ferrell LD. (2000) Liver pathology: Cirrhosis, hepatitis and primary liver problems. Modern Pathol 13:679–704. 23. Ferrell LD, Crawford JM, Dhillon AP, et al. (1993) Proposal for standardized criteria for the diagnosis of benign, borderline, and malignant hepatocellular lesions arising in chronic advanced liver-disease. Am J Surg Pathol 17: 1113–1123. 24. Falk H, Thomas LB, Popper H, et al. (1979) Hepatic angiosarcoma associated with androgenic-anabolic steroids. Lancet 2:1120–1123. 25. Gupta SK, Das DK, Rajwanslin A, et al. (1986) Cytology of hepatocellular carcinoma. Diagn Cytopathol 2:291–294. 26. Hemming AW, Cattral MS, Reed AI, et al. (2001) Liver transplantation for hepatocellular carcinoma. Ann Surg 233:652–659. 27. Hidvegi DF. (1988) Guides to Clinical Aspiration Biopsy: Liver and Pancreas. New York, Igaku-Shoin. 28. Ho CS, McLaughlin MJ, Tao LC, et al. (1981) Guided percutaneous fine-needle aspiration biopsy of the liver. Cancer 47:1781–1785. 29. Ikeda K, Saitoh S, Koida I, et al. (1993) A multivariate-analysis of risk-factors for hepatocellular carcinogenesis — A prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 18:47–53. 30. Ishak KG,Goodman ZD, Stocker JT. (2001) Tumors of the liver and intrahepatic bile ducts. Atlas of Tumor Pathology, 3rd Series, Fascicle 31. Washington, DC, AFIP. 31. Ishak KG, Sesterhemm IA, Goodman ZD, et al. (1984) Epitheloid hemangioendothelioma of the liver: A clinicopathologic and follow-up study of 32 cases. Hum Pathol 15: 839–852. 32. Iwarson S, Lindberg J, Lundin P. (1979) Progression of hepatitis non-A, non-B to chronic active hepatitis. J Clin Pathol 32:351–355. 33. Jaffe BM. (1968) Factors influencing survival in patients with untreated metastases. Sorg Gynecol Obstet 127:1–6. 34. Kaw YT, Esparza AR. (1991) Cytologic diagnosis of cavernous hemangioma of the liver with fine-needle biopsy. Diagn Cytopathol 7:628–630. 35. Klatskin G. (1976) Hepatic granulomata: Problems in interpretation. Ann NY Acad Sci 278:427–432.

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36. Klatskin G. (1977) Hepatic tumors: Possible relationship to use of oral contraceptives. Gastroenterology 73:386–394. 37. Marino IR, Todo S, Tzakis AG, et al. (1988) Treatment of hepatic epithelioid hamangioendothelioma with liver transplantation. Cancer 62:2079–2084. 38. Lander JJ, Stanley RJ, Sumner HW, et al. (1975) Angiosarcoma of the liver associated with Fowler’s solution (potassium arsenite). Gastroenterology 68: 1582–1586. 39. Lencioni RA, Allgaier HP, Cioni D, et al. (2003) Small hepatocellular carcinoma in cirrhosis: Randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 228:235–240. 40. Lingao AL, Domingo ED, Nishioka K. (1981) Hepatitis B virus profile of hepatocellular carcinoma in the Philippines. Cancer 48:1590–1595. 41. Locker GY, Doroshow JH, Zwelling LA, et al. (1979) The clinical features of hepatic angiosarcoma: A report of four cases and a review of the English literature. Medicine 58:48–64. 42. Ludwing J, Hoffman HN II. (1975) Hemangiosarcoma of the liver: Spectrum of morphologic changes and clinical findings. Mayo Clin Proc 50:255–263. 43. Lundqvist A. (1970) Fine-needle aspiration biopsy for cytodiagnosis of malignant tumor in the liver. Acta Med Scand 188:465–470. 44. Lutz H, Weidenhiller S, Rettenmaier G. (1973) Ultrasonically-guided fine-needle aspiration biopsy of the liver. Schweiz Med Wochenschr 103:1030–1033. 45. Morrison C, Marsh W, Frankel WL. (2002) A comparison of CD10 to pCEA, MOC-31, and hepatocyte for the distinction of malignant tumors in the liver. Mod Pathol 15:1279–1287. 46. Nguyen GK, McHattie JD, Jeannot A. (1982) Cytomorphologic aspects of hepatic angiosarcoma: Fine-needle aspiration biopsy of a case. Acta Cytol 26:527–531. 47. Peers FG, Linsell CA. (1973) Dietary aflatoxins and liver cancer: A population based study in Kenya. Br J Cancer 27:473–484. 48. Pilotti S, Rilke F, Claren R, et al. (1988) Conclusive diagnosis of hepatic and pancreatic malignancies by fine needle aspiration. Acta Cytol 32:27–38. 49. Pimentel JC, Menezes AP. (1977) Liver diseases in vineyard sprayers. Gastroenterology 72:275–283. 50. Pinto MM, Avila NA, Heller CI, et al. (1988) Fine-needle aspiration of the liver. Acta Cytol 32:15–21. 51. Prince AM. (1981) Hepatitis B virus and hepatocellular carcinoma: Molecular biology provides further evidence for an etiologic association. Hepatology 1:73–75.

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52. Rasmussen SN, Holm HH, Kristensen JK, et al. (1972) Ultrasonically-guided liver biopsy. Br Med J 2:500–502. 53. Rosenblatt R, Kutcher R, Moussouris HF, et al. (1982) Sonographically guided fine needle aspiration of liver lesions. JAMA 248:1639–1641. 54. Saenz-Santamaria J, Moreno-Casado J, Nunez C. (1995) Role of fine-needle biopsy in the diagnosis of hydatid cyst. Diagn Cytopathol 13:229–232. 55. Sakai K, Shina M, Ishihara N, et al. (1984) Thorotrast-induced multiple primary malignant tumors of the liver-Cholangiocarcinoma and malignant hemangioendothelioma. Jpn J Clin Oncol 14:411–416. 56. Soslow RA, Yin P, Steinberg CR, Yang GCH. (1997) Cytopathologic features of hepatic epithelioid hemangioendothelioma. Diagn Cytopathol 17:50–53. 57. Schwert WB, Schmitz-Moormann P. (1981) Ultrasonically guided fine-needle biopsies in neoplastic liver disease. Cancer 48:1469–1477. 58. Shar SR, Kew MC. (1982) Oral contraceptives and hepatocellular carcinoma. Cancer 49:407–410. 59. Soderstrom N. (1966) Fine-Needle Aspiration Biopsy. Orlando, FL, Grune & Stratton. 60. Suen KC. (1986) Diagnosis of primary hepatic neoplasms by fine-needle aspiration cytology. Diagn Cytopathol 2:99–109. 61. Suen KC, Magee JF, Halparine LS, et al. (1985) Fine-needle aspiration cytology of fibrolamellar hepatocellular carcinoma. Acta Cytol 29:867–872. 62. Tao LC, Donat EE, Ho CS, et al. (1979) Percutaneous fine-needle aspiration of the liver: Cytodiagnosis of hepatic cancer. Acta Cytol 23:287–291. 63. Tao LC, Ho CS, McLoughlin MJ, et al. (1984) Cytologic diagnosis of hepatocellular carcinoma by fine-needle aspiration biopsy. Cancer 53:547–552. 64. Tao LC. (1991) Oral contraceptive-associated liver cell adenoma and hepatocellular carcinoma: Cytomorphology and mechanism of malignant transformation. Cancer 68:341–347. 65. Tagger A, Donato F, Ribero ML, et al. (1999) Case-control study on hepatitis C virus (HCV) as a risk factor for hepatocellular carcinoma: The role of HCV genotypes and the synergism with hepatitis B virus and alcohol. Brescia HCC Study. Int J Cancer 81:695–699. 66. Tanaka K, Nakamura S, Numata K, et al. (1998) The long term efficacy of combined transcatheter arterial embolization and percutaneous ethanol injection in the treatment of patients with large hepatocellular carcinoma and cirrhosis. Cancer 82:78–85. 67. Tatsuta M, Yamamoto R, Kasugai H. (1984) Cytohistologic diagnosis of neoplasms of the liver by ultrasonically guided fine-needle aspiration biopsy. Cancer 54: 1682–1686.

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68. Thomas LB, Popper H, Berk PD, et al. (1975) Vinyl-chloride-induced liver disease. From idiopathic portal hypertension (Banti’s syndrome) to angiosarcomas. N Engl Med J 292:17–22. 69. Tong MJ, Sun SC, Schaeffer BT. (1971) Hepatitis associated antigen and hepatocellular carcinoma in Taiwan. Ann Intern Med 75:687–691. 70. Van Pelt JF, Severi T, Crabbe T, et al. (2004) Expression of hepatitis C virus core protein impairs DNA repair in human hepatoma cells. Cancer Lett 209:197–205. 71. Van Rensburg SJ, Van der Watt JJ, Purchase IF. (1974) Primary liver cancer and aflatoxin intake in a high cancer area. S Afr Med J 48:2508A–2508D. 72. Wang NP, Zee S, Zarbo RJ, et al. (1995) Coordinate expression of cytokeratins-7 and cytokeratins-20 defines unique subsets of carcinomas. Appl Immunohistochem 3:99–107. 73. Wanless I, Callea F, Craig J, et al. (1995) Terminology of nodular hepatocellular lesions. International Working Party. Hepatology 22:983–993. 74. Wasastjerna C. (1979) Liver. In: Zajicek J (ed.), Aspiration Biopsy Cytology. Part 11. Cytology of Infradiaphragmatic Organs. Basel, S Karger AG. 75. Watanabe S, Okita K, Harada T, et al. (1983) Morphologic studies of the liver cell dysplasia. Cancer 51:2197–2220. 76. Weinberg AG, Mize CE, Worthen HG. (1976) The occurrence of hepatoma in the chronic form of hereditary tyrosinemia. J Paediatr 88:434–438. 77. Weinberg CD, Ranchod M. (1979) Thorotrast-induced hepatic cholangiocarcinoma and angiosarcoma. Hum Pathol 10:108–112. 78. Wu HH, Tao LC, Cramer HM. (1996) Vimentin-positive spider-shaped Kupffer cells. A new clue to cytologic diagnosis of primary and metastatic hepatocellular carcinoma by fine-needle aspiration biopsy. Am J Clin Pathol 106:517–521. 79. Yang GCH, Yang G-Y, Tao LC. (2004) Distinguishing well-differentiated hepatocellular carcinoma from benign liver by the physical features of fine needle aspirates. Modern Pathol 17:789–802. 80. Yang GCH, Yang G-Y, Tao LC. (2004) Cytologic features and histologic correlations of microacinar and microtrabecular types of well-differentiated hepatocellular carcinoma in fine needle aspiration biopsy. Cancer (Cancer Cytopathol) 102:27–33.

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Fig. 4.1 Benign hepatocytes. (A) Small flat plates of hepatocytes and bile ductules. UFP, 40×; (B) Polygonal cells with variation in nuclear size and lipofuscin. UFP, 1000×; (C) Bile plugs in liver with cholestasis. UFP, 400×; (D) Glycogenated nuclei in diabetes mellitus. UFP, 1000×.

Fig. 4.2

Bile ductule with oval bland nuclei with several indistinct nucleoli. UFP.

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Fig. 4.3 Sinusoidal endothelial cells and Kupffer cells. UFP, 1000×. (A) Sinusoidal endothelial cells (arrow) wrapping around carcinoma cells; (B) Kupffer cells have ovoid or elongated nuclei and small amounts of cytoplasm. Arrow points to 2 Kupffer cells attached to hepatocytes.

Fig. 4.4 CT-scan of a 34-year-old healthy female immigrant from Bosnia with elevated liver function tests demonstrated a 7.5 cm benign-appearing circumscribed right liver mass with focal calcification on CT-scan.

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Fig. 4.5 Ecchinococcal liver cyst. (A) Fragments of laminated layer of the cyst wall in a dirty background. UFP, 100×; (B) Hocklets (arrows) and calcareous corpuscles embedded in debris. UFP, 1000×; (C) Arrow points to germinal layer that the ecchinococcus buds off. DQ, 100×; (D) A scolex was found after careful search. UFP, 1000×.

Fig. 4.6 Histoplasmosis granuloma. Arrows points to intracytoplasmic tiny histoplasma spores. (A) DQ, 400×; (B) DQ, 400×; (C) UFP, 400×; (D) Cell block, H&E, 400×.

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CT-scan of cavernous hemangioma.

Fig. 4.8 Cavernous hemangioma of the liver. (A) Bloody aspirate containing rare clusters of spindle cells. DQ, 400×; (B) Fibrous tissue with cavernous spaces closely correlated to histology. DQ, 40×; (C) Arrow points to a cavernous space to be enlarged in D. UFP, 40×; (D) Rows of spindle stromal cells lined by endothelium. UFP, 400×.

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Fig. 4.9 CT scan of a 29-year-old healthy white male with elevated liver function test demonstrated a circumscribed, hetergeneous liver mass with fibrous septa radiating from a central scar. Radiologic impression: focal nodular hyperplasia vs. fibrolamellar hepatoma.

Fig. 4.10 Focal nodular hyperplasia. (A) Low power shows cohesive liver aspirate with cores of liver. UFP, 40×; (B) Rows of fibroblasts with metachromatic stroma traversing liver. DQ, 100×; (C) Polygonal hepatocytes traversed by a row of fibrocytes. UFP, 400×; (D) Fibroblasts intermingled with benign hepatocytes. UFP, 400×.

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Fig. 4.11 Liver cell adenoma. (A) Rigid core of liver aspirated from a 51-year-old female. UFP, 40×; (B) Polyhedral hepatocytes with normal N/C ratio. UFP, 400×; (C) Small fragments with capillaries (arrow) from a 41-year-old male. UFP, 40×; (D) Polyhedral hepatocytes with normal N/C ratio. UFP, 400×.

Fig. 4.12 Liver cell adenoma, in a 44-year-old female. (A) Rigid core of liver seen at low power. UFP, 40×; (B) Polyhedral hepatocytes with slightly increased N/C ratio. UFP, 400×; (C) Monotonous hepatocytes arranged in single rows. Cell block, H&E, 40×; (D) Intact reticular fibers. Cell block, reticulin, 40×.

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Fig. 4.13 Macroregenerative nodule (cirrhosis). (A) Cores of cirrhrotic liver difficult to smear except at the edges. UFP, 100×; (B) Large cell change (arrow) is present among normal hepatocytes. UFP, 400×; (C) Binucleated hepatocytes (arrow) are present. UFP, 400×; (D) Intact reticulin network, including area with fatty change. Cell block, 40×.

Fig. 4.14 Borderline nodule, aspirated from a 1.3 cm liver nodule. (A) Dyscohesive microacini. DQ, 100×; (B) Hepatocytes without any nuclear atypia, but reduced cytoplasm in a microacinar pattern. UFP, 1000×; (C) Increase nuclear density, i.e. small cell change. Cell block, H&E, 100×; (D) Decreased reticulin fibers. Cell block, reticulin, 100×.

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Fig. 4.15 Borderline nodule, aspirated from a 1.5 cm solid, hypervascular nodule, reported as hepatocellular carcinoma, which in 6 months regressed to a 0.9 cm small cell (high grade) dysplastic nodule.80 (A) Numerous microtrabeculae are present. UFP, 100×; (B) Monotonous small hepatocytes with prominent nucleoli, UFP, 1000×; (C) Microtrabecular pattern in cell block, H&E, 100×; (D) Decreased reticulin fibers. Cell block, reticulin, 400×.

Fig. 4.16 CT-guided FNA biopsy of hepatocellular carcinomas: anterior approach (left) and lateral approach (right).

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Fig. 4.17 Comparison of benign liver aspirate and malignant liver aspirate.79 (A) Benign liver aspirates present as cores of tissue, difficult to smear. UFP, 1×; (B) Malignant liver aspirates present as finely granular smears. UFP, 1×; (C) Reticulin fibers wrap along single plate of hepatocytes in benign hepatic lesions, thus difficult to smear. Cell block, reticulin, 400×; (D) Reticulin fibers are decreased in hepatocellular carcinoma, including very well differentiated type, thus easily smeared. Cell block, reticulin, 400×.

Fig. 4.18 Well-differentiated hepatocellular carcinoma. (A) Exception to the rule, rigid cores in 9% of the cases.79 UFP, 40×, Insert : 1×; (B) Tightly packed hepatocytes with frankly malignant nuclei. UFP, 400×; (C) Absence of reticulin demonstrated by reticulin stain. Cell block, 40×; (D) Compact type, cell block H&E, 400× left; E-cadherin, 400×, right.

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Fig. 4.19 Hepatocellular carcinoma, well-differentiated, classic type. (A) Retraction halos (arrow) highlights the trabeculae. UFP, 40×; (B) Retraction halo is an artifact of UFP, 100×; (C) Arrow points to endothelium that wraps the thick trabeculae. UFP, 400×; (D) Wrapping endothelium is marked by CD34 immunostain. Cell block, 100×.

Fig. 4.20 Hepatocellular carcinoma, microtrabecular type. (A) Numerous dyscohesive thin and long microtrabeculae. UFP, 100×; (B) Branching interconnecting microtrabeculae. UFP, 100×; (C) Microtrabeculae composed of one to two miniature hepatocytes with normal sized nuclei but reduced cytoplasm. UFP, 400×; (D) Cell block shows compact cell type of hepatocellular carcinoma. H&E, 100×.

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Fig. 4.21 Hepatocellular carcinoma, microtrabecular type. (A) Dyscohesive tissue fragments, separated by the smearing. UFP, 40×; (B) High power shows very thin microtrabeculae. UFP, 100×; (C) The narrowest areas are one-hepatocyte thick. UFP, 400×; (D) Peripheral endothelium wrapped trabecular of two-cell thick. H&E, 400×.

Fig. 4.22 Hepatocellular carcinoma, microacinar type. (A) Low power showed dyscohesive rosette-like microacini. UFP, 40×; (B) The microacini are composed of cells as few as 5–6 cells. UFP, 400×; (C) Microacini with peripheral nuclei with no atypia but markedly reduced cytoplasm. UFP, 1000×; (D) Compact cell type of hepatocellular carcinoma. Core biopsy, H&E, 40×.

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Fig. 4.23 Hepatocellular carcinoma, well-differentiated cell type. (A) Numerous dyscohesive cells separated from large fragment. UFP, 40×; (B) Rare microacini in background of single cells. UFP, 100×; (C) Plasmacytoid single cells resemble neuroendocrine tumor. UFP, 400×; (D) Microacinar variant of hepatocellular carcinoma. Core biopsy. H&E, 400×.

Fig. 4.24 Hepatocellular carcinoma, steatotic clear cell variant. (A) Dyscohesive hepatocytes with extensive steatosis resembling fat droplets at low magnification. UFP, 100×; (B) Majority of the cells are distented by a single fat globule. UFP, 400×; (C) Occasional tumor cells show smaller fat globules. UFP, 1000×; (D) Glycogen shown by PAS stain with and without diastase. Cell block, 400×.

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Fig. 4.25 Hepatocellular carcinoma, moderately-differentiated cell type. (A) Tissue fragments in a background of numerous naked nuclei. UFP, 40×; (B) The naked nuclei derived from the fragile cells bursted by smearing. UFP, 100×; (C) The naked nuclei are round with prominent central nucleoli. UFP, 400×; (D) The nuclear feature of intact fragment are same as the naked nuclei. UFP, 400×.

Fig. 4.26 Hepatocellular carcinoma, moderately-differentiated cell type. (A) Single cells and small fragments without trabecular arrangement. UFP, 100×; (B) Small fragment of miniature hepatocytes with reduced cytoplasm. UFP, 400×; (C) Peripheral endothelium is inapparent on smears. UFP, 400×; (D) Peripheral endothelium wrapping thick trabeculae. Cell block. H&E, 100×.

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Fig. 4.27 Hepatocellular carcinoma, moderately-differentiated cell type. (A) Dispersed naked nuclei, single cells and small tissue fragment. UFP, 40×; (B) Small tissue fragment without wrapping endothelium. UFP, 400×; (C) Tumor cells may have nuclear pseudoinclusions. UFP, 1000×; (D) Cell block shows pseudoglands with entral lumen. H&E, 100×.

Fig. 4.28 Hepatocellular carcinoma, moderately-differentiated cell type. (A) Small hepatocytes with fragile plasma membrane. UFP, 400×; (B) Numerous naked atypical nuclei in the background. UFP, 400×; (C) Giant donut-shaped nuclei and two regular sized nuclei. UFP, 400×; (D) Tumor cells with retained cytoplasm resemble hepatocytes. UFP, 1000×.

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Fig. 4.29 Hepatocellular carcinoma, poorly-differentiated cell type. (A) Solitary cells and cohesive tumor fragments. UFP, 100×; (B) Bizarre tumor cells with large nuclei and prominent nucleoli. UFP, 400×; (C) High magnification of cohesive tumor fragments, UFP, 400×; (D) High magnification of solitary cells. Some are binucleated. UFP, 1000×.

Fig. 4.30 Hepatocellular carcinoma, poorly-differentiated cell type. (A) Numerous single cells with occasional transgressing capillaries. UFP, 100×; (B) The cells appear similar but size ranges from small to very large. UFP, 100×; (C) Note the multinucleated cell with round nuclei & distinct nucleoi. UFP, 400×; (D) A giant biinucleated tumor cell with moderate amount of cytoplasm. UFP, 400×.

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Fig. 4.31 Hepatocellular carcinoma, poorly-differentiated cell type. (A) Cohesive fragments and naked nuclei from burst fragile cytoplasm. 40c,DQ; (B) Negative image of droplets in the cytoplasm and in the background. DQ, 400×; (C) Pleomorphic nuclei with no resemblance to hepatocytes. UFP, 400×; (D) Cell block, H&E. left Immunostain: α-fetoprotein (+), right.

Fig. 4.32 Hepatocellular carcinoma, pleomorphic large cell type. (A) Low power shows numerous solitary tumor cells. UFP, 40×; (B) A rare loosely cohesive fragment. UFP, 100×; (C) Solitary, multinucleated tumor giant cells. UFP, 400×; (D) Note multiple nucleoli in the nuclei of tumor cells. UFP, 400×.

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Fig. 4.33 Hepatocellular carcinoma, fibrolamellar type, in a 34-year-old male. (A) Solitary cells with abundant cytoplasm and metachromatic strands. DQ, 100×; (B) Note the nuclei have vesicular chromatin and pin-point nucleoli. UFP, 400×; (C) A giant tumor cell with 16 nuclei. UFP, 400×; (D) Eccentric nuclei with single nucleolus and abundant cytoplasm. UFP, 1000×.

Fig. 4.34 Hepatocellular carcinoma, fibrolamellar type, in a 37-year-old female. (A) Dispersed solitary giant tumor cells and some fibrous tissue. UFP, 100×; (B) Giant tumor cells with large bland nuclei and distinct nucleoli. UFP, 400×; (C) Histology shows giant tumor cells associated with fibrosis. H&E, 100×; (D) Cytoplasm of tumor cells is packed with abnormal mitochondria. Electron micrograph, 12,000×.

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Fig. 4.35 Hepatoblastoma, fetal type, from a 2-year-old male. (A) Loosely cohesive fragments and a megakaryocyte (arrow). UFP, 100×; (B) Small tumor fragments and hematopoiesis. UFP, 400×; (C) A different area shows large fragments and megakaryocytes. UFP, 100×; (D) Small hepatocytes with bland nuclei but reduced cytoplasm. UFP, 400×.

Fig. 4.36 Hepatoblastoma, fetal type, from one-year-old female. (A) Granular smears containing fetal hepatocytes with vessels. UFP, 100×; (B) Monotonous population of small hepatocytes. UFP, 400×; (C) Small hepatocytes with typical nuclei but reduced cytoplasm. UFP, 1000×; (D) Extensive fatty change in the tumor in this case. Cell block, H&E, 100×.

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Fig. 4.37 Hepatoblastoma, embryonal and fetal type. (A) Embryonal epithelial component has scanty cytoplasm. UFP, 400×; (B) Fetal component resembles hepatocytes. Note hematopoeitic cells. UFP, 400×; (C) Embryonal component wraps around the fetal component. Cell block, H&E, 100×; (D) Only embryonal tumor cells express AE1/3 cytokeratin. Cell block, 100×.

Fig. 4.38 Hepatoblastoma, mixed mesenchymal and epithelial type. (A) Embryonal epithelial hepatocytes have scanty cytoplasm. UFP, 400×; (B) Fetal epithelial hepatocytes have more cytoplasm. UFP, 400×; (C) Arrows point to two mesenchymal component. UFP, 100×; (D) Primitive mesenchymal component is best demonstrated in DQ. 40×.

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Fig. 4.39 Bile duct adenoma, 2 cm, from a 50-year-old female. (A) Small cohesive groupings of epithelium. DQ, 40×; (B) The nuclear size is 4× RBCs. DQ, 400×; (C) Note oval bland nuclei and rectangular dense cytoplasm. UFP, 400×; (D) Bile ductal cells are immunoreactive to CK19. Cell block, 400×.

Fig. 4.40 Cholangiocarcinoma, 2.8 cm, from an 82-year-old male. (A) Small groupings of epithelium attached to fibrous tissue. UFP, 40×; (B) Oval nuclei with coarse chromatin and rectangular dense cytoplasm. UFP, 400×; (C) Ductal cells seen on cell block: H&E, left-CK19 immunostain, right, 400×; (D) Desmoplastic reaction. Cell block, H&E. left 40×, middle 100×, right 400×.

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Fig. 4.41 Cholangiocarcinoma, nonsecretory cell type, well-differentiated. (A) Loosely cohesive tumor cells. Arrow points to a cluster, shown in (B) DQ, 100×; (B) Oval nuclei (4–5 RBC) and dense eccentric cytoplasm. DQ, 400×; (C) Loosely cohesive tumor cells. Arrow points to a cluster, shown in (D) UFP, 100×; D: Tadpole-shaped cells with oval nuclei with minimal atypia. UFP, 400×.

Fig. 4.42 Cholangiocarcinoma, nonsecretory cell type, well-differentiated. (A) Small ductal-type epithelium aspirated from a lymph node. DQ, 100×; (B) Ductal type epithelium in flat sheets. UFP, 100×; (C) Oval nuclei with small nucleoli and variation in nuclear size. UFP, 600×; (D) Simple columnar epithelium with basal nuclei. Cell block, H&E, 100×.

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Fig. 4.43 Cholangiocarcinoma, nonsecretory cell type, moderately-differentiated. (A) Low power shows loosely cohesive cell groups. UFP, 40×; (B) High power shows monotonous tumor cell with scanty cytoplasm. UFP, 400×; (C) Smaller groupings. UFP, 400×; (D) Oval nuclei with pale chromatin and rod-shaped red nucleoli. UFP, 1000×.

Fig. 4.44 Cholangiocarcinoma, secretory cell type, from an 85-year-old male. (A) Abundant mucin containing small groupings of epithelium. DQ, 100×; (B) Small neoplastic ductules with bland nuclei. UFP, 400×; (C) Numerous ductules with luminal mucin, correlating to (D) UFP, 400×; (D) Numerous ductules with luminal mucin. Cell block, H&E, 400×.

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Fig. 4.45 Cholangiocarcinoma, adenosquamous variant, from a 45-year-old male. (A) Orangeophilic keratin scattered among tumor cells. UFP, 100×; (B) Squamous component (left) and glandular component (right). UFP, 400×; (C) Glandular component with columnar cells correlates to (D) UFP, 400×; (D) Histology. Cell block, H&E, 400×.

Fig. 4.46 Angiosarcoma of the liver from a 79-year-old male. (A) Bloody aspirate containing rare clusters of mesenchymal tissue. DQ, 100×; (B) Well-formed blood vessels. (left) 100×; Atypical lining cells (right). UFP, 400×; (C) Tumor fragment with undeveloped vessel (left) 100×; (right) UFP, 400×; (D) Histology of Angiosarcoma. 100× (left). H&E (right). CD34+ immunostain.

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Fig. 4.47 Epitheloid hemangioendothelioma of liver from a 52-year-old male. (A) Epitheloid cells with intracytoplasmic lumina (white arrow). UFP, 400×; (B) A fragment of epitheloid tumor cells in a bloody background. UFP, 1000×; (C) Tumor cells with intracytoplasmic lumina (arrow). Cell block, Trichrome, 400×; (D) Intracytoplasmic lumens (arrow) and convoluted nuclei. EM, 3500×.

Fig. 4.48 Embryonal sarcoma of the liver, from a 31-year-old female. (A) Low power show fragment of tumor surrounded by solitary naked cells. UFP, 100×; (B) The hyperchromatic nuclei are held by a network of stroma. UFP, 400×; (C) Mainly spindly nuclei radiating from the fibrillary stroma of the tumor. UFP, 1000×; (D) A large hyperchromatic nuclei with delicate cytoplasm. UFP, 1000×.

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Fig. 4.49 Keratinizing squamous cell carcinoma of the lung. (A) & (B) Tumor cells derived from the superficial layer have pyknotic nuclei and keratinizing cytoplasm, in loose groupings and as solitary cells. UFP, 400×; (C) Proliferating cells derived from the basal layer have viable nuclei. UFP, 400×; (D) Correlating proliferating layer is pointed by arrows in histology. Cell block, H&E, 400×.

Fig. 4.50 Squamous cell carcinoma of the lung, nonkeratinizing large cell type. (A) Cohesive groups of tumor cells with large nuclei, dense cytoplasm. UFP, 400×; (B) Nucleoli can be prominent, but cytoplasm is dense. UFP, 1000×; (C) Rows of spindly nuclei in parallel arrangement like squamous cells. UFP, 400×; (D) Correlating histology shows sparse keratin. Cell block, H&E, 400×.

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Fig. 4.51 Small cell carcinoma of the lung, oat cell type. (A) Nuclear streaks (arrow) but no lymphoglandular bodies. DQ, 100×; (B) Paranuclear blue body (arrow) and nuclear molding. DQ, 400×; (C) Small tumor cells with salt and pepper chromatin and fragile nuclei. UFP, 100×; (D) Paranuclear blue body (arrow), left, and nuclear molding, right. UFP, 400×.

Fig. 4.52 Small cell carcinoma of the lung, intermediate cell type. (A) Low power shows extensive nuclear streaking. UFP, 100×; (B) Salt and pepper chromatin similar to oat cell type. UFP, 400×; (C) The nuclei can be as large as 10× size of a RBC. DQ, 400×; (D) Chromogranin + cytoplasm and TTF1 + nuclei. Immunostains, cell block, 100×.

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Fig. 4.53 Adenocarcinoma of the lung, well-differentiated cell type. (A) Abundant mucin containing tumor groupings. DQ, 400×; (B) Note the pink mucin in the cytoplasm of tumor cells. DQ, 1000×; (C) Round to ovoid nuclei with single small nucleoli. UFP, 1000×; (D) Correlating histology. Resected tumor, Mucicarmine stain.

Fig. 4.54 Adenocarcinoma of the lung, poorly differentiated cell type. Tumor cells have large, round nuclei of variable sizes with prominent nucleoli. The appearance in different preparations. (A) DQ, 400×; (B) & (C) UFP, 400×; (D) Cell block, H&E, 400×.

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Fig. 4.55 Bronchioloalveolar carcinoma of the lung, nonsecretory cell type. (A) Numerous sheets of tumor cells in a non-mucinous background. UFP, 100×; (B) Flat sheet of cells with round nuclei and small nucleoli. UFP, 400×; (C) Fine chromatin with red nucleoli, but no blue chromocenters. UFP, 1000×; (D) Histology shows tumor cells growing along alveoli, Resected tumor, H&E, 100×.

Fig. 4.56 Bronchioloalveolar carcinoma of the lung, secretory cell type. (A) Abundant mucin containing fragments of tumor. DQ, 400×; (B) Columnar cells with basally located nuclei below mucin. UFP, 400×; (C) On-face view of a honeycoomb sheet of tumor epithelium. UFP, 1000×; (D) Histology of resected tumor shows similarity to the cytology shown in B. H&E, 400×.

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Fig. 4.57 Undifferentiated large cell carcinoma of the lung. Tumor cells have pleomorphic nuclei with a coarsely granular chromatin, occurring as solitary cells. UFP (A) 40×; (B) 100×; (C) 400×; (D) 400×.

Fig. 4.58 Giant cell carcinoma of the lung. (A) Absence of metachromatic matrix associated with tumor cells in DQ, 400×; (B) Solitary giant tumor cells with neutrophils in the background. UFP, 400×; (C) Multinucleated cell & cytoplasmic neutrophilic infiltration. UFP, 1000×; (D) Coexpression of cytokeratin and vimentin. Cell block, immunostains, 400×.

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Fig. 4.59 Spindle cell carcinoma of the lung. (A) Dyscohesive spindle tumor cells at low power. UFP, 40×; (B) Numerous spindle cells with ovoid nuclei and tapered cytoplasm. UFP, 100×; (C) A giant cell in B showing multinucleation. UFP, 400×; (D) Immunoreactive to cytokeratin and vimentin. Immunostain on cell block.

Fig. 4.60 Spindle cell carcinoma of the lung. (A) A cluster of spindle cells with bipolar tapered cytoplasm. UFP, 100×; (B) Arrow points to binucleated tumor cells. Note a few lymphocytes. UFP, 100×; (C) Note the absence of metachromatic matrix associated with sarcoma. DQ, 400×, Insert + cytokeratin associated with sarcoma; (D) The binucleated spindle cell looks like two peas in a pod. UFP, 400×.

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Fig. 4.61 Adenocarcinoma of the prostate, well-differentiated cell type. (A) Low power shows cohesive groupings. UFP, 100×; (B) High magnification shows round nuclei with scanty cytoplasm. UFP, 400×; (C) Nuclear size is 1× RBCs in the background. DQ, 400×; (D) Prostate-specific protein immunostain on cell block. 100×.

Fig. 4.62 Adenocarcinoma of the prostate, poorly-differentiated cell type. (A) Low power shows loosely cohesive tumor cells. UFP, 40×; (B) High power shows invisible cytoplasm. UFP, 100×; (C) Prominent single red nucleolus in each tumor cells. UFP, 400×; (D) PSAP immunostain demonstrates the tumor cytoplasm on cell block. 400×.

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Fig. 4.63 Lobular carcinoma of the breast. (A) Cohesive cluster on the left and an “Indianfile” on the right. UFP, 100×; (B) Signet ring-like tumor cells in “Indian-file.” UFP, top: 400×, bottom. 1000×; (C) Different case of metastatic lobular carcinoma shows single cells. UFP, 400×; (D) Less intracytoplasmic mucin in this case. UFP, 1000×.

Fig. 4.64 Ductal carcinoma of the breast, small cell type. 400×; (A) Dyscohesive small cells with retained cytoplasm. DQ; (B) Dyscohesive small cells with retained cytoplasm. UFP, Left, 1000×; (C) Cohesive fragments of small tumor cell (nuclear size is 1–2× RBC). DQ, 400×; (D) Cohesive fragments of small tumor cells. UFP, 400×.

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Fig. 4.65 Ductal carcinoma of the breast, intermediate cell type. (A) Dyscohesive tumor cells that have round or ovoid nuclei 5–6× RBC. DQ, 400×; (B) Eccentric nuclei with moderate amount of cytoplasm. UFP, 400×; (C) Cohesive tumor cells that have round or ovoid nuclei 5–6× RBC. DQ, 400×; (D) Cohesive tumor grouping with indistinct nucleoli. UFP, 400×.

Fig. 4.66 Ductal carcinoma of the breast, large cell type. (A) Noncohesive grouping of large tumor cells (×10 RBC). DQ, 400×; (B) Note the prominent nucleoli and moderate amount of cytoplasm. UFP, 400×; (C) ER immunostain on archival UFP-stained smear. 100×; (D) 3+ Her2/neu immunostain on archival UFP stained smear. 400×.

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Fig. 4.67 Malignant melanoma, round cell type, of the skin, metastatic to liver. (A) Solitary cells with round nuclei and cytoplasm containing vacuoles. DQ, 400×; (B) Amelanotic round cells with single nucleolus. UFP, 400×; (C) A different case with loosely cohesive round tumor cells. UFP, 400×; (D) Several red nucleoli and nuclear pseudoinclusion. UFP, 1000×.

Fig. 4.68 Malignant melanoma, spindle cell type, of the skin, metastatic to liver. (A) Loosely cohesive spindle cells. UFP, 100×; (B) Amelanotic spindle cells with bipolar cytoplasm. UFP, 400×; (C) Note the negative images of dots in the background correlating to premelanosomes released from the cytoplasm, ruptured by smearing. DQ, 400×; (D) HMB-45 immunostain. Cell block, 400×.

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Fig. 4.69 Malignant melanoma, pleomorphic large cell type. (A) Loosely attached tumor cells with melanin (arrow). UFP, 400×; (B) Negative images of dots, representing premelanosomes, seen in DQ, 400×; (C) Multilobated nuclei and melanin-laden wispy cytoplasm (arrow). UFP, 1000×; (D) Intranuclear inclusions in large cells with irregular nucleoli. UFP, 1000×.

Fig. 4.70 Malignant melanoma, small cell type, of the eye, metastatic to liver. (A) Small tumor cells with nuclear size close to 1× RBC. DQ, 400×; (B) Brown melanin pigments are present in two of the small cells. UFP, 400×; (C) Melanin stains green-blue in DQ, 1000×; (D) Small cells with round nuclei and distinct nucleoli. UFP, 1000×.

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CHAPTER 5

The Pancreas

The pancreas is relatively inaccessible to the conventional method of study and is difficult to investigate because of its anatomical location. Clinically, carcinomas of the pancreas are sometimes very difficult to diagnose with certainty, even during laparotomy. The gross appearance of chronic pancreatitis may look similar to that of carcinoma of the pancreas. In the literature, Cote found that intraoperative wedge biopsy failed to reveal carcinoma in 54% of the patients with carcinoma of the pancreas, and the Vim-Silverman needle missed the diagnosis in 32% of cases.9 Moreover, wedge biopsy or large-bore needle biopsy often leads to serious complications, e.g. hemorrhage, fistula formation, pancreatitis, pseudocyst and even death. The complication rate has been reported as up to 20%.29 For many years, attempts at the cytologic diagnosis of carcinoma of the pancreas were mostly confined to the duodenal drainage method with or without intravenous injection of secretin. Bowen and Papanicolaou reported positive cytology in 47% of patients with proven carcinoma.5 The diagnostic rate of carcinoma of the pancreas by using the duodenal drainage method is generally low and the false-positive rate is high. The poor results are probably due to the small numbers of exfoliated malignant cells and the many artifacts caused by the duodenal contents and enzymatic digestion. Thus duodenal drainage is limited in usefulness for the diagnosis of carcinoma of the pancreas.59 With the introduction of modern imaging techniques, percutaneous fine-needle aspiration biopsy has been recognized as an excellent diagnostic method in obtaining a pathologic diagnosis among patients with malignant lesions in the pancreas.12,18,33 The major problem in the diagnosis of 121

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carcinoma of the pancreas arises from the difficulty in obtaining representative material, which in turn relies on the techniques used to localize the lesions. Biopsy has been achieved during selective angiography of the celiac artery with test injections of contrast medium under fluoroscopic control, during ultrasonography using a special biopsy transducer53 with CT scan to image the position of the biopsy needle,15 and by endoscopic retrograde cholangiopancreatography.19 In recent years, improved ultrasonography with a special biopsy transducer became the preferential method used for localization and aspiration biopsy of pancreatic mass lesions in many hospitals because of its ease and accuracy in obtaining representative samples.59 CT scan is also often used, especially if the first attempt under the guidance of ultrasound is unsuccessful. In the Toronto General Hospital series of 584 cases of aspiration biopsy of the pancreas, the diagnostic rate of carcinomas of the pancreas by guided fine-needle aspiration biopsy has increased from 82% in the 1970s to the 94% in late 1980s. Complications resulting from aspiration biopsy were unusual. Therefore, the accuracy and safety of guided aspiration biopsy of the pancreas are superior to those of wedge biopsy or large-bore needle biopsy. There were five cases of carcinoma of the pancreas in this series, with negative intraoperative tissue biopsy which were eventually proven to be malignant by transabdominal fine-needle aspiration biopsy. Since the early 1990s, endoscopic ultrasound guided fine-needle aspiration biopsy has been used by gastroenterologists to sample pancreatic masses. However, the patients need to be under general anesthesia, the procedure lasts for hours, and the diagnostic yield is highly dependent on the skill and experience of the aspirator. In addition, contaminations from the normal gastric and duodenum epithelium on route to the pancreas make the diagnosis of well-differentiated epithelial neoplasms difficult.

NORMAL CELLULAR COMPONENTS The pancreas is composed of an exocrine portion and an endocrine portion (Fig. 5.1). The exocrine portion consists of serous acini and ducts. The acini are arranged in many small lobules, and produce digestive enzymes that are drained into the duodenum through the pancreatic duct system. The acinar cells have round nuclei and abundant granular cytoplasm. The intralobular

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ducts are lined by a flattened epithelium, and the epithelium of the interlobular ducts consists of cuboidal cells. The main ducts are lined by columnar epithelial cells with interspersed goblet cells. The endocrine portion consists of numerous islets of Langerhans. The islets are dispersed in the pancreas and more concentrated in the body and tail. The islet cells are arranged in cords, separated by capillaries. They may be classified into at least six types on the basis of the hormones produced, namely, α-cells (glucagon), β-cells (insulin), δ-cells (somatostatin), and PP cells (pancreatic polypeptide). The islet cells can be identified by electron microscopy or immunohistochemical study. They are, however, indistinguishable under light microscopy. Aspirate preparations from a normal pancreas usually contain mainly acinar cells with minimal numbers of islet cells, ductal cells, endothelial cells, and mesothelial cells if any (often seen in aspirates from lesions in the body of the pancreas). If the lesion is in the head of the pancreas, the aspirate may contain some hepatocytes.

Acinar Cells (Fig. 5.2) In aspirate preparations, acinar cells are present in small clusters with good intercellular cohesion. The nuclear size of acinar cells in general measures 7 µm, the size of red blood cells in Diff-Quik stain.66 The nuclei are round or ovoid and have uniformly distributed, finely granular chromatin. They are often eccentrically placed and are uniform and regular. The nuclear membranes are smooth and thin. Nucleoli are small but may be conspicuous in some cells. The cytoplasm is abundant and appears granular.

Islet Cells (Fig. 5.3) Islets of Langerhans are a rare finding in aspirate preparations. They occur in small cohesive groupings. The cytologic features of individual islet cells are difficult to analyze, as the islet cells are enmeshed in three-dimensional tissue fragment, unlike tissue sections.

Pancreatic Duct Epithelial Cells Histologically, normal pancreatic ducts are lined by a cuboidal to lowcolumnar epithelium with amphophilic cytoplasm. Epithelial cells of the

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small pancreatic ducts are often in sheet arrangements in aspirate preparations. They have relatively scanty, poorly defined cytoplasm and round nuclei with indistinct nucleoli. The chromatin pattern of the nuclei is slightly coarsely granular but evenly distributed. Columnar epithelial cells of the larger pancreatic ducts are an infrequent finding in aspirate preparations. They occur in cohesive groupings or in palisading arrangements, or lie singly. They have moderate amounts of well defined cytoplasm and ovoid nuclei. Some of them show vacuolated or foamy cytoplasm, indicative of secretory activity. In everyday practice, normal pancreatic aspirates are composed of predominantly acinar cells, whereas ductal cells and islet cells are difficult to find in the aspiration samples.

Other Cells In aspirate preparations, mesothelial cells are often seen in aspirates from lesions in the body of the pancreas which is covered by a mesothelial lining. They have round or ovoid nuclei and are in sheet arrangements, often with slits between cells. Endothelial cells from small blood vessels may also be noted. They have ovoid nuclei and abundant cytoplasm. They are also in sheet arrangements like mesothelial cells, but the endothelial sheets usually contain fewer cells. Unlike mesothelial cells, there are no slits between cells.

Pancreatitis (Fig. 5.4) Inflammation of the pancreas constitutes a spectrum of disorders that ranges from acute hemorrhagic pancreatitis, a prostrating disease, to chronic relapsing pancreatitis with eventual pancreatic insufficiency. A late complication of acute pancreatitis is the development of a pseudocyst or an abscess.

Acute Pancreatitis Acute pancreatitis occurs in adults between 40 and 70 years of age and often follows a heavy meal or an alcoholic debauch. It is a debilitating illness with an abrupt onset. Early in the disease, pancreatic enzymes, such as amylase and lipase, are liberated into the bloodstream. The pathogenesis

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of acute pancreatitis is still not clear. The pancreas appears swollen and edematous. The injury to acinar cells causes release and activation of the digestive enzymes, resulting in necrosis and inflammation of the pancreas and the surrounding tissues. The pancreas contains patches of coagulative necrosis rimmed by heavy neutrophilic infiltrates. Foci of fat necrosis in the peripancreatic tissue, mesentery, and omentum may appear as small ovoid yellow white nodules, due to the formation of calcium soaps through the mechanism of saponification. These foci may be detected by imaging techniques. Aspirate preparations contain tightly packed clusters of necrotic acinar cells with pyknotic nuclei. In the background, finely and coarsely granular necrotic debris is usually present and intermingled with numerous neutrophils. Necrotic ductal cells showing karyorrhexis or appearing as ghost cells are sometimes noted. Degenerating fat cells, lipid droplets and lipidladen macrophages with foamy or vacuolated cytoplasm are also noted. The von Cosa stain may demonstrate some granular deposition of calcium salts within the necrotic debris. The formation of calcium salts is an indication of fat necrosis. Irritated mesothelial cells may be seen if the material is aspirated from the body of the pancreas. They have slightly enlarged, ovoid nuclei and small nucleoli, and occur in groupings with overlapping of cells or in disorderly arrangements. Occasional slits between cells are seen.

Chronic Pancreatitis In approximately one-third of all patients who survive episodes of acute pancreatitis, the disease progresses to chronic pancreatitis. The pancreas is firm and nodular, with areas of dense fibrosis, loss of acinar and islet tissues, and infiltration of lymphocytes and plasma cells. Proliferation of ducts and hyperplasia of ductal epithelial cells with some atypia are noted. Areas of calcification in the interstitial tissue and pancreatic ducts are present. The destruction of the pancreas eventually results in pancreatic insufficiency. A distinct form of chronic pancreatitis first reported in Japan, as“autoimmune pancreatitis” with a 1.86% incidence,22a is now recognized worldwide. Clinically, most patients present with a pancreatic head mass, often with stricture of the distal ducts, causing obstructive jaundice mimicking cancer clinically and radiologically. The mean age of the patients is the late 50s,

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with more males than females affected. Histologically, it is characterized by dense infiltrates of T-lymphocytes and IgG4-positive plasma cells around small and large interlobular ducts, accompanied by fibrosis and expansion of periductal tissue and atrophy of acini.2a A high index of suspicion is needed for cytopathologists to diagnose this entity to avoid pancreatoduodectomy. Autoimmune pancreatitis can be confirmed by elevated actum IgG4, and dramatic response to steroid therapy. Fine-needle aspiration findings were recently reported.10a The aspirates contain many lymphocytes and plasma cells, and more ductal cells. If the material is aspirated from areas of dense fibrosis, the aspirates are often scantily cellular. Fibrocytes and fragments of fibrous tissue are usually present. Groupings of atypical ductal cells are also present. They tend to be in sheet arrangements, but overlapping of cells and disorderly arrangements are often noted, mimicking adenocarcinoma. The nuclei of atypical ductal cells are larger than those of normal ones and have variations in nuclear size and shape. Conspicuous nucleoli may be seen. The cytologic differentiation between chronic pancreatitis and well differentiated adenocarcinoma of the pancreas is mainly the quantity of ductal epithelium: Sparse cellularity in the former and tumor cellularity in the latter.

Pseudocyst (Fig. 5.5) Pseudocysts of the pancreas are closely related to acute pancreatitis, operative trauma, or reflux of bile into the pancreatic duct. They develop as a result of blockage of the ducts and leakage of the pancreatic juice from the injured pancreatic tissue, which leads to an accumulation of secretion and cyst formation, usually unilocular. The fluid within them has a high amylase content. The cyst gradually increases in size and spreads into the lesser peritoneal cavity. Bile is found in the cavity of the cystic lesion in some cases. Late complications, such as hemorrhage, have occurred. The splenic artery is the most common source of intracystic hemorrhage, which can be massive and result in sudden death. The aspiration of fluid from a pancreatic pseudocyst may have not only diagnostic, but also therapeutic significance. In fact, pseudocysts of the pancreas may disappear after percutaneous aspiration of the fluid, obviating further management. In aspirate which are prepared using filtration or centrifugation technique, there are varying amounts of mixed inflammatory

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cells and coarsely granular necrotic debris. Fibroblasts, fibrocytes, or small fragments of fibrous tissue may be present. Irritated mesothelial cells are usually seen, some of which are extremely atypical. They may be gigantic and have giant-sized nuclei and large nucleoli, mimicking malignancy. However, the nuclear cytoplasmic ratio of these cells remains low. In some cases, bile and bile-laden macrophages are abundant.

TUMORS OF THE PANCREAS Caroli’s Disease (Fig. 5.6) Patients with Caroli’s disease have liver cysts and pancreatic cysts lined by bile ductal epithelium. The aspirate preparations contain large sheets of bile ductal epithelium with small nuclei in the background containing debris.

Ciliated Foregut Cyst (Fig. 5.7) This type of pancreatic cyst is lined by a respiratory epithelium. Ciliated foregut cysts are rare, and are believed to arise from the embryonic foregut and to differentiate toward bronchial structures in the pancreas and liver.7,34 The aspirate preparations contain serous fluid and numerous ciliated bronchial cells.

Serous Cystadenoma (Figs. 5.8–5.10) Serous (microcystic or glycogen-rich) cystadenomas are benign and can be located anywhere in the pancreas. They are normally single lesions and usually large (mean 6.0 cm). CT scan shows a honeycomb pattern of microlacunae, with thin septae separating different segments.43 The patients are usually older, and the disease is either discovered incidentally or manifests as an abdominal mass with local discomfort or pain. Grossly, they are welldemarcated, somewhat bosselated masses, composed of innumerable small thin-walled cysts, imparting a sponge-like appearance on cross-section. A stellate scar may appear in the center of the neoplasm and is often calcified. Histologically, the cavities of the cysts are lined by cuboidal or columnar epithelial cells containing abundant glycogen. Ultrastructural studies have

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shown that the features of the neoplastic epithelial cells are comparable to those of normal centroacinar cells. Serous cystadenomas are difficult to aspirate. The aspirates consist of clear fluid containing very scanty ductal epithelium arranged in sheets or in a palisading fashion. The epithelial cells are either columnar or cuboidal in shape. They have moderate amounts of cytoplasm and small, round or ovoid nuclei. The nucleoli are indistinct. A few foamy macrophages may be present. Other cellular components are rarely seen in the aspirate preparations from serous cystadenomas.

Solid-Pseudopapillary Neoplasm (Figs. 5.11–5.12) Solid-pseudopapillary neoplasm of the pancreas are a low-grade malignant tumor, most frequently found in adolescent girls and young women. The prognosis is good following surgical excision. On CT scan, solidpseudopapillary neoplasms typically appear as large sharply circumscribed hypodense lesions at the body or tail of the pancreas.13 Small tumors show no cystic change, whereas larger tumors show cystic areas, which represent necrosis and hemorrhage with drop-out of the neoplastic cells. Histologic examination shows a highly cellular tumor composed of pseudopapillae, which represent a perivascular rim of viable tumor cells, when tumor cells situated away from the vessels begin to drop out. The neoplastic cells express CD10, vimentin, α-1-antitrypsin, and show an abnormal nuclear expression of β-catenin.58 In community practices that do not stock rarely used antibodies, one can simply order vimentin and AE1/AE3, because solid pseudopapillary neoplasm is the only epithelial tumor in the pancreas that is cytokeratin-negative and vimentin-positive. Fine-needle aspiration cytology of this tumor has been well described in the literature.35,39 The aspirate preparations contain bundles of long branching delicate blood vessels coated by a thin layer of small epithelial cells with bland round to ovoid, occasionally indented nuclei. The nuclear indentation is an important feature to distinguish this tumor from islet cell tumor and acinar cell carcinoma. The tumor cells have a small amount of delicate and fragile cytoplasm, which is easily ruptured by the force of smearing.

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Mucinous Cystic Neoplasm (Fig. 5.13) Mucinous cystic neoplasms accounts for 5.7% of primary pancreatic tumors with a female to male ratio of 90:10 with a mean age between 40 to 50 years.64 Approximately 70–90% of mucinous cystic neoplasms arise in the body or tail of the pancreas. The tumors are usually multiloculated or rarely uniloculated. The cavities contain mucous material. CT scans usually demonstrate a thick-walled cystic mass without connection to the ductal system. Histologically, the cysts are lined by tall columnar cells with basal nuclei and abundant intracytoplasmic apical mucin in flat sheets or papillae, frequently with ovarian-type stroma.57,64 Mucinous cystic neoplasms are classified as adenoma, borderline, carcinoma-in-situ and invasive based on the severity of the dysplasia of the lining epithelium or the presence of stromal invasion.67 Approximately one-third are associated with invasive ductal carcinoma. Both benign and malignant varieties exist, and the distinction is not always clearcut and requires an extensive sampling of the specimen. Therefore, all of these mucinous tumors should be regarded as potentially malignant.8 There have been well-documented cases of “mucinous cystadenoma” recurring as cystadenocarcinoma. Thus, total excision of the tumors is required. The aspirate preparations are usually highly cellular, containing numerous epithelial cells with vacuolated cytoplasm, resembling benign cells from the endocervix.11 The tumor cells occur either in papillary or sheet arrangements with a honeycomb pattern or lie singly, often appearing as goblet cells. The nuclei are round and may have small nucleoli. In the borderline neoplasms, carcinoma-in-situ or mucinous cystadenocarcinomas, atypical epithelial cells are a common finding. They are larger, and the nucleocytoplasmic ratio is higher. Their nuclei often show variation in size and have conspicuous nucleoli and finely or slightly coarsely granular chromatin. In some cases, atypical epithelial cells showing malignant transformation are noticed. These highly abnormal cells that have large nuclei with variations in size and shape and slightly coarse chromatin occur in disorderly arrangements.23

Intraductal Papillary Mucinous Neoplasm (Figs. 5.14–5.15) Intraductal papillary mucinous neoplasms occur more often in elderly men in their 70s and 80s.30 They involve the main pancreatic duct and major

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branches. The tumor secrete copious amount of mucin, leading to ductal dilatation and with the mucin frequently oozing out from ampulla of Vater seen endoscopically. CT scans will typically show a lobulated multilocular cystic lesion located in the uncinate process and in contiguity with the dilated main pancreatic duct.42 In some patients, a bulging papilla and papillary projections are present in the ducts. The bulging papilla and the caliber of the main pancreatic duct help differentiate malignant from benign intraductal papillary mucinous tumors on CT scan.14 Papillae can be lined by intestinal type epithelium or pancreatobiliary type epithelium. The former is lined by pseudostratified tall columnar cells with occasional goblet cells, and the latter is lined by complex branchings of cuboidal cells. Similar to mucinous cystic neoplasms, intraductal papillary neoplasms are also categorized into adenomas (simple columnar epithelium with apical mucin); borderline (pseudostratified columnar epithelium); carcinoma-in-situ (fusion of papillae); and invasive (colloid) carcinoma, which occurs in 35% of the cases.29

Colloid Carcinoma (Fig. 5.16) Colloid carcinoma, defined as nodular extracellular mucin lakes containing floating signet ring cells, has been separated from mucinous ductal adenocarcinoma because of much better prognosis. In a 2001 study of 17 patients with a mean follow-up of 57 months, 10 patients were alive with no evidence of the disease, including four with lymph node metastasis, three others with perineurial invasion, and another with vascular invasion.1 Colloid carcinoma is frequently associated with an intraductal papillary mucinous neoplasm, which is believed to be its precursor. Both indolent tumors are marked by MUC2 expression, in contrast to the MUC1 expression by the usual pancreatic adenocarcinomas.2 Aspirate preparations from colloid carcinoma contain scattered vacuolated or signet ring cells in a pool of thick mucin. The aspirates from such tumors are scantily cellular, and tumor cells are present in small groupings. The intracytoplasmic vacuoles displace the nuclei to the periphery of the signet ring cells. In other tumors, the aspirates are highly cellular, and groups of benign-looking duct epithelial epithelium with nuclei in palisading arrangement are noted in addition to groups of recognizable malignant cells, indicative of malignant transformation from a benign precursor.60

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Ductal Adenocarcinoma Invasive ductal adenocarcinoma progressing from pancreatic intraepithelial neoplasia22 involving the small ducts has a dismal prognosis of 5-year survival of < 15%.19 This aggressive pathway is marked by MUC1 expression.2 Adenocarcinomas arising from the pancreatic ducts comprise 80 to 90% of all cases of malignant neoplasms of the pancreas. They occur in the head of the pancreas in about two-thirds of the patients, and in the body and tail in the other one-third. Most patients are in their 5th to 7th decades of life. Carcinomas of the head of the pancreas usually cause progressive jaundice, associated with pain, resulting from tumor invasion of the wall of the common bile duct. Carcinomas of the body and tail of the pancreas are, on the average, larger than those of the head at the time of diagnosis, because the tumors rarely produce early symptoms. More than 90% of the patients die within one year of diagnosis. Histologic examinations show that carcinomas of the pancreas are often well differentiated adenocarcinomas. However, the degree of differentiation may vary from neoplasms with well-defined ductal structures to those with anaplastic undifferentiated cells. Pleomorphic giant cell carcinoma, adenosquamous carcinoma and cystadenocarcinoma also occur but are uncommon malignant neoplasms of the pancreas. As can be expected, aspirate preparations from carcinomas of the pancreas from different patients may exhibit various cytomorphologic patterns and features as discussed in the following sections.

Well-Differentiated Cell Type (Figs. 5.17–5.21) The aspirates from ductal adenocarcinomas of the pancreas of the welldifferentiated type are usually highly cellular. Tumor cells (cohesion factor, 4 to 5) occur in cohesive groupings. They tend to form large tightly packed flat sheets and cell clusters. Their nuclei are larger than those of normal ductal cells and are round or ovoid, with slightly coarse chromatin, and have conspicuous nucleoli in some tumor cells. The variation in nuclear size is noted in some clusters, and uniformity of nuclei is seen in other groups. The cytoplasm is relatively scanty in nonsecretory tumor cells but may be abundant and appear vacuolated in some tumor cells, indicative of mucin secretion. On some occasions, it may be difficult

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to differentiate atypical ductal cells in chronic pancreatitis from neoplastic cells from a well differentiated carcinoma in aspirate preparations. The individual cells of these two conditions may look alike in the smears. However, the large quantity of ductal epithelium no matter how bland66 as well as the findings of three-dimensional, tightly packed cell clusters with irregularity in cell arrangement and the more apparent difference in the degree of cellular atypia within the same cell clusters, are indicative of adenocarcinoma.

Moderately Differentiated Cell Type (Figs. 5.22–5.24) The cytologic diagnosis of ductal adenocarcinomas of the pancreas of the moderately differentiated type is easy and straightforward, because the tumor cells are frankly malignant. Large tumor cells (cohesion factor, 2 to 3) occur in cohesive clusters, in noncohesive groupings, or lie singly. They are bizarre looking with pleomorphism and irregularity of the nuclei. The nuclei have variations in size and shape, a coarse chromatin pattern, and frequent prominent nucleoli. The amount of cytoplasm is variable, from scanty to abundant. Mucin-secreting cells are rare, and mitotic figures are common.

Mucinous Ductal Adenocarcinoma (Figs. 5.25–5.29) The dismal prognosis and derivation from pancreatic intraepithelial neoplasia in mucin-producing ductal adenocarcinoma are the same as the ductal adenocarcinoma that does not produce mucin. A wide variety of patterns can occur. Some show abundant extracellular mucin, whereas others show mostly intracellular mucin. Some have dystrophic goblet cells with loss of nuclear polarity. Fine-needle aspiration cytology of this tumor has been described.44 The aspirate preparations show abundant background mucin containing fragments of neoplastic epithelium.

Poorly Differentiated Ductal Adenocarcinoma (Fig. 5.30) Poorly differentiated adenocarcinomas of the pancreas are uncommon. In aspirate preparations, tumor cells (cohesion factor, 1 to 2) either occur in noncohesive groupings or lie singly. The nuclei are generally small, tend to be round, and have prominent nucleoli and coarsely granular chromatin. The

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cytoplasm is scanty and poorly defined. At first glance, dispersed neoplastic cells with round nuclei and prominent nucleoli resemble malignant lymphoma of the immunoblastic type. Immunohistochemistry is helpful in the differential diagnosis. Immunostainings for epithelial markers are positive and lymphoid markers are negative.

Undifferentiated Small Cell Carcinoma Undifferentiated small cell carcinomas of the pancreas are rare and highly aggressive.45 They probably arise from Kulschitsky’s cells, which are normally present in this organ in connection with the exocrine ducts. In aspirate preparation, tumor cells (cohesion factor, 1 to 2) are small and occur singly or in loose groupings. The nuclei are irregular and small. The cytoplasm is very scanty and poorly defined. The tumor cells often appear as stripped nuclei in aspirate preparations. The chromatin is usually heavily stained, and the nucleoli are indistinct. Nuclear molding may be seen. Cytomorphologically, undifferentiated small cell carcinoma of the pancreas is indistinguishable from small cell carcinoma of the lung, which can metastatize to the pancreas from an occult primary. Radiological evidence of clear lungs and pancreatic tumor with peripancreatic nodal involvement are necessary to establish pancreatic primary. TTF-1 immunostain, a marker for lung and thyroid, was reported to be expressed in 44% of small cell carcinoma of primaries other than lung.3

Anaplastic Carcinoma Anaplastic carcinoma is a rare, highly aggressive tumor, usually in the head or tail of the pancreas. In a study from the Armed Forces Institute of Pathology (AFIP),37 31 of 35 cases (89%) were pleomorphic giant cell type and four cases (11%) are spindle cells type. Metastases invariably develop, and hematogenous spread is very common. Seventy-eight percent of the tumors had a K-ras oncogene mutation, similar to ductal adenocarcinoma.

Pleomorphic Giant Cell Carcinoma (Figs. 5.30–5.32) Pleomorphic giant cell carcinomas of the pancreas are characterized by the presence of a large number of bizarre, mononuclear or multinucleated, giant

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tumor cells. In some tumors, osteoclast-like giant cells31,63 intermingled with bizarre tumor giant cells against a background of a sarcomatoid growth pattern are noted.31 There are some pathologists who believe that those tumors composed of osteoclast-like giant cells have a better prognosis and should be kept separately and termed “giant cell tumor of the pancreas.” 47 This belief is not supported by many studies which have attested to negligible patient salvage in tumors containing osteoclast-like giant cells.37,60 These osteoclastlike giant cells are demonstrated to be histiocytes by microdissection and immunomarkers.47 Fine-needle aspiration cytology of this tumor has been reported.31,51,63 The aspirates from some tumors (without osteoclast-like giant cells) contain numerous, dispersed, giant tumor cells (cohesion factor, 0 to 1). Some of them are mononuclear and have bizarre, hyperchromatic nuclei and prominent nucleoli. Other tumor cells are multinucleated and have several pleomorphic nuclei. The aspirates from other tumors contain some benignlooking, osteoclast-like giant histiocytes in addition to bizarre tumor giant cells. The nuclei of osteoclast-like giant histiocytes are uniformly small and regular. In the background there are relatively uniform spindle cells of mesenchymal appearance.

Adenosquamous Carcinoma (Figs. 5.33–5.34) Adenosquamous carcinomas may be seen in many organs. The pancreas is one of the more common sites for the occurrence of adenosquamous carcinoma. Adenosquamous carcinomas constitute about 3 to 4% of exocrine pancreatic neoplasms. They probably arise from squamous metaplasia of the terminal ducts.41 Pure squamous cell carcinomas of the pancreas are very rare. Fine-needle aspiration cytology of this tumor has been reported.46 The aspirates of adenosquamous carcinomas show a dual population: adenocarcinoma cells with evidence of secretory activity and squamous carcinoma cells showing keratinization.

Ampullary Carcinoma Carcinomas are much less frequent in the periampullary region than in the pancreas. Since obstruction of the bile duct by the tumor causes early onset

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of jaundice, ampullary carcinomas are often discovered at an early stage and are usually much more curable than carcinomas of the head of the pancreas. Most ampullary carcinomas are adenocarcinomas, many of which have a superficial papillary component.65 In aspirate preparations, the cytologic features are those of well differentiated adenocarcinomas of the pancreas arising from the pancreatic ducts.10 The differential diagnosis can be based only on clinical and radiographic findings. In advanced disease with the invasion of the adjacent structures and the head of the pancreas, it is often impossible to ascertain the exact source of the adenocarcinoma.

Pancreatic Endocrine Neoplasms6 Pancreatic endocrine neoplasms, including islet cell tumors and pancreatic carcinoid, make up a small fraction of all pancreatic neoplasms. The most common location for islet cell tumors is in the body or tail of the pancreas, where a greater islet cell concentration is normally present. Pancreatic carcinoid tumors arise from Kulchitsky cells in the pancreatic ducts. Islet cell tumor and carcinoid tumors are identical morphologically. Cytomorphologic appearances of endocrine tumors are generally not a good indicator for differentiating between benign and malignant lesions. Islet cell tumors composed of cells with uniform and regular nuclei do not necessarily indicate a benign lesion, and the presence of nuclear aberration and mitotic figures cannot be used as a criterion for malignancy. Therefore, “islet cell tumor” is the proper terminology in the cytologic diagnosis of neoplastic lesions of islet cell origin. Moreover, islet cell tumor and islet cell hyperplasia are indistinguishable on purely cytomorphologic grounds.

Islet Cell Tumor (Figs. 5.35–5.36) Islet cell tumors are slow growing neoplasms. They may arise from islet cells of any type and may be hormonally active or inactive. Studies of these tumors with immunocytochemical techniques have shown that the majority of them have more than one cell type and that the predominant cell type determines the clinical syndrome. Most of the tumors are solitary but may

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be multiple. Most of the tumors occur in adults. Depending on the type of hormones produced, islet cell tumors may be associated with a variety of clinical disorders, such as hyperinsulinism (β-cell tumor); glucagonoma syndrome (α-cell tumor); Zollinger-Ellison syndrome (ulcerogenic islet cell tumor); and Verner-Morrison syndrome62 (i.e. VIPoma, Cholera-like vasoactive intestinal peptide tumor), and somatostatinoma (nonspecific symptoms, including steatorrhea, diabetes, hypochlorhydria and cholelitheisis). Insulinproducing β-cell tumors constitute the most common variety of functioning islet cell tumors. Histologic examinations show that tumor cells resemble normal islet cells. They may be arranged in solid nests, ribbons, or festoons and are separated by highly vascular stroma. The only morphologic features that show some correlation with metastatic spread are stromal invasion and tumor thrombi in the blood vessels. The aspirates from islet cell tumors are usually highly cellular. In aspirate preparations, tumor cells (cohesion factor, 2 to 3) occur in noncohesive groupings and occasionally in cohesive groupings or lie singly. The tumor cells are generally small. Their nuclei tend to be round to ovoid and relatively uniform and regular. The nucleoli are inconspicuous, and the chromatin is fine and evenly distributed. The cytoplasm is scanty and poorly defined. At first glance, tumor cells from islet cell tumors may look like those from well-differentiated adenocarcinomas of the pancreas. The former is often mistaken by inexperienced examiners as the latter. It is important to distinguish this tumor from adenocarcinoma of the pancreas preoperatively, because the surgical approaches for these two conditions are different. At the Toronto General Hospital in the 1980s, the surgeons frequently requested intraoperative fine-needle aspiration to differentiate islet cell tumor from adenocarcinoma before deciding on the surgical approach. There were three cases of islet cell tumor diagnosed by intraoperative fine-needle aspiration; the remaining cases were adenocarcinoma. The diagnosis based on cytomorphology4,59 can be readily confirmed by positive synaptophysin or chromogranin immunostaining.

Islet Cell Hyperplasia Islet cell hyperplasia of the pancreas, like islet cell tumors, may also present as nodular lesions and may be hormonally active or inactive. The nodules

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are usually smaller. They are not neoplastic and are always benign. Histologic examinations show that islet cell hyperplasia consists of numerous large sized islets separated by fibrous stroma. The islets are not fused, and islet cells are not arranged in solid masses. In aspirate preparations, it is not always possible to distinguish islet cell hyperplasia from islet cell tumor. The cytomorphologic features of these two conditions are similar. However, aspirates from islet cell hyperplasia are usually scantily cellular and contain islet cells in small, noncohesive groupings, whereas aspirates from islet cell tumors are usually highly cellular, and the tumor cells are arranged in much larger, noncohesive and cohesive groupings. In practice, if the specimen is highly cellular and consists of tumor cells in large groupings, islet cell hyperplasia can be readily excluded. If the specimen is scantily cellular and the abnormal islet cells are present in small noncohesive groupings, islet cell hyperplasia cannot be distinguished from islet cell tumor.

Islet Cell Carcinoma Islet cell carcinomas are slow growing tumors which may be hormonally active or inactive. Metastases are restricted to peripancreatic lymph nodes and the liver in the majority of cases. About 10% of insulin-producing β-cell tumors are malignant, and approximately 60% of solitary gastrin-producing islet cell tumors are malignant. The majority of glucagon-producing α-cell tumors are malignant. Tumors associated with multihormone production that can be detected by serum determinations are often malignant. In general, the cytomorphologic criteria of tumors of islet cell origin are not good indicators for the differentiation between benign tumors and carcinomas.21,36 In practice, islet cell carcinomas cannot be identified as malignant tumors by aspiration biopsy specimens in most cases. However, in some cases, the overall cytologic findings were highly suggestive of malignancy, and all of these tumors were confirmed to be malignant in the followup. The cytologic indications of malignancy include: (a) Tumor cells show a significant increase in average nuclear size and variation in nuclear size; (b) Tumor cells are larger and have moderate amounts of well-defined cytoplasm and eccentrically located nuclei; (c) Multinucleated tumor cells are present; and (d) Mitotic figures are present.

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Acinar Cell Carcinoma (Figs. 5.37–5.38) Acinar cell carcinoma is rare, and constitutes only about 1% of all pancreatic cancers. It occurs at any age, including pediatric patients. Rarely, the tumor may release digestive enzymes, resulting in disseminated fat necrosis, polyarthralgia and eosinophilia. Histologic examination shows atypical acinar cells forming acinar or trabecular patterns.24 The aspirate of acinar cell carcinoma is hypercellular with atypical acinar cells as solitary cells, as acinar or large tissue fragments. The atypical acinar cells have round to ovoid central nuclei with single prominent nucleoli and granular cytoplasm. The cytoplasm ranges from being abundant in the acinar pattern, in moderate amounts in the trabecular pattern, to being scanty in the solid pattern.28,55,56 The tumor can be confirmed immunohistochemically by α-1-antitrypsin; histochemically by diastase-resistant PAS stain; or ultrastructurally by the presence of zymogen granules. Acinar cell carcinoma of the well-differentiated cell type closely resembles benign pancreatic acini; therefore, this type can only be diagnosed by the radiologic evidence of the precise needle sampling of a mass lesion in the pancreas. The moderately differentiated cell type is the most common of the acinar cell carcinoma and is illustrated in Fig. 5.37. Acinar cell carcinoma of the poorly differentiated cell type is frankly malignant, as illustrated in Fig. 5.38.

Pancreatoblastoma (Figs. 5.39–5.42) Pancreatoblastomas are embryonal-type tumors showing evidence of acinar, endocrine and ductal differentiation. In the series of Klimstra et al.,25 there was a bimodal age distribution, the mean ages being 2.4 and 33 years, respectively. The clinical presentations are usually non-specific, such as an incidental abdominal mass, abdominal pain, weight loss or obstructive jaundice. Metastases to the liver and lymph nodes are often present at diagnosis in adult cases. There are only three cases reported in cytologic literature17,40,52 ; thus, the experience is limited. We encountered one case in a 24-year-old black female patient at the New York University Medical Center.68 The patient presented with nausea and vomiting and was found to have a pancreatic mass (Fig. 5.39) and metastasis to the liver and peripancreatic lymph nodes.

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The aspiration smears of this case showed numerous fragments of cohesive epithelium (cohesion factor 5), wrapped by primitive mesenchymal tissue. The acinar component and a squamoid component were in the sample submitted for electron microscopy, whereas a neuroendocrine component was in the cell block sample with diffuse synaptophysin and chromogranin expression and only very focal diastase-resistant PAS positivity but no α-1antitrypsin expression.

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Fig. 5.1 Histology of the normal pancreas. H&E, 40×. Rare ducts (arrows) are present in benign pancreas, which is composed of mainly acini. If abundant ductal epithelium is aspirated, one can deduce that the pancreatic mass is ductal neoplasm. In chronic pancreatitis, the aspirates show sparse ductal epithelium among inflammatory cells, fibrosis and debris.

Fig. 5.2 Benign pancreatic aspirates in different preparations. (A) Fragments of tightly packed and scattered acini. DQ, 40×; (B) Small groupings and naked nuclei. DQ, 100×; (C) Fragments of tightly packed and scattered acini. UFP, 40×; (D) Acini at 1000×. (1) Stripped nuclei of acini, DQ (2) UFP, (3) Cell block. H&E.

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Fig. 5.3 Islet of Langerhans. (A) Rare islets of Langerhans can be found among numerous acini. UFP, 40×; (B) The normal islet cells are cohesive in contrast to islet cell tumors. UFP 1000×.

Fig. 5.4 Chronic pancreatitis. (A) Background of lymphoplasmacytic infiltrate, DQ, 40×; (B) Sheets of ductal epithelium among lymphoplasmacytic infiltrate. UFP, 100×; (C) Reactive ductal epithelium with prominent nucleoli in perfectly flat sheets. UFP, 400×; (D) Fibrotic stroma with ductules and fibroblasts and absence of pancreatic acini. H&E, 40×.

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Fig. 5.5 Pseudocyst. Abundant coarsely granular necrotic debris, but no epithelium. The crystals and background fluid are best seen in DQ (A, 40×), not in UFP (B, 40×).

Fig. 5.6 Caroli’s disease. Pancreatic cyst aspirated from a 69-year-old female with liver cysts and pancreatic cyst. (A) Cyst fluid contains occasional large flat sheets of bile ductal epithelium. DQ, 40×; (B) The nuclei the epithelium are small and bland. UFP, 40×.

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Fig. 5.7 Ciliated foregut cyst of the pancreas. (A) Serous fluid containing numerous “paintbrush” like ciliated columnar cells indistinguishable from ciliated bronchial cells. UFP, 400×; (B) High magnification shows long cilia. UFP, 1000×.

Fig. 5.8 Serous microcystic adenoma of pancreas: CT-scan shows circumscribed mass with small cysts. Gross specimen resembles a rubbery sponge, which yields serous fluid and scanty ductal epithelium when aspirated. Correlation with radiographs is as important as that of bone pathology.

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Fig. 5.9 Serous microcystic adenoma of the pancreas. (A) Low power shows scanty sheets of ductal epithelium in a serous fluid. DQ, 40×; (B) Serous fluid is invisible in UFP, 40×; (C) Monotonous small bland nuclei arranged in sheets. UFP, 400×; (D) Cell block histology confirms the cytologic diagnosis. H&E, 40×.

Fig. 5.10 Histology of serous microcystic adenoma of the pancreas. (A) Resected specimen. H&E, 40×; (B) Glycogen are present in the serous epithelium lining the cysts. PAS, 400×.

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Fig. 5.11 Solid-pseudopapillary neoplasm, aspirated from a 35-year-old female. (A) Branching vessels coated by small cells. DQ, 20×. Insert: Nuclei 1×RBC, 400×; (B) Small rigid cells scattered singly and coating chopstick-like vessels. UFP, 100×; (C) Bland, rigid, oval nuclei without molding. Insert: Indented nucleus. UFP, 600×; (D) Coexpression of β-catenin & α-1-antitrypsin. Immunostains on cell block, 40×.

Fig. 5.12 Solid-pseudopapillary neoplasm, aspirated from a 26-year-old female. (A) Branching long and slender vessels coated by small cells. DQ, 40×; (B) Numerous single rigid cells without nuclear streaking. UFP, 40×; (C) 100× view of a branch of the tumor. DQ, top, UFP bottom; (D) Tumor with indented nuclei (arrows) and delicate cytoplasm. UFP, 1000×.

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Fig. 5.13 Mucinous cystic neoplasm of the pancreas. (A) CT-guided fine-needle aspiration biopsy; (B) Abundant mucin containing sheets of epithelium. Smear, DQ, 100×; (C) Cytospin preparation dissolved the mucin. Pap stain, 100×; (D) Mucinous cytoplasm seen in profile view (arrows). Cytospin, Pap stain, 400×.

Fig. 5.14 Intraductal papillary mucinous neoplasm of the pancreas. (A) Abundant mucin containing papillary fragments of epithelium. DQ, 100×; (B) Cohesive epithelium with papillary architecture. UFP, 100×; (C) Columnar cells with oval nuclei and fine nuclear chromatin. UFP, 400×; (D) Cell block shows intestinal type epithelium with columnar cells.

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Fig. 5.15 Intraductal papillary mucinous neoplasm and colloid carcinoma. (A) Large papillary fragment and tiny papillary fragments (arrows). DQ, 40×; (B) Colloid carcinoma next to intraductal papillary mucinous neoplasm. DQ, 40×; (C) Nodular mucin containing single tumor cells in colloid carcinoma. DQ, 40×; (D) Single bland mucinous tumor cells in colloid carcinoma. UFP, 400×.

Fig. 5.16 Colloid carcinoma of the pancreas. (A) Low power shows pools of thick nodular mucin. DQ, 100×; (B) High power shows the tumor cells floating within thick nodular mucin. DQ, 400×; (C) Signet ring cells float in the thick nodular mucin. UFP, 400×; (D) Note the similarity between cytology in (C) and histology in cell block. H&E, 400×.

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Fig. 5.17 Very well-differentiated ductal adenocarcinoma of the pancreas. (A) Mucin containing tumor fragments in pre-operative FNA. DQ, 100×; (B) Equal-sized small nuclei without variation in size. UFP, 400×; (C) Malignant ducts of widely variable diameter. Intraoperative cytology. DQ, 40×; (D) Infiltrating ductal carcinoma lined by simple cuboidal epithelium. H&E, 100×.

Fig. 5.18 Correlation of cytology and histology of the previous case. (A) Interconnected narrow malignant ducts in FNA smear. UFP, 100×; (B) Narrow malignant ducts infiltrating smooth muscle. H&E, 100×; (C) A wide malignant duct. Smear, UFP, 100×; (D) A wide malignant duct infiltrating smooth muscle of the duodenum. H&E, 40×.

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Fig. 5.19 Well-differentiated ductal adenocarcinoma of the pancreas. Intra-op FNA. (A) Numerous sheets of ductal epithelium in acute inflammation. DQ, 40×; (B) Honeycomb sheets of epithelium without anisonucleosis. Pap stain, 400×; (C) Infiltrating ductal carcinoma. Frozen section, H&E, 40×; (D) Infiltrating simple cuboidal ducts with luminal abscess. H&E, 400×.

Fig. 5.20 Well-differentiated ductal adenocarcinoma of the pancreas. Intra-op FNA. (A) Many sheets of ductal epithelium, a clue for neoplasm in pancreas. UFP, 40×; (B) Flat sheets of ductal epithelium with minimal nuclear atypia. UFP, 400×; (C) Histology show space-occupying ductal proliferation in pancreas. H&E, 40×; (D) Back-to-back ducts lined by simple columnar epithelium without atypia. H&E, 400×.

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Fig. 5.21 Well-differentiated ductal adenocarcinoma of the pancreas. (A) Sheets of ductal epithelium in a background of acute inflammation. UFP, 100×; (B) Honeycomb sheets of ductal epithelium with sharp borders. UFP, 400×; (C) Histology shows infiltrating ductal carcinoma with luminal abscess. H&E, 100×.

Fig. 5.22 Moderately-differentiated ductal adenocarcinoma of the pancreas. (A) Malignant epithelium associated with desmoplastic stromal fragment. UFP, 100×; (B) Tridimensional tissue fragments in a inflammatory background. UFP, 400×; (C) No mucin present in DQ stain. 400×; (D) Tumor with nuclear enlargement and irregular nuclei. UFP, 1000×.

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Fig. 5.23 Moderately-differentiated ductal adenocarcinoma of the pancreas. (A) CTguided FNA of a mass at the uncinate process of the pancreas; (B) No mucin was present. DQ, 100×; (C) Delicate fronds of neoplastic ductal epithelium. UFP, 200×; (D) Pleomorphic nuclei and neutrophils-filled cytoplasm. UFP, 400×.

Fig. 5.24 Moderately-differentiated ductal adenocarcinoma of the pancreas. (A) Nuclear size 10× RBC (arrow). DQ, 100×; (B) Loss of polarity in the arrangement. DQ, 400×; (C) Hyperchromatic nuclei. UFP, 100×; (D) Great variation of nuclear size. UFP, 400×.

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Fig. 5.25 Mucinous ductal adenocarcinoma of the pancreas. (A) Abundant mucin containing small fragments of epithelium. DQ, 40×; (B) Numerous small fragments of mucinous epithelium. UFP, 40×; (C) High magnification of mucinous epithelium. 600×. DQ, left, UFP, right; (D) Delicate fronds of tumor with bridging. Resected tumor, H&E, 40×.

Fig. 5.26 Mucinous ductal adenocarcinoma with goblet cells. (A) Abundant mucin containing cohesive fragments of epithelium. DQ, 40×; (B) A fragment of pleomorphic cells in dirty background. UFP, 40×, left, 400× right; (C) Pleomorphic mucinous epithelium. Cell block, H&E, 100×; (D) Dystrophic goblet cells with loss of nuclear polarity. Cell block, H&E, 400×.

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Fig. 5.27 Mucinous ductal adenocarcinoma of the pancreas. (A) Mucinous epithelium with complicated architecture. DQ, 100×; (B) Mucin is inapparent in UFP, 100×; (C) Note the overlapping nuclei. UFP, 400×; (D) Mucinous epithelium with nuclei located in the middle. Cell block, H&E, 400×.

Fig. 5.28 Mucinous ductal adenocarcinoma of the pancreas. (A) A wisp of mucin attached to a large sheet of ductal epithelium. DQ, 40×; (B) A large sheet of ductal epithelium with light and dark areas. UFP, 100×; (C) Honeycomb sheet with nuclei in and out of focal plane. UFP, 400×; (D) Cuboidal mucinous epithelium losing nuclear polarity. Cell block, H&E, 400×.

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Fig. 5.29 Mucinous ductal adenocarcinoma, moderately differentiated. (A) Abundant mucin containg pleomorphic ductal cells. DQ, 200×; (B) Pleomorphic nuclear features. UFP, 400×; (C) A different case with pools of mucin and scattered tumor cells. DQ, 40×; (D) Nuclear feature of moderatedly differentiated ductal cells. UFP, 400×.

Fig. 5.30 Poorly differentiated ductal adenocarcinoma of the pancreas. (A) Low power shows numerous solitary round tumor cells. UFP, 100×; (B) Round nuclei with fine chromatin and distinct nucleoli. UFP, 400×; (C) Rare multinucleated tumor cell can be found. UFP, 400×; (D) Moderate amount of cytoplasm and the nuclear size is 4× RBC. DQ, 400×.

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Fig. 5.31 Anaplastic giant cell carcinoma of the pancreas (76-year-old male). (A) Many multinucleated giant tumor cells among solitary tumor cells. UFP, 100×; (B) Anaplastic cell with multiple convoluted nuclei and macronucleoli. UFP, 400×; (C) A binucleated giant cell with nuclear size 15–20× RBC. DQ, 400×; (D) AE1/AE3 cytokeratin positive immunostain on cell block. 100×.

Fig. 5.32 Anaplastic giant cell carcinoma of the pancreas. (A) Numerous solitary tumor cells. UFP, 40×; (B) Tumor with variable nuclear size and multinucleated tumor cells. UFP, 400×; (C) Spindle cells with oval nuclei. Note the binucleated cell (arrow). UFP, 400×; (D) A multinucleated tumor cell with cytoplasmic tail. UFP, 400×.

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Fig. 5.33 Adenosquamous carcinoma of the pancreas, well-differentiated. (A) Cohesive epithelium with dense cytoplasm. DQ, 400×; (B) Cohesive epithelium resemble section of skin in histology. Pap, 100×; (C) Cell block is diagnostic of adenosquamous carcinoma. H&E, 400×; (D) Intracytoplasmic mucin is confirmed by mucicarmine stain. Cell block, 400×.

Fig. 5.34 Adenosquamous carcinoma of the pancreas, poorly-differentiated. (A) Loosely cohesive cells in a dirty background. UFP, 100×; (B) Keratinizing squamous component. UFP, 400×; (C) Mainly glandular component. UFP, 400×; (D) Histology of the tumor, resected in a Whipple’s procedure. H&E, 100×.

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Fig. 5.35 Islet cell tumor of the pancreas. (A) Dyscohesive solitary cells easily smeared from the vascular network. UFP, 40×; (B) Plasmacytoid cells with “salt and pepper” chromatin. UFP, 1000×; (C) Rigid small blue cells without nuclear streaks or lymphoid tangles. DQ, 100×; (D) Cell block: synaptophysin immunostain, left, correlating histology. H&E right.

Fig. 5.36 Four islet cell tumors with inconspicuous “salt & pepper” chromatin. (A) Cohesive small group with great variation in nuclear size. UFP, 400×; (B) Dyscohesive oval nuclei with scanty cytoplasm. UFP, 400×; (C) Plasmacytoid cells with granular chromatin. UFP, 400×; (D) Gigantic nuclei among small nuclei are seen. UFP, 400×.

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Fig. 5.37 Acinar cell carcinoma of the pancreas, moderately differentiated. (Courtesy of Dr. W. Sun of M.D. Anderson Cancer Center.) (A) Cohesive tissue fragment. Papanicolaou stain, 200×; (B) High power shows round nuclei, prominent nucleoli, dense cytoplasm. 1000×; (C) Sheets of tumor cells. Cell block, H&E, 200×; (D) Cells have round nuclei, scanty cytoplasm. Cell block: H&E and immunostain.

Fig. 5.38 Acinar cell carcinoma of the pancreas, poorly differentiated. (67-year-old female with 3 cm mass). (A) Cohesive tissue fragment in a background of numerous necrotic single cells. Note the great variation in nuclear size. UFP, 200×. Insert : Occasional intact single tumor cells. UFP, 400×; (B) Cell block showed fine-needle cores of tightly packed tumor cells in nests. H&E, 100×; (C) Higher magnification showed pleomorphic cells with mitotic figures. H&E, 400×; (D) The tumor cells were α-1-antitrypsin (+), synaptophysin (−), and a CK7−/CK20− profile. α-1-antitrypsin immunostain on cell block, 400×. Insert : Cytoplasmic granules, seen in PASD stain. Cell block, 400×.

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Fig. 5.39 CT scan of a 24-year-old black female who presented with jaundice, nausea and vomiting, found to have a large pancreatic mass (arrow) and hepatic metastasis.

Fig. 5.40 Pancreatoblastoma65 : cytologic findings. (A) Metachromatic stroma seen only in DQ. 40×; (B) Cohesive fragments with sharp borders connected by fine threads. UFP, 40×; (C) Biphasic tumor with primitive stromal component. UFP, 100×; (D) Stromal component composed of stellate and spindle cells. UFP, 400×.

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Fig. 5.41 Pancreatoblastoma: cytologic findings. (A) Biphasic tumor with stromal component and epithelial component. UFP, 40×; (B) Stromal component and several fragments of epithelium. UFP, 40×; (C) High power of area in (A) pointed by the arrow. UFP, 1000×; (D) High power of area in (B) pointed by arrow. UFP, 1000×.

Fig. 5.42 Pancreatoblastoma: histologic findings. (A) Sheets of tumor cells with indistinct cell borders. Cell block, H&E, 400×; (B) Diastase resistant periodic acid Schiff positive in some tumor cells. PAS, 1000×; (C) 500–700 µm zymogen granules and numerous small intercellular junctions (arrows) resulting in the indistinct cell borders. EM, 12,000×; (D) The tumor cells are diffusely positive for synaptophysin and chromogranin.

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CHAPTER 6

Mass Lesions of the Kidney

The use of percutaneous large-bore needle biopsy of the kidney has become widespread since its introduction 60 years ago. It is a routine procedure for the evaluation of diffuse medical renal diseases in most medical centers. Percutaneous fine-needle aspiration biopsy of renal mass lesions has also gained recognition in the past 30 years.44,64 In our clinical practice, renal mass lesions are commonly detected by intravenous pyelography, but the latter is a very poor discriminator for mass lesions. Ultrasonography and CT-scan are useful techniques that can differentiate solid from cystic lesions. A percutaneous fine-needle aspiration biopsy of renal masses can be easily performed under the guidance of ultrasonography or CT-scan (Fig. 6.1), either to identify and evacuate benign cysts or abscesses or to diagnose small renal neoplasms, which may not be so obvious on imaging studies. Early detection of renal cell carcinoma may save lives. In addition, different surgical approaches are used for renal cell carcinoma and urothelial carcinoma. Preoperative diagnosis of renal neoplasms by transabdominal fine-needle aspiration biopsy may provide optimal patient management.37

NORMAL CELLULAR COMPONENTS The kidneys are situated in the retroperitoneum at a position lateral to the aorta and between the 11th rib and the transverse process of the 3rd lumbar vertebra. The right kidney is in relation to the hepatic flexure of the colon, the duodenum, and the right lobe of the liver. The left kidney is in relation to the

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tail of the pancreas and the posterior wall of the stomach. The adrenal glands are adherent superiorly. The kidney is composed of an excretory portion and a collecting portion. The excretory portion consists of glomeruli, proximal and distal convoluted tubules, and Henle’s loops, and the collecting portion consists of collecting tubules and renal pelvis. As blood flows through the glomerular capillaries, a protein-free filtrate of plasma is collected and flows down the tubules. During the tubular passage, there is resorption and secretion of electrolytes and water. The collecting tubules drain into the renal pelvis, which is continuous with the ureter. Aspirates from a normal kidney contain mostly tubular cells of various types. The glomeruli are occasionally aspirated.

Tubular Cells (Figs. 6.2A–C) Tubular cells of the proximal convoluted tubules are connected in a unique way. Ultrastructurally, the cell membranes of the lateral sides of contiguous cells interdigitate with one another in a complex fashion so that the sides of these cells are thrown into many complex ridges and grooves.23 Under light microscopy, in aspirates, they appear as syncytial sheets of large cells with finely granular cytoplasm. Tubular cells have round nuclei and small but distinct nucleoli. Distal convoluted tubular cells in aspiration preparations are smaller, and have darker, centrally located or eccentrically placed, round nuclei and less abundant, lightly stained cytoplasm with distinct cell junctions. The cells of collecting tubules are indistinguishable from distal tubular cells in aspirate preparations.

Glomeruli (Fig. 6.2D) The glomeruli are sometimes aspirated in renal cysts. When present in aspirate preparations, they appear as large ball-like structures, sometimes attached to Bowman’s capsule. Glomeruli without Bowman’s capsule may resemble papillary renal cell carcinoma at low power. At high power, a complicated network of capillary loops containing red blood cells are present. The capillary loops are lined by endothelial cells, covered by podocytes and supported by mesangial cells, however, these cells are difficult to see in aspirate preparations.

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NONNEOPLASTIC MASS LESIONS Common nonneoplastic lesions that may present as a space-occupying mass include renal cyst, tuberculosis, abscess and infarct. The use of modern imaging techniques, such as ultrasonography and CT-scan, aided by percutaneous fine-needle aspiration biopsy, has virtually eliminated the need for exploration of these nonneoplastic lesions.

Renal Cysts Cysts are the renal lesions most commonly aspirated. A multitude of cystic lesions involve the kidneys. They may be hereditary or acquired. Most renal cysts are asymptomatic, except for adult polycystic disease. However, rupture, hemorrhage or torsion may occasionally call attention to the lesions. The most common cystic lesion of the kidney encountered in the practice of aspiration biopsy is the simple cyst. One or more simple cysts are present in probably one-half of all individuals 50 years of age or older. They contain clear yellow fluid and displace renal parenchyma. Renal cell carcinomas may also undergo cystic degeneration, frequently with hemorrhagic contents in their cavities. In fact, at least one-third of all renal cysts with hemorrhagic contents are actually cystic carcinomas.1 It is, therefore, important to aspirate renal cysts of a debatable nature, detected by imaging techniques, for the purpose of diagnosis. Cytologic examination of the aspirated fluid contains few tubular cells with round nuclei. There are also scattered macrophages, often with abundant, foamy cytoplasm. In some cases, numerous hemosiderin-laden macrophages are present, indicative of prior hemorrhage into the cavity of the cyst. In occasional cases, irritated epithelial cells and reactive macrophages may mimic malignancy.27,48 However, they are usually intermingled with many recognizable benign cells, and do not form large tissue fragments, as in carcinomas, and there is absence of necrotic cells and debris. Ultrasonography, which demonstrates a smooth lining of the cystic cavity, confirms the diagnosis of a benign cyst.49

Tuberculosis Renal tuberculosis was a common disease in the past but is now rare in North America. It is hematogenous in origin, and the infection usually originates

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from foci in the lung. The lesion of renal tuberculosis may vary from minute areas of ulceration near the tips of papillae to huge cavitating masses. The infection may be unilateral or bilateral. Cytologic findings are essentially the same as those of tuberculous lesions elsewhere. The aspirate preparations contain lymphocytes, macrophages, multinucleated giant cells and epithelioid cells. Necrotic debris is usually found. A Ziehl-Neelsen stain may identify acid fast bacilli.

Abscess Renal abscesses are seen in patients with acute pyelonephritis or as part of the systemic inflammatory process. The patients with renal abscesses experience ipsilateral costovertebral angle pain and tenderness, chills and fever, and sometimes pyuria. The infection may be limited to the renal pelvis or may involve the entire kidney. Fine-needle aspiration biopsy can identify and evacuate the abscess.8 The aspirates consist of purulent exudate and contain abundant neutrophilic inflammatory cells and nuclear debris. If the biopsy is performed because of suspected infection or when purulent material is aspirated, the specimen should be sent for microbiologic studies, including Gram and Ziehl-Neelsen stains, and for aerobic, anaerobic, tuberculous and fungal cultures.

Infarct Infarction of the kidney is caused by occlusion of one renal artery that supplies the infarcted area. Occlusion of the renal artery commonly results from arteriosclerosis, thrombosis or atheromatous embolism. Occlusion of the major renal artery usually causes ischemic necrosis in several renal lobules and rarely leads to total infarction of the kidney. Collateral vascular supply from capsular or adrenal vessels usually suffices for viability of irregularly defined areas of renal cortex. The aspirate preparations contain many dying tubular cells with pyknotic nuclei; scattered necrotic tubular cells appearing as ghost cells; and necrotic cellular debris. Very few inflammatory cells are seen.

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BENIGN TUMORS Benign tumors of the kidney make up less than 5% of all renal neoplasms. They can arise from the epithelial elements or nonspecific stroma. Common benign tumors of the kidney include perirenal lipoma, angiomyolipoma and oncocytoma. Uncommon benign tumor of the kidney includes metanephric adenoma and mixed epithelial and mesenchymal tumor (adult mesoblastic nephroma).

Perirenal Lipoma Perirenal lipomas arise in the fat normally present in the perirenal regions. They may become huge. They are histologically similar to lipomas in any other part of the body. The empty sensation felt during aspiration biopsy when the needle tip enters a lesion is typical of fat-containing lesions. A computed tomogram, which demonstrates a low-density lesion, confirms the diagnosis. The aspirate preparations contain fragments of adipose tissue and scattered fat cells. Also encountered are many free oil droplets that are produced when the fat cells burst as a result of the aspiration procedure. Taken together, the cytologic findings, the CT-scan appearance, and the feeling of empty sensation during aspiration biopsy establish the diagnosis of lipoma.

Angiomyolipoma (Figs. 6.3–6.4) Angiomyolipoma is a uncommon soft tissue tumor involving the kidneys, liver and other organs. Long believed to be a benign hamartoma composed of thick-walled blood vessels, smooth muscle and mature adipose tissue, angiomyolipoma is now considered part of a family of neoplasms derived from perivascular epithelioid cells (PEComas), including also clear cell sugar tumor of the lung, clear cell myomelanocytic tumor of the falciform ligament, abdominopelvic sarcoma of perivascular epithelioid cells and lymphangioleiomyomatosis.14,45 The neoplastic cells of PEComas are characterized by expression of muscle and melanocytic (HMB-45) markers.2,46 Angiomyolipomas occur most commonly in middle aged and older women but may be seen in younger persons. They may be multiple or bilateral.

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Approximately one-third of the patients with renal angiomyolipoma are associated with tuberous sclerosis, a disorder involving gliosis of the brain, adenoma sebaceum of the face, and multiple hamartomas in the liver, pancreas and kidney. The incidence is higher in cases of multiple or bilateral angiomyolipomas. About 80% of the patients with the severe form of tuberous sclerosis have renal tumors of this type. At CT-scan, angiomyolipoma typically appears as a well-marginated, cortical, predominantly fat-attenuated mass with heterogeneous soft-tissue attenuation interspersed throughout the lesion.36 In tissue sections, the hyperchromatism, pleomorphism, and moderate mitotic activity of the tumor cells may result in a mistaken diagnosis of leiomyosarcoma, but the clinical course of this tumor is almost always benign.14 The use of fine-needle aspiration biopsy in establishing the diagnosis of this tumor has been reported.19,42 The preoperative diagnosis of angiomyolipoma may affect the surgical approach.4,19 The cytologic diagnosis of angiomyolipoma can be difficult and is often missed in inexperienced hands. The three components seen in tissue sections are either not seen or unusuallooking in aspirate preparations. Because there is no endothelial proliferation of the blood vessels within the tumor, endothelial components are not seen in aspirates. In some cases, fat cells are not seen in aspirates, because solitary and small clusters of fat cells tend to burst during the aspiration procedure. The neoplastic cells in angiomyolipomas are quite variable in cytomorphology and often show atypical appearances, mimicking malignancy.54 Since the neoplastic cells can appear as intermediate small round cells, spindle or epithelioid cells, the aspirates may demonstrate: 1. Lymphoma-like cells — small tumor cells that have slightly irregularshaped nuclei, some with cleavages that have little recognizable cytoplasm, mimicking lymphoma. 2. Spindle cells or fibroblast-like cells — tumor cells that have ovoid, elongated or spindle-shaped nuclei and no recognizable cytoplasm. 3. Sarcoma-like cells — solitary cells that have large, spindle-shaped nuclei with conspicuous nucleoli and variation in nuclear size, mimicking sarcoma. 4. Anaplastic carcinoma-like cells — epithelioid cells that have pleomorphic nuclei, mimicking anaplastic carcinoma.

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Lymphocytes are usually present and are intermingled with smooth muscle components. The aspirates from angiomyolipomas usually contain variable proportions of these smooth muscle components, even in different samples from the same tumor. Cytologic findings in any given case may be quite different, apparently due to sampling. The cytologic diagnosis of angiomyolipoma is therefore often difficult. Awareness of the variable cytologic appearances of neoplastic cells, the positive HMB-45 immunostain and the CT-scan finding of a fat-containing low-density lesion may establish the diagnosis.

CLASSIFICATION OF RENAL EPITHELIAL TUMORS BASED ON CYTOGENETICS In 1996, an international workshop was held in Heidelberg, Germany at which a classification of renal epithelial tumors based on cytogenetic abnormalities was proposed.30 This cytogenetic classification correlated well with histological findings and clinical outcome.41 This classification has been adopted with minor modifications by the Union Internationale Contre le Cancer and the American Joint Committee on Cancer and World Health Organization.52,55 Currently, renal epithelial tumors are classified into benign, malignant and undetermined malignant potential. Benign epithelial tumors are classified into metanephric adenoma51 ; mixed epithelial and stromal tumor (adult mesoblastic nephroma)47 ; papillary renal cell adenoma (7+, 17+, Y−)29 ; and oncocytoma (Y−, 1− most frequent).9 Malignant epithelial tumors are classified into conventional renal cell carcinoma (3p-27 mutations of Von Hippel-Lindau gene); papillary renal cell carcinoma29 (7+, 17+, Y− and 16+, 20+ or 12+); chromophobe renal cell carcinoma58 (Y−, 1− and 2−, 6−, 10−, 13−; hypodiploid DNA); collecting duct carcinoma16,24 (1−, 6−, 14−, 15− and 8p−, 13q−); and renal cell carcinoma, unclassified. Tumors of undetermined malignant potential include multilocular cystic renal cell carcinoma. Clinically, chromophobe renal cell carcinoma is associated with better prognosis than conventional renal cell carcinoma31 ; collecting duct carcinoma is associated with worse prognosis.24 Type 1 papillary renal cell carcinoma has better prognosis than Type 2 papillary renal cell carcinoma.10,12

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Sarcomatoid renal cell carcinoma is not included in the classification scheme, as genetic and morphologic evidence indicates that it is the common final pathway of de-differentiation of renal epithelial malignancy.11 Its associations with conventional, papillary, chromophobe renal cell carcinomas and collecting duct carcinoma have been reported. Today the term “granular cell renal cell carcinoma” without qualification is considered nonspecific, because it may include conventional, papillary, and the eosinophilic variant of chromophobe renal cell carcinomas.

Metanephric Adenoma (Fig. 6.5) Histology shows tightly packed small tubules made up of simple cuboidal epithelium accompanied by scanty stroma. Fine-needle aspiration cytology of metanephric adenoma has been reported.51 Aspirate preparations show numerous loosely cohesive small cells with minimal cytoplasm and small and bland nuclei forming vague tubules. An occasional row of cells survives the smearing artifact.

Mixed Epithelial and Stromal Tumor (Fig. 6.6) This tumor used to be called “adult mesoblastic nephroma” until 2001 when a cytogenetic study47 determined that it bears no relationship to childhood mesoblastic nephroma. Histologically, the tumor is composed of tubules scattered in a fibrotic stroma composed of spindly nuclei with eosinophilic fibrillary cytoplasm. Aspirate preparations show bundles of fibroblast-like spindle cells with bland nuclei and abundant fibrillary cytoplasm. The entrapped tubules are difficult to find.

Cystic Nephroma (Fig. 6.7) Histology shows multiple cysts in an ovarian-type cellular spindle cell stroma. The cysts are lined by flat to “hobnail” cells.

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The aspirate preparations show serous cyst fluid containing scattered atypical epithelial cells and fibrous stroma composed of spindle cells. The atypical epithelial cells are the hopnail cells from the lining of the cyst.

Oncocytoma (Figs. 6.8–6.9) Oncocytomas of the kidney, first described in 1942, was ignored in the literature until 1976 when Klein and Valensi26 published 13 additional cases. Oncocytoma, initially thought to be derived from proximal tubules, is now believed to be derived from the intercalated ducts. Oncocytomas are asymptomatic and usually discovered incidentally during work-up for other problems or at autopsy.26 The increasing use of imaging techniques led to the discovery of more oncocytomas. The preoperative diagnosis of oncocytoma by aspiration biopsy has been reported.38,60 Although most oncocytomas behave in a benign fashion, a few tumors were reported to be invasive and capable of metastasis.35 It is possible those cases may be misdiagnosed renal cell carcinomas. Histologic examination shows that the tumors are composed of epithelial cells with a granular, acidophilic cytoplasm due to the presence of abundant, large mitochondria. The tumor cells have uniform, round nuclei and are arranged in a cord, tubular or alveolar pattern. The aspirate preparations contain tumor cells (cohesion factor, 3 to 4) in small cohesive groupings, in sheet arrangements, and as solitary cells. They are polygonal, with an abundance of well-defined, granular cytoplasm and relatively uniform, round or ovoid nuclei. The nuclei are either centrally or eccentrically located. The nucleoli are inconspicuous or small, and the chromatin is finely granular. Cytomorphologically, they may resemble hepatocytes. It is, therefore, important to ascertain that the needle tip is definitely in the lesion when aspiration biopsy of the tumor is performed on the right kidney and, especially, when a transhepatic approach is used. Occasionally, renal cell carcinomas containing granular cells may have areas morphologically similar to oncocytoma. Aspiration biopsy and tissue core-needle biopsy may lead to an erroneous diagnosis of oncocytoma. Vimentin immunostain may resolve this diagnostic problem. Vimentin is negative in oncocytoma and positive in renal cell carcinoma.

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MALIGNANT TUMORS Primary malignant tumors of the kidney constitute 2 to 3% of human cancers.20 They can be divided into four pathologic types: Renal cell carcinoma, carcinomas of the renal pelvis, sarcomas and Wilms’ tumor.

Renal Cell Carcinoma Renal cell carcinomas are the most common tumor of the kidney and comprise 80% of all renal neoplasms. They arise from proximal tubular cells (conventional type); distal tubular cells (papillary type); intercalated duct cells (chromophobe type); and collecting duct cells of renal medulla (collecting duct carcinoma). These neoplasms occur twice as often in men as in women and are usually not discovered until they are sufficiently advanced to cause either a flank mass or hematuria. The average age at diagnosis is 50 to 60 years. They metastasize mainly through the bloodstream but also by the lymphogenous route. Lung and bones are the most common sites for metastasis. About one third of the patients have distant metastases at initial presentation. Some of the metastases occur before the primary lesion is discovered, whereas other metastases appear many years after the primary tumor has been removed. Many cases of so-called “silent metastatic cancer” of the lung that showed multiple lesions and were discovered incidentally by chest radiography, without known primary tumor at the time of investigation, were renal cell carcinoma. In Tao’s series, the most common primary site of silent metastatic cancers of the lung was the kidney.

Conventional Renal Cell Carcinoma Conventional renal cell carcinoma comprised 68% of malignant renal tumors in the Memorial Sloan-Kettering Cancer Center study,53 with a male:female ratio of 1.7–2:1. The age of presentation ranged from 34 to 90 years (mean 61 years). The putative cell of origin is the proximal convoluted tubules. Conventional renal cell carcinoma can be distinguished from proximal tubular epithelium by the well-defined cell borders in the former and invisible cell borders resulting from interdigitating cell membranes in the latter23 (Fig. 6.10). Conventional renal cell carcinomas are composed of clear cells and granular cells in various proportions. The popular Furhman17 nuclear

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grading (Fig. 6.11), based on nuclear size, nuclear shape and size of nucleoli, ranges from grade 1 (10 µm, round and uniform nuclei, inconspicuous to small nucleoli) to grade 4 (20+ µm, bizarre or multilobated nuclei with clumped chromatin and macronucleoli).

Conventional clear cell renal cell carcinoma (Figs. 6.10–6.16) Histologically, clear cell renal cell carcinoma is composed of clear cells arranged in solid sheets, cords, tubular or papillary growth patterns. The neoplastic cells have an abundance of clear cytoplasm that may appear foamy or vacuolated and have centrally located, round or ovoid nuclei. The vacuolated cytoplasm contains lipid (Fig. 6.12A) or glycogen (Fig. 6.13). The presentation in aspirate preparations is variable and includes single cells, small loose groupings, both in sheet arrangements and in cohesive groupings, and papillary fronds with a fibrovascular core. The cohesion factor is 4 to 5 in the majority of cases. The diagnosis of renal cell carcinoma should be based on cells in clusters and the finding of frequent prominent nucleoli.40,56,62 Of note, clear cell conventional renal cell carcinoma with a prominent papillary growth pattern (Figs. 6.15–6.16) was removed from “papillary renal cell carcinoma” when the cytogenetic abnormality was determined to be 3p−, the same as those tumors without the papillary growth pattern.18

Conventional granular cell renal cell carcinoma (Figs. 6.17–6.20) The aspirates of predominantly granular cell conventional renal cell carcinoma are more difficult to interpretate, because cells with granular cytoplasm are present in oncocytoma,38 eosinophilic chromophobe carcinoma,7,60 papillary renal cell carcinoma, proximal convoluted tubules or hepatocytes. Cytologically, conventional granular cell renal cell carcinoma occur in loose and cohesive grouping (cohesion factor, 4 to 5). They have moderate amounts of granular, often well-defined cytoplasm and large, centrally located, round nuclei. This may cause a diagnostic problem if a transhepatic approach (Fig. 6.17) is used for aspiration biopsy of the right kidney. The aspirate preparations should be carefully examined so as not to mistake hepatocytes for tumor cells. However, liver is reinforced with reticulin fibers; therefore,

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the aspirate should appear as rigid cores (Fig. 4.13). In addition, conventional granular cell renal cell carcinoma often has focal clear cells (Fig. 6.20B) and immunostaining for vimentin is positive for conventional granular cell renal cell carcinomas, but negative for hepatocytes and oncocytomas.

Papillary Renal Cell Carcinoma Papillary renal cell carcinoma is the second most common (7–14% in the Memorial Sloan-Kettering Cancer Center series53 ) renal cell carcinoma. The prognosis is better than conventional renal cell carcinoma, the 5-year disease free survival rate being 79–92%.53 Papillary renal cell carcinoma has a broad morphologic spectrum, ranging from papillary, papillary-trabecular to papillary-solid. The solid variant contains the same genetic alterations as other papillary renal cell carcinomas.10 Papillary renal cell carcinoma is subdivided into Type 1 and Type 2. Type 1 is more indolent than Type 2. Type 2 tumors are more common in patients younger than age 40, and present with larger tumor size and at a more advanced stage than were Type 1 tumors.12

Type 1 papillary renal cell carcinoma (Figs. 6.21–6.23) Histologically, this subtype consisted of papillae and tubular structures covered by simple cuboidal epithelium composed of small bland cells with pale cytoplasm and Furhman grade 1 nuclei, frequent glomeruloid papillae, foamy macrophages in papillary cores, and psammoma bodies. Cytokeratin 7 is expressed in most cases of this subtype. The aspirate preparations show cohesive, partially opened, papillary tissue fragments with fibrovascular cores in a background of macrophages (Fig. 6.21). Hemosiderin-laden epithelium was a frequent finding in the cases reported.22,39 Occasionally, (Fig. 6.23), the aspirate consists of many rosettelike small groupings with a connective tissue core, covered by small tumor cells with scanty granular cytoplasm and without any papillae. The nature of the tumor was not recognized until histologic follow-up, which showed a complicated arrangement of very long and very narrow papillae. Rosette-like small groupings in the aspirate represented the long papillae cross-sectioned by the biopsy needle. The cohesion factor of a Type 1 tumor is 4–5.

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Type 2 papillary renal cell carcinoma (Figs. 6.24–6.25) Histologically, this subtype consisted of papillae covered by pseudostratified epithelium composed of larger, more atypical cells with abundant eosinophilic cytoplasm with Furhman grade 2–4 nuclei. Cytokeratin 7 is not expressed in this subtype. In the aspirate preparations, loosely cohesive papillary tissue fragments are present in a background of solitary tumor cells removed by the force of smearing. The neoplastic cells are larger and the nucleoli are more prominent. The cohesion factor of Type 2 tumor is 2–3.

Chromophobe Renal Cell Carcinoma (Fig. 6.26) Chromophobe renal cell carcinoma, previously thought to be seen only in animals, was recognized in human by Thoenes et al. in 1995.58 The prognosis is much better than other types of renal cell carcinoma. In a Memorial SloanKettering Cancer Center study,53 the majority of tumors were large (− 9 cm), yet two-thirds were confined to the kidney at the time of diagnosis. In a mean follow-up period of 59 months, 94% of patients either were alive with no evidence of disease or died without evidence of disease. Chromophobe renal cell carcinomas account for about 4–6% of all renal tumors. Histologically, there are two variants.31 In the typical variant, the majority of the tumor cells have abundant cytoplasm with a perinuclear halo of fine reticular texture, outlined by a thick and eosinophilic cell border. In the eosinophilic variant, the majority of the tumor cells are smaller and have markedly eosinophilic cytoplasm, with only focal areas showing perinuclear halos. Histochemically, the tumor cells generally show a diffuse and strong reaction for Hale’s colloidal iron stain. Ultrastructurally, the cytoplasm of the tumor cells with a perinuclear halo is filled with microvesicles. Fine-needle aspiration cytology of chromophobe renal cell carcinoma has been reported.21,60 In the aspirate preparations, typical chromophobe renal cell carcinoma presents as dyscohesive solitary tumor cells with abundant cytoplasm and perinuclear halos filled with variable-sized vacuoles. The nuclei are hyperchromatic with indistinct nucleoli. The nuclear membrane is irregular, imparting a raisinoid appearance. Variation in nuclear size occurs. Many tumor cells are binucleated. The eosinophilic variant may lack the diagnostic

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cells with perinuclear halos in the aspirate and may look like oncocytomas or conventional granular cell renal cell carcinoma.60 Ancillary studies, including Hale colloidal iron, vimentin immunostain, electron microscopy or fluorescence in situ hybridization6 are helpful.

Collecting Duct Carcinoma of Renal Medulla (Figs. 6.27–6.28) Collecting duct carcinoma is rare and constitutes < 1% of renal epithelial tumors. It was not recognized as a clinicopathologic entity until 1986.16 It develops in younger patients, with a mean age of 34 years.23 It is aggressive; more than half of the patients have metastasis at the initial presentation. Typical collecting duct carcinoma consists of a grossly infiltrative neoplasm centered in the renal medulla. The usual histologic pattern is that of a tubular or tubulopapillary carcinoma with a desmoplastic stroma and less commonly, a papillary architecture. Origin in the collecting duct is suggested by the tumor’s medullary location and dysplasia of the epithelium in the collecting ducts adjacent to the tumor. Fine-needle aspiration cytology of collecting duct carcinoma has been reported.7,32 In the aspirate preparations, collecting duct carcinoma of the tubular type presents as cohesive sheets of epithelium with well-defined dense cytoplasm and hyperchromatic coarse granular nuclei with 1–2 distinct nucleoli. Collecting duct carcinoma of the papillary type is difficult to be distinguished from papillary renal cell carcinoma except for the anatomic site of renal medullary tumor as seen on CT-scan.

Sarcomatoid Renal Cell Carcinoma (Figs. 6.29–6.31) Sarcomatoid renal cell carcinoma is the high grade de-differentiation of other types of malignant renal cell neoplasms. The tumor shows marked proliferative activity in growth kinetic studies and is usually associated with a poor patient survival, best predicted by staging. Histologically, the tumor is composed of sheets of malignant spindle cells that have immunohistochemical and ultrastructural features of both stromal and epithelial cells, and may contain myxoid areas containing osteoclast-like giant cells or pleomorphic sarcomatoid spindle cells resembling rhabdomyoblasts. Fine-needle aspiration cytology of sarcomatoid renal cell carcinoma has been reported.3

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In the aspirate preparations, tumor cells (cohesion factor, 3 to 4) occur in noncohesive as well as cohesive groupings. They have ovoid, elongated, or spindle-shaped nuclei and poorly defined cytoplasm, neither vacuolated nor foamy. The cytologic feature of these tumor cells with good intercellular cohesion is helpful in differentiating this tumor from sarcomas, which have poor intercellular cohesion. Cytologic grading of renal cell carcinomas based on the degree of nuclear anaplasia has been described in the literature.43,63 It was found to be of prognostic value.43 However, attempts to reproduce the results have not been uniformly successful.54 It appears that cytologic grading was most reliable for high-grade tumors and was inaccurate as the differentiation improved.43 For instance, some renal cell carcinoma have uniform, regular, small-sized round nuclei and relatively scanty, poorly defined, lightly stained or clear cytoplasm. The chromatin is fine, and the nucleoli are usually indistinct (Images 6.32), yet the tumor is malignant. The cytologic diagnosis of renal cell carcinoma of this type is often missed by inexperienced examiners.

Carcinomas of the Renal Pelvis (Fig. 6.33) Carcinomas of the renal pelvis are uncommon tumors and are predominantly of the urothelial cell type. The remainder are either squamous cell carcinomas or adenocarcinomas. Urothelial carcinomas can be either papillary or nonpapillary. Most cases are seen in adults. They often diffusely involve the entire renal pelvis. Urothelial carcinomas of the nonpapillary type can spread massively into the renal parenchyma. It is not rare for urothelial carcinomas of the renal pelvis to have areas showing differentiation into adenocarcinoma or squamous cell carcinoma. Pure squamous cell carcinomas of the renal pelvis are rare tumors and are commonly associated with kidney stones and infection. However, metastatic tumors from urothelial carcinomas with some squamous cell carcinoma differentiation may appear as squamous cell carcinoma in metastatic sites. Adenocarcinomas of the renal pelvis are also rare tumors. Like squamous cell carcinomas, they are commonly associated with kidney stones and infection. In the aspirate preparations, tumor cells derived from papillary urothelial carcinomas (Figs. 6.34–6.35) are characterized by the so-called “cercariform” cells, a term coined by Powers and Elbadawi50 to describe tadpole-shaped

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cells with ovoid nuclei and long forked cytoplasmic tails. The cercariform cells often present as solitary cells (cohesion factor, 0 to 1) or as cohesive fragments around a vascular core. The tumor cells from nonpapillary urothelial carcinoma (Fig. 6.36) are generally larger and have round, ovoid or irregular-shaped nuclei with high nuclear/cytoplasmic ratio in solitary cells and in cohesive groupings (cohesion factor, 3 to 4). The tumor cells from poorly differentiated urothelial carcinomaUrothelial carcinoma are dyscohesive (cohesion factor, 0 to 1) with bizarre nuclei (Fig. 6.37) or multinucleation and may require immunohistochemistry using CK7+/CK20+ and uroplakin to confirm its urothelial nature. Tumor cells from squamous cell carcinomas are generally of the keratinizing type, with pyknotic nuclei and dense, sharply demarcated, often orangeophilic cytoplasm. The cytologic features of adenocarcinomas of the renal pelvis do not differ from those of the stomach or lung.

Sarcomas Primary sarcomas of the kidney are rare and constitute approximately 2% of all malignant neoplasms of the kidney. Leiomyosarcomas are by far the most common sarcoma of the kidney.15 Other sarcomas are rarely seen. The cytologic features of leiomyosarcomas are discussed in Chapter 8, in the section on Sarcomas.

Wilms’ Tumor (Figs. 6.38–6.40) Wilms’ tumors are the most common renal malignancy of infancy and children and rarely occur in adults.25,34,61 At least 50% of the cases occur before the age of 3 years and 90% before the age of 10 years. The first indication of this tumor is usually the presence of a large mass in the abdomen. Approximately 25% of patients have metastases to lymph nodes, lungs and liver when first diagnosed. Spread to other organs is rare, even in advanced cases. Establishing the preoperative pathologic diagnosis is important for optimal patient management.5 For patients with bulky tumors and vascular invasion, preoperative radiation and chemotherapy are strongly recommended. In Wilms’ tumors the occurrence of pulmonary metastases does not necessarily indicate a bad prognosis, but aggressive multimodal therapy

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is certainly needed.33 Fine-needle aspiration biopsy, in addition to establishing a primary diagnosis, can provide information on tumor recurrence and metastases and facilitate treatment decision. Histologic examination shows that this tumor contains elements of embryonal epithelium resembling tubules or glomeruli, elements of sarcoma, and undifferentiated tumor cells. The aspirate preparations contain tumor cells (cohesion factor, 2 to 3) in loose groupings, in cohesive clusters, and as solitary cells. They are relatively small and may be in an organoid arrangement with common cell borders or rosette formation. They have round, ovoid, elongated or spindle-shaped nuclei and no recognizable cytoplasm. A necrotic diathesis may be present.61 The cytologic features of Wilms’ tumor are similar to those of other small cell neoplasms of childhood, such as Ewing’s sarcoma, neuroblastoma and embryonal rhabdomyosarcoma. The finding of organoid arrangements of tumor cells with smooth, common cell borders provides a useful clue for the differential diagnosis. Immunostaining is also helpful in the differential diagnosis of small cell neoplasms of childhood (see Chapter 12).

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Fig. 6.1

CT-guided percutaneous FNA biopsy of a kidney mass approach posteriorly.

Fig. 6.2 Aspirate of normal kidney cortex. (A) Proximal tubule (→), distal tubule (↑) with attached glomerulus. UFP, 40×; (B) Proximal tubular epithelium appears syncytial with indistinct borders. DQ, 400×; (C) Distal tubular epithelium (top) and proximal tubular epithelium. UFP, 400×; (D) Note the RBC-filled capillary tufts in the glomerulus. UFP, 400×.

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Fig. 6.3 Angiomyolipoma. (A) Stromal tissue interspersed with fat and bizarre cells (to be enlarged in Fig 6.4A) (arrow). DQ, 100×; (B) Low power view looks like fragments of fibrofatty tissue. UFP, 100×; (C) Perivascular epithelioid cells have oval nuclei and distinct nucleoli. UFP, 400×; (D) Actin labels blood vessels, left ; HMB-45 labels the tumor cells. Cell block, 100×.

Fig. 6.4 Perivascular epithelioid cells of angiomyolipoma. (A) Binucleated cell with nuclei 5–7× RBC and abundant cytoplasm. DQ, 400×; (B) A multinucleated tumor cell. UFP, 400×; (C) A bilobated tumor cell with rectangular cytoplasm. UFP, 400×; (D) HMB-45, a melancytic marker, labels the tumor cells. Cell block, 400×.

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Fig. 6.5 Metanephric “embryonal” adenoma of kidney. (A) Numerous loosely cohesive tiny cells forming vague tubules. Pap, 100×; (B) Tiny cells with bland nuclei. Arrow points to a row of four cells. Pap, 400×; (C) Cell block contains numerous small tubules. H&E, 100×; (D) The tubules are lined by simple cuboidal epithelium. H&E, 400×.

Fig. 6.6 Mixed epithelial and stromal tumor (adult mesoblastic nephroma). (A) Bundles of fibroblast-like spindle cells with bland nuclei. UFP, 40×; (B) Close-up shows abundant fibrillary cytoplasm. UFP, 400×; (C) Resected tumor are composed of tubules in spindle stroma. H&E, 40×; (D) Spindly nuclei with eosinophilic fibrillary cytoplasm. H&E, 400×.

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Fig. 6.7 Multilocular cystic nephroma. (A) Serous fluid containing scattered epithelial cells and fibrous stroma. UFP, 40×; (B) Epithelial cells resembles renal cell carcinoma. UFP, 1000×; (C) Multiple cysts in a spindle cell stroma resembling ovarian stroma. H&E, 40×; (D) The “hobnail” cyst lining cells, correlated to (B). H&E, 1000×.

Fig. 6.8 Oncocytoma. (A) A fibrovascular core coated with tumor cells. UFP, 100×; (B) Thinly spread region shows numerous single tumor cells. UFP, 100×; (C) Dyscohesive solitary cells with equal-sized round nuclei. UFP, 400×; (D) Granular cytoplasm containing round nuclei with coarse chromatin. UFP, 1000×.

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Fig. 6.9 Oncocytoma. Correlation of cytology with histology. (A) Low power view soltary oncocytic cells with nuclear size 1× RBC. DQ, 100×; (B) Binucleated oncocytic cells can be found. UFP, 1000×; (C) Most oncocytic tumor cells have one nucleus. UFP, 1000×; (D) Histology of resected oncocytoma. H&E, 100×.

Fig. 6.10 Proximal tubular epithelium (top) vs. conventional RCC. (bottom). 400× Both have abundant granular cytoplasm and small round nuclei; however, the neighboring cells in proximal tubules possess interdigitating cell borders, which gives a syncytial appearance and is very difficult to smear apart. In contrast, conventional RCC are easily separated by smearing. (A, B): DQ; (C, D):UFP.

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Fig. 6.11 Furhman nuclear grades for conventional RCC. 400× UFP. (A) Grade 1: 10 µm, round and uniform, inconspicuous to small nucleoli. Arrow points to a PMN (12 µm); (B) Grade 2: 15 µm, irregular shaped, nucleoli present; (C) Grade 3: 20 µm, obvious irregularshape with macronucleoli; (D) Grade 4: 20+ µm, bizzare or multilobated, macronucleoli, clumped chromatin.

Fig. 6.12 Conventional clear cell renal cell carcinoma. (A) Note the tumor cells have distinct cell borders and lipid droplets. 400×; (B) Dyscohesive clear cells with abundant cytoplasm. UFP, 400×; (C) Clear cells with moderate amount of cytoplasm. UFP, 400×; (D) Histology of conventional clear cell RCC. H&E, 400×.

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Fig. 6.13 Conventional clear cell renal cell carcinoma, glycogen-rich. (A) Tigroid background is due to glycogen released from tumor cells. DQ, 100×; (B) Tumor cells with long clear cytoplasm in lymphocytic background. UFP, 100×; (C) A group of tumor cells infiltrated by lymphocytes. UFP, 400×; (D) Glycogen demonstrated by diastase digestable PAS stain. 100×.

Fig. 6.14 A 72-year-old asymptomatic male incidentally found to have a 1.5 cm renal mass. Radiological impression: cyst vs. solid. A CT-guided FNA biopsy using a 10-inch long 25G spinal needle, was performed. The aspirate is shown in the next figure.

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Fig. 6.15 Conventional clear cell renal cell carcinoma with papillary pattern. (A) Papillary fragments along metachromatic fibrovascular core. DQ, 40×; (B) Short and wide papillae attached to fibrovascular core. UFP, 40×; (C) Lipid droplets are present in the background and within tumor cells. DQ, 400×; (D) Clear tumor cell cytoplasm with Furhman grade 2 nuclei. UFP, 400×.

Fig. 6.16 Conventional clear cell renal cell carcinoma with papillary pattern. (A) Papillary fragments of tumor. DQ, 40×; (B) Opened papillary epithelium in a background of macrophages. UFP, 40×; (C) Cytoplasmic lipid droplets in DQ, and is clear in UFP. Furhman grade 1 nuclei. 200×; (D) Clear cells around macrophage-filled vascular cores. H&E, 400×, left; 40×, right.

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Fig. 6.17 Transhepatic approach to reach right renal mass may inadvertently sample hepatocytes.

Fig. 6.18 Conventional granular cell renal cell carcinoma. (A) Numerous ball-like structure connected by connective tissue. UFP, 40×; (B) Close-up shows smooth outline of tumor cell groups. UFP, 100×; (C) No lipid droplets, DQ (left) and Furhman grade 2 nuclei, UFP (right), 400×; (D) Histology in cell block (left) and resected tumor (right). H&E, 100×.

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Fig. 6.19 Conventional granular cell renal cell carcinoma. (A) Sheets of tumor with abundant cytoplasm devoid of lipid droplets. DQ, 100×; (B) Abundant granular cytoplasm. UFP, 100×; (C) Furhman grade 2 nuclei. UFP, 100×; (D) Histology resembles oncocytoma, but is vimentin positive. H&E, 100×.

Fig. 6.20 Conventional granular cell renal cell carcinoma, with focal clear cells. (A) Dense cytoplasm with rare l lipid droplets (arrow). DQ, 100×; (B) High magnification of the lipid droplets. DQ, 400×; (C) Blue granular cytoplasm seen in UFP, 100×; (D) High magnification shows Furhman grade 3 nuclei. UFP, 400×.

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Fig. 6.21 Papillary renal cell carcinoma, type 1. (A) Papillary tissue fragments without lipid droplets in the background. DQ, 40×; (B) Fibrovascular cores stripped off tumor in background macrophages. DQ, 100×; (C) Blood vessel protruding through tightly cohesive tissue fragment. UFP, 100×; (D) Granular cells with Furhman grade 1 nuclei. UFP, 400×.

Fig. 6.22 Papillary renal cell carcinoma, Type 1. (A) CT-guided FNA biopsy of a 63-yearold male having FNA of a 4 cm left renal cortical mass; (B) No lipid droplets in the papillary fragments or in the background. DQ, 100×; (C) Papillary fragments that resembles spherules. UFP, 40×; (D) Partially opened spherule shows Furhman grade 1 nuclei. UFP, 400×.

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Fig. 6.23 Papillary renal cell carcinoma, Type 1. Top row: FNA biopsy, 400×, (A) DQ; (B) UFP; (C) Cell block, trichrome stain. Numerous rosette-like groupings with metachromatic core; difficult to interpret. Bottom row: Nephrectomy showed long papillae with delicate fibrovascular core, which had been cut by the needle into rosette-like groupings shown in top row; (D) “Scratch and smear” 62 at bench. UFP, 40×; (E) Histology, PAS stain, 40×.

Fig. 6.24 Papillary renal cell carcinoma, Type 2. (A) Papillary fragments and solitary tumor cells without lipid droplets. DQ, 40×; (B) A fibrovascular core (arrow) stripped off tumor cells by the smear. UFP, 40×; (C) Furhman grade 2 nuclei seen. Arrow points to a fibrovascular core. UFP, 40×; (D) Papillary fragments of pseudostratified epithelium (arrow). H&E, 100×.

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Fig. 6.25 Papillary renal cell carcinoma, Type 2. (A) A large branching papillary tissue fragment. UFP, 20×; (B) Solitary tumor cells smeared off the papillary fragment. UFP, 100×; (C) Notice the absence of negative image of lipid droplets in DQ, 40×; (D) Granular cells with Furhman grade 2 nuclei. UFP, 400×.

Fig. 6.26 Chromophobe renal cell carcinoma. (A) Low power shows dyscohesive solitary tumor cells. UFP, 100×; (B) Perinuclear halo with vesicles lined by a thick cell borders. Hyperchromatic, wrinkled nuclei with frequent binucleation are present. UFP, 1000×; (C) Negative image of vesicles are seen in the cells and the background. DQ, 1000×; (D) Histology from nephrectomy specimen. H&E, 400×.

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Fig. 6.27 Collecting duct carcinoma of the renal medulla with tubular pattern. (A) Cohesive sheets of epithelium. DQ, 40×; (B) Tumor cells with eccentric nuclei and rectangular cytoplasm, UFP, 400×; (C) Sharp cell borders and nuclei with 1–2 nucleoli. UFP, 1000×; (D) Histology shows infiltrating tubules. (arrow) Left, 40×. in situ carcinoma. Right, 400×.

Fig. 6.28 Collecting duct carcinoma of renal medulla with papillary pattern. (A) Very long and slender papillary fragments of tumor. Pap stain, 40×; (B) Tumor cells are small cuboidal cells with minimal cytoplasm. Pap stain, 200×; (C) Metachromatic fibrovascular core coated by tumor cells. DQ, 400×; (D) Histology is similar to (C). Resected tumor. H&E, 400×.

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Fig. 6.29 CT-scan of a 73-year-old male presented with a 2.5 cm right renal cortical mass (arrow) and metastasis to right iliac bone and lung. The bone aspirate is shown in Fig. 6.26.

Fig. 6.30 Sarcomatoid renal cell carcinoma, same case as Fig. 6.9. (A) Loosely cohesive oval to spindle cells. UFP, 40×; (B) High power shows fine chromatin with no nucleoli. UFP, 400×; (C) The spindle cells in metachromatic matrix. DQ, 400×; (D) Histology. Cell block, H&E, 40×.

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Fig. 6.31 Sarcomatoid renal cell carcinoma from a male with sternal metastasis. (A) Cores of tumor and solitary tumor cells. UFP, 40×; (B) Metachromatic stroma (arrows) seen only in DQ. 400×; (C) Spindle tumor cells with oval nuclei and bipolar cytoplasm. UFP, 400×; (D) Histology. Cell block, H&E, 100×.

Fig. 6.32 Renal cell carcinoma, not otherwise specified. (A) Numerous glove-like projections of tumor cells. UFP, 100×; (B) Notice there is no fibrovascular core within the projections. UFP, 400×; (C) Furhman grade 1 nuclei. UFP, 1000×; (D) Nephrectomy specimen showed vascular invasion. H&E, 40×.

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Fig. 6.33 Posterior approach of a 10 inch long, 22 gauge spinal needle sampling a renal pelvic mass of a 72-year-old female. Notice the cortex is not involved by the mass.

Fig. 6.34 Papillary urothelial carcinoma, low grade. (A) Solitary cells without metachromatic stroma in a bloody background. DQ, 400×; (B) Cercariform cells with cytoplasmic tails. UFP, 1000×; (C) A fibrovascular core lined by a single layer of cercariform cells. UFP, 1000×; (D) Histology. Note the similarity between (C) and the basal layer of (D). H&E, 100×.

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Fig. 6.35 Urothelial carcinoma, intermediate grade. (A) Cercariform cells are evident in this case even in DQ, 400×; (B) A cluster of cercariform cells. UFP, 400×; (C) A tadpole-like cell with long cytoplasmic tail. UFP, 400×; (D) A large cercariform cell with crescent shaped red nucleolus. UFP, 400×.

Fig. 6.36 Urothelial carcinoma, high grade, ureteral origin. (A) Cohesive tissue fragments and solitary tumor cells. UFP, 40×; (B) Cohesive fragment show tumor cells with sharp cell borders. UFP, 400×; (C) High N/C ratio malignant cells, reminiscent of urine cytology. UFP, 400×; (D) Correlating histology from resected ureter. H&E, 200×.

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Fig. 6.37 Urothelial carcinoma, poorly differentiated. (A) Numerous solitary cells and a few dyscohesive groupings. UFP, 40×; (B) Occasional elongated cells seen among numerous tumor cells. UFP, 100×; (C) A giant tumor cell. UFP, 100×; (D) CK7+/CK20+. Immunostains on cell block. 100×.

Fig. 6.38 A 35-year-old male complained of fatigue for six months, found to have a huge multicystic right kidney mass, numerous lung nodules, and right pleural nodules.34 The aspirate of the pleural nodule is shown below.

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Fig. 6.39 Adult Wilms’ tumor,34 same case as Fig. 6.38. (A) Alternating bands of mesenchymal tissue and nests of blastema cells. UFP, 40×; (B) Branching mesenchymal tissue (arrow) to be enlarged in C. UFP, 40×; (C) The mesenchymal tissue is intimately associated with blastema cells. UFP, 400×; (D) The mesenchymal component is highlighted by metachromasia in DQ. The nephrectomy specimen showed Wilms’ tumor. DQ, 400×.

Fig. 6.40 Wilms’ tumor, in a 20-year-old female, who presented with a liver mass extending inferiorly to the kidney. The liver aspirate is shown. (A) Numerous rigid blastemal cells without nuclear streaks or molding. UFP, 400×; (B) Spindled mesenchymal component. UFP, 100×; (C) Blastema cells forming tubules correlated to the histology. UFP, 100×; (D) Partial hepatectomy and right nephrectomy specimen. H&E, 100×.

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CHAPTER 7

Primary Lesions of the Adrenal Gland

The adrenal is a common site harboring metastases,6,28,36,37 but nonfunctioning adenomas6,14,15,37 are also very common tumors. The latter were found in 2 to 8% of the population at autopsy and are rarely diagnosed during life.23 The increasing use of modern imaging techniques for metastatic work-up in cancer patients has led to the discovery of many incidental adrenal masses of varying sizes.15 It is important to obtain a definitive pathologic diagnosis of such mass lesions, because the nature of an adrenal mass may determine the staging of the cancer, the prognosis, and therapeutic strategy. Guided fine-needle aspiration biopsy of such a lesion (Fig. 7.1), without subjecting the patient to laparotomy, ideally suits this purpose. The value of fineneedle aspiration biopsy of adrenal lesions has been recognized in our clinical practice. In the recent years, ultrasonography and computed tomography have virtually replaced all other techniques in the assessment of this organ because of their sensitivity in detecting small lesions (Fig. 7.1). The improved imaging techniques can reliably localize space-occupying lesions in the adrenals as small as 1 cm in diameter.19,22

NORMAL CELLULAR COMPONENTS The two adrenal glands are situated in the retroperitoneum and rest on the superomedial borders of the two kidneys. They are composed of two portions, the cortex and the medulla, which have entirely different origins. The cortex arises from the mesoderm, whereas the medulla arises from neuroectodermal 206

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tissue. Cortical tissue is seen only within the anatomic confines of the adrenal glands. However, islands of chromaffin tissue morphologically identical to adrenal medulla are normally found along the descending aorta. This explains why similar tumors of the adrenal medulla may also be found in other sites. Histologic examination shows that the adrenal cortex contains three zones (Fig. 7.2). The outermost zone, the zona glomerulosa, is composed of small, dark, lipid-containing cells. It is the site of production of mineralocorticoids. The middle zone, the zona fasciculata, has lipid-rich cells with vacuolated cytoplasm, arranged in columns and fascicles, and is the broadest. The innermost zone, the zona reticularis, is composed of lipid-poor cells with granular cytoplasm, arranged in nests. The zona fasciculata and zona reticularis are the sites of the production of glucocorticoids and androgens. The adrenal medulla consists of medullary cells with eccentric nuclei and finely granular cytoplasm, grouped in nests and cords around the sinusoidal vessels. It synthesizes epinephrine and norepinephrine. In addition to medullary cells, some ganglion cells are interspersed.

Cortical Cells In aspirate preparations, the cytomorphologic features of the cortical cells from the zona fasciculata and the zona glomerulosa are similar. They have centrally located, round nuclei and an abundance of poorly defined cytoplasm which usually appears foamy, vacuolated due to intracytoplasmic lipids. They occur in cohesive and noncohesive groupings and as solitary cells. The cortical cells from the zona reticularis have round or ovoid nuclei and moderate amounts of deeply stained, finely granular cytoplasm and may contain lipofuscin pigments.14,24 They occur in sheet arrangements, in noncohesive groupings, and as solitary cells. The cytoplasm is neither foamy nor vacuolated as it is lipid-poor.

Medullary Cells In aspirate preparations, medullary cells have round nuclei and finely granular cytoplasm. They are relatively small. Their nuclei are either centrally located or eccentrically placed. The appearance of medullary cells in aspirate

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preparations resembles that of small-sized hepatocytes. Because a transhepatic approach is the common technique used to obtain cytologic samples from the right adrenal, there is often a variable number of hepatocytes present in aspirate preparations. It is, therefore, important to bear in mind this resemblance between medullary cells and small hepatocytes during microscopic examination and cytomorphologic interpretation, if the aspiration biopsy is performed on the right adrenal.

NONNEOPLASTIC LESIONS A diffuse or a nodular enlargement of the adrenal may result from nonneoplastic disorders, such as tuberculosis and acquired adrenocortical hyperplasia. Clinically and roentgenographically, they may produce a mass-like enlargement of the adrenals, mimicking malignant tumors.

Tuberculosis and Fungal Infections Adrenal tuberculosis is uncommon in North America. It is hematogenous in origin and usually originates from the foci in the lung. The infection is often bilateral. Both adrenals are enlarged and largely replaced by caseous granulomas. In microscopic examinations, exudative inflammation is uncommon in adrenal infections because of the antiphlogistic effects of corticosteroids. Necrosis always exceeds leukocytic infiltration in infections that involve the adrenals. Bilateral destructive adrenocortical tuberculosis is the classic cause of Addison’s disease. Twenty years ago at the Toronto General Hospital, the senior author encountered two cases of adrenal tuberculosis.40 A 69-year-old woman who presented with Addison’s disease and a 25 pound weight loss was found to have bilateral adrenal enlargement on CT-scan. Biochemistry tests confirmed adrenal insufficiency. The initial clinical impression was metastatic cancers of the adrenals. Percutaneous fine-needle aspiration biopsy of the left adrenal was performed. Microscopic examination showed a few lymphocytes and macrophages on a background of abundant necrotic debris. The aspirate was scantily cellular. Ziehl-Neelsen stain revealed scattered acid-fast bacilli. Epithelioid cells and multinucleated giant cells commonly seen in

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tuberculous lesions of other organs are usually not present in adrenal tuberculosis. The cytologic diagnosis in this case was reported as “tuberculosis of the adrenal.” The patient was then given antituberculosis treatment. The follow-up CT-scan after an 11-month treatment showed that both adrenals were reduced in size and appeared normal. In addition, all of the biochemistry tests also returned to normal values. Even the skin pigmentation disappeared. Another similar case of adrenal tuberculosis that presented with Addison’s disease and bilateral adrenal enlargement also showed excellent results after antituberculosis treatment. These were the first two reported cases of adrenal tuberculosis32 having fine-needle aspiration biopsy, leading to the diagnosis and appropriate treatment, and they demonstrated that both the size and function of seemingly destroyed adrenal glands may return to normal after proper treatment. These two patients were not candidates for diagnostic laparotomy because of the risk of adrenal crisis during surgery. Without establishing the pathologic diagnosis, these two patients probably would have been put on replacement therapy, causing further flare-up of tuberculosis. If these two patients had been given chemotherapy for treating suspected malignancy, it also would have caused more damaging effects. These two cases are probably the best examples for demonstrating the advantages of using the fine-needle aspiration technique. Disseminated fungal infections (Fig. 7.3) can also cause Addison’s disease. Diagnosis by fine-needle aspiration biopsy have been reported in histoplasmosis5,28 and cryptococosis.26

ADRENOCORTICAL NODULES Adrenocortical Hyperplasia (Fig. 7.5) Acquired adrenocortical hyperplasia is always bilateral in patients with both adrenals and may result in a nodular or in a diffuse enlargement of the adrenal glands. Adrenocortical nodular hyperplasia is a frequent autopsy finding. Cortical nodules increase in number with age but do not have clinical significance. Unilateral compensatory adrenal cortical hyperplasia occurs in patients who had contralateral adrenalectomy and nephrectomy for renal cell carcinoma. It is important not to overdiagnose recurrent renal cell carcinoma, as it may lead to the loss of both kidneys. On the other hand, one does

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not want to miss recurrent renal cell carcinoma in a patient with bilateral adrenal masses, who had adrenal-sparing nephrectomy (Fig. 7.4). Histologic examination of adrenal cortical hyperplasia shows an increased thickness of the zona reticularis and fasciculata in a diffuse fashion or in nodular arrangements. Occasionally, cells with large hyperchromatic nuclei are seen in some of the nodules. The aspirate preparations from adrenocortical hyperplasia contain cells that have round nuclei and an abundance of foamy cytoplasm, resembling cortical cells from the zona fasciculata or zona glomerulosa. But the aspirate preparations are usually cellular and the cells are more closely packed than normal cortical cells. Binucleated cells are frequent. For such lesions, it is important to verify the position of the tip of the biopsy needle during aspiration biopsy to ensure its correct placement within the lesion.

Cortical Nodules (Fig. 7.6) Cortical nodules are common in older individuals. Autopsy studies found cortical nodules in ∼ 25% of individuals.4 Nowadays, they are incidentally detected by abdominal CT scan in work-up for unrelated medical problems. They are roughly spherical, unencapsulated, usually multiple and range in size from microscopic to grossly apparent.27 Sometimes they present as single nodule up to ∼ 3 cm, leading to aspiration biopsy. Histologic examination shows normal adrenocortical tissue. The aspirate preparations from cortical nodules are identical to those of adrenocortical hyperplasia as described above.

TUMORS OF THE ADRENAL CORTEX Tumors of the adrenal cortex may be benign or malignant, and functioning or nonfunctioning. In general, functioning cortical adenomas manifest as hormonal disorders, whereas nonfunctioning cortical adenomas are usually small and rarely diagnosed during life. A palpable cortical neoplasm of the adrenal is a carcinoma in practically every instance.27 Functioning cortical tumors produce various steroid hormones. The most common hormonal activity causes Cushing’s syndrome, owing to the excessive production of

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cortisol. Virilization is less commonly seen and is a result of overproduction of adrenal androgens. Cortical tumors that produce aldosterone cause hyperaldosteronism (Conn’s syndrome).

Adrenocortical Adenoma (Figs. 7.7–7.9) Adrenocortical adenomas are usually solitary and well-encapsulated. They are found in 2 to 8% of the population at autopsy. They are generally small, usually < 5 cm in diameter. Most adenomas are nonfunctioning. Histologic examination shows that the tumor resembles the zona fasciculata and the zona glomerulosa in appearance. Occasional bizarre nuclear forms can be seen, but mitoses are exceptionally rare. The aspirate preparations contain dyscohesive cells (cohesion factor, 0 to 1) that have round nuclei and low nuclear grade and an abundance of lipidrich cytoplasm resembling cortical cells from the zona fasciculata or zona glomerulosa, but the cells are dyscohesive (Fig. 7.7). In the aspirate of one of the adenomas the first author examined, the neoplastic cells showed lipidrich cells with nuclear atypia (Fig. 7.8), while in another case, the aspirate showed lipid-poor cells with nuclear atypia (Fig. 7.9). In both instances, adrenalectomy was performed which showed small encapsulated tumor that do not fulfil the histologic criteria for malignancy.

Adrenocortical Carcinoma (Figs. 7.10–7.15) Adrenocortical carcinomas are relatively rare. It occurs most often in the fourth and fifth decade.17 They can be non-functioning or functioning, causing Cushing’s syndrome.4,17,27 They are usually large and may weigh as much as 1,000 g before discovery. These tumors are generally highly malignant neoplasms. They often recur following surgery, and their radiosensitivity is poor. Histologic examination shows that adrenocortical carcinomas have wide morphologic variability, ranging from areas wherein the tumor cells closely resemble the cortical cells to areas containing tumor cells with bizarre, hyperchromatic nuclei and multinucleated forms and numerous mitotic figures.17 Adrenal cortical carcinomas are rarely < 5 cm or < 50 g.17 Regarding the management of adrenal cortical lesions, Suen34 reported benign cytology and those with size < 5 cm can be managed conservatively

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with follow-up scans; those with atypical cytology or size > 5 cm warrant surgery. Adrenalectomy is recommended for any adrenal tumor associated with endocrine abnormality, irrespective of tumor size and cytology. Cytomorphologic features of adrenocortical carcinomas have been studied.14,18,28 In aspirate preparations, three common cytologic patterns can be recognized: 1. Well-differentiated small cell type (Figs. 7.10–7.11). Tumor cells (cohesion factor, 0 to 1) lie singly or occur in small loose groupings. They have small, ovoid or irregular-shaped nuclei, often eccentrically placed, and small amounts of lipid-poor cytoplasm. The nucleoli are indistinct, and chromatin is finely granular. 2. Well-differentiated large cell type (Fig. 7.12). Tumor cells (cohesion factor, 0 to 1) lie singly and occur in small loose groupings. They have large, round or ovoid nuclei, usually eccentrically located, and moderate amounts of foamy or vacuolated cytoplasm. The cytoplasm in some cells contains lipid droplets. The tumor cells may appear as stripped nuclei if the specimen is not properly smeared. Their nuclei contain a single prominent nucleoli or two or more small nucleoli, and slightly granular chromatin. Necrosis is common. 3. Poorly differentiated cell type (Figs. 7.13–7.15). Tumor cells (cohesion factor, 0 to 1) lie singly or occur in loose groupings. They have large to gigantic, hyperchromatic nuclei and an abundance of foamy cytoplasm. The nuclei have marked variation in size and frequently prominent nucleoli. The chromatin is coarsely granular. Multinucleation is common. Immunohistochemically, adenomas express low molecular weight cytokeratins and do not expression vimentin, whereas carcinomas are strongly vimentin-positive and have weak or no cytokeration expression.10 In addition, it was reported the immunostain for MIB 1 proliferation index was significantly higher in adrenal cortical carcinomas than adenomas.1

Problems in cytologic diagnosis of adrenal cortical nodules Adrenal cortical nodules include hyperplasia, cortical nodule, adenoma and carcinoma. Hyperplasia has no capsule and are thus easily recognized histologically. However the features of adenoma and carcinoma overlap, and

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it is difficult to distinguish small adenomas with atypical cytologic features from carcinoma. Weiss histological criteria37 favoring malignancy include: Furhman grade III or IV nuclei, mitosis >5/50 HPF, atypical mitosis, necrosis, clear cells < 25% and weight > 50 g. In reporting primary adrenal cortical nodules, it is important to consider the nodule size in conjunction with the cytologic findings. In the M.D. Anderson series28 of fine-needle aspiration biopsy of the adrenal gland, 61 benign cortical nodules/adenomas measured 1 to 4 cm (mean: 2.4 cm) and 11 cortical neoplasm/carcinoma measured 4 to 12 cm. In the Indiana series,38 40 benign adrenocortical nodules measured 1–5 cm (mean 2.5 cm). Fine-needle aspiration biopsy cannot be used to assess the status of encapsulation, but it can be used to assess the cohesiveness of cells in the smears. Similar to the normal adrenocortical tissue, cortical nodules and adrenocortical hyperplasia have tight junctions (cohesion factor, 4 to 5), and the smearing will produce cohesive fragments with numerous burst cells releasing oil droplets and naked nuclei in the background of the smears.38 Neoplastic adrenocortical nodules have defective junctions (cohesion factor, 0 to 2), and smearing will produce dyscohesive single cells with retained cytoplasm. The general trend toward the malignant end of the spectrum is less cytoplasmic lipids, higher nuclear grade, multinucleation, high proliferation index (MIB1), vimentin expression, a necrotic background, and large tumor size (> 5 cm) in radiology imaging. Cytomorphologically, there are overlapping features between adenoma with nuclear atypia (Figs. 7.8–7.9) and carcinoma of well-differentiated type. However, at the two ends of the spectrum, benign adrenocortical nodules (Figs. 7.5–7.6)28,38 and poorly differentiated adrenal cortical carcinoma (Figs. 7.14–7.15) can be separated. The current histologic criteria of separating adrenal cortical adenoma from carcinoma based on size and weight is reminiscent of the recent past histological practice of regarding small, clear cell renal cell carcinomas as clear cell renal cell adenomas, and is not scientifically sound. In the meantimes, what can cytopathologists do? As shown in Diagram 7.1, the first author uses the following strategy: 1) Aspirates with cohesive fragments with numerous burst cells and lipid background are reported as “benign adrenocortical nodule”38 if unilateral and “hyperplasia” if bilateral; 2) Dyscohesive single cells with lipid-rich cytoplasm and minimal nuclear atypia reported as “adenoma” if small (< 3.5 cm),

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Diagram 7.1

Strategy to triage adrenal cortical nodules in fine-needle aspiration biopsy.

and reported as “neoplasm” if large (> 5 cm); 3) Dyscohesive single cells with lipid-poor cytoplasm, reported as “neoplasm” if small and reported “carcinoma” if large (> 5 cm), high nuclear grade, necrotic background, supported by immunostains on cell block showing a high proliferation index by MIB1 and strong Vimentin expression.

TUMORS OF THE ADRENAL MEDULLA Tumors of the adrenal medulla consist of pheochromocytoma and tumors of the sympathetic nervous system, most frequently neuroblastoma, occasionally ganglioneuroblastoma, and rarely ganglioneuroma. Because chromaffin tissue identical to medullary cells and ganglion cells are normally found in other sites, tumors seen in the medulla are also present elsewhere. The most common locations of extraadrenal pheochromocytomas (designated as paragangliomas) are the retroperitoneum, mediastinum and the urinary bladder. Tumors of the sympathetic nervous systems can be found anywhere along the sympathetic chain, including the head and neck, mediastinum and retroperitoneum.

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Pheochromocytoma (Figs. 7.16–7.17) Pheochromocytomas of the adrenal medulla are tumors of neural origin and have their origins in the primitive neural crest. It has been called “the 10% tumor” — approximately 10% of cases are malignant, 10% occur in children, 10% are bilateral, and 10% are extraadrenal. About 30% of cases are hormonally active, secreting norepinephrine and epinephrine and causing hypertension.27 Aspiration biopsy of a hormonally active tumor is not without risk.20 In one of our cases of pheochromocytoma, the patient’s systolic blood pressure went up to 240 mm Hg during aspiration biopsy. Histologically, pheochromocytoma cells are arranged in alveolar (Zellballen), trabecular, or solid patterns.4 Most tumors are composed of intermediate to large-sized polygonal chromaffin cells, surrounded by sustencular cells (S100+). Some tumor may be composed of small cells resembling pheochromoblasts.4 Very large cells resembling ganglion cells are present in some tumors.4 Nuclear gigantism and hyperchromasia are common and are not an expression of malignancy,16 and there is no reliable morphologic markers of malignancy other than the presence of metastases.27 Fine-needle aspiration cytology of pheochromocytoma has been reported.2,8,12,14,25,28 The aspirate preparations contain tumor cells (cohesion factor, 3 to 4) in non-cohesive groupings (Fig. 7.16) and, less frequently, in cohesive groupings (Image 7.17). The aspirates consist of small bland cells interspersed with pleomorphic giant cells. The small bland cells have centrally or eccentrically located, round or ovoid nuclei and moderate amounts of finely granular cytoplasm, often poorly defined (Fig. 7.16B). Cytomorphologically, the small tumor cells with central nuclei resemble hepatocytes, while small cells with eccentric nuclei resemble carcinoid cells.32 If the tumor arises in the right adrenal or metastasizes to the liver, it will be difficult to establish the diagnosis on purely cytomorphologic grounds. In these instances, positive immunostainings for synaptophysin and chromogranin will be able to distinguish pheochromocytoma cells from hepatocytes, which are Hepar-1 positive.

Neuroblastic Tumors In 1999, the International Neuroblastoma Pathology Committee (INPC), led by Shimada, established a morphologic classification (Table 7.1) that was prognostically significant, biologically relevant and reproducible.30

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Undifferentiated

Poorly Differentiated

Neuroblasts

Neuroblasts Neuropils DN < 5%

Gangioneuroblastoma Differentiating Neuroblasts Neuropils↑ DN > 5% At periphery: ganglioneuromatous stroma < 50%

Nodular Neuroblasts Neuropils Ganglions Composite Schwannian stromapoor and stroma-rich background

Intermixed Neuroblasts Neuropils Ganglions Schwannian stroma-rich background

Ganglioneuroma Maturing Individual neuroblasts merge into immature ganglion cells

Matured Mature ganglions and mature Schwannian stroma

Ganglioneuromatous stroma > 50%

DN: Differentiated neuroblasts have distinct nucleolus and scant cytoplasm. Nodular: Nodules of neuroblastoma surrounded by gangioneuromatous stroma. Intermixed: Neuroblastoma intermixed with gangioneuromatous stroma.


Neuroblastoma


INPC Classification of Neuroblastic Tumors

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Table 7.1

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The important features of this classification include: 1) Degree of neuroblast differentiation (differentiated favorable); 2) Schwannian stromal development (stroma-rich favorable); 3) Mitosis-karyorrhexis index (MKI) (lower MKI favorable); 4) Growth pattern (without nodular pattern, favorable); and 5) Age (< 18 months favorable). Using these components, children with neuroblastomas can be classified into the following groups: • Favorable histologic group ◦ Any age with stroma-rich tumors and without a nodular growth pattern ◦ Age < 18 months with stroma-poor tumors, an MKI < 200/5000, and differentiated or undifferentiated neuroblasts ◦ Age < 60 months with stroma-poor tumors, an MKI < 100/5000, and differentiated neuroblasts • Unfavorable histologic group ◦ Any age, with stroma-rich tumors, and a nodular growth pattern ◦ Any age, with stroma-poor tumors, undifferentiated or differentiated neuroblasts, and MKI > 200/5000 ◦ Age > 18 months, with stroma-poor tumors, undifferentiated neuroblasts, and MKI/5000 > 100 ◦ Age > 18 months, with stroma-poor tumors, differentiated neuroblasts, and MKI/5000 = 100−200 ◦ Age > 60 months, with stroma-poor tumors, differentiated neuroblasts, and an MKI/5000 < 100 In 2001, this classification was evaluated retrospectively and correlated with the outcome in 295 patients with neuroblastoma who were treated by the Children’s Cancer Group.31

Neuroblastoma (Fig. 7.18) Neuroblastomas of the adrenal medulla are highly aggressive tumors and 80% of the patients are younger than 5 years. Rarely, it can occur in adults. It is the most common tumor in children under 1-year old, with 500 new cases per year in the United States.35 Over 25% occur in adrenal medulla, and the remainder along the sympathetic chain (neck, posterior mediastinum, paravertebral and retroperitoneum). In the adrenal medulla, it arises from

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the primitive neuroblasts or sympathetic ganglia. They are almost always unilateral. These tumors frequently contain foci of calcification which can be visualized during imaging studies. In most cases, an elevated level of catecholamines can be demonstrated in patients’ urine. Thirty percent of neuroblastomas regress or mature to ganglioneuroma. As the neuroblasts mature toward ganglions, Schwann cells appear and start to myelinate the axons, producing Schwannian stroma.4 Grossly, neuroblastomas are nonencapsulated and infiltrate the surrounding tissue. Histologically, the tumor are composed of small cells with little, poorly defined cytoplasm and 25–35% have Homer-Wright pseudorosettes. The tumor may have alveolar or pseudovascular appearance due to hemorrhage and may have prominent calcification. Necrosis is common.4,27 Immunohistochemically, the tumor cells express chromogranin, synaptophysin and neurofilament.4,27 Ultrastructurally, the neuroblasts contain neurosecretory granules with synaptic endings. Neuropils are unmyelinated axons containing neurofilaments and microtubules. The center of Homer-Wright pseudorosettes is composed of complex interdigitating meshwork of neuropils.4 The aspirate preparations contain small tumor cells in loose groupings and as solitary cells. They have very little or no recognizable cytoplasm and have small round, ovoid, spindle or irregular-shaped nuclei with coarsely clumped chromatin and indistinct nucleoli. Tumor cells in rosette or organoid arrangements may be seen.11,16,21 The cytologic appearance of this tumor resembles that of small cell malignant neoplasms of childhood of other origins, such as embryonal rhabdomyosarcoma and Ewing’s sarcoma.32,35 Tumor cells in an organoid arrangement with common cell borders or in a rosette formation may be seen in this tumor, but they do not show nuclear molding. Immunohistochemistry may be needed in difficult cases.

Ganglioneuroblastoma (Fig. 7.19) Ganglioneuroblastomas have a degree of differentiation that is intermediate between neuroblastoma and ganglioneuroma. The tumor occurs much more frequently in the posterior mediastinum and retroperitoneum than the adrenal medulla. It is placed here because of its link to neuroblastoma. Most tumors are seen in young children but may occur in adults.

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These tumors are often encapsulated and have a lobulated appearance. Focal deposits of calcium are commonly seen. As shown in Table 7.1, histologically, this group of tumor is subdivided into two groups: nodular: grossly visible nodules composed of neuroblastoma cells surrounded by ganglioneuromatous background; and intermixed: nest of neuroblastoma intermixed with a ganglioneuromatous background. By definition, ganglioneuromatous stroma constitutes > 50% of the tumor. The intermixed group has better prognosis than the nodular group, because the nodules represent foci of rapidly proliferating neuroblasts. The aspirate preparations show that neuroblasts and ganglion cells coexist in a background of various proportions of neuropils and Schwannian stroma. The neuroblasts are intermingled with much larger ganglion cells in different stages of maturation from differentiated neuroblasts. Lipofuscin pigment may be seen in the cytoplasm of some ganglion cells. A variable number of spindle cells (i.e. Schwannian stroma), as seen in ganglioneuroma, is present in the background.

Ganglioneuroma (Figs. 7.20–7.21) Ganglioneuromas represent the fully differentiated members of the neuroblastic tumors and are invariably benign. They occur in old persons. They can be multiple. Similar to ganglioneuroblastomas, they occur much more frequently in the posterior mediastinum and retroperitoneum than the adrenal medulla. These tumors are encapsulated and curable by excision. Catecholamine synthesis by the ganglions is an almost constant feature of all tumors, and, in most cases, catecholamine precursors and metabolites can be demonstrated in the urine. Histologic examination shows islands of ganglion cells, which may be multinucleated, surrounded by neuromatous stroma. The aspirate preparations contain ganglion cells intermingled with spindle cell stroma. Some ganglion cells are gigantic and have large round or ovoid nuclei, prominent nucleoli, and an abundance of dense cytoplasm. Other ganglion cells have several peripherally placed nuclei. Occasional loose groups of maturing ganglion cells with relatively scanty cytoplasm may also be present. The elongated or spindle-shaped nuclei of spindle cells are often in parallel or in polar arrangements. The fibrillary material between the elongated or spindle-shaped nuclei resembles that seen in Schwanomas.

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Adrenal Myelolipoma (Fig. 7.22) Myelolipoma is heterotopic bone marrow occurring as a mass lesion. It is found primarily within the adrenal gland but can occur in the presacral,39 mediastinal, perirenal, hepatic, gastric and paravertebral regions.9 They can be an incidental finding or grow into a massive size in the retroperitoneum that may be confused with well-differentiated liposarcoma.13 They are seen equally in middle-aged men and women. Adrenal myelolipoma diagnosed by fine-needle aspiration cytology have been reported.3,29 The aspiration preparation of myelolipoma in Diff-Quik is identical to a normal bone marrow aspirate, i.e. trilineage hematopoietic cells in various stages of maturation and marrow fat. However, if only Papanicolaou stain is used, myelolipoma had been misinterpreted as rare giant tumor cells (megakaryocytes) in a background of marked acute (neutrophils) and chronic (eosinophils and lymphocyte-looking normablasts and immature myelocytes) inflammation.

REFERENCES 1. Aubert S, Wacrenier A, Leroy X, et al. (2002) Weiss system revisited — A clinicopathologic and immunohistochemical study of 49 adrenocortical tumors. Am J Surg Pathol 26:1612–1619. 2. de Agustin P, Lopez-Rios F, Alberti N, Perez-Barrios A. (1999) Fine-needle aspiration biopsy of the adrenal glands: A ten-year experience. Diagn Cytopathol 21:92–97. 3. de Blois GG, DeMay RM. (1985) Adrenal myelolipoma diagnosis by computedtomography-guided fine-needle aspiration. A Case Report. Cancer 55:848–854. 4. DeLellis RA, Mangray S. (2004) In: Mills SE, et al. (eds), Sternberg’s Diagnostic Surgical Pathology, 4th ed. New York, Lippincott Williams & Wilkins. 5. Deodhare S, Sapp M. (1997) Adrenal histoplasmosis: Diagnosis by fine-needle aspiration biopsy. Diagn Cytopathol 17:42–44. 6. Dusenbery D, Dekker A. (1996) Needle biopsy of the adrenal gland: Retrospective review of 54 cases. Diagn Cytopathol 14:126–134. 7. Erlandson RA. (1994) Diagnostic Transmission Electron Microscopy of Tumors. Raven Press, New York, p. 555. 8. Fassina AS, Borsato S, Fedeli U. (2000) Fine-needle aspiration cytology of adrenal masses. Cytopathol 11:302–311.

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9. Fowler MR, Williams RB, Alba JM, Byrd CE. (1982) Extra-adrenal myelolipoma compared with extramedullary hematopoietic tumors. Am J Surg Pathol 6: 363–374. 10. Gaffey MJ, Traweek ST, Mills S, et al. (1992) Cytokeratin expression in adrenal cortical neoplasia: An immunohistochemical and biochemical study with implications for the differential diagnosis of adrenocortical, hepatocellular and renal cell carcinoma. Hum Pathol 23:144–153. 11. Geisinger KR, Silverman JF, Wakely PE. (1994) Pediatric Cytopathology. ASCP Press, Chicago, pp. 307–312. 12. Gonzalez-Campora R, Otal-Salaverri C, Planea-Flores P, et al. (1988) Fine-needle aspiration cytology of paraganglionic tumors. Acta Cytol 32:386–390. 13. Hruban RH, Bhagavan BS, Epstein JI. (1989) Massive retroperitoneal angiomyolipoma — A lesion that may be confused with well-differentiated liposarcoma. Am J Clin Pathol 93:805–808. 14. Katz RL, Patel S, Mackay B, et al. (1984) Fine-needle aspiration cytology of the adrenal gland. Acta Cytol 28:269–282. 15. Katz RL, Shirkhoda A. (1985) Diagnostic approach to incidental adrenal nodules in the cancer patient. Cancer 55:1995–2000. 16. Koss LG, Woyke S, Olszewski W. (1984) Aspiration Biopsy: Cytologic Interpretation and Histologic Bases. Igaku-Shoin, New York. 17. Lack EE. (1997) Tumors of the Adrenal Gland and Extra-adrenal Paraganglia. Armed Forces Institute of Pathology, Washington, D.C. 18. Levin NP. (1981) Fine-needle aspiration and histology of adrenal cortical carcinoma. A case report. Acta Cytol 25:421–424. 19. Luning M, Neuser D, Kursawe R, et al. (1983) CT guided percutaneous fineneedle biopsy in the diagnosis of small adrenal tumors. Eur J Radiol 3:358–361. 20. McCorkell SJ, Niles NL. (1985) Fine-needle aspiration of catecholamineproducing adrenal masses: A possibly fatal mistake. AJR 145:113–114. 21. Miller TR, Bottles K, Abele JS, et al. (1985) Neuroblastoma diagnosed by fineneedle aspiration biopsy. Acta Cytol 29:461–468. 22. Montali G, Solbiati L, Bossi MC. (1984) Sonographically guided fine-needle aspiration biopsy of adrenal masses. AJR 143:1081–1084. 23. Mostofi FK, Davis CJ Jr. (1983) Pathology of urologic cancer. In: Javadpour N (ed.), Principles and Management of Urologic Cancer. Baltimore, Williams & Wilkins. 24. Nguyen GK. (1987) Percutaneous fine-needle aspiration cytology of kidney and adrenal. Pathol Annu 22:163–191 (Part 1). 25. Nguyen GK. (1982) Cytopathologic aspects of adrenal pheochromocytoma in a fine-needle aspiration biopsy. Acta Cytol 26:354–358.

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26. Powers CN, Rupp GM, Maygarden SI, et al. (1991) Fine-needle aspiration cytology of adrenal cryptococcosis: A case report. Diagn Cytopathol 7:88–91. 27. Rosai J. (2004) Adrenal gland and other paraganglia. In: Rosai J (ed.), Rosai and Ackerman’s Surgical Pathology, 9th ed. St. Louis, Mosby. 28. Saboorian MH, Katz RL, Charnsangavej C. (1995) Fine-needle aspiration cytology of primary and metastatic lesions of the adrenal gland. A series of 188 biopsies with radiologic correlation. Acta Cytol 39:843–851. 29. Settakorn J, Sirivanichai C, Rangdaeng S, et al. (1999) Fine-needle aspiration cytology of adrenal myelolipoma: Case report and review of the literature. Diagn Cytopathol 21:409–412. 30. Shimada H, Ambros IM, Dehner LP, et al. (1999) Terminology and morphologic criteria of neuroblastic tumors. Recommendation by the International Neuroblastoma Pathology Committee. Cancer 86:349–363. 31. Shimada H, Umehara S, Monobe Y, et al. (2001) International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: A report from the Children’s Cancer Group. Cancer 92:2451–2461. 32. Silverman JF, Dabbs DJ, Ganick DJ, et al. (1988) Fine-needle aspiration cytology of neuroblastoma, including peripheral neuroectodermal tumor, with immunocytochemical and ultrastructural confirmation. Acta Cytol 32:367–376. 33. Skidham VB, Galindo LM. (1994) Pheochromocytoma. Cytologic findings on intraoperative scrape smears in five cases. Acta Cytol 43:207–213. 34. Suen KC, Chan NH. (1992) Fine-needle aspiration biopsy of the adrenalgland — Cytological features and clinical-applications. Endocr Pathol 3: 173–181. 35. Triche TJ, Askin FB. (1983) Neuroblastoma and the differential-diagnosis of small-cell, round-cell, blue-cell tumors. Hum Pathol 14:569–595. 36. Wadih GE, Nance KV, Silverman JF. (1992) Fine-needle aspiration cytology of adrenal gland. 50 biopsy in 48 patients. Arch Pathol Lab Med 116:841–846. 37. Weiss LM. (1984) Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 8:163–169. 38. Wu HHJ, Cramer HM, Kho J, Elsheikh TM. (1998) Fine-needle aspiration cytology of benign adrenal cortical nodules. A comparison of cytologic findings with those of primary and metastatic adrenal malignancies. Acta Cytol 42:1352–1358. 39. Yang GCH, Coleman B, Daly JM, Gupta PK. (1992) Presacral myelolipoma: Fine-needle aspiration cytology, immunohistochemical, histochemical studies, and review of the literature. Acta Cytol 36:932–936. 40. Yee ACN, Gopinath N, Ho CS, Tao LC. (1986) Fine-needle aspiration biopsy of adrenal tuberculosis. J Can Assoc Radiol 37:287–289.

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Fig. 7.1 Posterior approach was used in a CT-guided fine-needle aspiration biopsy of a 3.5 cm left adrenal nodule.

Fig. 7.2 Histology of the adrenal gland. (A) Top to bottom: zona glomerulosa, zone fasciculata, zona reticularis (lipofuscin pigments) and medulla; (B) Zona fasciculata resembles adrenocortical hyperplasia. The cells are tightly bound, and will burst but not be separated into single cells by the smearing. The cytoplasm is filled with lipid droplets of glucocorticoids.

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Fig. 7.3 Cryptococcosis. (A) Groups of Langerhans giant histiocytes. UFP, 100×; (B) High magnification reveals spores associated with Langherhans giant cells. UFP, 400×; (C) Variablesized thin wall spores with narrow based budding surround by halos. DQ, 400×; (D) The capsule surround the spores is composed of mucin. Mucicarmine, 1000×.

Fig. 7.4 Bilateral adrenal metastatic renal cell carcinoma (RCC). (A) Fragments of lipidrich cells, but no background lipid droplets. DQ, 400×; (B) Lipid-rich cells with tiny nucleoli resemble adrenal cortical cells. UFP, 400×; (C) Negative inhibin (adrenal cortical marker) immunostain on cell block. 100×; (D) Positive CD10 (RCC marker) immunostain on cell block. 400×.

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Fig. 7.5 Adrenocortical hyperplasia, in a patient with bilateral adrenal enlargement. (A) Lipid droplets from cells (bottom) bursted by the smearing. DQ, 400×; (B) Tightly bound intact cells with intracytoplasmic lipid droplets. DQ, 400×; (C) Background lipid droplets are invisible in UFP, 100×; (D) Cohesive cells with vacuolated cytoplasm showing anisonucleosis. UFP, 400×.

Fig. 7.6 Benign adrenocortical nodule, incidental finding in a metastatic work-up. (A) Cohesive lipid-rich cells associated with background lipid droplets. DQ, 100×; (B) Naked nuclei and lipid droplets in the background. DQ, 400×; (C) Cohesive cells with indistinct cell borders. UFP, 100×; (D) Anisonucleosis (variation of nuclear size) is present. UFP, 400×.

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Fig. 7.7 Adrenocortical adenoma, 3 cm. (A) and (B) Dyscohesive single cells with cytoplasm containing tiny lipid droplets (arrows). DQ, 400×; (C) Adrenal cortical cells with tiny intracytoplasmic lipid droplets. UFP, 400×; (D) Artifactual coalescence of lipid droplets into a large lipid droplets. UFP, 400×.

Fig. 7.8 Adrenocortical adenoma, 4.5 cm. (A) Numerous lipid droplets scattered in the background in DQ, 100×; (B) Lipid-rich cells next to a giant lipid-poor cell with large nucleus. UFP, 400×; (C) Large nuclei with variation in nuclear size. UFP, 1000×; (D) Adrenalectomy specimen show adrenal cortical adenoma. H&E, 100×.

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Fig. 7.9 Adrenocortical adenoma, 3.5 cm. (A) Single tumor cells and tumor fragment. DQ, 40×; (B) Pleomorphic lipid-poor cells associated with metachromatic matrix. DQ, 400×; (C) Barely noticeable lipid droplets seen only under oil immersion. DQ, 1000×; (D) Histology of resected tumor. H&E, 400×.

Fig. 7.10 Adrenocortical carcinoma, well-differentiated, small cell type, 10 cm. (A) Dyscohesive small single cells with retained lipid-poor cytoplasm. DQ, 40×; (B) Lipid-poor tumor cells have eccentric nuclei and dense cytoplasm. DQ, 400×; (C) Binucleated cells (arrows) are present, resembling hepatocytes. UFP, 400×; (D) Small eosinophilic cells in cell block. H&E, 400×. Capsular invasion is present in resected tumor.

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Fig. 7.11 Adrenocortical carcinoma, well-differentiated, small cell type, 12 cm. (A) Numerous dyscohesive single cells. UFP, 40×; (B) Cells with eccentric nuclei. Arrow points to a multinucleated cell. UFP, 400×; (C) Sparse lipid droplets are present mainly in the background. DQ, 400×; (D) Small cytoplasm and eccentric small bland nuclei. UFP, 1000×.

Fig. 7.12 Adrenocortical carcinoma, well-differentiated, large cell type, 8 cm. (A) No lipid droplets seen in the background at low power. DQ, 40×; (B) Lipid droplets seen in the background at high power. DQ, 400×; (C) Numerous single tumor cells arranged along capillaries. UFP, 100×; (D) Eccentrically nuclei and abundant cytoplasm are present. UFP, 400×.

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Fig. 7.13 Adrenocortical carcinoma, well-differentiated, large cell type, 9 cm. (A) No lipid droplets in the background. DQ, 100×; (B) Solitary cells arranged along vascular network. UFP, 100×; (C) Large lipid-poor cells with eccentric nuclei. UFP, 400×; (D) Furhman grade 3 nuclei. UFP, 1000×.

Fig. 7.14 Adrenocortical carcinoma, poorly differentiated cell type, 10 cm. (A) Dyscohesive solitary tumor cells with retained cytoplasm. UFP, 40×; (B) Eccentric nuclei and wide variation in nuclear size. UFP, 400×; (C) A multinucleated giant tumor cell, Furhman grade 4 nuclei. UFP, 400×; (D) Lipid droplets are present in the tumor cell cytoplasm. DQ, 1000×.

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Fig. 7.15 Adrenocortical carcinoma, poorly differentiated cell type. (A) Multinucleated tumor cells in a lipid-poor background. DQ, 400×; (B) High magnification shows minute lipid droplets. DQ, 1000×; (C) Giant tumor cells scattered among small tumor cells. UFP, 100×; (D) Ground glass cytoplasm and eccentric nucleus with macronucleoli. UFP, 1000×.

Fig. 7.16 Pheochromocytoma of the adrenal medulla. (A) A giant tumor cell among numerous small tumor cells (1× RBC). DQ, 100×; (B) Small tumor cells have small bland nuclei. UFP, 400×; (C) A multinucleated giant tumor cell with coarse nuclear chromatin. UFP, 400×; (D) Histology shows “Zellballen” pattern. H&E, 40×.

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Fig. 7.17 Pheochromocytoma of the adrenal medulla, 2.5 cm. (A) Cohesive pleomorphic cells with indistinct cell borders. DQ, 100×; (B) Unlike adrenal cortical cells, lipid droplets are absent. DQ, 400×; (C) Cohesive fragment of pleomorphic cells with indistinct cell borders. UFP, 400×; (D) Chromogranin (+) is limited to medullary tumor. Left, 100×; right, 400×.

Fig. 7.18 Neuroblastoma of the adrenal medulla from a 4-year-old male. (A) A few pseudorosettes in meshwork of neuritis and neuroblasts. DQ, 40×; (B) Pseudorosette (arrow) in meshwork of neuritis and neuroblasts. UFP, 100×; (C) Medium power of area marked by arrow in (B). UFP, 400×; (D) High power of the pseudorosette shows fibrillary center. UFP, 1000×.

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Fig. 7.19 Ganglioneuroblastoma of the adrenal, from a 16-year-old female. (A) HomerWright rosettes and scattered ganglion cells (arrow). DQ, 100×; (B) Red arrow points to a ganglion and green arrows point to rosettes. UFP, 100×; (C) High power of the ganglion cell pointed by the red arrow. UFP, 400×; (D) High power of one of the rosettes showing fibrillary center. UFP, 1000×.

Fig. 7.20 Ganglioneuroma, from a 32-year-old male with a retroperitoneal mass. (A) A curved fine needle core of flexible Schwannian stroma. DQ, 40×; (B) Close-up of the Schwannian stroma reveal ganglion cells (arrow). DQ, 200×; (C) A ganglion cell popped out by the smearing. DQ, 400×; (D) Correlating histology. Arrow points to a ganglion cell. Cell block, H&E, 200×.

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Fig. 7.21 Ganglioneuroma, from a 18-year-old girl with posterior mediastinal mass. (A) Ganglion cell popped out from the Schwannian stroma. UFP, 40×; (B) Ganglion cells without the spindly stroma resemble oncocytic cells. UFP, 400×; (C) Schwannian stroma consists of loosely packed bland spindly nuclei. UFP, 400×; (D) Correlating histology. Resected tumor. H&E, 100×.

Fig. 7.22 Adrenal myelolipoma. (A) Hematopoietic cells and marrow fat, identical to bone marrow. DQ, 100×; (B) Trilineage hematopoitic cells surround a megakaryocyte. DQ, 400×; (C)–(D) Myeolipoma sometimes misinterpreted as “Rare malignant cells in marked inflammation” in transparent stains; (C) UFP, 100×; (D) UFP, 400×.

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CHAPTER 8

Primary Retroperitoneal Mass Lesions

The retroperitoneal space is the part of the body least accessible to conventional diagnostic investigations and was, until the mid 1980s, accessible only by laparotomy in many instances. With the development of ultrasonography and CT-scan, which can ensure accurate placement of a needle within a lesion, transabdominal fine-needle aspiration biopsy provided information on the nature of a retroperitoneal mass otherwise obtainable only by laparotomy.7,10 In one series of 106 patients with abdominal lesions, percutaneous fine-needle aspiration biopsy was instrumental in avoiding 61 planned invasive investigations and 11 surgical explorations.8 The retroperitoneal space is that indefinite area in the lumbar and iliac regions that lies between the peritoneum and the posterior abdominal wall formed by the vertebral spine, psoas, and quadratus lumbora muscles. It extends superoinferiorly from the diaphragm and 12th ribs to the levator muscles of the pelvic diaphragm. An actual and a potential space exists within the retroperitoneum. The actual space consists of several organs, including the kidneys, pancreas, adrenals, and a portion of the duodenum, and the large blood vessels, including the aorta and vena cava. The potential space in normal persons is limited and refers to the space between the organs that contains loose areolar tissue, through which pass the nerves, smaller blood vessels, lymphatics and the ureters. Numerous small lymph nodes are normally found along the aorta and in the iliac fossa. This potential space can be greatly expanded under abnormal conditions and allows both primary and metastatic tumors to grow silently before clinical signs and symptoms appear (Fig. 8.1). 234

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In our daily work, the common retroperitoneal mass lesions visualized by imaging techniques include: 1. Nonneoplastic mass lesions — mycobacterial infections, abscess, and idiopathic retroperitoneal fibrosis. 2. Primary tumors a. Sarcomas — fibromatosis, fibrosarcoma, leiomyosarcoma, liposarcoma, rhabdomyosarcoma, angiosarcoma, malignant fibrous histiocytoma, hemangiopericytoma and Ewing’s sarcoma. b. Neurogenic tumors — schwannoma, neurofibroma, malignant peripheral nerve sheath tumor, paraganglioma, neuroblastoma, ganglioneuroma and ganglioneuroblastoma. c. Germ cell tumors — seminoma, embryonal carcinoma and yolk sac tumor. d. Malignant lymphomas. e. Other tumors — chordoma, alveolar soft tissue sarcoma and synovial sarcoma. 3. Cancers metastatic to the retroperitoneal lymph nodes. 4. Cancers of the pancreas, kidneys and adrenals. On the basis of our experience and the series reported in the literature, four-fifths of the retroperitoneal neoplasms are malignant,35 and metastatic neoplasms are more frequent than primary tumors. Benign tumors and tumor-like lesions arising in the retroperitoneal space are far less common than the malignant tumors and constitute only 15 to 17% of all retroperitoneal neoplasms.6 Cancers metastatic to the retroperitoneal nodes and cancers of the pancreas, kidneys and adrenals will not be discussed in this chapter.

NONNEOPLASTIC MASS LESIONS Nonneoplastic mass lesions of the retroperitoneum are usually those conditions that involve the paraaortic lymph nodes, such as tuberculosis. Other benign mass lesions, such as abscesses, and idiopathic retroperitoneal fibrosis may also be seen in this region.

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Tuberculosis and other Mycobacterial Infections Tuberculosis seen in the retroperitoneum commonly involves the paraaortic lymph nodes or bodies of vertebrae. Affected lymph nodes may become adherent to one another and form a large multinodular mass that can be confused with metastatic carcinoma. Tuberculosis of the spinal column is known as Pott’s disease. The exudate from these lesions may accumulate in the soft tissue in the paravertebral region, where it excites little inflammation (cold abscess). Radiographically, tuberculosis of the vertebrae may present as a paravertebral mass with bony destruction, mimicking malignancy. The exudate in a cold abscess may gravitate along the sheath of the psoas muscle. The senior author had encountered two such cases, of which the initial clinical impressions on the basis of radiographic findings were a primary or metastatic cancer. Aspiration biopsy readily resolved these diagnostic problems. Cytologic findings were essentially the same as those of tuberculous lesions elsewhere. The aspirates from the tuberculous lesions in immunocompetent patients contain well-formed granulomas composed of epithelioid histiocytes and lymphocytes in a necrotic background that demonstrate rare acid fast bacilli (Fig. 8.2). The aspirate from immunodeficient patients such as AIDS patients will show suppurative lymphadenitis with or without poorly-formed granulomas containing numerous acid fast bacilli. In addition, these patients are prone to opportunistic infections, such as Mycobacterial avium intracellulare, which are ingested by an army of macrophages. Those macrophages are unable to be transformed into epithelioid histiocytes due to the deficiency of T-helper lymphocytes. Numerous acid-fast bacilli can be seen as negative images in the macrophages by Diff-Quik stain, before confirmation by Ziehl-Neelsen stain (Fig. 8.3).

Abscess Most abscesses of the retroperitoneum are of bacterial pyogenic origin. They may be part of a systemic inflammatory process or of suppurative abdominal diseases, such as pyelonephritis and diverticulitis, or may appear following trauma or surgery. Occasionally, abscesses of the retroperitoneum are caused by Actinomyces israelii. The aspirates from the pyogenic abscesses are pus-like

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and contain heavy neutrophilic inflammatory exudate and nuclear debris. Special stains and cultures of the purulent material sometimes permit specific identification of the causative organism. Material aspirated from an actinomycotic abscess contains numerous neutrophils, phagocytic macrophages and reactive fibroblasts. The organisms appear as colonies (granules), which are composed of delicate, branching, intertwined, Gram-positive filaments with granular centers (Fig. 8.4).

Idiopathic Retroperitoneal Fibrosis (Fig. 8.5) Retroperitoneal fibrosis is an uncommon disease characterized pathologically by proliferation of fibrous tissue and various degrees of chronic inflammation in the retroperitoneal space.53 The etiology is unknown, although methysergide, tumors, aneurysms, surgery and radiotherapy can produce similar fibrosis. The fibrosis typically begins below the aortic bifurcation at the level of the sacral promontory or the 4th or 5th lumbar vertebra, and spreads along the anterior surface of the spine toward the renal hila, where, on rare occasions, it may envelope the renal pelvis and may involve the ureters and other structures.53 Nowadays the diagnosis can be established with near-certainty by CT-scan and confirmed by fine-needle aspiration biopsy. Prompt diagnosis improves the chance of preserving renal function, preventing involvement of other organs.35 The disease can be treated effectively with corticosteroids.29 In steroid-resistant cases, surgery (ureterolysis, stent replacement) may be considered. Long-term follow-up is recommended in all patients. Aspiration cytology findings have been reported.49 The aspirate preparations showed fibrous tissue and inflammatory cells, which occasionally occur together but often are separate. The inflammatory cells are predominantly small lymphocytes, with occasional plasma cells, histiocytes and neutrophils. The first author had encountered a case at the NYU medical center that is illustrated in Fig. 8.5.

SARCOMAS The retroperitoneum is one of the most frequent sites for the development of sarcomas, but their benign counterparts are relatively rare.6 They arise in

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the potential retroperitoneal space, and symptoms secondary to retroperitoneal neoplasms are vague and appear late in the course of the disease. The prognosis of retroperitoneal sarcomas is generally poor.44 Sarcomas that may occur in the retroperitoneum include fibrosarcoma, leiomyosarcoma, liposarcoma, rhabdomyosarcoma, angiosarcoma, malignant fibrous histiocytoma, hemangiopericytoma and Ewing’s sarcoma. Malignant nerve sheath tumor is discussed in the section on neurogenic tumors in this chapter. In our daily work, it is frequently possible to diagnose a tumor as sarcoma, although specific categorization may be difficult due to limited material available for examination in some cases.26 The use of fine-needle aspiration biopsy combined with ancillary studies are reported to be 95% sensitive and specific in the hands of experienced cytopathologists.12,30,45,54

Fibromatosis (Fig. 8.6) Fibromatosis (desmoid tumors) may arise after trauma, in the scar of a surgical excision, or post-radiation, most commonly at the ages 15 to 39 years.43 On CT scan, deep fibromatosis is a unicentric circumscribed mass usually involving the omentum or mesentery. Histologically, fibromatosis resembles scar tissue with an infiltrative growth pattern. The cellularity is between exuberant fibrous proliferations and low grade fibrosarcomas with lobulated proliferation of myofibroblasts.43 Ultrastructurally, tumor cells have the features of myofibroblasts. Aspiration cytology findings have been reported.38 In the aspirate preprations, cohesive fragments of mesenchymal tissue composed of spindle cells embedded in abundant collagenous matrix are found, with a few scattered single spindle cells in the background. The spindle cells have no cytologic atypia.

Fibrosarcoma Fibrosarcoma is less common nowadays, because what were formerly called fibrosarcomas are now called fibromatosis, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor or monophasic synovial sarcoma. Fibrosarcomas are relatively uncommon in the retroperitoneum. Histologic examination shows fibroblastic proliferation in a herringbone pattern. The

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tumor cells are immunoreactive only to vimentin. The fibroblastic nature is more difficult to recognize in the poorly differentiated tumors, which are composed of pleomorphic neoplastic cells. Cytomorphologically, fibrosarcomas can be classified into two types: 1. Well-differentiated cell type (low grade) (Fig. 8.7). Tumor cells (cohesion factor, 0 to 1) lie singly. The spindle cells have oval nuclei, with variation in size and a slightly coarse chromatin and have little recognizable cytoplasm. Multinucleated tumor cells are absent. Nucleoli are inconspicuous. 2. Poorly-differentiated cell type (high grade) (Fig. 8.8). The nuclei are variable in size and shape and show coarse clumping of chromatin. Conspicuous nucleoli are present in some tumor cells. Multinucleated tumor cells with moderate amounts of well-defined cytoplasm may be seen in aspirate preparations from some tumors. For such cases, the aspirate preparations are similar to pleomorphic rhabdomyosarcoma, pleomorphic liposarcoma and malignant fibrous histiocytoma. The latter tumors normally contain many multinucleated tumor cells. Immunostaining is often needed for differential diagnoses.

Leiomyosarcoma (Figs. 8.9–8.13) Leiomyosarcomas are the second most common sarcoma in the retroperitoneum, next only to liposarcoma. Most of them arise from the wall of arteries and veins, ranging from large ones to arterioles and venules. They are usually solid and bulky masses but have a particular tendency to undergo massive cystic degeneration when occurring in the retroperitoneum. The prognosis is generally poor. Histologically, the palisading spindle cells with cigar-shaped, blunt-ended nuclei are arranged in a fascicular growth pattern. The tumor cells are immunoreactive to desmin, smooth muscle actin and vimentin, and must be negative for c-Kit. Some of tumors previously regarded as leiomyomas of the small intestine and epithelioid leiomyosarcomas of the stomach were found to be c-Kit positive, a marker, discovered in late 1990s, for gastrointestinal stromal tumor (see Chapter 10). Proliferative index using MIB1 immunostain on cell block correlates with mitotic counts on tissue sections, and generally correlates with biologic behavior. Interestingly, some leiomyosarcomas in immunosuppressed patients (AIDS and

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post-transplant) are found to be associated Epstein Barr virus.34 Ultrastructurally, numerous actin filaments with focal densites, pinocytotic vesicles and thick basal lamina are found. These are features of smooth muscle cells. Cytomorphologically, the tumors can be classified into three types:50 1. Well-differentiated cell type. Tumor cells occur singly (Fig. 8.9), in loose groupings (Fig. 8.10), and in cohesive groupings (Fig. 8.11). They have elongated or cigar-shaped nuclei with blunt ends and have either a little recognizable cytoplasm or small amounts of well-defined cytoplasm. The elongated nuclei are often in parallel or in polar arrangements. Blood vessels are sometimes present (Fig. 8.10C). 2. Round cell type (Fig. 8.12). Tumor cells occur in cohesive groupings. They have small round to ovoid nuclei with scanty cytoplasm embedded in a matrix that varies from being myxoid to fibrous. 3. Pleomorphic cell type (Fig. 8.13). Tumor cells (cohesion factor, 0 to 1) lie singly. They are spindle-shaped cells with tapered cytoplasm and ovoid, elongated, or irregular-shaped nuclei with variation in size and coarse clumping of chromatin. Many multinucleated tumor cells are usually present. The cytoplasm of mononuclear tumor cells is scanty and poorly defined, whereas the multinucleated tumor cells have moderate amounts of well-defined cytoplasm.

Liposarcoma (Figs. 8.14–8.18) Liposarcomas are the most frequent retroperitoneal sarcoma, and liposarcomas of the retroperitoneum are common tumors in adults. They are prone to grow in the perirenal regions. The low-grade liposarcomas grow slowly and usually attain massive size before they are diagnosed. Nowadays, liposarcomas are divided into three major types: 1) Well-differentiated/dedifferentiated; 2) Myxoid/round cell; and 3) Pleomorphic.16 The myxoid type is by far the most common. Mixed forms occur. Tumors of the well-differentiated and myxoid types belong to the category of low-grade liposarcomas.16 Aspiration cytology findings have been reported.37 In correlation with histopathology, these three types can also be recognized in aspirate preparations: 1. Well-differentiated cell type. The cytologic appearance of this type resembles that of lipoma, but the nuclei appear larger and more plump and

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irregular than those of benign fat cells (Fig. 8.14). Fat cells of welldifferentiated liposarcoma (cohesion factor, 3 to 4) are more variable in size. They occur in loose or cohesive groupings and are often intersected by a varying amount of fibrous or myxoid tissue. Variants of this type include dedifferentied well-differentiated liposarcoma, i.e. coexistence of well-differentiated liposarcoma with a malignant fibrous histiocytomalike component (Fig. 8.15), or leiomyosarcomatous component.19 2. Myxoid/Round cell type. Both types share the same cytogenetic and molecular characteristics. Therefore, they are now grouped together and are considered as the well-differentiated and poorly differentiated types of the same tumor.43 Both types have a myxoid background rich in polymucosaccharides. A. Myxoid type (Fig. 8.16). This type is intermediate in malignant behavior. The aspirate preparations show fragments of lipomatous tissue with chicken-wire vasculature in a metachromatic myxoid background. B. Round cell type (Fig. 8.17). This type frequently metastasizes. Small tumor cells (cohesion factor, 1 to 2) occur in loose groupings or as solitary cells. They resemble epithelial cells and have relatively regular, round or ovoid nuclei. The cytoplasm is well-defined, basophilic and vacuolated in Diff-Quik stained smears. 3. Pleomorphic cell type (Fig. 8.18). Pleomorphic liposarcoma constitutes only 5% of liposarcomas.14 It occurs in older individuals (63–70 years). Tumor cells (cohesion factor, 0 to 1) occur singly and, less commonly, in loose groupings. They are pleomorphic and have bizarre nuclei, frequently with prominent nucleoli. The cytoplasm of some tumor cells may contain multiple cytoplasmic vacuoles which are lipid-rich and stainable with oilred O. Multinucleated tumor cells are a common finding and may also have multiple small intracytoplasmic lipid vacuoles.

Rhabdomyosarcoma Embryonal rhabdomyosarcomas affect mainly pediatric patients. They are most often observed in the head and neck region, the genitourinary organs, and, less commonly, in the retroperitonium. When growing beneath a

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mucous membrane, they frequently form large polypoid masses, resembling a bunch of grapes, hence, the name botryoid rhabdomyosarcoma. Another variant, alveolar rhabdomyosarcoma, is also related to the embryonal type, and it may coexist with embryonal rhabdomyosarcoma. Histologic examination shows that the small tumor cells of the alveolar variant are seen separated in nests by connective tissue septa, whereas the tumor cells of the embryonal type occur in a diffuse pattern. Although differing in the histologic pattern, both forms are identical in cytologic appearance in aspirate preparations. Pleomorphic rhabdomyosarcomas are rare tumors that occur in adults. They are most often seen in the large muscles of the extremities, but may arise from abdomen/retroperitoneum, chest/abdominal wall and spermatic cord/testes.20 Occasionally, rhabdomyosarcomas containing components of both the embryonal and pleomorphic types are seen in adolescents. The tumors cells are immunoreactive to myogenin,33 desmin, myosin, myoD1 and vimentin. These findings are helpful in differentiating this tumor of the embryonal type from other pediatric small, round cell tumors, e.g. neuroblastoma, Ewing’s sarcoma and lymphomas.1 Aspiration cytology findings have been reported.2,3 In the aspirate preparations, three cytologic patterns of rhabdomyosarcomas are recognized: 1. Embryonal cell type (Figs. 8.19–8.20). Tumor cells (cohesion factor, 0 to 1) lie singly. They have small or medium-sized, round, ovoid or irregularshaped nuclei, with a single small nucleolus and two or more inconspicuous nucleoli. They often have no recognizable cytoplasm. Binucleated tumor cells, when found, are an important clue for the diagnosis of rhabdomyosarcoma.3 2. Pleomorphic cell type (Fig. 8.21). The tumor cells resembles rhabdomyoblasts with a ribbon-like cytoplasm. The tumor cells (cohesion factor, 0 to 1) lie singly. They are extremely pleomorphic, and measure from a few to over 100 µm in size. The nuclei are bizarre and tend to be pyknotic and eccentrically located. Multinucleated tumor cells with pleomorphic nuclei are common. Rare spindle tumor cells with intracytoplasmic crossstriations may be present. 3. Mixed embryonal and pleomorphic cell type. The tumors contain malignant cells seen in both the embryonal cell type and the pleomorphic cell

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type. Small tumor cells are intermingled with gigantic multinucleated tumor cells.

Angiosarcoma (Figs. 8.22–8.25) Angiosarcomas are occasionally seen in the retroperitoneum. They arise from the endothelial cells of blood vessels. Angiography usually demonstrates a highly vascular mass and the venogram may show an abrupt obstruction (Fig. 8.22). Histologic examination shows that the tumor cells proliferate in the vascular lumina within a reticulin sheath. They form communicating vascular channels. In the more solid areas, the tumor cells acquire an epithelioid phenotype, mimicking carcinomas; therefore, angiosarcomas are sometimes very difficult to recognize in fine-needle aspiration biopsy, especially in cases without the metachromatic matrix (Fig. 8.25). The aspirate preparations show that the tumor cells have round or ovoid nuclei with an irregular nuclear outline (Fig. 8.23D). These tumor cells are not connected by cell-junctions ultrastructurally; therefore, the sarcoma cells, even in epithelioid form, occur singly (cohesion factor, 0 to 1) and in loose groupings in aspirate preparations. Some tumor cells of angiosarcomas have elongated or spindle-shaped nuclei and well-defined cytoplasm. This is another helpful distinguishing feature from carcinoma. In addition, sarcoma cells are often entrapped within a metachromatic matrix (Fig. 8.23A, B), a clue to their mesenchymal nature. Immunohistochemically, the tumor cells express vimentin as well as endothelial markers, including CD31, CD34 and Factor VIII. Those with the epithelioid phenotype21 also are immunoreactive to cytokeratins and EMA.

Malignant Fibrous Histiocytoma (Figs. 8.26–8.28) Malignant fibrous histiocytoma (MFH) is the most common soft tissue sarcoma of late adult life with a male-to-female ratio of 2:1. The designation of these tumors is controversial.9,18,42,57 Some even question whether MFH should be a specific entity as it likely represents the final common pathways of various types of sarcomas by tumor progression,18 especially fibrosarcoma.8,58 There are several types, the most common type in the

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retroperitoneum being the storiform-pleomorphic type. Histologic examination shows that the tumors have two major components in various proportions: A component in which the fibroblast-like spindly cells are arranged in bundles or in storiform arrangement and a component of large, bizarre, often multinucleated histiocyte-like cells. Aspiraton cytology of this tumor has been reported.4,56 The aspirates are usually highly cellular. Tumor cells (cohesion factor, 1 to 2) occur singly and in loose groupings. The fibroblast-like cells that have spindle or irregular-shaped nuclei and small amounts of fragile cytoplasm are intermingled with plumper, or even gigantic, histiocyte-like cells that are often multinucleated. The large tumor cells display great variations in size and shape. They have large, round, ovoid, or irregular-shaped nuclei, and delicate, often poorly defined cytoplasm. The chromatin is coarsely granular, and the nucleoli are distinct. The proportion of fibroblast-like cells and histiocytelike cells varies. Sometimes, fibroblast-like cells predominant (Fig. 8.28B, C), with very scanty histiocyte-like plump cells (Fig. 8.28D). In some cases, minute lipid droplets are found in the cytoplasm and in the background of the smear from burst cells in Diff-Quik stained smears (Fig. 8.26B). Most of the tumor cells, including the giant tumor cells show positive immunostaining for vimentin. A few tumor cells show positive immunostaining for lysozyme, α-1-antitrypsin and/or α-l-antichymotrypsin.30

Hemangiopericytoma (Figs. 8.29–8.30) The term “hemangiopericytoma” formerly included a variety of spindle cell soft tissue tumors that manifested a branching and staghorn open vascular pattern on histology. Now the term is restricted to those immunoreactive to CD34, CD99 and vimentin, but negative for epithelial (monophasic synovial sarcoma), muscle and nerve sheath markers.9 The tumor cells have the ultrastructural features of pericytes and are located outside the basal lamina that wrap around capillaries and venules. Hemangiopericytoma usually presents as a slowly enlarging, painless deep-seated mass, often in the thigh, lower extremity, pelvic and retroperitoneum. They are commonly locally invasive. Twenty percent to 50% of these tumors metastasize to the lungs, liver and bone. In general, the cytomorphologic features of tumor cells from hemangiopericytomas are not a reliable indicator of malignancy. A tumor composed

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of benign-looking tumor cells is not necessarily benign. Histologic examination shows that the tumor cells are usually spindly in shape, lack myofibrils with trichrome stains, and have a close relationship with blood vessels. They have ovoid or spindle-shaped nuclei. The neoplastic cells are individually wrapped by reticulin fibers thoughout the tumor. A staghorn vascular pattern is important histologically. In the aspirate preparations, low power examination show large fragments of loosely cohesive spindly cells with open vascular spaces in a background of single cells. At high power examination, ovoid cells with small amounts of cytoplasm are found to intermix with the spindle cells with illdefined cytoplasm. The third cell type is the endothelial cells that line the vascular spaces. The nuclei of the tumor cells are relatively bland with finely granular chromatin and inconspicuous nucleoli. If any hemangiopericytoma contains tumor cells with pleomorphic nuclei, frequent mitotic figures and tumor necrosis in aspirate preparations, it is likely to be aggressive.

Ewing’s Sarcoma (Figs. 8.31–8.33) Ewing’s sarcomas occur in children, adolescents, and young adults usually under 30 years of age. They are highly malignant tumors. Although Ewing’s sarcomas are primarily tumors of bone, they invade the surrounding soft tissue at an early stage of the disease. Minimal bone changes maybe undetectable by roentgenographic examinations, and thus, Ewing’s sarcomas may present as a soft tissue mass. True extraskeletal Ewing’s sarcomas also occur and are chiefly seen in the soft tissue of the paravertebral region, retroperitoneum, chest wall and lower extremities. In the last three years at the Toronto General Hospital, the senior author encountered five cases of Ewing’s sarcoma with aspiration biopsy. Only two cases presented as bone tumors, one as a pelvic mass and two as retroperitoneal masses. The aspirate preparations contain tumor cells (cohesion factor, 1 to 2) in loose groupings and as solitary cells. The neoplastic cells have small, round to ovoid nuclei and scanty cytoplasm on Diff-Quik stain. Occasionally, the tumor cells show rosette arrangements.2,22 At first glance Ewing’s sarcoma may look like other small round-cell tumors such as neuroblastoma, lymphocytic lymphoma and embryonal rhabdomyosarcoma. However, Ewing’s sarcomas lacks the fibrillary background of neuroblastoma and it lacks the

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lymphoglandular bodies of lymphocytic lymphoma on Diff-Quik stain. The tumor cells of Ewing’s sarcoma often contain large amounts of intracytoplasmic glycogen, which appears as negative images in Diff-Quik stain and can be readily demonstrated by PAS stain. This feature is shared by embryonal rhabdomyosarcoma (Fig. 8.20). Ancillary studies are required to distinguish the two entities.

NEUROGENIC TUMORS Neurogenic tumors are not nearly as common as in the mediastinum, and those which may occur in the retroperitoneum include: (a) Tumors arising from the peripheral nerves, such as neurofibromas, schwannomas and malignant nerve sheath tumors; (b) Tumors arising from the sympathetic nerve trunk, such as neuroblastomas, ganglioneuromas and ganglioneuroblastomas; and (c) Tumors arising from paraganglia associated with the sympathetic chain, such as paragangliomas. Neurogenic tumors arising from the sympathetic nerve trunks are rare in the retroperitoneum and are discussed in Chapter 7. Aspiration cytology findings have been reported.13,41

Neurofibroma (Fig. 8.34) Neurofibromas are derived from axis-cylinder, endoneurium and nerve sheath tissues. These tumors are nonencapsulated. They may be mistaken for a malignant neoplasm during surgical procedures because they have no capsule. Neurofibromas are benign tumors, but sometimes undergo malignant transformation. Microscopically, neurofibromas are formed by a combined proliferation of Schwann cells, axons and fibroblasts in a rich network of collagen fibers.43 The aspirate preparations show large cohesive fragments of mesenchymal tissue with haphazardly oriented spindle nuclei reminiscent of “carrot peels” in a loose connective tissue matrix. The nuclei are elongated with a wavy, serpentine shape and pointed ends. The cytomorphology of neurofibromas

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is similar to their histology except it is three-dimensional in aspirates. Unlike Schwannomas, there is no palisading or parallel arrangements of the nuclei.

Schwannoma (Figs. 8.35–8.37) Schwannomas (neurolemmoma) are always encapsulated and benign. Such tumors originate from Schwann cells. They grow slowly, and regressive changes within such tumors (e.g. fatty change and cystic formation) are common. We have encountered several cases of cystic Schwannoma, in which the cavities were filled with inspissated proteinaceous fluid or a gelatin-like material. Histologic examination shows that such tumors are composed of Antoni type A and B tissues. Antoni type A tissue consists of bands of spindle cells with the nuclei in a parallel or polar arrangement, which sometimes form characteristic Verocay bodies, where the tumor cell nuclei polarized toward the periphery. Antoni type B tissue consists of loose myxoid cystic spaces that contain the proteinaceous material. The aspirate preparations contain numerous spindle cells (cohesion factor, 2 to 3) in both loose groupings (Fig. 8.36) and cohesive groupings (Fig. 8.36B). Their nuclei are ovoid, elongated, or spindle-shaped with pointed ends and are often arranged in a parallel or palisading fashion. Cell structures that resemble the Verocay bodies (Fig. 8.36B) seen in histologic sections may be observed, and some fine fibrillary matrix (Fig. 8.36B) between nuclei may be seen in aspirate preparations. In the aspirates of ancient schwannoma (Fig. 8.37), some of the nuclei are large and hyperchromatic, which represents degenerative change.11 If a cytologic specimen has been aspirated from a cystic cavity of the tumor, the fluid in aspirate smears takes the form of finely granular debris, resembling caseating necrosis from a tuberculous lesion. Collections of foamy macrophages are often seen.

Malignant Peripheral Nerve Sheath Tumor (MPNST) (Figs. 8.38–8.39) MPNST (malignant schwannoma) are uncommon tumors, and about 10% occur in the retroperitoneum.17 They are typically encountered in young adults. Most such tumors develop in persons known to have neurofibromatosis (von Recklinghausen’s disease) or arise from preexisting neurofibromas. About 10% of patients with von Recklinghausen’s disease eventually

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present with MPNST, usually after a latent period of 10 to 20 years. Histologic examination demonstrates that most MPNST tumors resemble fibrosarcomas or other spindle cell sarcomas in their overall organization.43 Specific categorization is possible only when some of the schwannian features can be recognized. Heterotopic elements, such as cartilage, bone, skeletal muscle and mucin-secreting glands, seem to be more common in MPNST than in other sarcomas. A small portion of MPNSTs closely resemble neurofibromas, except that they have a greater degree of cellularity and, most importantly, mitotic activity. Aspiraton cytology of this tumor have been reported.27,31 There are three types of MPNST seen in aspirate preparations: 1) Spindle cell type (neurofibroma-like or fibrosarcoma-like). A high MIB1 proliferation index can rule out the former, and S100 immunoreactivity will rule out the latter. The spindle cells of MPNST have comma-like naked spindly nuclei in a fibrillary matrix with increased cellularity and mitotic figures; 2) Anaplastic type with anaplastic giant cells in addition to spindle cells; and 3) Epithelioid type with eccentric nuclei and well-defined cytoplasm.32,43 Clinical information and immunostain are essential in the difficult cases.

Paraganglioma (Figs. 8.40–8.41) Paragangliomas of the retroperitoneum arise from paraganglia associated with the sympathetic chain and may occur anywhere along the midline of the retroperitoneum. Such tumors may secrete epinephrine, norepinephrine, or both substances. Patients with functioning tumors may have paroxysmal or persistent hypertension, orthostatic hypotension, palpitation, headaches, and flushing or sweating spells in various combinations. The tumors are well or partially encapsulated. The majority of these neoplasms are benign. The incidence of malignant paragangliomas of the retroperitoneum is about 10%. Malignant and benign tumors may have similar microscopic appearances. The only two criterion on which a diagnosis of malignant paraganglioma can be based is distant metastasis or invasive destructive growth. Metastases occur most frequently in the regional lymph nodes, liver, lungs and bones. However, clinical and pathologic evidence of malignancy often develops years after resection of the original tumor, and the metastatic tumors may still appear benign microscopically. Histologic examination shows that

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such tumors are composed of small polygonal cells arranged in nests “Zellballen” wrapped around by S100 immunoreactive sustentacular cells and capillary blood vessels.43 The tumor cell outlines are often indistinct, so that the nests have a syncytial appearance. The cells are immunoreactive to synaptophysin and chromogranin and negative to cytokeratins, which is a helpful immunostain to exclude neuroendocrine carcinomas. Aspiration cytology of this tumor has been reported.24,39 The aspirate preparations contain tumor cells (cohesion factor, 3 to 4) in loose groupings and, less frequently, in cohesive fragments of syncytial cells with attached sustentacular cells similar to their histology (Fig. 8.41). Their nuclei are round or ovoid, and relatively uniform and regular. However, marked anisokaryosis has been reported in a few studies.23,38 Based on a study of six paragangliomas, Gonzalez-Campora et al. reported that paradoxically, malignant paragangliomas show less anisokaryosis than do their benign counterparts.24

GERM CELL TUMORS Germ cell tumors are neoplasms derived from the primitive germinal epithelium. They include seminoma, embryonal carcinoma, yolk sac tumor, teratoma and choriocarcinoma. They can occur as primary retroperitoneum tumors or retroperitoneal lymph node metastasis from testicular or ovarian primaries. The prognosis of germ cell tumor is generally good. Over 90% of patients with newly diagnosed germ cell tumors are cured if detected at an early stage,5 since they are sensitive to radiation and chemotherapy. Therefore, the early establishment of the correct diagnosis is crucial to the welfare of the patient. The application of fine-needle aspiration biopsy in the diagnosis of germ cell tumors allows rapid preoperative evaluation and early institution of treatment. The aspiration cytology findings of germ cell tumors have been reported.48

Seminoma (Fig. 8.42) Seminomas of the retroperitoneum without involvement of the testes are relatively rare tumors. The diagnosis of extratesticular seminoma can be

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established only after exclusion of a primary testicular tumor, which is the most common malignant germ cell neoplasm in males. In general, primary seminomas of the retroperitoneum presents as a single large mass, whereas metastatic seminomas from the testis tend to involve several nodes, often on both sides of the retroperitoneum. Histologic examination shows that such tumors are composed of neoplastic cells with large round nuclei and prominent nucleoli, with the presence of lymphocytes in variable proportions. The aspirate preparations contain tumor cells (cohesion factor, 1 to 2) in loose groupings and solitary neoplastic cells, accompanied by a varying number of lymphocytes. The tumor cells have moderate amounts of clear cytoplasm, large round nuclei, and prominent nucleoli. The nuclei are usually centrally located. The fragile tumor cell cytoplasm contains abundant glycogen, which frequently spills out onto the slide during smearing and forming a striped or “tigroid” background seen with Diff-Quik stain. This cytoplasmic “tigroid pattern” can be observed. (Fig. 8.42B). The diagnosis of seminoma can be confirmed by PLAP+ immunostain on a cell block sample. Unlike non-seminomatous germ cell tumors, the tumor cells are negative for cytokeratin immunostain.

Embryonal Carcinoma (Fig. 8.43) Embryonal carcinoma is composed of solid sheets of undifferentiated cells or cells that show early differentiation toward embryonic structure, embryonic trophoblast, or extraembryonic endoderm or mesoderm in the form of papillary or glandular formations.43 The aspirate preparations show cohesive epithelial tissue fragments (cohesion factor, 3 to 4) composed of large anaplastic cells with scanty cytoplasm, coarse chromatin and multiple large nucleoli. The cytologic features are that of a poorly differentiated carcinoma. The tumor cells are immunoreactive to cytokeratin, CD30 and β-HCG.

Yolk Sac Tumor (Figs. 8.44–8.47) Yolk sac tumor (endodermal sinus tumor) is a teratoma that recapitulates embryonal yolk sac tissue.25 Microscopically, the tumor shows intermingling

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of epithelial and mesenchymal elements in microcystic, glandular-alveolar and papillary formation. Perivascular Schiller-Duval bodies are the most distinctive features of yolk sac tumor.43 The neoplastic cells of yolk sac tumors are large and pleomorphic with round nuclei, prominent nucleoli and scanty cytoplasm. The tumor cells are immunoreactive to cytokeratin and α-fetoprotein. The aspirate preparations have at least three types of arrangement that the authors have encountered. 1. Microcystic type (Fig. 8.44). Complicated arrangement of tumor cells along delicate vessels from which microcystic structures branch out. The microcystic structure are coated by several layers of tumor cells. Intracytoplasmic α-fetoprotein + hyaline globules are present in some neoplastic cells. 2. Parietal yolk sac type52 (Fig. 8.45). Tightly packed tumor cells are associated with abundant metachromatic extracellular mucoid hyaline globules and substance (laminin and collagen type IV), which recapitulated the parietal yolk sac. The material is mucoid and slimy, easily streaked into thin lines by the smearing.59 3. Schiller-Duval bodies type (Figs. 8.46–8.47). Schiller-Duval body represents cross-sectional image of tumor cell-coated, anastomosing, thinwalled, rigid hematopoietic channels. Many segments of the allantoic viteline vascular network, fractured by smearing, exhibited three- or fourway branchings of widely variable diameter (Fig. 8.47A, B).60

MALIGNANT LYMPHOMAS Malignant lymphomas constitute the most common malignant disease observed in the retroperitoneal space. The lymphomas may occur as a primary disease in the retroperitoneum or as part of a generalized malignant lymphoma.

OTHER TUMORS Other tumors that present as a retroperitoneal mass include chordomas, alveolar soft part sarcoma and synovial sarcoma.

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Chordoma (Fig. 8.48) Chordomas are malignant tumors arising from the remnants of the fetal notochord, which is situated within the vertebral bodies and intravertebral discs. These tumors grow slowly. They occur at all ages, but are more frequently in the fifth and sixth decades of life. Fifty percent of cases arise in the sacrococcygeal area, with the remaining cases along the vertebral spine and in the sphenooccipital area. The retroperitoneum is often involved by direct extension, and the tumor may present as a retroperitoneal mass with bony destruction at the time of investigation. Grossly, this neoplasm is gelatinous and soft. Histologic examination shows that the tumor is composed of epithelial and mesenchymal tissues. Sheets of large epithelial cells with vacuolated cytoplasm and small nuclei (physaliferous cells) are separated by the septae of connective tissue and a homogeneous matrix reminiscent of cartilage. The fine-needle aspiration cytology of chordoma has been described.11,40,51 The aspirate preparations have often relative scanty cellularity and contain tumor cells (cohesion factor, 0 to 1) in loose groupings and solitary neoplastic cells in a strikingly metachromatic mucoid background with the Diff-Quik stain. The tumor cells exhibit a variable cytology. Some tumor cells are extremely large with large nuclei and an abundant vacuolated cytoplasm (physaliferous cells), while others are small with small amounts of non-vacuolated cytoplasm. Some tumor cells are binucleated, but multinucleated cells are uncommon. Their nuclei are often hyperchromatic. In aspirate preparations from dedifferentiated chordomas, physaliferous cells are absent.51 Chordoma cells coexpress S-100 and cytokeratins. The cytokeratin immunoreactivity is important to exclude chondrosarcoma (Fig. 8.49), which may appear similar to chordoma on smears with metachromatic matrix and even pseudo-physaliferous appearing cells.

Alveolar Soft Part Sarcoma (Figs. 8.50–8.51) This tumor represents 0.5–1.0% of all soft tissue neoplasms. It occurs in the deep soft tissues of the lower extremities, oral cavity, pharynx, mediastinum and retroperitoneum.43 It usually affects young females. The clinical course is indolent, but metastases may occur up to 30 years later. The major sites of metastasis are the liver, lungs and other sites, including the retroperitoneum.

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On imaging studies, this tumor usually presents as well circumscribed, large solid mass with foci of necrosis. Histologically, it is characterized by well defined nests of polygonal cells separated by a well-defined vascular stroma. It may have an alveolar pattern if neoplastic cells are dyscohesive. The tumor cells are large, polygonal with granular acidophilic cytoplasm, and the nuclei have vesicular chromatin with prominent nucleoli.43 Ultrastructurally, the cytoplasm contains specific rod-shaped crystals with a periodicity of 60– 100 nm, which are periodic acid-Schiff positive and diastase resistant histochemically. The tumor shows cytoplasmic expression of MyoD1, a muscle immunomarker.42 Aspiration cytology findings have been reported.47 The aspirate preparations show collapsed fibrovascular stroma and “eyeball”-like polygonal cells, with eccentric small round nuclei with single prominent nucleoli, as single cells and in loosely groupings. Occasional binucleated cells are present. The plasma membrane of the tumor cells is fragile and easily stripped by smearing, resulting in numerous naked nuclei. The tumor cells have abundant cytoplasm containing crystals, which can sometimes be seen on smears as negative images in Diff-Quik stain, or demonstrated by diastase resistant periodic acid-Schiff stain on cell block.

Synovial Sarcoma (Figs. 8.52–8.54) This tumor usually presents as a deep-seated soft tissue mass present for years around the knee and ankle joints in young adults (age 20–40). There is a male to female ratio of 1.5 to 1. Synovial sarcoma represents 10% of adult soft-tissue tumors with a five-year survival of 50–70%. It recurs locally and 10–15% metastasize to distant sites, including the retroperitoneum.43 Aggressiveness correlates with MIB-1 proliferation index.27 On imaging studies, the tumor usually presents as a well circumscribed, solid mass with focal calcifications. Histologically, there are three types: biphasic, monophasic and undifferentiated.42 The biphasic type has spindle cells resembling synoviocytes and plump epithelial cells forming glands/cords. The monophasic type has only spindle cells. Spindle cells are arranged in plump fascicles with hyalinization and distinct lobulation accompanied by mast cells, occasional osseous or cartilaginous metaplastic foci. Immunohistochemically, the spindle cells are immunoreactive to vimentin and the epithelial cells are

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immunoreactive to cytokeratins. The aspiration cytology findings have been described.1,45,54 The aspirate preparations show cohesive fragments of small to mediumsized ovoid to spindle-shaped cells with bland nuclei and inconspicuous nucleoli. In the biphasic variant, small glandular- or acinar-like structures composed of epithelial cells with well-defined cytoplasm are present. Often a branching network of vessels is present in the fragments. Histology in cell block is very helpful in recognizing the tumor and can be confirmed by ancillary tests. The aspirate of monophasic synovial sarcoma shows spindle cell tumors with vascular structures within the cell groups.54 It is difficult to distinguish monophasic synovial sarcoma from other spindle cell mesenchymal tumors without ancillary studies. Electron microscopic or molecular genetic analyses are better diagnostic adjuncts than immunocytochemistry.1

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25. Gonzalez-Crussi F. (1979) The human yolk sac and yolk sac (endodermal sinus) tumors. A review. Perspect Pediatr Pathol 5:179–215. 26. Goulouh R, Us-Krasovec M. (1985) Differential diagnosis of the pleomorphic aspiration biopsy sample of nonepithelial lesions. Diagn Cytopathol 1:308–316. 27. Jensen V, Sorensen FB, Bentzen SM, et al. (1998) Proliferative activity (MIB1 index) is an independent prognostic parameter in patients with high-grade soft tissue sarcomas of subtypes other than malignant fibrous histiocytomas: A retroactive immunohistological study including 216 soft tissue sarcomas. Histopathol 32: 536–546. 28. Jimenez-Hefferman JA, Lopez-Ferrer P,Vicandi B, et al. (1999) Cytologic features of malignant peripheral nerve sheath tumor. Acta Cytol 43:175–183. 29. Kardar AH, Kattan S, Lindstedt E, Hanash K. (2002) Steroid therapy for idiopathic retroperitoneal fibrosis: Dose and duration. J Urol 168:550–555. 30. Kawahara E, Nakanishi I, Kuroda Y, et al. (1988) Fine-needle aspiration biopsy of primary malignant fibrous histiocytoma of the lung. Acta Cytol 32:226–234. 31. Kilpatrick SE, Cappellari JO, Bos GD, et al. (2001) Is fine-needle aspiration biopsy a practical alternative to open biopsy for the primary diagnosis of sarcoma? Experience with 140 patients. Am J Clin Pathol 115:59–68. 32. Klijanienko J, Caillaud JM, Lagace R, Vielh P. (2002) Cytohistologic correlations of 24 malignant peripheral nerve sheath tumor (MPNST) in 17 patients: The Institut Curie experience. Diagn Cytopathol 27:103–108. 33. Kumar S, Perlman E, Harris CA, et al. (2000) Myogenin is a specific marker for rhabdomyosarcoma: An immunohistochemical study in paraffin-embedded tissues. Mod Pathol 13:988–993. 34. McClain KL, Leach CT, Jensen HB, et al. (1995) Association of Epstein-Barr virus with leiomyosarcomas in young people with AIDS. N Engl J Med 332:12–18. 35. Melieow MM. (1953) Primary tumors of the retroperitoneum: A clinicopathologic analysis of 162 cases. J Int Coll Surg 19:401–449. 36. Monev S. (2002) Idiopathic retroperitoneal fibrosis: Prompt diagnosis preserves organ function. Cleve Clin J Med 69(2):160–166. 37. Nemanqani D, Mourad WA. (1999) Cytomorphologic features of fine-needle aspiration of liposarcoma. Diagn Cytopathol 20:67–69. 38. Raab SS, Silverman JF, McLeod DI, et al. (1993) Fine-needle aspiration biopsy of fibromatoses. Acta Cytol 37:323–328. 39. Rana RS, Dey P, Das A. (1997) Fine-needle aspiration (FNA) cytology of extraadrenal paragangliomas. Cytopathol 8:108–113. 40. Rene R, Ramzy I, Duncan D. (1986) Anaplastic sacrococcygeal chordoma: Fineneedle aspiration cytologic findings and embryologic considerations. Acta Cytol 30:183–188.

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41. Resnick JM, Fanning CV, Caraway NP, et al. (1997) Percutaneous needle biopsy diagnosis of benign neurogenic neoplasms. Diagn Cytopathol 16:17–25. 42. Roholl PJ, Rutgers DH, Radenajers KH, et al. (1988) Characterization of human soft tissue sarcomas in nude mice. Evidence for histogenenic properties of malignant fibrous histiocytomas. Am J Pathol 131:559–568. 43. Rosai J. (2004) Soft tissues. In: Rosai J. (ed.), Rosai and Ackerman’s Surgical Pathology, 9th ed. St. Louis, Mosby, Chap. 25. 44. Rosenberg SA, Suit HD, Baker LH. (1985) Sarcomas of soft tissue. In: DeVita VT, Hellman S, Rosenberg SA (eds.), Cancer: Principles and Practice of Oncology, 2nd ed. Philadelphia, Lippincott. 45. Ryan MR, Stastny JF, Wakely PE Jr. (1998) The cytopathology of synovial sarcoma: A study of six cases, with emphasis on architecture and histopathologic correlation. Cancer Cytopathol 84:41–49. 46. Sapi Z, Antal I, Papai Z, et al. (2002) Diagnosis of soft tissue tumors by fineneedle aspiration with combined cytopathology and ancillary techniques. Diagn Cytopathol 26:232–242. 47. Shabb N, Sneige N, Fanning CV, Dekmezian R. (1991) Fine-needle aspiration cytology of alveolar soft-part sarcoma. Diagn Cytopathol 7:293–298. 48. Stanley MW, Powers CN, Pitman MB, et al. (1997) Cytology of germ cell tumors. Extragonal, extracranial masses and intraoperative problems. Cancer Cytopathol 81:220–227. 49. Stein AL, Bardawil RG, Silverman SG. (1997) Fine-needle aspiration biopsy of idiopathic retroperitoneal fibrosis. Acta Cytol 41:461–466. 50. Tao LC, Davidson DD. (1993) Aspiration biopsy cytology of smooth muscle tumors: A cytologic approach to the differentiation between leiomyosarcoma and leiomyoma. Acta Cytol 37:300–308. 51. Thompson SK, Callery RT. (1988) Cytologic diagnosis of a chordoma without physaliferous cells. Diagn Cytopathol 4:144–147. 52. Ulbright TM, Roth LM, Brodhecker CA. (1986) Yolk sac differentiation in germ cell tumors: A morphologic study of 50 cases with emphasis on hepatic, enteric and parietal yolk sac features. Am J Surg Pathol 10:151–164. 53. van Bommel EF, van Spengler J, van der Hoven B, Kramer P. (1991) Retroperitoneal fibrosis: Report of 12 cases and a review of the literature. Neth J Med 39:338–345. 54. Viguer JM, Jimenez-Hefferman JA,Vicandi B, et al. Cytologic features of synovial sarcoma with emphasis on the monophasic fibrous variant: A morphologic and immunocytological analysis of bcl-2 protein expression. Cancer Cytopathol 84: 50–56.

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55. Wakely PE, Kneisl JS. (2000) Soft tissue aspiration cytopathology — Diagnostic accuracy and limitations. Cancer Cytopathol 90:292–298. 56. Walaas L, Angervall L, Hagmar B, et al. (1986) A correlative cytologic and histologic study of malignant fibrous histiocytoma. Diagn Cytopathol 2:46–54. 57. Weiss SW. (2002) Soft tissue sarcomas: Lessons from the past, challenges for the future. 44th Maude Abbott lecture. Mod Pathol 15:77–86. 58. Wood GS, Beckstead JH, Turner RR, et al. (1986) Malignant fibrous histiocytoma tumor cells resemble fibroblasts. Am J Surg Pathol 10:323–335. 59. Yang GCH. (2000) Fine-needle aspiration cytology of Schiller-Duval bodies of yolk sac tumor. Diagn Cytopathol 23:228–232. 60. Yang GCH, Hwang SJ,Yee HT. (2002) Fine-needle aspiration cytology of unusual germ cell tumors of the mediastinum: Atypical seminoma and parietal yolk sac tumor. Diagn Cytopathol 27:69–74.

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Fig. 8.1 CT-guided fine-needle aspiration of a retroperitoneal mass in a 61-year-old male. The aspirate is shown in Fig. 8.27.

Fig. 8.2 Mycobacterium tuberculosis of the retroperitoneum in immunocompetent patients. (A) Caseous necrosis. DQ, 40×; (B) Granulomas. UFP, 100×; (C) Granuloma with epithelioid histiocytes with hockey-stick nuclei. UFP, 100×; (D) Sparse extracellular acid fast bacilli in Ziel-Nelson stain. 1000×.

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Fig. 8.3 Mycobacterium avium intracellulare of the retroperitoneum in a HIV+ patient. (A) Numerous foamy macrophages along delicate blood vessels. UFP, 40×; (B) High magnification of the macrophages with bland nuclei. UFP, 400×; (C) The macrophages are distended by numerous acid fast bacilli. Cell block, AFB stain; (D) Macrophage filled with MAI, termed originally as pseudo Gaucher cells. DQ, 1000×.

Fig. 8.4 Actinomyces abscess. (A) Organisms that appear as colonies among inflammatory background. UFP, 40×; (B) Close-up show colonies with granular centers that are surrounded by neutrophils. 400×; (C) Colony with granular center. DQ, 400×; (D) Granular center with delicate, branching, intertwined filamentous bacteria. DQ, 1000×.

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Fig. 8.5 Idiopathic retroperitoneal fibrosis. (A) The metachromatic fibrous tissue encasing pieces of deep blue skeletal muscle. DQ, 100×; (B) The metachromatic fibrous tissue has capillary network. DQ, 400×; (C) Pieces of skeletal muscle infiltrated by bland fibrous tissue. UFP, 100×; (D) The fibrous tissue is composed of fibroblasts and bundles of collagen fibers. UFP, 400×.

Fig. 8.6 Fibromatosis (desmoid tumor). (A) Cores of mesenchymal tissue difficult to smear. UFP, 40×; (B) Mesenchymal tissue is composed of haphazardly arranged spindle cells. UFP, 400×; (C) Metachromatic collagenous matrix. DQ, 400×; (D) Correlating histology (2-D), which shows less cellularity than cytology (3-D). H&E, 400×.

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Fig. 8.7 Fibrosarcoma, well-differentiated cell type. (A) Cores of mesenchymal tissue surrounded by spindle cells. DQ, 40×; (B) Area with dyscohesive single cells. UFP, 100×; (C) Fibroblast-like spindle cells adjacent to cores of mesenchymal tissue. UFP, 400×; (D) Histology from resected tumor showing herringbone pattern. H&E, 100×.

Fig. 8.8 Fibrosarcoma, poorly-differentiated. (A) Low power show fibrous tissue with large nuclei. DQ, 100×; (B) Pleomorphic spindle cells with large hyperchromatic nuclei. UFP, 400×; (C) Oil immersion shows irregular nuclear contour. 1000×; (D) Histology of poorlydifferentiated fibrosarcoma on cell block. H&E, 400×.

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Fig. 8.9 Leiomyosarcoma, well-differentiated cell type, dyscohesive presentation. (A) Loose groupings of solitary cells seen at low power. UFP, 40×; (B) Spindle cells and epithelioid cells with no resemblance to smooth muscle cells. UFP, 400×; (C) Spindle cells and epithelial cells associated with metachromatic matrix. DQ, 1000×; (D) The diagnosis was made on histology. Cell block with positive Actin immunostain. 100×.

Fig. 8.10 Leiomyosarcoma, well-differentiated cell type, of vena cava. (A) Spindle cells scattered singly and in loose groupings. DQ, 100×; (B) Cigar-shaped spindly nuclei, typical for smooth muscle cells. DQ, 400×; (C) Blood vessels transverse the loosely cohesive fragment of spindle cells. UFP, 100×; (D) Variation in nuclear size and shape is present. UFP, 400×.

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Fig. 8.11 Leiomyosarcoma, well-differentiated cell type, cohesive, of urinary bladder wall. (A) Cohesive fragments of spindle cells in parallel arrangement. UFP, 100×; (B) High magnification shows cigar-shaped nuclei and intact cytoplasm. UFP, 400×; (C) Cohesive spindle cells with a little metachromatic matrix. DQ, 400×; (D) Cohesive fragments with variation in size and shape. DQ, 400×.

Fig. 8.12 Leiomyosarcoma, round cell type, aspirated from abdominal mass. (A) A core of mesenchymal tissue studded with small cells. DQ, 100×; left, 400×; (B) A core of tumor showing a transparent region (left), and thicker region (right). UFP, 100×; (C) At the thicker region, small round cells are enmeshed in fibrous stroma. UFP, 400×; (D) At the transparent region, atypical round cells with scanty cytoplasm are seen. UFP, 1000×.

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Fig. 8.13 Leiomyosarcoma, pleomorphic cell type. (A) Dyscohesive cells separated from a metachromatic vessel by smearing. DQ, 400×; (B) A small loose cluster of spindle cells. UFP, 400×; (C) A binucleated pleomorphic tumor cells with convoluted nuclei. UFP, 1000×; (D) Histology in cell block shows sheets of tumor. H&E, 400×.

Fig. 8.14 Well-Differentiated liposarcoma. (A) Mature adipose tissue with malignant nuclei. UFP, 100×; (B) Large, hyperchromatic nucleus with rod-shaped nucleoli. UFP, 1000×; (C) Enlarged nucleus with nuclear grooves. UFP, 1000×; (D) “Bowling pin”-shaped nucleus with rod shaped nucleous. UFP, 1000×.

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Fig. 8.15 Dedifferentiated liposarcoma — MFH-like. (A) Pleomorphic nuclei in metachromatic myxoid matrix. DQ, 400×; (B) A multinucleated tumor cell. DQ, 400×; (C) Plump and pleomorphic neoplastic cells. UFP, 1000×; (D) Histology of dedifferentiated liposarcoma. Cell block, H&E, 400×.

Fig. 8.16 Myxoid liposarcoma, well-differentiated. (A) Metachromatic myxoid ground substance covering a fragment of liposarcoma. DQ, 40×; (B) A thin fragment of tumor with “chicken-wire” capillaries pattern. DQ, 100×; (C) A thick fragment of tumor with “chickenwire” capillary pattern. DQ, 100×; (D) Correlating histology of myxoid liposarcoma with “chicken-wire” capillaries. H&E, 100×.

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Fig. 8.17 Myxoid liposarcoma, poorly differentiated (round cell). (A) Myxoid ground substance. DQ, 100×; (B) High magnification shows spindle neoplastic cells. DQ, 400×; (C) In other regions of the smear, lipid-laden small round cells can be found. DQ, 400×; (D) Note lipid droplets in the blue cytoplasm. Nuclear size is 2–3× RBCs, DQ, 1000×.

Fig. 8.18 Pleomorphic liposarcoma. (A) A pleomorphic lipoblast with nuclear size 50× RBC in DQ stain. Negative image of small to large lipid droplets, best shown in DQ stain. 400×; (B) A cluster of tumor cells with the largest nuclei 50× the smallest nuclei. UFP, 400×; (C)–(D) A different case with spindly nuclei with abundant vacuolated cytoplasm. UFP, 400×.

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Fig. 8.19 Embryonal rhabdomyosarcoma. (A) Small blue cells scattered singly and in aggregates. DQ, 40×; (B) Small blue tumor cells without nuclear molding. UFP, 100×; (C) Solitary cells with round, ovoid, or irregular nuclei in UFP. 400×; (D) Histology of embryonal rhabdomyosarcoma. H&E, 100×.

Fig. 8.20 Embryonal rhabdomyosarcoma. (A) Oil immersion reveals irregular nuclear contour and several nucleoli. UFP, 1000×; (B) Note the intracytoplasmic glycogen droplets, best demonstrable in DQ. 1000×; (C) Negative image of glycogen lakes. Nuclei is 7–8× RBC. DQ, 1000×; (D) Myoglobulin (+) immunostain on cell block. 400×.

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Fig. 8.21 Pleomorphic rhabdomyosarcoma. (A) Stripped nuclei due to fragile cytoplasm. Notice the ribbon-like cytoplasm. DQ, 400×; (B) A rhabdomyoblast with ribbon-like cytoplasm containing a row of nuclei. UFP, 1000×; (C) Multinucleated tumor cells with cytoplasmic tails. UFP, 1000×; (D) A multilobated cell with pleomorphic nuclei and ribbon-like cytoplasm. UFP, 1000×.

Fig. 8.22 Venograms showing abrupt obstruction of right external iliac vein of a 28-yearold female who presented with leg swelling. FNA biopsy of a 4 cm mass in the right pelvic side wall mass is shown in Fig. 8.23.

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Fig. 8.23 Epithelioid angiosarcoma: Cytology. (A) Fibrous tissue studded by round tumor cells. Arrow points to area enlarged in (B). DQ, 100×; (B) Metachromatic matrix between epithelioid tumor cells is a clue to sarcoma. DQ, 400×; (C) Tumor attached to stromal tissue. Arrow points to area enlarged in (D). UFP, 100×; (D) Solitary tumor cells with dimpled nuclear contour (arrow). UFP, 1000×.

Fig. 8.24 Epithelioid angiosarcoma: Histology, same case as Fig. 8.23. (A) Boxed area in the adventitia of the external iliac vein is shown in (B) H&E, 40×; (B) Epithelioid tumor cells lining poorly formed blood vessel. H&E, 400×; (C) Tumor cells are positive for epithelial markers. Immunostain on cell block. 100×; (D) Tumor cells are positive for Vimentin and CD34, a vascular marker. 400×.

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Fig. 8.25 Angiosarcoma, from a 52-year-old man. (A) Epithelioid tumor cells associated with metachromatic matrix. DQ, 100×; (B) Oval nuclei with distinct nucleoli and angular cytoplasm. UFP, 400×; (C) Histology of resected tumor showing blood vessels lined by malignant cells. H&E, 100×; (D) Histology of intracytoplasmic lumina, marked by CD34. Immunostain, 100×. Insert, 1000×.

Fig. 8.26 Malignant fibrous histiocytoma. (A) Numerous spindle cells in background of myxoid substance. DQ, 100×; (B) High power shows variation of the size of fusiform tumor cells. DQ, 400×; (C) The tumor cells have hyperchromatic nuclei with indistinct nucleoli. UFP, 400×; (D) Histology of resected tumor, showing an abnormal mitotic figure. H&E, 100×.

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Fig. 8.27 Malignant fibrous histiocytoma (CT scan is shown in Fig. 8.1). (A) Fragments of tumor attached to branching vessel without metachromatic matrix. DQ, 100×; (B) Fibroblastlike spindle cells (left) rare histiocyte-like cells (right). DQ, 400×; (C) Fibroblast-like spindle cells with single prominent nucleolus. UFP, 400×; (D) Spindle cells in storiform pattern. Cell block, H&E stain. 100× (left); 400× (right).

Fig. 8.28 Malignant fibrous histiocytoma from a different case. (A) Fragments of spindle cells and scattered solitary neoplastic cells. DQ, 100×; (B) Very long spindled fibroblast-like neoplastic cells. UFP, 100×; (C) Note nuclear irregularity of fibroblast-like neoplastic cells. UFP, 400×; (D) Prominent nucleolus in the fibroblast-like cells and histiocyte-like cells. UFP, 400×.

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Fig. 8.29 Hemangiopericytoma. (A) Loosely cohesive spindle cells with large vague open spaces (arrows). UFP, 40×; (B) Parallel bundles of spindle cells surround staghorn-shaped open spaces. UFP, 400×; (C) Close-up reveal ovoid cells (arrowheads) intermixed with spindle cells. UFP, 600×; (D) Histology of staghorn vascular space surrounded by spindle cells. Cell block, H&E, 400×.

Fig. 8.30 Hemangiopericytoma, aspirated from a 66-year-old male with a 11 × 8 × 8 cm retroperitoneal mass anterior to psoas within the pelvis. The mass was heterogeneous, vascular with central necrosis on radiology imaging studies. (A) Cohesive mesenchymal fragments in bloody background. DQ, 100×; (B) At low power on UFP stain, pockets of open spaces were revealed within the mesenchymal tissue. 40×; (C) At high magnification, the open space is shown to be lined by endothelial cells, and the intervening stroma is composed of spindle cells, UFP 100×; (D) The tumor are CD34(+), immunostain on cell block, 100×; concurrent needle core biopsy showed staghorn spaces. H&E, 100×.

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Fig. 8.31 Ewing’s sarcoma. (A) Small cells forming rosettes in a background without lymphoglandular bodies. DQ, 100×; (B) Small blue cells without nuclear streaking or molding. UFP, 100×; (C) High magnification of a rosette. DQ, 400×; (D) Small hyperchromatic oval cells with fine nuclear chromatin. UFP, 400×.

Fig. 8.32 Ewing’s sarcoma. (A) & (B) Notice negative image of cytoplasmic glycogen. DQ, 1000×; (C) Thin rim of clear cytoplasm around the nuclei is due to glycogen. UFP, 1000×; (D) Histology on cell block. Glycogen particles demonstrated by PAS stain. 400×.

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Fig. 8.33 Ewing’s sarcoma. (A) Small blue neoplastic cells connected by thin vessels. UFP, 100×; (B) Rosette-like grouping of tumor cells. UFP, 400×; (C) Cell block shows monotonous population of small blue neoplastic cells. H&E, 100×; (D) Strong positive CD99 and Ewing 013 immunostaining on cell block. 100×.

Fig. 8.34 Neurofibroma of the retroperitoneum. (A) Cohesive fragment of spindle cells in lightly metachromatic matrix. DQ, 100×; (B) Cohesive fragment of neoplastic spindle cells UFP. 100×; (C) Coma shaped nuclei haphazardly arranged in a loose fibrillar stroma. UFP, 400×; (D) Correlating histology showing fragment of neurofibroma. Cell block, H&E, 100×.

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Fig. 8.35 Schwannoma, comparison to peripheral nerve. (A) Peripheral nerve. UFP, 400×; (B) Cohesive fragments of spindle cells with palisading of spindly cells (Verocay bodies). UFP, 400×.

Fig. 8.36 Schwannoma. (A) Spindly nuclei enmeshed in metachromatic fibrils. DQ, 400×; (B) Bland spindly nuclei with pointed ends in finely fibrillary background. UFP, 400×; (C) The fibrillary matrix is immunoreactive to S100 antibody as shown. 400×; (D) Histology show palisading rows of spindle nuclei (Verocay body). Cell block, H&E, 100×.

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Fig. 8.37 Ancient schwannoma. (A) Low power of the aspirate smear shows cohesive fragments of stromal tissue. UFP, 100×; (B) Pleomorphic large nuclei (arrows) interspersed among small nuclei. UFP, 1000×; (C) A similar field of neoplastic cells as in (B) with large and small nuclei. DQ, 400×; (D) Correlating histology of ancient schwannoma. Resected tumor. H&E, 400×.

Fig. 8.38 Malignant peripheral nerve sheath tumor, low nuclear grade. (A) Highly cellularity of neoplastic spindle cells. DQ, 100×; (B) Metachromatic background material and elongated tumor cell nuclei. DQ, 400×; (C) Fibrillary background in an area of high cellularity. UFP, 400×; (D) Bland neoplastic spindle cells with no obvious atypia. 1000×.

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Fig. 8.39 Malignant peripheral nerve sheath tumor, high nuclear grade. (A) Loosely cohesive mesenchymal tissue fragments rimmed by single cells. DQ, 40×; (B) High power shows metachromatic matrix between pleomorphic nuclei. DQ, 400×; (C) Spindle cells and bizzare cells (arrow) are connected to fibrillary cytoplasm. UFP, 400×; (D) Histology of the resected tumor showing areas with different cellularity. H&E, 40×.

Fig. 8.40 Paraganglioma. (A) Loosely cohesive tumor associated with a blood vessel seen. Pap stain, 20×; (B) Uniform tumor cells that have some variation in nuclear size. Pap stain, 100×; (C) An area with solitary tumor cells with small nuclei (2× RBC). DQ, 100×; (D) High magnification shows round nuclei and abundant foamy cytoplasm. DQ, 400×.

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Fig. 8.41 Paraganglioma. (A) Tumor nests outlined by vascularized septa. Note sustentacular cells (arrow). UFP, 100×; (B) The tumor cells have moderate amounts of granular cytoplasm. UFP, 400×; (C) The syncytial appearance due to indistinct cell borders. UFP, 400×; (D) Correlating “Zellballen” pattern seen in histology. Cell block, H&E, 100×.

Fig. 8.42 Seminoma. (A) Single tumor cells in a tigroid background with lymphocytes and plasma cells. DQ, 400×; (B) Cytoplasmic glycogen forming tigroid pattern seen in a neoplastic cell. DQ, 1000×; (C) Tumor cells with distinct nucleolus and lymphocytes (arrows). UFP, 400×; (D) The tumor cells are PLAP (+), cytokeratin (−). Immunostain on cell block.

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Fig. 8.43 Embryonal carcinoma. (A) Cohesive tumor cells easily mistaken for poorly differentiated adenocarcinoma. UFP, 100×; (B) Pleomorphic cells with multiple nucleoli and indistinct cell borders. UFP, 1000×; (C) Pleomorphic tumor cells with scanty blue cytoplasm. DQ, 400×; (D) Tumor cells are β-HCG (+) and cytokeratin (+). Immunostain on cell block. 40×.

Fig. 8.44 Yolk sac tumor, microcystic pattern. (A) A vessel coated with tumor cells and 2 microcystic structures (arrows). UFP, 40×; (B) Large microcystic structure shows pleomorphic cells with scanty cytoplasm. UFP, 400×; (C) Small microcystic structure; left, 400×. AFP+ hyaline globules. Right, 1000×; (D) Histology of resected tumor showing microcystic pattern. H&E, 100×.

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Fig. 8.45 Yolk sac tumor, parietal type, as a mediastinal mass in a 51-year-old female.60 (A) Metachromatic slimy extracellular hyaline material associated with tumor cell. DQ, 40×; (B) Parietal yolk sac is slimy, and easily streaked by the smearing. DQ, 100×; (C) Large vesicular chromatin and scanty to moderate amounts of cytoplasm. UFP, 400×; (D) Correlating histology on cell block. H&E, 40×.

Fig. 8.46 Cytologic equivalent of Schiller-Duval bodies, from a 29-year-old male. (A) Ramifications of tumor-coated allantoic channels, UFP, 40×; (B) Arrow points to a naked channel containing hematopoitic cells (insert, 400×). UFP, 100×; (C) A small caulifower-like segment of channel, coated by neoplastic cells. UFP, 100×; (D) A vessel with knobby protrusions, with tumor cells smeared to the side. UFP, 100×.

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Fig. 8.47 Yolk sac tumor with Schiller-Duval bodies, same case as Fig. 8.45. (A) A wide channel connected to a narrow channel, surrounded by tumor cells. UFP, 40×; (B) Branching vessel coated by tumor cells with abrupt variation in diameter. UFP, 400×; (C) Tumor cells have round nuclei with prominent nucleoli, enlarged from (B). UFP, 1000×; (D) Cell block shows Schiller-Duval bodies (X-section of allantoic channels). H&E, 400×.

Fig. 8.48 Chordoma. (A) Small non-vacuolated cells in mucoid metachromatic matrix. DQ (left) UFP (right), 400×; (B) Binucleated cell DQ (left). Physaliforous cells with bubbly cytoplasm. UFP (right), 400×; (C) Histology of chordoma with physaliforous cells. Cell block, H&E, 400×; (D) Tumor cells coexpress cytokeratin and S100. Immunostain on cell block. 400×.

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Fig. 8.49 Chondrosarcoma, look alike of chordoma, but is cytokeratin negative. (A) Brilliant metachromatic matrix studded with chondrocytes seen in DQ, 100×; (B) A chondrocyte surrounded by radiating fibrillary metachromatic matrix. DQ, 400×; (C) The matrix is inconspicuous in UFP, 100×; (D) Nuclear atypia with hyperchromatic coarse chromatin are better seen in UFP, 400×.

Fig. 8.50 Alveolar soft part sarcoma, from a 8 cm thigh mass of a 23-year-old female. (A) Low power shows scattered naked nuclei surround fibrous stroma (arrow). UFP, 100×; (B) Tumor cells with eccentric round nuclei and abundant cytoplasm. UFP, 1000×; (C) Thin metachromatic matrix wraps around the tumor cells. DQ, 1000×; (D) Histology shows nests of tumor outlined by fibrous septa. Resected specimen, H&E, 100×.

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Fig. 8.51 Alveolar soft part sarcoma, aspirated from a pelvic mass of a 57-year-old female. (A) Cells with eccentric nuclei and crystal-laden cytoplasm (negative image). DQ, 1000×; (B) A binucleated tumor cell with eccentric round nuclei and prominent nucleoli. UFP, 400×; (C) Intracytoplasmic crystals seen on cell block. PAS stain with diastase. 400×; (D) Crystalloid structure with 70 Å periodicity. Electron micrograph, 20,000×.

Fig. 8.52 Synovial sarcoma, biphasic type, with carcinoma in the center. (A) Spindle cell sarcomatous component without metachromatic matrix. DQ, 400×; (B) Spindle cell sarcomatous component. UFP, 400×; (C) Carcinoma cells have sharp cytoplasmic border, large nuclei with distinct nucleoli; (D) CK only labels carcinoma component in the center. Cell block, immunostain. 100×.

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Fig. 8.53 Synovial sarcoma, biphasic type, with carcinoma at periphery. (A) Spindle cell sarcomatous component, UFP, 100×. Insert : Carcinoma cells. 200×; (B) Sarcomatous component covered by carcinomatous columnar cells (arrow). UFP, 100×; (C) Columnar epithelium (arrow) covering the sarcoma. Cell block, H&E, 40×; (D) Cytokeratin labels the peripheral carcinoma. 40×. Diffuse MIB1 (+) immunolabeling of both components. Insert 100×.

Fig. 8.54 Synovial sarcoma, monophasic type, recurrent as lung metastasis. (A) Oval cells in loosely cohesive fragments with little metachromatic matrix. DQ, 100×; (B) Oval cells in loosely cohesive fragments. UFP, 100×; (C) Oval cells with bland nuclear feature. UFP, 1000×; (D) Histology of monophasic synovial sarcoma. Cell block, H&E, 100×.

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CHAPTER 9

Gynecologic Tumors

Even though the gynecologic tumors are rarely directly aspirated, we frequently encounter these tumors outside of the female genital tract as distant metastasis or local recurrence (Fig. 9.1). The cytomorphologic features of gynecologic lesions seen in aspirate preparations will be presented as outlined. Uterus Endometrium Endometriosis (Fig. 9.2) Endometrioid carcinoma (Figs. 9.3–9.5) Mucinous carcinoma (Fig. 9.6) Papillary serous carcinoma (Fig. 9.7) Clear cell carcinoma (Figs. 9.8–9.9) Carcinosarcoma (malignant mixed mullerian tumor) (Figs. 9.10–9.11) Stromal tumors Endometrial stromal sarcoma Low grade (Figs. 9.12–9.13) High grade (Figs. 9.14–9.15) Myometrium Leiomyoma (Fig. 9.16) Leiomyosarcoma Well-differentiated spindle cell type (Fig. 9.17) Poorly-differentiated spindle cell type (Fig. 9.18) Epithelioid cell type (Fig. 9.19) 286

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Cervix Mucinous adenocarcinoma (Figs. 9.20–9.21) Squamous carcinoma Keratinizing (Fig. 9.22) Non-keratinizing (Figs. 9.23–9.24) Ovary Surface epithelial tumors Borderline papillary serous tumor (Fig. 9.25) Papillary serous carcinoma (Figs. 9.26–9.27) Serous cystadenocarcinoma (Fig. 9.28) Mucinous adenocarcinoma (Fig. 9.29) Mucinous cystadenocarcinoma (Fig. 9.30) Endometrioid adenocarcinoma (Fig. 9.31) Carcinosarcoma (same as uterus) Sex-cord stromal tumors Granulosa cell tumor (Figs. 9.32–9.33) Fibrothecoma (Fig. 9.34) Germ cell tumors (see Chapter 8) Fallopian tube tumors Papillary serous carcinoma (same as ovary) Broad ligament Perivascular epithelioid cell tumor (PEComa) (Fig. 9.35) Ependymoma (Fig. 9.36)

Endometriosis (Fig. 9.2) This condition is the presence of endometrial tissue outside of the uterus. It affects women 20–39 years old, and up to 10% of all women are affected. Endometriosis consists of functional layers of endometrium that go through the menstrual cycle, and is more proliferative than normal endometrium. The major symptom is pain during mensus, and 1/3 of women are infertile. The sites affected include the ovaries, uterine ligaments, rectovaginal septum, and pelvic peritoneum. Endometriosis is treated by hormones and surgery. The aspirate preparation shows a cohesive epithelium in an orderly pattern and bland nuclei without any atypia, and loosely arranged stromal

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fragment with naked oval nuclei. The stromal component may be underrepresented in certain cases. The aspirates are easily overinterpreted as metastatic adenocarcinoma due to the presence of glandular tissue in the alien anatomic locations. Awareness of endometriosis in young women, and attention to the blandness of nuclei, orderliness of the epithelium, and the presence of stromal component can prevent overdiagnosis.

UTERINE TUMORS18 Endometrial carcinoma is the most common gynecologic malignancy in the United States. Currently, there are 33,000 cases/year identified, resulting in 4000 deaths. The incidence of endometrial carcinoma is increasing. Eighty percent occur in postmenopausal women who usually experience abnormal uterine bleeding.18 The risk factors are associated with obesity, diabetes, hypertension, infertility, anovulation and prolonged estrogen use. The tumor may recur as a pelvic mass, via lymphagitic spread to the pelvic and paraaortic nodes or via hematogenous dissemination to distant sites, including the lung, liver, bone and brain. Endometrial carcinoma is classified as follows18,33 :

Endometrioid Adenocarcinoma (Type 1 Endometrial Carcinoma) This tumor constitutes 80% of all endometrial carcinomas. It arises in a background of endometrial hyperplasia, linking this neoplasm to prolonged estrogenic stimulation without progestational agents, such as estrogen replacement therapy or estrogen secreting tumors. It is a relatively indolent tumor. Most women present with Stage I disease, resulting in 90% 5-year survival. The International Federation of Gynecology and Obstetrics (FIGO) designated three histologic grades based on architecture, elevated by nuclear grade, if discordant.33 1. FIGO grade 1 is composed of back-to-back endometrial type glands with little intervening stroma with grade 1 nuclei (Fig. 9.3). The villoglandular variant has thin, delicate fronds covered by columnar cells with grade 1 nuclei (Fig. 9.4). Occasionally, a mucinous component may be present. These cases are usually stage 1 and have a 95% relapse-free survival rate.

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2. FIGO grade 2 is composed of 6%–50% sheet-like tumor cells, without glands and with grade 2 nuclei. 3. FIGO grade 3 is composed of >50% sheet-like tumor cells lacking glands and with grade 3 nuclei (Fig. 9.5). The aspirate preparations of FIGO grade 1 endometrioid carcinoma show large cohesive fragments of epithelium in sheets (Fig. 9.3) or in papillary configuration (Image 9.4). The nuclei are elongated, granular with indistinct nucleoli (Fig. 9.4). In FIGO grade 3 carcinomas, the aspirate show large fragments of tridimensional epithelium with irregular nuclei having a vesicular chromatin pattern and distinct nucleoli (Image 9.5).

Mucinous Carcinoma (Fig. 9.6) Mucinous carcinomas are uncommon, constituting about 1–9% of endometrial carcinomas.33 Histologically, this tumor is similar to the mucinous carcinoma of the endocervix and behaves like the Type 1 endometrial carcinoma. The aspirate preparations from mucinous carcinoma show abundant background mucin containing fragments of bland epithelium in small and medium-sized groupings. Mucinous carcinoma of endometrial origin can be distinguished from those of endocervical origin by immunostains. Mucinous carcinomas from the endometrium are typically ER+, Vimentin+ and CEA+.

Uterine Papillary Serous Carcinoma (Fig. 9.7) Uterine papillary serous carcinoma (Type 2 endometrial carcinoma) arises in atrophic endometrium in elderly female. It is associated with p53 mutations and loss of heterozygosity. This neoplasm is aggressive. Forty percent of the patients with stage I disease will die of the disease. It may have only superficial endometrial invasion but is still an extensive peritoneal disease via tubal or angiolymphatic spread. Histologically, this tumor is similar to papillary serous carcinoma of the ovary. This tumor cells have grade 3 nuclei, typically in hobnail cells in a complex papillary architecture. The papillary fronds may be short and fibrotic at the base and thin and delicate with small detached buds and tufts at the tip.33 The tumor is associated with psammoma bodies

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in 40% of the cases. The nuclei are immunoreactive to p53, but negative for ER or PR. The aspirate preparations show single cells with retained cytoplasm surrounding very long fragments of thick fibrovascular cores covered by tumor cells. The nuclei are large, round, and have very pale chromatin with prominent nucleoli. (Fig. 9.7).

Clear Cell Carcinoma (Figs. 9.8–9.9) This high grade carcinoma is the least common of the endometrial epithelial malignancies, with a prevalence of 1–6% and a mean age in the late 60s.33 Histologically, this tumor is usually composed of large glycogen-rich, clear cells with papillary formations around hyalinized cores and hobnail cells with high grade nuclei. It may exhibit solid, papillary, tubular or cystic pattern. The tumor cells are ER+, PR+, less commonly p53+ compared with a uterine papillary serous carcinoma. The aspirate preparations show cohesive clear cells with papillary formation around a hyalinized core (Fig. 9.8) and hobnail cells with large nuclei with prominent nucleoli. The cytoplasm can sometimes be granular, but with at least focal cytoplasmic clearing. The architectural pattern can sometimes be glandular and the cytoplasm filled with neutrophils (Fig. 9.10).

Carcinosarcoma (Malignant Mixed Mullerian Tumor) (Figs. 9.10–9.11) Carcinosarcoma is now the preferred term18,33 since the mesenchymal component has been proven to be a high grade metaplastic carcinoma by molecular,20,43 immunohistochemical10 and ultrastructural studies.10 The tumor constitutes < 5% of uterine malignancies.40 The behavior of this tumor is significantly worse than papillary serous carcinoma and clear cell carcinoma with a five-year survival of 25–35%. This neoplasm typically occurs in elderly postmenopausal women with an average age of 65 years. It may occur in younger women with a history of prior pelvic radiation. Both carcinomatous and sarcomatous components of this biphasic tumor arise from a common precursor cell and subsequently manifest different phenotypes.20,43 Histologically, the carcinomatous component is glandular

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(endometrioid, clear cell, serous), and usually high grade. The sarcomatous components can be homologous (endometrial stromal sarcoma, leiomyosarcoma) or heterologous (skeletal muscle, cartilage, osteoid or fat). The aspirate preparations frequently sample only the carcinomatous component (Fig. 9.11), which is more invasive33 and apparently easier to aspirate than the sarcomatous component. Occasionally, both components are present in a sample (Fig. 9.10).

Endometrial Stromal Sarcoma (Figs. 9.12–9.15) This tumor constitutes 0.2–1.5% of uterine malignancies and < 20% of all uterine sarcomas.22,50 The mean age is 42–53 years and >50% of patients are premenopausal.8 Traditionally, endometrial stroma sarcoma is divided into low-grade and high grade.29 Although the validity of this division has recently been questioned,18 the subdivision is still popular.33 The vast majority of these tumors are of the low grade type, which is an indolent disease. Up to 50% of patients develop local recurrence in 10 years, and 15% may develop pulmonary metastases 20–30 years later. The metastatic tumor frequently respond to progestational therapy.6 Histologically, low-grade endometrial stromal sarcoma is composed of monotonous ovoid cells with indistinct nucleoli and minimal cytoplasm intimately associated with arborizing arterioles. This neoplasm resembles endometrial stroma in the proliferative phase. The high-grade type has more tumor cells with cytoplasm and larger, more vesicular nuclei with more prominent nucleoli and coarser chromatin. The vascular pattern and reticulin meshwork are irregular. Endometrial stromal sarcomas are immunoreactive to CD10, vimentin and ER/PR. Some cases may show smooth muscle differentiation expressing desmin. In that situation, CD10 immunostain positivity confirms the diagnosis and excludes a smooth muscle tumor.9 The aspiraton cytology of low48 as well as highgrade23,27 endometrial sarcoma has been reported. The aspirate preparations of low-grade endometrial stromal sarcoma show extremely cohesive (cohesion factor, 5) tissue fragments of monotonous small (8–9 µm) ovoid cells, tightly woven together by the metachromatic extracellular matrix. The nuclei are bland and normochromatic, and the

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cytoplasm indistinct. Occasional small arterioles transect the tissue fragments. (Fig. 9.12). The tumor cells are individually wrapped by reticulin fibers in a basket weave pattern on cell block (Fig. 9.13). The aspirates of high-grade endometrial stromal sarcoma are loosely cohesive (cohesion factor, 3 to 4) tissue fragments associated with blood vessels, with less metachromatic matrix (Fig. 9.14). Tumor cells have a moderate amount of cytoplasm with distinct cell borders, and the nuclei larger, with more vesicular chromatin pattern and with prominent nucleoli (Fig. 9.14). Multinucleated cells are occasionally present.

MYOMETRIAL TUMORS Leiomyoma (Fig. 9.16) Leiomyoma can occasionally present as a pelvic mass, from an exophytic leiomyoma, parasitic leiomyoma or retroperitoneal leiomyoma.3 This tumor is estrogen-promoted and is most frequently seen in women of fertility age. Histologically, it resembles myometrium, and is composed of uniform cells with elongated nuclei and moderate amount of cytoplasm. The nuclei have no atypia and there is minimal mitotic activity. Leiomyomas are ER+ and PR+. The aspirate preparations show large cohesive fragments (cohesion factor, 5) of parallel rows of spindle cells with cigar-shaped nuclei in the spindle cell type, and round to ovoid nuclei in the epithelioid type. Both types have abundant intact cytoplasm with indistinct cell borders, resulting in a syncytial appearance. The nuclear size is uniform with no clumping of chromatin and no nucleoli. Blood vessels are not seen.41

Leiomyosarcoma (Figs. 9.17–9.19) Leiomyosarcoma constitutes 1.9% of uterine malignancies and is the most common uterine sarcoma.51 It is highly aggressive. Survival is generally worse than carcinosarcoma.30 The mean age of patients with leiomyosarcoma is 50 years. It is very rare in women younger than 40 years. Most leiomyosarcomas are intramural, thus not accessible to endometrial biopsy. This neoplasm spreads to the regional lymph nodes and hematogeneously to the

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lung, liver, brain, kidney and bone. For stage I tumors, the size of the tumor is an important prognostic factor. All patients with tumors > 5 cm die of the disease, whereas three of eight die of the disease with tumors < 5 cm.13 Histologically, there are three types of leiomyosarcomas: the well-differentiated spindle cell type, the poorly-differentiated spindle cell type and the epithelioid type.31 The well-differentiated spindle cell type is composed of fascicles of spindle cells with abundant eosinophilic cytoplasm with spindly nuclei with rounded ends. The nuclei are hyperchromatic with coarse chromatin and prominent nucleoli. Cellular pleomorphism marks the poorlydifferentiated type. Multinucleated tumor cells are frequently found in the poorly differentiated tumors. The tumor cells in the epithelioid cell type have round nuclei with a plumper cell configuration.31 Leiomyosarcomas are immunoreactive to desmin, smooth muscle actin and vimentin, but not to CD10, a marker consistently expressed by low-grade endometrial stromal sarcomas.9 Cytomorphologically, the tumors can also be classified into three types.41

1.

Well-differentiated spindle cell type (Fig. 9.17)

Tumor cells occur in cohesive groupings with closely packed cells containing cigar-shaped nuclei in a parallel and side by side arrangement. The elongated or cigar-shaped nuclei have blunt ends and have little recognizable cytoplasm or small amounts of well-defined cytoplasm. As compared with normal smooth muscle cells, the nuclei of well-differentiated leiomyosarcoma are larger and slightly hyperchromatic. Blood vessels can be seen in the tumor fragments.41

2.

Poorly-differentiated spindle cell type (Fig. 9.18)

Tumor cells occur singly and in loose groupings with ovoid, elongated or irregular-shaped nuclei. Nuclear chromatin is coarse. The cytoplasm of the mononuclear tumor cells is scanty and poorly defined, whereas the multinucleated tumor cells have moderate amounts of well-defined cytoplasm. Many stripped nuclei are frequently present and possess small to moderate amounts of cytoplasm. Tumor necrosis may be present.41

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Epithelioid cell type (Fig. 9.19)

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The tumor cells (cohesion factor, 0 to 1) lie singly or in loose groupings. The nuclei are round to ovoid with variation in size and coarse clumping of chromatin. Nucleoli are present. The tumor cell cytoplasm is scanty and fragile and there are many stripped nuclei.41 Multinucleated tumor cells with moderate to abundant amount of cytoplasms are occasionally seen.

CERVIX Mucinous Adenocarcinoma (Figs. 9.20–9.21) Adenocarcinoma of the cervix is most commonly of the mucinous type, constituting 57%, in one series. The second most common type is endometrioid type, 30%, followed by clear cell type, (11%), and other types (3%).35 The precursor lesion, adenocarcinoma in situ, is associated with high risk human papillomavirus, HPV18 and HPV16 in a ratio of 2:1.15,42 There are three histologic types of mucinous adenocarcinoma47 : 1) Endocervical type: Mucinous epithelium with basal nuclei, arranged in a complex, racemose, glandular pattern; 2) Intestinal type: Similar to colonic adenocarcinoma — the cells are pseudostratified with scanty intracellular mucin, and with various amount of goblet cells; 3) Signet-ring cell type, which are usually intermixed with other types. Mucinous adenocarcinomas of the cervix are CEA+, ER/PR− and vimentin−. This panel of antibodies is useful to distinguish look-alike mucinous tumors primary in the endometrium.18 The aspirate preparations of endocervical type of mucinous adenocarcinoma typically show abundant mucin containing monolayers of bland epithelium composed of oval nuclei with an open chromatin pattern (Fig. 9.20). Rarely, the mucin is absent in a metastasis, and instead the tumor is associated with marked acute inflammation. The tumor cells are arranged in thick honeycomb sheets correlating to the pseudostratified epithelium on cell block, or thin sheets of honeycomb epithelium correlating to a simple cuboidal mucinous epithelium with basal nuclei on the cell block (Fig. 9.21).

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Squamous Cell Carcinoma (Figs. 9.22–9.24) Invasive squamous cell carcinoma of the cervix has decreased dramatically in incidence in North America due to the massive screening with the Pap test. We still encounter these tumors in patients immigrating from the developing countries, or in patients who have never had a Pap test. Metastasis or as local recurrence may be aspirated. The precursor, cervical intraepithelial lesion, is associated with human papilloma virus (HPV) infections, mainly HPV types 16, 18 and 31. HPV vaccines are currently under clinical trial. There are two main types squamous cell carcinoma: keratinizing and non-keratinizing, according to the current classification.47 The keratinizing type (Fig. 9.22) is characterized by well-differentiated squamous cells arranged in nests. In the exocervix, when the proliferating basal layer matures and makes keratin, the cells are being pushed toward the surface. The squamous cancer cells are arranged in nests with the proliferating cells oriented at the periphery, and maturing cells being pushed to the center, resulting in a concentric nest of keratin, i.e. the diagnostic squamous “pearl.” Tumor cells from the spinous layer have abundant eosinophilic cytoplasm and prominent intercellular bridges.47 The aspirate preparations show numerous orangeophilic refractile keratin, derived from the “pearls” and keratinized tumor cells scattered singly among fragments of cohesive epithelium (proliferating cells). The proliferating cells have round nuclei with distinct nucleoli and basophilic or amphophilic cytoplasm without any evidence of keratinization. The cytologic diagnosis is straightforward. The non-keratinizing type (Fig. 9.23) is characterized by nests of cells undergoing individual keratinization. The intercellular bridges are not as prominent as in the keratinizing type. The basaloid squamous cell carcinoma also belongs to this type.47 The aspirate preparations show cohesive fragments of epithelium with frequent individual cell keratinization. The tumor cells have scanty cytoplasm and round to oval nuclei with coarse chromatin. The squamous differentiation can be challenging to recognize. The key is to recognize individual cell keratinization, which sometimes pops out from the effect of smearing, leaving a intracytoplasmic vacuole (Fig. 9.23), mimicking adenosquamous carcinoma. In some cases, there is no individual cell keratinization and the cells

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have a soft cytoplasm and the nuclei have distinct nucleoli (Fig. 9.24). Without a cell block, it could be difficult to recognize squamous differentiation.

FALLOPIAN TUBE CANCERS Fallopian tube malignancies are rare, and constitutes only 0.3 to 2% of genital tract malignancies. Cancer of the fallopian tube usually presents at high stage with pelvic extension or positive peritoneal cytology. The mean patient age is 57 years. The five-year survival is 77% for stage 1 and 20% for stage 3. It is associated with BRACA1 and 2 gene mutations. Fifty percent of the tubal carcinomas are papillary serous; 25% are endometrioid; and 20% are undifferentiated.46 The aspiration cytology at metastatic sites is indistinguishable from similar tumors of the ovary and uterus.

OVARIAN CANCERS The 1998 WHO classication of primary ovarian tumors, that is unchanged from the previous classification based on cell differentiation, includes the surface epithelial cell type, the sex cord-stromal type, and the germ cell type.37

Surface Epithelial Tumors Malignant surface epithelial tumors represent about 90% of ovarian cancers in the Western world,34 but they account for considerably fewer ovarian neoplasms in the Far East. The tissue of origin is considered to be the surface celomic mesothelium that covers the ovary. This embroyonic origin is reflected in the various directions of müllerian differentiation, i.e. serous: fallopian tube, endometrioid: endometrium, and mucinous: endocervical.34 These tumors can be predominantly cystic and papillary, solid, or cystic and solid.

Serous neoplasms Serous neoplasms make up 25 to 30% of all ovarian tumors. In the overall spectrum of serous neoplasms, about 10% are benign, 30% borderline, and

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60% fully malignant. The histologic feature of malignancy is destructive invasive growth. Borderline serous tumors are often multilocular and have a complex papillary pattern, with closely packed, fine papillae (Figs. 9.25– 9.26). Variable degrees of dysplastic nuclear change and mitotic activity are present. Serous carcinoma is the most common (40–50%) ovarian cancer. Bilateral ovarian involvement occurs in about 2/3 of cases, and widely disseminated in 80–85% cases. The peak incidence is at 45–65 years. Histologically, this neoplasm is divided into three types34,37,38 : 1. Well-differentiated type: Papillae are large and clearly formed. 2. Moderately differentiated type. Micropapillae with finer and more crowded papillae. 3. Poorly-differentiated type: No papillae with solid sheets of small, dark cells and larger cells with moderate amphophilic cytoplasm; bizarre mononuclear or syncytial-like giant cells. The aspirates of serous carcinoma are usually highly cellular, and the aspirate preparations contain tumor cells (cohesion factor, 4 to 5) in cohesive groupings; in sheets; and in papillary arrangements (Fig. 9.27). The tumor cells have round or ovoid nuclei with coarsely granular chromatin and prominent nucleoli. They have small or moderate amounts of cytoplasm. Psammoma bodies are present in some papillary structures (Fig. 9.27C). In cases of borderline serous tumors, some tumor cells have uniform, round or ovoid nuclei and moderate amounts of cytoplasm (Fig. 9.24). In the examples of serous carcinoma, the tumor cells show nuclear pleomorphism with prominent nucleoli and increased nuclear-cytoplasmic ratio (Figs. 9.27– 9.28). Serous cystadenocarcinoma presents as an ovarian cystic mass. The aspiration samples mostly the cyst fluid, which needs to be concentrated by centrifugation prior to smearing. The tumor cells have the same surface tension artifacts as the effusion cytology (Fig. 9.28).

Endometrioid carcinoma This tumor is the second most frequent (20–25%) ovarian cancer.34 Morphologically, this tumor is indistinguishable from primary endometrial adenocarcinomas. It presents bilaterally in 28% of the cases. This neoplasm is

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confined to the ovaries and adjacent pelvic structures in most patients. Up to 31% of ovarian endometrioid carcinomas are associated with endometriosis. The peak incidence is 50–60 years. Similar to endometrial carcinomas, there are several subtypes. The aspirate illustrated (Fig. 9.29) shows dyscohesive glandular tumor cells. The tumor cells have ovoid nuclei, often with conspicuous nucleoli and small amounts of poorly defined cytoplasm. Intracytoplasmic mucin may be present in a few tumor cells.

Mucinous neoplasm Mucinous neoplasms are less common than the serous neoplasms and account for about 20% of all ovarian tumors.34 Unlike serous neoplasms, the mucinous cystadenomas are much more common than the mucinous cystadenocarcinomas, in a ratio of approximately 7 to 1. Therefore, the latter is relatively rare and accounts for only 3% of all ovarian cancers.34 The mucinous neoplasms are more likely to be unilateral than serous tumors. Approximately 5% of the mucinous cystadenoma and 20% of both borderline and malignant mucinous tumors are bilateral. These neoplasms also tend to be more strikingly multiloculated. Rupture of a malignant mucinous tumor may give rise to pseudomyxoma peritonea.

Borderline mucinous cystic neoplasm (Fig. 9.30) By histologic examination, piling up of epithelium, anaplasia of epithelial cells, formation of papillae, invasion of the capsule, and formation of solid masses of neoplastic cells are indicators of probable malignancy. In contrast, in borderline tumors, there is no stromal invasion, and the epithelial proliferation, although sometimes cytologically atypical, remains no more than three cells thick.37 The aspirate preparations of a case of borderline mucinous cystic neoplasm is illustrated in Fig. 9.30. An abundant soft background mucin containing long fragments of mucinous epithelium with minimal nuclear atypia is found. However, in borderline tumors, although a small number of tumor

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cells may show nuclear pleomorphism with prominent nucleoli, the overall findings are only suggestive but not conclusive of malignancy on purely cytomorphologic grounds.

Mucinous adenocarcinoma (Fig. 9.31) This tumor is the third most frequent (5–10%) of ovarian cancer and represents 5–10% of all ovarian mucinous tumors. 15–20% are bilateral. It presents as a large (15–30 cm), cystic, multilocular and solid mass. The peak incidence is at 40–70 years.34 Histologically, there are three types: 1. Well-differentiated type (Fig. 9.31), i.e. intestinal type with goblet cells, resembling mucinous adenocarcinoma of the large intestine. 2. Moderately differentiated type resembling colloid carcinoma, with nodular thick extracellular mucin containing cords and cresents of atypical cells with intracytoplasmic mucin. 3. Poorly-differentiated type resembling signet ring cell carcinoma with small clusters or single cells infiltrating a dense desmoplastic stroma. The aspirate preparations contain tumor cells (cohesion factor, 4 to 5) in cohesive clusters and some in papillary arrangements. The tumor cells have large, round or ovoid nuclei with coarse clumping of chromatin and frequent prominent nuclei and large amounts of vacuolated cytoplasm. In many groups of tumor cells, nuclear anaplasia and pleomorphism are apparent, and the nuclei show distinct morphologic features of malignancy. The aspirate preparation of a case of well-differentiated mucinous adenocarcinoma of the ovary is illustrated in Fig. 9.30. Though morphologically similar, the coordinated cytokeratin profile is different. CK7+/CK20+ for the mucinous ovarian tumor and CK7−/CK20+ for mucinous colonic tumor.45

Carcinosarcoma (malignant mixed mullerian tumor) This ovarian neoplasm represents 80% of the cases; 85% of the patients have no clinical evidence of the persistent or progressive disease on follow-up, and most remain well following resection of the recurrent tumor.3,50 The aspirate cytology is similar to the ovarian borderline serous tumors with small bland nuclei (Fig. 9.24).

Pseudomyxoma Peritonei (Fig. 10.5) Peritoneal spread of a mucinous neoplasms may be accompanied by pseudomyxoma peritonei. The peritoneal involvement is usually multifocal. It includes mucinous ascites, mucin deposits containing inflammatory and

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mesothelial cells, and dissection of mucin through dense collagenous tissue. Neoplastic cells are usually well-differentiated mucinous columnar cells of the intestinal type and occasionally signet ring cells. In the majority of cases, the primary is from the appendix. In a minority of cases, the primary is ovarian mucinous borderline tumors, or mucinous tumors in other sites. However, most studies reveal the majority of cystic ovarian mucinous tumors associated with pseudomyxoma peritonei are in fact metastasis from an appendiceal primary.35,37,52

MESOTHELIOMAS Peritoneal mesotheliomas are relatively uncommon. They are a primary neoplasm of the visceral and parietal mesothelial lining cells. The types of mesothelioma seen in the peritoneum are similar to those of the pleura, but the relative proportions vary a great deal. For example, the pure fibrous type, which is relatively common in the pleural space, constitutes only a minority of the peritoneal mesotheliomas. The majority of the peritoneal mesotheliomas are of the epithelial type, and most of them are either solitary and benign or diffuse and malignant. Mesotheliomas of the mixed type and the undifferentiated type are occasionally seen. Pleural and peritoneal mesotheliomas may coexist. Ultrasonography and CT-scan are helpful in the assessment of this disease.26,36

Malignant Epithelial Mesothelioma (Figs. 10.6–10.12) Most cases of malignant epithelial mesothelioma of the peritoneum occur in males over 40 years of age, usually with a history of asbestos exposure. The typical clinical presentations include recurrent ascites, abdominal cramps and intermittent partial bowel obstruction. The prognosis for malignant peritoneal mesotheliomas is extremely poor. Most patients die of the disease within two years of the diagnosis. Patients usually present as multiple plaques or nodules scattered over the visceral and parietal peritoneum. Mesothelioma may be accompanied by dense intraperitoneal adhesions with ascites. The tumor infiltrates adjacent tissues and organs by direct extension rather than by dissemination to distant organs, but mesothelioma frequently metastasize to the regional lymph

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nodes. In the advanced stages, the tumor may invade the gastrointestinal wall, the hilum of spleen and liver, the pancreas and the retroperitoneum. Complete obliteration of the peritoneal cavity may eventually develop. The prognosis is always poor. Malignant epithelial mesotheliomas of the peritoneum have a wide variety of histologic appearances. The epithelial elements may form tubules, pseudoacini, or papillae, lined by cuboidal cells (Fig. 10.12). Alternatively, they may grow as solid nests or be composed of cells that resemble the large, polygonal mesothelial cells (Fig. 10.7) seen in peritoneal effusions. As would be expected, the aspirate preparations from malignant epithelial mesotheliomas from different patients can have variable cytomorphologic appearances. On the basis of their cytomorphologic characteristics in relation to histologic features, malignant epithelial mesotheliomas can be divided into three types:

Cohesive Cell Type (Figs. 10.6–10.8) The aspirate preparations often contain tumor cells (cohesion factor, 4 to 5) in cohesive groupings and in sheets with occasional slits between the cells. Their nuclei are round or oval and are usually centrally located. There is often variation in nuclear size. The chromatin has a slightly coarsely granular pattern, and prominent nucleoli are seen in some tumor cells. The cytoplasm of some tumor cells is well-defined and dense. Multinucleation is not an uncommon finding.

Noncohesive Cell Type (Fig. 10.9) The aspirate preparations contain tumor cells (cohesion factor, 1 to 2) in non-cohesive groupings and solitary neoplastic cells. Flat sheets of tumor cells with prominent cell separation are usually encountered. The tumor cells are round, polygonal or spindle-shaped. Some of them have elongated cytoplasmic tails. Their nuclei are round or ovoid and centrally located. Conspicuous nucleoli may be seen. The tumor cells have moderate amounts of dense cytoplasm, resembling metaplastic squamous cells. A few binucleated and multinucleated tumor cells are also evident (Fig. 10.9A). Cells that have

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vacuolated cytoplasm are occasionally observed (Fig. 10.12C). The background hyaluronic acid is readily demonstrated by Alcian blue staining with and without hyaluronidase digestion (Fig. 10.12D).

Papillary Cell Type (Figs. 10.10–10.12) The aspirate preparations contain numerous papillary fragments and cohesive clusters, mimicking papillary adenocarcinoma (Fig. 10.10). The cuboidal tumor cells (cohesion factor, 4 to 5) have round or oval nuclei that often contain prominent nucleoli and moderate amounts of cytoplasm (Figs. 10.11–10.12). Papillary structures that have a central vascular core are occasionally encountered. Psammoma bodies may be visible within the papillary structures.

Reactive Mesothelial Hyperplasia (Fig. 10.13) The mesothelial lining of the peritoneum has a great capacity to undergo hyperplasia when irritated. This hyperplasia can occur in a diffuse fashion throughout the peritoneal cavity, e.g. in patients with cirrhosis of the liver and long-standing peritoneal effusion. It can occur in a localized fashion as a response to injury. In florid examples, solid, trabecular, papillary or tubulopapillary growth patterns with limited extention of the mesothelial cells into the underlying tissue is seen.8 Psammoma bodies may be present in the stroma of the papillary structures (Fig. 10.13D). Atypical mesothelial proliferation may persist over a year without any apparent cause. In the interpretation of peritoneal aspiration biopsy, it is important to bear in mind that both reactive mesothelial hyperplasia and adenocarcinomas of various origins may resemble malignant epithelial mesothelioma7 cytomorphologically. The aspirate preparations from reactive mesothelial hyperplasia contain an abundance of mesothelial cells with relatively regular, uniform nuclei and inconspicuous nucleoli. The mesothelial cells tend to be in sheet arrangements with slits between the cells. Inflammatory cells intermingled with mesothelial cells are a frequent finding. The cytologic differentiation between reactive mesothelial hyperplasia and benign mesothelioma of the predominantly epithelial cell type is impossible on purely

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cytomorphological grounds.44 However, reactive mesothelial hyperplasia of the peritoneum forming a mass lesion detectable by imaging techniques is unusual, and a benign epithelial mesothelioma of the peritoneum is also uncommon. In our cases, this cytologic differentiation rarely presents a diagnostic problem in the interpretation of aspiration biopsy of an intraabdominal mass. The cytologic differentiation between malignant epithelial mesotheliomas and minimally secretory adenocarcinomas may be difficult on purely cytomorphologic grounds. The findings of monolayered sheets showing slits between the tumor cells, and tumor cells having dense cytoplasm together with multinucleated cells favor a mesothelioma. Histochemically, the identification of intracytoplasmic hyaluronic acid (by Alcian blue staining with and without hyalmonidase digestion) in some tumor cells confirms the diagnosis of mesothelioma. In 1996, Doglion et al. reported a novel mesotheliumspecific antibody, calretinin,14 which has so far withstood the test of time. Calretinin immunoreactivity is present in almost all mesothelioma but absent in all adenocarcinomas. Calretinin is usually used in combination with adenocarcinoma markers, including CEA,48 LeuM138 and others. Attanoos et al.1 reported that calretinin used in combination with Ber-EP4 were the most useful discriminant markers to distinguish mesotheliomas from peritoneal papillary serous carcinoma. Epithelial mesotheliomas have characteristic ultrastructural features of long, branching microvilli and an abundance of cytoplasmic glycogen granules. Tumor cells can be retrieved from a cell block, dewaxed, dehydrated and processed for electron microscopy. Though the quality cannot be compared to that of fresh tissue, it is good enough to make a diagnosis of mesothelioma in the majority of the cases (Fig. 10.12D). Although the diagnosis of a mesothelioma is sometimes difficult on purely cytomorphologic grounds, it is possible to make a definitive diagnosis with the aid of ancillary studies in combination with radiologic findings and clinical history. A multidisciplinary approach is necessary in difficult cases.40,46

TUMORS OF THE GASTROINTESTINAL TRACT Common tumors of the gastrointestinal tract include adenocarcinoma of the stomach, adenocarcinoma of the colon, carcinoid tumors, mucinous cystic

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tumors of the appendix and stromal tumors of the gastrointestinal tract. Adenocarcinoma of the small bowel is 40 to 60 times less common than its counterpart in the large bowel and is rarely encountered among our daily cases.

Adenocarcinoma of the Stomach (Figs. 10.14–10.18) Practically all carcinomas of the stomach arise from the mucus-secreting cells of the gastric mucosa. They occur in patients over 50 years of age. The tumors spread rather quickly through the wall and to the lymph nodes in both immediate and distant zones, making curative resection impossible. With the involvement of lymph nodes, the prognosis is poor. Only about 10% of the patients survive five years.33 The microscopic grading of these adenocarcinomas is of little value in estimating prognosis. However, the depth of penetration of the gastric wall and the size of the tumor is of great importance. In general, the deeper the penetration and the larger the gastric cancer, the more likely the prognosis will be worse. Thus, superficial spreading tumors and papillary or polypoid tumors have a better prognosis. Ulcerating or penetrating tumors and diffusely spreading tumors have a poorer prognosis. Lauren grouped his 1344 cases of gastric carcinoma into two main histologic types: Intestinal (53%) and diffuse (33%).25 The remaining cases were heterogeneous in composition. The tumors of the intestinal type are composed of distinct glands, sometimes containing papillary infoldings, resembling intestinal adenocarcinoma. In carcinomas of the diffuse type, the tumor cells are scattered either singly or in small clusters, and often infiltrate diffusely into the stomach wall with marked reactive desmoplasia (linitis plastica). The aspirate preparations from gastric carcinomas of the intestinal type contain abundant tumor cells in cohesive clusters. Tumor cells (cohesion factor, 4 to 5) have medium-sized or large, eccentrically placed, round or ovoid nuclei with chromatin clumping and an abundance of foamy or vacuolated cytoplasm (Figs. 10.15–10.16). Prominent nucleoli are present in some tumor cells. Multinucleated tumor cells are rare. The aspirates from gastric carcinomas of the diffuse type are usually not as abundantly cellular as the intestinal type. The tumor cells (cohesion factor, 0 to 1) occur in loose groupings and as solitary cells. They have round or ovoid, eccentrically located nuclei with variation in size and occasional prominent nucleoli. A few

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tumor cells have two or more nuclei. The tumor cells have small to moderate amounts of cytoplasm, often with a foamy appearance. In some of them, the nuclei are displaced to one side by a large mucin vacuole giving a “signet ring” appearance (Fig. 10.17). The aspirate preparations from some anaplastic carcinomas of the stomach of the diffuse type contain dispersed single tumor cells. The tumor cells (cohesion factor, 0 to 1) have pleomorphic nuclei, many located eccentrically and with no recognizable nucleoli. The neoplastic cells have small amounts of cytoplasm. Many tumor cells have two or more nuclei. The cytologic diagnosis of gastric carcinomas is straightforward, because the cellular changes of malignancy are often quite distinctive.34

APPENDIX Mucinous Cystic Tumors of the Appendix (Fig. 10.19) The majority of mucinous cystic tumors of the appendix are benign, i.e. mucinous cystadenomas. They are lined by atypical mucinous epithelium with areas of papillary configuration. Their malignant counterpart, mucinous cystadenocarcinoma, has the same gross appearance and many microscopic features in common with the benign mucinous cystadenoma. They may reach enormous size and appear as a multiloculated mass lesion in periappendicular or the retroperitoneal region. The diagnosis of malignancy can be made if there is invasion of the appendiceal wall by atypical glands or in the presence of peritoneal mucinous deposits containing mucin-secreting epithelial cells. The latter condition, when generalized, is known as pseudomyxoma peritonei. In our cases, it is difficult to assess the presence of any invasion if the tumor is large and multiloculated lesions with adhesions. Furthermore, it is often impossible to distinguish between benign and malignant tumors on the basis of cytomorphologic findings. Therefore, mucinous cystic tumor appears to be the preferred terminology in the cytologic diagnosis of these neoplasms. Most studies have found that the majority of cystic ovarian mucinous tumor associated with pseudomyxoma peritonei are appendiceal in origin. The aspirate preparations demonstrate many benign-looking, often vacuolated columnar cells in a background of mucoid material (Fig. 10.19). The tumor cells (cohesion factor, 3 to 4), that have round or ovoid nuclei,

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frequently form cohesive clusters or papillary structures with common cell borders. Some tumor cells show cellular atypia with coarse clumping of nuclear chromatin and conspicuous nucleoli, but they are not frankly malignant-looking (Figs. 10.19C and D).

Carcinoid Tumors (Figs. 10.20–10.21) Carcinoid tumor is the most common tumor of the appendix. Carcinoid tumors originate from the neuroendocrine system of the gastrointestinal tract. As these endocrine cells are present anywhere from the stomach to the rectum, so are the carcinoid tumors. About one-third of all neoplasms of the small bowel are carcinoid tumors. Most are located in the ileum, followed by jejunum and the distal appendix. They are frequently multiple (16 to 34%). Carcinoid tumors of the large bowel are rare. They occur in any portion of the large bowel but are more common in the rectum. Multicentricity is not a feature of rectal carcinoid tumors. Carcinoid tumors are malignant neoplasms that have a slow growth rate but can eventually metastasize and cause the death of the patient. The overall five-year survival rate is about 50%. However, carcinoid tumors of the stomach and duodenum are microscopically and biologically similar to those seen in the lung. They are usually locally invasive, and long-term survival is the rule. The carcinoid syndrome, which is characterized by intermittent hypertension, cyanosis of the face, palpitation and frequent watery stools is nearly always associated with carcinoid tumors with liver metastases. The most striking feature in the histologic sections is the overall impression of cellular uniformity. Microscopically, carcinoid tumors differ according to their site. Those of the stomach and duodenum are composed of tumor cells arranged in ribbons, spherical aggregates, or trabeculae. The pattern of those of the jejuno-ileum is that of solid masses of monotonous-appearing cells. In some tumors, there are acinar formations and mucin secretion, e.g. adenocarcinoid, mimicking adenocarcinoma. The latter patterns are more often seen in carcinoid tumors of the appendix (Fig. 10.20). The aspirate preparations from carcinoid tumors of both the distal small bowel and the large bowel contain tumor cells (cohesion factor, 4 to 5) in noncohesive and cohesive groupings and solitary tumor cells (Fig. 10.21). They have uniform, regular, round nuclei and small amounts of cytoplasm

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(Fig. 10.21B). The nuclei have a finely granular chromatin pattern and inconspicuous nucleoli (Fig. 10.21C). Tumor cells with vacuolated cytoplasm may be seen in tumors of the appendix. The aspirate preparations from carcinoid tumors of the stomach and duodenum contain tumor cells in loose groupings and as solitary tumor cells. Most tumor cells (cohesion factor, 1 to 2) have little recognizable cytoplasm. A few neoplastic cells that have small to moderate amounts of well-defined cytoplasm may be observed in some cases. Mucin-secreting tumor cells with vacuolated cytoplasm are not present. The nuclei are round, ovoid or elongated, and are relatively uniform and regular. The nucleoli are not seen. These cytologic features are similar to those seen in carcinoid tumors of the lung. The cytologic diagnosis of a carcinoid tumor can be confirmed by immunoreactivity for chromogranin and synaptophysin.

Adenocarcinoma of the Colon (Figs. 10.22–10.26) Adenocarcinoma of the colon is common, exceeded in frequency only by cancer of the lung and prostate in men and carcinoma of the lung and breast in women.39 About 65% of cases occur in the rectum and sigmoid colon; 5% in the cecum; and the remainder occurring about equally in other parts of the colon.9 The etiology of colorectal carcinomas appears to be multifactorial. Epidemiologic studies indicate that the incidence of colorectal carcinomas is more closely related to dietary factors, particularly in terms of fats and animal proteins and their influence on the intestinal microflora and on the chemical composition of the intraluminal content. Patients with familial polyposis and with ulcerative colitis also have a predisposition to colorectal carcinomas. Microscopically, the usual carcinoma of the colon is a well-differentiated adenocarcinoma, with glandular or tubular formations, which secretes variable amounts of mucin. A desmoplastic reaction is consistently present at the edge of the tumor. In some instances, there are large lakes of mucin with scattered collections of mucin-secreting tumor cells (colloid carcinoma). These mucinous carcinomas constitute 15% of colorectal carcinomas. There are three patterns in aspiration preparations: 1) Intestinal pattern; 2) Mucinous pattern; 3) Signet ring pattern. The smears with the intestinal pattern (Fig. 10.24) contain tumor cells (cohesion factor, 4 to 5) in cohesive clusters with medium-sized or large,

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ovoid or elongated nuclei and small to moderate amounts of cytoplasm. It is common to find some cigar-shaped nuclei in a palisading arrangement (Fig. 10.24B), a characteristic feature of adenocarcinoma of the colon. Background dirty necrosis is present only in metastasis, a helpful clue for a colonic primary. The smear with the mucinous pattern (Fig. 10.25) consists of thick mucinous material intermingled with many mucin-laden macrophages and occasional groups of mucin-secreting tumor cells with round or ovoid nuclei and vacuolated cytoplasm. Smears with the signet ring pattern (Fig. 10.26) show signet ring cells in soft background mucin. Immunohistochemically, colonic adenocarcinomas are characterized by CK7−/CK20+,49 which is most useful in confirming a colonic primary.

Gastrointestinal Stromal Tumors In 1998, Hirota et al. discovered gain-of-function mutations of c-kit in human gastrointestinal stromal tumors (GIST). GISTs are defined as c-kit-positive23 spindle cell or epithelioid mesenchymal neoplasms primary in the gastrointestinal tract, omentum and mesentery.30 Most tumors previously regarded as leiomyoma, cellular leiomyoma, leiomyoblastoma and leiomyosarcoma were found to immunoreactive to c-Kit, and thus became GIST.29 GISTs are the most common mesenchymal tumors of the gastrointestinal tract. This tumor typically presents in older individuals, but can occur in pediatric patients,27 and is most common in the stomach (60–70%), followed by the small intestine (20–25%), colon and rectum (5%) and esophagus (< 5%). Approximately 70% of GISTs are positive for CD34; 20–30% are positive for smooth muscle actin (SMA); 10% positive for S100; and < 5% positive for desmin. GISTs have phenotypic similarities with the interstitial cells of Cajal, the pacemaker cells of gastrointestinal tract and, therefore, a histogenetic origin from these cells has been suggested.24 An alternative theory is that GIST originates from the pluripotential stem cells.32 This is supported by the fact that pluripotential stem cells are the origin of both Cajal cells and smooth muscle and by the common SMA expression in GISTs. GISTs differ clinically and pathogenetically from true leiomyosarcomas (very rare in the gastrointestinal tract) and leiomyomas. The latter occur predominantly in the esophagus and the colon and rectum. They also differ from schwannomas that are benign S100-positive spindle cell tumors usually presenting in

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the stomach. Gastrointestinal autonomic nerve tumors are probably a subset of GIST. The 2002 United States National Institutes of Health consensus17 noted that all GISTs as being at some risk of malignant behavior. In some cases even small benign-looking tumors that are not growing rapidly may metastasize. The location of the tumor seems to affect the tumor’s behavior. A small tumor from the small intestine may grow more quickly and be more likely to spread than a large tumor from the stomach. When a GIST metastasizes, it usually spreads to the liver or peritoneum and rarely metastasizes to the lymph nodes. Although the exact incidence is still somewhat unclear, it is now estimated that between 5,000 and 10,000 people develop GISTs each year. Men and women are equally affected. It is important for pathologists to recognize the various microscopic appearances of GISTs, because this tumor can be effectively treated by GleevecTM (Imatinib, ST1571), the first FDA-approved drug10 that directly turns off the signal pathway of kit-receptor tyrosine kinase, critical for tumor growth, located on the cell surface of the neoplastic cells. In the European trial of 40 patients, 69% of the GIST patients responded to GleevecTM , and several patients’ tumors totally disappeared.47 In the U.S. clinical trial of 147 patients, GleevecTM induced a sustained response in > 50% of patients with advanced unresectable or metastatic GISTs.13 The first author had a similar experience with a 50-year-old man who presented with a duodenal GIST with metastasis to liver and sacrum. The follow-up CT-scan taken 14 months following treatment with GleevecTM showed no radiologic evidence of the disease (Fig. 10.27). Fine-needle aspiration cytology of GISTs have been reported.15,28,51 There are two types: Spindle cell type and epithelioid cell type. The main differential of GISTs of spindle cell type is leiomyosarcoma.51 Wieczorek et al. compared 15 cases of GISTs and 23 cases of leiomyosarcomas and found that GISTs typically showed irregularly outlined clusters of bland spindle cells that were smeared easily without crush artifact. The cells had wispy cytoplasm with long, delicate, filamentous extensions, and with a prominent vascular pattern. In contrast, the leiomyosarcomas showed tridimensional, tightly cohesive, sharply marginated syncytia of pleomorphic spindle cells, often with nuclear crush artifact. The cytoplasm/stroma had a distinct wiry, refractile appearance, usually without prominent vessels. The main differential for GISTs of the epithelioid cell type is adenocarcinoma. The aspirates

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of epithelioid GISTs show mainly single or small clusters of epithelioid cells with a moderate amount of granular to clear cytoplasm, and small uniform nuclei with minimal nuclear atypia. Binucleation and intranuclear inclusions are frequent findings. Collagenous stroma is seen in most cases.15 At the NYU Medical Center, the first author encountered 11 cases of GISTs, and found that the clue to recognize GISTs of either types was a disconcordance of nuclear features and biologic behavior. The nuclear features typically predict biologic behavior,18 but GIST is an exception. This tumor may have very bland nuclear features yet be capable of widespread metastasis. GIST of spindle cell type is shown in Figs. 10.28 to 10.30. GIST of epithelioid type is shown in Figs. 10.31 and 10.32.

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Fig. 10.1 Intraabdominal desmoplastic small round cell tumor. Histology is characterized by groups of small blue cells associated with a desmoplastic stroma. Cytogenetics showed 11p22q translocation. Core biopsy. H&E, 20×.

Fig. 10.2 Intraabdominal desmoplastic small round cell tumor in a nine-year-old male. (A) CT scan shows three masses along the abdominal wall. One contains calcifications (arrow); (B) Calcifications (arrow) were aspirated. DQ, 40×; (C) Single small tumor cells in the absence of rosettes or lymphoglandular bodies DQ, 40×; (D) Small cells smeared from a tissue fragment, but no nuclear streaking. UFP, 100×.

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Fig. 10.3 Intraabdominal desmoplastic small round cell tumor, same case as Fig. 10.2. (A) Tissue fragments connected by capillaries. UFP, 100×; (B) Round, rigid nuclei with inconspicuous nucleoli and invisible cytoplasm. UFP, 400×; (C) Cell block shows clusters of small cells in dense stroma. H&E, 400×; (D) Coexpression of cytokeratin and desmin. Immunostain. Cell block, 400×.

Fig. 10.4 Primary papillary serous carcinoma of the peritoneum. (A) Papillary configuration intermixed with fat droplets. DQ, 40×; (B) Tumor cells attached to a curved fibrovascular core. UFP, 100×; (C) P53 positive nuclei. Immunostain on cell block, 40×; (D) Cell block shows papillary serous carcinoma with high grade nuclei. H&E, 400×.

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Fig. 10.5 Pseudomyxoma peritonei, aspirated from a 66-year-old male. (A) A fragment of tumor covered by mucin. UFP, 400×; (B) Intracytoplasmic mucin is seen in a few tumor cells. UFP, 400×; (C) A tumor nest floating in mucinous pool. Cell block, H&E, 100×; (D) Tumor cells with intracytoplasmic mucin. Cell block, H&E, 400×.

Fig. 10.6 Malignant mesothelioma of the peritoneum, recurrent in a 51-year-old male. (A) Papillary formations in a background of clusters and single tumor cells. DQ, 40×; (B) Papillary formation coated by mesothelial cells. UFP, 100×; (C) Atypical mesothelial cells with multinucleation and prominent nucleoli. UFP, 400×; (D) High malignification of large atypical mesothelial cells. UFP, 1000×.

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Fig. 10.7 Malignant mesothelioma of the peritoneum, cohesive cell type, same case as above. (A) Papillary formations. Arrow points to area to be enlarged in (B). UFP, 100×; (B) Mesothelial cells with even nuclear chromatin and small nucleoli. UFP, 1000×; (C) Few cells projected out of the papillary projections like hobnail cell. UFP, 400×; (D) A morula like arrangement, a pattern typical for mesothelial cells. UFP, 1000×.

Fig. 10.8 Malignant mesothelioma of the peritoneum, cohesive cell type (same case as above). (A) Cell block shows numerous small papillary fragments. H&E, 40×; (B) High magnification shows cross section of a fragment with fibrous core. H&E, 400×; (C) Calretinin nuclear and cytoplasmic expression give mesothelial cells a “fried egg” appearance. Cell block, 400×; (D) EMA labels the long microvilli of malignant mesothelial cells. Cell block, 400×.

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Fig. 10.9 Malignant mesothelioma, noncohesive cell type. (A) Dyscohesive tumor cell with a multinucleated tumor cell. UFP, 400×; (B) Single mesothelial cells with dense cytoplasm and irregular nucleoli. UFP, 400×; (C) Arrow points to a bundle of long microvilli projected into retraction halo. UFP, 1000×; (D) Background hyaluronic acid is highlighted by Alcian blue. Cell block, AB/PAS, 400×.

Fig. 10.10 Malignant mesothelioma of the peritoneum. Papillary type, architectural features. (A) Low power show papillary fragments with fibrovascular core. DQ, 40×; (B) Tumor cells along fibrovascular core. Cell block, calretinin immunostain, 400×; (C) Papillary formations of the tumor cell outlined by EMA. Cell block, immunostain, 100×; (D) Cell block shows distorted papillary and glandular groups. H&E, 100×.

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Fig. 10.11 Malignant mesothelioma of the peritoneum. Papillary type (same case as above). (A) Tumor cells are smeared off a branching fibrovascular cores. UFP, 40×; (B) A branching trabeculae. Arrow points to area to be enlarged in (C). UFP, 100×; (C) Rigid cuboidal cells with round nuclei and distinct nucleoli. UFP, 400×; (D) Cell block shows sheets of malignant mesothelial cells. H&E, 400×.

Fig. 10.12 Malignant mesothelioma of the peritoneum. Papillary type (same case as above). (A) Cohesive fragment with papillary and pointed projections. UFP, 100×; (B) High magnification of both projections shows the gap between tumor cells. UFP, 400×; (C) Loosely tumor cells with distinct nuclei and cytoplasmic glycogen (arrow). UFP, 400×; (D) Long microvilliseparated the tumor cells and the glycogen lake (g). EM, 6000×.

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Fig. 10.13 Reactive mesothelial hyperplasia. (A) Hyperplastic mesothelium in papillary projections. UFP, 40×; (B) Papillary fragments composed of small bland nuclei. UFP, 1000×; (C) Papillary mesothelial hyperplasia with psammoma bodies. UFP, 100×; (D) Note the cells around psammoma bodies are small and bland. UFP, 400×.

Fig. 10.14 Normal gastric glandular epithelium with flat sheets of uniform columnar cells seen both in profile and en-face. UFP, 400×.

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Fig. 10.15 Adenocarcinoma of the stomach; mucinous type. (A) Abundant mucin surround a cohesive fragment of epithelium, DQ, 40×; (B) Sheets of tumor epithelium. UFP, 100×; (C) Sharp cell borders separating tumor cells with round nuclei and small nucleoli. 400×; (D) Cell block shows well-differentiated adenocarcinoma. H&E, 400×.

Fig. 10.16 Adenocarcinoma of the stomach; intestinal type. (A) Large fragments of tumor with high cellularity. UFP, 100×; (B) A picket fence of columnar cells, typical for intestinal type of adenocarcinoma. UFP, 400×; (C) Cell block shows well-defined gland. H&E, 40×; (D) Note the similarity to (B). Cell block, H&E, 400×.

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Fig. 10.17 Adenocarcinoma of the stomach; signet ring cell type. (A) A cluster of signet ring cells with magenta-colored intracytoplasmic mucin. DQ, 400×; (B) Signet ring cells floating in mucin. UFP, 200×; (C) & (D) Malignant nuclear features with irregular prominent nucleoli and pale hypochromatic nuclei are clearly seen. UFP, 400×.

Fig. 10.18 Poorly differentiated adenocarcinoma of the stomach, aspirated from a lymph node of a 32-year-old female post gastrectomy and chemotherapy. (A) Numerous epithelial tumor cells a mucinous background. DQ, 40×; (B) Loosely cohesive cells with abundant cytoplasm. UFP, 400×; (C) & (D) Multinucleated tumor cells with prominent nucleoli, irregular nuclei. UFP, 1000×.

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Fig. 10.19 Mucinous cystadenocarcinoma, appendiceal origin. (A) Thick viscous mucin. DQ, 40×; (B) Higher magnification shows rare cells floating in the mucin. DQ, 400×; (C) A cluster of single neoplastic cells with distinct nuclei entrapped in mucin. UFP, 400×; (D) Single bland neoplastic cell with eccentric nucleus and abundant cytoplasm. UFP, 400×.

Fig. 10.20 Adenocarcinoid of the appendix, different case from Fig. 10.19. (A) Low power shows mucin at the left and vascular network at the right. DQ, 40×; (B) Neoplastic goblet cells and neoplastic cells without intracytoplasmic mucin. UFP, 1000×; (C) Correlating histology with dual cell type. Cell block, H&E, 400×; (D) Scattered neuroendocrine cells, immunostain on cell block. 400×.

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Fig. 10.21 Carcinoid (neuroendocrine carcinoma) of small intestine, as mesenteric mass. (A) CT scan of abdomen; arrow points to the mesenteric mass; (B) Loosely cohesive uniform oval cells. Nuclear size 1–2× RBC. DQ, 400×; (C) Nuclei have “salt & pepper” chromatin with indistinct nucleoli. UFP, 1000×; (D) The mesenteric mass was a lymph node with metastatic carcinoid from ileum. Resected ileal tumor. H&E, 100×.

Fig. 10.22 Normal colonic aspirate. (A) Low power shows highly cohesive tubular glands with orderly arrangement. UFP, 100×; (B) Higher magnification shows luminal center. UFP, 400×; (C) Mucin and tubular glands. DQ, 100×; (D) Test tube-like colonic glands attached to lamina propria. UFP, 100×.

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Fig. 10.23 Adenocarcinoma of the colon, presented as abdominal mass. (A) Loosely cohesive groupings smeared away from a vascular network (arrow). UFP, 40×; (B) Disorganized architecture of the glands. UFP, 100×; (C) Oval to round hyperchromatic nuclei with irregular contours. UFP, 400×; (D) Histology in cell block showing cribiform patterned adenocarcinoma. H&E, 400×.

Fig. 10.24 Adenocarcinoma of the colon, metastatic to liver. (A) Sheets of neoplastic cells in a background of dirty necrosis. UFP, 40×; (B) Palisading “cigar-shaped” nuclei, typical pattern for colonic primary. UFP, 400×; (C) A different case also had dirty necrosis surrounding tumor cell groups. UFP, 100×; (D) Arrow points to a lumen, recapitulating colonic epithelium. UFP, 400×.

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Fig. 10.25 Adenocarcinoma of the cecum, mucinous signet ring cell type. (A) Pools of nodular mucin (arrow) along with test tube-like cecal glands. DQ, 40×; (B) Fragment of cecum on the left and a pool of thick mucin on the right (arrow). UFP, 40×; (C) Clusters of tumor cells embedded within pool of thick mucin. UFP, 200×; (D) Signet ring cells within pool of mucin. 600×. UFP, left; Cell block, Mucicarmine, right.

Fig. 10.26 Adenocarcinoma of the colon; mucinous signet ring cell type. (A) Low power shows clusters of tumor cells associated with abundant mucin. UFP, 40×; (B) High power of area marked “B” reveals neoplastic cells and lymphocytes. UFP, 400×; (C) High power of area marked “C” reveals signet ring cells floating in mucin. UFP, 400×; (D) Signet ring cells infiltrating colonic mucosa. Colonic biopsy, H&E, 100×.

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Fig. 10.27 Abdominal CT scan of a 50-year-old white male presenting with duodenal mass and hepatic and sacral metastasis (A). FNA biopsy on 7/17/02 showed c-Kit+ gastrointestinal stromal tumor. He underwent GleevecTM therapy for 14 months. Follow-up CT scan on 10/22/03 showed no radiologic evidence of disease (B).

Fig. 10.28 Gastrointestinal stromal tumor, spindle cell type, same case as Fig. 10.27. (A) Single spindle cells separated from the tissue fragment. DQ, 100×; (B) Single spindle cells radiating from the tissue fragment. UFP, 100×; (C) Cigar-shaped nuclei with blunt ends. 400×. Left : DQ 400×; right : UFP, 400×; (D) Cell block of GIST. Left : H&E, 400×; right: C-kit immunostain. 100×.

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Fig. 10.29 Gastrointestinal stromal tumor, spindle cell type, small intestinal primary. (A) Single spindle cells at the periphery of a large tissue fragments. UFP, 100×; (B) Benignappearing cigar-shaped nuclei and very long cytoplasmic tails. UFP, 400×; (C) Scanty metachromatic matrix seen between the spindle cells. DQ, 400×; (D) Cell block of spindle cell GIST, 100×. Right : H&E; left : C-kit immunostain.

Fig. 10.30 Gastrointestinal stromal tumor, spindle cell type, aspirated from liver of an 87-year-old male, who complained of abdominal fullness. (A) CT scan showed a large mass protruding from the gastric wall, invading the left lobe of the liver with metastasis at the right lobe; (B) Densely packed spindle cells with scattered naked nuclei in the background. UFP, 100×; (C) The spindly nuclei with blunted ends are connected by the metachromatic matrix. DQ, 400×; (D) Additional pass was requested during on-site assessment for cell block in order to perform immunohistochemistry. H&E, 200×. (left), C-kit (CD117) immunostain.

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Fig. 10.31 Gastrointestinal stromal tumor, epithelioid cell type. (A) Focal metachromatric matrix is seen between epithelioid GIST cells. DQ, 400×; (B) Epithelioid GIST cells with nuclear size up to 8× RBC. DQ, 400×; (C) Benign-appearing nuclei with smooth nuclear contour, fine chromatin. UFP, 400×; (D) Cell block of epithelioid GIST. Left : H&E, 100×; right : C-kit immunostain. 100×.

Fig. 10.32 Gastrointestinal stromal tumor, epithelioid cell type, gastric primary. (A) Mesenchymal tissue traversed by capillaries. DQ, 40×; (B) Densely packed tumor cells traversed by capillaries. UFP, 100×; (C) Epitheloid cells with bland nuclei. Arrow points to binucleated cells. UFP, 400×; (D) Left, cell block, epithelioid neoplastic cells. H&E, 400×; right, immunostain, 40×.

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CHAPTER 11

Malignant Lymphomas

Malignant lymphomas are essentially monoclonal proliferative processes of abnormal lymphoid cells of the immune system. They primarily involve the lymph nodes and constitute the most common malignant disease observed in the retroperitoneal space. The majority of retroperitoneal lymphomas are non-Hodgkin lymphomas. Hodgkin lymphoma presenting initially as a retroperitoneal mass is relatively rare. The lymphomas may occur as primary tumors in the retroperitoneum or as a retroperitoneal manifestation of a disseminated process. The involved lymph nodes may either remain as discrete lesions or present as mass lesions after matting of adjacent lymph nodes, combined with infiltration of soft tissues. In addition, the gastrointestinal tract is the most frequent site of primary extranodal lymphomas. Malignant lymphomas of the stomach account for half of the cases of gastrointestinal tract lymphomas, and the small bowel is the site in about 30%.23 Primary gastrointestinal Hodgkin lymphoma is exceedingly uncommon. In the past, the definitive diagnosis of primary intraperitoneal or retroperitoneal lymphoma was usually made at laparotomy. With the advent of transabdominal fine-needle aspiration biopsy in 1975, the diagnosis can be established, in many cases, without the need for surgical intervention.37,49 There are limitations to the aspiration biopsy specimens. For example, it is impossible to determine whether follicular lymphomas are follicular or have a diffuse pattern in the aspirate preparations. However, this determination matters less with the current classification, which emphasizes cytomorphologic, immunophenotypical, genetic and clinical features and places less emphasis on architectural patterns. It is also impossible to sample only 360

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the lymphoma cells restricted to the marginal zone in marginal zone lymphoma without contamination from follicular center cells. However, flow cytometry can detect a small percentage of lymphoma cells with light chain restriction in a sample containing mainly normal lymphocytes. In addition to flow cytometry,33,46,53 the aspirated viable whole cells are ideally suitable for fluorescence in situ hybridization5,21,35,53 and molecular analysis. In some cases, the amount of aspirated material is insufficient to establish a diagnosis of lymphoma. Nonetheless, aspiration biopsy is a simple, safe procedure that can be performed on an outpatient basis and readily repeated. Aspiration biopsy does not interfere with subsequent histologic study of the lymph node when the cytologic findings are not diagnostic. There are other advantages to the use of aspiration biopsy for the diagnosis of nonpalpable malignant lymphomas.58,60 This technique is especially helpful in the following settings: 1. In cases in which there is clinical suspicion of malignant lymphoma and surgical intervention is contraindicated or the patient refuses to undergo surgery. 2. In cases of malignant lymphoma in which staging is necessary and surgical intervention is not desirable. Aspiration biopsy can determine whether other lymph node regions or extralymphatic organs are involved. 3. In cases of prior malignant lymphoma, aspiration biopsy can confirm the recurrence of the tumor. 4. In cases in which there is clinical suspicion of more than one type of malignant lesion, including malignant lymphoma. 5. In cases in which it is necessary to determine whether a malignant lymphoma has evolved to a more aggressive variant.

CLASSIFICATION OF NON-HODGKIN LYMPHOMAS Major classifications of non-Hodgkin lymphomas used in the past four decades includes Rappaport, Lukes and Collins and Kiel. The Rappaport classification,51 based solely on morphologic criteria, prevailed in the 1960s and early 1970s. After that, Lukes and Collins’ classification,40 based on the T- and B-cell systems and on abnormalities in lymphocytic transformation, became popular in North America, while in Europe and Asia the

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dominant classification was the Kiel classification, which was based on the functional characteristics of the T- and B-lymphocytes with consideration given to the prognoses for different subtypes.38,39 In 1982, the International Working Formulation combined Rappaport’s division of follicular and diffuse patterns, Kiel’s grading system, and Lukes and Collins’ terminology.45 In 1994, a Revised European American Lymphoma (REAL) Classification was proposed by the International Lymphoma Study Group.24 It differed from the earlier classifications in two ways. First, the emphasis was on defining disease entities. Second, greater emphasis was placed on combining cytomorphology with immunophenotypic profile, karyotype, and molecular analysis, and less on architectural pattern. This classification makes it possible to diagnose and classify many lymphomas by fine-needle aspiration.42,68 The demonstration of monoclonality and defining the immunophotypic features became an integral part of the diagnosis. The 2001 WHO Classification28 adopted the REAL system with minor modifications, and classified lymphomas primarily according to lineages. Within each category, distinct diseases are defined according to a combination of morphology, immunophenotype, genetic features and clinical syndromes. The classification recognized three major categories: B-cell, T/natural killer (NK) cell, and Hodgkin lymphoma. These three categories are then grouped according to the predominant clinical presentation: Disseminated (bone marrow), extranodal and nodal (Table 11.1). Table 11.1

WHO Classification of Non-Hodgkin Lymphoma (2001)

B-Cell Neoplasms Precursor B-lymphoblastic leukemia/lymphoma Mature B-cell neoplasms Disseminated (Bone marrow) B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (Figs. 11.2–11.3) B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia (Fig. 11.4) Hairy cell leukemia Plasma cell myeloma or plasmacytoma (bone or extraosseous) (Figs. 11.5–11.7) Splenic marginal zone Extranodal Mucosa-associated lymphoid tissue marginal zone B-cell (MALT) lymphoma (Figs. 11.8–11.9) (Continued)

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363

(Continued)

Nodal Mantle cell lymphoma (Figs. 11.10–11.11) Follicular lymphoma (Figs. 11.12–11.13) Nodal marginal zone (monocytoid B-cell lymphoma) Nodal or Extranodal Diffuse large B-cell lymphoma Centroblastic (Figs. 11.14–11.16) Immunoblastic (Fig. 11.17) T-cell/histiocyte rich (Figs. 11.18–11.19) Anaplastic (unrelated to T-anaplastic large cell lymphoma) Mediastinal (thymic) large B-cell lymphoma (Fig. 11.20) Intravascular large B-cell lymphoma Primary effusion lymphoma (Figs. 11.21–11.22) Burkitt lymphoma/leukemia (Figs. 11.23–11.24) T-Cell and Natural Killer (NK)-Cell Neoplasms Precursor T-cell neoplasms Precursor T-lymphoblastic lymphoma/leukemia (Figs. 11.25–11.26) Blastic NK-cell lymphoma Mature T-cell and NK-cell neoplasms Disseminated Adult T-cell leukemia/lymphoma (Fig. 11.27) Extranodal NK/T cell lymphoma (Figs. 11.28–11.29) Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma Cutaneous Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides/Sezary syndrome (Fig. 11.30) Primary cutaneous anaplastic large cell lymphoma Nodal Anaplastic large cell lymphoma (Figs. 11.31–11.33) Angioimmunoblastic T-cell lymphoma (Fig. 11.34) Peripheral T-cell lymphoma, unspecified (Figs. 11.35–11.36)

In the cytologic diagnosis of non-Hodgkin lymphomas by aspiration biopsy, six basic cytologic types can be recognized: Small lymphocytic, small cleaved, mixed small and large, large, Burkitt, and lymphoblastic (Table 11.2). These six types correspond well with the presumptive stage of differentiation in non-Hodgkin lymphomas, as illustrated in Diagram 11.1.

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Transabdominal Fine-Needle Aspiration Biopsy Table 11.2 Basic Cytologic Types of Non-Hodgkin Lymphomas 1. 2. 3 4.

Small lymphocyte Small cleaved cell (mantle cell, centrocyte, marginal zone cell) Mixed small cleaved (centrocyte) and large (centroblast) Large cell a) noncleaved (centroblast) b) cleaved c) immunoblast 5. Small noncleaved a) Burkitt b) Burkitt-like 6. Lymphoblast (precursor T-cell)

Diagram 11.1 B-lymphocyte differentiation and B-cell lymphomas (2001).25 ALL/LBL: acute lymphocytic leukemia/B-lymphoblastic lymphoma, B-CLL/SLL: chronic lymphocytic leukemia/small lymphocytic lymphoma.

CURRENT CONCEPT AND DEVELOPMENT OF LYMPHOMAS The scheme of B-lymphocyte differentiation and B-cell lymphoma based on the 2001 WHO classification is shown in Diagram 11.1. Understanding of the underlying theory of the current follicular center concept, which is the basis for the classification, is helpful in the cytologic

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diagnosis of malignant lymphomas. The follicular center concept has five main aspects, as follows: 1. A follicular center is the site of normal B-cell transformation, and follicular center cells are the precursors of plasma cells. Under the influence of an antigen and T-cells, naive B-lymphocytes become mantle cells and undergo transformation in the follicular centers from follicular B-blasts to centroblasts. Centroblasts mature into centrocytes and then move to the marginal zone becoming memory B-cells, which are then transformed into IgA/IgG plasma cells in the interfollicular area. 2. Malignant lymphomas of the follicular center cell type are the result of a block or “switch on” at a certain stage of lymphocytic transformation. Therefore, malignant lymphomas of the B- and T-cell systems represent masses of defective cells at certain levels of developmental abnormality of these two systems. The follicular center cells express pan-B-cell markers (CD19, CD20, CD79a), CD10, variably increased CD20, and monoclonal surface immunoglobulin. 3. Malignant lymphomas of the follicular center cell type occur in follicular and diffuse histologic patterns. Lymphomas of the small cleaved cell type commonly have some follicular pattern and are biologically least aggressive, having a slowly progressive course. Lymphomas of the large cleaved cell type are usually minimally follicular, and those of the centroblastic (large noncleaved and cleaved) cell and immunoblastic types are usually diffuse and biologically very aggressive, having a rapidly progressive course. 4. Histologically, malignant lymphomas of the follicular center cell type evolve from a follicular to partially follicular pattern to a minimally follicular pattern, then to a diffuse pattern. Cytologically, they evolve from small cleaved cells to centroblasts (large noncleaved and cleaved cell type). For lymphomas of the small cleaved cell type, some follicular pattern tends to be maintained in patients with slowly progressive disease. However, with change in the aggressiveness of the disease, the number of cleaved cells decreases, and the noncleaved cells become predominant. The noncleaved cells commonly dominate during the aggressive phase and in tissue examined at autopsy. 5. Malignant lymphomas of the large cell type, are neoplasms of transformed lymphoid cells, either as centroblasts (large cleaved or noncleaved cells), or as immunoblasts.

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GENERAL CYTOLOGIC CRITERIA FOR THE DIAGNOSIS OF NON-HODGKIN LYMPHOMAS In our clinical practice, reactive lymphoid hyperplasia sometimes mimics malignant lymphoma clinically, radiographically and histologically.17,26 Likewise, differentiation between malignant lymphoma and reactive lymphoid hyperplasia is sometimes difficult on purely cytomorphologic grounds.12 In our experience, the following cytologic criteria are useful in distinguishing these lesions from nonneoplastic reactive conditions: 1. Monomorphic appearance of lymphoid cells (Fig. 11.2). In cases of nonHodgkin lymphoma, only abnormal lymphoid cells that have similar cytomorphologic appearances (i.e. the same cellular origin) are present in aspirate preparations. However, in cases of reactive conditions, the cell population in aspirate preparations appears polymorphic (Fig. 11.1). Cells of different origins are seen in cytology specimens. Smears prepared from reactive lymphoid tissue often contain loose groupings of recognizable follicular center cells, indicative of germinal centers (Fig. 11.1A). Macrophages that contain nuclear debris or foreign material, epithelioid cells, histiocytes, and multinucleated giant cells of the foreign-body type are other findings consistent with a reactive condition. 2. Irregularity of nuclei of lymphoid cells (Fig. 11.15). In cases of nonHodgkin lymphoma, the nuclei of the abnormal lymphoid cells have more variability in size and shape than do those seen in reactive conditions. 3. Karyorrhexis of the nuclei of lymphoid cells (Fig. 11.22). Individual cell necrosis with fragmentation of nuclei is a common finding in cases of large cell lymphomas. In reactive conditions, individual cell necrosis is not observed. If there is a necrotic process in the lesion, it is usually massive. Many necrotic cells or an abundance of necrotic cellular debris is seen in cytology specimens, as occurs in tuberculosis or fungal infections. 4. Macronucleoli or multiple conspicuous nucleoli of lymphoid cells (Fig. 11.16). This cytologic feature is seen in some large cell lymphomas. The nuclei of lymphoma cells of the immunoblastic type often contain a prominent, centrally located nucleolus. The nuclei of lymphoma cells of the large noncleaved cell type commonly have multiple conspicuous, peripherally located nucleoli. In reactive conditions, a single macronucleolus or multiple conspicuous nucleoli are a rare finding,

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although small or inconspicuous nucleoli may be seen in the nuclei of follicular center cells. The foregoing cytologic criteria, in combination with the cytomorphologic features of lymphoid cells and the results of ancillary studies, can be used to distinguish non-Hodgkin lymphomas from reactive lymphoid hyperplasia55 and to type the lymphoma from specimens obtained by aspiration biopsy. The cohesion factor of malignant lymphomas is invariably low, from 0 to 1, and the presence of lymphoglandular bodies in the Diff-Quik stained smears differentiates lymphomas from most carcinomas.

CYTOLOGIC PRESENTATIONS OF NON-HODGKIN LYMPHOMAS It is now known that the each cell type may be shared by different entities, and one entity may have several cell types, requiring analysis by immunophenotyping, cytogenetic or molecular studies. Table 11.3 lists the differential diagnosis of each cell type and Table 11.4 lists the immunophenotypes and genetic features for each small B-cell lymphomas. The following entities are presented according to the 2001 WHO classification.

B-CELL NEOPLASMS Disseminated (Bone Marrow) Clinical Presentation Small lymphocytic lymphoma/chronic lymphocytic leukemia (Figs. 11.2–11.3) The typical clinical presentation of lymphomas of this type is one of indolent course in an elderly patient. Such lymphomas have a diffuse pattern and are considered to be the tissue manifestation of chronic lymphocytic leukemia. Bone marrow involvement by this lymphoma is very common. Immunophenotyping by flow cytometry typically shows kappa or lambda light chain restriction, positivity for CD20, CD5, CD23, and negativity for TdT, CD10 and cyclin D1. Cytogenetic study demonstrates deletion at 13q14 in 50% of the cases and trisomy 12 in 20% of the cases.44 The aspirate preparations contain a monotonous population of small round lymphoid cells that measure from 6 to 12 µm. The cells have little

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+

Mantle Cell Lymphoma

Marginal Zone (MALT) Lymphoma

+ (variant)

+

Small cleaved

+ (grade 1)

+ (common)

+

Mixed small and large

+ (grade 2)

+ (variant)

+

Lympho-plasmacytoid

+

+ + (variant)

Monocytoid Large round

+ (grade 3)

Large cleaved

+ (grade 3)

Large B Cell Reactive Lymphoma Lymph Node

+

T-cell Rich +

+ scattered

+ (variant)

LymphoPlasmacytic Lymphoma

+ +

Immunoblastic

+

Anaplastic

+

+


Small lymphocytic

Small Cell Lymphocytic Follicular Lymphoma Lymphoma


Cytology

Differential Diagnosis of Cytologic Presentations

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Table 11.3

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Immunophenotypic Profile and Cytogenetic Features of Small B-cell Lymphomas Mantle Cell Lymphoma

Follicular Lymphoma Grade 1

Marginal Zone (MALT) Lymphoma

Lymphoplasmacytic Lymphoma

Surface Ig

+

+

+

+

+

CD20

+

+

+

+

+

CD5

+

+

−

−

−

bcl 2

−

+

+

+

−

TdT

−

−

−

−

−

CD10

−

−

+

−

−

Cyclin D1

−

+

−

−

−

CD23

+

−

−

−

−

CD43

+

+/−

−

+/−

+/−

Ki-67

∼ 30%

∼ 40–70%

∼ 30%

∼ 30%

t(11;14)

t(14;18) of bcl 2

t(11;18); Trisomy 3

t(9;14) PAX 5 rearranged

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Deletion at 13q14; Trisomy 12


Small Cell Lymphocytic Lymphoma

Cytogenetics

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Table 11.4

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cytoplasm and occur singly. No follicular center cells are seen. No reactive cellular components are observed in smears. In well-fixed and well-prepared cytology specimens, irregularity of the nuclei, small or inconspicuous nucleoli in some cells, and coarse clumping of chromatin can be better appreciated (Fig. 11.2). Mitosis is rarely observed. This indolent disease may eventually be transformed into diffuse large cell lymphoma in some patients (Richter’s syndrome) (Fig. 11.3). Cytologic diagnosis of this lymphoma needs to be confirmed by flow cytometry, since a variant of mantle cell lymphoma, marginal zone lymphoma, may also show a similar cytologic presentation (Table 11.3).9,11

Lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia (Fig. 11.4) This lymphoma involves bone marrow, lymph nodes and spleen. It constitutes 1.5% of nodal lymphomas,8 with a median age of 63 years and a slightly male predominance. Some cases are associated with hepatitis C virus. Histology shows a mixture of small lymphocytes, plasmacytoid cells, and plasma cells in a diffuse pattern at low power, excluding those with pseudofollicles, marginal zone pattern or containing monocytoid B-cells. This type of lymphoma is often associated with a monoclonal gammopathy. The term “Waldenstrom’s macroglobulinemia”is used if the lymphoma is accompanied by IgM monoclonal dysproteinemia. Immunophenotyping by flow cytometry typically show positivity for surface immunoglobulin, CD20, CD38, and negativity for CD5, CD10, CD23, bcl 2, TdT and cyclin D1. Cytogenetic study shows t(9;14), rearrangement of PAX 5 gene.3 The aspirates typically shows small lymphocytes with increased numbers of plasmacytoid lymphoid cells and plasma cells, and is recognizable based on cytologic features (Fig. 11.4). The cytologic diagnosis needs to be confirmed by flow cytometry, since marginal zone lymphoma,11 and some follicular lymphomas may also show lymphoplasmacytic presentation in fine-needle aspiration biopsy (Table 11.3).

Plasma cell myeloma (Figs. 11.5–11.7) Plasma cell myeloma is a marrow-based plasma cell neoplasm. This disease spans a spectrum from localized, indolent to aggressive forms affecting

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multiple sites, plasma cell leukemia and deposition of abnormal immunoglobulins in various organs. This disease is common, representing 15% of all hematopoietic malignancies and is the most common lymphoid malignancy in African Americans. It affects older adults with a medium age of 69 years, with equal gender distribution. Immunophenotypically, neoplastic plasma cells are negative for LCA, surface immunoglobulin and pan-B markers, and positive for cytoplasmic immunoglobulin, CD38, CD79a and CD138. The aspirate shows a monotonous population of plasma cells. Plasma cells are characterized by eccentric nuclei with a cartwheel chromatin pattern, and blue cytoplasm with a perinuclear hof that represents the Golgi apparatus (Fig. 11.5B). However, neoplastic plasma cells may be binucleated (Fig. 11.5D) or multilobated (Fig. 11.6), and the cytoplasm may be pale and not all nuclei are eccentric in position (Fig. 11.7). The neoplastic plasma cells may be entrapped in abundant amyloid (Fig. 11.5A) that is not recognizable until a cell block is studied. In some cases, numerous immunoglobulin crystal deposits are present intracytoplasmically and in the background of the smear (Fig. 11.5C). The diagnosis for plasma cell myeloma is generally straightforward.

Extranodal Clinical Presentation Marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) (Figs. 11.8–11.9) MALT lymphoma was included in three categories in the Working Formulation: Small lymphocytic, lymphoplasmacytoid and diffuse small cleaved cell. This type of lymphoma is associated with Helicobacter pylori infection and autoimmune diseases such as Sjögren syndrome or Hashimoto’s thyroiditis. It comprises 7–8% of all B-cell lymphomas8 with a medium age of 61 years, and a slight female predominance. It has an indolent course; even involvement of bone marrow does not appear to confer a worse prognosis. It is curable by local radiation. Cases associated with Helicobacter pylori infection are curable by antibiotics for that organism. Flow cytometry shows positivity for surface immunoglobulin, CD20, and marginal zone associated proteins CD21 and CD35, and is negative for CD5, CD10, CD23, bcl 2, cyclin D1 and TdT. Cytogenetic study shows trisomy 3 in 60% of the cases, and t(11;18) translocation in 25–50% of the patients.27

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The aspirate contains heterogeneous intermediate-sized B-lymphocytes, including marginal zone cells (centrocyte-like nuclei with more cytoplasm), monocytoid B-lymphocytes, small lymphocytes and scattered immunoblast and centroblast-like cells, and even plasma cells in some cases. It is challenging to separate MALT lymphoma from other small B-cell lymphomas without immunophenotyping by flow cytometry (Table 11.4)9,11 (Images 11.8, 11.9).

Nodal Clinical Presentation Mantle cell lymphoma (Figs. 11.10–11.11) This is a rare type of non-Hodgkin’s lymphoma that has a moderately aggressive clinical course, generally between that of a low-grade and an intermediate-grade lymphomas. A small subset, the so-called “blastoid” variant, exhibits a poor prognosis and an aggressive clinical course. Mantle cell lymphoma has the worst combination clinically, as it is aggressive, yet incurable by current chemotherapy with a three-year medium survival. Mantle cell lymphoma has a whole spectrum of cytomorphology (Table 11.3). The most common pattern is small to medium sized cells with cleaved nuclei (Fig. 11.10). In the blastoid variant (Fig. 11.11), the mantle cell lymphoma may look like lymphoblasts (classic subtype) or may look like large cleaved cells with prominent nucleoli (pleomorphic subtype). Other variants of mantle cell lymphoma mimick small lymphocytic lymphoma and marginal zone lymphoma. Mantle cell lymphoma’s diverse cytology is reflected by the inclusion of this entity in the Working Formulation: Diffuse, small cleaved cell type (most common); follicular, small cleaved; diffuse, mixed small and large cell; or large cell types. With such a wide spectrum of cytology, it is impossible to establish the diagnosis of mantle cell lymphoma without flow cytometric analysis, which shows positivity for surface immunoglobulin, CD20, bcl 2, cyclin D1 and CD5 (rare case can be negative), and negativity for CD10, CD23 and TdT.60

Follicular lymphoma (Figs. 11.12–11.13) Follicular lymphoma constitutes 35% of adult non-Hodgkin lymphoma8 with a median age of 59 years, and slight female predominance. It is usually

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widespread at presentation, including involvement of abdominal and thoracic lymph nodes. Despite widespread disease, patients are usually asymptomatic except for lymphadenopathy. There are three grades: Grade 1: small cleaved cells (centrocytes); Grade 2: small cleaved cells, small centroblasts, large centroblasts; and Grade 3: mostly large centroblasts. Grade 1 is indolent and incurable, while Grade 3 is aggressive, but potentially curable with aggressive chemotherapy. Follicular lymphoma was included in the Working Formulation as small cleaved cell type (Grade 1); mixed cell type (Grade 2); and large cell type (Grade 3). Flow cytometry is positive for surface immunoglobulin, CD20, CD10, bcl 2 and cyclin D, and negative for CD5, CD23 and TdT. Cytogenetic studies shows a t(14;18) translocation. The grading of follicular lymphoma can be supported by Ki-67 proliferative index, as measured by image cytometry, in fine-needle aspiration samples.59 Grade 1 (small cleaved cell type) The aspirate preparations contain mostly small lymphoid cells that measure 6 to 18 µm in the greatest dimension. They have indistinct or scanty cytoplasm. Their nuclei have marked variation in shape, with angulated, twisted, elongated, indented and irregular forms. Nuclear chromatin is coarse and clumped. Although small or inconspicuous nucleoli may be seen in a few cells, no conspicuous nucleoli are observed (Fig. 11.12). The differential diagnosis of small cleaved cell lymphoma also includes mantle cell lymphoma and marginal zone lymphoma (Table 11.3). Flow cytometry is needed to separate these look alike entities (Table 11.4). The Ki-67 proliferation index is about 9.7 ± 2.9% in Grade 1 follicular lymphoma.59 Grade 2 (mixed small cleaved and large cell type) The aspirate preparations contain a mixture of small cleaved cells and large cells (cleaved and/or noncleaved cells) with no predominance of one cell type (Fig. 11.13). The large cell component should account for at least 20%, but not more than 50%, of the neoplastic cell population. Any lymphoma containing more than 50% of large cells should be classified as a large cell lymphoma. The differential diagnosis of mixed lymphoma also includes a variant of mantle cell lymphoma and marginal zone lymphoma (Table 11.3) and needs immunophenotyping by flow cytometry to separate these entities

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(Table 11.4). The Ki-67 proliferation index is about 24.7 ± 5.6% in Grade 2 follicular lymphoma.59 Grade 3 (large noncleaved cell type) The aspirate preparations contain abnormal lymphoid cells that measure 20 to 40 µm. They have indistinct cytoplasm and round vesicular nuclei that contain two or three conspicuous, peripherally located nucleoli (Fig. 11.14). Mitosis and individual cell necrosis are common findings. Cleaved lymphoid cells are usually seen. The Ki-67 proliferation index is about 48.4 ± 7.5% in Grade 3 follicular lymphoma.59 The differential diagnosis of large noncleaved cell lymphoma includes diffuse large B-cell lymphoma as described below.

Nodal and Extranodal Clinical Presentation Diffuse large B-cell lymphoma (Figs. 11.14–11.19) The size of the neoplastic cells measure 20 to 40 µm, encompassing in the Working Formulation: Diffuse large cell, large cell immunoblastic, and diffuse mixed small and large cell lymphoma. This neoplasm constitutes 30– 40% of adult non-Hodgkin lymphomas8 in the Western countries, and has an even higher incidence in the developing countries. The most common site is the gastrointestinal tract (stomach or ileocecal regon), but virtually any anatomic sites can be the primary presentation site, including the central nervous system, bone, testis, female genital tract, lung, kidney, liver and spleen. Patients typically present with a rapidly enlarging mass. Though aggressive, this disease is potentially curable with modern chemotherapy. Immunophenotyping shows positivity for LCA and pan-B cell markers (CD20, CD22, CD79a), CD30 (anaplastic variant), CD5 (10%) and CD10 (25–50%). The Ki-67 proliferation index is >90%. There are four types of diffuse large B-cell lymphoma.20 1.

Centroblastic

This subtype is the most common. It can be monomorphic or polymorphic with polylobated cells. The aspirate preparations of the monomorphic type contains lymphoid cells that measure 20 to 40 µm. The neoplastic cells have indistinct cytoplasm and round vesicular nuclei that contain two or three

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conspicuous peripherally located nucleoli (Fig. 11.14). Mitosis and individual cell necrosis are common findings. The aspirate preparations of the polymorphic variant have polylobated cells and contain mostly lymphoid cells that measure 15 to 30 µm (Fig. 11.15). They have small amounts of indistinct cytoplasm. There is prominent nuclear irregularity, and many nuclei show some degree of cleavage. The nuclear chromatin is coarsely granular, and the nucleoli are lacking or inconspicuous. A few mitotic figures are observed. Large noncleaved lymphoid cells may be seen. Lymphomas of this type frequently present in the mesentery, retroperitoneum or inguinal area. Extranodal involvement is a common occurrence. 2. Immunoblastic This subtype is defined by the presence of over 90% immunoblasts. The cells measure 20 to 40 µm with ovoid vesicular nuclei containing a prominent, centrally located nucleolus. There is margination of the chromatin, resulting in a thick nuclear membrane. Immunoblasts typically have moderate or large amounts of basophilic cytoplasm in Diff-Quik stained smears (Fig. 11.16). Plasmacytoid changes may be observed. This highly aggressive lymphoma may occur at any age but is most frequently observed in elderly patients or patients with an abnormal immune state, for example, immunodeficiency, drug hypersensitivity or systemic lupus erythematosus. Immunoblastic lymphoma has a rapidly progressive course. 3. T-cell/histiocyte rich The aspirates of this subtype contain scattered large neoplastic cells in a background of small lymphocytes mimicking Hodgkin lymphoma. By definition, 90% of the cells are T cells with or without histiocytes (Fig. 11.17). Less than 10% are neoplastic large B-cells, which may resemble L&H cells, Hodgkin cells or Reed-Sternberg cells. However, the nuclear membranes of these cells are less dimpled, the chromatin is coarser and the nucleoli smaller and less irregular than the CD30+ neoplastic cells of classic Hodgkin lymphoma (Fig. 11.18). The other differential diagnosis is nodular lymphocyte predominant Hodgkin lymphoma. Both entities have neoplastic large B-cells scattered among 90% reactive small lymphocytes. However, the background small lymphocytes are B-cells in the nodular lymphocyte predominant Hodgkin

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lymphoma. Diagnosis of T-cell rich large B-cell lymphoma by a combination of fine-needle aspiration cytology and immunohistochemistry was reported by Tani et al.62 4. Anaplastic In B-cell anaplastic lymphoma, pleomorphic cells in a cohesive pattern and in a sinusoidal distribution are found. Though CD30+, this lymphoma is unrelated to T-cell anaplastic lymphoma.

Mediastinal (thymic) large B-cell lymphoma (Figs. 11.19–11.20) Most patients are in their 30s–50s with a slight female predominance. The patients frequently present with superior vena cava syndrome from the rapidly enlarging anterior mediastinal mass. Thymic B-cell is the postulated cell of origin. Clinically, the response to intensive chemotherapy, with or without radiation, is good; however, long term remission correlates with the initial stage of disease.2 Cytogenetic study shows a hyperdiploid karyotype with gains of 9p and amplification of the REL gene and MAL gene.31 The aspirate preparations usually show a dual population of large neoplastic B-cells intermixed with small thymic T-lymphocytes (Fig. 11.20). The neoplastic cells vary in nuclear size and shape, but most have abundant pale cytoplasm and show positivity for LCA, CD20 and CD30 (focal to extensive), and negative for CD5, CD10 and bcl 2. Due to the dual cell type and the thymic location, the differential diagnosis in aspirate preparations includes thymoma. Immunohistochemistry on a cell block is essential in establishing the diagnosis (Figs. 11.19–11.20). Flow cytometry may be falsely negative and show only T lymphocytes due to the entrapment of large neoplastic cells in the thymic connective tissue, reducing their number in the aspirate.

Primary effusion lymphoma (Figs. 11.21–11.22) Primary effusion lymphoma is associated with Kaposi sarcoma-associated human Herpes 8 virus (KSHV/HHV8).6 The putative cell of origin is a post-germinal center B-cell. The morphology varies from plasmablastic, immunoblastic to anaplastic (Figs. 11.21–11.22) and is easily recognized as a high grade lymphoma. The lymphoma cells show immunoreactivity for HHV8/KSHV-associated latent protein, LCA, CD3 (+/−cytoplasmic) and

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plasma cell-related markers (CD30, CD38, CD138). The lymphoma cells are negative for B-cell markers. Flow cytometry is usually not helpful. It affects immunodeficient patients from various etiologies. The prognosis is dismal, with < 6 months survival, despite current chemotherapy.

Burkitt lymphoma (Fig. 11.23) Clinically,this lymphoma is highly aggressive but potentially curable. The cure rates can reach 90% in patients with low stage disease. There are three clinical variants: Endemic, sporadic and immunodeficiency associated.16 EpsteinBarr virus plays an important role in the endemic and sporadic variants. HIV infection is associated with the immunodeficiency related variant. The endemic variant typically occurs in young boys in Africa, with the jaws being most common site of presentation. The sporadic variant occurs in the U.S., and abdominal masses are the most common primary site with the ileocecal region being the most frequent. The immunodeficiency-related variant frequently involves lymph nodes and bone marrow. Genetic study shows clonal rearrangement of immunoglobulin heavy and light chain genes. Translocation of the c-myc gene at band q24 from chromosome 8 to the immunoglobulin heavy chain region on chromosome 14 t(8:14) is found.13 Immunophenotypes are positive for CD20, CD10 and bcl 6+, and negative for CD5, bcl 2, TdT, cyclin D1 and CD23. The Ki-67 proliferation index is nearly 100%. The aspirate of Burkitt lymphoma is characterized by a monotonous population of medium-sized cells with deep blue lipid-laden cytoplasm (DiffQuik stain) and round nuclei with a fine chromatin pattern. One to four nucleoli are located centrally or near the nuclear membrane. At low power, a “starry sky” pattern from tingible-body macrophages can be seen. Individual cell necrosis and mitotic figures are common findings14 (Fig. 11.23). The cytologic diagnosis is usually straightforward, but flow cytometry is not as helpful due to the rapid death of high grade lymphoma cells, and sharing of similar immunotype of other lymphomas of follicular center origin.

Burkitt-like lymphoma (Fig. 11.24) Similar to the classic Burkitt lymphoma, the lymphoma cell cytoplasm is deeply blue in Diff-Quik stained smear and filled with lipid vacuoles. There is a high degree of apoptosis and mitosis with a growth fraction of nearly 100%.

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In comparison to classic Burkitt lymphoma, this variant shows a greater variation in nuclear size and shape with more prominent nucleoli and fewer nucleoli (Fig. 11.24).

T-CELL NEOPLASMS Precursor T-Lymphoblastic Lymphoma/Leukemia (Figs. 11.25–11.26) This lymphoma arises in the thymus and presents as mediastinal masses in 50% of the cases. The disease most frequently affects adolescent males. Involvement of the central nervous system and bone marrow is a common occurrence. This highly aggressive lymphoma usually disseminates rapidly, and the response to modern therapy is as favorable as B-ALL. All lymphomas of the lymphoblastic type are of T-cell origin and have a diffuse pattern. The lymphoblasts are positive for TdT and T-cell markers (CD1, CD2, CD3, CD4, CD5, CD7 and CD8) and may express myeloid markers. CD3 is considered lineage specific.4 The differential diagnosis includes Burkitt lymphoma, and the blastoid variant of mantle cell lymphoma. The absence of TdT expression can exclude these lymphomas. This type of T-cell lymphoma includes convoluted cell and nonconvoluted cell subtypes. The aspirate preparations from the convoluted cell subtype contain lymphoblasts that measure 8 to 30 µm. They have little cytoplasm. The variable shapes of the nuclei are a striking finding. The nuclei of the small cells are round, whereas those of the large cells appear convoluted (Fig. 11.25). The nuclear chromatin has a fine pattern and is evenly distributed. The nucleoli are absent or inconspicuous, a characteristic for lymphoblasts. Numerous mitoses are observed. The aspirate preparations from the nonconvoluted cell subtype contain lymphoblasts that measure 18 µm in the greatest dimension, on average. The cells have round or ovoid nuclei with a fine chromatin pattern (Fig. 11.26). The nucleoli are absent or inconspicuous. The diagnosis of the nonconvoluted cell subtype needs to be confirmed by immunophenotyping.

Mature T-Cell and NK-Cell Neoplasms This group of tumors derives from post-thymic T cells. T-cell/NK-cell lymphomas accounted for 12% of non-Hodgkin lymphomas. The most common

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subtypes are peripheral T-cell lymphoma, unspecified (3.7%) and anaplastic large cell lymphoma (2.4%).8 As a group, T/NK-cell lymphomas are aggressive and have a much poorer response to modern therapy, and a shorter survival.29 The diagnosis of peripheral T-cell lymphomas by fine-needle aspiration cytology is difficult.9,48,67 This is mainly due to the rarity of the disease, the morphologic similarity to reactive lymphadenopathy, and the difficulty in identifying abnormal T-cell antigen expression by flow cytometry. In a study of 20 cases by Al Shanqeety and Mourad,1 70% showed polymorphous smears, and only 30% showed monomorphous smears. Abnormal cells ranged from 10–100% (median, 60%) of the aspirate. Abnormal T-cell antigen expression by flow cytometric analysis was seen in 85% of the cases. The most common aberrant T-cell antigen pattern was loss of three or more pan-T-cell antigens. The most common individual T-cell antigen loss was that of CD7, followed by loss of CD5. There was also loss of CD4 and CD8, loss of CD5 and CD7, and complete loss of CD3. The findings of Shanqeety and Mourad suggest that the diagnosis of peripheral T-cell lymphomas can be achieved by fine-needle aspiration biopsy in the majority of cases. Close analysis of the morphology and a critical analysis of the phenotype using two or three-color flow cytometry with an attempt at identification of one or more abnormal T-cell antigen expression and/or loss is required. This can be supplemented by CD4/CD8 ratios and identification of T-cell receptor genes.

LEUKEMIC OR DISSEMINATED LYMPHOMA Adult T-Cell Leukemia/Lymphoma (Fig. 11.27) This disease is caused by the human T-cell leukemia virus-1 (HTLV-1). It is endemic in the Caribbean, Japan and part of central Africa while presenting sporadically in the rest of the world. The virus may be transmitted by blood or blood product or breast milk. It has a long latency and affects adults with a medium age of 55 years. There is a male predominance of 1.5:1. Clinically, most patients present with leukemia and widespread lymph node and spleen involvement. Extranodal sites include skin, lung, liver, gastrointestinal tract and central nervous system.36 Tong et al. reported a case involving the parotid gland.63 There are four clinical variants: acute (leukemic), lymphomatous, chronic (cutaneous), and smoldering (skin and lung). In

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the acute and lymphomatous type, the neoplastic cells are medium-sized to large with pleomorphic nuclei and a coarse chromatin with distinct nucleoli (Fig. 11.27). The neoplastic cells may be multilobated and may have blue cytoplasm in Diff-Quik stained smears. Morphologically diverse, this neoplasm also has a small cell variant and Hodgkin-like variant (neoplastic cells are actually EBV+, CD15+, CD30+ B-cell-derived Reed-Sternberg cells) in the incipient phase, which convert to overt adult T-cell leukemia/lymphoma within months. Immunophenotypically, the neoplastic cells express CD2, CD3, CD5, but are usually CD7−, and CD25+ in all cases. The clonally integrated HTLV-1 gene is detected by molecular study in all cases. The postulated cell of origin is the T-helper cell (CD4) in various stage of activation.

EXTRANODAL T/NK CELL LYMPHOMAS Mature Extranodal T/NK-Cell Lymphomas (Figs. 11.28–11.29) This entity used to be termed “polymorphic reticulosis” “malignant midline reticulosis” and “angiocentric lymphoproliferative lesion.” This disease has a predilection for the nasopharynx. Other sites include the gastrointestinal tract, skin, soft tissue and testis. Epstein-Barr virus is implicated. This entity has a broad spectrum of cytologic features, ranging from small cells with minimal atypia to large cells with anaplastic features. This lymphoma is defined based on clinical features rather than cytology. This neoplasm has a cytotoxic T-cell or NK-cell phenotype with frequent apoptosis or necrosis. Both NK cells and cytotoxic T-cells contain cytotoxic granules, immunoreactive to TIA-1, perforin and granzyme B.7 In contrast to B-cell lymphomas, specific immunophotypic profiles are not associated with most T-cell lymphoma subtypes. At the NYU Medical Center, the first author and colleagues66 reported a case of mature extranodal T/NK-cell lymphoma of the anterior mediastinum in a 52-year-old Caucasian woman who presented with superior vena cava syndrome. This case is illustrated in Figs. 11.28 to 11.29.

Mycosis Fungoides/Sézary Syndrome (Fig. 11.30) Mycosis fungoides is an indolent disease, limited to the skin for years prior to systemic spread to the lymph nodes, liver, spleen, lung and blood. Sézary

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syndrome is an aggressive disease with 10–20% five-year survival. It involves the skin, lymph nodes and blood, but spares the bone marrow. Cytologically, the neoplastic cells are small to medium-sized with cerebriform nuclei (Fig. 11.30). Immunophenotyping shows CD2+, CD3+, CD5+ and CD4+/CD8-neoplastic cells.

NODAL T/NK CELL LYMPHOMAS Anaplastic Large Cell Lymphoma (Figs. 11.31–11.33) This disease, a.k.a. Ki1 large cell lymphoma, is characterized by large neoplastic cells with abundant cytoplasm and horseshoe-shaped nuclei (hall mark cells). The cells are LCA+ and CD30 (Ki1)+, and most express anaplastic large cell kinase (ALK) and have cytotoxic granules. Anaplastic large cell lymphoma accounts for 3% of adult non-Hodgkin lymphomas.8 It most frequently affects young men in 20s to 30s. An ALK (−) variant affects older patients with equal gender distribution. Genetic alteration is t(2;5) translocation. In addition to the lymph nodes, it can also involve the skin, bone, soft tissue, lung and liver. Seventy percent of the patients presents with advanced disease with peripheral and abdominal lymphadenopathy and show systemic symptoms with high fever.15 The neoplastic cells usually have more abundant cytoplasm than other lymphomas. In addition to the hallmark cells (Figs. 11.31–11.33), this lymphoma may have wreathlike nuclei (Fig. 11.31C), or doughnut-shaped nuclei (Fig. 11.33A). Nuclear chromatin is usually finely dispersed with multiple small basophilic nucleoli (Fig. 11.41), but can be coarse in some cases (Figs. 11.32–11.33). In addition to the common type, there are lymphohistiocytic type (10%) and small cell type (5–10%). Fine-needle aspiration cytology has been described in the literature.69 Ng et al. reported a series of 10 cases, including both the common variant and small cell variant.47 The common variant was easy to recognize due to the hallmark cells, doughnut cells and wreath-like cells, whereas the small cell variant was difficult to identify due to the predominance of the plasmacytoid cells and nondescript round cells over small hallmark cells. CD30 and ALK immunostains are important in establishing the correct diagnosis.

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Angioimmunoblastic T-Cell Lymphoma (Fig. 11.34) This entity was formerly regarded as an atypical reactive process, termed “angioimmunoblastic lymphadenopathy.” It carried an increased risk of progression to lymphoma. The current thinking is that it arises de novo as peripheral T-cell lymphoma.30 This lymphoma occurs in middle-aged and elderly patients with equal gender distribution and accounts for 1–2% of non-Hodgkin lymphomas. It usually presents with generalized peripheral lymphadenopathy, hepatosplenomegaly and frequent skin rash. The clinical course is aggressive with medium survival of three years. Patients often succumb to infectious complications. The aspirate is characterized by a polymorphous population of cells consisting of neoplastic T-cells intermixed with small reactive lymphocytes, plasma cells, eosinophils (Fig. 11.34B), and histiocytes with prominent arborizing blood vessels (Fig. 11.34A) and follicular dendritic cells (Fig. 11.34C). The neoplastic cells are characterized by small to medium-sized lymphocytes with pale cytoplasm and distinct cell membranes (Fig. 11.34D). The immunophenotype is an admixture of CD4 and CD8 (CD4 > CD8) positive cells. The follicular dendritic cells are CD21 positive.

Peripheral T-Cell Lymphoma, Unspecified (Figs. 11.35–11.36) Half of the peripheral T-cell lymphomas in the Western countries do not fit into specific clinical entities and are placed in this unspecified category. Consequently, this is a heterogeneous groups of lymphomas with a wide spectrum of morphology and clinical presentations. The cytological spectrum is also broad, but most cases show polymorphous population of mediumsized or large pleomorphic lymphoid cells with irregular nuclei (Fig. 11.35) intermixed with reactive eosinophils, plasma cells and epithelioid histiocytes (Lennert’s lymphoma, Fig. 11.36).34,48,67 Sometimes, a granulomatous inflammation in Lennert’s lymphoma may be so pronounced that an interpretation of granulomatous lymphadenitis may be rendered.67

HODGKIN LYMPHOMA (FIGS. 11.37–11.39) Hodgkin lymphoma is the most common type of malignant lymphoma in young adults. The diagnosis is based on finding Reed-Sternberg cells, which are derived from mature B-cells at the germinal center stage of differentiation

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in > 98% of the classical Hodgkin lymphoma.32,41 Most Hodgkin lymphomas spread by involvement of adjacent lymph node groups. The common sites of extranodal involvement are the spleen, liver, bone marrow, lungs, mediastinum and skin. Hodgkin lymphomas are characterized by a small number of large bizarre neoplastic cells in a background of reactive elements, including all types of inflammatory cells and histiocytes (Fig. 11.37A). The large bizarre neoplastic cells include multinucleated Reed-Sternberg cells (Fig. 11.38) and mononuclear Hodgkin cells (Fig. 11.39). The amount of cytoplasm in the Reed-Sternberg cells and Hodgkin cells is quite variable in aspirate preparations. Most of the neoplastic cells appear as stripped nuclei in aspirate smears, and a minority of the neoplastic cells have variable amounts of cytoplasm. The WHO classification56 separates Hodgkin lymphoma into nodular lymphocyte predominant type (LPH) and the classic type. The neoplastic cells in the LPH type are immunoreactive to LCA and B-cell markers (CD20), while the background small lymphocytes are B-cells. The neoplastic cells in the classic type are immunoreactive to fascin, CD30 and CD15, and negative to LCA and B-cell markers.

Nodular Lymphocyte Predominant Hodgkin Lymphoma LPH represents 5% of all Hodgkin lymphomas, affecting predominantly men with an age ranging from 30 to 50 years. It usually involves the cervical, axillary or inguinal lymph nodes. Most patients present with stage I disease. This disease develops slowly with frequent relapses, but is essentially never fatal.56 Histologically, it is characterized by nodular infiltrates of scattered neoplastic cells in a background of reactive cells. The neoplastic cells are the “popcorn” cells or L&H cells (lymphocytic and/histiocytic variant) with folded or multilobated nuclei with vesicular chromatin and multiple nucleoli. These cells can be found in aspiration biopsy smears.

Classic Hodgkin Lymphoma Classic Hodgkin lymphoma is divided into nodular sclerosis, mixed cellularity, lymphocyte rich and lymphocyte depleted. Each type may have different

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clinical presentations. Modern therapy has resulted in an excellent outcome and cure for the majority of patients with all subtypes of Hodgkin lymphoma. 1. Nodular sclerosis type. This subtype accounts for 70% of classic Hodgkin lymphoma. It affects young adults with a medium age of 28 years and with equal gender distribution. Mediastinal involvement occurs in 80% of the cases. Most patients present with stage II disease. B-symptoms, fevers and night sweats, are encountered in 40% of cases. Histologically, the lymph nodes are divided by fibrous bands into neoplastic proliferating nodules. In tissue sections, the Reed-Sternberg cells may appear as “lacunar” cells, which are characterized by abundant clear cytoplasm and multiple or multilobate single nuclei with multiple inclusion-like macronucleoli. In the aspirate preparations, there may be very few cells, if the needle hits the fibrous bands. If the sample is aspirated from the cellular area of the lymph node, scattered neoplastic cells and numerous lymphocytes with variable numbers of eosinophils, neutrophils and histiocytes cells are seen. Reed-Sternberg cells must be found to make the initial diagnosis. 2. Mixed cellularity type. This subtype accounts for 20–25% of classic Hodgkin lymphoma. The medium age is 37 years with a male predominance. Most patients present with stage III or IV disease and with B symptoms. Mixed cellularity Hodgkin lymphoma is more frequent in patients with HIV infection and in the developing countries. It involves peripheral lymph nodes, and mediastinal involvement is uncommon. In 70% of the cases Epstein-Barr virus latent protein is expressed by the neoplastic cells. Mixed inflammatory cells, including lymphocytes, plasma cells, eosinophils and neutrophils in variable proportions, and numerous histiocytes cells are observed in aspirates. There are many Reed-Sternberg cells. 3. Lymphocyte rich type. This subtype accounts for 5% of all Hodgkin lymphoma. The medium age is greater than other types with a male predominance. Most patients present with stage I or II disease. B symptoms are rare. There are numerous mature-looking lymphocytes and a few ReedSternberg cells. Many histiocytes are usually present. The Reed-Sternberg cells often have large, polypoid, twisted nuclei with a finely granular chromatin pattern and relatively small nucleoli. Lymphocyte rich Hodgkin lymphoma has a slow evolution.

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4. Lymphocyte depleted type. Many cases previously diagnosed as this entity are now recognized as non-Hodgkin lymphoma with anaplastic or pleomorphic large cells. Lymphocyte depleted Hodgkin lymphoma accounts for < 5% of classic Hodgkin lymphoma. The median age is 37 years with a male predominance. This subtype is often associated with HIV infections. It also often affects the abdominal organs, retroperitoneal lymph nodes and bone marrow with relative sparing of peripheral lymph nodes. Many mononuclear variants of Reed-Sternberg cells and some pleomorphic Reed-Sternberg cells with irregular nuclear contours and inclusion-like macronucleoli are encountered. Few lymphocytes are seen in the aspiration smears. In a few instances, the reactive cells in the lymphoid tissue from infectious mononucleosis, postvaccination and drug reactions mimic Reed-Sternberg cells cytomorphologically.17,26,57 For this reason, a diagnosis of Hodgkin lymphoma should not be made unless typical Reed-Sternberg cells are found. In aspirate preparations, Reed-Sternberg cells can be confirmed by positive cytoplasmic staining for fascin18,50 (Fig. 11.37), CD30 and CD15. The mononuclear Hodgkin cell look-alikes include the large B-cells in T-cell/histiocyte rich large B-cell lymphoma, and Ki-1 cells in cases of T-anaplastic large cell lymphoma. Although all of the neoplastic cells are large and bizzare, there are subtle difference as illustrated in Fig. 11.39 (Hodgkin cells), Fig. 11.40 (large B cells), and Fig. 11.41 (Ki-1 cells). In general, the nuclei of Hodgkin cells have more dimpling, their nuclear chromatin paler and finer and the nucleoli are larger, sharper and more inclusion-like. One helpful observation reported by Mourad et al.43 is that the percentage of abnormal cells is much higher in anaplastic large cell lymphoma (30%; range 10–90%) than that of Hodgkin lymphoma (3%; range 1–25%). The difference in the percentage of large bizarre cells between Ki1 anaplastic large cell lymphoma (Fig. 11.31A) and Hodgkin lymphoma (Fig. 11.37A) can be appreciated at low power examination of the UFP-stained aspiration smears. Due to the highly characteristic Reed-Sternberg cells and Hodgkin cells, cytologic diagnosis of Hodgkin lymphoma, supported by immunomarkers, is possible.10,43,71 However, it is challenging to subtype Hodgkin lymphoma reliably based solely on cytologic features unless combined with clinical presentation. At the NYU Medical Center, following an initial Hodgkin

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lymphoma diagnosis by fine-needle aspiration biopsy, the lymph node aspirated is usually excised for confirmation and subtyping. In conclusion, it is possible to diagnose malignant lymphoma by transabdominal aspiration biopsy on the basis of the cytomorphologic findings coupled with ancillary studies of the aspirated samples.22,33,54 The cytologic diagnosis of non-Hodgkin lymphomas is most reliable for intermediate-grade and high-grade lymphomas, particularly when the diagnosis has previously been established.49,70 The most difficult diagnosis is to distinguish low-grade lymphoma with a mixed population of lymphocytes from reactive lymphoid hyperplasia. Only flow cytometric analysis can determine whether a subpopulation of B-lymphocytes expressing light chain restriction will distinguish the various types of small B-cell lymphomas (Table 11.4). The cytologic diagnosis of Hodgkin lymphoma relies on the finding of Reed-Sternberg cells and Hodgkin cells, which are often clearer, and easier to locate in aspirate smears than in paraffin sections. Hodgkin lymphoma has been particularly amenable to follow-up by aspiration biopsy.18 At the NYU Medical Center, fine-needle aspiration biopsy is used as the first test for lymphadenopathy. Based on the cytologic finding, the cases are triaged into metastatic disease, Hodgkin lymphoma, non-Hodgkin lymphoma of high-grade or intermediate-grade, and low-grade lymphoma vs. reactive lymph node. In cases of Hodgkin lymphoma, additional samples are submitted for cell block for immmunohistochemical confirmation. In cases of non-Hodgkin lymphoma or reactive lymph nodes, additional samples are submitted for flow cytometry. Flow cytometry is most useful for reactive lymph nodes and low-to-intermediate grade B-cell lymphomas because the cells of interest remain viable for a long time. Flow cytometry is noncontributory in many instances of high-grade lymphoma because of the rapid death of the neoplastic cells.

HISTIOCYTIC AND DENDRITIC NEOPLASMS This group of neoplasms includes histiocytic sarcoma (CD68+), Langerhans cell histiocytosis (S100+, CD1a+, Birbeck granules), Langerhans cell sarcoma (S100+, CD1a+), interdigitating dendritic cell sarcoma (S100+, CD1a−), follicular dendritic cell sarcoma (CD21+, CD23+, CD35+), and dendritic cell sarcoma, NOS (S100+, CD1a+, but no Birbeck granules).

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Histiocytic and dendritic neoplasms are much less frequently diagnosed than in the past. Cases diagnosed previously as malignant histiocytosis were found by immunomarkers to be anaplastic large cell lymphoma, hemophagocytic syndrome or enteropathy type T-cell lymphoma.65 The true incidence of histiocytic and dendritic neoplasm is difficult to assess, but it probably constitutes < 1% of tumors of the lymph nodes. Only Langerhans cell histiocytosis and follicular dendritic cell sarcoma will be described.

Langerhans Cell Histiocytosis (Fig. 11.42) This disease affects mainly boys of northern European descent. Langerhans cell histiocytosis of the lung in adults is nearly always associated with smokers and probably represents a reactive disease entity.64 Clinically, Langerhans cell histiocytosis can present as unifocal disease involving the bone; less frequently involving the lymph nodes, skin or lung (eosinophilic granuloma); as multifocal, involving the bone (Hand-Schüller-Christian disease); or as a multisystem disease (Letterer-Siwe disease). The overall survival is 95% with unifocal disease, and 75% with two or more organs involved. In aspirate preparations, the neoplastic Langerhans cells measures 10– 15 µm and have oval, pale, grooved nuclei with inapparent nucleoli and moderate amounts of cytoplasm. These cells are immunoreactive to CD1a and S100 and contain Birbeck granules seen ultrastructurally. In aspiration smears, the Langerhans cells are scattered in a background of reactive eosinophils, lymphocytes, neutrophils and histiocytes (Fig. 11.42).

Follicular Dendritic Cell Sarcoma (Figs. 11.43–11.44) This disease affects patients of a wide age range with a median age of 40 years and a slight female predominance. It involves the lymph nodes or the lymphoid follicles of extranodal sites including the tonsils, spleen and gastrointestinal tract. It is a low-grade tumor with local recurrences followed by metastasis in 25% of cases. Follicular dendritic cell sarcoma can exhibit a broad spectrum of behavior, but the intraabdominal ones usually pursue an aggressive course. The neoplastic cells are derived from the antigen presenting dendritic cells of the lymphoid follicles. Histology (Fig. 11.43D) is characterized by storiform or fascicular array of tumor cells with frequently

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fibrillary cytoplasm. The neoplasm is immunoreactive to CD21, CD23 and CD35, markers for follicular dendritic cells. This tumor posseses a unique ultrastructural feature, i.e. dendritic cytoplasmic processes connected by desmosomes. In aspirate preparations, syncytial fragments of spindle, oval or polygonal neoplastic cells attached to long and thin branching blood vessels are present in the thick region of the smears, while single cells predominate in the thinly spread regions of the smear (Fig. 11.43A). The neoplastic cells have oval nuclei, fine nuclear chromatin and distinct small nucleoli. Occasional nuclear grooves and rare intranuclear pseudoinclusions can be found (Figs. 11.44). The ultrastructural feature of the dendritic cytoplasmic processes can be seen only in direct smears processed by UFP or similar protocols.73 In UFP preparations, the single cells are interconnected to neighboring single cells by long and thin cytoplasmic processes (Fig. 11.43B), and the neoplastic cells possess multipolar cytoplasmic processes (Fig. 11.43C). In Diff-Quik stained smears, the negative image of fine dendritic processes are obscured by the red blood cells in the background (Fig. 11.44A, B)

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Fig. 11.1 Reactive lymph node. (A) Lymphohistiocytic aggregate aspirated from germinal center. DQ, 100×; (B) A range of small, medium and large lymphocytes. DQ, 400×; (C) Lymphohistiocytic aggregates (arrows) and the absence of Hodgkin cells. UFP, 100×. (D) Heterogenous population of lymphocytes are present with no predominant cell type. UFP, 400×.

Fig. 11.2 Small lymphocytic lymphoma. (A) Monomorphic small round lymphocytes as compared to Fig. 11.1. DQ, 400×; (B) Arrow points to the “lymphoglandular bodies,” clue for lymphoid cells. DQ, 1000×; (C) Lymphoglandular bodies cannot be seen in transparent stains including UFP, 400×; (D) Lymphocytes of the same size and similar clumped chromatin pattern. UFP, 1000×.

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Fig. 11.3 Small lymphocytic lymphoma with Richter transformation. (A, B) Large cells intermixed with small lymphocytes. Lymphocytes are fragile and easily streaked by the smearing, resulting in “lymphoid tangles.” UFP 400×; (C, D) High magnification shows large cells (5× the size of small cells) with prominent red nucleoli and small cells with indistinct nucleoli. UFP, 1000×.

Fig. 11.4 Lymphoplasmocytic lymphoma (A) The aspirate contains small blue cells in a monotonous pattern. DQ, 100×; (B) Small lymphocytes, plasmacytoid lymphocytes, and plasma cells. DQ, 400×; (C) Lymph node shows diffuse pattern. Note “fried egg” appearance of the cells. H&E, 40×; (D) High power shows the absence of monocytoid B-cells. H&E, 100×.

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Fig. 11.5 Plasma cell myeloma. (A) Abundant amyloid associated with the small blue cells. DQ, 40×; (B) Plasma cells and stripped nuclei of plasma cells. Note the perinuclear hof. DQ, 400×; (C) Ig crystals (arrows) are present in the cytoplasm and in the background. DQ, 1000×; (D) Malignant plasma cell with binucleation. Note the perinuclear hof (arrow). DQ, 1000×.

Fig. 11.6 Plasma cell myeloma. Top row: The multilobated nuclei indicate malignancy and the dense blue cytoplasm with perinuclear hof is typical for plasma cells. DQ, 400×. Bottom row: High power shows bilobed nuclei and clover leaf-like nuclei in dense blue cytoplasm with perinuclear hofs. DQ, 1000×.

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Fig. 11.7 Plasma cell myeloma. (Myeloma cells with pale cytoplasm.) (A) Monotonous rigid small blue cells without lymphoid tangles. DQ, 40×; (B–D) Typical clockwork nuclei of plasma cells, but the cytoplasm are pale rather than blue, and the perinuclear hofs are invisible due to the pale cytoplasm. Note the absence of “lymphoglandular bodies” ruling out lymphoid in origin. DQ, 400×.

Fig. 11.8 Marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT). (A) Low power shows monotonous population of fragile small blue cells. DQ, 40×; (B) Variable-sized round to cleaved cells with small amount of cytoplasm. Note the lymphoglandular bodies (arrows), a clue for lymphoid cells. DQ, 400×; (C) & (D) Small cells with cleaved nuclei and the cell in (D) has prominent nucleoli. UFP, 1000×.

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Fig. 11.9 MALT lymphoma of parotid gland, aspirated from a 56-year-old man. (A) Rare large lymphoid cells with lipid droplets and small lymphocytes. DQ, 400×; (B) Mixed small lymphocytes and large noncleaved lymphocytes. DQ, 400×; (C) & (D) Large noncleaved cells with nucleoli and small lymphocytes, requiring flow cytometrysh from reactive lymph node. UFP, 400×.

Fig. 11.10 Marginal zone lymphoma. (A) The aspirate shows heterogeneous population of lymphocytes, because the needle sampled both the marginal zone and the follicles. UFP, 400×; (B) Lymphoma with irregular nucleus (arrow), small lymphocytes and large cells. UFP, 1000×; (C) Lymphoma cells resided in the marginal zone surrounding the follicle. H&E, 40×; (D) High power of marginal zone shows lymphoma cells with very irregular nuclei. H&E, 1000×.

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Fig. 11.11 Marginal zone lymphoma, blastic variant. (A) The aspirate shows monotonous population of large atypical lymphoid cells. UFP, 100×; (B) High power shows large vesicular nuclei and more distinct nucleoli. UFP, 400×; (C) Marginal zone of the follicle shows atypical lymphocytes. Lymph node biopsy, H&E, 100×; (D) High power shows large noncleaved and large cleaved cells. H&E, 400×.

Fig. 11.12 Small cleaved (Grade 1) follicular lymphoma. (A) Abundant small cells with deep nuclear cleavage (white arrows) are seen. DQ, 400×; (B) Monomorphic small lymphocytes with irregular, twisted nuclei. Papanicolaou stain, 400×; (C) Less irregular nuclei is an artifact seen in UFP stain, 400×; (D) Lymph node shows small cleaved cells of Grade 1 follicular lymphoma. H&E, 400×.

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Fig. 11.13 Mixed small cleaved and large noncleaved (Grade 2 follicular) lymphoma. (A) Dual population of small dark lymphocytes and large and paler lymphocytes. DQ, 400×; (B) High power shows the small cleaved cells and large noncleaved cells. DQ, 1000×; (C) Large pale lymphocytes scattered in a background of small lymphocytes. UFP, 400×; (D) Small cleaved cells and large noncleaved cells with multiple nucleoli. UFP, 1000×.

Fig. 11.14 Large B lymphoma, controblastic type. (A) Atypical lymphocytes among lymphoglandular bodies (arrows). DQ, 100×; (B) Large noncleaved cells with lymphoglandular bodies (arrows). DQ, 1000×; (C) Note the cells are smaller in UFP and the lymphoglandular bodies (arrows) are invisible 100×; (D) Large noncleaved cells with 1–3 small peripheral nucleoli. UFP, 1000×.

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Fig. 11.15 Large B-cell lymphoma, centroblastic type with multilobated cells. (A) Low power shows atypical lymphocytes with lymphoid tangles (arrows). DQ, 100×; (B) Clearly malignant single cells of small to large size. UFP, 400×; (C) High power shows the polylobated nuclei. UFP, 1000×; (D) Diffuse multilobated lymphoma cells in lymph node biopsy. H&E, 400×.

Fig. 11.16 Large B-cell lymphoma, immunoblastic type. (A) Large lymphoma cells, approximately 5× the size of RBCs. DQ, 400×; (B) Stripped nuclei and two cells with deep blue cytoplasm seen only in DQ stain. 1000×; (C) Prominent centrally located single nucleolus best seen in UFP. 400×; (D) Diffuse lymphoma cells with prominent nucleoli in lymph node biopsy. H&E, 100×.

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Fig. 11.17 Large B-cell lymphoma, T-cell/histiocyte rich. (A) A lymphohistiocytic aggregate in a background of single cells. UFP, 100×; (B) High power shows histiocytes (arrow) intermixed with small lymphocytes. UFP, 400×; (C) Two large lymphomas cells. Left, DQ. Vesicular chromatin. Right UFP, 1000×; (D) Large B lymphoma cells among small Tlymphocytes (CD3+). Cell block, H&E, 400×.

Fig. 11.18 Large B-cell lymphoma, T-cell rich. (A) Low power mimic Hodgkin with very large cells scattered among small cells. UFP, 100×; (B) Two Reed-Sternberg-like cells among small lymphocytes. DQ, 400×; (C) Left : Small cells are CD3+. Right : large cells (arrow) are CD20+. Immunostains, 400×; (D) Large cells have coarser chromatin and lack inclusion-like macronucleoli. UFP, 1000×.

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Fig. 11.19 Mediastinal (thymic) large B-cell lymphoma from a 46-year-old female. (A) Dual population of large neoplastic cells among small lymphocytes. DQ, 400×; (B) Large tumor cells scattered singly in a background of a few small lymphocytes. UFP, 400×; (C) Similar findings in cell block, H&E, 400×; (D) Note the fine cytoplasmic granules in the large cells. DQ, left; UFP, right; 1000×.

Fig. 11.20 Mediastinal (thymic) large B-cell lymphoma, same case as Fig. 11.19. (A) Intimate association of large neoplastic cells and small lymphocytes. DQ, 1000×; (B) Large cells have round to oval vesicular nuclei with small distinct nucleoli. UFP, 1000×; (C) Large lymphoma cells are CD20+ B-cells. Immunostain on cell block. 400×; (D) Small lymphocyts are CD3+ background T-cells. Immunostain on cell block. 400×.

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Fig. 11.21 Primary effusion lymphoma from a 34-year-old homosexual male. (A) Plasmablast-like lymphoma cells (5–8× size of RBC). DQ, 400×; (B) Plasmablast-like lymphoma cells. Cytospin, Papanicolaou stain, 400×; (C) Lymphoma cells seen in cell block. H&E, 400×; (D) Kaposi sarcoma-associated human Herpes 8 virus latent protein. Immunostain 400×.

Fig. 11.22 Primary effusion lymphoma from a 40-year-old female with pericardial tamponade. (A) Plasmablast-like cells with blue cytoplasm and perinuclear hof. DQ, 400×; (B) Small to medium to large lymphoma cells and neutrophils. UFP, 400×; (C) Note the nuclear convolution of various types. UFP, 1000×; (D) Kaposi sarcoma-associated human Herpes 8 viral latent protein. Immunostain on cell block.

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Fig. 11.23 Burkitt lymphoma, from a 45 HIV+ male with rapidly enlarging abdominal mass. (A) Note the “starry sky” appearance of scattered tangible-body macrophages. DQ, 100; (B) Medium-sized cells with lipid-laden blue cytoplasm (arrow). DQ, 1000×; (C) Oil droplets demonstrated on air-dried smears. Oil red O stain. 400×; (D) Noncleaved nuclei with 1–3 small nucleoli. UFP, 1000×.

Fig. 11.24 Burkitt-like lymphoma, from a 24-year-old female. (A) Lymphoma cells look similar to Burkitt lymphoma at first glance. DQ, 400×; (B) The nuclei are still fragile. Note the nuclear streak. DQ, 1000×; (C) Lipid droplets are in the cytoplasm and in the lymphoglandular bodies. DQ, 1000×; (D) The nuclei are more pleomorphic and nucleoli are more prominent than Burkitts. DQ, 1000×.

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Fig. 11.25 T-lymphoblastic lymphoma, convoluted cell type. Medium-sized uniform TdT+ lymphoblasts with fine chromatin and convoluted nuclei. Note doughnut-shaped nucleus on the left, and flower poded nucleus on the right. DQ, 4000×.

Fig. 11.26 T-lymphoblastic lymphoma, nonconvoluted cell type. (A) Monotonous population of lymphoid cells. DQ, 100×; (B) Medium-sized uniform TdT+ lymphoblasts with fine chromatin. DQ, 400×; (C) Note the rare lipid droplets in the lymphoma cells. DQ, 1000×; (D) Note the very fine chromatin typical for blasts. DQ, 1000×.

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Fig. 11.27 Adult T-cell leukemia/lymphoma (HTLV-1+, CD25+) aspirated from parotid.63 (A) Small, medium-sized and large lymphoma cells in a background of neutrophils. DQ, 400×; (B) Fine vacuoles are present in the cytoplasm and in the background. DQ, 1000×; (C) Note the irregular-shaped nuclei of lymphoma cells and tingible body macrophage. UFP, 400×; (D) A Reed-Sternberg like binucleated cell with prominent nucleoli. UFP, 1000×.

Fig. 11.28 T/Natural killer cell lymphoma, aspirated from anterior mediastinum.72 (A) Low power show cohesive fragments among background single cells. DQ, 40×; (B) Large cells with abundant cytoplasm associated with small lymphocytes. DQ, 400×; (C) Cohesive fragments among background single cells. UFP, 100×; (D) Two histiocyte-like binucleated lymphoma cells containing fine granules. UFP, 400×.

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Fig. 11.29 T/NK cell lymphoma of the mediastinum, same case as Fig. 11.28. (A) Dual population of large cells and small lymphocytes. Cell block, H&E, 100×; (B) Both large cells and small cells express LCA. Immunostain on cell block, 400×; (C) Cytotoxic granules with immunoreactivity to TIA-1. Cell block, 1000×; (D) Azurophilic coarse granules. DQ, 1000×; (E) Electron microscopy, 5000×.

Fig. 11.30 Mycosis fungoides/Sezary syndrome, from a 45-year-old male. (A) Monotonous population of small lymphocytes. DQ, 400×; (B) High magnification shows convoluted nuclei (arrows). DQ, 1000×; (C) Note two mitotic figures. DQ, 1000×; (D) CD3+; left, CD20 (−). Immunostain on cytospins, 400×.

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Fig. 11.31 Anaplastic large cell (Ki1) lymphoma, from a 43-year-old HIV+ male. (A) The percentage of large cell is 30–40%, much higher than Hodgkin lymphoma. UFP, 100×; (B) Horseshoe-shaped nuclei seen in hallmark cells. UFP, 1000×; (C) Note the absence of lymphoglandular bodies. DQ, 400×; (D) Resected bone tumor with CD30 (Ki1)+ membranous immunostaining. 1000×.

Fig. 11.32 Anaplastic large cell (Ki1) lymphoma, neutrophil rich. (A) Rare tumor cells in a background of marked acute inflammation. DQ, 1000×; (B) Multilobated cell with coarse chromatin. UFP, 1000×; (C) Multilobated or multinucleated cells with inclusion-like macronucleoli. UFP, 1000×; (D) A multinucleated cell containing 4 nuclei with inclusion-like macronucleoli. UFP, 1000×.

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Fig. 11.33 Anaplastic large cell (Ki1) lymphoma, from a 61-year-old female. (A) Arrow points to a Doughnut-shape nucleus. No lymphoglandular bodies seen. DQ 400×; (B) Horseshoe-shaped nucleus (arrow points to opening of the horseshoe). UFP, 400×; (C) Lymphoma cells have coarse nuclear chromatin and inconspicuous nucleoli. UFP, 400×; (D) Lymph node biopsy shows a diffuse pattern of anaplastic large lymphoma cells. H&E, 400×.

Fig. 11.34 Angioimmunoblastic T-cell lymphoma, aspirated from a 63-year-old female. (A) Prominent arborizing vascular network with attached lymphoid cells. DQ 40×; (B) Eosinophils (arrow), small lymphocytes, and medium sized cells. DQ, 100×; (C) Increased follicular dendritic cells. FNA smear with H&E stain, 400×; (D) Small to medium-sized lymphoma cells with sharp cell border and clear cytoplasm. 1000×.

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Fig. 11.35 Peripheral T-cell lymphoma. (A) T lymphoma cells among small lymphocytes, neutrophils and eosinophils. DQ, 400×; (B) Lymphoma cells have round nuclei and abnormal mottled nuclear chromatin. DQ, 1000×; (C) Two lymphocytes with small dark nuclei and lymphoma cells of different sizes. DQ, 1000×; (D) Lymph node biopsy. H&E, 100×.

Fig. 11.36 Peripheral T-cell lymphoma, Lennert’s type, from a 66-year-old male. (A) Low power shows granulomatous inflammation-like pattern of neoplastic cells. UFP, 40×; (B) Large neoplastic T cells, small lymphocytes and epithelioid histiocytes. UFP, 400×; (C) & (D) An epithelioid histiocyte (arrow), small lymphocytes and large T-lymphoma with pale nuclei with irregular chromatin distribution and prominent nucleoli. UFP, 1000×.

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Fig. 11.37 Classic Hodgkin lymphoma, aspirated from a 27-year-old female. (A) Dichotomy of small and large cells. The percentage of large cells is < 10%. UFP, 100×; (B) Eosinophils, plasma cells small B-lymphocytes and a Reed-Sternberg cell. DQ, 400×; (C) Reed-Sternberg cell and Hodgkin cell (arrows) among small B-cells. 400×, UFP, Insert : fascin. (D) Reed-Sternberg cells with inclusion-like macronucleoli and delicate cytoplasm. UFP, 1000×.

Fig. 11.38 Classic Hodgkin lymphoma. Spectrum of multinucleated and multilobated Reed-Sternberg cells. UFP, 1000×.

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Fig. 11.39 Classic Hodgkin lymphoma. Spectrum of mononuclear Hodgkin cells “popcorn cells.” Notice the polypoid nuclei, pale chromatin and inclusion-like nucleoli. UFP, 1000×.

Fig. 11.40 Hodgkin look alike: T-cell rich large B-cell lymphoma cells. Spectrum of large cells. Top: Large cells with pale nuclei and inclusion-like nucleoli, but smooth nuclei. UFP, 1000×; Bottom: Large cells with irregular membrane like Hodgkin cells. However, the chromatin is coarse and there is no inclusion-like macronucleoli (different case). UFP, 1000×.

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Fig. 11.41 Hodgkin look alike: Ki1 anaplastic large T-cells. Spectrum of large cells. UFP, 1000×. Hallmark cells with horseshoe-like nuclei, and one cell with wreath-like nucleus (left lower).

Fig. 11.42 Langerhans cell histiocytosis, aspirated from T9 vertebral lesion of a 9-year-old male. (A) Two Langerhans cells among eosinophils, which are seen best in DQ stain, 1000×; (B) & (C) Langerhans cells with pale grooved nuclei, which are seen best in UFP stain, 1000×; (D) Langerhans cells express S100 and CD1a. Immunostain on UFP-stained smear, 1000×.

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Fig. 11.43 Follicular dendritic cell sarcoma, from a 46-year-old male with GI tract primary.73 (A) Single cells smeared off vessel. UFP, 40×. Insert : syncytial fragment with lymphocytes. 200×; (B) The single cells are interconnected by spiderweb-like cytoplasmic processes. UFP, 100×; (C) Dendrite-like sarcoma cells with multipolar fibrillary cytoplasmic processes. UFP, 400×; (D) Fascicular array of spindle cells. (Left ): Cell block, H&E, 200×; (right ): immunostain, 100×.

Fig. 11.44 Follicular dendritic cell sarcoma (same as previous case). (A) Cohesive and single cells in a bloody background. DQ 100×. (B) At high magnification, the seemingly naked nuclei lie in a background of thread-like negative images. DQ 400×. (C) A network of dendritic cytoplasmic processes interconnecting single cells and clusters of cells. UFP 100×. Inserts Rare nuclear features: multinucleation (top), grooved nuclei (middle), intranuclear pseudoinclusion (bottom). UFP 1000×. (D) Dendritic network connecting cells of various sizes and most tumor cells have oval, hyperchromatic nucleus with multiple nucleoli. UFP 1000×.

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CHAPTER 12

Immunomarkers for Transabdominal Aspiration Biopsy

The use of diagnostic and prognostic immunomarkers has become standard in cytopathology. These markers exist at the cellular level and are located in the nucleus (e.g. integrated viral or oncogene DNA); cell surface membranes (e.g. leukocyte antigens); or cytoplasm, including specific intermediate filaments (e.g. cytokeratins), enzyme markers (e.g. prostatic acid phosphatase), hormones (e.g. PTH), and other selective proteins (e.g. prostate-specific antigen, Hepar-1, thyroglobulin, calretinin, etc.). In our practice, we encounter tumors that are difficult to diagnose by light microscopy such as spindle cell tumors and small round cell tumors. Differentiation between these malignant lesions is important because management differs. The application of immunohistochemistry may help resolve this diagnostic dilemma.19 There are many other examples in which light microscopy coupled with immunohistochemistry can provide solutions for diagnostic problems in aspiration biopsy.30,39 However, it is clear that not all diagnostic problems can be solved by immunohistochemistry. In many cases, immunohistochemical reactions are inconclusive due to background staining, scanty cellularity, problems in antigen retrievel, or rupture of the cells by force of the smearing.4 Further, unexpected positive and negative reactions are not uncommon in aspirate preparation.4 It is also clear that the diagnostic skills based on cytomorphologic analysis will not be replaced by “magic markers.” Immunohistochemical staining has, however, become an important component in cytologic diagnosis, and the reactions will continue to require a cytopathologist’s interpretation. A cytopathologist is best able to 416

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judge whether a given immunohistochemical reaction is consistent with the cytomorphology of a tumor. With the ever increasing number and availability of antibodies against cellular antigens, immunohistochemistry has become an important adjunct in the interpretation of transabdominal fine-needle aspiration biopsy specimens.18 However, it is costly and increases the “turnaround time” to order a battery of antibodies to solve every diagnostic problem. Moreover, only a limited sample is obtained by the aspiration method. Therefore, to select the best immunomarkers is important. The selection should be based on the cytomorphologic, laboratory and radiographic findings, and the clinical history. A negative immunohistochemical reaction should be interpreted with caution and with full knowledge of the limitations of immunohistochemistry in the setting of diagnostic cytopathology. In addition to solid tumors, a large number of monoclonal antibodies have been produced against cell surface antigens characteristic of the various stages of lymphoid differentiation. Monoclonal antibodies are much preferred over polyclonal antibodies. Diagnosis and classification of lymphomas by aspiration biopsy has become more precise and accurate by immunophenotyping.43

IMMUNOHISTOCHEMICAL STAINING FOR ASPIRATION BIOPSY Samples of aspirated material can be prepared for immunohistochemical staining in several ways, including direct smears, cytospins, liquid-based preparations and cell blocks. At the NYU Medical Center, compact cell blocks give the best results for immunohistochemistry, since the aspirated blood has been hemolysed, and positive controls and the titer of the antibodies have been standardized for histopathology. In other laboratories, cytospins are used, especially for lymphoid marker study,21 because the cells form a monolayer and many slides can be made. At the Indiana University Medical Center, the senior author routinely used the Cytospin II (Shandon Instruments. Sewickley, PA) technique for immunostaining. The procedure is as follows: A cell suspension sample is collected by expelling the remaining aspirated material into 20–30 ml of electron-buffered solution (Tis-u-sol solution, Travenol Laboratories, Deerfield, IL) and flushing the syringe and needle with this solution. Cell concentration can be adjusted by doing test runs. Resuspension of

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the cell button after centrifugation is recommended if the cell concentration is low. The operating detail for preparing Cytospin slides are provided in the Shandon Cytospin II manual. The Cytospin slides are fixed in high-quality acetone for 10 min at 4◦ C and stored dry in a refrigerator until they are stained.20 To achieve meaningful results, positive and negative controls must be processed along with the unknown sample to ensure the accuracy of the results obtained. For positive controls, tissue sections staining for the relevant antibody should be used if available. For negative controls, the corresponding cytology smears or paraffin sections from a cell block should be stained with normal serum.

AVIDIN-BIOTIN-IMMUNOPEROXIDASE STAINING PROCEDURE FOR ASPIRATION PREPARATIONS The avidin-biotin technique is based on the ability of avidin to bind nonimmunologically four molecules of biotin. Three reagents are used. The primary antibody is specific for the antigen to be localized.31 The secondary antibody is capable of binding to the primary antibody and is conjugated to biotin. The third reagent is a complex of peroxidase conjugated to avidin and biotin. The free sites of the avidin molecule allow binding to the biotin on the secondary antibody. The peroxidase enzyme and the original antigen are visualized with an appropriate chromagen. The avidin-biotin staining procedure consists of a series of five incubations that are carried out at room temperature (23◦ C). The step-by-step sequence of events in the avidin-biotin-peroxidase staining procedure for Cytospin preparation of aspirates is as follows: 1. Circle the area under study on the back of the Cytospin slide with a diamond pen. 2. Rehydrate the slide in decreasing grades of ethanol to water. 3. Block the endogenous peroxidase with 0.3% hydrogen peroxidase in methanol for 30 min. 4. Rinse the slide in tap water and wash it with phosphate-buffered saline for 5 min. 5. Lay the slide flat and cover the circle with normal goat serum (1:20) for 5 min.

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6. Decant the excess normal goat serum and apply a few drops of rabbit antibody to human adrenocorticotropic hormone (1:500 to 1:2000) for 60 min. 7. Rinse the slide with three changes of phosphate-buffered saline for 10 min each. 8. Apply a few drops of biotin-conjugated goat antibody to rabbit immunoglobulins (1:200 to 1:400) for 30 min. 9. Rinse the slide with three changes of phosphate-buffered saline for 10 min each. 10. Apply a few drops of peroxidase-conjugated biotin-avidin complex for 30 min. The avidin and biotinylated peroxidase are diluted equally (1:100 to 1:200). 11. Rinse the slide with three changes of phosphate-buffered saline for 10 min each. 12. Apply substrate solution to the slide to give a colored end product. 13. Rinse the slide with running tap water for 5 min. 14. Counterstain the slide with hematoxylin stain for 5 min. 15. Dehydrate the slide in increasing grades of ethanol, clear it in xylol, and apply a coverslip. For direct aspiration smears, the best result in the first author’s experience is obtained in UFP-stained smears, since the aspirated red blood cells have been hemolysed. The tumor cells are rehydrated and their antigenicity permanently preserved by the fixation of alcoholic formalin and they can then be used at a later time. From a single UFP-stained smear, many antibodies can be performed via the cell-transfer technique3,37 without the need of destaining.48 Following the examination of a smear, the cytopathologist locates the desirable areas and divides the smear into several parts labeled with desired antibodies using a marking pen. The remaining procedure is as follows48 : 1. A UFP-stained smear with the cytopathologist’s design is copied by Xerox. 2. The coverslip is removed by soaking in xylene. 3. The smear was then covered with Mount-Quick liquid medium (Newcomer Supply, Middleton, WI).

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4. Place the wet slide in a microwave oven for 5 min to polymerize the liquid plastic and for antigen retrieval. 5. Soak the slide with the polymerized plastic in warm water. 6. Peel off the plastic film containing smear-medium complex from the original glass slide. 7. Following the design, the plastic film is cut with a pair of scissors and then transferred onto several positively charged glass slides. 8. Place these glass slides, each with a subdivision of the smear, in the microwave for 5 min to secure the adherence. 9. Rinse in three changes of xylene for up to 30 min to thoroughly remove the Mount-Quick medium. 10. Rehydrate the slide in decreasing grades of ethanol to water. 11. Immunostain following step 3 to step 15 in the previous procedure.

TECHNICAL PROBLEMS IN IMMUNOHISTOCHEMICAL STAINING FOR ASPIRATION PREPARATIONS Endogenous peroxidase activity is confined mostly to red blood cells and white blood cells. If it is not deactivated before the marking enzyme is added, positive staining will occur. Fine-needle aspirates often contain large numbers of red blood cells; therefore, deactivation of endogenous peroxidase is essential to allow the correct interpretation. Endogenous peroxidase activity is minimized in UFP-stained smears and compact cell blocks, where the aspirated blood has been hemolysed. The most common cause for nonspecific background staining is attachment of protein to highly charged collagen and connective tissue elements in aspirate preparations. The primary antibody can be nonspecifically absorbed to these charged sites. The secondary antibody can still bind to the primary antibody, and the peroxidase color reaction will occur. The most effective way to prevent this nonspecific staining is to add nonimmune serum from the same species to the specimen before the primary antibody is applied. The serum protein will fill the charged sites, leaving no room for adsorption of the primary antibody. Unlike cell block paraffin sections, direct smears are relatively variable in quality. For thick smears, immunostaining often results in a heavily stained background, thus creating difficulty in distinguishing a negative from a

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positive reaction. The Cytospin technique for preparing slides can reduce background staining because of the dilution effect of saline. In UFP-stained smears combined with cell-transfer technique, the cytopathologist can select the thinly spread areas by microscopic examination, and thus thick areas can be avoided. In smear preparations, the plasma membrane of certain types of cells such as lymphocytes or seminoma cells tend to rupture by the force of smearing. This releases membranous and cytoplasmic antigens into the background of the smear, leading to a false-negative reaction. Further, if air-dried smears are stored for some time at room temperature without fixation, they can lose their antigenicity and, again, a false-negative result may be obtained. It is also important to bear in mind that aspirate smears often contain a mixed population of cells, and thus, nonneoplastic cells showing a positive reaction must be distinguished from neoplastic cells to avoid a false-positive reading. The significance of negative reactions is sometimes difficult to interpret. It is, therefore, desirable to use at least two antibodies in each case. In some instances, when reactions are expected to be variable, a number of antibodies are usually required.

USEFUL TUMOR MARKERS FOR THE INTERPRETATION OF TRANSABDOMINAL ASPIRATION BIOPSY SPECIMENS Antibodies to the intermediate filaments that are present in different types of normal cells and in tumors arising from such cells can be helpful in the interpretation of transabdominal aspiration biopsy specimens.10,11,29 The five classes of intermediate filament are keratins,7,32 vimentin, desmin, neurofilaments, and glial fibrillary acidic protein. In general, the intermediate filament content of a tumor reflects its cell type of origin. The distribution of intermediate filaments in normal cells17 and in tumor cells is summarized in Table 12.1. However, not all tumors have demonstrable amounts of any class of intermediate filament, and some tumors express more than one class. Furthermore, switches in the classes of intermediate filaments may occur during normal development in some neoplasms. In the interpretation of immunostaining reactions, it is important to bear in mind that many antibodies are still under investigation, and the implications may not be absolute. Also, unexpected or “aberrant” immunoreactions may occur and give rise to

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Table 12.1 Distribution of Intermediate Filaments in Normal Cells and Tumor Cells Cytokeratin

Vimentin

Desmin

Neurofilaments

GFAP

• Epithelial cells • Mesothelial cells

+ +

− +/−

− −

− −

• Muscle cells • Mesenchymal cells • Neurons • Astrocytes • Hematopoietic cells

− −

+ +

− + (reactive) + +/−

− −

− −

− − −

− − +

− − −

+ − −

− + −

+ + − +/− + − − −

+/− + + + − − − +

− − + +/− − − − −

− − − − + + − −

− − − − − − + −

Normal Cells

Tumor Cells • • • • • • • •

Carcinoma Mesothelioma Myosarcoma Sarcoma Neuroendocrine Neuroblastoma Astrocytoma Lymphoma

misleading results.46 For instance, nonepithelial neoplasms, including epithelioid sarcoma, synovial sarcoma, chordoma and plasmacytoma, may express cytokeratin and/or epithelial membrane antigen. Non-neuroectodermal neoplasms, including liposarcoma, chondrosarcoma, chordoma, pleomorphic adenoma of the salivary gland, and papillary carcinoma of the thyroid, may express S100 protein. Non-mesenchymal neoplasms, including renal cell carcinoma, melanoma, and papillary carcinoma of the thyroid and one third of bronchogenic carcinoma may express vimentin. On the contrary, epithelial neoplasms, such as adrenocortical carcinoma, may be non-reactive for cytokeratin and/or epithelial membrane antigen. Lymphoid neoplasm, such as plasmacytoma, may be non-reactive for common leukocyte antigen. These are some exceptions which may mislead the examiners; however, characterization of tumor cells can often be done with the more specific antibodies.

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One of the most useful immunomarkers is the coordinate cytokeratin 7 (CK7) and cytokeratin 20 (CK20). In 1995, Wang et al.42 reported that carcinomas can be divided into 4 subsets by their immunoreactivity to CK733 and CK20.27 The CK7+/CK20+ subset included virtually all the urothelial carcinomas and the majority of pancreatic adenocarcinomas; the CK7−/CK20− subset was largely restricted to hepatocellular, prostate, and renal cell carcinomas in addition to squamous cell and small cell carcinomas of lung. The CK7−/CK20+ subset was characteristic of colorectal adenocarcinoma, while the CK7+/CK20− subset was typically seen in the vast majority of carcinomas arising from other sites, including lung, ovary, endometrium, and breast as well as malignant mesothelioma. Gastric carcinomas were the most heterogeneous subgroup with respect to the CK7/CK20 immunophenotype. In the subset of mucinous tumors, striking immunophenotypic differences were reported among those primary to the breast (CK7+/CK20−), gastrointestinal tract (CK7−/CK20+), and ovary (CK7+/CK20+). The data of Wang et al. is shown in Table 12.2.

FREQUENTLY ORDERED IMMUNOMARKERS In a work-up to confirm suspected primaries based on cytomorphologic analysis, the following immunomarkers are frequently ordered by the first author: CK7/CK20 for colon; TTF-12,13,22 for lung; Hepar-144,47 for liver; ER/PR for breast and endometrium; PSA/PSAP for prostate; CD101,5,45 for renal cell carcinoma; inhibin and Melan A(A102) for adrenal cortical lesion8,12,15,34 ; chromogranin/synaptophysin for neuroendocrine carcinomas; thyroglobulin for papillary and follicular carcinoma of the thyroid; calcitonin for medullary thyroid carcinoma; and calretinin9 /EMA24 for mesothelioma (Table 12.3). To confirm the suspected type of spindle cell tumors following cytomorphological analysis, the immunomarker frequently ordered include actin for smooth muscle tumor; c-Kit for gastrointestinal stromal tumor; CD34 for solitary fibrous tumor; S100 for peripheral nerve shealth tumor; and S100/HMB45 for spindle cell melanoma and cytokeratin for spindle cell carcinoma (Table 12.4). To confirm the suspected type of small round cell tumors of childhood following cytomorphological analysis, the immunomarkers frequently ordered are shown in Table 12.5.

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Table 12.2 Coordinate Cytokeratin Expression of Common Carcinomas (Wang et al.42 ) CK7+/CK20+

%

Fraction

CK7+/CK20−

%

Fraction

Lung, BAC∗

Urothelial Ca Pancreatic Aca Gastric Aca Breast, ductal Ca Endometroid Ca Lung, non-small cell Ca Colorectal Aca Breast, lobular Ca Prostatic Aca Hepatocellular Ca Ovary Ca Lung, BAC Renal cell Ca Lung, squamous cell Ca Lung, small cell Ca Malignant mesothelioma

89 65 38 16 12 11 10 9 8 7 0 0 0 0 0 0

17/19 15/23 11/29 6/38 3/25 6/54 4/40 1/11 1/13 2/30 0/19 0/3 0/17 0/12 0/11 0/16

Ovary Ca Breast, lobular Ca Breast, ductal Ca Endometroid Ca Lung, non-small cell Ca Malignant mesothelioma Pancreatic ductal Aca Renal cell Ca Lung, small cell Ca Hepatocellular Ca Gastric Aca Urothelial Ca Prostatic Aca Lung, squamous cell Ca Colorectal Aca

100 100 91 82 80 72 69 26 24 18 17 17 11 8 0 0

3/3 19/19 10/11 31/38 20/25 39/54 11/16 6/23 4/17 2/11 5/30 5/29 2/19 1/13 0/12 0/40

CK7−/CK20+ Colorectal Aca Gastric Aca Prostatic Aca Pancreatic Aca Lung, squamous cell Ca Renal cell Ca Breast, ductal Ca Lung, BAC∗ Urothelial Ca Hepatocellular Ca Ovary Ca Endometrial Aca Lung, non-small cell Ca Lung, small cell Ca Breast, lobular Ca Malignant mesothelioma

% 75 35 23 9 8 6 3 0 0 0 0 0 0 0 0 0

30/40 10/29 3/13 2/23 1/12 1/17 1/38 0/3 0/19 0/30 0/19 0/25 0/54 0/11 0/11 0/16

CK7−/CK20− Lung, squamous cell Ca Lung, small cell Ca Hepatocellular Ca Renal cell Ca Prostatic Aca Malignant mesothelioma Lung, non-small cell Ca Colorectal Aca Gastric Aca Endometrial Aca Pancreatic Aca Urothelial Ca Lung, BAC Breast, ductal Ca Breast, lobular Ca Ovary Ca

% 92 82 77 71 62 31 17 15 10 8 0 0 0 0 0 0

11/12 9/11 23/30 12/17 8/13 5/16 9/54 6/40 3/29 2/25 0/23 0/19 0/3 0/38 0/11 0/19

Ca: carcinoma; Aca: adenocarcinoma, ∗ BAC: non-mucinous bronchioloalveolar carcinoma. The immunoprofile of mucinous BAC is CK7+/CK20+,16,23 TTF-1 (−)16,23 and villin (−).16

To distinguish non-mucinous adenocarcinoma from mesothelioma, the panel of immunomarkers used includes calretinin9 or CK 5/66 for mesothelioma, CEA, B72.3 or LeuM-136 for adenocarcinoma,40 with the addition of TTF-12,13,22 to confirm a lung primary. To differentiate between

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Immunomarkers for Transabdominal Aspiration Biopsy Table 12.3

425

Frequently Ordered Immunomarkers to Confirm the Primary

Thyroid Breast Lung Mesothelium Liver Pancreas, bile duct Colon Kidney Adrenal cortical Prostate Ovary Endometrium Urinary bladder Neuroendocrine Gastrointestinal stromal tumor

Thyroglobulin+, Calcitonin+ (medullary ca); TTF-1+ ER/PR+, GCDFP-15, Her2/Neu TTF-1 (nuclear), CK7+/CK20− Calretinin + (nuclear + cytoplasmic) Hepar-1+ CK7+/CK20±, CK19+ CK7−/CK20+, CDX2 CD10+, Vimentin+, CK−/CK20−, CK7 (papillary RCC) Inhibin+, Melan A (A103)+ PSA/PSAP+ CK7+/CK20−, ER+, WT1+ ER+, Vimentin+ CK7+/CK20±, Uroplakin Chromogranin+, Synaptophysin+, CD56+ CD117 (c-Kit)+, CD34+

Table 12.4 Frequently Ordered Immunomarkers for Spindle Cell Neoplasms Malignant fibrous histiocytoma

Peripheral nerve sheath tumors Fibrosarcoma Monophasic synovial sarcoma Leiomyosarcoma Gastrointestinal stromal tumor Solitary fibrous tumor, hemangiopericytoma Spindle cell melanoma Spindle cell carcinoma Spindle cell carcinoid Proliferation index

Vimentin, KP1, lysozyme, α-1-antitrypsin, α-l-antichymotrypsin S-100 Vimentin Vimentin, cytokeratin (EM study, molecular genetics are more helpful) Desmin, Actin CD117 (c-Kit), CD34 CD34, CD99, vimentin S100, HMB45 (Some+) AE1/AE3 cytokeratin Chromogranin, synaptophysin MIB-1 (Ki67)

mesothelioma and mesothelial hyperplasia, the markers ordered include EMA to evaluate the length of microvilli (mesothelioma has longer microvilli, thus thicker membranous staining)24 and MIB1 to evaluate the proliferation index (mesothelioma higher). The proliferation marker, MIB-1(Ki-67) is ordered frequently in grading a wide variety of tumors, including non-Hodgkin lymphoma,38

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Transabdominal Fine-Needle Aspiration Biopsy Table 12.5 Frequently Ordered Immunomarkers for Small Round Cell Tumors of Childhood Desmoplastic small round cell tumor Ewing’s sarcoma/PNET Wilm’s tumor Neuroblastoma Rhabdomyosarcoma, embroynal type

Cytokeratin, desmin Leu 7, CD99, FLI-1 Cytokeratin, vimentin, WT-1 Synaptophysin, neurofilament, S100, NSE Myogenin, MyoD1, myoglobin, desmin

neuroendocrine tumors,25 spindle cell sarcomas, and tumors with cytomorphologic features that lie on the borderline between benign and malignant. In conclusion, for the cytologic differential diagnosis, the use of antibodies, intermediate filaments and secreted cellular products, which can help define the lesion, can be especially useful in problematic cases.3,7,32,36,39–41 Coordinate CK7 and CK20 expression are helpful in the work-up of unknown primaries. A different panel of antibodies can be used to grade and type spindle cell neoplasms and to characterize the small round cell tumors of childhood. Commercially available antibodies useful for the interpretation of transabdominal aspiration biopsy specimens include the following:

AE1/AE3 Antibody to a cocktail of low molecular weight cytokeratin (AE1) and high molecular weight cytokeratin (AE3).

Alk (NPM-ALK) Normal: normal small intestine; T cells. Tumors: T or null cell anaplastic lymphomas (ALK+ have favorable prognosis); inflammatory myofibroblastic tumor.

Actin (Smooth Muscle Actin, Muscle Specific Actin) Normal: smooth muscle; striated muscle; pericytes; myoepithelial cells; myofibroblasts. Tumors: leiomyoma; leiomyosarcoma; fibroadenoma of the breast; fibrous histiocytoma; pleomorphic adenoma of the salivary gland.

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α -Fetoprotein Normal: fetal neural tube; fetal brain; liver (fetal and regenerating). Tumors: hepatocellular carcinoma; yolk sac tumor; embryonal carcinoma; carcinomas of the stomach and lung. α -1-Antichymotrypsin Normal: histiocytes; pancreatic arcini. Tumors: acinar cell carcinoma of the pancreas; histiocytic tumors. α -1-Antitrypsin Normal: histiocytes; pancreatic acini. Tumors: histiocytic tumors; acinar cell carcinoma; solid-pseudopapillary tumor of the pancreas. α -Lactalbumin Normal: ductal epithelium of the breast. Tumors: benign and malignant tumors of the breast; tumors of the salivary gland and skin appendages; mesothelioma. β -Catenin Normal: fibroblasts and endothelial cells. Tumors: solid pseudopapillary neoplasm of the pancreas; desmoid-type fibromatosis; solitary fibrous tumors.

B72.3 (TAG-72) Normal: fetal tissue; secretory endometrium. Tumors: adenocarcinomas of G1 tract; ovary; endometrium; breast; and lung.

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Bcl1 (Cyclin D1) Bcl2 (B Cell Lymphoma #2) Normal: small B lymphocytes in mantle zone and cells within T cell areas. Tumors: follicular lymphoma (germinal centers are bcl2+ in follicular lymphoma; bcl2− in follicular hyperplasia).

Ber-EP4 Normal: epithelial cells. Tumors: adenocarcinomas of the lung; mammary Paget’s disease.

Calretinin Normal: mesothelial cells; neuronal cells. Tumors: epithelial mesotheliomas; sex cord stromal tumors (50–100%).

Calcitonin Normal: C-cells of the thyroid, endocrine cells of lung, brain, pituitary. Tumors: medullary carcinoma of the thyroid; occasional other neuroendocrine tumors.

Calponin Normal: smooth muscle; myoepithelial cells. Tumors: myofibroblastic lesions; smooth muscle tumors; myofibroblastic stroma of carcinomas.

CAM 5.2 Antibody to a cocktail of cytokeratins 8 and 18.

CEA (Carcinoembryonic Antigen) Normal: fetal and adult colon; small intestine; regenerating liver; lung; celomic inclusion cyst.

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Tumors: carcinomas of the lung, breast, colon, endometrium, ovary, stomach, bile duct, urinary bladder, cervix, and pancreas; benign and malignant teratomas; embryonal carcinoma; hepatocellular carcinoma (canalicular pattern in polyclonal CEA); Brenner tumor; medullary, follicular, and papillary carcinoma of the thyroid.

Chromogranin Normal: adrenal medulla; anterior pituitary, parathyroid gland; all neuroendocrine cells with neurosecretory dense granules. Tumors: carcinoid; islet cell tumor; medullary carcinoma of the thyroid; pheochromocytoma; paraganglioma; neuroblastoma.

Chymotrypsin Normal: pancreatic acini; histiocytes. Tumors: acinar cell carcinoma of the pancreas; histiocytic tumors.

CD1a Normal: cortical thymocytes; Langerhans cells. Tumors: Langerhans cell histiocytosis (fairly specific); myeloid leukemias; mycosis fungoides (variable); almost all cutaneous T cell lymphomas; T-ALL.

CD3 Normal: thymocytes; peripheral T cells; NK cells (CD3 epsilon, cytoplasmic in 56%, not membranous). Tumor: 80% of T cell lymphomas; NK lymphoma (cytoplasmic, not membranous); lymphomatoid granulomatosis; lymphomatoid papulosis; variable in primary effusion lymphoma.

CD4 Normal: thymocytes (80–90%). T helper cells; macrophages; Langerhans cells; dendritic cells; granulocytes.

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Tumor: post-thymic T cell leukemia/lymphomas; blastic NK lymphoma; AML.

CD8 Normal: cortical thymocytes (70–80%); T cell suppressor/cytotoxic cells; NK cells (30%, which are also CD3 negative). Tumor: epidermotrophic lymphocytes in mycosis fungoides; sinus lining cells in splenic hemartoma; NK/T cell lymphoma (variable); some postthymic T cell lymphomas.

CD10 (CALLA) Normal: lymphocytes of follicular center; endometrial stromal cell; myoepithelial. Tumors: conventional renal cell carcinoma; canalicular pattern in hepatocellular carcinoma; solid and pseudopapillary tumor of the pancreas; endometrial stromal cells; ALL; lymphomas of follicular center origin; Burkitt lymphoma.

CD15 (LeuM1) Normal: activated B and T cells; proximal convoluted tubules of the kidney. Tumors: carcinomas (50%); Reed-Sternberg cells (classic and nodular Hodgkin lymphoma).

CD20 (L26) Normal: pan B cell antigen; also follicular dendritic cells. Tumor: 90% of B cell lymphomas; also B-CLL; spindle cell thymomas; 80% of nodular lymphocyte predominant Hodgkin lymphoma.

CD21 Normal: mature B cells (marginal and mantle cells); follicular dendritic cells. Tumors: follicular dendritic cell sarcoma; mantle and marginal zone; splenic littoral cell angiomas.

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CD30 (Ki1, Ber-H2) Normal: granulocytes; activated B, T and NK cells; monocytes. Tumors: embryonal carcinoma of the testis; anaplastic large cell lymphoma (90%); primary cutaneous CD30+ lymphoma; nasal NK/T cell lymphoma in Chinese patients; Hodgkin or Reed–Sternberg cells in classic Hodgkin lymphoma; also Reed–Sternberg-like cells in follicular lymphoma.

CD31 Normal: endothelial cells. Tumors: angiosarcoma; hemangioendothelioma; littoral cell angioma of the spleen; lymphangioendothelioma lymphangioma.

CD34 Normal: endothelial cells of blood vessels. Tumors: solitary fibrous tumor; gastrointestinal stromal tumor; vascular tumors.

CD35 Normal: follicular dendritic cells; granulocytes; monocytes; B cells; NK cell subset. Tumors: follicular dendritic cell sarcoma; mantle cell lymphoma; marginal zone lymphoma.

CD38 Normal: plasma cells; committed hematopoietic progenitor cells; NK cells; B and T cells. Tumors: plasma cell myeloma; plasmablastic primary effusion lymphoma; lymphoplasmacytic lymphoma; plasmablastic large cell lymphoma.

CD45 (LCA)

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CD56 Normal: NK cells (80–90%); activated T cells; neuroendocrine tissues. Tumors: plasma cell myeloma; neuroendocrine tumors; Wilm’s tumor; NK/T cell lymphomas; small cell carcinoma.

CD99 (MIC2, O13) Normal: endothelial cells; ependymal cells; hepatocytes; gastric foveolar epithelium; immature thymic lymphocytes; ovarian granulosa cells; pancreatic islets; Sertoli cells; T cells and activated B cells. Tumors: Ewing’s sarcoma/PNET; T-ALL.

CD138 Normal: B cell precursors; plasma cells. Tumors: plasma cell myeloma; primary effusion lymphoma.

CD117 See c-kit.

CDX2 Normal: intestinal epithelium lining colonic villi and crypts; subset of pancreatic epithelial cell; gastric; intestinal metaplasia of the esophagus and bladder. Tumors: adenocarcinomas of G1 tract and urinary bladder, mucinous adenocarcinomas of the ovary and lung.

C-kit (CD117) Normal: pacemaker cells of Cajal in gastrointestinal tract, hematopoietic progenitor cells. Tumors: gastrointestinal stromal tumor; CML.

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Cyclin D1 Normal: responsible for transition to S phase by phosphorylating the retinoblastoma gene product, which releases transcription factors to initiate DNA replication. Tumors: mantle cell lymphoma; plasma cell myeloma; parathyroid carcinomas.

Cyclin D2 Normal: cell cycle regulatory protein that facilitates G1 to S phase transition. Tumors: diffuse large B cell lymphoma (14%).

Cytokeratin Normal: epithelium and appendages of the skin; ducts of the epithelial glands; mesothelium; Hassall’s corpuscles; epithelium of the fallopian tube, salivary gland, bile duct, uterus, prostate, cervix, bronchus, and tongue; urothelium; Mallory bodies. Tumors: adamantinoma; carcinoma of the lung (squamous cell carcinoma, adenocarcinoma, and bronchioloalveolar carcinoma); transitional cell carcinoma; mesothelioma; pleomorphic adenoma of the salivary gland; mucoepidermal carcinoma; hepatocellular carcinoma; cholangiocarcinoma; thymoma; carcinomas of the esophagus, stomach, colon, rectum, cervix, endometrium, prostate, and nasopharynx; synovial sarcoma; chordoma; plasmacytoma.

Cytokeratin (Low Molecular Weight) Normal: hepatocytes; pancreatic acinar cells; ductal epithelium of the breast and liver; mesothelium; simple epithelium. Tumors: ductal carcinoma of the breast; cholangiocarcinoma; adenocarcinoma of the pancreas; hepatocellular carcinoma; ovarian adenocarcinoma; adenocarcinoma of the lung; mesothelioma; renal cell carcinoma; endometrial adenocarcinoma; colonic adenocarcinoma; carcinoid tumor; small cell anaplastic carcinoma of the lung; urothelial carcinoma; thymoma.

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Cytokeratin (High Molecular Weight) Normal: squamous epithelium; ductal epithelium; complex epithelium. Tumors: squamous cell carcinoma, ductal carcinoma of the breast; adenocarcinoma of the pancreas; ovarian adenocarcinoma; adenocarcinoma of the lung; urothelial carcinoma; mesothelioma; thymoma.

CK5/CK6 (Cytokeratin 5/Cytokeratin 6) Normal: breast myoepithelial layer. Tumors: Mesotheliomas; squamous component of tumors; basal phenotype breast carcinomas (high grade and ER/PR−).

CK7 (Cytokeratin 7) Normal: simple epithelial from gallbladder; hepatic ducts; pancreatic ducts; endometrium; fallopian tube; breast; bladder; lung. Tumors: papillary renal cell carcinoma; pancreaticobillary carcinomas; tumors of the female genital tract (endometrium, fallopian tube); urothelial carcinoma; breast carcinoma; lung carcinoma.

CK19 (Cytokeratin 19) Normal: bile duct; columnar epithelium; basal squamous epithelium. Tumors: cholangiocarcinomas; papillary thyroid carcinoma.

CK20 (Cytokeratin 20) Normal: gastric and intestinal mucosa; urothelium; squamous mucosa. Tumors: gastric and colorectal carcinoma.

D2-40 Normal: endothelium of lymphatic vessels. Tumors: lymphatic vascular tumor.

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Desmin Normal: smooth muscle; striated muscle, cardiac muscle, myoepithelial cells. Tumors: leiomyoma; leiomyosarcoma; rhabdomyoma; rhabdomyosarcoma; tumors of the salivary gland.

E-Cadherin Normal: intercellular adhesion molecule. Tumors: many cohesive carcinomas, including ductal breast carcinomas (absent in lobular breast carcinoma and signet ring cell gastric carcinoma).

EMA (Epithelial Membrane Antigen) Normal: most secretory epithelium of the gastrointestinal tract, bronchi, and biliary tract. Tumors: adenocarcinomas of various origins; squamous cell carcinoma; renal cell carcinoma; urothelial carcinoma; small cell carcinoma; mesothelioma (thick membranous staining); synovial sarcoma; chordoma; plasmacytoma.

ER (Estrogen Receptor) Normal: breast, endometrium, ovary. Tumors: breast carcinoma (varies by subtype and tumor grade); endometrial adenocarcinoma (75%); ovarian carcinomas, absent in endocervical adenocarcinoma.

Factor VIII Normal: vascular (but not lymphatic) endothelium; platelets; megakaryocytes. Tumors: angiosarcoma; hemangioma; Kaposi’s sarcoma.

Fascin Normal: specialized cells with extensive surfaces or migratory potential, such as neurons, glia, dendritic cells, macrophages, skeletal and smooth muscle; endothelial cells.

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Tumors: classic Hodgkin lymphoma; follicular dendritic cell tumors; Langerhans cell histiocytosis; urothelial carcinoma (invasive or papillary), carcinoma of biliary tract; breast; colon; lung; ovary; pancreas; skin.

FLI-1 Normal: endothelial cells; T cells; small lymphocytes. Tumors: Ewings sarcoma/PNET, vascular tumors; lymphomas.

GFAP (Glial Fibrillary Acidic Protein) Normal: intermediate filament for astrocytes. Tumors: CNS tumors.

GCDFP-15 (Gross Cystic Disease Fluid Protein 15) Normal: glycoprotein isolated in human breast gross cystic fluid. Tumors: lobular breast carcinoma (90%); primary breast carcinomas (72%); metastatic breast carcinoma (80%); also salivary gland and prostate carcinoma with apocrine differentiation.

HBME-1 (Dr. Hector Battifora and Mesothelioma) Normal: mesothelial cells. Tumors: mesotheliomas, thyroid carcinomas.

Hepatocyte Paraffin-1 (Hepar-1) Normal: hepatocytes. Tumors: hepatocellular carcinoma.

Her2/Neu (c-erb2) Normal: expression is regulated by transcription activation in normal breast.

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Tumors: overexpressed in 20–30% of breast cancers; associated with aggressive tumors. Amplification determines eligibility for Herceptin treatment for breast cancer.

HHF-35 (Muscle Actin) Normal: smooth and skeletal muscle; pericytes; myoepithelial cells; myofibroblasts. Tumors: rhabdomyosarcoma; leiomyosarcoma.

HHV-8 (Human Herpes Virus 8) Normal: endothelial cells, monocytes and B cells latently infected by HHV-8. Tumors: Kaposi’s sarcoma; associated with 3 HIV associated lymphoproliferative disorders — primary effusion lymphoma, multicentric Castleman’s disease, multicentric Castleman’s disease-associated plasmablastic lymphoma.

HMB-45 Normal: junctional melanocytes; scattered mononuclear cells in normal lymph nodes. Tumors: melanomas (except for some spindle cell melanomas and all desmoplastic melanomas), PEComas; soft part sarcomas; pigmented nerve sheath tumors; pheochromocytomas (30%).

Human Chorionic Gonadotropin (ß-HCG) Normal: syncytial trophblasts of the placenta; ovary. Tumors: choriocarcinoma; dysgerminoma; seminoma; malignant teratoma; embryonal carcinoma.

Inhibin A Normal: adrenal cortex; Sertoli cells; granulosa cells. Tumors: adrenocortical tumors; sex-cord stromal tumors; placental and gestational trophoblastic lesions.

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Ki1 (CD30) Ki67 (MIB1, proliferation index) Normal: minimal. Tumors: in proportion to the grade of tumors (nearly 100% for high grade lymphoma, high grade sarcoma, small cell carcinoma, often used in combination with p53).

KSHV/HHV8 (Kaposi’s Sarcoma-associated Herpes Virus/Human Herpes Virus 8) Tumors: Kaposi’s sarcoma; primary effusion lymphoma.

LANA (HHV8 Latency-associated Nuclear Antigen) Normal: highly expressed during latent HHV8 infection. Tumors: HHV8-associated Kaposi’s sarcoma (endothelial and spindle cells); primary effusion lymphoma; multicentric Castleman’s disease.

LCA (Leukocyte Common Antigen) (CD45) Normal: lymphocytes; monocytes; macrophages; mast cells. Tumors: AML, anaplastic large cell lymphoma; B and T cell lymphomas (including necrotic lymphomas); lymphocyte predominant Hodgkin’s lymphoma; primary effusion lymphoma.

Lysozyme (Muramidase) Normal: histiocytes; myeloid cells; Paneth cells; glands of the tracheobronchial submucosa. Tumors: meylocytic leukemia; hairy cell leukemia; benign and malignant histiocytomas; histiocytic tumors.

MART-1 (MELAN-A)

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Melan A (A103) Normal: adrenal cortex. Tumors: adenal cortical carcinoma; melanomas.

Mesothelin Normal: mesothelial cells. Tumors: mesotheliomas; ovarian surface carcinomas.

MIB-1 (Ki67) MUC1 Normal: membrane bound mucin salivary glands; type II pneumocytes. Tumors: breast, pancreatic and colorectal carcinoma; type II pneumocyte lesions, inverted localization in micropapillary subtype is associated with poor prognosis.

MUC2 Normal: secretory mucin of goblet cells; intestinal and airway epithelium. Tumors: mucinous carcinomas of the colon, breast, pancreas, ovary and stomach.

MUC3 Normal: membrane bound mucin distributed in intestine. Tumors: invasive breast carcinoma; gastric carcinoma (poor prognosis).

MUC4 Normal: tracheobronchial mucosa; colon; stomach; cervix; lung; salivary glands. Tumors: pancreatic, colonic, pulmonary and gastric carcinoma.

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MUC5 Normal: stomach (foveolar epithelium of the body and antrum); tracheobronchial mucosa. Tumors: extramammary Paget disease; mucinous carcinoma of the ovary; diffuse-type gastric carcinoma (83%).

MUC6 Normal: stomach (pyloric glands); gallbladder; colon; and endocervix. Tumors: invasive ductal carcinoma of the breast; gastric carcinomas.

Myoglobulin Normal: striated muscle; cardiac muscle. Tumors: rhabdomyoma; rhabdomyosarcoma; rhabdoid area in malignant mixed mullerian tumors.

MyoD1 Normal: fetal muscle. Tumors: rhabdomyosarcoma and leiomyosarcoma.

Myogenin Normal: fetal skeletal muscle; atrophic or regenerative skeletal muscle. Tumor: rhabdomyosarcoma.

Myosin Normal: striated muscle; cardiac muscle. Tumors: rhabdomyoma; rhabdomyosarcoma; rhabdoid area in malignant mixed mullerian tumor.

Neurofilament Normal: neuronal cells.

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Tumors: neuroblastoma; Merkel’s cell tumor of skin; pancreatic endocrine neoplasms; carcinoid tumors; parathyroid tumors.

NSE (Neuron Specific Enolase) Normal: neurons; neuroendocrine cells. Tumors: poorly differentiated neuroendocrine tumors.

P53 Most commonly detected genetic abnormalities in human neoplasia. Often used in combination with MIB1.

PAX-5 Normal: present in B cells from pro-B-cell stage to plasma cell stage where it is downregulated and absent. Tumors: pre-B and mature B cell lymphomas/leukemias; Hodgkin lymphoma (Reed–Sternberg cells); lymphoplasmacytic lymphoma; Merkel cell and small cell carcinoma.

PLAP (Placental Alkaline Phosphatase) Normal: some infantile germ cells until age 1. Tumors: seminoma.

PR (Progesterone RECEPTOR) Normal: breast and endometrium. Tumors: breast carcinoma; endometrial adenocarcinoma.

Prostatic Acid Phosphatase (PSA) Normal: glands of the prostate; granulocytes; islets of the pancreas; parietal cells of the stomach; tubular cells of the kidney. Tumor: carcinoma of the prostate and breast; carcinoid; islet cell tumor.

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Prostate-Specific Protein (PSAP) Normal: glands of the prostate. Tumor: carcinoma of the prostate.

RCC (Renal Cell Carcinoma marker) Normal: brush border of proximal tubules of the kidney. Tumors: renal cell carcinoma; clear cell or papillary.

S-100 Protein Normal: peripheral nerve; melanocytes; histiocytes; reticlar cells of the lymph node; chondrocytes, fat cells; myoepithelial cells. Tumors: Schwannoma; neurofibroma; malignant peripheral nerve sheath tumor; melanoma; retinoblastoa; pleomorphic adenoma of salivary gland; paragangloma; chondrosarcoma; chordoma; liposarcoma; papillary carcinoma of the thyroid; meduallary carcinoma of the breast.

Synaptophysin Normal: adenal medulla; anterior pituitary; parathyroid gland; C-cells of the thyroid, islet cells of the pancreas; enterochromaffin cells of the gastrointestinal tract. Tumors: pheochromocytoma; carcinoid; paraganglioma; neuroblastoma; islet cell tumor; meullary carcinoma of the thyroid.

TdT Normal: B and T cell precursors; cortical thymocytes. Tumors: ALL; lymphoblastic lymphoma.

Thrombomodulin Normal: keratinocytes; mesothelial cells; endothelial cells. Tumors: mesotheliomas; urothelial carcinomas; squamous cell carcinomas.

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Thyroglobulin Normal: thyroid follicles and colloid. Tumors: papillary and follicular carcinoma of the thyroid.

TIA-1 (T-cell Intracytoplasmic Antigen) Normal: cytotoxic granule-associated RNA binding protein in cytotoxic T-lymphocytes. Tumors: lymphomas or leukemias containing cytotoxic T cells such as T/NK cell lymphomas; Ki1 anaplastic large cell lymphomas (60–70%); large granular cell leukemias.

TTF-1 (Thyroid Transcription Factor-1) Normal: type II pneumocytes and clara cells of the lung; follicular and parafollicular c cells of the thyroid. Tumors: lung carcinoma: small cell (90%); adenocarcinoma (75%); large cell (40%); thyroid carcinomas.

Uroplakin III Normal: urothelium. Tumors: urothelial lesions (specific but only 50% sensitive).

Vimentin Normal: Intermediate filament for mesenchymal tissue. Tumors: mesenchymal tumors; renal cell carcinoma.

WT1 Normal: nephrogenic rates; fallopian tube; kidney; mesothelium; ovarian granulosa cells; Sertoli cells; spleen. Tumors: Wilm’s tumor; mesothelioma; papillary serious carcinoma; rhabdoid tumor; desmoplastic small round cell tumor.

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43. Warnke RA, Gatter KG, Falini B. (1983) Diagnosis of human lymphoma with monoclonal antileukocyte antibodies. N Engl J Med 309:1275–1281. 44. Wennerberg AE, Nalesnik MA, Coleman WB. (1993) Hepatocyte paraffin1 — A monoclonal-antibody that reacts with hepatocytes and can be used for differential-diagnosis of hepatic-tumors. Am J Surg Pathol 143:1050–1054. 45. Yang B, Ali SZ, Rosenthal DL. (2002) CD10 facilitates the diagnosis of metastatic renal cell carcinoma from primary adrenal cortical neoplasm in adrenal fineneedle aspiration. Diagn Cytopathol 27:149–152. 46. Yu GSM. (1987) Immunocytochemistry and electron microscopy. In: Suen KC (ed.), Guides to Clinical Aspiration Biopsy : Retroperitoneum and Intestine. Igaku-Shoin, New York. 47. Zimmerman RL, Burke MA, Young NA, et al. (2001) Diagnostic value of Hepatocyte Paraffin 1 antibody to discriminate hepatocellular carcinoma from metastatic carcinoma in fine-needle aspiration biopsies of the liver. Cancer Cytopathol 93:288–291. 48. Zu Y, Gangi MD, Yang GCH. (2002) Ultrafast Papanicolaou stain and celltransfer technique enhance cytologic diagnosis of Hodgkin lymphoma. Diagn Cytopathol 27:308–311.

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INDEX

A

cortical carcinoma, 212 small cell type, well-differentiated, Figs. 7.10, 7.11 large cell type, well-differentiated, Fig. 7.12 poorly differentiated, Figs. 7.13–7.15 cortical nodule, 209, Fig. 7.6 hyperplasia, 209, Fig. 7.4 vs. renal cell carcinoma, Fig. 7.5 infections Cryptococcus, 209, Fig. 7.3 Histoplasmosis, 209, Fig. 4.6 tuberculosis, 209, Fig. 8.2 triage of adrenal cortical nodules, 214 Adrenalectomy indications, 211, 212 Adrenal medulla tumors, 214 pheochromocytoma, 215, Figs. 7.16, 7.17 neuroblastic tumors, 216, 217, Table 7.1 ganglioneuroblastoma, 218, Fig. 7.19 ganglioneuroma, 219, Figs. 7.20, 7.21 neuroblastoma, 217, Fig. 7.18 prognostic indicators, 217 Adrenal myelolipoma, 220, Fig. 7.22 Adrenal tuberculosis, 209 Adult mesoblastic nephroma, 172, Fig. 6.6 Adult T-cell lymphoma/leukemia, 379, Fig. 11.27 AE1/AE3, 426, Figs. 4.37, 4.58, 5.31, 8.24, 8.48, 8.52, 8.53, 10.3

Abscesses, pyogenic Liver, 56 Kidney, 168 retroperitoneum, 236, Fig. 8.4 Acinar cells, pancreatic, 123, Fig. 5.2 Acinar cell carcinoma, 138, Figs. 5.37, 5.38 Actin, 426, Figs. 6.3, 8.9 Actinomyces Israelii in liver abscess, 56 in retroperitoneal abscess, 236, Fig. 8.4 Addison’s disease, 209 Adenocarcinoma breast, 78, 79, Figs. 4.63–4.66 colon, 337, Figs. 10.23–10.26 endometrioid, 288–291, Figs. 9.3–9.6 lung, 75–78, Figs. 4.53, 4.55–4.57 pancreatic ducts, 130–132, Figs. 5.17–5.28 prostate, 78, Figs. 4.61, 4.62 stomach, 334, Figs. 10.15–10.18 Adenomas adrenocortical, 211, Figs. 7.8, 7.9 bile duct, 68, Fig. 4.39 liver cell, 59, Figs. 4.11, 4.12 Adenosquamous carcinoma Liver, 70, Fig. 4.45 Pancreas, 134, Figs. 5.33, 5.34 Adrenal gland histology, 207 cytology, 207, 208 Adrenal cortical lesions cortical adenoma, 211, Figs. 7.8, 7.9 449

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Aflatoxins hepatic carcinogenesis and, 62 Alcoholic formalin, 25 Alpha-fetoprotein, 427, Fig. 4.31 Alpha-1-antitrypsin, 427, Figs. 5.11, 5.37, 5.38 Alveolar soft part sarcoma, 252, 253, Figs. 8.50, 8.51 Ampullary carcinoma, 134 Anabolic steroid, 71 Anaplastic large cell lymphoma B cell, 376 T cell, 381, Figs. 11.31–11.33 Ancient schwannoma, 247, Fig. 8.37 Angioimmunoblastic T-cell lymphoma, 382, Fig. 11.34 Angiography, 17 Angiomyolipoma kidney, 169, Figs. 6.3, 6.4 liver, 58 Angiosarcoma chemicals associated with, 71 liver, 71, Fig. 4.46 retroperitoneum, 243, Figs. 8.22–8.25 Appendiceal tumors, 335, 336 adenocarcinoid, 336, Fig. 10.20 carcinoid, 336, Figs. 10.20, 10.21 mucinous cystic tumor, 335, Fig. 10.19 Arsenic exposure, 71 Aspiration biopsy, 1–11 advantages, 5 complications, 6 disadvantages of, 9 history of, 2 indications and contraindications, 4 instruments and materials of, 18 localization methods, 16, 17 reliability, 7 accuracy of cytomorphologic interpretation, 9 accuracy of needling to obtain a representative sample, 8

B B-cell lymphomas, 367–378 B-cell transformation, site of, 364, Diagram 11.1 ßeta-Catenin, 427, Fig. 5.11 Bile duct adenoma, 70, Fig. 4.39 carcinoma, 70, Figs. 4.40–4.45 epithelial cells, 53, Fig. 4.2 Bile plugs, 53, Fig. 4.1C Biopsy types endoscopic ultrasound-guided FNA, 1, 10 FNA versus large-bore needle, 1, 8, 9, 51 large-bore needle, 1, 3 transabdominal FNA, 1 Borderline tumors of ovary mucinous 298, Fig. 9.30 papillary serous tumor, 297, Figs. 9.25, 9.26 Borderline tumor of peritoneum, 329, Fig. 9.25 Bronchioloalveolar carcinoma, 77 nonsecretory cell type, Fig. 4.55 secretory cell type, Fig. 4.56 BRCA gene mutation, 329 Breast, metastatic from ductal carcinoma, 79, Figs. 4.64–4.66 lobular carcinoma, 78, Fig. 4.63 Broad ligament tumors ependymoma, 303, Fig. 9.36 PEComa, 302, Fig. 9.35 Burkitt lymphoma, 377, Fig. 11.23 Burkitt-like lymphoma, 377, Fig. 11.24

C C-kit, 338, 430, Figs. 10.28–10.32 Calretinin, 333, 427, Figs. 10.8, 10.10 Cal-Exner bodies, 300, Fig. 9.32 Carcinoid syndrome, 336

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Index Carcinoid appendix and ileum, 336, Figs. 10.20, 10.21 Carcinoembryonic antigen (CEA), 428 Carcinosarcoma, 290, 299, Figs. 9.10, 9.11 Caroli’s disease, 127, Fig. 5.7 Cavernous hemangioma of liver, 57, Fig. 4.8 Cervical cancers, 294–296 Mucinous adenocarcinoma, 294, Figs. 9.20, 9.21 Squamous carcinoma, 295 Keratinizing, Fig. 9.22 Non-keratinizing, Figs. 9.23, 9.24 Cell block, compact protocol, 25 rationale, 26, Diagram 2.3 Cell-transfer technique, 419 Centroblastic large B-cell lymphoma, 374, Figs. 11.14–11.16 CD1a, 429, Fig. 11.42 CD3, 429, Figs. 10.18, 10.20, 10.30 CD10, 430, Fig. 7.5 CD20, 430, Figs. 10.18, 10.20 CD21, 430, Fig. 11.43 CD30, 431, Fig. 10.31 CD34, 431, Figs. 4.19, 4.46, 8.30, 8.34 CD99, 432, Fig. 8.33 Chiba needle, 18 Cholangiocarcinoma, 70 adenosquamous type, Fig. 4.45 nonsecretory type, Figs. 4.40–4.43 secretory type, Fig. 4.44 Cholestasis, Fig. 4.1 Chondrosarcoma, Fig. 8.49 Chordoma, 252, Fig. 8.47 Chromogranin, Figs. 4.52, 7.17, 10.20 Chronic lymphocytic leukemia, 367, Figs. 11.2, 11.3 Ciliated foregut cyst, 124, Fig. 5.6 Cirrhosis, 58, 60 CK7/CK20 expression of carcinomas, 423, Table 12.2 Classic Hodgkin lymphomas, 383–386 Clear cell carcinoma of endometrium, 290, 299, Figs. 9.8, 9.9 Clinical data useful for diagnosis, 37

451

Clonorchis sinensis, 70 Cohesion factor, 38, 39, Table 3.1 Colonic adenocarcinoma, 337, 338 intestinal type, Figs. 10.23, 10.24 mucinous type, Fig. 10.25 signet ring cell type, Fig. 10.26 Compact cell block, 417 Conn’s syndrome, 211 Copper sulfate, 71 Cortisol, excessive production of, 211 Contraceptives, oral liver carcinogenesis and, 62 liver cell adenoma and, 59 CT scan (computer tomography), 4, 16, 17 Cushing’s syndrome, 211 Cystic nephroma, multilocular, 172, Fig. 6.6 Cytogenetics renal cell carcinomas, 171 Cytokeratin, 7, 434, Fig. 6.37 Cytokeratin, 19, 434, Figs. 4.39, 4.40 Cytokeratin, 20, 434, Fig. 6.37 Cystadenocarcinoma of ovary mucinous type, 298, Fig. 9.30 serous, 297, Fig. 9.28 Cystadenomas mucinous, of appendix, 335, Fig. 10.19 mucinous cystic tumors of pancreas, 129, Fig. 5.13 serous of pancreas, 12, Figs. 5.8–5.10 Cystic nephroma, multilocular, 172, Fig. 6.6 Cytologic criteria, 38–43 cohesion factor, 38, Table 3.1 arrangement of tumor cells, 41 monolayer, Fig. 3.5A multilayer, Fig. 3.5B papillary, Fig. 3.5C unique features of tumor cells, 41 keratin, Figs. 2.4A, 3.6A endothelial wrapping, Fig. 3.6C psammoma bodies, Fig. 3.6D melanin pigments, Fig. 2.4C secretions, Figs. 2.2, 2.4B, 2.4D cytoplasm amount, 42 abundant, Fig. 4.33

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invisible, Fig. 4.51, Fig. 8.3, Fig. 10.3 texture, 42 multivacuolated, Fig. 3.7A, 3.7B dense, Fig. 3.7E fibrillary, Fig. 3.7C granular, Fig. 3.7F ground glass, Fig. 3.7D brown inclusion, Fig. 2.5 nucleus size, 39, 40 small, Fig. 3.3A intermediate, Fig. 3.3B large, Fig. 3.3C shape, 40 round, Fig. 3.4A ovoid/round, Fig. 3.4B elongated/spindle, Fig. 3.4C irregular, Fig. 3.4D multinucleated, Fig. 3.4E location, 42 eccentric, Fig. 3.7D central, Figs. 3.6C, 3.7E nucleolar size and number, 42 single, prominent, Fig. 11.16 multiple, Fig. 11.14 inconspicuous, Figs. 5.36, 10.21C Clues to interpretation cytologic clues background clues, 24, Fig. 2.2 negative image clues, 24, Fig. 2.3 polychromatic clues, 24, Figs. 2.4, 2.5 complementary clues, 24, Fig. 2.6 radiologic clues anatomic location, 36 size of lesion, 36 radiologic appearance, 36 consistency of lesion felt to needle during aspiration, 36 gross appearance of aspirate, 36 Conn’s syndrome, 211 Cushing’s syndrome, 210 CytoRich Red fixative, 19, 25

Cytostain, 25 Cytomorphologic interpretation accuracy, 9 pitfalls, 10, 43, 44 test turnaround time, 5 typing of tumors, 10 primary sites determination, 10 team approach, 35 radiologic data, 36 clinical data, 37

D Desmin, 435, Fig. 10.3 Desmoid tumor, 238, Fig. 8.6 Diabetes mellitus, 53, hepatocytes in, 53, Fig. 4.1D Diagnosis, team approach to, 35–37 Diff-Quik (Romanovsky) stain, 21, Figs. 2.2, 2.3, 2.6 Diffuse large B-cell lymphoma, 374–376, Figs. 11.14–11.19

E E-Cadherin, 435, Fig. 4.18 Echinococcus granulosus, 55, Fig. 4.5 Embryonal sarcoma of liver, 72, Fig. 4.48 Embryonal carcinoma, 250, Fig. 8.43 Embryonal rhabdomyosarcoma, Figs. 8.19, 8.20 Endometrial tumors carcinoma, 288–291 mucinous, 289, Fig. 9.6 type 1, endometrioid carcinoma, 288, Fig. 9.5 type 2, papillary serous carcinoma, 289, Fig. 9.7 stromal sarcoma, 291, 292 low grade, Figs. 9.12, 9.13 high grade, Figs. 9.14, 9.15

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Index Endometrioid carcinoma of endometrium, 288, 297, Figs. 9.3–9.5 of ovary, 297, Fig. 9.31 Endometriosis, 287, Fig. 9.2 Endometrial stromal sarcoma, 291, 292 low grade, Figs. 9.12, 9.13 high grade, Figs. 9.14, 9.15 Endothelial sinusoidal cells, 53, Fig. 4.3A Endoscopic retrograde cholangiopancreatography, 17 Endoscopic ultrasound guided FNA, 1, 10, 122 Epithelial membrane antigen, 435, Figs. 10.8, 10.10 Eosinophilic granuloma, 387, Fig. 11.42 - and smoking, 387 Ependymoma of broad ligament, 303, Fig. 9.36 Epithelioid hemangioendothelioma of liver, 72, Fig. 4.47 Epithelial mesothelioma, 330–332, Figs. 10.6–10.12 Estrogen receptor, 435, Fig. 3.8 Ewing’s sarcoma, 245, Figs. 8.31–8.33

F Factor VIII, 435 Fascin, 435, Fig. 11.37 Fallopian tube tumors, 296 False-negative results, 26–28 misinterpretation, 27 needle tip missing target, 27 sampling errors, 27 screening miss, 27 unsatisfactory specimen, 27 Fatty metamorphosis, 58 Fibrolamellar hepatocellular carcinoma, 67, Figs. 4.33, 4.34 Fibrosis, idiopathic, 237, Fig. 8.5 Fibrothecoma, 301, Fig. 9.34 Fibromatosis, 238, Fig. 8.6 Fibrosarcoma, 238, Figs. 8.7, 8.8

453

Fine-needle aspiration biopsy, see aspiration biopsy Fixative, CytoRich Red, 19, 25 Flow cytometry, 361 limitations in high grade lymphomas, 377 Fluorescence in situ hybridization, 361 Focal nodular hyperplasia, 59 Follicular center concept, 364, Diagram 11.1 Follicular dendritic cell sarcoma, 387, Figs. 11.43, 11.44 Follicular lymphoma, 371–374, Figs. 11.12, 11.13 Franseen needle, 19 Furhman nuclear grading, 174, 175, Fig. 6.11

G Ganglion cells in ganglioneuroma, 219 nuclei of, 219 Ganglioneuroblastoma, 218, 219, Figs. 7.19 Ganglioneuroma, 219, Figs. 7.20, 7.21 Gastric adenocarcinoma intestinal type, 334, Figs. 10.15–10.17 signet ring cell type, 334, Fig. 10.18 Gastrointestinal tract tumors, 334–340 Gastrointestinal stromal tumors (GIST), 338–340, Fig. 10.27 spindle cell type, Figs. 10.28–10.30 epithelioid cell type, Figs. 10.31, 10.32 Germ cell tumors, 249–251 non-seminomatous, 250, 251, Figs. 8.43–8.47 embryonal carcinoma, 250, Fig. 8.43 yolk sac tumor, 250, 251 microcystic type, Fig. 8.44 parietal type, Fig. 8.45 Schiller-Duval body type, Figs. 8.46, 8.47 seminoma, 249, 250, Fig. 8.42 GleevecTM , 329 Glucoagonoma, 136

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index


Granulomas, of liver, 56, Fig. 4.6 Granulosa cell tumor, 300, Figs. 9.32, 9.33 Greene needle, 18

H Hand-Schüller-Christian disease, 387, Fig. 11.42 Hemachromatosis, 70 Hemangiopericytoma, 244, 245, Figs. 8.29, 8.30 Hematoxylin II, 25 Hepatitis B and C hepatic carcinogenesis and, 61 Hepatoblastoma, 69 embryonal and fetal type, Figs. 4.35, 4.36 pure Fetal epithelial type, Fig. 4.37 mixed epithelial and mesenchymal type, Fig. 4.38 Hepatocellular lesions, benign cirrhosis, 60, Fig. 4.13 dysplastic nodule, large cell, 60, Fig. 4.13 fatty metamorphosis, 58 focal nodular hyperplasia, 59, Fig. 4.9, 4.10 macroregenerative nodule, 58, 60, Fig. 4.13 physical features of aspirates, 63, Fig. 4.17 Hepatocellular lesions, borderline borderline nodules, 61, Fig. 4.14 dysplastic nodules, small cell, high grade, 61, Fig. 4.15 Hepatocellular carcinoma, 61 cytomorphologic features of different types of, 68, Table 4.1 fibrolamellar, 67, Figs. 4.33, 4.34 incidence of, 61, 62 moderately differentiated, 65, Figs. 4.25–4.28 pleomorphic large cell type, 66, Figs. 4.32–4.34

poorly differentiated, 66, Figs. 4.29–4.31 well-differentiated classic trabecular, 64, Fig. 4.19 clear cell variant, 64, Fig. 4.24 microacinar variant, 65, Figs. 4.22, 4.23 microtrabecular variant, 65, Figs. 4.20, 4.21 Hepatocytes, 53, Fig. 4.1 Her2/Neu, 436, Fig. 4.66 Histiocytic and dendritic neoplasms, 386–388 Histology via cell block, 20, 25, 26 History large-bore needle biopsy, 2, 3 fine-needle aspiration biopsy, 3 transabdominal FNA, 2, 4, 7, Fig. 1.1 Ultrafast Papanicolaou stain, 21 compact cell block, 20, 25 CytoRich Red fixative, 25, 26 Histoplasmosis granulomas, 56, Fig. 4.6 HMB-45, 437, Figs. 4.68, 6.3, 6.4, 9.35 Hodgkin lymphoma, 382–386 classic, 384, 385, Figs. 11.37–11.39 lymphocyte depleted, 385 lymphocyte rich, 384 mixed cellularity, 384 nodular sclerosis, 384 nodular predominate, 383 Human chorionic gonadotrophin, 437, Fig. 8.43 Human Herpes virus, 8, 437, Figs. 10.20–10.22 Hydatid cyst, 55, Fig. 4.5

I Idiopathic retroperitoneal fibrosis, 237, Fig. 8.5 IgM monoclonal dysproteinemia, 370, Fig. 11.4 Ileum carcinoid tumors of, 336, Figs. 10.20, 10.21

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Index gastrointestinal stromal tumor of, 338–340 Imaging techniques, 16; see also specific techniques with aspiration biopsy, 16–18 development of, 2–4 localization by, 16–18 Immunohistochemistry avidin-biotin immunoperoxidase procedure, 418 difficulty of assessment of, 421 technical problems in, 420 Immunomarkers, 426–439 to confirm the primary site, 424, Table 12.3 to differentiate spindle cell neoplasms, 425, Table 12.4 to differentiate small round cell tumor of childhood, 425, Table 12.5 Infarct, renal, 168 Infections Actinomyces israelii, 56, 236, Fig.8.4 Cryptococcus, 209, Fig.7.3 Ecchinococcus, 88, Fig. 4.5 Histoplasmosis, 56, 209 Fig.4.6 Mycobacterium avium intracellulare, 33, 236, 260, Fig.8.3 tuberculosis, 259, Fig.8.2 Inhibin A, 437, Fig. 7.5 Insulinoma, 136 Intermediate filaments distribution, 422, Table 12.1 Intraabdominal desmoplastic small round cell tumor, 328, Figs. 10.1–10.3 Intraperitoneal masses, 327–340 Islet cell tumors, 135, Figs. 5.35, 5.36 Islet cell subtypes α cells (glucagon), 123 ß cells (insulin), 123 δ cells (somatostatin), 123 PP cells (pancreatic polypeptide), 123 Islet of Langerhans, 123, Fig. 5.3

455

K Karyorrhexis, 366, Fig. 11.22 Keratinizing squamous cell carcinoma, 75, Fig. 4.49 Ki-1, 438, Fig. 10.31 Ki1 large cell lymphoma, 381, Figs. 11.31–11.33 Kidney angiomyolipoma, 169, Figs. 6.3, 6.4 abscess, 168 benign epithelial tumors adult mesoblastic nephroma, 172, Fig. 6.6 metanephric adenoma, 172, Fig. 6.5 mixed epithelial and stromal tumor, 172, Fig. 6.6 cystic nephroma, multilocular, 172, Fig. 6.6 oncocytoma, 173, Figs. 6.8, 6.9 cysts, 167 glomeruli, 166, Fig. 6.2 infarct, 168 normal renal cortical aspirate, Fig. 6.2 tuberculosis, 167 tubular epithelium distal convoluted, 166, Fig. 6.2 proximal convoluted, 166, Fig. 6.2 vs. renal cell carcinoma, Fig. 6.10 lipoma, perinephric, 169 Kiel’s classification, 361 Kulschitsky’s cells, 135 Kupffers cells, 54, Fig. 4.3B

L Langerhans, islet of 123, Fig. 5.3 Langerhans histiocytosis, 387, Fig. 11.42 Laparotomy, contraindications to, 4 Large B-cell lymphomas, 374–376 centroblastic, Figs. 11.14, 11.15 immunoblastic, Fig. 11.16 T-cell/histiocyte rich, Figs. 11.17, 11.18 anaplastic, 376

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index


Large-bore needle, 3 complications with, 3, 5–7 Leiomyoma, 292, Fig. 9.16 Leiomyosarcoma uterine, 292–294, Figs. 9.17–9.19 epithelioid cell type, 294, Fig. 9.19 poorly-differentiated spindle cell type, 293, Fig. 9.18 well-differentiated spindle cell type, 293, Fig. 9.17 retroperitoneum, 239, 240 pleomorphic cell type, Fig. 8.13 round cell type, Fig. 8.12 well-differentiated, Figs. 8.9–8.11 Leukocyte common antigen, 438, Fig. 11.29 Lipofusin pigment, 53, Fig. 4.1B Lipomas of perirenal, 168 Liposarcoma, 240, 241 dedifferentiated, Fig. 8.15 myxoid type, Fig. 8.16 round cell type, Fig. 8.17 pleomorphic cell type, Fig. 8.18 well-differentiated, Fig. 8.14 Liver, see also hepatocellular lesions abscess, pyogenic, bacterial, 56 cavernous hemangioma, 57, Fig. 4.8 fatty metamorphosis, 58 granuloma, 56 tumors metastasis to, 73–80 Liver cell adenoma, 59, Figs. 4.11, 4.12 Liver cell dysplasia, 61, Figs. 4.14, 4.15 Liver cysts hydatid (Ecchinococcal), of liver, 55, Fig. 4.5 non-parasitic, of liver, 55 Liver sarcomas angiosarcoma, 71, Fig. 4.46 embryonal sarcoma, 72, Fig. 4.48 epithelioid hemangioendothelioma, 72, Fig. 4.47 metastatic sarcomas, 75 Localization methods, 16 CT scan, 4, 16, 17 endoscopic ultrasound, 1, 10 ultrasonography, 4, 16, 17

Lukes and Collins’ classification, 361, 362 Lung carcinoma, metastatic, 75–78 bronchioloalveolar carcinoma, 77 nonsecretory cell type, Fig. 4.55 secretory cell type, Fig. 4.56 giant cell carcinoma, 77, Fig. 4.58 spindle cell carcinoma, 78, Figs. 4.59, 4.60 small cell carcinoma, 76, Figs. 4.51, 4.52 undifferentiated large cell carcinoma, 77, Fig. 4.51 squamous cell carcinoma keratinizing, 75, Fig. 4.49 non-keratinizing, 76, Fig. 4.50 Lymphocytes, differentiation of during immune proliferation, 364, Diagram 11.1 Lymphocytic leukemia, chronic, 367, Figs. 11.2, 11.3 Lymphoid hyperplasia, reactive, 366, Fig. 11.1 Lymphoplasmacytic lymphoma, 370, Fig. 11.4 Lymphoblastic lymphoma/leukemia, 378, Figs. 11.25, 11.26 Lymphomas, see specific types

M Macroregenerative nodule of liver, 58, 60 Malignant fibrous histiocytoma, 243, Figs. 8.26–8.28 Malignant mixed mullerian tumor, Figs. 9.10, 9.11 Malignant peripheral nerve shealth tumor, 247 low nuclear grade, Fig. 8.38 high nuclear grade, Fig. 8.39 MALT lymphoma, 371, Figs. 11.8, 11.9 Mantle cell lymphoma, 371, Figs. 11.10, 11.11 Marginal zone lymphoma, 371, Figs. 11.8, 11.9 Mature T cell and NK cell lymphoma, 378–380, Figs. 11.28, 11.29

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Index Mediastinal (thymic) large B-cell lymphoma, 376, Fig. 11.20 Melanoma, metastatic, 79 pleomorphic large cell type, Fig. 4.69 round cell type, Fig. 4.67 small cell type, Fig. 4.70 spindle cell type, Fig. 4.68 Mesothelioma cohesive cell type, 331, Figs. 10.6–10.8 noncohesive cell type, 331, Fig. 10.9 papillary type, 332, Figs. 10.10–10.12 vs. reactive mesothelial hyperplasia, 332, Fig. 10.13 Metanephric adenoma, 172, Fig. 6.5 MIB-1, 439, Fig. 8.53 Mixed epithelial and stromal tumor of kidney, 172, Fig. 6.6 Mucinous carcinoma of endometrium, 289, 298, Fig. 9.6 Mucinous adenocarcinoma of ovary, 299, Fig. 9.29 Mucinous cystadenocarcinoma of ovary, 299, Fig. 9.30 Mucinous cystic tumor of appendix, 335, Fig. 10.19 Multiple myeloma, 370, 371, Figs. 11.5–11.7 Mycosis fungoides, 380, Fig. 11.30 Myeloma, 370, 371, Figs. 11.5–11.7 Myoglobulin, Fig. 8.20 Myometrial tumors, 292–294 Mycobacterium avium intracellulare, 236, Fig. 8.3 tuberculosis, kidney, 167 retroperitoneum, 236, Fig. 8.2 Myelolipoma of adrenal, 220, Fig. 7.22

N Needles used for aspiration biopsy size and gauge, 1, 3 type, 18, 19 Neurofibroma, 246, Fig. 8.34 NK/T cell lymphoma, 380–382, Figs. 11.28, 11.29

457

Non-Hodgkin lymphomas, 382, see specific types basic cell types, 364, Table 11.2 B-cell differentiation and lymphoma, 364, Diagram 11.1 classifications, WHO, 362, Table 11.1 differential diagnosis of cytologic presentations, 368, Table 11.3 immunophenotypes and cytogenetics of small B-cell lymphomas, 369, Table 11.4

O Oncocytoma, 173, Figs. 6.8, 6.9 Ovarian tumors, 296–301 sex-cord stromal tumors, 300, 301 granulosa theca tumor, Figs. 9.32, 9.33 fibrothecoma, Fig. 9.34 surface epithelial tumors, 296–300 borderline papillary serous tumor, Fig. 9.24 papillary serous carcinoma, Figs. 9.25, 9.26 serous cystadenocarcinoma, Fig. 9.28 mucinous carcinoma, Fig. 9.28 mucinous cystadenocarcinoma, Fig. 9.29 endometrioid carcinoma, Fig. 9.30

P P53, 441, Fig. 10.4 Pancreas acinar cell carcinoma, 138, Figs. 5.35–5.38 adenosquamous carcinoma, 134, Figs. 5.33, 5.34 anaplastic carcinoma, 133, Figs. 5.31, 5.32 benign aspirate, Fig. 5.2

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October 31, 1991 14:47

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index


Caroli’s disease, 127, Fig. 5.7 ciliated foregut cyst, 124, Fig. 5.6 colloid carcinoma, 130, Fig. 5.16 cysts, 124–127, Figs. 5.6, 5.7 ductal adenocarcinoma, 130–132 moderately differentiated, Figs. 5.22–5.24 mucinous, Figs. 5.25–5.29 poorly differentiated, Fig. 5.20 well-differentiated, Figs. 5.17–5.21 histology, Fig. 5.1 intraductal papillary mucinous neoplasm, 129, Figs. 5.14, 5.15 islet cell tumor, 135–137, Figs. 5.35, 5.36 islet of Langerhans, Fig. 5.3 microcystic cystadenoma, 127, Figs. 5.8–5.10 mucinous cystic neoplasm, 128, Fig. 5.13 pancreatic endocrine tumor, 135–137, Figs. 5.35, 5.36 pancreatoblastoma, 138, Figs. 5.39–5.42 pleomorphic giant cell carcinoma, 133, Figs. 5.30–5.32 pseudocyst, 126, Fig. 5.6 serous cystadenoma, 127, Figs. 5.8–5.10 solid-pseudopapillary neoplasm, 128, Figs. 5.11, 5.12 undifferentiated small cell carcinoma, 132 Pancreatitis, 124 acute, 124 chronic, 125, Fig. 5.4 vs. well-differentiated ductal carcinoma, 126 Papanicolaou stain, 21, Fig. 2.1 Papillary serous carcinoma ovarian, 297, Figs. 9.26, 9.27 fallopian tube, 296 peritoneum, 329, Fig. 10.4 uterine, 289, Fig. 9.7 Paraganglioma, 248, 249, Figs. 8.40, 8.41

PET scan (positron emission tomography), 18 Percutaneous retrograde cholangiopancreatography, 17 Peripheral T-cell lymphoma, 382, Figs. 11.35, 11.36 Perivascular epithelioid cell tumors (PEComas) angiomyolipoma, 169, Figs. 6.3, 6.4 of broad ligament, 302, Fig. 9.35 Phenylzine, 71 Pigments lipofuscin, Fig. 4.1 melanin, Fig. 4.70 Pitfalls and limitations of cytology, 43 benign-appearing malignant cells, 43, Fig. 3.1 different features from tumors of same origin, 44 malignant appearing irritated benign cells, 44, Fig. 3.2 similar features from different tumors, 43 variable features from different preparations, 44, Fig. 3.8 Placental Alkaline Phosphatase, 441, Fig. 8.42 Plasma cell myeloma, 370, 371, Figs. 11.5–11.7 Plasmacytoma, 370, 371, Figs. 11.5–11.7 Precursor T-cell lymphoblastic lymphoma/leukemia, 378, Figs. 11.25, 11.26 Preparations, cytologic, 20 air-dried rehydrated versus wet fixed, Diagram 2.2, Fig. 2.1 cell block, 20, 23, 26, Diagrams 2.2, 2.3 liquid-based preparations, 20, 23, Diagram 2.2 millipore filters, 20 smears, 5–23, Diagram 2.1 Primary effusion lymphoma, 376, Figs. 11.21, 11.22 Prostate, metastatic from, 78 well-differentiated, Fig. 4.62 poorly-differentiated, Fig. 4.62

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Index Prostate specific antigen, 441, Fig. 4.61 Prostatic acid phosphatase, 442, Fig. 4.62 Pseudomyxoma peritonei, 329, Fig. 10.5

R Radiographic data helpful for aspiration biopsy anatomic location, 36 size of lesion, 36 radiologic appearance of lesion, 36 consistency of lesion felt during aspiration, 36 gross appearance of aspirate, 36 REAL classification of lymphomas, 362 Renal cell carcinoma, 174–178 chromophobe, 177, Fig. 6.26 collecting duct, 178 tubular pattern, Fig. 6.27 papillary pattern, Fig. 6.28 conventional, 174–176 clear cell, 175, Figs. 6.10–6.16 granular cell, 175, Figs. 6.18–6.20 Furhman nuclear grading, Fig. 6.11 papillary growth pattern, 175, Figs. 6.15, 6.16 cytogenetics, 171 not otherwise specified, Fig. 6.32 papillary, 176 type 1, 176, Figs. 6.21–6.23 type 2, 177, Figs. 6.24, 6.25 sarcomatoid, 178, Figs. 6.30, 6.31 Renal sarcomas, 180 Reticulin stain, usefulness in liver biopsy, 64, Fig. 4.17 Rhabdomyosarcoma, 241–243 embryonal, Figs. 8.19, 8.20 pleomorphic, Fig. 8.21 Rotex screw needle, 19

S Sarcomas of kidney, 180

459

of liver, 71–73 of retroperitoneum, 237–246 S100, 442, Figs. 8.36, 11.42 Schwannoma, 247, Figs. 8.35–8.37 ancient, Fig. 8.37 malignant, 247, 248, Figs. 8.38, 8.39 Scolices, 55, Fig. 4.5 Seminoma, 249, 250, Fig. 8.42 Sex cord stromal tumors, see ovarian tumors Sezary syndrome, 380, Fig. 11.30 Signet ring cell carcinoma of breast (lobular carcinoma), Fig. 4.63 of colon, 328, Fig. 10.26 of stomach, 334, Fig. 10.18 Small intestinal tumors adenocarcinoid, 336, Fig. 10.20 carcinoid, 336, Fig. 10.21 gastrointestinal stromal tumors (GIST), 338–340 Smear preparation, 22, 23, Diagram 2.1 Small lymphocytic lymphoma, 367, Figs. 11.2, 11.3 Small B-cell lymphomas immunophenotypes and cytogenetics, 369, Table 11.4 Small round cell tumor of childhood Immunomarkers for, 425, Table 12.5 Soft tissue tumors, 237–254 Somatostatinoma, 136 Spindle cell neoplasms immunomarkers for, 425, Table 12.4 Spinal needle, 19 Spiral CT Scanner, 17, 18 Squamous cell carcinoma keratinizing, 75, Figs. 4.49, 9.22 Non-keratinizing, 76, Figs. 4.50, 9.23, 9.24 Stains used in cytology, 21, Figs. 2.1–2.6 Stomach adenocarcinoma of intestinal type, 334, Figs. 10.15–10.17 signet ring cell carcinoma, 334, Fig. 10.18

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October 31, 1991 14:47

460


index


gastrointestinal stromal tumors (GIST), 338–340 Synaptophysin, 442, Figs. 5.35, 5.42 Synovial sarcoma, 253, 254 biphasic, Figs. 8.51, 8.52 monophasic, Fig. 8.54

T T-cell/histiocyte rich large B-cell lymphoma, 375, Figs. 11.18, 11.19 T-cell lymphoblastic lymphoma/leukemia, 378, Figs. 11.25, 11.26 T-cell lymphomas, 378–382 T/NK cell lymphoma, 380–382, Figs. 11.28, 11.29 Thorotrast cholangiocarcinoma and, 70 Angiosarcoma and, 71 TIA-1, 443, Fig. 11.29 TTF-1, 443, Fig. 4.52 Transabdominal fine-needle aspiration biopsy advantages, 5, 6 cost saving, 5 fast result, 5 morbidity reduction, 6 complications, 6 hematogeneous/lymphagitic spread, 7 puncture trauma to bowels, vessels, ducts, 2, 6 tumor spread along needle tract, 3, 7 vasovagal reaction, 6 conclusions, 11 factors essential to success, 11 false-negative results, 26–28 indications and counterindications, 4 minimal invasiveness, 15 reliability, 7–9 accuracy of sampling, 8, 9 accuracy of cytomorphology, 9 pitfalls of cytomorphology, 9 techniques, 19

Transitional cell carcinomas, of renal pelvis, 179, 180, Fig. 6.33 Tuberculosis, see Mycobacterium Tubular cells, renal distal convoluted, 166, Fig. 6.2C proximal convoluted, 166, Figs. 6.2A, 6.2B vs. renal cell carcinoma, Fig. 6.10 Tumor cells arrangement of, 41 average nuclear size in, 39 cytoplasm in, 42 location of nuclei in, 42 nuclear shape in, 40 nuclear size in, 39 size and number of nucleoli in, 42 Turner needle, 18

U Ultrafast Papanicolaou stain, 21, 23–25, Table 2.1, Figs. 2.1, 2.4–2.6 Ultrasonography, 4, 16, 17 Unknown primaries Immunomarkers for, 424, Table 12.3 Urothelial carcinoma, 179, 180 Papillary, low grade, Figs. 6.34, 6.35 high grade, Fig. 6.36 poorly differentiated, Fig. 6.37

V Verner-Morrison syndrome, 136 Vimentin, 443, Fig. 4.58 Vinyl chloride, industrial exposure to, 71 VIPoma, 136 Viral-lymphoma associations EBV, 380, 384 HHV8, 376 HIV, 375, 377, 384 HTLV-1, 379 KSHV, 376

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October 31, 1991 14:47


index

Index

W Waldenstrom’s macroglobulinemia, 370, Fig. 11.4 Wescott needle, 18 Wilms’ tumor, 180, 181, Figs. 6.39, 6.40 WHO classification of lymphomas, 362

Y Yolk sac tumor, 250, 251 microcystic type, Fig. 8.44 parietal type, Fig. 8.45 Schiller-Duval body type, Figs. 8.46, 8.47

Z Zollinger-Ellison syndrome, 126

461

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